EP0836610A1 - 1,2-diols diglycosyles utilises comme agents mimetiques de sialyl-lewis x et de sialyl-lewis a - Google Patents

1,2-diols diglycosyles utilises comme agents mimetiques de sialyl-lewis x et de sialyl-lewis a

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Publication number
EP0836610A1
EP0836610A1 EP96922034A EP96922034A EP0836610A1 EP 0836610 A1 EP0836610 A1 EP 0836610A1 EP 96922034 A EP96922034 A EP 96922034A EP 96922034 A EP96922034 A EP 96922034A EP 0836610 A1 EP0836610 A1 EP 0836610A1
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European Patent Office
Prior art keywords
aryl
alkyl
cycloalkyl
substituted
group
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EP96922034A
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German (de)
English (en)
Inventor
Hartmuth Christian Kolb
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Novartis Pharma GmbH
Novartis AG
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Novartis Erfindungen Verwaltungs GmbH
Ciba Geigy AG
Novartis AG
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Publication of EP0836610A1 publication Critical patent/EP0836610A1/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
    • C07H15/20—Carbocyclic rings
    • C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

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

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Abstract

Cette invention concerne des composés représentés par la formule (I), dans laquelle X est le résidu d'un 1,2-diol aliphatique non glycosidique, R1 est un méthyle à structure en S substitué par un résidu de carboxyle et par un autre substituant, et R2 est hydrogène, C1-C12 alkyle ou C6 aryle. Ces composés sont utilisés comme agents mimétiques de sialyl-Lewis X et de sialyl-Lewis A.
EP96922034A 1995-06-29 1996-06-26 1,2-diols diglycosyles utilises comme agents mimetiques de sialyl-lewis x et de sialyl-lewis a Ceased EP0836610A1 (fr)

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PCT/EP1996/002785 WO1997001569A1 (fr) 1995-06-29 1996-06-26 1,2-diols diglycosyles utilises comme agents mimetiques de sialyl-lewis x et de sialyl-lewis a

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WO2002036587A2 (fr) 2000-11-01 2002-05-10 Cor Therapeutics, Inc. Composes heterocycliques azotes et procede de fabrication de ces composes et de leurs intermediaires
EP1577289A1 (fr) 2004-03-18 2005-09-21 Revotar Biopharmaceuticals AG Inhibiteurs de selectine a petites molecules non glycosylees/glycosidiques/peptidiques pour le traitement de troubles inflammatoires
LT2264043T (lt) 2005-09-02 2017-12-11 Glycomimetics, Inc. Heterobifunkciniai pan-selektino inhibitoriai
EP1764095A1 (fr) 2005-09-20 2007-03-21 Revotar Biopharmaceuticals AG Nouveaux derivés de nitrocatéchol ayant activité de ligande de selectine
EP1764096A1 (fr) 2005-09-20 2007-03-21 Revotar Biopharmaceuticals AG Nouveaux derivés de phloroglucinol ayant activité de ligande de selectine
EP1764093A1 (fr) 2005-09-20 2007-03-21 Revotar Biopharmaceuticals AG Nouveaux composés aromatiques et leur application médical
JP5298020B2 (ja) * 2006-10-12 2013-09-25 グリコミメティクス， インコーポレイテッド ヘキソースおよびｎ−アセチルヘキソサミンの糖模倣体置換
NZ598863A (en) * 2007-02-09 2013-11-29 Glycomimetics Inc Methods of use of glycomimetics with replacements for hexoses and n-acetyl hexosamines
WO2009126556A1 (fr) 2008-04-08 2009-10-15 Glycomimetics, Inc. Inhibiteur de pan-sélectine avec activité pharmacocinétique améliorée
US8921328B2 (en) 2010-09-14 2014-12-30 Glycomimetics, Inc. E-selectin antagonists
AU2012358150B2 (en) 2011-12-22 2017-07-20 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
CN104837492B (zh) 2012-12-07 2018-04-27 糖模拟物有限公司 使用e-选择素拮抗剂动员造血细胞的化合物、组合物和方法
EP3227310B1 (fr) 2014-12-03 2019-07-31 GlycoMimetics, Inc. Inhibiteurs hétérobifonctionnels des e-sélectines et des récepteurs aux chimiokines cxcr4
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
JP2019524791A (ja) 2016-08-08 2019-09-05 グリコミメティクス， インコーポレイテッド Ｅ−セレクチンの阻害剤もしくはｃｘｃｒ４の阻害剤との、またはｅ−セレクチンおよびｃｘｃｒ４両方のヘテロ二機能性阻害剤とのｔ細胞チェックポイント阻害剤の組み合わせ
US11072625B2 (en) 2016-10-07 2021-07-27 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
EP3596096A1 (fr) 2017-03-15 2020-01-22 GlycoMimetics, Inc. Dérivés de galactopyranosyle-cyclohexyle utilisés en tant qu'antagonistes d'e-sélectine
EP3717013A1 (fr) 2017-11-30 2020-10-07 GlycoMimetics, Inc. Méthodes de mobilisation de lymphocytes infiltrant la moelle et leurs utilisations
EP3732186A1 (fr) 2017-12-29 2020-11-04 GlycoMimetics, Inc. Inhibiteurs hétérobifonctionnels de e-sélectine et de galectine -3
EP3761994A1 (fr) 2018-03-05 2021-01-13 GlycoMimetics, Inc. Méthodes de traitement de la leucémie aiguë myéloïde et d'états pathologiques associés
WO2020139962A1 (fr) 2018-12-27 2020-07-02 Glycomimetics, Inc. Inhibiteurs hétérobifonctionnels d'e-sélectine et de galectine-3

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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
CA2100412A1 (fr) * 1992-07-15 1994-01-16 Yutaka Yamada Derives de glycolipides

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TR199701728T1 (xx) 1998-03-21
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IL118740A0 (en) 1996-10-16
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