CA2224346A1

CA2224346A1 - Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a

Info

Publication number: CA2224346A1
Application number: CA002224346A
Authority: CA
Inventors: Hartmuth Christian Kolb
Original assignee: Individual
Current assignee: Novartis AG
Priority date: 1995-06-29
Filing date: 1996-06-26
Publication date: 1997-01-16
Also published as: AU707474B2; SK177897A3; TR199701728T1; NZ311686A; EA199800103A1; HUP9801805A3; HUP9801805A2; NO976065D0; PL324258A1; CZ419797A3; SI9620099A; WO1997001569A1; MX9800218A; NO976065L; BR9609285A; IL118740A0; AU6305396A; KR19990028543A; CN1196731A; EA001356B1

Abstract

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

Description

W O 97/01569 PCTrEP96/02785 Diglycosylated 1.2-diols as mimetics of sialyl-Lewis X and sialyl-Lewis A.
.

The present invention relates to mimetics of sialyl-Lewis X and sialyl-Lewis A, in which, in the natural tetrasaccharide, the neuraminic acid residue is replaced by an S-configurated methyl substituted with one carboxyl residue and one other substituent and the N-acetyl-glucosamine residue is replaced by a non-glycosidic residue of a 1,2-diol, to processes for the preparation of these compounds and to the use of these mimetics in therapeutic methods.

The complex process of inflammation, which takes place in several stages, is the body's natural reaction to injuries in which, for example, there is also invasion by infectious agents.
Under the influence of cytokines, the endothelium which lines the blood vessels expresses adhesion proteins on its surface. The P and E selectins bring about, by a protein-carbo-hydrate interaction with glycolipids and glycoproteins on the leukocyte membrane, the so-called "rolling" of leukocytes. The latter are slowed down by this process, and there is acti-vation of certain proteins (integrins) on their surface which ensure firm adhesion of the leukocytes to the endothelium. This is followed by migration of the leukocytes into the damaged tissue.

When this process takes place in a controlled manner, the damage is eliminated after a certain time without major adverse effects remaining. It is otherwise in the case of certain acute and chronic inflammatory processes, in which the migration of leukocytes takes place in an uncontrolled manner, which leads to severe damage to the body. This is the case in disorders such as cardiogenic shock, myocardial infarct, thrombosis, rheumatism, psoriasis, dermatitis, acute respiratory distress syndrome and metastatic cancer [Dasgupta, F., Rao, B.N.N., Exp. Opin. Invest. Drugs 3:709-724 (1994)].

Several approaches to the development of medicaments which intervene at various points in these unwanted processes have already been pursued [Dasgupta, F., Rao, B.N.N., Exp.
Opin. Invest. Drugs 3:709-724 (1994)]. The aim of one route is to prevent the interaction between P and E selectins and their receptors on the leukocyte merrlbrane, thus to prevent the "rolling", by mimetics of the corresponding epitopes. This also results in suppression of W O 97/01~,69 PCT~EP96/02785 the subsequent processes. One of the smallest carbohydrate epitopes as ligand for E
select,n is sialyl-Lewis X [neuraminic acid-a(2~3)-galactose-~,(1 ~4)-(fucose-a(1 ~3))-N-acetylglucosamine (sLeX)].

EP-A-0 579 196 proposed as compounds competing with the natural ligands for binding to E selectin mimetics of sLeX in which the neuraminic acid residue is replaced by a lactic acid residue. WO 93/10796 describes compounds which comprise in place of the neuraminic acid residue the residue of an a-hydroxy acid. WO 93/23031 discloses mimetics in which the N-acetylglucosamine residue (GlcNAc residue) is replaced by an R,R-1,2-cyclohexane-dioxy. However, it is common to all these compounds that the binding affinity between them and the E selectin is increased only inconsiderably compared with that of sLeX, or is in fact worse, and is insufficient for a therapeutic effect.

It has now been found, surprisingly, that simultaneous replacement of the neuraminic acid residue by an S-configurated methyl substituted with one carboxyl residue and one other substituent and of the N-acetylglucosamine residue by a non-glycosidic residue of an ali-phatic diol results in an unexpectedly high binding affinity of the resulting mimetic. The novel compounds additionally represent a structural and chemical simplification, have a lower molecular weight and can be obtained in larger quantities by methods with low syn-thetic complexity.

The present invention relates to compounds of the formula I

R''o ~~ ~~X

HO OH O (I) R2~0H
¦ OH
OH

in which X is the residue of a non-glycosidic aliphatic 1,2-diol;

W O 97/OlS69 PCT/~I,~ 5 R, is an S-configurated methyl substituted with one carboxyl residue and one other substitu-ent; and R2 is hydrogen, C1-C12alkyl or C6aryl; where the alkyl and the aryl are unsubstituted or sub-~ stituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs" OC(O)Rs4~ C(O)Rs2~ nitro, NH2, cyano, S03My, OS03My, I\lR20SO3My~ C1-C12alkyl, C2-C,2alkenyl, C,-C,2alkoxy, C3-C,2cycloalkyl, C3-C,2cycloalkenyl, C2-C1,heterocycloalkyl, C2-C1,heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-Cgheteroaryl, Cs-c9heteroaryloxy~
C7-C"aralkyl, C,-C"aralkyloxy, C6-C,Oheteroaralkyl, C8-C"aralkenyl, C,-C,Oheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydr-azide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydro-gen, My~ C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C7-C"aralkyl or C6-C,Oheteroaralkyl, Rs4 is hydrogen, C,-C,2alkyl, C2-C~2alkenyl, C3-C~2cycloalkyl, C2-C"heterocycloalkyl, C6-C,Oaryl, C5-Cgheteroaryl, C,-C"aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C,2alkenyl, C3-C,2cycloalkyl, C3-C,2cycloalkenyl, C2-C"heterocycloalkyl, C2-C"-hetero-cycloalkenyl, C6-C,Oaryl, C5-C9heteroaryl, C,-C"aralkyl, C6-C,Oheteroaralkyl, C8-C"-aralkenyl or C,-C,Oheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo-alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero-aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal; including their physiologically tolerated salts.

Preferred aliphatic residues X are linear or branched C2-C20-, preferably C2-C,2- and particu-larly preferably C2-C6alkylene and -alkenylene, C3-C,2-, preferably C3-C8- and particularly preferably C5-C,cycloalkylene and cycloalkenylene, and C3-C"-, preferably C3-C,- and par-ticularly preferably C3-C5heterocycloalkylene and heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-.

The residue X can contain substituents such as OH, halogen, C(O)ORs1~ OC(O)Rs4 C(O)Rs2, nitro, NH2, cyano, SO3My~ OSO3My~ NR20SO3My~ C,-C,2alkyl, C2-C,2alkenyl, C~-C~2alkoxy, C3-C12cycloalkyl, C3-C,2cycloalkenyl, C2-C11heterocycloalkyl, C2-C"hetero-cycloalkenyl, C6-C,Oaryl, C6-C,Oaryloxy, C5-Cgheteroaryl, C5-C9heteroaryloxy, C,-C1,aralkyl, C,-C"aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C,-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and amidocarbonylamide, where Rs1 is hydrogen, My~
Cl-C12alkyl, C2-C~2alkenyl, C3-cl2cycloalkyl~ C2-cllheterocycloalkyl~ C6-ClOaryl~ C5-Cghetero-aryl, C,-Cllaralkyl or C6-ClOheteroaralkyl, Rs4 is hydrogen, Cl-Cl2alkyl, C2-Cl2alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cyclo-alkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C~0aryl, C5-C9heteroaryl, C,-C1,aralkyl, C6-C,Oheteroaralkyl, C8-C11-aralkenyl or C,-C1Oheteroar-alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo-alkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyi, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

In a preferred embodiment of the present invention, X is the residue of a 1 ,2-diol corresponding to formula 11 p~ R~ (Il) H H

in which R5 and R6 are, independently of one another, hydrogen, C,-C,2alkyl, C3-C,2cycloalkyl, C2-C"heterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C7-C"aralkyl or C6-C10heteroaralkyl; or R5 and R6 are, together with the -CH-CH- group, C3-C,2cycloalkylene, C3-C,2-cycloalken-ylene, C2-C"heterocycloalkylene and C3-C,1heterocycloalkenylene with hetero atoms selected from the group -O-, -S- and -N-;
where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclo-alkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halo-gen, C(O)ORs1, OC(O)Rs4~ C(O)Rs2~ nitro, NH2, cyano, SO3My~ OSO3My~ NR20SO3My~
Cl-Cl2alkyl, C2-Cl2alkenyl, Cl-C,2alkoxy, C3-C~2cycloalkyl, C3-Cl2cycloalkenyl, C2-Cllhetero-cycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-Cgheteroaryl, W O 97/01569 PCT~EP96/02785 C5-CgheterOarylOXy, C7-c1laralkyl~c7-c11aralkyloxy~c6-c1oheteroaralkyl1c8-c11aralkenyl~c7-Cl0heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonyl-amide, where Rsl is hydrogen, My~ Cl-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11hetero-cycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C,2alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-ClOaryl, C5-Cghetero-aryl, C,-C11aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, Cl-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-hetero-cycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C,-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo-alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero-aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

The other substituent in R1 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 C1-C12alkyl, C2-Cl2alkenyl, C3-Clzcycloalkyl, C3-C12cycloalkenyl, C2-Cllheterocycloalkyl, C2-Cllhetero-cycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C,-C11aralkyl, C6-C10heteroaralkyl, C8-C11aralkenyl and C7-C10heteroaralkenyl. The other substituent is particularly preferably substituted methyl, or 2-substituted ethyl or cyclohexyl. Examples of suitable substituents are the sub-stituents mentioned above in the definition of R2, especially OH, halogen (F, Cl or Br), carb-oxyl, -SO3H, C(O)OMy~ SO3My~ OSO3My~ NR20SO3My in which R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-hetero-cycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C,-C11aralkyl, C6-C,Oheteroaralkyl, C8-C,1-aralkenyl or C7-C10heteroaralkenyl, or C1-C,2alkyl, C,-C,2alkoxy, nitro, -NH2, primary amino with 1 to 20 C atoms, secondary amino with 2 to 30 C atoms, cyano, C3-C8cycloalkyl, C3-C6hetero-cycloalkyl, C6-C,0aryl, C3-C9heteroaryl, C7-C16heteroaralkyl, where the hetero atoms are selected from the group of O, S and N atoms, and carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide or aminocarbonylamide, whose N atoms are unsubstituted or s~hstihlted by a hydrocarbon group or hydroxy-hydrocarbon group with 1 to 20 C atoms.
The hydrocarbon groups and heterohydrocarbon groups in turn are unsubstituted or substi-W O 97/OlS69 PCTi~,~'02/xS

tuted, for example with C1-C6alkyl, C1-C6alkoxy, carboxyl, halogen (F, Cl or Br), -OH, -CN or -NO2.

In a particular embodiment of the compounds of the formula 1, Rl corresponds to a group of the formula lll, HR~;L (111), ' in which R3 is hydrogen or My; and R4 is C1-cl2alkyl~ C2-C,2alkenyl, C3-Cl2cycloalkyl~ C3-C,2cycloalkenyl~ C2-cllheterocycloalk C2-Cllheterocycloalkenyl, C6-ClOaryl, C5-Cgheteroaryl, C7-C,laralkyl, C6-C,Oheteroaralkyl, C8-C1,aralkenyl or C,-C,Oheteroaralkenyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1~ OC(O)Rs4 C(O)Rs2, nitro, NH2, cyano, SO3My~ OSO3My~ NR20SO3My~ C,-C,2alkyl, C2-C,2alkenyl, C,-C,2alkoxy, C3-C,2cycloalkyl, C3-C,2cycloalkenyl, C2-C,1heterocycloalkyl, C2-C1,heterocycloalkenyl, C6-C,0aryl, C6-C,0aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C1,aralkyl, C7-C"aralkyloxy, C6-C,Oheteroaralkyl, C8-C"aralkenyl, C7-C,Oheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfon-hydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs, is hydrogen, My~ C,-C,2alkyl, C2-C,2alkenyl, C3-C,2cycloalkyl, C2-C"heterocycloalkyl, C6-C~0aryl, C5-C9heteroaryl, C7-C"aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C,2alkenyl, C3-C,2cycloalkyl, C2-C"heterocycloalkyl, C6-C,0aryl, C5-C9hetero-aryl, C7-C"aralkyl or C6-C,Oheteroaralkyl, and Rs2 and R20 are hydrogen, C,-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C,2cycloalkenyl, C2-C"heterocycloalkyl, C2-C"-hetero-cycloalkenyl, C6-Cl0aryl, C5-C9heteroaryl, C7-C,1aralkyl, C6-C~Oheteroaralkyl, C8-C"-aralkenyl or C7-C,Oheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo-alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero-aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

CA 02224346 l997-l2-lO

W O 97/01569 PCT~EP96/02785 For the purposes of the present invention, a metal is to be understood as meaning an alkali metal [for example lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and caesium (Cs)], an alkaline earth metal [for example magnesium (Mg), calcium (Ca) and strontium - (Sr)] or manganese (Mn), iron (Fe), zinc (Zn) or silver (Ag). Physiologically tolerated salts are to be understood as meaning, in particular, the alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium and calcium salts. Sodium and potassium ions and their salts are preferred.

Halogen is to be understood as meaning a representative of the group consisting of fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred, especially fluorine and chlorine.

Alkyl can be linear or branched, preferably branched once or twice in the a position. Some examples of alkyl, which preferably contains 1 to 12 C atoms, are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
Preferred alkyl groups are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.

Examples of alkenyl are allyl, but-1-en-3-yl or -4-yl, pent-3- or 4-en-1-yl or -2-yl, hex-3- or -4-or-5-en-1-yl or-2-yl and (C1-C4alkyl)CH=CH-CH2-.

Cycloalkyl and cycloalkenyl can contain preferably 5 to 8 and particularly preferably 5 or 6 ring carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclo-hexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Cyclo-hexyl is a particularly preferred cycloalkyl group. Examples of cycloalkenyl are cyclopropen-yl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, cycloundecenyl and cyclododecenyl. Cyclohexenyl is a particularly preferred cycloalkenyl group.

Examples of alkylene are ethylene, 1,2-propylene, 1,2- or 2,3-butylene, 1,2- or 2,3-pentylene, 1,2-, 2,3- or 3,4-hexylene. Examples of cycloalkylene are 1,2-cyclopropylene, 1,2-cyclobutylene, 1,2-cyclopentylene, 1,2-cyclohexylene, 1,2-cycloheptylene and 1,2-cyclo-octylene. Examples of heterocycloalkylene are p~,,,ulidinylene, piperidinylene, tetrahydro-furanylene, di- and tetrahydropyranylene.

W O 97/01569 PcT/~l~5~ 5 Examples of heterocycloalkyl are derived from pyrrolidine, imidazolidine, oxazolidine, pyrazolidine, piperidine, piperazine and morpholine. Examples of heterocycloalkenyl are derived from 2- and 3-pyrroline, oxazoline, 2- and 4-imidazoline and 2- and 3-pyrazoline.

For the purposes of the present invention, aryl or heteroaryl is a five- or six-membered ring or a bicycle consisting of two condensed six- or five-membered rings or one six-membered and one five-membered ring, and in the case of heteroaryl one or more C atoms may be replaced, independently of one another, by an atom selected from the group consisting of oxygen, nitrogen and sulfur. Examples are derived from benzene, naphthalene, indene, furan, pyrrole, pyrazole, imidazole, isox~701e, oxazole, furazan, thiadiazole, thiophene, thiazole, ox~o~ ole, triazole, indole, indazole, purine, benzimidazole, benzoxazole, benzo-thiazole, pyran, pyridine, pyridazine, triazine, pyrimidine, pyrazine, isoquinoline, cinnoline, phthalazine, quinoline, quinazoline, pterdine, benzotriazine or quinoxaline. Aryl is preferably naphthyl and phenyl. Phenyl is particularly preferred. Heteroaryl is preferably furanyl, pyridinyl and pyrimidinyl.

Aralkyl preferably has 7 to 12 C atoms and can be phenyl-CnH2n- with n equal to a number from 1 to 6. Examples are benzyl, phenylethyl or phenylpropyl. Benzyl and 2-phenylethyl are preferred. Aralkenyl is preferably unsubstituted phenyl-CH=CH-CH2- (cinnamyl) and cinnamyl is substituted on the phenyl by a substituent selected from the group consisting of OH, halogen, COOH, C(O)OMy~ Cl-C,2alkyl, Cl-C6alkoxy, C6-C10aryl, SO3My~ OSO3M
NR20SO3My in which R20 is hydrogen, C,-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C,-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroar-alkenyl, and NO2, C1 C12primary amino, C2-C20secondary amino, amino and CN.

Heteroaralkyl and heteroaralkenyl are preferably C4-C5heteroarylmethyl and C4-C5hetero-arylethenyl with one or two hetero atoms from the group of O and N, and the heteroaryl can comprise the abovementioned heteroaryl residues.

Alkoxy can be linear or branched, preferably branched once or twice in the a 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.

W O 97/OlS69 PcTl~l55l~2/~s Examples of aryloxy and aralkoxy are phenoxy and benzyloxy. Heteroaryloxy is preferably furanyloxy, pyridinyloxy and pyrimidinyloxy.

The primary amino preferably contains 1 to 12, particularly preferably 1 to 6, C atoms.
Some examples are methyl-, ethyl-, hydroxyethyl-, n- or i-propyl-, n-, i- or t-butyl-, pentyl-, hexyl-, cyclopentyl-, cyclohexyl-, phenyl-, methylphenyl-, benzyl- and methylbenzylamino.
The secondary amino preferably contains 2 to 14, particularly preferably 2 to 8, C atoms.
Some examples are dimethyl-, diethyl-, methylethyl-, di-n-propyl-, di-i-propyl-, di-n-butyl-, diphenyl-, dibenzylamino, morpholino, piperidino and pyrrolidino.

NH2, primary amino, secondary amino, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide and aminocarbonylamide preferably correspond to a group R8C(O)(NH)pN(Rg)-, -C(O)(NH)pNR8Rg, R80C(O)(NH)pN(Rg)-, R~R40NC(O)(NH)pN(Rg)-, -OC(O)(NH)pNR8Rg~-N(R4o)c(o)(NH)pNR8R9~ R8s(o)2(NH)pN(R9)-;-s(o)2(NH)pNR8R9;
R8R40NS(0)2N(Rg)- or -NR40S(0)2NR8Rg, in which R8, Rg and R40 are, independently of one another, hydrogen, OH, C,-C12alkyl, C,-C,2alkenyl, C3-C,2cycloalkyl, C3-C,2cycloalkenyl, C2-C,1heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C7-C16aralkyl, C8-C,6aralkenyl with C2-C6alkenylene and C6-C,Oaryl, C6-Cl5heteroaralkyl, C6-C,5heteroar-alkenyl, or di-C6-C,Oaryl-C,-C6-alkyl, or R8 Rg N in which R8 and Rg are, independently of one another, hydrogen, OH, SO3My~ OSO3My~ C,-C,2alkyl, C3-C,2cycloalkyl, C2-C"hetero-cycloalkyl, C6-C,Oaryl, C5-Cgheteroaryl, C7-C"aralkyl, C6-C,Oheteroaralkyl, C8-C,6aralkenyl with C2-C6alkenylene and C6-C,Oaryl, or di-C6-C,Oaryl-C,-C6-alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisli"g of OH, halogen, C(O)ORs" OC(O)Rs4~ C(O)Rs2~ nitro, NH2, cyano, SO3My~ OSO3My~ NR20SO3My~ C,-C,2alkyl, C2-C,2alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterOCyCIOalkenyl~c6-c1oaryl~c6-c1oaryloxy~C5-Cgheteroaryl~C5-Cgheteroaryloxy~c7-C"aralkyl, C7-C"aralkyloxy, C6-C~Oheteroaralkyl, C8-C"aralkenyl, C7-C,Oheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxar"ic acid and aminocarbonylamide, where R
is hydrogen, My~ C,-Cj2alkyl, C2-C12alkenyl, C3-C,2cycloalkyl, C2-C1,heterocycloalkyl, C6-C,Oaryl, C5-Cgheteroaryl, C7-C"aralkyl or C6-C,Oheteroaralkyl, Rs4 is hydrogen, C~-C,2alkyl, C2-C12alkenyl, C3-C,2cycloalkyl, C2-C"heterocycloalkyl, C6-C10aryl, C5-Cghetero-aryl, C7-C"aralkyl or C6-C,Oheteroaralkyl and Rs2 is hydrogen, C,-C,2alkyl, C2-C,2alkenyl, C3-C~2cycloalkyl, C3-C12cycloalkenyl, C2-C"heterocycloalkyl, C2-C"-heterocycloalkenyl, W O 97/OlS69 PCT~EP96/02785 C6-C10aryl, C5-Cgheteroaryl, C7-C,1aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C,-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl, in turn are unsubstituted or substituted by one of the above-mentioned substituents; p is O or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M
is a divalent metal; or R8 and Rg or R8 and Rg or R8 and R40 in the case of -NR8Rg or -NR8 Rg or R8R40N- together are tetramethylene, pentamethylene, -(cH2)2-o-(cH2)2-~-(cH2)2 S-(CH2)2- or -(CH2)2-NR7-(CH2)2-, and R7is H, C,-C6alkyl, C7-C1,aralkyl, C(O)Rs2 or sulfonyl.

The sulfonyl substituent corresponds, for example, to the formula Rlo-SO2- in which R10 is C,-C12alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C7-C11ar-alkyl or C6-C,Oheteroaralkyl, which are unsubstituted or substituted by one or more substitu-ents selected from the group consisting of OH, halogen, C(O)ORs1~ OC(O)Rs4~ C(O)Rs2~
nitro, NH2, cyano, SO3My~ OSO3My~ NR20SO3My~ C1-c12alkyl~ C2-c12alkenyl~ C,-C,2alkoxy, C3-C,2cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C,1heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, Cs-Cgheteroaryl, C5-Cgheteroaryloxy, C7-C"aralkyl, C6-C,Ohetero-aralkyl, C8-C"aralkenyl, C,-C,Oheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My~ C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C~Oaryl, C5-Cgheteroaryl, C,-C"aralkyl or C6-C,Oheteroaralkyl, Rs4 is hydrogen, C,-C,2alkyl, C2-C~2alkenyl, C3-C~2cycloalkyl, C2-C~1heterocycloalkyl, C6-C,Oaryl, C5-Cgheteroaryl, C,-C"aralkyl or C6-C,Oheteroaralkyl, and Rs2 and R20 are hydrogen, C,-C,2alkyl, C2-C,2alkenyl, C3-C12cycloalkyl, C3-C,2cycloalkenyl, C2-C"heterocycloalkyl, C2-C,1-heterocycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C,-C11aralkyl, C6-C,Oheteroaralkyl, C8-C"-aralkenyl or C,-C,Oheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are substituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Preferred compounds of the formula I are those compounds in which X corresponds to a group of the formula ll in which R5 and R6 (a) are unsubstituted or substituted by C1-C,2alkyl, for example methyl, ethyl, or C,-C,2alk-oxy, for example methoxy, ethoxy;

W O 97/~lS69 PcT/~~ 5 (b) are, together with the group -CH-CH-, a 5- to 8-membered carbocycle, and particularly preferably, a 5- or 6-membered carbocycle, and are very particularly preferably R,R-1 ,2-cyclohexylene;
(c) are, together with the group -CH-CH-, a 5- to 8-membered heterocarbocycle, and parti-cularly preferably a 5- or 6-membered heterocarbocycle with nitrogen as hetero atom, and are very particularly preferably R,R-3,4-piperidylene;
(d) are, independently of one another, hydrogen, unsubstituted C1-C,2alkyl or C1-C,2alkyl which is substituted by a substituent selected from the group consisli~ Ig of -C(O)ORs1~
-OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C3-Cl2cycloalkyl, C,-C6alkoxy, phenyloxy and benzyloxy; unsubstituted C3-C~2cycloalkyl or C3-C12cycloalkyl which is substituted by a substituent selected from the group cons;~Li~ Ig of -C(O)ORsl~
-OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C,-C6alkyl, C~-C6alk-oxy, phenyloxy and benzyloxy; C6-C,0aryl which is unsubstituted or substituted by -C(O)ORsl, -OC(O)Rs4~ -C(O)ONa or -C(O)OK, primary amino, secondary amino, Cl-C6alkyl or C1-C6alkoxy; C3-Cgheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; or C,-C12aralkyl which is unsl Ihstitl-ted or substituted by -C(O)ORs" -OC(O)Rs4~ -C(O)ONa or -C(O)OK, primary amino, secondary amino, C1-C6alkyl or C1-C6alkoxy;
(e) are, together with the group -CH-CH-, a 5- to 12-membered carbocycle or 5- or 6-mem-bered heterocarbocycle with a hetero atom selected from the group consisli-,g of oxygen and nitrogen atoms; or (f) are, together with the -CH-CH- group, C3-C12cycloalkylene, C4-C12cycloalkenylene, C2-C"heterocycloalkylene and C3-C,1heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-;
where cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsl Ihstit~ ~ted or substituted by one or more s' lhstitl ~ents selected from the group consis~ing of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2~ nitro, NH2, cyano, SO3My~ OSO3My~
NR2oSO3My, C,-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C"heterocycloalkyl, C2-C,1heterocycloalkenyl, C6-C10aryl, C6-C,Oaryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, C7-C"aralkyl, C7-C"aralkyloxy, C6-C10heteroaralkyl, C8-C"aralkenyl, C,-C,Oheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and amino-carbonylamide, where Rs1 is hydrogen, My~ C1-C12alkyl, C2-C12alkenyl, C3-C,2cycloalkyl, C2-C~heterocycloalkyl, C6-C,Oaryl, C5-Cgheteroaryl, C,-C"aralkyl or C6-C,0heteroaralkyl, Rs4 CA 02224346 l997-l2-lO
W O 97/OlS69 PCT~EP96/02785 is hydrogen, Cl-C12alkyl, C2-Cl2alkenyl, C3-C,2cycloalkyl, C2-C"heterocycloalkyl, C6-Cl0aryl, C5-Cgheteroaryl, C7-C~laralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C,-C12alkyl, C2-C,2alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C~Oaryl, Cs-csheteroaryl~ C7-c11aralkyl~ C6-C~Oheteroaralkyl, C8-C,1-aralkenyl or C,-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Particularly preferred compounds are those in which X corresponds to a group of the formula 11 in which R5 and R6 are, together with the -CH-CH- group, C3-C~2cycloalkylene or C2-C"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 Rs and R6 are, together with the -CH-CH- group, C3-C,2cycloalkylene or C2-C"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(O)ORsl~ OC(O)Rs4~ C(O)Rsz~
NRgRg~ Cl-Cl2alkyl, RgC(O)(NH)pN(Rg)-, -C(O)(NH)pNR8Rg, R8s(o)2(NH)pN(Rg)-;
R8R40NC(O)(NH)pN(Rg)-~ R80C(O)(NH)pN(Rg)-~ -OC(O)(NH)pNR8Rg, and R10-S02-, in which R8, Rg, R1o and R40 are, independently of one another, hydrogen, OH, C,-C,2alkyl, C,-C,2alkenyl, C3-Cl2cycloalkyl, C3-C12cycloalkenyl, C2-C1,heterocycloalkyl, C2-C11hetero-cycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C7-C16aralkyl, C8-C16aralkenyl with C2-C6alken-ylene and C6-C10aryl, C6-C1sheteroaralkyl~ C6-C15heteroaralkenyl, or di-C6-C10aryl-C1-C6-alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4~ C(O)Rs2~ nitro, NH2, cyano, SO3My~
OSO3My~ NR20SO3My~ C1-c12alkyl~ C2-c12alkenyl~ C,-C12alkoxy~ C3-C12cyCloalkyl~ C3-C12cyclo-alkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, C,-C11aralkyl, C7-C1,aralkyloxy, C6-C10heteroaralkyl, C8-Cllaralkenyl, C7-C,Oheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfon-amide, ca.~a", '~, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide; Rs1 is hydrogen, My~ C,-C,2alkyl, C2-C~2alkenyl, C3-C,2cycloalkyl, C2-CA 02224346 l997-l2-lO

W 0 97/01569 PCT/~l-5.~270s C"heterocycloalkyl, C6-C,0aryl, Cs-Cgheteroaryl~ C7-Cl1aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C,-C,zalkyl, Cz-C~zalkenyl, C3-Clzcycloalkyl, C2-C,1heterocycloalkyl, C6-C~Oaryl, C5-Cgheteroaryl, C7-C~,aralkyl or C6-C,Oheteroaralkyl, Rs2 is hydrogen, C,-C,2alkyl, Cz-C,zalkenyl, C3-C,zcycloalkyl, C3-C,zcycloalkenyl, Cz-C"heterocycloalkyl, C2-C~hetero-cycloalkenyl, C6-C~0aryl, C5-Cgheteroaryl, C7-C1,aralkyl, C6-C,0heteroaralkyl, C8-C"-aralkenyl or C,-C,Oheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo-alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, ar-alkenyl and heteroaralkenyl as substituents in turn are unsubstituted or substituted by one of the abovementioned substituents; p is 0 or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

R8 and Rg are, in particular, independently of one another hydrogen; C,-C,zalkyl;
C3-C~2cycloalkyl, C6-C~0aryl, C7-C,6aralkyl with 1 to 6 C atoms in the alkylene group and C6-C~0aryl, C8-C~6aralkenyl with C2-C6alkenylene and C6-C10aryl, or di-C6-C,0aryl-Cl-C6-alkyl, for example diphenylmethyl or 2,2-diphenylethyl, where R8 and Rg are unsubstituted or sub-stituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O~OMy~ C1-Cl2alkyl, Cl-C6alkoxy, C6-Cl0aryl, C6-Cl0aryloxy, SO3My~ OSO3MNR20SO3My~ NO2, amino, primary amino, secondary amino and CN, R20 is hydrogen, Cl-C,2alkyl, C2-C,2alkenyl, C3-Cl2cycloalkyl, C3-Cl2cycloalkenyl, C2-C,lheterocycloalkyl, C2-C"-heterocycloalkenyl, C6-C,Oaryl, C5-Cgheteroaryl, C7-C"aralkyl, C6-C~Oheteroaralkyl, C8-C"-aralkenyl or C,-C10heteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

R10 corresponds, in particular, to Cl-Cl2alkyl; C3-Cl2cycloalkyl, C6-Cl0aryl, C7-Cl6aralkyl with 1 to 6 C atoms in the alkylene group and C6-Cl0aryl, C8-Cl6aralkenyl with C2-C6alkenylene and CB-C,0aryl, or di-C6-C,0aryl-Cl-C6alkyl, for example diphenylmethyl or 2,2-diphenylethyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O)OMy~ Cl-C,2alkyl, C,-C6alkoxy, C6-Cl0aryl, SO3My~
OSO3My~ NR20SO3My~ NO2, amino, primary amino, secondary amino and CN; where R20 is hydrogen, Cl-C,2alkyl, C2-Cl2alkenyl, C3-Cl2cycloalkyl, C3-Cl2cycloalkenyl, C2-Cllhetero-cycloalkyl, C2-C"-heterocycloalkenyl, C6-C,0aryl, C5-Cgheteroaryl, C7-C1laralkyl, C6-C~0heteroaralkyl, C8-C,l-aralkenyl or C7-Cl0heteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.
.

W O 97/01569 PCTrEPg6/02785 Furthermore, R10 is preferably C,-C12alkyl; C3-C12cycloalkyl, C6-C10aryl, C~-Cl6aralkyl Wittl 1 to 6 C atoms in the alkylene group and C6-C,0aryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(O)OMy~ C,-C,2alkyl, C,-C6alkoxy, C6-C~0aryl, SO3My~ nitro, amino, primary amino, secon-dary amino and cyano; or C8-C,6aralkenyl with C2-C6alkenylene and C6-C10ary!, ordi-C6-C,0aryl-C,-C6alkyl, for example diphenylmethyl or 2,2-diphenylethyl.

In a preferred subgroup of compounds, R5 and R6 are, together with the -CH-CH- group, C3-C,2cycloalkylene or C2-C"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(O)ORs,~ OC(O)Rs4, C(O)R
NH2, Cl-C12alkyl, R8C(O)N(Rg)-, -C(O)NR8Rg, R8S(0)2N(Rg)-; R8oc(o) N(Rg)- and R10-S02-, in which Rg is hydrogen and R8 is C,-C,2alkyl, C6-C,0aryl or C7-C"aralkyl, which are unsub-stituted or substituted by one or more C,-C,2alkoxy; R~o is C1-C12alkyl, C6-C10aryl or C,-C1,aralkyl which are unsubstituted or substituted by one or more C,-C,2alkyl; Rs1 and Rs4 are C,-C,2alkyl and R,~2 is C1-C12alkyl, C3-C12cycloalkenyl, C3-C12cycloalkyl or C6-C10aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are unsubstituted or substitu-ted by one or more substituents selected from the group consisting of OH, C(O)ORs1 and OC(O)Rs4 where Rs1- is My or C1-C,2alkyl and Rs4 is C,-C,2alkyl; y is 1 and M is a mono-valent metal or y is 1/2 and M is a divalent metal.

Particularly preferred compounds within this group are those in which R5 and R6 are, to-gether with the -CH-CH- group, cyclohexylene.

Another subgroup of preferred compounds are those compounds in which Rs and R6 are, to-gether with -CH-CH- group, piperidylene.

Particularly preferred compounds are those in which R5 and R6 are, together with the -CH-CH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(O)ORs1~ C(O)Rs2, C(O)NR8Rg, NH2, SO3My~ C,-C~2alkyl, C2-C,2alkenyl, C1-C,2alkoxy, C3-C12cycloalkyl, C3-C,2cycloalkenyl, C2-Cl~heterocycloalkyl, C2-C"heterocycloalkenyl, C6-C,Oaryl, C6-ClOaryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy~c7-c11aralkyl~c7-c11aralkyloxy~c6-c1oheteroaralkyl~c8-c11aralkenyl~c7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, sul-CA 02224346 l997-l2-lO

W O 97/OlS69 PCT~EPg6/02785 . -15-fonhydrazide; and one or more C atoms of the ring are unsubstituted or substituted by one - or more substituents selected from the group consisting of OH, OC(O)Rs4, NH2, OSO3My NR20SO3My~ C1-C,2alkoxy, C6-C1Oaryloxy, Cs-c9heteroaryioxy~ C7-C11aralkyloxy, primary amino, secondary amino, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsl is hydrogen, My~
C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-Cl~heterocycloalkyl, C6-C10aryl, C5-C9hetero-aryl, C,-C11aralkyl or C6-C1Oheteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C"heterocycloalkyl, C6-C,Oaryl, C5-C9heteroaryl, Crc~aralkyl or C6-C10heteroaralkyl, R8 and Rg are, independently of one another, hydrogen, OH, C1-C12alkyl, C3-Cl2cycloalkyl, C2-Cllheterocycloalkyl, C6-C,Oaryl, C5-Cgheteroaryl, C7-C16aralkyl, C6-C,5heteroaralkyl, C8-C,6aralkenyl with C2-C6alkenylene and C6-C1Oaryl, or di-C6-C10aryl-C1-C6-alkyl, or R8 and Rg together are tetramethylene, pentamethylene, -(CH2)2-O-(CH2)2-, -(CH2)2-S-(CH2)2- or -(CH2)2-NR,-(CH2)2-, and R, is H, C1-C6alkyl, C,-C11aralkyl, C(O)Rs2 or sulfonyl; and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C~2cycloalkenyl, C2-C"heterocycloalkyl, C2-C"-heterocycloalkenyl, C6-C,Oaryl,C5-Cgheteroaryl, C7-C11aralkyl, C6-C1Oheteroaralkyl, C8-C11-aralkenyl or C7-C1Oheteroar-alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsllhstitllted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Particularly preferred compounds are those in which R5 and R6 are, together with the -CH-CH- group, piperidylene; where the hetero atom is unsuhstitllted or substituted by a substituent selected from the group consisting of C(O)ORs1, C(O)Rs2, -C(O)NR8Rg and R~o-SO2- and one or more C atoms of the ring are unsubstituted or s' ~hstituted by one or more suhstitl lents selected from the group consisli"g of OH, NH2, R8S(0)2N(Rg)-;
R8C(O)N(Rg)- and R80C(O)N(Rg)-, where Rg is hydrogen and R8 is C,-C,2alkyl, C6-C,Oaryl or C,-C"aralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C,-C~2alkoxy; R~o is C1-C,2alkyl, C6-C,Oaryl or C7-C"aralkyl which are unsubstituted or sub-stituted by one or more C,-C,2alkyl; Rs1 is C,-C,2alkyl and Rs2 is C1-C12alkyl, C3-C,2cyclo-alkenyl, C3-C~2cycloalkyl or C6-C,Oaryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substi-tuents in turn are unsubstituted or substituted by one or more substituents selected from the -W O 97/01569 PcT/~l3G~ x5 group consisting of OH, C(O)ORs1~ and OC(O)Rs4 where Rs1 is My or C1-C12alkyl and Rs4 is C,-C12alkyl; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Another subgroup of preferred compounds are those compounds in which Rs and R6 are, together with the -CH-CH- group, piperidylene; which is unsubstituted or substituted by one or more substituents selected from the group cons;~Li"g of OH, C(O)ORs1~ OC(O)Rs4, C(O)Rsz~ NH2, C1-C12alkyl, R8c(o)N(Rs)-~ -C(O)NRaRg, R8s(o)2N(Rs)-; R8oc(o)N(Rg)R8R40NC(O)N(R9)-, -OC(O)NR8Rg and R10-SO2-, in which Rg is hydrogen and R8 is C1-C12alkyl, C6-C10aryl or C7-C11aralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C1-Cl2alkoxy or C7-C11aralkyloxy; R10 is C1-C12alkyl, C6-C10aryl or C7-C11aralkyl which are unsubstituted or substituted by one or more C1-C12alkyl; R40 is hydrogen, OH, C1-C12alkyl, C1-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C1,heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C,Oaryl, C5-Cgheteroaryl, C7-C,6aralkyl, C8-C16aralkenyl with C2-C6alkenylene and C6-C,0aryl, C6-C~sheteroaralkyl~ C6-C15heteroar-alkenyl, or di-C6-C10aryl-C1-C6-alkyl, Rs1 and Rs4 are C1-C~2alkyl and Rs2 is C~-C,2alkyl, C3-C~2cycloalkenyl, C3-C12cycloalkyl or C6-C10aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)ORs1 and OC(O)Rs4 where Rs1 is My or C1-C12alkyl and Rs4 is C1-C12alkyl; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Very particularly preferred compounds of the formula I are those in which X is cyclo-hexylene or piperidylene which is unsubstituted or substituted by one or more substituents selected from the group consisli~g of OH, NH2, C3H7, -C(O)CH3, -C(O)C6Hs, -C(O)(CH2)8C(O)OCH3, -C(O)[CH(OH)]2C(O)ONa, C(o)-c6H8(oH)3~ -C(O)-C6H11, -C(O)OC3H7, -C(O)NHC6Hs, -NHS(0)2CH2C6Hs, -NHC(O)OCH2C6Hs~ -NHc(o)c6H3(ocH3) -S(0)2-C4Hg, -NHC(O)NHC6Hs, -S(0)2-C6H4CH3, -s(o)2-cH2c6Hs and -S(0)2-(CH)2C10H,.

Preferred compounds of the formula I are those in which R1 corresponds to a group of the formula lll in which R3 is hydrogen or My and R4 is (a) unsubstituted C1-C,2alkyl; C,-C12alkyl which is substituted by one or more substituents selected from the group consisting of -NH2, primary amino, secondary amino, C1-C,2sul-fonyl, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide, aminocarbonyl-amido, C3-C,2cycloalkyl, C,-C6alkoxy, phenyloxy and benzyloxy; unsubstituted W O 97/OlS69 PCT~EPg6/02785 C3-C,2cycloalkyl; C3-C,2cycloalkyl which is substituted by one or more substituents selected ~ from the group consisting of C3-C12cycloalkyl, C1-C6alkyl, C,-C6alkoxy, Cl-Ct2sulfonyl, phenyloxy and benzyloxy; C6-C,0aryl; C3-Cgheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; C7-C16aralkyl with C,-C6alkyl and C6-C,0aryl; C4-C,6heteroaralkyl with C~-C6alkyl and C3-C~0heteroaryl 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; C6-C,0aryl, C3-Cgheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms, C7-C16aralkyl with C,-C6alkyl and C6-C,0aryl, C3-C,6heteroaralkyl with C,-C6alkyl and C4-C,Oheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to 5 carbon atoms, which are substituted by one or more substituents selected from the group consisting of OH, halogen, C,-C,2sulfonyl, carboxyl, C(O)OMy~ C1-C12alkyl, C1-C6alkoxy, C6-C,0aryl, SO3My~ OSO3My~ NR20SO3My in which R20 is hydrogen, C,-C,2alkyl, C2-C,2alkenyl, C3-Cl2cycloalkyl, C3-C12cycloalkenyl, C2-C~1heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C,0aryl, Cs-Cgheteroaryl, C,-C11aralkyl, C6-C10heteroaralkyl, C8-C"-aralkenyl or C7-C,Oheteroaralkenyl, and nitro, NH2, primary amino, secondary amino, carbamide, carb-amate, sulfonamide and cyano, in which y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, or (b) C,-C,2alkyl or C7-C11aralkyl which are unsubstituted or substituted by one or more substi-tuents selected from the group consisting of OH, halogen, C(O)ORs1~ OC(O)Rs4, C(O)R
nitro, NH2, cyano, SO3My~ OSO3My~ NR20SO3My~ C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-Cgheteroaryl, Cs-c9heteroaryloxy~ C7-C11aralkyl, C7-C1,aralkyl-oxy, C6-C,0heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My~ C,-C,2alkyl, C2-C12alkenyl~c3-c12cycloalkyl~C2-C11heterocycloalkyl~c6-c1oaryl~C5-Cgheteroaryl~c7-C1'aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C,2cyclo-alkyl, C2-C"heterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C,2alkenyl, C3-C,2cyclo-alkyl, C3-C,2cycloalkenyl, C2-C"heterocycloalkyl, C2-C"-heterocycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C7-C11aralkyl, C6-C,0heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroar-alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo-alkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl W O 97/01569 PCT~EP96/02785 and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

R3 in formula lll is preferably hydrogen, K or Na.

The following preferences apply to the group (a) of meanings for R4:

R4 is alkyl, preferably methyl, ethyl, n- or i-propyl and n-, i- or t-butyl. In the case of substitu-ted alkyl, the alkylene group is preferably ethylene and particularly methylene. A particularly preferred cycloalkyl group is cyclohexyl. Preferred as aryl and aralkyl are naphthyl and phenyl, particularly preferably phenyl and phenyl-CnH2n- with n equal to a number from 1 to 6, in particular benzyl and 2-phenylethyl. When R4 is heteroaryl, it is preferably C4-C5hetero-aryl with one or two hetero atoms from the group of O and N. Furanyl, pyridinyl and pyrimidinyl are preferred. R4 as heteroaralkyl is preferably C4-C5heteroarylmethyl with one or two hetero atoms from the group of O and N, it being possible for heteraryl to comprise the abovementioned heteroaryl groups.

Further preferred compounds are those in which R4 in formula lll is a C3-C12cycloalkyl, parti-cularly preferably cyclohexyl, C1-C4alkyl substituted, particularly methyl or ethyl, with C3-C12cycloalkyl or with C1-C4alkyl and particularly with cyclohexyl or methyl, C6-C10aryl and very particularly phenyl, or R4 is a C,-C12aralkyl with C1-C6alkyl and C6-C10aryl. Particularly preferred groups for R4 in this series are benzyl, naphthylmethyl, 2-phenylethyl, 3-phenyl-propyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclohexyl and isopropyl.

Carbamido, carbhydrazido, sulfonamido, sulfonhydrazido, aminocarbonylamide and carb-amate as substituent for R4 preferably mean groups of the formulae R8NHC(O)N(Rg)-, R8OC(O)N(Rg)-, R8C(O)(NH)pN(Rg)- and R8S(O)2(NH)pN(Rg)-, in which R8 is preferably H, C1-C12alkyl, C5- or C6cycloalkyl, C5- or C6cycloalkylmethyl or -ethyl-, C5- or C6heterocyclo-alkyl, C5- or C6heterocycloalkylmethyl or -ethyl-, phenyl, naphthyl, benzyl, 2-phenylethyl, di-phenylmethyl, which are unsubstituted or sllhstihlted by one or more substituents from the group of -OH, -NH2, C1-C8primary amino, C2-C14secondary amino, NO2, -CN, -F, -Cl, -C(O)OH, -C(O)ONa, -SO3H, -OSO3Na, NR20SO3Na in which R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11hetero-cycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C,-C11aralkyl, C6-C10heteroaralkyl, C8-C"-aralkenyl CA 02224346 l997-l2-lO
W O 97/OlS69 PCT/~l~5~ 5 or C7-C10heteroaralkenyi, and -SO3Na, C1-C4alkyl, C~-C4alkoxy and phenyl, and Rg is H, C,-C,Oalkyl, phenyl, naphthyl, benzyl, 2-phenylethyl or phenyl-CH=CH-CH2-, and p is 0 or 1.

Within group (a), a carbamido-substituted alkyl substituent for R4 particularly preferably means R8~C(O)NRg~(CH2)n~~ where n is 1 or 2, R8is hydrogen; C1-C12alkyl; C3-C12cycloalkyl;
C6-C~0aryl or C7-C,6aralkyl with C1-C6alkyl and C6-Cl0aryl; 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(O)OMy~ Cl-Cl2alkyl, Cl-C6alkoxy, C6-Cl0aryl, SO3M
OSO3My~ NR20SO3My~ C(O)ORsl~ OC(O)Rs4~ nitro, amino and cyano; or C8-Cl6aralkenyl with C2-C6alkenyl and C6-C,0aryl or di-C6-Cl0aryl-C1-C6alkyl; and Rg is H, linear or branched C1-C10alkyl, Cs- or C6cycloalkyl, C5- or C6cycloalkylmethyl- or -ethyl, phenyl, naphthyl or benzyl, 2-phenylethyl or phenyl-CH=CH-CH2-; y is 1 and M is an alkali metal or y is 1/2 and M is an allcaline earth metal, R20is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C~-Cgheteroaryl, C7-Cllaralkyl, C6-Cl0heteroaralkyl, C8-Cll-aralkenyl or C7-Cl0heteroar-alkenyl, Rs1 is hydrogen, My~ C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocyclo-alkyl, C6-C10aryl, Cs-C~heteroaryl, C7-C11aralkyl or C6-Cl0heteroaralkyl and Rs4 is hydrogen, Cl-Cl2alkyl, C2-Cl2alkenyl, C3-Cl2cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-Cghetero-aryl, C7-C11aralkyl or C6-C10heteroaralkyl. A sulfonamide-substituted alkyl substituent for R
particularly preferably means R8~SO2NRg~(CH2)n~ in which R8, Rg and n have the meanings in~ -~tecl previously for carbamido. An aminocarbonylamide- or carbamate-sl~hstitllted alkyl substituent for R1 particularly preferably means RgNHC(O)NH(CH2)n or RgOC(O)NH(CH2)n in which Rg has the meanings intl ,~ted in previously in connection with carbamido and addi-tionally phenyl and n has the meanings i~' c~ted previously in connection with carbamido.
A carbhydrazido-substituted alkyl substituent for R1 particularly preferably means R8C(O)NHNRg(CH2)n- in which R8, Rg and n have the meanings indicated previously in con-nection with carbamido. A sulfonhydrazido-substituted alkyl sl ~hstitl ~ent for R4 particularly preferably means R8-S02-NHNRg-(CH2)n- in which R8, Rg and n have the meanings indica-- ted previously in connection with carbamido.

Further particularly preferred compounds are those in which R4 in formula lll is an amide R8C(O)N(Rg)(CH2)n- or R8S(0)2N(Rg)(CH2)n~; where R8 and Rg are, independently of one an-other, hydrogen; unsubstituted C1-C,2alkyl; C1-Cl2alkyl which is substituted by one or more sl~h.stitoents selected from the group consisLi"g of OH, halogen, carboxyl, C(O)ONa, CA 02224346 l997-l2-lO

C,-C12alkyl, C1-C6alkoxy, C6-C10aryl, -SO3H, OSO3Na, NR20SO3Na, SO3Na, nitro and cyano;
unsubstituted C3-C12cycloalkyl; C3-C12cycloalkyl substituted by one or more OH; unsubstitu-ted C6-C~0aryl, unsubstituted C7-C12aralkyl with C,-C6alkyl and C6-C10aryl; C6-C10aryl, or C7-C12aralkyl with C1-C6alkyl and C6-C10aryl, which is substituted by one or more substitu-ents selected from the group consisting of OH, halogen, carboxyl, C(O)ONa, -C(O)OK, Cl-Cl2alkyl, C1-C6alkoxy, C6-C10aryl~ SO3Na, OSO3Na, NR20SO3Na, C(O)ORs1~ OC(O)Rs4 nitro, amino and cyano, R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-Cl2cycloalkenyl, C2-Cl,heterocycloalkyl, C2-Cll-heterocycloalkenyl, C6-C~Oaryl, C5-Cgheteroaryl, C7-C"aralkyl, C6-C1Oheteroaralkyl, C8-C,1-aralkenyl or C7-C10heteroar-alkenyl, Rs1 is hydrogen, My~ C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocyclo-alkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl and Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-Cghetero-aryl, C7-C11aralkyl or C6-C10heteroaralkyl; and n is 2 or 1.

Particularly preferred compounds are those in which R4 in formula 111 is an amide R8C(O)N(Rg)(CH2)n- or R8S(0)2N(Rg)(CH2)n-, where R8 is unsubstituted C1-C12alkyl;
C1-C8alkyl which is sl Ihstitl Ited by one or more substituents selected from the group con-sisting of OH, halogen, C(O)ONa and C6-C10aryl; unsubstituted C3-C12cycloalkyl; C3-C8cyclo-alkyl which is substituted by one or more OH; unsubstituted C6-C10aryl or C7-C12aralkyl with C1-C6alkyl; C6-C,0aryl, C7-C,2aralkyl with C1-C6alkyl and C6-C10aryl or C8-C16aralkenyl with C2-C6alkenyl and C6-C~0aryl, which is substituted by one or more substituents selected from the group consisting of halogen, -C(O)OH, C(O)ONa, C1-C12alkyl, C1-C6alkoxy, -SO3H, SO3Na, OSO3Na, NR20SO3Na in which R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C~C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C,-C10heteroaralkenyl, and nitro and cyano; and Rg is hydrogen; unsubstituted C1-C6alkyl, unsllhstitlltecl C6-ClOaryl, unsubstituted C7-Cl2aralkyl with Cl-C6alkyl and C6-ClOaryl; or C8-Cl6aralkenyl with C2-C6alkenyl and C6-Cl0aryl, and n is 2 and preferably 1.

Particularly preferred compounds are also those in which R4 in formula 111 is an amide R8C(O)N(Rg)(CH2)n-~ where R8 is unsubstituted C1-C12alkyl; C1-C12alkyl which is substituted by one or more substituents selected from the group consisting of cyclohexyl, OH, halogen, -C(O)OH, -C(O)ONa and phenyl; unsubstituted C3-C12cycloalkyl; C3-C12cycloalkyl which is suhstihlted by one or more OH; un~hstitl~ted C6-Cl0aryl; C6-Cl0aryl, which is substituted by CA 02224346 l997-l2-lO

W O 97/01569 PCT/~l,5.'~21~5 one or more substituents selected from the group consisting of halogen, C(O)ONa,-C(O)OH, C1-C6alkyl, C1-C6alkoxy, phenyl, -S03H, SO3Na, OSO3Na, NHSO3Na, nitro and cyano; or C7-C16aralkyl with C,-C6alkyl and C6-C~Oaryl, and Rg is hydrogen; unsubstituted q C1-C6alkyl, unsubstituted C7-C,6aralkyl with C,-C6alkyl and C6-C,Oaryl; or C8-C16aralkenyl with C2-C6alkenyl and C6-C~Oaryl, and n is 2 and preferably 1.

Further particularly preferred compounds are those in which R4 in formula lll is an amide R8C(O)N(Rg)(CH2)n-, where R8 is uns' Ihstituted C~-C12alkyl, C,-C4alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OH, C(O)ONa and phenyl; unsubstituted C3-C~2cycloalkyl, in particular C6H~; C3-C~2cycloalkyl which is substituted by one or more OH, unsubstituted C6-C,Oaryl, in particular C6H5 or C,OH7; C6-C,Oaryl which is substituted by one or more substituents selected from the group consisting of halogen, -C(O)OH, C(O)ONa, C,-C6alkyl, C1-C6alkoxy, -SO3H, SO3Na, OSO3Na, NHSO3Na, nitro and cyano, in particular C6H4CI, C6H4(3,43CI2, C6H4COONa,C6H4CH3, C6H40CH3, C6H4SO3Na, C6H4NO2 or C6H4CN; or unsuhstih~ted C7-C,6aralkyl with C~-C6alkyl and C6-C1Oaryl, in particular (CH2)2C6H5, and R9 is H, C,-C4alkyl, phenyl-CH2-, phenyl-CH2CH2, phenyl-(CH2)3- or phenyl-CH=CH-CH2-, and n is 2 and preferably 1.
Particularly preferred compounds are also those in which R4 in formula lll is an amide R8C(O)N(Rg)(CH2)n-~ where R8 is unsubstituted or substituted C,-C~2alkyl, cyclohexyl, naphthyl, biphenylyl, phenyl, benzyl, phenylethyl or diphenylmethyl, and Rg is C,-C4alkyl, phenyl-C,-C6alkyl, in particular CH2C6H5, (CH2)2C6H5 or (CH2)3C6H5; or phenyl-C2-C6-alkenyl, in particular C6H5-CH=CH-CH2, and n is 2 and preferably 1.

Further particularly preferred compounds are those in which R4 in formula lll is a sulfon-amido R8S(0)2N(R~)(CH2)n-, where R8 is C1-C,2alkyl, particularly C1-C6alkyl, which is unsub-stituted or substituted by one or more halogen atoms (for example Cl and especially F), in particular CF3; or C6-C,Oaryl, particularly phenyl or naphthyl, which is substituted by one or more C1-C4alkyl (for example methyl or ethyl), C,-C4alkoxy (for example methoxy or ethoxy), halogen, -CN or -NO2, and Rg is hydrogen or isobutyl, and n is 2 and preferably 1.

Further particularly preferred compounds are those in which R4 in formula lll is an amino-carbonyl residue of the formula R8~NH~C(O)~NH(CH2)n~~ in which R8 is Cl-C12alkyl or C6-C1Oaryl, particularly Cl-C6alkyl, which is unsubstituted or substituted by halogen, -CN, W O 97/OlS69 PCT~EP96/02785 -NO2, Cl-C4alkyl or C,-C4alkoxy, or C5- or C6cycloalkyl, C6-C10aryl such as phenyl or naphthyl, or C7-C12aralkyl such as benzyl, phenylethyl, phenylpropyl or phenylpropenyl, and n is 2 and preferably 1.

Particularly preferred compounds are furthermore those in which R4 in formula ll is an aminoalkyl, preferably R8 Rg N(CH2)n-1 where R8 and Rg are, independently of one another, hydrogen; unsubstituted C,-C12alkyl; C1-C12alkyl which is substituted by one or more substi-tuents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)NR11R12, C1-C,2alkyl, C1-C6alkoxy, C6-C,0aryl, -SO3H, SO3Na, OSO3Na, NR20SO3Na, nitro, amino and cyano; unsubstituted C3-C12cycloalkyl; C3-C12cycloalkyl which is substituted by one or more OH; C6-C,0aryl; C7-C,6aralkyl with C1-C6alkyl and C6-C10aryl; or C8-C16ar-alkenyl with C2-C6alkenyl and C6-C10aryl, where aryl and the aryl in the aralkyl and aralkenyl are unsubstituted or substituted by one or more substituents selected from the group con-sisting of OH, halogen, C(O)ORs11 OC(O)Rs41 -C(O)ONa, -C(O)OK, -C(O)-NR11R12, C1-C12alkyl, C1-C6alkoxy, C6-C10aryl, -SO3H, SO3Na, OSO3Na, NR20SO3Na, nitro, amino and cyano; wherein n is 2 and preferably 1, and Rs1 is hydrogen, K or Na, C1-C,2alkyl, C2-Cl2alkenyl, C3-Cl2cycloalkyl, C2-C11heterocycloalkyl, C6-ClOaryl, Cs-c9heteroaryl1 C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cyclo-alkyl, C2-C"heterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, R11 is H, C1-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and R12 in-dependently has the meaning of R11, or R11 and Rl2together are tetramethylene, penta-methylene or-CH2CH2-O-CH2CH2- and R20 is hydrogen, Cl-C12alkyl, C2-C12alkenyl, C3-Cl2cycloalkyl, C3-Cl2cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, Cs-Cgheteroaryl~ C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-ClOheteroaralkenyl .

Particularly preferred compounds are furthermore those in which R4 in formula 111 is an aminoalkyl R8RgNCH2-, in which R8 and Rg are, independently of one another, hydrogen;
C1-C8alkyl, cyclopentyl, cyclohexyl, C5- or C6cycloalkylmethyl, phenyl-C1-C~alkyl, in particular -CH2C6H5; or phenyl-C2-C4alkenyl, in particular -CH2CH=CHC6H5.

Particularly pre~er,ed compounds are furthermore those in which R4 in formula 111 is an amine R8RgNCH2-, where R8 and Rg are, independently of one another, H, C1-C6alkyl, phenyl-C1- or C2alkyl, in particular CH2C6H5.

WO 97/01569 PCT/~;~,''027~5 Preferred compounds of group (b) of meanings for R4, are those in which R4 is C,-C11ar-alkyl, in particular CH2-C6H5 and (CH2)2-C6H5, C3-C12cycloalkyl or C1-C12alkyl, which is un-substituted or substituted by one or more substituents selected from the group consisting of NH2, C3-C12cycloalkyl, primary amino, secondary amino, sulfonamide, carbamide and aminocarbonylamido. Particularly preferred substituents for C1-Cl2alkyl are NH2, cyclohexyl, C6-C10aryl, R8C(O)N(Rg)-, R8S(0)2N(R9)-, R8NHC(O)NR9-, NRgC(O)NHR8 and R8 RgN-~ in which R8 and Rg are, independently of one another, hydrogen, C1-C12alkyl, C3-C~2cycloalkyl, C2-C11heterocycloalkyl, C6-C,Oaryl, C5-Cgheteroaryl, C,-C11aralkyl or C6-C10heteroaralkyl and R8 and Rg are, independently of one another, hydrogen, OH, C~-C~2alkyl, C3-C,2cycloalkyl, C2-C"heterocycloalkyl, C6 C,Oaryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1~ OC(O)Rs4~ C(O)Rs2~ nitro, NH2, cyano, SO3My~
OSO3My~ NR20SO3My~ C1-C12alkyl, C2-C,2alkenyl, C,-C12alkoxy, C3-C~2cycloalkyl, C3-C,2cyclo-alkenyl, C2-C"heterocycloalkyl, C2-C"heterocycloalkenyl, C6-C,Oaryl, C6-C,Oaryloxy, C5-C9heteroaryl, Cs-Cgheteroaryloxy~ C,-C11 aralkyl, C,-C11aralkyloxy, C6-C1Oheteroaralkyl, C8-Cl1aralkenyl, C,-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfon-amide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rsl is hydrogen, My~ C,-C,2alkyl, C2-C,2alkenyl, C3-C,2cyclo-alkyl, C2-C1,heterocycloalkyl, C6-C,Oaryl, C5-Cgheteroaryl, C,-C11aralkyl or C6-C1Oheteroar-alkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C,Oaryl, C5-Cgheteroaryl, C,-C"aralkyl or C6-C,Oheteroaralkyl, and Rs2 and R20 are hydro-gen, C1-C,2alkyl, C2-C12alkenyl, C3-C,2cycloalkyl, C3-C,2cycloalkenyl, C2-C"heterocycloalkyl, C2-C"-heterocycloalkenyl, C6-C,Oaryl, C5-Cgheteroaryl, C,-C,1aralkyl, C6-C,Oheteroaralkyl, C8-C~1-aralkenyl or C,-C1Oheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or sub-stituted by one of the abovementioned substituents; p is O or 1 and y is 1 and M is a mono-valent metal or y is 1/2 and M is a divalent metal; or R8 and Rg together are tetramethylene, pentamethylene, -(CH2)2-O-(CH2)2-, -(CH2)2-S-(CH2)2- or -(CH2)2-NRr(CH2)2-, and R7 is H, C~-C6alkyl, C7-C"aralkyl, C(O)Rs2 or sulfonyl.

Particularly preferred compounds within this group are those in which R4 is CH2-C6H5, (CH2)2-C6H5, cyclohexyl, methyl, ethyl or isopropyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH2, cyclohexyl, C6-C,Oaryl, W O 97/OlS69 PCT~EPg6/02785 R8C(O)N(Rg)-, R8S(0)2N(R9)-, R8NHC(O)NRg-, NR9C(O)NHR8 and R8RgN-, in which R8, Rg, R8 and Rg are, independently of one another, hydrogen, C,-C12alkyl, C3-C12cycloalkyl, C6-C1Oaryl or C7-C11aralkyl, which are unsubstituted or substituted by one or more substitu-ents selected from the group consisting of OH, halogen, C(O)OMy~ nitro, cyano, SO3My~
OSO3My~ NHSO3My~ C1-C12alkyl, C,-C12alkoxy and C6-C,Oaryl, where y is 1 and M is a mono-valent metall or y is 1/2 and M is a divalent metal. Particularly preferred compounds are those in which R8, Rg, R8 and Ry are, independently of one another, hydrogen, C,-C,2alkyl, cyclohexyl, phenyl, naphthyl or C7-C"aralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, Cl, C(O)ONa, nitro, cyano, SO3Na, C~-C6alkyl, methoxy and phenyl.

In a preferred group of compounds of the formula 1, R, is formula 111, in which R4 is C6H", CH(CH3)2, CH2-phenyl, (CH2)2-phenyl, CH2NHC(O)-phenyl, CH2NHC(O)(CH2)3-phenyl, CH2NHC(O)(CH2)30H, CH2NHC(O)CF3, CH2NHC(O)C6H11, CH2NHC(O)C"H23, CH2NHC(O)CH(C6H5)2, CH2HNC(O)NHC6H5, CH2NHC(O)C2H4CO2Na, CH2NHC(O)C6[(1,3,4,5)0H]4H7, CH2NHC(O)C6H4-p-SO3Na, CH2NHC(O)C6H4CI, CH2NHC(O)C6H4NO2, CH2NHC(O)C6H40CH3, CH2NHC(O)C6H4(3,4)C12, CH2NHC(O)C6H4CH3, CH2NHC(O)C6H4C6Hs, CH2NHC(O)C6H4CN, CH2NHC(O)C,OH7, CH2NHC(O)C6H4COONa, CH2NHC(O)(CHOH)2COONa, CH2N(CH2CH=CH-phenyl)[C(O)-phenyl], CH2N[CH2CH(CH3)2][C(O)-phenyl], CH2N[C(O)C6H5]CH2C6Hs, CH2N~C(O)C6Hs](CH2)3C6H5, CH2C6H1" (CH2)2C6H", CH2NH2, CH2NHCH2CH=CH-phenyl, CH2NHCH2-phenyl, CH2NHCH2CH(CH3)2, CH2N(CH2-phenyl)2, CH2N[CH2CH(CH3)2]2, CH2NHSO2-p-nitrophenyl, CH2NHSO2-p-tolyl, CH2NHSO2CF3, CH2NHC(O)NHC6H5 or CH2N[SO2-p-nitrophenyl][CH2CH(CH3)2]2.

R2 as alkyl can contain preferably from 1 to 6 C atoms and particularly preferably from 4 C atoms. Methyl and ethyl are particularly preferred.

In the case of halogen for the substituents for R2, it can preferably be F, Cl and r case of -C(O)OMy preferably -C(O)ONa or -C(O)OK; in the case of alkyl prefer and particularly preferably C1-C4alkyl, such as methyl, ethyl, n- or i-propyl art-butyl; in the case of alkoxy preferably C1-C4alkoxy, for example methox case of aryl preferably phenyl or naphthyl; in the case of -SO3My prefer -SO3K; in the case of primary amino C1-C12primary amino such as mr W O 97/01569 PCT~EP96/02785 i-propyl-, n-, i- or t-butyl, pentyl, hexyl, cyclohexyl, phenyl or benzylamino; in the case of secondary amino C2-C20secondary amino such as dimethyl-, diethyl-, methylethyl-, di-n-propyl-, di-i-propyl-, di-n-butyl-, diphenyl-, dibenzylamino, morpholino, thiomorpholino, piperidino and pyrrolidino; -S02-NR8Rg; and -C(O)-NR8Rg in which R8 and Rg are, indepen-dently of one another, H, C,-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, or R8 and Rg to-gether with the N atom are morpholino, thiomorpholino, pyrrolidino or piperidino.

R8 and Rg as alkyl preferably contain 1 to 6, and particularly preferably 1 to 4, C atoms, and can be, for example, methyl, ethyl, n- or i-propyl or n-, i- or t-butyl. R8 and Rg as hydroxyalkyl preferably contain 1 to 6, and particularly preferably 1 to 4, C atoms, and can be, for example, hydroxymethyl or 2-hydroxyethyl. R8 and Rg as cycloalkyl are preferably cyclo-pentyl or cyclohexyl. Substituents for R8 and Rg as phenyl and benzyl are preferably F, Cl, methyl, ethyl, methoxy and ethoxy.

A preferred subgroup of compounds of the formula I are those in which R2 is hydrogen, un-substituted C1-C6alkyl, particularly preferably C,-C4alkyl, especially methyl or ethyl, or C~-C6alkyl, particularly preferably C1-C4alkyl, especially methyl or ethyl, which is s~bstihlted by C(O)OH, -C(O)ONa, -C(O)OK, -OH, -C(O)-NR8Rg or -SO2-NR8Rg, in which R8 is H, C~-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and Rg independently has the meaning of R8, or R8 and Rg are together tetramethylene, pentamethylene or -CH2CH2-O-CH2CH2-. Par-ticularly preferred compounds are those in which R2 is hydrogen, methyl, ethyl, HO(O)CCH2CH2-, NaOC(O)CH2CH2- or R8RgNC(O)CH2CH2-, and R8 and Rgare, indepen-dently of one another, H, C,-C6alkyl, C2-C4hydroxyalkyl, phenyl, benzyl or, together, morpholino.

A particularly preferred embodiment of the invention comprises compounds of the formula la COOR

HO~ ~ (la) H3C~
HO

in which R3 is hydrogen or My; and R4 is C,-C12alkyl, C2-C,2alkenyl, C3-c12cycloalkyl~ C3-C12cycloalkenyl~ C2-C1,heterocycloalkyl, C2-C"heterocycloalkenyl, C6-C,Oaryl, C5-Cgheteroaryl, C7-C"aralkyl, C6-C,Oheteroaralkyl, C8-C1,aralkenyl or C7-C10heteroaralkenyl, which are unsubstituted or substituted once or several times;
Rs and R6 are, independently of one another, hydrogen, C1-C12alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl; or Rs and R6 are, together with the -CH-CH- group, C3-C12cycloalkylene, C4-C12cycloalken-ylene, C2-C"heterocycloalkylene and C3-C"heterocycloalkenylene with hetero atomsselected from the group of -O-, -S- and -N-;
where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclo-alkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted once or several times;
where the substituent is selected from the group OH, halogen, C(O)ORs,~ OC(O)Rs4C(O)Rs2, nitro, NH2, cyano, SO3My~ OSO3My~ NR20SO3My in which R20 is hydrogen, C,-C,2alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C"heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C7-c11aralkyl~ C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and C1-C12alkyl, C2-C12alkenyl, C,-C,2alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, C7-C1,aralkyl, C7-C"ar-alkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C,-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carb-hydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My~
C1-c12alkyl~ C2-C12alkenyl, C3-C12cycloalkyl, C2-c11heterocycloalkyl~ C6-C,Oaryl, C5-Cghetero-aryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C~-C11aralkyl or C6-C10heteroaralkyl and Rs2 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-Cl0aryl, C5-Cgheteroaryl, C7-Ct~aralkyl, C6-C,0heteroaralkyl, C8-C1l-aralkenyl or C,-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are substituted or unsubstituted by one of the abovementioned substituents; and W O 97/01569 PCT~EP96/02785 y is 1 and M is a monovalent metal or y is a 1/2 and M is a divalent metal.
-Preferred compounds of the formula la are those in which ~ R3 is H, K or Na, R5 and R6 are, together with the -CH-CH- group, C3-C12cycloalkylene, C4-C12cycloalken-ylene, C2-C11heterocycloalkylene and C3-C,lheterocycloalkenylene 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(O)ORs1~
OC(O)Rs4~ C(O)Rs2~ nitro, NH2, cyano, SO3My~ OS03My~ NR20SO3My in which R20 is hydro-gen, C1-Cl2alkyl, C2-Cl2alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C1l-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C,-Cllaralkyl, C6-Cl0heteroaralkyl, C8-C1,-aralkenyl or C7-Cl0heteroaralkenyl, and Cl-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-ClOaryl, C6-ClOaryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, C,-Cllaralkyl, C,-C11ar-alkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C~-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carb-hydrazide, carbohydroxamic acid and aminocarbonylamide, in which Rs1 is hydrogen, My~
C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, CG-C10aryl, C5-Cghetero-aryl, C,-Cl1aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C,-C11aralkyl or C6-C10heteroaralkyl and Rs2 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C1lheterocycloalkyl. C2-Cll-heterocycloalkenyl, C6-ClOaryl, C5-Cgheteroaryl, C,-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C,-C10heteroar-alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo-alkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal;
(a) R4 is a residue Rl2-(CH2)n- or cyclohexyl, in which n is 1 or 2 and R12 is C1-C10alkyl, C5-C8cycloalkyl, especially cyclohexyl, C6-C10aryl, preferably phenyl, or C8-C12aralkenyl, preferably phenyl-C2-C4alkenyl, which are unsubstituted or substituted by C1-C4alkyl, C1-C4alkoxy, F, Cl, -CN or-NO2; or W O 97/01569 PcT~EP9G,r~27X5 Rl2 is an amino group -NRg Rg, and Rg and Rg are C1-C,2alkyl or unsubstituted orC1-C4alkyl-substituted C5- or C6cycloalkyl, C6-C10aryl, C7-C12aralkyl or C6-C12aralkenyl; very particularly preferably -CH2-CH(CH3)2,-CH2-C(CH3)3,-CH2-C(CH3)2-C2H5, C6Hs-cH2 C6H5CH2CH2-, C6H5-CH2-CH2-CH2- or C6HsCH=CH~CH2-, or R12is an amide group -N(Rg)C(O)R8,-N(Rg)S(0)2R8,-NRgC(O)NHR8 or -NRgC(O)NHR8 in which R8 is C6-C10aryl, preferably phenyl, which is unsubstituted or substituted by C1-C4alkyl, especially methyl, C1-C4alkoxy, especially methoxy, F, Cl, -CN or -NO2, or C1-C,0alkyl which is unsubstituted or substituted by F or Cl, and Rgis H, Cl-ClOalkyl, Cs- or C6cycloalkyl, C5- or C6cycloalkyl-C1-C6alkyl, phenyl-C1-C6alkyl or phenyl-C2-C6alkenyl, especially H, C1-C6alkyl, cyclohexyl, cyclohexyl-CH2-, cyclohexyl-CH2CH2-, cyclohexyl-CH2CH2CH2-, C6H5CH2,C6H5CH2CH2-, C6H5CH2CH2CH2- and C6H5CHCHCH2-, Rgis particularly H, linear and, prefe-rably, branched C1-C6alkyl, phenyl or phenyl(CH2)~- with z equal to a number from 1 to 4, for example methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, pentyl, isopentyl, hexyl, benzyl, phenyl-ethyl, phenylpropyl and phenyl-CH=CH-CH2-, very particularly preferably CH2-CH(CH3)2, benzyl, 2-phenylethyl and 3-phenylpropyl; or (b) R4 is C1-C12alkyl, C3-C12cycloalkyl or C7-C11aralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OR
OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My~ OSO3My~ NR20so3My in which R20is hydro-gen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C,-C10heteroaralkenyl, and C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C,-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1is hydrogen, My~
C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C1lheterocycloalkyl, C6-C10aryl, C5-Cghetero-aryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-Cgheteroaryl, C,-C11aralkyl or C6-C10heteroaralkyl and Rs2 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl~C2-C11heterocycloalkyl~c2-c11-heterocycloalkenyl~c6-c1oaryl~c5-Cgheteroaryl, C,-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroar-CA 02224346 l997-l2-lO

W O 97/01569 PCT/~l,'r~ S

alkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents;
and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

A preferred subgroup of compounds of group (a) are those in which (i) R4 is C6H1" C6H11-CH2, C6H11-CH2CH2-, C6H5-CH2-, C6H5-CH2CH2- or C6H5-CH=CH-CH2-;
(ii) R4 is C6H11, C6H11-CH2-, C6H11-CH2CH2-, C6Hs~CH2~, C6Hs-CH2CH2-, -CH2-NR19-S02R18, -CH2-NR19-C(O)R40, CH2NHC(O)NHR18, -CH2NHR21 or CH2N(R2,)2, in which R,8 is -C6H5, phenyl which is substituted by 1 to 3 methyl or methoxy or -NO2 or F or Cl, in particular p-CH3-C6H4-, p-CH30-C6H4- or 2,3,5,-CH3-C6H2- or p-02N-C6H4-, or C,-C4alkyl, which is sub-stituted by F, in particular -CF3; R40 is phenyl which is unsubstituted or substituted by 1 to 3 methyl or methoxy or -NO2 or F or Cl; R19 is H, C1-C6alkyl, phenyl-(CH2)z- with z equal to a number from 1 to 3, phenyl-CH=CH-CH2-, and especially -CH2-CH(CH3)2 or benzyl; and R
is -CH2-CR22R23R24 in which R22 and R23, methyl, ethyl or phenyl and R24 is H, ethyl or methyl, very particularly preferably R22 and R23 are methyl and R24 is H.

A preferred subgroup of the compounds of group (b) are those in which R4 is C6H11, CHz-C6H5, (CH2)2-C6H5, methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from the group consisli"g of NH2, cyclohexyl, C6-C10aryl, R8C(O)N(Rg)-, R8S(0)2N(Rg)-, NR9C(O)NHR8 and R8RgN- in which R8, Rg, R8 and Rg are, in-dependently of one another, hydrogen, C1-C12alkyl, C3-C,2cycloalkyl, C6-C10aryl or C7-C11ar-alkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OMy~ nitro, cyano, SO3My~ OSO3My~ NR20SO3My~ in which R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-Cgheteroaryl, C,-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C~Oheteroaralkenyl, and C1-C12alkyl, C1-C,2alkoxy and C6-C,Oaryl, where y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. Particularly preferred compounds are those in which R8, Rg, R8 and Rg are, indepen-dently of one another, hydrogen, C,-C12alkyl, cyclohexyl, phenyl, naphthyl or C7-C11aralkyl, which are unsubstituted or sl Ihstihlted by one or more substituents selected from the group consisting of OH, F, Cl, C(O)ONa, nitro, cyano, SO3Na, C1-C6alkyl, methoxy and phenyl.

In a preferred group of compounds of the formula la, R4 is C6H11, CH(CH3)2, CH2-phenyl, (CH2)2-phenyl, CH2NHC(O)-phenyl, CH2NHC(O)(CH2)3-phenyl, CH2NHC(O)(CH2)30H, W O 97/OlS69 PCT/~lr5~027~S

CH2NHC(O)CF3, CH2NHC(O)C6H11, CH2NHC(O)C11H23, CH2NHC(O)CH(C6H5)2, CH2HNC(O)NHC6H5, CH2NHC(O)C2H4CO2Na, CH2NHc(o)c6[(113~4~5)oH]4H7 CH2NHC(O)C6H4-p-SO3Na, CH2NHC(O)C6H4CI, CH2NHC(O)C6H4NO2, CH2NHC(O)C6H40CH3, CH2NHC(O)C6H4(3,4)CI2, CH2NHC(O)C6H4CH3, CH2NHC(O)C6H4C6H5, CH2NHC(O)C6H4CN, CH2NHC(O)C10H7, CH2NHC(O)C6H4COONa, CH2NHC(O)(CHOH)2COONa, CH2N(CH2CH=CH-phenyl)[C(O)-phenyl], CH2N[CH2CH(CH3)2][C(O)-phenyl], CH2N[C(O)C6H5]CH2C6H5, CH2N[C(O)C6H5](CH2)3C6H5,CH2C6H11, (CH2)2C6H1l, CH2NH2, CH2NHCH2CH=CH-phenyl, CH2NHCH2-phenyl, CH2NHCH2CH(CH3)2, CH2N(CH2-phenyl)2, CH2N[CH2CH(CH3)2]2, CH2NHSO2-p-nitrophenyl,CH2NHSO2-p-tolyl, CH2NHSO2CF3, CH2NHC(O)NHC6H5 or CH2N[SO2-p-nitrophenyl][CH2CH(CH3)2]2 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

HO ~0 ~0 ~X
R b OR ~2 ~/

¦ (V) R2~oR 12 R~2l 12 in which R2 and X have the abovementioned meanings, R12 is a protective group and R12' and R,2" are, independently of one another, hydrogen or a protective group, with a compound of the formula Vl .
R,-R13 (Vl) in which R1 has the abovementioned meaning and R13 is a leaving group, and eliminating the protective groups.

CA 02224346 l997-l2-lO

W O 97/01569 PcT/~l~Gl~7x5 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 C1-C4alkyl, C,-C4alkoxy, nitro, cyano or halogen (chlorine, bromine). Some examples of these acids are: methanesulfonic acid, mono-, di- or trifluoromethanesulfonic acids or p-nitrobenzenesulfonic acid. CF3-S02-O- (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-SO2-, in which R is C,-C12alkyl, in particular C1-C6alkyl, C5-C6cycloalkyl, phenyl, benzyl, C1-C12alkylphenyl, in particular C1-C4alkylphenyl, or C,-C12alkylbenzyl, in particular C1-C4alkylbenzyl, for example methane, ethane, propane, butane, benzene, benzyl- and p-methylbenzenesul-fonyl. Preferred leaving groups are Cl, Br, I, -SO2CF3 (triflate) and p-nitrobenzenesulfonyl, and -SO2CF3 is particularly preferred.

The compounds of the formula Vl 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, a-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 g~l~ctose and fucose or vice versa is advantageous.

For the preparation of the compounds of the formula V, firstly the pseudo-trisaccharide building blocks are synthesized. The pseudotrisaccharide is assembled either by glycosidic attachment for the activated and protected g~l~ctose 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.

W O 97/OlS69 PCT~ErS~ S

lt is then possible to introduce the group R, into the pseudotrisaccharide. The resulting com-pounds of the formula I can subsequently be modified. This modification may comprise hydrogenation of aromatic compounds to cycloaliphatic groups, which can take place, for example, at the same time as the hydrogenolytic elimination of protective groups. It is furthermore possible for an amino group to be acylated and/or alkylated and/or sulfonated.
The preparation of secondary and tertiary amines can be carried out by reductive amination.

It has proved advantageous to activate the 3-OH group of the galactose residue by etherifi-cation. Particularly suitable for this purpose are dialkyltin oxides, dialkyltin alkoxylates and bis(trialkyl)tin oxides. Some examples are dibutyltin oxide, dibutyltin(O-methyl)2 and (tributyl-tin)20. The activating agents are preferably used in stoichiometric amounts. In this case, the reaction is carried out in two stages, namely a) activation and b) coupling with the com-pounds of the formula Vl.

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 Vl can be employed in equimolar amounts. However, it has proved expedient to employ the compounds of the formula Vl in excess, for example in an amount which is up to 10 times, preferably up to 5 times, the amount of the compound of the formula V.

It is furthermore expedient to carry out the reaction in both reaction stages in the presence of an inert solvent or mixtures of solvents. Reactive protic solvents such as alkanols and, furthermore, acid amides are unsuitable in reaction stage b). It is possible to use non-polar aprotic and polar aprotic or polar protic solvents. These may be aliphatic or aromatic hydro-carbons such as pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene or xylene, halogenated hydrocarbons such as methylene chloride, chloroform, tetrachloro-methane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane and chloro-benzene, linear or cyclic ethers such as diethyl ether, dibutyl ether, ethylene glycol dimethyl or diethyl ether, tetrahydrofuran and dioxane, N,N-dialkylated carboxamides such as dimethylformamide, N-alkylated lactams such as N-methylpyrrolidone, ketones such as acetone and methyl isobutyl ketone, carboxylic esters such as methyl or ethyl acetate, or W 0 97/OlS69 PCT~EP96/02785 alkanols such as methanol, ethanol, propanol, butanol and ethylene glycol monoethyl ether.
Particularly preferred solvents are methanol, ethanol, benzene and toluene.

Protective groups and processes for derivatizing hydroxyl groups with such protective groups are generally known in sugar and nucleotide chemistry and are described, for example, by Beaucage, S.L. Iyer, R., Tetrahedron 48:2223-2311 (1992). Examples of such protective groups are: benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, dimethoxy-benzyl, bromobenzyl, 2,4-dichlorobenzyl; diphenylmethyl, di(methylphenyl)methyl, di(di-methylphenyl)methyl, di(methoxyphenyl)methyl, di(dimethoxyphenyl)methyl, triphenylmethyl, tris-4,4',4"-tert- butylphenylmethyl, di-p-anisylphenylmethyl, tri(methylphenyl)methyl, tri(dimethylphenyl)methyl, methoxyphenyl(diphenyl)methyl, di(methoxyphenyl)phenylmethyl, tri(methoxyphenyl)methyl, tri(dimethoxyphenyl)methyl; triphenylsilyl, alkyldiphenylsilyl, dialkylphenylsilyl and trialkylsilyl with 1 to 20, preferably 1 to 12, and particularly preferably 1 to 8 C atoms in the alkyl groups, for example triethylsilyl, tri-n-propylsilyl, i-propyl-dimethylsilyl, t-butyl-dimethylsilyl, t-butyl-diphenylsilyl, n-octyl-dimethylsilyl, (1,1,2,2-tetra-methylethyl)dimethylsilyl; C2-C~2-, in particular C2-C8acyl, such as acetyl, propanoyl, butan-oyl, pentanoyl, hexanoyl, benzoyl, methylbenzoyl, methoxybenzoyl, chlorobenzoyl and bromobenzoyl. The protective groups can be identical or different. Preferred protective groups are selected from the group consisting of linear and branched C,-C8alkyl, in particu-lar Cl-C4alkyl, for example methyl, ethyl, n- and i-propyl, n-, i- and t-butyl; C7-C,2aralkyl, for example benzyl; trialkylsilyl with 3 to 20 C atoms, in particular 3 to 12 C atoms, for example triethylsilyl, tri-n-propylsilyl, tri-i-propylsilyl, i-propyl-dimethylsilyl, t-butyl-dimethylsilyl, t-butyl-diphenylsilyl, n-octyl-dimethylsilyl, (1,1,2,2-tetramethylethyl)dimethylsilyl; substituted methyli-dene groups which are obtainable by acetal or ketal formation from adjacent hydroxyl groups of the sugars or sugar derivatives with aldehydes and ketones, which preferably contain 2 to 12 or 3 to 12 C atoms, for example C,-C12alkylidene, preferably C1-C6alkylidene and in particular C1-C4alkylidene, such as ethylidene, 1,1- and Z,2-propylidene, 1,1- and 2,2-butylidene, benzylidene; unsubstituted and halogenated C2-C12acyl, in particular C2-C8acyl, such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, pivaloyl and benzoyl.

The synthesis preferably takes place with protective groups for R~2' and R~2" which together form an alkylidene group with, preferably 1 to 12 and, more preferably 1 to 8 C atoms. In this connection, particularly preferred protective groups are those in which R,2' and R,2" to-gether are an alkylidene group with, in particular, 1 to 12 C atoms, with the alkylidene group W O 97/01569 PCT/~l~5lo27~s 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. R12' and R,2"
are, particularly preferably, together alkylidene, for example alkyl- or alkoxy- substituted benzylidene. R12' and R12" can, however, also be hydrogen, or one of R,2' and R12" can be a protective group such as benzyl and the other one of R12' and R,2" can be hydrogen.

Examples of protective carboxylate groups are alkoxy- and aralkoxycarbonyl groups, pre-ferably -CO2Bn, -CO2CH3.

The reaction for elimination of the protective groups is preferably carried out at a tempera-ture of 0~C to 50~C, and particular at room temperature.

Further details of the preparation of the compounds of the formula I are described in the examples.

An alternative synthetic route comprises glycosidic iinkage of the protected fucose hydroxy ether of the formula Vll HO~x O' R2~oR12 (Vll), ~R12 in which R2, R12 and X have the abovementioned meanings, with the protected galactose of the formula Vlll R1 ~R12 ~0~
f~ o ZR (Vlll), OR120Rl2 W O 971~1569 PCT~EP~ 7~5 . -35-in which R, has the abovementioned meaning, Z is O or S, R12 is a protective group and R
is a leaving group, and subsequent removal of the protective groups from the resulting com-pound.

It is possible to chose reaction conditions like those implemented for the process described previously. The leaving group R can be, for example, -C(=NH)-CC13 or 4-pentenyl. The com-pounds of the formula Vll can be obtained in a simple manner by glycosidic linkage of ap-propriately protected fucose with a compound of the formula HO-X-OH which is monopro-tected where appropriate. The compounds of the formula Vlll can be obtained by etherifi-cation of compounds of the formula R10H 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 r~spir~tory distress syndrome, asthma, arthritis and metastatic cancer. The invention furthermore relates to the compounds according to the invention for use in a therapeutic method for the treatment of disorders in warm-blooded animals, including humans. The dosage on administration to warm-blooded animals with a body weight of about 70 kg can be, for example, 0.01 to 1000 mg per day. Administration preferably takes place in the form of pharmaceutical compositions, parenterally, for example intravenously or intraperitoneally.

The invention furthermore relates to a pharmaceutical composition comprising an effective amount of the compound according to the invention, alone or together with other active sub-stances, a pharm~ceutic~l 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 Iyophilized compositions which co~"prise the active substance alone or together with a carrier, for example mannitol, before use. The pharmaceutical compositions can be sterilized and/or cor"prise excipients, for example pre-W O 97/01569 PCT/~l~5~ s servatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts to control the osmotic pressure and/or buffers. The pharmaceutical compositions, which may, if required, comprise other pharmacologically active substances such as antibiotics, are produced in a manner known per se, for example by conventional dissolving or Iyophilizing processes, and comprise about 0.1 % to 90 %, in particular from about 0.5 % to about 30 %, for example 1 to 5 %, of active substance(s).

The following examples illustrate the invention.
The following abbreviations are used:
Bz: Benzoyl; Bn: Benzyl; DMTST: Dimethyl(methylthio)sulfonium triflate; FAB: Fast atom bombardment mass spectroscopy; OTf: Triflate; Ph: Phenyl; SEt: C2H5S; THG: Thioglycerol;
THF: Tetrahydrofuran; NBA: m-Nitrobenzyl alcohol; DMF: N,N-Dimethylformamide; DME:
1,2-Dimethoxyethane; MeOH: Methanol; HRP: Horse radish peroxidase; BSA: Bovine serum albumin; PAA: Polyacryl amide; SA: Streptavidin An unconnected hyphen in the formulae means methyl.
Molecular sieves are activated at 300~C under high vacuum for 12 hours before use. They are used in powdered form.

A: r~ aldlion of sl~lli..y cG."pounds ExamPle A1: Preparation of compound No. A1 O O
a) N3 OH ~ N~ OBn OH OH

Benzyl chloride (660 ml, 5.72 mmol) is added at room temperature to a mixture ofR-3-azido-2-hydroxypropionic acid 28 [Dureault, A., Tranchepain, I., Depezay, J.C., t 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 1ll, 6.1 mmol) and benzyl chloride (660 ,ul, 5.72 mmol) are added. The reaction mixture is stirred for two days and then con-W O 97101569 PCT/~l~ /o~

centrated under high vacuum. The residue is taken up in water and the mixture is extracted several times with ethyl acetate. The combined organic phases are washed with saturated NaCI solution, dried (Na2SO4), filtered and concentrated in vacuo. The crude product (1 g) is purified by flash chromatography on silica gel (ethyl acetate/hexane 1 :4), resulting in benzyl R-3-azido-2-hydroxypropionate 29 (0.717 g, 85 %) as an oil. ~H NMR (250 MHz, CDCI3) ~ 7.36 (m, 5H), 5.25 (s, 2H), 4.39 (q, J=4.2 Hz,1 H), 3.65 (dd, J=3.3,12.9 Hz,1 H), 3.51 (dd, J=4.3,12.9 Hz,1H), 3.20 (d, J=4.0 Hz,1H).

b) 29 ~ N3/~OBn OTf Trifluoromethanesulfonic anhydride (770 ml, 4.41 mmol) is added at -20~C with stirring to a solution of the alcohol 29 (0.85 g, 3.84 mmol) and 2,6-di-tert-butylpyridine (1.12 ml, 4.99 mmol) in dry CH2CI2 (11.0 ml). The clear colourless solution is warmed to 0~C over ~he course of 40 minutes and is stirred at this temperature for a further 2 hours. The mixture is diluted with CH2CI2 (40 ml) and, while stirring vigorously,1 M aqueous KH2PO4 solution (30 ml) is added. The organic phase is separated off and the aqueous phase is extracted twice with CH2CI2. The combined organic phases are washed with H2O (30 ml), dried (Na2SO4), filtered and concentrated in vacuo. The oily residue (2.3 9) is purified by flash chromatography on a short silica gel column (ethyl acetate/hexane 1 :7), resulting in the benzyl R-3-azido-2-trifluoromethanesulfonyloxypropionate A1 (1.16 g,85 %) as a yellowish oil.1H NMR (250 MHz, CDCI3) ~ 7.38 (br s,5H), 5.32 (d, J=12,1 Hz,1H), 5.27 (d, J=12.1 Hz, 1 H), 5.24 (dd, J-4.2, 5.5 Hz,1 H), 3.90 - 3.75 (m, 2H); 13C NMR (63 MHz, CDCI3) ~ 164.4, 133.9,129.1,128.8,128.6, 120.9, 81.0, 69.0, 51.5.

W O 97/01569 PCT/~l~5~2lx5 Exam~le A2: Preparation of compound No. A2 ~ ~~
OH OH F C- ~
,OH 0,, ~OBn 3"'~'~0Bn Benzyl (~-4-phenyl-2-trifluoromethanesulfonyloxybutyrate (A2):
A solution of (R~-2-hydroxy-4-phenylbutyric acid 26 (0.2 g,1.11 mmol) in MeOH/ H2O (9:1, 1.3 ml) is adjusted to pH 8 with 20 % Cs2CO3 solution. The solution is concentrated in vacuo and azeotroped first with ethanol and then with hexane, subsequently dried under high vacuum in order to remove remaining H2O. The residue is mixed with N,N-dimethylform-amide (1.3 ml) and benzyl bromide (132,u1,1.11 mmol), and the mixture is stirred at room temperature for 75 minutes. Then further benzyl bromide (20,ul, 0.168 mmol) is added, and the mixture is stirred for a further 50 minutes. The white suspension is diluted with CH2CI2 (5 ml), filtered through HyfloSuperCel~ and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel (eluent: ethyl acetate/hexane 4:1) affords benzyl (R~- 2-hydroxy-4-phenylbutyrate 27 (0.21 g, 70 %). The product (0.3 g,1.11 mmol) is dissolved in CH2CI2 (4.5 ml), 2,6-di-tert-butylpyridine (323 ~11,1.44 mmol) is added, and the mixture is cooled to -20~C. Then trifluoromethanesulfonic anhydride (222 lli, 1.27 mmol) is added ~ p~rjsc over the course of 3 minutes, and the solution is warmed to 0~C over the course of 45 minutes. After 75 minutes at 0~C, the mixture is diluted with CH2CI2 (20 ml) and washed with 1 molar aqueous KH2PO4 solution (15 ml). The aqueous phase is extracted with CH2CI2 (2 x 10 ml), and the combined organic phases are washed with H2O (10 ml), dried (Na2SO4), 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 Bl.18). 'H NMR (250 MHz, CDCI3) ~ 7.50 - 7.17 (m,10H), 5.31 (s, 2H), 5.28 (dd, J=5.5,11.0 Hz, 1 H), 2.82 (m, 2H), 2.41 (m, 2H).

W O 97/OlS69 PCT~EP96/0278 . -39-ExamPle A3: Preparation of compound No. A3 .

OH ~S//
J ~, ~. u R-Hydromandelic acid is converted into the triflate A3 in accordance with Example A2.

Example A4: Preparation of compound No. A4 OH ~ //
\~OH ~ (A4) R-2-Hydroxy-3-methylbutyric acid is converted into the triflate A4 in accordance with Example A2.

Example A5: Preparation of compound No. A5 OH ~''S''O
J~OH F3C 'o ~ n ~ (A5) R-2-Hydroxy-3-cyclohexylpropionic acid is converted into the triflate A5 in accordance with Example A2.

W O 97/01569 PCT~E~S5.lv210S

. -40-B Preparation of the mimetics Example B1: Preparation of compound No. B1.1 OBZ
BzO OBz HO~ BZO~--O~

a) :co ~OBn BzO ~ OBn BnO OBn A mixture of the thioglycoside 1 (5.38 g, 8.40 mmol) [Biessen, E. A. L., Beuting, D.M., Roelen, H.C.P.F., van de Marel, G.A., van Boom, J.H., van Berkel, T.J.C., J. Med. Chem.
38:1538-1546 (1995)] and of the acceptor 2 (3.44 g, 6.46 mmol) is dried under high vacuum for one hour. Then activated 4A molecular sieves (20 g) and DMTST (4.17 g,16.14 mmol) are added under a nitrogen atmosphere, followed by CH2CI2 (70 ml). The yellowish suspen-sion is dried at room temperature and, after 3 hours,5 ml of a suspension consisting of DMTST (5.84 g, 22.61 mmol), 4A molecular sieves (4.0 g) and CH2CI2 (35 ml) are added.
Further 5 ml portions of this DMTST suspension are added after 30, 45 and 90 minutes respectively. The brown reaction mixture is then stirred for 15 hours, and thereafter filtered through Hyflo Super Cel~ ffilter aid), washing with CH2CI2 (300 ml). The filtrate is extracted by shaking first with 10 % aqueous NaHCO3 solution and then with saturated NaCI solution, and the organic phase is dried with Na2SO4, filtered and concentrated in a vacuum rotary evaporator. The remaining brown foam is purified by two column chromatographies on silica gel (eluent for 1 st 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.

CA 02224346 l997-l2-l0 W O 97/01S69 PCT~EP96/02785 OH
HO ~ O

HO \
b) ~ ZOBn BnO o A solution of the tetrabenzoate 3 (3.38 g, 3.04 mmol) and sodium methoxide (0.165 g, 3.05 mmol) in dr~ methanol (32 ml) is stirred at room temperature for 3 hours. The mixture is neutralized by adding a strongly acidic ion exchanger (Amberlyst 15) and then filtered through Hyflo Super Cel0, washing with CH2CI2. The filtrate is concentrated in vacuo, and the remaining yellow oil is purified by flash chromatography on silica gel (elution: CH2CI2/
methanol 19:1), resulting in the pure tetrol 4 (1.95 g, 92 %).

OH OH
~ o~ ~ HO~ - _o~

c) OH ~Oo ~OBn Ph ~OBn BnO n BnO OBn 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 NaHCO3 solution and then with saturated NaCI
solution, and the organic phase is dried (Na2SO4), filtered and concentrated in vacuo, resul-ting in 1.5 g of crude product. Purification of the crude product by flash ch~ul,laluyl~phy on silica gel (CH2CI2/MeOH 39:1) affords, besides the required benzylidene acetal 5 (0.475 g), W O 97/OlS69 PCT/~1'5i~2/~5 a mixture of less polar byproducts (0.4 9). The latter are treated once again under the reac-tion conditions described above and are purified, resulting in a further 0.08 g of the benzyli-dene acetal 5. The total yield of 5 is: 0.555 g (49 %): 'H NMR (500 MHz, CDCI3) ~ 7.53 -7.51 (m, 2H), 7.38 - 7.19 (m, 18H), 5.62 (s,1H), 4.83 (d, J=3.8 Hz,1H), 4.77 (d, J=12.1 Hz, 1H), 4.71 (d, J=11.5 Hz,1H), 4.70 (m,1H), 4.66 (d, J=12.0 Hz,1H), 4.62 (d, J=11.5 Hz, 1 H), 4.51 (d, J=11.1 Hz,1 H), 4.36 - 4.31 (m, 2H), 4.22 (br d, J=2.8 Hz,1 H), 4.06 (dd, J=1.7, 12.3 Hz, lH), 3.97 (dd, J=2.9,10.2 Hz,1H), 3.92 (d, J=12.0 Hz,1H), 3.90 (dd, J=3.8,10.2 Hz,1 H), 3.76 - 3.68 (m, 3H), 3.53 (ddd, J=4.9, 9.0,11.0 Hz,1 H), 3.43 (br s,1 H), 3.37 (d, J=2.5 Hz,1 H), 2.57 (d, J=8.0 Hz,1 H), 2.51 (s,1 H), 2.08 (m, 2H),1.73 (br d, J=9.5 Hz, 2H), 1.42 - 1.25 (m, 2H), 1.20 (br t, J=11.2 Hz, 2H),1.07 (d, J=6.3 Hz, 3H); MS (FAB, THG) 800 (M + NH4), 783 (M + H).

COOBn ~0~0 d) ~oO
~ZOBn BnO OBn A mixture of the diol 5 (0.098 9, 0.125 mmol), di-n-butyltin oxide (0.062 9, 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-cenl"lted once again. Dry CsF (dried under high vacuum at 300~C, 0.068 9, 0.45 mmol) is added under an argon atmosphere, and the mixture is further dried under high vacuum (30 minutes). After addition of anhydrous 1,2-dimethoxyethane (1.5 ml), a solution of benzyl R-3-phenyl-2-trifluoromethanesulfonyloxypropionate [Degerbeck, F., Fransson, B., Grehn, L., Ragnarsson, U., J. Chem. Soc. Perkin Trans.1:11-14 (1993)] (0.24 9, 0.62 mmol) in dry 1,2-dimethoxyethane (1.5 ml) is added. The mixture is first vigorously stirred at room temperature for 4 hours and then at 40~C for a further 2 hours. After addition of aqueous 1 M KH2PO4 solution, the mixture is diluted with water and extracted three times with ethyl acetate. The combined organic phases are extracted by shaking with diluted aqueous KF solution and then with saturated NaCI solution. The organic phase is dried W O 97/01569 PCT/~lr 5, ~L 1~5 . -43-(Na2SO4), filtered and concentrated in a vacuum rotary evaporator, resulting in the crude product. Purification by flash chromatography on silica gel (gradient elution: ethyl acetate/
toluene 1 :4 to 100 % ethyl acetate) affords the ether 6 (0.045 9, 35 %) and the more polar precursor S (0.043 g, 44 %): 1H NMR (250 MHz, CDC13) S 7.49 (br d, J=6.9 Hz, 2H), 7.37 -7.05 (m, 28H), 5.36 (s,1 H), 5.04 (d, J=12.0 Hz,1 H), 4.98 (d, J=12.0 Hz,1 H), 4.72 - 4.63 (m, 3H), 4.62 - 4.48 (m, 4H), 4.31 (d, J=11.2 Hz,1 H), 4.16 (m,1 H), 4.11 (d, J=7.9 Hz,1 H), 4.07 (d, J=3.4 Hz,1 H), 3.88 - 3.79 (m, 2H), 3.76 (dd, J=3.4,10.3 Hz,1 H), 3.66 (d, J=11.3 Hz,1 H), 3.62 - 3.47 (m, 2H), 3.44 - 3.35 (m,1 H), 3.36 (dd, J=3.5, 9.6 Hz,1 H),3.16 - 3.06 (m, 2H), 3.12 (br s,1 H), 3.01 (dd, J=8.4,13.9 Hz,1 H), 2.03 - 1.86 (m, 2H),1.93 (d, J=2.0 Hz,1 H),1.71 - 1.55 (m, 2H),1.36 - 1.00 (m, 4H), 0.99 (d, J=7.1 Hz, 3H).

COONa OH
6 ~ pr o~ro~
e) HO OH
~OH
HO OH
B1 .1 Dioxane (2.5 ml), water (1.2 ml) and giacial 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 9, 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,urn). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a Dowex50 ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.5 cm), washing with deionized water.
The clear filtrate is concenlrdted and purified by reverse phase chromatography (RP18 silica gel, column diameter 1.4 cm, length 7.0 cm, gradient elution: 40 % MeOH/ H2O
through 45 % MeOH/H2O to 50 % MeOH/H2O), resulting in the target molecule B1.1 (0.015 g, 78 %) as a colourless solid: 'H NMR (500 MHz, D2O) ~ 7.38 - 7.30 (m, 4H), 7.29 - 7.23 (m,1 H), 4.92 (d, J=4.0 Hz,1 H), 4.55 (q, J=6.7 Hz,1 H), 4.35 (d, J=7.8 Hz,1 H), 4.11 (dd, J=4.8, 8.5 Hz,1 H), 3.86 (dl J=3.6 Hz,1 H),3.84 (dd, J=3.3,10.5 Hz,1 H), 3.74 (d, J=3.5 Hz, W O 97/OlS69 PCT~EP96/0278S

1H), 3.71 (dd, J=3.9,10.5 Hz,1H), 3.69 - 3.62 (m, 3H), 3.50 (ddd, J=1.0, 4.5, 7.1 Hz,1H), 3.48 - 3.41 (m,1 H), 3.43 (dd, J=8.0, 9.7 Hz,1 H), 3.24 (dd, J=3.5, 9.7 Hz,1 H), 3.09 (dd, J=4.6,14.0 Hz,1 H), 2.92 (dd, J=8.8,14.0 Hz,1 H), 2.06 - 1.97 (m, 2H),1.63 (br s, 2H),1.24 - 1.14 (m, 4H),1.13 (d, J=7.0 Hz, 3H); 13C NMR (100.6 MHz, APT, D20) d 139.5 (Cq)~ 130.7 (2 CH),129.9 (2 CH),128.0 (CH),100.8 (CH), 96.8 (CH), 84.0 (CH), 83.3 (CH), 79.6 (CH), 78.4 (CH), 75.6 (CH), 73.3 (CH), 71.4 (CH), 70.9 (CH), 69.2 (CH), 67.7 (CH), 67.4 (CH), 62.8 (CH2), 40.6 (CH2), 30.9 (CH2), 30.4 (CH2), 24.4 (2 CH2),16.6 (CH3); MS (FAB, THG) 595 (M+Na), 573 (M+H).

COOBn HO~--O~ Ph ~~
f) HO OH HO OH
~OBn ~ZOBn BnO o BnO OBn A mixture of the tetrol 4 (0.038 g, 0.055 mmol) and di-n-butyltin oxide (0.029 g, 0.117 mmol) in dry methanol (2.0 ml) is heated under reflux in an argon atmosphere. After 2.25 hours, the clear, colourless solution is concenl~ d in vacuo, and the residue is mixed with benzene and concentrated several times in order to remove excess MeOH. It is then dried under high vacuum for 30 minutes, and the residue is mixed under an argon atmosphere with CsF (dried under high vacuum at 300~C, 0.03 9, 0.197 mmol) and dry 1,2-dimethoxy-ethane (0.4 ml). The mixture is cooled to 0~C, and a solution of benzyl R-3-phenyl-2-tri-fluoromethanesulfonyloxypropionate [Degerbeck, F., Fransson, B., Grehn, L., Ragnarsson, U., J. Chem. Soc. Perkin Trans.1 :11-14 (1993)] (0.085 9, 0.219 mmol) in dry 1,2-dimeth-oxyethane (0.4 ml) is added using a syringe. The reaction mixture is then warmed to room temperature and stirred for one hour, after which it is stirred at 40~C for a further 2 hours.
After addition of aqueous 1 M KH2PO4 solution, the mixture is diluted with water and extracted three times with CH2CI2 The combined organic phases are washed with aqueous KF solution and then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue takes place by flash chromatography twice on silica gel (first chromatography: 2 %

W O 97/01569 PCT~EP96/02785 MeOH/CHCI3; second chromatography: 45 % ethyl acetate/toluene), resulting in the ether 8 as an oil (0.013 g, 25 %): 1H NMR (250 MHz, CDcb) ~ 7.40 - 7.00 (m, 25H), 5.15 (d, J=11.6 Hz,1 H), 5.09 (d, J=11.6 Hz,1 H), 4.89 (d, J=11.8 Hz,1 H), 4.86 (d, J=3.2 Hz,1 H), 4.77 (d, J=11,6 Hz,1 H), 4.69 (d, J=12.0 Hz, 2H), 4.57 (d, J=12.0 Hz,1 H), 4.56 (d, J=11.8 Hz,1 H), 4.35 (q, J=6.5 Hz, lH), 4.28 (dd, J=4.0, 9.5 Hz, lH), 4.11 (d, J=7.6 Hz, lH), 4.02 - 3.88 (m, 2H), 3.79 (dd, J=7.3,11.9 Hz,1 H), 3.66 (br s,1 H), 3.63 - 3.40 (m, 5H), 3.22 (m,1 H), 3.10 (dd, J=4.0,14.0 Hz, 1 H), 3.09 (br s,1 H), 3.03 (dd, J=3.5, 9.3 Hz,1 H), 2.90 (dd, J=9.5,14.0 Hz,1 H),1.97 - 1.84 (m, 2H),1.75 (d, J=1.9 Hz,1 H),1.59 (br s, 2H),1.29 - 1.07 (m,4H), 1.01 (d, J=6.4 Hz, 3H).

COONa OH
8 ~ f ~O
HO OH
g) ~OH
HO OH
B1 .1 1,4-Dioxane/water (2.0 ml of a 4:1 mixture) is added to the protected carbohydrate 8 (0.03 g, 0.032 mmol) and Pd/C (0.03 g, Pd content 10 %), followed by glacial acetic acid (0.1 ml).
The flask is evacuated and flushed with argon several times. This procedure is repeated with hydrogen. The mixture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring until a test by thin-layer cl-r. matography (silica gel plates n~uOH:
H20:acetone:glacial acetic acid: NH40H 70:60:50:18:1.5) indicates absence of the precur-sor and of the intermediates (about 3.5 hours). The black suspension is filtered twice through a cellulose filter (pore size 45,um), and the filtrate is concentrated in vacuo. The residue is taken up in water and the solution is passed through an ion exchanger column (Dowex 50, Na+ form, column diameter 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated and purified by reverse phase chromatography (RP18 silica gel, column diameter 1.4 cm, length 7.0 cm, gradient elution: 40 % MeOH/H2O
through 45 % MeOH/H2O to 50 % MeOH/H2O), resulting in the target molecule B1.1 (0.015 g, 78 %) as a colourless solid.

W O 97/OlS69 PCT~EP96/02785 Example B2: Preparation of compound No. B1.2 COONa OH
Bl.l ~ ~ ~O' HO OH
~OH
HO OH
Bl .2 The aromatic compound Bl.l (0.152 g, 0.256 mmol) and 5 % Rh/AI2O3 (0.2 9) are taken up in H2O (5.5 ml), dioxane (3.5 ml) and acetic acid (1.0 mi). 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 llm). 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 9) is puri-fied by gel filtration on Bio-Gel P2 (particle size 65,urn, 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/H2O), resulting in the target molecule B1.2 (0.11 g, 73 %) as a fluffy white solid (after Iyophilization). lH NMR (500 MHz, D20) ~ 4.93 (d, J=3.8 Hz, 1 H), 4.58 (q, J=6.4 Hz, 1 H), 4.43 (d, J=7.5 Hz,1 H), 3.91 (dd, J=3.5, 9.0 Hz,1 H), 3.88 - 3.83 (m, 2H), 3.75 (d, J=3.3 Hz,1 H), 3.73 - 3.64 (m, 4H), 3.57 - 3.53 (m, 1 H), 3.49 (dd, J-7.3, 9.0 Hz,1 H), 3.50 - 3.43 (m,1 H), 3.33 (dd, J-3.2, 9.2 Hz,1 H), 2.10 - 1.99 (m, 2H), 1.73 (br d, J=12.0 Hz,1 H),1.69 - 1.44 (m, 9H),1.29 - 1.07 (m, 7H), 1.14 (d, J=6.5 Hz, 3H), 0.96 - 0.80 (m, 2H); MS (FAB, THG) 623 (M+Na), 601 (M+H).

CA 02224346 l997-l2-lO

W 0 97/01569 PcT~ h~

Example B3: Preparation of compound No. B1.3 .

o a) HO~ SEt ~ HO~ SEt OH OH

A suspension consisting of the benzylidene acetal 9 (0.5 g, 1.60 mmol) (EP 671,406), sodium cyanoborohydride (0.9 g,14.3 mmol), activated 4A molecular sieves (1.0 g) and dry tetrahydrofuran (30 ml) is cooled to 0~C under a nitrogen atmosphere. The pH of the mix-ture is adjusted to 1 by cautious addition of a saturated solution of HCI 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 HCI solution. After 10 hours, cold, saturated aqueous NaHCO3 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 (Na2SO4), filtered and concentrated in vacuo, resulting in 1.3 g of the crude product. Purification takes place by flash chromatography on silica gel (CHCI3/isopropanol 19:1), resulting in the required 6-benzyl ether 10 (0.3 g, 60 %) and a somewhat less polar byproduct (0.045 g): lH NMR (250 MHz, CDCI3) ~ 7.47 - 7.33 (m, 5H), 4.64 (s, 2H), 4.37 (d, J=9.3 Hz,1 H), 4.13 (br d, J=3.0 Hz,1 H), 3.89 - 3.69 (m, 4H), 3.64 (dd, J=3.1, 9.0 Hz,1 H), 2.89 - 2.70 (m, 2H),1.38 (t, J=7.3 Hz, 3H).

BzO~3n b) 10 ~ BzO~_SEt BzO

Pyridine (0.45 ml, 5.56 mmol) and benzoyl chloride (0.49 ml, 4.22 mmol) are added to a solution of the triol 10 (0.296 g, 0.941 mmol) in CH2C12 (3.0 ml) at 0~C. The reaction mixture is stirred at 0~C for 3.5 hours and then 1 M aqueous KH2PO4 solution is added, and the mixture is extracted three times with CH2CI2. The combined organic phases are washed W O 97/01569 PCT~EF95.'~27X5 with water, dried (Na2SO4), filtered and concentrated in vacuo, resulting in 1.0 g of crude product. Purification by flash chromatography on silica gel (hexane/ethyl acetate 4:1) gives the tribenzoate 11 as yellowish crystals (0.517 g, 88 %). 'H NMR (250 MHz, CDCI3) ~ 8.09 (d, J=7.5 Hz, 2H), 8.02 (d, J=7.5 Hz, 2H), 7.85 (d, J=7.5 Hz, 2H), 7.68 (t, J=7.4 Hz, 1 H), 7.63 - 7.39 (m, 7H), 7.38 - 7.23 (m, 6H), 6.06 (d, J=3.3 Hz,1 H), 5.85 (t, J=10.0 Hz,1 H), 5.66 (dd, J=3.5, 10.0 Hz,1 H), 4.88 (d, J=10.0 Hz,1 H), 4.60 (d, J=11.9 Hz,1 H), 4.49 (d, J=11.9 Hz,1 H), 4.23 (t, J=6.3 Hz,1 H), 3.84 - 3.64 (m, 2H), 3.02 - 2.80 (m, 2H), 1.38 (t, J=7.5 Hz, 3H).

OBz 11 + HO ~ BzO ~ O
C) ~ OBn BzO OBn BnO OBn ~ OBn BnO OBn Dry CH2CI2 (8.0 ml) is added to a mixture of the thioglycoside 11 (0.377 g, 0.60 mmol), the glycosyl acceptor 2 (0.32 g, 0.60 mmol) (EP 671,409) and activated 4A molecular sieves (2.5 g) under an argon atmosphere. A suspension of DMTST (0.39 g,1.51 mmol) and acti-vated 4A molecular sieves (0.8 g) in dry CH2CI2 (5.0 ml) is prepared in a second round-bottom flask. Both suspensions are stirred at room temperature for 3.5 hours. Then 3 por-tions of 1 ml of the DMTST suspension are added over a course of one hour to the glycosyl donor/acceptor mixture. The ycllol/risll reaction mixture is stirred at room temperature for a further 1.5 hours and then filtered through Hyflo Super Cel~, washing with CH2CI2. The fil-trate is extracted by shaking with aqueous NaHCO3 solution and then with water. The aqueous phases are reextracted with CH2CI2, and the combined organic phases are dried (Na2SO4), filtered and concentrated in vacuo, resulting in 0.67 g of the crude product. Puri-fication takes place by flash chromatography twice on silica gel (first chromatography:
toluene/ethyl acetate 14:1; second chromatography: hexane/ethyl acetate 4:1), resulting in the product 12 (0.404 g, 61 %) as a colourless foam.

CA 02224346 1997-12-lO

W O 97/01569 PCT~EP96/02785 OH
HO~--O~
12 ~ HO ~OB

~ d) ~ZOBn BnO

A solution of the tribenzoate 12 (3.42 g, 3.12 mmol) and sodium methoxide (0.169 g, 3.12 mmol) in methanol (65 ml) is stirred at room temperature for 6 hours. The base is then neutralized by adding acidic ion exchanger (Amberlyst 15), and the suspension is filtered through Hyflo Super Cel0. The filtrate is concentrated in vacuo, and the remaining yellow oil (3.35 g) is purified by flash chromatography on silica gel (CH2CI2/MeOH,19:1), resulting in the triol 13 (2.15 g, 88 %) as a colourless foam: lH NMR (500 MHz, CDCI3) ~ 7.41 - 7.24 (m, 20H), 4.99 (d, J=3.6 Hz,1 H), 4.95 (d, J=11.2 Hz,1 H), 4.83 (d, J=11.2 Hz,1H), 4.77 (d, J=11.3 Hz,1 H), 4.69 (d, J=11.3 Hz,1 H), 4.68 (d, J=11.5 Hz,1 H), 4.61 (d, J=11.5 Hz,1 H), 4.53 (s, 2H), 4.34 (d, J=7.0 Hz,1 H), 4.33 (m,1 H), 4.04 (dd, J=3.7,10.1 Hz,1 H), 4.02 (m, 1 H), 3.97 (dd, J=2.9,10.0 Hz,1 H), 3.81 - 3.77 (m,1 H), 3.77 (dd, J=6.0,9.4 Hz,1 H), 3.70 (dd, J=5.0, 9.6 Hz,1 H), 3.65 (d, J=2.0 Hz,1 H), 3.63 - 3.54 (m, 4H), 2.95 (br s,1 H),2.60 (br d, J=2.0 Hz, 2H), 2.07 (m,1H), 2.01 (m,1H),1.69 (m, 2H),1.45 - 1.30 (m, 2H),1.29 - 1.18 (m, 2H),1.10 (d, J=6.5 Hz, 3H); MS (FAB, THG) 783 (M-H), 693 (M-PhCH2).

O CooBn OH ll I OH
HO~--O~ + N~OBn f ~ f~
HO OBn HO OBn e\ A1 ~_OBn ~~ZOBn BnO OBn BnO OBn A mixture of the triol 13 (0.515 g, 0.656 mmol) and di-n-butyltin oxide (0.245 g, 0.984 mmol) in dry methanol (15 ml) is heated under reflux in a nitrogen atmosphere for 2 hours. The clear solution is concentrated in vacuo and taken up in benzene and concentrated three W O 97/01569 PCT~EP96/02785 times in order to remove excess MeOH. The residue is dried under high vacuum and then dry CsF (dried under high vacuum at 300~C, 0.5 9, 3.29 mmol) is added under an argon atmosphere, followed by dry 1,2-dimethoxyethane (4.0 ml) and a solution of benzyl R-3-azido-2-trifluoromethanesulfonyloxypropionate A1 (1.16 9, 3.28 mmol) in dry 1,2-di-methoxyethane (8.0 ml). The reaction mixture is stirred at room temperature for 6 hours, and then 1 M aqueous KH2PO4 solution (60 ml) is added. The mixture is extracted three times with ethyl acetate, and the combined organic phases are washed first with aqueous NaHCO3 solution and then with NaCI solution, dried (Na2SO4), filtered and concentrated in vacuo. The oily residue (1.15 9) is purified by flash chromatography on silica gel (elution of the product with toluene/ethyl acetate 4:1, then elution of the precursor with CH2CI2/MeOH
19:1), resulting in the ether 14 (0.488 g, 75 %) as a colourless foam and the precursor 13 (0.075 g,15 %). 14: 1H NMR (500 MHz, CDCI3) ~ 7.40 - 7.22 (m, 25H), 5.25 (d, J=11.7 Hz, 1 H), 5.16 (d, J=11.8 Hz,1 H), 4.96 (d, J=10.9 Hz,1 H), 4.95 (d, J=3.1 Hz,1 H), 4.82 (d, J=10.8 Hz,1H), 4.76 (d, J=11.1 Hz,1H), 4.72 - 4.66 (m, 2H), 4.62 (d, J=11.0 Hz,1H), 4.57 (dd, J=3.2, 6.0 Hz, 1 H), 4.53 (d, J=11.3 Hz,1 H), 4.50 (d, J=11.3 Hz,1 H), 4.39 (q, J=6.2 Hz, 1 H), 4.31 (d, J=7.4 Hz, 1 H), 4.04 (br s, 1 H), 4.02 (dd, J=3.0, 9.5 Hz,1 H), 3.99 (dd, J=2.4, 9.5 Hz,1 H), 3.82 (ddd, J=1.9, 7.3, 8.9 Hz,1 H), 3.77 (dd, J=6.0, 9.2 Hz,1 H), 3.78 - 3.74 (m, lH), 3.70 - 3.65 (m, 2H), 3.63 (dd, J=3.0,12.3 Hz, lH), 3.58 (ddd, J=4.2, 8.0, 9.5 Hz,1H), 3.53 (dd, J=6.0,12.5 Hz, 1H), 3.55 - 3.51 (m,1H), 3.44 (dd, J=3.1, 9.0 Hz,1H), 2.90 (dd, J=1.2, 1.8 Hz, 1 OH), 2.86 (d, 2.0 Hz,1 OH), 2.09 - 1.96 (m, 2H),1.68 (m, 2H), 1.44- 1.18 (m, 4H),1.11 (d, J=6.3 Hz, 3H); MS (FAB, THG) 1010 (M+Na), 984 (M+Na+2H-N2), 962(M+3H-N2).

COOBn OH
14 ~ ~~O~
f) HO OBn ~OBn BnO OBn PVBaSO4 (0.35 9, Pt content: 5 %) is added to a solution of the azide 14 (0.11 g, 0.111 mmol) in ethyl acetate (12 ml). The flask is evacuated and flushed with argon several CA 02224346 l997-l2-lO

W O 97/01569 PCT~EP96/02785 times. It is then flushed with hydrogen, and the mixture is hydrogenated under atmospheric pressure with vigorous stirring. The hydrogenation is stopped after 2.5 hours, the suspen-sion is filtered through a cellulose filter (pore size 45 ~lm), and the fitrate is concentrated in vacuo. The residue (0.115 g) is purified by flash chromatography on silica gel (CH2CI2/
MeOH 19:1), resulting not only in the required amine 16 (0.055 g, 51 %) but also the less polar precursor 14 (0.042 g, 38 %). The amine 16 is unstable and is used immediately for further experiments.

COONa COOBn 16 ~ J~~~~o~ ~ ~ 110 OH
g) HO OBn l O
~OBn ~Z_OH
BnO
17 Bl.3 (i) Preparation of the benzamide intermediate 17: diisopropylethylamine (3.5 ml, 0.02 mmol) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.012 g, 0.0271 mmol) are added at 0~C to a solution of the ,B-amino acid derivative 16 (0.013 g, 0.0135 mmol) and benzoic acid (0.0033 g, 0.027 mmol) in dry THF (0.5 ml). The reaction mixture is stirred for 45 minutes, after which saturated aqueous NaHCO3 solution is added.
The mixture is extracted three times with CH2CI2, and the combined organic phases are washed first with 1 M aqueous KH2PO4 solution (pH 1-2, adjusted with 1 M aqueous HCI) and then with aqueous NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel (gradient elution:
35 % ethyi acetate/toluene to 40 % ethyl acetate/toluene), resulting in the benzamide 17 (0.0098 g, 68 %).
(ii) Deprotection of 17: dioxane (1.5 ml), water (0.7 ml) and glacial acetic acid (0.1 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.011 g) and the benzyl ether 17 (0.0097g, 0.0091 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black rnixture is hydrogenated under slightly elevated pressure with vigorous stirring for 14 hours. The mixture is filtered through a cellulose filter (pore size 45 ~um), and the filtrate is concentrated in vacuo. The residue is taken up in water and concentrated several times in order to remove excess acetic acid. A
solution of the crude product with a little water is then passed through an ion exchanger column (Dowex 50, Na+ form, column diameter 0.9 cm, length 3.5 cm), washing with deioni-zed water. The filtrate is concentrated in vacuo, and the residue (0.007 g) is purified by gel filtration on Bio-Gel P2 (particle size 65 ~Lm, 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/H2O to 45 % MeOH/H2O), resulting in the target molecule B1.3 (3.3 mg,58 %) as a fluffy white solid, (after Iyophili-zation). 'H NMR (500 MHz, D20) ~ 7.74 (d, J=7.5 Hz, 2H), 7.57 (t, J=7.2 Hz,1 H), 7.48 (t, J=7.6 Hz, 2H), 4.92 (d, J=4.0 Hz,1H), 4.57 (q, J=6.7 Hz, lH), 4.44 (d, J=7.8 Hz, lH),4.17 (dd, J=3.9,8.1 Hz,1 H),3.94 (d, J=3.0 Hz,1 H), 3.86 (d, J=3.5 Hz,1 H), 3.84 (t, J=4.0 Hz, 1 H), 3.74 (d, J=3.5 Hz,1 H), 3.75 - 3.65 (m, 4H),3.60 - 3.52 (m, 3H), 3.49 - 3.44 (m,1 H), 3.45 (dd, J=3.5, 9.3 Hz,1 H), 2.03 (m, 2H),1.64 (br s, 2H),1.26 - 1.13 (m, 4H),1.11 (d, J=6.5 Hz,3H); MS (FAB, THG) 660 (M+Na),638 (M+H).

Example B4: Preparation of compound No. B1.4 COOBn ICOONa Ph ~ HO O:n ~ ~ ~~

~OBn Ph ~OH

19 Bl.4 (a) Preparation of the amide intermediate 19: diisopropylcarbodiimide (20 ml,0.129 mmol) is added at room temperature to a solution of the amine 16 (0.032 g,0.033 mmol), dihydro-cinnamic acid (0.015 9, 0.1 mmol),1-hydroxybenzotriazole (0.025 9,0.185 mmol) in dry THF (1.0 ml). The reaction mixture is stirred for 30 minutes and then concentrated in vacuo.
The residue (0.09 g) is purified by flash chromatography twice on silica gel (eluent for the first chromatography: CH2CI2/MeOH 39:1, for the second chromatography: CH2CI2rlsopro-panol 39:1), resulting in the pure amide 19 (0.031 g,86 %).

W O 97/OlS69 PCT/~lr-~78s . -53-(b) Deprotection of 19: dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.035 g) and the benzyl ether 19 (0.031g, 0.0283 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black mixture is hydrogenated under a slightly eievated pressure of hydrogen with vigorous stirring for 18 hours. The mixture is filtered through a cellulose filter (pore size 45 ~Lm), 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/H2O) and subsequent gel filtra-tion on Bio-Gel P2 (particle size 65 ~Lm, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 mUmin, detection at 215 nm), resulting in the target molecule B1.4 (0.014 g, 74 %) as a fluffy colourless solid (after Iyophilization). 1H NMR (500 MHz, D2O) ~ 7.32 (m, 2H), 7.24 (m, 3H), 4.93 (d, J=4,1 Hz,1 H), 4.57 (q, J=6.7 Hz,1 H), 4.40 (d, J=8.0 Hz,1 H),3.9 -3.84 (m, 3H), 3.75 - 3.66 (m, 5H), 3.63 (dd, J=3.8,14.0 Hz,1 H), 3.53 (br dd, J=4.5, 7.5 Hz, 1H), 3.49 (dd, J=7.9, 9.6 Hz,1H), 3.50 - 3.44 (m,1H), 3.23 (dd, J=7.8,14.0 Hz,1H),3.15 (dd, J=3.2, 9.8 Hz,1 H), 2.88 (br t, J=7.3 Hz, 2H), 2.59 - 2.45 (m, 2H), 2.09 (m,1 H), 2.03 (m, 1H),1.67 (brs, 2H),1.30- 1.15 (m, 4H),1.13 (d, J=6.6 Hz, 3H); MS (FAB) 666 (M+H), 643 (M+H-Na).

Example B5: Preparation of compound No. B1.5 COOBn COONa OH I OH
16 ~ NH ~~ NH
~~ HO OBn ~~ HO OH
~> ~OBn ~> ~OH
BnO OBn HO OH
HO HO
21 B1.5 W O 97/01569 PcT/~5~ 7~5 (a) Preparation of the amide intermediate 21: diisopropylcarbodiimide (16 ml, 0.103 mmol) is added with stirring at room temperature to a solution of the amine 16 (0.026 g, 0.027 mmol), sodium 4-hydroxybutyrate (0.010 g, 0.079 mmol), 1-hydroxybenzotriazole (0.020 g, 0.148 mmol) in a mixture of dry THF (1.0 ml) and DMF (0.2 ml). After 4 hours, further DMF (dimethylformamide) (0.2 ml) is added, and the mixture is stirred for a further 13 hours. After the volatile constituents (including DMF) have been distilled off under high vacuum, the residue (0.09 g) is purified by flash chromatography on silica gel (CH2CI2/
MeOH 29:1), resulting in the amide 21 (0.02 g, 71 %).
(b) Deprotection of 21: dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.04 g) and the benzyl ether 21 (0.036 g, 0.034 mmol). The flask is evacuated and flushed with argon seve-ral times. It is then flushed with hydrogen, and the black mixture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 18 hours. The mixture is filtered through a cellulose filter (pore size 45 ,um), and the filtrate is concentrated in vacuo.
The residue is mixed with toluene (about 2 ml) and concentrated several times in order to remove excess acetic acid. A solution of the crude product (0.022 9) in a little water is then passed through an ion exchanger column (Dowex 50, Na+ form, column diameter 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated in vacuo, and the residue (0.02 g) is purified by gel filtration on Bio-Gel P2 (particle size 65 llm, 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/H2O 1:4), resulting in the target molecule B1.5 (0.015 g, 70 %) as a fluffy colourless solid (after Iyophilization). 1H NMR (500 MHz, D20) ~ 4.93 (d, J=3.9 Hz, 1 H), 4.59 (q, J=6.7 Hz, 1 H), 4.47 (d, J=7.5 Hz, 1 H), 4.04 (dd, J=3.8, 7.3 Hz, 1 H), 3.92 (d, J=3.2 Hz, 1 H), 3.86 (dd, J=3.4, 10.2 Hz, 1 H), 3.75 (d, J=3.5 Hz, 1 H), 3.74 - 3.65 (m, 4H), 3.62 (dd, J=3.9, 14.0 Hz, 1H), 3.59 - 3.51 (m, 2H), 3.55 (t, J=6.3 Hz, 2H), 3.50 - 3.44 (m, 1H), 3.43 (dd, J=3.5, 9.8 Hz, 1H), 3.38 (dd, J=7.5, 14.0 Hz, 1H), 2.27 (t, J=7.4 Hz, 2H), 2.11 ~ 2.00 (m, 2H), 1.77 (p, J=7.1 Hz, 2H), 1.65 (br s, 2H), 1.29 - 1.13 (m, 4H), 1.15 (d, J=6.8 Hz, 3H). MS (FAB) 643 (M+H-Na), 620 (M+H), 598 (M+2H-Na).

W O 97/01~69 PCT~EPg6/02785 ExamPle B6: Preparation of compound No. B1.6 COOBn co2 rlo ~ o~ NHz ~
HO OBn HO OH
~~ZOBn ~ZOH
BnO HO OH

14 B1.6 Dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.03 g) and the azide 14 (0.03 g, 0.03 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black mixture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 16 hours. The mixture is filtered through a cellulose filter (pore size 45 ~Lm), and the filtrate is concentrated in vacuo. The residue is purified by gel filtration on Bio-Gel P2 (particle size 65,um, 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/H2O), resulting in the target molecule B1.6 (0.011 g, 70 %) as a fluffy colourless solid (after Iyo-phili~lion).1H NMR (500 MHz, D2O) ~ 4.93 (d, J=3.9 Hz,1 H), 4.58 (q, J=6.7 Hz,1 H), 4.48 (d, J=7.9 Hz, lH), 4.22 (dd, J=3.7, 8.4 Hz, lH), 3.99 (d, J=3.1 Hz,1H), 3.86 (dd, J=3.3, 9.9 Hz,1 H), 3.75 (d, J=3.3 Hz,1 H), 3.74 - 3.65 (m, 4H), 3.61 - 3.55 (m, 2H),3.50 (dd, J=3.0, 9.3 Hz,1H), 3.48 (m,1H), 3.35 (dd, J=3.7,12.9 Hz,1H), 3.16 (dd, J=8.5,13.5 Hz,1H), 2.10 - 2.00 (m, 2H),1.65 (m, 2H),1.29 - 1.15 (m, 4H),1.14 (d, J=6.5 Hz, 3H); MS (FAB, THG) 510 (M-H).

W O 97tO1569 PCT/~.6~ 5 Example B7: Preparation of compound No. B1.7 Ph~/ O~ -- O~
B1.6 >
HO OH
~OH
HO OH

B1 .7 The amine B1.6 (0.09 g, 0.176 mmol) is dissolved in dry MeOH (1.5 ml) and CH2CI2 (1.8 ml) and activated 3A molecular sieves (about 0.2 g), cinnamaldehyde (24,ul, 0.19 mmol) and acetic acid (9 ~I) are added. The yellowish suspension is stirred for 2 minutes and then NaBH3(CN) (0.018 g, 0.286 mmol) is added. After 1.5 hours, the mixture is filtered through a cellulose filter (pore size 45 ,um), the filter is washed with 1 :1 MeOH/ CH2CI2, and the filtrate is concentrated in vacuo. The glassy residue is taken up in water (5 ml), and the solution is acidified (about pH 1-2) with 1 M hydrochloric acid (0.7 ml). The cloudy solution is again filtered through a cellulose filter (pore size 45,um), 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 ~lm, 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/H2O to 70 ~/O MeOH/
H20), resulting in the target molecule B1.7 (0.03 g, 27 %) as a fluffy white solid (after Iyophi-lization). lH NMR (500 MHz, D20) â 7.48 (d, J=8.0 Hz, 2H), 7.41 - 7.31 (m, 3H), 6.83 (d, J=15.4 Hz,1 H), 6.26 (dt, J=15.4, 7.0 Hz, 1 H), 4.92 (d, J=3.8 Hz,1 H), 4.56 (q, J=6.3 Hz, 1 H), 4.43 (d, J=7.6 Hz,1 H), 4.31 (dd, J=3.5, 8.2 Hz,1 H), 3.98 (d, J=3.0 Hz,1 H), 3.88 - 3.81 (m, 2H), 3.84 (d, J=6.0 Hz, 1 H), 3.76 - 3.63 (m, 5H), 3.60 - 3.51 (m, 2H), 3.49 (dd, J=3.0, 10.4 Hz,1H), 3.49 - 3.41 (m, 1H), 3.41 (dd, J=3.5, 13.2 Hz, lH), 3.26 (dd, J=8.5,13.2 Hz, 1H), 2.02 (m, 2H), 1.64 (br s, 2H),1.27 - 1.12 (m, 4H),1.12 (d, J=6.3 Hz, 3H); MS (FAB, THG) 650 (M+Na), 628 (M+H).

W O 97/01569 PCT/~1,5.'~7X5 Examr le B8: Preparation of the compound No. B1.8 C~ CO2Na ~0~0 Bl.7 > HO OH

~OH
HO OH
Bl .8 A solution of the amino acid B1.7 (0.01 9, 0.0159 mmol) in 1 M aq. NaHCO3 (0.1 ml) is cooled to 0~C and, while stirring vigorously, a 1 M solution of benzoyl chloride in benzene (16.0 ~11) is added. After 40 minutes, a further 8.0,ul of the benzoyl chloride solution is added, after 130 minutes a further 3.0111 and after a total of 3.5 hours a further 1.0 ~11. After a total of 4 hours, the reaction mixture is diluted with water and extracted with CH2CI2 in order to remove the excess reagent. The aqueous phase is concentrated in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65,um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.49 ml/min, detection at 215 nm) and subse-quent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 60 % MeOH/
H20 to 70 % MeOH/H20), resulting in the target molecule B1.8 (7.9 mg, 66 %) as a fluffy white solid (after Iyophilization).1H NMR (500 MHz, D2O): 1.4:1 mixture of rotamers, charac-teristic signals: ~ 7.52 - 7.24 (m,1 OH, 2xPh), 6.71 (d, J=15.5 Hz, 0.42H, PhCH=CH), 6.42 (dt, J=15.5, 6.1 Hz, 0.42H, PhCH=CH), 6.39 (d, J=15.5 Hz, 0.58H, PhCH=CH), 6.13 (dt, J=15.5, 5.6 Hz, 0.58H, PhCH=CH), 4.92 (d, J=4.0 Hz,1H, Fuc-1H),7.16 (d, J=7.0 Hz, 1.26H, Fuc-6H),1.11 (d, J=6.8 Hz,1.74H, Fuc-6H); MS (FAB, THG) 776 (M+Na), 754 (M+H).

CA 02224346 l997-l2-lO
W O 97/01569 PCT~EF9''~2/~5 Example B9: Preparation of compound No. B1.9 and No. B1.10 rH ~ ~ ~0 l H2 HO OH CH2 CH2 HO OH
Ph fo~ Ph Ph ~ 7 B1.9- B1.10 A CH2CI2 solution of freshly distilled benzaldehyde (0.083 g in 1.0 ml CH2CI2, 0.1 ml, 0.078 mmol), activated 3A molecular sieves (0.1 g) and glacial acetic acid (5 1ll, 0.087 mmol) are added to a solution of the amino acid B1.6 (0.04 g, 0.078 mmol) in MeOH/
CH2CI2 (1 :1,1.0 ml). The suspension is stirred at room temperature and, after 2 minutes, NaBH3(CN) (0.008 g, 0.129 mmol) is added. After 2.5 hours, a further 15 ~11 of the benzalde-hyde solution are added, and the mixture is stirred for a further hour. The reaction mixture is diluted with water, acidified with dilute acetic acid and filtered through a cellulose filter (pore size 45 ~lm), and the filtrate is adjusted to pH 8-9 with 1 M aqueous NaHCO3 solution and then concentrated. The residue is purified by gel filtration on Bio-Gel P2 (particle size 65 ,um, 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/H2O to 60 % MeOH/H2O), with elution first of the monobenzylamine B1.9 (0.020 g, 41 %) and then of the dibenzylamine B1.10 (0.005 g, 9 %).
Monobenzylamine B1.9: 'H NMR (500 MHz, D2O) ~ 7.45 (s, 5H), 4.93 (d, J=4.0 Hz,1H), 4.57 (q, J=6.7 Hz, lH), 4.45 (d, J=7.6 Hz,1H), 4.33 (dd, J=3.8, 8.8 Hz,1H), 4.28 (d, J=13.3 Hz,1H), 4.24 (d, J=13.3 Hz,1H), 3.99 (d, J=3.1 Hz,1H), 3.85 (dd, J=3.5,10.2 Hz,1H), 3.74 - 3.65 (m, 5H), 3.59 - 3.54 (m, 2H), 3.49 (dd, J=3.2, 9.7 Hz,1 H), 3.48 - 3.44 (m,1 H), 3.42 (dd, J=3.7,13.2 Hz, 1 H), 3.26 (dd, J=8.9, 13.2 Hz, 1 H), 2.04 (m, 2H),1.65 (br s, 2H),1.28 -1.14 (m, 4H),1.12 (d, J=6.7 Hz, 3H); MS (FAB, THG) 624 (M+Na), 602 (M+H).
Dibenzylamine B1.10: 1H NMR (500 MHz, D20): the signals of the 6 H a to the N are very broad at room temperature (d 4.10 - 3.60, 4H and 3.12 - 2.67, 2H) ~ 7.38 (s,10H), 4.93 (d, W O 97/OlS69 PCT~EP96/0278S
. -59-J=4.0 Hz,1 H), 4.60 (q, J=6.6 Hz,1 H), 4.43 (d, J=8.0 Hz,1 H), 4.23 (dd, J=3.6, 8.5 Hz,1 H), 3.88 - 3.83 (m, 2H), 3.75 - 3.63 (m, 5H), 3.56 (dd, J=8.0, 9.3 Hz,1 H~, 3.53 - 3.44 (m,2H), 3.32 (dd, J=3.0, 9.5 Hz,1H), 2.13 - 1.98 (m, 2H),1.66 (br s, 2H),1.31 - 1.10 (m, 4H),1.14 (d, J=6.6 Hz, 3H); MS (FAB, THG) 714 (M~Na), 692 (M+H).

Example B10: Preparation of compounds No. B1.11 and No. B1.12 COOH COOH
OH I OH
Bl.6 ~ ~ ~~ ~--H3C CH ~OH )~ ~ ~OH
HoOHH3C CH3 H3C CH3 HoOH

B1.11 Bl.12 A 1 M CH2CI2 solution of isobutyraldehyde (0.156 ml), activated 3A molecular sieves (0.2 g) and glacial acetic acid (10 ~I, 0.17 mmol) are added to a solution of the amino acid B1.6 (0.08 g, 0.156 mmol) in MeOH/ CH2CI2 (1 :1, 2.0 ml). The suspension is stirred at room tem-perature and, after one minute, NaBH3(CN) (0.016 g, 0.258 mmol) is added. After 60 minutes, the reaction mixture is diluted with water and filtered through a cellulose filter (pore size 45 ~Lm), and the filtrate is adjusted to pH 8-9 with 1 M aqueous NaHCO3 solution and then concentrated. The residue is purified by gel ~ill,~Lion on Bio-Gel P2 (particle size 65,um, 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/H2O to 50 % MeOH/H2O), with elution first of the monoisobutylamine B1.11 (0.041 g, 46 %) and then of the diisobutylamine B1.12 (0.01 g, 10 %).
Monoisobutylamine B1.11: 'H NMR (500 MHz, D2O) ~ 4.92 (d, J=4.0 Hz,1H), 4.59 (q, J=6.7 Hz,1 H), 4.47 (d, J=7.6 Hz,1 H), 4.29 (dd, J=4.0, 9.0 Hz,1 H), 3.98 (d, J=3.5 Hz,1 H), 3.85 (dd, J=3.3,10.0 Hz,1 H), 3.76 - 3.65 (m, 5H), 3.56 (dd, J=7.5, 9.3 Hz,1 H), 3.59 - 3.54 (m, 1 H), 3.50 (dd, J=3.0, 9.7 Hz,1 H), 3.50 - 3.43 (m,1 H), 3.34 (dd, J=3.9,13.0 Hz,1 H), 3.20 (dd, J=9.2,13.2 Hz, lH), 2.90 (dd, J=7.6,12.0 Hz, lH), 2.86 (dd, J=7.3,12.0 Hz, lH), 2.11 -W O 97/OlS69 PCT/~1,5.~7~5 1.99 (m, 2H),1.96 (non, J=6.9 Hz,1H),1.65 (m, 2H),1.28 - 1.11 (m, 4H),1.14 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 6H); MS (FAB, THG) 590 (M+Na), 568 (M+H) Diisobutylamine B1.12: 'H NMR (500 MHz, D20) ~ 4.92 (d, J=4.1 Hz,1 H), 4.59 (q, J=6.7 Hz, 1 H), 4.46 (d, J=7.1 Hz,1 H), 4.36 (t, J=6.6 Hz,1 H), 4.02 (br s,1 H), 3.85 (dd, J=3.3,10.3 Hz, 1 H), 3.76 - 3.66 (m, (m, 5H), 3.57 (dd, J=4.7, 7.5 Hz,1 H), 3.55 - 3.50 (m, 2H), 3.49 - 3.39 (m, 3H), 3.07 (br s, 4H), 2.12 (non, J=6.8 Hz, 2H), 2.12 - 1.99 (m, 2H),1.65 (br s, 2H),1.28 -1.11 (m, 4H),1.13 (d, J=6.7 Hz, 3H), 0.97 (d, J=6.8 Hz,12H); MS (FAB, THG) 646 (M+Na), 624 (M+H).

Example B11: Preparation of compound No. B1.13 COONa ~0~~0~
B1.11 ' o~N~ HO OH

Ph H ClCH ~OH

Bl .13 A 1 M solution of benzoyl chloride in toluene (41 ,ul) 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 NaHCO3 (100 ~11). The mixture is stirred vigorously and, after 1 hour, further benzoyl chloride (41 ~l of the 1 M solu-tion) is added. After the reaction is complete, the volatile constituents are removed under high vacuum, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65,um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chrlj",atography (Merck RP18 silica gel, elution:
45 % MeOH/H2O) and then Iyophilized, resulting in the benzamide B1.13 as a fluffy powder, (0.014 g, 59 %). 'H NMR (500 MHz, D20): 1:1 rotamer mixture: ~ 7.50 - 7.37 (m, 5H), 4.93 (d, J=4.0 Hz, 0.5H), 4.92 (d, J=4.0 Hz, 0.5H), 4.60 (q, J=6.4 Hz,1 H), 4.48 (d, J=8.0 Hz, 0.5H), 4.37 (d, J=8.0 Hz, 0.5H), 4.32 (dd, J=4.5, 8.0 Hz, 0.5H), 4.02 (dd, J=4.3, 8.7 Hz, 0.5H), 3.94 (d, J=3.2 Hz, 0.5H), 3.89 - 3.83 (m,1.5H), 3.82 - 3.61 (m, 7H), 3.60 - 3.52 (m, 1.5H), 3.51 - 3.43 (m, 2.5H), 3.25 (dd, J=7.9, 14.2 Hz, 0.5H), 3.20 (dd, J=7.9,14.2 Hz, W O 97/01569 PCT~EPg6/02785 0.5H), 3.17 - 3.10 (m,1 H), 2.16 - 1.97 (m, 2.5H),1.86 (non, J=6.9 Hz, 0.5H),1.65 (br s, 2H), ~ 1.29 - 1.14 (m, 4H),1.17 (d, J=6.4 Hz,1.5H),1.11 (d, J=6.6 Hz,1.5H), 0.95 (d, J=6.5 Hz, 1.5H), 0.92 (d, J=6.6 Hz, 1.5H), 0.65 (d, J=6.4 Hz,1.5H), 0.65 (d, J=6.5 Hz,1.5H); MS
(FAB, THG) 716 (M+Na), 694 (M+H).

Example B12: Preparation of compound No. B1.14 COONa ~0~00~
B1.G ~ ,NH OH

$1 H~

Bl .1 4 A 1 molar solution of ~nitrobenzenesulfonyl chloride in toluene (43,ul) is added with vigorous stirring to a solution of the amino acid B1.6 (0.02 g, 0.039 mmol) in 1 molar aqueous NaHCO3 solution (0.2 ml). The reaction mixture is stirred at room temperature for 16 hours and then concentrated in vacuo. The residue is taken up in water (0.3 ml) and purified by gel filtration on Bio-Gel P2 (particle size 65 ,um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm). The crude product (0.025 g) is further purified by two reverse phase chromatographies (Merck RP18 silica gel,1st chromatography: elution with 50 % MeOH/H2O; 2nd chromatography: elution with 40 %
MeOH/H2O) and subsequently Iyophilized, resulting in the target compound as a fluffy powder (0.0105 9, 39 %).1H NMR (400 MHz, D2O) ~ 8.39 (m, 2H), 8.07 (m, 2H), 4.93 (d, J=4.0 Hz, 1 H), 4.56 (q, J=6.6 Hz, 1 H), 4.43 (d, J=7.9 Hz,1 H), 3.96 (dd, J=3.5, 7.1 Hz,1 H), 3.88 - 3.83 (m, 2H), 3.76 - 3.64 (m, 5H), 3.54 - 3.44 (m, 3H), 3.38 (dd, J=3.5,13.7 Hz,1 H), 3.33 (dd, J=3.2, 9.6 Hz, 1H), 3.19 (dd, J=7.3,13.7 Hz, 1H), 2.05 (br t, J=13.4 Hz, 2H),1.66 (br s, 2H), 1.30 - 1.12 (m, 4H), 1.14 (d, J=6.6 Hz, 3H); MS (FAB, THG) 719 (M+Na), 697 (M+H).

CA 02224346 l997-l2-lO
W O 97/01569 PcT/EP~ 7XS

~62-ExamPle B13: Preparation of compound No. B1.15 COONa Bl.6 ~NH

Bl .1 5 A 1 molar solution of p-toluenesulfonyl chloride in toluene (22 ~LI) 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 NaHCO3 solution (0.1 ml). The reaction mixture is stirred at 0~C for 90 minutes, after which further p-toluenesulfonyl chloride (10,ul 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 llm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 mUmin, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution with 45 % MeOH/H2O) and subsequently Iyophilized, resulting in the target compound as a fluffy powder (0.004 g, 30 %). 'H NMR (400 MHz, D2O) ~ 7.69 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 4.88 (d, J=3.9 Hz,1 H), 4.52 (q, J=6.6 Hz, 1 H), 4.35 (d, J=7.9 Hz,1 H), 3.85 - 3.78 (m, 2H), 3.74 (d, J=2,8 Hz,1 H), 3.71 - 3.56 (m, 5H), 3.50 -3.39 (m, 3H), 3.29 (dd, J=3.4,13.8 Hz,1H), 3.10 (dd, J=3.1, 9.6 Hz,1H), 3.03 (dd, J=8.0, 13.8 Hz, lH), 2.34 (s, 3H), 2.08 - 1.93 (m, 2H),1.61 (brs, 2H), 1.26 - 1.07 (m, 4H),1.09 (d, J=6.6 Hz, 3H).

W O 97/OlS69 PcT/~~ o~7#5 . -63-Example B14: Preparation of compound No. B1.16 CO2Bn S:02Na OH ¦ OH
16 ~ f ~ ~?-- ~ NH ~~
~~ HO OBn ¦ O:~ HO OH
CF3 ~OBn CF3 --~OH
BnO OBn HO OH

24 B1.1 6 Pentafluorophenyl trifluoroacetate (4.5 ml, 0.026 mmol) is added at room temperature with stirring to a solution of the isoserine derivative 16 (0.025 g, 0.026 mmol) and triethylamine (0.7 ml, 0.005 mmol) in DMF (100 ml). After 15 min, further pentafluorophenyl trifluoro-acetate (2.5 ml, 0.015 mmol) is added. 30 minutes later, further triethylamine (2.8 ml, 0.02 mmol) and pentafluorophenyl trifluoroacetate (4.5 ml, 0.026 mmol) are added. The same amount of the latter reagent is added once again 20 minutes later. The mixture is stirred for a further 45 minutes and than saturated aqueous NaHCO3 solution (0.2 ml) is added, ancl the mixture is diluted with water and extracted several times with ethyl acetate.
The combined organic phases are dried (Na2SO4), filtered and concentrated in vacuo. The crude product (0.04 g) is purified by flash chro",atcgraphy on silica gel as eluent: ethyl acetate/toluene 1 :3), resulting in the trifluoroacetamide 24 (0.022 g, 83 %).
Deprotection of 24: dioxane (1.4 ml), water (0.7 ml) and glacial acetic acid (0.35 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20 %, 0.02 g) and the benzyl ether 24 (0.021g, 0.021 mmol). The flask is evacuated and flushed with argon several times. lt is then flushed with hydrogen, and the black mixture is hydrogenated under slightly elevated pressure for 3.5 hours. The reaction mixture is filtered through a cellulose filter (pore size 45 ,um), and the filtrate is concentrated in vacuo. A solution of the residue in a little water is passed through an ion exchanger column (Dowex 50, Na+ form, column dia-meter 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 ~lm, 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/H2O to 40 % MeOH/H2O), resulting in the target W O 97t01569 PCT~EP96/02785 molecule B1.16 (0.0085 g, 68 %) as a fluffy colourless solid (after Iyophilization). 'H NMR
(500 MHz, D20) â 4.93 (d, J=3.9 Hz,1 H), 4.59 (q, J=6.5 Hz,1 H), 4.45 (d, J=8.2 Hz,1 H), 4.08 (dd, J=3.4, 8.2 Hz, lH), 3.91 (d, J=3.1 Hz, lH), 3.86 (dd, J=3.1,10.0 Hz, lH), 3.75 (d, J=3.1 Hz, lH), 3.72 (dd, J=3.9, 10.0 Hz,1H), 3.73 - 3.65 (m, 4H), 3.61 - 3.50 (m, 3H), 3.50 -3.44 (m, lH), 3.42 (dd, J=3.1, 9.6 Hz, lH), 2.10 - 2.00 (m, 2H),1.65 (m, 2H), 1.28 - 1.15 (m, 4H),1.14 (d, J=6.5 Hz, 3H); MS (FAB, THG) 652 (M+Na), 630 (M+H), 608 (M+2H-Na).

Example B15: Preparation of compound No. B1.17 CO2Bn CO2Na OH I OH
16 ~ NH ~~ ~~~~~~~
~==r< HO OBn ~==~ HO OH
~OBn ~ ~OH

26 B1.17 (a) Preparation of the amide 26. Diisopropylcarbodiimide(17 ml, 0.11 mmol) is added at room temperature with stirring to a mixture of the amine 16 (0.027 9, 0.028 mmol), cyclo-hexanecarboxylic acid (0.011 9, 0.086 mmol),1-hydroxybenzotriazole (0.021 9, 0.155 mmol) and dry THF (0.9 ml). After 20 minutes, dry DMF (0.4 ml) is added, and the mixture is stirred for a further hour. The reaction mixture is concentrated in vacuo, and the remaining DMF removed under high vacuum. The residue is purified by flash chromatogra-phy on silica gel (CH2CI2/isopropanol 39:1), resulting in the amide 26 (0.024 9, 80 %).
(b) Deprotection of 26: dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) are added to a mixture of Pd(OH)21C (Pearlman catalyst, Pd content 20%, 0.03 9) and the benzyl ether 26 (0.024 9, 0.022 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black mixture is hydrogenated under slightly elevated pressure for 18 hours. The reaction mixture is filtered through a cellulose filter (pore size 45 ~m), and the filtrate is concentrated in vacuo. A solution of the residue in a little water is passed through an ion exchanger column (Dowex 50, Na+ form, column diameter 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated CA 02224346 l997-l2-lO

W O 97/01569 PCT/~,5.'0~7~S

in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 llm, ~ column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH/H2O 3:2), resulting in the target moiecule B1.17 (0.008 g, 56 %) as a fluffy colourless solid (after Iyophilization). 'H NMR (500 MHz, D2O) 4.93 (d, J=4.0 Hz, 1 H), 4.60 (q, J=6.7 Hz,1 H), 4.47 (d, J=8.0 Hz,1 H), 4.04 (dd, J=3.8, 7.5 Hz,1H), 3.92 (d, J=2.8 Hz,1H), 3.86 (dd, J=3.2,10.3 Hz, lH), 3.75 (d, J=3.3 Hz, lH), 3.74-3.64 (m, 4H), 3.61 (dd, J=3.8,13.8 Hz,1H), 3.59 - 3.52 (m, 2H), 3.50 - 3.44 (m,1H), 3.42 (dd, J=3.3, 9.8 Hz,1 H), 3.35 (dd, J=7.7,14.0 Hz,1 H), 2.19 (tt, J=3.3,11.5 Hz,1 H), 2.11 -2.00 (m, 2H),1.78 - 1.57 (m, 7H),1.34- 1.08 (m. 9H),1.15 (d, J=6.5 Hz, 3H); MS (FAB, THG) 644 (M + H), 622 (M+ 2H - Na).

Example B16: Preparation of the compound B1.18 CO Bn 13 + A2 Phf H~O~n BnO

A solution of the triol 13 (0.129 g, 0.17 mmol) in dry MeOH (4.0 ml) and di-n-butyltin oxide (0.064 g, 0.258 mmol) is boiled under reflux in an argon atmosphere for 2 hours. The clear solution is concentrated in vacuo, and the residue is mixed with pentane (2 ml), again con-cenlr~ted and then dried under high vacuum for 30 minuten in order to remove remainin MeOH. The residue is mixed under an argon atmosphere with dry CsF (0.131 g, 0.86 mmol, weighed under argon) and dry 1,2-dimethoxyethan (0.5 ml) followed by a solution of benzyl (R)-4-phenyl-2-trifluoromethanesulfonyloxybutyrate (A2) (0.3 g, 0.861 mmol) in dry 1,2-di-methoxyethane (1.0 ml). The reaction mixture is stirred at room temperature for 75 minutes and 1 M of aqueous KH2PO4 is added, and the mixture is diluted with water and extracted with ethyl acetate (phase separation is facilitated by adding a little aqueous KF solution).
The organic extracts are combined, dried with Na2SO4, filtered and concentrated in vacuo, W O 97/01569 PCT~EP96/02785 resulting in the crude product as an oil (0.39 g). Purification by flash chromatography on siiica gel (eluent: toluene/ethyi acetate 5:1) results in the pure ether30 (0.143 g, 81 %). 'H
NMR (250 MHz, CDCI3) ~ 7.35 - 7.05 (m, 30H), 5.13 (d, J=12.1 Hz,1H), 5.03 (d, J=12.1 Hz, 1 H), 4.88 (d, J=11.4 Hz, 1 H), 4.87 (d, J=2.0 Hz,1 H), 4.78 - 4.50 (m, 5H), 4.46 (d, J=12,5 Hz,1H), 4.40 (d, J=12.5 Hz, 1H), 4.33 (q, J=6.5 Hz,1H), 4.24 (d, J=7.8 Hz,1H), 4.09 (dd, J=4.0, 8.5 Hz,1 H), 3.93 (br s, 2H), 3.80 - 3.38 (m, 7H), 3.26 - 3.17 (m, 2H), 2.86 - 2.62 (m, 2H), 2.59 (d, J=2.0 Hz, 1 OH), 2.29 (br s,1 OH), 2.11 - 1.85 (m, 4H), 1.67 - 1.52 (m, 2H), 1.40 - 1.06 (m, 4H), 1.03 (d, J=6.5 Hz, 3H).

CO2Na OH
~ ~~~--~o~

b) ~ZOH
HO OH
B1.18 The benzyl ether 30 (0.14 9, 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 ~lm), 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 Dowex50 (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/H2O) and subsequent gel filtration on Bio-Gel P2 (particle size 65 llm, column diameter 2.5 cm, length 35 cm, eluent:
water, flow rate 0.5 ml/min, detection at 215 nm) and then Iyophilized, resulting in the target compound B1.18 as a fluffy powder (0 045 9, 55 %). 1H NMR (500 MHz, D2O) ~ 7.35 - 7.27 (m, 4H), 7.22 (tt, J=1.5, 7.0 Hz, 1 H), 4.93 (d, J=4.0 Hz,1 H), 4.60 (q, J=6.7 Hz, 1 H), 4.47 (d, J=7.8 Hz, 1 H), 3.89 - 3.82 (m, 3H), 3.76 (d, J=3.5 Hz,1 H), 3.74 - 3.63 (m, 4H), 3.59 - 3.52 (m, 2H), 3.51 - 3.45 (m,1H), 3.37 (dd, J=3.5, 9.8 Hz,1H), 2.80 - 2.68 (m, 2H), 2.12 - 1.99 CA 02224346 l997-l2-lO

W O 97/OlS69 PCT~EP96/02785 (m, 3H),1.98 - 1.89 (m,1H), 1.65 (brs, 2H),1.30 - 1.13 (m, 4H),1.15 (d, J=6.6 Hz, 3H); MS
(FAB, THG) 609 (M+Na), 587 (M+H).

Example B17: Preparation of the compound No. B1.19 C02Na OH
B1.18 ~ ~~~~O~

OH

B1.19 The aromatic compound B1.18 (0.02 g, 0.033 mmol) is dissolved in water (1.8 ml), dioxane (1.2 ml), glacial acetic acid (0.3 ml). and 5% Rh/AI203 (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 llm) 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 ,um, 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 ~lm) 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 ~rn, 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/H2O) and subsequently Iyophi-lized, resulting in the target compound B1.19 as a fluffy powder (0.01 g, 50 %). 'H NMR
(250 MHz, D2O) ~ 4.83 (d, J=4.0 Hz,1 H), 4.48 (q, J=6.7 Hz, 1 H), 4.35 (d, J=7.8 Hz,1 H), 3.81 - 3.69 (m, 3H), 3.67 - 3.53 (m, 5H), 3.49 - 3.31 (m, 3H), 3.25 (dd, J=3.1, 9.7 Hz,1H), W O 97/OlS69 PCT~EP96/02785 2.03 - 1.87 (m, 2H), 1.72 - 1.38 (m, 9H),1.24 - 0.97 (m,10H),1.04 (d, J=6.6 Hz, 3H), 0.75 (br s, 2H); MS (FAB, THG) 615 (M+Na), 593 (M+H).

Example B18: Preparation of the compound B1.38 COONa B1.11 ~ O2N~S\ ~O~O~
~ HO OH
H3C CH3 H~OH

Bl .38 A solution of ~nitrobenzenesulfonyl chloride in toluene (1 M,150,ul) is added to a solution of amino acid B1.11 (0.035 g, 0.0617 mmol) in 1 molar aqueous NaHCO3 solution (315 ,ul).
The mixture is vigorously stirred at room temperature and, after 17 hours, further ~nitro-benzenesulfonyl chloride solution (120 ,ul) 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 ,um, 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/H2O) and then Iyophilized, resulting in the sulfonamide Bl .38 (0.013 g, 27%) as a colourless fluffy powder. 'H NMR (400 MHz, D20) ~ 8.34 (m,2H), 8.05(m, 2H), 4.88 (d, J=4.0Hz,1 H), 4.53 (q,J=6.5Hz,1 H), 4.38 (d, J=7.9 Hz,1 H) 4.06 (dd, J=3.9, 8.2 Hz,1 H) 3.84-3.79 (m, 2H), 3.70 (d, J=3.0 Hz,1 H), 3.67 (dd, J=3.9,10.4 Hz,1 H), 3.69 - 3.58 (m, 3H), 3.57 - 3.38 (m, 5H) 3.25 (dd, J=3.2, 9.5 Hz,1H) 3.10 (dd, J=7.7,14.1 Hz,1H) 3.05 (dd, J=7.7,14.1 Hz, 1 H), 2.07-1.94 (m, 2H) 1.89 (hep, J=6.7 Hz,1 H),1.61 (br s, 2H),1.25 -1.07 (m, 4H),1.10 (d, J=6.6 Hz, 3H) 0.70 (d, J=6.6 Hz, 3H), 0.63 (d, J=6.6Hz, 3H).

The following compounds are prepared in analogy to the above examples:

W O 97/OlS69 PCTnEP96102785 C~2R3 Table 1: R~--O~
HO OH
H3C~OH
¦ OH
OH

Preparation Compound No. R3 ' R4 FAB-MS
according to - THG
Example No.
B15 B1.20 Na CH2NHC(O)C11H23 716(M+H) 738(M+Na) B15 B1.21 Na CH2NHC(O)CH(C6Hs)2 723(M+H) 750(M+Na) B12(') B1.22 Na CH2NHC(O)C2H4CO2Na 656(M~H) 678(M+Na) B15 B1.23 Na CH2NHC(O)C6t(1,3,4,5)0H]4H7 708(M+
quinamide B15 B1.24 Na CH2NHC(O)C6H4-p-SO3Na 740(M+H) 762(M+Na) B12 B1.25 Na CH2NHC(O)C6H4CI 672(M+H) 694(M+Na) B12 B1.26 Na CH2NHC(O)C6H4NO2 683(M+H) 705(M+Na) B12 B1.27 Na CH2NHC(O)C6H40CH3 668(M+H) 690(M+Na) B12 B1.28 Na CH2NHC(O)C6H4(3.4)C12 706(M~H) 728(M~Na) B12 B1.29 Na CH2NHC(O)C6H4CH3 652(M~H) 674(M+Na) B1 2(2) B1.30 Na CH2NHC(O)C6H4C6H5 714(M+H) 736(M+Na) W O 97101569 PCT~EP96/02785 . -70-Preparation Compound No. R3 R4 FAB-MS
according to THG
Example No.
B1 2(3) B1 .31 Na CH2NHC(O)C6H4CN 663~M+H) 655~M+Na) B1 2 B1 .32 Na CH2NHC(O)CloH7 688~M+H) 710~M+Na) B1 2(4) B1 .33 Na CH2NHC(O)C6H4COONa 704~M+H) 726(M+Na) B1 2(5) B1 .34 Na CH2NHC(O)(CHOH)2COONa 688~M+H) 710~M+Na) B1 1 B1 .35 Na CH2N[C(O)C6H5]CH2C6H5 728~M+H) 750~M+Na) B1 1 B1 .36 Na CH2N[C(O)C6H5](CH2)3C6H5 756(M+H) 778(M+Na) B1 5(6) B1 .37 Na CH2NHSO2CF3 666(M+H) 688(M+Na) (') using a solution of succinic anhydride in DMF as reagent (2) using a solution of pentafluorophenyl biphenylcarboxylate in dioxane as reagent (3) using a solution of pentafluorophenyl p-cyanobenzoate in dioxane as reagent 4) using a solution of methyl pentafluorophenyl terephthalate in dioxane as reagent. After completion of amide formation, 1 M aqueous NaOH is added to the reaction mixture, which is heated at 65~C until hydrolysis of the methyl ester is complete.
5) 1 M NaOH is used in place of 1 M NaHCO3. A solution of (+)-di-O-acetyl-L-tartaric an-hydride in dioxane is used as reagent.
The formation of the amide takes place in CH2CI2 at 0~C using trifluoromethanesulfonic anhydride as reagent.

CA 02224346 l997-l2-lO

W O 97/01569 PCT~EP96/02785 Example B19: Preparation of compound No. B1.39 .

OH COOBn HO ~ o ~~ ~~/ H~l_ O~
f~O O F3C~ 'o ~ ~~~ ~

Bn~oBn C~ OBn ~ d ~ O~OBn A suspension of 13 (0.086 g, 0.11 mmol) and di-n-butyltin oxide (0.05 g, 0.19 mmol) in dry benzene (3.3 ml) is boiled under reflux in an argon atmosphere for 12 hours. The reaction mixture is concentrated in vacuo and dried under high vacuum for one hour. Then CsF
(dried under high vacuum at 300~C for several hours, 0.042 g, 0.274 mmol) is added under an argon atmosphere, followed by dry 1,2-dimethoxyethane (0.6 ml) and a solution of triflate A3 (0.25 g, 0.66 mmol) in dry 1,2-dimethoxyethane (0.4 ml). The reaction mixture is heated to 35 to 40~C and stirred at this temperature for 5 hours. Then a solution of 15% KF in 1 M
aqueous KH2PO4 solution (30 ml) is added, and the mixture is extracted three times with CH2CI2, and the combined organic phases are dried (Na2SO4), filtered and concentrated in vacuo. The oily residue (0.16 g) is purified by column chromatography on silica gel (gradient elution: toluene/ethyl acetate 80:20 to 75:25, then CH2CI2/MeOH 19:1), resulting in the ether 31 (0.049 g, 44 %) as a colourless foam and the precursor 13 (0.035 g, 40 %).

COOBn OH COONa _o ~ H,~ OH
r r ~o O ~'r ~0 0 HO ~ OBn ~ ~OH
~OBn ~ OH
n I OH
BnO HO
31 B1.39 Dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.028 g) and the benzyl ether 31 (0.048 g, 0.047 mmol). The flask is evacuated and flushed with argon several times. lt is then CA 02224346 l997-l2-lO

flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly ele-vated pressure of hydrogen at room temperature for 17 hours and then filtered through a cellulose filter (pore size 45 ~lm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a Dowex50 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,Lm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 230 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution with 7:3 H20/methanol), resulting in the target molecule B1.39 (0.014 9, 51 %) as a fluffy white solid (after Iyophilization): 'H NMR (400 MHz, D2O) ~ 4.83 (d, J=4.0 Hz, 1 H), 4.49 (q, J=6.6 Hz,1 H), 4.33 (d, J=7.7 Hz,1 H), 3.74 (d, J=3.1 Hz,1 H), 3.22 (dd, J=2.6, 9.5 Hz,1H); 13C NMR (100.6 MHz, D2O) ~ 181.5 (Cq)~ 100.2 (CH), 95.7 (CH); MS (FAB, THG) 609 (M+Na), 587 (M+H).

Example B20: Preparation of compound B1.40.

The coupling of the alcohol 13 with the triflate A4 is carried out in accordance with Example B19 (preparation of compound 31).

W O 97/OlS69 PcT/~~ v2l~s COOBn O COONa ~~0 ~ ~0~ ~0 ~ 0~
HO _~OBn HO _~OH

BnO n HO
32 - B1.40 The hydrogenation of the benzyl ether and subsequent purification is carried out in accordance with Example B19 (preparation of compound B1.39): 1H NMR (400 MHz, D2O) 4.88 (d, J=4.1 Hz,1 H), 4.53 (q, J=6.7 Hz,1 H), 4.39 (d, J=7.7 Hz,1 H), 3.29 (dd, J=2.9, 9.8 Hz,1H),1.10 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H), 0.82 (d, J=6.8 Hz, 3H).

Example B21: Preparation of compound B1.41 ~NH ~bNJ~O ~
HO HO

-The hydroxypiperidine (6.0 g, 34.6 mmol, prepared from D~ lyxose in accordance with Ichikawa and Igarashi [Ichikawa, Y., Igarashi, Y., Tetrahedron Letters 36:4585-4586 (1995)]
and triethylamine (18.1 ml,130 mmol) are dissolved in dry tetrahydrofuran (100 ml) and the solution is cooled to -10~C under an argon atmosphere. Allyl chloroformate (3.87 ml, 36.4~mmol) is slowly added over the course of one hour, a white suspension being formed.
The reaction mixture is stirred at -10~C for a further hour, then 1 M aqueous KH2PO4 solution (150 ml) is added, and the mixture is extracted three times with CH2CI2. The combined organic phases are dried (Na2SO4) and concenlr~ted in vacuo, resulting in a yellow oil (9 g).
Purification by column chromatography on silica gel (hexane/ethyl acetate 1 :1) results in the allyl carbamate 34 (7.66 g, 86 %).

W O 97/OlS69 PCT~EP96.0 /~5 HO ~N J~O ~ BzO ~ O~N J~O
BzO

4A molecular sieves (dried under high vacuum at 300~C,15 9) are added to a solution of the acceptor 34 (7.66 g, 29.8 mmol) in dry CH2CI2 (150 ml) under an argon atmosphere, and the suspension is stirred at room temperature for one hour. In parallel with this, a suspen-sion of DMTST (15.4 g, 59.6 mmol) and 4A molecular sieves (15 g) in dry CH2CI2 (150 ml) is prepared under an argon atmosphere in a second round-bottom flask and is stirred for one hour. The DMTST mixture is then added in 4 portions over the course of a further hour to the solution of the acceptor, and the mixture is then stirred for one hour. The reaction mix-ture is filtered through Hyflo Super Cel~ washing thoroughly with CH2CI2. The filtrate is ex-tracted by shaking with 10% aqueous NaHCO3 solution, the aqueous phase is reextracted three times with CH2CI2, and the combined organic phases are dried (Na2SO4), 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 %) .

o o OBz ~~O NJ~~~ OBz HO ~ NJ~~~
--~--o~2~ BzO
BzO OBn B O OBn The acetonide 35 (13.1 9,15.94 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 ~cet~t.q/hexane 2:1), resulting in the diol 36 (11, 23 g, 90 %).

W O 97/OlS69 PCTrEP96/02785 SE~ BzO OBz HO~N J~O

~o~, Bz~ 36 BnO
O
BzO ~j OBn BzO
~ ~ OBn BnO

A mixture of the diol 36 (11.63 g,14.88 mmol), tetra-n-butylammonium bromide (12.7 g, 39.4 mmol) and 4A molecular sieves (dried under high vacuum at 300~C 22 g) is dried under high vacuum for 30 minutes and then, under an argon atmosphere, dry CH2CI2(62 ml) and dimethylformamide (36 ml) are added. The grey suspension is stirred at room temperature for 30 minutes. In parallel with this, a solution of ethyl -2,3,4-tri-~benzyl-1 -thio-L-fucopyranoside (7.48 g,15.62 mmol, prepared by the method of Lonn [Lonn, H.
Carbohydr. Res.139:105-113 (1985)] in dry CH2CI2 (49 ml) is prepared under an argon atmosphere in a second round-bottomed flask and, at 0~C, a bromine solution (2.85 g Br2, 17,84 mmol) in CH2CI2 (25 ml) is added. The red solution is stirred at 0~C for 30 minutes, and the excess bromine is destroyed by adding a few drops of cyclohexene. This solution is then added using a needle to the solution of the acceptor, and the reaction mixture is stirred at room temperature for 40 hours. The reaction mixture is then filtered through Hyflo Super Cel~ and thoroughly washed with CH2CI2 and the filtrate is washed with 10 % aqueous NaHCO3 solution. The aqueous phase is reextracted three times with CH2CI2, and the com-bined organic phases are dried (Na2SO4), 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.

W O 97/01569 PCT/~,5.'~2 O o jZBn ~ O n?
~OBn ~OBn n n BnO BnO

A solution of the ester 37 (2.4 g, 2.0 mmol) and sodium methoxide (0.11 g, 2.0 mmol) in methanol (48 ml) is stirred at room temperature for 8 hours. The clear colourless solution is then neutralized by adding a strongly acidic ion exchanger (Amberlyst15), then filtered through Hyflo Super Cel~ and concenll~ted in vacuo. The oily residue is purified by column chromatography on silica gel (gradient elution: CH2CI2/methanol 98:2 to 95:5), resulting in the triol 38 (1.72 g, 97 %).

Ho~ O~N 0 HO OBn 1~ Ph HO
~OBn ~ZOBn BnOOBn BnO

A suspension of 38 (1.0 g, 1.13 mmol) and di-n-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 concenl-ated in vacuo and dried under high vacuum for one hour. Then CsF
(dried under high vacuum at 300~C for several hours, 0.43 g, 2.82 mmol) is added under an argon atmosphere, followed by dry 1,2-dimethoxyethane (7.4 ml) and a solution of benzyl R-3-phenyl-2-trifluoromethanesulfonyloxypropionate (2.6 g, 6.77 mmol) in dry 1,2-di-methoxyethane (4.9 ml). The reaction mixture is heated to 35 to 40~C and stirred at this temperature for 3 hours. Then a solution of 15% KF in 1 M aqueous KH2PO4 solution (100 ml) is added, and the mixture is extracted three times with CH2CI2, and the combined organic phases are dried (Na2SO4), filtered and concentrated in vacuo. The oily residue W O 97/OlS69 PcT/~~ 7o5 (3.2 g) is purified by column chromatography on silica gel (elution: toluene/ethyl acetate 70:30), resulting in the ether 39 (0.98 g, 78 %) as a colourless foam.

~_ f~ ~, COON~NJ~o~/

h HO OBn I h H OH
~,OBn ~OH
BnO Hd 39 B1.41 Dioxane (3.5 ml), water (1.7 ml) and glacial acetic acid (0.25 ml) are added to a mixture of Pd(OH)2/C (F ,iman catalyst, Pd content 20%, 0.035 g) and the benzyl ether 39 (0.038 g, 0.034 mmoi). The flask is ev~cu~ted and flushed with argon several times. lt is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly ele-vated pressure of hydrogen at room temperature for 24 hours and then filtered through a cellulose filter (pore size 45 ~lm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A solution of the residue in water is passed through a Dowex50 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 ,um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: H20/methanol 65:35 to 55:45), resulting in the target molecule B1.~1 (0.014 g, 5g %) as a fluffy white solid (after Iyophilization): 'H NMR (500 MHz, D2O, +50~C) ~ 7.58 - 7.53 (m, 4H), 7.51 - 7.46 (m,1 H), 5.22 (d, J=4.0 Hz,1 H), 4.57 (d, J=7.6 Hz,1 H), 4.56 (q, J=6.4 Hz, 1 H), 4.33 (dd, J=4.2, 8.6 Hz, 1 H), 4.30 (dt, J=6.3, 3.2 Hz,1 H), 3.66 (dd, J=8.0, 9.4 Hz, 1H), 3.59 (dd, J=3.0,13.8 Hz, 1H), 3.33 (dd, J=4.2, 14.0 Hz, 1H), 3.13 (dd, J=9.0, 14.0 Hz, 1H), 1.82 (sex, J=6.9 Hz, 2H),1.36 (d, J=6.4 Hz, 3H),1.10 (t, J=7.5 Hz, 3H);
MS (FAB, NBA) 720 (M+Na), 698 (M+H).

W O 97/OlS69 PCT~EPg5.'~7~5 Example B22: Preparation of compound B1.42.

o~o HO~ ~~ ~ o A suspension of 38 (0.65 g, 0.73 mmol) and di-n-butyltin oxide (0.32 g,1.28 mmol) in dry benzene (22 ml) is boiled under reflux in an argon atmosphere for 16 hours. The reaction mixture is concentrated in vacuo and dried under high vacuum for one hour. Then CsF
(dried under high vacuum at 300~C for several hours, 0.28 g, 1.83 mmol) is added under an argon atmosphere, followed by dry 1,2-dimethoxyethane (4.0 ml) and a solution of the triflate A5 (1.74 g, 4.4 mmol) in dry 1,2-dimethoxyethane (2.7 ml). The reaction mixture is heated to 35 to 40~C and stirred at this temperature for 3 hours. Then a solution of 15% KF
in 1 M aqueous KH2PO4 solution (100 mL), is added, and the mixture is extracted three times with CH2CI2, and the combined organic phases are dried (Na2SO4), filtered and con-centrated in vacuo. The oily residue (2.6 g) is purified by column chromatography on silica gel (elution: toluene/ethyl acetate 3:1, then CH2CI2/methanol 19:1) resulting in the ether40 (0.33 g, 40 %) as a colourless foam, and partial recovery of the precursor 38 (0.167 g, 26 %).

~OBn --~OH
Bnd O'Bn Hd B1.42 W O 97/01569 PCT~EP96/02785 . -79-Dioxane t1.2 ml), water (0.6 ml) and glacial acetic acid (0.3 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.025 9) and the benzyl ether 40 (0.036 g, 0.032 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 8 hours and then filtered through a cellulose filter (pore size 45 llm). The filtrate is concenl~ted 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 Dowex50 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 ~acuo and purified by gel filtration on Bio-Gel P2 (particle size 65 ~Lm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: H20/methanol 1:1), resulting in the target molecule B1.42 (0.009 g, 41 %) as a fluffy white solid (after Iyophilization): 'H NMR (400 MHz, D2O) ~ 5.09 (d, J=3.7 Hz,1 H), 4.58 - 4.46 (m, 2H), 3.94 (d, J=2.2 Hz, 1 H), 3.58 (t, J=8.4 Hz, 1 H), 3.43 (dd, J=1.8, 9.5 Hz, 1H),1.83 (d, J=12.2 Hz, 1H), 1.23 (d, J=6.7 Hz, 3H), 0.95 (t, J=7.6 Hz, 3H); 13C NMR (100.6 MHz, D2O) ~ 183.0 (Cq)~ 101.6 (CH), 98.0 (CH); MS (FAB, THG) 704 (M+H).

W O 97/OlS69 PCT~EP~5.~2/~5 . -80-Example B23: Preparation of compound B1.43.

COOB~

~OBn 39 n BnO

o ~ ~~ NH ~ o ~ N~

HO ¦ + HO
~OBn ~OBn BnO n BnO n Morpholine (1.1 ml) and Pd(PPh3)4 (0.071 g, 0.062 mmol) are added to a solution of the allyl carbamate 39 (0.695 g, 0.618 mmol) in tetrahydrofuran (8.5 ml). After exactly 15 minutes the solution is concentrated and the residue is dried under high vacuum for one hour. Purification of the residue by column chromatography on silica gel (eluent: CH2CI2/
methanol 98:2, contains 0.3 % concentrated aqueous ammonia solution) gives initially the less polar allylamine 46 (0.24 9, 36 %) followed by the more polar piperidine 41 (0.39 g, 60 %).

W O 97/01569 PCT/~5l~7xs h~ HO ~ Bn ' ~ ~ ~ ~ N

Bn~OBn ~OBn BnO

Pyridine (5 lli, 0.06 mmol) and acetic anhydride (1,8 ~L 1, 0.04 mmoi) are added under an argon atmosphere to a solution of the piperidine derivative 41 (0.035 g, 0.0336 mmol) in dry CH2CI2 (0.6 ml) at 0~C. The solution is stirred at 0~C for 45 minutes and then washed with 5% aqueous NaHCO3 solution, and the aqueous phase is reextracted three times with CH2CI2.The combined organic phases are dried with Na2SO4, filtered and concentrated in vacuo. The residue (0.05 g) is purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 4:1), resulting in the acetylpiperidine 42 (0.033 g, 91 %) as a colourless foam.

~o~N o~
h HO OBn I h H OH
~OBn ~OH
B O OBn HO dH

42 B1.43 Dioxane (1.4 ml), water (0.7 ml) and glacial acetic acid (0.35 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.03 g) and the benzyl ether 42 (0.04 g, 0.037 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 48 hours and then filtered through a cellulose filter (pore size 45 ,um). The filtrate is concent~ated 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 Dowex50 ion exchange column W O 97/OlS69 PCT/~l~5~ 5 . -82-(Natform, 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 ~lm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: methanol/H20 2:3 via 1 :1 to 3:2), resulting in the target molecule B1.43 (0.014 g, 64 %) as a fluffy white solid (after Iyophilization): tH NMR (400 MHz, D2O) ~ 7.22 -7.06 (m, 5H), 4.86 (m, 1 H), 1.95 (s, 3H), 0.98 (d, J=6.7 Hz, 3H); MS (FAB, THG) 654 (M+H), 632 (M~2H-Na).

Example B24: Preparation of compound B1.44.

COOBn COOB~ O~ o OH OH I h~~HO~Bn ~OBn ~~OBn Bn BnO

Compound 43 is prepared from the piperidine 41 (0.02 9, 0.019 mmol) and benzoyl chloride (2.5 ~11, 0.021 mmol) in analogy to a method for the acetylpiperidine 42 (Example B23). The yield is 0.02 g (90 %).

HU I h H~OH
~OBn ~OH
Bnd n Hd 43 B1.44 The target compound B1.44 is prepared by hydrogenation of the benzyl ether 43 (0.042 9, 0.0367 mmol) and subsequent purification in analogy to the acetyl derivative B1.43. The W 0 97/OlS69 PcT/~l~5l~27o5 product results after Iyophilization as a fluffy white solid. Yield: 0.015 g (57 %): MS (FAB, THG) 716 (M+H), 694 (M+2H-Na).

Example B25: Preparation of compound B1.45.

COONa ll ~,~J ~ J~COOMe HO ¦ B1.45 ~OH
Hd OH

The target compound B1.45 is prepared in analogy to Example 23 (preparation of com-pound B1.43) from the piperidine derivative 41: 1H NMR (400 MHz, D2O) ~ 7.28 - 7.13 (m, 5H), 4.95 (m, 1 H), 4.37 - 4.23 (m, 2H), 3.56 (s, 3H), 3.04 (m, 1 H), 2.84 (m,1 H), 2.26 (t, J=7.6 Hz, 2H),1.08 (d, J=7.4 Hz, 3H); MS (FAB, THG) 810 (M+H).

ExamPle B26: Preparation of compound B1.46.

COOBn O o ~0 Bn~oBn Bn~OBn Pyridine (4 ~11, 0.05 mmol) and cyclohexanecarbonyl chloride (7.2 ~11, 0.05 mmol) are added at 0~C to a solution of the piperidine derivative 41 (0.04 g, 0.038 mmol) in dry CH2CI2 (0.7 ml). After 20 minutes, the reaction mixture is washed with 10 % aqueous NaHCO3 solution, and the aqueous phase is reextracted three times with CH2CI2 The combined organic phases are dried (Na2SO4), filtered and concenl~aled in vacuo. Pu,irication by W O 97/OlS69 PCT~EP96/02785 column chromatography as the crude product (0.09 g) on silica gel (eluent: hexane/ethyl acetate 1 :1) gives the amide 45 (0.03 9, 68 %).

HO ' N~O COON o J~o ~OBn ~OH
B o OBn Hd B1.46 Dioxane (1.1 ml), water (0.55 ml) and glacial acetic acid (0.27 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.05 g) and the benzyl ether 45 (0.029 g, 0.025 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 24 hours. Then, for hydrogenation of the aro-matic ring, 5% Rh/C (0.02 g) is added and hydrogenation is continued for 24 hours. The reaction mixture is filtered through a cellulose filter (pore size 45 ,um), 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 Dowex50 ion exchange column (Na+ form, diameter of the column 0.9 cm, length 3.5 cm), washing with deionized water. The clear filtrate is concenl,~ted in vacuo and puri-fied by gel filtration on Bio-Gel P2 (particle size 65 ,um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H2O 60:40), resulting in the target molecule B1.46 (0.012 g, 64 %) as a fluffy white solid (after Iyophilization): 1H
NMR (400 MHz, D2O) ~ 5.04 (m, 1H), 4.48 (m, 1H), 4.45 - 4.32 (m, 1H), 2.72 (m, 1H), 1.17 (d, J=5.8 Hz, 3H); MS (FAB, THG) 728 (M+H), 706 (M+2H-Na).

CA 02224346 l997-l2-lO

W O 97/01569 PCT~EPg6/02785 Example B27: Preparation of compound B1.47.

COOH e N~

~OBn ~_OH

46 B1.47 Dioxane (1.4 ml), water (0.7 ml) and glacial acetic acid (0.35 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.03 9) and the benzyl ether 46 (0.042 9, 0.039 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 16 hours and then filtered through a cellulose filter (pore size 45 ~un). The filtrate is concentrated in vacuo, and the residue is taken up in water and concenl,~ted again several times in order to remove excess acetic acid. The crude product (0.014 g) is purified by gel filtration on Bio-Gel P2 (particle size 65,um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatoyl~phy (Merck RP18 silica gel, elution:
methanol/H20 1 :3) resulting in the target molecule B1.47 (0.009 g, 36 %) as a fluffy white solid (after Iyo,l~hili,ation): 'H NMR (400 MHz, D20) ~ 7.10 - 7.02 (m, 4H), 7.01 - 6.94 (m, 1 H), 4.80 (br s, 1 H), 4.10 (d, J=7.0 Hz, 1 H), 3.84 (dd, J=4.7, 8.5 Hz, 1 H), 3.20 (t, J=8.7 Hz, 1H), 2.97 (dd, J=3.3, 9.7 Hz,1H), 2.83 (dd, J=4.7, 13.1 Hz, 1H), 2.63 (dd, J=8.5,13.1 Hz, 1 H), 0.87 (d, J=7.0 Hz, 3H), 0.63 (t, J=7.3 Hz, 3H); MS (FAB, THG) 654 (M+Na), 632 (M+H).

CA 02224346 l997-l2-lO
W O 97/01569 PCT~EP96/02785 Example B28: Preparation of compound B1.48.

H~-- C~ COOB~n-C 4Hg Bn~OBn Bn~OBn Triethylamine (7 ,~LI, 0.05 mmol) and n-butanesulfonyl chloride (3.7 ,ul, 0.029 mmol) are added at 0~C to a solution of the piperidine 41 (0.025 g, 0.024 mmol) in CH2CI2 (0.3 ml).
After 45 minutes, the reaction mixture is washed with 10 % aqueous NaHCO3 solution, and the aqueous phase is reextracted three times with CH2CI2. The combined organic phases are dried (Na2SO4), 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 %).

H~-- ~~ N' n~ 411, 71_o~-- ~N'~--n-C 4Hg ~OBn H~OH

47 Bl.48 Dioxane (1.0 ml), water (0.5 ml) and glacial acetic acid (0.25 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.013 g) and the benzyl ether 47 (0.027 g, 0.023 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 24 hours and then filtered through a cellulose filter (pore size 45 ~lm). 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 W O 97/OlS69 PCT~EP96/02785 acid. A solution of the residue in water is passed through a Dowex50 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,um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.4~
ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: methanol/H20 35:65 to 45:55), resulting in the target molecule B1.48 (0.011 g, 65 %) as a fluffy white solid (after Iyophilization): 1H NMR (400 MHz, D20) ~ 7.51 - 7.35 (m, 5H), 5.15 (d, J=3.4 Hz,1H), 4.54 (q, J=6.2 Hz, 1H), 4.51 (d, J=8.0 Hz,1H) 4.03 (dd, J=2.8, 10.4 Hz,1 H), 3.59 (t, J=8.9 Hz, 1 H), 3.23 (dd, J=4.8,13.4 Hz, 1 H), 3.05 (dd, J=8.6, 13.4 Hz, 1 H), 1.84 (pen, J=7.6 Hz, 2H), 1.54 (sex, J=7.3 Hz, 2H), 1.27 (d, J=6.6 Hz, 3H),1.02 (t, J=7.5 Hz, 3H); MS (FAB, THG) 732 (M+H).

Example B29: Preparation of compound B1.49.

COONa ~ ~

HO B 1.49 ~o~
k;Z--~OH
H

The target compound B1.49 is prepared in analogy to Example B28 (preparation of com-pound B1.48) starting from the piperidine derivative 41 and ~toluenesulfonyl chloride: lH
NMR (400 MHz, D20) ~ 7.56 (d, J=7.2 Hz, 2H), 7.33 (d, J=7.2 Hz, 2H), 7.28 - 7.11 (m,5H), 4.81 (d, J=3.4 Hz,1 H), 4.22 (d, J=7,9 Hz, 1 H), 3.75 (d, J=2.4 Hz,1 H), 3.65 (dd, J=2.4,10.2 Hz, 1H), 3.41 (t, J=5.7 Hz,1H), 3.32 (t, J=8.7 Hz, 1H), 3.13 (dd, J=2.5, 9.3 Hz,1H), 3.00 (dd, J=4.0,13.6 Hz, 1 H), 2.81 (dd, J=8.9, 13.6 Hz,1 H), 2.67 (br s,1 H), 2.29 (s, 3H), 0.95 (d, J=7.1 Hz, 3H); MS (FAB, THG) 788 (M+Na), 766 (M+H).

W O 97/OlS69 PCT~EP96/02785 Example B30: Preparation of compound B1.50.

I h~ o~ r~ C ~H9 ~OBn ~OH

47B1.50 Dioxane (1.5 ml), water (0.75 ml) and glacial acetic acid (0.38 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.02 g) and the benzyl ether 47 (0.041 g, 0.035 mmol) The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 16 hours. Then, to hydrogenate the aromatic ring, 5% Rh/C (0.025 g) is added, and hydrogenation is continued for 16 hours. The reac-tion mixture is filtered through a cellulose filter (pore size 45 ~Lm), 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 Dowex50 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 ~lm, column diameter 2.5 cm, length 35 cm, eluent:
water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromato-graphy (Merck RP18 silica gel, gradient elution: methanol/H20 40:60 to 50:50), resulting in the target molecule B1.50 (0.021 g, 82 %) as a fluffy white solid (after Iyophilization). 'H
NMR (400 MHz, D2O) ~ 4.97 (d, J=3.7 Hz,1 H), 4.41 (d, J=7.7 Hz, 1 H), 4.36 (q, J=6.7 Hz, 1 H), 3.81 (d, J=2.6 Hz, 1 H), 3.76 (dd, J=2.4, 7.3 Hz, 1 H), 3.55 (dd, J=4.4, 7.2 Hz,1 H), 3.30 (dd, J=2.7, 9.7 Hz, 1H), 1.34 (sex, J=7.4 Hz, 2H),1.10 (d, J=6.7 Hz, 3H), 0.81 (t, J=7.5 Hz, 3H); MS (FAB, THG) 738 (M+H), 716 (M+2H-Na).

CA 02224346 l997-l2-lO

W O 97/01569 PcT/~ s ExamPle B31: Preparation of compound B1.51.

OB,~

OBn I ~ ~ H OBn Bn~OBn ~ Bn~OBn Morpholine (0.37 ml) and Pd(PPh3)4 (0.025 g, 0.021 mmol) are added to a solution of the allyl carbamate 40 (0.24 g, 0.212 mmol) in tetrahydrofuran (2.9 ml). After exactly 15 minu-tes, the solution is concentrated and the residue is dried under high vacuum for one hour.
Purification of the residue (0.38 9) by column chromatography on silica gel (eluent: CH2C12/
methanol 19:1, contains 0.3 % concenlr~ted aqueous ammonia solution) gives the piperi-dine derivative 49 (0.17 g, 76 %).

H~ H,Ph BnO OBn Bn~OBn Phenyl isocyanate (4.6 ~11, 0.042 mmol) and diisopropylethylamine (8.5 ~LI, 0.05 mmol) are added at 0~C to a solution of the piperidine derivative 49 (0.04 g, 0.038 mmol) in CH2C12 (0.6 ml). After 90 minutes, the reaction mixture is washed with 1 M aqueous KH2PO4 solution and the aqueous phase is reextracted three times with CH2CI2. The combined organic phases are dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude product (0.047 g) by column chromatography on silica gel (eluent: hexane/ethyl acetate 58:42) provides the urea derivative 50 (0.035 g, 78 %).

CA 02224346 l997-l2-lO
W O 97/01569 PCT~EP~CI~2~5 COOBn O COONa O
O ~ ~ NJ~N ~Of--~ o ~ H

~OBn H~OH

B1.51 Dioxane (1.3 ml), water (0.65 ml) and glacial acetic acid (0.33 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.018 g) and the benzyl ether 50 (0.036 g, 0.031 mmol). The flask is evacuated and flushed with argon several times. lt is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 16 hours and then filtered through a cellulose filter (pore size 45 ,um). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. A
solution of the residue in water is passed through a Dowex50 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 ~Lm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H2O 1:1), resulting in the target molecule B1.51 (0.018 g, 80 %) as a fluffy white solid lafter Iyophilization): 1H NMR (400 MHz, D2O) ~ 7.14 (t, J=7.9 Hz, 2H), 7.02 (d, J=8.2 Hz, 2H), 6.95 (t, J=7.7 Hz,1 H), 4.87 (d, J=4.0 Hz, 1 H), 4.30 (d, J=7.4 Hz, 1H), 4.23 (q, J=6.6 Hz, 1H), 3.66 (d, J=2.8 Hz, 1H), 3.42 (dd, J=4.4, 7.7 Hz,1H), 3.16 (dd, J=2.6, 9.5 Hz,1H), 1.00 (d, J=6.6 Hz, 3H); MS (FAB, THG) 737 (M+H), 715 (M+2H-Na).

CA 02224346 l997-l2-lO
PCTAEPg6/02785 W 0 97/OlS69 Example B32: Preparation of compound B1.52.
COOB~NH f ~ u ~" Ph H OBn I ' ~ HO OBn ~OBn ~J ~OBn B O OBn 49 BnO

~_o ~ ~Y~Ph ~OH
HO
Bl .52 The piperidine derivative 49 is converted in analogy to Exampie B28 (preparation of com-pound B1.48) using phenylmethanesulfonyl chloride as reagent into the target compound B1.52: 1H NMR (400 MHz, D20) ~ 7.50 (m, 5H), 5.02 (d, J=3.5 Hz,1H), 4.61 (d, J=13.7 Hz, 1 H), 4.54 (d, J=13.7 Hz,1 H), 4.32 (d, J=8.0 Hz,1 H), 3.62 (t, J=6.0 Hz,1 H), 3.52 (dd, J=7.7, 8.4 Hz,1 H), 3.36 (dd, J_3.2, 9.6 Hz,1 H), 3.22 (br d, J=12.6 Hz,1 H),1.17 (d, J=6.5 Hz, 3H);
MS (FAB, THG) 772 (M+H),750 (M+2H-Na).

Example B33: Preparation of compound Bl.53.

COOBn COOH
-- ~Z~H

~OBn ~J OH
BnO ~ OH
49 B1.53 , W O 97/OlS69 PCT~EP~5.'~2/~5 Dioxane (3.7 ml), water (1.8 ml) and glacial acetic acid (0.9 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.05 g) and the benzyl ether 49 (0.09 g, 0.086 mmol). The flask is evacuated and flushed with argon several times. lt is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 48 hours and then filtered through a cellulose filter (pore size 45 llm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. The crude product (0.044 g) is purified by gel filtration on Bio-Gel P2 (particle size 65,um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detektion at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: methanol/H20 30:70 to 50:50), resulting in the target molecule B1.53 (0.04 g, 78 %) as a fluffy white solid (after Iyophilization): 'H NMR (400 MHz, D20) ~ 5.04 (d, J=4.2 Hz, 1 H), 4.43 (d, J=7.6 Hz, 1 H), 4.27 (m, 2H), 4.20 (q, J=6.5 Hz,1 H), 4.02 (dd, J=2.6, 6.6 Hz, 1H), 3.51 (dd, J=7.8, 9.5 Hz,1H),1.12 (d, J=6.2 Hz, 3H); MS (FAB, THG) 618 (M+Na),596 (M+H).

Example B34: Preparation of compound B1.54.

~0~ ~O~N ~
H~OH H~OH

B1.53 B1.54 A 1 M solution of 2-(1-naphthyl)ethanesulfonyl chloride in toluene (46 ~11) is added at room temperature to a solution of the piperidine derivative B1.53 (0.025 g, 0.042 mmol) in 1 M
aqueous NaHCO3 solution (0.22 ml). The mixture is vigorously stirred for 22 hours and then concentrated in vacuo and dried under high vacuum for 15 minutes. The crude product is purified by gel filtration on Bio-Gel P2 (particle size 65,um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse -W O 97101569 PCT~EP96/02785 phase chromatography (Merck RP18 silica gel, elution: methanol/H2O 7:3), resulting in the - target molecule B1.54 (0.011 g, 31 %) as a fluffy white solid (after Iyophilization): 1H NMR
(400 MHz, D20) â 7.72 (d, J=8.8 Hz,1 H), 7.54 (d, J=8.8 Hz,1 H), 7.44 (d, J=8.6 Hz,1 H), 7.28 (t, J=7.2 Hz,1H), 7.22 (t, J=7.2 Hz, lH), 7.14 (t, J=7.2 Hz,1H), 7.08 (d, J=8.7 Hz,1H), 4.91 (d, J=4.1 Hz,1 H), 4.20 (d, J=7.0 Hz,1 H), 3.99 (br s,1 H), 3.90 (br s,1 H),1.09 (d, J=6.3 Hz, 3H); MS (FAB, THG) 858 (M+Na),836 (M+H).

Example B35: Preparation of compound B1.55.

H~_ o ~ o B1.53 B1.55 A 0.5 M solution of acetic anhydride in toluene is added in small portions (50 to 100 ~11) at room temperature to a solution of the piperidine derivative B1.53 (0.035 9, 0.059 mmoi) in 1 M aqueous NaHCO3 solution (0.5 ml) until all the precursor is consumed (test by thin-layer chromatography: silica gel TLC plates, mobile phase: n-butanol/ water/acetone/glacial acetic acid/NH40H 70:60:50:18:1.5). The reaction is complete after about one hour, and the mixture is concentrated in vacuo and dried under high vacuum for 15 minutes. The crude product is purified by gel filtration on Bio-Gel P2 (particle size 65 ~lm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subse-quent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H2O 3:7), resulting in the target molecule B1.55 (0.026 9, 67 %) as a fluffy white solid (after Iyophiliza-tion): 'H NMR (400 MHz, D2O) ~ 5.01 (d, J=4.2 Hz, 0.5H), 4.99 (d, J=4.2 Hz, 0.5H), 4.44 (d, J=7.3 Hz,1H), 4.32 (q, J=6.6 Hz, 0.5H), 3.14 (dd, J=8.0,12.9 Hz, 0.5H), 2.10 (s,1.5H), 2.08 (s,1.511),1.13 (d, J=6.6 Hz, 3H).

CA 02224346 l997-l2-lO

. -94-Example B36: Preparation of compound B1.56.

; -- C ~_o~,l~,ON~

B1.53 B1.56 A 1.5 M solution (+)-di-O-acetyl-L-tartaric anhydride in 1,4-dioxane is added in small portions (50 to 100 ~LI) at room temperature to a solution of the piperidine derivative B1.53 (0.03 g, 0.05 mmol) in 1 A/l 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/NH40H 70:60:50:18:1.5). 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 ~um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/
H20 1 :9), resulting in the target molecule B1.56 (0.020 g, 52 %) as a fluffy white solid (after Iyophilization): MS (FAB, THG) 794 (M+Na), 772 (M+H), 750 (M+2H-Na).

Examcle B37: Preparation of compound B1.57.

H~ ~H

B1.53 B1.57 W O 97/01569 PCT/~l~ o~

N,N-Diisopropylcarbodiimide (11.7 ~LI, 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 (0.015 g, 0.025 mmol) is added. After 3 hours, 10 % aqueous NaHCO3 solution is added (0.15 ml), and the reaction mixture is stirred for a further 20 minutes and then concentrated under high vacuum. The residue is taken up in water, filtered through a cellulose filter (pore size 45 ,~m) and then passed through a Dowex50 ion exchange column (Na~ form, diameter of thecolumn 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 ~um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subse-quent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H2O 1:9), resulting in the target molecule B1.57 (0.007 9, 33 %) as a fluffy white solid (after Iyophiliza-tion): 1H NMR (400 MHz, D2O) ~ 5.8 (br s, 1 H), 4.94 (m, 1 H), 2.55 (m, 1 H), 2.10 (m, 1 H), 1.07 (d, J=6.0 Hz, 3H); MS (FAB, THG) 796 (M+Na), 774 (M+H).

ExamPle B38: Preparation of compound B1.58.

O 02N_~
~ ~NJ~O~ OBz 'b B O OBn ~~ O~N O~
~OBn BzO
BnO ~~OBn BnO

N,N-Dimethylaminopyridine (1.03 g, 8.44 mmol) and ~nitrobenzenesulfonyl chloride(1.65 g, 7.44 mmol) are added at room temperature to a solution of the alcohol 37 (6.11 g, ~ ~.1 mmol) in CH2C12 (35 ml). After 52 hours, the reaction mixture is washed with 10 %
aqueous NaHCO3 solution, and the aqueous phase is reextracted three times with CH2CI2.The combined organic phases are dried (Na2SO4), filtered and concentrated in W O 97/01569 PCT/~ 27x5 vacuo. The crude product (10 g) is purified by column chromatography on silica gel (eluent:
ethyl acetate/hexane 35:65), resulting in the nosylate 52 (6.58 g, 93 %).

02N~
~/s~ . ~ o ~ O ~ BzO ~ - ~ N ~ O
BzO OBn ¦ BzO OBn ¦ N3 OBn ~ OBn n _ n BnO Bn~

A solution of the nosylate 52 (7.78 g, 5.62 mmol) and dry LiN3 (0.99 g, 20.21 mmol) in dry N,N-dimethylformamide (50 ml) is heated to 50-60~C under an argon atmosphere. After 16 hours, the solvent is removed under high vacuum, and the residue is taken up in CH2CI2 and washed with 10 % aqueous NaHCO3 solution. The aqueous phase is extracted three times with CH2CI2 and the combined organic phases are dried (Na2SO4), 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).

o o z ~ N ~ O ~ HO ~ N ~ O
B OBn I N3 H OBn ¦ N3 ~ OBn ~ OBn BnO OBn BnO n A solution of the tribenzoate 53 (4.22 g, 3.45 mmol) and sodium methoxide (0.55 g, 10.2 mmol) in methanol (110 ml) and dioxane (5 ml) is stirred at room temperature for 2.5 hours. The pH of the reaction mixture is then made neutral by adding strongly acidic ion exchanger (Amberlystl 5, H+ Form), the suspension is filtered, and the filtrate is concentra-PCT~EP96/02785 ted in vacuo. The crude product (4.5 g) is purified by column chromatography on silica gel ~ (eluent: CH2CI2/methanol 19:1) to give the triol 54 (2.89 g, 92 %).

F C~S~o HO NJ~O ~OBnCO 2Bn OH
~?--o ~ I A-5 r ~0 ~N

Hd ~OBn ~~ Hd _~ N 3 1~
Bn _ BnO n A suspension of 54 (2.89 9, 3.17 mmol) and di-n-butyltin oxide (1.56 g, 6.27 mmol) in dry benzene (95 ml) is boiled under reflux in an argon atmosphere for 16 hours. The reaction mixture is concer,l,~ted in vacuo and dried under high vacuum for one hour. Then CsF
(dried under high vacuum at 300~C for several hours, 1.2 g, 7.9 mmol) is added under an argon atmosphere, followed by dry 1,2-dimethoxyethane (80 ml) and a solution of the triflate A5 (6.3 g, 15.97 mmol) in dry 1,2-dimethoxyethane (50 ml). The reaction mixture is heated to 35 to 40~C and stirred at this temperature for 3 hours. The mixture is then washed with a solution of 15% KF in lM aqueous KH2PO4 (150 ml) and the aqueous phase is extracted three times with CH2CI2, and the combined organic phases are dried (Na2SO4), filtered and concentrated in vacuo. The oily residue (10.9 g) is purified by column chromatography on silica gel (elution: toluene/ethyl acetate 4:1, then CH2CI2/methanol 19:1 to recover the pre-cursor), resulting in the ether 55 (1.94 g, 53 %) as a colourless foam and partial recovery of the precursor (1.1 g, 26 %).

CO 2Bn OH 1 CO 2Bn OH ~S
_ ~~o~N O~ ~ N' ~n-C ~H9 OBn I N 3 ' ~ Hd OBn I N
~ ~OBn l ~OBn BnO n BnO n W O 97/01569 PCT/~,'''~7.7 Morpholine (215 !li) and Pd(PPh3)4 (0.015 g, 0.013 mmol) are added under an argon atmo-sphere to a solution of the allyl carbamate 55 (0.15 g, 0.13 mmol) in tetrahydrofuran (1.7 ml). After exactly 15 minutes, the solution is concentrated and the residue is dried under high vacuum for one hour. The crude product is purified on a short silica gel column (eluent: CH2CI2/methanol 19:1, contains 0.3 % concentrated aqueous ammonia solution) and then dried under high vacuum for one hour. The residue is then taken up in dry CH2CI2 (1.7 ml), the solution is cooled to 0~C, and triethylamine (43 !11, 0.31 mmol) and n-butane-sulfonyl chloride (18 1ll, 0.14 mmol) are added. After 15 minutes, the reaction mixture is warmed to room temperature and washed with 10 % aqueous NaHCO3 solution. The aqueous phase is reextracted three times with CH2CI2, and the organic phases are com-bined, dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude product by column chromatography on silica gel (eluent: ethyl acetate/hexane 30:70) gives the sulfonamide 56 (0.12 g, 77 %).

CO 2Bn OH ~/ CO 2Na OH \~
Jl_o ~ 7 N~ ~n-C ~Hs J--O ~7--O~ N~ ~n-C ~Hg r ~0 0~ r ~o 0~
~n~OBnN3 [~ Hd ~ HN ~MOMe 56 B1.58 Dioxane (1.2 ml), water (0.6 ml) and glacial acetic acid (0.25 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.035 g) and the benzyl ether 56 (0.027 g, 0.023 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly ele-vated pressure of hydrogen at room temperature for 12 hours and then filtered through a c~'lu'ose filter (pore size 45 llm). The filtrate is concentrated in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. The crude intermediate (0.017 9, Iyophilized) is taken up in 1 M aqueous NaHCO3 solution (0.3 ml) and over the course of 5 hours, several small portions (30 bis 50,ul) 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: n-butanol/water/acetone/

CA 02224346 1997-12-lO

W O 97/01569 PCT/EPg6/02785 _ 99 _ glacial acetic acid/NH40H 70:60:50:18:1.5) indicates complete conversion of the intermedi-~ ate. The pH of the solution is kept basic during this reaction by adding several portions of solid NaHCO3 (about 0.025 9 in total). The reaction mixture is then concentrated in vacuo, and the residue is taken up in a little water and purified by gel filtration on Bio-Gel P2 (particle size 65 ,um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP 18 silica gel, elution: methanol/H20 65:35), resulting in the target molecule B1.58 (0.008 g, 39 %) as a fluffy white solid (after Iyophilization): lH NMR (400 MHz, D2O) ~ 7.41 (br d, J=8.3 Hz, 1 H), 7.32 (br s, 1 H), 7.04 (d, J=8.3 Hz, 1 H), 5.05 (d, J=3.9 Hz, 1 H), 4.51 (d, J=7.8 Hz, lH), 4.14 (q, J=6.7 Hz, 1H), 4.09 (t, J=4.1 Hz, 1H), 3.82 (s, 6H), 3.33 (dd, J=3.1, 9.6 Hz, 1H), 1.13 (d, J=6.3 Hz, 3H), 0.68 (t, J=7.6 Hz, 3H); MS (FAB, THG) 923 (M+Na), 901 (M+H), 879 (M+2H-Na).

Example B39: Preparation of compound B1.59.

CO 2Bn O O CO 2Na OH ~g//
J o~--O~N' ~n-C 4H9 J_o~--O~N~ ~n-C 4Hg d~~ 0~ 1 ~0 0~

BnO H
56 B1.59 Dioxane (5.3 ml), water (2.6 ml) and acetic acid (1.1 ml) are added to a mixture of Pd(OH)2/C (Pearlman catalyst, Pd content 20%, 0.13 g) and the benzyl ether 56 (0.12 g, 0.1 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 24 hours and then filtered through a cellulose filter (pore size 45 ,um). The filtrate is concenlr~ted in vacuo, and the residue is taken up with water and concentrated again several times in order to remove excess acetic acid. The crude amine (0.074 9) is taken up in a little water and purified by gel filtration on Bio-Gel P2 (particle size 65 ~um, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 mllmin, detection at 215 nm) and subsequent reverse phase chromatography (Merck W O 97/OlS69 PCT~EP96/0278S

RP18 silica gel, elution: methanol/H20 1:1), resulting in the target molecule B1.59 (0.052 g, 73 %) as a fluffy white solid (after Iyophilization): 'H NMR (400 MHz, D20) ~ 5.00 (d, J=3.6 Hz,1 H), 4.41 (d, J=7,7 Hz,1 H), 4.28 (q, J=6.5 Hz,1 H), 3.83 (d, J=3.1 Hz,1 H), 3.79 (dd, J=3.1, 9.7 Hz,1H), 3.32 (dd, J=3.2, 9.6 Hz,1H),1.12 (d, J=6.1 Hz, 3H), 0.83 (t, J=7.9 Hz, 3H); MS (FAB, THG) 737 (M+Na), 713 (M+H).

Example B40: Preparation of compound B1.60.

CO 2Na OH \~/CO 2Na OH \'~/
J--o~--O~N~ ~n-C 4Hg J--O~--o~N~ ~n-C 4Hg d~~' o-~~ I f~o 0~
H~ ' ~ d ,~ HN ?~

B1.59 B1.60 The amine B1.59 (0.027 g, 0.038 mmol) is taken up in 1 M aqueous NaHCO3 solution(0.35 ml) and, over the course of 4 hours, several small portions (30 to 50 ~L) of an approx.
0.5 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/
NH40H 70:60:50:18:1.5) indicates complete conversion. The pH of the solution is kept basic throughout the reaction by adding several portions of solid NaHCO3 (about 0.01 g in total).
The reaction mixture is then concentrated in vacuo, and the residue is taken up in a little water and purified by gel filtration on Bio-Gel P2 (particle size 65 ~Lm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subse-quent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/H2O 1:1), resulting in the target molecule B1.60 (0.027 g, 85 %) as a fluffy white solid (after Iyophiliza-tion): 'H NMR (400 MHz, D20) ~ 7.72 (d, J=8.0 Hz, 2H), 7.52 (t, J=6.9 Hz,1 H), 7.44 (t, J=7.5 Hz, 2H), 5.05 (d, J=3.8 Hz,1 H), 4.50 (d, J=8.1 Hz,1 H), 4.17 (q, J=6.6 Hz,1 H), 3.92 (br d, J=10.4 Hz,1H), 3.85 (d, J=2.8 Hz, 1H), 3.80 (dd, J=3.1,10.4 Hz,1H), 3.33 (dd, J=2.8, 9.8 Hz,1H),1.12 (d, J=7,1 Hz, 3H), 0.70 (t, J=8.2 Hz, 3H); MS (FAB, THG) 863 (M+Na), 841 (M~H).

CA 02224346 l997-l2-lO

W O 97/01569 PCT~EP96/02785 . -101-Example B41: Preparation of compound B1.61.

CO 2Na OH \~/ CO 2Na OH \~
10~--O~N~ ~n-c4H9 J~o~~o ;~ N~ ~n-c4H9 r ~o 0~ ~ f~~ 0~
Hd OH I H2N ' ~ HO OH I HN
H~OH H~OH ~

B1.59 B1.61 The carbamate B1.61 is prepared starting from the amine B1.59 (0.027 g, 0.038 mmol) using benzyl chloroformate as reagent in analogy to Example B40 (Preparation of com-pound B1.60). The yield is 0.007 9 (21 %): 1H NMR (400 MHz, D2O) ~ 7.31 (m, 5H), 5.06 (d, J=12.0 Hz, 1 H), 4.97 (d, J=12.0 Hz, 1 H), 4.96 (d, J=4.0 Hz, 1 H), 4.42 (d, J=7.7 Hz, 1H), 4.19(q, J=6.6 Hz, 1 H), 3.96 (br s, 1 H), 3.80 (d, J=2.9 Hz, 1 H), 3.50 (dd, J=8.2, 9.4 Hz, 1 H), 3.29 (dd, J=2.9, 9.7 Hz, 1 H), 3.20 (br d, J=12.2 Hz, 1 H), 1.06 (d, J=6.5 Hz, 3H), 0.77 (t, J=8.0 Hz, 3H); MS (FAB, THG) 871 (M+H), 849 (M+2H-Na).

The following compounds are prepared in analogy to the above examples:

~--O~'~,~RHA
Table la: ~ HO

~J H3C~OH
OH
HO

Compound No. R3 RHA
B1.64 Na C(O)-3,4-(OH)2-C6H5 B1.65 Na C(O)CH(C6Hs)2 B1.68 Na C(O)-3,4-(OCH2C6H5)2-C6H5 CA 02224346 l997-l2-lO
W O 97/01569 PCT/EPg6~2705 . -102-Compound No. R3 RHA
Bl.70 Na C(0)-3,4,5-(OH)3-C6H6 B1.72 Na C(O)[CH(OH)]2C(O)ONa B1.73 Na C(O)CH3 B1.77 Na S(O)2(CH2)2C1oH7 B1.78 H H
B1.80 Na S(0)2CH2C6H5 B1.81 Na C(O)NHC6H5 B1.82 Na C(O)C6Ht 1 B1.83 Na S(0)2(CH2)3CH3 B1.84 Na C(O)O(CH2)2CH3 ~OR3 OH N~ RHA

Table 1a': ~ OH ¦ RCA

H3C~OH
HO

Compound No. R3 RHA RCA
B1.62 Na C(O)CH3 NHC(O)C10H7 B1.63 Na C(O)CH3 NHC(O)OCH2C6H5 B1.66 Na C(O)CH3 NHC(O)CH2C6H5 B1.67 Na C(O)CH3 NHC(O)CH20C6H5 B1.69 Na C(O)CH3 NHC(O)CH2NHC(O)OCH2C6H5 B1.71 Na C(O)O(CH2)2CH3 NHS(0)2CH2C6H5 B1.74 Na S(0)2(CH2)3CH3 NHC(O)OCH2C6H5 B1.75 Na S(0)2(CH2)3CH3 NHC(O)C6H5 B1.76 H S(0)2(CH2)3CH3 NH2 B1.79 Na S(0)2(CH2)3CH3 NHC(0)-3,4-(OCH3)2C6H3 CA 02224346 l997-l2-lO

W O 97/01569 PCT~EP96/02785 -1~3-Table lb~ ~RHA

Compound No. R3 RHA
B1.85 Na S(O)2-4-CH3-C6H4 B1.86 Na C(O)(CH2)aC(O)OCH3 B1.87 Na S(O)2(CH2)3CH3 B1.88 H (CH2)2CH3 B1.89 Na C(O)C6H5 B1.90 Na C(O)CH3 B1.91 Na C(O)O(CH2)2CH3 C. Ligand Binding Assay for Determination of ICso Values-conserved use of positive controls E-selectin/human IgG chimera [cloned and expressed according to Kolbinger et al.Biochemistry 35:6385-6392 (1996)] are incubated in Falcon probindTM microtiter plate (Plate 1) at a concentration of 200 ng/well in 0.01 M Tris, 0.15 M NaCI,1 mM CaCI2, pH 7.4 (Tris-Ca++ buffer). Thus the plating solution is dispensed as 100,ul/well of 2,ug/ml E-chimera.
Row 12 is left blank with only buffer. Plate 1 is incubated covered at 37~C for 2 hours. After incubation 100,ul/well of 2 % BSA in Tris Ca++ buffer is added and incubated at room temperature for 1 hour. During incubation the compounds (2x serial dilution) are titrated in 1 % BSA in Tris-Ca++ using U-shaped low bind microtiter plates (Plate 2). The rows are serially diluted up to row 9. Rows 10,11, and 12 are just buffer. Final volume is 60,ul/well and the first well contains 10 mM of compound with the exception of the positive controls, A
(SLeX-Lemieux) and B are used as positive controls for each plate and the first well contains 5 mM of these compounds. PolySLeaSA-HRP conjugate is prepared in advance by incubating Sialyl Lea-PAA-biotin (cat #01-044, GlycoTech Corp., Rockville, MD) with Streptavidin-HRP in a molar ratio of 1 :2. 60 ~ul/well of 1 ng/,ul of polySLeaSA-HRP conjugate in 1 % BSA in Tris-Ca++ are added to all wells except row 11 in Plate 2. Plate 1 is W O 97/OlS69 PCT/EP96/02785 washed four times with Tris-Ca++ in the automatic plate washer. 100 ~ul/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 ,ul/well of Substrate [Mix 3,3',5,5'-tetramethylbenzidine reagent and H2~2. 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 1 OO,ul/well of 1 M H3PO4 using the 8 channel pipettor from right to left. Absorbance of light at 450nm is measured in a microtiter plate reader.

HO O~ONa OH OH

~ HO' .~ ~&OJ~) Control compound A: H3C~O OH ~ = ~

H3C~J ~ ~ IOH3 OH

HO O~ONa OH
HO~O~.~
Control compound B: OH"~ HO' OJ - J
H3C O OH 0~

H3~ ~OH
OH

IC50 is calculated by determining the concentration of compound required to inhibit maximal binding of the polySialylLeaHRP conjugate to immobilized E-selectin/human IgG chimera by 50%. The relative IC50 is c~lcu~t~d by determining the ratio of the ICso of an internal control compound to the IC50 of the test compound.

CA 02224346 l997-l2-lO

W O 97/01569 PCT~EP96/02785 IC 0(Test compound) In the following tables RIC50 means 5 ICs0(Control compound A) H~R3 R4 ~O~O
Table 2: O O
HO OH
H3C~ZOH
I OH
OH

Comp. No. R3 R4 RIC

B1.1 Na -CH2C6H5 0.35 B1.2 Na CH2C6H11 0.08 B1.3 Na -CH2NHC(O)C6H5 1.11 B1.4 Na -CH2NHC(O)(CH2)2C6Hs 1.85 B1.5 Na -CH2NHC(O)(CH2)30H 1.23 B1.6 H -CH2NH2 0.96 B1.7 H -CH2NHCH2(CH)2C6H5 1.15 B1.8 Na -CH2N[C(O)C6H5]CH2(CH)2C6H5 0.90 B1.9 H CH2NHCH2C6H5 0.61 B1.10 Na -CH2N(CH2C6H5)2 0.60 B1.11 H -CH2NH[CH2CH(CH3)2 0-74 B1.12 H -CH2N[CH2CH(CH3)2]2 0.32 B1.13 Na -CH2N[C(O)C6H5][CH2CH(CH3)2] 0.21 - B1.14 Na -CH2NH[S02(C6H4)NO2] 0.12 B1.15 Na -CH2NHSO2C6H4CH3 0.13 B1.16 Na -CH2NHC(O)CF3 0.64 B1.17 Na -CH2NHC(O)C6H11 1.33 B1.18 Na -CH2CH2C6H5 0.14 B1.19 Na -CH2CH2C6H11 0.17 W O 97101S69 PCT~EP96/02785 Comp. No. R3 R4 RIC

B1.20 Na -CH2NHC(O)C11H23 1.76 B1.21 Na -CH2NHC(O)CH(C6H5)2 0.71 B1.22 Na -CH2NHC(O)C2H4CO2Na 1.05 B1.23 Na -CH2NHC(O)C6[(1,3,4,5)OH]4H7 0.79 B1.24 Na -CH2NHC(O)C6H4SO3Na 0.93 Bl.25 Na -CH2NHC(O)C6H4CI 1.29 Bl.26 Na -CH2NHC(O)C6H4NO2 1.21 Bl.27 Na -CH2NHC(O)C6H4OCH3 1.15 Bl.28 Na -CH2NHC(O)C6H4(3,4)C12 2.04 B1.29 Na -CH2NHC(O)C6H4CH3 1.30 B1.30 Na -CH2NHC(O)C6H4C6H5 1.65 B1.31 Na -CH2NHC(O)C6H4CN 1.04 B1.32 Na -CH2NHC(O)C10H7 1.44 B1.9 Na -CH2NHCH2C6H5 0.61 B1.33 Na -CH2NHC(O)C6H4COONa 0.96 B1.34 Na -CH2NHC(O)(CHOH)2COONa 0.78 Bl.35 Na -CH2N[C(O)C6H5]CH2C6H5 0.44 B1.36 Na -CH2N[C(O)C6H5](CH2)3C6Hs 0.57 B1.37 Na -CH2NHSO2CF3 0.26 B1.38 Na -CH2N[CH2CH(CH3)]SO2C6H4NO2 0.32 PCT~EP96/02785 Table2a:

Compound No. RIC50 Compound No. RICso B1.62 0.949 B1.77 0.618 B1.64 0.287 B1.78 0.304 B1.65 0.862 B1.79 0.196 B1.66 1.112 B1.80 0.203 B1.67 0.564 B1.81 0.216 B1.68 0.696 B1.82 0.195 B1.69 2.661 ~ B1.83 0.176 B1.70 0.199 B1.84 0.169 B1.71 0.414 B1.85 1.28 B1.72 0.186 B1.86 2.733 ~ B1.73 0.249 B1.87 0.520 B1. 74 0.134 B1.88 1.257 B1.75 0.102 B1.89 0.696 B1.76 0.451 B1.90 0.569 B1.63 0.087

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula I

in which X is the residue of a non-glycosidic aliphatic 1 ,2-diol;
R1 is an S-configurated methyl substituted with one carboxyl residue and one other substituent; and R2 is hydrogen, C1-C12alkyl or C6aryl; where the alkyl and the aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH halogen, C(O)ORs1, OC(O)Rs4,C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl; C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy. C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamine, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C6-C9heteroaryl, C7-C11aralkyl or C8-C10heteroaralkyl, R34 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9hetero-aryl, C7-C11aralkyl or C6-C10heteroaralkyl, and R32 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11hetero-cycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C6-C11aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo-alkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, hetero-aralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal; including its physiologically tolerated salts.

2. A compound according to claim 1, wherein (a) NH2, primary amino, secondary amino, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide and aminocarbonylamide is a representative selected from the group of R8C(O)(NH)pN(R9)-,-C(O)(NH)pNR8R9, R8OC(O)(NH)pN(R9)-, R8R40NC(O)(NH)pN(R9)-,-OC(O)(NH)pNR8R9,-N(R40)C(O)(NH)pNR8R9, R8S(O)2(NH)pN(R9)-;
-S(O)2(NH)pNR8R9; R8R40NS(O)2N(R9)- or -NR40S(O)2NR8R9, in which R8, R9 and R40 are, independently of one another, hydrogen, OH, C1-C12alkyl, C1-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C16aralkyl, C8-C16aralkenyl with C2-C6alkenylene and C6-C10aryl, C6-C15heteroaralkyl, C6-C15heteroaralkenyl, or di-C6-C10aryl-C1-C6-alkyl, or R8, R9, N in which R8, and R9, are, independently of one another, hydrogen, OH, SO3My, OSO3My, C1-C12alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroalyl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C16aralkenyl with C2-C6alkenylene and C6-C10aryl, or di-C6-C10aryl-C1-C6-alkyl, which are unsubstituted or substituted by one or more substituents; or R8 and R9 or R8, and R9, or R8 and R40 in the case of -NR8R9 or -NR8 R9, or R8R40N- together are tetramethylene, pentamethylene, -(CH2)2-O-(CH2)2-, -(CH2)2-S-(CH2)2- or -(CH2)2-NR7-(CH2)2-,and R7 is H, C1-C6alkyl, C7-C11aralkyl, C(O)Rs2 or sulfonyl; and (b) sulfonyl is a representative of the formula R10-SO2- in which R10is C1-C12alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, which are unsubstituted or substituted by one or more substituents;
wherein the substituents are selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-Cl2cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are substituted or substituted by one of the abovementioned substituents;
p is 0 or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

3. A compound according to claim 1, wherein X is a linear or branched C2-C20-alkylene, -alkenylene, C3-C12-cycloalkylene, -cycloalkenylene, C3-C11-heterocycloalkylene or-hetero-cycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-.

4. A compound according to claim 1, wherein X is substituted by a substituent selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryl-oxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and amidocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C3-C12aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

5. A compound as claimed in claim 1, wherein X is the residue of a 1,2-diol corresponding to formula II

in which R5 and R6 are, independently of one another, hydrogen, C1-C12alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl; or R5 and R6 are, together with the -CH-CH- group, C3-C12cycloalkylene, C3-C12-cycloalkenylene, C2-C11heterocycloalkylene and C3-C11heterocycloalkenylene with hetero atoms selected from the group -O-, -S- and -N-;
where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C1, heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C,Oheteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

6. A compound according to claim 5, wherein R5 and R6 (a) are unsubstituted or substituted by C1-C12alkyl or C1-C12alkoxy;
(b) are, together with the group -CH-CH-, a 5- to 8-membered carbocycle;
(c) are, together with the group -CH-CH-, a 5- to 8-membered heterocarbocycle;
(d) are, independently of one another, hydrogen, unsubstituted C1-C12alkyl or C1-C12alkyl which is substituted by a substituent selected from the group consisting of -C(O)ORs1, -OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C3-C12cycloalkyl, C1-C6alkoxy, phenyloxy and benzyloxy; unsubstituted C3-C12cycloalkyl or C3-C12cycloalkyl which is substituted by a substituent selected from the group consisting of -C(O)ORs1, -OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C1-C6alkyl, C1-C6alkoxy, phenyloxy and benzyloxy; C6-C10aryl which is unsubstituted or substituted by -C(O)ORs1, -OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C1-C6alkyl or C1-C6alkoxy; C3-C9heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; or C1-C12aralkyl which is unsubstituted or substituted by -C(O)ORs1, -OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C1-C6alkyl or C1-C6alkoxy;
(e) are, together with the group -CH-CH-, a 5- to 12-membered carbocycle or 5- or 6-membered heterocarbocycle with a hetero atom selected from the group consisting of oxygenand nitrogen atoms; or (f) are, together with the -CH-CH- group, C3-C12cycloalkylene, C4-C12cycloalkenylene, C2-C11heterocycloalkylene or C3-C11heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-;
where cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydlazide, carbhydrazide, carbohydroxamic acid and amino-carbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycioalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

7. A compound according to claim 6, wherein R5 and R6 are, together with the -CH-CH-group, C3-C12cycloalkylene or C2-C11heterocycloalkylene with nitrogen as hetero atom;
where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents according to claim 6.

8. A compound according to claim 7, wherein R5 and R6 are, together with the -CH-CH-group, C3-C12cycloalkylene or C2-C11heterocycloalkylene 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)ORs1, OC(O)Rs4, C(O)Rs2, NR8R9, C1-C12alkyl, R8C(O)(NH)pN(R9)-, -C(O)(NH)pNR8R9, R8S(O)2(NH)pN(R9)-;
R8R40NC(O)(NH)pN(R9)-, R8OC(O)(NH)pN(R9)-, -OC(O)(NH)pNR8R9, and R10-SO2-,in which R8, R9, R10 and R40 are, independently of one another, hydrogen, OH, C1-C12alkyl, C1-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C16aralkyl, C8-C16aralkenyl with C2-C6alkenyleneand C6-C10aryl, C6-C15heteroaralkyl, C6-C15heteroaralkenyl, or di-C6-C10aryl-C1-C6-alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide; Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl as substituents in turn are unsubstituted or substituted by one of the abovementioned substituents; p is 0 or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M
is a divalent metal.

9. A compound according to claim 8, wherein R8 and R9 are, independently of one another hydrogen; C1-C12alkyl; C3-C12cycloalkyl, C6-C10aryl, C7-C16aralkyl with 1 to 6 C atoms in the alkylene group and C6-C10aryl, C8-C16aralkenyl with C2-C6alkenylene and C6-C10aryl, or di-C6-C10aryl-C1-C6-alkyl, where R8 and R9 are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O)OMy, C1-C12alkyl, C1-C6alkoxy, C6-C10aryl, C6-C10aryloxy, SO3My, OSO3My, NR20SO3My, NO2, amino, primary amino, secondary amino and CN, and R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

10. A compound according to claim 8, wherein R10 is C1-C12alkyl; C3-C12cycloalkyl, C6-C10aryl, C7-C16aralkyl with 1 to 6 C atoms in the alkylene group and C6-C10aryl,C8-C16aralkenyl with C2-C6alkenylene and C6-C10aryl, or di-C6-C10aryl-C1-C6alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O)OMy, C1-C12alkyl, C1-C6alkoxy, C6-C10aryl, SO3My, OSO3My, NR20SO3My, NO2, amino, primary amino, secondary amino and CN; where R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

11. A compound according to claim 10, wherein R10 is C1-C12alkyl; C3-C12cycloalkyl, C8-C10aryl, C7-C16aralkyl with 1 to 6 C atoms in the alkylene group and C6-C10aryl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(O)OMy, C1-C12alkyl, C1-C6alkoxy, C6-C10aryl, SO3My, nitro, amino, primary amino, secondary amino and cyano; or C8-C16aralkenyl with C2-C6alkenylene and C6-C10aryl, or di-C6-C10aryl-C1-C6alkyl.

12. A compound according to claim 8, wherein R5 and R6 are, together with the -CH-CH-group, C3-C12cycloalkylene or C2-C11heterocycloalkylene 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)ORs1, OC(O)Rs4, C(O)Rs2, NH2, C1-C12alkyl, R8C(O)N(R9)-, -C(O)NR8R9, R8S(O)2N(R9)-; R8OC(O) N(R9)- and R10-SO2-,in which R9 is hydrogen and R8 is C1-C12alkyl, C6-C10aryl or C7-11aralkyl, which are unsubstituted or substituted by one or more C1-C12alkoxy; R10 is C1-C12alkyl, C6-C10aryl or C7-C11aralkyl which are unsubstituted or substituted by one or more C1-C12alkyl; Rs1 and Rs4 are C1-C12alkyl and Rs2 is C1-C12alkyl, C3-C12cycloalkenyl, C3-C12cycloalkyl or C6-C10aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)ORs1, and OC(O)Rs4 where Rs1 is My or C1-C12alkyl and Rs4 is C1-C12alkyl; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

13. A compound according to claim 12, wherein R5 and R6 are, together with the -CH-CH-group, cyclohexylene.

14. A compound according to claim 8, wherein R5 and R6 are, together with the -CH-CH-group, piperidylene.

15. A compound according to claim 14, wherein R5 and R6 are, together with the -CH-CH-group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(O)ORs1, C(O)Rs2, C(O)NR8R9, NH2, SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, sulfonhydrazide, and one or more C atoms of the ring are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, OC(O)Rs4, NH2, OSO3My NR20SO3My, C1-C12alkoxy, C6-C10aryloxy, C5-C9heteroaryloxy, C7-C11aralkyloxy, primary amino, secondary amino, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, R8 and R9 are, independently of one another, hydrogen, OH, C1-C12alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C16aralkyl, C6-C15heteroaralkyl, C8-C16aralkenyl with C2-C6alkenylene and C6-C10aryl, or di-C6-C10aryl-C1-C6-alkyl, or R8 and R9 together are tetramethylene, pentamethylene, -(CH2)2-O-(CH2)2-, -(CH2)2-S-(CH2)2- or -(CH2)2-NR7-(CH2)2-, and R7 is H, C1-C6alkyl, C7-C11aralkyl, C(O)Rs2 or sulfonyl; and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

16. A compound according to claim 15, wherein R5 and R6 are, together with the -CH-CH-group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(O)ORs1, C(O)Rs2, -C(O)NR8R9 and R10-SO2- and one or more C atoms of the ring are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH2, R8S(O)2N(R9)-; R8C(O)N(R9)- and R8OC(O)N(R9)-, where R9 is hydrogen and R8 is C1-C12alkyl, C6-C10aryl or C7-C11aralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C1-C12alkoxy;
R10 is C1-C12alkyl, C6-C10aryl or C7-C11aralkyl which are unsubstituted or substituted by one or more C1-C12alkyl; Rs1 is C1-C12alkyl and Rs2 is C1-C12alkyl, C3-C12cycloalkenyl, C3-C12cycloalkyl or C6-C10aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)ORs1, and OC(O)Rs4, where Rs1, is My or C1-C12alkyl and Rs4, is C1-C12alkyl; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

17. A compound according to claim 8, wherein R5 and R6 are, together with the -CH-CH-group, piperidylene; which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)ORs1, OC(O)Rs4, C(O)Rs2, NH2, C1-C12alkyl, R8C(O)N(R9)-, -C(O) NR8R9, R8S(O)2N(R9)-; R8OC(O)N(R9)-, R8R40NC(O)N(R9)-, -OC(O)NR8R9 and R10-SO2-, in which R9 is hydrogen and R8 is C1-C12alkyl, C6-C10aryl or C7-C11aralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C1-C12alkoxy or C7-C11aralkyloxy; R10 is C1-C12alkyl, C6-C10aryl or C7-C11aralkyl which are unsubstituted or substituted by one or more C1-C12alkyl; R40 is hydrogen, C1-C12alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl; Rs1 and Rs4 are C1-C12alkyl and Rs2 is C1-C12alkyl, C3-C12cycloalkenyl, C3-C12cycloalkyl or C6-C10aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)ORs1, and OC(O)Rs4, where Rs1 is My or C1-C12alkyl and Rs4, is C1-C12alkyl; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

18. A compound according to claim 1, wherein X is cyclohexylene or piperidylene which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH2, C3H7, -C(O)CH3, -C(O)C6H5, -C(O)(CH2)8C(O)OCH3, -C(O)[CH(OH)]2C(O)ONa, C(O)-C6H8(OH)3, -C(O)-C6H11, -C(O)OC3H7, -C(O)NHC6H5, -NHS(O)2CH2C6H5, -NHC(O)OCH2C6H5, -NHC(O)C6H3(OCH3)2, -S(O)2-C4H9, -NHC(O)NHC6H5, -S(O)2-C6H4CH3,-S(O)2-CH2C6H5 and -S(O)2-(CH)2C10H7.

19. A compound according to claim 1, wherein R2 is C1-C6alkyl.

20. A compound according to claim 1, wherein substituents for R2 are selected from halogen, -C(O)OMy, C1-C6alkyl, C1-C4alkoxy, phenyl, naphthyl, -SO3My, C1-C12primary amino, C2-C20secondary amino, -SO2-NR8R9 and -C(O)-NR8R9 in which R8 and R9 are, independently of one another, H, C1-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, or R8 and R9 together with the N atom are morpholino, thiomorpholino, pyrrolidino or piperidino.

21. A compound according to claim 1, wherein R2 is hydrogen, unsubstituted C1-C6alkyl or C1-C6alkyl, which is substituted by C(O)OH, -C(O)ONa, -C(O)OK, -OH, -C(O)-NR8R9 or -SO2-NR8R9, in which R8 is H, C1-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and R9 dependently has the meaning of R8, or R8 and R9 are together tetramethylene, pentamethylene or -CH2CH2-O-CH2CH2-.

22. A compound according to claim 21, wherein R2 is hydrogen, methyl, ethyl, HO(O)C-CH2CH2-, NaOC(O)-CH2CH2- or R8R9N-C(O)-CH2CH2-, and R8 and R9 are, independently of one another, H, C1-C6alkyl, C2-C4hydroxyalkyl, phenyl, benzyl or, together, morpholino.

23. A compound according to claim 1, wherein the other substituent in R1 has 1 to 20 C
atoms.

24. A compound according to claim 23, wherein the other substituent is selected from the group consisting of unsubstituted and substituted C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11aralkenyl and C7-C10heteroaralkenyl.

25. A compound according to claim 24, wherein the other substituent is substituted methyl, or 2-substituted ethyl or cyclohexyl.

26. A compound as claimed in claim 1, wherein R1 corresponds to a group of the formula III, in which R3 is hydrogen or My; and R4 is C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11aralkenyl or C7-C10heteroaralkenyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl,C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

27. A compound according to claim 26, wherein R3 is hydrogen or My and R4 is (a) unsubstituted C1-C12alkyl; C1-C12alkyl which is substituted by one or more substituent selected from the group consisting of -NH2, primary amino, secondary amino, C1-C12sulfonyl, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide, aminocarbonylamino, C3-C12cycloalkyl, C1-C6alkoxy, phenyloxy and benzyloxy; unsubstituted C3-C12cycloalkyl; C3-C12cycloalkyl which is substituted by one or more substituents selected from the group consisting of C3-C12cycloalkyl, C1-C6alkyl, C1-C6alkoxy, C1-C12sulfonyl, phenyloxy and benzyloxy; C6-C10aryl; C3-C9heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; C7-C16aralkyl with C1-C6alkyl and C6-C10aryl; C4-C16heteroaralkyl with C1-C6alkyl and C3-C10heteroaryl 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; C6-C10aryl, C3-C9heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms, C7-C16aralkyl with C1-C6alkyl and C6-C10aryl, C3-C16heteroaralkyl with C1-C6alkyl and C4-C10heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to 5 carbon atoms, which are substituted by one or more substituents selected from the group consisting of OH, halogen, C1-C12sulfonyl, carboxyl, C(O)OMy, C1-C12alkyl, C1-C6alkoxy, C6-C10aryl, SO3My, OSO3My, NR20SO3My, nitro, NH2, primary amino, secondary amino, carbamide,carbamate, sulfonamide and cyano, in which y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, or (b) C1-C12alkyl or C7-C11aralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl-or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl,C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

28. A compound according to claim 27, wherein R3 is hydrogen, K or Na.

29. A compound according to claim 27, wherein R4 is methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, cyclohexyl, naphthyl, phenyl, benzyl, naphthylmethyl, 2-phenylethyl, 3-phenylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, furanyl, pyridinyl or pyrimidinyl.

30. A compound according to claim 27, wherein carbamido, carbhydrazido, sulfonamido, sulfonhydrazido, aminocarbonylamide and carbamate as substituent for R4 mean groups of the formulae R8NHC(O)N(R9)-, R8OC(O)N(R9)-, R8C(O)(NH)pN(R9)- and R8S(O)2(NH)pN(R9)-, in which R8 is H, C1-C12alkyl, C5- or C6cycloalkyl, C5- or C6cycloalkylmethyl or -ethyl-, C5- or C6heterocycloalkyl, C5- or C6heterocycloalkylmethyl or -ethyl-, phenyl, naphthyl, benzyl, 2-phenylethyl, diphenylmethyl, which are unsubstituted or substituted by one or more substituents from the group of -OH, -NH2, C1-C8primary amino, C2-C14secondary amino, NO2, -CN, -F, -Cl, -C(O)OH, -C(O)ONa, -SO3H, -OSO3Na, NR20SO3Na in which R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and -SO3Na, C1-C4alkyl, C1-C4alkoxy and phenyl, and R9 is H, C1-C10alkyl, phenyl, naphthyl, benzyl, 2-phenylethyl or phenyl-CH=CH-CH2-, and p is 0 or 1.

31. A compound according to claim 27, wherein R4 is a (a) carbamido-substituted alkyl group R8-C(O)NR9-(CH2)n-, where n is 1 or 2, R8 is hydrogen;
C1-C12alkyl; C3-C12cycloalkyl; C6-C10aryl or C7-C16aralkyl with C1-C6alkyl and C6-C10aryl;
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(O)OMy, C1-C12alkyl, C1-C6alkoxy, C6-C10aryl, SO3My, OSO3My, NR20SO3My, C(O)ORs1, OC(O)Rs4, nitro, amino and cyano; or C8-C16aralkenyl with C2-C6alkenyl and C6-C10aryl or di-C6-C10aryl-C1-C6alkyl; and R9 is H, linear or branched C1-C10alkyl, C5- or C6cycloalkyl, C5- or C6cycloalkylmethyl- or -ethyl, phenyl, naphthyl or benzyl, 2-phenylethyl or phenyl-CH=CH-CH2-; y is 1 and M is an alkali metal or y is 1/2 and M is an alkaline earth metal, R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl and Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl;
(b) a sulfonamide-substituted alkyl group R8-SO2NR9-(CH2)n- in which R8, R9 and n have the meanings indicated in (a);
(c) an aminocarbonylamide- or carbamate-substituted alkyl group R9NH-C(O)-NH-(CH2)n or R9O-C(O)-NH-(CH2)n in which R9 has the meanings indicated in (a) and additionally phenyl and n has the meanings indicated in (a);
(d) a carbhydrazido-substituted alkyl group R8-C(O)-NHNR9-(CH2)n- in which R8, R9 and n have the meanings indicated in (a); or (e) a sulfonhydrazido-substituted alkyl group R8-SO2-NHNR9-(CH2)n- in which R8, R9 and n have the meanings indicated in (a).

32. A compound according to claim 27, wherein R4 is an (a) amide R8C(O)N(R9)(CH2)n- or R8S(O)2N(R9)(CH2)n-; where R8 and R9 are, independently of one another, hydrogen; unsubstituted C1-C12alkyl; C1-C12alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(O)ONa, C1-C12alkyl, C1-C6alkoxy, C6-C10aryl, -SO3H, OSO3Na, NR20SO3Na, SO3Na, nitro and cyano; unsubstituted C3-C12cycloalkyl; C3-C12cycloalkyl substituted by one or more OH;
unsubstituted C6-C10aryl, unsubstituted C7-C12aralkyl with C1-C6alkyl and C6-C10aryl;
C6-C10aryl, or C7-C12aralkyl with C1-C6alkyl and C6-C10aryl, which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(O)ONa, -C(O)OK, C1-C12alkyl, C1-C6alkoxy, C6-C10aryl, SO3Na, OSO3Na, NR20SO3Na, C(O)ORs1, OC(O)Rs4, nitro, amino and cyano, R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl and Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl; and n is 2 or 1; or (b) sulfonamide R8S(O)2N(R9)(CH2)n-, where R8 is C1-C12alkyl, which is unsubstituted or substituted by one or more halogen atoms; or C6-C10aryl, which is substituted by one or more C1-C4alkyl, C1-C4alkoxy, halogen, -CN or -NO2, and R9 is hydrogen or isobutyl, and n is 2 or 1 ; or (c) aminocarbonylamide R8-NH-C(O)-NH(CH2)n-, in which R8 is C1-C12alkyl or C6-C10aryl, which is unsubstituted or substituted by halogen, -CN, -NO2, C1-C4alkyl, C1-C4alkoxy, C5- or C6cycloalkyl, C6-C10aryl or C7-C12aralkyl, and n is 2 or 1; or (d) aminoalkyl R8, R9, N(CH2)n-, where R8, and R9, are, independently of one another, hydrogen;
unsubstituted C1-C12alkyl; C1-C12alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)-NR11R12, C1-C12alkyl, C1-C6alkoxy, C6-C10aryl, -SO3H, SO3Na, OSO3Na, NR20SO3Na, nitro, amino and cyano; unsubstituted C3-C12cycloalkyl; C3-C12cycloalkyl which is substituted by one or more OH; C6-C10aryl; C7-C16aralkyl with C1-C6alkyl and C6-C10aryl; or C8-C16aralkenyl with C2-C6alkenyl and C6-C10aryl, where aryl and the aryl in the aralkyl and aralkenyl are unsubstituted or substituted by one or more substituents selected from the group consisting ofOH, halogen, C(O)ORs1, OC(O)Rs4, -C(O)ONa, -C(O)OK, -C(O)-NR11R12, C1-C12alkyl, C1-C6alkoxy, C6-C10aryl, -SO3H, SO3Na, OSO3Na, NR20SO3Na, nitro, amino and cyano;

wherein n is 2 and preferably 1, and Rs1 is hydrogen, K or Na, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, R11 is H, C1-C4alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and R12 independently has the meaning of R11 or R11 and R12 together are tetramethylene, pentamethylene or -CH2CH2-O-CH2CH2- and R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl.

33. A compound according to claim 32, wherein R4 is an amide R8C(O)N(R9)(CH2)n- or R8S(O)2N(R9)(CH2)n-, where R8 is unsubstituted C1-C12alkyl; C1-C8alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ONa and C6-C10aryl; unsubstituted C3-C12cycloalkyl; C3-C8cycloalkyl which is substituted by one or more OH; unsubstituted C6-C10aryl or C1-C12aralkyl with C1-C6alkyl; C6-C10aryl, C1-C12aralkyl with C1-C6alkyl and C6-C10aryl or C8-C16aralkenyl with C2-C6-alkenyl and C6-C10aryl, which is substituted by one or more substituents selected from the group consisting of halogen, -C(O)OH, C(O)ONa, C1-C12alkyl, C1-C6alkoxy, -SO3H, SO3Na, OSO3Na, NR20SO3Na in which R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and nitro and cyano; and R9 is hydrogen; unsubstituted C1-C6alkyl, unsubstituted C6-C10aryl, unsubstituted C1-C12aralkyl with C1-C6alkyl and C6-C10aryl; or C8-C16aralkenyl with C2-C6alkenyl and C6-C10aryl, and n is 2 or 1.

34. A compound according to claim 32, wherein R4 is an amide R8C(O)N(R9)(CH2)n-, where R8 is unsubstituted C1-C12alkyl; C1-C12alkyl which is substituted by one or more substituents selected from the group consisting of cyclohexyl, OH, halogen, -C(O)OH, -C(O)ONa and phenyl; unsubstituted C3-C12cycloalkyl; C3-C12cycloalkyl which is substituted by one or more OH; unsubstituted C6-C10aryl; C6-C10aryl, which is suhstituted by one or more substituents selected from the group consisting of halogen, C(O)ONa, -C(O)OH, C1-C6alkyl, C1-C6alkoxy, phenyl, -SO3H, SO3Na, OSO3Na, NHSO3Na, nitro and cyano; or C7-C16aralkyl with C1-C6alkyl and C6-C10aryl, and R9 is hydrogen; unsubstituted C1-C6alkyl, unsubstituted C7-C16aralkyl with C1-C6alkyl and C6-C10aryl; or C8-C16aralkenyl with C2-C6alkenyl and C6-C10aryl, and n is 2 or 1.

35. A compound according to claim 34, wherein R8 is unsubstituted C1-C12alkyl; C1-C4alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OH, C(O)ONa and phenyl; unsubstituted C3-C12cycloalkyl; C3-C12cycloalkyl which is substituted by one or more OH, unsubstituted C6-C10aryl; C6-C10aryl which is substituted by one or more substituents selected from the group consisitng of halogen, -C(O)OH, C(O)ONa, C1-C6alkyl, C1-C6alkoxy, -SO3H, SO3Na, OSO3Na, NHSO3Na, nitro and cyano; or unsubstituted C7-C16aralkyl with C1-C6alkyl and C6-C10aryl, and R9 is H, C1-C4alkyl, phenyl-CH2-, phenyl-CH2CH2, phenyl-(CH2)3- or phenyl-CH=CH-CH2-, and n is 2 or 1.

36. A compound according to claim 32, wherein R4 is an amino alkyl R8, R9,NCH2-, in which R8, and R9, are, independently of one another, hydrogen; C1-C8alkyl, cyclopentyl, cyclohexyl, C5- or C6cycloalkylmethyl, phenyl-C1-C4alkyl or phenyl-C2-C4alkenyl.

37. A compound according to claim 32, wherein R4 is an amine R8, R9, NCH2-, where R8, and R9, are, independently of one another, H, C1-C6alkyl, phenyl-C1- or -C2alkyl.

38. A compound according to claim 26, wherein R4 is C7-C11aralkyl, C3-C12cycloalkyl or C1-C12alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of NH2, C3-C12cycloalkyl, primary amino, secondary amino, sulfonamide and carbamide and aminocarbonylamido.

39. A compound according to claim 38, wherein the substituents for C1-C12alkyl are selected from the group consisting of NH2, cyclohexyl, C6-C10aryl, R8C(O)N(R9)-, R8S(O)2N(R9)-, R8NHC(O)NR9- and R8,R9,N-, in which R8 and R9 are, independently of one another, hydrogen, C1-C12alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl and R8, and R9, are, independently of one another, hydrogen, OH, C1-C12alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6,C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11 aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroalkyl, C7-C11aralkyl or C6-C10heteroaralkyl and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C1-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C1-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; p is 0 or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal; or R8, and R9, together are tetramethylene, pentamethylene, -(CH2)2-O-(CH2)2-, -(CH2)2-S-(CH2)2- or -(CH2)2-NR,-(CH2)2-, and R7 is H, C1-C6alkyl, C7-C11 aralkyl, C(O)Rs2 or sulfonyl.

40. A compound according to claim 39, wherein R4 is CH2-C6H5, (CH2)2-C6H5, cyclohexyl, methyl, ethyl or isopropyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH2, cyclohexyl, C6-C10aryl, R8C(O)N(R9)-,R8S(O)2N(R9)-, R8NHC(O)NR9-, NR9C(O)NHR8 and R8, R9,N-, in which R8, R9, R8, and R9 are, independently of one another, hydrogen, C1-C12alkyl, C3-C12cycloalkyl, C6-C10aryl or C7-C11aralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OMy, nitro, cyano, SO3My, OSO3My, NHSO3My, C1-C12alkyl, C1-Cl2alkoxy and C6-C10aryl, where y is 1 and M is a monovalent metall or y is 1/2 and M is a divalent metal.

41. A compound according to claim 26, wherein R4 is C6H11, CH(CH3)2, CH2-phenyl, (CH2)2-phenyl, CH2NHC(O)-phenyl, CH2NHC(O)(CH2)3-phenyl, CH2NHC(O)(CH2)3OH, CH2NHC(O)CF3, CH2NHC(O)C6H11. CH2NHC(O)C11H23, CH2NHC(O)CH(C6H5)2, CH2HNC(O)NHC6H5,CH2NHC(O)C2H4CO2Na,CH2NHC(O)C6[(1,3,4,5)OH]4H7, CH2NHC(O)C6H4-p-SO3Na, CH2NHC(O)C6H4Cl, CH2NHC(O)C6H4NO2, CH2NHC(O)C6H4OCH3, CH2NHC(O)C6H4(3,4)Cl2, CH2NHC(O)C6H4CH3, CH2NHC(O)C6H4C6H5, CH2NHC(O)C6H4CN, CH2NHC(O)C10H7, CH2NHC(O)C6H4COONa, CH2NHC(O)(CHOH)2COONa, CH2N(CH2CH=CH-phenyl)[C(O)-phenyl], CH2N[CH2CH(CH3)2][C(O)-phenyl], CH2N[C(O)C6H5]CH2C6H5, CH2N[C(O)C6H5](CH2)3C6H5, CH2C6H11, (CH2)2C6H11, CH2NH2, CH2NHCH2CH=CH-phenyl, CH2NHCH2-phenyl, CH2NHCH2CH(CH3)2, CH2N(CH2-phenyl)2, CH2N[CH2CH(CH3)2]2, CH2NHSO2-p-nitrophenyl, CH2NHSO2-p-tolyl, CH2NHSO2CF3, CH2NHC(O)NHC6H5 or CH2N[SO2-p-nitrophenyl][CH2CH(CH3)2]2.

42. A compound according to claim 1, which corresponds to the formula la in which R3 is hydrogen or My; and R4 is C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-ClOheteroaralkyl, C8-C11aralkenyl or C7-C10heteroaralkenyl, which are unsubstituted or substituted once or several times;
R5 and R6 are, independently of one another, hydrogen, C1-C12alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl; or R5 and R6 are, together with the -CH-CH- group, C3-C12cycloalkylene, C4-C12cycloalkenylene, C2-C11heterocycloalkylene and C3-C11heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-;
where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted once or several times; where the substituent is selected from the group OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C1,heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are substituted or unsubstituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is a 1/2 and M is a divalent metal.

43. A compound according to claim 42, wherein R3 is H, K or Na; R5 and R6 are, together with the -CH-CH- group, C3-C12cycloalkylene, C4-C12cycloalkenylene, C2-C11heterocycloalkylene and C3-C11heterocycloalkenylene 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(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, in which Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11,-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal;
(a) R4 is a residue R12-(CH2)n- or cyclohexyl, in which n is 1 or 2 and R12 is C1-C10alkyl, C5-C8cycloalkyl, C6-C10aryl or C8-C12aralkenyl, which are unsubstituted or substituted by C1-C4alkyl, C1-C4alkoxy, F, Cl, -CN or-NO2; or R12 is an amino group -NR8 R9, and R8 and R9 are C1-C12alkyl or unsubstituted orC1-C4alkyl-substituted C5- or C6cycloalkyl, C6-C10aryl, C7-C12aralkyl or C8-C12aralkenyl; or R12 is an amide group -N(R9)C(O)R8, -N(R9)S(O)2R8, -NR9C(O)NHR8 or -NR9C(O)NHR8 in which R8 is C6-C10aryl, which is unsubstituted or substituted by C1-C4alkyl, C1-C4alkoxy, F, Cl, -CN or -NO2, or C1-C10alkyl which is unsubstituted or substituted by F or C1, and R9 is H, C1-C10alkyl: C5- or C6cycloalkyl, C5- or C6cycloalkyl-C1-C6alkyl, phenyl-C1-C6alkyl or phenyl-C2-C6alkenyl; or (b) R4 is C1-C12alkyl, C3-C12cycloalkyl or C7-C11aralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkellyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

44. A compound according to claim 43, wherein (i) R4 is C6H11, C6H11-CH2, C6H11-CH2CH2-, C6H5-CH2-, C6H5-CH2CH2- or C6H5-CH=CH-CH2-;
(ii) R4 is C6H11, C6H11-CH2-, C6H11-CH2CH2-, C6H5-CH2-, C6H5-CH2CH2-,-CH2-NR19-SO2R18, -CH2-NR19-C(O)R40, CH2NHC(O)NHR18, -CH2NHR21 or CH2N(R21)2, in which R18 is -C8H5, phenyl which is substituted by 1 to 3 methyl or methoxy or -NO2 or F or Cl, or C1-C4alkyl, which is substituted by F; R40 is phenyl which is unsubstituted or substituted by 1 to 3 methyl or methoxy or -NO2 or F or Cl; R19 is H, C1-C6alkyl, phenyl-(CH2)z- with z equal to a number from 1 to 3, phenyl-CH=CH-CH2-, -CH2-CH(CH3)2 or benzyl; and R21 is -CH2-CR22R23R24 in which R22 and R23, methyl, ethyl or phenyl and R24 is H, ethyl or methyl;
or (iii) R4 is C6H11, CH2-C6H5, (CH2)2-C6H5, methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH2, cyclohexyl, C6-C10aryl, R8C(O)N(R9)-, R8S(O)2N(R9)-, NR9C(O)NHR8 and R8, R9, N- in which R8, R9, R8, and R9, are, independently of one another, hydrogen, C1-C12alkyl, C3-C12cycloalkyl, C6-C10aryl or C7-C11aralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OMy, nitro, cyano, SO3My,OSO3My, NR20SO3My, C1-C12alkyl, C1-C12alkoxy and C6-C10aryl, where R20 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C6-C11-aralkenyl or C7-C10heteroaralkenyl, y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

45. A compound according to claim 42, wherein R4 is C6H11, CH(CH3)2, CH2-phenyl,(CH2)2-phenyl, CH2NHC(O)-phenyl, CH2NHC(O)(CH2)3-phenyl, CH2NHC(O)(CH2)3OH, CH2NHC(O)CF3, CH2NHC(O)C6H11, CH2NHC(O)C11H23, CH2NHC(O)CH(C6H5)2, CH2HNC(O)NHC6H5, CH2NHC(O)C2H4CO2Na, CH2NHC(O)C6[(1,3,4,5)OH]4H7, CH2NHC(O)C6H4-p-SO3Na, CH2NHC(O)C6H4Cl, CH2NHC(O)C6H4NO2, CH2NHC(O)C6H4OCH3, CH2NHC(O)C6H4(3,4)Cl2, CH2NHC(O)C6H4CH3, CH2NHC(O)C6H4C6H5, CH2NHC(O)C6H4CN, CH2NHC(O)C10H7, CH2NHC(O)C6H4COONa, CH2NHC(O)(CHOH)2COONa, CH2N(CH2CH=CH-phenyl)[C(O)-phenyl], CH2N[CH2CH(CH3)2][C(O)-phenyl], CH2N[C(O)C6H5]CH2C6H5, CH2N[C(O)C6H5](CH2)3C6H5, CH2C6H11,(CH2)2C6H11, CH2NH2, CH2NHH2H=CH-phenyl, CH2NHCH2-phenyl, CH2NHCH2CH(CH3)2, CH2N(CH2-phenyl)2, CH2N[CH2CH(CH3)2]2, CH2NHSO2-p-nitrophenyl, CH2NHSO2-p-tolyl, CH2NHSO2CF3, CH2NHC(O)NHC6H5 or CH2N[SO2-p-nitrophenyl][CH2CH(CH3)2]2.

46. A process for the preparation of the compounds of the formula I according to claim 1 which comprises etherifying the 3-OH group of a compound of the formula V

in which R2 and X have the meanings mentioned in claim 1, R12 is a protective group and R12' and R12" are, independently of one another, hydrogen or a protective group, with a compound of the formula Vl R1-R13 (VI) in which R1 has the meaning mentioned in claim 1 and R13 is a leaving group, and eliminating the protective groups.

47. A process for the preparation of the compounds of the formula I according to claim 1 which comprises glycosidically linking the protected fucose hydroxy ether of the formula VII

in which R2 and X have the meanings mentioned in claim 1, and R12 is a protective group, with the protected galactose of the formula VIII

in which R1 and R12 have the meanings mentioned in claim 1, Z is O or S, and R is a leaving group, and subsequently removing the protective groups from the resulting compound.

48. A compound of the formula V

in which R2 is hydrogen, C1-C12alkyl or C6aryl; where the alkyl and the aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C-C9-heteroalkyl, C7-C11aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl,C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal;
R5 and R6 are, together with the -CH-CH- group, C3-C12cycloalkylene, C3-C12-cycloalkenylene, C2-C11heterocycloalkylene and C3-C11heterocycloalkenylene with hetero atoms selected from the group -O-, -S- and -N-; where cycloaalkylene, cycloalkenylene,heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more of the above substituents;
R12 is a protective group and R12' and R12" are, independently of one another, hydrogen or a protective group.

49. A process for the preparation of a compound of the formula V according to claim 48 which comprises initially synthesizing pseudo-trisaccharide building blocks by glycosidic attachment for the activated and protected galactose to the fucose-O-X-OH building block or by glycosidic attachment of suitably protected and activated fucose to a galactose-O-X-OH building block, then introducing the group R1 into the pseudotrisaccharide and subsequently modifying the resulting compounds in the desired manner.

50. A compound according to claim 1, for use in a therapeutic method for the treatment of disorders in warm-blooded animals, including humans.

51. A pharmaceutical composition comprising an effective amount of the compound according to claim 1, alone or together with other active substances, a pharmaceutical carrier, and, where appropriate, excipients.