WO1998006730A1 - Oligosaccharides modifies - Google Patents

Oligosaccharides modifies Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
aryl
cycloalkenyl
alkenyl
Prior art date
Application number
PCT/EP1997/004279
Other languages
English (en)
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 EP97941916A priority Critical patent/EP0920437A1/fr
Priority to AU43788/97A priority patent/AU720381B2/en
Priority to IL12790897A priority patent/IL127908A0/xx
Priority to PL97331286A priority patent/PL331286A1/xx
Priority to SK156-99A priority patent/SK15699A3/sk
Priority to CA002260854A priority patent/CA2260854A1/fr
Priority to BR9711117-1A priority patent/BR9711117A/pt
Priority to JP10509358A priority patent/JP2000516224A/ja
Priority to NZ334048A priority patent/NZ334048A/xx
Publication of WO1998006730A1 publication Critical patent/WO1998006730A1/fr
Priority to NO990497A priority patent/NO990497L/no

Links

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    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen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 %.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Saccharide Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Dérivés des syalyles de Lewis X et A, dans lesquels le fragment acide neuraminique naturel et le monomère de N-acétylglucosamine naturel sont substitués.
PCT/EP1997/004279 1996-08-08 1997-08-06 Oligosaccharides modifies WO1998006730A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EP97941916A EP0920437A1 (fr) 1996-08-08 1997-08-06 Oligosaccharides modifies
AU43788/97A AU720381B2 (en) 1996-08-08 1997-08-06 Modified oligosaccharides
IL12790897A IL127908A0 (en) 1996-08-08 1997-08-06 Modified oligosaccharides
PL97331286A PL331286A1 (en) 1996-08-08 1997-08-06 Modified oligosaccharides
SK156-99A SK15699A3 (en) 1996-08-08 1997-08-06 Modified oligosaccharides, process for their preparation and pharmaceutical composition containing them
CA002260854A CA2260854A1 (fr) 1996-08-08 1997-08-06 Oligosaccharides modifies
BR9711117-1A BR9711117A (pt) 1996-08-08 1997-08-06 Oligossacarídios modificados.
JP10509358A JP2000516224A (ja) 1996-08-08 1997-08-06 修飾オリゴサッカライド
NZ334048A NZ334048A (en) 1996-08-08 1997-08-06 Mimetics of natural carbohydrate epitotes as ligands for E and P Selectin
NO990497A NO990497L (no) 1996-08-08 1999-02-03 Modifiserte oligosakkarider

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP96810527 1996-08-08
EP96810526 1996-08-08
EP96810636.9 1996-09-26
EP96810527.0 1996-09-26
EP96810636 1996-09-26
EP96810526.2 1996-09-26

Publications (1)

Publication Number Publication Date
WO1998006730A1 true WO1998006730A1 (fr) 1998-02-19

Family

ID=27237868

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/004279 WO1998006730A1 (fr) 1996-08-08 1997-08-06 Oligosaccharides modifies

Country Status (19)

Country Link
EP (1) EP0920437A1 (fr)
JP (1) JP2000516224A (fr)
KR (1) KR20000029862A (fr)
CN (1) CN1227563A (fr)
AR (1) AR008283A1 (fr)
AU (1) AU720381B2 (fr)
BR (1) BR9711117A (fr)
CA (1) CA2260854A1 (fr)
CO (1) CO4900075A1 (fr)
CZ (1) CZ39099A3 (fr)
ID (1) ID18010A (fr)
IL (1) IL127908A0 (fr)
NO (1) NO990497L (fr)
NZ (1) NZ334048A (fr)
PE (1) PE99298A1 (fr)
PL (1) PL331286A1 (fr)
SK (1) SK15699A3 (fr)
TR (1) TR199900245T2 (fr)
WO (1) WO1998006730A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1165097A2 (fr) * 1999-02-01 2002-01-02 Dermal Research Laboratories, Inc. Composition pharmaceutique d'hydrates de carbone complexes et d'huiles essentielles et methode d'utilisation de celle-ci
WO2004004636A2 (fr) * 2002-07-03 2004-01-15 Glycomimetics, Inc. Compositions et methodes permettant le diagnostic et le traitement d'etats pathologiques impliquant l'angiogenese
WO2004033473A1 (fr) 2002-10-11 2004-04-22 Yamanouchi Europe B.V. Composes a base de glucose presentant une affinite pour la selectine-p
WO2005054264A2 (fr) * 2003-11-19 2005-06-16 Glycomimetics, Inc. Antagonistes glycomimetiques pour les selectines de type e et p
US6911436B2 (en) * 1994-05-12 2005-06-28 Dermal Reserach Laboratories, Inc. Pharmaceutical composition of complex carbohydrates and essential oils and methods of using the same
WO2006127906A1 (fr) * 2005-05-25 2006-11-30 Glycomimetics, Inc. Composes heterobifonctionnels pour l’inhibition de la selectine
WO2008100453A1 (fr) * 2007-02-09 2008-08-21 Glycomimetics, Inc. Procédés d'utilisation de glycomimétiques avec des remplacements d'hexoses et d'hexosamines d'acétyle n
US7879824B2 (en) 2001-07-31 2011-02-01 Dermal Research Laboratories, Inc. Methods of preventing or treating diseases and conditions using complex carbohydrates
USRE44778E1 (en) 2005-09-02 2014-02-25 Glycomimetics, Inc. Heterobifunctional pan-selectin inhibitors
US8895510B2 (en) 2008-04-08 2014-11-25 Glycomimetics, Inc. Pan-selectin inhibitor with enhanced pharmacokinetic activity
US8921328B2 (en) 2010-09-14 2014-12-30 Glycomimetics, Inc. E-selectin antagonists
US9109002B2 (en) 2011-12-22 2015-08-18 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
EP2915539A1 (fr) 2007-12-10 2015-09-09 Mater Medical Research Institute Traitement d'états immunodéprimés par un antagoniste de l'E-Sélectine et le G-CSF
US9867841B2 (en) 2012-12-07 2018-01-16 Glycomimetics, Inc. Compounds, compositions and methods using E-selectin antagonists for mobilization of hematopoietic cells
US10519181B2 (en) 2014-12-03 2019-12-31 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectins and CXCR4 chemokine receptors
US11045485B2 (en) 2016-01-22 2021-06-29 Glycomimetics, Inc. Glycomimetic inhibitors of PA-IL and PA-IIL lectins
US11072625B2 (en) 2016-10-07 2021-07-27 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
US11197877B2 (en) 2017-03-15 2021-12-14 Glycomimetics. Inc. Galactopyranosyl-cyclohexyl derivauves as E-selectin antagonists
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
US11548908B2 (en) 2017-12-29 2023-01-10 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3
US11707474B2 (en) 2018-03-05 2023-07-25 Glycomimetics, Inc. Methods for treating acute myeloid leukemia and related conditions
US11712446B2 (en) 2017-11-30 2023-08-01 Glycomimetics, Inc. Methods of mobilizing marrow infiltrating lymphocytes and uses thereof
US11845771B2 (en) 2018-12-27 2023-12-19 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108299525B (zh) * 2018-01-05 2021-03-26 佛山科学技术学院 路易斯寡糖-x的合成方法
CN109762032A (zh) * 2019-01-16 2019-05-17 天津科技大学 一种磺酸化路易斯x三糖及其合成方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023031A1 (fr) * 1992-05-08 1993-11-25 The Biomembrane Institute Substances mimetiques polyvalentes et substances mimetiques peptidiques destinees a bloquer l'interaction cellulaire dependant de l'hydrate de carbone et a provoquer la reponse anti-hydrate de carbone des lymphocytes t
WO1994026760A1 (fr) * 1993-05-14 1994-11-24 Cytel Corporation ANALOGUES DE SIALYLE Lex UTILES EN TANT QU'INHIBITEURS DE L'ADHESION CELLULAIRE
EP0687684A1 (fr) * 1993-03-04 1995-12-20 Mect Corporation Compose associe au systeme de lewis, procede d'obtention de ce compose et anti-inflammatoire
WO1996020204A1 (fr) * 1994-12-28 1996-07-04 Sumitomo Pharmaceuticals Company, Limited Derive x de lewis et procede de production correspondant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023031A1 (fr) * 1992-05-08 1993-11-25 The Biomembrane Institute Substances mimetiques polyvalentes et substances mimetiques peptidiques destinees a bloquer l'interaction cellulaire dependant de l'hydrate de carbone et a provoquer la reponse anti-hydrate de carbone des lymphocytes t
EP0687684A1 (fr) * 1993-03-04 1995-12-20 Mect Corporation Compose associe au systeme de lewis, procede d'obtention de ce compose et anti-inflammatoire
WO1994026760A1 (fr) * 1993-05-14 1994-11-24 Cytel Corporation ANALOGUES DE SIALYLE Lex UTILES EN TANT QU'INHIBITEURS DE L'ADHESION CELLULAIRE
WO1996020204A1 (fr) * 1994-12-28 1996-07-04 Sumitomo Pharmaceuticals Company, Limited Derive x de lewis et procede de production correspondant
EP0801071A1 (fr) * 1994-12-28 1997-10-15 Sumitomo Pharmaceuticals Company, Limited Derive x de lewis et procede de production correspondant

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ATHANASSIOS GIANNIS: "DIE SIALYL-LEWIS-X-GRUPPE UND IHRE ANALOGA ALS LIGANDEN FUER SELEKTINE: CHEMOENZYMATISCHE SYNTHESEN UND BIOLOGISCHE FUNKTIONEN", ANGEWANDTE CHEMIE, vol. 106, no. 2, 1 January 1994 (1994-01-01), pages 188 - 191, XP000570918 *
DASGUPTA F ET AL: "ANTI-ADHESIVE THERAPEUTICS: A NEW CLASS OF ANTI-INFLAMMATORY AGENTS", EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 3, no. 7, 1 July 1994 (1994-07-01), pages 709 - 724, XP000579145 *
M.HAYASHI ET AL.: "A Convenient and Efficient Synthesis of SLeX Analogs.", JOURNAL OF ORGANIC CHEMISTRY., vol. 61, no. 3, 3 May 1996 (1996-05-03), EASTON US, pages 2938 - 2945, XP002048563 *
OHMOTO H ET AL: "STUDIES ON SELECTIN BLOCKER. 1. STRUCTURE-ACTIVITY REALTIONSHIPS OF SIALYL LEWIS X ANALOGS", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 6, 1996, pages 1339 - 1343, XP000652017 *

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6911436B2 (en) * 1994-05-12 2005-06-28 Dermal Reserach Laboratories, Inc. Pharmaceutical composition of complex carbohydrates and essential oils and methods of using the same
US9220290B2 (en) 1999-02-01 2015-12-29 Dermal Research Laboratories, Inc. Pharmaceutical composition of complex carbohydrates and essential oils and methods of using the same
US8003782B1 (en) 1999-02-01 2011-08-23 Dermal Research Laboratories, Inc. Pharmaceutical composition of complex carbohydrates and essential oils and methods of using the same
EP1165097A2 (fr) * 1999-02-01 2002-01-02 Dermal Research Laboratories, Inc. Composition pharmaceutique d'hydrates de carbone complexes et d'huiles essentielles et methode d'utilisation de celle-ci
US8367642B2 (en) 2000-07-31 2013-02-05 Dermal Research Laboratories, Inc. Methods of preventing or treating diseases and conditions using complex carbohydrates
US7879824B2 (en) 2001-07-31 2011-02-01 Dermal Research Laboratories, Inc. Methods of preventing or treating diseases and conditions using complex carbohydrates
WO2004004636A2 (fr) * 2002-07-03 2004-01-15 Glycomimetics, Inc. Compositions et methodes permettant le diagnostic et le traitement d'etats pathologiques impliquant l'angiogenese
WO2004004636A3 (fr) * 2002-07-03 2004-02-26 Glycomimetics Inc Compositions et methodes permettant le diagnostic et le traitement d'etats pathologiques impliquant l'angiogenese
WO2004033473A1 (fr) 2002-10-11 2004-04-22 Yamanouchi Europe B.V. Composes a base de glucose presentant une affinite pour la selectine-p
WO2005054264A2 (fr) * 2003-11-19 2005-06-16 Glycomimetics, Inc. Antagonistes glycomimetiques pour les selectines de type e et p
WO2005054264A3 (fr) * 2003-11-19 2007-03-22 Glycomimetics Inc Antagonistes glycomimetiques pour les selectines de type e et p
WO2006127906A1 (fr) * 2005-05-25 2006-11-30 Glycomimetics, Inc. Composes heterobifonctionnels pour l’inhibition de la selectine
USRE44778E1 (en) 2005-09-02 2014-02-25 Glycomimetics, Inc. Heterobifunctional pan-selectin inhibitors
EP2457573A1 (fr) * 2007-02-09 2012-05-30 GlycoMimetics, Inc. Procédés d'utilisation de glycomimétiques avec remplacements pour hexoses et hexosamines n-acétyle
WO2008100453A1 (fr) * 2007-02-09 2008-08-21 Glycomimetics, Inc. Procédés d'utilisation de glycomimétiques avec des remplacements d'hexoses et d'hexosamines d'acétyle n
EP2915539A1 (fr) 2007-12-10 2015-09-09 Mater Medical Research Institute Traitement d'états immunodéprimés par un antagoniste de l'E-Sélectine et le G-CSF
US9534009B2 (en) 2008-04-08 2017-01-03 Glycomimetics, Inc. Pan-selectin inhibitor with enhanced pharmacokinetic activity
US8895510B2 (en) 2008-04-08 2014-11-25 Glycomimetics, Inc. Pan-selectin inhibitor with enhanced pharmacokinetic activity
US8921328B2 (en) 2010-09-14 2014-12-30 Glycomimetics, Inc. E-selectin antagonists
US9109002B2 (en) 2011-12-22 2015-08-18 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US9796745B2 (en) 2011-12-22 2017-10-24 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US11332491B2 (en) 2011-12-22 2022-05-17 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US10526361B2 (en) 2011-12-22 2020-01-07 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US10766916B2 (en) 2011-12-22 2020-09-08 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US11987598B2 (en) 2011-12-22 2024-05-21 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US9867841B2 (en) 2012-12-07 2018-01-16 Glycomimetics, Inc. Compounds, compositions and methods using E-selectin antagonists for mobilization of hematopoietic cells
US10519181B2 (en) 2014-12-03 2019-12-31 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectins and CXCR4 chemokine receptors
US11045485B2 (en) 2016-01-22 2021-06-29 Glycomimetics, Inc. Glycomimetic inhibitors of PA-IL and PA-IIL lectins
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
US11072625B2 (en) 2016-10-07 2021-07-27 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
US11780873B2 (en) 2016-10-07 2023-10-10 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
US11197877B2 (en) 2017-03-15 2021-12-14 Glycomimetics. Inc. Galactopyranosyl-cyclohexyl derivauves as E-selectin antagonists
US11878026B2 (en) 2017-03-15 2024-01-23 Glycomimetics, Inc. Galactopyranosyl-cyclohexyl derivatives as e-selectin antagonists
US11712446B2 (en) 2017-11-30 2023-08-01 Glycomimetics, Inc. Methods of mobilizing marrow infiltrating lymphocytes and uses thereof
US11548908B2 (en) 2017-12-29 2023-01-10 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3
US11707474B2 (en) 2018-03-05 2023-07-25 Glycomimetics, Inc. Methods for treating acute myeloid leukemia and related conditions
US11845771B2 (en) 2018-12-27 2023-12-19 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3

Also Published As

Publication number Publication date
NZ334048A (en) 2000-05-26
CN1227563A (zh) 1999-09-01
ID18010A (id) 1998-02-19
CZ39099A3 (cs) 1999-05-12
NO990497L (no) 1999-03-24
TR199900245T2 (xx) 1999-05-21
AU720381B2 (en) 2000-06-01
CA2260854A1 (fr) 1998-02-19
PE99298A1 (es) 1999-01-21
EP0920437A1 (fr) 1999-06-09
AU4378897A (en) 1998-03-06
PL331286A1 (en) 1999-07-05
CO4900075A1 (es) 2000-03-27
BR9711117A (pt) 1999-09-08
AR008283A1 (es) 1999-12-29
KR20000029862A (ko) 2000-05-25
SK15699A3 (en) 1999-07-12
IL127908A0 (en) 1999-11-30
JP2000516224A (ja) 2000-12-05
NO990497D0 (no) 1999-02-03

Similar Documents

Publication Publication Date Title
WO1998006730A1 (fr) Oligosaccharides modifies
CA1105011A (fr) Traduction non-disponible
CN106536537B (zh) 半乳凝素的新型杂合半乳糖苷抑制剂
JPS61148193A (ja) 腫瘍治療剤
JP2004509902A5 (fr)
AU707474B2 (en) Diglycosylated 1,2-diols as mimetics of sialyl-lewis X and sialyl-lewis A
OA10190A (en) Sialyl lex analogues as inhibitors of cellular adhesion
JPH0899989A (ja) 新規糖脂質誘導体およびその製造用中間体
EP0801071A1 (fr) Derive x de lewis et procede de production correspondant
JPS61246195A (ja) リピドａ型の新規な二糖及び三糖誘導体
FR2751334A1 (fr) Polysaccharides synthetiques, procede pour leur preparation et compositions pharmaceutiques les contenant
FI113540B (fi) Menetelmä terapeuttisesti käyttökelpoisten biskonjugaattien valmistamiseksi, jotka sisältävät kaksi sakkaridia ja spacer-osan
Sanders et al. Synthesis of sulfated trisaccharide ligands for the selectins
HU196818B (en) Process for producing syalinic acid derivatives
Hashihayata et al. Convergent total syntheses of oligosaccharides by one-pot sequential stereoselective glycosylations
Sivets Regio-and stereoselective syntheses of L-pentose derivatives from L-arabinose
JP4555466B2 (ja) 置換されたテトラヒドロピラン誘導体、それらの製造方法、医薬または診断剤としてのそれらの使用およびそれらを含有する医薬
EP0643718A1 (fr) COMPOSES LEWIS?C ET LacNAc MODIFIES A EFFET IMMUNOSUPPRESSEUR ET INDUCTEUR DE TOLERANCE
US4891425A (en) N-glycosylamide derivatives, processes for their preparation and their use as medicaments
MXPA99001287A (en) Modified oligosaccharides
JPS6330495A (ja) リピドａ単糖類縁体の立体異性体
JP2625620B2 (ja) フコシル‐グルコサミン誘導体
JPH09301988A (ja) グルコサミン誘導体
CA2431589A1 (fr) Lipides d'ether de glycolyse c
JPH06104677B2 (ja) 新規シクロホスファミド化合物およびその合成法

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 97197077.7

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1997941916

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1199900007

Country of ref document: VN

ENP Entry into the national phase

Ref document number: 2260854

Country of ref document: CA

Ref document number: 2260854

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/1999/001287

Country of ref document: MX

Ref document number: PV1999-390

Country of ref document: CZ

Ref document number: 334048

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 1998 509358

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 15699

Country of ref document: SK

Ref document number: 1999/00245

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 1019997001025

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 09230797

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: PV1999-390

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1997941916

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1019997001025

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV1999-390

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1019997001025

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1997941916

Country of ref document: EP