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WO1997001569A1 - Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a - Google Patents

Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a Download PDF

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Publication number
WO1997001569A1
WO1997001569A1 PCT/EP1996/002785 EP9602785W WO9701569A1 WO 1997001569 A1 WO1997001569 A1 WO 1997001569A1 EP 9602785 W EP9602785 W EP 9602785W WO 9701569 A1 WO9701569 A1 WO 9701569A1
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Prior art keywords
aryl
alkyl
cycloalkyl
substituted
group
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PCT/EP1996/002785
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French (fr)
Inventor
Hartmuth Christian Kolb
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Novartis Ag
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Application filed by Novartis Ag filed Critical Novartis Ag
Priority to AU63053/96A priority Critical patent/AU707474B2/en
Priority to PL96324258A priority patent/PL324258A1/en
Priority to EP96922034A priority patent/EP0836610A1/en
Priority to SI9620099A priority patent/SI9620099A/en
Priority to NZ311686A priority patent/NZ311686A/en
Priority to BR9609285A priority patent/BR9609285A/en
Priority to SK1778-97A priority patent/SK177897A3/en
Priority to JP9504171A priority patent/JPH11508548A/en
Priority to EA199800103A priority patent/EA001356B1/en
Publication of WO1997001569A1 publication Critical patent/WO1997001569A1/en
Priority to NO976065A priority patent/NO976065L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • the present invention relates to mimetics of sialyl-Lewis X and sialyl-Lewis A, in which, in the natural tetrasaccharide, the neuraminic acid residue is replaced by an S-configurated methyl substituted with one carboxyl residue and one other substituent and the N-acetyl- glucosamine residue is replaced by a non-glycosidic residue of a 1 ,2-diol, to processes for the preparation of these compounds and to the use of these mimetics in therapeutic methods.
  • the complex process of inflammation which takes place in several stages, is the body's natural reaction to injuries in which, for example, there is also invasion by infectious agents.
  • the endothelium which lines the blood vessels expresses adhesion proteins on its surface.
  • the P and E selectins bring about, by a protein-carbo ⁇ hydrate interaction with glycolipids and glycoproteins on the leukocyte membrane, the so ⁇ called “rolling" of leukocytes.
  • the latter are slowed down by this process, and there is acti ⁇ vation of certain proteins (integrins) on their surface which ensure firm adhesion of the leukocytes to the endothelium. This is followed by migration of the leukocytes into the damaged tissue.
  • EP-A-0 579 196 proposed as compounds competing with the natural ligands for binding to E selectin mimetics of sLe x in which the neuraminic acid residue is replaced by a lactic acid residue.
  • WO 93/10796 describes compounds which comprise in place of the neuraminic acid residue the residue of an ⁇ -hydroxy acid.
  • WO 93/23031 discloses mimetics in which the N-acetylglucosamine residue (GlcNAc residue) is replaced by an R,R-1 ,2-cyclohexane- dioxy.
  • GlcNAc residue N-acetylglucosamine residue
  • the present invention relates to compounds of the formula I
  • X is the residue of a non-glycosidic aliphatic 1 ,2-diol
  • Ri is an S-configurated methyl substituted with one carboxyl residue and one other substitu ⁇ ent
  • R 2 is hydrogen, d-C ⁇ 2 alkyl or C 6 aryl; where the alkyl and the aryl are unsubstituted or sub ⁇ stituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OR s1 , OC(O)R s4 , C(O)R s2 , nitro, NH 2 , cyano, SO 3 M y , OSO 3 M y , NR 2 oSO 3 M y) C ⁇ -C 12 alkyl, C 2 -C 12 alkenyl, CrC 12 alkoxy, C 3 -C ⁇ 2 cycloalkyl, C 3 -C ⁇ 2 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C-VCuheterocycloalkenyl, C 6 -C ⁇ 0 aryl, C 6 -C 10 aryloxy, Cs-Cgheteroaryl, C
  • Preferred aliphatic residues X are linear or branched C 2 -C 2 o-. preferably C 2 -C 12 - and particu ⁇ larly preferably C 2 -C 6 alkylene and -alkenylene, C 3 -C ⁇ 2 -, preferably C 3 -C 8 - and particularly preferably C 5 -C 7 cycloalkylene and cycloalkenylene, and C 3 -Cn-, preferably C 3 -C 7 - and par ⁇ ticularly preferably C 3 -C 5 heterocycloalkylene and heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-.
  • the residue X can contain substituents such as OH, halogen, C(O)OR s1 , OC(O)R s4 , C(O)R s2 , nitro, NH 2 , cyano, SO 3 M y.
  • X is the residue of a 1 ,2-diol corresponding to formula II
  • R 5 and R 6 are, independently of one another, hydrogen, C C 12 alkyI, C 3 -C ⁇ 2 cycloalkyl, C 2 -Cnheterocycloalkyl, C 6 -C ⁇ 0 aryl, Cs-Cgheteroaryl, C 7 -Cnaralkyl or C 6 -C 10 heteroaralkyl; or R 5 and R 6 are, together with the -CH-CH- group, C 3 -C 12 cycloalkylene, C 3 -C 12 -cycloalken- ylene, C 2 -Cn heterocycloalkylene and C 3 -Cn heterocycloalkenylene with hetero atoms selected from the group -O-, -S- and -N-; where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclo ⁇ alkylene, cyctoalkenylene, heterocycl
  • R s1 is hydrogen, M y , C.-C ⁇ 2 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -Cnhetero- cycloalkyl, C 6 -C ⁇ 0 aryl, C 5 -C 9 heteroaryl, Cy-Cnaralkyl or C 6 -C ⁇ 0 heteroaralkyl, R s4 is hydrogen, C C ⁇ alkyl, C
  • the other substituent in R has preferably 1 to 20, more preferably 1 to 16, particularly pre ⁇ ferably 1 to 12, and especially preferably 1 to 8, C atoms.
  • the other substituent is preferab ⁇ ly selected from the group consisting of unsubstituted and substituted d-C ⁇ 2 alkyl, C 2 -C ⁇ 2 alkenyl, C 3 -C 12 cycloalkyl, C 3 -d 2 cycloalkenyl, C 2 -Cnheterocycloalkyl, C 2 -Cnhetero- cycloalkenyl, C 6 -C 10 aryl, Cs-Cgheteroaryl, Cy-Cnaralkyl, Ce-CioheteroaralkyI, C 8 -Cnaralkenyl and Cy-doheteroaralkenyl.
  • the other substituent is particularly preferably substituted methyl, or 2-substituted ethyl or cyclohexyl.
  • suitable substituents are the sub ⁇ stituents mentioned above in the definition of R 2 , especially OH, halogen (F, Cl or Br), carb ⁇ oxyl, -SO 3 H, C(O)OM y , SO 3 M y , OSO 3 M y , NR 20 SO 3 M y in which R 20 is hydrogen, d-C 12 alkyl, C 2 -C ⁇ 2 alkenyl, C 3 -d 2 cycloalkyl, C -C ⁇ 2 cycloalkenyl, C 2 -Cnheterocycloalkyl, C 2 -Cn-hetero- cycloalkenyl, C 6 -Ci 0 aryl, C 5 -Cgheteroaryl, Cy-Cnaralkyl, Ce-doheteroaralkyl, C 8
  • hydrocarbon groups and heterohydrocarbon groups in turn are unsubstituted or substi- tuted, for example with d-C 6 alkyl, Ci-Cealkoxy, carboxyl, halogen (F, Cl or Br), -OH, -CN or -N0 2 .
  • Ri corresponds to a group of the formula III
  • R 3 is hydrogen or M y ;
  • R 4 is C ⁇ -C ⁇ 2 alkyl, C 2 -C 12 alkenyl, C 3 -d 2 cycloalkyl, C 3 -C ⁇ 2 cycloalkenyl, C 2 -Cnheterocycloalkyl, C 2 -C ⁇ heterocycloalkenyl, C 6 -C ⁇ 0 aryl, C 5 -C 9 heteroaryl, Cy-Cnaralkyl, C 6 -C ⁇ oheteroaralkyl, C 8 -Cnaralkenyl or C 7 -C ⁇ 0 heteroaralkenyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)OR s ⁇ , OC(0)R s4 , C(O)R s2 , nitro, NH 2 , cyano, SO 3 M y , OSO 3 M y , NR 20 SO 3 lv1 y ,
  • a metal is to be understood as meaning an alkali metal [for example lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and caesium (Cs)], an alkaline earth metal [for example magnesium (Mg), calcium (Ca) and strontium (Sr)] or manganese (Mn), iron (Fe), zinc (Zn) or silver (Ag).
  • Physiologically tolerated salts are to be understood as meaning, in particular, the alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium and calcium salts. Sodium and potassium ions and their salts are preferred.
  • Halogen is to be understood as meaning a representative of the group consisting of fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred, especially fluorine and chlorine.
  • Alkyl can be linear or branched, preferably branched once or twice in the ⁇ position.
  • Some examples of alkyl, which preferably contains 1 to 12 C atoms, are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
  • Preferred alkyl groups are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.
  • Cycloalkyl and cycloalkenyl can contain preferably 5 to 8 and particularly preferably 5 or 6 ring carbon atoms.
  • Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclo ⁇ hexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • Cyclo ⁇ hexyl is a particularly preferred cycloalkyl group.
  • cycloalkenyl examples include cyclopropen- yl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, cycloundecenyl and cyclododecenyl.
  • Cyclohexenyl is a particularly preferred cycloalkenyl group.
  • alkylene examples include ethylene, 1 ,2-propylene, 1 ,2- or 2,3-butylene, 1 ,2- or 2.3- pentylene, 1 ,2-, 2,3- or 3,4-hexylene.
  • cycloalkylene examples include 1 ,2-cyclopropylene, 1 ,2-cyclobutylene, 1 ,2-cyclopentylene, 1 ,2-cyclohexylene, 1 ,2-cycloheptylene and 1 ,2-cyclo- octylene.
  • heterocycloalkylene examples include pyrrolidinylene, piperidinylene, tetrahydro- furanylene, di- and tetrahydropyranylene.
  • heterocycloalkyl examples are derived from pyrrolidine, imidazolidine, oxazolidine, pyrazolidine, piperidine, piperazine and morpholine.
  • heterocycloalkenyl examples are derived from 2- and 3-pyrroline, oxazoline, 2- and 4-imidazoline and 2- and 3-pyrazoline.
  • aryl or heteroaryl is a five- or six-membered ring or a bicycle consisting of two condensed six- or five-membered rings or one six-membered and one five-membered ring, and in the case of heteroaryl one or more C atoms may be replaced, independently of one another, by an atom selected from the group consisting of oxygen, nitrogen and sulfur.
  • Examples are derived from benzene, naphthalene, indene, furan, pyrrole, pyrazole, imidazole, isoxazole, oxazole, furazan, thiadiazole, thiophene, thiazole, oxadiazole, triazole, indole, indazole, purine, benzimidazole, benzoxazole, benzo ⁇ thiazole, pyran, pyridine, pyridazine, triazine, pyrimidine, pyrazine, isoquinoline, cinnoline, phthalazine, quinoline, quinazoline, pterdine, benzotriazine or quinoxaline.
  • Aryl is preferably naphthyl and phenyl. Phenyl is particularly preferred.
  • Heteroaryl is preferably furanyl, pyridinyl and pyrimidinyl.
  • Aralkyl preferably has 7 to 12 C atoms and can be phenyl-C n H 2n - with n equal to a number from 1 to 6. Examples are benzyl, phenylethyl or phenylpropyl. Benzyl and 2-phenylethyl are preferred.
  • Heteroaralkyl and heteroaralkenyl are preferably C -C 5 heteroarylmethyl and C 4 -C 5 hetero- arylethenyl with one or two hetero atoms from the group of O and N, and the heteroaryl can comprise the abovementioned heteroaryl residues.
  • Alkoxy can be linear or branched, preferably branched once or twice in the ⁇ position.
  • Some examples of alkoxy, which preferably contains 1 to 12 C atoms, are methoxy, ethoxy and the isomers of propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undec- oxy and dodecoxy.
  • Preferred alkoxy groups are methoxy and ethoxy.
  • Examples of aryloxy and aralkoxy are phenoxy and benzyloxy.
  • Heteroaryloxy is preferably furanyloxy, pyridinyloxy and pyrimidinyloxy.
  • the primary amino preferably contains 1 to 12, particularly preferably 1 to 6, C atoms. Some examples are methyl-, ethyl-, hydroxyethyl-, n- or i-propyl-, n-, i- or t-butyl-, pentyl-, hexyl-, cyclopentyl-, cyclohexyl-, phenyl-, methylphenyl-, benzyl- and methylbenzylamino.
  • the secondary amino preferably contains 2 to 14, particularly preferably 2 to 8, C atoms.
  • Some examples are dimethyl-, diethyl-, methylethyl-, di-n-propyl-, di-i-propyl-, di-n-butyl-, diphenyl-, dibenzylamino, morpholino, piperidino and pyrrolidino.
  • NH 2 primary amino, secondary amino, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide and aminocarbonylamide preferably correspond to a group R 8 C(O)(NH)pN(Rg)-, -C(O)(NH) p NR 8 R 9 , R 8 OC(O)(NH) p N(R 9 )-, R 8 R 40 NC(O)(NH)pN(Rg)-, -OC(O)(NH) p NR 8 R 9 , -N(R 40 )C(O)(NH) P NR 8 R 9 , R 8 S(O) 2 (NH) p N(R 9 )-; -S(O) 2 (NH) p NR 8 R 9 ; R 8 R 40 NS(O) 2 N(R 9 )- or -NR 40 S(O) 2 NR 8 R 9 , in which R 8 , R 9 and R 40 are, independently
  • the sulfonyl substituent corresponds, for example, to the formula R i0 -SO 2 - in which R ⁇ 0 is Ci-CealkyI, C 3 -C ⁇ 2 cycloalkyl, C 2 -Cnheterocycloalkyl, C 6 -C ⁇ oaryl, Cs-Cgheteroaryl, C 7 -Cnar- alkyl or C 6 -C ⁇ 0 heteroaralkyl, which are unsubstituted or substituted by one or more substitu ⁇ ents selected from the group consisting of OH, halogen, C(O)OR s ⁇ , OCfOJR.*, C(O)R s2 , nitro, NH 2 , cyano, SO 3 M y , OSO 3 M y , NR 20 SO 3 M y , C ⁇ -C ⁇ 2 alkyl, C 2 -C ⁇ 2 alkenyl, C ⁇ -C ⁇ 2 alkoxy, C
  • Preferred compounds of the formula I are those compounds in which X corresponds to a group of the formula li in which R 5 and R 6
  • (a) are unsubstituted or substituted by d-C 12 alkyl, for example methyl, ethyl, or Ci-Cealk ⁇ oxy, for example methoxy, ethoxy; (b) are, together with the group -CH-CH-, a 5- to 8-membered carbocycle, and particularly preferably, a 5- or 6-membered carbocycle, and are very particularly preferably
  • (c) are, together with the group -CH-CH-, a 5- to 8-membered heterocarbocycle, and parti ⁇ cularly preferably a 5- or 6-membered heterocarbocycle with nitrogen as hetero atom, and are very particularly preferably R,R-3,4-piperidylene;
  • (d) are, independently of one another, hydrogen, unsubstituted C ⁇ -C ⁇ 2 alkyl or C ⁇ -C ⁇ 2 alkyl which is substituted by a substituent selected from the group consisting of -C(O)OR s ⁇ , -OC(O)R s4 , -C(O)ONa or -C(O)OK, primary amino, secondary amino, C 3 -d 2 cycloalkyl, Ci-Cealkoxy, phenyloxy and benzyloxy; unsubstituted C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkyl which is substituted by a substituent selected from the group consisting of -C(O)OR s ⁇ , -OC(O)R s4 , -C(O)ONa or -C(O)OK, primary amino, secondary amino, d-C 6 alkyl, Ci-Cealk ⁇ oxy, phenyloxy and benz
  • (e) are, together with the group -CH-CH-, a 5- to 12-membered carbocycle or 5- or 6-mem ⁇ bered heterocarbocycle with a hetero atom selected from the group consisting of oxygen and nitrogen atoms; or
  • (f) are, together with the -CH-CH- group, C 3 -C ⁇ 2 cycloalkylene, C -C ⁇ 2 cycloalkenylene, C 2 -Cn heterocycloalkylene and C 3 -Cnheterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-; where cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OR s1) OCfOJR.*, C(O)R s2 , nitro, NH 2 , cyano, SO 3 M y , OSO 3 M y , NR 20 SO 3 M y , C ⁇ -C ⁇ 2 alkyl, C 2 -C ⁇ 2 alkenyl, C ⁇ -C 12 alkoxy, C
  • Particularly preferred compounds are those in which X corresponds to a group of the formula II in which R 5 and R 6 are, together with the -CH-CH- group, C 3 -d 2 cycloalkylene or C 2 -Cn heterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and hetero ⁇ cycloalkylene are unsubstituted or substituted by one or more of the above substituents.
  • Particularly preferred compounds are those in which R 5 and R 6 are, together with the -CH-CH- group, C 3 -C ⁇ 2 cycloalkylene or C 2 -Cnheterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)OR s ⁇ , OCfOJR.
  • R 8 and R 9 are, in particular, independently of one another hydrogen; d-C ⁇ 2 alkyl; C 3 -C ⁇ 2 cycloalkyl, C 6 -doaryl, C 7 -d 6 aralkyl with 1 to 6 C atoms in the alkylene group and Ce-Cioaryl, C 8 -C ⁇ 6 aralkenyl with C 2 -C 6 alkenylene and Ce-Cioaryl, or di-Ce-Cioaryl-Ci-Ce-alkyl, for example diphenylmethyl or 2,2-diphenylethyl, where R 8 and Rg are unsubstituted or sub ⁇ stituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O)OM y , C ⁇ -C ⁇ 2 alkyl, d-C 6 alkoxy, C 6 -C ⁇ 0 aryl, C 6 -C ⁇ 0 aryloxy,
  • Rio corresponds, in particular, to C ⁇ -C ⁇ 2 alkyl; C 3 -d 2 cycloalkyl, C 6 -C ⁇ oaryl, C 7 -C 16 aralkyl with 1 to 6 C atoms in the alkylene group and C 6 -C ⁇ 0 aryl, C 8 -C ⁇ 6 aralkenyl with C 2 -C 6 alkenylene and C 6 -C ⁇ 0 aryl, or di-Ce-doaryl-d-Cealkyl, for example diphenylmethyl or 2,2-diphenylethyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O)OM y , C C 12 alkyl, d-C 6 alkoxy, C 6 -C ⁇ 0 aryl, SO 3 M y , OSO M y , NR 20 SO 3 M y , NO 2 , amino
  • R10 is preferably Ci-CealkyI; C 3 -C ⁇ 2 cycloalkyl, C 6 -C ⁇ oaryl, C 7 -C 16 aralkyl with 1 to 6 C atoms in the alkylene group and C 6 -C ⁇ 0 aryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(0)OM y , C -C ⁇ 2 alkyl, d-C 6 alkoxy, C 6 -C ⁇ 0 aryl, S0 3 M y , nitro, amino, primary amino, secon ⁇ dary amino and cyano; or C 8 -C ⁇ 6 aralkenyl with C 2 -C 6 alkenylene and C 6 -C ⁇ 0 aryl, or di-C 6 -C ⁇ oaryl-C ⁇ -C 6 alkyl, for example diphenylmethyl or 2,2-diphenylethyl
  • R 5 and R 6 are, together with the -CH-CH- group, C 3 -C ⁇ 2 cycloalkylene or C 2 -Cn heterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(0)OR s1 , OC(0)R s4 , C(0)R s2 , NH 2 , C ⁇ -C ⁇ 2 alkyl, R 8 C(0)N(R 9 )-, -C(0)NR 8 R 9 , R 8 S(0) 2 N(R 9 )-; R 8 OC(0) N(R 9 )- and R ⁇ 0 -SO 2 -, in which R 9 is hydrogen and R 8 is C ⁇ -C ⁇ 2 alkyl, C 6 -C ⁇ 0 aryl or C -Cnaralkyl, which are unsub ⁇ stituted or substituted
  • Particularly preferred compounds within this group are those in which R 5 and R 6 are, to ⁇ gether with the -CH-CH- group, cyclohexylene.
  • Another subgroup of preferred compounds are those compounds in which R 5 and R 6 are, to ⁇ gether with -CH-CH- group, piperidylene.
  • R 5 and R 6 are, together with the -CH-CH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(0)OR s ⁇ , C(0)R s2 , C(0)NR 8 R 9 , NH 2 , S0 3 M y , C ⁇ -C ⁇ 2 alkyl, C 2 -C ⁇ 2 alkenyl, C C ⁇ 2 alkoxy, C 3 -C 2 cycloalkyl, C 3 -C ⁇ 2 cycloalkenyl, C 2 -Cnheterocycloalkyl, C 2 -Cn heterocycloalkenyl, C 6 -C 10 aryl, C 6 -C ⁇ 0 aryloxy, Cs-Cgheteroaryl, C 5 -Cgheteroaryloxy, C 7 -Cn aralkyl, C 7 -Cnaralkyloxy, C 6
  • Particularly preferred compounds are those in which R 5 and R 6 are, together with the -CH-CH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(0)OR s ⁇ , C(O)R s2 , -C(0)NR 8 R 9 and R ⁇ o-S0 2 - and one or more C atoms of the ring are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH 2 , R 8 S(0) 2 N(R 9 )-; R 8 C(0)N(R 9 )- and R 8 OC(0)N(R 9 )-, where R 9 is hydrogen and R 8 is d-C ⁇ 2 alkyl, C 6 -C ⁇ 0 aryl or C -Cnaralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C ⁇ -C ⁇ 2 alkoxy
  • R 5 and R 6 are, together with the -CH-CH- group, piperidylene; which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(0)OR s ⁇ , OC(0)R s , C(0)R S2 , NH 2 , d-C 12 alkyl, R 8 C(O)N(R 9 )-, -C(O)NR 8 R 9 , R 8 S(O) 2 N(R 9 )-; R 8 OC(0)N(R 9 )-, R 8 R 40 NC(O)N(R 9 )-, -OC(0)NR 8 R 9 and R ⁇ 0 -SO 2 -, in which R 9 is hydrogen and R 8 is C C ⁇ 2 alkyl, C 6 -C 10 aryl or C 7 -Cnaralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or
  • Very particularly preferred compounds of the formula I are those in which X is cyclo- hexylene or piperidylene which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH 2 , C 3 H 7 , -C(0)CH 3 , -C(0)C 6 H 5 , -C(0)(CH 2 ) 8 C(0)OCH 3 , -C(O)[CH(OH)] 2 C(0)ONa, C(0)-C 6 H 8 (OH) 3 , -C(0)-C 6 Hn, -C(0)OC 3 H 7 , -C(0)NHC 6 H 5 , -NHS(O) 2 CH 2 C 6 H 5 , -NHC(0)OCH 2 C 6 H 5 , -NHC(0)C 6 H 3 (OCH 3 ) 2 , -S(0) 2 -C 4 H 9 , -NHC(O)NHC 6 H 5 , -S(O) 2 -C 6 H 4 CH
  • Preferred compounds of the formula I are those in which Ri corresponds to a group of the formula III in which R 3 is hydrogen or M y and R 4 is
  • C 3 -C 12 cycloalkyl C 3 -C ⁇ 2 cycloalkyl which is substituted by one or more substituents selected from the group consisting of C 3 -d 2 cycloalkyl, d-C 6 alkyl, C C 6 alkoxy, C C ⁇ 2 sulfonyl, phenyloxy and benzyloxy; C 6 -C 10 aryl; C 3 -C 8 heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; C 7 -d 6 aralkyl with d-C 6 alkyl and C 6 -C 10 aryl; d-Cieheteroaralkyl with d-C 6 alkyl and C 3 -C ⁇ 0 heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to 5 carbon atoms; Ce
  • R 3 in formula III is preferably hydrogen, K or Na.
  • R is alkyl, preferably methyl, ethyl, n- or i-propyl and n-, i- or t-butyi.
  • the alkylene group is preferably ethylene and particularly methylene.
  • a particularly preferred cycloalkyl group is cyclohexyl.
  • Preferred as aryl and aralkyl are naphthyl and phenyl, particularly preferably phenyl and phenyl-C n H 2n - with n equal to a number from 1 to 6, in particular benzyl and 2-phenylethyl.
  • R 4 is heteroaryl, it is preferably C 4 -C 5 hetero- aryl with one or two hetero atoms from the group of O and N. Furanyl, pyridinyl and pyrimidinyl are preferred.
  • R as heteroaralkyl is preferably C -C 5 heteroarylmethyl with one or two hetero atoms from the group of O and N, it being possible for heteraryl to comprise the abovementioned heteroaryl groups.
  • R 4 in formula III is a C 3 -d 2 cycloalkyl, parti ⁇ cularly preferably cyclohexyl, C ⁇ -C 4 alkyl substituted, particularly methyl or ethyl, with C 3 -C ⁇ 2 cycloalkyl or with d-C alkyl and particularly with cyclohexyl or methyl, C 6 -C ⁇ 0 aryl and very particularly phenyl, or R 4 is a C -C 12 aralkyl with d-C 6 alkyl and C 6 -C ⁇ 0 aryl.
  • R 4 in this series are benzyl, naphthylmethyl, 2-phenylethyl, 3-phenyl- propyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclohexyl and isopropyl.
  • R 4 preferably mean groups of the formulae R 8 NHC(0)N(R 9 )-, R 8 OC(0)N(R 9 )-, R 8 C(0)(NH) p N(Rg)- and R 8 S(0) 2 (NH) p N(R 9 )-, in which R 8 is preferably H, C ⁇ -C ⁇ 2 alkyl, C 5 - or C 6 cycloalkyl, C 5 - or C 6 cycloalkylmethyl or -ethyl-, C 5 - or C 6 heterocyclo- alkyl, C 5 - or C 6 heterocycloalkylmethyl or -ethyl-, phenyl, naphthyl, benzyl, 2-phenylethyl, di ⁇ phenylmethyl, which are unsubstituted or substituted by one
  • a carbam ido-substituted alkyl substituent for R 4 particularly preferably means R 8 -C(0)NR 9 -(CH 2 ) n -, where n is 1 or 2, R 8 is hydrogen; C ⁇ -C ⁇ 2 alkyl; C 3 -d 2 cycloalkyl; C 6 -C ⁇ 0 aryl or C 7 -C ⁇ 6 aralkyl with d-C 6 alkyl and C 6 -C ⁇ 0 aryl; wherein alkyl, cycloalkyl, aryl and aralkyl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, -C(0)OM y , C ⁇ -C 12 alkyl, d-C 6 alkoxy, C 6 -C ⁇ 0 aryl, S0 3 M y , OS0 3 M y , NR 20 SO 3 M y , C
  • a sulfonamide-substituted alkyl substituent for R T particularly preferably means R 8 -S0 2 NR g -(CH 2 ) n - in which R 8 , Rg and n have the meanings indicated previously for carbamido.
  • An aminocarbonylamide- or carbamate-substituted alkyl substituent for Ri particularly preferably means RgNHC(0)NH(CH 2 ) n or R 9 OC(0)NH(CH 2 ) n in which Rg has the meanings indicated in previously in connection with carbamido and addi ⁇ tionally phenyl and n has the meanings indicated previously in connection with carbamido.
  • a carbhydrazido-substituted alkyl substituent for Ri particularly preferably means R 8 C(0)NHNRg(CH 2 ) ⁇ - in which R 8 , Rg and n have the meanings indicated previously in con ⁇ nection with carbamido.
  • a sulfonhydrazido-substituted alkyl substituent for R particularly preferably means R 8 -S0 2 -NHNR 9 -(CH 2 ) n - in which R 8 , R 9 and n have the meanings indica ⁇ ted previously in connection with carbamido.
  • R 4 in formula III is an amide R 8 C(O)N(Rg)(CH 2 ) n - or R 8 S(O) 2 N(R 9 )(CH 2 ) n -; where R 8 and R 9 are, independently of one an ⁇ other, hydrogen; unsubstituted C ⁇ -C ⁇ 2 alkyl; C ⁇ -C ⁇ 2 alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(0)ONa, d-C ⁇ 2 alkyl, d-C 6 alkoxy, C 6 -C ⁇ 0 aryl, -S0 3 H, OS0 3 Na, NR 20 SO 3 Na, S0 3 Na, nitro and cyano; unsubstituted C 3 -C ⁇ 2 cycloalkyl; C 3 -C ⁇ 2 cycloalkyl substituted by one or more OH; unsubstitu ⁇ ted Ce-Cioary
  • R 4 in formula III is an amide R 8 C(0)N(R 9 )(CH 2 ) n - or R 8 S(0) 2 N(R 9 )(CH 2 ) n -, where R 8 is unsubstituted C ⁇ -C ⁇ 2 alkyl; C ⁇ -C 8 alkyl which is substituted by one or more substituents selected from the group con ⁇ sisting of OH, halogen, C(0)ONa and C 6 -C ⁇ 0 aryl; unsubstituted C 3 -d 2 cycloalkyl; C 3 -C 8 cyclo- alkyl which is substituted by one or more OH; unsubstituted C 6 -C ⁇ 0 aryl or C 7 -C ⁇ 2 aralkyl with C ⁇ -C 6 alkyl; C 6 -C ⁇ 0 aryl, C 7 -C ⁇ 2 aralkyl with d-C 6 alkyl and C 6 -C ⁇ oary
  • R 4 in formula III is an amide R 8 C(0)N(R 9 )(CH 2 ) n -, where R 8 is unsubstituted d-C 12 alkyl; C ⁇ -C ⁇ 2 alkyl which is substituted by one or more substituents selected from the group consisting of cyclohexyl, OH, halogen, -C(0)OH, -C(0)ONa and phenyl; unsubstituted C 3 -C ⁇ 2 cycloalkyl; C 3 -C ⁇ 2 cycloalkyl which is substituted by one or more OH; unsubstituted Ce-Cioaryl; C 6 -C ⁇ 0 aryl, which is substituted by one or more substituents selected from the group consisting of halogen, C(0)ONa, -C(0)OH, C ⁇ -C 6 alkyl, d-C 6 alkoxy, phenyl, -S0 3 H, S0 3 Na,
  • R 4 in formula III is an amide R 8 C(0)N(R 9 )(CH 2 ) n -, where R 8 is unsubstituted d-Cealkyl.
  • C ⁇ -C 4 alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)OH, C(0)ONa and phenyl; unsubstituted C 3 -d 2 cycloalkyl, in particular C 6 Hn; C 3 -d 2 cycloalkyl which is substituted by one or more OH, unsubstituted C 6 -C ⁇ 0 aryl, in particular C 6 H 5 or C ⁇ 0 H 7 ; C 6 -C ⁇ 0 aryl which is substituted by one or more substituents selected from the group consisting of halogen, -C(0)OH, C(0)ONa, d-C 6 alkyl, d-C 6 alkoxy, -S0 3 H, S
  • R 4 in formula III is a sulfon ⁇ amido R 8 S(0) 2 N(R 9 )(CH 2 ) n -, where R 8 is C ⁇ -C ⁇ 2 alkyl, particularly d-C 6 alkyl, which is unsub ⁇ stituted or substituted by one or more halogen atoms (for example Cl and especially F), in particular CF 3 ; or C 6 -C ⁇ 0 aryl, particularly phenyl or naphthyl, which is substituted by one or more d-C alkyl (for example methyl or ethyl), C ⁇ -C 4 alkoxy (for example methoxy or ethoxy), halogen, -CN or -N0 2 , and R 9 is hydrogen or isobutyl, and n is 2 and preferably 1.
  • R 4 in formula III is an amino ⁇ carbonyl residue of the formula R 8 -NH-C(O)-NH(CH 2 ) n -, in which R 8 is C C ⁇ 2 alkyl or Ce-Cioaryl, particularly Ci-CealkyI, which is unsubstituted or substituted by halogen, -CN, -N0 2 , d-dalkyl or d-C 4 alkoxy, or C 5 - or C 6 cycloalkyl, C 6 -C 10 aryl such as phenyl or naphthyl, or C 7 -C ⁇ 2 aralkyl such as benzyl, phenylethyl, phenylpropyl or phenylpropenyl, and n is 2 and preferably 1.
  • R 4 in formula II is an aminoalkyl, preferably R 8 R 9 N(CH 2 ) n -, where R 8 - and R ff are, independently of one another, hydrogen; unsubstituted Ci-CealkyI; C C ⁇ 2 alkyl which is substituted by one or more substi ⁇ tuents selected from the group consisting of OH, halogen, C(0)OR s1 , OC(0)R s4 , C(0)NR ⁇ R ⁇ 2 , C C ⁇ 2 alkyl, d-C 6 alkoxy, C 6 -C ⁇ 0 aryl, -S0 3 H, S0 3 Na, OS0 3 Na, NR 20 SO 3 Na, nitro, amino and cyano; unsubstituted C 3 -C 12 cycloalkyl; C 3 -C ⁇ 2 cycloalkyl which is substituted by one or more OH; C 6 -C ⁇ 0 aryl; C 7
  • R s4 is hydrogen, C ⁇ -C ⁇ 2 alkyl, C 2 -C 12 alkenyl, C 3 -C ⁇ 2 cyclo- alkyl, C 2 -Cnheterocycloalkyl, C 6 -C ⁇ 0 aryl, C 5 -C 9 heteroaryl, C 7 -Cnaralkyl or Ce-CioheteroaralkyI
  • Rn is H, d-C 4 alkyl, C 2 -C hydroxyalkyl, phenyl or benzyl, and R 2 in ⁇ dependently has the meaning of Rn, or R and Re together are tetramethylene, penta ⁇ methylene or -CH 2 CH 2 -0-CH 2 CH 2 - and R 20 is hydrogen, C ⁇ -C ⁇ 2 alkyl, C 2 -C ⁇ 2 alkenyl, C 3 -C ⁇ 2 cycloalkyl,
  • R 4 in formula III is an amine R 8 -R 9 .NCH 2 -, where R ff and R ff are, independently of one another, H, CrCealkyl, phenyl-d- or C 2 alkyl, in particular CH 2 C 6 H 5 .
  • Preferred compounds of group (b) of meanings for R 4 are those in which R is Cy-Cnar- alkyl, in particular CH 2 -C 6 H 5 and (CH 2 ) 2 -C 6 H 5 , C 3 -C ⁇ 2 cycloalkyl or CrCealkyl, which is un ⁇ substituted or substituted by one or more substituents selected from the group consisting of NH 2 , C 3 -C ⁇ 2 cycloalkyl, primary amino, secondary amino, sulfonamide, carbamide and aminocarbonylamido.
  • substituents for C C 12 alkyl are NH 2 , cyclohexyl, Ce-doaryl, R 8 C(0)N(R 9 )-, R 8 S(0) 2 N(R 9 )-, R 8 NHC(0)NR 9 -, NR 9 C(0)NHR 8 and R 8 .R 9 .N-, in which R 8 and R 9 are, independently of one another, hydrogen, CrCealkyl, C 3 -C ⁇ 2 cycloalkyl, C 2 -Cnheterocycloalkyl, C 6 -C ⁇ 0 aryl, C 5 -C 9 heteroaryl, C 7 -Cnaralkyl or C 6 -C ⁇ oheteroaralkyl and R 8 ' and R s - are, independently of one another, hydrogen, OH, C ⁇ -C ⁇ 2 alkyl, C 3 -d 2 cycloalkyl, C 2 -Cnheterocycloalkyl, Ce-C ⁇ 0
  • Particularly preferred compounds within this group are those in which R is CH 2 -C 6 H 5 , (CH 2 ) 2 -C 6 H 5 , cyclohexyl, methyl, ethyl or isopropyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH 2 , cyclohexyl, C 6 -C ⁇ oaryl, R 8 C(0)N(R 9 )-, R 8 S(0) 2 N(R 9 )- .
  • R 8 NHC(0)NR 9 -, NR 9 C(0)NHR 8 and R 8 R 9 N-, in which R 8 , R 9 , R 8 ' and R ff are, independently of one another, hydrogen, C ⁇ -d 2 alkyl, C 3 -C ⁇ 2 cycloalkyl, C 6 -C ⁇ 0 aryl or Cy-Cnaralkyl, which are unsubstituted or substituted by one or more substitu ⁇ ents selected from the group consisting of OH, halogen, C(0)OM y , nitro, cyano, S0 3 M y , OS0 3 M y , NHS0 3 M y , C ⁇ -d 2 alkyl, Ci-Cealkoxy and C 6 -C ⁇ 0 aryl, where y is 1 and M is a mono ⁇ valent metall or y is 1/2 and M is a divalent metal.
  • R 8 , R 9 are, independently of one another, hydrogen, C ⁇ -C ⁇ 2 alkyl, cyclohexyl, phenyl, naphthyl or Cy-Cnaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, Cl, C(0)ONa, nitro, cyano, S0 3 Na, d-C 6 alkyl, methoxy and phenyl.
  • Ri is formula III, in which R 4 is C 6 Hn, CH(CH 3 ) 2 , CH 2 -phenyl, (CH 2 ) 2 -phenyl, CH 2 NHC(0)-phenyl, CH 2 NHC(0)(CH 2 ) 3 -phenyl, CH 2 NHC(0)(CH 2 ) 3 OH, CH 2 NHC(0)CF 3) CH 2 NHC(0)C 6 Hn, CH 2 NHC(0)CnH 23 , CH 2 NHC(0)CH(C 6 H 5 ) 2 , CH 2 HNC(0)NHC 6 H 5 , CH 2 NHC(0)C 2 H 4 C0 2 Na, CH 2 NHC(0)C 6 [(1 ,3,4,5)OH] 4 H 7 , CH 2 NHC(0)C 6 H 4 -p-S0 3 Na, CH 2 NHC(0)C 6 H 4 CI, CH 2 NHC(0)C 6 H 4 N0 2l CH 2 NHC(0)C 6 H 4 OCH 3 , CH 2 NHC(0)C 6 H
  • R 2 as alkyl can contain preferably from 1 to 6 C atoms and particularly preferably from 1 to 4 C atoms. Methyl and ethyl are particularly preferred.
  • halogen for the substituents for R 2 , it can preferably be F, Cl and Br; in the case of -C(0)OM y preferably -C(0)ONa or -C(0)OK; in the case of alkyl preferably d-C 6 - and particularly preferably d-C alkyl, such as methyl, ethyl, n- or i-propyl and n-, i- or t-butyl; in the case of alkoxy preferably C ⁇ -C 4 alkoxy, for example methoxy and ethoxy; in the case of aryl preferably phenyl or naphthyl; in the case of -S0 3 M y preferably -S0 3 Na or -S0 3 K; in the case of primary amino C ⁇ -C ⁇ 2 primary amino such as methyl-, ethyl-, n- or i-propyl-, n-, i- or t-butyl, pentyl,
  • R 8 and R 9 as alkyl preferably contain 1 to 6, and particularly preferably 1 to 4, C atoms, and can be, for example, methyl, ethyl, n- or i-propyl or n-, i- or t-butyl.
  • R 8 and R 9 as hydroxyalkyl preferably contain 1 to 6, and particularly preferably 1 to 4, C atoms, and can be, for example, hydroxymethyl or 2-hydroxyethyl.
  • R 8 and R 9 as cycloalkyl are preferably cyclo ⁇ pentyl or cyclohexyl.
  • Substituents for R 8 and R 9 as phenyl and benzyl are preferably F, Cl, methyl, ethyl, methoxy and ethoxy.
  • a preferred subgroup of compounds of the formula I are those in which R 2 is hydrogen, un ⁇ substituted C ⁇ -C 6 alkyl, particularly preferably C ⁇ -C alkyl, especially methyl or ethyl, or C ⁇ -C 6 alkyl, particularly preferably C -C alkyl, especially methyl or ethyl, which is substituted by C(0)OH, -C(0)ONa, -C(0)OK, -OH, -C(0)-NR 8 R 9 or -S0 2 -NR 8 R 9 , in which R 8 is H, C ⁇ -C 4 alkyl, C 2 -C 4 hydroxyalkyl, phenyl or benzyl, and R 9 independently has the meaning of R 8 , or R 8 and Rg are together tetramethylene, pentamethylene or -CH 2 CH 2 -0-CH 2 CH 2 -.
  • Par ⁇ ticularly preferred compounds are those in which R 2 is hydrogen, methyl, ethyl, HO(0)CCH 2 CH 2 -, NaOC(0)CH 2 CH 2 - or R 8 R 9 NC(0)CH 2 CH 2 -, and R 8 and R 9 are, indepen ⁇ dently of one another, H, C ⁇ -C 6 alkyl, C 2 -C 4 hydroxyalkyl, phenyl, benzyl or, together, morpholino.
  • R 3 is hydrogen or M y ;
  • R is d-C 12 alkyl, C 2 -C ⁇ 2 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C eterocycloalkyl, C 2 -Cnheterocycloalkenyl, C 6 -C ⁇ 0 aryl, C 5 -C 9 heteroaryl, C 7 -Cnaralkyl, C 6 -C 10 heteroaralkyl, C 8 -Cn aralkenyl or C 7 -C ⁇ oheteroaralkenyl, which are unsubstituted or substituted once or several times;
  • R 5 and R 6 are, independently of one another, hydrogen, Ci-CealkyI, C 3 -C 12 cycloalkyl, C 2 -Cnheterocycloalkyl, C 6 -C ⁇ 0 aryl, C 5 -C 9 heteroaryl, C 7 -Cnaralkyl or C 6 -C ⁇ 0 heteroaralkyl; or R 5 and R 6 are, together with the -CH-CH- group, C 3 -C ⁇ 2 cycloalkylene, C -C 12 cycloalken- ylene, C 2 -Cn heterocycloalkylene and C 3 -Cn heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-; where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclo ⁇ alkylene, cycloalkenylene, heterocyclo
  • Preferred compounds of the formula la are those in which R 3 is H, K or Na,
  • R 5 and R 6 are, together with the -CH-CH- group, C 3 -C ⁇ 2 cycloalkylene, C -d 2 cycloalken- ylene, C 2 -Cn heterocycloalkylene and C 3 -Cnheterocycloalkenylene with hetero atoms selected from the group -O-, -S- and -N-; which are unsubstituted or substituted once or several times; where the substituent is selected from the group consisting of OH, halogen, C(0)OR s ⁇ , OC(0)R s4 , C(0)R s2 , nitro, NH 2 , cyano, S0 3 M y , OS0 3 M y , NR 20 SO 3 M y in which R 20 is hydro ⁇ gen, d-Cealkyl, C 2 -C ⁇ 2 alkenyl, C 3 -Cecycloalkyl, C 3 -CecycloalkenyI, C 2
  • Re is an amide group -N(R 9 )C(0)R 8 , -N(R 9 )S(0) 2 R 8 , -NR 9 C(0)NHR 8 or -NR 9 C(0)NHR 8 in which R 8 is C 6 -C ⁇ 0 aryl, preferably phenyl, which is unsubstituted or substituted by d-C alkyl, especially methyl, C C 4 alkoxy, especially methoxy, F, Cl, -CN or -N0 2 , or d-C 10 alkyl which is unsubstituted or substituted by F or Cl, and R 9 is H, CrC ⁇ 0 alkyl, C 5 - or C 6 cycloalkyl, C 5 - or C 6 cycloalkyl-CrC 6 alkyl, phenyl-d-C 6 alkyl or phenyl-C 2 -C 6 alkenyl, especially H, CrC 6 alkyl, cyclohexyl, cycl
  • R 4 is CrCealkyl, C 3 -C ⁇ 2 cycloalkyl or C -Cnaralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)OR s ⁇ , OC(0)R s4 , C(0)R S2 , nitro, NH 2 , cyano, S0 3 M y , OS0 3 M y , NR 20 SO 3 M y in which R 20 is hydro ⁇ gen, d-Cealkyl, C 2 -C 12 alkenyl, C 3 -C ⁇ 2 cycloalkyl, C 3 -d 2 cycloalkenyl, C 2 -Cnheterocycloalkyl, C 2 -Cn-heterocycloalkenyl, C 6 -C ⁇ 0 aryl, C 5 -C 9 heteroaryl, C 7 -C ⁇ aralkyl, C 6 -C
  • a preferred subgroup of compounds of group (a) are those in which
  • R is C ⁇ Hn, CeHn-CH 2 -, CeHn-CH 2 CH 2 -, CeHs-CH 2 -, CeHs-CH 2 CH 2 -, -CH 2 -NR ⁇ g-S0 2 R ⁇ 8 , -CH 2 -NRi 9 -C(O)R 40 , CH 2 NHC(0)NHR ⁇ 8 , -CH 2 NHR 2 ⁇ or CH 2 N(R 2 ⁇ ) 2 , in which R 1 ⁇ is -C 6 H 5 , phenyl which is substituted by 1 to 3 methyl or methoxy or -N0 2 or F or Cl, in particular p-CH 3 -C 6 H 4 -, p-CH 3 0-C 6 H 4 - or
  • a preferred subgroup of the compounds of group (b) are those in which R 4 is CeHn, CH 2 -C 6 H 5 , (CH 2 ) 2 -C 6 H 5 , methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH 2 , cyclohexyl, C 6 -C ⁇ 0 aryl, R 8 C(0)N(R 9 )-, R 8 S(0) 2 N(R 9 )-, NR 9 C(0)NHR 8 and R 8 R 9 N- in which R 8 , R 9 , R 8 . and R 9 .
  • R 20 is hydrogen, d-Cealkyl, C 2 -d 2 alkenyl, C 3 -d 2 cycloalkyl, C 3 -Cecycloalkenyl, C 2 -C ⁇ heterocycloalkyl, C 2 -Cn-heterocycloalkenyl, C 6 -C ⁇ 0 aryl, C 5 -C 9 heteroaryl, Cy-Cnaralkyl, Ce-Cioheteroaralkyl, Ce-Cioheteroaralkyl, Ce-Cioheteroaralkyl
  • Particularly preferred compounds are those in which R 8 , R 9 , R 8 - and R 9 - are, indepen ⁇ dently of one another, hydrogen, CrCealkyl, cyclohexyl, phenyl, naphthyl or C 7 -Cnaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, Cl, C(0)ONa, nitro, cyano, S0 3 Na, C C 6 alkyl, methoxy and phenyl.
  • R is C 6 Hn, CH(CH 3 ) 2 , CH 2 -phenyl, (CH 2 ) 2 -phenyl, CH 2 NHC(0)-phenyl, CH 2 NHC(0)(CH 2 ) 3 -phenyl, CH 2 NHC(0)(CH 2 ) 3 0H, CH 2 NHC(0)CF 3 , CH 2 NHC(0)C 6 H ⁇ , CH 2 NHC(0)CnH 23 , CH 2 NHC(0)CH(C 6 H 5 ) 2 , CH 2 HNC(0)NHC 6 H 5 , CH 2 NHC(0)C 2 H 4 C0 2 Na, CH 2 NHC(0)C 6 [(1 ,3,4,5)OH] 4 H 7 , CH 2 NHC(0)C 6 H 4 -p-S0 3 Na, CH 2 NHC(0)C 6 H 4 CI, CH 2 NHC(0)C 6 H 4 N0 2 , CH 2 NHC(0)C 6 H 4 OCH 3 , CH 2 NHC(0)C 6 H 4 (3,4)CI
  • the present invention additionally relates to a process for the preparation of the compounds of the formula I which comprises etherifying the 3-OH group of a compound of the formula V
  • R 12 is a protective group and Re' and Re" are, independently of one another, hydrogen or a protective group, with a compound of the formula VI
  • Ri has the abovementioned meaning and Re is a leaving group, and eliminating the protective groups.
  • Leaving groups can be: halides, such as chloride, bromide and iodide, and sulfonic acids, for example trifluoromethanesulfonate, aliphatic, cycloaliphatic or aromatic sulfonic acids which are unsubstituted or substituted by d-C alkyl; d-C alkoxy, nitro, cyano or halogen (chlorine, bromine).
  • Some examples of these acids are: methanesulfonic acid, mono-, di- or trifluoromethanesulfonic acids or p-nitrobenzenesulfonic acid.
  • CF 3 -S0 2 -0 " (also referred to as triflate) is particularly preferably used.
  • the leaving group is advantageously selected from the group consisting of halogen and unsubstituted and halogenated R-S0 2 -, in which R is CrCealkyl, in particular d-C 6 alkyl, C 5 -C 6 cycloalkyl, phenyl, benzyl, C ⁇ -C ⁇ 2 alkylphenyl, in particular d-C 4 alkylphenyl, or C ⁇ -d 2 alkylbenzyl, in particular d-C alkylbenzyl, for example methane, ethane, propane, butane, benzene, benzyl- and p-methylbenzenesul- fonyl.
  • Preferred leaving groups are Cl, Br, I, -S0 2 CF 3 (triflate) and p-nitrobenzenesulfonyl, and -S0
  • the compounds of the formula VI are known in some cases or can be obtained by known processes, as described by Degerbeck et al. [Degerbeck, F., Fransson, B., Grehn, L., Ragnarsson, U., J. Chem. Soc. Perkin Trans. 1 :11-14 (1993)] and by Dureault et al. [Dureault, A., Tranchepain, I., Depezay, J.C, Synthesis 491-493 (1987)].
  • Optically pure compounds can be obtained by using optically pure starting compounds (e.g. amino acids, ⁇ -hydroxylic acids) or by chromatographic separation processes, for example with chiral solid phases.
  • the compounds of the formula V are novel and the invention likewise relates to them. They can be obtained by known glycosylation methods starting from known fucosyl and galacto- syl donors and diols of the formula HO-X-OH. Stepwise introduction of galactose and fucose or vice versa is advantageous.
  • the pseudo-trisaccharide building blocks are synthesized.
  • the pseudotrisaccharide is assembled either by glycosidic attachment for the activated and protected galactose onto the fucose-O-X-OH building block or by glycosidic attachment of suitably protected and activated fucose onto a galac- tose-O-X-OH building block.
  • Glycosylation reactions are known on a large scale and are described in the specialist literature. It is then possible to introduce the group Ri into the pseudotrisaccharide. The resulting com ⁇ pounds of the formula I can subsequently be modified.
  • This modification may comprise hydrogenation of aromatic compounds to cycloaliphatic groups, which can take place, for example, at the same time as the hydrogenolytic elimination of protective groups. It is furthermore possible for an amino group to be acylated and/or alkylated and/or sulfonated.
  • the preparation of secondary and tertiary amines can be carried out by reductive amination.
  • dialkyltin oxides dialkyltin alkoxylates and bis(trialkyl)tin oxides.
  • Some examples are dibutyltin oxide, dibutyltin(0-methyl) 2 and (tributyl- tin) 2 0.
  • the activating agents are preferably used in stoichiometric amounts. In this case, the reaction is carried out in two stages, namely a) activation and b) coupling with the com ⁇ pounds of the formula VI.
  • the activation process can be carried out at temperatures from 40 to 200°C, preferably 60 to 120°C.
  • the compounds of the formula V and of the formula VI can be employed in equimolar amounts. However, it has proved expedient to employ the compounds of the formula VI in excess, for example in an amount which is up to 10 times, preferably up to 5 times, the amount of the compound of the formula V.
  • reaction stage b It is furthermore expedient to carry out the reaction in both reaction stages in the presence of an inert solvent or mixtures of solvents.
  • Reactive protic solvents such as alkanols and, furthermore, acid amides are unsuitable in reaction stage b). It is possible to use non-polar aprotie and polar aprotie or polar protic solvents.
  • These may be aliphatic or aromatic hydro ⁇ carbons such as pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene or xylene, halogenated hydrocarbons such as methylene chloride, chloroform, tetrachloro ⁇ methane, 1 ,2-dichloroethane, 1 ,1 ,2-trichloroethane, 1 ,1 ,2,2-tetrachloroethane and chloro ⁇ benzene, linear or cyclic ethers such as diethyl ether, dibutyl ether, ethylene glycol dimethyl or diethyl ether, tetrahydrofuran and dioxane, N,N-dialkylated carboxamides such as dimethylformamide, N-alkylated lactams such as N-methylpyrrolidone, ketones such as acetone and methyl isobutyl ketone
  • Protective groups and processes for derivatizing hydroxyl groups with such protective groups are generally known in sugar and nucleotide chemistry and are described, for example, by Beaucage, S.L. Iyer, R., Tetrahedron 48:2223-2311 (1992).
  • Examples of such protective groups are: benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, dimethoxy- benzyl, bromobenzyl, 2,4-dichlorobenzyl; diphenylmethyl, di(methylphenyl)methyl, di(di- methylphenyl)methyl, di(methoxyphenyl)methyl, di(dimethoxyphenyl)methyl, triphenylmethyl, tris-4,4',4"-tert-butylphenylmethyl, di-p-anisylphenylmethyl, tri(methylphenyl)methyl, tri(dimethylphenyl)methyl, methoxyphenyl(diphenyl)methyl, di(methoxyphenyl)phenylmethyl, tri(methoxyphenyl)methyl, tri(dimethoxyphenyl)methyl; triphenylsilyl, alkyldiphenylsilyl, dialkylphenylsilyl and trialkylsily
  • the protective groups can be identical or different.
  • Preferred protective groups are selected from the group consisting of linear and branched CrC 8 alkyl, in particu ⁇ lar d-dalkyl, for example methyl, ethyl, n- and i-propyl, n-, i- and t-butyl; C 7 -C ⁇ 2 aralkyl, for example benzyl; trialkylsilyl with 3 to 20 C atoms, in particular 3 to 12 C atoms, for example triethylsilyl, tri-n-propylsilyl, tri-i-propylsilyl, i-propyl-dimethylsilyl, t-butyl-dimethylsilyl, t-butyl- diphenylsilyl, n-octyl-dimethylsilyl, (1 ,1 ,2,2-tetramethylethyl)dimethylsilyl; substituted methyli ⁇ den
  • the synthesis preferably takes place with protective groups for Re' and Re" which together form an alkylidene group with, preferably 1 to 12 and, more preferably 1 to 8 C atoms.
  • particularly preferred protective groups are those in which R 12 ' and Re" to ⁇ gether are an alkylidene group with, in particular, 1 to 12 C atoms, with the alkylidene group forming an acetal or ketal with the oxygen atoms.
  • These protective groups are ones which can be eliminated under neutral or weakly acidic conditions.
  • Particularly suitable protective groups are acyl, benzyl, substituted benzyl, benzyloxymethyl, alkyl and silyl.
  • R ' and Re are, particularly preferably, together alkylidene, for example alkyl- or alkoxy- substituted benzylidene.
  • Re' and R i2 " can, however, also be hydrogen, or one of Re' and Re" can be a protective group such as benzyl and the other one of Re' and Re" can be hydrogen.
  • protective carboxylate groups are alkoxy- and aralkoxycarbonyl groups, pre ⁇ ferably -C0 2 Bn, -C0 2 CH 3 .
  • the reaction for elimination of the protective groups is preferably carried out at a tempera ⁇ ture of 0°C to 50°C, and particular at room temperature.
  • An alternative synthetic route comprises glycosidic linkage of the protected fucose hydroxy ether of the formula VII
  • Ri has the abovementioned meaning
  • Z is O or S
  • R 12 is a protective group and R is a leaving group, and subsequent removal of the protective groups from the resulting com ⁇ pound.
  • the com ⁇ pounds of the formula VII can be obtained in a simple manner by glycosidic linkage of ap ⁇ intestinaltely protected fucose with a compound of the formula HO-X-OH which is monopro ⁇ tected where appropriate.
  • the compounds of the formula VIII can be obtained by etherifi ⁇ cation of compounds of the formula R 1 OH with galactose which is protected where appropri ⁇ ate.
  • the compounds according to the invention have antiinflammatory properties and can accordingly be used as medicaments. It is possible with them in particular to alleviate dis ⁇ orders such as cardiogenic shock, myocardial infarct, thrombosis, rheumatism, psoriasis, dermatitis, acute respiratory distress syndrome, asthma, arthritis and metastatic cancer.
  • the invention furthermore relates to the compounds according to the invention for use in a therapeutic method for the treatment of disorders in warm-blooded animals, including humans.
  • the dosage on administration to warm-blooded animals with a body weight of about 70 kg can be, for example, 0.01 to 1000 mg per day. Administration preferably takes place in the form of pharmaceutical compositions, parenterally, for example intravenously or intraperitoneally.
  • the invention furthermore relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the compound according to the invention, alone or together with other active sub ⁇ stances, a pharmaceutical carrier, preferably in a significant amount, and, where appropri ⁇ ate, excipients.
  • the pharmacologically active compounds according to the invention can be used in the form of compositions which can be administered parenterally or of infusion solutions.
  • Solu ⁇ tions of this type are preferably isotonic aqueous solutions or suspensions, it being possible to prepare the latter, for example in the case of lyophilized compositions which comprise the active substance alone or together with a carrier, for example mannitol, before use.
  • the pharmaceutical compositions can be sterilized and/or comprise excipients, for example pre- servatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts to control the osmotic pressure and/or buffers.
  • compositions which may, if required, comprise other pharmacologically active substances such as antibiotics, are produced in a manner known per se, for example by conventional dissolving or lyophilizing processes, and comprise about 0.1 % to 90 %, in particular from about 0.5 % to about 30 %, for example 1 to 5 %, of active substance(s).
  • THF Tetrahydrofuran
  • NBA m-Nitrobenzyl alcohol
  • DMF N,N-Dimethylformamide
  • DME N,N-Dimethylformamide
  • An unconnected hyphen in the formulae means methyl.
  • Molecular sieves are activated at 300°C under high vacuum for 12 hours before use. They are used in powdered form.
  • Benzyl chloride (660 ml, 5.72 mmol) is added at room temperature to a mixture of R-3-azido-2-hydroxypropionic acid 28 [Dureault, A., Tranchepain, I., Depezay, J.C, Synthesis 491-493 (1987)], triethylamine (850 ml, 6.1 mmol) and DMF (7.0 ml). The mixture is stirred for 16 hours, and then further triethylamine (850 ⁇ l, 6.1 mmol) and benzyl chloride (660 ⁇ l, 5.72 mmol) are added. The reaction mixture is stirred for two days and then con- centrated under high vacuum.
  • Trifluoromethanesulfonic anhydride (770 ml, 4.41 mmol) is added at -20°C with stirring to a solution of the alcohol 29 (0.85 g, 3.84 mmol) and 2,6-di-tert-butylpyridine (1.12 ml, 4.99 mmol) in dry CH 2 CI 2 (11.0 ml).
  • the clear colourless solution is warmed to 0°C over the course of 40 minutes and is stirred at this temperature for a further 2 hours.
  • the mixture is diluted with CH 2 CI 2 (40 ml) and, while stirring vigorously, 1 M aqueous KH 2 P0 solution (30 ml) is added.
  • the organic phase is separated off and the aqueous phase is extracted twice with CH 2 CI 2 .
  • the combined organic phases are washed with H 2 0 (30 ml), dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • the oily residue (2.3 g) is purified by flash chromatography on a short silica gel column (ethyl acetate/hexane 1 :7), resulting in the benzyl R-3-azido-2-trifluoromethanesulfonyloxypropionate A1 (1.16 g, 85 %) as a yellowish oil.
  • the aqueous phase is extracted with CH 2 CI 2 (2 x 10 ml), and the combined organic phases are washed with H 2 0 (10 ml), dried (Na 2 S0 ), filtered and concentrated in vacuo.
  • the residue is purified roughly by column filtration on silica gel (eluent: ethyl acetate/hexane 1 :9), resulting in the crude triflate A2 (0.311 g, 70 %) as an oil.
  • the product is used immediately for the next stage (prepara ⁇ tion of B1.18).
  • the yellowish suspen ⁇ sion is dried at room temperature and, after 3 hours, 5 ml of a suspension consisting of DMTST (5.84 g, 22.61 mmol), 4A molecular sieves (4.0 g) and CH 2 CI 2 (35 ml) are added. Further 5 ml portions of this DMTST suspension are added after 30, 45 and 90 minutes respectively. The brown reaction mixture is then stirred for 15 hours, and thereafter filtered through Hyflo Super Cef (filter aid), washing with CH 2 CI 2 (300 ml).
  • the filtrate is extracted by shaking first with 10 % aqueous NaHC0 3 solution and then with saturated NaCl solution, and the organic phase is dried with Na 2 S0 4
  • the remaining brown foam is purified by two column chromatographies on silica gel (eluent for 1st chromatography: ethyl acetate/hexane 1 :4; 2nd chromatography: ethyl acetate/toluene 1 :9), resulting in the pure product 3 as a colourless solid (4.28 g, 60 %), which is immediately used further.
  • a solution of the tetrol 4 (1.0 g, 1.44 mmol), benzaldehyde dimethyl acetal (430 ml, 2.86 mmol) and camphorsulfonic acid (0.1 g, 0.43 mmol) in acetonitrile (20 ml) is stirred at room temperature. After 4 hours, further camphorsulfonic acid (0.15 g, 0.65 mmol) is added and the mixture is stirred for a further 6 hours at room temperature, after which it is heated at 35°C for a further 6 hours. Then further camphorsulfonic acid (0.06 g, 0.26 mmol) is added, and the solution is stirred at room temperature for 6 hours.
  • the reaction mixture is filtered through Hyflo Super Cel ® , washing with ethyl acetate.
  • the filtrate is extracted by shaking first with saturated aqueous NaHC0 3 solution and then with saturated NaCl solution, and the organic phase is dried (Na 2 S0 ), filtered and concentrated in vacuo, resul ⁇ ting in 1.5 g of crude product.
  • Purification of the crude product by flash chromatography on silica gel (CH 2 CI 2 /MeOH 39:1) affords, besides the required benzylidene acetal 5 (0.475 g), a mixture of less polar byproducts (0.4 g).
  • a mixture of the diol 5 (0.098 g, 0.125 mmol), di-n-butyltin oxide (0.062 g, 0.25 mmol) and methanol (5 ml) is heated under reflux in an argon atmosphere for 2 hours.
  • the reaction mixture is concentrated in vacuo, and pentane is added to the residue, after which it is con ⁇ centrated once again.
  • Dry CsF (dried under high vacuum at 300°C, 0.068 g, 0.45 mmol) is added under an argon atmosphere, and the mixture is further dried under high vacuum (30 minutes).
  • Dioxane (2.5 ml), water (1.2 ml) and glacial acetic acid (0.1 ml) are added to a mixture of Pd(OH) 2 /C (Pearlman catalyst, Pd content 20 %, 0.03 g) and the protected compound 6 (0.03 g, 0.029 mmol).
  • the flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly ele ⁇ vated pressure of hydrogen at room temperature for 13 hours, and then filtered through a cellulose filter (pore size 45 ⁇ m). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid.
  • the aromatic compound B1.1 (0.152 g, 0.256 mmol) and 5 % Rh/Al 2 0 3 (0.2 g) are taken up in H 2 0 (5.5 ml), dioxane (3.5 ml) and acetic acid (1.0 ml). Air is replaced by multiple evacua ⁇ tion, firstly by argon and then by hydrogen.
  • the black suspension is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 2 days and then filtered through a cellulose filter (pore size 45 ⁇ m).
  • the clear, colourless solution is concentrated in vacuo, and the residue is taken up in water and concentrated several times in order to remove excess acetic acid.
  • a solution of the crude product in water is filtered through a Dowex 50 ion exchanger column (Na + form, length: 9 cm, diameter: 1.3 cm), and the column is washed with water.
  • the filtrate is concentrated in vacuo, and the residue (0.16 g) is puri ⁇ fied by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.55 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: 55 % MeOH/H 2 0), resulting in the target molecule B1.2 (0.11 g, 73 %) as a fluffy white solid (after lyophiiization).
  • the pH of the mix ⁇ ture is adjusted to 1 by cautious addition of a saturated solution of HCl gas in dry diethyl ether.
  • the suspension is stirred at 0°C, and the pH is kept at 1 by occasional addition of the ethereal HCl solution. After 10 hours, cold, saturated aqueous NaHC0 3 solution is added (30 ml).
  • the organic phase is separated off, and the aqueous phase is extracted twice with ethyl acetate (70 ml each time).
  • the combined organic phases are dried (Na 2 S0 ), filtered and concentrated in vacuo, resulting in 1.3 g of the crude product.
  • Dry CH 2 CI 2 (8.0 ml) is added to a mixture of the thioglycoside 11 (0.377 g, 0.60 mmol), the glycosyl acceptor 2 (0.32 g, 0.60 mmol) (EP 671 ,409) and activated 4A molecular sieves (2.5 g) under an argon atmosphere.
  • a suspension of DMTST (0.39 g, 1.51 mmol) and acti ⁇ vated 4A molecular sieves (0.8 g) in dry CH 2 CI 2 (5.0 ml) is prepared in a second round- bottom flask. Both suspensions are stirred at room temperature for 3.5 hours.
  • the mixture is extracted three times with ethyl acetate, and the combined organic phases are washed first with aqueous NaHC0 3 solution and then with NaCl solution, dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • the oily residue (1.15 g) is purified by flash chromatography on silica gel (elution of the product with toluene/ethyl acetate 4:1 , then elution of the precursor with CH 2 CI 2 /MeOH 19:1), resulting in the ether 14 (0.488 g, 75 %) as a colourless foam and the precursor 13 (0.075 g, 15 %).
  • Pt BaS0 4 (0.35 g, Pt content: 5 %) is added to a solution of the azide 14 (0.11 g,
  • the mixture is extracted three times with CH 2 CI 2 , and the combined organic phases are washed first with 1 M aqueous KH 2 P0 4 solution (pH 1-2, adjusted with 1 M aqueous HCl) and then with aqueous NaHC0 3 solution, dried (Na 2 S0 ), filtered and concentrated in vacuo.
  • the residue is purified by column chromatography on silica gel (gradient elution: 35 % ethyl acetate/toluene to 40 % ethyl acetate/toluene), resulting in the benzamide 17 (0.0098 g, 68 %).
  • the filtrate is concentrated in vacuo, and the residue (0.007 g) is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.59 ml/min, detection at 230 nm) and subsequent reverse phase chromato ⁇ graphy (Merck RP18 silica gel, gradient elution: 37 % MeOH/H 2 0 to 45 % MeOH/H 2 0), resulting in the target molecule B1.3 (3.3 mg, 58 %) as a fluffy white solid, (after lyophiii ⁇ zation).
  • the flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black mixture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 18 hours.
  • the mixture is filtered through a cellulose filter (pore size 45 ⁇ m), and the filtrate is concentrated in vacuo.
  • the residue is mixed with toluene (about 2 ml) and concentrated several times in order to remove excess acetic acid.
  • a solution of the crude product (0.021 g) in a little water is then passed through an ion exchanger column (Dowex 50, Na + form, column diameter 0.9 cm, length 3.5 cm), washing with deionized water.
  • the filtrate is concentrated in vacuo, and the residue (0.02 g) is purified by reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: 60 % MeOH/H 2 0) and subsequent gel filtra ⁇ tion on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm), resulting in the target molecule B1.4 (0.014 g, 74 %) as a fluffy colourless solid (after lyophiiization).
  • the filtrate is concentrated in vacuo, and the residue (0.02 g) is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column dia ⁇ meter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm) and subse ⁇ quent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH/H 2 0 1 :4), resulting in the target molecule B1.5 (0.015 g, 70 %) as a fluffy colourless solid (after lyophiiization).
  • the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, water, flow rate 0.55 ml/min, detection 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 7 cm, eluent: 25 % MeOH/H 2 0), resulting in the target molecule B1.6 (0.011 g, 70 %) as a fluffy colourless solid (after lyo ⁇ phiiization).
  • the amine B1.6 (0.09 g, 0.176 mmol) is dissolved in dry MeOH (1.5 ml) and CH 2 CI 2 (1.8 ml) and activated 3A molecular sieves (about 0.2 g), cinnamaldehyde (24 ⁇ l, 0.19 mmol) and acetic acid (9 ⁇ l) are added.
  • the yellowish suspension is stirred for 2 minutes and then NaBH 3 (CN) (0.018 g, 0.286 mmol) is added. After 1.5 hours, the mixture is filtered through a cellulose filter (pore size 45 ⁇ m), the filter is washed with 1 :1 MeOH/ CH 2 CI 2 , and the filtrate is concentrated in vacuo.
  • the glassy residue is taken up in water (5 ml), and the solution is acidified (about pH 1-2) with 1 M hydrochloric acid (0.7 ml).
  • the cloudy solution is again filtered through a cellulose filter (pore size 45 ⁇ m), and the filtrate is adjusted to pH 7 with 1 M sodium hydroxide solution (about 1 ml) and then concentrated.
  • the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.6 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 50 % MeOH/H 2 0 to 70 % MeOH/ H 2 0), resulting in the target molecule B1.7 (0.03 g, 27 %) as a fluffy white solid (after lyophi ⁇ iization).
  • a solution of the amino acid B1.7 (0.01 g, 0.0159 mmol) in 1 M aq. NaHC0 3 (0.1 ml) is cooled to 0°C and, while stirring vigorously, a 1 M solution of benzoyl chloride in benzene (16.0 ⁇ l) is added. After 40 minutes, a further 8.0 ⁇ l of the benzoyl chloride solution is added, after 130 minutes a further 3.0 ⁇ l and after a total of 3.5 hours a further 1.0 ⁇ l. After a total of 4 hours, the reaction mixture is diluted with water and extracted with CH 2 CI 2 in order to remove the excess reagent.
  • the aqueous phase is concentrated in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.49 ml/min, detection at 215 nm) and subse ⁇ quent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 60 % MeOH/ H 2 0 to 70 % MeOH/H 2 0), resulting in the target molecule B1.8 (7.9 mg, 66 %) as a fluffy white solid (after lyophiiization).
  • a CH 2 CI 2 solution of freshly distilled benzaldehyde (0.083 g in 1.0 ml CH 2 CI 2 , 0.1 ml, 0.078 mmol), activated 3A molecular sieves (0.1 g) and glacial acetic acid (5 ⁇ l, 0.087 mmol) are added to a solution of the amino acid B1.6 (0.04 g, 0.078 mmol) in MeOH/ CH 2 CI 2 (1 :1 , 1.0 ml).
  • the suspension is stirred at room temperature and, after 2 minutes, NaBH 3 (CN) (0.008 g, 0.129 mmol) is added.
  • the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 35 % MeOH/H 2 0 to 60 % MeOH/H 2 0), with elution first of the monobenzylamine B1.9 (0.020 g, 41 %) and then of the dibenzylamine B1.10 (0.005 g, 9 %).
  • the reaction mixture is diluted with water and filtered through a cellulose filter (pore size 45 ⁇ m), and the filtrate is adjusted to pH 8-9 with 1 M aqueous NaHC0 3 solution and then concentrated.
  • the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 35 % MeOH/H 2 0 to 50 % MeOH/H 2 0), with elution first of the monoisobutylamine B1.11 (0.041 g, 46 %) and then of the diisobutylamine B1.12 (0.01 g, 10 %).
  • a 1 M solution of benzoyl chloride in toluene (41 ⁇ l) is added at room temperature to a solu ⁇ tion of the amino acid B1.11 (0.020 g, 0.0339 mmol) in 1 M aqueous NaHC0 3 (100 ⁇ l).
  • the mixture is stirred vigorously and, after 1 hour, further benzoyl chloride (41 ⁇ l of the 1 M solu ⁇ tion) is added.
  • the volatile constituents are removed under high vacuum, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: 45 % MeOH/H 2 0) and then lyophilized, resulting in the benzamide B1.13 as a fluffy powder, (0.014 g, 59 %).
  • the crude product (0.025 g) is further purified by two reverse phase chromatographies (Merck RP18 silica gel, 1st chromatography: elution with 50 % MeOH/H 2 0; 2nd chromatography: elution with 40 % MeOH/H 2 0) and subsequently lyophilized, resulting in the target compound as a fluffy powder (0.0105 g, 39 %).
  • a 1 molar solution of p-toluenesulfonyl chloride in toluene (22 ⁇ l) is added at 0°C with vigorous stirring to a solution of the amino acid B1.6 (0.01 g, 0.02 mmol) in 1 molar aqueous NaHC0 3 solution (0.1 ml).
  • the reaction mixture is stirred at 0°C for 90 minutes, after which further p-toluenesulfonyl chloride (10 ⁇ l of the 1 M solution) is added.
  • the reac ⁇ tion mixture is then warmed to room temperature, stirred for 18 hours and then concentra ⁇ ted in vacuo.
  • the residue is taken up in water and purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution with 45 % MeOH/H 2 0) and subsequently lyophilized, resulting in the target compound as a fluffy powder (0.004 g, 30 %).
  • Pentafluorophenyl trifluoroacetate (4.5 ml, 0.026 mmol) is added at room temperature with stirring to a solution of the isoserine derivative 16 (0.025 g, 0.026 mmol) and triethylamine (0.7 ml, 0.005 mmol) in DMF (100 ml). After 15 min, further pentafluorophenyl trifluoro ⁇ acetate (2.5 ml, 0.015 mmol) is added. 30 minutes later, further triethylamine (2.8 ml, 0.02 mmol) and pentafluorophenyl trifluoroacetate (4.5 ml, 0.026 mmol) are added.
  • a solution of the residue in a little water is passed through an ion exchanger column (Dowex 50, Na + form, column dia ⁇ meter 0.9 cm, length 3.5 cm), washing with deionized water.
  • the filtrate is concentrated in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm) and subse ⁇ quent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 7 cm, gradient elution: 30 % MeOH/H 2 0 to 40 % MeOH/H 2 0), resulting in the target molecule B1.16 (0.0085 g, 68 %) as a fluffy colourless solid (after lyophiiization).
  • a solution of the residue in a little water is passed through an ion exchanger column (Dowex 50, Na + form, column diameter 0.9 cm, length 3.5 cm), washing with deionized water.
  • the filtrate is concentrated in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m , column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH/H 2 O 3:2), resulting in the target molecule B1.17 (0.008 g, 56 %) as a fluffy colourless solid (after lyophiiization).
  • the residue is mixed under an argon atmosphere with dry CsF (0.131 g, 0.86 mmol, weighed under argon) and dry 1 ,2-dimethoxyethan (0.5 ml) followed by a solution of benzyl (R)-4-phenyl-2-trifluoromethanesulfonyloxybutyrate (A2) (0.3 g, 0.861 mmol) in dry 1 ,2-di- methoxyethane (1.0 ml).
  • the reaction mixture is stirred at room temperature for 75 minutes and 1 M of aqueous KH 2 P0 is added, and the mixture is diluted with water and extracted with ethyl acetate (phase separation is facilitated by adding a little aqueous KF solution).
  • the benzyl ether 30 (0.14 g, 0.135 mmol) is dissolved in dioxane (4 ml) and water (2 ml), glacial acetic acid (1 ml) and 20% Pd(OH) 2 /C (0.14 g) are added.
  • the air in the reaction vessel is replaced initially by argon, by evacuation and flushing several times, and then by hydrogen.
  • the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen for 90 minutes and then filtered through a cellulose filter (pore size 45 ⁇ m), washing with water. The filtrate is concentrated, and the residue is taken up in toluene and concentrated several times in order to remove remaining acetic acid.
  • the crude product (0.095 g) is dissolved in a little water and filtered through a Dowex ⁇ O (Na + ) ion exchanger column.
  • the filtrate is freeze-dried and the residue (0.085 g) is purified by reverse phase chromatography (Merck RP18 silica gel, elution: 40 % MeOH/H 2 0) and subsequent gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and then lyophilized, resulting in the target compound B1.18 as a fluffy powder (0.045 g, 55 %).
  • the aromatic compound B1.18 (0.02 g, 0.033 mmol) is dissolved in water (1.8 ml), dioxane (1.2 ml), glacial acetic acid (0.3 ml), and 5% Rh/Al 2 0 3 (0.04 g) is added.
  • the air in the reac ⁇ tion vessel is replaced by hydrogen by evacuation and flushing several times, and the mix ⁇ ture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 1.5 days. It is then filtered through a cellulose filter (pore size 45 ⁇ m) and washed with water, the filtrate is concentrated, and the residue is taken up in toluene and concentrated several times in order to remove remaining acetic acid.
  • the crude product is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and then hydrogenated again under the above conditions for 2 days.
  • the reaction mixture is then filtered through a cellulose filter (pore size 45 ⁇ m) and washed with water, and the filtrate is concentrated, after which the residue is taken up in toluene and concentrated several times.
  • the crude product is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: 50 % MeOH/H 2 0) and subsequently lyophi ⁇ lized, resulting in the target compound B1.19 as a fluffy powder (0.01 g, 50 %).
  • a solution of p-nitrobenzenesulfonyl chloride in toluene (1 M, 150 ⁇ l) is added to a solution of amino acid B1.11(0.035 g, 0.0617 mmol) in 1 molar aqueous NaHC0 3 solution (315 ⁇ l).
  • the mixture is vigorously stirred at room temperature and, after 17 hours, further p-nitro ⁇ benzenesulfonyl chloride solution (120 ⁇ l) is added.
  • the reaction mixture is stirred for a further 24 hours, then diluted with water and washed twice with ethyl acetate.
  • the aqueous phase is concentrated to a volume of 0.5 ml in vacuo, and this solution is purified by gel fil ⁇ tration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm).
  • the crude product (0.06g) is then further purified by reverse phase chromatography three times (Merck RP 18 silica gel, elution: 40% MeOH/H 2 0) and then lyophilized, resulting in the sulfonamide B1.38 (0.013 g, 27%) as a colourless fluffy powder.
  • reaction mixture is heated to 35 to 40°C and stirred at this temperature for 5 hours. Then a solution of 15% KF in 1 M aqueous KH 2 P0 solution (30 ml) is added, and the mixture is extracted three times with CH 2 CI 2 , and the combined organic phases are dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • the oily residue (0.16 g) is purified by column chromatography on silica gel (gradient elution: toluene/ethyl acetate 80:20 to 75:25, then CH 2 CI 2 /Me0H 19:1), resulting in the ether 31 (0.049 g, 44 %) as a colourless foam and the precursor 13 (0.035 g, 40 %).
  • hydroxypiperidine (6.0 g, 34.6 mmol, prepared from D-(-)-lyxose in accordance with lchikawa and Igarashi [lchikawa, Y., Igarashi, Y., Tetrahedron Letters 36:4585-4586 (1995)] and triethylamine (18.1 ml, 130 mmol) are dissolved in dry tetrahydrofuran (100 ml) and the solution is cooled to -10°C under an argon atmosphere. Allyl chloroformate (3.87 ml, 36.4°mmol) is slowly added over the course of one hour, a white suspension being formed.
  • 4A molecular sieves (dried under high vacuum at 300°C, 15 g) are added to a solution of the acceptor 34 (7.66 g, 29.8 mmol) in dry CH 2 CI 2 (150 ml) under an argon atmosphere, and the suspension is stirred at room temperature for one hour.
  • a suspen ⁇ sion of DMTST (15.4 g, 59.6 mmol) and 4A molecular sieves (15 g) in dry CH 2 CI 2 (150 ml) is prepared under an argon atmosphere in a second round-bottom flask and is stirred for one hour.
  • the DMTST mixture is then added in 4 portions over the course of a further hour to the solution of the acceptor, and the mixture is then stirred for one hour.
  • the reaction mix ⁇ ture is filtered through Hyflo Super Cel ® washing thoroughly with CH 2 CI 2 .
  • the filtrate is ex ⁇ tracted by shaking with 10% aqueous NaHC0 3 solution, the aqueous phase is reextracted three times with CH 2 CI 2 , and the combined organic phases are dried (Na 2 S0 ), filtered and concentrated in vacuo.
  • the remaining yellow oil (36 g) is purified by column chromatogra ⁇ phy on silica gel (gradient elution: hexane/ethyl acetate 3:1 to 3:2), resulting in the glycoside 35 (13.1 g, 54 %).
  • the acetonide 35 (13.1 g, 15.94 mmol) is dissolved in dioxane (140 ml) and, at room tem ⁇ perature 50 % aqueous trifluoroacetic acid (250 ml) is added. After 2 hours, the reaction mixture is concentrated under high vacuum, and the residue is purified by column chroma ⁇ tography on silica gel (ethyl acetate/hexane 2:1), resulting in the diol 36 (11, 23 g, 90 %).
  • a mixture of the diol 36 (11.63 g, 14.88 mmol), tetra-t.-butylammonium bromide (12.7 g, 39.4 mmol) and 4A molecular sieves is dried under high vacuum for 30 minutes and then, under an argon atmosphere, dry CH 2 CI 2 (62 ml) and dimethylformamide (36 ml) are added. The grey suspension is stirred at room temperature for 30 minutes.
  • the red solution is stirred at 0°C for 30 minutes, and the excess bromine is destroyed by adding a few drops of cyclohexene.
  • This solution is then added using a needle to the solution of the acceptor, and the reaction mixture is stirred at room temperature for 40 hours.
  • the reaction mixture is then filtered through Hyflo Super Cel ® and thoroughly washed with CH 2 CI 2 , and the filtrate is washed with 10 % aqueous NaHC0 3 solution.
  • the aqueous phase is reextracted three times with CH 2 CI 2 , and the com ⁇ bined organic phases are dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • the residue is purified by column chromatography on silica gel (ethyl acetate/hexane 35:65), with the required product 37 (7.85 g, 44 %) being eluted.
  • a suspension of 38 (1.0 g, 1.13 mmol) and di-tj-butyltin oxide (0.49 g, 1.98 mmol) in dry benzene (33 ml) is boiled under reflux in an argon atmosphere for 5 hours.
  • the reaction mixture is concentrated in vacuo and dried under high vacuum for one hour.
  • the reaction mixture is heated to 35 to 40°C and stirred at this temperature for 3 hours. Then a solution of 15% KF in 1 M aqueous KH 2 P0 4 solution (100 mL), is added, and the mixture is extracted three times with CH 2 CI 2 , and the combined organic phases are dried (Na 2 S0 4 ), filtered and con ⁇ centrated in vacuo.
  • the oily residue (2.6 g) is purified by column chromatography on silica gel (elution: toluene/ethyl acetate 3:1 , then CH 2 CI 2 /methanol 19:1) resulting in the ether 40 (0.33 g, 40 %) as a colourless foam, and partial recovery of the precursor 38 (0.167 g, 26 %).
  • Morpholine (1.1 ml) and Pd(PPh 3 ) 4 (0.071 g, 0.062 mmol) are added to a solution of the allyl carbamate 39 (0.695 g, 0.618 mmol) in tetrahydrofuran (8.5 ml). After exactly 15 minutes the solution is concentrated and the residue is dried under high vacuum for one hour. Purification of the residue by column chromatography on silica gel (eluent: CH 2 CI 2 / methanol 98:2, contains 0.3 % concentrated aqueous ammonia solution) gives initially the less polar allylamine 46 (0.24 g, 36 %) followed by the more polar piperidine 41 (0.39 g, 60 %).
  • the residue (0.05 g) is purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 4:1), resulting in the acetylpiperidine 42 (0.033 g, 91 %) as a colourless foam.
  • Compound 43 is prepared from the piperidine 41 (0.02 g, 0.019 mmol) and benzoyl chloride (2.5 ⁇ l, 0.021 mmol) in analogy to a method for the acetylpiperidine 42 (Example B23). The yield is 0.02 g (90 %).
  • the target compound B1.44 is prepared by hydrogenation of the benzyl ether 43 (0.042 g, 0.0367 mmol) and subsequent purification in analogy to the acetyl derivative B1.43. The product results after lyophiiization as a fluffy white solid. Yield: 0.015 g (57 %): MS (FAB, THG) 716 (M+H), 694 (M+2H-Na).
  • reaction mixture is filtered through a cellulose filter (pore size 45 ⁇ m), the filtrate is concen ⁇ trated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid.
  • a solution of the residue in water is passed through a Dowex ⁇ O ion exchange column (Na + form, diameter of the column 0.9 cm, length 3.5 cm), washing with deionized water.
  • Triethylamine (7 ⁇ l, 0.05 mmol) and n-butanesulfonyl chloride (3.7 ⁇ l, 0.029 mmol) are added at 0°C to a solution of the piperidine 41 (0.025 g, 0.024 mmol) in CH 2 CI 2 (0.3 ml). After 45 minutes, the reaction mixture is washed with 10 % aqueous NaHC0 3 solution, and the aqueous phase is reextracted three times with CH 2 CI 2 . The combined organic phases are dried (Na 2 S0 4 ), filtered and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (eluent: hexane/ethyl acetate 60:40), resulting in the sulfonamide 47 (0.022 g, 79 %).
  • the reac ⁇ tion mixture is filtered through a cellulose filter (pore size 45 ⁇ m), the filtrate is concentrated in vacuo, and the residue is taken up in water and concentrated again several times in order to remove excess acetic acid.
  • a solution of the residue in water is passed through a Dowex ⁇ O ion exchange column (Na + form, diameter of the column 0.9 cm, length 3.5 cm), washing with deionized water.
  • the clear filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromato ⁇ graphy (Merck RP18 silica gel, gradient elution: methanol/H 2 0 40:60 to 50:50), resulting in the target molecule B1.50 (0.021 g, 82 %) as a fluffy white solid (after lyophiiization).
  • Morpholine (0.37 ml) and Pd(PPh 3 ) 4 (0.025 g, 0.021 mmol) are added to a solution of the allyl carbamate 40 (0.24 g, 0.212 mmol) in tetrahydrofuran (2.9 ml). After exactly 15 minu ⁇ tes, the solution is concentrated and the residue is dried under high vacuum for one hour. Purification of the residue (0.38 g) by column chromatography on silica gel (eluent: CH 2 CI 2 / methanol 19:1 , contains 0.3 % concentrated aqueous ammonia solution) gives the piperi ⁇ dine derivative 49 (0.17 g, 76 %).
  • Phenyl isocyanate (4.6 ⁇ l, 0.042 mmol) and diisopropylethylamine (8.5 ⁇ l, 0.05 mmol) are added at 0°C to a solution of the piperidine derivative 49 (0.04 g, 0.038 mmol) in CH 2 CI 2 (0.6 ml). After 90 minutes, the reaction mixture is washed with 1 M aqueous KH 2 P0 4 solution and the aqueous phase is reextracted three times with CH 2 CI 2 . The combined organic phases are dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • the piperidine derivative 49 is converted in analogy to Example B28 (preparation of com ⁇ pound B1.48) using phenylmethanesulfonyl chloride as reagent into the target compound B1.52:
  • the filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid.
  • a 0.5 M solution of acetic anhydride in toluene is added in small portions (50 to 100 ⁇ l) at room temperature to a solution of the piperidine derivative B1.53 (0.035 g, 0.059 mmol) in 1 M aqueous NaHC0 3 solution (0.5 ml) until all the precursor is consumed (test by thin-layer chromatography: silica gel TLC plates, mobile phase: t.-butanol/ water/acetone/glacial acetic acid/NH 4 OH 70:60:50:18:1.6). The reaction is complete after about one hour, and the mixture is concentrated in vacuo and dried under high vacuum for 15 minutes.
  • a 1.5 M solution (+)-di-0-acetyl-L-tartaric anhydride in 1 ,4-dioxane is added in small portions (50 to 100 ⁇ l) at room temperature to a solution of the piperidine derivative B1.53 (0.03 g, 0.05 mmol) in 1 M aqueous NaOH solution (0.15 ml) until all the precursor is con ⁇ sumed (test by thin-layer chromatography: silica gel TLC plates, mobile phase: n-butanol/ water/acetone/glacial acetic acid/NH 4 OH 70:60:50:18:1.6). The mixture is kept basic throughout the reaction by periodic addition of 1 M NaOH solution.
  • the starting material is consumed after about two hours and then a further 1 M sodium hydroxide solution (0.13 ml) is added and the mixture is heated to 40°C in order to hydrolyse the ester groups. After one hour, the mixture is concentrated in vacuo and dried under high vacuum for 15 minutes.
  • the crude product is purified by gel filtration on Bio-Gel P2 (particle size 65 ⁇ m, column diameter 2.5 cm, length 3 ⁇ cm, eluent: water, flow rate 0.4 ⁇ ml/min, detection at 216 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/ H 2 0 1 :9), resulting in the target molecule B1.56 (0.020 g, 62 %) as a fluffy white solid (after lyophiiization): MS (FAB, THG) 794 (M+Na), 772 (M+H), 7 ⁇ 0 (M+2H-Na).
  • N,N-Diisopropylcarbodiimide (11.7 ⁇ l, 0.075 mmol) is added at 0°C to a solution of shikimic acid (0.013 g, 0.075 mmol) and 1 -hydroxybenzotriazole (0.01 g, 0.075 mmol) in dry N,N-di- methylformamide (0.37 ml), and the mixture is then stirred for 30 minutes. The mixture is then warmed to room temperature and the piperidine derivative B1.53 (0.01 ⁇ g, 0.025 mmol) is added.
  • N,N-Dimethylaminopyridine (1.03 g, 8.44 mmol) and p-nitrobenzenesulfonyl chloride (1.66 g, 7.44 mmol) are added at room temperature to a solution of the alcohol 37 (6.11 g, ⁇ .1 mmol) in CH 2 CI 2 (35 ml). After 52 hours, the reaction mixture is washed with 10 % aqueous NaHC0 3 solution, and the aqueous phase is reextracted three times with CH 2 CI 2 . The combined organic phases are dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • the crude product (10 g) is purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 3 ⁇ :6 ⁇ ), resulting in the nosylate 52 (6.58 g, 93 %).
  • a solution of the nosylate 52 (7.78 g, 5.62 mmol) and dry LiN 3 (0.99 g, 20.21 mmol) in dry N,N-dimethylformamide ( ⁇ O ml) is heated to 60-60°C under an argon atmosphere. After 16 hours, the solvent is removed under high vacuum, and the residue is taken up in CH 2 CI 2 and washed with 10 % aqueous NaHC0 3 solution. The aqueous phase is extracted three times with CH 2 CI 2 and the combined organic phases are dried (Na 2 S0 4 ), filtered and con ⁇ centrated in vacuo.
  • the crude product is purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 30:70), with elution first of the required azide 53 (4.22 g, 61 %), followed by the alcohol 37 (2.5 g).
  • reaction mixture is heated to 35 to 40°C and stirred at this temperature for 3 hours.
  • the mixture is then washed with a solution of 15% KF in 1 M aqueous KH 2 P0 4 (150 ml) and the aqueous phase is extracted three times with CH 2 CI 2 , and the combined organic phases are dried (Na 2 S0 ), filtered and concentrated in vacuo.
  • the oily residue (10.9 g) is purified by column chromatography on silica gel (elution: toluene/ethyl acetate 4:1 , then CH 2 CI 2 /methanol 19:1 to recover the pre ⁇ cursor), resulting in the ether 55 (1.94 g, 63 %) as a colourless foam and partial recovery of the precursor (1.1 g, 26 %).
  • the crude intermediate (0.017 g, lyophilized) is taken up in 1 M aqueous NaHC0 3 solution (0.3 ml) and over the course of 5 hours, several small portions (30 bis 60 ⁇ l) of an approx. 1 M solution of 3,4-dimethoxybenzoyl chloride in toluene are added, until a test by thin-layer chromatography (silica gel TLC plates, mobile phase: ⁇ -butanol/water/acetone/ glacial acetic acid/NH 4 OH 70:60:60:18:1.6) indicates complete conversion of the intermedi ⁇ ate.
  • the pH of the solution is kept basic during this reaction by adding several portions of solid NaHC0 3 (about 0.026 g in total).
  • the amine B1.59 (0.027 g, 0.038 mmol) is taken up in 1 M aqueous NaHC0 3 solution (0.35 ml) and, over the course of 4 hours, several small portions (30 to 60 ⁇ L) of an approx. O. ⁇ M solution of benzoyl chloride in toluene are added until a test by thin-layer chromato ⁇ graphy (silica gel TLC plates, mobile phase: n-butanol/water/acetone/glacial acetic acid/ NH 4 OH 70:60:60:18:1.5) indicates complete conversion.
  • the pH of the solution is kept basic throughout the reaction by adding several portions of solid NaHC0 3 (about 0.01 g in total).
  • the carbamate B1.61 is prepared starting from the amine B1.59 (0.027 g, 0.038 mmol) using benzyl chloroformate as reagent in analogy to Example B40 (Preparation of com ⁇ pound B1.60).
  • E-selectin/human IgG chimera [cloned and expressed according to Kolbinger et al. Biochemistry 36:6386-6392 (1996)] are incubated in Falcon probindTM microtiter plate (Plate 1) at a concentration of 200 ng/well in 0.01 M Tris, 0.16 M NaCl, 1 mM CaCI 2 , pH 7.4 (Tris- Ca ++ buffer). Thus the plating solution is dispensed as 100 ⁇ l/well of 2 ⁇ g/ml E-chimera. Row 12 is left blank with only buffer. Plate 1 is incubated covered at 37°C for 2 hours.
  • PolySLe a SA-HRP conjugate is prepared in advance by incubating Sialyl Le a -PAA-biotin (cat #01-044, GiycoTech Corp., Rockville, MD) with Streptavidin-HRP in a molar ratio of 1 :2. 60 ⁇ l/well of 1 ng/ ⁇ l of polySLe a SA-HRP conjugate in 1 % BSA in Tris-Ca ++ are added to all wells except row 11 in Plate 2. Plate 1 is washed four times with Tris-Ca ++ in the automatic plate washer. 100 ⁇ l/well are transferred from Plate 2 to Plate 1 starting from lowest concentration of compound. Plate 2 is dis ⁇ carded. The plate is incubated while rocking at room temperature for 2 hours.
  • the plate is washed 4 times with Tris-Ca ++ using automatic plate washer.
  • 100 ⁇ l/well of Substrate [Mix 3,3',5, ⁇ '-tetramethylbenzidine reagent and H 2 0 2 , at 1 :1 ratio] are added with an 8 channel pipettor from right to left.
  • the plate is incubated at room temperature for 2 minutes.
  • the reaction is stopped by adding 100 ⁇ l/well of 1 M H 3 P0 4 using the 8 channel pipettor from right to left.
  • Absorbance of light at 450nm is measured in a microtiter plate reader.
  • IC 50 is calculated by determining the concentration of compound required to inhibit maximal binding of the polySialylLe a HRP conjugate to immobilized E-selectin/human IgG chimera by 50%.
  • the relative IC 50 is calculated by determining the ratio of the IC 50 of an internal control compound to the IC 5 o of the test compound.
  • IC 5ff Test compound

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Abstract

Compounds of formula (I) in which X is the residue of a non-glycosidic aliphatic 1,2-diol; R1 is an S-configurated methyl substituted with one carboxyl residue and one other substituent; and R2 is hydrogen, C1-C12alkyl or C6aryl; as mimetics of sialyl-Lewis X and sialyl-Lewis A.

Description

Diqlvcosylated 1.2-diols as mimetics of sialyl-Lewis X and sialyl-Lewis A.
The present invention relates to mimetics of sialyl-Lewis X and sialyl-Lewis A, in which, in the natural tetrasaccharide, the neuraminic acid residue is replaced by an S-configurated methyl substituted with one carboxyl residue and one other substituent and the N-acetyl- glucosamine residue is replaced by a non-glycosidic residue of a 1 ,2-diol, to processes for the preparation of these compounds and to the use of these mimetics in therapeutic methods.
The complex process of inflammation, which takes place in several stages, is the body's natural reaction to injuries in which, for example, there is also invasion by infectious agents. Under the influence of cytokines, the endothelium which lines the blood vessels expresses adhesion proteins on its surface. The P and E selectins bring about, by a protein-carbo¬ hydrate interaction with glycolipids and glycoproteins on the leukocyte membrane, the so¬ called "rolling" of leukocytes. The latter are slowed down by this process, and there is acti¬ vation of certain proteins (integrins) on their surface which ensure firm adhesion of the leukocytes to the endothelium. This is followed by migration of the leukocytes into the damaged tissue.
When this process takes place in a controlled manner, the damage is eliminated after a certain time without major adverse effects remaining. It is otherwise in the case of certain acute and chronic inflammatory processes, in which the migration of leukocytes takes place in an uncontrolled manner, which leads to severe damage to the body. This is the case in disorders such as cardiogenic shock, myocardial infarct, thrombosis, rheumatism, psoriasis, dermatitis, acute respiratory distress syndrome and metastatic cancer [Dasgupta, F., Rao, B.N.N., Exp. Opin. Invest. Drugs 3:709-724 (1994)].
Several approaches to the development of medicaments which intervene at various points in these unwanted processes have already been pursued [Dasgupta, F., Rao, B.N.N., Exp. Opin. Invest. Drugs 3:709-724 (1994)]. The aim of one route is to prevent the interaction between P and E selectins and their receptors on the leukocyte membrane, thus to prevent the "rolling", by mimetics of the corresponding epitopes. This also results in suppression of the subsequent processes. One of the smallest carbohydrate epitopes as ligand for E selectin is sialyl-Lewis X [neuraminic acid-α(2→3)-galactose-β(1 →4)-(fucose-α(1->3))-N- acetylglucosamine (sLex)].
EP-A-0 579 196 proposed as compounds competing with the natural ligands for binding to E selectin mimetics of sLex in which the neuraminic acid residue is replaced by a lactic acid residue. WO 93/10796 describes compounds which comprise in place of the neuraminic acid residue the residue of an α-hydroxy acid. WO 93/23031 discloses mimetics in which the N-acetylglucosamine residue (GlcNAc residue) is replaced by an R,R-1 ,2-cyclohexane- dioxy. However, it is common to all these compounds that the binding affinity between them and the E selectin is increased only inconsiderably compared with that of sLex, or is in fact worse, and is insufficient for a therapeutic effect.
It has now been found, surprisingly, that simultaneous replacement of the neuraminic acid residue by an S-configurated methyl substituted with one carboxyl residue and one other substituent and of the N-acetylglucosamine residue by a non-glycosidic residue of an ali¬ phatic diol results in an unexpectedly high binding affinity of the resulting mimetic. The novel compounds additionally represent a structural and chemical simplification, have a lower molecular weight and can be obtained in larger quantities by methods with low syn¬ thetic complexity.
The present invention relates to compounds of the formula I
Figure imgf000004_0001
in which
X is the residue of a non-glycosidic aliphatic 1 ,2-diol; Ri is an S-configurated methyl substituted with one carboxyl residue and one other substitu¬ ent; and
R2 is hydrogen, d-Cι2alkyl or C6aryl; where the alkyl and the aryl are unsubstituted or sub¬ stituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR2oSO3My) Cι-C12alkyl, C2-C12alkenyl, CrC12alkoxy, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-C11heterocycloalkyl, C-VCuheterocycloalkenyl, C6-Cι0aryl, C6-C10aryloxy, Cs-Cgheteroaryl, C5-Cgheteroaryloxy, C7-d aralkyl, Cy-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cn aralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydr- azide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsi is hydro¬ gen, My, C Cι2alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-Cuheterocycloalkyl, C6-Cιoaryl, C5-C9heteroaryl, C -Cnaralkyl or C6-C10heteroaralkyl, Rs is hydrogen, d-C^alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-Cnheterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, Cy-Ci aralkyl or C6-Cι0heteroaralkyl, and Rs2 and R2o are hydrogen, CrC12alkyl, C2-C12alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyI, C2-Cn heterocycloalkyl, C2-Cn -hetero¬ cycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C7-Cn aralkyl, C6-C10heteroaralkyl, C8-Cn-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo¬ alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero¬ aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal; including their physiologically tolerated salts.
Preferred aliphatic residues X are linear or branched C2-C2o-. preferably C2-C12- and particu¬ larly preferably C2-C6alkylene and -alkenylene, C3-Cι2-, preferably C3-C8- and particularly preferably C5-C7cycloalkylene and cycloalkenylene, and C3-Cn-, preferably C3-C7- and par¬ ticularly preferably C3-C5heterocycloalkylene and heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-.
The residue X can contain substituents such as OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My. OSO3My, NR20SO3My, C.-C12alkyl, C2-Cι2alkenyl, C C12alkoxy, C3-Cι2cycloalkyl, C3-C12cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, Ce-doaryl, C6-Cι0aryloxy. C5-Cgheteroaryl, C5-Cgheteroaryioxy, C7-Cnaralkyl, Cy-Ci aralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and amidocarbonyiamide, where Rs1 is hydrogen, My, Cι-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9hetero- aryi, C7-Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, C Cι2alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-Cnheterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, Cι-C12alkyl, C2-C12alkenyl, C3-Cι2cyclo- alkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-C10aryl, Cs-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cι (.heteroar¬ alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo¬ alkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
In a preferred embodiment of the present invention, X is the residue of a 1 ,2-diol corresponding to formula II
Figure imgf000006_0001
in which
R5 and R6 are, independently of one another, hydrogen, C C12alkyI, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cgheteroaryl, C7-Cnaralkyl or C6-C10heteroaralkyl; or R5 and R6 are, together with the -CH-CH- group, C3-C12cycloalkylene, C3-C12-cycloalken- ylene, C2-Cn heterocycloalkylene and C3-Cn heterocycloalkenylene with hetero atoms selected from the group -O-, -S- and -N-; where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclo¬ alkylene, cyctoalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halo¬ gen, C(O)ORsι, OCfOJRs-,, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR2oSO3My, C C12alkyI, C2-Cι2alkenyl, Cι-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-Cnhetero- cycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C6-Cι0aryloxy, C5-C9heteroaryl. C5-C9heteroaryloxy, Cy-Cnaralkyl, Cy-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7- Cioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonyl¬ amide, where Rs1 is hydrogen, My, C.-Cι2alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-Cnhetero- cycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, Cy-Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, C C^alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, Cy-Cnaralkyl or C6-Cι0heteroaralkyl, and Rs2 and R20 are hydrogen, d-C^alkyl, C2-Cι2alkenyl, C3-C12cycloalkyl, C3-Cι2cycloalkenyl, C2-C heterocycloalkyl, C2-Cn-hetero- cycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, Cy-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or Cy-Cioheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo¬ alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero¬ aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
The other substituent in R, has preferably 1 to 20, more preferably 1 to 16, particularly pre¬ ferably 1 to 12, and especially preferably 1 to 8, C atoms. The other substituent is preferab¬ ly selected from the group consisting of unsubstituted and substituted d-Cι2alkyl, C2-Cι2alkenyl, C3-C12cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-C10aryl, Cs-Cgheteroaryl, Cy-Cnaralkyl, Ce-CioheteroaralkyI, C8-Cnaralkenyl and Cy-doheteroaralkenyl. The other substituent is particularly preferably substituted methyl, or 2-substituted ethyl or cyclohexyl. Examples of suitable substituents are the sub¬ stituents mentioned above in the definition of R2, especially OH, halogen (F, Cl or Br), carb¬ oxyl, -SO3H, C(O)OMy, SO3My, OSO3My, NR20SO3My in which R20 is hydrogen, d-C12alkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C -Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-hetero- cycloalkenyl, C6-Ci0aryl, C5-Cgheteroaryl, Cy-Cnaralkyl, Ce-doheteroaralkyl, C8-Cn-aralkenyl or Cy-Cioheteroaralkenyl, or Cι-Cι2alkyl, Cι-Cι2alkoxy, nitro, -NH2, primary amino with 1 to 20 C atoms, secondary amino with 2 to 30 C atoms, cyano, C3-C8cycloalkyl, C3-C6hetero- cycloalkyl, C6-Cι0aryl, C3-Cgheteroaryl, Cy-Cι6heteroaralkyl, where the hetero atoms are selected from the group of O, S and N atoms, and carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide or aminocarbonylamide, whose N atoms are unsubstituted or substituted by a hydrocarbon group or hydroxy-hydrocarbon group with 1 to 20 C atoms. The hydrocarbon groups and heterohydrocarbon groups in turn are unsubstituted or substi- tuted, for example with d-C6alkyl, Ci-Cealkoxy, carboxyl, halogen (F, Cl or Br), -OH, -CN or -N02.
In a particular embodiment of the compounds of the formula I, Ri corresponds to a group of the formula III,
Figure imgf000008_0001
in which
R3 is hydrogen or My; and
R4 is Cι-Cι2alkyl, C2-C12alkenyl, C3-d2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cιιheterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, Cy-Cnaralkyl, C6-Cιoheteroaralkyl, C8-Cnaralkenyl or C7-Cι0heteroaralkenyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ORsι, OC(0)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3lv1y, d-C12alkyl, C2-Cι2alkenyl, C Cι2alkoxy, C3-Cι2cycloalkyl, C3-C 2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn heterocycloalkenyl, C6-Cιoaryl, C6-Cιoaryloxy, C5-Cgheteroaryl, C5-C9heteroaryloxy, Cy-Cnaralkyl, Cy-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfon¬ hydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, C Cι2alkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6-C10aryl, Cs-Cgheteroaryl, C -Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, Ci-CealkyI, C2-C12alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, Cy-Cnaralkyl or C6-Cι0heteroaralkyl, and Rs2 and R20 are hydrogen, d-C 2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C -C12cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-hetero- cycloalkenyl, Cβ-Cioaryl, C5-Cgheteroaryl, Cy-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or Cy-Cioheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo¬ alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero¬ aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. For the purposes of the present invention, a metal is to be understood as meaning an alkali metal [for example lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and caesium (Cs)], an alkaline earth metal [for example magnesium (Mg), calcium (Ca) and strontium (Sr)] or manganese (Mn), iron (Fe), zinc (Zn) or silver (Ag). Physiologically tolerated salts are to be understood as meaning, in particular, the alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium and calcium salts. Sodium and potassium ions and their salts are preferred.
Halogen is to be understood as meaning a representative of the group consisting of fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred, especially fluorine and chlorine.
Alkyl can be linear or branched, preferably branched once or twice in the α position. Some examples of alkyl, which preferably contains 1 to 12 C atoms, are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. Preferred alkyl groups are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.
Examples of alkenyl are allyl, but-1-en-3-yl or -4-yl, pent-3- or 4-en-1-yl or -2-yl, hex-3- or -4- or -5-en-1-yl or -2-yl and (Cι-C4alkyl)CH=CH-CH2-.
Cycloalkyl and cycloalkenyl can contain preferably 5 to 8 and particularly preferably 5 or 6 ring carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclo¬ hexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Cyclo¬ hexyl is a particularly preferred cycloalkyl group. Examples of cycloalkenyl are cyclopropen- yl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, cycloundecenyl and cyclododecenyl. Cyclohexenyl is a particularly preferred cycloalkenyl group.
Examples of alkylene are ethylene, 1 ,2-propylene, 1 ,2- or 2,3-butylene, 1 ,2- or 2.3- pentylene, 1 ,2-, 2,3- or 3,4-hexylene. Examples of cycloalkylene are 1 ,2-cyclopropylene, 1 ,2-cyclobutylene, 1 ,2-cyclopentylene, 1 ,2-cyclohexylene, 1 ,2-cycloheptylene and 1 ,2-cyclo- octylene. Examples of heterocycloalkylene are pyrrolidinylene, piperidinylene, tetrahydro- furanylene, di- and tetrahydropyranylene. Examples of heterocycloalkyl are derived from pyrrolidine, imidazolidine, oxazolidine, pyrazolidine, piperidine, piperazine and morpholine. Examples of heterocycloalkenyl are derived from 2- and 3-pyrroline, oxazoline, 2- and 4-imidazoline and 2- and 3-pyrazoline.
For the purposes of the present invention, aryl or heteroaryl is a five- or six-membered ring or a bicycle consisting of two condensed six- or five-membered rings or one six-membered and one five-membered ring, and in the case of heteroaryl one or more C atoms may be replaced, independently of one another, by an atom selected from the group consisting of oxygen, nitrogen and sulfur. Examples are derived from benzene, naphthalene, indene, furan, pyrrole, pyrazole, imidazole, isoxazole, oxazole, furazan, thiadiazole, thiophene, thiazole, oxadiazole, triazole, indole, indazole, purine, benzimidazole, benzoxazole, benzo¬ thiazole, pyran, pyridine, pyridazine, triazine, pyrimidine, pyrazine, isoquinoline, cinnoline, phthalazine, quinoline, quinazoline, pterdine, benzotriazine or quinoxaline. Aryl is preferably naphthyl and phenyl. Phenyl is particularly preferred. Heteroaryl is preferably furanyl, pyridinyl and pyrimidinyl.
Aralkyl preferably has 7 to 12 C atoms and can be phenyl-CnH2n- with n equal to a number from 1 to 6. Examples are benzyl, phenylethyl or phenylpropyl. Benzyl and 2-phenylethyl are preferred. Aralkenyl is preferably unsubstituted pheny!-CH=CH-CH - (cinnamyl) and cinnamyl is substituted on the phenyl by a substituent selected from the group consisting of OH, halogen, COOH, C(O)OMy, Cι-C12alkyl, CrC6alkoxy, C6-Cι0aryl, SO3My, OSO3My, NR20SO3My in which R20 is hydrogen,
Figure imgf000010_0001
C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, Cs-Cgheteroaryl, Cy-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or Cy-Cioheteroar¬ alkenyl, and NO2, Cι.C12primary amino, C2-C20secondary amino, amino and CN.
Heteroaralkyl and heteroaralkenyl are preferably C -C5heteroarylmethyl and C4-C5hetero- arylethenyl with one or two hetero atoms from the group of O and N, and the heteroaryl can comprise the abovementioned heteroaryl residues.
Alkoxy can be linear or branched, preferably branched once or twice in the α position. Some examples of alkoxy, which preferably contains 1 to 12 C atoms, are methoxy, ethoxy and the isomers of propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undec- oxy and dodecoxy. Preferred alkoxy groups are methoxy and ethoxy. Examples of aryloxy and aralkoxy are phenoxy and benzyloxy. Heteroaryloxy is preferably furanyloxy, pyridinyloxy and pyrimidinyloxy.
The primary amino preferably contains 1 to 12, particularly preferably 1 to 6, C atoms. Some examples are methyl-, ethyl-, hydroxyethyl-, n- or i-propyl-, n-, i- or t-butyl-, pentyl-, hexyl-, cyclopentyl-, cyclohexyl-, phenyl-, methylphenyl-, benzyl- and methylbenzylamino. The secondary amino preferably contains 2 to 14, particularly preferably 2 to 8, C atoms. Some examples are dimethyl-, diethyl-, methylethyl-, di-n-propyl-, di-i-propyl-, di-n-butyl-, diphenyl-, dibenzylamino, morpholino, piperidino and pyrrolidino.
NH2, primary amino, secondary amino, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide and aminocarbonylamide preferably correspond to a group R8C(O)(NH)pN(Rg)-, -C(O)(NH)pNR8R9, R8OC(O)(NH)pN(R9)-, R8R40NC(O)(NH)pN(Rg)-, -OC(O)(NH)pNR8R9, -N(R40)C(O)(NH)PNR8R9, R8S(O)2(NH)pN(R9)-; -S(O)2(NH)pNR8R9; R8R40NS(O)2N(R9)- or -NR40S(O)2NR8R9, in which R8, R9 and R40 are, independently of one another, hydrogen, OH, d-Cι2alkyl, Cι-Cι2alkenyl, C3-d2cycloalkyl, C3-d2cycloalkenyl, C2-C11 heterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cι6aralkyl, C8-Cι6aralkenyl with C2-C6alkenylene and C6-Cι0aryl, C6-Cι5heteroaralkyl, C6-Cι5heteroar- alkenyl, or di-Ce-Cioaryl-d-Ce-alkyl, or R8R9N in which Rff and Rg- are, independently of one another, hydrogen, OH, SO My, OSO My, Cι-Cι2alkyl, C -Cι2cycloalkyl, C2-Cnhetero- cycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, Cy-Cnaralkyl, C6-C10heteroaralkyl, C8-d6aralkenyl with C2-C6alkenylene and C6-Cι0aryl, or di-Ce-Cioaryl-Ci-Ce-alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORsι, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, Cι-Cι2alkyl, C2-Cι2alkenyl, d-Cι2alkoxy, C3-C12cycloalkyl, C3-d2cycloalkenyl, C2-Cn heterocycloalkyl, C2- Cnheterocycloalkenyl, C6-Cι0aryl, C6-Cι0aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, Cy- Cnaralkyl, C7-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cn aralkenyl, C7-Cιoheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, Cι-Cι2alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-Cnheterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, Cy-Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, Cι-Cι2alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, Cs-Cghetero¬ aryl, Cy-Cnaralkyl or C6-Cι0heteroaralkyl and Rs2 is hydrogen, Cι-Cι2alkyl, C2-C12alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-C10heteroaralkyl, C8-Cn-aralkenyl or C7-Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl, in turn are unsubstituted or substituted by one of the above¬ mentioned substituents; p is 0 or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal; or R8 and R9 or Rff and Rff or R8 and R 0 in the case of -NR8Rg or - NR8 R9- or R8R40N- together are tetramethylene, pentamethylene, -(CH2)2-O-(CH2)2-, -(CH2)2- S-(CH2)2- or -(CH2)2-NR7-(CH2)2-, and R7 is H, d-C6alkyl, C7-Cnaralkyl, C(O)Rs2 or sulfonyl.
The sulfonyl substituent corresponds, for example, to the formula Ri0-SO2- in which Rι0 is Ci-CealkyI, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, Cs-Cgheteroaryl, C7-Cnar- alkyl or C6-Cι0heteroaralkyl, which are unsubstituted or substituted by one or more substitu¬ ents selected from the group consisting of OH, halogen, C(O)ORsι, OCfOJR.*, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, Cι-Cι2alkyl, C2-Cι2alkenyl, Cι-Cι2alkoxy, C -Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn heterocycloalkenyl, Ce-Cioaryl, C6-Cι0aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-Cnaralkyl, C6-C10hetero- aralkyl, C8-Cnaralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, Cι-C12alkyl, C2-Cι2alkenyl, C3- Cι2cycloalkyl, C2-Cn heterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6- Cioheteroaralkyl, Rs4 is hydrogen, Cι-C12alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C2- Cnheterocycloalkyl, C6-Cιoaryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, and Rs2 and R20 are hydrogen, Ci-CealkyI, C2-C12alkenyl, C3-d2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cιι heterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, Ce-doheteroaraikyl, C8-Cn-aralkenyl or C7-Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are substituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
Preferred compounds of the formula I are those compounds in which X corresponds to a group of the formula li in which R5 and R6
(a) are unsubstituted or substituted by d-C12alkyl, for example methyl, ethyl, or Ci-Cealk¬ oxy, for example methoxy, ethoxy; (b) are, together with the group -CH-CH-, a 5- to 8-membered carbocycle, and particularly preferably, a 5- or 6-membered carbocycle, and are very particularly preferably
R,R-1 ,2-cyclohexylene;
(c) are, together with the group -CH-CH-, a 5- to 8-membered heterocarbocycle, and parti¬ cularly preferably a 5- or 6-membered heterocarbocycle with nitrogen as hetero atom, and are very particularly preferably R,R-3,4-piperidylene;
(d) are, independently of one another, hydrogen, unsubstituted Cι-Cι2alkyl or Cι-Cι2alkyl which is substituted by a substituent selected from the group consisting of -C(O)ORsι, -OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C3-d2cycloalkyl, Ci-Cealkoxy, phenyloxy and benzyloxy; unsubstituted C3-C12cycloalkyl or C3-C12cycloalkyl which is substituted by a substituent selected from the group consisting of -C(O)ORsι, -OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, d-C6alkyl, Ci-Cealk¬ oxy, phenyloxy and benzyloxy; C6-d0aryl which is unsubstituted or substituted by -C(O)ORsι, -OC(O)Rs4, -C(O)ONa or -C(0)OK, primary amino, secondary amino, d-C6alkyl or Ci-Cealkoxy; C3-C9heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; or C7-Cι2aralkyl which is unsubstituted or substituted by -C(O)ORs1, -OCfOJRsa, -C(O)ONa or -C(O)OK, primary amino, secondary amino, d-C6alkyl or d-C6alkoxy;
(e) are, together with the group -CH-CH-, a 5- to 12-membered carbocycle or 5- or 6-mem¬ bered heterocarbocycle with a hetero atom selected from the group consisting of oxygen and nitrogen atoms; or
(f) are, together with the -CH-CH- group, C3-Cι2cycloalkylene, C -Cι2cycloalkenylene, C2-Cn heterocycloalkylene and C3-Cnheterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-; where cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1) OCfOJR.*, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, Cι-Cι2alkyl, C2-Cι2alkenyl, Cι-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-C10aryl, C6-Cι0aryloxy, C5-Cgheteroaryl, Cs-Cgheteroaryloxy, Cy-Cnaralkyl, C7-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7- C oheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and amino¬ carbonylamide, where Rsι is hydrogen, My, Cι-C12alkyl, C2-C12alkenyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0arylr C5-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, R^ is hydrogen, Cι-Cι2alkyl, C2-d2alkenyl, C3-C12cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cι aralkyl or C6-Cιoheteroaralkyl, and Rs2 and R20 are hydrogen, d-Cι2alkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-C oheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
Particularly preferred compounds are those in which X corresponds to a group of the formula II in which R5 and R6 are, together with the -CH-CH- group, C3-d2cycloalkylene or C2-Cn heterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and hetero¬ cycloalkylene are unsubstituted or substituted by one or more of the above substituents.
Particularly preferred compounds are those in which R5 and R6 are, together with the -CH-CH- group, C3-Cι2cycloalkylene or C2-Cnheterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)ORsι, OCfOJR. , C(0)Rs2, NR8R9, d-Cι2alkyl, R8C(O)(NH)pN(R9)-, -C(O)(NH)pNR8R9, R8S(O)2(NH)pN(R9)-; R8R40NC(O)(NH)pN(Rg)-, R8OC(O)(NH)pN(R9)-, -OC(O)(NH)pNR8Rg, and Rι0-SO2-, in which R8, R9, Rι0 and R 0 are, independently of one another, hydrogen, OH, Cι-Cι2alkyl, Cι-Cι2alkenyl, C3-C12cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-Ci0aryl, C5-C9heteroaryl, C -Cι6aralkyl, C8-d6aralkenyl with C2-C6alken- ylene and C6-Cι0aryl, C6-Cι5heteroaralkyl, C6-Cι5heteroaralkenyl, or di-Ce-Cioaryl-Ci-Ce- alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORsι, OC^R^, C(O)Rs2, nitro, NH2, cyano, S03My, OSO3My, NR20SO3My, d-Cι2alkyl. C2-Cι2alkenyl, C Cι2alkoxy, C3-Cι2cycloalkyl, C3-d2cyclo- alkenyl, C2-Cn heterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C6-Cι0aryloxy, Cs-Cgheteroaryl, C5-C9heteroaryloxy, C7-Cnaralkyl, C -Cnaralkyloxy, C6-C10heteroaralkyl, C8-Cnaralkenyl, C7-Cιoheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfon¬ amide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide; Rsι is hydrogen, My, Ci-CealkyI, C2-Cι2alkenyl, C3-C12cycloalkyl, C2- Cnheterocycloalkyl, C6-C 0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-C10heteroaralkyl, Rs is hydrogen, d-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, Cs-Cgheteroaryl, C -Cnaralkyl or C6-C10heteroaralkyl, Rs2 is hydrogen, d-C12alkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn -aralkenyl or C7-Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo¬ alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, ar¬ alkenyl and heteroaralkenyl as substituents in turn are unsubstituted or substituted by one of the abovementioned substituents; p is 0 or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
R8 and R9 are, in particular, independently of one another hydrogen; d-Cι2alkyl; C3-Cι2cycloalkyl, C6-doaryl, C7-d6aralkyl with 1 to 6 C atoms in the alkylene group and Ce-Cioaryl, C8-Cι6aralkenyl with C2-C6alkenylene and Ce-Cioaryl, or di-Ce-Cioaryl-Ci-Ce-alkyl, for example diphenylmethyl or 2,2-diphenylethyl, where R8 and Rg are unsubstituted or sub¬ stituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O)OMy, Cι-Cι2alkyl, d-C6alkoxy, C6-Cι0aryl, C6-Cι0aryloxy, SO3My, OSO3My, NR20SO3My, NO2, amino, primary amino, secondary amino and CN, R20 is hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3-C 2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cιoheteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
Rio corresponds, in particular, to Cι-Cι2alkyl; C3-d2cycloalkyl, C6-Cιoaryl, C7-C16aralkyl with 1 to 6 C atoms in the alkylene group and C6-Cι0aryl, C8-Cι6aralkenyl with C2-C6alkenylene and C6-Cι0aryl, or di-Ce-doaryl-d-Cealkyl, for example diphenylmethyl or 2,2-diphenylethyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O)OMy, C C12alkyl, d-C6alkoxy, C6-Cι0aryl, SO3My, OSO My, NR20SO3My, NO2, amino, primary amino, secondary amino and CN; where R20 is hydrogen, d-Cealkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnhetero- cycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-C8heteroaryl, C7-Cnaralkyl, Ce-doheteroaralkyl, C8-Cn-aralkenyl or C7-Cιoheteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. Furthermore, R10 is preferably Ci-CealkyI; C3-Cι2cycloalkyl, C6-Cιoaryl, C7-C16aralkyl with 1 to 6 C atoms in the alkylene group and C6-Cι0aryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(0)OMy, C -Cι2alkyl, d-C6alkoxy, C6-Cι0aryl, S03My, nitro, amino, primary amino, secon¬ dary amino and cyano; or C8-Cι6aralkenyl with C2-C6alkenylene and C6-Cι0aryl, or di-C6-Cιoaryl-Cι-C6alkyl, for example diphenylmethyl or 2,2-diphenylethyl.
In a preferred subgroup of compounds, R5 and R6 are, together with the -CH-CH- group, C3-Cι2cycloalkylene or C2-Cn heterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(0)ORs1, OC(0)Rs4, C(0)Rs2, NH2, Cι-Cι2alkyl, R8C(0)N(R9)-, -C(0)NR8R9, R8S(0)2N(R9)-; R8OC(0) N(R9)- and Rι0-SO2-, in which R9 is hydrogen and R8 is Cι-Cι2alkyl, C6-Cι0aryl or C -Cnaralkyl, which are unsub¬ stituted or substituted by one or more Cι-Cι2alkoxy; Rι0 is Cι-Cι2alkyl,
Figure imgf000016_0001
or C7-Cιιaralkyl which are unsubstituted or substituted by one or more Cι-Cι2alkyl; Rsi and Rs4 are Cι-C12alkyl and Rs2 is d-Cι2alkyl, C3-d2cycloalkenyl, C3-Cι2cycloalkyl or C6-Cιoaryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are unsubstituted or substitu¬ ted by one or more substituents selected from the group consisting of OH, C(0)ORsV and OC(0)Rs4- where Rs is My or Cι-Cι2alkyl and Rs4> is d-C12alkyl; y is 1 and M is a mono¬ valent metal or y is 1/2 and M is a divalent metal.
Particularly preferred compounds within this group are those in which R5 and R6 are, to¬ gether with the -CH-CH- group, cyclohexylene.
Another subgroup of preferred compounds are those compounds in which R5 and R6are, to¬ gether with -CH-CH- group, piperidylene.
Particularly preferred compounds are those in which R5 and R6 are, together with the -CH-CH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(0)ORsι, C(0)Rs2, C(0)NR8R9, NH2, S03My, Cι-Cι2alkyl, C2-Cι2alkenyl, C Cι2alkoxy, C3-C 2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn heterocycloalkenyl, C6-C10aryl, C6-Cι0aryloxy, Cs-Cgheteroaryl, C5-Cgheteroaryloxy, C7-Cn aralkyl, C7-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7- Cioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, sul- fonhydrazide; and one or more C atoms of the ring are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, OC(0)Rs4, NH2, OS03My NR20SO3My, Cι-Cι2alkoxy, Ce-Cι0aryloxy, C5-Cgheteroaryloxy, Cy-Cnaralkyloxy, primary amino, secondary amino, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, Ci-CealkyI, C2-Cι2alkenyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, C7-Cιιaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3- d2cycloalkyl, C2-Cn heterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6- Cioheteroaralkyl, R8 and R9 are, independently of one another, hydrogen, OH, Cι-C12alkyl, C3-C 2cycloalkyl, C2-Cn heterocycloalkyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-d6aralkyl, C6- Cisheteroaralkyl, C8-C16aralkenyl with C2-C6alkenylene and C6-Cι0aryl, or di-C6-Cι0aryl-Cι- Ce-alkyl, or R8 and R9 together are tetramethylene, pentamethylene, -(CH2)2-0-(CH2)2-, - (CH2)2-S-(CH2)2- or -(CH2)2-NR7-(CH2)2-, and R7 is H, Cι-C6alkyl, C7-Cn aralkyl, C(0)Rs2 or sulfonyl; and Rs2 and R20 are hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl, C6-C10heteroaralkyl, C8-Cn -aralkenyl or C7-Cιoheteroar- alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
Particularly preferred compounds are those in which R5 and R6 are, together with the -CH-CH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(0)ORsι, C(O)Rs2, -C(0)NR8R9 and Rιo-S02- and one or more C atoms of the ring are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH2, R8S(0)2N(R9)-; R8C(0)N(R9)- and R8OC(0)N(R9)-, where R9 is hydrogen and R8 is d-Cι2alkyl, C6-Cι0aryl or C -Cnaralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more Cι-Cι2alkoxy; R10 is Cι-Cι2alkyl, C6-Cι0aryl or C7-Cnaralkyl which are unsubstituted or sub¬ stituted by one or more Cι-Cι2alkyl; Rsι is Cι-Cι2alkyl and Rs2 is CrC12alkyl, C3-d2cyclo- alkenyl, C3-d2cycloalkyl or C6-Cι0aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substi¬ tuents in turn are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(0)ORs and OC(0)Rs-v where Rsr is My or Ci-CealkyI and Rs4' is d-Cι2alkyi; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
Another subgroup of preferred compounds are those compounds in which R5 and R6 are, together with the -CH-CH- group, piperidylene; which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(0)ORsι, OC(0)Rs , C(0)RS2, NH2, d-C12alkyl, R8C(O)N(R9)-, -C(O)NR8R9, R8S(O)2N(R9)-; R8OC(0)N(R9)-, R8R40NC(O)N(R9)-, -OC(0)NR8R9 and Rι0-SO2-, in which R9 is hydrogen and R8 is C Cι2alkyl, C6-C10aryl or C7-Cnaralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C Cι2alkoxy or C -Cnaralkyloxy; Rι0 is CrCι2alkyl, C6-C10aryl or C7-Cιιaralkyl which are unsubstituted or substituted by one or more C Cι2alkyl; R 0 is hydrogen, OH, d-Cι2alkyl, d-Cι2alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn heterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cι8aralkyl, C8-Cι6aralkenyl with C2-C6alkenylene and C6-Cι0aryl, C6-Ci5heteroaralkyl, C6-Cι5heteroar- alkenyl, or di-C6-Cι0aryl-C -C6-alkyl, Rsι and Rs4 are C Cι2alkyl and Rs2 is Cι-Cι2alkyl, C3-Cι2cycloalkenyl, C3-Cι2cycloalkyl or C6-Cι0aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(0)ORsr and OC(0)Rs - where Rsv is My or C Cι2alkyl and Rs4> is Cι-Cι2alkyl; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
Very particularly preferred compounds of the formula I are those in which X is cyclo- hexylene or piperidylene which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH2, C3H7, -C(0)CH3, -C(0)C6H5, -C(0)(CH2)8C(0)OCH3, -C(O)[CH(OH)]2C(0)ONa, C(0)-C6H8(OH)3, -C(0)-C6Hn, -C(0)OC3H7, -C(0)NHC6H5, -NHS(O)2CH2C6H5, -NHC(0)OCH2C6H5, -NHC(0)C6H3(OCH3)2, -S(0)2-C4H9, -NHC(O)NHC6H5, -S(O)2-C6H4CH3, -S(O)2-CH2C6H5 and -S(0)2-(CH)2CιoH7.
Preferred compounds of the formula I are those in which Ri corresponds to a group of the formula III in which R3 is hydrogen or My and R4 is
(a) unsubstituted d-C12alkyl; Cι-C12alkyl which is substituted by one or more substituents selected from the group consisting of -NH2, primary amino, secondary amino, Cι-Cι2sul- fonyl, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide, aminocarbonyl- amido, C3-d2cycloalkyl, Cι-C6alkoxy. phenyloxy and benzyloxy; unsubstituted C3-C12cycloalkyl; C3-Cι2cycloalkyl which is substituted by one or more substituents selected from the group consisting of C3-d2cycloalkyl, d-C6alkyl, C C6alkoxy, C Cι2sulfonyl, phenyloxy and benzyloxy; C6-C10aryl; C3-C8heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; C7-d6aralkyl with d-C6alkyl and C6-C10aryl; d-Cieheteroaralkyl with d-C6alkyl and C3-Cι0heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to 5 carbon atoms; Ce-Cioaryl, C3-C9heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms, C7-d6aralkyl with d-C6alkyl and C6-Cι0aryl, C3-Cι6heteroaralkyl with d-C6alkyl and C4-Cι0heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to 5 carbon atoms, which are substituted by one or more substituents selected from the group consisting of OH, halogen, d-Cι2sulfonyl, carboxyl, C(0)OMy, Cι-Cι2alkyl, d-C6alkoxy, C6-Cι0aryl, S03My, OS03My, NR20SO3My in which R20 is hydrogen, CrCι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C -Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cι0heteroaralkenyl, and nitro, NH2, primary amino, secondary amino, carbamide, carb¬ amate, sulfonamide and cyano, in which y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, or
(b) Cι-Cι2alkyl or C -Cι aralkyl which are unsubstituted or substituted by one or more substi¬ tuents selected from the group consisting of OH, halogen, C(0)ORsι, OC(0)Rs4, C(0)Rs2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My, Cι-Cι2alkyl, C2-Cι2alkenyl, Cι-Cι2alkoxy, C3-Cι2cycloalkyI, C3-Cι2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cnheterocycloalkenyl, C6-C10aryl, C6-Cι0aryloxy, C5-Cgheteroaryl, C5-C9heteroaryloxy, Cy-Cnaralkyl, Cy-Cnaralkyl¬ oxy, C6-Cιoheteroaralkyl, C8-Cnaralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, Cι-Cι2alkyl, C2- Cι2alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Ci0aryl, Cs-Cgheteroaryl, C7- Cnaralkyl or C6-Cι0heteroaralkyl, R^ is hydrogen, Cι-Cι2alkyl, C2-C 2alkenyl, C3-Cι2cyclo- alkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, C5-Cgheteroaryl, C7-Cnaralkyl or Ce-CioheteroaralkyI and Rs2 and R20 are hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cyclo- alkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, Cs-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cιoheteroar- alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo¬ alkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
R3 in formula III is preferably hydrogen, K or Na.
The following preferences apply to the group (a) of meanings for R4:
R is alkyl, preferably methyl, ethyl, n- or i-propyl and n-, i- or t-butyi. In the case of substitu¬ ted alkyl, the alkylene group is preferably ethylene and particularly methylene. A particularly preferred cycloalkyl group is cyclohexyl. Preferred as aryl and aralkyl are naphthyl and phenyl, particularly preferably phenyl and phenyl-CnH2n- with n equal to a number from 1 to 6, in particular benzyl and 2-phenylethyl. When R4 is heteroaryl, it is preferably C4-C5hetero- aryl with one or two hetero atoms from the group of O and N. Furanyl, pyridinyl and pyrimidinyl are preferred. R as heteroaralkyl is preferably C -C5heteroarylmethyl with one or two hetero atoms from the group of O and N, it being possible for heteraryl to comprise the abovementioned heteroaryl groups.
Further preferred compounds are those in which R4 in formula III is a C3-d2cycloalkyl, parti¬ cularly preferably cyclohexyl, Cι-C4alkyl substituted, particularly methyl or ethyl, with C3-Cι2cycloalkyl or with d-C alkyl and particularly with cyclohexyl or methyl, C6-Cι0aryl and very particularly phenyl, or R4 is a C -C12aralkyl with d-C6alkyl and C6-Cι0aryl. Particularly preferred groups for R4 in this series are benzyl, naphthylmethyl, 2-phenylethyl, 3-phenyl- propyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclohexyl and isopropyl.
Carbamido, carbhydrazido, sulfonamido, sulfonhydrazido, aminocarbonylamide and carb¬ amate as substituent for R4 preferably mean groups of the formulae R8NHC(0)N(R9)-, R8OC(0)N(R9)-, R8C(0)(NH)pN(Rg)- and R8S(0)2(NH)pN(R9)-, in which R8 is preferably H, Cι-Cι2alkyl, C5- or C6cycloalkyl, C5- or C6cycloalkylmethyl or -ethyl-, C5- or C6heterocyclo- alkyl, C5- or C6heterocycloalkylmethyl or -ethyl-, phenyl, naphthyl, benzyl, 2-phenylethyl, di¬ phenylmethyl, which are unsubstituted or substituted by one or more substituents from the group of -OH, -NH2, C C8primary amino, C2-Cι secondary amino, N02, -CN, -F, -Cl, - C(0)OH, -C(0)ONa, -S03H, -OS03Na, NR20SO3Na in which R20 is hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-C10heteroaralkyl, C8-C1 aralkenyl or C -Cιoheteroaralkenyl, and -S03Na, Cι-C4alkyl, Cι-C alkoxy and phenyl, and R9 is H, Cι-Cιoalkyl, phenyl, naphthyl, benzyl, 2-phenylethyl or phenyl-CH=CH-CH2-, and p is 0 or 1.
Within group (a), a carbam ido-substituted alkyl substituent for R4 particularly preferably means R8-C(0)NR9-(CH2)n-, where n is 1 or 2, R8 is hydrogen; Cι-Cι2alkyl; C3-d2cycloalkyl; C6-Cι0aryl or C7-Cι6aralkyl with d-C6alkyl and C6-Cι0aryl; wherein alkyl, cycloalkyl, aryl and aralkyl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, -C(0)OMy, Cι-C12alkyl, d-C6alkoxy, C6-Cι0aryl, S03My, OS03My, NR20SO3My, C(0)ORsι, OC(0)Rs4, nitro, amino and cyano; or C8-C16aralkenyl with C2-C6alkenyl and C6-Cι0aryl or di-C6-Cι0aryl-Cι-C6alkyl; and R9 is H, linear or branched Cι-Cι0alkyl, C5- or C6cycloalkyl, C5- or C6cycloalkylmethyl- or -ethyl, phenyl, naphthyl or benzyl, 2-phenylethyl or phenyl-CH=CH-CH2-; y is 1 and M is an alkali metal or y is 1/2 and M is an alkaline earth metal, R20 is hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, Cs-Cgheteroaryl, C7-Cnaralkyl, C6-Ci0heteroaralkyl, C8-Cn -aralkenyl or C7-Cι0heteroar- alkenyl, Rsι is hydrogen, My, C Cι2alkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C2-Cn heterocyclo¬ alkyl, C6-Cι0aryl, C5-Cgheteroaryl, Cy-Cnaralkyl or C6-Ci0heteroaralkyl and Rs is hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3-C12cycloalkyl, C2-Cn heterocycloalkyl, C6-Cιoaryl, Cs-Cghetero¬ aryl, Cy-Cnaralkyl or C6-Cι0heteroaralkyl. A sulfonamide-substituted alkyl substituent for RT particularly preferably means R8-S02NRg-(CH2)n- in which R8, Rg and n have the meanings indicated previously for carbamido. An aminocarbonylamide- or carbamate-substituted alkyl substituent for Ri particularly preferably means RgNHC(0)NH(CH2)n or R9OC(0)NH(CH2)n in which Rg has the meanings indicated in previously in connection with carbamido and addi¬ tionally phenyl and n has the meanings indicated previously in connection with carbamido. A carbhydrazido-substituted alkyl substituent for Ri particularly preferably means R8C(0)NHNRg(CH2)π- in which R8, Rg and n have the meanings indicated previously in con¬ nection with carbamido. A sulfonhydrazido-substituted alkyl substituent for R particularly preferably means R8-S02-NHNR9-(CH2)n- in which R8, R9 and n have the meanings indica¬ ted previously in connection with carbamido.
Further particularly preferred compounds are those in which R4 in formula III is an amide R8C(O)N(Rg)(CH2)n- or R8S(O)2N(R9)(CH2)n-; where R8 and R9 are, independently of one an¬ other, hydrogen; unsubstituted Cι-Cι2alkyl; Cι-Cι2alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(0)ONa, d-Cι2alkyl, d-C6alkoxy, C6-Cι0aryl, -S03H, OS03Na, NR20SO3Na, S03Na, nitro and cyano; unsubstituted C3-Cι2cycloalkyl; C3-Cι2cycloalkyl substituted by one or more OH; unsubstitu¬ ted Ce-Cioaryl, unsubstituted Cy-Cι2aralkyl with d-C6alkyl and C6-d0aryl; C6-Cιoaryl, or Cy-Cnaralkyl with d-C6alkyl and C6-Cι0aryl, which is substituted by one or more substitu¬ ents selected from the group consisting of OH, halogen, carboxyl, C(0)ONa, -C(0)OK, Cι-Cι2alkyl, C C6alkoxy, C6-Cιoaryl, S03Na, OS03Na, NR20SO3Na, C(0)ORsι, OC(0)Rs4, nitro, amino and cyano, R20 is hydrogen, C Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, Cs-Cgheteroaryl, Cy-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or Cy-Cioheteroar¬ alkenyl, Rsι is hydrogen, My, d-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C2-Cn heterocyclo¬ alkyl, C6-Cι0aryl, C5-Cgheteroaryl, Cy-Cnaralkyl or C6-Cι0heteroaralkyl and Rs4 is hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C2-CnheterocycloalkyI, C6-Cι0aryl, Cs-Cghetero¬ aryl, Cy-Cnaralkyl or C6-Cι0heteroaralkyl; and n is 2 or 1.
Particularly preferred compounds are those in which R4 in formula III is an amide R8C(0)N(R9)(CH2)n- or R8S(0)2N(R9)(CH2)n-, where R8is unsubstituted Cι-Cι2alkyl; Cι-C8alkyl which is substituted by one or more substituents selected from the group con¬ sisting of OH, halogen, C(0)ONa and C6-Cι0aryl; unsubstituted C3-d2cycloalkyl; C3-C8cyclo- alkyl which is substituted by one or more OH; unsubstituted C6-Cι0aryl or C7-Cι2aralkyl with Cι-C6alkyl; C6-Cι0aryl, C7-Cι2aralkyl with d-C6alkyl and C6-Cιoaryl or C8-d6aralkenyl with C2-C6alkenyl and C6-C10aryl, which is substituted by one or more substituents selected from the group consisting of halogen, -C(0)OH, C(0)ONa, Cι-Cι2alkyl, Cι-C6alkoxy, -S03H, S03Na, OS03Na, NR20SO3Na in which R20 is hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn -aralkenyl or C7-Cιoheteroaralkenyl, and nitro and cyano; and Rg is hydrogen; unsubstituted Ci-CealkyI, unsubstituted C6-Cιoaryl, unsubstituted C7-C12aralkyl with Cι-C6alkyl and C6-Cιoaryl; or C8-Cι6aralkenyl with C2-C6alkenyl and C6-C10aryl, and n is 2 and preferably 1.
Particularly preferred compounds are also those in which R4 in formula III is an amide R8C(0)N(R9)(CH2)n-, where R8 is unsubstituted d-C12alkyl; Cι-Cι2alkyl which is substituted by one or more substituents selected from the group consisting of cyclohexyl, OH, halogen, -C(0)OH, -C(0)ONa and phenyl; unsubstituted C3-Cι2cycloalkyl; C3-Cι2cycloalkyl which is substituted by one or more OH; unsubstituted Ce-Cioaryl; C6-Cι0aryl, which is substituted by one or more substituents selected from the group consisting of halogen, C(0)ONa, -C(0)OH, Cι-C6alkyl, d-C6alkoxy, phenyl, -S03H, S03Na, OS03Na, NHS03Na, nitro and cyano; or C7-Cι6aralkyl with d-C6alkyl and C6-Cι0aryl, and R9 is hydrogen; unsubstituted d-Cealkyl, unsubstituted C7-d6aralkyl with Cι-C6alkyl and C6-Cι0aryl; or C8-d6aralkenyl with C2-C6alkenyl and C6-Cιoaryl, and n is 2 and preferably 1.
Further particularly preferred compounds are those in which R4 in formula III is an amide R8C(0)N(R9)(CH2)n-, where R8 is unsubstituted d-Cealkyl. Cι-C4alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)OH, C(0)ONa and phenyl; unsubstituted C3-d2cycloalkyl, in particular C6Hn; C3-d2cycloalkyl which is substituted by one or more OH, unsubstituted C6-Cι0aryl, in particular C6H5 or Cι0H7; C6-Cι0aryl which is substituted by one or more substituents selected from the group consisting of halogen, -C(0)OH, C(0)ONa, d-C6alkyl, d-C6alkoxy, -S03H, S03Na, OS03Na, NHS03Na, nitro and cyano, in particular C6H4CI, C6H4(3,4)CI2, C6H4COONa, C6H4CH3, C6H OCH3, C6H4S03Na, C6H4NO2 or C6H4CN; or unsubstituted C7-d6aralkyl with d-Cβalkyl and C6-Cι0aryl, in particular (CH2)2C8H5, and R9 is H, Cι-C4alkyl, phenyl-CH2-, phenyl-CH2CH2, phenyl-(CH2)3- or phenyl-CH=CH-CH2-, and n is 2 and preferably 1.
Particularly preferred compounds are also those in which R4 in formula III is an amide R8C(0)N(R9)(CH2)n-, where R8 is unsubstituted or substituted d-C12alkyl, cyclohexyl, naphthyl, biphenylyl, phenyl, benzyl, phenylethyl or diphenylmethyl, and R9 is d-C4alkyl, phenyl-d-C6alkyl, in particular CH2C6H5, (CH2)2C6H5 or (CH2)3C6H5; or phenyl-C2-C6-alkenyl, in particular C6H5-CH=CH-CH2, and n is 2 and preferably 1.
Further particularly preferred compounds are those in which R4 in formula III is a sulfon¬ amido R8S(0)2N(R9)(CH2)n-, where R8 is Cι-Cι2alkyl, particularly d-C6alkyl, which is unsub¬ stituted or substituted by one or more halogen atoms (for example Cl and especially F), in particular CF3; or C6-Cι0aryl, particularly phenyl or naphthyl, which is substituted by one or more d-C alkyl (for example methyl or ethyl), Cι-C4alkoxy (for example methoxy or ethoxy), halogen, -CN or -N02, and R9 is hydrogen or isobutyl, and n is 2 and preferably 1.
Further particularly preferred compounds are those in which R4 in formula III is an amino¬ carbonyl residue of the formula R8-NH-C(O)-NH(CH2)n-, in which R8 is C Cι2alkyl or Ce-Cioaryl, particularly Ci-CealkyI, which is unsubstituted or substituted by halogen, -CN, -N02, d-dalkyl or d-C4alkoxy, or C5- or C6cycloalkyl, C6-C10aryl such as phenyl or naphthyl, or C7-Cι2aralkyl such as benzyl, phenylethyl, phenylpropyl or phenylpropenyl, and n is 2 and preferably 1.
Particularly preferred compounds are furthermore those in which R4 in formula II is an aminoalkyl, preferably R8R9N(CH2)n-, where R8- and Rff are, independently of one another, hydrogen; unsubstituted Ci-CealkyI; C Cι2alkyl which is substituted by one or more substi¬ tuents selected from the group consisting of OH, halogen, C(0)ORs1, OC(0)Rs4, C(0)NRιιRι2, C Cι2alkyl, d-C6alkoxy, C6-Cι0aryl, -S03H, S03Na, OS03Na, NR20SO3Na, nitro, amino and cyano; unsubstituted C3-C12cycloalkyl; C3-Cι2cycloalkyl which is substituted by one or more OH; C6-Cι0aryl; C7-d6aralkyl with d-C6alkyl and C6-d0aryl; or C8-Cι6ar- alkenyl with C2-C6alkenyl and C6-Cι0aryl, where aryl and the aryl in the aralkyl and aralkenyl are unsubstituted or substituted by one or more substituents selected from the group con¬ sisting of OH, halogen, C(0)ORsι, OC(0)Rs4, -C(0)ONa, -C(0)OK, -C(0)-NRnRι2, Cι-Cι2alkyl, Cι-C6alkoxy, C6-Cι0aryl, -S03H, S03Na, OS03Na, NR20SO3Na, nitro, amino and cyano; wherein n is 2 and preferably 1 , and Rs1 is hydrogen, K or Na, CrCealkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C2-Cn heterocycloalkyl, C6-Cιoaryl, C5-C9heteroaryl. C7-Cιιaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, Cι-Cι2alkyl, C2-C12alkenyl, C3-Cι2cyclo- alkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or Ce-CioheteroaralkyI, Rn is H, d-C4alkyl, C2-C hydroxyalkyl, phenyl or benzyl, and R 2 in¬ dependently has the meaning of Rn, or R and Re together are tetramethylene, penta¬ methylene or -CH2CH2-0-CH2CH2- and R20 is hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-d2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C -Cιoheteroaralkenyl.
Particularly preferred compounds are furthermore those in which R4 in formula III is an aminoalkyl RffR9-NCH2-, in which R8- and R9' are, independently of one another, hydrogen; Cι-C8alkyl, cyclopentyl, cyclohexyl, C5- or C6cycloalkylmethyl, phenyl-Cι-C4alkyl, in particular -CH2C6H5; or phenyl-C2-C4alkenyl, in particular -CH2CH=CHC6H5.
Particularly preferred compounds are furthermore those in which R4 in formula III is an amine R8-R9.NCH2-, where Rff and Rff are, independently of one another, H, CrCealkyl, phenyl-d- or C2alkyl, in particular CH2C6H5. Preferred compounds of group (b) of meanings for R4, are those in which R is Cy-Cnar- alkyl, in particular CH2-C6H5 and (CH2)2-C6H5, C3-Cι2cycloalkyl or CrCealkyl, which is un¬ substituted or substituted by one or more substituents selected from the group consisting of NH2, C3-Cι2cycloalkyl, primary amino, secondary amino, sulfonamide, carbamide and aminocarbonylamido. Particularly preferred substituents for C C12alkyl are NH2, cyclohexyl, Ce-doaryl, R8C(0)N(R9)-, R8S(0)2N(R9)-, R8NHC(0)NR9-, NR9C(0)NHR8 and R8.R9.N-, in which R8 and R9 are, independently of one another, hydrogen, CrCealkyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cιoheteroaralkyl and R8' and Rs- are, independently of one another, hydrogen, OH, Cι-Cι2alkyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, Ce-Cι0aryl, Cs-Cgheteroaryl, C7-Cnaralkyl or C6-Cιoheteroaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ORsι, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OS03My, NR20SO3My, Cι-d2alkyl, C2-Cι2alkenyl, CrCι2alkoxy, C3-Cι2cycloalkyl, C3-d2cyclo- alkenyl, C2-Cn heterocycloalkyl, C2-Cnheterocycloalkenyl, C6-C10aryl, C6-Cιoaryloxy, Cs-Cgheteroaryl, C5-Cgheteroaryloxy, C7-Cn aralkyl, C -Cnaralkyloxy, C6-Cιoheteroaralkyl, C8-Cnaralkenyl, C7-Cιoheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfon¬ amide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, d-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cyclo- alkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, Cs-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroar- alkyl, Rs4 is hydrogen, Ci-CealkyI, C2-Cι2alkenyl, C3-d2cycloalkyl, C2-Cn heterocycloalkyl, C6-Ci0aryl, C5-Cgheteroaryl, C7-Cnaralkyl or C6-Cioheteroaralkyl, and Rs2 and R20 are hydro¬ gen, Ci-CealkyI, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cιι-heterocycloalkenyl, C6-Cι0aryl, C5-C heteroaryl, C7-Cnaralkyl, C6-Ci0heteroaralkyl, C8-Cn-aralkenyl or C -Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or sub¬ stituted by one of the abovementioned substituents; p is 0 or 1 and y is 1 and M is a mono¬ valent metal or y is 1/2 and M is a divalent metal; or Rff and R9- together are tetramethylene, pentamethylene, -(CH2)2-0-(CH2)2-, -(CH2)2-S-(CH2)2- or -(CH2)2-NR7-(CH2)2-, and R7 is H, C -C6alkyl, Cy-Cnaralkyl, C(O)Rs2 or sulfonyl.
Particularly preferred compounds within this group are those in which R is CH2-C6H5, (CH2)2-C6H5, cyclohexyl, methyl, ethyl or isopropyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH2, cyclohexyl, C6-Cιoaryl, R8C(0)N(R9)-, R8S(0)2N(R9)-. R8NHC(0)NR9-, NR9C(0)NHR8 and R8 R9N-, in which R8, R9, R8' and Rff are, independently of one another, hydrogen, Cι-d2alkyl, C3-Cι2cycloalkyl, C6-Cι0aryl or Cy-Cnaralkyl, which are unsubstituted or substituted by one or more substitu¬ ents selected from the group consisting of OH, halogen, C(0)OMy, nitro, cyano, S03My, OS03My, NHS03My, Cι-d2alkyl, Ci-Cealkoxy and C6-Cι0aryl, where y is 1 and M is a mono¬ valent metall or y is 1/2 and M is a divalent metal. Particularly preferred compounds are those in which R8, R9) RB- and Ra- are, independently of one another, hydrogen, Cι-Cι2alkyl, cyclohexyl, phenyl, naphthyl or Cy-Cnaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, Cl, C(0)ONa, nitro, cyano, S03Na, d-C6alkyl, methoxy and phenyl.
In a preferred group of compounds of the formula I, Ri is formula III, in which R4 is C6Hn, CH(CH3)2, CH2-phenyl, (CH2)2-phenyl, CH2NHC(0)-phenyl, CH2NHC(0)(CH2)3-phenyl, CH2NHC(0)(CH2)3OH, CH2NHC(0)CF3) CH2NHC(0)C6Hn, CH2NHC(0)CnH23, CH2NHC(0)CH(C6H5)2, CH2HNC(0)NHC6H5, CH2NHC(0)C2H4C02Na, CH2NHC(0)C6[(1 ,3,4,5)OH]4H7, CH2NHC(0)C6H4-p-S03Na, CH2NHC(0)C6H4CI, CH2NHC(0)C6H4N02l CH2NHC(0)C6H4OCH3, CH2NHC(0)C6H4(3,4)CI2, CH2NHC(0)C6H4CH3, CH2NHC(0)C6H4C6H5, CH2NHC(0)C6H4CN, CH2NHC(O)d0H7, CH2NHC(0)C6H4COONa, CH2NHC(0)(CHOH)2COONa, CH2N(CH2CH=CH-pheπyl)[C(0)-phenyl], CH2N[CH2CH(CH3)2][C(0)-phenyl], CH2N[C(0)C6H5]CH2C6H5, CH2N[C(0)C6H5](CH2)3C6Hs, CH2C6Hn, (CH2)2C6Hn, CH2NH2, CH2NHCH2CH=CH-phenyl, CH2NHCH2-phenyl, CH2NHCH2CH(CH3)2, CH2N(CH2-phenyl)2, CH2N[CH2CH(CH3)2]2, CH2NHS02-p-nitrophenyl, CH2NHS02-p-tolyl, CH2NHS02CF3l CH2NHC(0)NHC6H5 or CH2N[S02-p-nitrophenyl][CH2CH(CH3)2]2.
R2 as alkyl can contain preferably from 1 to 6 C atoms and particularly preferably from 1 to 4 C atoms. Methyl and ethyl are particularly preferred.
In the case of halogen for the substituents for R2, it can preferably be F, Cl and Br; in the case of -C(0)OMy preferably -C(0)ONa or -C(0)OK; in the case of alkyl preferably d-C6- and particularly preferably d-C alkyl, such as methyl, ethyl, n- or i-propyl and n-, i- or t-butyl; in the case of alkoxy preferably Cι-C4alkoxy, for example methoxy and ethoxy; in the case of aryl preferably phenyl or naphthyl; in the case of -S03My preferably -S03Na or -S03K; in the case of primary amino Cι-Cι2primary amino such as methyl-, ethyl-, n- or i-propyl-, n-, i- or t-butyl, pentyl, hexyl, cyclohexyl, phenyl or benzylamino; in the case of secondary amino C2-C20secondary amino such as dimethyl-, diethyl-, methylethyl-, di- n-propyl-, di-i-propyl-, di-n-butyl-, diphenyl-, dibenzylamino, morpholino, thiomorpholino, piperidino and pyrrolidino; -S02-NR8R9; and -C(0)-NR8R9 in which R8 and R9 are, indepen¬ dently of one another, H, d-C4alkyl, C2-C hydroxyalkyl, phenyl or benzyl, or R8 and R9 to¬ gether with the N atom are morpholino, thiomorpholino, pyrrolidino or piperidino.
R8 and R9 as alkyl preferably contain 1 to 6, and particularly preferably 1 to 4, C atoms, and can be, for example, methyl, ethyl, n- or i-propyl or n-, i- or t-butyl. R8 and R9 as hydroxyalkyl preferably contain 1 to 6, and particularly preferably 1 to 4, C atoms, and can be, for example, hydroxymethyl or 2-hydroxyethyl. R8 and R9 as cycloalkyl are preferably cyclo¬ pentyl or cyclohexyl. Substituents for R8 and R9 as phenyl and benzyl are preferably F, Cl, methyl, ethyl, methoxy and ethoxy.
A preferred subgroup of compounds of the formula I are those in which R2 is hydrogen, un¬ substituted Cι-C6alkyl, particularly preferably Cι-C alkyl, especially methyl or ethyl, or Cι-C6alkyl, particularly preferably C -C alkyl, especially methyl or ethyl, which is substituted by C(0)OH, -C(0)ONa, -C(0)OK, -OH, -C(0)-NR8R9 or -S02-NR8R9, in which R8 is H, Cι-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and R9 independently has the meaning of R8, or R8 and Rg are together tetramethylene, pentamethylene or -CH2CH2-0-CH2CH2-. Par¬ ticularly preferred compounds are those in which R2 is hydrogen, methyl, ethyl, HO(0)CCH2CH2-, NaOC(0)CH2CH2- or R8R9NC(0)CH2CH2-, and R8 and R9are, indepen¬ dently of one another, H, Cι-C6alkyl, C2-C4hydroxyalkyl, phenyl, benzyl or, together, morpholino.
A particularly preferred embodiment of the invention comprises compounds of the formula la
Figure imgf000027_0001
in which
R3 is hydrogen or My; and
R is d-C12alkyl, C2-Cι2alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C eterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-C10heteroaralkyl, C8-Cn aralkenyl or C7-Cιoheteroaralkenyl, which are unsubstituted or substituted once or several times;
R5 and R6 are, independently of one another, hydrogen, Ci-CealkyI, C3-C12cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl; or R5 and R6 are, together with the -CH-CH- group, C3-Cι2cycloalkylene, C -C12cycloalken- ylene, C2-Cn heterocycloalkylene and C3-Cn heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-; where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclo¬ alkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted once or several times; where the substituent is selected from the group OH, halogen, C(0)ORsι, OdOJR.*, C(0)Rs2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My in which R20 is hydrogen, Cι-d2alkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cιoaryl, C5-Cgheteroaryl, C7-Cnaralkyl, C6-Cιoheteroaralkyl, Cβ-Cn-aralkenyl or C7-Cιoheteroaralkenyl, and CrCealkyl, C2-Cealkenyl, Ci-Cealkoxy, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cnheterocycloalkenyl, Ce-Cioaryl, C6-Cι0aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-Cnaralkyl, C7-Cnar- alkyloxy, C6-Cioheteroaralkyl, C8-Cnaralkenyl, C7-Cιoheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carb¬ hydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, Crd2alkyl, C2-d2alkenyl, C3-Cι2cycloalkyI, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-Cghetero-aryl, C7-Cnaralkyl or C6-C 0heteroaralkyl, R^ is hydrogen, Ci-CealkyI, C2-d2alkenyl, C3-C12cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cιιaralkyl or C6-Cι0heteroaralkyl and Rs2 is hydrogen, CrCealkyl, C2-d2alkenyl, C3-C12cycloalkyl, C3-Cecycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, Ce-Cioaryl, Cs-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or Cy-Cioheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are substituted or unsubstituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is a 1/2 and M is a divalent metal.
Preferred compounds of the formula la are those in which R3 is H, K or Na,
R5 and R6 are, together with the -CH-CH- group, C3-Cι2cycloalkylene, C -d2cycloalken- ylene, C2-Cn heterocycloalkylene and C3-Cnheterocycloalkenylene with hetero atoms selected from the group -O-, -S- and -N-; which are unsubstituted or substituted once or several times; where the substituent is selected from the group consisting of OH, halogen, C(0)ORsι, OC(0)Rs4, C(0)Rs2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My in which R20 is hydro¬ gen, d-Cealkyl, C2-Cι2alkenyl, C3-Cecycloalkyl, C3-CecycloalkenyI, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, Cy-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cι0heteroaralkenyl, and d-Cealkyl, C2-Cealkenyl, Ci-Cealkoxy, C3-C12cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C6-Cι0aryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, C7-Cnaralkyl, C7-Cnar- alkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carb¬ hydrazide, carbohydroxamic acid and aminocarbonylamide, in which Rs1 is hydrogen, My, d-Cealkyl, C2-d2alkenyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, C -Cnaralkyl or C6-Cι0heteroaralkyl, Rs is hydrogen, Crd2alkyl, C2-Cealkenyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl or C6-C oheteroaralkyl and Rs2 is hydrogen, CrCealkyl, C2-d2alkenyl, C3-Cecycloalkyl, C3-Cecycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cioaryl, C5-Cgheteroaryl, C7-Cnaralkyl, Ce-CioheteroaralkyI, C8-Cn-aralkenyl or C7-Cιoheteroar- alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo¬ alkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal; (a) R is a residue Re-(CH2)n- or cyclohexyl, in which n is 1 or 2 and Re is d-Cioalkyl, C5-C8cycloalkyl, especially cyclohexyl, C6-Cι0aryl, preferably phenyl, or C8-Cearalkenyl, preferably phenyl-C2-C alkenyl, which are unsubstituted or substituted by d-dalkyl, C C4alkoxy, F, Cl, -CN or -N02; or Re is an amino group -NR8'R9', and R8' and Rff are d-C12alkyl or unsubstituted or CrC alkyl-substituted C5- or C6cycloalkyl, C6-Cι0aryl, C7-Cearalkyl or C8-Cι2aralkenyl; very particularly preferably -CH2-CH(CH3)2, -CH2-C(CH3)3, -CH2-C(CH3)2-C2H5, C6H5-CH2-, C6H5CH2CH2-, C6H5-CH2-CH2-CH2- or C6H5CH=CH-CH2-, or
Re is an amide group -N(R9)C(0)R8, -N(R9)S(0)2R8, -NR9C(0)NHR8 or -NR9C(0)NHR8 in which R8 is C6-Cι0aryl, preferably phenyl, which is unsubstituted or substituted by d-C alkyl, especially methyl, C C4alkoxy, especially methoxy, F, Cl, -CN or -N02, or d-C10alkyl which is unsubstituted or substituted by F or Cl, and R9 is H, CrCι0alkyl, C5- or C6cycloalkyl, C5- or C6cycloalkyl-CrC6alkyl, phenyl-d-C6alkyl or phenyl-C2-C6alkenyl, especially H, CrC6alkyl, cyclohexyl, cyclohexyl-CH2-, cyclohexyl-CH2CH2-, cyclohexyl-CH2CH2CH2-, C6H5CH2, C6H5CH2CH2-, C6H5CH2CH2CH2- and C6H5CHCHCH2-, R9 is particularly H, linear and, prefe¬ rably, branched CrC6alkyl, phenyl or phenyl(CH2)z- with z equal to a number from 1 to 4, for example methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, pentyl, isopentyl, hexyl, benzyl, phenyl¬ ethyl, phenylpropyl and phenyl-CH=CH-CH2-, very particularly preferably CH2-CH(CH3)2, benzyl, 2-phenylethyl and 3-phenylpropyl; or
(b) R4 is CrCealkyl, C3-Cι2cycloalkyl or C -Cnaralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ORsι, OC(0)Rs4, C(0)RS2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My in which R20 is hydro¬ gen, d-Cealkyl, C2-C12alkenyl, C3-Cι2cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cπ aralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-C10heteroaralkenyl, and CrCealkyl, C2-Cι2alkenyl, CrC12alkoxy, C3-Cι2cycloalkyl, C3-Cecycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C6-Cι0aryloxy, C5-Cgheteroaryl, C5-C9heteroaryloxy, C7-Cnaralkyl, C7-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7-Cιoheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, CrCealkyl, C2-d2alkenyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, CrCealkyl, C2-C12alkenyl, C3- Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl or C6- Cioheteroaralkyl and Rs2 is hydrogen, d-Cealkyl, C2-d2alkenyl, C3-Cι2cycloalkyl, C3- Cecycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn-heterocycloalkenyl,
Figure imgf000030_0001
Cs- Cgheteroaryl, C7-Cnaralkyl, C6-Cιoheteroaralkyl, C8-Cn-aralkenyl or C -Cιoheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroar- alkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
A preferred subgroup of compounds of group (a) are those in which
(i) R is CeHn, CeHιrCH2, CeHn-CH2CH2-, CeHs-CH2-, CeHs-CH2CH2- or CeHs-CH=CH-CH2-; (ii) R is CβHn, CeHn-CH2-, CeHn-CH2CH2-, CeHs-CH2-, CeHs-CH2CH2-, -CH2-NRιg-S02Rι8, -CH2-NRi9-C(O)R40, CH2NHC(0)NHRι8, -CH2NHR2ι or CH2N(R2ι)2, in which R1β is -C6H5, phenyl which is substituted by 1 to 3 methyl or methoxy or -N02 or F or Cl, in particular p-CH3-C6H4-, p-CH30-C6H4- or 2,3,5,-CH3-C6H2- or p-02N-C6H4-, or d-C4alkyl, which is sub¬ stituted by F, in particular -CF3; R40 is phenyl which is unsubstituted or substituted by 1 to 3 methyl or methoxy or -N02 or F or Cl; Re is H, CrC6alkyl, phenyl-(CH2)2- with z equal to a number from 1 to 3, phenyl-CH=CH-CH2-, and especially -CH2-CH(CH3)2 or benzyl; and R2ι is -CH2-CR22R23R24 in which R22 and R23, methyl, ethyl or phenyl and R24 is H, ethyl or methyl, very particularly preferably R22 and R23 are methyl and R24 is H.
A preferred subgroup of the compounds of group (b) are those in which R4 is CeHn, CH2-C6H5, (CH2)2-C6H5, methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH2, cyclohexyl, C6-Cι0aryl, R8C(0)N(R9)-, R8S(0)2N(R9)-, NR9C(0)NHR8 and R8R9N- in which R8, R9, R8. and R9. are, in¬ dependently of one another, hydrogen, d-Cealkyl, C3-d2cycloalkyl, C6-Cι0aryl or C7-Cnar- alkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)OMy, nitro, cyano, S03My, OS03My, NR20SO3My, in which R20 is hydrogen, d-Cealkyl, C2-d2alkenyl, C3-d2cycloalkyl, C3-Cecycloalkenyl, C2-Cιιheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, Cy-Cnaralkyl, Ce-CioheteroaralkyI, C8-Cn-aralkenyl or C7-Cι0heteroaralkenyl, and CrCealkyl, Ci-Cealkoxy and Ce-Cioaryl, where y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. Particularly preferred compounds are those in which R8, R9, R8- and R9- are, indepen¬ dently of one another, hydrogen, CrCealkyl, cyclohexyl, phenyl, naphthyl or C7-Cnaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, Cl, C(0)ONa, nitro, cyano, S03Na, C C6alkyl, methoxy and phenyl.
In a preferred group of compounds of the formula la, R is C6Hn, CH(CH3)2, CH2-phenyl, (CH2)2-phenyl, CH2NHC(0)-phenyl, CH2NHC(0)(CH2)3-phenyl, CH2NHC(0)(CH2)30H, CH2NHC(0)CF3, CH2NHC(0)C6Hιι, CH2NHC(0)CnH23, CH2NHC(0)CH(C6H5)2, CH2HNC(0)NHC6H5, CH2NHC(0)C2H4C02Na, CH2NHC(0)C6[(1 ,3,4,5)OH]4H7, CH2NHC(0)C6H4-p-S03Na, CH2NHC(0)C6H4CI, CH2NHC(0)C6H4N02, CH2NHC(0)C6H4OCH3, CH2NHC(0)C6H4(3,4)CI2, CH2NHC(0)C6H4CH3, CH2NHC(0)C6H4C6H5, CH2NHC(0)C6H4CN, CH2NHC(0)CioH7, CH2NHC(0)C6H4COONa, CH2NHC(0)(CHOH)2COONa, CH2N(CH2CH=CH-phenyl)[C(0)-phenyl], CH2N[CH2CH(CH3)2][C(0)-phenyl], CH2N[C(0)C6H5]CH2C6H5, CH2N[C(0)C6H5](CH2)3C6Hs, CH2C6Hn, (CH2)2C6Hιι, CH2NH2, CH2NHCH2CH=CH-phenyl, CH2NHCH2-phenyl, CH2NHCH2CH(CH3)2, CH2N(CH2-phenyl)2, CH2N[CH2CH(CH3)2]2, CH2NHS02-p-nitrophenyl, CH2NHS02-p-tolyl, CH2NHS02CF3, CH2NHC(0)NHC6H5 or CH2N[S02-p-nitrophenyl][CH2CH(CH3)2]2.
The present invention additionally relates to a process for the preparation of the compounds of the formula I which comprises etherifying the 3-OH group of a compound of the formula V
Figure imgf000032_0001
in which R2 and X have the abovementioned meanings, R12 is a protective group and Re' and Re" are, independently of one another, hydrogen or a protective group, with a compound of the formula VI
R,-R 13 (VI)
in which Ri has the abovementioned meaning and Re is a leaving group, and eliminating the protective groups. Leaving groups can be: halides, such as chloride, bromide and iodide, and sulfonic acids, for example trifluoromethanesulfonate, aliphatic, cycloaliphatic or aromatic sulfonic acids which are unsubstituted or substituted by d-C alkyl; d-C alkoxy, nitro, cyano or halogen (chlorine, bromine). Some examples of these acids are: methanesulfonic acid, mono-, di- or trifluoromethanesulfonic acids or p-nitrobenzenesulfonic acid. CF3-S02-0" (also referred to as triflate) is particularly preferably used. The leaving group is advantageously selected from the group consisting of halogen and unsubstituted and halogenated R-S02-, in which R is CrCealkyl, in particular d-C6alkyl, C5-C6cycloalkyl, phenyl, benzyl, Cι-Cι2alkylphenyl, in particular d-C4alkylphenyl, or Cι-d2alkylbenzyl, in particular d-C alkylbenzyl, for example methane, ethane, propane, butane, benzene, benzyl- and p-methylbenzenesul- fonyl. Preferred leaving groups are Cl, Br, I, -S02CF3 (triflate) and p-nitrobenzenesulfonyl, and -S02CF3 is particularly preferred.
The compounds of the formula VI are known in some cases or can be obtained by known processes, as described by Degerbeck et al. [Degerbeck, F., Fransson, B., Grehn, L., Ragnarsson, U., J. Chem. Soc. Perkin Trans. 1 :11-14 (1993)] and by Dureault et al. [Dureault, A., Tranchepain, I., Depezay, J.C, Synthesis 491-493 (1987)]. Optically pure compounds can be obtained by using optically pure starting compounds (e.g. amino acids, α-hydroxylic acids) or by chromatographic separation processes, for example with chiral solid phases.
The compounds of the formula V are novel and the invention likewise relates to them. They can be obtained by known glycosylation methods starting from known fucosyl and galacto- syl donors and diols of the formula HO-X-OH. Stepwise introduction of galactose and fucose or vice versa is advantageous.
For the preparation of the compounds of the formula V, firstly the pseudo-trisaccharide building blocks are synthesized. The pseudotrisaccharide is assembled either by glycosidic attachment for the activated and protected galactose onto the fucose-O-X-OH building block or by glycosidic attachment of suitably protected and activated fucose onto a galac- tose-O-X-OH building block. Glycosylation reactions are known on a large scale and are described in the specialist literature. It is then possible to introduce the group Ri into the pseudotrisaccharide. The resulting com¬ pounds of the formula I can subsequently be modified. This modification may comprise hydrogenation of aromatic compounds to cycloaliphatic groups, which can take place, for example, at the same time as the hydrogenolytic elimination of protective groups. It is furthermore possible for an amino group to be acylated and/or alkylated and/or sulfonated. The preparation of secondary and tertiary amines can be carried out by reductive amination.
It has proved advantageous to activate the 3-OH group of the galactose residue by etherifi¬ cation. Particularly suitable for this purpose are dialkyltin oxides, dialkyltin alkoxylates and bis(trialkyl)tin oxides. Some examples are dibutyltin oxide, dibutyltin(0-methyl)2 and (tributyl- tin)20. The activating agents are preferably used in stoichiometric amounts. In this case, the reaction is carried out in two stages, namely a) activation and b) coupling with the com¬ pounds of the formula VI.
The activation process can be carried out at temperatures from 40 to 200°C, preferably 60 to 120°C.
The compounds of the formula V and of the formula VI can be employed in equimolar amounts. However, it has proved expedient to employ the compounds of the formula VI in excess, for example in an amount which is up to 10 times, preferably up to 5 times, the amount of the compound of the formula V.
It is furthermore expedient to carry out the reaction in both reaction stages in the presence of an inert solvent or mixtures of solvents. Reactive protic solvents such as alkanols and, furthermore, acid amides are unsuitable in reaction stage b). It is possible to use non-polar aprotie and polar aprotie or polar protic solvents. These may be aliphatic or aromatic hydro¬ carbons such as pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene or xylene, halogenated hydrocarbons such as methylene chloride, chloroform, tetrachloro¬ methane, 1 ,2-dichloroethane, 1 ,1 ,2-trichloroethane, 1 ,1 ,2,2-tetrachloroethane and chloro¬ benzene, linear or cyclic ethers such as diethyl ether, dibutyl ether, ethylene glycol dimethyl or diethyl ether, tetrahydrofuran and dioxane, N,N-dialkylated carboxamides such as dimethylformamide, N-alkylated lactams such as N-methylpyrrolidone, ketones such as acetone and methyl isobutyl ketone, carboxylic esters such as methyl or ethyl acetate, or alkanols such as methanol, ethanol, propanol, butanol and ethylene glycol monoethyl ether. Particularly preferred solvents are methanol, ethanol, benzene and toluene.
Protective groups and processes for derivatizing hydroxyl groups with such protective groups are generally known in sugar and nucleotide chemistry and are described, for example, by Beaucage, S.L. Iyer, R., Tetrahedron 48:2223-2311 (1992). Examples of such protective groups are: benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, dimethoxy- benzyl, bromobenzyl, 2,4-dichlorobenzyl; diphenylmethyl, di(methylphenyl)methyl, di(di- methylphenyl)methyl, di(methoxyphenyl)methyl, di(dimethoxyphenyl)methyl, triphenylmethyl, tris-4,4',4"-tert-butylphenylmethyl, di-p-anisylphenylmethyl, tri(methylphenyl)methyl, tri(dimethylphenyl)methyl, methoxyphenyl(diphenyl)methyl, di(methoxyphenyl)phenylmethyl, tri(methoxyphenyl)methyl, tri(dimethoxyphenyl)methyl; triphenylsilyl, alkyldiphenylsilyl, dialkylphenylsilyl and trialkylsilyl with 1 to 20, preferably 1 to 12, and particularly preferably 1 to 8 C atoms in the alkyl groups, for example triethylsilyl, tri-n-propylsilyl, i-propyl- dimethylsilyl, t-butyl-dimethylsilyl, t-butyl-diphenylsilyl, n-octyl-dimethylsilyl, (1 ,1 ,2,2-tetra- methylethyl)dimethylsilyl; C2-Ce-, in particular C2-C8acyl, such as acetyl, propanoyl, butan- oyl, pentanoyl, hexanoyl, benzoyl, methyl benzoyl, methoxybenzoyl, chlorobenzoyl and bromobenzoyl. The protective groups can be identical or different. Preferred protective groups are selected from the group consisting of linear and branched CrC8alkyl, in particu¬ lar d-dalkyl, for example methyl, ethyl, n- and i-propyl, n-, i- and t-butyl; C7-Cι2aralkyl, for example benzyl; trialkylsilyl with 3 to 20 C atoms, in particular 3 to 12 C atoms, for example triethylsilyl, tri-n-propylsilyl, tri-i-propylsilyl, i-propyl-dimethylsilyl, t-butyl-dimethylsilyl, t-butyl- diphenylsilyl, n-octyl-dimethylsilyl, (1 ,1 ,2,2-tetramethylethyl)dimethylsilyl; substituted methyli¬ dene groups which are obtainable by acetal or ketal formation from adjacent hydroxyl groups of the sugars or sugar derivatives with aldehydes and ketones, which preferably contain 2 to 12 or 3 to 12 C atoms, for example Crd2alkylidene, preferably Ci-Cealkylidene and in particular d-C alkylidene, such as ethylidene, 1 ,1- and 2,2-propylidene, 1 ,1- and 2,2-butylidene, benzylidene; unsubstituted and halogenated C2-Ceacyl, in particular C2-C8acyl, such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, pivaloyl and benzoyl.
The synthesis preferably takes place with protective groups for Re' and Re" which together form an alkylidene group with, preferably 1 to 12 and, more preferably 1 to 8 C atoms. In this connection, particularly preferred protective groups are those in which R12' and Re" to¬ gether are an alkylidene group with, in particular, 1 to 12 C atoms, with the alkylidene group forming an acetal or ketal with the oxygen atoms. These protective groups are ones which can be eliminated under neutral or weakly acidic conditions. Particularly suitable protective groups are acyl, benzyl, substituted benzyl, benzyloxymethyl, alkyl and silyl. R ' and Re" are, particularly preferably, together alkylidene, for example alkyl- or alkoxy- substituted benzylidene. Re' and Ri2" can, however, also be hydrogen, or one of Re' and Re" can be a protective group such as benzyl and the other one of Re' and Re" can be hydrogen.
Examples of protective carboxylate groups are alkoxy- and aralkoxycarbonyl groups, pre¬ ferably -C02Bn, -C02CH3.
The reaction for elimination of the protective groups is preferably carried out at a tempera¬ ture of 0°C to 50°C, and particular at room temperature.
Further details of the preparation of the compounds of the formula I are described in the examples.
An alternative synthetic route comprises glycosidic linkage of the protected fucose hydroxy ether of the formula VII
Figure imgf000036_0001
in which R2, Re and X have the abovementioned meanings, with the protected galactose of the formula VIII
Figure imgf000036_0002
in which Ri has the abovementioned meaning, Z is O or S, R12 is a protective group and R is a leaving group, and subsequent removal of the protective groups from the resulting com¬ pound.
It is possible to chose reaction conditions like those implemented for the process described previously. The leaving group R can be, for example, -C(=NH)-CCI3 or 4-pentenyl. The com¬ pounds of the formula VII can be obtained in a simple manner by glycosidic linkage of ap¬ propriately protected fucose with a compound of the formula HO-X-OH which is monopro¬ tected where appropriate. The compounds of the formula VIII can be obtained by etherifi¬ cation of compounds of the formula R1OH with galactose which is protected where appropri¬ ate.
The compounds according to the invention have antiinflammatory properties and can accordingly be used as medicaments. It is possible with them in particular to alleviate dis¬ orders such as cardiogenic shock, myocardial infarct, thrombosis, rheumatism, psoriasis, dermatitis, acute respiratory distress syndrome, asthma, arthritis and metastatic cancer. The invention furthermore relates to the compounds according to the invention for use in a therapeutic method for the treatment of disorders in warm-blooded animals, including humans. The dosage on administration to warm-blooded animals with a body weight of about 70 kg can be, for example, 0.01 to 1000 mg per day. Administration preferably takes place in the form of pharmaceutical compositions, parenterally, for example intravenously or intraperitoneally.
The invention furthermore relates to a pharmaceutical composition comprising an effective amount of the compound according to the invention, alone or together with other active sub¬ stances, a pharmaceutical carrier, preferably in a significant amount, and, where appropri¬ ate, excipients.
The pharmacologically active compounds according to the invention can be used in the form of compositions which can be administered parenterally or of infusion solutions. Solu¬ tions of this type are preferably isotonic aqueous solutions or suspensions, it being possible to prepare the latter, for example in the case of lyophilized compositions which comprise the active substance alone or together with a carrier, for example mannitol, before use. The pharmaceutical compositions can be sterilized and/or comprise excipients, for example pre- servatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts to control the osmotic pressure and/or buffers. The pharmaceutical compositions, which may, if required, comprise other pharmacologically active substances such as antibiotics, are produced in a manner known per se, for example by conventional dissolving or lyophilizing processes, and comprise about 0.1 % to 90 %, in particular from about 0.5 % to about 30 %, for example 1 to 5 %, of active substance(s).
The following examples illustrate the invention.
The following abbreviations are used:
Bz: Benzoyl; Bn: Benzyl; DMTST: Dimethyl(methylthio)sulfonium triflate; FAB: Fast atom bombardment mass spectroscopy; OTf: Triflate; Ph: Phenyl; SEt: C2H5S; THG: Thioglycerol;
THF: Tetrahydrofuran; NBA: m-Nitrobenzyl alcohol; DMF: N,N-Dimethylformamide; DME:
1 ,2-Dimethoxyethane; MeOH: Methanol; HRP: Horse radish peroxidase; BSA: Bovine serum albumin; PAA: Polyacryl amide; SA: Streptavidin
An unconnected hyphen in the formulae means methyl.
Molecular sieves are activated at 300°C under high vacuum for 12 hours before use. They are used in powdered form.
A: Preparation of starting compounds
Example A1 : Preparation of compound No. A1
Figure imgf000038_0001
OH OH 28 29
Benzyl chloride (660 ml, 5.72 mmol) is added at room temperature to a mixture of R-3-azido-2-hydroxypropionic acid 28 [Dureault, A., Tranchepain, I., Depezay, J.C, Synthesis 491-493 (1987)], triethylamine (850 ml, 6.1 mmol) and DMF (7.0 ml). The mixture is stirred for 16 hours, and then further triethylamine (850 μl, 6.1 mmol) and benzyl chloride (660 μl, 5.72 mmol) are added. The reaction mixture is stirred for two days and then con- centrated under high vacuum. The residue is taken up in water and the mixture is extracted several times with ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried (Na2S04), filtered and concentrated in vacuo. The crude product (1 g) is purified by flash chromatography on silica gel (ethyl acetate/hexane 1 :4), resulting in benzyl R-3-azido-2-hydroxypropionate 29 (0.717 g, 85 %) as an oil. 1H NMR (250 MHz, CDCI3) δ 7.36 (m, 5H), 5.25 (s, 2H), 4.39 (q, J=4.2 Hz, 1H), 3.65 (dd, J=3.3, 12.9 Hz, 1H), 3.51 (dd, J=4.3, 12.9 Hz, 1 H), 3.20 (d, J=4.0 Hz, 1 H).
O
29 ► N^^^ ^OBn b) 3 =
OTf
A1
Trifluoromethanesulfonic anhydride (770 ml, 4.41 mmol) is added at -20°C with stirring to a solution of the alcohol 29 (0.85 g, 3.84 mmol) and 2,6-di-tert-butylpyridine (1.12 ml, 4.99 mmol) in dry CH2CI2 (11.0 ml). The clear colourless solution is warmed to 0°C over the course of 40 minutes and is stirred at this temperature for a further 2 hours. The mixture is diluted with CH2CI2 (40 ml) and, while stirring vigorously, 1 M aqueous KH2P0 solution (30 ml) is added. The organic phase is separated off and the aqueous phase is extracted twice with CH2CI2. The combined organic phases are washed with H20 (30 ml), dried (Na2S04), filtered and concentrated in vacuo. The oily residue (2.3 g) is purified by flash chromatography on a short silica gel column (ethyl acetate/hexane 1 :7), resulting in the benzyl R-3-azido-2-trifluoromethanesulfonyloxypropionate A1 (1.16 g, 85 %) as a yellowish oil. 1H NMR (250 MHz, CDCI3) δ 7.38 (br s, 5H), 5.32 (d, J=12,1 Hz, 1 H), 5.27 (d, J=12.1 Hz, 1H), 5.24 (dd, J=4.2, 5.5 Hz, 1 H), 3.90 - 3.75 (m, 2H); 13C NMR (63 MHz, CDCI3) δ 164.4, 133.9, 129.1 , 128.8, 128.6, 120.9, 81.0, 69.0, 51.5. Example A2: Preparation of compound No. A2
Figure imgf000040_0001
26 27 A2
Benzyl (ft^-phenyl^-trifluoromethanesulfonyloxybutyrate (A2):
A solution of (fl)-2-hydroxy-4-phenylbutyric acid 26 (0.2 g, 1.11 mmol) in MeOH/ H20 (9:1 , 1.3 ml) is adjusted to pH 8 with 20 % Cs2C03 solution. The solution is concentrated in vacuo and azeotroped first with ethanol and then with hexane, subsequently dried under high vacuum in order to remove remaining H20. The residue is mixed with N,N-dimethylform- amide (1.3 ml) and benzyl bromide (132 μl, 1.11 mmol) , and the mixture is stirred at room temperature for 75 minutes. Then further benzyl bromide (20 μl, 0.168 mmol) is added, and the mixture is stirred for a further 50 minutes. The white suspension is diluted with CH2CI2 (5 ml), filtered through HyfloSuperCel® and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel (eluent: ethyl acetate/hexane 4:1) affords benzyl (f?)- 2-hydroxy-4-phenylbutyrate 27 (0.21 g, 70 %). The product (0.3 g, 1.11 mmol) is dissolved in CH2CI2 (4.5 ml), 2,6-di-tetf-butylpyridine (323 μl, 1.44 mmol) is added, and the mixture is cooled to -20°C. Then trifluoromethanesulfonic anhydride (222 μl, 1.27 mmol) is added dropwise over the course of 3 minutes, and the solution is warmed to 0°C over the course of 45 minutes. After 75 minutes at 0°C, the mixture is diluted with CH2CI2 (20 ml) and washed with 1 molar aqueous KH2P0 solution (15 ml). The aqueous phase is extracted with CH2CI2 (2 x 10 ml), and the combined organic phases are washed with H20 (10 ml), dried (Na2S0 ), filtered and concentrated in vacuo. The residue is purified roughly by column filtration on silica gel (eluent: ethyl acetate/hexane 1 :9), resulting in the crude triflate A2 (0.311 g, 70 %) as an oil. The product is used immediately for the next stage (prepara¬ tion of B1.18). 1H NMR (250 MHz, CDCI3) δ 7.50 - 7.17 (m, 10H), 5.31 (s, 2H), 5.28 (dd, J=5.5, 11.0 Hz, 1 H), 2.82 (m, 2H), 2.41 (m, 2H). Example A3: Preparation of compound No. A3
Figure imgf000041_0001
fl-Hydromandelic acid is converted into the triflate A3 in accordance with Example A2.
Example A4: Preparation of compound No. A4
Figure imgf000041_0002
ft-2-Hydroxy-3-methylbutyric acid is converted into the triflate A4 in accordance with Example A2.
Example A5: Preparation of compound No. A5
Figure imgf000041_0003
R-2-Hydroxy-3-cyclohexylpropionic acid is converted into the triflate A5 in accordance with Example A2. B Preparation of the mimetics
Example B1 : Preparation of compound No. B1.1
Figure imgf000042_0001
A mixture of the thioglycoside 1 (5.38 g, 8.40 mmol) [Biessen, E. A. L., Beuting, D.M., Roelen, H.C.P.F., van de Marel, G.A., van Boom, J.H., van Berkel, T.J.C, J. Med. Chem. 38:1538-1546 (1995)] and of the acceptor 2 (3.44 g, 6.46 mmol) is dried under high vacuum for one hour. Then activated 4A molecular sieves (20 g) and DMTST (4.17 g, 16.14 mmol) are added under a nitrogen atmosphere, followed by CH2CI2 (70 ml). The yellowish suspen¬ sion is dried at room temperature and, after 3 hours, 5 ml of a suspension consisting of DMTST (5.84 g, 22.61 mmol), 4A molecular sieves (4.0 g) and CH2CI2 (35 ml) are added. Further 5 ml portions of this DMTST suspension are added after 30, 45 and 90 minutes respectively. The brown reaction mixture is then stirred for 15 hours, and thereafter filtered through Hyflo Super Cef (filter aid), washing with CH2CI2 (300 ml). The filtrate is extracted by shaking first with 10 % aqueous NaHC03 solution and then with saturated NaCl solution, and the organic phase is dried with Na2S04| filtered and concentrated in a vacuum rotary evaporator. The remaining brown foam is purified by two column chromatographies on silica gel (eluent for 1st chromatography: ethyl acetate/hexane 1 :4; 2nd chromatography: ethyl acetate/toluene 1 :9), resulting in the pure product 3 as a colourless solid (4.28 g, 60 %), which is immediately used further.
Figure imgf000043_0001
A solution of the tetrabenzoate 3 (3.38 g, 3.04 mmol) and sodium methoxide (0.165 g, 3.05 mmol) in dry methanol (32 ml) is stirred at room temperature for 3 hours. The mixture is neutralized by adding a strongly acidic ion exchanger (Amberlyst 15) and then filtered through Hyflo Super Cel®, washing with CH2CI2. The filtrate is concentrated in vacuo, and the remaining yellow oil is purified by flash chromatography on silica gel (elution: CH2CI2/ methanol 19:1), resulting in the pure tetrol 4 (1.95 g, 92 %).
Figure imgf000043_0002
A solution of the tetrol 4 (1.0 g, 1.44 mmol), benzaldehyde dimethyl acetal (430 ml, 2.86 mmol) and camphorsulfonic acid (0.1 g, 0.43 mmol) in acetonitrile (20 ml) is stirred at room temperature. After 4 hours, further camphorsulfonic acid (0.15 g, 0.65 mmol) is added and the mixture is stirred for a further 6 hours at room temperature, after which it is heated at 35°C for a further 6 hours. Then further camphorsulfonic acid (0.06 g, 0.26 mmol) is added, and the solution is stirred at room temperature for 6 hours. The reaction mixture is filtered through Hyflo Super Cel®, washing with ethyl acetate. The filtrate is extracted by shaking first with saturated aqueous NaHC03 solution and then with saturated NaCl solution, and the organic phase is dried (Na2S0 ), filtered and concentrated in vacuo, resul¬ ting in 1.5 g of crude product. Purification of the crude product by flash chromatography on silica gel (CH2CI2/MeOH 39:1) affords, besides the required benzylidene acetal 5 (0.475 g), a mixture of less polar byproducts (0.4 g). The latter are treated once again under the reac¬ tion conditions described above and are purified, resulting in a further 0.08 g of the benzyli¬ dene acetal 5. The total yield of 5 is: 0.555 g (49 %): 1H NMR (500 MHz, CDCI3) δ 7.53 - 7.51 (m, 2H), 7.38 - 7.19 (m, 18H), 5.62 (s, 1 H), 4.83 (d, J=3.8 Hz, 1 H), 4.77 (d, J=12.1 Hz, 1 H), 4.71 (d, J=11.5 Hz, 1 H), 4.70 (m, 1 H), 4.66 (d, J=12.0 Hz, 1 H), 4.62 (d, J=11.5 Hz, 1 H), 4.51 (d, J=11.1 Hz, 1 H), 4.36 - 4.31 (m, 2H), 4.22 (br d, J=2.8 Hz, 1 H), 4.06 (dd, J=1.7, 12.3 Hz, 1 H), 3.97 (dd, J=2.9, 10.2 Hz, 1H), 3.92 (d, J=12.0 Hz, 1 H), 3.90 (dd, J=3.8, 10.2 Hz, 1 H), 3.76 - 3.68 (m, 3H), 3.53 (ddd, J=4.9, 9.0, 11.0 Hz, 1 H), 3.43 (br s, 1 H), 3.37 (d, J=2.5 Hz, 1H), 2.57 (d, J=8.0 Hz, 1 H), 2.51 (s, 1 H), 2.08 (m, 2H), 1.73 (br d, J=9.5 Hz, 2H), 1.42 - 1.25 (m, 2H), 1.20 (br t, J=11.2 Hz, 2H), 1.07 (d, J=6.3 Hz, 3H); MS (FAB, THG) 800 (M + NH4), 783 (M + H).
Figure imgf000044_0001
6
A mixture of the diol 5 (0.098 g, 0.125 mmol), di-n-butyltin oxide (0.062 g, 0.25 mmol) and methanol (5 ml) is heated under reflux in an argon atmosphere for 2 hours. The reaction mixture is concentrated in vacuo, and pentane is added to the residue, after which it is con¬ centrated once again. Dry CsF (dried under high vacuum at 300°C, 0.068 g, 0.45 mmol) is added under an argon atmosphere, and the mixture is further dried under high vacuum (30 minutes). After addition of anhydrous 1 ,2-dimethoxyethane (1.5 ml), a solution of benzyl fl-3-phenyl-2-trifluoromethanesulfonyloxypropionate [Degerbeck, F., Fransson, B., Grehn, L., Ragnarsson, U., J. Chem. Soc. Perkin Trans. 1:11-14 (1993)] (0.24 g, 0.62 mmol) in dry 1 ,2-dimethoxyethane (1.5 ml) is added. The mixture is first vigorously stirred at room temperature for 4 hours and then at 40°C for a further 2 hours. After addition of aqueous 1 M KH2P04 solution, the mixture is diluted with water and extracted three times with ethyl acetate. The combined organic phases are extracted by shaking with diluted aqueous KF solution and then with saturated NaCl solution. The organic phase is dried (Na2S0 ), filtered and concentrated in a vacuum rotary evaporator, resulting in the crude product. Purification by flash chromatography on silica gel (gradient elution: ethyl acetate/ toluene 1 :4 to 100 % ethyl acetate) affords the ether 6 (0.045 g, 35 %) and the more polar precursor 5 (0.043 g, 44 %): 1H NMR (250 MHz, CDCI3) δ 7.49 (br d, J=6.9 Hz, 2H), 7.37 - 7.05 (m, 28H), 5.36 (s, 1 H), 5.04 (d, J=12.0 Hz, 1 H), 4.98 (d, J=12.0 Hz, 1 H), 4.72 - 4.63 (m, 3H), 4.62 - 4.48 (m, 4H), 4.31 (d, J=11.2 Hz, 1 H), 4.16 (m, 1 H), 4.11 (d, J=7.9 Hz, 1 H), 4.07 (d, J=3.4 Hz, 1 H), 3.88 - 3.79 (m, 2H), 3.76 (dd, J=3.4, 10.3 Hz, 1 H), 3.66 (d, J=11.3 Hz, 1 H), 3.62 - 3.47 (m, 2H), 3.44 - 3.35 (m, 1 H), 3.36 (dd, J=3.5, 9.6 Hz, 1 H), 3.16 - 3.06 (m, 2H), 3.12 (br s, 1 H), 3.01 (dd, J=8.4, 13.9 Hz, 1 H), 2.03 - 1.86 (m, 2H), 1.93 (d, J=2.0 Hz, 1 H), 1.71 - 1.55 (m, 2H), 1.36 - 1.00 (m, 4H), 0.99 (d, J=7.1 Hz, 3H).
Figure imgf000045_0001
B1.1
Dioxane (2.5 ml), water (1.2 ml) and glacial acetic acid (0.1 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20 %, 0.03 g) and the protected compound 6 (0.03 g, 0.029 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly ele¬ vated pressure of hydrogen at room temperature for 13 hours, and then filtered through a cellulose filter (pore size 45 μm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a DowexδO ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.5 cm), washing with deionized water. The clear filtrate is concentrated and purified by reverse phase chromatography (RP18 silica gel, column diameter 1.4 cm, length 7.0 cm, gradient elution: 40 % MeOH/ H20 through 45 % MeOH/H2θ to 50 % MeOH/H2θ), resulting in the target molecule B1.1 (0.015 g, 78 %) as a colourless solid: 1H NMR (500 MHz, D20) δ 7.38 - 7.30 (m, 4H), 7.29 - 7.23 (m, 1H), 4.92 (d, J=4.0 Hz, 1 H), 4.55 (q, J=6.7 Hz, 1H), 4.35 (d, J=7.8 Hz, 1 H), 4.11 (dd, J=4.8, 8.5 Hz, 1 H), 3.86 (d, J=3.6 Hz, 1 H), 3.84 (dd, J=3.3, 10.5 Hz, 1 H), 3.74 (d, J=3.5 Hz, 1 H), 3.71 (dd, J=3.9, 10.5 Hz, 1 H), 3.69 - 3.62 (m, 3H), 3.50 (ddd, J=1.0, 4.5, 7.1 Hz, 1 H), 3.48 - 3.41 (m, 1 H), 3.43 (dd, J=8.0, 9.7 Hz, 1H), 3.24 (dd, J=3.5, 9.7 Hz, 1 H), 3.09 (dd, J=4.6, 14.0 Hz, 1 H), 2.92 (dd, J=8.8, 14.0 Hz, 1 H), 2.06 - 1.97 (m, 2H), 1.63 (br s, 2H), 1.24 - 1.14 (m, 4H), 1.13 (d, J=7.0 Hz, 3H); 13C NMR (100.6 MHz, APT, D20) d 139.5 (Cq), 130.7 (2 CH), 129.9 (2 CH), 128.0 (CH), 100.8 (CH), 96.8 (CH), 84.0 (CH), 83.3 (CH), 79.6 (CH), 78.4 (CH), 75.6 (CH), 73.3 (CH), 71.4 (CH), 70.9 (CH), 69.2 (CH), 67.7 (CH), 67.4 (CH), 62.8 (CH2), 40.6 (CH2), 30.9 (CH2), 30.4 (CH2), 24.4 (2 CH2), 16.6 (CH3); MS (FAB, THG) 595 (M+Na), 573 (M+H).
Figure imgf000046_0001
A mixture of the tetrol 4 (0.038 g, 0.055 mmol) and di-π-butyltin oxide (0.029 g, 0.117 mmol) in dry methanol (2.0 ml) is heated under reflux in an argon atmosphere. After 2.25 hours, the clear, colourless solution is concentrated in vacuo, and the residue is mixed with benzene and concentrated several times in order to remove excess MeOH. It is then dried under high vacuum for 30 minutes, and the residue is mixed under an argon atmosphere with CsF (dried under high vacuum at 300°C, 0.03 g, 0.197 mmol) and dry 1 ,2-dimethoxy- ethane (0.4 ml). The mixture is cooled to 0°C, and a solution of benzyl R-3-phenyl-2-tri- fluoromethanesulfonyloxypropionate [Degerbeck, F., Fransson, B., Grehn, L., Ragnarsson, U., J. Chem. Soc. Perkin Trans. 1 :11-14 (1993)] (0.085 g, 0.219 mmol) in dry 1 ,2-dimeth- oxyethane (0.4 ml) is added using a syringe. The reaction mixture is then warmed to room temperature and stirred for one hour, after which it is stirred at 40°C for a further 2 hours. After addition of aqueous 1 M KH2P04 solution, the mixture is diluted with water and extracted three times with CH2CI2. The combined organic phases are washed with aqueous KF solution and then dried (Na2S04), filtered and concentrated in vacuo. Purification of the residue takes place by flash chromatography twice on silica gel (first chromatography: 2 % MeOH/CHCI3; second chromatography: 45 % ethyl acetate/toluene), resulting in the ether 8 as an oil (0.013 g, 25 %): 1H NMR (250 MHz, CDCI3) δ 7.40 - 7.00 (m, 25H), 5.15 (d, J=11.6 Hz, 1 H), 5.09 (d, J=11.6 Hz, 1 H), 4.89 (d, J=11.8 Hz, 1 H), 4.86 (d, J=3.2 Hz, 1 H), 4.77 (d, J=11 ,6 Hz, 1 H), 4.69 (d, J=12.0 Hz, 2H), 4.57 (d, J=12.0 Hz, 1 H), 4.56 (d, J=11.8 Hz, 1H), 4.35 (q, J=6.5 Hz, 1 H), 4.28 (dd, J=4.0, 9.5 Hz, 1 H), 4.11 (d, J=7.6 Hz, 1 H), 4.02 - 3.88 (m, 2H), 3.79 (dd, J=7.3, 11.9 Hz, 1 H), 3.66 (br s, 1 H), 3.63 - 3.40 (m, 5H), 3.22 (m, 1 H), 3.10 (dd, J=4.0, 14.0 Hz, 1 H), 3.09 (br s, 1 H), 3.03 (dd, J=3.5, 9.3 Hz, 1 H), 2.90 (dd, J=9.5, 14.0 Hz, 1 H), 1.97 - 1.84 (m, 2H), 1.75 (d, J=1.9 Hz, 1 H), 1.59 (br s, 2H), 1.29 - 1.07 (m, 4H), 1.01 (d, J=6.4 Hz, 3H).
Figure imgf000047_0001
B1.1
1 ,4-Dioxane/water (2.0 ml of a 4:1 mixture) is added to the protected carbohydrate 8 (0.03 g, 0.032 mmol) and Pd/C (0.03 g, Pd content 10 %), followed by glacial acetic acid (0.1 ml). The flask is evacuated and flushed with argon several times. This procedure is repeated with hydrogen. The mixture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring until a test by thin-layer chromatography (silica gel plates n-BuOH: H20:acetone:glacial acetic acid: NH4OH 70:60:50:18:1.5) indicates absence of the precur¬ sor and of the intermediates (about 3.5 hours). The black suspension is filtered twice through a cellulose filter (pore size 45 μm), and the filtrate is concentrated in vacuo. The residue is taken up in water and the solution is passed through an ion exchanger column (Dowex 50, Na+ form, column diameter 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated and purified by reverse phase chromatography (RP18 silica gel, column diameter 1.4 cm, length 7.0 cm, gradient elution: 40 % MeOH/H20 through 45 % MeOH/H20 to 50 % MeOH/H20), resulting in the target molecule B1.1 (0.015 g, 78 %) as a colourless solid. Example B2: Preparation of compound No. B1.2
Figure imgf000048_0001
B1.2
The aromatic compound B1.1 (0.152 g, 0.256 mmol) and 5 % Rh/Al203 (0.2 g) are taken up in H20 (5.5 ml), dioxane (3.5 ml) and acetic acid (1.0 ml). Air is replaced by multiple evacua¬ tion, firstly by argon and then by hydrogen. The black suspension is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 2 days and then filtered through a cellulose filter (pore size 45 μm). The clear, colourless solution is concentrated in vacuo, and the residue is taken up in water and concentrated several times in order to remove excess acetic acid. A solution of the crude product in water is filtered through a Dowex 50 ion exchanger column (Na+form, length: 9 cm, diameter: 1.3 cm), and the column is washed with water. The filtrate is concentrated in vacuo, and the residue (0.16 g) is puri¬ fied by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.55 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: 55 % MeOH/H20), resulting in the target molecule B1.2 (0.11 g, 73 %) as a fluffy white solid (after lyophiiization). 1H NMR (500 MHz, D20) δ 4.93 (d, J=3.8 Hz, 1 H), 4.58 (q, J=6.4 Hz, 1H), 4.43 (d, J=7.5 Hz, 1 H), 3.91 (dd, J=3.5, 9.0 Hz, 1 H), 3.88 - 3.83 (m, 2H), 3.75 (d, J=3.3 Hz, 1H), 3.73 - 3.64 (m, 4H), 3.57 - 3.53 (m, 1 H), 3.49 (dd, J=7.3, 9.0 Hz, 1 H), 3.50 - 3.43 (m, 1 H), 3.33 (dd, J=3.2, 9.2 Hz, 1H), 2.10 - 1.99 (m, 2H), 1.73 (br d, J=12.0 Hz, 1 H), 1.69 - 1.44 (m, 9H), 1.29 - 1.07 (m, 7H), 1.14 (d, J=6.5 Hz, 3H), 0.96 - 0.80 (m, 2H); MS (FAB, THG) 623 (M+Na), 601 (M+H). Example B3: Preparation of compound No. B1.3
Figure imgf000049_0001
A suspension consisting of the benzylidene acetal 9 (0.5 g, 1.60 mmol) (EP 671 ,406), sodium cyanoborohydride (0.9 g, 14.3 mmol), activated 4A molecular sieves (1.0 g) and dry tetrahydrofuran (30 ml) is cooled to 0°C under a nitrogen atmosphere. The pH of the mix¬ ture is adjusted to 1 by cautious addition of a saturated solution of HCl gas in dry diethyl ether. The suspension is stirred at 0°C, and the pH is kept at 1 by occasional addition of the ethereal HCl solution. After 10 hours, cold, saturated aqueous NaHC03 solution is added (30 ml). The organic phase is separated off, and the aqueous phase is extracted twice with ethyl acetate (70 ml each time). The combined organic phases are dried (Na2S0 ), filtered and concentrated in vacuo, resulting in 1.3 g of the crude product. Purification takes place by flash chromatography on silica gel (CHCIs/isopropanol 19:1), resulting in the required 6- benzyl ether 10 (0.3 g, 60 %) and a somewhat less polar byproduct (0.045 g): 1H NMR (250 MHz, CDCI3) δ 7.47 - 7.33 (m, 5H), 4.64 (s, 2H), 4.37 (d, J=9.3 Hz, 1 H), 4.13 (br d, J=3.0 Hz, 1 H), 3.89 - 3.69 (m, 4H), 3.64 (dd, J=3.1 , 9.0 Hz, 1 H), 2.89 - 2.70 (m, 2H), 1.38 (t, J=7.3 Hz, 3H).
Figure imgf000049_0002
11
Pyridine (0.45 ml, 5.56 mmol) and benzoyl chloride (0.49 ml, 4.22 mmol) are added to a solution of the triol 10 (0.296 g, 0.941 mmol) in CH2CI2 (3.0 ml) at 0°C The reaction mixture is stirred at 0°C for 3.5 hours and then 1 M aqueous KH2P0 solution is added, and the mixture is extracted three times with CH2CI2. The combined organic phases are washed with water, dried (Na2S04), filtered and concentrated in vacuo, resulting in 1.0 g of crude product. Purification by flash chromatography on silica gel (hexane/ethyl acetate 4:1 ) gives the tribenzoate 11 as yellowish crystals (0.517 g, 88 %). 1H NMR (250 MHz, CDCI3) δ 8.09 (d, J=7.5 Hz, 2H), 8.02 (d, J=7.5 Hz, 2H), 7.85 (d, J=7.5 Hz, 2H), 7.68 (t, J=7.4 Hz, 1H), 7.63 - 7.39 (m, 7H), 7.38 - 7.23 (m, 6H), 6.06 (d, J=3.3 Hz, 1 H), 5.85 (t, J=10.0 Hz, 1H), 5.66 (dd, J=3.5, 10.0 Hz, 1 H), 4.88 (d, J=10.0 Hz, 1 H), 4.60 (d, J=11.9 Hz, 1 H), 4.49 (d, J=11.9 Hz, 1 H), 4.23 (t, J=6.3 Hz, 1 H), 3.84 - 3.64 (m, 2H), 3.02 - 2.80 (m, 2H), 1.38 (t, J=7.5 Hz, 3H).
Figure imgf000050_0001
12
Dry CH2CI2 (8.0 ml) is added to a mixture of the thioglycoside 11 (0.377 g, 0.60 mmol), the glycosyl acceptor 2 (0.32 g, 0.60 mmol) (EP 671 ,409) and activated 4A molecular sieves (2.5 g) under an argon atmosphere. A suspension of DMTST (0.39 g, 1.51 mmol) and acti¬ vated 4A molecular sieves (0.8 g) in dry CH2CI2 (5.0 ml) is prepared in a second round- bottom flask. Both suspensions are stirred at room temperature for 3.5 hours. Then 3 por¬ tions of 1 ml of the DMTST suspension are added over a course of one hour to the glycosyl donor/acceptor mixture. The yellowish reaction mixture is stirred at room temperature for a further 1.5 hours and then filtered through Hyflo Super Cel*. washing with CH2CI2. The fil¬ trate is extracted by shaking with aqueous NaHC03 solution and then with water. The aqueous phases are reextracted with CH2CI2, and the combined organic phases are dried (Na2S04), filtered and concentrated in vacuo, resulting in 0.67 g of the crude product. Puri¬ fication takes place by flash chromatography twice on silica gel (first chromatography: toluene/ethyl acetate 14:1 ; second chromatography: hexane/ethyl acetate 4:1 ), resulting in the product 12 (0.404 g, 61 %) as a colourless foam.
Figure imgf000051_0001
13
A solution of the tribenzoate 12 (3.42 g, 3.12 mmol) and sodium methoxide (0.169 g, 3.12 mmol) in methanol (65 ml) is stirred at room temperature for 6 hours. The base is then neutralized by adding acidic ion exchanger (Amberlyst 15), and the suspension is filtered through Hyflo Super Cel®. The filtrate is concentrated in vacuo, and the remaining yellow oil (3.35 g) is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 19:1), resulting in the triol 13 (2.15 g, 88 %) as a colourless foam: 1H NMR (500 MHz, CDCI3) δ 7.41 - 7.24 (m, 20H), 4.99 (d, J=3.6 Hz, 1H), 4.95 (d, J=11.2 Hz, 1H), 4.83 (d, J=11.2 Hz, 1H), 4.77 (d, J=11.3 Hz, 1 H), 4.69 (d, J=11.3 Hz, 1 H), 4.68 (d, J=11.5 Hz, 1 H), 4.61 (d, J=11.5 Hz, 1 H), 4.53 (s, 2H), 4.34 (d, J=7.0 Hz, 1 H), 4.33 (m, 1 H), 4.04 (dd, J=3.7, 10.1 Hz, 1 H), 4.02 (m, 1H), 3.97 (dd, J=2.9, 10.0 Hz, 1H), 3.81 - 3.77 (m, 1 H), 3.77 (dd, J=6.0, 9.4 Hz, 1H), 3.70 (dd, J=5.0, 9.6 Hz, 1H), 3.65 (d, J=2.0 Hz, 1H), 3.63 - 3.54 (m, 4H), 2.95 (br s, 1 H), 2.60 (br d, J=2.0 Hz, 2H), 2.07 (m, 1H), 2.01 (m, 1H), 1.69 (m, 2H), 1.45 - 1.30 (m, 2H), 1.29 - 1.18 (m, 2H), 1.10 (d, J=6.5 Hz, 3H); MS (FAB, THG) 783 (M-H), 693 (M-PhCH2).
Figure imgf000051_0002
13 14
A mixture of the triol 13 (0.515 g, 0.656 mmol) and di-n-butyltin oxide (0.245 g, 0.984 mmol) in dry methanol (15 ml) is heated under reflux in a nitrogen atmosphere for 2 hours. The clear solution is concentrated in vacuo and taken up in benzene and concentrated three times in order to remove excess MeOH. The residue is dried under high vacuum and then dry CsF (dried under high vacuum at 300°C, 0.5 g, 3.29 mmol) is added under an argon atmosphere, followed by dry 1 ,2-dimethoxyethane (4.0 ml) and a solution of benzyl fl-S-azido^-trifluoromethanesulfonyloxypropionate A1 (1.16 g, 3.28 mmol) in dry 1 ,2-di- methoxyethane (8.0 ml). The reaction mixture is stirred at room temperature for 6 hours, and then 1 M aqueous KH2P04 solution (60 ml) is added. The mixture is extracted three times with ethyl acetate, and the combined organic phases are washed first with aqueous NaHC03 solution and then with NaCl solution, dried (Na2S04), filtered and concentrated in vacuo. The oily residue (1.15 g) is purified by flash chromatography on silica gel (elution of the product with toluene/ethyl acetate 4:1 , then elution of the precursor with CH2CI2/MeOH 19:1), resulting in the ether 14 (0.488 g, 75 %) as a colourless foam and the precursor 13 (0.075 g, 15 %). 14: 1H NMR (500 MHz, CDCI3) δ 7.40 - 7.22 (m, 25H), 5.25 (d, J--.11.7 Hz, 1H), 5.16 (d, J=11.8 Hz, 1 H), 4.96 (d, J=10.9 Hz, 1 H), 4.95 (d, J=3.1 Hz, 1 H), 4.82 (d, J=10.8 Hz, 1 H), 4.76 (d, J=11.1 Hz, 1 H), 4.72 - 4.66 (m, 2H), 4.62 (d, J=11.0 Hz, 1 H), 4.57 (dd, J=3.2, 6.0 Hz, 1 H), 4.53 (d, J=11.3 Hz, 1 H), 4.50 (d, J=11.3 Hz, 1 H), 4.39 (q, J=6.2 Hz, 1 H), 4.31 (d, J=7.4 Hz, 1 H), 4.04 (br s, 1H), 4.02 (dd, J=3.0, 9.5 Hz, 1 H), 3.99 (dd, J=2.4, 9.5 Hz, 1 H), 3.82 (ddd, J=1.9, 7.3, 8.9 Hz, 1H), 3.77 (dd, J=6.0, 9.2 Hz, 1 H), 3.78 - 3.74 (m, 1 H), 3.70 - 3.65 (m, 2H), 3.63 (dd, J=3.0, 12.3 Hz, 1 H), 3.58 (ddd, J=4.2, 8.0, 9.5 Hz, 1 H), 3.53 (dd, J=6.0, 12.5 Hz, 1 H), 3.55 - 3.51 (m, 1H), 3.44 (dd, J=3.1 , 9.0 Hz, 1 H), 2.90 (dd, J=1.2, 1.8 Hz, 1 OH), 2.86 (d, 2.0 Hz, 1 OH), 2.09 - 1.96 (m, 2H), 1.68 (m, 2H), 1.44 - 1.18 (m, 4H), 1.11 (d, J=6.3 Hz, 3H); MS (FAB, THG) 1010 (M+Na), 984 (M+Na+2H-N2), 962 (M+3H-N2).
Figure imgf000052_0001
16
Pt BaS04 (0.35 g, Pt content: 5 %) is added to a solution of the azide 14 (0.11 g,
0.111 mmol) in ethyl acetate (12 ml). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the mixture is hydrogenated under atmospheric pressure with vigorous stirring. The hydrogenation is stopped after 2.5 hours, the suspen¬ sion is filtered through a cellulose filter (pore size 45 μm), and the titrate is concentrated in vacuo. The residue (0.115 g) is purified by flash chromatography on silica gel (CH2CI2/ MeOH 19:1), resulting not only in the required amine 16 (0.055 g, 51 %) but also the less polar precursor 14 (0.042 g, 38 %). The amine 16 is unstable and is used immediately for further experiments.
Figure imgf000053_0001
17 B1.3
(i) Preparation of the benzamide intermediate 17: diisopropylethylamine (3.5 ml, 0.02 mmol) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.012 g, 0.0271 mmol) are added at 0°C to a solution of the β-amino acid derivative 16 (0.013 g, 0.0135 mmol) and benzoic acid (0.0033 g, 0.027 mmol) in dry THF (0.5 ml). The reaction mixture is stirred for 45 minutes, after which saturated aqueous NaHC03 solution is added. The mixture is extracted three times with CH2CI2, and the combined organic phases are washed first with 1 M aqueous KH2P04 solution (pH 1-2, adjusted with 1 M aqueous HCl) and then with aqueous NaHC03 solution, dried (Na2S0 ), filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel (gradient elution: 35 % ethyl acetate/toluene to 40 % ethyl acetate/toluene), resulting in the benzamide 17 (0.0098 g, 68 %).
(ii) Deprotection of 17: dioxane (1.5 ml), water (0.7 ml) and glacial acetic acid (0.1 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.011 g) and the benzyl ether 17 (0.0097g, 0.0091 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black mixture is hydrogenated under slightly elevated pressure with vigorous stirring for 14 hours. The mixture is filtered through a cellulose filter (pore size 45 μm), and the filtrate is concentrated in vacuo. The residue is taken up in water and concentrated several times in order to remove excess acetic acid. A solution of the crude product with a little water is then passed through an ion exchanger column (Dowex 50, Na+ form, column diameter 0.9 cm, length 3.5 cm), washing with deioni¬ zed water. The filtrate is concentrated in vacuo, and the residue (0.007 g) is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.59 ml/min, detection at 230 nm) and subsequent reverse phase chromato¬ graphy (Merck RP18 silica gel, gradient elution: 37 % MeOH/H20 to 45 % MeOH/H20), resulting in the target molecule B1.3 (3.3 mg, 58 %) as a fluffy white solid, (after lyophiii¬ zation). 1H NMR (500 MHz, D20) δ 7.74 (d, J=7.5 Hz, 2H), 7.57 (t, J=7.2 Hz, 1 H), 7.48 (t, J=7.6 Hz, 2H), 4.92 (d, J=4.0 Hz, 1 H), 4.57 (q, J=6.7 Hz, 1 H), 4.44 (d, J=7.8 Hz, 1 H), 4.17 (dd, J=3.9, 8.1 Hz, 1 H), 3.94 (d, J=3.0 Hz, 1 H), 3.86 (d, J=3.5 Hz, 1 H), 3.84 (t, J=4.0 Hz, 1 H), 3.74 (d, J=3.5 Hz, 1 H), 3.75 - 3.65 (m, 4H), 3.60 - 3.52 (m, 3H), 3.49 - 3.44 (m, 1 H), 3.45 (dd, J=3.5, 9.3 Hz, 1 H), 2.03 (m, 2H), 1.64 (br s, 2H), 1.26 - 1.13 (m, 4H), 1.11 (d, J=6.5 Hz, 3H); MS (FAB, THG) 660 (M+Na), 638 (M+H).
Example B4: Preparation of compound No. B1.4
Figure imgf000054_0001
19 B1.4
(a) Preparation of the amide intermediate 19: diisopropylcarbodiimide (20 ml, 0.129 mmol) is added at room temperature to a solution of the amine 16 (0.032 g, 0.033 mmol), dihydro¬ cinnamic acid (0.015 g, 0.1 mmol), 1 -hydroxybenzotriazole (0.025 g, 0.185 mmol) in dry THF (1.0 ml). The reaction mixture is stirred for 30 minutes and then concentrated in vacuo. The residue (0.09 g) is purified by flash chromatography twice on silica gel (eluent for the first chromatography: CH2CI2/MeOH 39:1 , for the second chromatography: CH2CI2/isopro- panol 39:1), resulting in the pure amide 19 (0.031 g, 86 %). (b) Deprotection of 19: dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.035 g) and the benzyl ether 19 (0.031 g, 0.0283 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black mixture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 18 hours. The mixture is filtered through a cellulose filter (pore size 45 μm), and the filtrate is concentrated in vacuo. The residue is mixed with toluene (about 2 ml) and concentrated several times in order to remove excess acetic acid. A solution of the crude product (0.021 g) in a little water is then passed through an ion exchanger column (Dowex 50, Na+ form, column diameter 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated in vacuo, and the residue (0.02 g) is purified by reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: 60 % MeOH/H20) and subsequent gel filtra¬ tion on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm), resulting in the target molecule B1.4 (0.014 g, 74 %) as a fluffy colourless solid (after lyophiiization). 1H NMR (500 MHz, D20) δ 7.32 (m, 2H), 7.24 (m, 3H), 4.93 (d, J=4,1 Hz, 1 H), 4.57 (q, J=6.7 Hz, 1 H), 4.40 (d, J=8.0 Hz, 1H), 3.9 - 3.84 (m, 3H), 3.75 - 3.66 (m, 5H), 3.63 (dd, J=3.8, 14.0 Hz, 1 H), 3.53 (br dd, J=4.5, 7.5 Hz, 1H), 3.49 (dd, J=7.9, 9.6 Hz, 1 H), 3.50 - 3.44 (m, 1 H), 3.23 (dd, J=7.8, 14.0 Hz, 1 H), 3.15 (dd, J=3.2, 9.8 Hz, 1 H), 2.88 (br t, J=7.3 Hz, 2H), 2.59 - 2.45 (m, 2H), 2.09 (m, 1 H), 2.03 (m, 1H), 1.67 (br s, 2H), 1.30 - 1.15 (m, 4H), 1.13 (d, J=6.6 Hz, 3H); MS (FAB) 666 (M+H), 643 (M+H-Na).
Example B5: Preparation of compound No. B1.5
Figure imgf000055_0001
21 B1.5 (a) Preparation of the amide intermediate 21 : diisopropylcarbodiimide (16 ml, 0.103 mmol) is added with stirring at room temperature to a solution of the amine 16 (0.026 g,
0.027 mmol), sodium 4-hydroxybutyrate (0.010 g, 0.079 mmol), 1 -hydroxybenzotriazole (0.020 g, 0.148 mmol) in a mixture of dry THF (1.0 ml) and DMF (0.2 ml). After 4 hours, further DMF (dimethylformamide) (0.2 ml) is added, and the mixture is stirred for a further 13 hours. After the volatile constituents (including DMF) have been distilled off under high vacuum, the residue (0.09 g) is purified by flash chromatography on silica gel (CH2CI2/ MeOH 29:1 ), resulting in the amide 21 (0.02 g, 71 %).
(b) Deprotection of 21 : dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.04 g) and the benzyl ether 21 (0.036 g, 0.034 mmol). The flask is evacuated and flushed with argon seve¬ ral times. It is then flushed with hydrogen, and the black mixture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 18 hours. The mixture is filtered through a cellulose filter (pore size 45 μm), and the filtrate is concentrated in vacuo. The residue is mixed with toluene (about 2 ml) and concentrated several times in order to remove excess acetic acid. A solution of the crude product (0.022 g) in a little water is then passed through an ion exchanger column (Dowex 50, Na+ form, column diameter 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated in vacuo, and the residue (0.02 g) is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column dia¬ meter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm) and subse¬ quent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH/H20 1 :4), resulting in the target molecule B1.5 (0.015 g, 70 %) as a fluffy colourless solid (after lyophiiization). 1H NMR (500 MHz, D20) δ 4.93 (d, J=3.9 Hz, 1 H), 4.59 (q, J=6.7 Hz, 1 H), 4.47 (d, J=7.5 Hz, 1 H), 4.04 (dd, J=3.8, 7.3 Hz, 1H), 3.92 (d, J=3.2 Hz, 1 H), 3.86 (dd, J=3.4, 10.2 Hz, 1 H), 3.75 (d, J=3.5 Hz, 1 H), 3.74 - 3.65 (m, 4H), 3.62 (dd, J=3.9, 14.0 Hz, 1 H), 3.59 - 3.51 (m, 2H), 3.55 (t, J=6.3 Hz, 2H), 3.50 - 3.44 (m, 1 H), 3.43 (dd, J=3.5, 9.8 Hz, 1 H), 3.38 (dd, J=7.5, 14.0 Hz, 1 H), 2.27 (t, J=7.4 Hz, 2H), 2.11 - 2.00 (m, 2H), 1.77 (p, J=7.1 Hz, 2H), 1.65 (br s, 2H), 1.29 - 1.13 (m, 4H), 1.15 (d, J=6.8 Hz, 3H). MS (FAB) 643 (M+H-Na), 620 (M+H), 598 (M+2H-Na). Example B6: Preparation of compound No. B1.6
Figure imgf000057_0001
14 B1.6
Dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.03 g) and the azide 14 (0.03 g, 0.03 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black mixture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 16 hours. The mixture is filtered through a cellulose filter (pore size 45 μm), and the filtrate is concentrated in vacuo. The residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, water, flow rate 0.55 ml/min, detection 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 7 cm, eluent: 25 % MeOH/H20), resulting in the target molecule B1.6 (0.011 g, 70 %) as a fluffy colourless solid (after lyo¬ phiiization). 1H NMR (500 MHz, D20) δ 4.93 (d, J=3.9 Hz, 1 H), 4.58 (q, J=6.7 Hz, 1 H), 4.48 (d, J=7.9 Hz, 1H), 4.22 (dd, J=3.7, 8.4 Hz, 1 H), 3.99 (d, J=3.1 Hz, 1 H), 3.86 (dd, J=3.3, 9.9 Hz, 1 H), 3.75 (d, J=3.3 Hz, 1H), 3.74 - 3.65 (m, 4H), 3.61 - 3.55 (m, 2H), 3.50 (dd, J=3.0, 9.3 Hz, 1H), 3.48 (m, 1H), 3.35 (dd, J=3.7, 12.9 Hz, 1 H), 3.16 (dd, J=8.5, 13.5 Hz, 1H), 2.10 - 2.00 (m, 2H), 1.65 (m, 2H), 1.29 - 1.15 (m, 4H), 1.14 (d, J=6.5 Hz, 3H); MS (FAB, THG) 510 (M-H). Example B7: Preparation of compound No. B1.7
Figure imgf000058_0001
B1.7
The amine B1.6 (0.09 g, 0.176 mmol) is dissolved in dry MeOH (1.5 ml) and CH2CI2 (1.8 ml) and activated 3A molecular sieves (about 0.2 g), cinnamaldehyde (24 μl, 0.19 mmol) and acetic acid (9 μl) are added. The yellowish suspension is stirred for 2 minutes and then NaBH3(CN) (0.018 g, 0.286 mmol) is added. After 1.5 hours, the mixture is filtered through a cellulose filter (pore size 45 μm), the filter is washed with 1 :1 MeOH/ CH2CI2, and the filtrate is concentrated in vacuo. The glassy residue is taken up in water (5 ml), and the solution is acidified (about pH 1-2) with 1 M hydrochloric acid (0.7 ml). The cloudy solution is again filtered through a cellulose filter (pore size 45 μm), and the filtrate is adjusted to pH 7 with 1 M sodium hydroxide solution (about 1 ml) and then concentrated. The residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.6 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 50 % MeOH/H20 to 70 % MeOH/ H20), resulting in the target molecule B1.7 (0.03 g, 27 %) as a fluffy white solid (after lyophi¬ iization). 1H NMR (500 MHz, D20) δ 7.48 (d, J=8.0 Hz, 2H), 7.41 - 7.31 (m, 3H), 6.83 (d, J=15.4 Hz, 1 H), 6.26 (dt, J=15.4, 7.0 Hz, 1 H), 4.92 (d, J=3.8 Hz, 1 H), 4.56 (q, J=6.3 Hz, 1H), 4.43 (d, J=7.6 Hz, 1H), 4.31 (dd, J=3.5, 8.2 Hz, 1H), 3.98 (d, J=3.0 Hz, 1H), 3.88 - 3.81 (m, 2H), 3.84 (d, J=6.0 Hz, 1 H), 3.76 - 3.63 (m, 5H), 3.60 - 3.51 (m, 2H), 3.49 (dd, J=3.0, 10.4 Hz, 1H), 3.49 - 3.41 (m, 1 H), 3.41 (dd, J=3.5, 13.2 Hz, 1 H), 3.26 (dd, J=8.5, 13.2 Hz, 1H), 2.02 (m, 2H), 1.64 (br s, 2H), 1.27 - 1.12 (m, 4H), 1.12 (d, J=6.3 Hz, 3H); MS (FAB, THG) 650 (M+Na), 628 (M+H). Example B8: Preparation of the compound No. B1.8
Figure imgf000059_0001
B1.8
A solution of the amino acid B1.7 (0.01 g, 0.0159 mmol) in 1 M aq. NaHC03 (0.1 ml) is cooled to 0°C and, while stirring vigorously, a 1 M solution of benzoyl chloride in benzene (16.0 μl) is added. After 40 minutes, a further 8.0 μl of the benzoyl chloride solution is added, after 130 minutes a further 3.0 μl and after a total of 3.5 hours a further 1.0 μl. After a total of 4 hours, the reaction mixture is diluted with water and extracted with CH2CI2 in order to remove the excess reagent. The aqueous phase is concentrated in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.49 ml/min, detection at 215 nm) and subse¬ quent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 60 % MeOH/ H20 to 70 % MeOH/H20), resulting in the target molecule B1.8 (7.9 mg, 66 %) as a fluffy white solid (after lyophiiization). 1H NMR (500 MHz, D20): 1.4:1 mixture of rotamers, charac¬ teristic signals: δ 7.52 - 7.24 (m, 10H, 2xPh), 6.71 (d, J=15.5 Hz, 0.42H, PhCH=CH), 6.42 (dt, J=15.5, 6.1 Hz, 0.42H, PhCH=CH), 6.39 (d, J=15.5 Hz, 0.58H, PhCH=CH), 6.13 (dt, J=15.5, 5.6 Hz, 0.58H, PhCH=CH), 4.92 (d, J=4.0 Hz, 1 H, Fuc-1 H), 1.16 (d, J=7.0 Hz, 1.26H, Fuc-6H), 1.11 (d, J=6.8 Hz, 1.74H, Fuc-6H); MS (FAB, THG) 776 (M+Na), 754 (M+H). Example B9: Preparation of compound No. B1.9 and No. B1.10
Figure imgf000060_0001
B1.9
B1.10
A CH2CI2 solution of freshly distilled benzaldehyde (0.083 g in 1.0 ml CH2CI2, 0.1 ml, 0.078 mmol), activated 3A molecular sieves (0.1 g) and glacial acetic acid (5 μl, 0.087 mmol) are added to a solution of the amino acid B1.6 (0.04 g, 0.078 mmol) in MeOH/ CH2CI2 (1 :1 , 1.0 ml). The suspension is stirred at room temperature and, after 2 minutes, NaBH3(CN) (0.008 g, 0.129 mmol) is added. After 2.5 hours, a further 15 μl of the benzalde¬ hyde solution are added, and the mixture is stirred for a further hour. The reaction mixture is diluted with water, acidified with dilute acetic acid and filtered through a cellulose filter (pore size 45 μm), and the filtrate is adjusted to pH 8-9 with 1 M aqueous NaHC03 solution and then concentrated. The residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 35 % MeOH/H20 to 60 % MeOH/H20), with elution first of the monobenzylamine B1.9 (0.020 g, 41 %) and then of the dibenzylamine B1.10 (0.005 g, 9 %). Monobenzylamine B1.9: 1H NMR (500 MHz, D20) δ 7.45 (s, 5H), 4.93 (d, J=4.0 Hz, 1H), 4.57 (q, J=6.7 Hz, 1 H), 4.45 (d, J=7.6 Hz, 1 H), 4.33 (dd, J=3.8, 8.8 Hz, 1 H), 4.28 (d, J=13.3 Hz, 1 H), 4.24 (d, J=13.3 Hz, 1 H), 3.99 (d, J=3.1 Hz, 1 H), 3.85 (dd, J=3.5, 10.2 Hz, 1 H), 3.74 - 3.65 (m, 5H), 3.59 - 3.54 (m, 2H), 3.49 (dd, J=3.2, 9.7 Hz, 1H), 3.48 - 3.44 (m, 1 H), 3.42 (dd, J=3.7, 13.2 Hz, 1 H), 3.26 (dd, J=8.9, 13.2 Hz, 1H), 2.04 (m, 2H), 1.65 (br s, 2H), 1.28 - 1.14 (m, 4H), 1.12 (d, J=6.7 Hz, 3H); MS (FAB, THG) 624 (M+Na), 602 (M+H). Dibenzylamine B1.10: 1H NMR (500 MHz, D20): the signals of the 6 H α to the N are very broad at room temperature (d 4.10 - 3.60, 4H and 3.12 - 2.67, 2H) δ 7.38 (s, 10H), 4.93 (d, J=4.0 Hz, 1 H), 4.60 (q, J=6.6 Hz, 1 H), 4.43 (d, J=8.0 Hz, 1 H), 4.23 (dd, J=3.6, 8.5 Hz, 1 H), 3.88 - 3.83 (m, 2H), 3.75 - 3.63 (m, 5H), 3.56 (dd, J=8.0, 9.3 Hz, 1 H), 3.53 - 3.44 (m, 2H), 3.32 (dd, J=3.0, 9.5 Hz, 1 H), 2.13 - 1.98 (m, 2H), 1.66 (br s, 2H), 1.31 - 1.10 (m, 4H), 1.14 (d, J=6.6 Hz, 3H); MS (FAB, THG) 714 (M+Na), 692 (M+H).
Example B10: Preparation of compounds No. B1.11 and No. B1.12
B1
Figure imgf000061_0001
B1.11
B1.12
A 1 M CH2CI2 solution of isobutyraldehyde (0.156 ml), activated 3A molecular sieves (0.2 g) and glacial acetic acid (10 μl, 0.17 mmol) are added to a solution of the amino acid B1.6 (0.08 g, 0.156 mmol) in MeOH/ CH2CI2 (1 :1 , 2.0 ml). The suspension is stirred at room tem¬ perature and, after one minute, NaBH3(CN) (0.016 g, 0.258 mmol) is added. After 60 minutes, the reaction mixture is diluted with water and filtered through a cellulose filter (pore size 45 μm), and the filtrate is adjusted to pH 8-9 with 1 M aqueous NaHC03 solution and then concentrated. The residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 35 % MeOH/H20 to 50 % MeOH/H20), with elution first of the monoisobutylamine B1.11 (0.041 g, 46 %) and then of the diisobutylamine B1.12 (0.01 g, 10 %). Monoisobutylamine B1.11 : 1H NMR (500 MHz, D20) δ 4.92 (d, J=4.0 Hz, 1H), 4.59 (q, J=6.7 Hz, 1H), 4.47 (d, J=7.6 Hz, 1 H), 4.29 (dd, J=4.0, 9.0 Hz, 1H), 3.98 (d, J=3.5 Hz, 1H), 3.85 (dd, J=3.3, 10.0 Hz, 1H), 3.76 - 3.65 (m, 5H), 3.56 (dd, J=7.5, 9.3 Hz, 1 H), 3.59 - 3.54 (m, 1H), 3.50 (dd, J=3.0, 9.7 Hz, 1H), 3.50 - 3.43 (m, 1H), 3.34 (dd, J=3.9, 13.0 Hz, 1H), 3.20 (dd, J=9.2, 13.2 Hz, 1 H), 2.90 (dd, J=7.6, 12.0 Hz, 1 H), 2.86 (dd, J=7.3, 12.0 Hz, 1H), 2.11 - 1.99 (m, 2H), 1.96 (non, J=6.9 Hz, 1 H), 1.65 (m, 2H), 1.28 - 1.11 (m, 4H), 1.14 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 6H); MS (FAB, THG) 590 (M+Na), 568 (M+H). Diisobutylamine B1.12: 1H NMR (500 MHz, D20) δ 4.92 (d, J=4.1 Hz, 1 H), 4.59 (q, J=6.7 Hz, 1H), 4.46 (d, J=7.1 Hz, 1 H), 4.36 (t, J=6.6 Hz, 1 H), 4.02 (br s, 1 H), 3.85 (dd, J=3.3, 10.3 Hz, 1 H), 3.76 - 3.66 (m, (m, 5H), 3.57 (dd, J=4.7, 7.5 Hz, 1 H), 3.55 - 3.50 (m, 2H), 3.49 - 3.39 (m, 3H), 3.07 (br s, 4H), 2.12 (non, J=6.8 Hz, 2H), 2.12 - 1.99 (m, 2H), 1.65 (br s, 2H), 1.28 - 1.11 (m, 4H), 1.13 (d, J=6.7 Hz, 3H), 0.97 (d, J=6.8 Hz, 12H); MS (FAB, THG) 646 (M+Na), 624 (M+H).
Example B11 : Preparation of compound No. B1.13
Figure imgf000062_0001
B1.13
A 1 M solution of benzoyl chloride in toluene (41 μl) is added at room temperature to a solu¬ tion of the amino acid B1.11 (0.020 g, 0.0339 mmol) in 1 M aqueous NaHC03 (100 μl). The mixture is stirred vigorously and, after 1 hour, further benzoyl chloride (41 μl of the 1 M solu¬ tion) is added. After the reaction is complete, the volatile constituents are removed under high vacuum, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: 45 % MeOH/H20) and then lyophilized, resulting in the benzamide B1.13 as a fluffy powder, (0.014 g, 59 %). 1H NMR (500 MHz, D20): 1:1 rotamer mixture: δ 7.50 - 7.37 (m, 5H), 4.93 (d, J=4.0 Hz, 0.5H), 4.92 (d, J=4.0 Hz, 0.5H), 4.60 (q, J=6.4 Hz, 1H), 4.48 (d, J=8.0 Hz, 0.5H), 4.37 (d, J=8.0 Hz, 0.5H), 4.32 (dd, J=4.5, 8.0 Hz, 0.5H), 4.02 (dd, J=4.3, 8.7 Hz, 0.5H), 3.94 (d, J=3.2 Hz, 0.5H), 3.89 - 3.83 (m, 1.5H), 3.82 - 3.61 (m, 7H), 3.60 - 3.52 (m, 1.5H), 3.51 - 3.43 (m, 2.5H), 3.25 (dd, J=7.9, 14.2 Hz, 0.5H), 3.20 (dd, J=7.9, 14.2 Hz, 0.5H), 3.17 - 3.10 (m, 1 H), 2.16 - 1.97 (m, 2.5H), 1.86 (non, J=6.9 Hz, 0.5H), 1.65 (br s, 2H), 1.29 - 1.14 (m, 4H), 1.17 (d, J=6.4 Hz, 1.5H), 1.11 (d, J=6.6 Hz, 1.5H), 0.95 (d, J=6.5 Hz, 1.5H), 0.92 (d, J=6.6 Hz, 1.5H), 0.65 (d, J=6.4 Hz, 1.5H), 0.65 (d, J=6.5 Hz, 1.5H); MS (FAB, THG) 716 (M+Na), 694 (M+H).
Example B12: Preparation of compound No. B1.14
Figure imgf000063_0001
B1.14
A 1 molar solution of p-nitrobenzenesulfonyl chloride in toluene (43 μl) is added with vigorous stirring to a solution of the amino acid B1.6 (0.02 g, 0.039 mmol) in 1 molar aqueous NaHC03 solution (0.2 ml). The reaction mixture is stirred at room temperature for 16 hours and then concentrated in vacuo. The residue is taken up in water (0.3 ml) and purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm). The crude product (0.025 g) is further purified by two reverse phase chromatographies (Merck RP18 silica gel, 1st chromatography: elution with 50 % MeOH/H20; 2nd chromatography: elution with 40 % MeOH/H20) and subsequently lyophilized, resulting in the target compound as a fluffy powder (0.0105 g, 39 %). 1H NMR (400 MHz, D20) δ 8.39 (m, 2H), 8.07 (m, 2H), 4.93 (d, J=4.0 Hz, 1 H), 4.56 (q, J=6.6 Hz, 1 H), 4.43 (d, J=7.9 Hz, 1 H), 3.96 (dd, J=3.5, 7.1 Hz, 1 H), 3.88 - 3.83 (m, 2H), 3.76 - 3.64 (m, 5H), 3.54 - 3.44 (m, 3H), 3.38 (dd, J=3.5, 13.7 Hz, 1 H), 3.33 (dd, J=3.2, 9.6 Hz, 1 H), 3.19 (dd, J=7.3, 13.7 Hz, 1 H), 2.05 (br t, J=13.4 Hz, 2H), 1.66 (br s, 2H), 1.30 - 1.12 (m, 4H), 1.14 (d, J=6.6 Hz, 3H); MS (FAB, THG) 719 (M+Na), 697 (M+H). Example B13: Preparation of compound No. B1.15
Figure imgf000064_0001
B1.15
A 1 molar solution of p-toluenesulfonyl chloride in toluene (22 μl) is added at 0°C with vigorous stirring to a solution of the amino acid B1.6 (0.01 g, 0.02 mmol) in 1 molar aqueous NaHC03 solution (0.1 ml). The reaction mixture is stirred at 0°C for 90 minutes, after which further p-toluenesulfonyl chloride (10 μl of the 1 M solution) is added. The reac¬ tion mixture is then warmed to room temperature, stirred for 18 hours and then concentra¬ ted in vacuo. The residue is taken up in water and purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution with 45 % MeOH/H20) and subsequently lyophilized, resulting in the target compound as a fluffy powder (0.004 g, 30 %). 1H NMR (400 MHz, D20) δ 7.69 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 4.88 (d, J=3.9 Hz, 1 H), 4.52 (q, J=6.6 Hz, 1 H), 4.35 (d, J=7.9 Hz, 1H), 3.85 - 3.78 (m, 2H), 3.74 (d, J=2,8 Hz, 1H), 3.71 - 3.56 (m, 5H), 3.50 - 3.39 (m, 3H), 3.29 (dd, J=3.4, 13.8 Hz, 1H), 3.10 (dd, J=3.1 , 9.6 Hz, 1 H), 3.03 (dd, J=8.0, 13.8 Hz, 1 H), 2.34 (s, 3H), 2.08 - 1.93 (m, 2H), 1.61 (br s, 2H), 1.26 - 1.07 (m, 4H), 1.09 (d, J=6.6 Hz, 3H). Example B14: Preparation of compound No. B1.16
Figure imgf000065_0001
24 B1.16
Pentafluorophenyl trifluoroacetate (4.5 ml, 0.026 mmol) is added at room temperature with stirring to a solution of the isoserine derivative 16 (0.025 g, 0.026 mmol) and triethylamine (0.7 ml, 0.005 mmol) in DMF (100 ml). After 15 min, further pentafluorophenyl trifluoro¬ acetate (2.5 ml, 0.015 mmol) is added. 30 minutes later, further triethylamine (2.8 ml, 0.02 mmol) and pentafluorophenyl trifluoroacetate (4.5 ml, 0.026 mmol) are added. The same amount of the latter reagent is added once again 20 minutes later. The mixture is stirred for a further 45 minutes and then saturated aqueous NaHC03 solution (0.2 ml) is added, and the mixture is diluted with water and extracted several times with ethyl acetate. The combined organic phases are dried (Na2S04), filtered and concentrated in vacuo. The crude product (0.04 g) is purified by flash chromatography on silica gel as eluent: ethyl acetate/toluene 1 :3), resulting in the trifluoroacetamide 24 (0.022 g, 83 %). Deprotection of 24: dioxane (1.4 ml), water (0.7 ml) and glacial acetic acid (0.35 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20 %, 0.02 g) and the benzyl ether 24 (0.021 g, 0.021 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black mixture is hydrogenated under slightly elevated pressure for 3.5 hours. The reaction mixture is filtered through a cellulose filter (pore size 45 μm), and the filtrate is concentrated in vacuo. A solution of the residue in a little water is passed through an ion exchanger column (Dowex 50, Na+ form, column dia¬ meter 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm) and subse¬ quent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 7 cm, gradient elution: 30 % MeOH/H20 to 40 % MeOH/H20), resulting in the target molecule B1.16 (0.0085 g, 68 %) as a fluffy colourless solid (after lyophiiization). H NMR (500 MHz, D20) δ 4.93 (d, J=3.9 Hz, 1 H), 4.59 (q, J=6.5 Hz, 1 H), 4.45 (d, J=8.2 Hz, 1 H), 4.08 (dd, J=3.4, 8.2 Hz, 1 H), 3.91 (d, J=3.1 Hz, 1 H), 3.86 (dd, J=3.1 , 10.0 Hz, 1 H), 3.75 (d, J=3.1 Hz, 1 H), 3.72 (dd, J=3.9, 10.0 Hz, 1 H), 3.73 - 3.65 (m, 4H), 3.61 - 3.50 (m, 3H), 3.50 - 3.44 (m, 1 H), 3.42 (dd, J=3.1 , 9.6 Hz, 1 H), 2.10 - 2.00 (m, 2H), 1.65 (m, 2H), 1.28 - 1.15 (m, 4H), 1.14 (d, J=6.5 Hz, 3H); MS (FAB, THG) 652 (M+Na), 630 (M+H), 608 (M+2H-Na).
Example B15: Preparation of compound No. B1.17
Figure imgf000066_0001
26 B1.17
(a) Preparation of the amide 26. Diisopropylcarbodiimide(17 ml, 0.11 mmol) is added at room temperature with stirring to a mixture of the amine 16 (0.027 g, 0.028 mmol), cyclo- hexanecarboxylic acid (0.011 g, 0.086 mmol), 1 -hydroxybenzotriazole (0.021 g,
0.155 mmol) and dry THF (0.9 ml). After 20 minutes, dry DMF (0.4 ml) is added, and the mixture is stirred for a further hour. The reaction mixture is concentrated in vacuo, and the remaining DMF removed under high vacuum. The residue is purified by flash chromatogra¬ phy on silica gel (CH2CI2/isopropanol 39:1), resulting in the amide 26 (0.024 g, 80 %).
(b) Deprotection of 26: dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.03 g) and the benzyl ether 26 (0.024 g, 0.022 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black mixture is hydrogenated under slightly elevated pressure for 18 hours. The reaction mixture is filtered through a cellulose filter (pore size 45 μm), and the filtrate is concentrated in vacuo. A solution of the residue in a little water is passed through an ion exchanger column (Dowex 50, Na+ form, column diameter 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μm , column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH/H2O 3:2), resulting in the target molecule B1.17 (0.008 g, 56 %) as a fluffy colourless solid (after lyophiiization). H NMR (500 MHz, D20) δ 4.93 (d, J=4.0 Hz, 1 H), 4.60 (q, J=6.7 Hz, 1 H), 4.47 (d, J=8.0 Hz, 1 H), 4.04 (dd, J=3.8, 7.5 Hz, 1H), 3.92 (d, J=2.8 Hz, 1 H), 3.86 (dd, J=3.2, 10.3 Hz, 1H), 3.75 (d, J=3.3 Hz, 1H), 3.74 3.64 (m, 4H), 3.61 (dd, J=3.8, 13.8 Hz, 1 H), 3.59 - 3.52 (m, 2H), 3.50 - 3.44 (m, 1 H), 3.42 (dd, J=3.3, 9.8 Hz, 1H), 3.35 (dd, J=7.7, 14.0 Hz, 1H), 2.19 (tt, J=3.3, 11.5 Hz, 1H), 2.11 - 2.00 (m, 2H), 1.78 - 1.57 (m, 7H), 1.34 - 1.08 (m. 9H), 1.15 (d, J=6.5 Hz, 3H); MS (FAB, THG) 644 (M + H), 622 (M+ 2H - Na).
Example B16: Preparation of the compound B1.18
Figure imgf000067_0001
30
A solution of the triol 13 (0.129 g, 0.17 mmol) in dry MeOH (4.0 ml) and di-n-butyltin oxide (0.064 g, 0.258 mmol) is boiled under reflux in an argon atmosphere for 2 hours. The clear solution is concentrated in vacuo, and the residue is mixed with pentane (2 ml), again con¬ centrated and then dried under high vacuum for 30 minuten in order to remove remaining MeOH. The residue is mixed under an argon atmosphere with dry CsF (0.131 g, 0.86 mmol, weighed under argon) and dry 1 ,2-dimethoxyethan (0.5 ml) followed by a solution of benzyl (R)-4-phenyl-2-trifluoromethanesulfonyloxybutyrate (A2) (0.3 g, 0.861 mmol) in dry 1 ,2-di- methoxyethane (1.0 ml). The reaction mixture is stirred at room temperature for 75 minutes and 1 M of aqueous KH2P0 is added, and the mixture is diluted with water and extracted with ethyl acetate (phase separation is facilitated by adding a little aqueous KF solution). The organic extracts are combined, dried with Na2S04, filtered and concentrated in vacuo, resulting in the crude product as an oil (0.39 g). Purification by flash chromatography on silica gel (eluent: toluene/ethyl acetate 5:1) results in the pure ether 30 (0.143 g, 81 %). 1H NMR (250 MHz, CDCI3) δ 7.35 - 7.05 (m, 30H), 5.13 (d, J=12.1 Hz, 1 H), 5.03 (d, J=12.1 Hz, 1 H), 4.88 (d, J=11.4 Hz, 1 H), 4.87 (d, J=2.0 Hz, 1 H), 4.78 - 4.50 (m, 5H), 4.46 (d, J=12,5 Hz, 1 H), 4.40 (d, J=12.5 Hz, 1 H), 4.33 (q, J=6.5 Hz, 1 H), 4.24 (d, J=7.8 Hz, 1 H), 4.09 (dd, J=4.0, 8.5 Hz, 1 H), 3.93 (br s, 2H), 3.80 - 3.38 (m, 7H), 3.26 - 3.17 (m, 2H), 2.86 - 2.62 (m, 2H), 2.59 (d, J=2.0 Hz, 1 OH), 2.29 (br s, 1 OH), 2.11 - 1.85 (m, 4H), 1.67 - 1.52 (m, 2H), 1.40 - 1.06 (m, 4H), 1.03 (d, J=6.5 Hz, 3H).
Figure imgf000068_0001
B1.18
The benzyl ether 30 (0.14 g, 0.135 mmol) is dissolved in dioxane (4 ml) and water (2 ml), glacial acetic acid (1 ml) and 20% Pd(OH)2/C (0.14 g) are added.The air in the reaction vessel is replaced initially by argon, by evacuation and flushing several times, and then by hydrogen. The black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen for 90 minutes and then filtered through a cellulose filter (pore size 45 μm), washing with water. The filtrate is concentrated, and the residue is taken up in toluene and concentrated several times in order to remove remaining acetic acid. The crude product (0.095 g) is dissolved in a little water and filtered through a DowexδO (Na+) ion exchanger column. The filtrate is freeze-dried and the residue (0.085 g) is purified by reverse phase chromatography (Merck RP18 silica gel, elution: 40 % MeOH/H20) and subsequent gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and then lyophilized, resulting in the target compound B1.18 as a fluffy powder (0.045 g, 55 %). 1H NMR (500 MHz, D20) δ 7.35 - 7.27 (m, 4H), 7.22 (tt, J=1.5, 7.0 Hz, 1H), 4.93 (d, J=4.0 Hz, 1H), 4.60 (q, J=6.7 Hz, 1 H), 4.47 (d, J=7.8 Hz, 1 H), 3.89 - 3.82 (m, 3H), 3.76 (d, J=3.5 Hz, 1 H), 3.74 - 3.63 (m, 4H), 3.59 - 3.52 (m, 2H), 3.51 - 3.45 (m, 1H), 3.37 (dd, J=3.5, 9.8 Hz, 1H), 2.80 - 2.68 (m, 2H), 2.12 - 1.99 (m, 3H), 1.98 - 1.89 (m, 1 H), 1.65 (br s, 2H), 1.30 - 1.13 (m, 4H), 1.15 (d, J=6.6 Hz, 3H); MS (FAB, THG) 609 (M+Na), 587 (M+H).
Example B17: Preparation of the compound No. B1.19
Figure imgf000069_0001
B1.19
The aromatic compound B1.18 (0.02 g, 0.033 mmol) is dissolved in water (1.8 ml), dioxane (1.2 ml), glacial acetic acid (0.3 ml), and 5% Rh/Al203 (0.04 g) is added. The air in the reac¬ tion vessel is replaced by hydrogen by evacuation and flushing several times, and the mix¬ ture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 1.5 days. It is then filtered through a cellulose filter (pore size 45 μm) and washed with water, the filtrate is concentrated, and the residue is taken up in toluene and concentrated several times in order to remove remaining acetic acid. The crude product is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and then hydrogenated again under the above conditions for 2 days. The reaction mixture is then filtered through a cellulose filter (pore size 45 μm) and washed with water, and the filtrate is concentrated, after which the residue is taken up in toluene and concentrated several times. The crude product is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: 50 % MeOH/H20) and subsequently lyophi¬ lized, resulting in the target compound B1.19 as a fluffy powder (0.01 g, 50 %). 1H NMR (250 MHz, D20) δ 4.83 (d, J=4.0 Hz, 1 H), 4.48 (q, J=6.7 Hz, 1 H), 4.35 (d, J=7.8 Hz, 1 H), 3.81 - 3.69 (m, 3H), 3.67 - 3.53 (m, 5H), 3.49 - 3.31 (m, 3H), 3.25 (dd, J=3.1 , 9.7 Hz, 1 H), 2.03 - 1.87 (m, 2H), 1.72 - 1.38 (m, 9H), 1.24 - 0.97 (m, 10H), 1.04 (d, J=6.6 Hz, 3H), 0.75 (br s, 2H); MS (FAB, THG) 615 (M+Na), 593 (M+H).
Example B18: Preparation of the compound B1.38
Figure imgf000070_0001
B1.38
A solution of p-nitrobenzenesulfonyl chloride in toluene (1 M, 150μl) is added to a solution of amino acid B1.11(0.035 g, 0.0617 mmol) in 1 molar aqueous NaHC03 solution (315 μl). The mixture is vigorously stirred at room temperature and, after 17 hours, further p-nitro¬ benzenesulfonyl chloride solution (120 μl) is added. The reaction mixture is stirred for a further 24 hours, then diluted with water and washed twice with ethyl acetate. The aqueous phase is concentrated to a volume of 0.5 ml in vacuo, and this solution is purified by gel fil¬ tration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm). The crude product (0.06g) is then further purified by reverse phase chromatography three times (Merck RP 18 silica gel, elution: 40% MeOH/H20) and then lyophilized, resulting in the sulfonamide B1.38 (0.013 g, 27%) as a colourless fluffy powder. 1H NMR (400 MHz, D20) δ 8.34 (m,2H), 8.05(m, 2H), 4.88 (d, J=4.0Hz, 1 H), 4.53 (q,J=6.5Hz, 1 H), 4.38 (d, J=7.9 Hz, 1 H) 4.06 (dd, J=3.9, 8.2 Hz, 1 H) 3.84-3.79 (m, 2H), 3.70 (d, J=3.0 Hz, 1H), 3.67 (dd, J=3.9, 10.4 Hz, 1 H), 3.69 - 3.58 (m, 3H), 3.57 - 3.38 (m, 5H) 3.25 (dd, J=3.2, 9.5 Hz, 1 H) 3.10 (dd, J=7.7, 14.1 Hz, 1 H) 3.05 (dd, J=7.7, 14.1 Hz, 1 H), 2.07-1.94 (m, 2H) 1.89 (hep, J=6.7 Hz, 1 H), 1.61 (br s, 2H), 1.25 -1.07 (m, 4H), 1.10 (d, J=6.6 Hz, 3H) 0.70 (d, J=6.6 Hz, 3H), 0.63 (d, J=6.6Hz, 3H).
The following compounds are prepared in analogy to the above examples: Table 1 :
Figure imgf000071_0001
Preparation Compound No. R3 R4 FAB-MS according to THG
Example No.
B15 B1.20 Na CH2NHC(0)CnH23 716(M+H) .738(M+Na)
B15 B1.21 Na 728(M+H)
CH2NHC(0)CH(C6H5)2 750(M+Na)
B12(1) B1.22 Na CH2NHC(0)C2H4C02Na 656( +H) 678(M+Na)
B15 B1.23 Na CH2NHC(0)C6[(1 ,3,4,5)OH]4H7 708(M+H) quinamide 730(M+Na)
B15 B1.24 Na CH2NHC(0)C6H4 -p-S03Na 7 0(M+H) 762( +Na)
B12 B1.25 Na CH2NHC(0)C6H4CI 672(M+H) 694(M+Na)
B12 B1.26 Na CH2NHC(0)C6H4N02 683(M+H) 705(M+Na)
B12 B1.27 Na CH2NHC(0)C6H4OCH3 668(M+H) 690(M+Na)
B12 B1.28 Na CH2NHC(0)C6H4(3,4)CI2 706(M+H) 728(M+Na)
B12 B1.29 Na CH2NHC(0)C6H4CH3 652( +H) 67 (M+Na)
B12(2' B1.30 Na CH2NHC(0)C6H4C6H5 714( +H) 736(M+Na) Preparation Compound No. R3 R4 FAB-MS according to THG
Example No.
B12(3) B1.31 Na CH2NHC(0)C6H4CN 663( +H) 685(M+Na)
B12 B1.32 Na CH2NHC(O)C10H7 688(M+H) 710( +Na)
B12(4» B1.33 Na CH2NHC(0)C6H4COONa 7<M(M+H) 726( +Na)
B1 2(5) B1.34 Na CH2NHC(0)(CHOH)2COONa 688(M+H) 710( +Na)
B1.35 Na 728( +H)
B11 CH2N[C(0)C6H5]CH2C6H5 750(M+Na)
B11 B1.36 Na CH2N[C(0)C6H5](CH2)3C6H5 756( +H) 778(M+Na)
B15(6) B1.37 Na CH2NHS02CF3 666.M+H) 688(M+Na)
(1) using a solution of succinic anhydride in DMF as reagent
( ) using a solution of pentafluorophenyl biphenylcarboxylate in dioxane as reagent
(3) using a solution of pentafluorophenyl p-cyanobenzoate in dioxane as reagent
(4) using a solution of methyl pentafluorophenyl terephthalate in dioxane as reagent. After completion of amide formation, 1 M aqueous NaOH is added to the reaction mixture, which is heated at 65°C until hydrolysis of the methyl ester is complete.
(5) 1 M NaOH is used in place of 1 M NaHC03. A solution of (+)-di-0-acetyl-L-tartaric an¬ hydride in dioxane is used as reagent.
(6)The formation of the amide takes place in CH2CI2 at 0°C using trifluoromethanesulfonic anhydride as reagent. Example B19: Preparation of compound No. B1.39
Figure imgf000073_0001
13 A3 31
A suspension of 13 (0.086 g, 0.11 mmol) and di-n-butyltin oxide (0.05 g, 0.19 mmol) in dry benzene (3.3 ml) is boiled under reflux in an argon atmosphere for 12 hours. The reaction mixture is concentrated in vacuo and dried under high vacuum for one hour. Then CsF (dried under high vacuum at 300°C for several hours, 0.042 g, 0.274 mmol) is added under an argon atmosphere, followed by dry 1 ,2-dimethoxyethane (0.6 ml) and a solution of triflate A3 (0.25 g, 0.66 mmol) in dry 1 ,2-dimethoxyethane (0.4 ml). The reaction mixture is heated to 35 to 40°C and stirred at this temperature for 5 hours. Then a solution of 15% KF in 1 M aqueous KH2P0 solution (30 ml) is added, and the mixture is extracted three times with CH2CI2, and the combined organic phases are dried (Na2S04), filtered and concentrated in vacuo. The oily residue (0.16 g) is purified by column chromatography on silica gel (gradient elution: toluene/ethyl acetate 80:20 to 75:25, then CH2CI2/Me0H 19:1), resulting in the ether 31 (0.049 g, 44 %) as a colourless foam and the precursor 13 (0.035 g, 40 %).
Figure imgf000073_0002
Dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.028 g) and the benzyl ether 31 (0.048 g, 0.047 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly ele¬ vated pressure of hydrogen at room temperature for 17 hours and then filtered through a cellulose filter (pore size 45 μm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a DowexδO ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.5 cm) washing with deionized water. The clear filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 230 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution with 7:3 H20/methanol), resulting in the target molecule B1.39 (0.014 g, 51 %) as a fluffy white solid (after lyophiiization): 1H NMR (400 MHz, D20) δ 4.83 (d, J=4.0 Hz, 1 H), 4.49 (q, J=6.6 Hz, 1 H), 4.33 (d, J=7.7 Hz, 1 H), 3.74 (d, J=3.1 Hz, 1 H), 3.22 (dd, J=2.6, 9.5 Hz, 1 H); 13C NMR (100.6 MHz, D20) δ 181.5 (Cq), 100.2 (CH), 95.7 (CH); MS (FAB, THG) 609 (M+Na), 587 (M+H).
Example B20: Preparation of compound B1.40
Figure imgf000074_0001
13 A4 32
The coupling of the alcohol 13 with the triflate A4 is carried out in accordance with Example B19 (preparation of compound 31).
Figure imgf000075_0001
32 B1.40
The hydrogenation of the benzyl ether and subsequent purification is carried out in accordance with Example B19 (preparation of compound B1.39): 1H NMR (400 MHz, D20) δ 4.88 (d, J=4.1 Hz, 1 H), 4.53 (q, J=6.7 Hz, 1 H), 4.39 (d, J=7.7 Hz, 1 H), 3.29 (dd, J=2.9, 9.8 Hz, 1 H), 1.10 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H), 0.82 (d, J=6.8 Hz, 3H).
Example B21 : Preparation of compound B1.41
Figure imgf000075_0002
33 34
The hydroxypiperidine (6.0 g, 34.6 mmol, prepared from D-(-)-lyxose in accordance with lchikawa and Igarashi [lchikawa, Y., Igarashi, Y., Tetrahedron Letters 36:4585-4586 (1995)] and triethylamine (18.1 ml, 130 mmol) are dissolved in dry tetrahydrofuran (100 ml) and the solution is cooled to -10°C under an argon atmosphere. Allyl chloroformate (3.87 ml, 36.4°mmol) is slowly added over the course of one hour, a white suspension being formed. The reaction mixture is stirred at -10°C for a further hour, then 1 M aqueous KH2P0 solution (150 ml) is added, and the mixture is extracted three times with CH2CI2. The combined organic phases are dried (Na2S04) and concentrated in vacuo, resulting in a yellow oil (9 g). Purification by column chromatography on silica gel (hexane/ethyl acetate 1 :1) results in the allyl carbamate 34 (7.66 g, 86 %).
Figure imgf000076_0001
34 35
4A molecular sieves (dried under high vacuum at 300°C, 15 g) are added to a solution of the acceptor 34 (7.66 g, 29.8 mmol) in dry CH2CI2 (150 ml) under an argon atmosphere, and the suspension is stirred at room temperature for one hour. In parallel with this, a suspen¬ sion of DMTST (15.4 g, 59.6 mmol) and 4A molecular sieves (15 g) in dry CH2CI2 (150 ml) is prepared under an argon atmosphere in a second round-bottom flask and is stirred for one hour. The DMTST mixture is then added in 4 portions over the course of a further hour to the solution of the acceptor, and the mixture is then stirred for one hour. The reaction mix¬ ture is filtered through Hyflo Super Cel® washing thoroughly with CH2CI2. The filtrate is ex¬ tracted by shaking with 10% aqueous NaHC03 solution, the aqueous phase is reextracted three times with CH2CI2, and the combined organic phases are dried (Na2S0 ), filtered and concentrated in vacuo. The remaining yellow oil (36 g) is purified by column chromatogra¬ phy on silica gel (gradient elution: hexane/ethyl acetate 3:1 to 3:2), resulting in the glycoside 35 (13.1 g, 54 %).
Figure imgf000076_0002
35 36
The acetonide 35 (13.1 g, 15.94 mmol) is dissolved in dioxane (140 ml) and, at room tem¬ perature 50 % aqueous trifluoroacetic acid (250 ml) is added. After 2 hours, the reaction mixture is concentrated under high vacuum, and the residue is purified by column chroma¬ tography on silica gel (ethyl acetate/hexane 2:1), resulting in the diol 36 (11, 23 g, 90 %).
Figure imgf000077_0001
37
A mixture of the diol 36 (11.63 g, 14.88 mmol), tetra-t.-butylammonium bromide (12.7 g, 39.4 mmol) and 4A molecular sieves (dried under high vacuum at 300°C 22 g) is dried under high vacuum for 30 minutes and then, under an argon atmosphere, dry CH2CI2 (62 ml) and dimethylformamide (36 ml) are added. The grey suspension is stirred at room temperature for 30 minutes. In parallel with this, a solution of ethyl -2,3,4-tri-O-benzyl- 1 -thio-L-fucopyranoside (7.48 g, 15.62 mmol, prepared by the method of Lonn [Lonn, H. Carbohydr. Res. 139:105-113 (1985)] in dry CH2CI2 (49 ml) is prepared under an argon atmosphere in a second round-bottomed flask and, at 0°C, a bromine solution (2.85 g Br2, 17,84 mmol) in CH2CI2 (25 ml) is added. The red solution is stirred at 0°C for 30 minutes, and the excess bromine is destroyed by adding a few drops of cyclohexene. This solution is then added using a needle to the solution of the acceptor, and the reaction mixture is stirred at room temperature for 40 hours. The reaction mixture is then filtered through Hyflo Super Cel® and thoroughly washed with CH2CI2, and the filtrate is washed with 10 % aqueous NaHC03 solution. The aqueous phase is reextracted three times with CH2CI2, and the com¬ bined organic phases are dried (Na2S04), filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel (ethyl acetate/hexane 35:65), with the required product 37 (7.85 g, 44 %) being eluted.
Figure imgf000078_0001
37 38
A solution of the ester 37 (2.4 g, 2.0 mmol) and sodium methoxide (0.11 g, 2.0 mmol) in methanol (48 ml) is stirred at room temperature for 8 hours. The clear colourless solution is then neutralized by adding a strongly acidic ion exchanger (Amberlyst15), then filtered through Hyflo Super Cel® and concentrated in vacuo. The oily residue is purified by column chromatography on silica gel (gradient elution: CH2CI2/methanol 98:2 to 95:5), resulting in the triol 38 (1.72 g, 97 %).
Figure imgf000078_0002
38 39
A suspension of 38 (1.0 g, 1.13 mmol) and di-tj-butyltin oxide (0.49 g, 1.98 mmol) in dry benzene (33 ml) is boiled under reflux in an argon atmosphere for 5 hours. The reaction mixture is concentrated in vacuo and dried under high vacuum for one hour. Then CsF (dried under high vacuum at 300°C for several hours, 0.43 g, 2.82 mmol) is added under an argon atmosphere, followed by dry 1 ,2-dimethoxyethane (7.4 ml) and a solution of benzyl f?-3-phenyl-2-trifluoromethanesulfonyloxypropionate (2.6 g, 6.77 mmol) in dry 1 ,2-di- methoxyethane (4.9 ml). The reaction mixture is heated to 35 to 40°C and stirred at this temperature for 3 hours. Then a solution of 15% KF in 1 M aqueous KH2P04 solution (100 ml) is added, and the mixture is extracted three times with CH2CI2, and the combined organic phases are dried (Na2S0 ), filtered and concentrated in vacuo. The oily residue (3.2 g) is purified by column chromatography on silica gel (elution: toluene/ethyl acetate 70:30), resulting in the ether 39 (0.98 g, 78 %) as a colourless foam.
Figure imgf000079_0001
39 B1.41
Dioxane (3.5 ml), water (1.7 ml) and glacial acetic acid (0.25 ml) are added to a mixture of Pd(OH)2/C iman catalyst, Pd content 20%, 0.035 g) and the benzyl ether 39 (0.038 g, 0.034 mmoi). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly ele¬ vated pressure of hydrogen at room temperature for 24 hours and then filtered through a cellulose filter (pore size 45 μm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a DowexδO ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.5 cm) washing with deionized water. The clear filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: H20/methanol 65:35 to 55:45), resulting in the target molecule B1.41 (0.014 g, 59 %) as a fluffy white solid (after lyophiiization): 1H NMR (500 MHz, D20, +50°C) δ 7.58 - 7.53 (m, 4H), 7.51 - 7.46 (m, 1H), 5.22 (d, J=4.0 Hz, 1H), 4.57 (d, J=7.6 Hz, 1H), 4.56 (q, J=6.4 Hz, 1H), 4.33 (dd, J=4.2, 8.6 Hz, 1H), 4.30 (dt, J=6.3, 3.2 Hz, 1H), 3.66 (dd, J=8.0, 9.4 Hz, 1H), 3.59 (dd, J=3.0, 13.8 Hz, 1H), 3.33 (dd, J=4.2, 14.0 Hz, 1 H), 3.13 (dd, J=9.0, 14.0 Hz, 1H), 1.82 (sex, J=6.9 Hz, 2H), 1.36 (d, J=6.4 Hz, 3H), 1.10 (t, J=7.5 Hz, 3H); MS (FAB, NBA) 720 (M+Na), 698 (M+H). Example B22: Preparation of compound B1.42.
Figure imgf000080_0001
38 40
A suspension of 38 (0.65 g, 0.73 mmol) and di-π-butyltin oxide (0.32 g, 1.28 mmol) in dry benzene (22 ml) is boiled under reflux in an argon atmosphere for 16 hours. The reaction mixture is concentrated in vacuo and dried under high vacuum for one hour. Then CsF (dried under high vacuum at 300°C for several hours, 0.28 g, 1.83 mmol) is added under an argon atmosphere, followed by dry 1 ,2-dimethoxyethane (4.0 ml) and a solution of the triflate A5 (1.74 g, 4.4 mmol) in dry 1 ,2-dimethoxyethane (2.7 ml). The reaction mixture is heated to 35 to 40°C and stirred at this temperature for 3 hours. Then a solution of 15% KF in 1 M aqueous KH2P04 solution (100 mL), is added, and the mixture is extracted three times with CH2CI2, and the combined organic phases are dried (Na2S04), filtered and con¬ centrated in vacuo. The oily residue (2.6 g) is purified by column chromatography on silica gel (elution: toluene/ethyl acetate 3:1 , then CH2CI2/methanol 19:1) resulting in the ether 40 (0.33 g, 40 %) as a colourless foam, and partial recovery of the precursor 38 (0.167 g, 26 %).
Figure imgf000080_0002
40 B1.42 Dioxane (1.2 ml), water (0.6 ml) and glacial acetic acid (0.3 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.025 g) and the benzyl ether 40 (0.036 g, 0.032 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 8 hours and then filtered through a cellulose filter (pore size 45 μm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a DowexδO ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.5 cm) washing with deionized water. The clear filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 μm , column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: H20/methanol 1:1), resulting in the target molecule B1.42 (0.009 g, 41 %) as a fluffy white solid (after lyophiiization): 1H NMR (400 MHz, D20) δ 5.09 (d, J=3.7 Hz, 1 H), 4.58 - 4.46 (m, 2H), 3.94 (d, J=2.2 Hz, 1H), 3.58 (t, J=8.4 Hz, 1 H), 3.43 (dd, J=1.8, 9.5 Hz, 1 H), 1.83 (d, J=12.2 Hz, 1H), 1.23 (d, J=6.7 Hz, 3H), 0.95 (t, J=7.6 Hz, 3H); 13C NMR (100.6 MHz, D20) δ 183.0 (Cq), 101.6 (CH), 98.0 (CH); MS (FAB, THG) 704 (M+H).
Example B23: Preparation of compound B1.43.
Figure imgf000082_0001
Figure imgf000082_0002
41 46
Morpholine (1.1 ml) and Pd(PPh3)4 (0.071 g, 0.062 mmol) are added to a solution of the allyl carbamate 39 (0.695 g, 0.618 mmol) in tetrahydrofuran (8.5 ml). After exactly 15 minutes the solution is concentrated and the residue is dried under high vacuum for one hour. Purification of the residue by column chromatography on silica gel (eluent: CH2CI2/ methanol 98:2, contains 0.3 % concentrated aqueous ammonia solution) gives initially the less polar allylamine 46 (0.24 g, 36 %) followed by the more polar piperidine 41 (0.39 g, 60 %).
Figure imgf000083_0001
41 42
Pyridine (5 μl, 0.06 mmol) and acetic anhydride (1 ,8 μ I, 0.04 mmol) are added under an argon atmosphere to a solution of the piperidine derivative 41 (0.035 g, 0.0336 mmol) in dry CH2CI2 (0.6 ml) at 0°C. The solution is stirred at 0°C for 45 minutes and then washed with 5% aqueous NaHC03 solution, and the aqueous phase is reextracted three times with CH2CI2.The combined organic phases are dried with Na2S0 , filtered and concentrated in vacuo. The residue (0.05 g) is purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 4:1), resulting in the acetylpiperidine 42 (0.033 g, 91 %) as a colourless foam.
Figure imgf000083_0002
42 B1.43
Dioxane (1.4 ml), water (0.7 ml) and glacial acetic acid (0.35 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.03 g) and the benzyl ether 42 (0.04 g, 0.037 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 48 hours and then filtered through a cellulose filter (pore size 45 μm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a DowexδO ion exchange column (Na+form, diameter of the column 0.9 cm, length 3.5 cm), washing with deionized water. The clear filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: methanol/H20 2:3 via 1 :1 to 3:2), resulting in the target molecule B1.43 (0.014 g, 64 %) as a fluffy white solid (after lyophiiization): 1H NMR (400 MHz, D20) δ 7.22 - 7.06 (m, 5H), 4.86 (m, 1 H), 1.95 (s, 3H), 0.98 (d, J=6.7 Hz, 3H); MS (FAB, THG) 654 (M+H), 632 (M+2H-Na).
Example B24: Preparation of compound B1.44.
Figure imgf000084_0001
41 43
Compound 43 is prepared from the piperidine 41 (0.02 g, 0.019 mmol) and benzoyl chloride (2.5 μl, 0.021 mmol) in analogy to a method for the acetylpiperidine 42 (Example B23). The yield is 0.02 g (90 %).
Figure imgf000084_0002
43 B1.44
The target compound B1.44 is prepared by hydrogenation of the benzyl ether 43 (0.042 g, 0.0367 mmol) and subsequent purification in analogy to the acetyl derivative B1.43. The product results after lyophiiization as a fluffy white solid. Yield: 0.015 g (57 %): MS (FAB, THG) 716 (M+H), 694 (M+2H-Na).
Example B25: Preparation of compound B1.45.
Figure imgf000085_0001
The target compound B1.45 is prepared in analogy to Example 23 (preparation of com¬ pound B1.43) from the piperidine derivative 41: 1H NMR (400 MHz, D20) δ 7.28 - 7.13 (m, 5H), 4.95 (m, 1H), 4.37 - 4.23 (m, 2H), 3.56 (s, 3H), 3.04 (m, 1H), 2.84 (m, 1H), 2.26 (t, J=7.6 Hz, 2H), 1.08 (d, J=7.4 Hz, 3H); MS (FAB, THG) 810 (M+H).
Example B26: Preparation of compound B1.46.
Figure imgf000085_0002
41 45
Pyridine (4 μl, 0.05 mmol) and cyclohexanecarbonyl chloride (7.2 μl, 0.05 mmol) are added at 0°C to a solution of the piperidine derivative 41 (0.04 g, 0.038 mmol) in dry CH2CI2 (0.7 ml). After 20 minutes, the reaction mixture is washed with 10 % aqueous NaHC03 solution, and the aqueous phase is reextracted three times with CH2CI2. The combined organic phases are dried (Na2S04), filtered and concentrated in vacuo. Purification by column chromatography as the crude product (0.09 g) on silica gel (eluent: hexane/ethyl acetate 1 :1) gives the amide 45 (0.03 g, 68 %).
Figure imgf000086_0001
45 B1.46
Dioxane (1.1 ml), water (0.55 ml) and glacial acetic acid (0.27 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.05 g) and the benzyl ether 45 (0.029 g, 0.025 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 24 hours. Then, for hydrogenation of the aro¬ matic ring, 5% Rh/C (0.02 g) is added and hydrogenation is continued for 24 hours. The reaction mixture is filtered through a cellulose filter (pore size 45 μm), the filtrate is concen¬ trated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a DowexδO ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.5 cm), washing with deionized water. The clear filtrate is concentrated in vacuo and puri¬ fied by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H20 60:40), resulting in the target molecule B1.46 (0.012 g, 64 %) as a fluffy white solid (after lyophiiization): 1H NMR (400 MHz, D20) δ 5.04 (m, 1H), 4.48 (m, 1H), 4.45 - 4.32 (m, 1H), 2.72 (m, 1H), 1.17 (d, J=5.8 Hz, 3H); MS (FAB, THG) 728 (M+H), 706 (M+2H-Na). Example B27: Preparation of compound B1.47.
Figure imgf000087_0001
46 B1.47
Dioxane (1.4 ml), water (0.7 ml) and glacial acetic acid (0.35 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.03 g) and the benzyl ether 46 (0.042 g, 0.039 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 16 hours and then filtered through a cellulose filter (pore size 45 μm). The filtrate is concentrated in vacuo, and the residue is taken up in water and concentrated again several times in order to remove excess acetic acid. The crude product (0.014 g) is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H20 1:3) resulting in the target molecule B1.47 (0.009 g, 36 %) as a fluffy white solid (after lyophiiization): 1H NMR (400 MHz, DzO) δ 7.10 - 7.02 (m, 4H), 7.01 - 6.94 (m, 1H), 4.80 (br s, 1H), 4.10 (d, J=7.0 Hz, 1H), 3.84 (dd, J=4.7, 8.5 Hz, 1H), 3.20 (t, J=8.7 Hz, 1H), 2.97 (dd, J=3.3, 9.7 Hz, 1 H), 2.83 (dd, J=4.7, 13.1 Hz, 1H), 2.63 (dd, J=8.5, 13.1 Hz, 1H), 0.87 (d, J=7.0 Hz, 3H), 0.63 (t, J=7.3 Hz, 3H); MS (FAB, THG) 654 (M+Na), 632 (M+H). Example B28: Preparation of compound B1.48.
Figure imgf000088_0001
41 47
Triethylamine (7 μl, 0.05 mmol) and n-butanesulfonyl chloride (3.7 μl, 0.029 mmol) are added at 0°C to a solution of the piperidine 41 (0.025 g, 0.024 mmol) in CH2CI2 (0.3 ml). After 45 minutes, the reaction mixture is washed with 10 % aqueous NaHC03 solution, and the aqueous phase is reextracted three times with CH2CI2. The combined organic phases are dried (Na2S04), filtered and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (eluent: hexane/ethyl acetate 60:40), resulting in the sulfonamide 47 (0.022 g, 79 %).
Figure imgf000088_0002
47 B1.48
Dioxane (1.0 ml), water (0.5 ml) and glacial acetic acid (0.25 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.013 g) and the benzyl ether 47 (0.027 g, 0.023 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 24 hours and then filtered through a cellulose filter (pore size 45 μm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a DowexδO ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.5 cm), washing with deionized water. The clear filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: methanol/H20 35:65 to 45:55), resulting in the target molecule B1.48 (0.011 g, 65 %) as a fluffy white solid (after lyophiiization): 1H NMR (400 MHz, D20) δ 7.51 - 7.35 (m, 5H), 5.15 (d, J=3.4 Hz, 1 H), 4.54 (q, J=6.2 Hz, 1H), 4.51 (d, J=8.0 Hz, 1H), 4.03 (dd, J=2.8, 10.4 Hz, 1 H), 3.59 (t, J=8.9 Hz, 1 H), 3.23 (dd, J=4.8, 13.4 Hz, 1 H), 3.05 (dd, J=8.6, 13.4 Hz, 1H), 1.84 (pen, J=7.6 Hz, 2H), 1.54 (sex, J=7.3 Hz, 2H), 1.27 (d, J=6.6 Hz, 3H), 1.02 (t, J=7.5 Hz, 3H); MS (FAB, THG) 732 (M+H).
Example B29: Preparation of compound B1.49.
Figure imgf000089_0001
The target compound B1.49 is prepared in analogy to Example B28 (preparation of com¬ pound B1.48) starting from the piperidine derivative 41 and p-toluenesulfonyl chloride: 1H NMR (400 MHz, D2O) δ 7.56 (d, J=7.2 Hz, 2H), 7.33 (d, J=7.2 Hz, 2H), 7.28 - 7.11 (m, 5H), 4.81 (d, J=3.4 Hz, 1H), 4.22 (d, J=7,9 Hz, 1H), 3.75 (d, J=2.4 Hz, 1H), 3.65 (dd, J=2.4, 10.2 Hz, 1H), 3.41 (t, J=5.7 Hz, 1 H), 3.32 (t, J=8.7 Hz, 1 H), 3.13 (dd, J=2.5, 9.3 Hz, 1 H), 3.00 (dd, J=4.0, 13.6 Hz, 1H), 2.81 (dd, J=8.9, 13.6 Hz, 1H), 2.67 (br s, 1H), 2.29 (s, 3H), 0.95 (d, J=7.1 Hz, 3H); MS (FAB, THG) 788 (M+Na), 766 (M+H). Example B30: Preparation of compound B1.50.
Figure imgf000090_0001
47 B1.50
Dioxane (1.5 ml), water (0.75 ml) and glacial acetic acid (0.38 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.02 g) and the benzyl ether 47 (0.041 g, 0.035 mmol) The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 16 hours. Then, to hydrogenate the aromatic ring, 5% Rh/C (0.025 g) is added, and hydrogenation is continued for 16 hours. The reac¬ tion mixture is filtered through a cellulose filter (pore size 45 μm), the filtrate is concentrated in vacuo, and the residue is taken up in water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a DowexδO ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.5 cm), washing with deionized water. The clear filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromato¬ graphy (Merck RP18 silica gel, gradient elution: methanol/H20 40:60 to 50:50), resulting in the target molecule B1.50 (0.021 g, 82 %) as a fluffy white solid (after lyophiiization). 1H NMR (400 MHz, D20) δ 4.97 (d, J=3.7 Hz, 1H), 4.41 (d, J=7.7 Hz, 1 H), 4.36 (q, J=6.7 Hz, 1 H), 3.81 (d, J=2.6 Hz, 1 H), 3.76 (dd, J=2.4, 7.3 Hz, 1 H), 3.55 (dd, J=4.4, 7.2 Hz, 1 H), 3.30 (dd, J=2.7, 9.7 Hz, 1H), 1.34 (sex, J=7.4 Hz, 2H), 1.10 (d, J=6.7 Hz, 3H), 0.81 (t, J=7.5 Hz, 3H); MS (FAB, THG) 738 (M+H), 716 (M+2H-Na). Example B31 : Preparation of compound B1.51.
Figure imgf000091_0001
40 49
Morpholine (0.37 ml) and Pd(PPh3)4 (0.025 g, 0.021 mmol) are added to a solution of the allyl carbamate 40 (0.24 g, 0.212 mmol) in tetrahydrofuran (2.9 ml). After exactly 15 minu¬ tes, the solution is concentrated and the residue is dried under high vacuum for one hour. Purification of the residue (0.38 g) by column chromatography on silica gel (eluent: CH2CI2/ methanol 19:1 , contains 0.3 % concentrated aqueous ammonia solution) gives the piperi¬ dine derivative 49 (0.17 g, 76 %).
Figure imgf000091_0002
49 50
Phenyl isocyanate (4.6 μl, 0.042 mmol) and diisopropylethylamine (8.5 μl, 0.05 mmol) are added at 0°C to a solution of the piperidine derivative 49 (0.04 g, 0.038 mmol) in CH2CI2 (0.6 ml). After 90 minutes, the reaction mixture is washed with 1 M aqueous KH2P04 solution and the aqueous phase is reextracted three times with CH2CI2. The combined organic phases are dried (Na2S04), filtered and concentrated in vacuo. Purification of the crude product (0.047 g) by column chromatography on silica gel (eluent: hexane/ethyl acetate 58:42) provides the urea derivative 50 (0.035 g, 78 %).
Figure imgf000092_0001
Dioxane (1.3 ml), water (0.65 ml) and glacial acetic acid (0.33 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.018 g) and the benzyl ether 50 (0.036 g, 0.031 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 16 hours and then filtered through a cellulose filter (pore size 45 μm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a DowexδO ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.5 cm), washing with deionized water. The clear filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 3δ cm, eluent: water, flow rate 0.4δ ml/min, detection at 21 δ nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H20 1 :1), resulting in the target molecule B1.51 (0.018 g, 80 %) as a fluffy white solid (after lyophiiization): H NMR (400 MHz, D20) δ 7.14 (t, J=7.9 Hz, 2H), 7.02 (d, J=8.2 Hz, 2H), 6.9δ (t, J=7.7 Hz, 1 H), 4.87 (d, J=4.0 Hz, 1 H), 4.30 (d, J=7.4 Hz, 1H), 4.23 (q, J=6.6 Hz, 1H), 3.66 (d, J=2.8 Hz, 1 H), 3.42 (dd, J=4.4, 7.7 Hz, 1 H), 3.16 (dd, J=2.6, 9.δ Hz, 1 H), 1.00 (d, J=6.6 Hz, 3H); MS (FAB, THG) 737 (M+H), 71 δ (M+2H-Na).
Example B32: Preparation of compound B1.52.
Figure imgf000093_0001
B1.52
The piperidine derivative 49 is converted in analogy to Example B28 (preparation of com¬ pound B1.48) using phenylmethanesulfonyl chloride as reagent into the target compound B1.52: 1H NMR (400 MHz, D20) δ 7.50 (m, 5H), δ.02 (d, J=3.5 Hz, 1 H), 4.61 (d, J=13.7 Hz, 1H), 4.54 (d, J=13.7 Hz, 1H), 4.32 (d, J=8.0 Hz, 1H), 3.62 (t, J=6.0 Hz, 1H), 3.52 (dd, J=7.7, 8.4 Hz, 1H), 3.36 (dd, J=3.2, 9.6 Hz, 1H), 3.22 (br d, J=12.6 Hz, 1 H), 1.17 (d, J=6.δ Hz, 3H); MS (FAB, THG) 772 (M+H), 7δ0 (M+2H-Na).
Example B33: Preparation of compound B1.53.
Figure imgf000093_0002
49 B1.53 Dioxane (3.7 ml), water (1.8 ml) and glacial acetic acid (0.9 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, O.Oδ g) and the benzyl ether 49 (0.09 g, 0.086 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 48 hours and then filtered through a cellulose filter (pore size 4δ μm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. The crude product (0.044 g) is purified by gel filtration on Bio-Gel P2 (particle size 6δ μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detektion at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: methanol/H20 30:70 to δ0:δ0), resulting in the target molecule B1.53 (0.04 g, 78 %) as a fluffy white solid (after lyophiiization): 1H NMR (400 MHz, D20) δ 5.04 (d, J=4.2 Hz, 1H), 4.43 (d, J=7.6 Hz, 1H), 4.27 (m, 2H), 4.20 (q, J=6.δ Hz, 1H), 4.02 (dd, J=2.6, 6.6 Hz, 1 H), 3.δ1 (dd, J=7.8, 9.5 Hz, 1 H), 1.12 (d, J=6.2 Hz, 3H); MS (FAB, THG) 618 (M+Na), 596 (M+H).
Example B34: Preparation of compound B1.54.
Figure imgf000094_0001
B1.53 B1.54
A 1 M solution of 2-(1-naphthyl)ethanesulfonyl chloride in toluene (46 μl) is added at room temperature to a solution of the piperidine derivative B1.53 (0.025 g, 0.042 mmol) in 1M aqueous NaHC03 solution (0.22 ml). The mixture is vigorously stirred for 22 hours and then concentrated in vacuo and dried under high vacuum for 15 minutes. The crude product is purified by gel filtration on Bio-Gel P2 (particle size 6δ μm, column diameter 2.δ cm, length 3δ cm, eluent: water, flow rate 0.4δ ml/min, detection at 21 δ nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H20 7:3), resulting in the target molecule B1.54 (0.011 g, 31 %) as a fluffy white solid (after lyophiiization): 1H NMR (400 MHz, D20) δ 7.72 (d, J=8.8 Hz, 1H), 7.δ4 (d, J=8.8 Hz, 1H), 7.44 (d, J=8.6 Hz, 1 H), 7.28 (t, J=7.2 Hz, 1 H), 7.22 (t, J=7.2 Hz, 1 H), 7.14 (t, J=7.2 Hz, 1 H), 7.08 (d, J=8.7 Hz, 1 H), 4.91 (d, J=4.1 Hz, 1 H), 4.20 (d, J=7.0 Hz, 1 H), 3.99 (br s, 1 H), 3.90 (br s, 1 H), 1.09 (d, J=6.3 Hz, 3H); MS (FAB, THG) 8δ8 (M+Na), 836 (M+H).
Example B3δ: Preparation of compound B1.55.
Figure imgf000095_0001
B1.53 B1.55
A 0.5 M solution of acetic anhydride in toluene is added in small portions (50 to 100 μl) at room temperature to a solution of the piperidine derivative B1.53 (0.035 g, 0.059 mmol) in 1 M aqueous NaHC03 solution (0.5 ml) until all the precursor is consumed (test by thin-layer chromatography: silica gel TLC plates, mobile phase: t.-butanol/ water/acetone/glacial acetic acid/NH4OH 70:60:50:18:1.6). The reaction is complete after about one hour, and the mixture is concentrated in vacuo and dried under high vacuum for 15 minutes. The crude product is purified by gel filtration on Bio-Gel P2 (particle size 6δ μm, column diameter 2.δ cm, length 3δ cm, eluent: water, flow rate 0.4δ ml/min, detection at 21 δ nm) and subse¬ quent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H20 3:7), resulting in the target molecule B1.55 (0.026 g, 67 %) as a fluffy white solid (after lyophiiiza¬ tion): 1H NMR (400 MHz, D20) δ 5.01 (d, J=4.2 Hz, 0.5H), 4.99 (d, J=4.2 Hz, O.δH), 4.44 (d, J=7.3 Hz, 1 H), 4.32 (q, J=6.6 Hz, O.δH), 3.14 (dd, J=8.0, 12.9 Hz, O.δH), 2.10 (s, 1.δH), 2.08 (s, 1.δH), 1.13 (d, J=6.6 Hz, 3H). Example B36: Preparation of compound B1.56
Figure imgf000096_0001
B1.53 B1.56
A 1.5 M solution (+)-di-0-acetyl-L-tartaric anhydride in 1 ,4-dioxane is added in small portions (50 to 100 μl) at room temperature to a solution of the piperidine derivative B1.53 (0.03 g, 0.05 mmol) in 1 M aqueous NaOH solution (0.15 ml) until all the precursor is con¬ sumed (test by thin-layer chromatography: silica gel TLC plates, mobile phase: n-butanol/ water/acetone/glacial acetic acid/NH4OH 70:60:50:18:1.6). The mixture is kept basic throughout the reaction by periodic addition of 1 M NaOH solution. The starting material is consumed after about two hours and then a further 1 M sodium hydroxide solution (0.13 ml) is added and the mixture is heated to 40°C in order to hydrolyse the ester groups. After one hour, the mixture is concentrated in vacuo and dried under high vacuum for 15 minutes. The crude product is purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 3δ cm, eluent: water, flow rate 0.4δ ml/min, detection at 216 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/ H20 1 :9), resulting in the target molecule B1.56 (0.020 g, 62 %) as a fluffy white solid (after lyophiiization): MS (FAB, THG) 794 (M+Na), 772 (M+H), 7δ0 (M+2H-Na).
Example B37: Preparation of compound B1.57.
Figure imgf000096_0002
B1.53 B1.57 N,N-Diisopropylcarbodiimide (11.7 μl, 0.075 mmol) is added at 0°C to a solution of shikimic acid (0.013 g, 0.075 mmol) and 1 -hydroxybenzotriazole (0.01 g, 0.075 mmol) in dry N,N-di- methylformamide (0.37 ml), and the mixture is then stirred for 30 minutes. The mixture is then warmed to room temperature and the piperidine derivative B1.53 (0.01 δ g, 0.025 mmol) is added. After 3 hours, 10 % aqueous NaHC03 solution is added (0.15 ml), and the reaction mixture is stirred for a further 20 minutes and then concentrated under high vacuum. The residue is taken up in water, filtered through a cellulose filter (pore size 45 μm) and then passed through a DowexδO ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.δ cm), washing with deionized water. The filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 6δ μm, column diameter 2.δ cm, length 3δ cm, eluent: water, flow rate 0.4δ ml/min, detection at 21 δ nm) and subse¬ quent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H20 1 :9), resulting in the target molecule B1.57 (0.007 g, 33 %) as a fluffy white solid (after lyophiiiza¬ tion): 1H NMR (400 MHz, D20) δ δ.8 (br s, 1H), 4.94 (m, 1H), 2.δδ (m, 1H), 2.10 (m, 1H), 1.07 (d, J=6.0 Hz, 3H); MS (FAB, THG) 796 (M+Na), 774 (M+H).
Example B38: Preparation of compound B1.58.
Figure imgf000097_0001
37 52
N,N-Dimethylaminopyridine (1.03 g, 8.44 mmol) and p-nitrobenzenesulfonyl chloride (1.66 g, 7.44 mmol) are added at room temperature to a solution of the alcohol 37 (6.11 g, δ.1 mmol) in CH2CI2 (35 ml). After 52 hours, the reaction mixture is washed with 10 % aqueous NaHC03 solution, and the aqueous phase is reextracted three times with CH2CI2.The combined organic phases are dried (Na2S04), filtered and concentrated in vacuo. The crude product (10 g) is purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 3δ:6δ), resulting in the nosylate 52 (6.58 g, 93 %).
Figure imgf000098_0001
52 53
A solution of the nosylate 52 (7.78 g, 5.62 mmol) and dry LiN3 (0.99 g, 20.21 mmol) in dry N,N-dimethylformamide (δO ml) is heated to 60-60°C under an argon atmosphere. After 16 hours, the solvent is removed under high vacuum, and the residue is taken up in CH2CI2 and washed with 10 % aqueous NaHC03 solution. The aqueous phase is extracted three times with CH2CI2 and the combined organic phases are dried (Na2S04), filtered and con¬ centrated in vacuo. The crude product is purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 30:70), with elution first of the required azide 53 (4.22 g, 61 %), followed by the alcohol 37 (2.5 g).
Figure imgf000098_0002
53 54
A solution of the tribenzoate 53 (4.22 g, 3.4δ mmol) and sodium methoxide (0.δ5 g, 10.2 mmol) in methanol (110 ml) and dioxane (5 ml) is stirred at room temperature for 2.6 hours. The pH of the reaction mixture is then made neutral by adding strongly acidic ion exchanger (Amberlystlδ, H+ Form), the suspension is filtered, and the filtrate is concentra- ted in vacuo. The crude product (4.5 g) is purified by column chromatography on silica gel (eluent: CH2CI2/methanol 19:1 ) to give the triol 54 (2.89 g, 92 %).
Figure imgf000099_0001
54 55
A suspension of 54 (2.89 g, 3.17 mmol) and di-n-butyltin oxide (1.56 g, 6.27 mmol) in dry benzene (95 ml) is boiled under reflux in an argon atmosphere for 16 hours. The reaction mixture is concentrated in vacuo and dried under high vacuum for one hour. Then CsF (dried under high vacuum at 300°C for several hours, 1.2 g, 7.9 mmol) is added under an argon atmosphere, followed by dry 1 ,2-dimethoxyethane (80 ml) and a solution of the triflate A5 (6.3 g, 15.97 mmol) in dry 1 ,2-dimethoxyethane (50 ml). The reaction mixture is heated to 35 to 40°C and stirred at this temperature for 3 hours. The mixture is then washed with a solution of 15% KF in 1 M aqueous KH2P04 (150 ml) and the aqueous phase is extracted three times with CH2CI2, and the combined organic phases are dried (Na2S0 ), filtered and concentrated in vacuo. The oily residue (10.9 g) is purified by column chromatography on silica gel (elution: toluene/ethyl acetate 4:1 , then CH2CI2/methanol 19:1 to recover the pre¬ cursor), resulting in the ether 55 (1.94 g, 63 %) as a colourless foam and partial recovery of the precursor (1.1 g, 26 %).
Figure imgf000099_0002
55 56 Morpholine (215 μl) and Pd(PPh3)4 (0.015 g, 0.013 mmol) are added under an argon atmo¬ sphere to a solution of the allyl carbamate 55 (0.15 g, 0.13 mmol) in tetrahydrofuran (1.7 ml). After exactly 15 minutes, the solution is concentrated and the residue is dried under high vacuum for one hour. The crude product is purified on a short silica gel column (eluent: CH2CI2/methanol 19:1 , contains 0.3 % concentrated aqueous ammonia solution) and then dried under high vacuum for one hour. The residue is then taken up in dry CH2CI2 (1.7 ml), the solution is cooled to 0°C, and triethylamine (43 μl, 0.31 mmol) and n-butane- sulfonyl chloride (18 μl, 0.14 mmol) are added. After 1δ minutes, the reaction mixture is warmed to room temperature and washed with 10 % aqueous NaHC03 solution. The aqueous phase is reextracted three times with CH2CI2, and the organic phases are com¬ bined, dried (Na2S04), filtered and concentrated in vacuo. Purification of the crude product by column chromatography on silica gel (eluent: ethyl acetate/hexane 30:70) gives the sulfonamide 56 (0.12 g, 77 %).
Figure imgf000100_0001
56 B1.58
Dioxane (1.2 ml), water (0.6 ml) and glacial acetic acid (0.25 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.035 g) and the benzyl ether 56 (0.027 g, 0.023 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly ele¬ vated pressure of hydrogen at room temperature for 12 hours and then filtered through a cellulose filter (pore size 45 μm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. The crude intermediate (0.017 g, lyophilized) is taken up in 1 M aqueous NaHC03 solution (0.3 ml) and over the course of 5 hours, several small portions (30 bis 60 μl) of an approx. 1 M solution of 3,4-dimethoxybenzoyl chloride in toluene are added, until a test by thin-layer chromatography (silica gel TLC plates, mobile phase: π-butanol/water/acetone/ glacial acetic acid/NH4OH 70:60:60:18:1.6) indicates complete conversion of the intermedi¬ ate. The pH of the solution is kept basic during this reaction by adding several portions of solid NaHC03 (about 0.026 g in total). The reaction mixture is then concentrated in vacuo, and the residue is taken up in a little water and purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.δ cm, length 3δ cm, eluent: water, flow rate 0.46 ml/min, detection at 216 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H20 6δ:3δ), resulting in the target molecule B1.58 (0.008 g, 39 %) as a fluffy white solid (after lyophiiization): H NMR (400 MHz, D20) δ 7.41 (br d, J=8.3 Hz, 1 H), 7.32 (br s, 1 H), 7.04 (d, J=8.3 Hz, 1 H), 5.06 (d, J=3.9 Hz, 1 H), 4.51 (d, J=7.8 Hz, 1 H), 4.14 (q, J=6.7 Hz, 1H), 4.09 (t, J=4.1 Hz, 1 H), 3.82 (s, 6H), 3.33 (dd, J=3.1 , 9.6 Hz, 1H), 1.13 (d, J=6.3 Hz, 3H), 0.68 (t, J=7.6 Hz, 3H); MS (FAB, THG) 923 (M+Na), 901 (M+H), 879 (M+2H-Na).
Example B39: Preparation of compound B1.59.
Figure imgf000101_0001
56 B1.59
Dioxane (5.3 ml), water (2.6 ml) and acetic acid (1.1 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.13 g) and the benzyl ether 56 (0.12 g, 0.1 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 24 hours and then filtered through a cellulose filter (pore size 4δ μm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. The crude amine (0.074 g) is taken up in a little water and purified by gel filtration on Bio-Gel P2 (particle size 6δ μm, column diameter 2.δ cm, length 3δ cm, eluent: water, flow rate 0.46 ml/min, detection at 21 δ nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H20 1 :1 ), resulting in the target molecule B1.59 (0.052 g, 73 %) as a fluffy white solid (after lyophiiization): 1H NMR (400 MHz, D20) δ 5.00 (d, J=3.6 Hz, 1 H), 4.41 (d, J=7,7 Hz, 1 H), 4.28 (q, J=6.5 Hz, 1 H), 3.83 (d, J=3.1 Hz, 1 H), 3.79 (dd, J=3.1 , 9.7 Hz, 1 H), 3.32 (dd, J=3.2, 9.6 Hz, 1 H), 1.12 (d, J=6.1 Hz, 3H), 0.83 (t, J=7.9 Hz, 3H); MS (FAB, THG) 737 (M+Na), 713 (M+H).
Example B40: Preparation of compound B1.60.
Figure imgf000102_0001
The amine B1.59 (0.027 g, 0.038 mmol) is taken up in 1 M aqueous NaHC03 solution (0.35 ml) and, over the course of 4 hours, several small portions (30 to 60 μL) of an approx. O.δ M solution of benzoyl chloride in toluene are added until a test by thin-layer chromato¬ graphy (silica gel TLC plates, mobile phase: n-butanol/water/acetone/glacial acetic acid/ NH4OH 70:60:60:18:1.5) indicates complete conversion. The pH of the solution is kept basic throughout the reaction by adding several portions of solid NaHC03 (about 0.01 g in total). The reaction mixture is then concentrated in vacuo, and the residue is taken up in a little water and purified by gel filtration on Bio-Gel P2 (particle size 65 μm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subse¬ quent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H20 1:1), resulting in the target molecule B1.60 (0.027 g, 8δ %) as a fluffy white solid (after lyophiiiza¬ tion): 1H NMR (400 MHz, D20) δ 7.72 (d, J=8.0 Hz, 2H), 7.62 (t, J=6.9 Hz, 1H), 7.44 (t, J=7.δ Hz, 2H), δ.Oδ (d, J=3.8 Hz, 1 H), 4.60 (d, J=8.1 Hz, 1 H), 4.17 (q, J=6.6 Hz, 1 H), 3.92 (br d, J=10.4 Hz, 1H), 3.8δ (d, J=2.8 Hz, 1H), 3.80 (dd, J=3.1 , 10.4 Hz, 1H), 3.33 (dd, J=2.8, 9.8 Hz, 1H), 1.12 (d, J=7,1 Hz, 3H), 0.70 (t, J=8.2 Hz, 3H); MS (FAB, THG) 863 (M+Na), 841 (M+H). Example B41 : Preparation of compound B1.61.
Figure imgf000103_0001
B1.59 B1.61
The carbamate B1.61 is prepared starting from the amine B1.59 (0.027 g, 0.038 mmol) using benzyl chloroformate as reagent in analogy to Example B40 (Preparation of com¬ pound B1.60). The yield is 0.007 g (21 %): 1H NMR (400 MHz, D20) δ 7.31 (m, 5H), δ.06 (d, J=12.0 Hz, 1 H), 4.97 (d, J=12.0 Hz, 1H), 4.96 (d, J=4.0 Hz, 1 H), 4.42 (d, J=7.7 Hz, 1 H), 4.19 (q, J=6.6 Hz, 1H), 3.96 (br s, 1H), 3.80 (d, J=2.9 Hz, 1 H), 3.60 (dd, J=8.2, 9.4 Hz, 1H), 3.29 (dd, J=2.9, 9.7 Hz, 1 H), 3.20 (br d, J=12.2 Hz, 1 H), 1.06 (d, J=6.δ Hz, 3H), 0.77 (t, J=8.0 Hz, 3H); MS (FAB, THG) 871 (M+H), 849 (M+2H-Na).
The following compounds are prepared in analogy to the above examples:
Table 1a:
Figure imgf000103_0002
Compound No. R3 RHA
B1.64 Na C(0)-3,4-(OH)2-C6H5 B1.66 Na C(0)CH(C6H5)2 B1.68 Na C(0)-3,4-(OCH2C6H5)2-C6H5 Compound No. R3 RHA
B1.70 Na C(0)-3,4,δ-(OH)3-C6H6
B1.72 Na C(0)[CH(OH)]2C(0)ONa
B1.73 Na C(0)CH3
B1.77 Na S(O)2(CH2)2C10H7
B1.78 H H
B1.80 Na S(0)2CH2C6H5
B1.81 Na C(0)NHC6H5
B1.82 Na C(0)C6Hn
B1.83 Na S(0)2(CH2)3CH3
B1.84 Na C(0)0(CH2)2CH3
Table 1a':
Figure imgf000104_0001
Compound No. R3 RHA RCA
B1.62 Na C(0)CH3 NHC(O)Cι0H7
B1.63 Na C(0)CH3 NHC(0)OCH2C6H5
B1.66 Na C(0)CH3 NHC(0)CH2C6H5
B1.67 Na C(0)CH3 NHC(0)CH20C6H5
B1.69 Na C(0)CH3 NHC(0)CH2NHC(0)OCH2C6H5
B1.71 Na C(0)0(CH2)2CH3 NHS(0)2CH2C6H5
B1.74 Na S(0)2(CH2)3CH3 NHC(0)OCH2C6H5
B1.76 Na S(0)2(CH2)3CH3 NHC(0)C6H5
B1.76 H S(0)2(CH2)3CH3 NH2
B1.79 Na S(0)2(CH2)3CH3 NHC(0)-3,4-(OCH3)2C6H3 Table 1b:
Figure imgf000105_0001
Compound No. R3 RHA
B1.86 Na S(0)2-4-CH3-C6H4
B1.86 Na C(0)(CH2)8C(0)OCH3
B1.87 Na S(0)2(CH2)3CH3
B1.88 H (CH2)2CH3
B1.89 Na C(0)C6H5
B1.90 Na C(0)CH3
B1.91 Na C(0)0(CH2)2CH3
C. Ligand Binding Assay for Determination of IC50 Values-conserved use of positive controls E-selectin/human IgG chimera [cloned and expressed according to Kolbinger et al. Biochemistry 36:6386-6392 (1996)] are incubated in Falcon probind™ microtiter plate (Plate 1) at a concentration of 200 ng/well in 0.01 M Tris, 0.16 M NaCl, 1 mM CaCI2, pH 7.4 (Tris- Ca++ buffer). Thus the plating solution is dispensed as 100 μl/well of 2 μg/ml E-chimera. Row 12 is left blank with only buffer. Plate 1 is incubated covered at 37°C for 2 hours. After incubation 100 μl/well of 2 % BSA in Tris Ca++ buffer is added and incubated at room temperature for 1 hour. During incubation the compounds (2x serial dilution) are titrated in 1 % BSA in Tris-Ca++ using U-shaped low bind microtiter plates (Plate 2). The rows are serially diluted up to row 9. Rows 10, 11 , and 12 are just buffer. Final volume is 60 μl/well and the first well contains 10 mM of compound with the exception of the positive controls, A (SLeΑemieux) and B are used as positive controls for each plate and the first well contains 5 mM of these compounds. PolySLeaSA-HRP conjugate is prepared in advance by incubating Sialyl Lea-PAA-biotin (cat #01-044, GiycoTech Corp., Rockville, MD) with Streptavidin-HRP in a molar ratio of 1 :2. 60 μl/well of 1 ng/μl of polySLeaSA-HRP conjugate in 1 % BSA in Tris-Ca++ are added to all wells except row 11 in Plate 2. Plate 1 is washed four times with Tris-Ca++ in the automatic plate washer. 100 μl/well are transferred from Plate 2 to Plate 1 starting from lowest concentration of compound. Plate 2 is dis¬ carded. The plate is incubated while rocking at room temperature for 2 hours. The plate is washed 4 times with Tris-Ca++ using automatic plate washer. 100 μl/well of Substrate [Mix 3,3',5,δ'-tetramethylbenzidine reagent and H202, at 1 :1 ratio] are added with an 8 channel pipettor from right to left. The plate is incubated at room temperature for 2 minutes. The reaction is stopped by adding 100μl/well of 1 M H3P04 using the 8 channel pipettor from right to left. Absorbance of light at 450nm is measured in a microtiter plate reader.
Control compound A:
Figure imgf000106_0001
Control compound B:
Figure imgf000106_0002
IC50 is calculated by determining the concentration of compound required to inhibit maximal binding of the polySialylLeaHRP conjugate to immobilized E-selectin/human IgG chimera by 50%. The relative IC50 is calculated by determining the ratio of the IC50 of an internal control compound to the IC5o of the test compound. IC 5ff (Test compound)
In the following tables RIC50 means
IC (Control compound A)
Table 2:
Figure imgf000107_0001
Comp. No. R3 R4 RIC50
B1.1 Na -CH2C6H5 0.35
B1.2 Na CH2C6Hn 0.08
B1.3 Na -CH2NHC(0)C6H5 1.11
B1.4 Na -CH2NHC(0)(CH2)2C6H5 1.85
B1.5 Na -CH2NHC(0)(CH2)3OH 1.23
B1.6 H -CH2NH2 0.96
B1.7 H -CH2NHCH2(CH)2C6H5 1.15
B1.8 Na -CH2N[C(0)C6H5]CH2(CH)2C6H5 0.90
B1.9 H CH2NHCH2C6H5 0.61
B1.10 Na -CH2N(CH2C6H5)2 0.60
B1.11 H -CH2NH[CH2CH(CH3)2 0.74
B1.12 H -CH2N[CH2CH(CH3)2]2 0.32
B1.13 Na -CH2N[C(0)C6H5][CH2CH(CH3)2] 0.21
B1.14 Na -CH2NH[S02(C6H4)N02] 0.12
B1.15 Na -CH2NHS02C6H4CH3 0.13
B1.16 Na -CH2NHC(0)CF3 0.64
B1.17 Na -CH2NHC(0)C6Hn 1.33
B1.18 Na -CH2CH2C6H5 0.14
B1.19 Na -CH2CH2C6Hn 0.17 Comp. No. R3 R4 RIC 50
B1.20 Na -CH2NHC(0)CιιH23 1.76
B1.21 Na -CH2NHC(0)CH(C6H5)2 0.71
B1.22 Na -CH2NHC(0)C2H4C02Na 1.05
B1.23 Na -CH2NHC(0)C6[(1 ,3,4,5)OH]4H7 0.79
B1.24 Na -CH2NHC(0)C6H4S03Na 0.93
B1.26 Na -CH2NHC(0)C6H4CI 1.29
B1.26 Na -CH2NHC(0)C6H4NO2 1.21
B1.27 Na -CH2NHC(0)C6H4OCH3 1.15
B1.28 Na -CH2NHC(0)C6H4(3,4)CI2 2.04
B1.29 Na -CH2NHC(0)C6H4CH3 1.30
B1.30 Na -CH2NHC(0)C6H4C6H5 1.65
B1.31 Na -CH2NHC(0)C6H4CN 1.04
B1.32 Na -CH2NHC(O)C10H7 1.44
B1.9 Na -CH2NHCH2C6H5 0.61
B1.33 Na -CH2NHC(0)C6H4COONa 0.96
B1.34 Na -CH2NHC(0)(CHOH)2COONa 0.78
B1.36 Na -CH2N[C(0)C6H5]CH2C6H5 0.44
B1.36 Na -CH2N[C(0)C6H5](CH2)3C6H5 0.57
B1.37 Na -CH2NHS02CF3 0.26
B1.38 Na -CH2N[CH2CH(CH3)]S02C6H4N02 . 0.32
Table 2a:
Compound No. RIC50 Compound No. RIC50
B1.62 0.949 B1.77 0.618
B1.64 0.287 B1.78 0.304
B1.65 0.862 B1.79 0.196
B1.66 1.112 B1.80 0.203
B1.67 0.664 B1.81 0.216
B1.68 0.696 B1.82 0.196
B1.69 2.661 B1.83 0.176
B1.70 0.199 B1.84 0.169
B1.71 0.414 B1.86 1.28
B1.72 0.186 B1.86 2.733
B1.73 0.249 B1.87 0.620
B1.74 0.134 B1.88 1.267
B1.75 0.102 B1.89 0.696
B1.76 0.461 B1.90 0.569
B1.63 0.087

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula I
Figure imgf000110_0001
in which
X is the residue of a non-glycosidic aliphatic 1 ,2-diol;
R ι is an S-configurated methyl substituted with one carboxyl residue and one other substitu¬ ent; and
R2 is hydrogen,
Figure imgf000110_0002
or C6aryl; where the alkyl and the aryl are unsubstituted or sub¬ stituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ORsι, OC(0)Rs4, C(0)Rs2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My, Cι-C12alkyl, C2-C12alkenyl, Cι-Cι2alkoxy, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-Cn aralkyl, C7-Cn aralkyloxy, C6-Ci0heteroaralkyl, C8-Cnaralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, Cι-C12alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, Ce-Cioaryl, Cs-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, R^ is hydrogen, Cι-C12alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, and Rs2 and R20 are hydrogen, d-Cealkyl, C2-C12alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn -hetero¬ cycloalkenyl, Ce-Cioaryl, C5-Cgheteroaryl, C -Cnaralkyl, C6-C10heteroaralkyl, C8-Cn-aralkenyl or C7-Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo¬ alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero¬ aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal; including its physiologically tolerated salts.
2. A compound according to claim 1 , wherein
(a) NH2, primary amino, secondary amino, carbamide, carbamate, carbhydrazide, sulfon¬ amide, sulfonhydrazide and aminocarbonylamide is a representative selected from the group of R8C(0)(NH)pN(R9)-, -C(0)(NH)pNR8R9, R8OC(O)(NH)pN(R9)-, R8R40NC(O)(NH)pN(R9)-, -OC(0)(NH)pNR8R9, -N(R40)C(O)(NH)PNR8R9, R8S(0)2(NH)pN(R9)-; -S(0)2(NH)pNR8R9; R8R40NS(O)2N(R9)- or -NR40S(O)2NR8R9, in which R8, R9 and R40 are, independently of one another, hydrogen, OH, C -d2alkyl, CrCι2alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloaIkenyl, C2-Cn heterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, Cs-Cgheteroaryl, C7-d6aralkyl, C8-Cιearalkenyl with C2-C6alkenylene and C6-C10aryl, C6-C15heteroaralkyl, C6-Cι5heteroaralkenyl, or di-C6-Cιoaryl-C -C6-alkyl, or R8-R9N in which Rff and & are, independently of one another, hydrogen, OH, SO3My, OS03My, Cι-C12alkyl, C3-C12cycloalkyl, CrCuheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6- Cioheteroaralkyl, C8-Cι6aralkenyl with C2-C6alkenylene and C6-C10aryl, or di-C6-Cιoaryl-Cι- C6-alkyl, which are unsubstituted or substituted by one or more substituents; or R8 and R9 or R8' and R9< or R8 and R40 in the case of -NR8Rg or -NR8R9' or R8R 0N- together are tetra¬ methylene, pentamethylene, -(CH2)2-O-(CH2)2-, -(CH2)2-S-(CH2)2- or -(CH2)2-NR7-(CH2)2-, and R7 is H, CrC6alkyl, C7-Cnaralkyl, C(O)Rs2 or sulfonyl; and
(b) sulfonyl is a representative of the formula Rι0-SO2- in which Rι0 is Ci-CealkyI, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or Ce-CioheteroaralkyI, which are unsubstituted or substituted by one or more substituents; wherein the substituents are selected from the group consisting of OH, halogen, C(0)ORsι, OCfOJR.*, C(0)Rs2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My, d-Cι2alkyl, C2-Cealkenyl, Ci-Cealkoxy, C3-C12cycloalkyl, C3-d2cycloalkenyl, C2-Cn heterocycloalkyl, C2- C11 heterocycloalkenyl, Ce-Cioaryl, C6-Cι0aryloxy, C5-C9heteroaryl, C5-Cgheteroaryloxy, C7- Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carb¬ hydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, d-Cealkyl, C2-Cealkenyl, C3-d2cycloalkyl, C2-Cn heterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, C7-Cιιaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, Ci-CealkyI, C2-d2alkenyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or Ce-CioheteroaralkyI, and Rs2 and R20 are hydrogen, Ci-CealkyI, C2-d2alkenyl, C3-Cι2cyclo- alkyl, C3-Cecycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-C oaryl, Cs-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cι0heteroar- alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo- alkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and hetero¬ aralkenyl in turn are substituted or substituted by one of the abovementioned substituents; p is 0 or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
3. A compound according to claim 1 , wherein X is a linear or branched C2-C20-alkylene, -alkenylene, C3-d2-cycloalkylene, -cycloalkenylene, C3-Cn-heterocycloalkylene or -hetero¬ cycloalkenylene with hetero atoms selected from the group of -0-, -S- and -N-.
4. A compound according to claim 1 , wherein X is substituted by a substituent selected from the group consisting of OH, halogen, C(0)ORsι, OC(0)Rs4, C(0)Rs2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My, Cι-C12alkylf C2-Cι2alkenyl, C Cealkoxy, C3-d2cycloalkyl, C3-Cecycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cιoaryl, C6-Cι0aryl- oxy, Cs-Cgheteroaryl, C5-C9heteroaryloxy, C7-Cnaralkyl, C7-Cnaralkyloxy, C6-Cι0heteroar- alkyl, C8-Cnaralkenyl, C7-Cιoheteroaralkenyl, primary amino, secondary amino, sulfonyl, sul¬ fonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and amidocarbonylamide, where Rsι is hydrogen, My, Cι-d2alkyl, C2-C12alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cgheteroaryl, C7-Cnaralkyl or C6-Cιoheteroaralkyl, Rs4 is hydrogen, Ci-CealkyI, C2-d2alkenyl, C3-C12cycloalkyl, C2-Cιιheterocycloalkyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, and Rs2 and R20 are hydrogen, CrCealkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-Cecycloalkenyl, C2-Cιιheterocycloalkyl, d-Cn-heterocycloalkenyl, Ce-Cioaryl, Cs-Cgheteroaryl, C7-Cn aralkyl, C6-Cιoheteroaralkyl, C8-Cn -aralkenyl or C7-Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
5. A compound as claimed in claim 1 , wherein X is the residue of a 1 ,2-diol corresponding to formula II
Figure imgf000113_0001
in which
R5 and R6 are, independently of one another, hydrogen, d-C12alkyl, C3-d2cycloalkyl, C2-Cιιheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl; or R5 and R6 are, together with the -CH-CH- group, C3-d2cycloalkylene, C3-C12-cycloalken- ylene, C2-Cnheterocycloalkylene and C3-Cn heterocycloalkenylene with hetero atoms selected from the group -O-, -S- and -N-; where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclo¬ alkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halo¬ gen, C(0)ORs1, OC(O)Rs4, C(0)RS2, nitro, NH2, cyano, SO3My, OS03My, NR20SO3My> d-Cealkyl, C2-d2alkenyl, Ci-Cealkoxy, C3-d2cycloalkyl, C3-d2cycloalkenyl, C2-Cnhetero- cycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C6-Cιoaryloxy, C5-C9heteroaryl, Cs-Cgheteroaryloxy, C7-Cn aralkyl, C7-Cι aralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7- Cioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonyl¬ amide, where Rsι is hydrogen, My, d-Cealkyl, C2-d2alkenyl, C3-d2cycloalkyl, C2-Cnhetero- cycloalkyl, C6-Cιoaryl, C5-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, R^ is hydrogen, Cι-Cι2alkyl, C2-Cealkenyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cgheteroaryl, C -Cnaralkyl or C6-Cι0heteroaralkyl, and Rs2 and R20 are hydrogen, Ci- Cealkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-d2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn- heterocycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-dr aralkenyl or C7-Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyl¬ oxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
6. A compound according to claim 5, wherein R5 and R6
(a) are unsubstituted or substituted by d-d2alkyl or C d2alkoxy;
(b) are, together with the group -CH-CH-, a 5- to 8-membered carbocycle;
(c) are, together with the group -CH-CH-, a 5- to 8-membered heterocarbocycle;
(d) are, independently of one another, hydrogen, unsubstituted C Cealkyl or Cι-d2alkyl which is substituted by a substituent selected from the group consisting of -C(0)ORsι, -OC(0)Rs , -C(0)ONa or -C(0)OK, primary amino, secondary amino, C3-d2cycloalkyl, Cι-C6alkoxy, phenyloxy and benzyloxy; unsubstituted C3-d2cycloalkyl or C3-Cι2cycloalkyl which is substituted by a substituent selected from the group consisting of -C(0)ORsι, -OC(0)Rs4, -C(0)ONa or -C(0)OK, primary amino, secondary amino, CrC6alkyl, Ci-Cealk¬ oxy, phenyloxy and benzyloxy; C6-Cι0aryl which is unsubstituted or substituted by -C(0)ORsι, -OC(0)Rs4, -C(0)ONa or -C(0)OK, primary amino, secondary amino, d-C6alkyl or d-C6alkoxy; C3-Cgheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; or C7-d2aralkyl which is unsubstituted or substituted by -C(0)ORsι, -OCfOJR. , -C(0)ONa or -C(0)OK, primary amino, secondary amino, d-C6alkyl or Ci-Cealkoxy;
(e) are, together with the group -CH-CH-, a 5- to 12-membered carbocycle or 5- or 6-mem¬ bered heterocarbocycle with a hetero atom selected from the group consisting of oxygen and nitrogen atoms; or
(f) are, together with the -CH-CH- group, C3-C12cycloalkylene, C -d2cycloalkenylene, C2-Cιι heterocycloalkylene or C3-Cn heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-; where cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ORsι, OCfOJR. , C(0)Rs2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My, d-Cealkyl, C2-Cealkenyl, Cι-C12alkoxy, C3-Cι2cycloalkyl, C3-d2cycloalkenyl, C2-Cιιheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, Ce-C^aryloxy, Cs-Cgheteroaryl, C5-C9heteroaryloxy, C7-Cnaralkyl, C7-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7- C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and amino¬ carbonylamide, where Rsι is hydrogen, My, Cι-d2alkyl, C2-Cealkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, C5-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, R^ is hydrogen, Cι-C12alkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C2-Cn heterocycloalkyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, and Rs2 and R20 are hydrogen, Cι-C 2alkyl, C2-Cι2alkenyl, C3-Cecycloalkyl, C3-Cι2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Ci0aryl, C5-C9heteroaryl, C7-Cn aralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cιoheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
7. A compound according to claim 6, wherein R5 and R6 are, together with the -CH-CH- group, C3-Cecycloalkylene or C2-Cn heterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents according to claim 6.
8. A compound according to claim 7, wherein R5 and R6 are, together with the -CH-CH- group, C3-Cecycloalkylene or C2-Cnheterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(0)ORsι, OC(0)Rs4, C(0)Rs2, NR8R9, Ci-CealkyI, R8C(0)(NH)pN(R9)-, -C(0)(NH)pNR8R9, R8S(0)2(NH)pN(R9)-; R8R40NC(O)(NH)pN(Rg)-, R8OC(0)(NH)pN(R9)-, -OC(0)(NH)pNR8R9, and Rι0-SO2-, in which R8, Rg, Rι0 and R 0 are, independently of one another, hydrogen, OH, Ci-CealkyI, d-Cealkenyl, C3-Cι2cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cι6aralkyl, C8-d6aralkenyl with C2-C6alken- ylene and C6-Cιoaryl, C6-Cι5heteroaralkyl, C6-Cιsheteroaralkenyl, or di-C6-Cι0aryl- Cι-C6-alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ORsι, OCfOJR^, C(0)Rs2l nitro, NH2, cyano, S03My, OS03My, NR20SO3My, Ci-CealkyI, C2-d2alkenyl, Ci-Cealkoxy, C3-C12cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn heterocycloalkenyl, C6-Cι0aryl, Ce-Cι0aryl- oxy, Cs-Cgheteroaryl, Cs-Cgheteroaryloxy, C7-Cnaralkyl, C7-Cn aralkyloxy, Ce-CioheteroaralkyI, C8-Cnaralkenyl, C -Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide; Rsι is hydrogen, My, Ci-CealkyI, C2-d2alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, C5-Cgheteroaryl, C7-Cιιaralkyl or C6-Cι0heteroaralkyl, R^ is hydrogen, Ci-CealkyI, C2-Cι2alkenyl, C3-d2cyclo- alkyl, C2-Cnheterocycloalkyl, C6-Ci0aryl, Cs-Cgheteroaryl, C7-Cnaralkyl or Ce-Cioheteroaralkyl, and Rs2 and R20 are hydrogen, Cι-C12alkyl, C2-Cealkenyl, C3-C12cyclo- alkyl, C3-Cecycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-C10aryl, Cs-Cgheteroaryl, C -Cnaralkyl, C6-C 0heteroaralkyl, C8-Cn-aralkenyl or C7-Cιoheteroar- alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo¬ alkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and hetero¬ aralkenyl as substituents in turn are unsubstituted or substituted by one of the above¬ mentioned substituents; p is 0 or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
9. A compound according to claim 8, wherein R8 and Rg are, independently of one another hydrogen; Ci-CealkyI; C3-Cι2cycloalkyl, C6-Cι0aryl, C7-d6aralkyl with 1 to 6 C atoms in the alkylene group and C6-Cι0aryl, C8-d6aralkenyl with C2-C6alkenylene and Ce-Cioaryl, or di- C6-Cι0aryl-Cι-C6-alkyl, where R8 and Rg are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(0)OMy, Ci-CealkyI, d-C6alkoxy, C6-C10aryl, C6-Cι0aryloxy, S03My, OS03My, NR20SO3My, N02, amino, primary amino, secondary amino and CN, and R20 is hydrogen, d-Cealkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-hetero- cycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cn aralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cι0heteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
10. A compound according to claim 8, wherein Rι0 is Ci-CealkyI; C3-d2cycloalkyl, C6-Cι0aryl, C7-Cι6aralkyl with 1 to 6 C atoms in the alkylene group and C6-Cι0aryl, C8-Cι6ar- alkenyl with C2-C6alkenylene and C6-Cι0aryl, or di-Ce-doaryl-d-Cealkyl, which are unsubsti¬ tuted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(0)OMy, Ci-CealkyI, Cι-C6alkoxy, C6-Cιoaryl, S03My, OS03My, NR20SO3My, N02, amino, primary amino, secondary amino and CN; where R20 is hydrogen, CrCealkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-Cecycloalkenyl, C2-Cn heterocycloalkyl, C2- Cn-heterocycloalkenyl, Ce-Cioaryl, C5-Cgheteroaryl, C7-Cnaralkyl, Ce-Cι0heteroaralkyl, C8-Cn-aralkenyl or C -Cιoheteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
11. A compound according to claim 10, wherein Rι0 is Cι-d2alkyl; C3-d2cycloalkyl, Ce-Cioaryl, C7-d6aralkyl with 1 to 6 C atoms in the alkylene group and C6-Cι0aryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(0)OMy, Cι-C12alkyl, d-C6alkoxy, C6-Cι0aryl, S03My, nitro, amino, primary amino, secondary amino and cyano; or C8-Cι6aralkenyl with C2-C6alkenylene and C6-Cι0aryl, or di-C6-Cιoaryl-Cι-C6alkyl.
12. A compound according to claim 8, wherein R5 and R6 are, together with the -CH-CH- group, C3-Cι2cycloalkylene or C2-Cnheterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(0)ORsι, OC(0)Rs4, C(0)Rs2, NH2, Ci-CealkyI, R8C(0)N(R9)-, -C(0)NR8R9, R8S(0)2N(R9)-; R8OC(0) N(R9)- and Rι0-SO2-, in which R9 is hydrogen and R8 is d-Cealkyl, C6-Cι0aryl or C7-Cnaralkyl, which are unsub¬ stituted or substituted by one or more Cι-Cι2alkoxy; Rι0 is d-Cealkyl, C6-Cιoaryl or C7-Cιιaralkyl which are unsubstituted or substituted by one or more CrCealkyl; Rsι and Rs are CrCealkyl and Rs2 is CrCealkyl, C3-d2cycloalkenyl, C3-C12cycloalkyl or C6-Cι0aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are unsubstituted or substitu¬ ted by one or more substituents selected from the group consisting of OH, C(0)ORsv and OC(0)Rs4' where Rs is My or CrCealkyl and Rs4' is d-Cealkyl; y is 1 and M is a mono¬ valent metal or y is 1/2 and M is a divalent metal.
13. A compound according to claim 12, wherein R5 and R6 are, together with the -CH-CH- group, cyclohexylene.
14. A compound according to claim 8, wherein R5 and Re are, together with the -CH-CH- group, piperidylene.
15. A compound according to claim 14, wherein R5 and R6 are, together with the -CH-CH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(0)ORs1, C(0)Rs2, C(0)NR8R9, NH2, S03My, CrCealkyl, C2-Cealkenyl, d-Cealkoxy, C3-C12cycloalkyl, C3-d2cycloalkenyl, C2-Cnhetero- cycloalkyl, C2-Cnheterocycloalkenyl, C6-Cιoaryl, C6-Cι0aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C -Cnaralkyl, C7-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7- Cioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, sulfon¬ hydrazide, and one or more C atoms of the ring are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, OC(0)Rs4, NH2, OS03My NR20SO3My, Ci-Cealkoxy, C6-Cι0aryloxy, C5-C9heteroaryloxy, C -Cnaralkyloxy, primary amino, secondary amino, sulfonamide, carbamide, carbamate, sulfonhydrazide, carb¬ hydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, d-Cealkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C2-Cn heterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, CrCealkyl, C2-Cι2alkenyl, C3- Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6- C oheteroaralkyl, R8 and R9 are, independently of one another, hydrogen, OH, CrCealkyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cι6aralkyl, C6- Cisheteroaralkyl, C8-Cι8aralkenyl with C2-C6alkenylene and C6-Cιoaryl, or di-C6-Cι0aryl-Cr Ce-alkyl, or R8 and R9 together are tetramethylene, pentamethylene, -(CH2)2-0-(CH2)2-, - (CH2)2-S-(CH2)2- or -(CH2)2-NR7-(CH2)2-, and R7 is H, CrC6alkyl, C7-Cnaralkyl, C(0)Rs2 or sulfonyl; and Rs2 and R20 are hydrogen, CrC12alkyl, C2-d2alkenyl, C3-Cecycloalkyl, C3-Cecycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycioalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cn aralkyl, Ce-CioheteroaralkyI, C8-Cι r aralkenyl or C7-Cιoheteroar- alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
16. A compound according to claim 15, wherein R5 and R6 are, together with the -CH-CH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(0)ORsι, C(0)Rs2, -C(0)NR8R9 and Rι0-SO2- and one or more C atoms of the ring are unsubstituted or substituted by one or more substitu¬ ents selected from the group consisting of OH, NH2, R8S(0)2N(Rg)-; R8C(0)N(R9)- and R8OC(0)N(R9)-, where R9 is hydrogen and R8 is Cι-C12alkyl, C6-Cι0aryl or C7-Cnaralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more Crd2alkoxy; Rio is d-Cealkyl, C6-Cι0aryl or C7-Cuaralkyl which are unsubstituted or substituted by one or more d-Cealkyl; Rsι is d-Cealkyl and Rs2 is d-Cealkyl, C3-Cι2cycloalkenyl, C3-Cι2cyclo- alkyl or Ce-Cioaryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are un¬ substituted or substituted by one or more substituents selected from the group consisting of OH, C(0)ORsV and OC^R^- where RsV is My or d-Cealkyl and R^- is d-Cealkyl; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
17. A compound according to claim 8, wherein R5 and R6 are, together with the -CH-CH- group, piperidylene; which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(0)ORs1, OC(0)Rs4, C(0)Rs2, NH2, d-C^alkyl, R8C(0)N(R9)-, -C(O) NR8R9, R8S(0)2N(R9)-; R8OC(0)N(R9)-, R8R40NC(O)N(R9)-, -OC(0)NR8R9 and Rι0-SO2-, in which R9 is hydrogen and R8 is d-Cealkyl, Ce-C10aryl or C7-Cιιaralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more Crd2alkoxy or C7-Cnaralkyloxy; Rι0 is d-Cealkyl, C6-Cι0aryl or C7-Cnaralkyl which are unsubstituted or substituted by one or more Crd2alkyl; R 0 is hydrogen, d-Cealkyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or Ce-CioheteroaralkyI; Rsι and R^ are Crd2alkyl and Rs2 is d-Cealkyl, C3-Cecycloalkenyl, C3-C12cycloalkyl or C6-Cι0aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(0)ORsr and OC(0)Rs ' where Rs is My or d-Cealkyl and R^- is CrCealkyl; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
18. A compound according to claim 1 , wherein X is cyclohexylene or piperidylene which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH2, C3H7, -C(0)CH3, -C(0)C6H5, -C(0)(CH2)8C(0)OCH3, -C(0)[CH(OH)]2C(0)ONa, C(0)-C6H8(OH)3, -C(0)-C6Hιι, -C(0)OC3H7, -C(0)NHC6H5, -NHS(0)2CH2C6H5, -NHC(0)OCH2C6H5, -NHC(0)C6H3(OCH3)2, -S(0)2-C4H9, -NHC(0)NHC6H5, -S(0)2-C6H4CH3, -S(0)2-CH2C6H5 and -S(O)2-(CH)2Cι0H7.
19. A compound according to claim 1 , wherein R2 is d-C6alkyl.
20. A compound according to claim 1 , wherein substituents for R2 are selected from halo¬ gen, -C(0)OMy, d-Cealkyl, d-C4alkoxy, phenyl, naphthyl, -S03My, d-Ceprimary amino, C2-C20secondary amino, -S02-NR8R9 and -C(0)-NR8R9 in which R8 and R9 are, independent¬ ly of one another, H, d-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, or R8 and R9 together with the N atom are morpholino, thiomorpholino, pyrrolidino or piperidino.
21. A compound according to claim 1 , wherein R2 is hydrogen, unsubstituted d-C6alkyl or CrCealkyl, which is substituted by C(0)OH, -C(0)ONa, -C(0)OK, -OH, -C(0)-NR8R9 or -S02-NR8R9, in which R8 is H, d-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and R9 in- dependently has the meaning of R8, or R8 and Rg are together tetramethylene, penta¬ methylene or -CH2CH2-0-CH2CH2-.
22. A compound according to claim 21 , wherein R2 is hydrogen, methyl, ethyl, HO(0)C-CH2CH2-, NaOC(0)-CH2CH2- or R8R9N-C(0)-CH2CH2-, and R8 and R9are, indepen dently of one another, H, CrC6alkyl, C2-C4hydroxyalkyl, phenyl, benzyl or, together, morpholino.
23. A compound according to claim 1 , wherein the other substituent in Ri has 1 to 20 C atoms.
24. A compound according to claim 23, wherein the other substituent is selected from the group consisting of unsubstituted and substituted d-Cealkyl, C2-d2alkenyl, C3-d2cyclo- alkyl, C3-d2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn aralkenyl and C7-Cιoheteroar- alkenyl.
25. A compound according to claim 24, wherein the other substituent is substituted methyl, or 2-substituted ethyl or cyclohexyl.
26. A compound as claimed in claim 1 , wherein Ri corresponds to a group of the formula III,
Figure imgf000120_0001
in which
R3 is hydrogen or My; and
R4 is d-Cealkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, d-Cnheterocycloalkenyl, C6-Cιoaryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl,
C8-Cn aralkenyl or C7-Cι0heteroaralkenyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ORsι, OC(0)Rs4,
C(0)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, d-Cealkyl, C2-d2alkenyl, d- C12alkoxy, C3-Cι2cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2- C11 heterocycloalkenyl, C6-Cι0aryl, C6-Cι0aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7- Cuaralkyl, C7-Cnaralkyloxy. C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7-Cιoheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfon¬ hydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, CrCealkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, CrC12alkyl, C2-d2alkenyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, C7-Cιιaralkyl or C6-Cι0heteroaralkyl, and Rs2 and R20 are hydrogen, d-Cealkyl, C2-Cealkenyl, C3-Cecycloalkyl, C3-Cι2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn-hetero- cycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cι aralkeny or C7-Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo¬ alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero¬ aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
27. A compound according to claim 26, wherein R3 is hydrogen or My and R is (a) unsubstituted d-Cealkyl; CrCealkyl which is substituted by one or more substituents selected from the group consisting of -NH2, primary amino, secondary amino, Crd2sul- fonyl, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide, aminocarbonyl- amido, C3-d2cycloalkyl, CrC6alkoxy, phenyloxy and benzyloxy; unsubstituted C3-Cecycloalkyl; C3-d2cycloalkyl which is substituted by one or more substituents selected from the group consisting of C3-Cι2cycloalkyl, Cι-C6alkyl, Ci-Cealkoxy, Crd2sulfonyl, phenyloxy and benzyloxy; C6-Cι0aryl; C3-C9heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; C7-Cι6aralkyl with CrC6alkyl and C6-Cι0aryl; C4-d6heteroaralkyl with d-Cealkyl and C3-Cι0heteroaryl with 1 or 2 hetero atom selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to 5 carbon atoms; Ce-Cioaryl, C3-Cgheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms, C7-d6aralkyl with d-Cealkyl and C6-Cι0aryl, C3-Cι6heteroaralkyl with d-C6alkyl and C4-Cι0heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to 5 carbon atoms, which are substituted by one or more substituents selected from the group consisting of OH, halogen, d-CeSUlfonyl, carboxyl, C(0)OMy, CrCealkyl, CrC6alkoxy, C6-C10aryl, S03My, OS03My, NR20SO3My, nitro, NH2, primary amino, secondary amino, carbamide, car amate, sulfonamide and cyano, in which y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, or
(b) CrCealkyl or C7-Cnaralkyl which are unsubstituted or substituted by one or more subs tuents selected from the group consisting of OH, halogen, C(0)ORs1, OC(0)Rs4, C(0)Rs2) nitro, NH2, cyano, S03My, OS03My, NR20SO3My, C Cι2alkyl, C2-Cealkenyl, Crd2alkoxy, C3-Cι2cycloalkyl, C3-d2cycloalkenyl, C2-CnheterocycloalkyJ, C2-Cnheterocycloalkenyl, C6-Cιoaryl, Ce-Cι0aryloxy, C5-Cgheteroaryl, C5-C9heteroaryloxy, C7-Cn aralkyl, C7-Cn aralkyl¬ oxy, Ce-CioheteroaralkyI, C8-Cuaralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondar amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, d-Cealkyl, C2-Cealkenyl, C3-d2cycloalkyl, C2-Cn heterocyclo¬ alkyl, C6-Cι0aryl, Cs-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, CrCealkyl, C2-Cealkenyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cghetero aryl, d-Cnaralkyl or C6-Cι0heteroaralkyl and Rs2 and R20 are hydrogen, d-Cealkyl, C2-Cι2alkenyl, C3-d2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-hetero- cycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cι aralken or C7-Cιoheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo¬ alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 an M is a divalent metal.
28. A compound according to claim 27, wherein R3 is hydrogen, K or Na.
29. A compound according to claim 27, wherein R4 is methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, cyclohexyl, naphthyl, phenyl, benzyl, naphthylmethyl, 2-phenylethyl, 3-phenylpropyl cyclohexylmethyl, 2-cyclohexylethyl, furanyl, pyridinyl or pyrimidinyl.
30. A compound according to claim 27, wherein carbamido, carbhydrazido, sulfonamido, sulfonhydrazido, aminocarbonylamide and carbamate as substituent for R4 mean groups o the formulae R8NHC(0)N(R9)-, R8OC(0)N(R9)-, R8C(O)(NH)pN(R9)- and R8S(O)2(NH)pN(R9) in which R8 is H, CrCealkyl, C5- or C6cycloalkyl, C5- or C6cycloalkylmethyl or -ethyl-, C5- or Ceheterocycloalkyl, C5- or C6heterocycloalkylmethyl or -ethyl-, phenyl, naphthyl, benzyl, 2-phenylethyl, diphenylmethyl, which are unsubstituted or substituted by one or more sub¬ stituents from the group of -OH, -NH2, CrC8primary amino, C2-Cι4secondary amino, N02, - CN, -F, -Cl, -C(0)OH, -C(0)ONa, -S03H, -OS03Na, NR20SO3Na in which R20 is hydrogen, CrCealkyl, C2-d2alkenyl, C3-d2cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cιι-heterocycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cιoheteroaralkenyl, and -S03Na, CrC4alkyl, d-C4alkoxy and phenyl, and R9 is H, d-Cioalkyl, phenyl, naphthyl, benzyl, 2-phenylethyl or phenyl-CH=CH-CH2-, and p is 0 or 1.
31. A compound according to claim 27, wherein R4 is a
(a) carbamido-substituted alkyl group R8-C(0)NR9-(CH2)n-, where n is 1 or 2, R8 is hydrogen; CrCealkyl; C3-Cι2cycloalkyl; C6-Cι0aryl or C -d6aralkyl with d-Cealkyl and C6-Cι0aryl; wherein alkyl, cycloalkyl, aryl and aralkyl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, -C(0)OMy, CrCealkyl, CrC6alkoxy, Ce-Cioaryl, S03My, OS03My, NR20SO3My, C(0)ORs1, OC(0)Rs4, nitro, amino and cyano; or C8-Cι6aralkenyl with C2-C6alkenyl and C6-Cιoaryl or di-C6-Cι0aryl- d-C6alkyl; and R9 is H, linear or branched Cι-Cι0alkyl, C5- or C6cycloalkyl, C5- or C6cyclo- alkylmethyl- or -ethyl, phenyl, naphthyl or benzyl, 2-phenylethyl or phenyl-CH=CH-CH2-; y is 1 and M is an alkali metal or y is 1/2 and M is an alkaline earth metal, R20 is hydrogen, CrCealkyl, C2-Cι2alkenyl, C3-Cecycloalkyl, C3-Cecycloalkenyl, Cg-Cnheterocycloalkyl, C2-drheterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cι0heteroaralkenyl, Rsι is hydrogen, My, d-Cealkyl, C2-d2alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, Cs-Cgheteroaryl, C7-Cnaralkyl or Ce-CioheteroaralkyI and R^ is hydrogen, d-Cealkyl, C2-d2alkenyl, C3-d2cycloalkyl, C2-Cιιheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl;
(b) a sulfonamide-substituted alkyl group R8-S02NR9-(CH2)n- in which R8, R9 and n have the meanings indicated in (a);
(c) an aminocarbonylamide- or carbamate-substituted alkyl group RgNH-C(0)-NH-(CH2)„ or RgO-C(0)-NH-(CH2)n in which Rg has the meanings indicated in (a) and additionally phenyl and n has the meanings indicated in (a);
(d) a carbhydrazido-substituted alkyl group R8-C(0)-NHNR9-(CH2)n- in which R8, R9 and n have the meanings indicated in (a); or
(e) a sulfonhydrazido-substituted alkyl group R8-S02-NHNRg-(CH2)n- in which R8, R9 and n have the meanings indicated in (a).
32. A compound according to claim 27, wherein R is an
(a) amide R8C(0)N(R9)(CH2)n- or R8S(0)2N(R9)(CH2)n-; where R8 and R9 are, independently of one another, hydrogen; unsubstituted d-C12alkyl; CrCealkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(0)ONa, d-Cealkyl, CrC6alkoxy, C6-C10aryl, -S03H, OS03Na, NR20SO3Na, S03Na, nitro and cyano; unsubstituted C3-d2cycloalkyl; C3-d2cycloalkyl substituted by one or more OH; unsubstituted C6-Cι0aryl, unsubstituted C7-Cι2aralkyl with d-C6alkyl and C6-Cι0aryl; C6-Cι0aryl, or C -Cearalkyl with d-C6alkyl and C6-C10aryl, which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(0)ONa, -C(0)OK, Cι-C12alkyl, CrC6alkoxy, Ce-Cioaryl, S03Na, OS03Na, NR20SO3Na, C(0)ORsι, OC(0)Rs , nitro, amino and cyano, R20 is hydrogen, d-Cealkyl, C2-Cealkenyl, C3-Cι2cyclo- alkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, Cs-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cι0heteroar- alkenyl, Rsi is hydrogen, My, d-Cealkyl, C2-Cι2alkenyl, C3-Cecycloalkyl, C2-Cn heterocyclo¬ alkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl and Rs4 is hydrogen, CrCealkyl, C2-d2alkenyl, C3-Cι2cycloalkyl, C2-Cn heterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, C7-Cιιaralkyl or C6-Cι0heteroaralkyl; and n is 2 or 1 ; or
(b) sulfonamide R8S(0)2N(R9)(CH2)n-, where R8 is CrCealkyl, which is unsubstituted or sub¬ stituted by one or more halogen atoms; or C6-C 0aryl, which is substituted by one or more d-dalkyl, d-C alkoxy, halogen, -CN or -N02, and Rg is hydrogen or isobutyl, and n is 2 or 1 ; or
(c) aminocarbonylamide R8-NH-C(0)-NH(CH2)n-, in which R8 is CrCealkyl or Ce-Cioaryl, which is unsubstituted or substituted by halogen, -CN, -N02, d-C alkyl, d-C4alkoxy, C5- or Cecycloalkyl, C6-Cι0aryl or C7-Cearalkyl, and n is 2 or 1 ; or
(d) aminoalkyl R8'R9'N(CH2)n-, where R8- and R9- are, independently of one another, hydro¬ gen; unsubstituted d-Cealkyl; d-Cealkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ORsι, OC(0)Rs4, C(0)-NRnRe, CrCealkyl, CrC6alkoxy, C6-Cι0aryl, -S03H, S03Na, OS03Na, NR20SO3Na, nitro, amino and cyano; unsubstituted C3-d2cycloalkyl; C3-d2cycloalkyl which is substituted by one or more OH; Ce-Cioaryl; C -d6aralkyl with d-C6alkyl and C6-Cι0aryl; or C8-Cι6aralkenyl with C2-C6alkenyl and C6-Cι0aryl, where aryl and the aryl in the aralkyl and aralkenyl are unsub¬ stituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORsι, OCfOJR. , -C(O)ONa, -C(O)OK, -C(0)-NR,ιRe, Crd2alkyl, CrC6alkoxy, C6-Cιoaryl, -S03H, S03Na, OS03Na, NR20SO3Na, nitro, amino and cyano; wherein n is 2 and preferably 1 , and Rsι is hydrogen, K or Na, C C12alkyl, C2-d2alkenyl, C3-C12cycloalkyl, C2-Cn heterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-C10heteroaralkyl, Rs is hydrogen, d-Cealkyl, C2-d2alkenyl, C3-C12cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, Rn is H, d-dalkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and Ri2 independently has the meaning of Rn, or Rn and Re together are tetramethylene, pentamethylene or -CH2CH2-0-CH2CH2- and R20 is hydrogen, d-Cealkyl, C2-d2alkenyl, C3-Cι2cycloalkyl, C3-Cecycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, Cs-Cgheteroaryl, C -Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-Cιoheteroar- alkenyl.
33. A compound according to claim 32, wherein R is an amide R8C(0)N(R9)(CH2)n- or R8S(0)2N(Rg)(CH2)n-, where R8is unsubstituted d-Cealkyl; CrC8alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ONa and C6-Ci0aryl; unsubstituted C3-Cι2cycloalkyl; C3-C8cycloalkyl which is substituted by one or more OH; unsubstituted C6-Cι0aryl or C7-Cearalkyl with d-C6alkyl; C6-Cι0aryl, C7-C 2ar- alkyl with CrC6alkyl and C6-Cι0aryl or C8-Cι6aralkenyl with C2-C6-alkenyl and C6-Cι0aryl, which is substituted by one or more substituents selected from the group consisting of halo¬ gen, -C(0)OH, C(0)ONa, d-Cealkyl, CrC6alkoxy, -S03H, S03Na, OS03Na, NR20SO3Na in which R20 is hydrogen, d-Cealkyl, C2-Cealkenyl, C3-Cι2cycloalkyl, C3-Cecycloalkenyl, C2-Cιιheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-C oheteroaralkyl, C8-Cn-aralkenyl or C7-Cι0heteroaralkenyl, and nitro and cyano; and R9 is hydrogen; unsubstituted CrC6alkyl, unsubstituted C6-Cι0aryl, unsubstituted C7-Cι2aralkyl with CrC6alkyl and C6-Cι0aryl; or C8-d6aralkenyl with C2-C6alkenyl and C6-Cι0aryl, and n is 2 or 1.
34. A compound according to claim 32, wherein R4 is an amide R8C(0)N(R9)(CH2)n-, where R8 is unsubstituted CrCealkyl; d-Cealkyl which is substituted by one or more substituents selected from the group consisting of cyclohexyl, OH, halogen, -C(0)OH, -C(0)ONa and phenyl; unsubstituted C3-d2cycloalkyl; C3-d2cycloalkyl which is substituted by one or more OH; unsubstituted C6-Cι0aryl; C6-Cι0aryl, which is substituted by one or more substituents selected from the group consisting of halogen, C(0)ONa, -C(O)OH, CrC6alkyl, CrC6alkoxy, phenyl, -S03H, S03Na, OSO3Na, NHS03Na, nitro and cyano; or C7-Cι6aralkyl with d- C6alkyl and C6-Cιoaryl, and Rg is hydrogen; unsubstituted CrC6alkyl, unsubstituted C7- Cι6aralkyl with d-C6alkyl and C6-Cι0aryl; or C8-d6aralkenyl with C2-C6alkenyl and C6-Cι0aryl, and n is 2 or 1.
35. A compound according to claim 34, wherein R8 is unsubstituted d-Cealkyl; d-dalkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)OH, C(0)ONa and phenyl; unsubstituted C3-d2cycloalkyl; C3-Cι2cycloalkyl which is substituted by one or more OH, unsubstituted C6-Cι0aryl; C6-Cι0aryl which is substi¬ tuted by one or more substituents selected from the group consisting of halogen, -C(O)OH, C(0)ONa, d-Cealkyl, CrC6alkoxy, -S03H, S03Na, OS03Na, NHS03Na, nitro and cyano; or unsubstituted C7-Cι6aralkyl with d-Cealkyl and Ce-Cioaryl, and R9 is H, d-C4alkyl, phenyl- CH2-, phenyl-CH2CH2, phenyl-(CH2)3- or phenyl-CH=CH-CH2-, and n is 2 or 1.
36. A compound according to claim 32, wherein R is an amino alkyl R8-R9'NCH2-, in which Rff and R# are, independently of one another, hydrogen; d-C8alkyl, cyclopentyl, cyclohexyl, C5- or C6cycloalkylmethyl, phenyl-CrC4alkyl or phenyl-C2-C alkenyl.
37. A compound according to claim 32, wherein R4 is an amine R8'RgNCH2-, where R8- and Rg> are, independently of one another, H, CrC6alkyl, phenyl-d- or -C2alkyl.
38. A compound according to claim 26, wherein R4 is C7-Cnaralkyl, C3-d2cycloalkyl or CrCealkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of NH2, C3-d2cycloalkyl, primary amino, secondary amino, sulfonamide and carbamide and aminocarbonylamido.
39. A compound according to claim 38, wherein the substituents for d-Cealkyl are selected from the group consisting of NH2, cyclohexyl, C6-Cι0aryl, R8C(0)N(R9)-, R8S(0)2N(R9)-, R8NHC(0)NR9- and RffRgN-, in which R8 and R9 are, independently of one another, hydro¬ gen, CrCealkyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryI, C7-Cιιaralkyl or C6-Cι0heteroaralkyl and Rff and R9- are, independently of one another, hydrogen, OH, CrC12alkyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, Cs-Cghetero¬ aryl, C7-Cnaralkyl or C6-Ci0heteroaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ORsι, OC(0)Rs4) C(0)RS2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My, CrC12alkyl, C2-Cι2alkenyi, d-Cealkoxy, C3-Cecycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C -Cn aralkyl, C7-Cnaralkyloxy, C6-Cιoheteroaraikyl, C8-Cnaralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, d-Cealkyl, C2-d2alkenyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, Ce-Cioaryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, R^ is hydrogen, C C12alkyl, C2-Cealkenyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl and Rs2 and R20 are hydrogen, CrCealkyl, C2-Cealkenyl, C3-Cecycloalkyl, C3-d2cycloalkenyl, C2-C heterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-Cι0aryl, Cs-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, Cs-Cn-aralkenyl or C7-Cιoheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo¬ alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero¬ aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; p is 0 or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal; or R8. and Rff together are tetramethylene, pentamethylene, -(CH2)2-0-(CH2)2-, -(CH2)2-S-(CH2)2- or -(CH2)2-NR7-(CH2)2-, and R7 is H, d-C6alkyl. C7-Cnar- alkyl, C(0)Rs2 or sulfonyl.
40. A compound according to claim 39, wherein R4 is CH2-C6Hs, (CH2)2-C6H5, cyclohexyl, methyl, ethyl or isopropyl which are unsubstituted or substituted by one or more substitu¬ ents selected from the group consisting of NH2, cyclohexyl, C6-Cι0aryl, R8C(0)N(R9)-, R8S(0)2N(R9)-, R8NHC(0)NR9-, NR9C(0)NHR8 and R8.R9N-, in which R8, R9, R8. and R9. are, independently of one another, hydrogen, d-Cealkyl, C3-d2cycloalkyl, C6-Cι0aryl or C7-C ιaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)OMy, nitro, cyano, S03My, OS03My, NHS03My, CrCealkyl, CrCι2alkoxy and C6-Cιoaryl, where y is 1 and M is a monovalent metall or y is 1/2 and M is a divalent metal.
41. A compound according to claim 26, wherein R4 is C6Hn, CH(CH3)2, CH2-phenyl, (CH2)2-phenyl, CH2NHC(O)-phenyl, CH2NHC(O)(CH2)3-phenyl, CH2NHC(0)(CH2)3OH, CH2NHC(0)CF3, CH2NHC(O)C6Hn, CH2NHC(O)CnH23, CH2NHC(0)CH(C6Hs)2, CH2HNC(0)NHC6H5, CH2NHC(0)C2H4C02Na, CH2NHC(0)C6[(1 ,3,4,5)OH]4H7, CH2NHC(0)C6H4-p-S03Na, CH2NHC(0)C6H4CI, CH2NHC(0)C6H4N02> CH2NHC(0)C6H4OCH3, CH2NHC(0)C6H4(3,4)CI2, CH2NHC(0)C6H4CH3, CH2NHC(0)C6H4C6H5, CH2NHC(0)C6H4CN, CH2NHC(O)C10H7, CH2NHC(0)C6H4COONa, CH2NHC(0)(CHOH)2COONa, CH2N(CH2CH=CH-phenyl)[C(0)-phenyl], CH2N[CH2CH(CH3)2][C(0)-phenyl], CH2N[C(0)C6H5]CH2C6H5, CH2N[C(0)C6H5](CH2)3C6H5l CHzCβHn, (CH2)2C6Hιι, CH2NH2, CH2NHCH2CH=CH-phenyl, CH2NHCH2-phenyl, CH2NHCH2CH(CH3)2, CH2N(CH2-phenyl)2, CH2N[CH2CH(CH3)2]2, CH2NHS02-p-nitrophenyl, CH2NHS02-p-tolyl, CH2NHS02CF3, CH2NHC(0)NHC6H5 or CH2N[S02-p-nitrophenyl][CH2CH(CH3)2]2.
42. A compound according to claim 1 , which corresponds to the formula la
Figure imgf000128_0001
in which
R3 is hydrogen or My; and
R is Crd2alkyl, C2-d2alkenyl, C3-d2cycloalkyl, C3-d2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C -Cnaralkyl, C6-Ci0heteroaralkyl, C8-Cnaralkenyl or C7-Cι0heteroaralkenyl, which are unsubstituted or substituted once or several times;
R5 and R6 are, independently of one another, hydrogen, d-Cealkyl, C3-d2cycloalkyl, C2-Cιι heterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-C10heteroaralkyl; or R5 and R6 are, together with the -CH-CH- group, C3-d2cycloalkylene, C4-Cι2cycloalken- ylene, C2-Cnheterocycloalkylene and C3-Cnheterocycloalkenylene with hetero atoms selected from the group of -0-, -S- and -N-; where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclo¬ alkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted once or several times; where the substituent is selected from the group OH, halogen, C(0)ORsι, OC(O)Rs , C(O)Rs2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My, d-Cealkyl, C2-d2alkenyl, Crd2alkoxy, C3-Cι2cycloalkyl, C3-C12cycloalkenyl, C2-Cnhetero- cycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-Cnaralkyl, C7-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7- Cioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonyl¬ amide, where Rsι is hydrogen, My, d-Cealkyl, C2-d2alkenyl, C3-Cι2cycloalkyl, C2-Cnhetero- cycloalkyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, CrC12alkyl, C2-d2alkenyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cghetero¬ aryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl and Rs2 and R20 are hydrogen, d-C12alkyl, C2- Cealkenyl, C3-Cecycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-d .- heterocycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C -Cnaralkyl, C6-Cι0heteroaralkyl, C8-dr aralkenyl or C7-Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are substituted or unsubstituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is a 1/2 and M is a divalent metal.
43. A compound according to claim 42, wherein R3 is H, K or Na; R5 and R6 are, together with the -CH-CH- group, C3-d2cycloalkylene, C -d2cycloalkenylene, C2-Cn heterocyclo¬ alkylene and C3-Cιι heterocycloalkenylene with hetero atoms selected from the group -0-, -S- and -N-; which are unsubstituted or substituted once or several times; where the sub¬ stituent is selected from the group consisting of OH, halogen, C(0)ORsι, OC^R^, C(0)Rs2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My, Crd2alkyl, C2-d2alkenyl, CrCealkoxy, C3-d2cycloalkyI, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-Cι0aryl, C6-Cιoaryloxy, Cs-Cgheteroaryl, C5-C9heteroaryloxy, C7-Cnaralkyl, C7-Cnaralkyloxy, C6-Cιoheteroaralkyl, C8-Cn aralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, in which Rsι is hydrogen, My, d-Cealkyl, C2-Cealkenyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, Cs-Cgheteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, d-Cealkyl, C2-Cι2alkenyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl and Rs2 and R20 are hydrogen, CrCealkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-Cecycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn -aralkenyl or C7-Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo- alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero¬ aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal;
(a) R is a residue Re-(CH2)n- or cyclohexyl, in which n is 1 or 2 and
Re is Cι-Cι0alkyl, C5-C8cycloalkyl, C6-Cι0aryl or C8-Cearalkenyl, which are unsubstituted or substituted by d-C4alkyl, C C4alkoxy, F, Cl, -CN or -N02; or Re is an amino group -NR8R9, and R8- and Rff are Crd2alkyl or unsubstituted or d-dalkyl-substituted C5- or C6cycloalkyl, Ce-Cioaryl, C7-Cearalkyl or C8-d2aralkenyl; or Re is an amide group -N(R9)C(0)R8, -N(R9)S(0)2R8, -NR9C(0)NHR8 or -NR9C(0)NHR8 in which R8 is C6-Cιoaryl, which is unsubstituted or substituted by d-C alkyl, d-C4alkoxy, F, Cl, -CN or -N02, or d-Cι0alkyl which is unsubstituted or substituted by F or Cl, and R9 is H, d-Cioalkyl, C5- or C6cycloalkyl, C5- or C6cycloalkyl-CrC6alkyl, phenyl-CrC6alkyl or phenyl- C2-C6alkenyl; or
(b) R is CrC12alkyl, C3-Cecycloalkyl or C7-Cnaralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(0)ORsι, OC(0)Rs4, C(0)Rs2, nitro, NH2, cyano, S03My, OS03My, NR20SO3My, d-Cealkyl, C2-Cι2alkenyl, Ci-Cealkoxy, C3-Cι2cycloalkyl, C3-Cecycloalkenyl, C2-Cn heterocycloalkyl, C2- C11 heterocycloalkenyl, C6-Cι0aryl, Cβ-Cioaryloxy, C5-C9heteroaryl, C5-Cgheteroaryloxy, C7- Cnaralkyl, C7-Cnaralkyloxy, C6-Ci0heteroaralkyl, C8-Cn aralkenyl, C -Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sul¬ fonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, CrCealkyl, C2-d2alkenyl, C3-d2cycloalkyl, C2-Cn heterocycloalkyl, Ce-Cioaryl, C5-C9heteroaryl, C -Cnaralkyl or C6-Cι0heteroaralkyl, is hydrogen, d-Cealkyl, C2-d2alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, Cs-Cghetero¬ aryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl and Rs2 and R20 are hydrogen, d-Cealkyl, C2-Cι2alkenyl, C3-Cecycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C -Cι0heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo¬ alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero¬ aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
44. A compound according to claim 43, wherein
(i) R is CeHn, CeH -CH2, CeHιrCH2CH2-, CeHs-CH2-, CeHs-CH2CH2- or CeH5-CH=CH-CH2-; (ii) R is CeHn, CeHn-CH2-, C6HιrCH2CH2-, CeHs-CH2-, CeHs-CH2CH2-, -CH2-NRι9-S02Rι8, -CH2-NRi9-C(O)R40, CH2NHC(0)NHRι8, -CH2NHR21 or CH2N(R2ι)2, in which R1β is -C6H5, phenyl which is substituted by 1 to 3 methyl or methoxy or -N02 or F or Cl, or d-C4alkyl, which is substituted by F; Fu0 is phenyl which is unsubstituted or substituted by 1 to 3 methyl or methoxy or -NO2 or F or Cl; Re is H, d-Cealkyl, phenyl-(CH2)z- with z equal to a number from 1 to 3, phenyl-CH=CH-CH2-, -CH2-CH(CH3)2 or benzyl; and R2 is -CH2-CR22R23R24 in which R22 and R23, methyl, ethyl or phenyl and R2 is H, ethyl or methyl; or
(iii) R4 is C6Hn, CH2-C6H5, (CH2)2-CeH5, methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH2, cyclo¬ hexyl, C6-Cιoaryl, R8C(0)N(R9)-, R8S(0)2N(R9)-, NR9C(O)NHR8 and R8R9-N- in which R8, R9, R8- and Rff are, independently of one another, hydrogen, d-Cealkyl, C3-Cι2cycloalkyl, C6-Cιoaryl or C7-Cnaralkyl which are unsubstituted or substituted by one or more substitu¬ ents selected from the group consisting of OH, halogen, C(0)OMy, nitro, cyano, S03My, OS03My, NR20SO3My, d-Cealkyl, Cι-Cι2alkoxy and C6-Cι0aryl, where R20 is hydrogen, d-Cealkyl, C2-C12alkenyl, C3-Cι2cycloalkyl, C3-Cecycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn-heterocycloalkenyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cn aralkyl, C6-Cιoheteroaralkyl, Cs-Cn-aralkenyl or C7-Cι0heteroaralkenyl, y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
45. A compound according to claim 42, wherein R4 is CeHn, CH(CH3)2, CH2-phenyl, (CH2)2-phenyl, CH2NHC(0)-phenyI, CH2NHC(0)(CH2)3-phenyl, CH2NHC(0)(CH2)3OH, CH2NHC(0)CF3, CH2NHC(0)C6H,ι, CH2NHC(0)CnH23, CH2NHC(0)CH(C6H5)2, CH2HNC(0)NHC6H5, CH2NHC(0)C2H4CO2Na, CH2NHC(0)C6[(1 ,3,4,5)OH]4H7, CH2NHC(0)C6H4-p-S03Na, CH2NHC(0)C6H4CI, CH2NHC(0)C6H4N02, CH2NHC(0)C6H4OCH3, CH2NHC(0)C6H4(3,4)CI2, CH2NHC(0)C6H4CH3, CH2NHC(0)C6H4C6Hs, CH2NHC(0)C6H4CN, CH2NHC(0)CioH7, CH2NHC(0)C6H4COONa, CH2NHC(0)(CHOH)2COONa, CH2N(CH2CH=CH-phenyl)[C(0)-phenyl], CH2N[CH2CH(CH3)2][C(O)-phenyl], CH2N[C(0)C6H5]CH2C6H5, CH2N[C(0)C6H5](CH2)3C6H5, CH2C6Hn, (CH2)2C6Hn, CH2NH2, CH2NHCH2CH=CH-phenyl, CH2NHCH2-phenyl, CH2NHCH2CH(CH3)2, CH2N(CH2-phenyl)2, CH2N[CH2CH(CH3)2]2, CH2NHS02-p-nitrophenyl, CH2NHS02-p-tolyl, CH2NHS02CF3, CH2NHC(0)NHC6H5 or CH2N[S02-p-nitrophenyl][CH2CH(CH3)2]2.
46. A process for the preparation of the compounds of the formula I according to claim 1 which comprises etherifying the 3-OH group of a compound of the formula V
Figure imgf000132_0001
in which R2and X have the meanings mentioned in claim 1 , Re is a protective group and Re' and Re" are, independently of one another, hydrogen or a protective group, with a compound of the formula VI
RrR 13 (VI)
in which Ri has the meaning mentioned in claim 1 and Reis a leaving group, and elimina¬ ting the protective groups.
47. A process for the preparation of the compounds of the formula I according to claim 1 which comprises glycosidically linking the protected fucose hydroxy ether of the formula VII
Figure imgf000132_0002
(VII), in which R2 and X have the meanings mentioned in claim 1 , and R is a protective group, with the protected galactose of the formula VIII
Figure imgf000133_0001
in which Ri and Re have the meanings mentioned in claim 1 , Z is O or S, and R is a leaving group, and subsequently removing the protective groups from the resulting compound.
48. A compound of the formula V
Figure imgf000133_0002
in which
X is the residue of a non-glycosidic aliphatic 1 ,2-diol;
R2 is hydrogen, Crd2alkyl or C6aryl; where the alkyl and the aryl are unsubstituted or sub¬ stituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORsι, OC JR^, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, d-Cealkyl, C2-d2alkenyl, Crd2alkoxy, C3-d2cycloalkyl, C3-d2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cιιheterocycloalkenyl, C6-Cιoaryl, C6-Cι0aryloxy, Cs-Cgheteroaryl, C5-Cgheteroaryloxy, C7-Cnaralkyl, C -d aralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7-Cιoheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsι is hydrogen, My, d-Cealkyl, C2-d2alkenyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, Rs4 is hydrogen, d-Cι2alkyl, C2-Cι2alkenyl, C3-Cecycloalkyl, C2-Cnheterocycloalkyl, C6-C10aryl, Cs-Cghetero¬ aryl, C7-Cnaralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, d-C12alkyl, C2-Cealkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-Cιoaryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cn-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo¬ alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero¬ aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal;
Re is a protective group and Re' and R12" are, independently of one another, hydrogen or a protective group.
49. A process for the preparation of a compound of the formula V according to claim 48 which comprises initially synthesizing pseudo-trisaccharide building blocks by glycosidic attachment for the activated and protected galactose to the fucose-O-X-OH building block or by glycosidic attachment of suitably protected and activated fucose to a galactose- O-X-OH building block, then introducing the group Ri into the pseudotrisaccharide and subsequently modifying the resulting compounds in the desired manner.
50. A compound according to claim 1 , for use in a therapeutic method for the treatment of disorders in warm-blooded animals, including humans.
51. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 , alone or together with other active substances, a pharmaceutical carrier, and, where appropriate, excipients.
PCT/EP1996/002785 1995-06-29 1996-06-26 Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a WO1997001569A1 (en)

Priority Applications (10)

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AU63053/96A AU707474B2 (en) 1995-06-29 1996-06-26 Diglycosylated 1,2-diols as mimetics of sialyl-lewis X and sialyl-lewis A
PL96324258A PL324258A1 (en) 1995-06-29 1996-06-26 Diglycosiled 1,2-dioles mimetisingly acting on sialed lewis x and sialed lewis a
EP96922034A EP0836610A1 (en) 1995-06-29 1996-06-26 Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a
SI9620099A SI9620099A (en) 1995-06-29 1996-06-26 Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a
NZ311686A NZ311686A (en) 1995-06-29 1996-06-26 Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a
BR9609285A BR9609285A (en) 1995-06-29 1996-06-26 Diglycosylated diols-1,2 as mimetics of sialyl-lewis x and sialyl-lewis a
SK1778-97A SK177897A3 (en) 1995-06-29 1996-06-26 Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a
JP9504171A JPH11508548A (en) 1995-06-29 1996-06-26 Diglycosylated 1,2-diols as mimics of sialyl-Lewis X and sialyl-Lewis A
EA199800103A EA001356B1 (en) 1995-06-29 1996-06-26 Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a
NO976065A NO976065L (en) 1995-06-29 1997-12-23 Diglucosylated 1,2-diols as mimetics of sialyl-Lewis X and sialyl-Lewis A

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US7361644B2 (en) 2003-11-19 2008-04-22 Glycomimetics, Inc. Specific antagonist for both E- and P-selectins
WO2008100453A1 (en) * 2007-02-09 2008-08-21 Glycomimetics, Inc. Methods of use of glycomimetics with replacements for hexoses and n-acetyl hexosamines
WO2008060378A3 (en) * 2006-10-12 2008-10-02 Glycomimetics Inc Glycomimetic replacements for hexoses and n-acetyl hexosamines
US7517980B2 (en) 2005-08-09 2009-04-14 Glycomimetics, Inc. Glycomimetric inhibitors of the PA-IL lectin, PA-IIL lectin or both the lectins from Pseudomonas
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US10519181B2 (en) 2014-12-03 2019-12-31 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectins and CXCR4 chemokine receptors
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US11433086B2 (en) 2016-08-08 2022-09-06 Glycomimetics, Inc. Combination of T-cell checkpoint inhibitors with inhibitors of e-selectin or CXCR4, or with heterobifunctional inhibitors of both E-selectin and CXCR4
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CA2224346A1 (en) 1997-01-16
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JPH11508548A (en) 1999-07-27
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IL118740A0 (en) 1996-10-16
HUP9801805A2 (en) 1998-12-28
EP0836610A1 (en) 1998-04-22
EA001356B1 (en) 2001-02-26
SK177897A3 (en) 1998-08-05
EA199800103A1 (en) 1998-08-27

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