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WO1998006730A1 - Modified oligosaccharides - Google Patents

Modified oligosaccharides Download PDF

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Publication number
WO1998006730A1
WO1998006730A1 PCT/EP1997/004279 EP9704279W WO9806730A1 WO 1998006730 A1 WO1998006730 A1 WO 1998006730A1 EP 9704279 W EP9704279 W EP 9704279W WO 9806730 A1 WO9806730 A1 WO 9806730A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
aryl
cycloalkenyl
alkenyl
Prior art date
Application number
PCT/EP1997/004279
Other languages
French (fr)
Inventor
Gebhard Thoma
Rolf BÄNTELI
Willy Kinzy
Original Assignee
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to IL12790897A priority Critical patent/IL127908A0/en
Priority to SK156-99A priority patent/SK15699A3/en
Priority to CA002260854A priority patent/CA2260854A1/en
Priority to NZ334048A priority patent/NZ334048A/en
Priority to AU43788/97A priority patent/AU720381B2/en
Priority to PL97331286A priority patent/PL331286A1/en
Priority to EP97941916A priority patent/EP0920437A1/en
Priority to BR9711117-1A priority patent/BR9711117A/en
Priority to JP10509358A priority patent/JP2000516224A/en
Publication of WO1998006730A1 publication Critical patent/WO1998006730A1/en
Priority to NO990497A priority patent/NO990497L/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages

Definitions

  • the present invention relates to mimetics of sialyl-Lewis X and A, in which, in the natural tetrasaccha ⁇ de, the neuraminic acid residue is replaced by an S-configu rated methyl substituted with one carboxyl residue and one other substituent and the natural N-acetyl group in the N-acetylglucosamine monomer is replaced by a variety of different aliphatic and aromatic substituents or the N-acetylglucosamine residue is replaced by a tetrahydropyran derivative, to processes for the preparation of these compounds, to their use as a pharmaceutical and to pharmaceutical compositions comprising them.
  • 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 endothe u ⁇ r which lines the blood vessels expresses adhesion proteins on its surface.
  • the P and E selectins bring about, by a protein-carbohydrate 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 activation of certain proteins (integnns) on their surface which ensure firm adhesion of the leukocytes to the endothe um This is followed by migration of the leukocytes into the damaged tissue.
  • R is an S-configurated methyl substituted with a carboxy and one other substituent
  • R 2 is hydrogen, d-C 12 alkyl or C 6 aryl; where the alkyl and the aryl are unsubstituted or substituted by one or more substituents
  • Z is a group of the formula Ma, lib or He
  • X is -C(O)-, -C(S)-, -S(O) 2 -, -C(O)Q- or -C(S)Q-, in which Q is NH, O, S, S-C,-C 6 alkylene,
  • R T1 is C,-C 12 alkyl, C 2 -C ⁇ 2 alkenyl, CrC ⁇ 2 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C ⁇ 2 cycloalkenyl,
  • R T2 is C 3 -C ⁇ 2 cycloalkyl, C 3 -C ⁇ 2 cycloalkenyl, C 2 -Cnheterocycloalkyl, C 2 -d ⁇ heterocycloalkenyl,
  • R B5 is NH 2 , primary amino, secondary amino or amido
  • R 5 is X'-R T1C , C(O)NR T2C R T3C , C(O)R T4C or C(O)OR T5C , wherein X' is C,-C 4 alkylene,
  • R T1C is hydrogen, halogen, d-C ⁇ alkyl, C r Cnheteroalkyl, C 3 -C 12 alkenyl, C 3 -C 12 cycloalkyl,
  • each of R T2C , R T3C and R T4C is independently hydrogen, d-C 12 alkyl, d-Cuheteroalkyl,
  • each of R T5C , R 770 and R T8C is independently hydrogen, M y , d-C ⁇ 2 alkyl, d-C n heteroalkyl,
  • R T6C is hydrogen, d-C 12 alkyl, C ⁇ -d ⁇ heteroalkyl, C 3 -C ⁇ 2 alkenyl, C 3 -d 2 cycloalkyl,
  • R T9C is C C 12 alkyl, C,-d ⁇ heteroalkyl, C 3 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl,
  • R s1 is hydro- gen, M y , C,-C ⁇ 2 alkyl, C 2 -C ⁇ 2 alkenyl, C 3 -C ⁇ 2 cycloalkyl, C 2 -d ⁇ heterocycloalkyl, C 6 -C ⁇ 0 aryl, Cs-Cgheteroaryl, C 7 -C ⁇ aralkyl or C 6 -C 10 heteroaralkyl
  • R 54 is hydrogen, d-C 12 alkyl, C
  • Z is bound to the galactose moiety via the carbon atom 4 in case of formula lla and via the carbon atom 3 in case of formulae lib and lie.
  • M is preferably an alkali metal (for example lithium, sodium, potassium, rubidium and caesium), an alkaline earth metal (for example magnesium, calcium and strontium) or manganese, iron, zinc or silver.
  • alkali metal for example lithium, sodium, potassium, rubidium and caesium
  • alkaline earth metal for example magnesium, calcium and strontium
  • manganese iron, zinc or silver.
  • Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, especially fluorine or chlorine.
  • Alkyl may be linear or branched, preferably branched once or twice in the ⁇ position.
  • alkyl include e.g. methyl, ethyl and the isomers of propyl, butyl, pentyl, h ⁇ xyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl, preferably methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.
  • alkylene examples 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.
  • Cycloalkyl and cycloalkenyl may contain 5 to 8, preferably 5 or 6 carbon atoms.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclohexyl.
  • cycloalkenyl examples include cyclopropenyl, cyclobutenyl, cyclopent- enyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, preferably cyclohexenyl.
  • Examples of cycloalkylene are 1,2-cyclopropylene, 1 ,2-cyclobutylene, 1 ,2-cyclopentylene, 1,2-cyclo- hexylene, 1 ,2-cycloheptylene and 1 ,2-cyclooctylene.
  • Examples of heterocycloalkylene are pyrroiidinylene, piperidinylene, tetrahydrofuranylene, 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.
  • 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 oxygen, nitrogen and sulfur.
  • Examples are derived from benzene, naphthalene, indene, furan, pyrrole, pyrazole, imidazole, isoxazole, oxazole, furazan, thia- diazole, thiophene, thiazole, oxadiazole, triazole, indole, indazole, purine, benzimidazole, benzoxazole, benzothiazole, pyran, pyridine, pyridazine, triazine, pyrimidine, pyrazine, iso- quinoline, cinnoline, phthalazine, quinoline, quinazoline, pterdine, benzotriazine or quinoxa- line.
  • Aryl is preferably naphthyl and phenyl, particularly phenyl.
  • Heteroaryl is preferably furanyl, pyridinyl and pyrimidinyl.
  • Aralkyi preferably has 7 to 12 C atoms and may 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.
  • Aralkenyl is preferably unsubstituted cinnamyl or cinnamyl ring-substituted by a substituent selected from the group consisting of OH, halogen, COOH, C(O)OM y , d-C 12 alkyl, C,-C 6 alkoxy, C 6 -C ⁇ 0 aryl, SO 3 M y , OSO 3 M y , NR 20 SO 3 M y in which R 20 is as defined above.
  • Heteroaralkyl and heteroaralkenyl are preferably C 4 -C 5 heteroarylmethyl and C 4 -C 5 heteroarylethenyl with one or two hetero atoms from the group of O and N, and the heteroaryl may comprise the abovementioned heteroaryl residues.
  • Alkoxy may be linear or branched, preferably branched once or twice in the ⁇ position.
  • alkoxy include e.g. methoxy, ethoxy and the isomers of propoxy, butoxy, pent- oxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy and dodecoxy, preferred are methoxy and ethoxy.
  • 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, and may be e.g. 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, and may be e.g.
  • Primary amino and secondary ammo preferably correspond to R 8 R 9 N in which each R 8 and R 9 is independently hydrogen, OH, SO 3 M y , OSO 3 M y , C ⁇ -C ⁇ 2 alkyl, C 3 -C ⁇ 2 cycioalkyl, C 2 -Cnheterocycloalkyl, C 6 -C 10 aryl, C 5 -Cgheteroaryl, C -Cnaralkyl, C 6 -C 10 heteroaralkyl, C 8 -d 6 aralkenyl with C 2 -C 6 alkenylene and C 6 -C ⁇ oaryl, or di-C ⁇ -doaryl-d-Ce-alkyl, which are unsubstituted or substituted by one or more of the above substituents; or R 8 and R 9 together are tetramethylene, pentamethylene, -(CH 2 ) 2 O(CH 2 ) 2 -, -(CH 2 ) 2
  • Carbamido, carbamate, carbhydrazido, sulfonamido, sulfonhydrazido and aminocarbonyl- amido preferably correspond to a group R 8 C(O)(NH) p N(R 9 )-, -C(O)(NH) p NR 8 R 9 , R 8 OC(O)(NH) p N(R 9 )-, R 8 R 40 NC(O)(NH) P N(R 9 )-, -OC(O)(NH) p NR 8 R 9 , -N(R 0 )C(O)(NH) P NR 8 R 9 , R B 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 )-, -NR 40 S(O) 2 NR 8 R 9 or -N(R 0 )C(O)
  • the sulfonyl substituent corresponds, for example, to the formula R 10 -SO 2 - in which R 0 is C ⁇ -C 12 alkyl, C 3 -C ⁇ 2 cycloalkyl, C 2 -Cnheterocycloalkyl, Ce-doaryl, C 5 -Cgheteroaryl, C T -Cnar- alkyl or C 6 -C ⁇ oheteroaralkyl.
  • the other substituent in R 1 has preferably 1 to 20, more preferably 1 to 16, particularly preferably 1 to 12, and especially preferably 1 to 8 C atoms.
  • the other substituent is preferably selected from the group consisting of unsubstituted and substituted C ⁇ -C ⁇ 2 alkyl, C 2 -C ⁇ 2 alkenyl, C 3 -C ⁇ 2 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -Cnheterocycloalkyl, C 2 -Cnhetero- cycloalkenyl, Ce-Cioaryl, C 5 -C 9 heteroaryl, C 7 -d ⁇ aralkyl, Ce-Cioheteroaralkyl, C 8 -Cnaralkenyl and C 7 -C 10 heteroaralkenyl.
  • the other substituent is particularly substituted methyl, or 2-sub- stituted ethyl or unsubstituted cyclohexyl.
  • suitable substituents are the substituents mentioned above in the definition of R 2 , especially OH, halogen (F, CI or Br), carboxyl, -SO 3 H, C(O)OM y , SO 3 M y , OSO 3 y , NR 20 SO 3 M y in which R 20 is as defined above, or d-C 12 alkyl, C ⁇ -C ⁇ 2 alkoxy, nitro, -NH 2 , primary amino with 1 to 20 C atoms, secondary amino with 2 to 30 C atoms, cyano, C 3 -C 8 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl, C 7 -d 6 heteroaralkyl, where the hetero atoms are selected from the group of O, S
  • hydrocarbon groups and heterohydrocarbon groups in turn are unsubstituted or substituted, for example with C,-C 6 alkyl, C C 6 alkoxy, carboxyl, halogen (F, CI or Br), -OH, -CN or -NO 2 .
  • R corresponds to a group of the formula II
  • R 3 is hydrogen or M y ; and R 4 is C ⁇ -C ⁇ 2 alkyl, C 2 -C ⁇ 2 alkenyl, C 3 -C ⁇ 2 cycloalkyl, C 3 -C ⁇ 2 cycloalkenyl, C 2 -Cnheterocycloalkyl, C 2 -Cn heterocycloalkenyl, C 6 -C ⁇ oaryl, Cs-Cgheteroaryl, C -Cnaralkyl, C 6 -C ⁇ 0 heteroaralkyl, C 8 -Cnaralkenyl or C 7 -C 10 heteroar- alkenyl, which are unsubstituted or substituted by one or more substituents selected from the abovementioned group of substituents.
  • Preferred compounds of the formula I are those in which R 1 corresponds to a group of the formula II in which R 3 is hydrogen or M y and R 4 is
  • substituent for R 4 is selected from the group consisting of NH 2l C 3 -d 2 cycloalkyl, primary amino, secondary amino, sulfonamido, carbamido and aminocarbonylamido.
  • substituents for d-C ⁇ 2 alkyl are NH 2 , cyclohexyl, C 6 -C,oaryl, R 8 R 9 N-, R 8 C(O)N(R 9 )-, R 8 S(O) 2 N(R 9 )-, R 8 NHC(O)NR 9 - and NR 9 C(O)NHR 8 in which R 8 , R 9 , R 8 and R 9 are as defined above.
  • R 4 is R' 4 , R' 4 being CHrC 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, Ce-Cioaryl, R 8 C(O)N(R 9 )-, R 8 S(O) 2 N(R 9 )-, R ⁇ NHC(O)NR 9 -, NR 9 C(O)NHR 8 and R 8 R 9 N-, in which each R 8 , R 9 , R 8 and R 9 is independently hydrogen, C ⁇ -C ⁇ 2 alkyl, C 3 -C ⁇ cycloalkyl, C 6 -C ⁇ 0 aryl or C 7 -Cnaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of
  • R 1 corresponds to formula II, in which R 4 is R" 4 , R" 4 being C ⁇ Hu, CH(CH 3 ) 2) CH 2 -phenyl, (CH 2 ) 2 -phenyl, CH 2 NHC(O)-phenyl, CH 2 NHC(O)(CH 2 ) 3 -phenyl, CH 2 NHC(O)(CH 2 ) 3 OH, CH 2 NHC(O)CF 3 , CHaNHCfOJCeH,, CH 2 NHC(O)C, ⁇ H 23 , CH 2 NHC(O)CH(C 6 H 5 ) 2 , CH 2 HNC(O)NHC 6 H 5 , CH 2 NHC(O)C 2 H 4 CO 2 Na, CH 2 NHC(O)C 6 [(1 ,3,4,5)OH] 4 H 7 , CH 2 NHC(O)C 6 H 4 -p-SO 3 Na, CH 2 NHC(O)C 6 H 4 CI, CH
  • a preferred group of compounds of the formula I are those in which R 2 is hydrogen, unsubstituted or substituted C C 6 alkyl, preferably d-C 4 alkyl, especially methyl or ethyl, wherein the substituent is selected from C(O)OH, -C(O)ONa, -C(O)OK, -OH, -C(O)-NR 8" R 9" and -S0 2 -NR B R 9 , in which R 8" is H, d-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 R 9 are together tetramethylene, pentamethylene or -CH 2 CH 2 -0-CH 2 CH 2 -.
  • Particularly preferred compounds are those in which R 2 is hydrogen, methyl, ethyl, HO(O)CCH 2 CH 2 -, NaOC(O)CH 2 CH 2 - or R 8 " R 9" NC(0)CH 2 CH 2 -, and R 8 and R 9 are, independently of one another, H, CrC 6 alkyl, C 2 -C 4 hydroxyalkyl, phenyl, benzyl or, together, morpholino.
  • X is preferably NH, O or S.
  • X is preferably -C(O)-, -C(S)-, -C(O)O- or -C(S)O-, more preferably -C(O)- or -C(O)O-.
  • a preferred embodiment of the invention are those compounds of the formula IA wherein R T is d-C 12 alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OR s1 , OCfOJR 54 , CfOJR 82 , nitro, NH 2 , cyano, SO 3 M y , OSO 3 M y , NR 20 SO 3 M y , where R s1 , R 84 , R 52 , R 20 , y and M are as defined above.
  • a more preferred embodiment of the invention are those compounds of the formula IA wherein R T1 is C ⁇ -C ⁇ 2 alkyl, which is unsubstituted or substituted by one or more, preferably one C(O)OR s1 , where R sl is as defined above. Most preferably R T1 is C ⁇ -C ⁇ 2 alkyl, which is substituted by C(O)OC ⁇ -C ⁇ 2 alkyl or C(O)ONa.
  • R T1 is (CH 2 ) 8 C(O)OCH 3 or (CH 2 ) ⁇ C(O)ONa.
  • a preferred embodiment of the invention are those compounds of the formula IA wherein R T2 is C 3 -C, 2 cycloalkyl, C 2 -Cnheterocycloalkyl, C 6 -C ⁇ 0 aryl or C 5 -Cgheteroaryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, nitro, NH 2 , cyano, 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 -Cnheterocycloalkenyl, C 6 -C 10 aryl, C 6 -C ⁇ 0 aryl- oxy, C 5 -C 9 heteroaryl, C 5 -C heteroaryloxy, C 7
  • R T2 is C 3 -C ⁇ 2 cycloalkyl, C 2 -Cnheterocycloalkyl, C 6 -C ⁇ 0 aryl or Cs-Cgheteroaryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, d-C ⁇ 2 alkyl, C 6 -C ⁇ 0 aryl or Cs-Cgheteroaryl.
  • R ⁇ z are -3,5-(OH) 2 C 6 H 3 , -3,4-(OH) 2 C 6 H 3 , -3,4-(OCH 3 ) 2 C 6 H 3 , -2-(OH)C 6 H 4 and thyminyl, especially preferred are -3,4-(OH) 2 C 6 H 3 and -3,4-(OCH 3 ) 2 C 6 H 3 .
  • a particularly preferred embodiment of the invention comprises compounds of the formula laA wherein X, R 3 , R 4 , R T1 and R T2 are as defined above.
  • Preferred compounds of the formula laA are those in which X is -C(O)-, -C(S)-, -S(O) 2 -, -C(O)Q- or -C(S)Q-, in which Q is NH, O or S; R 3 is hydrogen or M y ; R 4 is C 7 -Cnaralkyl, C 3 -C ⁇ 2 cycloalkyl or C ⁇ -C 12 alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of NH 2 , C 3 -C ⁇ 2 cycloalkyl, primary amino, secondary ammo, sulfonamido, carbamido and aminocarbonylamido; R T1 is C ⁇ -C ⁇ 2 alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OR s1 , OC(O)R s
  • More preferred compounds of the formula laA are those in which X is -C(O)-, -C(S)-, -C(O)O- or -C(S)O-; R 3 is hydrogen or M y where y and M are as defined above; R 4 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 , C 3 -C 12 cycloalkyl, primary amino, secondary amino, sulfonamido, carbamido and aminocarbonylamido; R T1 is d-C ⁇ 2 alkyl, which is unsubstituted or substituted by one or more C(O)OR s ⁇ where R s1 is as defined above; and R T2 is C 3 -C ⁇ 2 cycloalkyl, C
  • Most preferred compounds of the formula laA are those in which X is -C(O)- or -C(O)O-; R 3 is hydrogen or M y where y and M are as defined above; R 4 is R' 4 ; R T1 is C C ⁇ 2 alkyl, which is substituted by C(O)OR s1 , where R s1 is as defined above; and R T2 is -3,5-(OH) 2 C 6 H 3 , -3,4-(OH) 2 C 6 H 3l -3,4-(OCH 3 ) 2 C 6 H 3 , -2-(OH)C 6 H 4 or thyminyl.
  • Especially preferred compounds of the formula laA are those in which X is -C(O)- or -C(O)O-; R 3 is hydrogen or M y ; R 4 is CH 2 -C 6 H 5 , (CH 2 ) 2 -C 6 H 5 , cyclohexyl, methyl, ethyl or iso- propyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH 2 , cyclohexyl, C 6 -C 10 aryl, R 8 C(O)N(R 9 )-, R 8 S(O) 2 N(R 9 )-, R 8 NHC(O)NR 9 -, NR 9 C(O)NHR 8 and R 8 R 9 N-, in which R 8 , R 9 , R 8' and R 9' are, independently of one another, hydrogen, C ⁇ -C 12 alkyl, cyclohexyl, phenyl, naphthyl or
  • RR 33 iiss hhyyddrogen, K or Na;
  • R 4 is R" 4 ;
  • R T1 is CH 3 ; and
  • R T2 is -3,4-(OH) 2 C 6 H 3 or
  • R 2 , R 3 , R 4 and R B5 have the above meanings.
  • R B5 corresponds to a group of the formula llaB or HbB
  • R B6 is hydrogen, d-C ⁇ 2 alkyl, C 3 -C ⁇ 2 alkenyl, C 3 -C ⁇ 2 cycloalkyl, C 3 -d 2 cycloalkenyl,
  • R B7 is C,-C ⁇ 2 alkyl, C 3 -C 12 alkenyl, C 3 -C ⁇ 2 cycloalkyl, C 3 -C ⁇ 2 cycloalkenyl, C 2 -Cnheterocyclo- alkyl, C 2 -C heterocycloalkenyl, C 6 - or C ⁇ 0 aryl, C 5 -Cgheteroaryl, C 7 -Cnaralkyl, C 6 -C ⁇ 0 hetero- aralkyl, C 9 -C,,aralkenyl, C 8 -C ⁇ 0 heteroaralkenyl, C(O)OR s1 , CfOJR 88 , SO 2 R 10 or SO 3 M y , wherein R B8 is hydrogen, C(O)OR s1 , C ⁇ -C ⁇ 2 alkyl, C 3 -C ⁇ 2 alkenyl, C 3 -C 12 cycloalkyl,
  • R s1 , R 10 , y and M are as defined above;
  • R B11 is C 2 -C 4 alkylene, C 2 -C 4 alkenylene, 1 ,2-C 3 -C ⁇ 2 cycloalkylene, 1 ,2-C 3 -C 12 cycloalkenylene,
  • alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, aralkyi, heteroaralkyi, aralkenyl and heteroaralkenyl are unsubstituted or substituted by one or more substituents selected from the abovementioned group of substituents.
  • Preferred compounds of the formula IB are those in which R 3 is H, K or Na.
  • Preferred compounds of the formula IB are those compounds in which R 4 is R 4 b, R b being C ⁇ -C, 2 alkyl, C 3 -C ⁇ 2 cycloalkyl or C 2 -Cn heterocycloalkyl, where alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by one or more substituents as defined above, preferably R 4 is optionally substituted C ⁇ -C 6 alkyl, more preferably methyl substituted by C 3 -C ⁇ 2 cycloalkyl.
  • Particularly preferred compounds of the formula IB are those compounds in which R 4 is cyclohexyl-methyl.
  • R B5 is primary amino or amido, preferably amido.
  • R B5 corresponds to a group of the formula llaB or HbB, in which R 86 is hydrogen, C ⁇ -C 12 alkyl, C 3 -C ⁇ 2 cycloalkyl, C 2 -Cnheterocycloalkyl, C 6 - or Cioaryl, C 5 -C 9 heteroaryl, C 7 -Cnaralkyl or C 6 -C ⁇ 0 heteroaralkyl; R B7 is d-C ⁇ 2 alkyl, C 3 -C ⁇ 2 cycloalkyl, C 2 -Cn heterocycloalkyl, C 6 - or C 10 aryl, C 5 -C 9 heteroaryl, C 7 -Cnaralkyl, C 6 -C ⁇ 0 heteroaralkyl, C(O)OR' s1 , C(O)R B8 , SO 2 R 10 or SOaMy, wherein R 0 , y and M are as defined above, R' s1 is M
  • R B5 corresponds to a group of the formula llaB or llbB, in which R 86 is hydrogen, C ⁇ -C ⁇ 2 alkyl, C 3 -C ⁇ 2 cycloalkyl or C 6 - or Cioaryl; R B7 is C ⁇ -C ⁇ 2 alkyl, C 3 -C ⁇ 2 cycloalkyl, C 6 - or C ⁇ 0 aryl, C(0)OR ,,sl , C(O)R ,B8 , SO 2 R' 10 or SO 3 M y , wherein R" s1 is M y , C ⁇ -C ⁇ 2 alkyl, C 3 -C ⁇ 2 cycloalkyl or C 6 - or C, 0 aryl; R' 88 is hydrogen, C(O)OR" s ', C ⁇ -C, 2 alkyl, C 3 -C ⁇ 2 cycloalkyl or C 6 - or C ⁇ 0 aryl, primary amino or secondary amino; R'
  • R B5 corresponds to a group of the formula llaB, in which R 86 is hydrogen, d-C ⁇ 2 alkyl, C 3 - C, 2 cycloalkyl or C 6 - or Cioaryl; R B7 is d-C ⁇ alkyl, C 3 -C ⁇ 2 cycloalkyl, C 6 - or Cioaryl, C(O)OR" s1 , C(O)R ,BS , SO 2 R' 10 or SO 3 M y , wherein R" sl , R ,B8 , R ,1 °, y and M are as defined above; and alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, C ⁇ -C ⁇ 2 alkyl, d-C ⁇ 2 alkoxy, C 3 -C ⁇ 2 cycloalkyl or C 6 - or Cioaryl.
  • R 85 corresponds to a group of the formula llaB, in which R 86 is hydrogen or C ⁇ -C ⁇ 2 alkyl; R B7 is Crd 2 alkyl, C(O)Od-C ⁇ 2 alkyl, CfOJR 88 , SO 2 C 6 - or Cioaryl or SO 3 M y ; R 88 is C(O)OM y , d-C 12 alkyl, C 3 -C 12 cycloalkyl, C 6 - or Cioaryl or primary amino; and alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, C ⁇ -C ⁇ 2 alkyl, d-C ⁇ 2 alkoxy or C 6 - or Cioaryl.
  • R 85 corresponds to a group of the formula llaB, in which R 86 is hydrogen, methyl or benzyl; R 87 is methyl, benzyl, C(O)OR s1a , C(O)R B8a , SO 2 R 10a or SO 3 Na, wherein R s1a is methyl or methyl substituted with one or more substituents selected from phenyl, phenyl substituted with one or more substituents selected from methoxy and nitro, and naphthyl; R 88 * is C(O)ONa, methyl substituted with one or more phenyl, ethyl substituted with phenyl, cyclohexyl, phenyl, phenyl substituted with one or more substituents selected from methoxy, chlorine, nitro, phenyl and t ⁇ fluormethyl, naphthyl, NH(CH 2 ) 2 COONa, NHC 6 H 5 or NHCH
  • R B5 is R ,B5 , R' 85 being -NHC(O)CH 2 C 6 H 5 , -NHC(O)CH(C 6 H 5 ) 2 , -NHSO 3 Na, -NHC(O)(CH 2 ) 2 C 6 H 5 , -NHC(O)C 6 Hn, -NHC(O)C 6 H 5 , -NHC(O)C 6 H 4 (4-OCH 3 ), -NHCH 2 C 6 H S , -NHC(O)C 6 H 3 (3,4-OCH 3 ) 2 , -NHC(O)C 6 H 4 (4-CI), -NHC(O)C 6 H 4 (4-NO 2 ), -NHC(O)C 6 H 4 (4-C 6 H 5 ), -NHC(O)C 6 H 4 (4-CF 3 ), -NHC(O)COONa, -NHC(O)-2-naphthyl, -NHC(O)
  • R B5 are -NHC(O)CH(C 6 H 5 ) 2 , -NHC(O)C 6 Hn, -NHC(O)C 6 H 4 (4-C 6 Hs), -NHC(O)C 6 H 5 , -NHC(O)C 6 H 4 (4-OCH 3 ), -NHC(O)C 6 H 3 (3,4-OCH 3 ) 2 , -NHC(O)C 6 H 4 (4-CI), -NHC(0)C 6 H 4 (4-NO 2 ), -NHC(O)-2-naphthyl, -NHC(O)NHC 6 H 5 , -NHC(O)OCH 2 C 6 H 5 , -NHSO 3 Na, -NHCH 2 C 6 H 5 or -N(CH 2 C 6 H 5 ) 2 .
  • R 3 is hydrogen or M y and R 85 is a group of formula llaB or HbB as defined above.
  • Preferred compounds of the formula laB are those in which R 3 is H, K or Na;
  • R 06 is hydrogen, C ⁇ -C 12 alkyl, C 3 -d 2 cycloalkyl, C 2 -Cnheterocycloalkyl, C 6 - or C ⁇ 0 aryl, C 5 -C 9 heteroaryl, C 7 -Cnaralkyl or C 6 -C ⁇ 0 heteroaralkyl;
  • R 87 is C ⁇ -d 2 alkyl, C 3 -C ⁇ 2 cycloalkyl, C 2 -Cnheterocyclo- alkyl, C 6 - or Cioaryl, C 5 -Cgheteroaryl, C 7 -C,,aralkyl, C 6 -C, 0 heteroaralkyl, C(O)OR s1 , C(O)R 88
  • R 3 is H, K or Na
  • R 86 is hydrogen, C ⁇ -C 12 alkyl, C 3 -C ⁇ 2 cycloalkyl or C 6 - or Cioaryl
  • R B7 is C ⁇ -C 12 alkyl, C 3 -d 2 cycloalkyl, C 6 - or territoryyl, C(O)OR" s1 , C(O)R ,B8 , SO 2 R' 10 or SO 3 M y , wherein R' ,s1 , R' 88 , R ,1 °, y and M are as defined above
  • R 811 is 1 ,2-C 6 - or C ⁇ 0 arylene
  • alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, C ⁇ -C 12 alkyl, C ⁇ -C 12 alkoxy, C 3 -C ⁇ 2
  • R 3 is H, K or Na
  • R 86 is hydrogen, d-C, .alkyl, C 3 -C ⁇ 2 cycloalkyl or C 6 - or Cioaryl
  • R 87 is C ⁇ -C ⁇ 2 alkyl, C 3 -C ⁇ 2 cycloalkyl, C 6 - or territoryyl, C(O)OR" s1 , C(O)R ,B8 , SO 2 R' 10 or SO 3 M y , wherein R" s1 , R ,B8 , R' 10 , y and M are as defined above
  • alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, C ⁇ -C 12 alkyl, C,-C ⁇ 2 alkoxy, C 3 -C ⁇ 2 cycloalkyl or C 6 - or Cioaryl.
  • R 3 is H, K or Na
  • R 86 is hydrogen or d-C ⁇ alkyl
  • R 87 is C ⁇ -C ⁇ 2 alkyl, C(O)Od-C ⁇ 2 alkyl, CfOJR 88 , SO 2 C 6 - or Cioaryl or SO 3 M y
  • R 88 is C(O)OM y , C ⁇ -C ⁇ 2 alkyl, C 3 -C ⁇ 2 cycloalkyl, C 6 - or Cioaryl or primary am o
  • alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, C ⁇ -C ⁇ 2 alkyl, C ⁇ -C 12 alkoxy or C 6 - or C ⁇ 0 aryl.
  • R 3 is H, K or Na
  • R E is hydrogen, methy /Il oorr bbeennzzyyll
  • RR 8877 iiss methyl, benzyl, C(O)OR s1a , C(O)R B8a , SO 2 R 10a or SO 3 Na, wherein R s1a , R 883 and R ,0a are as defined above.
  • R ,2 , r R ⁇ 3 , R ri" and R have the above meanings.
  • Preferred compounds of the formula IC are those in which R 3 is H, K or Na.
  • Preferred compounds of the formula IC are those compounds in which R is R as defined above.
  • R 5 is X'-R T1C , C(O)NR T2C R T3C or C(O)OR T5C , wherein X' is C,-C 4 alkylene and R T1C , R T C , R T C and R T5C are as defined above.
  • R 5 is X'-R T1C or C(O)OR T5C , wherein X', R ⁇ ,c and R T5C are as defined above.
  • R 5 is X'-R T1Ca or C(O)OR T5C , wherein X' and R T5C are as defined above and R T1Ca is hydrogen or OR T6C wherein R T6C is as defined above.
  • R 5 is X'-R T1C or C(O)OR T5C , wherein X' is C ⁇ -C 4 alkylene, R T1C is hydrogen or OH; and R T5C is hydrogen or M y .
  • R 5 is CH 2 OH, CH 3 or C(O)ONa.
  • Particularly preferred compounds of the formula IC are compounds of the formula laC
  • R 3 is hydrogen, K or Na; and R 5 is X'-R T1C , C(O)NR T2C R T3C or C(O)OR T5C , wherein X', R T1C , R T2C , R T3C and R T5C are as defined above.
  • R 3 is hydrogen, K or Na
  • R 5 is X'-R T1Ca or C(O)OR T5Ca , wherein X', R T1Ca and R T5C are as defined above.
  • R 3 is hydrogen, K or Na
  • R 5 is X'-R ⁇ ,c or C(O)OR TSC , wherein X' is C,-C 4 alkylene, R T1C is hydrogen or OH; and R T5C is hydrogen or M y . More preferably R 5 is CH 2 OH, CH 3 or C(O)ONa.
  • the present invention also comprises a process for the preparation of the compounds of the formula I wherein the corresponding galactose-GlcNAc-disaccharide or galactose-tetra- hydropyran dimer is linked with the corresponding fucose-derivative or the corresponding fucose-GlcNAc-disaccharide or fucose-tetrahydropyran dimer is linked with the corresponding galactose, wherein the groups R 1 , R T1 , X-R T2 , R 85 and or R 5 are optionally introduced before or after the formation of the dimer or trimer. Where required, one or more protecting groups are removed and the compounds thus obtained are converted into salts.
  • the corresponding galactose-GlcNAc-disaccharide is linked with the corresponding fucose-derivative or the corresponding fucose-GlcNAc-disaccharide is linked with the corresponding galactose wherein the groups R 1 , R T1 and X-R T2 are optionally introduced before or after the formation of the dimer or trimer.
  • the process for the preparation of the compounds of the formula IA comprises (A1 ) reacting a compound of the formula IIIA
  • each R 12 independently is hydrogen or a protecting group
  • R 60 is R 1 or a protecting group
  • R 15 is a leaving group, with a compound of the formula IVA
  • R 12 is as defined above, R 61 is R T1 or a protecting group, or OR 61 is R 15 , R 62 is hydrogen, a protecting group or X-R T2 , R 63 is hydrogen or a protecting group and R 64 is hydrogen or a protecting group or R 12 and R 64 together form a protecting group, and (A2) reacting the resulting disaccharide with a compound of the formula VA
  • R 2 , R 12 and R 5 are as defined above; wherein the groups R 1 , R T1 and X-R T2 are optionally introduced before or after step (A1 ) or step (A2); and, where required, removing the protecting groups; or
  • step (B1 ) reacting a compound of the formula VA with a compound of the formula IVA, and (B2) reacting the resulting disaccharide with a compound of the formula IIIA; wherein the groups R 1 , R T1 and X-R T2 are optionally introduced before or after step (B1 ) or step (B2); and, where required, removing the protecting groups.
  • a compound of formula ia may be prepared by reacting a compound of formula IVA with R T, -OH, followed by a reaction with a compound of formula VA. The resulting compound is reacted with R T2 -X-R 14 , wherein R 14 is a leaving group, then with a compound of formula IIIA and finally with R 1 -R 13 , wherein R 13 is a leaving group. Where required, the protecting groups are removed and the compounds of formula IA are converted into salts.
  • reaction scheme is an example and may be carried out in a different sequence to produce a compound of formula IA.
  • Hydroxy protecting groups are generally known in the sugar and nucleotide chemistry and are described, for example, by Greene and Wuts [Protective Groups in Organic Synthesis, Wiley, New York (1991 )].
  • Examples of such protecting groups are: linear and branched C ⁇ -C ⁇ alkyl, in particular d-C alkyl, for example methyl, ethyl, n- and i-propyl, n-, i- and t-butyl; benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, dimethoxybenzyl, bromo- benzyl, 2,4-d ⁇ chlorobenzyl; diphenylmethyl, di(methylphenyl)methyl, di(dimethylphenyl)- methyl, d ⁇ (methoxyphenyl)methyl, di(d ⁇ methoxyphenyl)methyl, tnphenylmethyl, tr ⁇ s-4,4',4"- tert
  • R 12 and R 64 together form an alkylidene group with, preferably 1 to 12 and, more preferably 1 to 8 C atoms. These protecting groups may be removed under neutral or weak- ly acidic conditions.
  • R 12 and R 64 are, particularly, together alkylidene, for example unsubstituted or alkyl- or alkoxy- substituted benzylidene.
  • R B7 is C,-C 12 alkyl, C 3 -C 12 alkenyl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C ⁇ aralkenyl,
  • R B7 CHO (VB) wherein R B7 is hydrogen, 0,-0, ..alkyl, C 2 -C 11 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C, heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 7 -C 10 aralkyl, C 6 - or C 10 aryl, C 6 -C 9 heteroaralkyl, C 5 -C 9 heteroaryl, C 8 -C 10 aralkenyl or C 7 -C 9 heteroaralkenyl, which are unsubstituted or substituted by one or more substituents; or
  • R B7 is d j -C ⁇ alkyl, C 3 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -O, 1 hetero- cycloalkyl, C 2 -C propositionheterocycloalkenyl, C 7 -C aralkyi, C 6 -C 10 heteroaralkyl, C 8 -C ⁇ aralkenyl, C 8 -C 10 heteroaralkenyl, which are unsubstituted or substituted by one or more substituents, with a ketone of formula VlaB or VlbB
  • each of R 87 and R B independently is d-Cnalkyl, C 2 -Cnalkenyl, C 3 -C 2 cycloalkyl, C 3 -C ⁇ 2 cycloalkenyl, C 2 -Cn heterocycloalkyl, C 2 -Cn heterocycloalkenyl, C 7 -C ⁇ 0 aralkyl, C 6 - or C ⁇ 0 aryl, C 6 -C 9 heteroaralkyl, C 5 -C 9 heteroaryl, C 8 -C ⁇ oaralkenyl, which are unsubstituted or substituted by one or more substituents; and R B12 is C 3 -C 10 alkylene or C 3 -C ⁇ 0 alkenylene, for example cyclobutanon, cyclodecanon, cyclobutenon and cyclodecen- on, which are unsubstituted or substituted by one or more substituents; or (a3) R B7 is C
  • R 3 R B7" (VIIB) wherein R B7" is C(O)OR s1 , CfOJR 88 or SO 2 R 10 , wherein R s1 , R 88 and R 0 are as defined above; and R 13 is a leaving group; or (a4) R B7 is C(O)R 88 , wherein R 88 is primary amino or secondary amino; with an isocyanate
  • R B is hydrogen, SO 2 R 10 , OSO 2 R 10 , d-C ⁇ 2 alkyl, C 3 -C, 2 cycloalkyl, C 2 -C,, heterocycloalkyl, C 6 - or Cioaryl, C 5 -C 9 heteroaryl, C 7 -Cn aralkyi, C 6 -C 10 heteroaralkyl, C 8 -C ⁇ 6 aralkenyl, which are unsubstituted or substituted by one or more substituents; (a5) R B7 is SO 3 M y , wherein M y has the abovementioned meanings, with a complex of formula IXB
  • R 86 is C C ⁇ 2 alkyl, C 3 -C ⁇ 2 alkenyl, C 7 -Cnaralkyl, C 6 -C ⁇ 0 heteroaralkyl, Cg-Cnaralkenyl or C 8 -C ⁇ 0 heteroaralkenyl;
  • R B7 is C,-C 12 alkyl, C 3 -C ⁇ 2 alkenyl, C 3 -C ⁇ 2 cycloalkyl, C 3 -C ⁇ 2 cycloalkenyl, C 2 -Cnhet ⁇ ro- cycloalkyl, C 2 -Cnheterocycloalkenyl,C 7 -C, ⁇ aralkyl, C 6 -C ⁇ 0 heteroaralkyl, Cg-Cnaralkenyl or C 8 -C ⁇ 0 heteroaralkenyl, which are unsubstituted or substituted by one or more substituents subsequently with an aldehyde of formula VB or a ketone of formula VlaB or VlbB; (b2) R 87 is C(O)OR s , CfOJR 88 or SO 2 R 10 , wherein R s1 is hydrogen, M y , C,-C, 2 alkyl, C 3 -C ⁇ 2
  • R 87 is CfOJR 88 , wherein R 88 is primary amino or secondary amino; subsequently with an aldehyde of formula VB and a compound of formula VIIIB;
  • R 87 is SO 3 M y , subsequently with an aldehyde of formula VB and a compound of formula IXB.
  • R 2 , R 3 and R 4 are as defined above and R 12 is hydrogen or a protecting group with an aromatic amme, optionally removing the protecting groups, and further reacting the resulting compound as described in (b) above.
  • R has the abovementioned meanings; and each R 13 is independently a leaving group.
  • Leaving groups may be: halides, such as chloride, bromide and iodide, and oates for example of the formula R 8r -O ' (in which case formula VIIB is an anhydride R Br -O-R B ) or alkoxides (alkylO ).
  • the compounds of the formula VB to IXB are known or may be obtained by known methods.
  • the compounds of the formula IVB and IVbB are novel and form part of the present invention. They may be obtained starting from commercially available 3,4,6-triacetoxyglucal by
  • the abovementioned strategies (a) to (e) may for example be performed by using a suitably protected and activated galactose which already contains the group -CH(COOR B8 )R 4 .
  • This compound may for example be obtained starting from an activated galactose by introducing a protecting group at the anomenc position, deprotecting said compound, introducing the group -CH(COOR B8 )R 4 protecting the residual hydroxyl groups, deprotecting and activating the anomenc position.
  • Suitable activating groups for sugars and glycosylation are known to the person skilled in the art and are described for example by Toshima and Tatsuta [Chem. Rev. 93:1503 (1993)], Paulsen [Angew. Chem. Int. Ed. Engl. 21 :155 (1982)] and Schmidt and Kmzy [Adv. Carbohydr. Chem Biochem. 50:21 (1994)].
  • N-nucleophiles are NaN 3 , NH 3 , primary amines and secondary amines, preferably the N-nucleophile is NaN 3 .
  • Suitable reducing conditions are for example H 2 , Pd/C 10%, MeOH; H 2 , Pd(OH) 2 /C 10%, dioxane/water 2/1 ; or H 2 , Rh/AI 2 O 3 5%, dioxane/water 2/1.
  • the compounds of formula IVB, IVbB and VB, VIB, VIIB, VIIIB and IXB respectively may be employed in equimolar amounts or, advantageously, in excess, for example in an amount which is up to 5 times, preferably 2 times the amount of the compound of formula IVB or IVbB
  • carboxylate protective groups are esters, preferably methyl and benzyl esters Methyl esters are preferably cleaved under the abovementioned basic conditions and benzyl esters are preferably cleaved under the abovementioned reducing conditions.
  • R 2 and R 4 have the abovementioned meanings
  • R 3 has the meanings of R 3 or is a protecting group
  • R 12 means a protecting group applying procedures known in the art.
  • the compounds of the formula IIC are new and form part of the present invention. They may be produced by linking the corresponding galactose-1 ,2-d ⁇ deoxyglucose-d ⁇ sacchar ⁇ de with the corresponding fucose-derivative or the corresponding fucose-1 ,2-d ⁇ deoxyglucose- disaccha ⁇ de with the corresponding galactose wherein the group -CH(COOR 3 )R 4 is optionally introduced before or after the formation of the dimer or trimer.
  • the compounds of formula IIC may be obtained by following a procedure as disclosed for the compounds of formula IA above, the group -CH(COOR 3 )R 4 being introduced by reaction with R 13 -CH(COOR 3 )R 4 .
  • Leaving groups as R 13 may be a halide or unsubstituted or halogenated R-SO 2 -, in which R is C ⁇ -C ⁇ 2 alkyl, in particular d-C 6 alkyl and mono-, di- or trifluoromethyl, C 5 -C 6 cycloalkyl, phenyl, benzyl, C ⁇ -C ⁇ 2 alkylphenyl, in particular C ⁇ -C alkylphenyl, nitrophenyl, or C ⁇ -C ⁇ 2 alkyl- benzyl, in particular d-C 4 alkylbenzyl, for example methane, ethane, propane, butane, benzene, benzyl- and p-methylbenzenesulfonyl.
  • Preferred leaving groups are CI, Br, I, -SO 2 CF 3 (triflate) and p-nitrobenzenesulfonyl, -SO 2 CF 3 being more preferred.
  • Leaving groups in the meaning of R 4 are for example halides, such as preferably chloride and bromide, and especially in the case when X is -C(O)- carboxylates and groups of for example the formulae
  • These leaving groups can be in the axial or in the equatorial position.
  • dialkylt oxides dialkyltin alkoxylates and b ⁇ s(tr ⁇ alkyl)t ⁇ n oxides.
  • Some examples are dibutyltin oxide, dibutyl- t ⁇ n(O-methyl) 2 and (tr ⁇ butylt ⁇ n) 2 O.
  • the activating agents are preferably used in stoichiomet ⁇ c amounts. In this case, the reaction is carried out in two stages, namely a) activation and b) coupling with e.g. R T1 -OH.
  • the compounds of formula I exhibit valuable pharmacological properties as indicated in tests and are therefore indicated for therapy.
  • the compounds of formula I inhibit the binding of E-selectin to SLe a as disclosed in Example C1 and the interaction of E- selectin and its natural ligand as disclosed in Example C2.
  • the compounds are accordingly indicated for preventing or treating conditions or diseases which are mediated by the binding of selectin in cellular adhesion, e.g.
  • acute or chronic inflammatory or autoimmune diseases such as rheumatoid arthritis, asthma, allergy conditions, psoriasis, contact dermatitis, adult respiratory distress syndrome, inflammatory bowel disease and ophthalmic inflammatory diseases, infection diseases such as septic shock, traumatic shock, thrombosis and inappropriate platelet aggregation conditions, cardiovascular diseases such as heart attacks, reperfusion injury, multiple sclerosis and neoplastic diseases including metastasis conditions, strokes and acute or chronic rejection of organ or tissue transplants.
  • inflammatory or autoimmune diseases such as rheumatoid arthritis, asthma, allergy conditions, psoriasis, contact dermatitis, adult respiratory distress syndrome, inflammatory bowel disease and ophthalmic inflammatory diseases, infection diseases such as septic shock, traumatic shock, thrombosis and inappropriate platelet aggregation conditions, cardiovascular diseases such as heart attacks, reperfusion injury, multiple sclerosis and neoplastic diseases including metastasis conditions, strokes and acute or chronic rejection
  • Acute and chronic rejection play a role in the transplantation of organs or tissues from a donor to a recipient of the same species (allograft) or different species (xenograft).
  • organs or tissues and given illustratively are heart, lung, combined heart- lung, trachea, liver, kidney, spleen, pancreatic (complete or partial, e.g. Langerhans islets), skin, bowel, or cornea or a combination of any of the foregoing.
  • Suitable daily dosages for oral administration to larger mammals are generally about 50 to 1500 mg, preferably in the order of from 200 to 800 mg.
  • Unit dosage forms suitably comprise from about 25 mg to 0.750 g of a compound of the invention, together with a pharmaceutical acceptable diluent or carrier therefor.
  • the compounds of formula I may be administered by any conventional route of administration, e.g. enterally, preferably orally, e.g. in the form of tablets or capsules, or par- enterally e.g. in form of injectable solutions or suspensions.
  • 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.
  • the present invention further provides:
  • composition comprising a pharmaceutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier;
  • the compound may be administered alone or in combination with one or more other anti-inflammatory or immunosuppressive agents, for example in combination with cyclosporin A and analogs thereof, FK-506 and analogs thereof, rapamycin and analogs thereof, myco- phenolic acid, mycophenolate mofetil, mizoribine, 15-deoxyspergualine, leflunomide, steroids, cyclophosphamide, azathioprene (AZA), or anti-lymphocyte antibodies or immuno- toxins such as monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, or CD25; especially in combination with a T-cell suppressant, e.g., cyclosporin A or FK-506.
  • anti-inflammatory or immunosuppressive agents for example in combination with cyclosporin A and analogs thereof, FK-506 and analogs thereof, rapamycin and analogs thereof, myco- phenolic acid, mycophenolate mofetil, mizoribine,
  • Such combination therapy is further comprised within the scope of the invention, e.g., a method according to 1 above further comprising administration concomitantly or in sequence of a therapeutically or synergistically effective amount of such a second immunosuppressive or anti-inflammatory agent.
  • the clear solution B is added dropwise to suspension A within 1 h. Having stirred for 2 h at RT the mixture is diluted with ethylacetate (200 ml) and filtered through Hyflo Super Cel. The solution is extracted with Na 2 S 2 O 3 solution (100 ml), water (2 x 100 ml) and brine (100 ml). The organic layer is concentrated and the residue dissolved in diethylether (25 ml) and formic acid (5 ml). Having stirred for 3 h the solvents are removed and the residue is pu ⁇ fied by chromatography on silica gel (ethylacetate/hexane 2:1 ) to give A1c as a colorless oil.
  • Triacetate 3a (10.40 g, 18.60 mmol) is dissolved in abs. methanol (150 ml), mixed with Amberlite IRA 910 in methanol (15 ml) and stirred at RT for 16 h. The mixture is filtered through Hyflo Super Cef, the solvent is removed and the residue is dried in vacuo to afford giucosamine derivative 4a.
  • the clear solution B is added dropwise to suspension A within 1 h. Having stirred for 16 h the mixture is diluted with ethyl acetate (50 ml) and filtered through Hyflo Super Cel ⁇ The solution is successively extracted with sodium thiosulfate solution (50 ml), twice with water (50 ml each) and saturated NaCl solution (50 ml each).
  • Ammo sugar 9a (370 mg, 0.433 mmol) and active ester 10a (206 mg, 0.591 mmol) are dissolved in abs. N,N-d ⁇ methylformamide (3.5 ml) (argon atmosphere). 2,6-Lutidine (0.7 ml) is added and the solution is warmed to 70°C for 4 h. Another 50 mg (0.143 mmol) of 10a are added and the solution is stirred for 16 h at 70°C. Then another 30 mg (0.086 mmol) of 10a are added and the solution is warmed to 70°C for 3 h.
  • Tnsaccharide 15a (80 mg, 0.063 mmol) is dissolved in an argon atmosphere in abs. benzene (2 ml), dibutyltinoxide (28 mg, 0.110 mmol) is added and the mixture is heated under reflux for 16 h The solvent is removed, the residue is dried for 1h at 40°C in high vacuum and dissolved in abs dimethoxyethane (1.6 ml) A solution of triflate 16a (125 mg, 0 315 mmol)
  • the suspension is stirred for 15 min in an argon atmosphere. Then the mixture is hydrogenated for 16 h at RT.
  • the catalyst is filtered off through a HPLC filter, the solvent is removed, the residue is dissolved in water/methanol (2:1) and passed through a sodium ion exchange column (water). Product containing fractions are combined and concentrated.
  • Methyl ester B1a (10 mg, 0.010 mmol) is dissolved in water (1 ml), mixed with 2 N NaOH (20 ⁇ l) and stirred for 16 h at RT. Reverse phase chromatography on RP 18 (water ⁇ water/methanol 3:1 ) affords carboxylate B4a.
  • the pH of the reaction mixture is adjusted to 8-10 by the addition of 1 N NaOH solution and maintained at 8-10 throughout the whole reaction.
  • additional diphenylacetyl chloride (3.7 mg, 0.016 mmol, 0.5 eq.) is added and after a total of 42 h the reaction mixture is partially evaporated to remove THF.
  • the now aqueous solution is purified by RP C18 (column size 1 x 10 cm) through stepwise elution with acetonitrile/water 30/70 and then acetonitrile/water 40/60.
  • C 4 ,H 56 NO, 5 Na (MW 825.88): MS (FAB positive mode, THG) 826 (M+H), 804 (M- Na+H).
  • Borane pyndine complex (BH 3 .C 5 H 5 N, 0.013 ml, 0.131 mmol) is added to a mixture of A1b (40 mg, 0.066 mmol), benzaldehyde (0.033 ml, 0.328 mmol) and freshly dried 4A molecular sieves (ca. 500 mg) in dry MeOH (0.5 ml).
  • Fraction 1 is further purified by P2 gelfiltration eluting with water and then filtered on Dowex ion exchange resin Na + form eluting with water to give after freeze drying B14b as a white foam.
  • Fraction 2 is also further purified by P2 gelfiltration eluting with water and then filtered on Dowex ion exchange resin Na + form eluting with water to give after freeze drying B13b as a white foam
  • N-hydroxysuccinimide (2.3 mg, 0.02 mmol, 0.2 eq) and abs. pyridine (31.6 mg, 0.40 mmol, 4 eq) in abs. benzene (1 ml) is heated under reflux for 2 h.
  • the clear solution is diluted with ethylacetate (20 ml) and extracted with HCI (0.5 n, 2 x 20 ml), NaHCO 3 (20 ml) and brine (20 ml). The solvent is removed and the residue subjected to chromatography (silicagel, toluene/ethylacetate 5:1 ).
  • Compound 14c is isolated as a colorless foam.
  • Example C1 Ligand Binding Assay for Determination of IC S0 Values-conserved use of positive controls
  • This assay is performed as disclosed in Example D1 of WO 97/19,105 the contents thereof relating to this assay being incorporated hereinwith and wherein the E-selectin/human IgG chimera are cloned and expressed according to Kolbinger, F., Patton, J.T., Geisenhoff, G., Aenis, A., Li, X., Katopodis, A., Biochemistry 35:6385-6392 (1996).
  • the compounds of formula I have an RIC 50 value of from 0.01 to 1.0.
  • RIC 50 means IC 50 (test compound)/IC 5 o(control compound A)
  • Example C2 Cell Adhesion under Flow Conditions
  • This assay is performed as disclosed in Example D3 of WO 97/19,105 the contents thereof relating to this assay being incorporated hereinwith.
  • the compounds of formula I show a reduction of number of interacting cells at 50 ⁇ M of in the range from 40 % to 90 %.

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Abstract

Derivatives of sialyl-Lewis X and A, in which the natural neuraminic acid residue and the natural N-acetylglucosamine monomer are replaced.

Description

Modified ohαosaccharides
The present invention relates to mimetics of sialyl-Lewis X and A, in which, in the natural tetrasacchaπde, the neuraminic acid residue is replaced by an S-configu rated methyl substituted with one carboxyl residue and one other substituent and the natural N-acetyl group in the N-acetylglucosamine monomer is replaced by a variety of different aliphatic and aromatic substituents or the N-acetylglucosamine residue is replaced by a tetrahydropyran derivative, to processes for the preparation of these compounds, to their use as a pharmaceutical and to pharmaceutical compositions comprising them.
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 endothe uπrwhich lines the blood vessels expresses adhesion proteins on its surface. The P and E selectins bring about, by a protein-carbohydrate 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 activation of certain proteins (integnns) on their surface which ensure firm adhesion of the leukocytes to the endothe um This is followed by migration of the leukocytes into the damaged tissue.
There are many situations in which the recruitment of leukocytes by adhesion to the endo- thelial cells is abnormal and in excess resulting in tissue damage instead of repair. This is the case in disorders such as cardiogenic shock, myocardial infarct, thrombosis, rheumatism, psoriasis, arthritis, dermatitis, acute respiratory distress syndrome, metastatic cancer and transplantation.
One of the smallest natural carbohydrate epitopes as ligand for E selectin is sialyl-Lewis X [neuraminic acιd-α(2→3)-D-galactose-β(1 →4)-L-(fucose-α(1 →3))-N-acetyl-D-glucosamιne (sLe*)] Although it has been considered to be potentially useful as an antiinflammatory agent it can only be used as an injectable form as it is orally inactive and has a short half- life in blood Thus, there is a need for compounds which prevent the interaction between P and E selectins and their receptors on the leukocyte membrane and which prevent the initial cellular adhesion process. It has now been found, surprisingly, that simultaneous replacement of the neuraminic acid residue by an S-configu rated methyl substituted with one carboxyl residue and one other substituent and of the natural N-acetyl group in the GlcNAc monomer by a variety of different aliphatic and aromatic substituents or of the GlcNAc residue by a tetrahydropyran derivative results in SLex mimetics having interesting binding affinity properties.
According to the invention there is provided a compound of the formula
Figure imgf000004_0001
wherein
R is an S-configurated methyl substituted with a carboxy and one other substituent; R2 is hydrogen, d-C12alkyl or C6aryl; where the alkyl and the aryl are unsubstituted or substituted by one or more substituents; and Z is a group of the formula Ma, lib or He
Figure imgf000004_0002
wherein
X is -C(O)-, -C(S)-, -S(O)2-, -C(O)Q- or -C(S)Q-, in which Q is NH, O, S, S-C,-C6alkylene,
NH-C C6alkylene or O-d-Cealkylene;
RT1 is C,-C12alkyl, C2-Cι2alkenyl, CrCι2alkoxy, C3-C12cycloalkyl, C3-Cι2cycloalkenyl,
Cz-Cnheterocycloalkyl, C2-Cuheterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, Cs-Cgheteroaryl,
C5-C9heteroaryloxy, C -Cnaralkyl, C7-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl or C7-C10heteroaralkenyl, which are unsubstituted or substituted by one or more substituents; and
RT2 is C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-dιheterocycloalkenyl,
C6-Cι0aryl, C6-C10aryloxy, C5-Cgheteroaryl, C5-C heteroaryloxy, C7-Cπaralkyl, C7-Cι,aralkyl- oxy, C6-Cιohθteroaralkyl, C8-Cnaralkenyl or C7-Ci0heteroaralkenyl, which are unsubstituted or substituted by one or more substituents;
RB5 is NH2, primary amino, secondary amino or amido;
R5 is X'-RT1C, C(O)NRT2CRT3C, C(O)RT4C or C(O)ORT5C, wherein X' is C,-C4alkylene,
RT1C is hydrogen, halogen, d-C^alkyl, CrCnheteroalkyl, C3-C12alkenyl, C3-C12cycloalkyl,
C3-Ci2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-, C10- or C14aryl,
C2-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, Cg-d-aralkenyl, C8-C10heteroaralkenyl,
ORT6C, OC(O)RT4C, SRT4C, SO2RT9C or SO3RT5C; each of RT2C, RT3C and RT4C is independently hydrogen, d-C12alkyl, d-Cuheteroalkyl,
C3-C,2alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-dιheterocycloalkyl, C2-dιhetero- cycloalkenyl, C6-, C10- or d4aryl, C2-Cgheteroaryl, d-Cuaralkyl, C6-C10heteroaralkyl,
Cg-Ci iaralkenyl or C8-Cι0heteroaralkenyl; each of RT5C, R770 and RT8C is independently hydrogen, My, d-Cι2alkyl, d-Cnheteroalkyl,
C3-Cι alkenyl, C3-Cι2cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-dιhetero- cycloalkenyl, C6-, C10- or C1daryl, C2-C9heteroaryl, C7-dιaralkyl, C6-C10heteroaralkyl,
Cg-Cnaralkenyl or C8-doheteroaralkenyl;
RT6C is hydrogen, d-C12alkyl, Cι-dιheteroalkyl, C3-Cι2alkenyl, C3-d2cycloalkyl,
C3-C,2cycioalkenyl, CrCiiheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-, C10- or Cι4aryl,
C2-C9heteroaryl, C7-Cnaralkyl, C6-C10heteroaralkyl, Cg-Cnaralkenyl, C8-C 0heteroaralkenyl,
SO3RT5C, PO3RT7CRT8C, C(O)ORT9C, C(S)NRT CRT3C or C(O)NRT2CRT3C; and
RT9C is C C12alkyl, C,-dιheteroalkyl, C3-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl,
C2-Cιιheterocycloalkyl, C2-dιheterocycloalkenyl, C6-, Cι0- or C 4aryl, C2-Cgheteroaryl,
Cy-Cπaralkyl, C6-Ci0heteroaralkyl, C9-dιaralkenyl or C8-Cιoheteroaralkenyl; wherein the substituent is selected from the group consisting of OH, halogen, NH2, C(O)Rs2,
C(O)ORs1, OC(O)Rs4, nitro, cyano, SO3H, OSO3H, SO3My, OSO3My, NR20SO3My, C C12alkyl,
C2-Cι2alkenyl, d-C12alkoxy, C3-C12cycloalkyl, C3-C 2cycloalkenyl, C2-C11heterocycloalkyl,
C2-C,,heterocycloalkenyl, C6-Cι0aryl, C6-Cιoaryloxy, C5-Cgheteroaryl, C5-C9heteroaryloxy,
C -Cnaralkyl, C7-Cnaralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamido, carbamido, carbamate, sulfonhydr- azido, carbhydrazido, carbohydroxamic acid and aminocarbonylamido, where Rs1 is hydro- gen, My, C,-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C2-dιheterocycloalkyl, C6-Cι0aryl, Cs-Cgheteroaryl, C7-Cπaralkyl or C6-C10heteroaralkyl, R54 is hydrogen, d-C12alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl, C5-Cgheteroaryl, C7-Cιιaralkyl or C6-Cι0heteroaralkyl, and Rs2 and R20 are hydrogen, Cι-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn -heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, d-Cnaralkyl, C6-C10heteroaralkyl, C8-dι-aralkenyl or C7-Cιoheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo- alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyi, 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; and a derivative thereof wherein at least one OH is substituted with SO3RT5C, POaR^R™0, C(O)RT9C, C(O)ORT9C, C(S)NRT2CRT3C, C(O)NRT2CRT3C, d-C12alkyl, C3-C12al- keπyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, d-Cnheteroalkyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-, Cio- or C14aryl, C2-C9heteroaryl, C7-Cnaralkyl, Ce-CioheteroaralkyI, Cg-daralkenyl or C8-Cι0heteroaralkenyl; in free form or in salt form.
Preferably, Z is bound to the galactose moiety via the carbon atom 4 in case of formula lla and via the carbon atom 3 in case of formulae lib and lie.
M is preferably an alkali metal (for example lithium, sodium, potassium, rubidium and caesium), an alkaline earth metal (for example magnesium, calcium and strontium) or manganese, iron, zinc or silver.
Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, especially fluorine or chlorine.
Alkyl may be linear or branched, preferably branched once or twice in the α position. Examples of alkyl include e.g. methyl, ethyl and the isomers of propyl, butyl, pentyl, hβxyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl, preferably 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 (d-C alkyl)CH=CH-CH2-. 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. Cycloalkyl and cycloalkenyl may contain 5 to 8, preferably 5 or 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclohexyl. Examples of cycloalkenyl are cyclopropenyl, cyclobutenyl, cyclopent- enyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, preferably cyclohexenyl. Examples of cycloalkylene are 1,2-cyclopropylene, 1 ,2-cyclobutylene, 1 ,2-cyclopentylene, 1,2-cyclo- hexylene, 1 ,2-cycloheptylene and 1 ,2-cyclooctylene. Examples of heterocycloalkylene are pyrroiidinylene, piperidinylene, tetrahydrofuranylene, 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.
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 oxygen, nitrogen and sulfur. Examples are derived from benzene, naphthalene, indene, furan, pyrrole, pyrazole, imidazole, isoxazole, oxazole, furazan, thia- diazole, thiophene, thiazole, oxadiazole, triazole, indole, indazole, purine, benzimidazole, benzoxazole, benzothiazole, pyran, pyridine, pyridazine, triazine, pyrimidine, pyrazine, iso- quinoline, cinnoline, phthalazine, quinoline, quinazoline, pterdine, benzotriazine or quinoxa- line. Aryl is preferably naphthyl and phenyl, particularly phenyl. Heteroaryl is preferably furanyl, pyridinyl and pyrimidinyl.
Aralkyi preferably has 7 to 12 C atoms and may 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 cinnamyl or cinnamyl ring-substituted by a substituent selected from the group consisting of OH, halogen, COOH, C(O)OMy, d-C12alkyl, C,-C6alkoxy, C6-Cι0aryl, SO3My, OSO3My, NR20SO3My in which R20 is as defined above. Heteroaralkyl and heteroaralkenyl are preferably C4-C5heteroarylmethyl and C4-C5heteroarylethenyl with one or two hetero atoms from the group of O and N, and the heteroaryl may comprise the abovementioned heteroaryl residues.
Alkoxy may be linear or branched, preferably branched once or twice in the α position. Examples of alkoxy include e.g. methoxy, ethoxy and the isomers of propoxy, butoxy, pent- oxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy and dodecoxy, preferred 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, and may be e.g. 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, and may be e.g. dimethyl-, diethyl-, methylethyl-, di-n-propyl-, di-i-propyl-, di-n-butyl-, diphenyl-, dibenzylamino, morpholino, piperidino and pyrrolidino.
Primary amino and secondary ammo preferably correspond to R8R9N in which each R8 and R9 is independently hydrogen, OH, SO3My, OSO3My, Cι-Cι2alkyl, C3-Cι2cycioalkyl, C2-Cnheterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C -Cnaralkyl, C6-C10heteroaralkyl, C8-d6aralkenyl with C2-C6alkenylene and C6-Cιoaryl, or di-Cβ-doaryl-d-Ce-alkyl, which are unsubstituted or substituted by one or more of the above substituents; or R8 and R9 together are tetramethylene, pentamethylene, -(CH2)2O(CH2)2-, -(CH2)2S(CH2)2- or -(CH2)2NR7(CH2)2-, and R7 is H, C,-C6alkyl, C7-Cnaralkyl, C(O)Rs2 or sulfonyl.
Carbamido, carbamate, carbhydrazido, sulfonamido, sulfonhydrazido and aminocarbonyl- amido preferably correspond to a group R8C(O)(NH)pN(R9)-, -C(O)(NH)pNR8R9, R8OC(O)(NH)pN(R9)-, R8R40NC(O)(NH)PN(R9)-, -OC(O)(NH)pNR8R9, -N(R 0)C(O)(NH)PNR8R9, RBS(O)2(NH)pN(R9)-; -S(O)2(NH)pNR8R9; R8R40NS(O)2N(R9)-, -NR40S(O)2NR8R9 or -N(R 0)C(O)C(O)NR8R9, in which each of R8, R9 and R40 is independently hydrogen, OH, C C12alkyl, C,-C12alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-CnheterocycloalkyI, C2- Cn heterocycloalkenyl, C6-Ci0aryl, C5-C9heteroaryl, C7-C 6aralkyl, C8-Cι6aralkenyl with C2- C6alkenylene and C6-Cι0aryl, C6-Cι5heteroaralkyl, C6-Cι5heteroaralkenyl, or di-C6-Cι0aryl-Cι- C6-alkyl; or R8 and R9 or R8 and R40 in the case of -NR8R9 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, C -d,aralkyl, C(O)Rs2 or sulfonyl.
The sulfonyl substituent corresponds, for example, to the formula R10-SO2- in which R 0 is Cι-C12alkyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, Ce-doaryl, C5-Cgheteroaryl, CT-Cnar- alkyl or C6-Cιoheteroaralkyl. The other substituent in R1 has preferably 1 to 20, more preferably 1 to 16, particularly preferably 1 to 12, and especially preferably 1 to 8 C atoms. The other substituent is preferably selected from the group consisting of unsubstituted and substituted Cι-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-C12cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, Ce-Cioaryl, C5-C9heteroaryl, C7-dιaralkyl, Ce-Cioheteroaralkyl, C8-Cnaralkenyl and C7-C10heteroaralkenyl. The other substituent is particularly substituted methyl, or 2-sub- stituted ethyl or unsubstituted cyclohexyl. Examples of suitable substituents are the substituents mentioned above in the definition of R2, especially OH, halogen (F, CI or Br), carboxyl, -SO3H, C(O)OMy, SO3My, OSO3 y, NR20SO3My in which R20 is as defined above, or d-C12alkyl, Cι-Cι2alkoxy, nitro, -NH2, primary amino with 1 to 20 C atoms, secondary amino with 2 to 30 C atoms, cyano, C3-C8cycloalkyl, C3-C6heterocycloalkyl, C6-C10aryl, C3-C9heteroaryl, C7-d6heteroaralkyl, where the hetero atoms are selected from the group of O, S and N atoms, and carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydr- azide 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 substituted, for example with C,-C6alkyl, C C6alkoxy, carboxyl, halogen (F, CI or Br), -OH, -CN or -NO2.
In a particular embodiment of the compounds of the formula I, R corresponds to a group of the formula II,
Figure imgf000009_0001
in which R3 is hydrogen or My; and R4 is Cι-Cι2alkyl, C2-Cι2alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn heterocycloalkenyl, C6-Cιoaryl, Cs-Cgheteroaryl, C -Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cnaralkenyl or C7-C10heteroar- alkenyl, which are unsubstituted or substituted by one or more substituents selected from the abovementioned group of substituents.
Preferred compounds of the formula I are those in which R1 corresponds to a group of the formula II in which R3 is hydrogen or My and R4 is
(a) unsubstituted d-d2alkyl; 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, ammo- carbonylamido, C3-Cι2cycloalkyl, CrCβalkoxy, phenyloxy and benzyloxy; unsubstituted C3-Cι2cycloalkyl; C3-C12cycloalkyl which is substituted by one or more substituents selected from the group consisting of d-C6alkyl, d-C6alkoxy, d-C12sulfonyl, phenyloxy and benzyloxy; Ce-doaryl; C3-C9heteroaryl with 1 or 2 hetero atoms selected from oxygen and nitrogen; C7-Cι6aralkyl with d-C6alkyl and C6-C10aryl; C -Cι6heteroaralkyl with d-C6alkyl and C3- Cioheteroaryl with 1 or 2 hetero atoms selected from oxygen and nitrogen and a total of 3 to 5 carbon atoms; or such C6-Cι0aryl, C3-C9heteroaryl, C7-d6aralkyl and C3-d6heteroaralkyl which are substituted by one or more substituents selected from the group consisting of OH, halogen, Cι-C12sulfonyl, carboxyl, C(O)OMy, d-Cι2alkyl, Cι-C6alkoxy, C6-Cι0aryl, SO3My, OSO3 y, NR20SO3My in which R20, y and M are as defined above; or (b) d-Ci.alkyl, C3-Cι2cycloalkyl or C7-Cnaralkyl, in particular CH2-C6H5 and (CH2)2-C6H5, which are unsubstituted or substituted by one or more substituents selected from the abovementioned group of substituents.
More preferred are those compounds in which the substituent for R4 is selected from the group consisting of NH2l C3-d2cycloalkyl, primary amino, secondary amino, sulfonamido, carbamido and aminocarbonylamido. Particularly preferred substituents for d-Cι2alkyl are NH2, cyclohexyl, C6-C,oaryl, R8 R9N-, R8C(O)N(R9)-, R8S(O)2N(R9)-, R8NHC(O)NR9- and NR9C(O)NHR8 in which R8 , R9 , R8 and R9 are as defined above.
Particularly preferred compounds within this group are those in which R4 is R'4, R'4 being CHrC6H5, (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, Ce-Cioaryl, R8C(O)N(R9)-, R8S(O)2N(R9)-, RβNHC(O)NR9-, NR9C(O)NHR8 and R8R9N-, in which each R8, R9, R8 and R9 is independently hydrogen, Cι-Cι2alkyl, C3-Cι cycloalkyl, C6-Cι0aryl or C7-Cnaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OMy, nitro, cyano, SO3My, OSO3My, NHSO3My, Cι-C12alkyl, Cι-C12alkoxy and C6-C10aryl, where y and M are as defined above Particularly preferred compounds are those in which each R8, R9, R8 and R9 is independently hydrogen, Cι-Cι2alkyl, cyclohexyl, phenyl, naphthyl or C7-Cnaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, CI, C(O)ONa, nitro, cyano, SO3Na, Cι-C6alkyl, methoxy and phenyl. In a preferred group of compounds of the formula I, R1 corresponds to formula II, in which R4 is R"4, R"4 being CβHu, CH(CH3)2) CH2-phenyl, (CH2)2-phenyl, CH2NHC(O)-phenyl, CH2NHC(O)(CH2)3-phenyl, CH2NHC(O)(CH2)3OH, CH2NHC(O)CF3, CHaNHCfOJCeH,,, CH2NHC(O)C,ιH23, CH2NHC(O)CH(C6H5)2, CH2HNC(O)NHC6H5, CH2NHC(O)C2H4CO2Na, CH2NHC(O)C6[(1 ,3,4,5)OH]4H7, CH2NHC(O)C6H4-p-SO3Na, CH2NHC(O)C6H4CI, CH2CβH„f (CH2)2C6Hιι, CH2NH2l CH2NHC(O)C6H4NO2, CH2NHC(O)C6H4OCH3, CH2NHC(O)C10H7, CH2NHC(O)C6H4(3,4)CI2, CH2NHC(O)C6H4CH3, CH2NHC(O)C6H4C6H5, CH2NHC(O)C6H4CN, CH2NHC(O)C6H4COONa, CH2NHC(O)(CHOH)2COONa, CH2N[CH2CH(CH3)2][C(O)-phenyl], CH2N(CH2CH=CH-phenyl)[C(O)-phenyl], CH2N[C(O)C6H5]CH2C6H5, CH2NHCH2-phenyl, CH2N[C(O)C6H5](CH2)3C6H5, CH2NHCH2CH=CH-phenyl, CH2NHCH2CH(CH3)2, CH2N(CH2-phenyl)2, CH2N[CH2CH(CH3)2]2, CH2NHSO2-p-nitrophenyl, CH2NHSO2-p-tolyl, CH2NHSO2CF3, CH2NHC(O)NHC6H5 or CH2N[SO2-p-nitrophenyl][CH2CH(CH3)2]2.
A preferred group of compounds of the formula I are those in which R2 is hydrogen, unsubstituted or substituted C C6alkyl, preferably d-C4alkyl, especially methyl or ethyl, wherein the substituent is selected from C(O)OH, -C(O)ONa, -C(O)OK, -OH, -C(O)-NR8"R9" and -S02-NRB R9 , in which R8" is H, d-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and R9" independently has the meaning of R8 , or R8 and R9 are together tetramethylene, pentamethylene or -CH2CH2-0-CH2CH2-. Particularly preferred compounds are those in which R2 is hydrogen, methyl, ethyl, HO(O)CCH2CH2-, NaOC(O)CH2CH2- or R8 "R9"NC(0)CH2CH2-, and R8 and R9 are, independently of one another, H, CrC6alkyl, C2-C4hydroxyalkyl, phenyl, benzyl or, together, morpholino.
A first preferred embodiment of the invention comprises the compounds of formula IA
Figure imgf000011_0001
in which X, R1, R2, RT1 and RT2 have the above meanings. Q in X is preferably NH, O or S. X is preferably -C(O)-, -C(S)-, -C(O)O- or -C(S)O-, more preferably -C(O)- or -C(O)O-.
A preferred embodiment of the invention are those compounds of the formula IA wherein RT is d-C12alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OCfOJR54, CfOJR82, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, where Rs1, R84, R52, R20, y and M are as defined above. A more preferred embodiment of the invention are those compounds of the formula IA wherein RT1 is Cι-Cι2alkyl, which is unsubstituted or substituted by one or more, preferably one C(O)ORs1, where Rsl is as defined above. Most preferably RT1 is Cι-Cι2alkyl, which is substituted by C(O)OCι-Cι2alkyl or C(O)ONa. A specially preferred meaning of RT1 is (CH2)8C(O)OCH3 or (CH2)βC(O)ONa.
A preferred embodiment of the invention are those compounds of the formula IA wherein RT2 is C3-C,2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl or C5-Cgheteroaryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, nitro, NH2, cyano, C Cι2alkyl, C2-Cι2alkenyl, Cι-Cι2alkoxy, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-C10aryl, C6-Cι0aryl- oxy, C5-C9heteroaryl, C5-C heteroaryloxy, C7-dιaralkyl, C7-Cι aralkyloxy, C6-C10heteroar- alkyl, CB-Cι ,aralkenyl, C7-Cι0heteroaralkenyl. More preferred are those compounds of the formula IA wherein RT2 is C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl or Cs-Cgheteroaryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, d-Cι2alkyl, C6-Cι0aryl or Cs-Cgheteroaryl. Most preferred meanings of Rτz are -3,5-(OH)2C6H3, -3,4-(OH)2C6H3, -3,4-(OCH3)2C6H3, -2-(OH)C6H4 and thyminyl, especially preferred are -3,4-(OH)2C6H3 and -3,4-(OCH3)2C6H3.
A particularly preferred embodiment of the invention comprises compounds of the formula laA
Figure imgf000013_0001
wherein X, R3, R4, RT1 and RT2 are as defined above.
Preferred compounds of the formula laA are those in which X is -C(O)-, -C(S)-, -S(O)2-, -C(O)Q- or -C(S)Q-, in which Q is NH, O or S; R3 is hydrogen or My; R4 is C7-Cnaralkyl, C3-Cι2cycloalkyl or Cι-C12alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of NH2, C3-Cι2cycloalkyl, primary amino, secondary ammo, sulfonamido, carbamido and aminocarbonylamido; RT1 is Cι-Cι2alkyl, which is unsubstituted or substituted 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, NR20SO3My, where Rs1, R84, Rs2, R20, y and M are as defined above; and RT2 is C3-C,2cyclo- alkyl, C2-Cnheterocycloalkyl, C6-Cι0aryl or C5-Cgheteroaryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, nitro, NH2, cyano, Cι-C,2alkyl, C2-C12alkenyl, Cι-C12alkoxy, C3-Cι2cycloalkyl, C3-C12cyclo- alkenyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6-Cι0aryl, C6-Cιoaryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, Crd.aralkyl, C7-C1 aralkyloxy, C6-C10heteroaralkyl, Cβ-Cnaralkenyl and C7-Cιoheteroaralkenyl.
More preferred compounds of the formula laA are those in which X is -C(O)-, -C(S)-, -C(O)O- or -C(S)O-; R3 is hydrogen or My where y and M are as defined above; R4 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, C3-C12cycloalkyl, primary amino, secondary amino, sulfonamido, carbamido and aminocarbonylamido; RT1 is d-Cι2alkyl, which is unsubstituted or substituted by one or more C(O)ORs\ where Rs1 is as defined above; and RT2 is C3-Cι2cycloalkyl, C2-Cnheterocyclo- alkyl, C6-Cι0aryl or C5-C9heteroaryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, Cι-C12alkyl, C6-C10aryl or C5-C9heteroaryl.
Most preferred compounds of the formula laA are those in which X is -C(O)- or -C(O)O-; R3 is hydrogen or My where y and M are as defined above; R4 is R'4; RT1 is C Cι2alkyl, which is substituted by C(O)ORs1 , where Rs1 is as defined above; and RT2 is -3,5-(OH)2C6H3, -3,4-(OH)2C6H3l -3,4-(OCH3)2C6H3, -2-(OH)C6H4 or thyminyl.
Especially preferred compounds of the formula laA are those in which X is -C(O)- or -C(O)O-; R3 is hydrogen or My; R4 is CH2-C6H5, (CH2)2-C6H5, cyclohexyl, methyl, ethyl or iso- propyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH2, cyclohexyl, C6-C10aryl, R8C(O)N(R9)-, R8S(O)2N(R9)-, R8NHC(O)NR9-, NR9C(O)NHR8 and R8R9N-, in which R8, R9, R8' and R9' are, independently of one another, hydrogen, Cι-C12alkyl, cyclohexyl, phenyl, naphthyl or C7-Cnaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, CI, C(O)ONa, nitro, cyano, SO3Na, d-C6alkyl, methoxy and phenyl; RT1 is C,-C,2alkyl, which is substituted by C(O)OC,-C12alkyl; and RT2 is -3,4-(OH)2C6H3 and -3,4-(OCH3)2C6H3.
Among these compounds of the formula laA those are preferred wherein X is -C(O)- or
- -CC((OO))OO--;; RR33 iiss hhyyddrogen, K or Na; R4 is R"4; RT1 is CH3; and RT2 is -3,4-(OH)2C6H3 or
-3,4-(OCH3)2C6H3.
A second preferred embodiment of the present invention relates to compounds of the formula IB
(IB)
Figure imgf000014_0001
in which R2, R3, R4 and RB5 have the above meanings.
In a particular embodiment of the compounds of the formula IB, RB5 corresponds to a group of the formula llaB or HbB
-NRB6RB7 (llaB), C|bB)
Figure imgf000015_0001
in which
RB6 is hydrogen, d-Cι2alkyl, C3-Cι2alkenyl, C3-Cι2cycloalkyl, C3-d2cycloalkenyl,
C2-Cnheterocycloalkyl, C2-C heterocycloalkenyl, C6- or Cι0aryl, C5-C9heteroaryl, C7-C,ιar- alkyl, C6-Cι0heteroaralkyl, Cg-Cnaralkenyl or C8-C10heteroaralkenyl;
RB7 is C,-Cι2alkyl, C3-C12alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocyclo- alkyl, C2-C heterocycloalkenyl, C6- or Cι0aryl, C5-Cgheteroaryl, C7-Cnaralkyl, C6-Cι0hetero- aralkyl, C9-C,,aralkenyl, C8-Cι0heteroaralkenyl, C(O)ORs1, CfOJR88, SO2R10 or SO3My, wherein RB8 is hydrogen, C(O)ORs1, Cι-Cι2alkyl, C3-Cι2alkenyl, C3-C12cycloalkyl,
C3-C,2cycloalkenyl, C2-C,ιheterocycloalkyl, C2-C heterocycloalkenyl, C6- or C10aryl,
C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C9-Cnaralkenyl, C8-Cιoheteroaralkenyl, primary ammo or secondary amino; Rs1, R10, y and M are as defined above; and
RB11 is C2-C4alkylene, C2-C4alkenylene, 1 ,2-C3-Cι2cycloalkylene, 1 ,2-C3-C12cycloalkenylene,
1 ,2-C2-Cnheterocycloalkylene, 1 ,2-C2-Cnheterocycloalkenylene, 1 ,2-C6- or Cioarylene,
1 ,2-C5-C9heteroarylene, 1 ,2-C8-Cnaralkylene or 1 ,2-C6-Cιoheteroaralkylene; and alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, aralkyi, heteroaralkyi, aralkenyl and heteroaralkenyl are unsubstituted or substituted by one or more substituents selected from the abovementioned group of substituents.
Preferred compounds of the formula IB are those in which R3 is H, K or Na.
Preferred compounds of the formula IB are those compounds in which R4 is R4b, R b being Cι-C,2alkyl, C3-Cι2cycloalkyl or C2-Cn heterocycloalkyl, where alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by one or more substituents as defined above, preferably R4 is optionally substituted Cι-C6alkyl, more preferably methyl substituted by C3-Cι2cycloalkyl. Particularly preferred compounds of the formula IB are those compounds in which R4 is cyclohexyl-methyl.
In a particular embodiment of the invention RB5 is primary amino or amido, preferably amido.
Preferably RB5 corresponds to a group of the formula llaB or HbB, in which R86 is hydrogen, Cι-C12alkyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6- or Cioaryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl; RB7 is d-Cι2alkyl, C3-Cι2cycloalkyl, C2-Cn heterocycloalkyl, C6- or C10aryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C(O)OR's1, C(O)RB8, SO2R10 or SOaMy, wherein R 0, y and M are as defined above, R's1 is My, Cι-Cι2alkyl, C3-C12cycloalkyl, C2-Cn heterocycloalkyl, C6- or C10aryl, C5-C9heteroaryl, C7-C,, aralkyi or C6-Cιoheteroaralkyl; R88 is hydrogen, C(O)ORs1, Cι-Cι2alkyl, C3-d2cycloalkyl, C2-dιhetero- cycloalkyl, C6- or Cioaryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, primary amino or secondary amino; and RB11 is C2-C alkylene, 1 ,2-C3-d2cycloalkylene or 1 ,2-C6- or C10arylene; and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyi and heteroaralkyi are unsubstituted or substituted by one or more substituents as defined above. Preferably RB5 corresponds to a group of the formula llaB or llbB, in which R86 is hydrogen, Cι-Cι2alkyl, C3-Cι2cycloalkyl or C6- or Cioaryl; RB7 is Cι-Cι2alkyl, C3-Cι2cycloalkyl, C6- or Cι0aryl, C(0)OR,,sl, C(O)R,B8, SO2R'10 or SO3My, wherein R"s1 is My, Cι-Cι2alkyl, C3-Cι2cycloalkyl or C6- or C,0aryl; R'88 is hydrogen, C(O)OR"s', Cι-C,2alkyl, C3-Cι2cycloalkyl or C6- or Cι0aryl, primary amino or secondary amino; R'10 is d-Cι2alkyl, C3-Cι2cycloalkyl or C6- or Cioaryl; and RB" is 1 ,2-C6- or Cioarylene; and alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, d- Cι2alkyl, d-Cι2alkoxy, C3-C12cycloalkyl or C6- or Cioaryl; and My is K or Na. More preferably RB5 corresponds to a group of the formula llaB, in which R86 is hydrogen, d-Cι2alkyl, C3- C,2cycloalkyl or C6- or Cioaryl; RB7 is d-C^alkyl, C3-Cι2cycloalkyl, C6- or Cioaryl, C(O)OR"s1, C(O)R,BS, SO2R'10 or SO3My, wherein R"sl, R,B8, R,1°, y and M are as defined above; and alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, Cι-Cι2alkyl, d-Cι2alkoxy, C3-Cι2cycloalkyl or C6- or Cioaryl. Most preferably R85 corresponds to a group of the formula llaB, in which R86 is hydrogen or Cι-Cι2alkyl; RB7 is Crd2alkyl, C(O)Od-Cι2alkyl, CfOJR88, SO2C6- or Cioaryl or SO3My; R88 is C(O)OMy, d-C12alkyl, C3-C12cycloalkyl, C6- or Cioaryl or primary amino; and alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, Cι-Cι2alkyl, d-Cι2alkoxy or C6- or Cioaryl. Especially preferred compounds are those in which R85 corresponds to a group of the formula llaB, in which R86 is hydrogen, methyl or benzyl; R87 is methyl, benzyl, C(O)ORs1a, C(O)RB8a, SO2R10a or SO3Na, wherein Rs1a is methyl or methyl substituted with one or more substituents selected from phenyl, phenyl substituted with one or more substituents selected from methoxy and nitro, and naphthyl; R88* is C(O)ONa, methyl substituted with one or more phenyl, ethyl substituted with phenyl, cyclohexyl, phenyl, phenyl substituted with one or more substituents selected from methoxy, chlorine, nitro, phenyl and tπfluormethyl, naphthyl, NH(CH2)2COONa, NHC6H5 or NHCH2CH3; and R10a is tolyl.
Most preferably RB5 is R,B5, R'85 being -NHC(O)CH2C6H5, -NHC(O)CH(C6H5)2, -NHSO3Na, -NHC(O)(CH2)2C6H5, -NHC(O)C6Hn, -NHC(O)C6H5, -NHC(O)C6H4(4-OCH3), -NHCH2C6HS, -NHC(O)C6H3(3,4-OCH3)2, -NHC(O)C6H4(4-CI), -NHC(O)C6H4(4-NO2), -NHC(O)C6H4(4-C6H5), -NHC(O)C6H4(4-CF3), -NHC(O)COONa, -NHC(O)-2-naphthyl, -NHC(O)-1 -naphthyl, -NHC(O)NH(CH2)2COONa, -NHC(O)NHC6H5, -NHC(O)NHCH2CH3; -NHC(O)OCH2C6H5l -NHC(O)OCH2C6H2(4,5-OCH3)2(2-NO2), -NHC(O)OCH2C6H4(4-NO2), -NHSO2C6H4(4-CH3), -NHC(O)OCH2-2-naphthyl, -NHCH3, -N(CH2C6H5)2, -N(CH3)C(O)C6H5, -N(CH2C6H5)C(O)C6H5 or -phthalimido.
Especially preferred as RB5 are -NHC(O)CH(C6H5)2, -NHC(O)C6Hn, -NHC(O)C6H4(4-C6Hs), -NHC(O)C6H5, -NHC(O)C6H4(4-OCH3), -NHC(O)C6H3(3,4-OCH3)2, -NHC(O)C6H4(4-CI), -NHC(0)C6H4(4-NO2), -NHC(O)-2-naphthyl, -NHC(O)NHC6H5, -NHC(O)OCH2C6H5, -NHSO3Na, -NHCH2C6H5 or -N(CH2C6H5)2.
A particularly preferred embodiment of the invention comprises compounds of the formula laB
Figure imgf000017_0001
in which R3 is hydrogen or My and R85 is a group of formula llaB or HbB as defined above. Preferred compounds of the formula laB are those in which R3 is H, K or Na; R06 is hydrogen, Cι-C12alkyl, C3-d2cycloalkyl, C2-Cnheterocycloalkyl, C6- or Cι0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl; R87 is Cι-d2alkyl, C3-Cι2cycloalkyl, C2-Cnheterocyclo- alkyl, C6- or Cioaryl, C5-Cgheteroaryl, C7-C,,aralkyl, C6-C,0heteroaralkyl, C(O)ORs1, C(O)R88, SO2R10 or SO3Myι wherein R's1, R10, y and M are as defined above; R88 is hydrogen, C(O)OR's1, Cι-Cι2alkyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6- or Cioaryl, Cs-Cgheteroaryl, C7-Cιιaralkyl, C6-Cι0heteroaralkyl, primary amino or secondary amino; and RB11 is C2-C4alkylene, 1 ,2-C3-Cι2cycloalkylene or 1 ,2-C6- or Cι0arylene; and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyi and heteroaralkyi are unsubstituted or substituted by one or more substituents as defined above.
More preferred compounds of the formula laB are those in which R3 is H, K or Na; R86 is hydrogen, Cι-C12alkyl, C3-Cι2cycloalkyl or C6- or Cioaryl; RB7 is Cι-C12alkyl, C3-d2cycloalkyl, C6- or doaryl, C(O)OR"s1, C(O)R,B8, SO2R'10 or SO3My, wherein R',s1, R'88, R,1°, y and M are as defined above; and R811 is 1 ,2-C6- or Cι0arylene; and alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, Cι-C12alkyl, Cι-C12alkoxy, C3-Cι2cycloalkyl or C6- or C10aryl.
Most preferred compounds of the formula laB are those in which R3 is H, K or Na; R86 is hydrogen, d-C, .alkyl, C3-Cι2cycloalkyl or C6- or Cioaryl; R87 is Cι-Cι2alkyl, C3-Cι2cycloalkyl, C6- or doaryl, C(O)OR"s1, C(O)R,B8, SO2R'10 or SO3My, wherein R"s1, R,B8, R'10, y and M are as defined above; and alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, Cι-C12alkyl, C,-Cι2alkoxy, C3-Cι2cycloalkyl or C6- or Cioaryl.
Especially preferred compounds of the formula laB are those in which R3 is H, K or Na; R86 is hydrogen or d-C^alkyl; R87 is Cι-Cι2alkyl, C(O)Od-Cι2alkyl, CfOJR88, SO2C6- or Cioaryl or SO3My, wherein R88 is C(O)OMy, Cι-Cι2alkyl, C3-Cι2cycloalkyl, C6- or Cioaryl or primary am o; and alkyl, cycloalkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, nitro, Cι-Cι2alkyl, Cι-C12alkoxy or C6- or Cι0aryl. Especially preferred compounds of the formula laB are those in which R3 is H, K or Na; RE is hydrogen, methy /Il oorr bbeennzzyyll;; RR8877 iiss methyl, benzyl, C(O)ORs1a, C(O)RB8a, SO2R10a or SO3Na, wherein Rs1a, R883 and R,0a are as defined above.
A third preferred embodiment of the present invention relates to compounds of the formula IC
Figure imgf000019_0001
in which R ,2 , r Rι3 , R ri" and R have the above meanings.
Preferred compounds of the formula IC are those in which R3 is H, K or Na.
Preferred compounds of the formula IC are those compounds in which R is R as defined above.
In a particular embodiment of the invention R5 is X'-RT1C, C(O)NRT2CRT3C or C(O)ORT5C, wherein X' is C,-C4alkylene and RT1C, RT C, RT C and RT5C are as defined above.
Preferably R5 is X'-RT1C or C(O)ORT5C, wherein X', Rτ,c and RT5C are as defined above.
More preferred are compounds of the formula IC wherein R5 is X'-RT1Ca or C(O)ORT5C, wherein X' and RT5C are as defined above and RT1Ca is hydrogen or ORT6C wherein RT6C is as defined above.
Most preferred are compounds of the formula IC wherein R5 is X'-RT1C or C(O)ORT5C, wherein X' is Cι-C4alkylene, RT1C is hydrogen or OH; and RT5C is hydrogen or My. Preferably R5 is CH2OH, CH3 or C(O)ONa. Particularly preferred compounds of the formula IC are compounds of the formula laC
Figure imgf000020_0001
in which R3 is hydrogen, K or Na; and R5 is X'-RT1C, C(O)NRT2CRT3C or C(O)ORT5C, wherein X', RT1C, RT2C, RT3C and RT5C are as defined above.
More preferred are compounds of the formula laC wherein R3 is hydrogen, K or Na; and R5 is X'-RT1Ca or C(O)ORT5Ca, wherein X', RT1Ca and RT5C are as defined above.
Most preferred are compounds of the formula laC wherein R3 is hydrogen, K or Na; and R5 is X'-Rτ,c or C(O)ORTSC, wherein X' is C,-C4alkylene, RT1C is hydrogen or OH; and RT5C is hydrogen or My. More preferably R5 is CH2OH, CH3 or C(O)ONa.
The present invention also comprises a process for the preparation of the compounds of the formula I wherein the corresponding galactose-GlcNAc-disaccharide or galactose-tetra- hydropyran dimer is linked with the corresponding fucose-derivative or the corresponding fucose-GlcNAc-disaccharide or fucose-tetrahydropyran dimer is linked with the corresponding galactose, wherein the groups R1, RT1, X-RT2, R85 and or R5 are optionally introduced before or after the formation of the dimer or trimer. Where required, one or more protecting groups are removed and the compounds thus obtained are converted into salts.
In a preferred process for the preparation of the compounds of the formula IA the corresponding galactose-GlcNAc-disaccharide is linked with the corresponding fucose-derivative or the corresponding fucose-GlcNAc-disaccharide is linked with the corresponding galactose wherein the groups R1, RT1 and X-RT2 are optionally introduced before or after the formation of the dimer or trimer. Typically the process for the preparation of the compounds of the formula IA comprises (A1 ) reacting a compound of the formula IIIA
Figure imgf000021_0001
wherein each R12 independently is hydrogen or a protecting group, R60 is R1 or a protecting group and R15 is a leaving group, with a compound of the formula IVA
Figure imgf000021_0002
wherein R12 is as defined above, R61 is RT1 or a protecting group, or OR61 is R15, R62 is hydrogen, a protecting group or X-RT2, R63 is hydrogen or a protecting group and R64 is hydrogen or a protecting group or R12 and R64 together form a protecting group, and (A2) reacting the resulting disaccharide with a compound of the formula VA
Figure imgf000021_0003
wherein R2, R12 and R 5 are as defined above; wherein the groups R1, RT1 and X-RT2 are optionally introduced before or after step (A1 ) or step (A2); and, where required, removing the protecting groups; or
(B1 ) reacting a compound of the formula VA with a compound of the formula IVA, and (B2) reacting the resulting disaccharide with a compound of the formula IIIA; wherein the groups R1, RT1 and X-RT2 are optionally introduced before or after step (B1 ) or step (B2); and, where required, removing the protecting groups.
For example, a compound of formula ia may be prepared by reacting a compound of formula IVA with RT,-OH, followed by a reaction with a compound of formula VA. The resulting compound is reacted with RT2-X-R14, wherein R14 is a leaving group, then with a compound of formula IIIA and finally with R1-R13, wherein R13 is a leaving group. Where required, the protecting groups are removed and the compounds of formula IA are converted into salts.
As it will be appreciated, this reaction scheme is an example and may be carried out in a different sequence to produce a compound of formula IA.
The compounds of the formula IIIA, IVA and VA are known or may be obtained in accordance with methods known and practiced in the art.
Hydroxy protecting groups are generally known in the sugar and nucleotide chemistry and are described, for example, by Greene and Wuts [Protective Groups in Organic Synthesis, Wiley, New York (1991 )]. Examples of such protecting groups are: linear and branched Cι-Cθalkyl, in particular d-C alkyl, for example methyl, ethyl, n- and i-propyl, n-, i- and t-butyl; benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, dimethoxybenzyl, bromo- benzyl, 2,4-dιchlorobenzyl; diphenylmethyl, di(methylphenyl)methyl, di(dimethylphenyl)- methyl, dι(methoxyphenyl)methyl, di(dιmethoxyphenyl)methyl, tnphenylmethyl, trιs-4,4',4"- tert-butylphenylmethyl, di-p-anisylphenylmethyl, trι(methylphenyl)methyl, tri(dιmethylphenyl)- methyl, methoxyphenyl(dιphenyl)methyl, di(methoxyphenyl)phenylmethyl, trι(methoxy- phenyl)methyl, trι(dιmethoxyphenyl)methyl; triphenylsilyl, alkyldiphenylsilyl, dialkylphenylsilyl and tπalkylsilyl with 1 to 20, preferably 1 to 12, and particularly preferably 1 to 8 C atoms in the alkyl groups, for example triethylsilyl, tπ-n-propylsilyl, i-propyl-dimethylsilyl, t-butyl-di- methylsilyl, t-butyl-diphenylsilyl, n-octyl-dimethylsilyl, (1 ,1 ,2,2-tetramethylethyl)dιmethylsilyl; C2-Cι2-, in particular C2-C8acyl, such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, benzoyl, methylbenzoyl, methoxybenzoyl, chlorobenzoyl and bromobenzoyl; substituted methy 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 d-C^alkylidene, preferably Cι-C6alkylιdene and in particular C,-C4alkylidene, such as ethylidene, 1 ,1- and 2,2-propyl- idene, 1 ,1 - and 2,2-butylιdene, benzylidene. The protecting groups may be identical or different.
Preferably R12 and R64 together form an alkylidene group with, preferably 1 to 12 and, more preferably 1 to 8 C atoms. These protecting groups may be removed under neutral or weak- ly acidic conditions. R12 and R64 are, particularly, together alkylidene, for example unsubstituted or alkyl- or alkoxy- substituted benzylidene.
Compounds of the formula IB wherein R85 is a group of formula llaB may be produced by reacting a compound of the formula IVB
Figure imgf000023_0001
wherein R2 and R4 have the abovementioned meanings
(a) in the case where R86 is hydrogen and
(a1 ) RB7 is C,-C12alkyl, C3-C12alkenyl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C^aralkenyl,
C8-C10heteroaralkenyl, which are unsubstituted or substituted by one or more substituents, with an aldehyde of formula VB
RB7CHO (VB) wherein RB7 is hydrogen, 0,-0, ..alkyl, C2-C11alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C, heterocycloalkyl, C2-C11 heterocycloalkenyl, C7-C10aralkyl, C6- or C10aryl, C6-C9heteroaralkyl, C5-C9heteroaryl, C8-C10aralkenyl or C7-C9heteroaralkenyl, which are unsubstituted or substituted by one or more substituents; or
(a2) RB7 is dj-C^alkyl, C3-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-O,1hetero- cycloalkyl, C2-C„heterocycloalkenyl, C7-C aralkyi, C6-C10heteroaralkyl, C8-C^aralkenyl, C8-C10heteroaralkenyl, which are unsubstituted or substituted by one or more substituents, with a ketone of formula VlaB or VlbB
RBrCORBr" (VlaB) o=(^ RB1 (VlbB)
wherein each of R87 and RB independently is d-Cnalkyl, C2-Cnalkenyl, C3-C 2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn heterocycloalkenyl, C7-Cι0aralkyl, C6- or Cι0aryl, C6-C9heteroaralkyl, C5-C9heteroaryl, C8-Cιoaralkenyl,
Figure imgf000023_0002
which are unsubstituted or substituted by one or more substituents; and RB12 is C3-C10alkylene or C3-Cι0alkenylene, for example cyclobutanon, cyclodecanon, cyclobutenon and cyclodecen- on, which are unsubstituted or substituted by one or more substituents; or (a3) RB7 is C(O)ORs1, CfOJR88 or SO2R10, wherein Rs1 and R10 are as defined above and R88 is hydrogen, C(O)ORs1, Cι-Cι2alkyl, C3-Cι2alkenyl, C3-C12cycloalkyl, C3-C 2cycloalkenyl, C2-C heterocycloalkyl, C2-Cι heterocycloalkenyl, C6- or Cioaryl, C3-C9heteroaryl, d-Cπar- alkyl, C6-Cι0heteroaralkyl, Cg-Cnaralkenyl or C8-Cι0heteroaralkenyl; and alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, aralkyi, heteroaralkyi, aralkenyl and heteroaralkenyl are unsubstituted or substituted by one or more substituents, with a compound of formula VIIB
R 3RB7" (VIIB) wherein RB7" is C(O)ORs1, CfOJR88 or SO2R10, wherein Rs1, R88 and R 0 are as defined above; and R13 is a leaving group; or (a4) RB7 is C(O)R88, wherein R88 is primary amino or secondary amino; with an isocyanate
OCNR8 (VIIIB) wherein RB is hydrogen, SO2R10, OSO2R10, d-Cι2alkyl, C3-C,2cycloalkyl, C2-C,, heterocycloalkyl, C6- or Cioaryl, C5-C9heteroaryl, C7-Cn aralkyi, C6-C10heteroaralkyl, C8-Cι6aralkenyl, which are unsubstituted or substituted by one or more substituents; (a5) RB7 is SO3My, wherein My has the abovementioned meanings, with a complex of formula IXB
SO3 • NC5H5 (IXB);
(b) in the case where R86 is C Cι2alkyl, C3-Cι2alkenyl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, Cg-Cnaralkenyl or C8-Cι0heteroaralkenyl; and
(b1 ) RB7 is C,-C12alkyl, C3-Cι2alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnhetβro- cycloalkyl, C2-Cnheterocycloalkenyl,C7-C,ιaralkyl, C6-Cι0heteroaralkyl, Cg-Cnaralkenyl or C8-Cι0heteroaralkenyl, which are unsubstituted or substituted by one or more substituents subsequently with an aldehyde of formula VB or a ketone of formula VlaB or VlbB; (b2) R87 is C(O)ORs , CfOJR88 or SO2R10, wherein Rs1 is hydrogen, My, C,-C,2alkyl, C3-Cι2alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6- or Cioaryl, C5-Cgheteroaryl, C7-C aralkyl or C6-Cι0heteroaralkyl; R88 is hydrogen, C(O)ORs1, C Cι2alkyl, C3-Cι2alkenyl, C3-C12cyctoalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnheterocycloalkenyl, C6- or Cι0aryl, C5-C9heteroaryl, C -Cnaralkyl, C6-Cι0heteroaralkyl, C9-Cnaralkenyl or Cβ-doheteroaralkenyl; R10 is C,-Cι2alkyl, C3-C 2cycloalkyl, C2-Cnheterocycloalkyl, C6- or Cioaryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-C 0heteroaralkyl, which are unsubstituted or substituted by one or more substituents; subsequently with an aldehyde of formula VB and a compound of formula VIIB; or
(b3) R87 is CfOJR88, wherein R88 is primary amino or secondary amino; subsequently with an aldehyde of formula VB and a compound of formula VIIIB;
(b4) R87 is SO3My, subsequently with an aldehyde of formula VB and a compound of formula IXB.
Compounds of formula IB wherein R85 is a group of formula llaB wherein R87 is C6- or C10aryl or C5-Cgheteroaryl, may be produced by reductively aminating a compound of formula IVbB
Figure imgf000025_0001
wherein R2, R3 and R4 are as defined above and R12 is hydrogen or a protecting group with an aromatic amme, optionally removing the protecting groups, and further reacting the resulting compound as described in (b) above.
Compounds of formula IB wherein R85 is a group of formula llbB may be produced by reacting a compound of the formula IVB wherein R2, R3 and R4 are as defined above with a compound of formula VllbB
(VllbB)
Figure imgf000025_0002
wherein R has the abovementioned meanings; and each R13 is independently a leaving group. Leaving groups may be: halides, such as chloride, bromide and iodide, and oates for example of the formula R8r-O' (in which case formula VIIB is an anhydride RBr-O-RB ) or alkoxides (alkylO ).
The compounds of the formula VB to IXB are known or may be obtained by known methods.
The compounds of the formula IVB and IVbB are novel and form part of the present invention. They may be obtained starting from commercially available 3,4,6-triacetoxyglucal by
(a) deprotecting said compound, protecting its 6-position, coupling with a suitably protected and activated galactose, replacing the 6-protecting group by a leaving group, substituting with an N-nucleophile, coupling with a suitably protected and activated L-fucose, introducing the group -CH(COORB8)R4, in which R88 is a carboxylate protecting group and R4 has the abovementioned meanings, into the prior deprotected galactose residue, reducing the glucal residue, removing the fucose protecting groups and optionally reducing the residue R4; or
(b) reducing said compound, deprotecting and converting the 6-position into a leaving group, coupling with a suitably protected and activated galactose, coupling with a suitably protected and activated L-fucose, substituting the 6-posιtιon with an N-nucleophile, introducing the group -CH(COOR88)R4 into the prior deprotected galactose residue and removing the protecting groups; or
(c) reducing said compound, deprotecting and protecting its 4- and 6-posιtιon, coupling with a suitably protected and activated galactose, removing the 4- and 6-protectιng groups, converting the 6-posιtιon into a leaving group, substituting with an N-nucleophile, coupling with a suitably protected and activated L-fucose, introducing the group -CH(COORB8)R4 into the prior deprotected galactose residue, reducing the glucal residue and removing the fucose protecting groups; or
(d) deprotecting said compound, converting the 6-position into a leaving group, substituting with an N-nucleophile, coupling with a suitably protected and activated galactose, coupling with a suitably protected and activated L-fucose, introducing the group -CHfCOOR88^4 into the prior deprotected galactose residue, reducing the glucal residue, removing the fucose protecting groups and optionally reducing the residue R4; or
(e) deprotecting said compound, protecting its 6-position, coupling with a suitably protected and activated galactose, reducing the glucal double bond, converting the 6-position into a leaving group, substituting with an N-nucleophile, coupling with a suitably protected and activated L-fucose, introducing the group -CHfCOOR88^4 into the prior deprotected galactose residue, reducing the glucal residue and removing the fucose protecting groups; or (f) deprotecting said compound, protecting its 6-positιon, coupling with a suitably protected and activated galactose and subsequently with a suitably protected and activated L-fucose, introducing the group -CH(COORB8)R4 into the prior deprotected galactose residue, protecting the remaining galactose hydroxy groups, deprotecting the 6-protectιng group of the glucal and oxidizing said position.
The abovementioned strategies (a) to (e) may for example be performed by using a suitably protected and activated galactose which already contains the group -CH(COORB8)R4. This compound may for example be obtained starting from an activated galactose by introducing a protecting group at the anomenc position, deprotecting said compound, introducing the group -CH(COORB8)R4 protecting the residual hydroxyl groups, deprotecting and activating the anomenc position.
Suitable activating groups for sugars and glycosylation are known to the person skilled in the art and are described for example by Toshima and Tatsuta [Chem. Rev. 93:1503 (1993)], Paulsen [Angew. Chem. Int. Ed. Engl. 21 :155 (1982)] and Schmidt and Kmzy [Adv. Carbohydr. Chem Biochem. 50:21 (1994)].
Examples for N-nucleophiles are NaN3, NH3, primary amines and secondary amines, preferably the N-nucleophile is NaN3.
Suitable reducing conditions are for example H2, Pd/C 10%, MeOH; H2, Pd(OH)2/C 10%, dioxane/water 2/1 ; or H2, Rh/AI2O3 5%, dioxane/water 2/1.
The compounds of formula IVB, IVbB and VB, VIB, VIIB, VIIIB and IXB respectively may be employed in equimolar amounts or, advantageously, in excess, for example in an amount which is up to 5 times, preferably 2 times the amount of the compound of formula IVB or IVbB Examples of carboxylate protective groups are esters, preferably methyl and benzyl esters Methyl esters are preferably cleaved under the abovementioned basic conditions and benzyl esters are preferably cleaved under the abovementioned reducing conditions.
Compounds of formula IC may be prepared by converting a compound of the formula IIC
Figure imgf000028_0001
wherein R2 and R4 have the abovementioned meanings, R3 has the meanings of R3 or is a protecting group and R12 means a protecting group applying procedures known in the art.
Examples of such conversions are e.g.
(A) in the case that R5 is X'-RT1C, wherein X' is methylene and RT1C is
(a) hydrogen: removing the alcohol functionality;
(b) halogen: transforming the alcohol function into a halide function;
(c) C,-Cι2alkyl, d-Cnheteroalkyl, C3-d2alkenyl, C3-Cι2cycloalkyl, C3-d2cycloalkenyl, C2-Cnheterocycloalkyl, C2-dιheterocycloalkenyl, C6-, Cι0- or Cι4aryl, C2-C9heteroaryl, C7-Cιιaralkyl, C6-Cι0heteroaralkyl, C9-Cnaralkenyl or C8-Cι0heteroaralkenyl: oxidizing the alcohol, reacting the resulting aldehyde with a suitable C-nucleophile and removing the resulting secondary alcohol functionality;
(d) ORT6C, wherein RT6C is
(α) hydrogen: removing the protecting groups;
(β) CrCι2alkyl, d-Cnheteroalkyl, C3-C12alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl,
C2-Cι, heterocycloalkyl, C2-Cnheterocycloalkenyl, C6-. Cι0- or Cι aryl, C2-C9heteroaryl,
C7-Cnaralkyl, C6-Ci0heteroaralkyl, Cg-Cnaralkenyl or C8-Cιoheteroaralkenyl: forming the corresponding ether;
(γ) SO3RT5C or PO3RT7CRT8C: introducing the SO4- or PO4-function using a suitable SO3- or
PO3-donor (eg. SO3 • pyridme); (δ) C(O)ORT9C: reacting with a compound of formula Hal-C(O)-ORT9C; (ε) C(S)NRT CRT3C or C(O)NRT2CRT3C: reacting with for example phosgene [C(O)CI2] or thiophosgene [C(S)CI2], and substituting the resulting carbonic/thiocarbonic acid chloride with HNRT2CRT3C;
(e) OC(O)RT4C: forming the corresponding ester;
(f) SRT4C, SO2RT9C or SO3RT5C: transforming the alcohol group into a leaving group, reacting with a suitable S-nucleophile and optionally oxidizing the resulting SR group;
(B) in the case that R5 is X'-RT1C, wherein X' is C2-C4alkylene: proceeding as in (A(c)) followed by one of the procedural variants A(a) to A(f);
(C) in the case that R5 is C(O)NRT2CRT3C: oxidizing the alcohol and reacting the resulting carboxyiic acid to form the corresponding amide;
(D) in the case that R5 is C(O)RT4C- oxidizing the alcohol and optionally reacting the resulting aldehyde with a suitable C-nucleophile and oxidizing the resulting secondary alcohol functionality to the corresponding ketone;
(E) in the case that R5 is C(O)ORT5C: oxidizing the alcohol and optionally reacting the resulting carboxyiic acid to form the corresponding ester; wherein each of the above variants (except of [A(d)(α)]) is followed by the removal of the protecting groups
The compounds of the formula IIC are new and form part of the present invention. They may be produced by linking the corresponding galactose-1 ,2-dιdeoxyglucose-dιsaccharιde with the corresponding fucose-derivative or the corresponding fucose-1 ,2-dιdeoxyglucose- disacchaπde with the corresponding galactose wherein the group -CH(COOR3)R4 is optionally introduced before or after the formation of the dimer or trimer. The compounds of formula IIC may be obtained by following a procedure as disclosed for the compounds of formula IA above, the group -CH(COOR3)R4 being introduced by reaction with R13-CH(COOR3)R4.
Leaving groups as R13 may be a halide or unsubstituted or halogenated R-SO2-, in which R is Cι-Cι2alkyl, in particular d-C6alkyl and mono-, di- or trifluoromethyl, C5-C6cycloalkyl, phenyl, benzyl, Cι-Cι2alkylphenyl, in particular Cι-C alkylphenyl, nitrophenyl, or Cι-Cι2alkyl- benzyl, in particular d-C4alkylbenzyl, for example methane, ethane, propane, butane, benzene, benzyl- and p-methylbenzenesulfonyl. Preferred leaving groups are CI, Br, I, -SO2CF3 (triflate) and p-nitrobenzenesulfonyl, -SO2CF3 being more preferred.
Leaving groups in the meaning of R 4 are for example halides, such as preferably chloride and bromide, and especially in the case when X is -C(O)- carboxylates and groups of for example the formulae
where,n
Figure imgf000030_0001
Examples of leaving groups which are especially useful in glycosylation reactions, i.e. here in the meaning of R15 are -S-CH3, -S-CH2-CH3, -S-Ph, -O-C(=NH)-CCI3, -O-C(-O)-CH3, OP(OR)2 and halogen for example CI, Br and I. These leaving groups can be in the axial or in the equatorial position.
It has proved advantageous to activate the 3-OH group of the galactose residue prior to etheπfication by stannylation. Particularly suitable for this purpose are dialkylt oxides, dialkyltin alkoxylates and bιs(trιalkyl)tιn oxides. Some examples are dibutyltin oxide, dibutyl- tιn(O-methyl)2 and (trιbutyltιn)2O. The activating agents are preferably used in stoichiometπc amounts. In this case, the reaction is carried out in two stages, namely a) activation and b) coupling with e.g. RT1-OH.
Further details of the preparation of the compounds of the formula IA, IB and IC are described e.g. in the examples.
The compounds of formula I exhibit valuable pharmacological properties as indicated in tests and are therefore indicated for therapy. In particular the compounds of formula I inhibit the binding of E-selectin to SLea as disclosed in Example C1 and the interaction of E- selectin and its natural ligand as disclosed in Example C2. The compounds are accordingly indicated for preventing or treating conditions or diseases which are mediated by the binding of selectin in cellular adhesion, e.g. acute or chronic inflammatory or autoimmune diseases such as rheumatoid arthritis, asthma, allergy conditions, psoriasis, contact dermatitis, adult respiratory distress syndrome, inflammatory bowel disease and ophthalmic inflammatory diseases, infection diseases such as septic shock, traumatic shock, thrombosis and inappropriate platelet aggregation conditions, cardiovascular diseases such as heart attacks, reperfusion injury, multiple sclerosis and neoplastic diseases including metastasis conditions, strokes and acute or chronic rejection of organ or tissue transplants.
Acute and chronic rejection play a role in the transplantation of organs or tissues from a donor to a recipient of the same species (allograft) or different species (xenograft). Among such transplanted organs or tissues and given illustratively are heart, lung, combined heart- lung, trachea, liver, kidney, spleen, pancreatic (complete or partial, e.g. Langerhans islets), skin, bowel, or cornea or a combination of any of the foregoing.
For the above uses the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired, In general, however, satisfactory results are achieved at dosage rates of from 0.1 to about 100 mg/kg/day, administered in 1 , 2, 3, or 4 doses/day, or in sustained release form. Suitable daily dosages for oral administration to larger mammals, e.g., humans, are generally about 50 to 1500 mg, preferably in the order of from 200 to 800 mg. Unit dosage forms suitably comprise from about 25 mg to 0.750 g of a compound of the invention, together with a pharmaceutical acceptable diluent or carrier therefor.
The compounds of formula I may be administered by any conventional route of administration, e.g. enterally, preferably orally, e.g. in the form of tablets or capsules, or par- enterally e.g. in form of injectable solutions or suspensions.
Pharmaceutically acceptable 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. In accordance with the foregoing the present invention further provides:
(a) a compound of formula I or a pharmaceutically acceptable salt thereof for use as a pharmaceutical;
(b) a method for preventing or treating disorders as indicated above in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
(c) a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier;
(d) a compound of formula I or a pharmaceutically acceptable salt thereof for use in the manufacturing of a medicament for use in the method as in (b) above.
The compound may be administered alone or in combination with one or more other anti-inflammatory or immunosuppressive agents, for example in combination with cyclosporin A and analogs thereof, FK-506 and analogs thereof, rapamycin and analogs thereof, myco- phenolic acid, mycophenolate mofetil, mizoribine, 15-deoxyspergualine, leflunomide, steroids, cyclophosphamide, azathioprene (AZA), or anti-lymphocyte antibodies or immuno- toxins such as monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, or CD25; especially in combination with a T-cell suppressant, e.g., cyclosporin A or FK-506. Such combination therapy is further comprised within the scope of the invention, e.g., a method according to 1 above further comprising administration concomitantly or in sequence of a therapeutically or synergistically effective amount of such a second immunosuppressive or anti-inflammatory agent.
The following examples are offered as a way for illustration of this invention and not in a way of limitation.
Abbreviations used are:
Ac: Acetyl; Bz: Benzoyl; Bn: Benzyl; Ph: Phenyl; SEt: C2H5S; HRP: Horse radish peroxid- ase; BSA: Bovine serum albumin; DMTST: Dimethyl(methylthio)sulfonium triflate; OTf: Tri- flate; THG: Thioglycerol; THF: Tetrahydrofuran; NBA: m-Nitrobenzyl alcohol; DMF: N,N-Di- methylformamide; DME: 1 ,2-Dimethoxyethane; MeOH: Methanol; PAA: Polyacryl amide; SA: Streptavidin; TBDMS: tert.butyldimethylsilyl; PTSA: p-toluene sulfonic acid; RT: room temperature; MW: molecular weight; MS: mass spectroscopy; FAB: Fast atom bombardment mass spectroscopy. An unconnected hyphen in the formulae means methyl.
A: Preparation of starting compounds
Example A1b: Preparation of compound No. A1b
Figure imgf000033_0001
HO a) 2 (3.74 g, 14 mmol)
Figure imgf000033_0002
prepared according to Kinzy and Schmidt, Tetrahedron Lett. 28:1981-1984 (1987) and imidate 3
Figure imgf000033_0003
[Rio et al., Carbohyd. Res. 219:71-90 (1991)] (12.76 g, 17 mmol) are dissolved in dry CH2CI2 (100 ml) under argon at 0°C. 100 μl (1.8 mmol) of a solution of triethylsilyltriflate (117 μi in 2 ml CH2CI2) are added. After 4 h the reaction mixture is treated with NEt3 (0.5 ml) and evaporated. Purification by repeated flash chromatography on silica (ethyl acetate/- hexane = 1/3) affords 4 as a white solid.
Figure imgf000034_0005
Figure imgf000034_0001
b) 4 (740 mg, 0.88 mmol) is dissolved in 120 ml THF/pyridine 1/1 in a plastic container. At 0°C HF-pyridine complex 70/30 (20 ml) is added. After 2 h sat. NaHCO3 solution is added and the mixture is extracted with ethyl acetate. The organic layer is washed with sat. NH4CI dried with MgSO4 and evaporated. Purification by flash chromatography on silica (ethyl acetate/hexane = 1/1 ) gives 6 which is used directly in the next step.
Figure imgf000034_0002
c) A solution of 6 (1.145 mg, 1.15 mmol), para-tolouenesulfonyl chloride (361 mg, 1 .89 mmol) and dry pyridine (10 ml) in dry CH2CI2 (100 ml) is heated under reflux for 7 d. The reaction mixture is evaporated and purified by flash chromatography on silica (ethyl acetate/hexane = 2/3) to give in the order of elution 7 and recovered starting material.
Figure imgf000034_0003
d) A solution of 7 (855 mg, 0.97 mmol) and NaN3 (253 mg, 3.89 mmol) in dry DMF (10 ml) is stirred for 16 h. The reaction mixture is extracted with ethyl acetate, the organic layer is washed with water, dried with MgSO4, evaporated and purified by flash chromatography on silica (ethyl acetate/petrol ether = 1/2) to give 8.
Figure imgf000034_0004
e) 8 (50 mg, 0.066 mmol) and imidate 9
Figure imgf000035_0001
[Wegmann and Schmidt, Carbohyd. Res. 184:254-261 (1988)] (58 mg, 0.100 mmol) are dissolved in ether (5 ml) under argon. 50 μl (0.05 eq.) of a solution of triethylsilyltriflate (60 μl in 4 ml ether) are added. After 15 min the reaction mixture is treated with NEt3, evaporated and purified by repeated flash chromatography on silica (ethyl acetate/hexane = 1/2) and subsequently by gel filtration on sephadex LH20 eluting with MeOH to give 10.
Figure imgf000035_0002
f) A solution of 10 (160 mg, 0.137 mmol) in degassed MeOH (10 ml) is treated with a catalytic amount of NaOMe solution. After 3 h the reaction mixture is neutralized with crushed Amberlyst 15, filtered over hyflo, evaporated and purified by flash chromatography on silica (chloroform/isopropanol = 8/1 ) to give 11.
Figure imgf000035_0003
g) 11 (1.17 g, 1.56 mmol) and dibutyltinoxide (Bu2SnO) (388 mg, 1.56 mmol) are suspended in MeOH under argon and refluxed for 2 h. The resulting clear solution is evaporated. The vacuum of the rotatory evaporator is released by flushing with argon not with air. The residue is once evaporated with benzene and dried on high vacuum. Dried CsF (1.18 g, 7.8 mmol) is added under argon to the resulting residue and subsequently a solution of (fl)-benzyl-3-phenyl-2-trifluoromethanesulfonyloxypropionate 12
Figure imgf000036_0001
[Degerbeck et al., J. Chem. Soc. Perkin Trans. 1 :1 1 -14 (1993)] (3.0 g, 7.8 mmol) in DME (50 ml). After stirring for 18 h at room temperature the mixture is diluted with ethyl acetate and washed with sat. KH2PO4 and water, dried with MgSO and purified by flash chromatography on silica (ethyl acetate/hexane = 2/1) to give 13.
Figure imgf000036_0002
BnO h) A mixture of 13 (902 mg, 0.91 mmol) dissolved in MeOH/H2O/AcOH 50/50/1 (30.3 ml) and Pd/C 10% (1 g) is stirred under H2 (balloon) for 50 h. Some ml of CH2CI2 are added. The mixture is filtered over hyflo, evaporated, dissolved in water and freeze dried. The resulting residue (527 mg) is purified by P2 gelfiltration eluting with water to give 14.
Figure imgf000036_0003
i) A mixture of 14 (361 mg, 0.60 mmol) dissolved in H2O/dioxane 3/2 (45 ml) and Rh 5%/AI2O3 (180 mg) is stirred under H2 (balloon) for 2 d. The mixture is filtered over hyflo, evaporated, dissolved in water and purified by P2 gelfiltration eluting with water to give after freeze drying pure A1b and an impure sample of A1b as white foams. C27H47NO,4 (MW=609.67): MS (FAB positive mode, THG) 632 (M+Na), 610 (M+H). 1H NMR (500 MHz, D2O) δ 4.85 (d, 1 H, Fuel ), 4.62 (q, 1H, Fuc5), 4.46 (d, 1 H, Gall), 4.05-3.96 (m, 2H), 3.94- 3.89 ( , 1 H), 3.85 (d, 1 H, Gal4), 3.82 (dd, 1 H, Fuc3), 3.76-3.72 (m, 2H), 3.70-3.64 (m, 2H), 3.61 -3.50 (m, 4H), 3.50-3.39 (m, 2H), 3.34 (dd, 1 H, Gal3), 3.14 (dd, 1 H), 2.21-2.16 (m, 1 H), 1.78-1.71 (m, 1 H), 1.68-1.44 (m, 8H), 1.22-1.08 (m, 6H, including at 1.15 (d, Fuc6)), 0.94- 0.80 (m, 2H).
Example A1c: Preparation of compound No. A1c
Figure imgf000037_0001
a) A mixture of 1 c (1.00 g, 3.18 mmol)
Figure imgf000037_0002
and dibutyltinoxide (1.38 g; 5.57 mmol, 1.75 eq) in 50 ml of dry methanol is heated under reflux for 2 h in an argon atmosphere. The solvent is removed and the residue dried in high vacuo for 16 h. The colorless oil is dissolved in 50 ml of abs. dimethoxyethane. Under argon, 2c (2.82 g, 9.54 mmol, 3.0 eq)
(2C)
Figure imgf000037_0003
and dry cesiumfluoride (1.21 g, 7.95 mmol, 2.5 eq) are added and the resulting suspension stirred at RT for 6 h. Then, 200 ml of a 1 N KH2PO4 solution containig 2 g of potassium- fluoride is added followed by the extraction with chloroform (3 x 175 ml). The combined organic layers are washed with brine (2 x 200 ml) and the solvent is removed. Flash chromatography on silica gel (toluene/ethylacetate 5:1) gives 3c as a colorless oil.
Figure imgf000038_0001
b) To a solution of 3c (2.00 g, 4.03 mmol) in 18 ml of abs. pyridine benzoylchloride (2.8 ml, 24.1 mmol, 3.0 eq) and 4-(dimethylamino)-pyridine (0.147 g, 1.2 mmol, 0.3 eq) are added at 0°C. The mixture is stirred at RT for 16 h. Ethylacetate (300 ml) is added followed by the extraction with 0.1 N HCI (5 x 100 ml), sat. NaHCO3 solution (5 x 100 ml) and brine (2 x 100 ml). The organic layer is dried with Na2SO4, the solvent is removed and the residue is subjected to flash chromatography on silica gel (hexane/ethylacetate 4:1-→2:1). Compound 4c is isolated as a colorless solid.
Figure imgf000038_0002
c) A suspension of 5c (4.00 g, 27.0 mmol)
Figure imgf000038_0003
6c (9.12 ml, 53.6 mmol)
/_. OMe MeO— <^ >— < (6c)
OMe and PTSA (0.60 g) in 150 ml abs. acetonitrile is stirred at RT for 2 h. After the addition of 1.5 g solid NaHCO3 the solvent is removed and the residue is subjected to flash chromatography on silica gel (toluene/ethylacetate 2:1→1:1 ). Compound 7c is isolated as a colorless foam.
Figure imgf000039_0001
d) A suspension of 4c (1.00 g, 1.42 mmol), 7c (0.756 g, 2.84 mmol, 2.0 eq) and molecular sieves (3 A, 1.0 g) in abs. CH2CI2 (5 ml) is stirred for 2 h under argon. Within 1 h a solution of 8c (0.55 g, 2.13 mmol, 1.5 eq)
Figure imgf000039_0002
[Garegg, P.E., Carbohydrate Research 149:69 (1986)] in abs. CH2CI2 (4 ml) is added drop- wise at RT and the mixture is stirred for 1 h. Then, 50 ml of a sat. NaHCO3 solution are added, the layers are separated and the aquous layer is extracted with CH2CI2 (2 x 25 ml). The combined organic layers are dried with Na2SO4, the solvent is removed and the residue is dissolved in a mixture of CH2CI2 (50 ml) and methanol (10 ml). Camphersulfonic acid (50 mg) is added and the mixture is stirred for 2 h at RT. The solvents are removed and the residue is subjected to flash chromatography on silica gel (toluene/ethylacetate 2:1 ). Compound 9c is isolated as a colorless oil.
Figure imgf000039_0003
e) A solution of 9c (847 mmg, 0.821 mmol) and triphenylmethyl chloride (343 mg, 1.23 mmol, 1.5 eq) in abs. pyridine (18 ml) is stirred under argon for 24h at 70°C. Then, additional triphenylmethyl chloride (171 mg, 0.615 mmol, 0.75 eq) is added and stirring continued for 24 h. The solvent is removed in vacuo and the residue purified by flash chromatography on silica gel (toluene/ethylacetate 8:1→5:1 ) to yield 10c as a colorless foam.
Figure imgf000040_0001
f) A suspension of 10c (1000 mg, 0.969 mmol), tetraethylammonium bromide (405 mg, 1.94 mmol, 2.0 eq) and molecular sieves (3A, 1.2 g) in abs. CH2CI2 (4.5 ml) and abs. DMF (4.5 ml) is stirred under Argon for 2 h at RT (suspension A).
In a separate reaction flask a solution of bromine (357 mg, 2.23 mmol, 2.3 eq) in abs. CH2CI2 is added at 0°C within 15 min to a solution of 11c (926 mg, 1.94 mmol, 2.0 eq),
Figure imgf000040_0002
in abs. CH2CI2 (1.5 ml). After stirring for 30 min cyclohexene (0.2 ml) is added and the mixture is warmed to RT (solution B).
The clear solution B is added dropwise to suspension A within 1 h. Having stirred for 2 h at RT the mixture is diluted with ethylacetate (200 ml) and filtered through Hyflo Super Cel. The solution is extracted with Na2S2O3 solution (100 ml), water (2 x 100 ml) and brine (100 ml). The organic layer is concentrated and the residue dissolved in diethylether (25 ml) and formic acid (5 ml). Having stirred for 3 h the solvents are removed and the residue is puπfied by chromatography on silica gel (ethylacetate/hexane 2:1 ) to give A1c as a colorless oil. 1H NMR (400 MHz, CDCI3) δ 0.50-1.42 (14 H, m, -Chfe-cCeHn, H^), 1.17 (3 H, t, 7.0 Hz, CO2-CH2-CH3), 1.34 (3 H, d, 6.5 Hz, H-6 Fuc), 1.94 (1 H, dd, 13.0/5.0 Hz, H- 2βq). 2.24 (1 H, t, 6.5 Hz, C6-OH), 3.16 (1 H, dt, 9.5/3.5 Hz, H-5), 3.29 (1 H, t (br), 12.0 Hz, H-1aχ), 3.52 (1 H, d (br), 2.5 Hz, H-4 Fuc), 3.56 (1 H, dd, 10.0/6.5 Hz, H-6 Gal), 3.57 (1 H, t, 9.5 Hz, H-4), 3.66 (1 H, dd, 10.0/5.5 Hz, H-6' Gal), 3.74 (2 H, m, H-6, H-6'), 3.79 (1 H, dd, 12.0/5.0 Hz, H-1βq), 3.84-3.89 (3 H, m, H-3, H-3 Gal, H-5 Gal), 3.92 (1 H, dd, 10.0/2.5 Hz, H- 3 Fuc), 4.05 (1 H, dd, 10.0/3.5 Hz, H-2 Fuc), 4.07-4.15 (3 H, m, -CO2-CH2-CH3, -CH-CH2- cC6H,ι), 4.38 (1 H, d, 11.5 Hz, -OCH2-Ph), 4.43 (1 H, d, 11.5 Hz, -OCH2-Ph), 4.47 (1 H, d, 11.5 Hz, -OCH2-Ph), 4.48 (1 H, d, 11.5 Hz, -OCH2-Ph), 4.57 (1 H, d, 11.5 Hz, -OCH2-Ph), 4.61 (1 H, q (br), 6.5 Hz, H-5 Fuc), 4.65 (1 H, d, 8.0 Hz, H-1 Gal), 4.68 (1 H, d, 11.5 Hz, - OCH2-Ph), 4.79 (1 H, d, 11.5 Hz, -OCH2-Ph), 4.81 (1 H, d, 11.5 Hz, -OCH2-Ph), 5.07 (1 H, d, 3.5 Hz, H-1 Fuc), 5.38 (1 H, dd, 10.0/8.0 Hz, H-2 Gal), 5.89 (1 H, d, 3.5 Hz, H-4 Gal), 7.16- 8.12 (30 H, m, Ar-H); MS (FAB/EI) 1229 (M+Na)+.
B Preparation of the mimetics
Example B(a): Preparation of compounds of the formula IEXM
Figure imgf000041_0001
(1 ) Preparation of compound No. B1a [R4: CH∑CβHn; RT1: (CH2)βC02CH3; RT2: 3,4-(OCH3)2C6H3] a) Within 1 h at -35°C in an argon atmosphere trimethylsilyl triflate (15.40 g; 69.50 mmol) is added dropwise to a solution of tetraacetate 1a (12.00 g; 27.81 mmol)
Figure imgf000041_0002
and 2a [HO(CH2)θCO2CH3] (7.84 g; 41.70 mmol) in abs. methylene chloride (150 ml). The mixture is warmed to RT within 2 h and triethylamine (15 ml) are added. The mixture is extracted successively with 0.1 n HCI, 0.1 n NaOH, water and saturated NaOH solution (250 ml each). After filtration of the organic phase glycoside 3a is obtained by chromatography on silica gel (ether/hexane 3:1).
Figure imgf000041_0003
b) Triacetate 3a (10.40 g, 18.60 mmol) is dissolved in abs. methanol (150 ml), mixed with Amberlite IRA 910 in methanol (15 ml) and stirred at RT for 16 h. The mixture is filtered through Hyflo Super Cef, the solvent is removed and the residue is dried in vacuo to afford giucosamine derivative 4a.
Figure imgf000042_0001
c) Giucosamine derivative 4a (3.20 g; 7.39 mmol) is suspended in abs acetonitπle (70 ml). Benzaldehyde dimethylacetate (2.21 ml; 14.71 mmol) is added. Then p-toluenesulfonic acid monohydrate (160 mg) is added and the mixture is stirred at Rt for 16 h and neutralized with NaHC03 (400 mg) The solvent is removed in vacuo. Chromatography on silica gel (chloroform/acetone 10:1 ) affords the partially protected carbohydrate 5a
Figure imgf000042_0002
d) Giucosamine derivative 5a (452 mg, 0 870 mmol), tetraethylammonium bromide (400 mg; 1 90 mmol) and 1.0 g activated molecular sieves (4 A) are suspended in a mixture of abs methylene chloride (6 0 ml) and abs N,N-dιmethylformamιde (4.3 ml) and stirred in an argon atmosphere at RT for 1 h (suspension A) In a separate reaction vessel a solution of bromine in abs. methylene chloride (0 10 ml in
0 5 ml) is added (argon atmosphere, 0°C) to a solution of fucose derivative 11c (830 mg;
1 74 mmol) in abs. methylene chloride (2.5 ml) within 15 mm. Having stirred for 30 mm cyclohexene (0.25 ml) is added and the mixture is warmed to RT (solution B).
The clear solution B is added dropwise to suspension A within 1 h. Having stirred for 16 h the mixture is diluted with ethyl acetate (50 ml) and filtered through Hyflo Super Celφ The solution is successively extracted with sodium thiosulfate solution (50 ml), twice with water (50 ml each) and saturated NaCl solution (50 ml each). The organic phase is dried over sodium sulfate and concentrated in vacuo Chromatography on silica gel (hexane/ethyl acetate 2.1 ) affords disaccharide 7a
Figure imgf000043_0001
e) Disaccharide 7a (1.00 g; 1 .07 mmol), sodium cyano borohydπde (670 mg; 10.70 mmol) and 2.0 g activated molecular sieves (3 A) are suspended in abs. THF (20 ml). At 0°C a saturated solution of HCI gas in abs. ether is added dropwise. Before the complete consumption of 7a ethyl acetate (50 ml) is added and the solution is filtered through Hyflo Super Cel*. The solution is successively extracted twice with NaHCO3 solution (50 ml each), water (50 ml each) and saturated NaCl solution (50 ml each). The organic phase is dried over Na2SO4 and concentrated in vacuo. Chromatography on silica gel (hexane/ethyl acetate 2:1 ) affords disaccharide 8a.
Figure imgf000043_0002
f) Disaccharide 8a (460 mg, 490 mmol) and morpholine (1400 mg, 16.0 mmol) are dissolved in abs. THF (10 ml) (RT; argon atmosphere). Pd[P(Ph)3]4 (58 mg, 0.050 mmol) is added and the solution is stirred for 15 mm at RT. The volatile components are removed in vacuo. Chromatography on silica gel (ethyl acetate/hexane 1 :1 →2:1) affords amino sugar 9a.
Figure imgf000043_0003
g) Ammo sugar 9a (370 mg, 0.433 mmol) and active ester 10a (206 mg, 0.591 mmol)
Figure imgf000044_0001
are dissolved in abs. N,N-dιmethylformamide (3.5 ml) (argon atmosphere). 2,6-Lutidine (0.7 ml) is added and the solution is warmed to 70°C for 4 h. Another 50 mg (0.143 mmol) of 10a are added and the solution is stirred for 16 h at 70°C. Then another 30 mg (0.086 mmol) of 10a are added and the solution is warmed to 70°C for 3 h. Ethyl acetate (50 ml) is added and the solution is successively extracted twice with ammonium sulfate solution (50 ml each), NaHCO3 solution (50 ml each) and saturated NaCl solution (50 ml each) After filtration through cotton wool the solvent is evaporated in vacuo. Chromatography of the residue on silica gel (chloroform/ethyl acetate 3:1) affords amide 11a.
Figure imgf000044_0002
h) Disaccharide 11a (190 mg, 0.186 mmol), thiogiycoside 12a (175 mg, 0.279 mmol)
Figure imgf000044_0003
and activated molecular sieves (4 A)(500 mg) are suspended in 1.5 ml abs. methylene chloride and stirred in an argon atmosphere for 1 h at RT (solution A). In a separate reaction vessel activated molecular sieves (3 A)(500 mg) are added to a solution of dιmethyl(methylthio)sulfonium triflate 8c (144 mg, 0.558 mmol) in abs. methylene chloride (1.5 ml) and the mixture is stirred for 1 h at RT in an argon atmosphere (solution B). Solution B is added dropwise to solution A within 4 h. Then the mixture is diluted with ethyl acetate (50 ml), filtered through Hyflo Super Cel" and successively extracted with NaHCO3 solution (50 ml) and twice with saturated NaCl solution (25 ml each). The organic phase is dried over sodium sulfate and concentrated. Chromatography on silica gel (chloroforme/ ethyl acetate 6:1 ) affords trisaccharide 14a. i) Tnsaccharide 14a (205 mg, 0.129 mmol) is dissolved in abs. methanol (5 ml) in an argon atmosphere Then 0.065 ml of a 2.0 M solution of sodium methanolate (0.13 mmol) in abs. methanol are added and the solution is stirred for 3 h at RT. The solution is neutralized by the addition of acetic acid (0.01 ml) and the solvent is removed in vacuo.Chromatography on silica gel (chloroform/acetone 2:1 ) affords partially deprotected tnsaccharide 15a.
Figure imgf000045_0002
j) Tnsaccharide 15a (80 mg, 0.063 mmol) is dissolved in an argon atmosphere in abs. benzene (2 ml), dibutyltinoxide (28 mg, 0.110 mmol) is added and the mixture is heated under reflux for 16 h The solvent is removed, the residue is dried for 1h at 40°C in high vacuum and dissolved in abs dimethoxyethane (1.6 ml) A solution of triflate 16a (125 mg, 0 315 mmol)
Figure imgf000045_0003
in abs dimethoxyethane (1 ml) is added and the mixture is stirred for 6 h at 40°C. Then 25 ml
Figure imgf000045_0004
fluoride solution is added and the solution is extracted twice with chloroform (25 ml each). The solution is dried with sodium sulfate and the solvent is removed Chromatography on silica gel (chloroform/acetone 15:1) affords tnsaccharide 17a.
Figure imgf000046_0001
k) Tnsaccharide 17a (44 mg, 29 μmol) is dissolved in a mixture of dioxane (4 ml), water (1.5 ml) and acetic acid (0.25 ml). Having thoroughly degassed palladiumhydroxide (20%) on coal (100 mg) is added. The suspension is stirred for 15 min in an argon atmosphere. Then the mixture is hydrogenated for 16 h at RT. The catalyst is filtered off through a HPLC filter, the solvent is removed, the residue is dissolved in water/methanol (2:1) and passed through a sodium ion exchange column (water). Product containing fractions are combined and concentrated. The residue is dissolved in water and lyophilized to obtain compound B1a Η-NMR (400 MHz, D2O) δ 0.50-1.70 (25 H, m, -O-CH2(CH2)6CH2CO2CH3, -CH^c- C6H„), 1.07 (3 H, d, 6.5 Hz, 3 x H-6 Fuc), 2.06 (2 H, t, 7.5 Hz,
Figure imgf000046_0002
3.30 (1 H, dd, 9 5/3 0 Hz), 3.42-4.15 (17 H, m), 3.54 (3 H, s, -CO2CH3), 3.77 (3 H, s, Ar-OCH3), 3.78 (3 H, s, Ar-OCH3), 4.37 (1 H, d, 8.0 Hz, H-1 Gal), 4.55 (1 H, s (br), H-1 Glc), 4.71 (1 H, q, 6.5 Hz, H-5 Fuc), 5.02 (1 H, d, 3.5 Hz, H-1 Fuc), 7.01 (1 H, d, 8.5 Hz, Arhf), 7.32 (1 H, d, 2.0 Hz, ArH), 7.38 (1 H, dd, 8.5/2.0 Hz, ArH); MS (FAB/EI) 974 (M - Na).
(2) Preparation of compound No. B2a [R4: CH2C6Hn; RT1: (CH2)8Cθ2CH3; RT2: 3,4-(OH)2C6H3]
Starting with ammo sugar 9a (150 mg, 0.175 mmol) and active ester 28a (175 mg, 0.351 mmol)
Figure imgf000046_0003
compound No. B2a is prepared according to Example B(a)(1). 1H-NMR (400 MHz, D2O) δ 0.60-1 73 (25 H, m, -O-CH2(CH2)6CH2CO2CH3, -CH2-c-CBHu), 1.07 (3 H, d, 6.5 Hz, 3 x H-6 Fuc), 2 13 (2 H, t, 7.5 Hz, -CH2CH2CO2Me), 3.32 (1 H, dd, 9.5/3.0 Hz), 3.44-3.95 (17 H, m), 3.57 (3 H, s, -CO2CH3), 4.39 (1 H, d, 8.0 Hz, H-1 Gal), 4.56 (1 H, s (br), H-1 Glc), 4.71 (1 H, q, 6.5 Hz, H-5 Fuc), 5.02 (1 H, d, 3.5 Hz, H-1 Fuc), 6.87 (1 H, d, 8.5 Hz, ArH), 7.21 (1 H, dd, 8.5/2.0 Hz, ArH), 7.24 (1 H, d, 2.0 Hz, ArH); MS (FAB/EI) 946 (M - H)".
(3) Preparation of compound No. B3a [R4: C6Hn; RT1: (CH2)8CO2CH3; RT2: 3,4-(OCH3)2C6H3] a) Starting from trisaccharide 15a (77 mg, 0.061 mmol) and triflate 23a (120 mg, 0.303 mmol)
Figure imgf000047_0001
compound No. B3a is prepared according to Example B(a)(1 ). H-NMR (400 MHz, D2O) δ 0.50-1 .63 (23 H, m, -O-CH2(CH2)6CH2CO2CH3, c-C6H ), 1.06 (3 H, d, 6.5 Hz, 3 x H-6 Fuc), 2.04 (2 H, t, 7.5 Hz, -CH2CH2CO2Me), 3.26 (1 H, dd, 9.5/3.0 Hz), 3.39-3.92 (17 H, m), 3.54 (3 H, s, -CO2CH3), 3.77 (3 H, s, Ar-OCH3), 3.78 (3 H, s, Ar-OCH3), 4.36 (1 H, d, 8.0 Hz, H-1 Gal), 4.55 (1 H, s (br), HA Glc), 4.71 (1 H, q, 6.5 Hz, H-5 Fuc), 5.00 (1 H, d, 3.5 Hz, H-1 Fuc), 6.98 (1 H, d, 8.5 Hz, ArH), 7.31 (1 H, d, 2.0 Hz, ArH), 7.37 (1 H, dd, 8.5/2.0 Hz, ArH); MS (FAB/EI) 960 (M - Na)'.
(4) Preparation of compound No. B4a [R4: CH2C6Hn; RT1: (CH2)BCθ2 a; RT2: 3,4-(OCH3)2C6H3]
Methyl ester B1a (10 mg, 0.010 mmol) is dissolved in water (1 ml), mixed with 2 N NaOH (20 μl) and stirred for 16 h at RT. Reverse phase chromatography on RP 18 (water→ water/methanol 3:1 ) affords carboxylate B4a. 'H-NMR (400 MHz, D2O) δ 0.49-1.70 (25 H, m, -O-CH2(CH2)6CH2CO2CH3, -CH^-c-CeHu), 1.06 (3 H, d, 6.5 Hz, 3 x H-6 Fuc), 1.92 (2 H, t (br), 7.5 Hz, -CH2Ctf2CO2Me), 3.28 (1 H, dd, 9.5/3.0 Hz), 3.42-4.15 (17 H, m), 3.77 (3 H, s, Ar-OCH3), 3.78 (3 H, s, Ar-OCH3), 4.36 (1 H, d, 8.0 Hz, H-1 Gal), 4.53 (1 H, s (br), H-1 Glc), 4.71 (1 H, q, 6.5 Hz, H-5 Fuc), 5.02 (1 H, d, 3.5 Hz, H-1 Fuc), 7.00 (1 H, d, 8.5 Hz, ArH), 7.31 (1 H, d, 2.0 Hz, ArH), 7.37 (1 H, dd, 8.5/2.0 Hz, ArH); MS (FAB/EI) 1004 (M - H)-. Example B(b): Preparation of compounds of the formula lEχ(b)
Figure imgf000048_0001
(1 ) Preparation of compound No. B1 b [RB6: H, RB7: C(O)CH(C6H5)2]
A solution of commercially available diphenylacetyl chloride (11.3 mg, 0.049 mmol, 1.5 eq.) in THF (0.5 ml) is added at 0°C to a solution of A1b (20 mg, 0.033 mmol) in THF/H2O 1/1 (2 ml). The pH of the reaction mixture is adjusted to 8-10 by the addition of 1 N NaOH solution and maintained at 8-10 throughout the whole reaction. After 18 h additional diphenylacetyl chloride (3.7 mg, 0.016 mmol, 0.5 eq.) is added and after a total of 42 h the reaction mixture is partially evaporated to remove THF. The now aqueous solution is purified by RP C18 (column size 1 x 10 cm) through stepwise elution with acetonitrile/water 30/70 and then acetonitrile/water 40/60. The product obtained is further purified by flash chromatography on silica (ethyl acetate/isopropanol/water = 4/2/1 ) to give after freeze drying B1b as a white foam. C4,H56NO,5Na (MW=825.88): MS (FAB positive mode, THG) 826 (M+H), 804 (M- Na+H). 'H NMR (500 MHz, D2O) δ 7.42-7.22 (m, 20H), 5.16 (s, 1 H, CHPh2), 4.78 (d, 1 H, Fuel ), 4.64 (q, 1 H, Fuc5), 4.46 (d, 1 H, Gall), 4.02-3.88 (m, 3H), 3.87 (d, 1 H, Gal4), 3.82 (dd, 1 H, Fuc3), 3.78-3.65 (m, 5H), 3.62-3.49 (m, 3H), 3.45-3.32 (m, 4H), 2.19-2.11 (m, 1H), 1 .79-1.72 (m, 1 H), 1.68-1.46 (m, 8H), 1.22-1.08 (m, 6H, including at 1.15 (d, Fuc6)), 0.96- 0.82 (m, 2H).
The following compounds are prepared in analogy to the above example whereas for the purification one to three of the following purification steps are applied in any order desired to obtain analytically pure compounds: a) Reverse phase C18 column chromatography (column size 1 x 10 cm) using stepwise elution with acetonitrile/water starting with low acetonitrile content ending with high acetonitrile content. b) Flash chromatography on silica (ethyl acetate/isopropanol/water = 4/2/1 ) c) P2 gelfiltration using water as eluent. (2) Preparation of compound No. B2b [RB6: H, RB7: CtOJCβH,,]
Figure imgf000049_0001
(MW=741.80): MS (FAB positive mode, THG) 742 (M+H), 720 (M-Na+H). *H NMR (500 MHz, D2O) δ 4.86 (d, 1H, Fuel), 4.67 (q, 1 H, Fuc5), 4.48 (d, 1 H, GaM ), 4.05-3.91 (m, 3H), 3.87 (d, 1 H, Gal4), 3.83 (dd, 1 H, Fuc3), 3.77 (d, 1H, Fuc4), 3.74 (dd, 1H, Fuc2), 3.72-3.68 (m, 2H), 3.63-3.55 (m, 3H), 3.53-3.40 (m, 4H), 3.36 (dd, 1H, Gal3), 2.27-2.16 (m, 2H), 1.79-1.68 (m, 5H), 1.68-1.47 (m, 9H), 1.37-1.08 (m, 11 H, including at 1.17 (d, Fuc6)), 0.97-0.83 (m, 2H).
(3) Preparation of compound No. B3b [RB6: H, RB7: C(0)C6Hs]
Figure imgf000049_0002
(MW=735.76): MS (FAB negative mode, THG) 712 (M-Na). 1H NMR (400 MHz, D2O) δ 7.66 (d, 2H), 7.52 (m, 1 H), 7.42 (t, 2H), 4.93 (d, 1 H, Fuel), 4.64 (q, 1 H, Fuc5), 4.42 (d, 1 H, GaM ), 4.04-3.90 (m, 3H), 3.88-3.75 (m, 3H including: 3.85 (d, 1 H, Gal4), 3.80 (dd, 1 H, Fuc3)), 3.75-3.68 (m, 2H, Fuc4, Fuc2), 3.69-3.36 (m, 8H), 3.32 (dd, 1 H, Gal3), 2.18-2.10 (m, 1 H), 1.73-1.65 (m, 1 H), 1.65-1.39 (m, 8H), 1.21-1.00 (m, 6H, including at 1.13 (d, Fuc6)), 0.92-0.73 (m, 2H).
(4) Preparation of compound No. B4b [RB6: H, RB7: C(0)C6H4(4-OCH3)]
C35H52NO,6Na (MW=765.78): MS (FAB negative mode, THG) 742 (M-Na). 'H NMR (400 MHz, D2O) δ 7.66 (m, 2H), 6.98 (m, 2H), 4.92 (d, 1 H, Fuel ), 4.63 (q, 1 H, Fuc5), 4.42 (d, 1 H, Gall ), 4.04-3.85 (m, 3H), 3.83-3.75 (m, 6H including: 3.81 (d, 1 H, GaM), 3.79 (s, 3H, OCH3), 3.78 (dd, 1 H, Fuc3)), 3.73-3.68 (m, 2H, Fuc4, Fuc2), 3.68-3.35 (m, 8H), 3.30 (dd, 1 H, Gal3), 2.18-2.11 (m, 1 H), 1.73-1.65 (m, 1 H), 1.65-1.39 (m, 8H), 1.21-1.00 (m, 6H, including: 1.10 (d, Fuc6)), 0.92-0.75 (m, 2H).
(5) Preparation of compound No. B5b [RB6: H, RBr: C(0)C6H3(3,4-OCH3)2]
CaeH^NO^Na (MW=795.81): MS (FAB negative mode, THG) 794 (M-H), 772 (M-Na). 1H NMR (500 MHz, D2O) δ 7.40 (dd, 1 H), 7.35 (d, 1 H), 7.06 (d, 1 H), 4.98 (d, 1 H, Fuel), 4.69 (q, 1 H, Fuc5), 4.49 (d, 1H, Gall ), 4.05 (m, 1 H), 3.99 (m, 1 H), 3.93 (m, 1 H), 3.90-3.81 (m, 9H including: 3.87 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.75 (dd, 1 H, Fuc3)), 3.80-3.75 ( , 2H, Fuc4, Fuc2), 3.74-3.54 (m, 6H), 3.54-3.44 (m, 2H), 3.36 (dd, 1 H, Gal3), 2.24-2.19 (m, 1H), 1.78-1.72 (m, 1 H), 1.69-1.45 (m, 8H), 1.24-1.08 (m, 6H, including: 1.17 (d, Fuc6)), 0.96-0.82 (m, 2H). (6) Preparation of compound No. B6b [RB6: H, RB7: C(0)C6H4(4-CI)]
C34H49NOι5NaCI (MW=770.20): MS (FAB negative mode, THG) 768 (M-H), 746 (M-Na). 'H NMR (400 MHz, D2O) δ 7.62 (m, 2H), 7.42 (m, 2H), 4.92 (d, 1 H, Fuel ), 4.63 (q, 1 H, Fuc5), 4.42 (d, 1H, Ga!1), 4.04-3.84 (m, 3H), 3.83-3.75 (m, 3H including: 3.81 (d, 1H, Gal4), 3.78 (dd, 1 H, Fuc3)), 3.73-3.68 (m, 2H, Fuc4, Fuc2), 3.68-3.35 (m, 8H), 3.30 (dd, 1 H, Gal3), 2.18-2.10 (m, 1 H), 1.73-1.65 (m, 1H), 1.65-1.37 (m, 8H), 1.21-1.00 (m, 6H, including: 1.10 (d, Fuc6)), 0.92-0.72 (m, 2H).
(7) Preparation of compound No. B7b [RB6: H, RB7: C(0)C6H4(4-N02)]
C34H49N2O,7Na (MW=780.75): MS (FAB negative mode, THG) 779 (M-H), 757 (M-Na). 1H NMR (400 MHz, D2O) δ 8.25 (m, 2H), 7.83 (m, 2H), 4.92 (d, 1H, Fuel), 4.63 (q, 1 H, Fuc5), 4 42 (d, 1 H, GaM ), 4.04-3.84 (m, 4H), 3.83-3.76 (m, 2H, Gal4, Fuc3), 3.74-3.58 (m, 5H), 3.68-3.35 (m, 5H), 3.29 (dd, 1 H, Gal3), 2.18-2.08 (m, 1H), 1.72-1.64 (m, 1 H), 1.64-1.36 (m, 8H), 1.21 -0.96 ( , 6H, including: 1.10 (d, Fuc6)), 0.90-0.75 (m, 2H).
(8) Preparation of compound No. B8b [RB6: H, RB7: C(0)C6H4(4-C6H5)]
C40H55NO,5Na (MW=812.86): MS (FAB positive mode, THG) 790 (M-Na+H). 1H NMR (400 MHz, D2O) δ 7.78 (d, 2H), 7.75-7.65 (m, 4H), 7.48 (t, 2H), 7.42 (m, 1H), 4.97 (d, 1H, Fuel), 4.66 (q, 1 H, Fuc5), 4.45 (d, 1 H, Gall), 4.08-3.80 (m, 6H), 3.80-3.72 (m, 2H, Fuc4, Fuc2), 3.72-3.62 (m, 3H), 3.62-3.38 (m, 5H), 3.32 (dd, 1 H, Gal3), 2.21-2.13 (m, 1 H), 1.76-1.68 (m, 1 H), 1.68-1.40 (m, 8H), 1.22-1.00 (m, 6H, including: 1.13 (d, Fuc6)), 0.95-0.78 (m, 2H).
(9) Preparation of compound No. B9b [RB6: H, RB7: C(0)-2-naphthyl]
C38H52NO,5Na (MW=785.82): MS (FAB negative mode, THG) 762 (M-Na). *H NMR (500 MHz, D2O) δ 8.28 (s, 1 H), 8.02-7.93 (m, 3H), 7.78-7.74 (m, 1 H), 7.65-7.58 (m, 2H), 5.01 (d, 1 H, Fuel ), 4.70 (q, 1 H, Fuc5), 4.49 (d, 1 H, Gall ), 4.01-3.97 (m, 2H), 3.96-3.85 (m, 4H including Gal4, Fuc3), 3.81-3.76 (m, 2H, Fuc4, Fuc2), 3.76-3.68 (m, 3H), 3.65-3.45 (m, 5H), 3.36 (dd, 1 H, Gal3), 2.24-2.18 (m, 1H), 1.79-1.72 (m, 1 H), 1.72-1.46 (m, 8H), 1.24-1.06 (m, 6H, including: 1.10 (d, Fuc6)), 1.00-0.81 (m, 2H).
(10) Preparation of compound No. B10b [RB6: H, RB7: C(0)OCH2CβHs]
C35H52NO,6Na (MW=765.82): MS (FAB negative mode, THG) 742 (M-Na). 'H NMR (500 MHz, D2O) δ 7.42-7.33 (m, 5H), 5.06 (d, 2H, ChbPh), 4.86 (d, 1H, Fuel ), 4.66 (q, 1H, Fuc5), 4.45 (d, 1H, GaM ), 4.01 -3.95 (m, 1 H), 3.95-3.89 (m, 2H), 3.85 (d, 1 H, Gal4), 3.81 (dd, 1 H, Fuc3), 3.76-3.66 (m, 4H), 3.62-3.54 (m, 3H), 3.44-3.31 (m, 5H), 2.18-2.12 (m, 1 H), 1.76- 1.71 (m, 1H), 1.65-1.44 (m, 8H), 1.21-1.03 (m, 6H, including: 1.13 (d, Fuc6)), 0.94-0.80 (m, 2H).
(11 ) Preparation of compound No. B11 b [RB6: H, RB7: C(O)NHC6Hs]
A solution of phenylisocyanate (4 mg, 0.033 mmol, 1.2 eq.) in 0.5 N NaOH is added at 0CC to a solution of A1b (17 mg, 0.027 mmol) in 0.5 N NaOH (1 ml). Addition of phenylisocyanate is continued until after 11 d a total amount of 6 equivalents is added. The product is puπfied by flash chromatography on silica (ethyl acetate/isopropanol/water = 4/2/1 ), filtered on Dowex ion exchange resin Na+ form eluting with water, further purified by P2 gelfiltration using water as eluent and again filtered on Dowex Na+ form to give after freeze drying B11b as a white foam.
Figure imgf000051_0001
(MW=750.77): Η NMR (400 MHz, D2O) δ 7.27 (m, 2H), 7.18 (d, 2H), 7.03 (t, 1 H), 4.86 (d, 1 H, Fuel), 4.64 (q, 1H, Fuc5), 4.39 (d, 1 H, Gall), 4.08- 3.85 (m, 3H), 3.84 (s, 1H, Gal4), 3.76 (dd, 1 H, Fuc3), 3.72-3.64 (m, 2H, Fuc4, Fuc2), 3.63- 3 46 (m, 6H), 3.46-3.28 (m, 4H), 2.16-2.06 (m, 1 H), 1.73-1.63 (m, 1H), 1.72-1.38 (m, 8H), 1.20-0.97 (m, 6H, including: 1.09 (d, Fuc6)), 0.92-0.72 (m, 2H).
(12) Preparation of compound No. B12b [RB6: H, RB7: SO3Na]
Commercially available sulfur tnoxide pyπdine complex (7.8 mg, 0.049 mmol, 1.5 eq.) is added to a solution of A1b (20 mg, 0.033 mmol) in H2O (2 ml) with enough 2 N NaOH to obtain a pH of above 1 1. After 16 h another portion of sulfur trioxide pyridine complex (7.8 mg, 0.049 mmol, 1.5 eq.) is added. After 40 h the reaction mixture is evaporated and purified by P2 gelfiltration eluting with water and the product is subsequently purified by C18 reverse phase chromatography (using a SepPac syringe adapter) through stepwise elution with acetonitrile/water 10/90 → 90/10 to give after evaporation and freeze drying B12b as a white foam. C27H45NOι7SNa2 (MW=733.70): MS (FAB negative mode, THG) 710 (M-Na), 688 (M-2Na+H). 1H NMR (400 MHz, D2O) δ 4.98 (d, 1 H, Fuel), 4.68 (q, 1 H, Fuc5), 4.42 (d, 1 H, Gall), 3.99-3.86 (m, 3H), 3.82 (d, 1H, Gal4), 3.78 (dd, 1 H, Fuc3), 3.73-3.67 (m, 2H, Fuc4, Fuc2), 3.67-3.59 (m, 2H), 3.58-3.48 (m, 2H), 3.48-3.32 (m, 4H), 3.30 (dd, 1H, Gal3), 3.12 (dd, 1 H), 2.17-2.08 (m, 1 H), 1.74-1.66 (m, 1 H), 1.63-1.39 (m, 8H), 1.21-1.00 (m, 6H, including at 1.12 (d, Fuc6)), 0.92-0.75 (m, 2H). (13) Preparation of compound No. B13b [RB6: H, RB7: CH2C6H5] and compound No.
B14b [R ,Bβ66:. »B7. CH2CβH5, R°': CHΪC6HS]
Borane pyndine complex (BH3.C5H5N, 0.013 ml, 0.131 mmol) is added to a mixture of A1b (40 mg, 0.066 mmol), benzaldehyde (0.033 ml, 0.328 mmol) and freshly dried 4A molecular sieves (ca. 500 mg) in dry MeOH (0.5 ml). After 20 h two new products have formed and the reaction mixture is filtered, evaporated and the two products are separated by flash chromatography on silica (ethyl acetate/isopropanol/water = 4/2/1 ) to give in the order of elution fraction 1 and fraction 2 Fraction 1 is further purified by P2 gelfiltration eluting with water and then filtered on Dowex ion exchange resin Na+ form eluting with water to give after freeze drying B14b as a white foam. Fraction 2 is also further purified by P2 gelfiltration eluting with water and then filtered on Dowex ion exchange resin Na+ form eluting with water to give after freeze drying B13b as a white foam
B14b C4,H58NOι4Na (MW=811.91): MS (FAB negative mode, THG) 788 (M-Na) 1H NMR (400 MHz, D2O) δ 7 41 (m, 10H), 4.64 (d, 1 H, Fuel ), 4 43 (q, 1 H, Fuc5), 4.37 (d, 1 H, GaM ), 4 46-4 12 (m, 3H), 3.93-3.83 (m, 2H), 3.81 (s, 1 H Gal4), 3.78-3.58 (m, 7H), 3.58-3.37 (m, 3H), 3 37-3.19 (m, 3H), 2.12-2.02 (m, 1 H), 1 74-1.65 (m, 1 H), 1.73-1.38 (m, 8H), 1.22-0.97 (m, 6H, including 1 08 (d, Fuc6)), 0.92-0.75 (m, 2H).
B13b C34H52NO,4Na (MW=721.77) MS (FAB negative mode, THG) 698 (M-Na) 1H NMR (400 MHz, D2O) δ 7.38 (m, 5H), 4 72 (d, 1H, Fuel ), 4.52 (q, 1 H, Fuc5), 4 41 (d, 1H, GaM ), 4 19 (d, 1 H, CH2Ph), 4 14 (d, 1 H, CH2Ph), 4.00-3 84 (m, 3H), 3.81 (s, 1 H, Gal4), 3.73 (dd, 1 H, Fuc3), 3.69 (d, 1 H), 3.68-3 59 (m, 3H), 3.59-3 45 (m, 4H), 3 44-3.32 (m, 2H), 3.29 (dd, 1 H, Gal3), 3 18 (dd, 1 H), 2.18-2 08 (m, 1 H), 1.73-1.65 (m, 1 H), 1.72-1.38 (m, 8H), 1.21-0.95 (m, 6H, including: 1.09 (d, Fucδ)), 0.92-0.72 (m, 2H).
The following compounds are prepared in analogy to the above examples:
Figure imgf000052_0001
Figure imgf000053_0002
Example B(c): Preparation of compounds of the formula IEX(C)
Figure imgf000053_0001
(1 ) Preparation of compound No. B1 c [R5: CH2OH]
To a solution of A1c (75 mg, 0.062 mmol) in dioxane (1 ml) 0.5 ml of 0.5 N NaOH are added and the mixture is stirred at RT for 1 h. Then, 0.05 ml of acetic acid are added and the solvent is removed in vacuo. The residue is dissolved in abs. methanol (1 ml) and hydrogenated in the presence of Pd(10%) on charcoal (75 mg) for 16 h at RT. The catalyst is filtered off, the solvent is removed and the residue is purified by reversed phase chromatography (RP18, water/methanol 3:1→1 :2). Passage through a sodium ion exchange column followed by lyophilization gives B1c as a colorless powder. 1H NMR (400 MHz, D2O) δ 0.75-1.72 (13 H, m. -Ctb-cCβHu, H-2.J, 1.09 (3 H, d, 6.5 Hz, H-6 Fuc), 2.12 (1 H, dd, 13.0/5.0 Hz, H- 2βq), 3.28 (2 H, m, H-5, H-3 Gal), 3.38 (1 H, t (br), 12.5 Hz, H-1^), 3.47 (1 H, t, 9.5 Hz, H-4), 3.50 (1 H, m, H-5 Gal), 3.52 (1 H, t, 8.5 Hz, H-2 Gal), 3.62 (2 H, m, H-6 Gal, H-6' Gal), 3.67 (1 H, dd, 10.5/4.0 Hz, H-2 Fuc), 3.69 (1 H, d (br), 3.0 Hz, H-4 Fuc), 3.74 (1 H, dd, 7.0/4.0 Hz, H-6), 3.78 (1 H, dd, 10.0/3.0 Hz, H-3 Fuc), 3.80 (1 H, d (br), 3.0 Hz, H-4 Gal), 3.84 (1 H, dd, 7.0/2.0 Hz, H-6'), 3.88 (2 H, m, H-1,*,, -CH-CH2-cC6Hn), 3.94 (1 H, td, 9.5/5.0 Hz, H-3), 4.41 (1 H, d, 8,5 Hz, H-1 Gal), 4.71 (1 H, q (br), 6.5 Hz, H-5 Fuc), 4.86 (1 H, d, 3.5 Hz, H-1 Fuc); MS (FAB/EI) 632 (M+H)+.
(2) Preparation of compound No. B2c [R5: CH3] a) A solution of A1c (120 mg, 0.10 mmol), 13c (53 mg, 0.20 mmol, 2 eq)
Figure imgf000054_0001
N-hydroxysuccinimide (2.3 mg, 0.02 mmol, 0.2 eq) and abs. pyridine (31.6 mg, 0.40 mmol, 4 eq) in abs. benzene (1 ml) is heated under reflux for 2 h. The clear solution is diluted with ethylacetate (20 ml) and extracted with HCI (0.5 n, 2 x 20 ml), NaHCO3 (20 ml) and brine (20 ml). The solvent is removed and the residue subjected to chromatography (silicagel, toluene/ethylacetate 5:1 ). Compound 14c is isolated as a colorless foam.
Figure imgf000054_0002
b) A solution of 14c (105 mg, 0.073 mmol), Bu3SnH (32 mg, 0.110 mmol, 1.5 eq), N,N'-azo- bisisobutyronitriie (2 mg) in 3 ml of abs. benzene is heated under reflux for 1 h. Then, additional Bu3SnH (32 mg) and N,N'-azobisisobutyronitrile (2 mg) are added and heating is continued for 1 h. The solvent is removed and the residue subjected to chromatography (toluene/ethylacetate 4:1). Compound 15c is isolated as a colorless oil.
Figure imgf000054_0003
c) A solution of 15c (15.0 mg, 0.013 mmol) in dioxane (1 ml), methanol (0.3 ml) and 2 N NaOH (0.2 ml) is stirred at RT for 24 h. Then, 0.1 ml acetic acid is added, the solvents are removed and the residue is passed through a short column (silicagel, isopropanol/ethylace- tate/water 10:10:1 ). Following evaporation of the solvents the crude material is dissolved in a mixture of methanol (1.5 ml) and acetic acid (0.1 ml). Palladium hydroxide (20%) on carbon (20 mg) is added and the mixture is hydrogenated at ambient pressure at RT for 16 h. The solvents are removed and the residue is purified by reversed phase chromatography (RP18, water/methanol 5:1 →2:1 ). Product containing fractions are combined, the solvent is removed, the residue is dissolved in water and passed through a sodium ion exchange column. Following lyophilization compound B2c is isolated as a colorless powder. *H NMR (400 MHz, CDCI3) δ 0.77-1.72 (14 H, m, -CHrcCeH,,, H-2ax), 1.10 (3 H, d, 6.5 Hz, H-6 Fuc), 1.22 (3 H, d, 6.5 Hz, H-6), 2.13 (1 H, dd (br), 13.0/5.0 Hz, H-2βq), 3.19 (1 H, t, 9.0 Hz, H-4), 3.30 (1 H, dd, 9.5/3.0 Hz, H-3 Gal), 3.36 (1 H, dq, 9.0/6.5 Hz, H-5), 3.41 (1 H, t (br), 12.0 Hz, H-1a ), 3.51 (1 H, t, 6.0 Hz, H-5 Gal), 3.53 (1 H, dd, 9.5/8.0 Hz, H-2 Gal), 3.63 (2 H, d, 6.0 Hz, H-6 Gal, H-6' Gal), 3.68 (1 H, dd, 10.5/4.0 Hz, H-2 Fuc), 3.72 (1 H, d (br), 3.5 Hz, H-
4 Fuc), 3.78 (1 H, dd, 10.5/3.5 Hz, H-3 Fuc), 3.82 (1 H, d (br), 3.0 Hz, H-4 Gal), 3.83 - 3.97 (3 H, m, -CH-CH2-cC6Hιι, H-1eq, H-3), 4.41 (1 H, d, 8.0 Hz, H-1 Gal), 4.69 (1 H, q, 6.5 Hz, H-
5 Fuc), 4.95 (1 H, d, 4.0 Hz, H-1 Fuc); MS (FAB/EI) 617 (M+H)+.
(3) Preparation of compound No. B3c [R5: C02Na] a) To a solution of A1c (150 mg, 0.124 mmol) in abs. CH2CI2 (5 ml) 16c (158 mg, 0.373 mmol)
Figure imgf000055_0001
is added and stirred at RT for 1 h. Then, an aqueous solution (20 ml) of Na2S2O3 (400 mg) and NaHCO3 (200 mg) is added. The mixture is extracted with CH2CI2 (2 15 ml), the combined organic layers are dried over Na2SO4 and the solvent is removed. The residue is dissolved in a mixture of 2-methyl-2-butene (3 ml) and tert. butanol (4 ml). An aqueous solution (3 ml) of NaCIO2 (250 mg) and NaH2PO4 (200 mg) is added and the heterogeneous mixture is stirred vigorously for 1 h. Then, water (20 ml) and CH2CI2 (20 ml) are added, the layers are separated and the aqueous layer is extracted with CH2CI2 (2 x 20 ml). The combined organic layers are dried with Na2SO4, the solvent is removed and the residue is subjected to flash chromatography (silicagel, isopropanol/ethylacetate/water 25:25:5). Compound 17c is isolated as a colorless foam.
Figure imgf000056_0001
b) A solution of 17c (30.0 mg, 0.025 mmol) in dioxane (1.5 ml), methanol (0.5 ml) and 2 N NaOH (0.3 ml) is stirred at RT for 24 h. Then, 0.1 ml acetic acid is added, the solvents are removed and the residue is passed through a short column (silicagel, isopropanol/ethylacetate/water 10:10:1). Following evaporation of the solvents the crude material is dissolved in a mixture of methanol (1.5 ml) and acetic acid (0.3 ml). Palladium hydroxide (20 %) on carbon (60 mg) is added and the mixture is hydrogenated at ambient pressure at RT for 16 h. The solvents are removed and the residue is purified by reversed phase chromatography (RP18, water/methanol 5:1→2:1). Product containing fractions are combined, the solvent is removed, the residue is dissolved in water and passed through a sodium ion exchange column. Following lyophilization compound B3c is isolated as a colorless powder. 1H NMR (400 MHz, CDCI3) δ 0.75-1.72 (14 H, m, -CH cCeJHn, H-1ax), 1.09 (3 H, d, 6.5 Hz, H-6 Fuc), 2.07 (1 H, m, H-2βq), 3.27 (1 H, dd, 9.5/3.0 Hz, H-3 Gal), 3.42 (1 H, ddd, 12.0/10.0/3.0 Hz, 3.50 (1 H, dd, 9.5/8.0 Hz, H-2 Gal), 3.52 (1 H, dt, 0.5 7.5 Hz, H-5 Gal), 3.59-3.71 (6 H, m, H-4, H-5, H-2 Fuc, H-4 Fuc, H-6 Gal, H-6' Gal), 3.77 (1 H, dd, 10.5/3.5 Hz, H-3 Fuc), 3.82 (1 H, dd, 3.0/0.5 Hz, H-4 Gal), 3.87 (1 H, dd, 10.0/3.5 Hz, -CH-CH2- cC6H„), 3.93-4.02 (2 H, m, H-1βq, H-3), 4.37 (1 H, d, 8.0 Hz, H-1 Gal), 4.47 (1 H, q, 6.5 Hz, H-5 Fuc), 4.89 (1 H, d, 4.0 Hz, H-1 Fuc); MS (FAB/EI) 617 (M+H)\ C. Biological Activities of the Mimetics
Example C1 : Ligand Binding Assay for Determination of ICS0 Values-conserved use of positive controls
This assay is performed as disclosed in Example D1 of WO 97/19,105 the contents thereof relating to this assay being incorporated hereinwith and wherein the E-selectin/human IgG chimera are cloned and expressed according to Kolbinger, F., Patton, J.T., Geisenhoff, G., Aenis, A., Li, X., Katopodis, A., Biochemistry 35:6385-6392 (1996).
In this assay the compounds of formula I have an RIC50 value of from 0.01 to 1.0.
Figure imgf000057_0001
* RIC50 means IC50(test compound)/IC5o(control compound A)
Example C2: Cell Adhesion under Flow Conditions
This assay is performed as disclosed in Example D3 of WO 97/19,105 the contents thereof relating to this assay being incorporated hereinwith.
The compounds of formula I show a reduction of number of interacting cells at 50 μM of in the range from 40 % to 90 %.
Figure imgf000057_0002

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula I
(I)
Figure imgf000058_0002
wherein
R1 is an S-configurated methyl substituted with a carboxy and one other substituent; R2 is hydrogen, C Cι2alkyl or C6aryl; where the alkyl and the aryl are unsubstituted or substituted by one or more substituents; and Z is a group of the formula lla, Mb or lie
Figure imgf000058_0001
wherein
X is -C(O)-, -C(S)-, -S(O)2-, -C(O)Q- or -C(S)Q-, in which Q is NH, O, S, S-C,-C6alkylene,
NH-C,-C6alkylene or O-C C6alkylene;
RT1 is CrC12alkyl, C2-Cι2alkenyl, Cι-Cι2alkoxy, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl,
C2-C ii heterocycloalkyl, C2-Cnheterocycloalkenyl, C6-C,0aryl, C6-Cιoaryloxy, Cs-Cgheteroaryl,
Cs-Cgheteroaryloxy, C7-C,ιaralkyl, C7-Cn aralkyloxy, C6-Cι0heteroaralkyl, Ce-Cnaralkenyl or
C7-Cι0heteroaralkenyl, which are unsubstituted or substituted by one or more substituents; and
RT2 is C3-Cι2cycloalkyl, C3-C12cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cnheterocycloalkenyl,
C6-C10aryl, C6-Cι0aryloxy, C5-C9heteroaryl, Cs-Cgheteroaryloxy, C7-Cι,aralkyl, C7-Cnaralkyl- oxy, Ce-Cioheteroaralkyl, C8-Cnaralkenyl or C -Cι0heteroaralkenyl, which are unsubstituted or substituted by one or more substituents; RB5 is NH2, primary amino, secondary amino or amido;
R5 is X'-RT1C, C(O)NRT2CRT3C, C(O)RT4C or C(O)ORT5C, wherein X' is C,-C4alkylene, RT1C is hydrogen, halogen, Cι-C12alkyl, Ci-Cnheteroalkyl, C3-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-Cι heterocycloalkyl, C2-Cnheterocycloalkenyl, C6-, Cι0- or C 4aryl, C2-C9heteroaryl, C7-C, aralkyi, C6-Cι0heteroaralkyl, Cg-Cnaralkenyl, C8-Cι0heteroaralkenyl, ORT6C, OC(O)RT4C, SRT4C, SO2RT9C or SO3RT5C; each of RT2C, RT3C and RT4C is independently hydrogen, Cι-Cι2alkyl, C-dheteroalkyl, C3-C12alkenyl, C3-Cι2cycloalkyl, C3-C12cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-, Cι0- or Cι4aryl, C2-C9heteroaryl, C7-Cn aralkyi, C6-C 0heteroaralkyl, Cg-daralkenyl or C8-Cι0heteroaralkenyl; each of RT5C, Rπc and RT8C is independently hydrogen, My, Cι-Cι2alkyl, Ci-Cnheteroalkyl, C3-Cι2alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cnhetero- cycloalkenyl, C6-, Cι0- or Cι aryl, C2-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, Cg-Ci aralkenyl or CB-Cι0heteroaralkenyl;
RT6C is hydrogen, d-C^alkyl, Ci-Cnheteroalkyl, C3-C 2alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-Cn heterocycloalkyl, C2-Cn heterocycloalkenyl, C6-, Cι0- or Cι aryl, C2-C9heteroaryl, C7-Cn aralkyi, C6-Cι0heteroaralkyl, Cg-Cnaralkenyl, C8-Cι0heteroaralkenyl, SO3RT5C, POaR^R780, C(O)ORT9C, C(S)NRT2CRT3C or C(O)NRT2CRT3C; and R is C,-Cι2alkyl, Ci-Cnheteroalkyl, C3-Cι2alkenyl, C3-Cι2cycloalkyl, C3-C12cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn heterocycloalkenyl, C6-, Cι0- or C14aryl, C2-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, Cg-Cnaralkenyl or C8-Cι0heteroaralkenyl; wherein the substituent is selected from the group consisting of OH, halogen, NH2, C(O)RsZ, C(O)OR5', OC(O)Rs4, nitro, cyano, SO3H, OSO3H, SO3My, OSO3My, NR 0SO3My, C,-d2alkyl, C2-C,2alkenyl, Cι-Cι2alkoxy, C3-C12cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-Cn heterocycloalkenyl, C6-C10aryl, C6-Cι0aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C,ιaralkyl, C7-Cn aralkyloxy, C6-Cι0heteroaralkyl, C8-Cnaralkenyl, C7-Cι0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamido, carbamido, carbamate, sulfonhydr- azido, carbhydrazido, carbohydroxamic acid and aminocarbonylamido, where Rs1 is hydrogen, My, Cι-Cι2alkyl, C2-C12alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-C,0aryl, C5-C9heteroaryl, C7-Cnaralkyl or C6-Cι0heteroaralkyl, R54 is hydrogen, Cι-C12alkyl, C2-C12alkenyl, C3-Cι2cycloalkyl, C2-Cnheterocycloalkyl, C6-Cιoaryl, Cs-Cgheteroaryl, C7-Cιιaralkyl or C6-Cι0heteroaralkyl, and Rs2 and R20 are hydrogen, d-C^alkyl, C2-C12alkenyl, C3-Cι2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnheterocycloalkyl, C2-C -hetero- cycloalkenyl, C6-Cιoaryl, C5-Cgheteroaryl, C Cnaralkyl, C6-C10heteroaralkyl, C8-Cn-aralkenyl or C7-Cιoheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyi, aralkyloxy, heteroaralkyi, 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; and a derivative thereof wherein at least one OH is substituted with SO3RT5C,
Figure imgf000060_0001
C(O)RT9C, C(O)ORT9C, C(S)NRT2CRT3C, C(O)NRT2CRT3C, Cι-C,2alkyl, C3-Cι2al- kenyl, C3-C12cycloalkyl, C3-Cι2cycloalkenyl, Ci-Cnheteroalkyl, C2-Cnheterocycloalkyl, C2-Cιιheterocycloalkenyl, C6-, C)0- or Cι aryl, C2-C9heteroaryl, C7-Cnaralkyl, C6-Cι0hetero- aralkyl, C9-Cnaralkenyl or C8-Cι0heteroaralkenyl; in free form or in salt form.
2. The compound according to claim 1 , wherein R2 is hydrogen, unsubstituted or substituted C,-C6alkyl, wherein the substituent is selected from C(O)OH, -C(O)ONa, -C(O)OK, -OH, -C(O)-NRB "R9" and -SO2-NR8"R9", in which R8" is H, C,-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and R9 independently has the meaning of R8 , or R8 and R9 are together tetramethylene, pentamethylene or -CH2CH2-O-CH2CH2-.
3. The compound according to claim 1 having the formula IA, IB or IC
Figure imgf000060_0002
Figure imgf000061_0001
wherein X, R1, R2, RT1, RT2, RB5 and R5 are as defined in claim 1 and R3 is hydrogen or My; and R4 is Cι-C12alkyl, C2-C12alkenyl, C3-C 2cycloalkyl, C3-Cι2cycloalkenyl, C2-Cnhetero- cycloalkyl, C2-Cnheterocycloalkenyl, C6-Cιoaryl, C5-C9heteroaryl, C7-Cnaralkyl, C6-Cι0heteroaralkyl, C8-Cnaralkenyl or C -Cι0heteroaralkenyl, which are unsubstituted or substituted by one or more substituents selected from the group of substituents according to claim 1.
4. A process for the preparation of a compound according to claim 1 wherein the corresponding galactose-GlcNAc-disaccharide or galactose-tetrahydropyran dimer is linked with the corresponding fucose-derivative or the corresponding fucose-GlcNAc-disaccharide or fucose-tetrahydropyran dimer is linked with the corresponding galactose, wherein the groups R1, Rτ\ X-RT2, RB5 and/or R5 are optionally introduced before or after the formation of the dimer or trimer.
5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.
6. A method for preventing or treating disorders in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.
8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in the manufacturing of a medicament for use in the method according to claim 6.
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US7361644B2 (en) 2003-11-19 2008-04-22 Glycomimetics, Inc. Specific antagonist for both E- and P-selectins
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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
USRE44778E1 (en) 2005-09-02 2014-02-25 Glycomimetics, Inc. Heterobifunctional pan-selectin inhibitors
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US11291678B2 (en) 2016-03-02 2022-04-05 Glycomimetics, Inc Methods for the treatment and/or prevention of cardiovascular disease by inhibition of E-selectin
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
US11780873B2 (en) 2016-10-07 2023-10-10 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
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