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WO1998018805A2 - Composes organiques - Google Patents

Composes organiques Download PDF

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Publication number
WO1998018805A2
WO1998018805A2 PCT/EP1997/005909 EP9705909W WO9818805A2 WO 1998018805 A2 WO1998018805 A2 WO 1998018805A2 EP 9705909 W EP9705909 W EP 9705909W WO 9818805 A2 WO9818805 A2 WO 9818805A2
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WIPO (PCT)
Prior art keywords
alkyl
substituted
mmol
solution
added
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PCT/EP1997/005909
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English (en)
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WO1998018805A3 (fr
Inventor
Chi-Huey Wong
Francisco Moris-Varas
Chun-Cheng Lin
Thomas G. Marron
Thomas Woltering
Gabriele Weitz-Schmidt
Jill Jablonowski
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Novartis Ag
The Scripps Research Institute
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Priority claimed from US08/744,744 external-priority patent/US5830871A/en
Priority claimed from US08/764,315 external-priority patent/US5837862A/en
Application filed by Novartis Ag, The Scripps Research Institute filed Critical Novartis Ag
Priority to AU53137/98A priority Critical patent/AU5313798A/en
Publication of WO1998018805A2 publication Critical patent/WO1998018805A2/fr
Publication of WO1998018805A3 publication Critical patent/WO1998018805A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • the present invention relates to compounds that inhibit cellular adhesion. More particularly, the present invention relates to sialyl Lewis X mimetics which mimic the inhibition of selectin-mediated cellular adhesion by sialyl Lewis X.
  • the complex process of inflammation which takes place in several stages, is the body's natural reaction to injuries in which, for example, there is also invasion by infectious agents.
  • the endothelium which lines the blood vessels expresses adhesion proteins on its surface.
  • the P and E selectins bring about, by a protein-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 (integrins) on their surface which ensure firm adhesion of the leukocytes to the endothelium. This is followed by migration of the leukocytes into the damaged tissue.
  • SLe x mimetics which are easy to synthesize, more stable and more active than SLe", and preferably orally active.
  • Y is -O- or C C ⁇ lkylene which is unsubstituted or substituted by one or two substituents selected from OR 3 and C(O)NH[CH 2 ] m C(O)NHC 10 -C 16 alkyl;
  • R 2 is CHOHCHOHC(O)(CH 2 ) n R 5 ;
  • R 3 is aralkyl with C r C 6 alkyl and C 6 -C 10 aryl or CH 2 C(O)NHC ⁇ -C 2 oalkyl which is unsubstituted or substituted by one or two OC(O)C ⁇ 0 -C 16 alkyl;
  • R 5 is OPO 3 H 2 or PO 3 H 2 ;
  • m is a number from 1 to 6; and
  • n is 1 or 2; or
  • Y is C C ⁇ alkylene which is unsubstituted or substituted by one or two substituents selected from OR 3 and C(O)NH[CH 2 ] rn C(O)NHC 1 o-C 16 alkyl;
  • R 2 is -NR 6 R 7 ;
  • R 3 is aralkyl with d-C 6 alkyl and C 6 -C ⁇ 0 aryl or CH 2 C(O)NHC 1 -C 20 alkyl which is unsubstituted or substituted by one or two OC(O)C ⁇ 0 -C ⁇ 6 alkyl;
  • R 6 is C(O)CHR 8 NHC(O)(CH 2 ) q C(O)OH;
  • R 7 is (CH 2 ) m C(O)NHC 4 -C ⁇ 8 alkyl or (CH 2 ) r ⁇ ,C(O)NHC 6 -C ⁇ 0 aryl wherein aryl is optionally substituted by OH or C 5 -C 16 alkyl;
  • R 8 is C ⁇ -C 6 alkyl unsubstituted or substituted with one or two OH; m is a number from 0 to 6; and q is 2 or 3; or
  • R 1 is OH
  • Y is -CH 2 -;
  • R 2 is -NR 6 H
  • R 6 is C(O)-C 1 -C 30 alkyl which is substituted by C(O)OH; or
  • R 1 is a group of formula la
  • Y is -CH 2 -; R 2 is OH; and n is 0, 1 or 2; or
  • R 1 is Y'-R 2' ;
  • Y is -CH 2 -;
  • R 2 is H, -OH, -N 3 , -OSO 3 2' , -O-C(O)-C 4 -C 30 alkyl, -O-C r C 30 alkyl which is unsubstituted or substituted with C 6 -C 10 aryl; -O-C 6 -C ⁇ 0 aryl which is unsubstituted or substituted with d-Caalkyl; -O-C(O)-CH 2 CH 2 C(O)NHCH(CH 2 CO 2 H)CO 2 H or NHR 6 ;
  • Y' is C ⁇ -C 5 alkylene or O-d-C alkylene ;
  • R 2' is -CHOHCHOHC(O)(CH 2 ) n R 5 ; -CHOHCHOHC(O)[CH 2 ] n C(O)OH;
  • R 4 is H, C r C 6 alkyl which is substituted by C(O)OH; CH 2 hydroxyphenyl; benzyl or the radical of an amino acid;
  • R 5 is OPO 3 H 2 or PO 3 H 2 ;
  • R 6 is C C 3 oalkyl which is unsubstituted or substituted by C 6 -C ⁇ 0 aryl, CCOJ-d-Csoalkyl which is unsubstituted or substituted by C 6 -C ⁇ 0 aryl or C(O)OH, C(O)-C -C 3 oalkenyl with 1 to 4 double bonds which is unsubstituted or substituted by C(O)OH, C(O)-C 6 - C 10 aryl which is unsubstituted or substituted by one or two OH, C(O)(CH 2 ) m NHCr C 6 alkyl, C(O)(CH 2 ) r CON(CH 2 CONH(CH 2 )CH 3 )HCONH(CH 2 ) s CH 3 or C(O)(CH 2 ) p NHC(O)(CH 2 ) q C(O)OH; m is a number from 1 to 6; n is 1 or 2
  • the compounds of formula I may comprise one or more asymmetric carbon atoms. It will be understood that the present invention includes all individual isomeric forms, enantiomers and diastereoisomers as well as mixtures, e.g. racemates, unless otherwise stated.
  • R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is H; -OH; -O-C,-C 6 alkyl; -OBn; -N 3 ; -OSO 3 2" ; -O-C(O)- CH 2 CH 2 C(O)NHCH(CH 2 CO 2 H)CO 2 H or NHR 6 ; Y' is C r C 5 alkylene; R 2' is -CHOHCHOHC(O)CH 2 R 5 ; R 5 is OPO 3 H 2 or PO 3 H 2 ; and R 6 is d-C 6 alkyl; acyl; decanoyl, phenylacetyl or C(O)CH 2 CH 2 C(O)OH; or (b1) R 1 is CH 3 ; Y is -CH 2 -; R 2 is CHOHCHOHC(O)CH 2 R 5 ; and R 5 is OPO 3 H 2 or PO 3 H 2 ; or (c1) R 1 is CH 3
  • R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is -OH; Y' is -CH 2 -; R 2' is C(O)NHCHR 4 C(O)OH; and R 4 is the radical of an amino acid selected from the group consisting of Ala, Val, Leu, lie, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr, Asn, Gin, Asp, Glu, Lys, Arg and His; or
  • R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is -OH; Y' is -CH 2 -; R 2' is -CHOHCHOHC(O)NHCHR 4 C(O)OH; and R 4 is the radical of an amino acid selected from the group consisting of Ala, Val, Leu, He, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr, Asn, Gin, Asp, Glu, Lys, Arg and His; or
  • R 1 is a group of formula la; Y is -CH 2 -; R 2 is OH; and n is 0, 1 or 2; or (d2) R 1 is OH; Y is -CH 2 -; R 2 is -NR 6 H; and R 6 is C(O)-C 2 -C 3 alkyl which is substituted by C(O)OH.
  • R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is NHR 6 ; Y' is -CH 2 -; R 2' is C(O)NHCHR 4 C(O)OH; R 4 is C 2 alkyl which is substituted by C(O)OH; R 6 is hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, laurate, tridecanoyl, myristate, pentadecanoyl, palmitate, hepta- decanoyl, stearate, nonadecanoyl, eicosanoyl, hexaicosanoyl, docosanoyl, tricosanoyl, tetracosanoyl, hexacosanoyl, heptacosanoyl, octaco
  • SUBSTTTUTE SHEET (RULE 25) ane, O-docosane, O-ethyl-naphthalene, O-methyl-naphthalene, O-ethyl-benzene, O-phenyl-propane, O-heptanoyl, O-octanoyl, O-nonaoyl, O-decanoyl, O-undecanoyl, O-lauroyl, O-myristoyl, O-palmitoyl, O-heptadecanoyl or O-stearoyl; Y' is -CH 2 -; R 2 is C(O)NHCHR 4 C(O)OH; and R 4 is C 2 alkyl which is substituted by C(O)OH; or
  • R 1 is Y'-R 2 ; Y is -CH 2 -; R 2 is -OH, O-propane, O-butane, O-pentane, O-hexane, O-heptane, O-octane, O-nonane, O-decane, O-undecane, O-dodecane, O-tri- decane, O-tetradecane, O-pentadecane, O-hexadecane, O-octadecane, O-eicos- ane, O-docosane, O-ethyl-naphthalene, O-methyl-naphthalene, O-ethyl-benzene, O-phenyl-propane, O-heptanoyl, O-octanoyl, O-nonaoyl, O-decanoyl, O-undecanoyl, O-lauroy
  • R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is -OH, O-propane, O-butane, O-pentane, O-hexane, O-heptane, O-octane, O-nonane, O-decane, O-undecane, O-dodecane, O-tri- decane, O-tetradecane, O-pentadecane, O-hexadecane, O-octadecane, O-eicos- ane, O-docosane, O-ethyl-naphthalene, O-methyl-naphthalene, O-ethyl-benzene, O-phenyl-propane, O-heptanoyl, O-octanoyl, O-nonaoyl, O-decanoyl, O-undecanoyl, O-lau
  • R 1 is Y'-R 2' ; Y is -CH -; R 2 is -OH, O-propane, O-butane, O-pentane, O-hexane, O-heptane, O-octane, O-nonane, O-decane, O-undecane, O-dodecane, O-tri- decane, O-tetradecane, O-pentadecane, O-hexadecane, O-octadecane, O-eicos- ane, O-docosane, O-ethyl-naphthalene, O-methyl-naphthalene, O-ethyl-benzene, O-phenyl-propane, O-heptanoyl, O-octanoyl, O-nonaoyl, O-decanoyl, O-undecanoyl, O-lauroy
  • R 1 is CH 3 ; Y is C 2 alkylene; R 2 is -NR 6 R 7 ; R 6 is C(O)CHR 8 NHC(O)(CH 2 ) 3 C(O)OH; R 7 is (CH 2 ) m C(O)R 9 ; R 8 is CHOHCH 2 OH; R 9 is butyl amine, amyl amine, hexyl amine, heptyl amine, octyl amine, nonylamine, octadecyl amine, 1 -amino naphthalene, 2-amino naphthalene, 2-amino-2-naphthol perhydrochloride, 4-pentyl aniline, 4-hexyl aniline, 4-heptyl aniline, 4-octyl aniline, 4-decyl aniline, 4-dodecyl aniline, 4-tetra- decyl aniline or 4-hexadecyl
  • R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is -OH; Y' is -CH 2 -; R 2' is C(O)NHCHR 4 C(O)OH; and R 4 is the radical of an amino acid selected from the group consisting of Ala, Val, Leu, lie, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr, Asn, Gin, Asp, Glu, Lys, Arg and His.
  • SUBSTITUTE SHEET (RULE 25) Within group (b) the most preferred compounds are 27(15) and 29(15) as exemplified in Examples B.
  • Another preferred embodiment comprises compounds of group (d) wherein R 1 is Y'-R 2 ; Y is -CH 2 -; Y' is -CH 2 - or -O-CH 2 -; R 2 is OH; R 2' is CHOHCHOHC(O)(CH 2 ) n R 5 ; R 5 is OPO 3 H 2 or PO 3 H 2 ; and n is 1 or 2.
  • Most preferred compounds are 6(14), 4(3), 4a(3), 7(14) and 13(14) as exemplified in Examples B.
  • R 1 is Y'-R 2 ; Y is -CH 2 -; R 2 is OH; Y' is -CH 2 -; R 2' is -CHOHCHOHC(O)(CH 2 ) 2 C(O)OH; -C(O)NHCH 2 C(O)OH -CHOHCHOHC(O)CH 2 CH[benzyl]C(O)OH; -CHOHCHOHC(O)NHCHR C(O)OH; or C(O)NHCHR 4 C(O)OH; and R 4 is H, d-C 6 alkyl which is substituted by C(O)OH; CH 2 hydroxy- phenyl or benzyl.
  • Most preferred compounds are 5(15), 6(15), 102(3), 103(3), 104(3), 105(3) and 106(3) as exemplified in Examples B.
  • Another preferred embodiment comprises compounds of group (d) wherein R 1 is Y'-R 2 ; Y is -CH 2 -; Y' is -CH 2 -; R 2 is -O-d-C ⁇ alkyl and R 2' is -C(O)NHCHR 4 C(O)OH wherein R 4 is CH 2 CH 2 C(O)OH; or -C(O)NHphenyl which is substituted by one C(O)OH.
  • Most preferred compounds are 3(3) and 3a(3) as exemplified in Examples B.
  • R 1 is Y'-R 2 ; Y is -CH 2 -; Y' is -CH 2 - or -O-CH 2 -; R 2 is -NHR 6 ; R 2' is - CHOHCHOHC(O)CH 2 R 5 or C(O)NHCHR C(O)OH; R 5 is OPO 3 H 2 or PO 3 H 2 ; R 6 is d-Csoalkyl which is unsubstituted or substituted by Ce-Cioaryl, C(O)-d-C 30 alkyl which is unsubstituted or substituted by Ce- Cioaryl or C(O)OH; C(O)(CH 2 ) p NHC(O)(CH 2 ) q C(O)OH; C(O)(CH 2 ) m NHC ⁇ -C 6 alkyl; or C(O)(CH2) r CON(CH 2 CONH(CH 2 )CH 3 )HCON
  • the present invention also comprises a process for the preparation of the compounds of the formula I wherein the corresponding radicals -Y-R 2 and -Y'-R 2 are coupled, optionally via more than one step, to the corresponding sugar moiety.
  • the procedures are generally known to the skilled person or can be deduced from the Examples, describing further non- limiting details of the preparation.
  • the coupling step within the synthesis of C-glycosides of group (d), eg. 6(14) and 4(3) which may be performed in the presence of a DHAP dependent aldolase.
  • the DHAP substrate is a compound selected from the group consisting of e.g. dihydroxyacetone phosphate and 3-keto- 4-hydroxy-butanyl-1-phosphonate.
  • the DHAP dependent aldolase is selected from the group consisting of FDPA, FucA, RhaA and TagA.
  • 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 HL-60 cells as disclosed in Example D.
  • the compounds are particularly 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 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
  • 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.
  • SUBSTTTUTE SHEET (RULE 25) nostimulated 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 parenterally e.g. in form of injectable solutions or suspensions.
  • OPO 3 H 2 , PO 3 H 2 and the carboxyl group may be in free acid form or in salt form.
  • 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.
  • 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 immuno- suppressive or anti-inflammatory agent.
  • BnBr benzyl bromide
  • CSA camphorsulfonic acid
  • DCM dichloro- methane
  • DEAD diethylazodicarboxylate
  • C-DHAP 3-keto-4-hydroxy-butanyl-1-phosphon- ate
  • DHAP dihydroxyacetone phosphate
  • dppb 1 ,4-bis(diphenylphosphino)butane
  • DMAP 4-dimethylaminopyridine
  • DMF dimethylformamide
  • DMS dimethylsulfide
  • EDC 1-(3-di- methylaminopropyl)-3-ethylcarbodiimide hydrochloride; eq: equivalent
  • ESI electrospray ionization
  • HOBt 1-hydroxybenzotriazole
  • HOSu N-hydroxy succinimide
  • NBA m-nitro- benzylalcohol
  • NMM 4-methyl morpholine
  • PPh 3 4-methyl morpholine
  • the diols are prepared from the unsaturated esters according to the literature protocol as follows: A solution of AD-mix ( ⁇ or ⁇ ) (1.4 g/mmol olefin) in tert.-butanol (5 ml) and H 2 O (5 ml) is cooled to 0°C, MeSO 2 NH 2 and the olefin (1 mmol) are added and the heterogeneous mixture is stirred at 4°C until completion is indicated by tic (up to 48 h, to avoid very slow conversion, addition of extra potassium osmate (1.3 mg) is recommended). Sodium sulfite (1.5 g) is added at 4°C and stirring is continued at 23°C for 30 min.
  • GP B A solution of the amine, HOBt, the carboxylic acid and NMM in dry CH 2 CI 2 is cooled to 0°C and EDC is added in one portion. The reaction mixture is stirred several h at 0°C and
  • An aqueous solution of the residue is either directly filtered through a Whatman ® Anotop inorganic membrane filter (Anotop 25 (0.2 ⁇ m) or Anotop 10 (0.02 ⁇ m)) or, if necessary, purified by Biogel P2 or Sephadex G10 column chromatography (H 2 O as eluent) and lyophilized to give the completely deprotected compound as a white solid.
  • GP B A solution of the benzyl protected compound in EtOH/H 2 O (2:1 ) is hydrogenated at 1 atm in the presence of Pd(OH) 2 /C (Degussa type, 20% Pd(OH) 2 on activated carbon) for several hours. The reaction is worked up as described above in GP A.
  • the reaction mixture is stirred at -20°C for 1 h and then allowed to reach 23°C slowly. After 16 to 36 h the reaction is taken up in ethyl acetate and extracted with 5% w/v citric acid solution (20 ml). The aqueous layer is further extracted with ethyl acetate (4 x 20 ml) and the combined oranic layers are washed with sat. NaHCO 3 -sol. (40 ml) and brine (40 ml) followed by drying over MgSO 4 . After evaporation under reduced pressure the residual oil is purified by SGCC (gradient elution with 30% ⁇ 100% EtOAc in hexanes) to give the coupled protected mimetic.
  • SGCC gradient elution with 30% ⁇ 100% EtOAc in hexanes
  • An aqueous solution of the residue is either directly filtered through a Whatman ® Anotop inorganic membrane filter (Anotop 25 (0.2 ⁇ m) or Anotop 10 (0.02 ⁇ m)) or, if necessary, purified by Biogel P2 or Sephadex G10 column chromatography (H 2 O as eluent) and lyophilized to give the completely deprotected compound as a white solid.
  • SUBSTTTUTE SHEET (RULE 25) tion is indicated by tic (up to 48h, to avoid very slow conversion, addition of extra potassium osmate (1.3 mg) is recommended). Sodium sulfite (1.5g) is added at 4°C and stirring is continued at 23°C for 30min. Triple extraction with EtOAc is followed by washings with 1 N NaOH and brine. After drying over Na 2 SO and removal of the solvent in vacuo the residual slightly yellow solid is purified by SGCC (gradient elution EtOAc in hexanes) to give the desired diol.
  • SGCC gradient elution EtOAc in hexanes
  • Procedure B A solution of the amine, HOBt, the carboxylic acid and NMM in dry CH 2 CI 2 is cooled to 0°C and EDC is added in one portion. The reaction mixture is stirred several h at 0°C and then allowed to reach 23°C slowly. After 4 to 18h the reaction is worked up as described above in Procedure A.
  • the reaction mixture is treated with NMM until a basic pH is achieved.
  • the reaction mixture is stirred at 0°C for several h and then allowed to reach 23°C slowly.
  • the reaction is taken up in ethyl acetate and extracted with 5% w/v citric acid solution (20 ml).
  • the aqueous layer is further extracted with ethyl acetate (4 x 20 ml) and the combined organic layers are washed with sat. NaHCO 3 -sol. (40 ml) and brine (40 ml) followed by drying over MgSO 4 or Na 2 SO in the case of unprotected diols.
  • the residual oil is purified by SGCC (gradient elution with 40% ⁇ 100% EtOAc in hexanes) to give the coupled compound.
  • SUBSTITUTE SHEET (RULE 25) (d) 2 mol (1132mg) of 4(14) is dissolved in a mixture of THF and water (3:1) and hydrogenated at 1 atm in the presence of a catalytic amount of Pd/C (Aldrich; 10% Pd/C). The mixture is allowed to react overnight and the catalyst is filtered off using a celite pad. The solvent is evaporated under vacuum and 5(14) is isolated as a mixture of aldehyde and dihydrate.
  • Example A4 Preparation of Compound 22(14) 20(14) is treated with 1.1 eq of succinic anhydride in pyridine as solvent and in the presence of a catalytic amount of DMAP; conditions and workup are as above.
  • the product so obtained is subjected to ozonolysis in DCM/MeOH (5:1), quenched by DMS and extracted from ether. Hydrogenation of the benzyl groups is carried out in THF:H 2 O mixture under 50 psi of H 2 to yield 22(14).
  • the O-allyl, O-propenyl, O-butenyl, and O-pentenyl ⁇ -(D)-glucoside 23(14) is prepared according to Fraser-Reid et al [Syntlett 927 (1992)] wherein the O-methyl ⁇ -(D)-mannoside is stirred in neat solvent (e.g. 1.0 propenol (for the O-propenyl derivative), 1.0 allyl alcohol (for the O-allyl derivative), 1.0 butenol (for the O-butenyl derivative) or 1.0 O-pentenol (for the O-pentenyl derivative) at 90°C for 12 h.
  • solvent e.g. 1.0 propenol (for the O-propenyl derivative), 1.0 allyl alcohol (for the O-allyl derivative), 1.0 butenol (for the O-butenyl derivative) or 1.0 O-pentenol (for the O-pentenyl derivative) at 90°C for
  • the crude oil is purified by SGFC (CH 2 CI 2 :MeOH) giving the perbenzyl aldehyde.
  • the tertbutyldiphenylsilyl moiety is then removed by adding 1.0 M solvent THF to the perbenzyl aldehyde followed by the addition of TBAF (1.0 eq; 1.0 M solution).
  • the reaction mixture is stirred for 2 h at 0°C.
  • the reaction mixture is evaporated and partitioned between a saturated NaHCO 3 solution (50ml) and EtOAc (5ml).
  • the aqueous phase is extracted with EtOAc (2x30ml) and the combined organic phases are dried and concentrated under reduced pressure.
  • the crude oil is purified by SGFC (CH 2 CI 2 :MeOH) giving the perbenzylated aldehyde 25(14).
  • R'-bromide chloride or iodide is also acceptable
  • the reaction mixture is warmed to 23°C, diluted with CH 2 CI 2 (100 ml), washed with saturated NaHCO 3 (50 ml), and dried (MgSO 4 ).
  • the crude product is used directly in the next step without further purification.
  • the aldehyde prepared above is dissolved in acetone (3 ml) and cooled to 0°C. Jones reagent is added drop-wise until a orange color persists. iPrOH (1 ml) is added to quench any excess Jones reagent and the reaction mixture is then partitioned between methylene chloride (50 ml) and 1 N HCI (50 ml). The aqueous layer is extracted with CH 2 CI 2 (50 ml) and the combined organic phases are dried (MgSO 4 ), concentrated under reduced pressure, and purified by SGFC (100% EtOAc) giving 18(15).
  • Example A17 Preparation of methyl-2-[N-(2,3,4,6-tetrabenzyloxy- ⁇ -D-mannopyran- oside)carbonyl]amino-3-[(2-acetic acid)oxy]-4,6-0-dibenzylidine-galac- topyranoside 13(3)
  • reaction is diluted with CH CI 2 (10 ml) and the resulting solution is quenched by saturated NaHCO.
  • the aqueous layer is extracted with CH 2 CI 2 (2 x 10 ml) and the combined organic layers are washed with brine, dried with MgSO 4 , filtered, evaporated and purified by column chromatography to provide 8(3).
  • alkyl halide or acyl halide may be used in lieu of 1 -bromohexadecane: 1-chloropropane, 1-chlorobutane, 1-chloropentane, 1-chlorohexane, 1-chloro- heptane, 1-chlorooctane, 1-chlorononane, 1-chlorodecane, 1-bromoundecane, 1-bromo- dodecane, 1-bromotridecane, 1-bromotetradecane, 1-bromopentadecane, 1 -bromohexadecane, 1 -bromooctadecane, 1-bromoeicosane, 1-bromodocosane, 2-bromomethyl-naph- thalene, 1-chloromethyl-naphthalene, 2-bromoethyl-benzene, 1-bromo-3-phenyl-propane, h
  • D-Mannose (1500 mg, 8.3 mmol) is added to 10 ml of allyl alcohol together with a catalytic amount (10 mg) of camphorsulfonic acid. The mixture is heated to 90°C overnight and then the excess allyl alcohol is evaporated in vacuo. Flash chromatography of the residue (EtOAc:MeOH, 6:1 -4:1) gives 1400 mg (76%) of ⁇ -O-allylmannopyranoside. To a solution of the above compound is added 1.1 eq TBDPSOTf (1.1 eq) in anhydrous methylene chloride (.10 M) at 0°C and allowed to stir for 2 h.
  • TBDPSOTf 1.1 eq
  • the ozonolysis of 9a(3) is performed as described above.
  • the aldehyde product (2 mmol, 1.1 g) is dissolved in a 3:1 mixture of THF and water and hydrogenated overnight at 1 atm in the presence of a catalytic amount of Pd-C. After filtration through Celite and evaporation of the solvent, the deprotected aldehyde 18a(3) is isolated.
  • reaction is diluted with CH 2 CI 2 (10 ml) and the resulting solution is quenched by saturated NaHCO 3 .
  • the aqueous layer is extracted with CH 2 CI 2 (2 x 10 ml) and the combined organic layers are washed with brine, dried with MgSO , filtered, evaporated and purified by column chromatography to provide the acetate.
  • the crude acetate is dissolved in MeOH and a catalytic amount of 25% NaOMe by weight is added in MeOH. After 2 h Dowex H + resin is added until the pH of the solution is approximately 1-2. The residue is then dissolved in CH 2 CI 2 and the solution is washed with 5% aq. citric acid solution , sat. NaHCO 3 soln., and brine. This solution is then dried over Na 2 SO and concentrated under reduced pressure. The crude material is purified by flash chromatography with silica gel using 25%-35% ethyl acetate in hexane as the eluent.
  • reaction After stirring overnight, the reaction is quenched by the addition of 1 g Na 2 S 2 Os, 10 g Florisil and 25 ml of H 2 O. After 30 min, the reaction mixture is concentrated under reduced pressure and the residue is treated with EtOAc and water. The solution is decanted away from the Florisil and the aqueous portion is extracted four times with EtOAc. The combined organic extracts are dried over MgSO 4 and concentrated under reduced pressure. The diol is immediately used in the next reaction.
  • the reaction is quenched with isopropanol, 5 g of celite is added and the reaction is stirred for 20 min.
  • the solution is decanted into a separatory funnel and EtOAc is added.
  • the aqueous portion is extracted three times with EtOAc.
  • the combined organic extracts are dried over MgSO 4 and concentrated under reduced pressure. The acid is sufficiently pure for use in the next reaction.
  • reaction is allowed to stir for 24 h before being diluted with CH 2 CI 2 (20 ml) and washed successively with a 1 N hydrochloric acid solution (15 ml), saturated NaHCO 3 solution (15 ml) and brine (15 ml).
  • the organic phase is dried with MgSO 4 , concentrated and purified by silica gel chromatoaraphy to yield 81(3).
  • the reaction is allowed to stir for 24 h before being diluted with CH 2 CI 2 (50 ml) and washed successively with a 5% citric acid solution (25 ml), saturated NaHCO 3 solution (25 ml), and brine (25 ml).
  • the organic phase is dried (MgSO 4 ), concentrated under reduced pressure, and purified by silica gel chromatography (EtOAc:Hexane 1 :1) giving 102i(3).
  • the ⁇ , ⁇ -unsaturated ester (211 mg, 331 ⁇ mol) is subjected to the general procedure described for the asymmetric dihydroxylation reaction (AD-reaction) to provide diol 113(3).
  • Example B5 Preparation of (2S,3fl)-N-carboxylmethyl-2,3-dihydroxy-4-( ⁇ -D-manno- pyranosyl)-butyramide 5(15)
  • 26(15) (61 mg, 0.169 mmol) is dissolved in 90% TFA:water (3 ml) and stirred for 4 h. The reaction mixture is evaporated down under reduced pressure and any residual TFA is removed by two co-evaporations with toluene (2 x 25 ml). The crude mimic is dissolved in water (10 ml), filtered, and lyophilized giving 27(15): HRMS calcd for C 10 H 18 O 8 N (M + H), 280.1032, found 280.1038.
  • Example B11 Preparation of methyl-2-[N-(2,3,4,6-hydroxy- ⁇ -D-mannopyranoside) carbonyl]amino-3-[(2-aceticacid)oxy]-4,6-hydroxy-galactopyranoside
  • DHAP 1.2-1.5 mmol of 18(3) is dissolved in a solution of DHAP, (1 mmol, 3 ml of a 330 mM solution).
  • the pH is adjusted to 6.7 by adding NaOH and 200 u of FDP aldolase (Sigma) is added.
  • FDP aldolase Sigma
  • the pH is adjusted to 8 and 1 g of BaCI 2 • 2 H 2 O (4.4 mmol) in 5 ml of water is added slowly.
  • the cloudy mixture is kept in an ice bath for 15 min and the precipitates are removed by centrifugation. Two volumes of acetone are added to the supernate and the mixture is stored at 0°C for 1 h.
  • the precipitates are collected by centrifugation and the supernatant is discarded.
  • the pellet is treated with Dowex-50 H + until the solid is completely dissolved (ca. 30min), and the resin is filtered off.
  • the pH of the filtrate is adjusted to 7.0 by adding NaOH. Lyophilisation of the solution yields a mixture of the phosphonates that are
  • SUBSTITUTE SHEET (RULE 25) mixture is filtered off using celite pad. The solvent is removed under vacuum to give free amine compound which can be used in the next step without further purification.
  • OSu activated ester RCOOSu (1.1 eq; R is a radical derived from the following acids; the activated ester is derived by reacting 1.1 eq of succinic anhydride with 1.0 eq of the following commercially available acids in 0.10 M methylene chloride at 0°C for 6 h: the acids are as follows: hexanoic acid, heptan- oic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, lauric acid, tri- decanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid
  • the Boc compound 71(3) (1.0 mmol) is dissolved in a 50:50 mixture of CH 2 CI 2 :TFA and the mixture is cooled to 0°C. After 30 min, the residue is concentrated to remove the excess TFA and CH 2 CI 2 and the residue is rinsed with CHCI 3 and concentrated to remove any traces of TFA.
  • the TFA amine salt is the one used in the general procedure for coupling a carboxylic acid and an amine, using an additional equivalent of NMM.
  • the activated ester is derived by reacting 1.1 eq of succinic anhydride with 1.0 eq of an acid in 0.10 M methylene chloride at 0°C for 6 h: useful acids are mentioned in example B14), HOBt (1.2 mmol), the amine (2.0 mmol) and NMM (2.5 mmol) in CH 2 CI 2 (0.5 M) is added EDC (1.3 mmol). After stirring overnight and subsequent warming to RT sat. NaHCO 3 soln. and CH 2 CI 2 are added to the reaction mixture. The aqueous portion is extracted twice with CH 2 CI 2 .
  • Example B17 Preparation of 3- ⁇ N-[1-(6-O-Hexadecanyl- ⁇ -D-mannopyranosyl)]- acetyl)aminobenzoic acid 3a(3)
  • a soluble form of E-selectin (sol-E-selectin) is prepared for inhibition assays of the SLe x mimetics.
  • a 1.67 kbp DNA fragment encoding a truncated structural gene for E-selectin is isolated by PCR amplification of cDNA derived from mRNA that is isolated from IL-1 activated human endotheiial cells.
  • the cDNA is subcloned into the vector pBluescript II and is trans- fected into 293 cells.
  • the clones are screened for the production of sol-E-selectin, and the clone 293#3 is selected as the stable cell line that produces the greatest amount of sol-E- selectin per cell.
  • Sol-E-selectin is produced on a large scale from this line using a Nunc cell factory. Recombinant sol-E-selectin is isolated from the media using immunoaffinity chromatography.
  • the SLe mimetics are assayed for ability to block the adhesion of HL-60 cells to immobilized sol-E-selectin.
  • Immobilized E-selectin is incubated first with inhibitor and then with HL- 60 cells.
  • the bound cells are lysed, and myeloperoxidase released from the bound cells is detected with o-phenylenediamine and hydrogen peroxide.
  • the percentage inhibition is determined by comparing the absorbance of the resulting solution at 492 nm to that in wells containing no inhibitor.
  • Each data point in the E-selectin assay is a direct measure of cells bound using a quantitative enzyme assay. The values are then plotted to give the titration curve and IC 50 values.
  • the procedure described herein is adopted from Wong et. al. [J. Am. Chem. Soc. 177:66- 79 (1995)].
  • the compounds of formula I show an inhibition at 3 mM of 70% to 80%, or an IC 50 value of from 0.1 mM to 0.2 mM.

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Abstract

Composés mimétiques de sialyle Lewis X qui imitent l'inhibition de l'adhésion cellulaire à médiation de sélectine par le sialyl Lewis X, et qui présentent une partie centrale représentée par la formule (I).
PCT/EP1997/005909 1996-10-28 1997-10-27 Composes organiques WO1998018805A2 (fr)

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US08/744,744 US5830871A (en) 1996-10-28 1996-10-28 Inhibitors of E-, P- and L-selectin binding
US08/744,744 1996-10-28
US08/764,315 1996-12-12
US08/764,315 US5837862A (en) 1996-12-12 1996-12-12 Sialyl Lewis X mimetics incorporating mannopeptides
US89645297A 1997-07-18 1997-07-18
US08/896,452 1997-07-18

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999010359A3 (fr) * 1997-08-26 1999-11-11 Novartis Ag Composes organiques
EP2608796A2 (fr) * 2010-08-05 2013-07-03 Seattle Genetics, Inc. Procédés d'inhibition de la fucosylation in vivo de protéines en utilisant des analogues du fucose

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
LUENGO, JUAN I. ET AL: "Synthesis of C-fucopyranosyl analogs of GDP-L-fucose as inhibitors of fucosyltransferases" TETRAHEDRON LETT. (1992), 33(46), 6911-14 CODEN: TELEAY;ISSN: 0040-4039, 1992, XP002054598 *
UCHIYAMA, TAKETO ET AL: "Design and Synthesis of Sialyl Lewis X Mimetics" J. AM. CHEM. SOC. (1995), 117(19), 5395-6 CODEN: JACSAT;ISSN: 0002-7863, 1995, XP000570082 *
UCHIYAMA, TRAKETO ET AL: "Design and synthesis of C-linked fucosides as inhibitors of E-selectin" BIOORG. MED. CHEM. (1996), 4(7), 1149-1165 CODEN: BMECEP;ISSN: 0968-0896, 9 July 1996, XP002054353 *
WONG, CHI-HUEY ET AL: "Small Molecules as Structural and Functional Mimics of Sialyl Lewis X in Selectin Inhibition: A Remarkable Enhancement of Inhibition by Additional Negative Charge and/or Hydrophobic Group" J. AM. CHEM. SOC. (1997), 119(35), 8152-8158 CODEN: JACSAT;ISSN: 0002-7863, 1997, XP002054599 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999010359A3 (fr) * 1997-08-26 1999-11-11 Novartis Ag Composes organiques
EP2608796A2 (fr) * 2010-08-05 2013-07-03 Seattle Genetics, Inc. Procédés d'inhibition de la fucosylation in vivo de protéines en utilisant des analogues du fucose
CN103402525A (zh) * 2010-08-05 2013-11-20 西雅图基因公司 使用岩藻糖类似物在体内抑制蛋白质岩藻糖基化的方法
EP2608796A4 (fr) * 2010-08-05 2014-06-11 Seattle Genetics Inc Procédés d'inhibition de la fucosylation in vivo de protéines en utilisant des analogues du fucose
AU2011285490B2 (en) * 2010-08-05 2016-04-21 Seagen Inc. Methods of inhibition of protein fucosylation in vivo using fucose analogs
US9504702B2 (en) 2010-08-05 2016-11-29 Seattle Genetics, Inc. Methods of inhibition of protein fucosylation in vivo using fucose analogs
CN103402525B (zh) * 2010-08-05 2017-03-01 西雅图基因公司 使用岩藻糖类似物在体内抑制蛋白质岩藻糖基化的方法
RU2625768C2 (ru) * 2010-08-05 2017-07-18 Сиэтл Дженетикс, Инк. Способы ингибирования фукозилирования белков in vivo с использованием аналогов фукозы
US10342811B2 (en) 2010-08-05 2019-07-09 Seattle Genetics, Inc. Methods of inhibition of protein fucosylation in vivo using fucose analogs
EP3513794A3 (fr) * 2010-08-05 2019-10-16 Seattle Genetics, Inc. Analogues du fucose pour inhibition de la fucosylation de protéines in vivo
US11033561B2 (en) 2010-08-05 2021-06-15 Seagen Inc. Methods of inhibition of protein fucosylation in vivo using fucose analogs

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