AU707474B2 - Diglycosylated 1,2-diols as mimetics of sialyl-lewis X and sialyl-lewis A - Google Patents

Description

WO 97/01569 PCT/EP96/02 7 8 1 Dilycosylated 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-acetylglucosamine 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-carbohydrate interaction with glycolipids and glycoproteins on the leukocyte membrane, the socalled "rolling" of leukocytes. The latter are slowed down by this process, and there is activation of certain proteins (integrins) on their surface which ensure firm adhesion of the leukocytes to the endothelium. This is followed by migration of the leukocytes into the damaged tissue.

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, Rao, 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, Rao, 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 membrane, thus to prevent the "rolling", by mimetics of the corresponding epitopes. This also results in suppression of WO 97/01569 PCT/EP96/02 7 8 -2the subsequent processes. One of the smallest carbohydrate epitopes as ligand for E selectin is sialyl-Lewis X [neuraminic acid-a(2-3)-galactose-(1-- 4 )-(fucose-a(1 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-cyclohexanedioxy. 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 aliphatic 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 synthetic complexity.

The present invention relates to compounds of the formula

I

1 'OH HO OH 0

(I)

R

2 0 OH

OH

OH

in which X is the residue of a non-glycosidic aliphatic 1,2-diol; WO 97/01569 PCTIEP96/02785 -3- R, is an S-configurated methyl substituted with one carboxyl residue and one other substituent; and

R

2 is hydrogen, Cl-Cl 2 alkyl or C 6 aryl; where the alkyl and the aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, O(O)ORs 1 OC(O)R.1 4

C(O)R,,

2 nitro, NH 2 cyano, SO 3 MY, OSO 3 My, NR 20

SO

3 MY, CI-C 12 alkyl, C2-Cl 2 alkenyl, Cl-Cl 2 alkoxy, C3-C1 2 cycloalkyl, C3-Cl 2 cycloalkenyl, 02-Cl iheterocycloalkyl, 02-Ciliheterocycloalkenyl, C6-Cloaryl, 06-Cloaryloxy, 05-Ogheteroaryl, CS-Cgheteroaryloxy, 0 r-Ciaralkyl, 07-011 aralkyloxy, C6-Cloheteroaralkyl, 08-Cil aralkenyl, C7-Cloheteroaralkenyl,.

primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rj 1 is hydrogen, My, 0 1 -Cl 2 alkyl, C2-Cl 2 alkenyl, C3-C1 2 cycloalkyl, 02-01 iheterocycloalkyl, C6-Cloaryl, CS-Cgheteroaryl, 07-Claralkyl or 06-Cloheteroaralkyl, Rr, 4 is hydrogen, Cl-Cl 2 alkyl, 02-Cl 2 alkenyl, C3-Cl2CYCloalkyl, 1 Clheterocycloalkyl, 06-Cl oaryl, C7-Cllaralkyl or C6-Cloheteroaralkyl, and 131 2 and R 20 are hydrogen, Cl-Cl 2 alkyl, C2-Cl2alkenyl, 03-C1 2 cycloalkyl, 03-C12cycloalkenyl, 02-Cl iheterocycloalkyl, C2C1-heterocycloalkenyl, O6-Cloaryl, C5-Cgheteroaryl, 07-01 1 aralkyl, C6-Cloheteroaralkyl, 08-Cl i-aralkenyl or C7-Cloheteroaralkenyl, 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; including their physiologically tolerated salts.

Preferred aliphatic residues X are linear or branched 02-020-, preferably 02-012- and particularly preferably C2-C 6 alkylene and -alkenylene, 03-012-, preferably 03-Ca- and particularly preferably CS-C7cycloalkylene and cycloalkenylene, and 03-011I-, preferably 03-07- and particularly preferably C3-Csheterocycloalkylene and hete rocycloalkenylene with hetero atoms selected from the group of and The residue X can contain substituents such as OH, halogen, C(O)0R 31 OC(O)RI4,

C(O)R.,

2 nitro, NH 2 cyano, SO 3 MY, OSO 3 My, NR 20

SO

3 My, CI-Cl 2 alkyl, C2-Cl 2 alkenyl, Cl -Cl 2 alkoxy, C3-C12cycloalkyl, 0 3-Cl2cycloalkenyl, 02-01ilheterocycloalkyl, C2-C1 1 heterocycloalkenyl, 06-Cloaryl, C6-Cloaryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, 07-Cl iaralkyl, 07-Cl iaralkyloxy, 06-Cloheteroaralkyl, C8Claralkenyl, C7-Cioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, WO 97/01569 PCTJEP96/02785 -4carbhydrazide, carbohydroxamic acid and amidocarbonylamide, where R~j is hydrogen, My, Cl -Cl 2 alkyl, 02-Cl2alkenyl,

C

3 -C1 2 cycloalkyl, 02-011 heterocycloalkyl, 0 6 -Cloaryi, C 5 -Cgheteroaryl, C7-Cl 1 aralkyl or C6-Cloheteroaralkyl, R1 4 is hydrogen,

-C

12 alkyI, C2-Cl 2 alkenyl, C.3-C1 2 cycloalkyl, 02-Cil heterocycloalkyl, 06-Cloaryl, C5-Cgheteroaryl, 07-Cl iaralkyl or C6-Cloheteroaralkyl, and R.

2 and R 2 o are hydrogen, Cl-Cl 2 aikyl, C2-Cl 2 alkenyl, C3-C1 2

CYCIO-

alkyl, C3-Cl2cycloaikenyl, 02-Cl iheterocycloalkyl, 02-Cl i-heterocycloalkenyl, C6-Cloaryl, C7-C 1 aralkyl, C6-Cloheteroaralkyl, 08-Cl 1-aralkenyl or 07-Cloheteroar.

alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloaikenyl, 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.

In a preferred embodiment of the present invention, X is the residue of a 1 ,2-diol corresponding to formula 11

H

H

H

in which

R

5 and R 6 are, independently of one another, hydrogen, Cl-Cl 2 alkyl, 03-C1 2 CYCloalkyl, C2-C1 iheterocycloalkyl,

C

6 -Cl 0 aryI, C5-Cgheteroaryl, C7rCi aralkyl or C6-Cloheteroaralkyl; or

R

5 and R 6 are, together with the -OH-OH- group, C:3-Cl2cycloalkylene, C3-C12-cycloalkenylene, C2-Cllheterocycloalkylene and C3-Cllheterocycloalkenylene with hetero atoms selected from the group and 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)OR, 1 OC(O)R,4, C(O)R1 2 nitro, NH 2 cyano, SO 3 My, OSO 3 My, NR 20

SO

3 MY1 Ci-Cl 2 alkyl, C2-Cl 2 alkenyl, Cl-Cl 2 alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-Cl 1 heterocycloalkyl, 02-Cl iheterocycloalkenyl, C6-Cloaryl, C6-Cloaryloxy, WO 97/01569 PCT/EP96/ij2785

C

5 -Cgheteroaryloxy, C7-C1 1 aralkyl, 07-Cl 1 aralkyloxy, C6-Cioheteroaralkyl, 08-Cil aralkenyl, C7-

C,

0 heteroaralkenyi, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs, is hydrogen, My, CI-C, 2 alkyl, C2-Cl 2 alkenyl, C3-C12cycloalkyl,

C

2 -Cliheterocycloalkyl,

C

6 -Cloaryl, C5-Cgheteroaryl, 07-Ollaralkyl or C6-Cloheteroaralkyl, R1 4 is hydrogen, Cl -Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, 1 Clheterocycloalkyl, C6-Cloaryl, 0 5 -Cgheteroaryl, 07-Cliaralkyl or C6-Cloheteroaralkyl, and RS 2 and R 20 are hydrogen, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, C3-Cl 2 cycloalkenyl, 02-Cl iheterocycloalkyl, C2C1-heterocycloalkenyl, C6-Cloaryl, C5-Cgheteroaryl, 07-Cl 1 aralkyl, C6-Cloheteroaralkyl, 08-Cl 1 -aralkenyl or C7-Cloheteroaralkenyl, 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.

The other substituent in R, has preferably 1 to 20, more preferably 1 to 16, particularly preferably 1 to 12, and especially preferably 1 to 8, C atoms. The other substituent is preferably selected from the group consisting of unsubstituted and substituted Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C 3 -C1 2 Cycloalkyl, C3-C12cycloalkenyl, 02-Cl iheterocycloalkyl, 02-Cl 1 heterocycloalkenyl, OG-Cloaryl, C5-Cgheteroaryl, 07-Cl 1 aralkyl, C6-Cloheteroaralkyl, 08-Cl 1 aralkenyl and C7-Cloheteroaralkenyl. The other substituent is particularly preferably substituted methyl, or 2-substituted ethyl or cyclohexyl. Examples of suitable substituents are the substituents; mentioned above in the definition of R 2 especially OH, halogen Cl or Br), carb- OXYl, -SO 3 H, C(O)OMy,

SO

3 MY, OSO 3 My, NR 20

SO

3 My in which R 20 is hydrogen, CI-C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, 03-Cl 2cycloalkenyl, 02-Cl iheterocycloalkyl, 02-Cl 1-heterocycloalkenyl, 06-Cloaryl, Cs-Cgheteroaryl, 07-Cllaralkyl, C6-Cloheteroaralkyl, 08-CIl-aralkenyl or C7-Cloheteroaralkenyl, or 0 1 -Cl 2 alkyl, CI-Cl 2 alkoxy, nitro, -NH 2 primary amino with 1 to C atoms, secondary amino with 2 to 30 C atoms, cyano, 03-C8cycloalkyl, 03-C 6 heterocycloalkyl, 06-Cloaryl, C3-Cgheteroaryl, C7rCl6heteroaralkyl, where the hetero atoms are selected from the group of 0, S and N atoms, and carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide or aminocarbonylamide, whose N atoms are unsubstituted or substituted by a hydrocarbon group or hydroxy-hydrocarbon group with 1 to 20 0 atoms.

The hydrocarbon groups and heterohydrocarbon groups in turn are unsubstituted or substi- WO 97/01569 PCT/EP96/02785 -6tuted, for example with Cl-C 6 alkyl, Cl-C 6 alkoxy, carboxyl, halogen Cl or Br), -OH, -ON or

-NO

2 In a particular embodiment of the compounds of the formula 1, R, corresponds to a group of the formula Ill,

COOR

3

R

4 in which

R

3 is hydrogen or My~; and

R

4 is C 1 -Cl 2 alkyI, 0 2

-C

12 alkenyl, C3-C1 2 cycloalkyl, C3-C12cycloalkenyl, 02-Cl iheterocycloalkyl, C2-C1 iheterocycloalkenyl, C6-Cloaryl,

C

5 -Cgheteroaryl, 07-01 1 aralkyl, C6-Cloheteroaralkyl, C8-Ci 1 aralkenyl or C7-Cloheteroaralkenyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs 1 OC(O)R1 4

C(O)R,

2 nitro, NH 2 cyano, SO 3 My, OSO 3 My, NR 20

SO

3 MY, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, Cj- C1 2alkoxy, C3-C12CYCloalkyl, C3-C12cycloalkenyl, C2-C1 iheterocycloalkyl, 02-C iiheterocycloalkenyl, C6-C 10 aryl, 06-Cloaryloxy, 0 5 -Cghete roaryl, C7-Cl 1 aralkyl, 07-Cl 1 aralkyloxy, OG,-Cloheteroaralkyl, 08-Cl 1 aralkenyl, 0 7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where-R~j is hydrogen, My, Cl-Cl 2 alkyl, C 2 -Cl 2 alkenyl, C3-Cl 2 cycloalkyl, 02-Cl iheterocycloalkyl, 0 6-Cloaryl, O5-Cgheteroaryl, OCiCiaralkyl or C6-Oloheteroaralkyl,

RS

4 is hydrogen, Cl-Cl 2 alkyl, 02-Ol 2 alkenyl, 03-C1 2 cycloalkyl, C2-011 heterocycloalkyl, C6-Cloaryl, aryl, C7-Cliaralkyl or C6-Cloheteroaralkyl, and R., 2 and R 20 are hydrogen, C 1 -Cl 2 alkyl, C2-Ol 2 alkenyl, C3-C1 2 cycloalkyl, C3-C1 2 cycloalkenyl, 02-01 iheterocycloalkyl, 02-01 i-heterocycloalkenyl, 06-Oloaryl, C5-Cgheteroaryl, C7-Cl 1 aralkyl, Ce-Cloheteroaralkyl, 08-Cil -aralkenyl or C7-Cloheteroaralkenyl, 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.

WO 97/01569 PCTIEP96/02785 -7- For the purposes of the present invention, a metal is to be understood as meaning an alkali metal [for example lithium sodium potassium rubidium (Rb) and caesium an alkaline earth metal [for example magnesium calcium (Ca) and strontium or manganese iron zinc (Zn) or silver 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, 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 -4or -5-en-1-yl or -2-yl and (C 1

-C

4 alkyl)CH=CH-CH 2 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, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Cyclohexyl is a particularly preferred cycloalkyl group. Examples of cycloalkenyl are cyclopropenyl, 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 2,3pentylene, 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-cyclooctylene. Examples of heterocycloalkylene are pyrrolidinylene, piperidinylene, tetrahydrofuranylene, di- and tetrahydropyranylene.

WO 97/01569 PCT/EP96/02785 -8- 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, isoxazole, oxazole, furazan, thiadiazole, thiophene, thiazole, oxadiazole, triazole, indole, indazole, purine, benzimidazole, benzoxazole, benzothiazole, 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-CnH 2 n- 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-CH 2 (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 12 alkyl, C 1

-C

6 alkoxy, C 6 -Co 10 aryl, SO 3 My, OS03My,

NR

2 0SO 3 My in which R 2 0 is hydrogen, C 1

-C

12 alkyl, C 2

-C

12 alkenyl, C 3

-C

12 cycloalkyl,

C

3

-C

12 cycloalkenyl, C2-C1 heterocycloalkyl, 02-01C -heterocycloalkenyl, C 6 -Co 10 aryl, Cs-Cgheteroaryl, C7-Cliaralkyl, C 6 -Co 10 heteroaralkyl, C-C11-aralkenyl or C- 7

-C

1 oheteroaralkenyl, and NO 2

C

1

.C

1 2 primary amino, C 2

-C

20 secondary amino, amino and CN.

Heteroaralkyl and heteroaralkenyl are preferably C 4

-C

5 heteroarylmethyl and C 4

-C

5 heteroarylethenyl with one or two hetero atoms from the group of O and N, and the heteroaryl 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, undecoxy and dodecoxy. Preferred alkoxy groups are methoxy and ethoxy.

WO 97/01569 PCTIEP96/02785 -9- 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-, i- or t-butyl-, pentyl-, hexyl-, cyclopentyl-, cyclohexyl-, phenyl-, methylphenyl-, benzyl- and methylbenzylamino.

The secondary amino preferably contains 2 to 14, particularly preferably 2 to 8, C atoms.

Some examples are dimethyl-, diethyl-, methylethyl-, di-n-propyl-, di-i-propyl-, di-n-butyl-, diphenyl-, dibenzylamino, morpholino, piperidino and pyrrolidino.

NH

2 primary amino, secondary amino, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide and aminocarbonylamide preferably correspond to a group

R

8 C(O)(NH)pN(R 9 -C(O)(NH)pNR 8

R

9

R

8 OC(O)(NH)pN(R 9 RaR 4 oNC(O)(NH)pN(R 9 -OC(O)(NH)pNR 8

R

9

-N(R

4 0)C(O)(NH)pNR 8

R

9 R8S(O) 2 (NH)pN(R 9

-S(O)

2 (NH)pNRBR 9

R

8

R

4 oNS(0) 2

N(R

9 or -NR 40

S(O)

2

NR

8

R

9 in which R 8

R

9 and R 40 are, independently of one another, hydrogen, OH, C 1 -Cl 2 alkyl, CI-Cl 2 alkenyl, C3-Cl 2 cycloalky, C3-Cl2cycloalkenyl, C2-Clheterocycloalkyl, 02-Cl iheterocycloal kenyl, C6-Cloaryl, C5-Cgheteroaryl, C7-Cl 6 aralkyl, C8-Cl 6 aralkenyl with C 2 -C~alkenylene and Ce-Cloaryl, C6-Cl 5 heteroaralkyl,

C

6

-C

15 heteroaralkenyl, or di-C6-C1Oaryl-Cj-C6-alkyl, or R 8

R

9 N in which R 8 and R 9 are, independently of one another, hydrogen, OH, SO 3 My, OSO 3 MY, CI-C 12 alkyl, C3-C12CYCloalkyl, C2-Cilheterocycloalkyl, 06-Cloaryl, 05-Ogheteroaryl, 07-Cl 1 aralkyl, 06-Cloheteroaralkyl, C8-Cl 6 aralkenyl with 02-O~alkenylene and C6-ClOaryl, or di-C6-CjOaryl-Cj-C 6 -alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)0R,, 1

OC(O)R,

4

C(O)RS

2 nitro, NH 2 cyano, SO 3 My, OSO 3 My, NR 20

SO

3 My, CI-C 12 alkyl, 02-Cl 2 alkenyl, CI -C 12 alkoXy, C3-Cl 2 cycloalkyl, 0 3-Cl2cycloalkenyl, 02-Cl iheterocycloalkyl, C2- C11 heterocycloalkenyl, 06-ClOaryl, 06-Cloaryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, C7- Cil 1 aralkyl, C 7 1 aralkyloxy, C6-Cloheteroaralkyl, CCi aralkenyl, 07-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazidle, carbohydroxamic acid and aminocarbonylamide, where IRS, is hydrogen,

CI-C

12 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, 02-Cl iheterocycloaky, C6-Cloaryl, 05-Cgheteroaryl, 07-Cl 1 aralkyl or 06-Cloheteroaralkyl, R 4 is hydrogen, Cl -C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkYl, C2Ciheterocycloalkyl, C6-Cloaryl, C 5 -Cgheteroaryl, 07-Cllaralkyl or 06-Cloheteroaralkyl and RS 2 is hydrogen, CI-Cl 2 alkyl, 0 2

-C

12 alkenyl, C3-C12cycloalkyl, C,3-Cl 2 cycloalkenyl, 02-Cl iheterocycloalkyl, 02-Cl i-heterocycloalkenyl, WO 97/01569 PCT/EP96/02785

C

6 -Cj 0 aryl, 0 5-Cgheteroaryl,

C

7

-C

1 1 aralkyl, C6-Cloheteroaralkyl, 083-Cl i-aralkenyl or

C

7 -Cl 0 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryi, 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 R 8 and R 9 or R 8 and R 9 or R 8 and R 40 in the case of -NR 8

R

9 or

NR

8

.R

9 or RBR 4 oN- together are tetramethylene, pentamethylene,

-(CH

2 2 -O-(0H 2 2

-(OH

2 2 S-(C2)2-or -(CH 2 2

-NR

7

-(CH

2 2 and R 7 is H, C 1

-C

6 alkyl, 07-Cliaralkyl, C(O)Rs 2 or sulfonyl.

The sulfonyl substituent corresponds, for example, to the formula RIO-S0 2 in which RIO is Cl-Cl 2 alkyl, C3-C1 2 cycloalkyl, C2-C1 iheterocycloalkyl, C6-Cloaryl, C5-Cgheteroaryl, C7-C1 1 aralkyl or C 6 -Cloheteroaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs 1 OC(O)R14,

C(O)R,

2 nitro, NH 2 cyano, SO 3 OS0 3 My, NR 20

SO

3 My, Cl-Cl,,alkyl, C2-Cl 2 alkenyl, Cl-C 12 ,alkoxy, C3-01 2cycloalkyl, 03-Cl 2 cycloalkenyl, 02-011 heterocycloalkyl, C2-C1ilheterocycloalkenyl, 06-Cloaryl, C 6 -0 1 0 aryloxy, C5-Cgheteroaryl, 05-Ogheteroaryloxy, C7-Cl 1 aralkyl, 06-ClOheteroaralkyl, C8-C 1 1 aralkenyl, C7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamnate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs, is hydrogen, My, Cl-C 12 alkyl, C2-Cl 2 alkenyl, C3- C1 2 cycloalkyl, 02-01 iheterocycloalkyl, 0 6 -CIOaryl, C5-Cgheteroaryl, 07-011 aralkyl or C6- Cioheteroaralkyl, R.1 4 is hydrogen, Cl-C, 2 alkyl, C2-Cl 2 alkenyl, C3-C12cycloalkyl, C2- Ciiheterocycloalkyl, C6-Cloaryl, C5-Cgheteroaryl, 07-Ollaralkyl or C6-Cloheteroaralkyl, and

R,

2 and R 2 0 are hydrogen,

C

1

-C

12 alkyl, C2-Cl 2 alkenyl, C3-C 12 cycloalkyl, C3-C 1 2 CYCloalkenyl, C2-Cl iheterocycloalkyl, C2-C1 i-heterocycloalkenyl, 06,-ClOaryl, C5-Cgheteroaryl, C7-Cl 1 aralkyl, C6,-Cloheteroaralkyl, CB-Cli-aralkenyl or C7-Cloheteroaralkenyl, 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 11 in which R 5 and R 6 are unsubstituted or substituted by Cl-Cl 2 alkyl, for example methyl, ethyl, or CI-C 12 alkoxy, for example methoxy, ethoxy; WO097/01569 PCT/EP96/02785 are, together with the group -OH-OH-, 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; are, together with the group -CH-CH-, a 5- to 8-membered heterocarbocycle, and particularly preferably a 5- or 6-membered heterocarbocycle with nitrogen as hetero atom, and are very particularly preferably R,R-3,4-piperidylene; are, independently of one another, hydrogen, unsubstituted

CI-O

12 alkyl or 0 1

-O

12 alkyl which is substituted by a substituent selected from the group consisting of -C(O)ORsl, -OO(O)Rs4, -C(O)ONa or -C(0)0K, primary amino, secondary amino, O'3-C12cycloalkyl, Cl-C 6 alkoxy, phenyloxy and be -nzyloxy; unsubstituted 03-C1 2 cycloalkyl or O3-C12cycloalkyl which is substituted by a substituent selected from the group consisting of -CO)0R, -0C(0)RS 4 -O(O)0Na or -C(0)0K, primary amino, secondary amino, 0 1

-C

6 alkyl, C 1

-C

6 alkoxy, phenyloxy and benzyloxy; O6-Cloaryl which is unsubstituted or substituted by -CO)0Rs 1 -CO)ONa or -C(0)0K, primary amino, secondary amino, 0 1

-O

6 alkyl or Cl-C 6 alkoxy; C3-Cgheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; or C 7

-O

12 aralkyl which is unsubstituted or substituted by -C(0)0Rs 1 -CO)0Na or -C(0)0K, primary amino, secondary amino, 0 1

-O

6 alkyl or Cl-C 6 alkoxy; are, together with the group -OH-OH-, a 5- to 1 2-membered carbocycle or 5- or 6-membered heterocarbocycle with a hetero atom selected from the group consisting of oxygen and nitrogen atoms; or are, together with the -OH-OH- group, O3-Ol2cycloalkylene, O4-Ol2cycloalkenylene, 02-01 iheterocycloalkylene and 03-01 iheterocycloalkenylene with hetero atoms selected from the group of and where cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, CO)0R~j, CO)Rs 2 nitro, NH 2 cyano, S0 3 My, 0S0 3

MY,

NR

20 S0 3 My, 01 -O 12 alkyl, O2-Ol 2 alkenyl, 01 -O 12 alkoxy, Oa-O1 2 cycloalkyl, Oa-O 12 cycloalkenyl, 02-01 iheterocycloalkyl, 02-01 iheterocycloalkenyl, O6-Oloaryl, 06-Oloaryloxy, 0-7-01 1 aralkyl, 07-01 1 aralkyloxy, 06-Oloheteroaralkyl, 08-Oliaralkenyl, 07- Oioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where is hydrogen, My, 0 1

-O

12 alkyl, 02-Ol 2 alkenyl, 03-Ol 2 cycloalkyl, 02-01 iheterocycloalkyl, C6-Oloaryl, 05-Ogheteroaryl, O7-OC 1 aralkyl or 06-Olaheteroaralkyl, R1 4 WO 97/01569 PCTIEP96/02785 12is hydrogen,

CI-C

12 alkyl, C2-Cl 2 alkenyI, C:3-Cl 2 cycloalkyl, C2-011 heterocycloalkyl, 06-CjOar-yl, C7-Cllaralkyl or C6-Cloheteroaralkyl, and R1 2 and R 2 o are hydrogen, Ol-Cl 2 alkyi, O2-OI2alkenyl, C3-Cl 2 cycloalkYl, O3-Cl2cycloalkenyl, 02-01 iheterocycloalkyl, 02-Cl i-heterocycloalkenyl, C6-ClOaryl, C5-Ogheteroaryl, C7-Cl iaralkyl, O6-Cloheteroaral kyl, 08-Oll-aralkenyl or 0 7-Oloheteroaralkenyl, 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 R 5 and R 6 are, together with the -OH-OH- group, C3-C12cycloalkylene or C2-Cllheterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more of the above substituents.

Particularly preferred compounds are those in which R 5 and R 6 are, together with the -OH-OH- group, O3-Ol2cycloalkylene or O2-llheterocycloalkylene 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, O(O)ORsj, OC(O)R 4 O(O)R 2

NR

8

R

9

OI-O

12 alkyl, R 8 O(O)(NH)pN(R 9 -C(O)(NH)pNR 8 n 9 RaS(O) 2 (NH)pN(R 9

RBR

4 oNO(O)(NH)pN(R 9 R8OO(O)(NH)pN(R 9 -OO(O)(NH)pNR 8

R

9 and R 10 -S0 2 in which R 8

R

9

R

10 and R 4 o are, independently of one another, hydrogen, OH, Oi-O 12 alkyl, Oi-O 12 alkenyl, O3-Ol 2 cycloalkyl, O3-Ol2cycloalkenyl, C2-01 iheterocycloalkyl, 02-01 1 heterocycloalkenyl, Oe-CO 1 aryl, Cs-Cgheteroaryl, C7-Ol 6 aralkyl, Oe-Ol 6 aralkenyl with C 2 -C~alkenylene and Oe-COiaryl, Ce-Oi5heteroaralkyl, C6-Ol5heteroaralkenyl, or di-Oe-Cloaryl-Cl-O 6 alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen,

C(O)OR.

1 OC(O)R",

C(O)RI

2 nitro, NH 2 cyano, SO 3

MY,

OSO

3 My, NR 20

SO

3 My, Ci -Cl 2 alkyl, C2-Ol 2 alkenyl, CI-C 12 alkoxy, O3-Ol 2 cycloalkyl, C3-Ol 2 cyclOalkenyl, C2-C1 iheterocycloalkyl, C2-C1 iheterocycloalkenyl, C6-Cloaryl, C6-Cloaryloxy, Os-Ogheteroaryl, CS-Cgheteroaryloxy, C-Cli aralkyl, C7-01 iaralkyloxy, 06-Cloheteroaralkyl, CB-Oliaralkenyl, CCoheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamidle; R~j is hydrogen, My, C 1

-C

12 alkyl, C2-Cl 2 alkenyl, C3-C 12 CYCloalkyl, 02- WO 97/01569 PCT/EP96/02785 -13- Ci heterocycloalkyl, C6-CIOaryl, C5-CgheteroaryI, 07-Cl 1 aralkyl or C6-Cijoheteroaralkyl, R1 4 is hydrogen, CI-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-C12cycloalkyl, 02-01 iheterocycloalkyl, CG-Cloaryl, CS,-Cgheteroaryl, C7-Cllaralkyl or C6-Cloheteroaralkyl, R1 2 is hydrogen, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Ci 2 CYCloalkyl, C:3-C12cycloalkenyl, 02-Cl iheterocycloalkyl, CCI heterocycloalkenyl, C6-CI 0 aryl, C5-Cgheteroaryl, C7-Cl 1 aralkyl, C6-Cloheteroaralkyl, C8-Cl i-aralkenyl or C7-Cloheteroaralkenyl, 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.

R

8 and R 9 are, in particular, independently of one another hydrogen; Cl-Cl 2 alkyl; C3-C12cycloalkyl, C6-Cloaryl, C7rClearalkyl with 1 to 6 C atoms in the alkylene group and C6-Cioaryl, Ca-C, 6 aralkenyl with C2-C6alkenylene and C6-CloaryI, or di-C6-Cloaryl-Cl-C6ealkyl, for example diphenylmethyl or 2,2-dip henyl ethyl, where R 8 and R 9 are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O)OMy, 0 1

-C

12 alkyl, Cl-C 6 alkoxy, C6-Cloaryl, C6-Cloaryloxy,

SO

3 My, OSO 3

MY,

NR

20

SO

3 My, NO 2 amino, primary amino, secondary amino and ON, R 20 is hydrogen, CI -C 12 alkyl, C2-Cl2alkenyl, C3-C12cycloalkYl, 03-Cl 2cycloalkenyl, C2-Cl iheterocycloalkyl, C2-Cl i-heterocycloalkenyl, C6-Cloaryl, C5-Cgheteroaryl, 07-01 1 aralkyl, C6-Cloheteroaralkyl, CB-Cll-aralkenyl or C7-Claheteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

RIO corresponds, in particular, to Cl-Cl 2 alkyl; C3-Cl2cycloalkyl, C6-CIOaryl, C7-Cl 6 aralkyl with 1 to 6 C atoms in the alkylene group and C6-CI~aryl, C8-Oiearalkenyl with C2-C6alkenylene and C6-Cloaryl, or di-C6-Cloaryl-Cl-C 6 alkyl, 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-Cl 2 alkyl, CI-C 6 alkoxy, C6-0IOaryl,

SO

3

MY,

OSO

3 My, NR 2 0SO 3 My, NO 2 amino, primary amino, secondary amino and ON; where R 20 is hydrogen,

CI-C

12 alkyl, C2-Cl 2 alkenyl, C3-C1 2 cycloalkyl, C3-C12CYCloalkenyl, C2-C1 1 heterocycloalkyl, 02-Cl i-heterocycloalkenyl, C6-Cloaryl, C5-Cgheteroaryl, CCi aralkyl, C6-Cioheteroaralkyl, Ce-Cli-aralkenyl or C7-Cloheteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

WO 97/01569 PCT/EP96/02785 -14- Furthermore, Rio is preferably Cl-Cl 2 alkyl; C3-C12cycloalkyl, 0 6

-C

10 aryi, C7-Cl 6 aralkyl with 1 to 6 C atoms in the alkylene group and C 6 -Cloaryl, which are unsubstituted or substituted by one or more substituents seiected from the group consisting of OH, halogen, carboxyl, C(O)OMY, Cl-Cl 2 alkyl, Cl-C 6 alkoxy, C 6 -Cl 0 aryl, SO 3 My, nitro, amino, primary amino, secondary amino and cyano; or CS-Cl6aralkenyl with C2-C6alkenylene and C6-Cloaryl, or di-06-Cloaryl-Cl-C~alkyl, for example diphenylmethyl or 2 ,2-diphenylethyl.

In a preferred subgroup of compounds,

R

5 and R 6 are, together with the -CH-CH- group, C3-Cl2CYCloalkylene or C2-Cll1heterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)OR~j,

OC(O)RS

4

C(O)RS

2

NH

2 Cl-C 12 alkyl, R 8

C(O)N(R

9

-C(O)NR

8

R

9 R8S(O) 2

N(R

9

R

8 OC(O) N(R 9 and R 10 -S0 2 in which R 9 is hydrogen and R 8 is Cl-Cl 2 alkyl, C 6 -Cloaryl or C7-Cllaralkyl, which are unsubstituted or substituted by one or more CI-Cl 2 alkoxy; R 10 is C 1 -Cl 2 alkyI, C6-Cioaryl or C7-Cllaralkyl which are unsubstituted or substituted by one or more Ci-Ci 2 alkyl; R~j and Rs4 are C 1 -Cl 2 alkyl and RS 2 is Cl-Cl 2 alkyl, C3-Cl 2 CYCloalkenyl, C3-Cl 2 cycloalkyl or C 6 -Cloaryi, 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)ORsl. and

OC(O)RS

4 where R., 1 is My or C 1 -Cl 2 alkyl and R, 4 is Cl-Cl 2 alkyI; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Particularly preferred compounds within this group are those in which R 5 and 9 6 are, together with the -CH-CH- group, cyclohexylene.

Another subgroup of preferred compounds are those compounds in which R 5 and l 6 are, together with -CH-CH- group, piperidylene.

Particularly preferred compounds are those in which R 5 and 3 6 are, together with the -CH-CH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(O)OR, 1

C(O)RS

2

C(O)NR

8

R

9

NH

2

SO

3 MY, Cl -Cl 2 alkyl, C 2 -Cl 2 alkenyI, Cl-Cl 2 alkoxy, C3-Ci 2 cycloalkyl, C3-Cl 2 CYCloalkenyl,

C

2

-C

11 heterocycloalkyl,

C

2 -Cl 1 heterocycloalkenyl,

C

6 -Cl 0 aryl, C6-Cloaryloxy,

C

5 -Cgheteroaryl,

C

7

-C

11 aralkyl,

C

7 -0 11 aralkyloxy, C6-Cloheteroaralkyl, CB-Cl 1 aralkenyl, O7- Cioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, sul- WO 97/01569 PCT/EP96/02785 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)RI 4

NH

2

OS

3

MY

NR

20

SO

3 MY, Ci -C 12 aikoxy, C 6 -Cl 0 aryloxy, C5-Cgheteroaryloxy, C7-Cl 1 aralkyloxy, primary amino, secondary amino, sulfonamide, carbamide, carbamnate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs, is hydrogen, My, Cl-Cl 2 alkyI, C2-Cl 2 alkenyI, 03-Cl 2 cycloalkyl, C2-C11 heterocycloalkyl, OG-Cloaryl, aryl, 07-Ollaralkyl or 06-Cloheteroaralkyl, R.1 4 is hydrogen,

CI-C

12 alkyl, 0 2-Cl2alkenyl, 03- Cl2cycloalkyl, C2-Cilheterocycloalkyl,

C

6 -Cloaryl, Cs-Ogheteroaryl, 07-Cliaralkyl or 06- Cloheteroaralkyl,

R

8 and R 9 are, independently of one another, hydrogen, OH, Cl-0 12 alkyl, 03-C1 2CYCloalkyl, 02-01 iheterocycloalkyl, 0 6-Cloaryl, C 5 -Cghete roaryl, 07-Cl 6 aralkyl, 06- C8-C, 6 aralkenyl with C2-C6alkenylene and C6-Cloaryl, or di-C6-Cloaryl-Cl- 0 6 -alkyl, or R 8 and R 9 together are tetramethylene, pentamethylene,

-(CH

2 2

-O-(CH

2 2

(CH

2 2

-S-(CH

2 2 or -(CH 2 2

-NR

7

-(CH

2 2 and R 7 is H, CI-C 6 alkyi, 07-Ollaralkyl,

C(O)RI

2 or sulfonyl; and R, 2 and R 2 o are hydrogen, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Cl2cycloalkyl, C3-Cl2CYCloalkenyl, 02-011 heterocycloalkyl, C2-C1 i-heterocycloalkenyl, C6-Cloaryl, 07-Cl 1 aralkyl, 0 6-Cloheteroaralkyl, C8-Cli -aralkenyl or 07-Cloheteroaralkenyl, 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 R 5 and R 6 are, together with the -CH-CH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(O)OR.,l,

C(O)R,,

2

-C(O)NR

8

R

9 and

R

10 -S0 2 and one or more C atoms of the ring are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH 2

RBS(O)

2

N(R

9 R8C(O)N(R 9 and R 8 00(O)N(R 9 where R 9 is hydrogen and R 8 is Cl-Cl 2 alkyl, C6-Cloaryl or 07-Cliaralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more Cl-C 12 alkoxy; R 1 0 is Cl-Cl 2 alkyI, OG-Cloaryl or C7-Cllaralkyl which are unsubstituted or substituted by one or more 0 1 -Cl 2 alkyl; Rs, is Cl-Cl 2 alkyl and R.

2 is CI-C 12 alkyI, C 3 -Cl 2 CYCloalkenyl, C3-CI2cycloalkyl or C6-ClOaryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are unsubstituted or substituted by one or more substituents selected from the WO 97/01569 PCTIEP96I02785 group consisting of OH, C(O)OR 1 and 0C(O)R1 4 where R~ 1 is My or Cl-Cl 2 alkyl and R, 4 is Cl-Cl 2 alkyl; 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 R 5 and R 6 are, together with the -CH-CH- group, piperidylene; which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)ORs 1

OC(O)RS

4

C(O)R.

2

NH

2

C

1 -Cl 2 alkyl, R 8

C(O)N(R

9

-C(O)NRBR

9

R

8

S(O)

2

N(R

9

R

8

OC(O)N(R

9

RSR

4

ONC(O)N(R

9

-OC(O)NRBR

9 and RIO-S0 2 in which R 9 is hydrogen and R 8 is Cl-Cl 2 alkyl, C 6 -Cloaryl or C7-Cllaralkyl, where alkyl, aryi and aralkyl are unsubstituted or substituted by one or more Cl-Cl 2 alkoxy or C7-Cllaralkyloxy; RIO is Cl-Cl 2 alkyl, C 6 -Cloaryl or 07-Ollaralkyl which are unsubstituted or substituted by one or more CI-Cl 2 alkyl; R 40 is hydrogen, OH, C 1

-C

12 alkyl, Cl-Cl 2 alkenyl, C3-Cl2cycloalkyl, C3-C12cycloalkenyl,

C

2

-C

1 iheterocycloalkyl,

C

2

-C

11 heterocycloalkenyl,

C

6 -Cj 0 aryl, C5-Cgheteroaryl, C7-Cl 6 aralkyl, C8-Cl6aralkenyl with C2-C 6 alkenylene and C 6 -Cloaryl, C6-Cl 5 heteroaralkyl, C6-Clsheteroaralkenyl, or di-C6-CjOaryl-Cj-C 6 -allyl and RS 4 are 0 1 -Cl 2 alkyl and R1 2 is Cl-C 12 alkyl, C3-Cl2cycloalkenyl, C3-C 12 cycloalkyl or C 6

-C

10 aryi, 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)On.

1 and where RI 1 is My or CI-Cl 2 alkyl and RS 4 is Cl-Cl 2 alkyl; 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 cyclohexylene or piperidylene which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH 2

C

3

H-

7

-C(O)CH

3

-C(O)C

6

H

5

-C(O)(CH

2 8

C(O)OCH

3 C(O)[CH(OH)1 2 C(O)ONa,

C(O)-C

6

H

8

(OH)

3 -C(O)-0 6

H

1

-C(O)OC

3

H

7

-C(O)NHC

6 Hs, -NHS(O) 2

CH

2 0 6 Hs, -NHC(O)OCH 2

C

6

H

5

-NHC(O)CGH

3

(OCH

3 2

-S(O)

2

-C

4

H

9

-NHC(O)NHC

6 Hs, -S(O) 2

-C

6

H

4

CH

3

-S(O)

2

-CH

2

C

6

H

5 and -S(O) 2

-(CH)

2

C

0

H

7 Preferred compounds of the formula I are those in which R, corresponds to a group of the formula Ill in which R 3 is hydrogen or My and R 4 is unsubstituted Cl-Cl 2 alkyl; Ci-Cl 2 alkyl which is substituted by one or more substituents selected from the group consisting of -NH 2 primary amino, secondary amino, C 1

-C

12 sulfonyl, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide, aminocarbonylamido, C3-C 12 CYCloalkyl, Cl-C 6 alkoxy, phenyloxy and benzyloxy; unsubstituted WO 97/01569 WO 9701569PCT/EP96/02785 -17- C3-C1 2 cycloalkyl; 0 3 -Cl 2 cycloalkyl which is substituted by one or more substituents selected from the group consisting Of 0 3

-C

12 cycloalkyl, Cl-C 6 alkyl, C 1

-C

6 alkoxy, C1-C12SUlfonyl, phenyloxy and benzyloxy; C 6 -Cl 10 aryl; 0 3 -Cgheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; C 7 -Cl 6 aralky with 0 1

-C

6 alkyl and

C

6 -Cloaryl; 0 4 -Cl 6 heteroaralkyl with C 1

-C

6 alkyI and C 3 -Cloheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to carbon atoms; 0 6 -Cloaryl, 0 3 -Cgheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms, 0 7 -Cl 6 aralkyl with 0 1

-C

6 alkyl and 0 6 -Cloaryl, 03-Cl 6 heteroaralkyl with C 1

-C

6 alkyl and C 4 -Cloheteroaryl 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, CI-C 12 SUlfonyl, carboxyl, C(O)OMy, 0 1

-C

12 alkyl, 0 1

-C

6 alkoxy, Cr,-Cloaryl,

SO

3 My, OSO 3 My, NR 20

SO

3 My in which R 20 is hydrogen, 0 1 -Cl 2 alkyl, 0 2 -Cl 2 alkenyl, 03-C1 2 cycloalkyl, C3-C1 2 cycloalkenyl, 02-011 heterocycloalkyl, C2-Cl1 -hete rocycloal kenyl, 0 6 -Cloaryl, C 5 -Cgheteroaryl, C7-C1 1 aralkyl, 0 6 -Cl 0 heteroaralkyl, 08-Cl 1 -aralkenyl or 0 7 -Cloheteroaralkenyl, and nitro, NH 2 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 0 1 -Cl 2 alkyl or 0 7 -Cl 1 aralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OR.

1

OC(O)RI

4

C(O)R,

2 nitro, NH 2 cyano, SO 3 MY, OSO 3 MY, NR 20

SO

3 My, 0 1 -Cl 2 alkyl, C 2 -Cl 2 alkenyl, 0 1 -Cl 2 alkoxy, 0 3

-C

12 cycloalkyl, 0 3 -Cl 2 cycloal kenyl, C2-C1 1 heterocycloalkyl, C2-C1 1 heterocycloalkenyl, 06-Cloaryl, 06-Cloaryloxy, 0 5 -Cgheteroaryl, C 5 -Cgheteroaryloxy, C7-C1 1 aralkyl, C7-C1 1 aralkyloxy, C 6 -Cloheteroaralkyl, 08-Cl 1 aralkenyl, C 7 -Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where is hydrogen, My, Cl-C 12 alkyl, C2-

C

1 2 alkenyl, 0 3

-C

12 cycloalkyl, C2-C1 1 heterocycloalkyl, C6-Cloaryl, C 5 -Cgheteroaryl, C7-

C

1 1 aralkyl or C 6 -Cloheteroaralkyl, R 4 is hydrogen, C 1

-C

12 alkyl, C 2 -Cl 2 alkenyl, C 3

-C

12 cycloalkyl, 02-01 1 heterocycloalkyl, C 6 -Cl 0 aryl, 0 5 -Cgheteroaryl, C7-C11 aralkyl or

C

6 -Cl 0 heteroaralkyl and R,, 2 and R 2 o are hydrogen, C 1 -Cl 2 alkyl, C 2 -Cl 2 alkenyl, 0 3

-CI

2 CYCloalkyl, 0 3

-C

12 CYCloalkenyl, 02-01 1 heterocycloalkyl, C2-C1 1 -heterocycloalkenyl, 06-Cloaryl,

C

5 -Cgheteroaryl, 07-01 1 aralkyl, Cr-C 10 heteroaralkyl, C8-C11-aralkenyl or C 7 -Cloheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl WO 97/01569 PCTIEP96/02785 18and 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.

R

3 in formula Ill is preferably hydrogen, K or Na.

The following preferences apply to the group of meanings for R 4

R

4 is alkyl, preferably methyl, ethyl, n- or i-propyl and i- or t-butyl. In the case of substituted 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-CnH 2 n- with n equal to a number from 1 to 6, in particular benzyl and 2-phenylethyl. When R 4 is heteroaryl, it is preferably aryl with one or two hetero atoms from the group of O and N. Furanyl, pyridinyl and pyrimidinyl are preferred.

R

4 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 R 4 in formula Ill is a C,3-C12Cycloalkyl, particularly preferably cyclohexyl, Cl-C 4 alkyl substituted, particularly methyl or ethyl, with C3-Cl2cycloalkyl or with Cl-C 4 alkyl and particularly with cyclohexyl or methyl, C6-Coaryl and very particularly phenyl, or R 4 is a C7-Cl 2 aralkyl with Cl-C 6 alkyl and C6-Cloaryl. Particularly preferred groups for R 4 in this series are benzyl, naphthylmethyl, 2-phenylethyl, 3-phenylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclohexyl and isopropyl.

Carbamido, carbhydrazido, sulfonamido, sulfonhydrazido, aminocarbonylamide and carbamate as substituent for R 4 preferably mean groups of the formulae

R

8

NHC(O)N(R)-,

R

8 RBC(O)(NH)N(R 9 and RsS(0) 2 (NH)pN(R 9 in which R 8 is preferably

H,

Ci-Ci 2 alkyl, C5- or C6cycloalkyl, C5- or Ccycloalkylmethyl or -ethyl-, C5- or C 6 heterocycloalkyl, Cs- 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, -NH 2 Cl-C8primary amino, C2-Cl4secondary amino, NO 2 -CN, -CI, C(O)OH, -C(O)ONa, -S03H, -OSO 3 Na, NR20SO 3 Na in which R 20 is hydrogen,

C

1

-C

12 alkyl, C2-Cl 2 alkenyl, C-C1 2 cycloalkyl, C3-C12cycloalkenyl, C2-Cl heterocycloalkyl, C2-C 11heterocycloalkenyl, C6-ClOaryl, C-Cgheteroaryl, C7-Cliaralkyl, C6-Cloheteroaralkyl, CB-C i-aralkenyl WO 97/01569 PCT1EP96I02785 -19or C7-CloheterOaralkeflyl, and -SO 3 Na, C1-C 4 aikyl, Ci-C4alkoxy and phenyl, and R 9 is H,

C

1

-C

10 alkyl, phenyl, naphthyl, benzyl, 2-phenylethyl or phenyl-CH=CH.0H 2 and p is 0 or 1.

Within group a carbamido-substituted alkyl substituent for R 4 particularly preferably means

R

8

-C(O)NR

9

-(CH

2 where n is 1 or 2, R 8 is hydrogen; CI-Cl 2 alkyl; C3-Cl2CYCloalkyl; C6-Cloaryl or C7-Cl~aralkyl with Cl-C 6 alkyl and C6-Cloaryl; 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-Cl 2 alkyl,

CI-C

6 alkoxy, C6-Cloaryl,

SO

3

MY,

OSO

3 My, NR 2 0SO 3 My, C(O)OR,, 1

OC(O)R,

4 nitro, amino and cyano; or C8-Cl6aralkenyl with 0 2-C6alkenyl and C6-Cloaryi or di-C6-C1Oaryl-Cl-Cealkyl; and R9 is H, linear or branched Cl-Cioalkyl, C5- or C6cycloalkyl,

C

5 or Cecycloalkylm ethyl- or -ethyl, phenyl, naphthyl or benzyl, 2-phenylethyl or phenyl-CH=CH-C 2 Y is 1 and M is an alkali metal or y is 1/2 and M is an alkaline earth metal, R 20 is hydrogen, Cl-Cl 2 alkyl, C2-Cl2alkenyl, C3-Cl2cycloalkyl, 03-Cl 2cycloalkenyl, C2-C11 heterocycloalkyl, 1 Cl-heterocycloalkenyl, C6-Cloaryl, C7-Cl ~aralkyl, C6-Cloheteroaralkyl, C8-Cl i-aralkenyl or COrCioheteroar.

alkenyl, R~j is hydrogen, My, Ci-Cl 2 alkyl, C2-Cl2alkenyl, C3-Cl2cycloalkyl, C2-Cllheterocyco.

alkyl, C6-Cloaryl, Cs-Cgheteroaryl, 0 7-Cliaralkyl or C6-Cloheteroaralkyl and Rm is hydrogen, Cl-Cl2alkyl, C2-Cl 2 alkenyl, 0 3-C12cycloakyl, 02-Cl iheterocycloalkyl, C6-Cloaryl, aryl, C7-Cllaralkyl or O-Cioheteroaralkyl. A sulfonamide-substituted alkyl substituent for R, particularly preferably means

RB-SO

2

NR

9

-(CH

2 )11 in which

R

8

R

9 and n have the meanings indicated previously for carbamido. An aminocarbonylamide. or carbamate-substituted alkyl substituent for R, particularly preferably means R9NHC(O)NH(CH 2 )n or RDOC(O)NH(CH 2 )n in which

R

9 has the meanings indicated in previously in connection with carbamido and additionally phenyl and n has the meanings indicated previously in connection with carbamido.

A cabyrzd-usiue alkyl substituent for R, particularly preferably means R8C(O)NHNR9(CH 2 in which

R

8

R

9 and n have the meanings indicated previously in connection with carbamido. A sufnyrzd-usiue alkyl substituent for R 4 particularly preferably means R13-S0 2 -NHNR9..(CH 2 in which

R

8

R

9 and n have the meanings indicated previously in connection with carbamido.

Further particularly preferred compounds are those in which

R

4 in formula Ill is an amide R8C(O)N(R 9

)(CH

2 or R8S(O) 2

N(RB)(CH

2 where

R

8 and R 9 are, independently of one another, hydrogen; unsubstituted Ci-Ci 2 alkyl; Cl-C 12 alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(O)ONa, WO 97/01569 PCT/EP96/02785 20 Cl-Cl 2 alkyl, C 1 -C~alkoxy,

C

6

-C

10 aryl, -SO 3 H, OS03Na,

NR

2 oSO 3 Na, SO 3 Na, nitro and cyano; unsubstituted Cs-C 12 cycloalkyl; C3-Cl2cycloalkyl substituted by one or more OH; unsubstituted C6-Cloaryl, unsubstituted C7-Cl 2 aralkyl with CI-C 6 alkyl and C6-Cloaryl; C6-Cloaryl, or C7-Cl 2 aralkyl with Cl-C 6 alkyl and C6-Cloaryl, which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(O)ONa,

-C(O)OK,

C

1 -Cl 2 alkyl, Cl-C 6 alkoxy,

C

6 -Cloaryl,

SO

3 Na, OSO 3 Na, NR 2 0SO 3 Na, C(O)ORj 1

OC(O)RS

4 nitro, amino and cyano, R 20 is hydrogen, Cl-Cl 2 alkyl, C2-Cl2alkenyl, C3-Cl 2 cycloalkyi, C3-C1 2 CYCloalkenyl, C2-Cl1 heterocycloalkyl,

C

2 -Cll -heterocycloalkenyl, C6-Cloaryl, 07-Cl 1 aralkyl, C6-Cloheteroaralkyl,

C

8

-C

1 i-aralkenyl or C7-Cloheteroar.

alkenyl, Rs, is hydrogen, My, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-C1 2 CYCloalkyl, C2-Cllheterocyclo.

alkyl, C6-Cloaryl, C5-Cgheteroaryl, C7-Cllaralkyl or C6-Cloheteroaralkyl and RS 4 is hydrogen, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-C1 2 CYCloalkyl,

C

2

-C

11 heterocycloalkyl, C6-Cloaryl, Cs-Cgheteroaryl, C7-Cllaralkyl or C6-Cloheteroaralkyl; and n is 2 or 1.

Particularly preferred compounds are those in which R 4 in formula Ill is an amide R8C(O)N(R 9

)(CH

2 or R8S(O) 2

N(R

9

)(CH

2 where R 8 is unsubstituted CI-Cl2alkyl; Cl-C 8 alkyI which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ONa and C6-ClOaryl; unsubstituted C3-Cl2cycloalkyl; C3-CBcycIOalkyl which is substituted by one or more OH; unsubstituted C6-Cloaryl or C7-Cl 2 aralkyl with

C

1 -C~alkyl; C6-Cloaryl, C7-Cl 2 aralkyl with Cl-Cralkyl and C6-Cloaryl or C8-Cl~aralkenyl with C2-C6alkenyl and C6-Cloaryl, which is substituted by one or more substituents selected from the group consisting of halogen, -C(O)OH, C(O)ONa, Cl-Cl 2 alkyl, Cl-C 6 alkoxy,

-SO

3

H,

SO

3 Na, OSO 3 Na, NR 2 0SO 3 Na in which R 20 is hydrogen, CI-Ci 2 alkyl, C2-Cl 2 alkenyl, C3-C1 2 cycloalkyl, C3-Cl2cycloalkenyl, 02-011 heterocycloalkyl, 02-Cl 1-heterocycloalkenyl, 06-Cloaryl, C.5-Cgheteroaryl, 07-Cl 1 aralkyl, C6-Cloheteroaralkyl, C8-Cli -aralkenyl or C7-Cloheteroaralkenyl, and nitro and cyano; and R 9 is hydrogen; unsubstituted CI-C~alkyl, unsubstituted C6-Cloaryl, unsubstituted C7-Cl 2 aralkyI with CI-C~alkyl and C6-Cloaryl; or 08-Cl~aralkenyl with C2-Cealkenyl and Ce-Cloaryl, and n is 2 and preferably 1.

Particularly preferred Compounds are also those in which R 4 in formula Ill is an amide R8C(O)N(R 9

)(CH

2 where R 8 is unsubstituted Cl-Cl 2 alkyl; Cl-Cl 2 alkyl 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-Cl 2 cycloalkyl; C3-Cl2cycloalky which is substituted by one or more OH; unsubstituted C6-Oloaryl; C6-Cioaryl, which is substituted by WO 97/01569 PCT/E-P96/0278 21 one or more substituents selected from the group consisting of halogen, C(O)ONa, -C(O)OH, Ci-Cralkyl, O1-C 6 alkoxy, phenyl,

-SO

3 H, S03Na,

OSO

3 Na, NHSO,3Na, nitro and cyano; or C7-Cl6aralkyl with Cl-C 6 alkyl and C6-Cl 0 aryl, and R 9 is hydrogen; unsubstituted Cl-C 6 alkyI, unsubstituted C7-Cl 6 aralkyl with CI-Cealkyl and C6-Cloaryl; or 0 8-Cl6aralkenyl with C2-C6alkenyl and C6-Cloaryl, and n is 2 and preferably 1.

Further particularly preferred compounds are those in which

R

4 in formula Ill is an amide R8C(O)N(R 9

)(CH

2 -where

R

8 is unsubstituted Cl-C 12 alkyl,

CI-C

4 alkyl 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, in particular 0 6

H-

11 C3-Ol2cycloalkyl which is substituted by one or more OH, unsubstituted C6-Cloaryl, in particular

C

6

H-

5 or CjolH 7 C6-Cloaryl which is substituted by one or more substituents selected from the group consisting of halogen, -C(O)OH, C(O)ONa, Cj-C 6 alkyI, C1-C6alkoxy,

-SO

3 H, SO 3 Na,

OSO

3 Na, NHSO 3 Na, nitro and cyano, in particular

C

6

H-

4 CI, C 6 H4(3,4)CI 2 C6H 4 COONa,

C

6

H-

4

CH

3

C

6

H

4 00H 3 C6H 4

SO

3 Na, 0 6

H

4 N0 2 or C 6

H-

4 CN; or unsubstituted C7-Cl 6 aralkyl with C1-C 6 alkyl and C6-Cloaryl, in particular

(CH

2 2

C

6

H

5 and R 9 is H, CI-C 4 alkyl, phenyl-CH 2 phenyl-CH 2

CH

2 phenyl-(CH 2 3 or phenyl-CHCHH~ 2 and n is 2 and preferably 1.

Particularly preferred compounds are also those in which

R

4 in formula Ill is an amide R8C(O)N(R 9

)(CH

2 where

R

8 is unsubstituted or substituted Cl-Cl 2 alkyl, cyclohexyl, naphthyl, biphenylyl, phenyl, benzyl, phenylethyl or diphenylmethyl, and R 9 is Cl-C 4 alkyl, phenyl-Cl-C 6 alkyl, in particular

CH

2 C6Hs, (0H 2 2

C

6 Hs or (CH 2 3

C

6

H

5 or phenyl-C 2 -C6-alkenyl, in particular C6H5-CH=CH-CH 2 and n is 2 and preferably 1.

Further particularly preferred compounds are those in which

R

4 in formula Ill is a sulfonamido R8S(O) 2

N(R

9

)(CH

2 where

R

8 is C1-Cl2alkyl, Particularly Cl-C 6 alkyl, which is unsubstituted or substituted by one or more halogen atoms (for example Cl and especially in particular

OF

3 or C6-Cloaryl, particularly phenyl or naphthyl, which is substituted by one or more

OI-C

4 alkyl (for example methyl or ethyl),

OI-C

4 alkoxy (for example methoxy or ethoxy), halogen, -ON or -NO 2 and R 9 is hydrogen or isobutyl, and n is 2 and preferably 1.

Further particularly preferred compounds are those in which

R

4 in formula Ill is an aminocarbonyl residue of the formula

R.-NH-C(O)-NH(CH

2 in which

R

8 is OI-Cl 2 alkyl or C6-Cloaryl, particularly Cl-O~alkyl, which is unsubstituted or substituted by halogen,

-ON,

WO 97/01569 PCT/EP96/02785 22

-NO

2

CI-C

4 alkyl or C1-C4alkoxy, or C5- or C6cycloalkyl, 0 6-CIOaryl such as phenyl or naphthyl, or C7-Cl 2 aralkyl such as benzyl, phenylethyl, phenyipropyl or Phenyipropenyl, and n is 2 and preferably 1.

Particularly preferred compounds are furthermore those in which

R

4 in formula Illis an aminoalkyl, preferably

R

8

'R

9

.N(CH

2 where

R

8 and R 9 are, independently of one another, hydrogen; unsubstituted Cl-C, 2 alkyl; CI-Cl2alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs 1 OC(0)R1 4

C(O)NR

11 R1 1 2 Ci-Cl 2 alkyl, Cl-C6alkoxy, C6-Cioaryl,

-SO

3 H, SO 3 Na, OSO 3 Na, NR 2 OSO3Na, nitro, amino and cyano; unsubstituted C3-Cl2cycloalkyl; C3-C12cycloalkyl which is substituted by one or more OH; C6-Cloaryl; C7-C, 6 aralkyl with Cl-C 6 alkyl and 0 6,-Cloaryl; or 0 8-Cl6aralkenyl with 0 2-C6alkenyl and C6-Cloaryl, where aryl and the aryl in the aralkyl and aralkenyl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORo 1

OC(O)RS

4 -C(O)ONa, -C(0)0K,

-C(O)-NR

1 Rl 2 Cl-Ci 2 alkyl, Ci-Coalkoxy, C6-Cloaryl,

-SO

3 H, SO 3 Na, OSO 3 Na, NR 2 0SO3Na, nitro, amino and cyano; wherein n is 2 and preferably 1, and R~j is hydrogen, K or Na, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-C1 2 cycloalkyl, C2-C11 heterocycloalkyl, 06-Cloaryl, C7-Cllaralkyl or C6-Cloheteroaralkyl, R 4 is hydrogen, Cl-C 12 alkyl, 0 2-Cl2alkenyl, C3-Cl 2 cycIOalkyl, C2-Cllheterocycloalkyl, C6-Cloaryl, Cs,-Cgheteroaryl, C7-Cllaralkyl or C6-Cloheteroaralkyl,

R

1 1 is H, Cl-C 4 alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and R 1 2 independently has the meaning of R 11 or R, I and R 1 2 together are tetramethylene, pentamethylene or -CH2CH 2

-O-CH

2 0H 2 and R 20 is hydrogen, Cl-Cl2alkyl, C2-Cl2alkenyl, CS-Ci 2 cycloalkyl, C3-C12CYCloalkenyl, C2-C11 heterocycloalkyl, 02-Cl 1-heterocycloalkenyl, C6-Cloaryl, C5-Cgheteroaryl, C7-Cl 1 aralkyl, C6-Cloheteroaralkyl, 08-011 -aralkenyl or C7-Cloheteroaralkenyl.

Particularly preferred compounds are furthermore those in which

R

4 in formula Ill is an aminoalkyl

R

8

*R

9

,NCH

2 in which

R

8 and R 9 are, independently of one another, hydrogen; Ci-Csalkyl, cyclopentyl, cyclohexyl, C5- or C6cycloalkyl methyl, phenyl-CiC 4 alkyl, in particular

-CH

2

C

6

H

5 or phenyl-C 2

-C

4 alkenyl, in particular

-CH

2

CH=CHC

6

H

5 Particularly preferred compounds are furthermore those in which

R

4 in formula Ill is an amine

R

8

,R

9

*NCH

2 where

R

8 and R 9 are, independently of one another, H, Cl-C 6 alkyl, phenyl-C 1 or C 2 alkyl, in particular

CH

2

C

6

H

5 WO 97/01569 PCTJEP96/02785 23 Preferred compounds of group of meanings for R 4 are those in which R 4 is C7-Cliaralkyi, in particular

CH

2

-C

6

H

5 and (CH 2 2

-C

6

H

5 C3-Cl 2 cycloalkyl or Cl-Cl 2 alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of

NH

2 C3-C1 2 cycloalkyl, primary amino, secondary amino, sulfonamide, carbamide and aminocarbonylamido. Particularly preferred substituents for CI-C 12 alkyl are NH 2 cyclohexyl, 0 6-Cloaryl,

REIC(O)N(R

9

RBS(O)

2

N(R

9

R

8

NHC(O)NR

9

NR

9

C(O)NHR

8 and R 8

,R

9 in which R 8 and R 9 are, independently of one another, hydrogen, Ci-Cl 2 alkyl, C3-Cl2cycloalkyl, 0 2-Clliheterocycloalkyl, C6-Cloaryl, C5-Cgheteroaryl, C7-Cllaralkyl or C6-Cloheteroaralkyl and

R

8 and R 9 are, independently of one another, hydrogen, OH, Cl-Cl 2 alkyl, C3-Cl 2 CYCloalkyl, C2-C11 heterocycloalkyl, C6-ClOaryl, C!5-Cqheteroaryl, 07-Cj aralkyl or C6-Cloheteroaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORr.l, OC(O)Rr 5 4

C(O)R.,

2 nitro, NH 2 cyano,

SO

3

MY,

OSO

3 My, NR 20

SO

3 My, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl,

CI-C

12 alkoxy, C3-CI2cycloalkylC3-Cl2Cycloalkenyl, C2-Cl heterocycloalkyl, C2-C11 heterocycloalkenyl, C6-Cloaryl, C6-Cloaryloxy, Cs-Cgheteroaryloxy, 07-011 aralkyl, C7-Ciaralkyloxy, C6-Cloheteroaralkyl, C8-Ciiaralkenyl, 0 7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where is hydrogen, My, Ci-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Cl2CYCloalkyl, 02-011 heterocycloalkyl, C6-Cl 0 aryl, C5-CgheteroarylCCi aralkyl or C6-Cloheteroaralkyl, Rs 4 is hydrogen, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, 0 3-Cl2cycloalkyl, C2-Cllheterocycloalkyl, OG-Cloaryl, C5-CgheteroarylC7-Cllaralkyl or C6-Cloheteroaralkyl, and Rs 2 and R 2 o are hydrogen, C1-C 12 alkyl, C2-CI 2 alkenyl, C3-Cl2CYCloalkyl, 0 3-C12cycloalkenyl, C2-Cl iheterocycloalkyl, 02-Cl i-heterocycloalkenyl, 06-Cloaryl, C5-Cqheteroaryl, C7-C 1 aralkyl, C6-Cloheteroaralkyl 08-Cl i-aralkenyl or C7-Cloheteroaralkenyl, 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 R 8 and R9, together are tetramethylene, pentamethylene,

-(CH

2 2

-O-(CH

2 2

-(CH

2 2

-S-(CH

2 2 -or -(CH2)2-NR7-(CH 2 2 and R 7 is H, Cl-C 6 alkyl, 0 7-Cllaralkyl,

C(O)RS

2 or sulfonyl.

Particularly preferred compounds within this group are those in which R 4 is 0H 2

-C

6

H

5

(CH

2 2 -C6Hs, cyclohexyl, methyl, ethyl or isopropyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH 2 cyclohexyl, C6-Cloaryl, WO 97/01569 PCTIEP96/02785 24

R

8

C(O)N(R

9

R

8

S(O)

2 R8NHC(O)NR 9

NR

9

C(O)NHR

8 and R 8

,R

9 in which R 8

R

9

R

8 and R 9 are, independently of one another, hydrogen, Cl-Cl 2 alkyl, C3-Cl2cycloalkyl, C6-Cloaryl or 07-Ollaralkyl, which are unsubstituted or substituted by one or more substtuents selected from the group consisting of OH, halogen, C(O)OMy, nitro, cyano, SO 3

MY,

OSO

3 My, NHSO 3 MY, Cl-Cl 2 alkyl, C 1

-C

12 alkoxy and C6-Cloaryl, where y is 1 and M is a monovalent metall or y is 1/2 and M is a divalent metal. Particularly preferred compounds are those in which R 8

R

9

R

8 and R 9 are, independently of one another, hydrogen, Cl-C 12 alkyl, cyclohexyl, phenyl, naphthyl or 07-Claralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, Cl, C(O)ONa, nitro, cyano, SO 3 Na, C 1

-C

6 alkyl, methoxy and phenyl.

In a preferred group of compounds of the formula 1, R, is formula Ill, in which R 4 is C 6

H-

11

CH(CH

3 2

CH

2 -phenyl, (CH2) 2 -phenyl, CH 2 NHC(O)-phenyl, CH2NHC(O)(CH 2 3 -phenyl,

CH

2

NHC(O)(CH

2 )3OH, CH 2

NHC(O)CF

3

CH

2 NHC(O)0 6

H

11

CH

2 NHC(O)0 11

H

2 3

CH

2

NHC(O)CH(C

6

HS)

2

CH

2

HNC(O)NHC

6

H

5 CH2NHC(O)C 2

H

4 00 2 Na,

CH

2 NHC(O)C6[(1 ,3,4,5)OH 4

H

7 CH2NHC(O)C 6

H

4 -P-SO3Na,

CH

2 NHC(O)C6H 4

CI,

CH

2

NHC(O)C

6

H

4 N0 2

CH

2

NHC(O)C

6

H

4

OCH

3

CH

2

NHC(O)C

6

H

4 (3,4)CI 2

CH

2

NHC(O)C

6

H

4

CH

3

CH

2

NHC(O)C

6

H

4

C

6

H

5

CH

2 NHC(O)C6H 4 CN, CH 2

NHC(O)C

10

H

7 CH2NHC(O)C6H 4 000Na, CH2NHC(O)(CHOH) 2 COONa, CH2N(CH2CH=CH-phenyl)[C(o).phenyl], CH2N[CH2CH(CH 3 2 ][C(O)..pheny],

CH

2

N[C(O)C

6

H

5

]CH

2

C

6

H

5 CH2N[C(O)C6H 5

](CH

2 3

C

6

H

5

CH

2

C

6

H

11

(CH

2 2

C

6

H

11

CH

2

NH

2 CH2NHCH 2 CH=CH..phenyl,

CH

2

NHCH

2 -phenyl, CH 2

NHCH

2

CH(CH

3 2 CH2N(CH 2 -phenyl) 2

CH

2

N[CH

2 CH(0H 3 2 2 CH2NHSO 2 -p-nitrophenyl,

CH

2

NHSO

2 -P-tOIYI, CH 2

NHSO

2

CF

3

CH

2

NHC(O)NHC

6

H

5 or CH2N[SO2-p-nitrophenyl][CH 2

CH(CH

3 2 2

R

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

In the case of halogen for the substituents for R 2 it can preferably be F, Cl and Br; in the case of -C(O)OMy preferably -C(O)ONa or -C(0)0K; in the case of alkyl preferably 01-06and particularly preferably

C

1

-C

4 alkyl, such as methyl, ethyl, n- or i-propyl and i- or t-butyl; in the case of alkoxy preferably

CI-C

4 alkoxy, for example methoxy and ethoxy; in the case of aryl preferably phenyl or naphthyl; in the case Of -SO 3 MY preferably

-SO

3 Na or

-SO

3 K; in the case of primary amino Cl-Ci 2 primary amino such as methyl-, ethyl-, n- or WO 97/01569 PCT/EP96/02785 i-propyl-, i- or t-butyl, pentyl, hexyl, cyclohexyl, phenyl or benzylamino; in the case of secondary amino C2-C2osecondary amino such as dimethyl-, diethyl-, methylethyl-, din-propyl-, di-i-propyl-, di-n-butyl-, diphenyl-, dibenzylamino, morpholino, thiomorpholino, piperidino and pyrrolidino;

-SO

2

-NR

8

R

9 and -C(O)-NR 8

R

9 in which R 8 and R 9 are, independently of one another, H, C 1

-C

4 alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, or Ra and R 9 together with the N atom are morpholino, thiomorpholino, pyrrolidino or piperidino.

RB and R 9 as alkyl preferably contain 1 to 6, and particularly preferably 1 to 4, C atoms, and can be, for example, methyl, ethyl, n- or i-propyl or i- or t-butyl.

R

8 and R 9 as hydroxyalkyl preferably contain 1 to 6, and particularly preferably 1 to 4, C atoms, and can be, for example, hydroxymethyl or 2-hydroxyethyl.

R

8 and R 9 as cycloalkyl are preferably cyclopentyl or cyclohexyl. Substituents for R 8 and R 9 as phenyl and benzyl are preferably F, CI, methyl, ethyl, methoxy and ethoxy.

A preferred subgroup of compounds of the formula I are those in which R 2 is hydrogen, unsubstituted

CI-C

6 alkyl, particularly preferably

C

1

-C

4 alkyl, especially methyl or ethyl, or

C

1

-C

6 alkyl, particularly preferably

C

1

-C

4 alkyl, especially methyl or ethyl, which is substituted by C(O)OH, -C(O)ONa, -C(O)OK, -OH, -C(O)-NR 8

R

9 or -S0 2

-NR

8

R

9 in which Re is H, Cl-C 4 alkyl, C2-C 4 hydroxyalkyl, phenyl or benzyl, and R 9 independently has the meaning of

R

8 or R 8 and R, are together tetramethylene, pentamethylene or -CH2CH 2

-O-CH

2

CH

2 Particularly preferred compounds are those in which R 2 is hydrogen, methyl, ethyl,

HO(O)CCH

2

CH

2 NaOC(O)CH 2

CH

2 or R8R 9

NC(O)CH

2

CH

2 and R 8 and R 9 are, independently of one another, H, C 1

-C

6 alkyl, C2-C 4 hydroxyalkyl, phenyl, benzyl or, together, morpholino.

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

COOR

HRO OH

R,

HO OH (la) WO 97/01569 PCT/EP96/02785 26 in which

R

3 is hydrogen or My; and

R

4 is Cl-O 12 alkyl, C2-Ol 2 alkenyl, 0 3

-C

12 CYCloalkyl, 0 3-Ol2cycloalkenyl, 02-011 heterocycloalkyl, C2-Cll heterocycloalkenyl, CE3-Cl 0 aryl, Cs-Cgheteroaryl, C7-Cl 1 aralkyl, C6-Cloheteroaralkyl, C8-Cliaralkenyl or 0 7-Cloheteroaralkenyl, which are Unsubstituted or substituted once or several times;

R

5 and R 6 are, independently of one another, hydrogen, Cl-Cl 2 alkyl, 0 3-Ol2cycloalkyl, 0 2-Cllheterocycloalkyl, C6-Cloaryl, C5-Cgheteroaryl, C7-Cl 1 aralkyl or C6-Cloheteroaralky; or

R

5 and R 6 are, together with the -CH-CH- group, C3-C12cycloalkylene, C4-Cl2cycloalken.

ylene, 0 2-Cllheterocycloalkylene and C3-Cilheterocycloalkenylene with hetero atoms selected from the group of and 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)ORS

1

OC(O)RS

4

C(O)R,

2 nitro, NH- 2 cyano, SO 3 My, OSO 3 My, NR 20

SO

3 My in which R 20 is hydrogen, C, -Cl 2 alkyl, C2-Cl 2 alkenyl, 0 3-Cl2cycloalkyl, C3-C12cycloalkenyl, 02-011 heterocycloalkyl, 02-Cl i-heterocycloalkenyl, 06-Cloaryl, C5-Cgheteroaryl, 07-Cl 1 aralkyl, C6-Cloheteroaralkyl, C8-C1l-aralkenyl or 0 7-Cloheteroaralkenyl, and Cl-C 12 alkyl, C2-Cl 2 alkenyl, Cl-C12alkoxy, C3-Cl2cycloalkyl, C3-Cl 2 cycloalkenyl, 02-Ciliheterocycloalkyl, C2-011 heterocycloalkenyl, C6-CloaryI, C6-Cloaryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, C7iaralkyl, 07-C1 1 aralkyloxy, 0 6-Cloheteroaralkyl, C8-Cl iaralkenyl, C7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamnate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs, is hydrogen,

MY,

CI-Cl 2 alkyl, C2-Cl 2 alkenyl, 0 3-Cl2cycloalkyl, 02-Cl iheterocycloalkyl, 0 6-Cloaryl, C7-Cl 1 aralkyl or C6-Cloheteroaralkyl, RS4 is hydrogen, C, -Cl 2 alkyl, C2-Cl 2 alkenyl, C3-C1 2 CYCloalkyl, 02-Cl iheterocycloalkyl, C6-ClOaryI, C7-Cliaralkyl or C6-Cloheteroaralkyl and R 52 is hydrogen, Cl-0 12 alkyl, C2-Cl 2 alkenyl, C3-Cl2cycloalkyl, C3-Cl2cycloalkenyl, 02-01ilheterocycloalkyl, 02-Cl i-heterocycloalkenyl, C6-Cloaryl, C5-Cgheteroaryl, C7-Cllaralkyl, O6-Cloheteroaralkyl, C8-Cll-aralkenyl or C7-Cloheteroaralkenyl, 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 WO 97/01569 PCTIEP96/02785 27 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

R

3 is H, K or Na,

R

5 and R 6 are, together with the -OH-OH- group, C3-Ol2cycloalkylene, C4-Cl2CYCloalken.

ylene, C2-Cllheterocycloalkylene and C3-Cliheterocycloalkenylene with hetero atoms selected from the group and which are unsubstituted or substituted once or several times; where the substituent is selected from the group consisting of OH, halogen,

C(O)OR,

OC(O)RI

4 C(O)Rs 2 nitro, NH 2 cyano, SONY, OSO 3 My, NR 20

SO

3 My in which R 20 is hydrogen, CI-0 12 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, C3-C12cycloalkenyl, 02-Cl iheterocycloalkyl, 02-Cl i-heterocycloalkenyl, C6-Cloaryl,

C

5 -Cgheteroaryl, 07-Cl 1 aralkyl, C6-Cioheteroaralkyl, O8-Cl i-aralkenyl or C7-Cloheteroaralkenyl, and Cl-Cl 2 alkyl, O2-Cl2alkenyl, Ci-Cl 2 alkoxy, C3-C12cycloalkyl, C3-Cl2cycloalkenyl, 02-Cil heterocycloalkyl, O2-Cli heterocycloalkenyl,

C

6 -Cloaryl, C6-Cloaryloxy, Cs-Cgheteroaryl, O5-Ceheteroaryloxy, 07-Cl 1 aralkyl, C7-Clj aralkyloxy, C6-Cioheteroaralkyl, Ce-Cl 1 aralkenyl, C7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamnate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, in which Rs, is hydrogen,

MY,

CI -C 12 alkyl, 02-Cl 2alkenyl, C3-Ol2cycloalkyl, 02-C11 heterocycloalkyl, C6-Cloaryl, aryl, 07-Olaralkyl or C6-Cloheteroaralkyl, R.1 4 is hydrogen, 0 1 -Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, 02-01 iheterocycloalkyl, C6-Cloaryl, C5-Cgheteroaryl, C7-Cl 1 aralkyl or C6-Cloheteroaralkyl and R1 2 is hydrogen, Cl-Cl 2 alkyl, C2-Ol 2 alkenyl, C3-Cl2cycloalkyl, O3-Cl2cycloalkenyl, 1 Clheterocycloalkyl, 02-Cili-heterocycloalkenyl, C6-Cloaryl, 07-Cl 1 aralkyl, C6-Oloheteroaralkyl, 08-011 -aralkenyl or C7-Cloheteroaralkenyl, 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;

R

4 is a residue R 12

-(CH

2 or cyclohexyl, in which n is 1 or 2 and

R

12 is Cl-C 10 alkyl, 05-OBcycloalkyl, especially cyclohexyl, 06-Cloaryl, preferably phenyl, or C8-Cl2aralkenyl, preferably phenyl-C 2

-C

4 alkenyl, which are unsubstituted or substituted by

CI-C

4 alkyl, Cl-C 4 alkoxy, F, Cl, -ON or -NO 2 or WO 97/01569 PCTJEP96/02785 28

R

12 is an amino group -NRBR 9 and R 8 and R 9 are CI-C 12 alkyl or unsubstituted or Cl-C4alkyl-substituted 05- or C6cycloalkyl, C6-Cl 0 aryl, C7-Cl 2 aralkyl or 0 8-Cl2aralkenyl; very particularly preferably

-CH

2

-CH(CH

3 2

-CH

2

-C(CH

3 3

-CH

2

-C(CH

3 2

-C

2

H

5

C

6

H

5 -0H 2

C

6

H

5

CH

2

CH

2 C6H5-CH 2

-CH

2 -CH2- or C6HsCH=CH-CH 2 or

R

12 is an amide group -N(R 9

)C(O)R

8

-N(R

9

)S(O)

2 RB, -NR 9

C(O)NHR

8 or -NR 9

C(O)NHR

8 in which R 8 is C6-Cloaryl, preferably phenyl, which is unsubstituted or substituted by CI-C 4 alkyl, especially methyl, CI-C4alkoxy, especially methoxy, F, Cl, -ON or -NO 2 or Cl-C 10 alkyl which is unsubstituted or substituted by F or Cl, and R 9 is H, Cl-Cloalkyl, C5- or C6cycloalkyl, C5- or, C6cycloalkyl-C 1

-C

6 alkyl, phenyl-C 1

-C

6 alkyl or phenYl-C 2

-C

6 alkenyl, especially H, Cl -C 6 alkyl, cyclohexyl, cyclohexyl-CH 2 cyclohexyl-CH 2

CH

2 cyclohexyl-CH 2

CH

2

CH

2 C6HSCH 2 2

CH

2 CSH5CH 2

CH

2

CH

2 and C 6

H

5

CHCHCH

2

R

9 is particularly H, linear and, preferably, branched

CI-C

6 alkyl, phenyl or phenyl(CH 2 with z equal to a number from 1 to 4, for example methyl, ethyl, n- or i-propyl, i- or t-butyl, pentyl, isopentyl, hexyl, benzyl, phenylethyl, phenylpropyl and phenyl-CH=CH-CH 2 very particularly preferably

CH

2

-CH(CH

3 2 benzyl, 2-phenylethyl and 3-phenylpropyl; or

R

4 is Cl-Cl 2 alkyl, C3-C12cycloalkyl or C7-Cliaralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen,

C(O)OR,

OC(O)RI

4

C(O)RS

2 nitro, NH 2 cyano, S0 3 My, OSO 3 My, NR 20

SO

3 My in which R 20 is hydrogen, CI -C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 CYCloalkyl, C3-Cl2CYCloalkenyl, 02-Cl iheterocycloalkyl, 1 Cl-heterocycloalkenyl, C6-ClOaryl, Cs-Cgheteroaryl, 07-Cl 1 aralkyl, Os-Cloheteroaralkyl, 08-Cl 1-aralkenyl or C7-Cloheteroaralkenyl, and Cl-Cl 2 alkyl, C2-Cl2alkenyI, CI-C1 2 alkoxy, C3-Cl 2 cycloalkyl, C3-Cl2cycloalkenyl,

C

2

-C

11 heterocycloalkyl, 02-011 heterocycloalkenyl, C6-Cloaryl, C6-Cloaryloxy, C5-Cgheteroaryl, Cs-Cgheteroaryloxy, 07-Cl iaralkyl, 07-Cl iaralkyloxy, C6-Cloheteroaralkyl, 08-Cl iaralkenyl, C7rCioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where is hydrogen, My, CI -C 12 alkyl, C2-Cl 2 alkenyl, C3-C1 2 cycloalkyl,

C

2

-C

1 iheterocycloalkyl, C6-Cloaryl, aryl, C7-Ciiaralkyl or C6-Cloheteroaralkyl,

RS

4 is hydrogen, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C3- C1 2cycloalkyl, 02-Cl iheterocycloalkyl, C6-ClOaryl, Cs-Cgheteroaryl, 07-Cl 1 aralkyl or C6- Cioheteroaralkyl and RS 2 is hydrogen, Cl -C 12 alkyl, C2-Cl 2 alkenyl, C3-C12cycloalkyl, C3- Cl2cycloalkenyl, 02-Cl iheterocycloalkyl, 02-Cl i-heterocycloalkenyl, Os,-Cioaryl, Cgheteroaryl, 07-Cl 1 aralkyl, C6-Cloheteroaralkyl, 08-Cl i-aralkenyl or C7-Cloheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroar- WO 97/01569 PCT/EP96/02785 29 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 are those in which

R

4 is C 6 1- 11 0 6

H-

11

-CH

2

C

6

H

11

-CH

2

CH

2

C

6

H

5

-CH

2 0 6

H

5

-CH

2

CH

2 or C6H5-CH=CH-CH 2 (ii) R 4 is C 6

H-

11

C

6

H

11

-CH

2

C

6

H

11

-CH

2

CH

2 0 6

H

5

-CH

2

C

6

H

5

-CH

2

CH

2 -0H 2 -NR1 9 -S0 2

R,

8

-CH

2

-NR

19

-C(O)R

4 0

CH

2

NHC(O)NHR,

8

-CH

2

NHR

2 1 or CH 2

N(R

21 2 in which RIB is -C 6

H

5 phenyl which is substituted by 1 to 3 methyl or methoxy or -NO 2 or F or Cl, in particular p-CH 3

-C

6

H

4 p-CH 3

O-C

6

H

4 or 2,3,5,-CH 3

-C

6

H

2 or P-0 2

N-C

6

H

4 or CI-C 4 alkyl, which is substituted by F, in particular

-OF

3

R

40 is phenyl which is unsubstituted or substituted by 1 to 3 methyl or methoxy or -NO 2 or F or Cl; R 19 is H, Cl-C 6 alkyl, phenyl-(CH 2 with z equal to a number from 1 to 3, phenyl-CH=CH-CH 2 and especially

-CH

2

-CH(CH

3 2 or benzyl; and R 21 is -CH 2

-CR

22

R

23

R

24 in which R 22 and R 23 methyl, ethyl or phenyl and R 24 is H, ethyl or methyl, very particularly preferably

R

22 and R 23 are methyl and R 24 is H.

A preferred subgroup of the compounds of group are those in which R, is C 6

H-

11

CH

2

-C

6

H

5

(CH

2 2

-C

6

H

5 methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH 2 cyclohexyl, 06-Cloaryl,

R

8

C(O)N(R

9

R

8

S(O)

2

N(R

9

NR

9 C(O)NHRB and R 8

,R

9 in which R,9, R 9

R

8 and R 9 are, independently of one another, hydrogen, CI-Cl 2 alkyl, C3-Cl 2 cycloalkyl, C6-Cloaryl or C 7

-C

11 aralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OMy, nitro, cyano, SONY~, OSO 3 My, NR 20

SO

3 My, in which R 20 is hydrogen, 01 -Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, C3-C12cycloalkenyl, C2-011 heterocycloalkyl, 02-011 -heterocycloalkenyl, C6-Cloaryl, C5-Cgheteroaryl, C7-Cj 1 aralkyl, Ce-Cloheteroaralkyl, 08-Cll-aralkenyl or C7-Cloheteroaralkenyl, and C 1 -Cl 2 alkyl, CI-Cl 2 alkoxy and C6-Cloaryl, 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 R 8

R

9

R

8 and R 9 are, independently of one another, hydrogen, Cl-C 12 alkyl, cyclohexyl, phenyl, naphthyl or 07-Cllaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, Cl, C(O)ONa, nitro, cyano, SO 3 Na, C 1

-C

6 alkyl, methoxy and phenyl.

In a preferred group of compounds of the formula Ia, R 4 is C 6 1- 11 CH(0H 3 2 0H 2 -phenyl, (CH2) 2 -phenyl, CH 2 NHC(O)-phenyl, CH2NHC(O)(CH 2 3 -phenyl, CH 2

NHC(O)(CH

2 3 0H, WO 97/01569 PCTJEP96/02785 30

CH

2

NHC(O)CF

3

CH

2 NHC(O)0 6

H

1

CH

2 NHC(O)CllH 2 3

CH

2

NHC(O)CH(C

6

HS)

2

CH

2

HNC(O)NHC

6 H5, CH 2

NHC(O)C

2

H

4 00 2 Na, CH 2

NHC(O)C

6 ,3,4,5)0H 4

H

7

CH

2

NHC(O)C

6

H

4 -P-SO3Na,

CH

2

NHC(O)C

6

H

4 Cl, CH 2 NHC(O)0 6

H

4

NO

2

CH

2 NHC(O)0 6

H

4 0CH 3

CH

2

NHC(O)C

6

H

4 (3,4)0l 2

CH

2 NHC(O)0 6

H

4

CH

3

CH

2

NHC(O)C

6

H

4 0 6

H

5

CH

2

NHC(O)C

6

H

4 CN, CH 2

NHC(O)C

10

H

7 CH2NHC(O)C 6

H

4 COONa, CH2NHC(O)(CHOH) 2 000Na, CH2N(CH 2 CH=CH-phenyl)[C(o).phenyl], CH2N[CH 2

CH(CH

3 2 1tC(O)..phenylI,

CH

2

N[C(O)C;H

5

]CH

2 Cc 6 H5, CH2NrC(o)C 6

H

5

](CH

2 3

C

6

H

5

CH

2

C

6

H

11

(CH

2 2 0 6

H

11

CH

2

NH

2 CH2NHCH 2 CH=CH-phenyl,

CH

2

NHCH

2 -phenyl,

CH

2

NHCH

2

CH(CH

3 2

CH

2

N(CH

2 -phenyl) 2

CH

2

N[CH

2 CH(0H 3 2 2 CH2NHSO 2 -p-nitrophenyl, CH2NHSO 2 -P-tolyl, CH 2

NHSO

2

CF

3

CH

2

NHC(O)NHC

6

H

5 or 2 -P-nitrophenyl][CH 2

CH(CH

3 )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

3 OH HO 0 01 R2 0 OR 12 OR12 in which R 2 and X have the abovementioned meanings,

R

1 2 is a protective group and 13 12 and R 12 are, independently of one another, hydrogen or a protective group, with a compound of the formula VI

R

1

-R

1 3

(VI)

in which R, has the abovementioned meaning and R 13 is a leaving group, and eliminating the protective groups.

WO 97/01569 PCT/EP96/02785 -31 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 CI-C4alkyl,

CI-C

4 alkoxy, nitro, cyano or halogen (chlorine, bromine). Some examples of these acids are: methanesulfonic acid, mono-, di- or trifluoromethanesulfonic acids or p-nitrobenzenesulfonic acid. CF 3

-SO

2 -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 C1-Clalkyl, in particular

C

1

-C

6 alkyl, Cs-Cecycloalkyl, phenyl, benzyl, Cl-C, 2 alkylphenyl, in particular C1-C4alkylphenyl, or C1-Cl2alkylbenzyl, in particular C1-C4alkylbenzyl, for example methane, ethane, propane, butane, benzene, benzyl- and p-methylbenzenesulfonyl. Preferred leaving groups are CI, Br, I, -SO 2

CF

3 (triflate) and p-nitrobenzenesulfonyl, and -SO 2

CF

3 is particularly preferred.

The compounds of the formula VI are known in some cases or can be obtained by known processes, as described by Degerbeck et al. [Degerbeck, Fransson, Grehn,

L.,

Ragnarsson, J. Chem. Soc. Perkin Trans. 1:11-14 (1993)] and by Dureault et al.

[Dureault, Tranchepain, Depezay, Synthesis 491-493 (1987)]. Optically pure compounds can be obtained by using optically pure starting compounds 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 galactosyl donors and diols of the formula HO-X-OH. Stepwise introduction of galactose 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 galactose onto the fucose-O-X-OH building block or by glycosidic attachment of suitably protected and activated fucose onto a galactose-O-X-OH building block. Glycosylation reactions are known on a large scale and are described in the specialist literature.

WO 97/01569 PCT/EP96/027 8 -32- It is then possible to introduce the group R, into the pseudotrisaccharide. The resulting compounds 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 etherification. 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 (tributyltin) 2 0. The activating agents are preferably used in stoichiometric amounts. In this case, the reaction is carried out in two stages, namely a) activation and b) coupling with the compounds of the formula

VI.

The activation process can be carried out at temperatures from 40 to 2000C, preferably to 1200C.

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

V.

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 It is possible to use non-polar aprotic and polar aprotic or polar protic solvents. These may be aliphatic or aromatic hydrocarbons such as pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene or xylene, halogenated hydrocarbons such as methylene chloride, chloroform, tetrachloromethane, 1, 2 -dichloroethane, 1,1, 2 -trichloroethane, 1,1, 2 2 -tetrachloroethane and chlorobenzene, 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 WO 97/01569 PCT/EP96/02785 -33alkanols 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. lyer, Tetrahedron 48:2223-2311 (1992). Examples of such protective groups are: benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, dimethoxybenzyl, bromobenzyl, 2,4-dichlorobenzyl; diphenylmethyl, di(methylphenyl)methyl, di(dimethylphenyl)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-propyldimethylsilyl, t-butyl-dimethylsilyl, t-butyl-diphenylsilyl, n-octyl-dimethylsilyl, (1,1, 2 ,2-tetramethylethyl)dimethylsilyl;

C

2

-C

12 in particular C2-CBacyl, such as acetyl, propanoyl, butanoyl, 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

1

-C

8 alkyl, in particular Cl-C 4 alkyl, for example methyl, ethyl, n- and i-propyl, i- and t-butyl; C7-Cl 2 aralkyl, for example benzyl; trialkylsilyl with 3 to 20 C atoms, in particular 3 to 12 C atoms, for example triethylsilyl, tri-n-propylsilyl, tri-i-propylsilyl, i-propyl-dimethylsilyl, t-butyl-dimethylsilyl, t-butyldiphenylsilyl, n-octyl-dimethylsilyl, (1,1,2,2-tetramethylethyl)dimethylsilyl; substituted methylidene 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 C1-Cl2alkylidene, preferably C1-C6alkylidene and in particular Cl-C4alkylidene, such as ethylidene, 1,1- and 2 2 -propylidene, 1,1- and 2 2 -butylidene, benzylidene; unsubstituted and halogenated

C

2

-C

1 2 acyl, in particular C2-C8acyl, such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, pivaloyl and benzoyl.

The synthesis preferably takes place with protective groups for R 12 and R 12 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

12 and R 12 together are an alkylidene group with, in particular, 1 to 12 C atoms, with the alkylidene group WO 97/01569 PCT/EP96/027 8 -34forming an acetal or ketal with the oxygen atoms. These protective groups are ones which can be eliminated under neutral or weakly acidic conditions. Particularly suitable protective groups are acyl, benzyl, substituted benzyl, benzyloxymethyl, alkyl and silyl. R 12 and R 12 are, particularly preferably, together alkylidene, for example alkyl- or alkoxy- substituted benzylidene.

R

1 2 and R 1 2 can, however, also be hydrogen, or one of R 12 and R 12 can be a protective group such as benzyl and the other one of R 1 2 and R 1 2 can be hydrogen.

Examples of protective carboxylate groups are alkoxy- and aralkoxycarbonyl groups, preferably

-CO

2 Bn, -CO 2

CH

3 The reaction for elimination of the protective groups is preferably carried out at a temperature of 0°C to 500C, 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 linkage of the protected fucose hydroxy ether of the formula

VII

HO.

0 R2 OR 12

(VII),

r OR 1 2

OR

12 in which

R

2

R

12 and X have the abovementioned meanings, with the protected galactose of the formula

VIII

R

OR

S Z R (Vill), WO 97/01569 PCT/EP96/02785 in which R 1 has the abovementioned meaning, Z is O or S, R 12 is a protective group and R is a leaving group, and subsequent removal of the protective groups from the resulting compound.

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)-CCI 3 or 4-pentenyl. The compounds of the formula VII can be obtained in a simple manner by glycosidic linkage of appropriately protected fucose with a compound of the formula HO-X-OH which is monoprotected where appropriate. The compounds of the formula VIII can be obtained by etherification of compounds of the formula R 1 OH with galactose which is protected where appropriate.

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 disorders such as cardiogenic shock, myocardial infarct, thrombosis, rheumatism, psoriasis, dermatitis, acute respiratory distress syndrome, asthma, arthritis and metastatic cancer. The invention furthermore relates to the compounds according to the invention for use in a therapeutic method for the treatment of disorders in warm-blooded animals, including humans. The dosage on administration to warm-blooded animals with a body weight of about 70 kg can be, for example, 0.01 to 1000 mg per day. Administration preferably takes place in the form of pharmaceutical compositions, parenterally, for example intravenously or intraperitoneally.

The invention furthermore relates to a pharmaceutical composition comprising an effective amount of the compound according to the invention, alone or together with other active substances, a pharmaceutical carrier, preferably in a significant amount, and, where appropriate, 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. Solutions of this type are preferably isotonic aqueous solutions or suspensions, it being possible to prepare the latter, for example in the case of lyophilized compositions which comprise the active substance alone or together with a carrier, for example mannitol, before use. The pharmaceutical compositions can be sterilized and/or comprise excipients, for example pre- WO 97/01569 PCT/EP96/02785 -36servatives, 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 lyophilizing processes, and comprise about 0.1 to 90 in particular from about 0.5 to about 30 for example 1 to 5 of active substance(s).

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: C 2

H

5 S; 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: Preparation of starting compounds Example Al: Preparation of compound No. Al 0 0 a) N 3 OH 3 N OBn OH

OH

28 29 Benzyl chloride (660 ml, 5.72 mmol) is added at room temperature to a mixture of

R-

3 -azido-2-hydroxypropionic acid 28 [Dureault, Tranchepain, Depezay,

J.C.,

Synthesis 491-493 (1987)], triethylamine (850 ml, 6.1 mmol) and DMF (7.0 ml). The mixture is stirred for 16 hours, and then further triethylamine (850 6.1 mmol) and benzyl chloride (660 p1, 5.72 mmol) are added. The reaction mixture is stirred for two days and then con- WO 97/01569 PCT/EP96/02785 -37centrated 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 (Na 2 SO4), filtered and concentrated in vacuo. The crude product (1 g) is purified by flash chromatography on silica gel (ethyl acetate/hexane resulting in benzyl R- 3 -azido-2-hydroxypropionate 29 (0.717 g, 85 as an oil. 'H NMR (250 MHz, CDCl 3 8 7.36 5H), 5.25 2H), 4.39 J=4.2 Hz, 1H), 3.65 (dd, J=3.3, 12.9 Hz, 1H), 3.51 (dd, J=4.3, 12.9 Hz, 1H), 3.20 J=4.0 Hz, 1H).

0 b) 29 NOBn OTf Al Trifluoromethanesulfonic anhydride (770 ml, 4.41 mmol) is added at -20 0 C with stirring to a solution of the alcohol 29 (0.85 g, 3.84 mmol) and 2 6 -di-tert-butylpyridine (1.12 ml, 4.99 mmol) in dry CH 2

CI

2 (11.0 ml). The clear colourless solution is warmed to 0°C over the course of 40 minutes and is stirred at this temperature for a further 2 hours. The mixture is diluted with CH 2 CI2 (40 ml) and, while stirring vigorously, 1 M aqueous

KH

2

PO

4 solution ml) is added. The organic phase is separated off and the aqueous phase is extracted twice with CH 2

CI

2 The combined organic phases are washed with H 2 0 (30 ml), dried (Na 2

SO

4 filtered and concentrated in vacuo. The oily residue (2.3 g) is purified by flash chromatography on a short silica gel column (ethyl acetate/hexane resulting in the benzyl R-3-azido-2-trifluoromethanesulfonyloxypropionate Al (1.16 g, 85 as a yellowish oil. 'H NMR (250 MHz, CDC3) 6 7.38 (br s, 5H), 5.32 J=12,1 Hz, 1H), 5.27 J=12.1 Hz, 1H), 5.24 (dd, J=4.2, 5.5 Hz, 1H), 3.90 3.75 2H); 13C NMR (63 MHz, CDCl1) 8 164.4, 133.9, 129.1, 128.8, 128.6, 120.9, 81.0, 69.0, 51.5.

WO 97/01569 PCT/EP96/02785 -38- Example A2: Preparation of compound No. A2 0 o OH OH F3C S OH OBn OBn 0 0 26 27 A2 Benzyl (R)-4-phenyl-2-trifluoromethanesulfonyloxybutyrate (A2): A solution of 2 -hydroxy-4-phenylbutyric acid 26 (0.2 g, 1.11 mmol) in MeOH/

H

2 0 (9:1, 1.3 ml) is adjusted to pH 8 with 20 Cs 2

CO

3 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

H

2 0. The residue is mixed with N,N-dimethylformamide (1.3 ml) and benzyl bromide (132 pl, 1.11 mmol) and the mixture is stirred at room temperature for 75 minutes. Then further benzyl bromide (20 pl, 0.168 mmol) is added, and the mixture is stirred for a further 50 minutes. The white suspension is diluted with CH 2

CI

2 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 2 -hydroxy-4-phenylbutyrate 27 (0.21 g, 70 The product (0.3 g, 1.11 mmol) is dissolved in CH 2

CI

2 (4.5 ml), 2 6 -di-tert-butylpyridine (323 1, 1.44 mmol) is added, and the mixture is cooled to -200C. Then trifluoromethanesulfonic anhydride (222 pl, 1.27 mmol) is added dropwise over the course of 3 minutes, and the solution is warmed to 00C over the course of 45 minutes. After 75 minutes at 00C, the mixture is diluted with CH 2

CI

2 (20 ml) and washed with 1 molar aqueous

KH

2

PO

4 solution (15 ml). The aqueous phase is extracted with CH 2

CI

2 (2 x 10 ml), and the combined organic phases are washed with H 2 0 (10 ml), dried (Na 2 SO4), filtered and concentrated in vacuo. The residue is purified roughly by column filtration on silica gel (eluent: ethyl acetate/hexane resulting in the crude triflate A2 (0.311 g, 70 as an oil. The product is used immediately for the next stage (preparation of B1.18). 1H NMR (250 MHz, CDCI 3 7.50 7.17 10H), 5.31 2H), 5.28 (dd, 11.0 Hz, 1H), 2.82 2H), 2.41 2H).

WO 97/01569 PCT/EP96/0278 39 Example A3: Preparation Of compound No. A3

OH

C I yoOH 0',0

F

3 C.S 0 yoOBn (A3) F-Hydromandelic acid is converted into the triflate A3 in accordance with Example A2.

Example A4: Preparation of compound No. A4

OH

YY0

OH

0 0

F

3 ml -TJY O~n (M4)

R-

2 -Hydroxy.3methylbutyric acid is converted into the trif late A4 in accordance with Example A2.

Exampe A5: Preparation of compound No.

F

3 C S 0

R-

2 -Hydroxy3cyclohexylPropionic acid is converted into the trif late A5 in accordance with Example A2.

WO 97/01569 PCT/EP96/02785 B Preparation of the mimetics Example B1: Preparation of compound No. B1.1 OBz Bzo St 0O BzO O a) BzO OBn OBz BnO OBn O B OBn BnOOBn 1 2 3 A mixture of the thioglycoside 1 (5.38 g, 8.40 mmol) [Biessen, E. A. Beuting, D.M., Roelen, van de Marel, van Boom, van Berkel, 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 CH 2

CI

2 (70 ml). The yellowish suspension is dried at room temperature and, after 3 hours, 5 ml of a suspension consisting of DMTST (5.84 g, 22.61 mmol), 4A molecular sieves (4.0 g) and CH 2

CI

2 (35 ml) are added.

Further 5 ml portions of this DMTST suspension are added after 30, 45 and 90 minutes respectively. The brown reaction mixture is then stirred for 15 hours, and thereafter filtered through Hyflo Super Cel (filter aid), washing with CH 2

CI

2 (300 ml). The filtrate is extracted by shaking first with 10 aqueous NaHCO 3 solution and then with saturated NaCI solution, and the organic phase is dried with Na 2

SO

4 filtered and concentrated in a vacuum rotary evaporator. The remaining brown foam is purified by two column chromatographies on silica gel (eluent for 1st chromatography: ethyl acetate/hexane 1:4; 2nd chromatography: ethyl acetate/toluene resulting in the pure product 3 as a colourless solid (4.28 g, 60 which is immediately used further.

WO 97/01569 PCT/EP96/02785 -41 3

OH

HO

OH

OOH

O OBn BnO OBn 4 A solution of the tetrabenzoate 3 (3.38 g, 3.04 mmol) and sodium methoxide (0.165 g, 3.05 mmol) in dry 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 Cel®, washing with CH 2 CI2. The filtrate is concentrated in vacuo, and the remaining yellow oil is purified by flash chromatography on silica gel (elution:

CH

2

CI

2 methanol 19:1), resulting in the pure tetrol 4 (1.95 g, 92

OH

HO

HO

OH

O OBn BnOOBn

OH

Ph 0 Ph O OBn Bn 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 NaHCO 3 solution and then with saturated NaCI solution, and the organic phase is dried (Na 2

SO

4 filtered and concentrated in vacuo, resulting in 1.5 g of crude product. Purification of the crude product by flash chromatography on silica gel (CH 2

CI

2 /MeOH 39:1) affords, besides the required benzylidene acetal 5 (0.475 g), 1~1 WO 97/01569 PCT/EP96/02785 -42a mixture of less polar byproducts (0.4 The latter are treated once again under the reaction conditions described above and are purified, resulting in a further 0.08 g of the benzylidene acetal 5. The total yield of 5 is: 0.555 g (49 'H NMR (500 MHz, CDCI 3 8 7.53 7.51 2H), 7.38 7.19 18H), 5.62 1H), 4.83 J=3.8 Hz, 1H), 4.77 J=12.1 Hz, 1H), 4.71 J=11.5 Hz, 1H), 4.70 1H), 4.66 J=12.0 Hz, 1H), 4.62 J=11.5 Hz, 1H), 4.51 J=11.1 Hz, 1H), 4.36 4.31 2H), 4.22 (brd, J=2.8 Hz, 1H), 4.06 (dd, J=1.7, 12.3 Hz, 1H), 3.97 (dd, J=2.9, 10.2 Hz, 1H), 3.92 J=12.0 Hz, 1H), 3.90 (dd, J=3.8, 10.2 Hz, 1H), 3.76 3.68 3H), 3.53 (ddd, J=4.9, 9.0, 11.0 Hz, 1H), 3.43 (br s, 1H), 3.37 (d, Hz, 1H), 2.57 J=8.0 Hz, 1H), 2.51 1H), 2.08 2H), 1.73 (br d, J=9.5 Hz, 2H), 1.42 1.25 2H), 1.20 (br t, J=11.2 Hz, 2H), 1.07 J=6.3 Hz, 3H); MS (FAB, THG) 800 (M NH 4 783 (M H).

COOBn Ph

/OH

d) o0 Ph

OB

OBn BnO OBn 6 A mixture of the diol 5 (0.098 g, 0.125 mmol), di-n-butyltin oxide (0.062 g, 0.25 mmol) and methanol (5 ml) is heated under reflux in an argon atmosphere for 2 hours. The reaction mixture is concentrated in vacuo, and pentane is added to the residue, after which it is concentrated once again. Dry CsF (dried under high vacuum at 300°C, 0.068 g, 0.45 mmol) is added under an argon atmosphere, and the mixture is further dried under high vacuum minutes). After addition of anhydrous 1, 2 -dimethoxyethane (1.5 ml), a solution of benzyl R-3-phenyl-2-trifluoromethanesulfonyloxypropionate [Degerbeck, Fransson,

B.,

Grehn, Ragnarsson, J. Chem. Soc. Perkin Trans. 1:11-14 (1993)] (0.24 g, 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 1M KH 2

PO

4 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 gl WO 97/01569 WO 97/01569 PCT/EP96/0278 -43- (Na 2 SO4), 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 g, 35 and the more polar precursor 5 (0.043 g, 44 'H NMR (250 MHz, CDCI 3 7.49 (br d, J=6.9 Hz, 2H), 7.37 7.05 28H), 5.36 1H), 5.04 J=12.0 Hz, 1H), 4.98 J=12.0 Hz, 1H), 4.72 4.63 3H), 4.62 4.48 4H), 4.31 J=11.2 Hz, 1H), 4.16 1H), 4.11 J=7.9 Hz, 1H), 4.07 J=3.4 Hz, 1H), 3.88 3.79 2H), 3.76 (dd, J=3.4, 10.3 Hz, 1H), 3.66 J=1 1.3 Hz, 1H), 3.62 3.47 2H), 3.44 3.35 1H), 3.36 (dd, J=3.5, 9.6 Hz, 1H), 3.16 3.06 2H), 3.12 (br s, 1H), 3.01 (dd, J=8.4, 13.9 Hz, 1H), 2.03 1.86 2H), 1.93 Hz, 1H), 1.71 -1.55 2H), 1.36 -1.00 4H), 0.99 J=7.1 Hz, 3H).

COONa 6 O O

OH

6 -0 r o

OH-

Ph 0 e) HO OH

OH

HOOH

B1.1 Dioxane (2.5 ml), water (1.2 ml) and glacial acetic acid (0.1 ml) are added to a mixture of Pd(OH) 2 /C (Pearlman catalyst, Pd content 20 0.03 g) and the protected compound 6 (0.03 g, 0.029 mmol). The flask is evacuated and flushed with argon several times. It is then flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 13 hours, and then filtered through a cellulose filter (pore size 45 imr). 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 and purified by reverse phase chromatography (RP18 silica gel, column diameter 1.4 cm, length 7.0 cm, gradient elution: 40 MeOH/ H 2 0 through 45 MeOH/H 2 0 to 50 MeOH/H 2 resulting in the target molecule B1.1 (0.015 g, 78 as a colourless solid: 'H NMR (500 MHz, D20) 8 7.38 7.30 4H), 7.29 7.23 1H), 4.92 J=4.0 Hz, 1H), 4.55 J=6.7 Hz, 1H), 4.35 J=7.8 Hz, 1H), 4.11 (dd, J=4.8, 8.5 Hz, 1H), 3.86 J=3.6 Hz, 1H), 3.84 (dd, J=3.3, 10.5 Hz, 1H), 3.74 J=3.5 Hz, WO 97/01569 PCT/EP96/027 8 -44- 1H), 3.71 (dd, J=3.9, 10.5 Hz, 1H), 3.69 3.62 3H), 3.50 (ddd, J=1.0, 4.5, 7.1 Hz, 1H), 3.48 3.41 1H), 3.43 (dd, J=8.0, 9.7 Hz, 1H), 3.24 (dd, J=3.5, 9.7 Hz, 1H), 3.09 (dd, J=4.6, 14.0 Hz, 1H), 2.92 (dd, J=8.8, 14.0 Hz, 1H), 2.06 1.97 2H), 1.63 (br s, 2H), 1.24 1.14 4H), 1.13 J=7.0 Hz, 3H); 13C NMR (100.6 MHz, APT, D20) d 139.5 130.7 (2 CH), 129.9 (2 CH), 128.0 100.8 96.8 84.0 83.3 79.6 (CH), 78.4 75.6 73.3 71.4 70.9 69.2 67.7 67.4 (CH), 62.8 (CH 2 40.6 (CH 2 30.9 (CH 2 30.4 (CH 2 24.4 (2 CH 2 16.6 (CH 3 MS (FAB, THG) 595 573 COOBn OH

O

HO-? 7 I 0 0 Ph 0 f) HO OH HO OH O OBn 0OBn BnOOBn Bn OBn 4 8 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 concentrated 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 g, 0.197 mmol) and dry 1,2-dimethoxyethane (0.4 ml). The mixture is cooled to 0°C, and a solution of benzyl R-3-phenyl-2-trifluoromethanesulfonyloxypropionate [Degerbeck, Fransson, Grehn, Ragnarsson J. Chem. Soc. Perkin Trans. 1:11-14 (1993)] (0.085 g, 0.219 mmol) in dry 1,2-dimethoxyethane (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 1M KH 2

PO

4 solution, the mixture is diluted with water and extracted three times with CH 2 CI2. The combined organic phases are washed with aqueous KF solution and then dried (Na 2 SO4), filtered and concentrated in vacuo. Purification of the residue takes place by flash chromatography twice on silica gel (first chromatography: 2 WO 97/01569 PCT/EP96/02785 MeOH/CHCI 3 second chromatography: 45 ethyl acetate/toluene), resulting in the ether 8 as an oil (0.013 g, 25 'H NMR (250 MHz, CDCI 3 8 7.40 7.00 25H), 5.15 J=11.6 Hz, 1H), 5.09 J=11.6 Hz, 1H), 4.89 J=11.8 Hz, 1H), 4.86 J=3.2 Hz, 1 4.77 (d, J=11,6 Hz, 1H), 4.69 J=12.0 Hz, 2H), 4.57 J=12.0 Hz, 1H), 4.56 J=11.

8 Hz, 1H), 4.35 J=6.5 Hz, 1H), 4.28 (dd, J=4.0, 9.5 Hz, 1H), 4.11 J=7.6 Hz, 1H), 4.02 3.88 (m, 2H), 3.79 (dd, J=7.3, 11.9 Hz, 1H), 3.66 (br s, 1H), 3.63 3.40 5H), 3.22 1H), 3.10 (dd, J=4.0, 14.0 Hz, 1H), 3.09 (br s, 1H), 3.03 (dd, J=3.5, 9.3 Hz, 1H), 2.90 (dd, J=9.5, 14.0 Hz, 1H), 1.97 1.84 2H), 1.75 J=1.9 Hz, 1H), 1.59 (br s, 2H), 1.29 1.07 4H), 1.01 J=6.4 Hz, 3H).

COONa

OH

8 -0 H 0 Ph g HO OH 0 0

OH

HOOH

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 chromatography (silica gel plates n-BuOH: acetic acid: NH40H 70:60:50:18:1.5) indicates absence of the precursor and of the intermediates (about 3.5 hours). The black suspension is filtered twice through a cellulose filter (pore size 45 gm), 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/H 2 0 through 45 MeOH/H 2 0 to 50 MeOH/H 2 resulting in the target molecule B1.1 (0.015 g, 78 as a colourless solid.

WO 97/01569 WO 97/01569 PCT/EP96/02785 -46- ExamDle B2: Preparation of compound No. B1.2 COONa HO OH 0 OH HO

OH

B1.2 The aromatic compound B1.1 (0.152 g, 0.256 mmol) and 5 Rh/A1 2 0 3 (0.2 g) are taken up in H 2 0 (5.5 ml), dioxane (3.5 ml) and acetic acid (1.0 ml). Air is replaced by multiple evacuation, 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 gm). The clear, colourless solution is concentrated in vacuo, and the residue is taken up in water and concentrated several times in order to remove excess acetic acid. A solution of the crude product in water is filtered through a Dowex 50 ion exchanger column (Na' form, length: 9 cm, diameter: 1.3 cm), and the column is washed with water. The filtrate is concentrated in vacuo, and the residue (0.16 g) is purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.55 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: 55 MeOH/H 2 resulting in the target molecule B1.2 (0.11 g, 73 as a fluffy white solid (after lyophilization). 'H NMR (500 MHz, D 2 0) 8 4.93 J=3.8 Hz, 1H), 4.58 J=6.4 Hz, 1H), 4.43 J=7.5 Hz, 1H), 3.91 (dd, J=3.5, 9.0 Hz, 1H), 3.88 3.83 2H), 3.75 J=3.3 Hz, 1H), 3.73 3.64 4H), 3.57 3.53 1H), 3.49 (dd, J=7.3, 9.0 Hz, 1H), 3.50 3.43 1H), 3.33 (dd, J=3.2, 9.2 Hz, 1H), 2.10- 1.99 2H), 1.73 (brd, J=12.0 Hz, 1H), 1.69- 1.44 9H), 1.29- 1.07 (m, 7H), 1.14 J=6.5 Hz, 3H), 0.96 0.80 2H); MS (FAB, THG) 623 601

L

WO 97/01569 PCT/EP96/02785 -47- Example B3: Preparation of compound No. B1.3 Ph a) 0 0 HO SEt HO SEt OH

OH

9 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 mixture is adjusted to 1 by cautious addition of a saturated solution of HCI gas in dry diethyl ether. The suspension is stirred at O0C, 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 ml). The organic phase is separated off, and the aqueous phase is extracted twice with ethyl acetate (70 ml each time). The combined organic phases are dried (Na 2

SO

4 filtered and concentrated in vacuo, resulting in 1.3 g of the crude product. Purification takes place by flash chromatography on silica gel (CHCl/isopropanol 19:1), resulting in the required 6benzyl ether 10 (0.3 g, 60 and a somewhat less polar byproduct (0.045 'H NMR (250 MHz, CDCI 3 8 7.47 7.33 5H), 4.64 2H), 4.37 J=9.3 Hz, 1H), 4.13 (br d, Hz, 1H), 3.89 3.69 4H), 3.64 (dd, J=3.1, 9.0 Hz, 1H), 2.89 2.70 2H), 1.38 J=7.3 Hz, 3H).

Bz OBn b) 10 BzO SEt BzO 11 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 CH 2

CI

2 (3.0 ml) at OC. The reaction mixture is stirred at 00C for 3.5 hours and then 1 M aqueous

KH

2

PO

4 solution is added, and the mixture is extracted three times with CH 2

CI

2 The combined organic phases are washed WO 97/01569 PCT/EP96/0278 -48with water, dried (Na 2

SO

4 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, CDCI 3 5 8.09 J=7.5 Hz, 2H), 8.02 J=7.5 Hz, 2H), 7.85 J=7.5 Hz, 2H), 7.68 J=7.4 Hz, 1H), 7.63 7.39 7H), 7.38 7.23 6H), 6.06 J=3.3 Hz, 1H), 5.85 J=10.0 Hz, 1H), 5.66 (dd, J=3.5, 10.0 Hz, 1H), 4.88 J=10.0 Hz, 1H), 4.60 J=11.9 Hz, 1H), 4.49 (d, J=11.9 Hz, 1H), 4.23 J=6.3 Hz, 1H), 3.84 3.64 2H), 3.02 2.80 2H), 1.38 (t, Hz, 3H).

OBz 11O-~ OBzO

O'

C) TOB OBn Bd OB OOBn 0OBn BnO OBn BnA 0

O

8 2 12 Dry CH 2

CI

2 (8.0 ml) is added to a mixture of the thioglycoside 11 (0.377 g, 0.60 mmol), the glycosyl acceptor 2 (0.32 g, 0.60 mmol) (EP 671,409) and activated 4A molecular sieves g) under an argon atmosphere. A suspension of DMTST (0.39 g, 1.51 mmol) and activated 4A molecular sieves (0.8 g) in dry CH 2

CI

2 (5.0 ml) is prepared in a second roundbottom flask. Both suspensions are stirred at room temperature for 3.5 hours. Then 3 portions of 1 ml of the DMTST suspension are added over a course of one hour to the glycosyl donor/acceptor mixture. The yellowish reaction mixture is stirred at room temperature for a further 1.5 hours and then filtered through Hyflo Super Cel washing with CH 2

CI

2 The filtrate is extracted by shaking with aqueous NaHCO 3 solution and then with water. The aqueous phases are reextracted with CH 2 Cl 2 and the combined organic phases are dried (Na 2

SO

4 filtered and concentrated in vacuo, resulting in 0.67 g of the crude product. Purification takes place by flash chromatography twice on silica gel (first chromatography: toluene/ethyl acetate 14:1; second chromatography: hexane/ethyl acetate resulting in the product 12 (0.404 g, 61 as a colourless foam.

WO 97/01569 PCT/EP96/02785 -49- 12

OH

HOB

HO OBn OBn Bn OBn 13 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 Cel'. The filtrate is concentrated in vacuo, and the remaining yellow oil (3.35 g) is purified by flash chromatography on silica gel (CH 2

CI

2 /MeOH, 19:1), resulting in the triol 13 (2.15 g, 88 as a colourless foam: 'H NMR (500 MHz, CDCI 3 8 7.41 7.24 (m, 4.99 J=3.6 Hz, 1H), 4.95 J=11.2 Hz, 1H), 4.83 J=11.2 Hz, 1H), 4.77 (d, J=11.3 Hz, 1H), 4.69 J=11.3 Hz, 1H), 4.68 J=11.5 Hz, 1H), 4.61 J=11.5 Hz, 1H), 4.53 2H), 4.34 J=7.0 Hz, 1H), 4.33 1H), 4.04 (dd, J=3.7, 10.1 Hz, 1H), 4.02 (m, 1H), 3.97 (dd, J=2.9, 10.0 Hz, 1H), 3.81 3.77 1H), 3.77 (dd, J=6.0, 9.4 Hz, 1H), 3.70 (dd, J=5.0, 9.6 Hz, 1H), 3.65 J=2.0 Hz, 1H), 3.63 3.54 4H), 2.95 (br s, 1H), 2.60 (br d, J=2.0 Hz, 2H), 2.07 1H), 2.01 1H), 1.69 2H), 1.45 -1.30 2H), 1.29 -1.18 2H), 1.10 J=6.5 Hz, 3H); MS (FAB, THG) 783 693 (M-PhCH 2 OH 0 0_ 0 NVOBn HO OBn OTf e) Al 0 OBn BnO OBn 13 COOBn HO OBn O

OH

HO OBn -o OBn BnO OBn 14 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 WO 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 0 C, 0.5 g, 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 g, 3.28 mmol) in dry 1,2-dimethoxyethane (8.0 ml). The reaction mixture is stirred at room temperature for 6 hours, and then 1 M aqueous KH 2

PO

4 solution (60 ml) is added. The mixture is extracted three times with ethyl acetate, and the combined organic phases are washed first with aqueous NaHCO 3 solution and then with NaCI solution, dried (Na 2 SO4), filtered and concentrated in vacuo. The oily residue (1.15 g) is purified by flash chromatography on silica gel (elution of the product with toluene/ethyl acetate 4:1, then elution of the precursor with CH 2

CI

2 /MeOH 19:1), resulting in the ether 14 (0.488 g, 75 as a colourless foam and the precursor 13 (0.075 g, 15 14: 'H NMR (500 MHz, CDCI3) 5 7.40 7.22 25H), 5.25 J=11.7 Hz, 1H), 5.16 J=11.8 Hz, 1H), 4.96 J=10.9 Hz, 1H), 4.95 J=3.1 Hz, 1H), 4.82 (d, J=10.8 Hz, 1H), 4.76 J=11.1 Hz, 1H), 4.72 4.66 2H), 4.62 J=11.0 Hz, 1H), 4.57 (dd, J=3.2, 6.0 Hz, 1H), 4.53 J=11.3 Hz, 1H), 4.50 J=11.3 Hz, 1H), 4.39 J=6.2 Hz, 1H), 4.31 J=7.4 Hz, 1H), 4.04 (br s, 1H), 4.02 (dd, J=3.0, 9.5 Hz, 1H), 3.99 (dd, J=2.4, Hz, 1H), 3.82 (ddd, J=1.9, 7.3, 8.9 Hz, 1H), 3.77 (dd, J=6.0, 9.2 Hz, 1H), 3.78 3.74 (m, 1H), 3.70 3.65 2H), 3.63 (dd, J=3.0, 12.3 Hz, 1H), 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 1H), 3.44 (dd, J=3.1, 9.0 Hz, 1H), 2.90 (dd, J=1.2, 1.8 Hz, 1 OH), 2.86 2.0 Hz, 1 OH), 2.09 1.96 2H), 1.68 2H), 1.44 -1.18 4H), 1.11 J=6.3 Hz, 3H); MS (FAB, THG) 1010 984 (M+Na+2H-N 2 962 (M+3H-N 2 COOBn 14 -IN 070 NH 2 HO OBn Bn O OBn BnO 0 8 16 Pt/BaSO 4 (0.35 g, 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 WO 97/01569 PCT/EP96/02785 -51 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 suspension is filtered through a cellulose filter (pore size 45 pm), and the fitrate is concentrated in vacuo. The residue (0.115 g) is purified by flash chromatography on silica gel (CH 2 CI2 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.

COOBn COONa Ph j OH OH 16 goVr 16 O o- Ph NH

H

O

9) HO OBn HO OH O OBn J OH BnO OBn

HOOH

17 B1.3 Preparation of the benzamide intermediate 17: diisopropylethylamine (3.5 ml, 0.02 mmol) and benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.012 g, 0.0271 mmol) are added at 0°C to a solution of the p-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 NaHCO 3 solution is added.

The mixture is extracted three times with CH 2

CI

2 and the combined organic phases are washed first with 1 M aqueous

KH

2 PO4 solution (pH 1-2, adjusted with 1 M aqueous

HCI)

and then with aqueous NaHCO 3 solution, dried (Na 2

SO

4 filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel (gradient elution: ethyl 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 mixture is hydrogenated under slightly elevated pressure with vigorous stirring for 14 hours. The mixture is filtered through a cellulose filter (pore size 45 lam), and the filtrate is concentrated in vacuo. The residue is WO 97/01569 PCT/EP96/02785 -52taken 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 deionized 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 gm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.59 ml/min, detection at 230 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 37 MeOH/H 2 0 to 45 MeOH/H 2 0), resulting in the target molecule B1.3 (3.3 mg, 58 as a fluffy white solid, (after lyophilization). 'H NMR (500 MHz, D20) 8 7.74 J=7.5 Hz, 2H), 7.57 J=7.2 Hz, 1H), 7.48 (t, J=7.6 Hz, 2H), 4.92 J=4.0 Hz, 1H), 4.57 J=6.7 Hz, 1H), 4.44 J=7.8 Hz, 1H), 4.17 (dd, J=3.9, 8.1 Hz, 1H), 3.94 J=3.0 Hz, 1H), 3.86 J=3.5 Hz, 1H), 3.84 J=4.0 Hz, 1H), 3.74 J=3.5 Hz, 1H), 3.75 3.65 4H), 3.60 3.52 3H), 3.49 3.44 1H), 3.45 (dd, J=3.5, 9.3 Hz, 1H), 2.03 2H), 1.64 (brs, 2H), 1.26 1.13 4H), 1.11 (d, Hz, 3H); MS (FAB, THG) 660 638 Example B4: Preparation of compound No. B1.4 COOBn COONa OH O 0 0 NH O OBn HO OH 0 OBn OH BnO Ph HO OH B1.4 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), dihydrocinnamic acid (0.015 g, 0.1 mmol), 1-hydroxybenzotriazole (0.025 g, 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:

CH

2 Cl 2 /MeOH 39:1, for the second chromatography:

CH

2

CI

2 /isopropanol 39:1), resulting in the pure amide 19 (0.031 g, 86 WO 97/01569 PCT/EP96/0278 -53- 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 elevated pressure of hydrogen with vigorous stirring for 18 hours. The mixture is filtered through a cellulose filter (pore size 45 jm), and the filtrate is concentrated in vacuo.

The residue is mixed with toluene (about 2 ml) and concentrated several times in order to remove excess acetic acid. A solution of the crude product (0.021 g) in a little water is then passed through an ion exchanger column (Dowex 50, Na' form, column diameter 0.9 cm, length 3.5 cm), washing with deionized water. The filtrate is concentrated in vacuo, and the residue (0.02 g) is purified by reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: 60 MeOH/H 2 0) and subsequent gel filtration on Bio-Gel P2 (particle size 65 am, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm), resulting in the target molecule B1.4 (0.014 g, 74 as a fluffy colourless solid (after lyophilization). 'H NMR (500 MHz, D 2 0) 8 7.32 2H), 7.24 3H), 4.93 J=4,1 Hz, 1H), 4.57 J=6.7 Hz, 1H), 4.40 J=8.0 Hz, 1H), 3.9 3.84 3H), 3.75 3.66 5H), 3.63 (dd, J=3.8, 14.0 Hz, 1H), 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 1H), 3.23 (dd, J=7.8, 14.0 Hz, 1H), 3.15 (dd, J=3.2, 9.8 Hz, 1H), 2.88 (br t, J=7.3 Hz, 2H), 2.59 2.45 2H), 2.09 1H), 2.03 (m, 1H), 1.67 (br s, 2H), 1.30 1.15 4H), 1.13 J=6.6 Hz, 3H); MS (FAB) 666 643 (M+H-Na).

Example B5: Preparation of compound No. COOBn COONa 1 0 OH 0

OH

0 HO OBn 0 HO OH

OOH

OBn 0 OH BnOOBn HO OH HO WO 97/01569 PCT/EP96/02785 -54- 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 (CH 2

CI

2 MeOH 29:1), resulting in the amide 21 (0.02 g, 71 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 several times. It is then flushed with hydrogen, and the black mixture is hydrogenated under a slightly elevated pressure of hydrogen with vigorous stirring for 18 hours. The mixture is filtered through a cellulose filter (pore size 45 gm), 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 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 gel filtration on Bio-Gel P2 (particle size 65 lam, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH/H 2 0 resulting in the target molecule B1.5 (0.015 g, 70 as a fluffy colourless solid (after lyophilization). 'H NMR (500 MHz, D 2 0) 8 4.93 J=3.9 Hz, 1H), 4.59 J=6.7 Hz, 1H), 4.47 J=7.5 Hz, 1H), 4.04 (dd, J=3.8, 7.3 Hz, 1H), 3.92 J=3.2 Hz, 1H), 3.86 (dd, J=3.4, 10.2 Hz, 1H), 3.75 J=3.5 Hz, 1H), 3.74 3.65 4H), 3.62 (dd, J=3.9, 14.0 Hz, 1H), 3.59 3.51 2H), 3.55 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 J=7.4 Hz, 2H), 2.11 2.00 2H), 1.77 J=7.1 Hz, 2H), 1.65 (br s, 2H), 1.29 1.13 4H), 1.15 J=6.8 Hz, 3H). MS (FAB) 643 620 598 (M+2H-Na).

WO 97/01569 PCT/EP96/02785 Example B6: Preparation of compound No. B1.6 COOBn CO2,H OH

OH

N O NH 2 HO OBn HO OH 0

O

O OBn O OH BnOOBn

HOOH

14 81.6 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 pm), and the filtrate is concentrated in vacuo. The residue is purified by gel filtration on Bio-Gel P2 (particle size 65 gm, column diameter 2.5 cm, length 35 cm, water, flow rate 0.55 ml/min, detection 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 7 cm, eluent: 25 MeOH/H 2 0), resulting in the target molecule B1.6 (0.011 g, 70 as a fluffy colourless solid (after lyophilization). H NMR (500 MHz, D 2 0) 8 4.93 J=3.9 Hz, 1H), 4.58 J=6.7 Hz, 1H), 4.48 J=7.9 Hz, 1H), 4.22 (dd, J=3.7, 8.4 Hz, 1H), 3.99 J=3.1 Hz, 1H), 3.86 (dd, J=3.3, 9.9 Hz, 1H), 3.75 J=3.3 Hz, 1H), 3.74 3.65 4H), 3.61 3.55 2H), 3.50 (dd, 9.3 Hz, 1H), 3.48 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 2H), 1.65 2H), 1.29 -1.15 4H), 1.14 J=6.5 Hz, 3H); MS (FAB, THG) 510 WO 97/01569 PCT/EP96/02785 -56- Example B7: Preparation of compound No. B1.7

CO

2

H

Ph ,NH J OH 61.6 0 HO OH 0 OH

HOOH

B1.7 The amine B1.6 (0.09 g, 0.176 mmol) is dissolved in dry MeOH (1.5 ml) and CH 2

CI

2 (1.8 ml) and activated 3A molecular sieves (about 0.2 cinnamaldehyde (24 L1, 0.19 mmol) and acetic acid (9 gl) are added. The yellowish suspension is stirred for 2 minutes and then NaBH 3 (CN) (0.018 g, 0.286 mmol) is added. After 1.5 hours, the mixture is filtered through a cellulose filter (pore size 45 gm), the filter is washed with 1:1 MeOH/ CH 2

C

2 and the filtrate is concentrated in vacuo. The glassy residue is taken up in water (5 ml), and the solution is acidified (about pH 1-2) with 1 M hydrochloric acid (0.7 ml). The cloudy solution is again filtered through a cellulose filter (pore size 45 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 jm, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.6 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 50 MeOH/H 2 0 to 70 MeOH/

H

2 resulting in the target molecule B1.7 (0.03 g, 27 as a fluffy white solid (after lyophilization). 'H NMR (500 MHz, D 2 0) 8 7.48 J=8.0 Hz, 2H), 7.41 7.31 3H), 6.83 (d, J=15.4 Hz, 1H), 6.26 (dt, J=15.4, 7.0 Hz, 1H), 4.92 J=3.8 Hz, 1H), 4.56 J=6.3 Hz, 1H), 4.43 J=7.6 Hz, 1H), 4.31 (dd, J=3.5, 8.2 Hz, 1H), 3.98 J=3.0 Hz, 1H), 3.88 3.81 2H), 3.84 J=6.0 Hz, 1H), 3.76 3.63 5H), 3.60 3.51 2H), 3.49 (dd, 10.4 Hz, 1H), 3.49 3.41 1H), 3.41 (dd, J=3.5, 13.2 Hz, 1H), 3.26 (dd, J=8.5, 13.2 Hz, 1H), 2.02 2H), 1.64 (br s, 2H), 1.27 1.12 4H), 1.12 J=6.3 Hz, 3H); MS (FAB, THG) 650 628 WO 97/01569 PCT/EP96/02785 -57- Example B8: Preparation of the compound No. B1.8 Ph o C

CO

2 Na Ph N OH o B1.7 o 0 HO OH O

OH

HO OH B1.8 A solution of the amino acid B1.7 (0.01 g, 0.0159 mmol) in 1 M aq. NaHCO 3 (0.1 ml) is cooled to 0°C and, while stirring vigorously, a 1 M solution of benzoyl chloride in benzene (16.0 p1) is added. After 40 minutes, a further 8.0 pl of the benzoyl chloride solution is added, after 130 minutes a further 3.0 p1 and after a total of 3.5 hours a further 1.0 pl. 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 cm, length 35 cm, eluent: water, flow rate 0.49 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 60 MeOH/

H

2 0 to 70 MeOH/H 2 resulting in the target molecule B1.8 (7.9 mg, 66 as a fluffy white solid (after lyophilization). H NMR (500 MHz, D 2 1.4:1 mixture of rotamers, characteristic signals: 5 7.52 7.24 10H, 2xPh), 6.71 J=15.5 Hz, 0.42H, PhCH=CH), 6.42 (dt, J=15.5, 6.1 Hz, 0.42H, PhCH=CH), 6.39 J=15.5 Hz, 0.58H, PhCH=CH), 6.13 (dt, J=15.5, 5.6 Hz, 0.58H, PhCH=CH), 4.92 J=4.0 Hz, 1H, Fuc-1H), 1.16 J=7.0 Hz, 1.26H, Fuc-6H), 1.11 J=6.8 Hz, 1.74H, Fuc-6H); MS (FAB, THG) 776 754 WO 97/01569 PCT/EP96/02785 -58- Example B9: Preparation of compound No. B1.9 and No. B1.10

COH

HCO

H

B1.6 0

O

/NH V 0+ N 0 CH2 HO H CH HOOHCH CH HO OH Ph I I O OH Ph Ph

O

O H O H

HOOH

HO

OH

B1.9 B1.10 A CH 2

CI

2 solution of freshly distilled benzaldehyde (0.083 g in 1.0 ml CH 2

CI

2 0.1 ml, 0.078 mmol), activated 3A molecular sieves (0.1 g) and glacial acetic acid (5 .I, 0.087 mmol) are added to a solution of the amino acid B1.6 (0.04 g, 0.078 mmol) in MeOH/ CH2C 2 1.0 ml). The suspension is stirred at room temperature and, after 2 minutes, NaBH 3 (CN) (0.008 g, 0.129 mmol) is added. After 2.5 hours, a further 15 1 of the benzaldehyde 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 pm), and the filtrate is adjusted to pH 8-9 with 1 M aqueous NaHCO 3 solution and then concentrated. The residue is purified by gel filtration on Bio-Gel P2 (particle size lpm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 35 MeOH/H 2 0 to 60 MeOH/H 2 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, D 2 0) 8 7.45 5H), 4.93 J=4.0 Hz, 1H), 4.57 J=6.7 Hz, 1H), 4.45 J=7.6 Hz, 1H), 4.33 (dd, J=3.8, 8.8 Hz, 1H), 4.28 J=13.3 Hz, 1H), 4.24 J=13.3 Hz, 1H), 3.99 J=3.1 Hz, 1H), 3.85 (dd, J=3.5, 10.2 Hz, 1H), 3.74 3.65 5H), 3.59 3.54 2H), 3.49 (dd, J=3.2, 9.7 Hz, 1H), 3.48 3.44 1H), 3.42 (dd, J=3.7, 13.2 Hz, 1H), 3.26 (dd, J=8.9, 13.2 Hz, 1H), 2.04 2H), 1.65 (br s, 2H), 1.28 1.14 4H), 1.12 J=6.7 Hz, 3H); MS (FAB, THG) 624 602 Dibenzylamine B1.10: 'H 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) 6 7.38 10H), 4.93 (d, WO 97/01569 PCT/EP96/02785 -59- Hz, 1H), 4.60 J=6.6 Hz, 1H), 4.43 J=8.0 Hz, 1H), 4.23 (dd, J=3.6, 8.5 Hz, 1H), 3.88 3.83 2H), 3.75 3.63 5H), 3.56 (dd, J=8.0, 9.3 Hz, 1H), 3.53 3.44 2H), 3.32 (dd, J=3.0, 9.5 Hz, 1H), 2.13 1.98 2H), 1.66 (br s, 2H), 1.31 1.10 4H), 1.14 J=6.6 Hz, 3H); MS (FAB, THG) 714 692 Example B10: Preparation of compounds No. B1.11 and No. 81.12

COOH

COOH OH

COOH

0 0 J O 0 B1.6 OH O(

O

CH H OH H OH

H

3 C CH 3 0 OH 0OH HO

H

3 C CH, HC CH HOOH 81.11 B1.12 A 1 M CH 2

CI

2 solution of isobutyraldehyde (0.156 ml), activated 3A molecular sieves (0.2 g) and glacial acetic acid (10 l, 0.17 mmol) are added to a solution of the amino acid B1.6 (0.08 g, 0.156 mmol) in MeOH/ CH 2

CI

2 (1:1,2.0 ml). The suspension is stirred at room temperature and, after one minute, NaBH 3 (CN) (0.016 g, 0.258 mmol) is added. After minutes, the reaction mixture is diluted with water and filtered through a cellulose filter (pore size 45 gm), and the filtrate is adjusted to pH 8-9 with 1 M aqueous NaHCOa solution and then concentrated. The residue is purified by gel filtration on Bio-Gel P2 (particle size jLm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, gradient elution: 35 MeOH/H 2 0 to 50 MeOH/H20), with elution first of the monoisobutylamine B1.11 (0.041 g, 46 and then of the diisobutylamine B1.12 (0.01 g, 10 Monoisobutylamine 81.11: 'H NMR (500 MHz, D 2 0) 5 4.92 J=4.0 Hz, 1H), 4.59 J=6.7 Hz, 1H), 4.47 J=7.6 Hz, 1H), 4.29 (dd, J=4.0, 9.0 Hz, 1H), 3.98 J=3.5 Hz, 1H), 3.85 (dd, J=3.3, 10.0 Hz, 1H), 3.76 3.65 5H), 3.56 (dd, J=7.5, 9.3 Hz, 1H), 3.59 3.54 (m, 1H), 3.50 (dd, J=3.0, 9.7 Hz, 1H), 3.50 3.43 1H), 3.34 (dd, J=3.9, 13.0 Hz, 1H), 3.20 (dd, J=9.2, 13.2 Hz, 1H), 2.90 (dd, J=7.6, 12.0 Hz, 1H), 2.86 (dd, J=7.3, 12.0 Hz, 1H), 2.11 WO 97/01569 PCT/EP96/02785 1.99 2H), 1.96 (non, J=6.9 Hz, 1H), 1.65 2H), 1.28 1.11 4H), 1.14 J=6.6 Hz, 3H), 0.94 J=6.6 Hz, 6H); MS (FAB, THG) 590 568 Diisobutylamine B1.12: 'H NMR (500 MHz, D 2 0) 5 4.92 J=4.1 Hz, 1H), 4.59 J=6.7 Hz, 1H), 4.46 J=7.1 Hz, 1H), 4.36 J=6.6 Hz, 1H), 4.02 (br s, 1H), 3.85 (dd, J=3.3, 10.3 Hz, 1H), 3.76 3.66 5H), 3.57 (dd, J=4.7, 7.5 Hz, 1H), 3.55 3.50 2H), 3.49 3.39 3H), 3.07 (br s, 4H), 2.12 (non, J=6.8 Hz, 2H), 2.12 1.99 2H), 1.65 (br s, 2H), 1.28 1.11 4H), 1.13 J=6.7 Hz, 3H), 0.97 J=6.8 Hz, 12H); MS (FAB, THG) 646 (M+Na), 624 Example B11: Preparation of compound No. B1.13 COONa

OH

B1.11 0 N H OH Ph c O O 0

OH

H

3 C

CH

3 H

HOO

B1.13 A 1 M solution of benzoyl chloride in toluene (41 pl) is added at room temperature to a solution of the amino acid B1.11 (0.020 g, 0.0339 mmol) in 1 M aqueous NaHCO 3 (100 pl). The mixture is stirred vigorously and, after 1 hour, further benzoyl chloride (41 p1 of the 1 M solution) 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 gm, 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: MeOH/H 2 0) and then lyophilized, resulting in the benzamide B1.13 as a fluffy powder, (0.014 g, 59 'H NMR (500 MHz, D 2 1:1 rotamer mixture: 8 7.50 7.37 5H), 4.93 J=4.0 Hz, 0.5H), 4.92 J=4.0 Hz, 0.5H), 4.60 J=6.4 Hz, 1H), 4.48 J=8.0 Hz, 4.37 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, 3.94 J=3.2 Hz, 0.5H), 3.89 3.83 1.5H), 3.82 3.61 7H), 3.60 3.52 (m, 3.51 3.43 2.5H), 3.25 (dd, J=7.9, 14.2 Hz, 0.5H), 3.20 (dd, J=7.9, 14.2 Hz,

I~

WO 97/01569 PCT/EP96/02785 -61 3.17 3.10 1H), 2.16 1.97 2.5H), 1.86 (non, J=6.9 Hz, 0.5H), 1.65 (br s, 2H), 1.29 1.14 4H), 1.17 J=6.4 Hz, 1.5H), 1.11 J=6.6 Hz, 1.5H), 0.95 J=6.5 Hz, 0.92 J=6.6 Hz, 1.5H), 0.65 J=6.4 Hz, 1.5H), 0.65 J=6.5 Hz, 1.5H); MS (FAB, THG) 716 694 Example 812: Preparation of compound No. B1.14 COONa

OH

BNH I .N B1.6 SO2 HO OH S HOOH O H

NO

2 B1.14 A 1 molar solution of p-nitrobenzenesulfonyl chloride in toluene (43 4l) is added with vigorous stirring to a solution of the amino acid B1.6 (0.02 g, 0.039 mmol) in 1 molar aqueous NaHCO 3 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 lm, column diameter 2.5 cm, length 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/H 2 0; 2nd chromatography: elution with 40 MeOH/H 2 0) and subsequently lyophilized, resulting in the target compound as a fluffy powder (0.0105 g, 39 'H NMR (400 MHz, D 2 0) 5 8.39 2H), 8.07 2H), 4.93 (d, Hz, 1H), 4.56 J=6.6 Hz, 1H), 4.43 J=7.9 Hz, 1H), 3.96 (dd, J=3.5, 7.1 Hz, 1H), 3.88 3.83 2H), 3.76 3.64 5H), 3.54 3.44 3H), 3.38 (dd, J=3.5, 13.7 Hz, 1H), 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 4H), 1.14 J=6.6 Hz, 3H); MS (FAB, THG) 719 697 WO 97/01569 PCT/EP96/02785 -62- Example B13: Preparation of compound No. B1.15 COONa

OH

/NH

B1.6 SO 2 HO OH

OOH

U

HOOH

CH

3 B1.15 A 1 molar solution of p-toluenesulfonyl chloride in toluene (22 p1) 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 NaHCO 3 solution (0.1 ml). The reaction mixture is stirred at 0°C for 90 minutes, after which further p-toluenesulfonyl chloride (10 al of the 1 M solution) is added. The reaction mixture is then warmed to room temperature, stirred for 18 hours and then concentrated in vacuo. The residue is taken up in water and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution with 45 MeOH/H 2 0) and subsequently lyophilized, resulting in the target compound as a fluffy powder (0.004 g, 30 1 H NMR (400 MHz, D 2 0) 6 7.69 (d, J=8.2 Hz, 2H), 7.37 J=8.1 Hz, 2H), 4.88 J=3.9 Hz, 1H), 4.52 J=6.6 Hz, 1H), 4.35 J=7.9 Hz, 1H), 3.85 3.78 2H), 3.74 J=2,8 Hz, 1H), 3.71 3.56 5H), 3.50 3.39 3H), 3.29 (dd, J=3.4, 13.8 Hz, 1H), 3.10 (dd, J=3.1, 9.6 Hz, 1H), 3.03 (dd, 13.8 Hz, 1H), 2.34 3H), 2.08 1.93 2H), 1.61 (brs, 2H), 1.26 1.07 4H), 1.09 (d, J=6.6 Hz, 3H).

WO 97/01569 PCT/EP96/02785 -63- Example B14: Preparation of compound No. B1.16 COBn

CO

2 Na 16 0

N

NH NH S

H

O OBn O HO OH

CF~

3 0 On 0

OH

BnO

O

Bn

HOOH

24 B1.16 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 trifluoroacetate (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 then saturated aqueous NaHCO 3 solution (0.2 ml) is added, and the mixture is diluted with water and extracted several times with ethyl acetate.

The combined organic phases are dried (Na 2

SO

4 filtered and concentrated in vacuo. The crude product (0.04 g) is purified by flash chromatography on silica gel as eluent: ethyl acetate/toluene 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. It 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 gm), 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 in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 jm, 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 7 cm, gradient elution: 30 MeOH/H20 to 40 MeOH/H 2 resulting in the target ~m~lg~ WO 97/01569 PCT/EP96/027 8 -64molecule B1.16 (0.0085 g, 68 as a fluffy colourless solid (after lyophilization). H NMR (500 MHz, D 2 0) 5 4.93 J=3.9 Hz, 1H), 4.59 J=6.5 Hz, 1H), 4.45 J=8.2 Hz, 1H), 4.08 (dd, J=3.4, 8.2 Hz, 1H), 3.91 J=3.1 Hz, 1H), 3.86 (dd, J=3.1, 10.0 Hz, 1H), 3.75 (d, J=3.1 Hz, 1H), 3.72 (dd, J=3.9, 10.0 Hz, 1H), 3.73 3.65 4H), 3.61 3.50 3H), 3.50- 3.44 1H), 3.42 (dd, J=3.1, 9.6 Hz, 1H), 2.10 2.00 2H), 1.65 2H), 1.28 1.15 (m, 4H), 1.14 J=6.5 Hz, 3H); MS (FAB, THG) 652 630 608 (M+2H-Na).

Example B15 Preparation of compound No. B1.17 COBn

CO

2 Na 0 HO OBOnn 0 HO OH Ba OBn j/ OH 3 BnO OBn O OH 26 81.17 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 g, 0.028 mmol), cyclohexanecarboxylic acid (0.011 g, 0.086 mmol), 1-hydroxybenzotriazole (0.021 g, 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 chromatography on silica gel (CH2CI 2 /isopropanol 39:1), resulting in the amide 26 (0.024 g, 80 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) 2 C (Pearlman catalyst, Pd content 20%, 0.03 g) and the benzyl ether 26 (0.024 g, 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 tm), 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 WO 97/01569 PCT/EP96/02785 in vacuo, and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 gm column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH/H 2 0 resulting in the target molecule B1.17 (0.008 g, 56 as a fluffy colourless solid (after lyophilization). 'H NMR (500 MHz, D 2 0) 8 4.93 J=4.0 Hz, 1H), 4.60 J=6.7 Hz, 1H), 4.47 J=8.0 Hz, 1H), 4.04 (dd, J=3.8, Hz, 1H), 3.92 J=2.8 Hz, 1H), 3.86 (dd, J=3.2, 10.3 Hz, 1H), 3.75 J=3.3 Hz, 1H), 3.74 3.64 4H), 3.61 (dd, J=3.8, 13.8 Hz, 1H), 3.59 3.52 2H), 3.50 3.44 1H), 3.42 (dd, J=3.3, 9.8 Hz, 1H), 3.35 (dd, J=7.7, 14.0 Hz, 1H), 2.19 (tt, J=3.3, 11.5 Hz, 1H), 2.11 2.00 2H), 1.78 1.57 7H), 1.34 -1.08 9H), 1.15 J=6.5 Hz, 3H); MS (FAB, THG) 644 (M 622 2H Na).

Example B16: Preparation of the compound B1.18

CO

2 Bn 13 A2 O -O a) Ph HO OBn 0 OBn OBn 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 concentrated and then dried under high vacuum for 30 minuten in order to remove remaining 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-dimethoxyethane (1.0 ml). The reaction mixture is stirred at room temperature for 75 minutes and 1 M of aqueous KH 2 PO4 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 Na 2

SO

4 filtered and concentrated in vacuo,

S*

WO 97/01569 PCT/EP96/0278 -66resulting in the crude product as an oil (0.39 Purification by flash chromatography on silica gel (eluent: toluene/ethyl acetate 5:1) results in the pure ether 30 (0.143 g, 81

'H

NMR (250 MHz, CDC, 3 7.35 7.05 30H), 5.13 J=12.1 Hz, 1H), 5.03 J=12.1 Hz, 1H), 4.88 J=11.

4 Hz, 1H), 4.87 J=2.0 Hz, 1H), 4.78 4.50 5H), 4.46 J=12,5 Hz, 1H), 4.40 J=12.5 Hz, 1H), 4.33 J=6.5 Hz, 1H), 4.24 J=7.8 Hz, 1H), 4.09 (dd, 8.5 Hz, 1H), 3.93 (br s 2H), 3.80 3.38 7H), 3.26 3.17 2H), 2.86 2.62 (m, 2H), 2.59 J=2.0 Hz, 1 OH), 2.29 (br s, 1 OH), 2.11 1.85 4H), 1.67 1.52 2H), 1.40 1.06 4H), 1.03 J=6.5 Hz, 3H).

CO

2 Na

OH

-O Or

HO

HOOH

B1.18 The benzyl ether 30 (0.14 g, 0.135 mmol) is dissolved in dioxane (4 ml) and water (2 ml), glacial acetic acid (1 ml) and 20% Pd(OH) 2 /C (0.14 g) are added.The air in the reaction vessel is replaced initially by argon, by evacuation and flushing several times, and then by hydrogen. The black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen for 90 minutes and then filtered through a cellulose filter (pore size 45 Am), 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 ion exchanger column. The filtrate is freeze-dried and the residue (0.085 g) is purified by reverse phase chromatography (Merck RP18 silica gel, elution: 40 MeOH/H 2 0) and subsequent gel filtration on Bio-Gel P2 (particle size 65 jam, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and then lyophilized, resulting in the target compound B1.18 as a fluffy powder (0.045 g, 55 'H NMR (500 MHz,

D

2 0) 8 7.35 7.27 4H), 7.22 (tt, J=1.5, 7.0 Hz, 1H), 4.93 J=4.0 Hz, 1H), 4.60 J=6.7 Hz, 1H), 4.47 (d, J=7.8 Hz, 1H), 3.89 3.82 3H), 3.76 J=3.5 Hz, 1H), 3.74 3.63 4H), 3.59 3.52 2H), 3.51 3.45 1H), 3.37 (dd, J=3.5, 9.8 Hz, 1H), 2.80 2.68 2H), 2.12 1.99 WO 97/01569 PCT/EP96/02785 -67- 3H), 1.98 1.89 1H), 1.65 (br s, 2H), 1.30- 1.13 4H), 1.15 J=6.6 Hz, 3H); MS (FAB, THG) 609 587 Example B17: Preparation of the compound No. B1.19 CONa B1.18 0 0o o HO OH

OH

HOOH

B1.19 The aromatic compound 81.18 (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/A1 2 0 3 (0.04 g) is added. The air in the reaction vessel is replaced by hydrogen by evacuation and flushing several times, and the mixture 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 gm) 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 pm, 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 gm) 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 gm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: 50 MeOH/H 2 0) and subsequently lyophilized, resulting in the target compound B1.19 as a fluffy powder (0.01 g, 50 'H NMR (250 MHz, D 2 0) 5 4.83 J=4.0 Hz, 1H), 4.48 J=6.7 Hz, 1H), 4.35 J=7.8 Hz, 1 H), 3.81 3.69 3H), 3.67 3.53 5H), 3.49 3.31 3H), 3.25 (dd, J=3.1, 9.7 Hz, 1H), WO 97/01569 PCT/EP96/02785 -68- 2.03 1.87 2H), 1.72 1.38 9H), 1.24 0.97 10H), 1.04 J=6.6 Hz, 3H), 0.75 (br s, 2H); MS (FAB, THG) 615 593 Example B18: Preparation of the compound B1.38 S COONa B1.11 0 0 2 N SO" 0O N HjS)

I

"OH

HO

B1.38 A solution of p-nitrobenzenesulfonyl chloride in toluene (1 M, 150pl) is added to a solution of amino acid B1.11(0.035 g, 0.0617 mmol) in 1 molar aqueous NaHCOs solution (315 pl).

The mixture is vigorously stirred at room temperature and, after 17 hours, further p-nitrobenzenesulfonyl chloride solution (120 pI) 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 filtration on Bio-Gel P2 (particle size 65 pm, 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: MeOH/H 2 0) and then lyophilized, resulting in the sulfonamide B1.38 (0.013 g, 27%) as a colourless fluffy powder. 'H NMR (400 MHz, D 2 0) 8 8.34 8 .05(m, 2H), 4.88 (d, 1H), 4.53 (q,J=6.5Hz, 1H), 4.38 J=7.9 Hz, 1H) 4.06 (dd, J=3.9, 8.2 Hz, 1H) 3.84-3.79 2H), 3.70 J=3.0 Hz, 1H), 3.67 (dd, J=3.9, 10.4 Hz, 1H), 3.69 3.58 (m, 3H), 3.57 3.38 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, 1H), 2.07-1.94 2H) 1.89 (hep, J=6.7 Hz, 1H), 1.61 (br s, 2H), 1.25 -1.07 4H), 1.10 J=6.6 Hz, 3H) 0.70 J=6.6 Hz, 3H), 0.63 J=6.6Hz, 3H).

The following compounds are prepared in analogy to the above examples: WO 97/01569 PCT/EP96/02785 69 ,0 2 R 3

OH

Table 1: Preparation according to Example No.

815 B 12(1) 815 812 B12 B12 B12 B12 B12 (2) Compound No. IR 3 R4FAB-MS _L

THG

B1 .20 Na

CHN

2 NHC(O)CllH 23 76 .738(M+Na) 731(M+ Na) 6 78(MiNa 81.23 Na

CH

2

NHC(O)CH

6 H5,,)H 4 7 78MH 831.24 Na

CH

2 NHC(O)C2H 4 C--ONa 740(M+H) 7(M+Na) 831.25 Na

CH

2

NHC(O)C

6 H(3 4 C OH4 672(M+H) quinamde694(M+Na) 81.26 Na CH2NHC(O)C 6

H

4 N--03N 743(M+H) 7 131.27 Na CH2NHC(O)C 6

H

4 OCH 67(M+H) 69(M+Na) B1.28 Na

CH

2

NHC(O)C

6

H

4 34 )C 68(M+) 78(M+Na) 81.29 Na CH2NHC(O)C 6

H

4

CH

3 66(M+H) 64(M+Na) 831.30 Na CH2NHC(O)C6H 4 C6H 714(M+H) 736(M+Na) WO 97/01569 PCT/EP96/02785 70 Preparation according to Example No.

B12 (3) B12 Compound No.

81.31 RI q9 B12( 5 B11 811 6 B1.33 131.34 B1.35 B1.36 81.37 J R 3 Na Na Na Na Na Na Na CH2NHC(O)C 6

H

4

CN

CH

2

NHC(O)C

10

H

7 CH2NHC(O)C6H 4 COONa CH2NHC(O)(CHOH) 2 000Na

CH

2

N[C(O)C

6

H

5

]CH

2

C

6 H5 CH2N[C(O)C 6

H

5

](CH

2 3

C

6

H

5 C H 2 N H S 2 C F 3

FAB-MS

THG

3 685(M+Na) 688(M+H) 710(M+Na) 704(M+H) 726(M+Na) 688(M.H) 710(M+Na) 728(M+H) 750(M+Na) 756(M+H) 778(M+Na) 666(M+H) using a solution of succinic anhydride in DMF as reagent using a solution of pentafluorophenyl biphenylcarboxylate in dioxane as reagent using a solution of pentafluorophenyl p-cyanobenzoate in dioxane as reagent 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 0 C until hydrolysis of the methyl ester is complete.

1 M NaOH is used in place of 1 M NaHCO 3 A solution of (+)-di-O-acetylLtartaric anhydride in dioxane is used as reagent.

6 The formation of the amide takes place in CH 2 C1 2 at 0 0 C using trifluoromethanesulfonic anhydride as reagent.

M

WO 97/01569 PCT/EP96/02785 -71 Example B19: Preparation of compound No. B1.39 OH COOBn HO F3 C C O O

O

O

O n OBn OBn HO OBOBn OBn 0 n LOBn BnO OBn BnO 13 A3 31 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 1M aqueous

KH

2

PO

4 solution (30 ml) is added, and the mixture is extracted three times with

CH

2

CI

2 and the combined organic phases are dried (Na 2 SO4), filtered and concentrated in vacuo. The oily residue (0.16 g) is purified by column chromatography on silica gel (gradient elution: toluene/ethyl acetate 80:20 to 75:25, then CH 2

CI

2 /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 BnO H OH COONa 0.047 mmol). The flask is evacuated and flushed with argon several times. It is then 0.047 mmol). The flask is evacuated and flushed with argon several times. It is then WO 97/01569 PCT/EP96/02785 -72flushed with hydrogen, and the black reaction mixture is hydrogenated under a slightly elevated pressure of hydrogen at room temperature for 17 hours and then filtered through a cellulose filter (pore size 45 gm). 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 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 g, 51 as a fluffy white solid (after lyophilization): 'H NMR (400 MHz, D 2 0) 8 4.83 J=4.0 Hz, 1H), 4.49 J=6.6 Hz, 1H), 4.33 J=7.7 Hz, 1H), 3.74 J=3.1 Hz, 1H), 3.22 (dd, J=2.6, Hz, 1H); 3C NMR (100.6 MHz, D 2 0) 5 181.5 100.2 95.7 MS (FAB, THG) 609 587 Example B20: Preparation of compound 81.40.

OH COOBn o 0 OBn ?7 OBn 0 HO O

O

0 OBn OBn

HO

SOBn nO BnO 13 A4 32 The coupling of the alcohol 13 with the triflate A4 is carried out in accordance with Example B19 (preparation of compound 31).

WO 97/01569 PCT/EP96/02785 -73- COOBn H, OH COONa OH

OH

HO H OH O B OBn n BnO OH

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): 1 H NMR (400 MHz, D 2 0) 6 4.88 J=4.1 Hz, 1H), 4.53 J=6.7 Hz, 1H), 4.39 J=7.7 Hz, 1H), 3.29 (dd, J=2.9, 9.8 Hz, 1H), 1.10 J=6.8 Hz, 3H), 0.89 J=6.8 Hz, 3H), 0.82 J=6.8 Hz, 3H).

Example B21: Preparation of compound B1.41 o 0oH 0 N o HO

HO

33 34 The hydroxypiperidine (6.0 g, 34.6 mmol, prepared from D-(-)-lyxose in accordance with Ichikawa and Igarashi [Ichikawa, Igarashi, 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, 3 6.4 0 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 1M aqueous

KH

2

PO

4 solution (150 ml) is added, and the mixture is extracted three times with CH 2 CI2. The combined organic phases are dried (Na 2

SO

4 and concentrated 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 WO 97/01569 PCT/EP96/02785 -74- HO O1 N0 O 0BN 0 O .o0 BzO OBn 34 4A molecular sieves (dried under high vacuum at 300°C, 15 g) are added to a solution of the acceptor 34 (7.66 g, 29.8 mmol) in dry CH 2

CI

2 (150 ml) under an argon atmosphere, and the suspension is stirred at room temperature for one hour. In parallel with this, a suspension of DMTST (15.4 g, 59.6 mmol) and 4A molecular sieves (15 g) in dry CH 2 CI, (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 mixture is filtered through Hyflo Super Cel® washing thoroughly with CH 2

CI

2 The filtrate is extracted by shaking with 10% aqueous NaHCO 3 solution, the aqueous phase is reextracted three times with CH 2

CI

2 and the combined organic phases are dried (Na 2 SO4), filtered and concentrated in vacuo. The remaining yellow oil (36 g) is purified by column chromatography on silica gel (gradient elution: hexane/ethyl acetate 3:1 to resulting in the glycoside (13.1 g, 54 BzO N BzO HO N O OOnn BzO BzO Bzo oBzo 36 The acetonide 35 (13.1 g, 15.94 mmol) is dissolved in dioxane (140 ml) and, at room temperature 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 chromatography on silica gel (ethyl acetate/hexane resulting in the diol 36 (11, 23 g, 90 WO 97/01569 PCT/EP96/02785 o OBz OH A SEt BzO HO O N 'O OBn

OB

I OBn BzO 36 BnO OBz BzO O zO O N O

O

BzO 0Bn OBn OBn BnO 37 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 0 C 22 g) is dried under high vacuum for 30 minutes and then, under an argon atmosphere, dry CH 2

CI

2 (62 ml) and dimethylformamide (36 ml) are added. The grey suspension is stirred at room temperature for 30 minutes. In parallel with this, a solution of ethyl 2 3 ,4-tri-O-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 CH 2

CI

2 (49 ml) is prepared under an argon atmosphere in a second round-bottomed flask and, at 0°C, a bromine solution (2.85 g Br 2 17,84 mmol) in CH 2

CI

2 (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 CH 2

CI

2 and the filtrate is washed with 10 aqueous NaHCO 3 solution. The aqueous phase is reextracted three times with CH 2

CI

2 and the combined organic phases are dried (Na 2

SO

4 filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel (ethyl acetate/hexane 35:65), with the required product 37 (7.85 g, 44 being eluted.

WO 97/01569 PCT/EP96/02785 -76- O

O

BzO OBz

N

OH HO OH OH N O BzO HO Bn iOZ 0 OBn 0 OBn OBn Bn On OBn BnO BnO Bn 37 38 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 concentrated in vacuo. The oily residue is purified by column chromatography on silica gel (gradient elution: CH2CI 2 /methanol 98:2 to 95:5), resulting in the triol 38 (1.72 g, 97 OH

O

OH O CO OBn

O

HO OBn Ph Or/°6J BnO OBn OB n BnOOBn BnO 38 39 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 concentrated in vacuo and dried under high vacuum for one hour. Then CsF (dried under high vacuum at 300 0 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-dimethoxyethane (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 1M aqueous KH 2

PO

4 solution (100 ml) is added, and the mixture is extracted three times with CH 2

CI

2 and the combined organic phases are dried (Na 2

SO

4 filtered and concentrated in vacuo. The oily residue WO 97/01569 PCT/EP96/02785 -77- (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.

COOBn

O

OB OH COONa O 0 hO h HO HO BnBn HO OH 39 B1.41 Dioxane (3.5 mi), water (1.7 ml) and glacial acetic acid (0.25 ml) are added to a mixture of Pd(OH) 2 /C :iman catalyst, Pd content 20%, 0.035 g) and the benzyl ether 39 (0.038 g, 0.034 mmoi). 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 pm). 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 jim, 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 81.41 (0.014 g, 59 as a fluffy white solid (after lyophilization): 'H NMR (500 MHz, D 2 0, 8 7.58 7.53 4H), 7.51 7.46 1H), 5.22 J=4.0 Hz, 1H), 4.57 J=7.6 Hz, 1H), 4.56 J=6.4 Hz, 1H), 4.33 (dd, J=4.2, 8.6 Hz, 1H), 4.30 (dt, J=6.3, 3.2 Hz, 1H), 3.66 (dd, 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, 14.0 Hz, 1H), 1.82 (sex, J=6.9 Hz, 2H), 1.36 J=6.4 Hz, 3H), 1.10 J=7.5 Hz, 3H); MS (FAB, NBA) 720 698 WO 97/01569 PCT/EP96/02785 -78- Example B22: Preparation of compound B1.42.

o o o F3CS- 0 OH OH OBn HCOOBn H HO N 05Q

OH

HOF Bn P A-5 J- I H OH Bn OBn

HO

0 OBn BnO Bn OBn BnO 38 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 0 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 400C and stirred at this temperature for 3 hours. Then a solution of 15% KF in 1M aqueous

KH

2 PO4 solution (100 mL), is added, and the mixture is extracted three times with CH 2 C2, and the combined organic phases are dried (Na 2 SO4), filtered and concentrated in vacuo. The oily residue (2.6 g) is purified by column chromatography on silica gel (elution: toluene/ethyl acetate 3:1, then CH2CI 2 /methanol 19:1) resulting in the ether (0.33 g, 40 as a colourless foam, and partial recovery of the precursor 38 (0.167 g, 26 COOBn OH COONa 0 Hoo HO He Bn OBn HO

OH

B1.42 WO 97/01569 PCT/EP96/02785 -79- Dioxane (1.2 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 g) 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 pm). 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 pm 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: H 2 0/methanol resulting in the target molecule B1.42 (0.009 g, 41 as a fluffy white solid (after lyophilization): 1 H NMR (400 MHz, D 2 0) 8 5.09 J=3.7 Hz, 1H), 4.58 4.46 2H), 3.94 J=2.2 Hz, 1H), 3.58 J=8.4 Hz, 1H), 3.43 (dd, J=1.8, 9.5 Hz, 1H), 1.83 J=12.2 Hz, 1H), 1.23 J=6.7 Hz, 3H), 0.95 J=7.6 Hz, 3H); 13C NMR (100.6 MHz, D 2 0) 8 183.0 101.6 98.0 MS (FAB, THG) 704 WO 97/01569 PCT/EP96/02785 Example B23: Preparation of compound 81.43.

COOBn 0

OH

rz^ o OBn BnO OBn COOBn 0 OBn BnO Morpholine (1.1 ml) and Pd(PPh 3 4 (0.071 g, 0.062 mmol) are added to a solution of the allyl carbamate 39 (0.695 g, 0.618 mmol) in tetrahydrofuran (8.5 ml). After exactly minutes the solution is concentrated and the residue is dried under high vacuum for one hour. Purification of the residue by column chromatography on silica gel (eluent: CH 2

CI

2 methanol 98:2, contains 0.3 concentrated aqueous ammonia solution) gives initially the less polar allylamine 46 (0.24 g, 36 followed by the more polar piperidine 41 (0.39 g, WO 97/01569 PCTEP96/02785 -81 COOBn O O

NH

nOB O B 'n O^ BnO COOBn

O

0 OH OH N HO OBn Bn O 7 O BnO 42 Pyridine (5 pl, 0.06 mmol) and acetic anhydride (1,8 g 1, 0.04 mmol) are added under an argon atmosphere to a solution of the piperidine derivative 41 (0.035 g, 0.0336 mmol) in dry

CH

2

CI

2 (0.6 ml) at 0°C. The solution is stirred at 0°C for 45 minutes and then washed with aqueous NaHCOs solution, and the aqueous phase is reextracted three times with

CH

2

CI

2 .The combined organic phases are dried with Na 2 SO4 filtered and concentrated in vacuo. The residue (0.05 g) is purified by column chromatography on silica gel (eluent: ethyl acetate/hexane resulting in the acetylpiperidine 42 (0.033 g, 91 as a colourless foam.

COOBn I OH OH J.

h HOI OBn Bn OBn 42 la OH

HLOH

0

OH

H OH 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 lpm). 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 WO 97/01569 PCT/EP96/02785 -82- (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 gm, 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/H 2 0 2:3 via 1:1 to resulting in the target molecule B1.43 (0.014 g, 64 as a fluffy white solid (after lyophilization): 1 H NMR (400 MHz, D 2 0) 8 7.22 7.06 5H), 4.86 1H), 1.95 3H), 0.98 J=6.7 Hz, 3H); MS (FAB, THG) 654 632 (M+2H-Na).

Example B24: Preparation of compound B1.44.

COOBn OH OH HO HO OBn 0 OBn Bn OBn 41 COOBn 0

O

H OH LPh

HO

HOn OBn BnO 43 Compound 43 is prepared from the piperidine 41 (0.02 g, 0.019 mmol) and benzoyl chloride pi, 0.021 mmol) in analogy to a method for the acetylpiperidine 42 (Example B23). The yield is 0.02 g (90 OBn BnO Bn COONa U H,0 OH OH )LPh Oh H O

N

H O

SOH

H OH

O

B1.44 The target compound B1.44 is prepared by hydrogenation of the benzyl ether 43 (0.042 g, 0.0367 mmol) and subsequent purification in analogy to the acetyl derivative B1.43. The WO 97/01569 WO 97/01569 PCT/EP96/02785 -83product results after lyophilization as a fluffy white solid. Yield: 0.015 g (57 MS (FAB, THG) 716 694 (M+2H-Na).

Example B25: Preparation of compound B1.45.

COONa

O

H O, OH OH COOMe -N 8 0 OH HO OH B1.45 The target compound B1.45 is prepared in analogy to Example 23 (preparation of compound B1.43) from the piperidine derivative 41: 1 H NMR (400 MHz, D 2 0) 8 7.28 7.13 (m, 4.95 1 4.37 4.23 2H), 3.56 3H), 3.04 1 2.84 1 2.26 (t, J=7.6 Hz, 2H), 1.08 J=7.4 Hz, 3H); MS (FAB, THG) 810 Example B26: Preparation of compound B1.46.

COOBn COOBn O Pyridine (4 0.05 mmol) and cyclohexanecarbonyl chloride (7.2 g1, 0.05 mmol) are added at 0 C to a solution of the piperidine derivative 41 (0.04 g, 0.038 mmol) in dry CH 2

CI

2 (0.7 ml). After 20 minutes, the reaction mixture is washed with 10 aqueous NaHCO 3 solution, and the aqueous phase is reextracted three times with CH 2

CI

2 The combined organic phases are dried (Na 2

SO

4 filtered and concentrated in vacuo. Purification by WO 97/01569 PCT/EP96/02785 -84column chromatography as the crude product (0.09 g) on silica gel (eluent: hexane/ethyl acetate 1:1) gives the amide 45 (0.03 g, 68 COOBn 0 COONa O SOH O H, OH

OH

HO

HO

0 OBn 0 OH BnO n HO 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 aromatic 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 irm), 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 cm), washing with deionized water. The clear filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 gm, column diameter 2.5 cm, length cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse phase chromatography (Merck RP18 silica gel, elution: methanol/HO 60:40), resulting in the target molecule B1.46 (0.012 g, 64 as a fluffy white solid (after lyophilization):

'H

NMR (400 MHz, D 2 0) 6 5.04 1H), 4.48 1H), 4.45 4.32 1H), 2.72 1H), 1.17 J=5.8 Hz, 3H); MS (FAB, THG) 728 706 (M+2H-Na).

WO 97/01569 PCT/EP96/02785 Example 827: Preparation of compound B1.47.

COOBn OH

COOH

r °7 ris O H

H

4 OH

OH

HO hO n OHO OBn 0 OH Bn JBn HO

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 g) and the benzyl ether 46 (0.042 g, 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 pm). 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. The crude product (0.014 g) is purified by gel filtration on Bio-Gel P2 (particle size 65 pm, 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/H 2 0 1:3) resulting in the target molecule B1.47 (0.009 g, 36 as a fluffy white solid (after lyophilization): 1 H NMR (400 MHz, D 2 0) 8 7.10 7.02 4H), 7.01 6.94 (m, 1H), 4.80 (br s, 1H), 4.10 J=7.0 Hz, 1H), 3.84 (dd, J=4.7, 8.5 Hz, 1H), 3.20 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, 1H), 0.87 J=7.0 Hz, 3H), 0.63 J=7.3 Hz, 3H); MS (FAB, THG) 654 632 WO 97/01569 PCT/EP96/02785 -86- Example B28: Preparation of compound B1.48.

COOBn COOBn Triethylamine (7 1I, 0.05 mmol) and n-butanesulfonyl chloride (3.7 R1, 0.029 mmol) are added at 0°C to a solution of the piperidine 41 (0.025 g, 0.024 mmol) in CH2C1 2 (0.3 ml).

After 45 minutes, the reaction mixture is washed with 10 aqueous NaHCO 3 solution, and the aqueous phase is reextracted three times with CH 2

CI

2 The combined organic phases are dried (Na 2

SO

4 filtered and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (eluent: hexane/ethyl acetate 60:40), resulting in the sulfonamide 47 (0.022 g, 79 COONa 0 OBn Bno 0 n B1.48 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 lim). 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 WO 97/01569 PCT/EP96/02785 -87acid. 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 pm, 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/H 2 0 35:65 to 45:55), resulting in the target molecule B1.48 (0.011 g, 65 as a fluffy white solid (after lyophilization): 'H NMR (400 MHz, D 2 0) 6 7.51 7.35 5H), 5.15 J=3.4 Hz, 1H), 4.54 J=6.2 Hz, 1H), 4.51 J=8.0 Hz, 1H), 4.03 (dd, J=2.8, 10.4 Hz, 1H), 3.59 J=8.9 Hz, 1H), 3.23 (dd, J=4.8, 13.4 Hz, 1H), 3.05 (dd, J=8.6, 13.4 Hz, 1H), 1.84 (pen, J=7.6 Hz, 2H), 1.54 (sex, J=7.3 Hz, 2H), 1.27 J=6.6 Hz, 3H), 1.02 J=7.5 Hz, 3H); MS (FAB, THG) 732 Example B29: Preparation of compound B1.49.

COONa 0O H OH OH

S

0 0 HO B1.49 0

OH

HO

The target compound B1.49 is prepared in analogy to Example B28 (preparation of compound B1.48) starting from the piperidine derivative 41 and p-toluenesulfonyl chloride:

'H

NMR (400 MHz, D 2 0) 8 7.56 J=7.2 Hz, 2H), 7.33 J=7.2 Hz, 2H), 7.28 7.11 4.81 J=3.4 Hz, 1H), 4.22 J=7,9 Hz, 1H), 3.75 J=2.4 Hz, 1H), 3.65 (dd, J=2.4, 10.2 Hz, 1H), 3.41 J=5.7 Hz, 1H), 3.32 J=8.7 Hz, 1H), 3.13 (dd, J=2.5, 9.3 Hz, 1H), 3.00 (dd, J=4.0, 13.6 Hz, 1H), 2.81 (dd, J=8.9, 13.6 Hz, 1H), 2.67 (brs, 1H), 2.29 3H), 0.95 J=7.1 Hz, 3H); MS (FAB, THG) 788 766 WO 97/01569 PCT/EP96/02785 -88- Example B30: Preparation of compound B1.50.

COOBn O O H OH COONa O O O H OH N n -C 4H 9 H OH OH N n-C4H9 HO

HO

HO

0O OBn

OH

Bn on HO OH 47 B1.50 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 reaction mixture is filtered through a cellulose filter (pore size 45 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 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 gm, 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/H 2 0 40:60 to 50:50), resulting in the target molecule B1.50 (0.021 g, 82 as a fluffy white solid (after lyophilization).

'H

NMR (400 MHz, D 2 0) 5 4.97 J=3.7 Hz, 1H), 4.41 J=7.7 Hz, 1 4.36 J=6.7 Hz, 1H), 3.81 J=2.6 Hz, 1H), 3.76 (dd, J=2.4, 7.3 Hz, 1H), 3.55 (dd, J=4.4, 7.2 Hz, 1H), 3.30 (dd, J=2.7, 9.7 Hz, 1H), 1.34 (sex, J=7.4 Hz, 2H), 1.10 J=6.7 Hz, 3H), 0.81 J=7.5 Hz, 3H); MS (FAB, THG) 738 716 (M+2H-Na).

WO 97/01569 PCT/EP96/02785 -89- ExamLe B31: Preparation of compound 81.51.

COOBn COOBn 49 Morpholine (0.37 ml) and Pd(PPh 3 4 (0.025 g, 0.021 mmol) are added to a solution of the allyl carbamate 40 (0.24 g, 0.212 mmol) in tetrahydrofuran (2.9 ml). After exactly 15 minutes, the solution is concentrated and the residue is dried under high vacuum for one hour.

Purification of the residue (0.38 g) by column chromatography on silica gel (eluent:

CH

2

C

2 methanol 19:1, contains 0.3 concentrated aqueous ammonia solution) gives the piperidine derivative 49 (0.17 g, 76 COOBn COOBn Phenyl isocyanate (4.6 p1, 0.042 mmol) and diisopropylethylamine (8.5 pl, 0.05 mmol) are added at 0°C to a solution of the piperidine derivative 49 (0.04 g, 0.038 mmol) in CH 2

CI

2 (0.6 ml). After 90 minutes, the reaction mixture is washed with 1 M aqueous

KH

2

PO

4 solution and the aqueous phase is reextracted three times with CH 2

CI

2 The combined organic phases are dried (Na 2 SO4), 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 WO 97/01569 PCT/EP96/02785 COOBn OH COONa HJ OH Ph H OH

H

B H H/ Bn 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. 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 pm). 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 pm, 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/H 2 0 resulting in the target molecule B1.51 (0.018 g, 80 as a fluffy white solid (after lyophilization): 'H NMR (400 MHz, D 2 0) 8 7.14 J=7.9 Hz, 2H), 7.02 J=8.2 Hz, 2H), 6.95 J=7.7 Hz, 1H), 4.87 J=4.0 Hz, 1H), 4.30 J=7.4 Hz, 1H), 4.23 J=6.6 Hz, 1H), 3.66 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 J=6.6 Hz, 3H); MS (FAB, THG) 737 715 (M+2H-Na).

WO 97/01569 PCT/EP96/02785 91- ExaMi~Ie B32.- Preparation of compound 891.52.

COOBn COOBn 131.52 The piperidine derivative 49 is converted in analogy to Example 828 (preparation of compound 831.48) using phenylmethanesulfonyl chloride as reagent into the target compound 131.52: 'H NMR (400 MHz, D 2 0) 8 7.50 (in, 5H), 5.02 J=3.5 Hz, 1 4.61 J=1 3.7 Hz, 1 4.54 J=1 3.7 Hz, 1 4.32 J=8.0 Hz, 1 3.62 J=6.0 Hz, 1 3.52 (dd, J=7.7, 8.4 Hz, 1 3.36 (dd, J=3.2, 9.6 Hz, 1 3.22 (br d, J=1 2.6 Hz, 1 1. 17 J=6.5 Hz, 3H); MS (FAB, THG) 772 750 (M+2H-Na).

Examnle B33: Preparation of compound 831.53.

COOBn

COOH

831.53 WO 97/01569 PCT/EP96/02785 -92- 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. 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 gm). 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 pm, 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 lyophilization): 1 H NMR (400 MHz, D 2 0) 8 5.04 J=4.2 Hz, 1H), 4.43 J=7.6 Hz, 1H), 4.27 2H), 4.20 J=6.5 Hz, 1H), 4.02 (dd, J=2.6, 6.6 Hz, 1H), 3.51 (dd, J=7.8, 9.5 Hz, 1H), 1.12 J=6.2 Hz, 3H); MS (FAB, THG) 618 596 ExamDple B34 Preparation of compound B1.54.

COOH

H, OH OH COONa O 0 Oo NH H H

OH

0 OH 0

OOH

HO OH

HO

B1.53 B1.54 A 1 M solution of 2-(1 -naphthyl)ethanesulfonyl chloride in toluene (46 il) is added at room temperature to a solution of the piperidine derivative B1.53 (0.025 g, 0.042 mmol) in 1M aqueous NaHCO 3 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 gm, column diameter 2.5 cm, length cm, eluent: water, flow rate 0.45 ml/min, detection at 215 nm) and subsequent reverse WO 97/01569 PCT/EP96/02785 -93phase chromatography (Merck RP18 silica gel, elution: methanol/H20 resulting in the target molecule B1.54 (0.011 g, 31 as a fluffy white solid (after lyophilization): 'H NMR (400 MHz, D 2 0) 5 7.72 J=8.8 Hz, 1H), 7.54 J=8.8 Hz, 1H), 7.44 J=8.6 Hz, 1H), 7.28 J=7.2 Hz, 1H), 7.22 J=7.2 Hz, 1H), 7.14 J=7.2 Hz, 1H), 7.08 J=8.7 Hz, 1H), 4.91 J=4.1 Hz, 1H), 4.20 J=7.0 Hz, 1H), 3.99 (br s, 1H), 3.90 (br s, 1H), 1.09 (d, J=6.3 Hz, 3H); MS (FAB, THG) 858 836 Examle B35: Preparation of compound B1.55.

COOH

H OH OH COONa OH HO O N H O ON

SHO

OHO

H OH 0

OH

HOH

OH

B1.53 B1.55 A 0.5 M solution of acetic anhydride in toluene is added in small portions (50 to 100 pa) at room temperature to a solution of the piperidine derivative B1.53 (0.035 g, 0.059 mmol) in 1 M aqueous NaHCO 3 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/NH 4 OH 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 4m, column diameter 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/H 2 0 3:7), resulting in the target molecule B1.55 (0.026 g, 67 as a fluffy white solid (after lyophilization): 'H NMR (400 MHz, D 2 0) 5 5.01 J=4.2 Hz, 0.5H), 4.99 J=4.2 Hz, 0.5H), 4.44 (d, J=7.3 Hz, 1H), 4.32 J=6.6 Hz, 0.5H), 3.14 (dd, J=8.0, 12.9 Hz, 0.5H), 2.10 2.08 1.5H), 1.13 J=6.6 Hz, 3H).

WO 97/01569 PCT/EP96/02785 -94- Example B36: Preparation of compound B1.56.

COOH

HI O H OH COONa 0 OH SOH-/ -N H O OHO OH ONa

HOH

S OH HO H OH

HO

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 pa) at room temperature to a solution of the piperidine derivative B1.53 (0.03 g, 0.05 mmol) in 1 M aqueous NaOH solution (0.15 ml) until all the precursor is consumed (test by thin-layer chromatography: silica gel TLC plates, mobile phase: n-butanol/ water/acetone/glacial acetic acid/NH 4 OH 70:60:50:18:1.5). 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 400C 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 pm, 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/

H

2 0 resulting in the target molecule B1.56 (0.020 g, 52 as a fluffy white solid (after lyophilization): MS (FAB, THG) 794 772 750 (M+2H-Na).

Examle B37: Preparation of compound B1.57.

B1.53 B1.57 WO 97/01569 PCT/EP96/02785 N,N-Diisopropylcarbodiimide (11.7 1i, 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-dimethylformamide (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 pm) and then 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 filtrate is concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 Am, column diameter 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/H 2 0 1:9), resulting in the target molecule B1.57 (0.007 g, 33 as a fluffy white solid (after lyophilization): 'H NMR (400 MHz, D 2 0) 85.8 (br s, 1H), 4.94 1H), 2.55 1H), 2.10 1H), 1.07 J=6.0 Hz, 3H); MS (FAB, THG) 796 774 Example B38; Preparation of compound B1.58.

0O O 2 N

O

BzO OBz OH 0 0 Bz 0 on OBz oo N -Oo z O nz7 Bn OBn OBn BBn BnOo 37 52 N,N-Dimethylaminopyridine (1.03 g, 8.44 mmol) and p-nitrobenzenesulfonyl chloride (1.65 g, 7.44 mmol) are added at room temperature to a solution of the alcohol 37 (6.11 g, 5.1 mmol) in CH 2

CI

2 (35 ml). After 52 hours, the reaction mixture is washed with 10 aqueous NaHCO 3 solution, and the aqueous phase is reextracted three times with

CH

2

CI

2 .The combined organic phases are dried (Na 2

SO

4 filtered and concentrated in WO 97/01569 WO 97/01569 PCT/EP96/02785 -96vacuo. 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 0 2 N 0 O o BzO OBz Nb 0 Bz OBn I nOBn Bn52 52 OBz BzO 0 O n

N

3 :0 OBn BnO 53 A solution of the nosylate 52 (7.78 g, 5.62 mmol) and dry LiN 3 (0.99 g, 20.21 mmol) in dry N,N-dimethylformamide (50 ml) is heated to 50-60 0 C under an argon atmosphere. After 16 hours, the solvent is removed under high vacuum, and the residue is taken up in CH 2

CI

2 and washed with 10 aqueous NaHCO 3 solution. The aqueous phase is extracted three times with CH 2

CI

2 and the combined organic phases are dried (Na 2 SO4), filtered and concentrated 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).

0 0 0 53 54 54 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 hours. The pH of the reaction mixture is then made neutral by adding strongly acidic ion exchanger (Amberlyst15, H+ Form), the suspension is filtered, and the filtrate is concentra- WO 97/01569 PCT/EP96/02785 -97ted in vacuo. The crude product (4.5 g) is purified by column chromatography on silica gel (eluent: CH2CI 2 /methanol 19:1) to give the triol 54 (2.89 g, 92 0oo

F

3 C O OB n CO 2 OH OBn co 2 Bn OHO HO 0N A- H HO O O

N

H OB-n OO OBn 0 0dnN oOBn Bn OBn Bn O 54 A suspension of 54 (2.89 g, 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 concentrated in vacuo and dried under high vacuum for one hour. Then CsF (dried under high vacuum at 3000C 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 (6.3 g, 15.97 mmol) in dry 1, 2 -dimethoxyethane (50 ml). The reaction mixture is heated to 35 to 400C and stirred at this temperature for 3 hours. The mixture is then washed with a solution of 15% KF in 1M aqueous

KH

2

PO

4 (150 ml) and the aqueous phase is extracted three times with CH 2

CI

2 and the combined organic phases are dried (Na 2 SO4), 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 CH2C2/methanol 19:1 to recover the precursor), resulting in the ether 55 (1.94 g, 53 as a colourless foam and partial recovery of the precursor (1.1 g, 26 0 2 n CO ,Bn 0 WO 97/01569 PCT/EP96/02785 -98- Morpholine (215 41) and Pd(PPh 3 4 (0.015 g, 0.013 mmol) are added under an argon atmosphere 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: CH2CI 2 /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 CH 2 Cl2 (1.7 ml), the solution is cooled to 0°C, and triethylamine (43 l1, 0.31 mmol) and n-butanesulfonyl chloride (18 1g, 0.14 mmol) are added. After 15 minutes, the reaction mixture is warmed to room temperature and washed with 10 aqueous NaHCO 3 solution. The aqueous phase is reextracted three times with CH 2

CI

2 and the organic phases are combined, dried (Na 2 SO4), 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 OH 00 CO Na 0 0 H OO- "n-C4H9 O N "'n-C4H 0"OBn O H \/Me BnC OBn HO OOMe 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 elevated pressure of hydrogen at room temperature for 12 hours and then filtered through a cellulose filter (pore size 45 prm). 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 g, lyophilized) is taken up in 1 M aqueous NaHCO 3 solution (0.3 ml) and over the course of 5 hours, several small portions (30 bis 50 p1) 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/ WO 97/01569 PCT/EP96/02785 -99glacial acetic acid/NH 4 OH 70:60:50:18:1.5) indicates complete conversion of the intermediate. The pH of the solution is kept basic during this reaction by adding several portions of solid NaHCO 3 (about 0.025 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 gm, 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/HO 65:35), resulting in the target molecule B1.58 (0.008 g, 39 as a fluffy white solid (after lyophilization): 1 H NMR (400 MHz, D 2 0) 6 7.41 (br d, J=8.3 Hz, 1H), 7.32 (br s, 1H), 7.04 J=8.3 Hz, 1H), 5.05 J=3.9 Hz, 1H), 4.51 J=7.8 Hz, 1H), 4.14 J=6.7 Hz, 1H), 4.09 J=4.1 Hz, 1H), 3.82 6H), 3.33 (dd, J=3.1, 9.6 Hz, 1H), 1.13 J=6.3 Hz, 3H), 0.68 J=7.6 Hz, 3H); MS (FAB, THG) 923 901 879 (M+2H-Na).

Examle B39- Preparation of compound B1.59.

CO2Bn 0 0 OH CONa O O O' n-C 4

H

9 N -n-C 4

H

9 HO

N

3 HO )H 2V 0 OBn 0

OH

BnO n H OH 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 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. The crude amine (0.074 g) is taken up in a little water and purified by gel filtration on Bio-Gel P2 (particle size 65 igm, 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 WO 97/01569 PCT/EP96/02785 100- RP18 silica gel, elution: methanol/H 2 0 resulting in the target molecule B1.59 (0.052 g, 73 as a fluffy white solid (after lyophilization): 'H NMR (400 MHz, D 2 0) 6 5.00 J=3.6 Hz, 1H), 4.41 J=7,7 Hz, 1H), 4.28 J=6.5 Hz, 1H), 3.83 J=3.1 Hz, 1H), 3.79 (dd, J=3.1, 9.7 Hz, 1H), 3.32 (dd, J=3.2, 9.6 Hz, 1H), 1.12 J=6.1 Hz, 3H), 0.83 J=7.9 Hz, 3H); MS (FAB, THG) 737 713 Example B40: Preparation of compound B1.60.

CO 2 Na OH CO Na 0 0 O0 "n-C4H 9 0OO N nC4H, OHO H o----O0O 0 HN HOH

OH

H OH HO H B1.59 B1.60 The amine B1.59 (0.027 g, 0.038 mmol) is taken up in 1 M aqueous NaHCO 3 solution (0.35 ml) and, over the course of 4 hours, several small portions (30 to 50 gL) of an approx.

M solution of benzoyl chloride in toluene are added until a test by thin-layer chromatography (silica gel TLC plates, mobile phase: n-butanol/water/acetone/glacial acetic acid/ 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 NaHCO 3 (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 pm, column diameter 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/H 2 0 1:1), resulting in the target molecule B1.60 (0.027 g, 85 as a fluffy white solid (after lyophilization): 'H NMR (400 MHz, D 2 0) 6 7.72 J=8.0 Hz, 2H), 7.52 J=6.9 Hz, 1H), 7.44 Hz, 2H), 5.05 J=3.8 Hz, 1H), 4.50 J=8.1 Hz, 1H), 4.17 J=6.6 Hz, 1H), 3.92 (br d, J=10.4 Hz, 1H), 3.85 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 J=7,1 Hz, 3H), 0.70 J=8.2 Hz, 3H); MS (FAB, THG) 863 841

E

WO 97/01569 PCT/EP96/02785 -101- Example B41: Preparation of compound 81.61.

Co 2 Na 0 0 131.59 B1.61 The carbamate B1.61 is prepared starting from the amine B1.59 (0.027 g, 0.038 mmol) using benzyl chioroformate as reagent in analogy to Example B40 (Preparation of compound 81.60). The yield is 0.007 g (21 'H NMR (400 MHz, D 2 0) 8 7.31 (in, 5H), 5.06 J=1 2.0 Hz, 1 4.97 J=1 2.0 Hz, 1 4.96 J=4.0 Hz, 1 4.42 J=7.7 Hz, 1 H), 4.19 J=6.6 Hz, 1 3.96 (br s, 1 3.80 J=2.9 Hz, 1 3.50 (dd, J=8.2, 9.4 Hz, 1 H), 3.29 (dd, J=2.9, 9.7 Hz, 1 3.20 (br d, J=1 2.2 Hz, 1 1.06 J=6.5 Hz, 3H), 0.77 (t, Hz, 3H); MS (FAB, THG) 871 849 (M+2H-Na).

The following compounds are prepared in analogy to the above examples: C00R 3

RHA

Table 1la: Compound

R

3

JRHA

B1 .64 1Na 1C(O)-3,4-(OH) 2

-C

6 Hs B1.65 JNa

C(O)CH(C

6

H

5 2 B1.68 Na jC(O)-3,4-(OCH 2

C

6

H)

2

.C

6

H

WO 97/01569 PCT/EP96/02785 -102 Compound No. _R 3 _RHA 81.70 NaC(O)-3,4,5-(OH) 3 6

H

6 81.72 Na C(O)[CH(OH)1 2 C(O)ONa B1.73 Na

C(O)CH

3 B1 .77 Na

S(O)

2

(CH

2 2

C

10

H

7 81.78 H

H

B1.80 Na

S(O)

2

CH

2

C

6

H

B1.81 Na

C(O)NHC

6

H

B1.82 Na C(O)0 6

H

11 B1.83 Na

S(O)

2

(CH

2 3

CH

3 81.84 Na

C(O)O(CH

2 2

CH

3 CooR 3 f-II, OH

H

00 Table 1la': OO(0)HRC

OH

OH

HO

Compound No. JR 3 J RHJ

RCA

81.62 Na

C(O)CH

3 NHC(O)C 10

H

7 81.63 Na

C(O)CH

3 NHC(O)00H 2 6

H

Bi .66 Na

C(O)CH

3 NHC(O)CH 2

C

6

H

81.67 Na

C(O)CH

3 NHC(O)CH 2 00 6

H

81.69 Na

C(O)CH

3 NHC(O)CH 2

NHC(O)OCH

2

C

6 Hs 81.71 Na

C(O)O(CH

2 2

CH

3

NHS(O)

2

CH

2 CrBH 81.74 Na S(0) 2

(CH

2 3

CH

3 NHC(O)OCH 2

C

6

H

81.75 Na

S(O)

2

(CH

2 3

CH

3 NHC(O)C 6

H

81.76 H S(0) 2

(CH

2 3

CH

3 NH 2 81.79 Na

S(O)

2

(CH

2 3 0H 3 NHC(O)-3,4-(OCH 3 2

C

6

H

3 WO 97/01569 PCT/EP96/0278 -103-

COOR

3 o O O Table 1b: OH

OH

HO

Compound No. R3

RHA

B1.85 Na S(0) 2 -4-CH 3

-C

6

H

4 B1.86 Na

C(O)(CH

2 8

C(O)OCH

3 B1.87 Na S(0) 2

(CH

2 3

CH

3 B1.88 H

(CH

2 2

CH

3 B1.89 Na

C(O)C

6 Hs B1.90 Na

C(O)CH

3 B1.91 Na

C(O)O(CH

2 2

CH

3 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 CaCI 2 pH 7.4 (Tris- Ca" buffer). Thus the plating solution is dispensed as 100 pl/well of 2 pg/ml E-chimera.

Row 12 is left blank with only buffer. Plate 1 is incubated covered at 370C for 2 hours. After incubation 100 pl/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 The rows are serially diluted up to row 9. Rows 10, 11, and 12 are just buffer. Final volume is 60 pl/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 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 pl/well of 1 ng/pl of polySLeaSA-HRP conjugate in 1 BSA in Tris-Ca" are added to all wells except row 11 in Plate 2. Plate 1 is WO 97/01569 PCT/EP96/02785 104washed four times with Tris-Ca" in the automatic plate washer. 100 pl/well are transferred from Plate 2 to Plate 1 starting from lowest concentration of compound. Plate 2 is discarded. 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 pl/well of Substrate [Mix 3,3', 5 ,5'-tetramethylbenzidine reagent and H 2 0 2 at 1:1 ratio] are added with an 8 channel pipettor from right to left. The plate is incubated at room temperature for 2 minutes. The reaction is stopped by adding 100pl/well of 1M H 3 PO4 using the 8 channel pipettor from right to left. Absorbance of light at 450nm is measured in a microtiter plate reader.

Control compound

A:

Control compound

B:

ICso 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 The relative ICso is calculated by determining the ratio of the IC50 of an internal control compound to the IC 50 of the test compound.

WO 97/01569 PCTIEP96/02785 -105 In the following tables RIO 50 means Ic,(etCompound) Ic,Cotl compound

A)

COCR

H o 2

OH

Table HO OH HOC 0

H

O H O H Comp. No.

R

3 R 4 RIC 50 B1.1 Na -CH 2

C

6

H

5 0.35 B1.2 Na 0H 2

C

6

H

11 0.08 B1.3 Na -OH 2

NHC(O)C

6

H

5 1.11 B1.4 Na -CH2NHC(O)(CH 2 2 0 6

H

5 1.85 Na -OH 2

NHO(O)(CH

2 3 0H 1.23 B1.6 H -OH 2

NH

2 0.96 B1.7 H -CH 2

NHOH

2

(CH)

2 0 6 Hs 1.15 81.8 Na -CH2N[O(O)C 6 H51CH 2 (oH) 2

C

6

H

5 0.90 B1.9 H CH 2

NHOH

2

O

6

H

5 0.61 B1.10 Na -OH 2

N(CH

2

C

6

H

5 2 0.60 B1.1 1 H -OH 2

NH[OH

2 CH(0H 3 2 0.74 81.12 H -CH 2

N[OH

2

OH(CH

3 2 2 0.32 B1 .13 Na -CH2N[C(O)0 6

H

5

][CH

2

OH(CH

3 2 1 0.21 B1 .14 Na -OH 2 NH[S0 2

(C

6

H

4 )N0 2 0.12 B1.15 Na -OH 2

NHSO

2

O

6

H

4

CH

3 0.13 81.16 Na -OH 2

NHO(O)CF

3 0.64 131.17 Na -CH 2

NHO(O)C

6

H

1 1.33 B1.18 Na -0H 2

CH

2 0 6

H

5 0.14 B1.19 Na -0H 2

CH

2 0 6

H

11 0.17 WO 97/01569 PCTIEP96/02785 -106- Comp. No.

R

3 R

IC

5 o B1.20 Na -CH 2

NHC(O)C

1

H

23 1.76 B1.21 Na -CH 2

NHC(O)CH(C

6

HS)

2 0.71 81.22 Na -CH2NHC(O)C 2

H

4

CO

2 Na 1.05 81.23 Na -CH 2

NHC(O)C

6 ,3,4,5)OH 4

H

7 0.79 81.24 Na CH2NHC(O)C6H 4 SO3Na 0.93 81.25 Na -CH 2

NHC(O)C

6

H

4 CI 1.29 81.26 Na -CH 2

NHC(O)C

6

H

4 N0 2 1.21 81.27 Na -CH 2

NHC(O)C

6

H

4 OCH3 1.15 81.28 Na -CH 2

NHC(O)C

6

H

4 (3,4)01 2 2.04 B1 .29 Na -CH 2

NHC(O)C

6

H

4

CH

3 1.30 81.30 Na -CH 2

NHC(O)C

6

H

4 0 6

H

5 1.65 81.31 Na -CH 2

NHC(O)C

6

H

4 CN 1.04 81.32 Na -CH 2 NHC(O)0 10

H

7 1.44 81.9 Na -CH 2

NHCH

2

C

6

H

5 0.61 81.33 Na -CH2NHC(O)C 6

H

4 COONa 0.96 81.34 Na -CH2NHC(O)(CHOH) 2 000Na 0.78 81.35 Na -CH2N[C(O)C6H 5

]CH

2

C

6

H

5 0.44 81.36 Na -CH2N[C(O)C 6

H

5 1(CH 2 3

C

6

H

5 0.57 81.37 Na -CH 2

NHSO

2

CF

3 0.26 81.38 Na -CH2N[CH 2

CH(CH

3 )]S0 2

C

6

H

4 N0, 0.32 107- Table 2a: Compound No. RIOC 50 Compound No. RIC 5

O

131.62 0.949 131.77 0.618 131.64 0.287 B1.78 0.304 131.65 0.862 131.79 0.196 131.66 1.112 131.80 0.203 131.67 0.564 B1.81 0.216 131.68 0.696 131.82 0.1951 B1.69 2.661 131.83 0.176 131.70 0.199 131.84 0.169 61.71 0.414 131.85 1.28 B1.72 0.186 131.86 2.733 831.73 0.249 131.87 0.520 B1.74 0.134 131.88 1.257 831.75 0.102 B1.89 0.696 131.76 0.451 131.90 0.569 131.63 0.087 S

S.

5 5 5O**

S

5* OS S

S.

S 0

SSS

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (12)

1. 02-Cl 2 alkenyl, CI -C, 2 alkoxy, C3-C 12 cycloalkyl, 0
2. 3-Cl2cycloalkenyl, 02-Cl iheterocycloalkyl, C 2 -C 11 heterocycloalkenyl,
3. 06-Cloaryl, C6-Cloaryloxy, C5-Cgheteroaryl,
4. 07-CIl aralkyl, C7Claralkyloxy, C6-Cloheteroaralkyl, C8-Cl iaralkenyl, C7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where is hydrogen, My, CI -C 12 alkyl, 0 2-Cl2alkenyl, C3-C12cycloalkyl, 02-Cl iheterocycloalkyl, C6-Cloaryi, C5-Cgheteroaryl, 07-Cl 1 aralkyl or C6-Cloheteroaralkyl, R1 4 is hydrogen, CI-C 12 alkyl, 02-Cl 2 alkenyl, C3-Ol 2 cycloalkYl, 02-Cl iheterocycloalkyl, O6-Cloaryl, aryl, C7-Cliaralkyl or C6-Cloheteroaralkyl, and R. 2 and R2a are hydrogen, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, 0 3-Cl2cycloalkenyl, 02-Cl iheterocycloalkyl, 02-Cl i-hetero- cycloalkenyl, C6-Cloaryl, C5-Cgheteroaryl, 07-Cl 1 aralkyl, O6-Cloheteroaralkyl, 0a3Cl i-aralkenyl or C7-Oloheteroaralkenyl, 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. WO 97/01569 PCT/EP96/o2785 -109- 2. A compound according to claim 1, wherein NH 2 primary amino, secondary amino, carbamide, carbamate, carbhydrazide, sulfon- amide, sulfonhydrazide and aminocarbonylamide is a representative selected from the group of RBC(O)(NH)pN(R 9 -C(O)(NH)pNR 8 R 9 R8OC(O)(NH)pN(R 9 R8R4oNC(O)(NH)pN(R 9 -OC(O)(NH)pNR 8 R 9 -N(R4o)C(O)(NH)pNR 8 R 9 R8S(O) 2 (NH)pN(Rg)-; -S(O) 2 (NH)pNR 8 R 9 RB3R 4 oNS(O) 2 N(R 9 or -NR 4 0S(O) 2 NR8R 9 in which R 8 R 9 and R 40 are, independently of one another, hydrogen, OH, C 1 -C 12 alkyl, C1-Cl2alkenyl, C3-Cl2cycloalkyl, 0 3 -C 1 2cycloalkenyl, 02-011 heterocycloalkyl, 02-011 heterocycloalkenyl, C6-Cloaryl, Cs-Cgheteroaryl, C7-Cl 6 aralkyl, C8-Cl 6 aralkenyl with C2-C6alkenylene and C6,-Cloaryl, 0 6-Clsheteroaralkenyl, or di-C6-Cloaryl-C 1 -C 6 -alkyl, or R 8 ,R 9 -N in which R 8 and R 9 are, independently of one another, hydrogen, OH, SONMY, OSO 3 MY, Cl-Cl 2 alkyl, C3-Cl 2 cycloalkyl, 02-011 heterocycloalkyl, C 6 -Cioaryl, C5-Cgheteroaryl, C7-C1 1 aralkyl, C6- Cloheteroaralkyl, C8-Cl6aralkenyl with C2-C6alkenylene and Ce-Cloaryl, or di-0 6 -Cliaryl-o 1 C 6 -alkyl, which are unsubstituted or substituted by one or more substituents; or R 8 and R 9 or R 8 and R 9 or R 8 and R 40 in the case of -NR 8 Rq or -NR 8 .R 9 or R 8 R 40 N- together are tetra- methylene, pentamethylene, -(CH 2 2 -O-(CH 2 2 -(CH 2 2 -S-(CH 2 2 or -(CH 2 2 -NR 7 -(0H 2 2 and R 7 is H, Cl-C 6 alkyl, C7-Cllaralkyl, C(O)R.1 2 or sulfonyl; and sulfonyl is a representative of the formula RIO-S0 2 in which R 1 0 is Cl-Cl 2 alkyl, C3-Cl2cycloalkyl, 02-Cl iheterocycloalkyl, C6-Cloaryl, O5-Cgheteroaryl, C7-Cl iaralkyl or C6-Cloheteroaralkyl, which are unsubstituted or substituted by one or more substituents; wherein the substituents are selected from the group consisting of OH, halogen, C(O)OR,, OC(O)R", C(O)R.1 2 nitro, NH 2 cyano, SO 3 MY, OSO 3 NR 20 SO 3 My, CI-C 12 alkyl, C2-Cl 2 alkenyl, CI-Cl 2 alkoxy, C3-Cl2cycloalkyl, C3-Cl2cycloalkenyl, 02-01 iheterocycloalkyl, C2- C1, heterocycloalkenyl, C6-Cloaryl, C6-Cloaryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, 07- Cil 1 aralkyl, C6-Cloheteroaralkyl, C8-Cl iaralkenyl, C7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carb- hydrazide, carbohydroxamic acid and aminocarbonylamide, where is hydrogen, MY, CI-Cl 2 alkyl, C2-Cl2alkenyl, C3-Cl2cycloalkyl, 02-Cl iheterocycloalkyl, C6-Cloaryl, Os-Oghetero- aryl, Cr-Ciiaralkyl or C6-Cloheteroaralkyl, R1 4 is hydrogen, Cl-C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl2cycloalkyl, C2-Cl iheterocycloalkyl, C6-C 10 aryI, C5-Cgheteroaryl, C7-Cl 1 aralkyl or C6-Cloheteroaralkyl, and R, 2 and R 2 o are hydrogen, CI-Cl 2 alkyl, C2-Cl2alkenyl, C3-Cl 2 cycIO- alkyl, C3-Cl2cycloalkenyl, 02-011 heterocycloalkyl, C2-Cl 1-heterocycloalkenyl, C6-Cloaryl, Os-Coheteroaryl, C7-C~ 1 aralkyl, C6-Cloheteroaralkyl, C8-Cl, -aralkenyl or C7-Cloheteroar. alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo- WO 97/01569 PCTIEP96/02785 -110 alkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroarakyl, aralkenyl and hetero- aralkenyl 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 O2-C20-alkylene, -alkenylene, C3-C12-CYCloalkylene, -cycloalkenylene, 03-Cil -heterocycloalkylene or -hetero- cycloalkenylene with hetero atoms selected from the group of and 4. A compound according to claim 1, wherein X is substituted by a substituent selected from the group consisting of OH, halogen, C(O)ORsj, OC(O)RS 4 C(O)RS 2 nitro, NH 2 cyano, SO 3 My, OSO 3 My, NR 20 SO 3 My, Ol-Ol 2 alkyl, O2-Cl 2 alkenyl, CI-C 1 2 alkoxy, O3-Ol2cycloalkyl, O3-Ol2cycloalkenyl, 02-Cl iheterocycloalkyl, 02-011 heterocycloalkenyl, C6-Cloaryl, O6-Cloaryl- oxy, C5-Cgheteroaryl, O5-Cgheteroaryloxy, 07-Cliaralkyl, C7-Cllaralkyloxy, C6-Cloheteroar. alkyl, Oa-Cliaralkenyl, O7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sul- fonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and amidocarbonylamide, where R 51 is hydrogen, My, Oi-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-C12cycloalkyl, 02-01 iheterocycloalkyl, C6-Cloaryl, C5-Cgheteroaryl, C 7 -0 11 aralkyl or C6-Cloheteroaralkyl, R,1 4 is hydrogen, Ol-C1 2 alkyl, O2-Cl2alkenyl, C3-C12cycloalkyl, 02-Cl iheterocycloalkyl, C6-Cloaryl, C5-Cgheteroaryl, 07-Cl 1 aralkyl or C6-Cloheteroaralkyl, and R, 2 and R 2 o are hydrogen, 0I-0 12 alkyl, C2-Cl2alkenyl, C3-Cl2cycloalkyl, Ca-Ol2cycloalkenyl, 02-Cl iheterocycloalkyl, 02-Cl 1-heterocycloalkenyl, O6-Oloaryl, Os-Ogheteroaryl, 07-Cl 1 aralkyl, C6-Cioheteroaralkyl, Oa-Cli-aralkenyl or O7-Cloheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, hete roaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstltuted 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 compound as claimed in claim 1, wherein X is the residue of a 1 ,2-diol corresponding to formula 11 WO 97/01569 PCTIEP96/02785 -H1 HH H R 6 R H H in which R 5 and R 6 are, independently of one another, hydrogen, CI-Cl 2 alkyl, C3-Cl2cycloalkyl, 1 Clheterocycloalkyl, Cr,-Cloaryl, C5-Cgheteroaryl, 07-Cl 1 aralkyl or C6-Cloheteroaralkyl; or R 5 and R6 are, together with the -OH-OH- group, C3-Cl2CYCloalkylene, C3-C12-CYCloalken- ylene, C2-Cllheterocycloalkylene and C3-Cllheterocycloalkenylene with hetero atoms selected from the group and 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)OR, 1 OC(O)RI 4 C(O)RS 2 nitro, NH 2 cyano, SO 3 MY, OSO 3 My, NR 20 SO 3 M~j Cl-C 12 alkyl, C2-Cl2alkenyl, Ci-Cl 2 alkoxy, C3-Cl2cycloalkyl, C3-Cl2cycloalkenyl, 02-Cl 1 hetero- cycloalkyl, 02-011 heterocycloalkenyl, C6-ClOaryl, C6-Cloaryloxy, C7-Cl 1 aralkyl, C7-Cl iaralkyloxy, C6-Cioheteroaralkyl, C8-0l aralkenyl, 07- Cioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamnate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonyl. amide, where R~j is hydrogen, My, Cl-C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl2cycloalkyl, C2-Cllhetero- cycloalkyl, 0 6-Cloaryl, 0 5-Cgheteroaryl, 0 7-Cllaralkyl or C6-Cloheteroaralkyl, R, 4 is hydrogen, C, -Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Cl2CYCloalkyl, C2-Cliheterocycloalkyl, C6-Cloaryl, Cs-Cgheteroaryl, 07-CllaralkyI or C6-Oloheteroaralkyl, and R,, 2 and R 20 are hydrogen, Cj- Ol2alkyl, C2-Cl 2 alkenyl, C3-C1 2 CYCloalkyl, O3-C12cycloalkenyl, 02-Cl iheterocycloalkyl, 0 2- 0 I 1- heterocycloalkenyl, C6-Cloaryl, C.5-Cgheteroaryl, C7-0l aralkyl, C6-Cloheteroaralkyl,
5. 08-Oil aralkenyl or C7-Cloheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyl- oxy, 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. WO 97/01569 PCTIEP96/o2785 -112- 6. A compound according to claim 5, wherein R 5 and Re, are unsubstituted or substituted by Cl-Cl2alkyl or C1-C12alkoxy; are, together with the group -CH-CH-, a 5- to 8-membered carbocycle; are, together with the group -CH-CH-, a 5- to 8-membered heterocarbocycle; are, independently of one another, hydrogen, unsubstituted Cl-C 12 alkyl or Cl-Cl 2 aikyl which is substituted by a substituent selected from the group consisting of -C(O)oR,, -OC(O)RS 4 -C(O)ONa or -C(O)OK, primary amino, secondary amino, C3-Cl2CYCloalkyl, Cl -C~alkoxy, phenyloxy and benzyloxy; unsubstituted C3-C1 2 cycloalkyl or C 3 -C 1 2cycloalkyl which is substituted by a substituent selected from the group consisting of -C(O)ORsl, -OC(O)R.1 4 -C(O)ONa or -C(O)OK, primary amino, secondary amino, C 1 -C 6 alkyl, C 1 -C 6 alk- oxy, phenyloxy and benzyloxy; CG-Cloaryl which is unsubstituted or substituted by -C(O)OR, 1 -OC(O)RI 4 -C(O)ONa or -C(O)OK, primary amino, secondary amino, C 1 -C 6 alkyl or CI-C 6 alkoxy; C3-Ogheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; or C7-Cl 2 aralkyl which is unsubstituted or substituted by -C(O)ORsj, -OC(O)Rs 4 -C(O)ONa or -C(O)OK, primary amino, secondary amino, C 1 -C 6 alky or CI-C 6 alkoxy; are, together with the group -CH-CH-, a 5- to 1 2-membered carbocycle or 5- or 6-mem- bered heterocarbocycle with a hetero atom selected from the group consisting of oxygen and nitrogen atoms; or are, together with the -CH-CH- group, C3-Cl2cycloalkylene, C4-Cl2CYCloalkenylene, C2-Cllheterocycloalkylene or C3-C1heterocycloalkenylene with hetero atoms selected from the group of and 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)ORs 1 OC(O)RS 4 C(O)R,1 2 nitro, NH 2 cyano, SO 3 My, OSO 3 MY, NR 20 SO 3 My, Cl -Cl 2 alkyl, C2-Cl 2 alkenyl, Cl-Cl 2 alkoxy, C:3-Ci 2 cycloalkyl, C3-Ci 2 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C6-Cloaryl, C6-Cloaryloxy, C 7 -C 1 1 aralkyl, C 7 -C 11 aralkyloxy, Ce-Cloheteroaralkyl, C 8 -C 11 aralkenyl, C 7 Cioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamnate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and amino- carbonylamide, where R 51 is hydrogen, My, C 1 -C 12 alkyl, C2-Cl 2 alkenyl, Ca-C 1 2 cycloalkyl, C 2 -C 11 heterocycloalkyl, C6-Cloaryl, C5-Cgheteroaryl, C 7 -C 11 aralkyl or C6-Cioheteroaralkyl, R,4 is hydrogen, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Cl2cycloalkyl, C 2 -C 11 heterocycloalkyl, C6-Cloaryl, Cr-CIiaralkyl or C6-Cloheteroaralkyl, and Rr, 2 and R 20 are hydrogen, WO 97/01569 PCTJEP96/02785
6. 113- CI-C 1 2 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, C3-Cl2cycloalkenyl, 02-Cl iheterocycloalkyl, 02-Cl i-heterocycloalkenyl, C 6 -Cl 0 aryl, 05-Ogheteroaryl, 07-Cl 1 aralkyl, C6-Cioheteroaralkyl, C 8 -C 11 -aralkenyl or C7-Cloheteroaralkenyl, 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 R 5 and R 6 are, together with the -CH-OH- group, C3-Cl2cycloalkylene or C2-Cllheterocycloalkylene 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 R 5 and R 6 are, together with the -OH-OH- group, C3-Cl2cycloalkylene or C2-Cliheterocycloalkylene 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 1 OC(O)RI 4 C(O)RS 2 NRBR 9 Cl-C 12 alkyl, R8C(O)(NH)pN(R 9 -C(O)(NH)pNn 8 R 9 R 8 S(O) 2 (NH)pN(Rg)-; RSR 4 0NC(O)(NH)pN(R 9 R8OC(O)(NH)pN(R 9 -OC(O)(NH)pNR 8 R 9 and R 10 -S0 2 in which R 8 R 9 Rio and R 4 o are, independently of one another, hydrogen, OH, Ci-Cl 2 alkyI, Cl-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, C3-Cl2cycloalkenyl, 1 Clheterocycloalkyl, 02-Cl ihetero- cycloalkenyl, Cr,-Cl 0 aryl, C5-Cgheteroaryl, C7-Cl 6 aralkyl, CB-Cl6aralkenyl with C 2 -Cr.alken- ylene and C6-Cloaryl, C6-C,5heteroaralkyl, 0 6-Clsheteroaralkenyl, or di-C 6 -Cl 0 aryl- CI-C 6 -alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs 1 OC(O)R,4, C(O)Rs 2 nitro, NH 2 cyano, SO 3 My, OSO 3 My, NR 20 SO 3 My, Cl-Cl 2 alkyl, C2-Cl 2 alkenyI, Cl-Cl 2 alkoxy, C3-Cl 2 cycloalkyl, C3-CI2cycloalkenyl, 02-Cl iheterocycloalkyl, C2-Cl iheterocycloalkenyl, C6-Cloaryl, C6-Cioaryi- oxy, C,5-Cgheteroaryl, C5-Ceheteroaryloxy, C7-Cl 1 aralkyl, C7-Cl iaralkyloxy, C6-Cloheteroaralkyl, 08-Cl iaralkenyl, C7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide; Rs, is hydrogen, My, Cl-Cl 2 alkyl, C2-Cl2alkenyl, C3-Cl2CYCloalkyl, 02-Cl iheterocycloalkyl, Ce-Cl 0 aryI, 07-Claralkyl or C6-Cioheteroaralkyl, Rs4 is hydrogen, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 CYClO- alkyl, C2-Cllheterocycloalkyl, C6-ClOaryl, C5-Cgheteroaryl, 07-Ollaralkyl or WO 97/01569 PCT1EP96/02785 -114- C6-Cloheteroaralkyl, and R1 2 and R 20 are hydrogen, CI-Cl 2 alkyl, C2-Cl2alkenyl, C3-C20YCI0- alkyl, C3-Cl2cycloalkenyl, C 2 -C 11 heterocycloalkyl, 1 Cl-heterocycloalkenyl, C6-Cloaryl, 07-Cl 1 aralkyl, O-Cloheteroaralkyl, 08-Cl 1-aralkenyl or C7-Cloheteroar- alkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo. alkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and hetero- aralkenyl as substituents in turn are unsubstituted or substituted by one of the above- mentioned 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 R 8 and R 9 are, independently of one another hydrogen; CI-C 12 alkyl; C3-Cl2cycloalkyl, C6-Cioaryl, C7-Cl 6 aralkyl with 1 to 6 C atoms in the alkylene group and C6-Cloaryl, CB-C 16 aralkenyl with C2-C6alkenylene and C6-Cloaryl, or di- C6-Cloaryl-Ci-C6-alkyl, where R 8 and R 9 are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O)OMY, CI-C 12 alkyl, Cl-C 6 alkoxy, C6-Cloaryl, C6-Cloaryloxy, SO 3 My, OSO 3 My, NR 20 SO 3 My, NO 2 amino, primary amino, secondary amino and CN, and R 20 is hydrogen, Cl-Cl 2 alkyl, C2-C1 2 alkenyl, C3-Cl2cycloalkyl, C3-C12cycloalkenyl, C 2 -C 11 heterocycloalkyl, 02-11 -hetero- cycloalkenyl, C6-Cloaryl, C5-Cgheteroaryl, C-Ci aralkyl, C6-Cloheteroaralkyl, C 8 -C 1 II-aralkenyl or C7-Cloheteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. A compound according to claim 8, wherein Rio is CI-C1 2 alkyl; C3-Cl2cycloalkyl, C6-Cloaryl, C7-Cl 6 aralkyl with 1 to 6 C atoms in the alkylene group and C6-Cloaryl, C 8 -C, 6 ar- alkenyl with C2-C~alkenylene and C6-Cloaryl, or di-C6-Cloaryl-Cl-C 6 alkyl, which are unsubsti- tuted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C(O)OMy, Cl-Cl 2 alkyl, Cl-C 6 alkoxy, C6-Cloaryl, SO 3 MY, OSO 3 M~f NR 2 0SO 3 My, NO 2 amino, primary amino, secondary amino and CN; where R 20 is hydrogen, Cl -C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl2CYCloalkyl, C3-Cl2cycloalkenyl, C2-C11 heterocycloalkyl, C2- Cii1-heterocycloalkenyl, C6-ClOaryl, C5-Cgheteroaryl, C7-C1 iaralkyl, C6-Cloheteroaralkyl, C8-Cll-aralkenyl or C7-Cloheteroaralkenyl, 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 Rio is CI-C 12 alkyl; C3-C12CYCloalkyl, C6-ClOaryl, C7-Cl6aralkyl with. 1 to 6 C atoms in the alkylene group and C6-Cloaryl, which are WO 97/01569 PCT/EP96/02785 -115- unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(O)OMY, 0 1 -Cl 2 alkyl, Cl-C 6 alkoxy, 06-Cl()aryl, SO 3 My, nitro, amino, primary amino, secondary amino and cyano; or C8-Ci 6 aralkenyl with C2-C6alkenylene and C6-Cloaryl, or di-C 6 -Cjoaryl-C 1 -C 6 alkyl. 12. A compound according to claim 8, wherein Rq and R 6 are, together with the -OH-OH- group, O 3 -C 12 cycloalkylene or C2-Cllheterocycloalkylene 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)ORsj, OC(O)RS 4 C(O)RS 2 NH 2 0 1 -Cl 2 alkyl, R8C(O)N(R 9 -C(O)NR 8 R 9 R 8 S(O) 2 R 8 00(O) N(R 9 and RIO-S0 2 in which R 9 is hydrogen and R 8 is Cl-Cl 2 alkyl, C6-Cloaryl or C7-Ollaralkyl, which are unsub- stituted or substituted by one or more 0 1 -Cl 2 alkoxy; Rio is Cl-Cl 2 alkyl, C6-Cioaryl or 07-Ollaralkyl which are unsubstituted or substituted by one or more Cl-Cl 2 alkyl; R~i and R1 4 are Cl-Cl 2 alkyl and R,, 2 is CI-C 12 alkyI, C3-Cl 2 cycloalkenyl, C3-Cl2cycloalkyl or C6-ClOaryl, 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)OR. 1 and OC(O)R,,4 where Rs 1 is My or Cl-Cl 2 alkyI and R1 4 is Cl-Cl 2 alkyl; y is 1 and M is a mono- valent metal or y is 1/2 and M is a divalent metal. 13. A compound according to claim 12, wherein R 5 and R 6 are, together with the -OH-OH- group, cyclohexylene. 14. A compound according to claim 8, wherein R 5 and R 6 are, together with the -OH-OH- group, piperidylene. A compound according to claim 14, wherein R 5 and R 6 are, together with the -OH-OH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of O(O)OR. 1 O(O)R 2 O(O)NR 8 R 9 NH 2 SO 3 MY, 0C -O 12 alkyl, C 2 -Cl 2 alkenyl, CI-Cl 2 alkoxy, C 3 -C 12 cycloalkyl, 03-Ol 2 cycloalkenyl, 02-011 hetero- cycloalkyl, 02-011 heterocycloalkenyl, 0 6 -C 1 oaryl, O6-Oloaryloxy, Os-Cgheteroaryl, C7rCiaralkyl, Ci 1 laralkyloxy, O-loheteroaralkyl, O8-Cl aralkenyl, C7- Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, sulfon- hydrazide, and one or more 0 atoms of the ring are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, OC(O)R, 4 NH 2 OS0 3 MY WO 97/01569 PCTJEP96/o2785 -116- NR 2 0SO 3 My, 0 1 -Cl 2 alkoxy, C 6 -Cloaryloxy, G5-Cgheteroaryloxy, 07-01 iaralkyloxy, primary amino, secondary amino, sulfonamide, carbamide, carbamate, Sulfonhydrazide, carb- hydrazide, carbohydroxamic acid and aminocarbonylamide, where R~j is hydrogen, My, Cl-Cl 2 alkyl, 0 2-Cl2alkenyl, C 3 -C 12 cycloalkyl, CCi heterocycloalkyl, 0 6-CoIaryl, aryl, 0 7 -Cl 1 aralkyl or 06-Cloheteroaralkyl, Rr 4 is hydrogen, Ci-Cl 2 alkyl, C2-Cl2alkenyl, C3- O 12 cycloalkyl, 02-011 heterocycloalkyl, 06-Cloaryl, C5-Cgheteroaryl, 07-01 iaralkyl or 06- C1oheteroaralkyl, R 8 and R 9 are, independently of one another, hydrogen, OH, CI-C 12 alkyl, C3-Cl2cycloalkyl, 02-011 heterocycloalkyl, C 6 -C 10 aryl, C5-Cgheteroaryl, 07-Cl 6 aralkyl, 06- Cisheteroaralkyl, C8-Ci 6 aralkenyl with O2-C6alkenylene and 06-Cloaryl, or di-0e-Cl 0 aryl-Cl- C 6 -alkyl, or R 8 and R 9 together are tetramethylene, pentamethylene, -(0H 2 2 -O-(0H 2 2 (0H 2 2 -S-(0H 2 2 or -(0H 2 2 -NR 7 -(CH 2 2 and R 7 is H, Cl-C 6 alkyl, C7-Cllaralkyl, C(O)RS 2 or sulfonyi; and R1 2 and R 20 are hydrogen, Cl-Cl 2 alkyl, O2-Cl 2 alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, 02-01 iheterocycloalkyl, 02-011 -heterocycloalkenyl, C6-Cloaryl, Cs-Cgheteroaryl, C7-01 1 aralkyl, C6-Cioheteroaralkyl, 08-Cl I-aralkenyl or C7-Cloheteroar- alkenyl, 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 R 5 and R 6 are, together with the -OH-OH- group, piperidylene; where the hetero atom is unsubstituted or substituted by a substituent selected from the group consisting of C(O)OR, 8 I, 0(O)R,1 2 -C(O)NR 8 R 9 and R 10 -S0 2 and one or more C atoms of the ring are unsubstituted or substituted by one or more substitu- ents; selected from the group consisting of OH, NH 2 R8S(O) 2 N(R 9 R 8 C(O)N(R 9 and R 8 0C(O)N(R 9 where R 9 is hydrogen and R 8 is CI-C 12 alkyl, C6-CjOaryl or 07-Cllaralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more Cl-C, 2 alkoxy; R 1 0 is 0i-Cl 2 alky, C6-Cloaryl or C7-Cllaralkyl which are unsubstituted or substituted by one or more CI-C 12 alkyl; R~j is OI-Cl 2 alkyl and R. 2 is C 1 -Cl 2 alkyl, C3-Cl2cycloalkenyl, Oa-CI 2 cycIo- alkyl or C6-Cloaryl, and alkyl, cycloalkenyl, cycloalkyl and aryl as substituents in turn are un- substituted or substituted by one or more substituents selected from the group consisting of OH, C(O)0R 1 and OC(O)R,4, where R 1 is My or Cl-C 12 alkyl and R,4 is 0 1 -Cl 2 alkyl; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. WO 97/01569 PCTIEP96/02785 -117- 17. A compound according to claim 8, wherein R 5 and R 6 are, together with the -OH-OH- group, piperidylene; which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)ORs 1 OC(O)RI 4 C(O)Rs 2 NH 2 Cl-Cl 2 alkyl, R 8 C(O)N(R 9 NR 8 Rq, R8S(O) 2 N(R 9 R 8 00(O)N(R 9 R8R 4 oNC(O)N(R 9 -OC(O)NR 8 R 9 and R 10 -SO 2 in which R 9 is hydrogen and R8 is CI-Cl 2 alkyl, C6-Cioaryl or C7-Cllaralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more Cl-Cl2alkoxy or C7-Claralkyloxy; Rio is Cl-C 12 alkyl, C6-Cloaryl or C7-Cllaralkyl which are unsubstituted or substituted by one or more Cl-Cl 2 alkyl; R 40 is hydrogen, Cl-Cl 2 alkyl, C3-Cl2cycloalkyl, C2-011 heterocycloalkyl, 06-Cloaryl, CS-Cgheteroaryl, C7-Cl iaralkyl or C6-Cloheteroaralkyl; Rrj and Rs 4 are CI-Cl 2 alkyl and Rs 2 is CI-C 12 alkyI, C3-Cl2cycloalkenyl, C3-C12cycloalkyI or 0 6-Cloaryl, 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)ORs 1 and OC(O)RS 4 where RsI 1 is My or Cl-Cl 2 alkyl and Rs4 is Cl-Cl 2 alkyl; 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, NH 2 C 3 H 7 -C(O)CH 3 -C(O)C 6 Hs, -C(O)(CH 2 8 C(O)OCH 3 -C(O)[CH(OH)I 2 C(O)ONa, C(O)-C 6 H8(OH) 3 -C(O)-C 6 H 11 -C(O)OC 3 H 7 -C(O)NHC 6 H 5 -NHS(O) 2 CH 2 0 6 H 5 -NHC(O)OCH 2 C 6 Hs, -NHC(O)c6H 3 (OCH 3 2 -S(O) 2 -C 4 H 9 -NHC(O)NHC 6 H 5 -S(O) 2 -C 6 H 4 CH 3 -S(O) 2 -CH 2 C 6 H 5 and -S(O) 2 -(CH) 2 C 0 H 7 19. A compound according to claim 1, wherein R 2 is 0 1 -C 6 alkyl. A compound according to claim 1, wherein substituents for R 2 are selected from halo- gen, -C(O)OMy, CI-C 6 alkyl, Cl-C 4 alkoxy, phenyl, naphthyl, -SO 3 MY, Cl-Cl 2 primary amino, C2-C2osecondary amino, -S0 2 -NRBR 9 and -C(O)-NR 8 R 9 in which R8 and R 9 are, independent- ly of one another, H, Cl-C 4 alkyI, C2-C4hydroxyalkyl, phenyl or benzyl, or R8 and R 9 together with the N atom are morpholino, thiomorpholino, pyrrolidino or piperidino. 21. A compound according to claim 1, wherein R 2 is hydrogen, unsubstituted C 1 -C 6 alkyI or Cl-C 6 alkyl, which is substituted by C(O)OH, -C(O)ONa, -C(0)0K, -OH, -C(0)-NR 8 R 9 or -SO 2 -NR 8 R 9 in which R 8 is H, Cl-C 4 alkyl, C2-C4hydroxyalkyl, phenyl or benzyl, and R 9 in- WO 97/01569 PCT/EP96/02785 -118- dependently has the meaning of R 8 or R 8 and R 9 are together tetramethylene, penta- methylene or -CH 2 CH 2 -0-CH 2 CH 2 22. A compound according to claim 21, wherein R 2 is hydrogen, methyl, ethyl, HO(O)C-CH 2 CH 2 NaOC(O)-CH 2 CH 2 or RaR9N-C(O)-CH 2 CH 2 and R 8 and R 9 are, indepen- dently of one another, H, Cl-C 6 alkyl, C2-C 4 hydroxyalkyl, phenyl, benzyl or, together, morpholino. 23. A compound according to claim 1, wherein the other substituent in R, 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 C 1 -C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycIO- alkyl, C3-C12cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C6-Cloaryl, C7-Cli aralkyl, C6-Cloheteroaralkyl, C 8 -C 11 aralkenyl and C7-Cloheteroar. alkenyl. 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 R, corresponds to a group of the formula 1ll, COOR H (Il1), in which R 3 is hydrogen or My; and R 4 is C 1 -Ci 2 alkyl, C2-Cl 2 alkenyl, C3-C1 2 cycloalkyl, C3-Cl2cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, Ce,-Cloaryl, Cs-Cgheteroaryl, C 7 -C 1 iaralkyl, C6-Cloheteroaralkyl, C8-Cllaralkenyl or C7-Cloheteroaralkenyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OR.1 1 OC(O)RS 4 C(O)n 5 2 nitro, NH 2 cyano, SO 3 My, OSO 3 My, NR 20 SO 3 My, Cl-Cl 2 alkyl, C2-Cl2alkenyl, C 1 WO 97/01569 PCT/EP96/02785 -119- C1 2 alkoxy, C3-Cl2cycloalkyl, C3-Cl 2 CYCloalkenyl, CCi heterocycloalkyl, C2- Cilheterocycloalkenyl, C6-Cl 0 aryl, C6,-Cloaryloxy, C5-Cgheteroaryl, C5-Cgheteroaryioxy, C7- Ci iaralkyl, 07-Cl iaralkyloxy, C6-Cloheteroaralkyl, 08-Cl iaralkenyl, C7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfon- hydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs, is hydrogen, My, Cl -C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl2cycloalkyl, CCi heterocycloalkyl, C6-Cloaryl, 05-Ogheteroaryl, 07-Cl iaralkyl or C6-Cloheteroaralkyl, R, 4 is hydrogen, CI -Cl 2 alkyl, 02-Cl 2 alkenyl, C3-C12CYCloalkYl, 02-011 heterocycloalkyl, C6-Cloaryl, aryl, C7-Cllaralkyl or C6-Cloheteroaralkyl, and R1 2 and R 2 o are hydrogen, Cl-C, 2 alkyl, C2-Cl2alkenyi, C3-Cl2cycloalkyl, C3-Cl2cycloalkenyl, 02-Cl iheterocycloalkyl 02-Cl 1-hetero- cycloalkenyl, 06-ClOaryl, C5-Cgheteroaryl, 07-Cl 1 aralkyl, C6-Cloheteroaralkyl, C8-Cl i-aralkenyl or C7-Cloheteroaralkenyl, 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. 27. A compound according to claim 26, wherein R 3 is hydrogen or My and R 4 is unsubstituted Cl-Cl 2 alkyl; Cl-Cl 2 alkyl which is substituted by one or more substituents selected from the group consisting of -NH 2 primary amino, secondary amino, CI-0 12 sul- fonyl, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide, aminocarbonyl- amido, C3-C12CYCloalkyl, Cl-C6alkoxy, phenyloxy and benzyloxy; unsubstituted C3-Cl 2 cycloalkyl; C3-Cl2cycloalkyl which is substituted by one or more substituents selected from the group consisting Of C3-Cl2cycloalkyl, CI -C 6 alkyl, CI-C~alkoxy, Cl-Cl 2 Sulfonyl, phenyloxy and benzyloxy; C6-Cloaryl; C3-Cgheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; C7-Clearalkyl with CI-C 6 alkyl and C6-Cloaryl; C4-Cleheteroaralkyl with C1-C 6 alkyl and C3-Cloheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to carbon atoms; OG,-Cloaryl, C3-Cgheteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms, C7-Cl 6 aralkyl with CI-C 6 alkyI and C6-Cloaryl, C3-Cl6heteroaralkyl with Cj-C 6 alkyI and C4-Cioheteroaryl 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, CI-C12Sulfonyl, carboxyl, C(O)OMY, Cl-Cl 2 alkyI, Cl-C~alkoxy, C6-Cloaryl, WO 97/01569 PCTIEP96/02785
7. 120- SO 3 MY, OSO 3 My, NR 2 0SO 3 My, nitro, NH 2 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 CI-C 12 alkyl or 07-Cliaralkyl which are unsubstituted or substituted by one or more substi- tuents selected from the group consisting of OH, halogen, C(O)ORs 1 OC(O)Rs 4 C(O)Rs 2 nitro, NH 2 cyano, S0 3 MY, OSO 3 My, NR 20 SO 3 My, Cl-Cl 2 alkyl, 0 2-Cl2alkenyl, CI-C1 2 alkoxy, 0 3-Cl2cycloalkyl, C3-CI2CYCloalkenyl, 02-011 heterocycloalkyl, 02-011 heterocycloalkenyl, C6-Cloaryl, C6-Cloaryloxy, C5-CgheterOaryl, C5-Cgheteroaryloxy, 07-Cl iaralkyl, 07-Cl iaralkyl- OXY, C6-Oloheteroaralkyl, C8-Cllaralkenyl, C7-Oloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamnate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs, is hydrogen, My, CI-C 12 alkyl, C2-Cl 2 alkenyl, C3-C12CYCloalkyl, C2-Cllheterocyclo. alkyl, 0 6-Cloaryl, C5-Ogheteroaryl, C7-Cllaralkyl or 0 6-Cloheteroaralkyl, R., 4 is hydrogen, 0C -0 12 alkyl, C2-Cl2alkenyl, O3-Cl2cycloalkYl, 02-011 heterocycloalkyl, C6-Cloaryl, aryl, C7-Ollaralkyl or C6-Cloheteroaralkyl and RS 2 and R 20 are hydrogen, Cl-C, 2 alkyl, C2-Cl2alkenyl, C3-Cl2CYCloalkyl, C3-C12CYCloalkenyl, 1 Clheterocycloalkyl, C2C-hetero- cycloalkenyl, O6-Oloaryl, C,5-Cgheteroaryl, 07-0j aralkyl, C6-Cloheteroaralkyl, 08-01II-aralkenyl or O7-Oloheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo. alkyl, 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 R 3 is hydrogen, K or Na. 29. A compound according to claim 27, wherein R 4 is methyl, ethyl, n- or i-propyl, i- or t-butyl, cyclohexyl, naphthyl, phenyl, benzyl, naphthylmethyl, 2 -phenylethyl, 3 -phenylpropyl, cyclohexylmethyl, 2 -cyclohexylethyl, furanyl, pyridinyl or pyrimidinyl. A compound according to claim 27, wherein carbamido, carbhydrazido, sulfonamido, sulfonhydrazido, aminocarbonylamide and carbamate as substituent for R 4 mean groups of the formulae R 8 NHC(O)N(R 9 R8OO(O)N(R 9 R8C(O)(NH)pN(R 9 and R8S(O) 2 (NH)pN(R 9 in which R 8 is H, Cl-Cl2alkyl, 05- or C6cycloalkyl, C5- or Cecycloalkylmethyl or -ethyl-, 05- or C6heterocycloalkyl, C5- or C6heterocycloalkylmethyl or -ethyl-, phenyl, naphthyl, benzyl, WO 97/01569 PCT/EP96/02785 121 2-phenylethyl, diphenylmethyl, which are unsubstituted or substituted by one or more sub- stituents from the group of -OH, -N H 2 Cl-C~primary amino, C2-Cl4secondary amino, NO 2 ON, -Cl, -C(O)OH, -C(O)ONa, -SO 3 H, -OSO 3 Na, NR 2 0SO 3 Na in which R 20 is hydrogen, CI -C1 2 alkyl, C 2 -Cl 2 alkenyl, 03-Cl 2 cycloalkyl, 0 3-C12CYCloalkenyl, 02-Cl iheterocycloalkyl, 02-Cl i-heterocycloalkenyl, C 6 -Cl 0 aryl, 05-Cgheteroaryl, 07-Cl iaralkyl, 0 6-Cloheteroaralkyl, C8-Cl 1 -aralkenyl or 07-ClOheteroaralkenyl, and -SO 3 Na, Cl-C 4 alkyl, CI-C 4 alkoxy and phenyl, and R 9 is H, Cl-Cloalkyl, phenyl, naphthyl, benzyl, 2-phenylethyl or phenyl-CH=CH-CH 2 and p is Qor 1. 31. A compound according to claim 27, wherein R 4 is a carbamido-substituted alkyl group R8-C(O)NR 9 -(CH 2 where n is 1 or 2, R 8 is hydrogen; Cl-Cl 2 alkyl; C3-Cl 2 cycloalkyl; C 6 -Cloaryl or C7-Cl 6 aralkyl with CI -Cralkyl and 06-Cloaryl; 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-Cl 2 alkyl, Cl-C 6 alkoxy, Ce-Cl 0 aryl, SO 3 My, OSO 3 My, NR 20 SO 3 My, C(O)ORs 1 OC(O)Rs4, nitro, amino and cyano; or C8-Cl 6 aralkenyl with C2-C 6 alkenyl and C6-Cloaryl or di-0 6 -Cloaryl- Cl-C 6 alkyI; and R 9 is H, linear or branched Cl-C 10 alkyl, C5- or C 6 cycloalkyl, C5- or C 6 cyclo- alkylmethyl- or -ethyl, phenyl, naphthyl or benzyl, 2-phenylethyl or phenyl-CH=CH-cH 2 Y is 1 and M is an alkali metal or y is 1/2 and M is an alkaline earth metal, R 20 is hydrogen, Cl-Cl 2 alkyl, C 2 -C 12 alkenyl, C3-C1 2 cycloalkYl, C3-Cl 2 cycloalkenyl, 1 Clheterocycloalkyl, 02-Cl i-heterocycloalkenyl, 06-Cloaryl, Cs-Cgheteroaryl, C7-Cl 1 aralkyl, 06-Cloheteroaralkyl, 08-Oll-aralkenyl or C7-Cloheteroaralkenyl, Rs, is hydrogen, My, CI-C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, C2-Cl iheterocycloalkyl, C6-Cloaryl, Cs-Cgheteroaryl, C7-Cl 1 aralkyl or 06-Cloheteroaralkyl and R" is hydrogen, 0 1 -Cl 2 alkyl, C2-Cl 2 alkenyl, 03-C1 2 cycloalkyl, C2-Cl iheterocycloalkyl, C6-Cloaryl, C,5-Cgheteroaryl, C7-Cl 1 aralkyl or 06-Cloheteroaralkyl; a sulfonamide-substituted alkyl group R 8 -SO 2 NR 9 -(CH 2 in which R 8 R 9 and n have the meanings indicated in an aminocarbonylamide- or carbamate-substituted alkyl group R 9 NH-C(O)-NH-(CH 2 or R 9 O-C(O)-NH-(CH 2 )n in which R 9 has the meanings indicated in and additionally phenyl and n has the meanings indicated in a carbhydrazido-substituted alkyl group R8-C(O)-NHNR 9 -(CH 2 in which R 8 R 9 and n have the meanings indicated in or a sulfonhydrazido-substituted alkyl group R 8 -SO 2 -NHNR 9 -(CH 2 in which R 8 R 9 and n have the meanings indicated in WO 97/01569 PCT1EP96/02785
8. 122- 32. A compound according to claim 27, wherein R 4 is an amide RBC(O)N(R 9 )(CH 2 or R 8 S(O) 2 N(R 9 )(CH 2 where R 8 and R 9 are, independently of one another, hydrogen; unsubstituted Cl-C, 2 alkyl; CI-Cl 2 alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(O)ONa, Cl-C 12 alkyl, Cl-Cealkoxy, C 6 -Cl 0 aryl, -SO 3 H, OSO 3 Na, NR 2 0SO3Na, SO 3 Na, nitro and cyano; unsubstituted 0 3-C12cycloalkyl; C3-C12cycloalkyl substituted by one or more OH; unsubstituted C6-Cloaryl, unsubstituted C7-Cl 2 aralkyl with Ci-C 6 alkyl and C6-Cloaryl; 06-Cloary!, or C7-Cl2aralkyl with Cl-C 6 alkyl and 06-Cloaryl, which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C(O)ONa, -C(0)0K, CI-C 12 alkyl, CI-C6alkoxy, C6-Cloaryl, SO 3 Na, OSO 3 Na, NR 2 oSO 3 Na, C(O)OR'j, OC(O)R, 4 nitro, amino and cyano, R 20 is hydrogen, CI-C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycIo- alkyl, 0 3-C12cycloalkenyl, 02-Oliheterocycloalkyl, C2-Cll -heterocycloalkenyl, C6-Cloaryl, C 7 -C 11 aralkyl, C6-C1 oheteroaralkyl, C8-C1, -aralkenyl or C7-Cloheteroar-. alkenyl, R~j is hydrogen, My, CI-C 12 alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, C2-Cllheterocyclo- alkyl, C6)-Cloaryl, C5-Cgheteroaryl, 07-Cilaralkyl or 0 6-Cloheteroaralkyl and R, 4 is hydrogen, -C 12 alkyl, C2-Cl2alkenyl, C3-Cl 2 cycloalkyl, C2-Cll heterocycloalkyl, C6-Cloaryl, Cs-Cghetero- aryl, C7-Cllaralkyl or C6-Cloheteroaralkyl; and n is 2 or 1; or sulfonamide R8S(O) 2 N(R 9 )(CH 2 where R 8 is Cl-Cl 2 alkyl, which is unsubstituted or sub- stituted by one or more halogen atoms; or C6-Cloaryl, which is substituted by one or more Cl-C 4 alkyl, CI-C 4 alkoxy, halogen, -ON or -NO 2 and R 9 is hydrogen or isobutyl, and n is 2 or 1; or aminocarbonylamidle RS3-NH-C(O)-NH(CH 2 in which R 8 is Cl-C 12 alkyl or 06-Cloaryl, which is unsubstituted or substituted by halogen, -ON, -NO 2 CI-C 4 alkyl, CI-C 4 alkoxy, 05- or C6cycloalkyl, 06-Cloaryl or C7-Cl 2 aralkyl, and n is 2 or 1; or aminoalkyl R8'Rg.N(CH 2 where R8, and R 9 are, independently of one another, hydro- gen; unsubstituted Cl-Cl 2 alkyl; CI-Cl 2 alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OR~j, OC(O)R, 4 C(O)-NRlIR 12 CI-C 12 alkyl, CI-C 6 alkoxy, 06-Cloaryl, -SO 3 H, SO 3 Na, OSO 3 Na, NR 2 0SO 3 Na, nitro, amino and cyano; unsubstituted C3-C12cycloalkyl; C3-Cl2cycloalkyl which is substituted by one or more OH; C6-Cloaryl; 07-Cl~aralkyl with CI-C 6 alkyl and C6-Cloaryl; or C8-Cl~aralkenyl with C2-C6alkenyl and OB-Cloaryl, where aryl and the aryl in the aralkyl and aralkenyl are unsub- stituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)0R. 1 OC(O)R,1 4 -C(O)ONa, -C(0)0K, -C(O)-NRllR 12 C 1 -C 12 alkyl, Cl-C6alkoxy, C6-Cloaryl, -SO 3 H, SO 3 Na, OSO 3 Na, NR 20 SO 3 Na, nitro, amino and cyano; WO97/01569 PCTTEP96O2785
9. 123- wherein n is 2 and preferably 1, and R 51 is hydrogen, K or Na, Cl-Cl 2 alkyl, C2-Cl2alkenyl, C3-Cl2cycloalkyl, 02-Cl iheterocycloalkyl, C6-Cloaryl, C5-Cgheteroaryl, C7-Cll aralkyl or C6-ClOheteroaralkyl, R 4 is hydrogen, Cl -Cl2alkyl, C2-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, 02-Cl iheterocycloalkyl, C6-ClOaryl, C5-Cgheteroary;, C7-Cj 1 aralkyl or 0 6-Cloheteroaralkyl, R 11 is H, Cl-C 4 alkyl, C2-C 4 hydroxyalkyl, phenyl or benzyl, and R 1 2 independently has the meaning of R 11 or R 11 and R 12 together are tetramethylene, pentamethylene or -CH 2 CH 2 -O-CH 2 CH 2 and R 20 is hydrogen, CI-Cl 2 alkyl, C2-Cl 2 alkenyl, 0 3-Cl2cycloalkyl, C3-Cl2cycloalkenyl, C2-Cl heterocycloalkyl, 02-Cl i-heterocycloalkenyl, C6-Cloaryl, 07-Cl 1 aralkyl, C6-Cloheteroaralkyl, 08-Cl i-aralkenyl or C7-Cloheteroar. alkenyl. 33. A compound according to claim 32, wherein R 4 is an amide RaC(O)N(Rg)(CH 2 or RaS(O) 2 N(R 9 )(CH 2 where R 8 is unsubstituted CI-C 12 alkyl; C 1 -C 8 alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ONa and C6-Cloaryl; unsubstituted C3-Cl2cycloalkyI; C3-C8cycloalkyl which is substituted by one or more OH; unsubstituted C6-Cloaryl or C7-Cl 2 aralkyl with Cl-C 6 alkyl; C6-Cloaryl, C7-C, 2 ar- alkyl with CI-C 6 alkyl and C6-Cloaryl or C8-Cl 6 aralkenyl with C2-C6-alkenyl and C6-Cloaryl, which is substituted by one or more substituents selected from the group consisting of halo- gen, -C(O)OH, C(O)ONa, Cl-C 12 alkyl, Cl-C~alkoxy, -SO 3 H, SO 3 Na, OSO 3 Na, NR 2 oSO 3 Na in which R 20 is hydrogen, CI-C 12 alkyl, C2-Cl2alkenyl, C3-Cl2CYCloalkyl, C3-Cl2CYCloalkenyl, C2-Cl iheterocycloalkyl, C2-C1 i-heterocycloalkenyl, C6-Cloaryl, C5-Cgheteroaryl, CCi aralkyl, C6-Cloheteroaralkyl, C8-Cll-aralkenyl or CCoheteroaralkenyl, and nitro and cyano; and R 9 is hydrogen; unsubstituted Cl -C 6 alkyl, unsubstituted Ce)-Cloaryl, unsubstituted C7-Cl 2 aralkyl with Cl-C~alkyl and C6-Cloaryl; or C8-Cl6aralkenyl with C2-C6alkenyl and C6-Cloaryl, and n is 2 or 1. 34. A compound according to claim 32, wherein R 4 is an amide RBC(O)NQg)(CH 2 where R 8 is unsubstituted Cl-Cl 2 alkyI; CI-C 12 alkyI 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-Cl2cycloalkyl; C3-C12cycloalkyl which is substituted by one or more OH; unsubstituted C6-C 10 aryl; Ce,-Cloaryl, which is substituted by one or more substituents selected from the group consisting of halogen, C(O)ONa, -C(O)OH, CI-C 6 alkyl, Cl-C6alkoxy, phenyl, -SO 3 H, SO 3 Na, OSO 3 Na, NHSO 3 Na, nitro and cyano; or C7-Cl 6 aralkyl with Cj- C 6 alkyl and C6-Cloaryl, and R 9 is hydrogen; unsubstituted Cl-C6alkyl, unsubstituted C7- WO 97/01569 PCTIEP96/02785 -124 C 1 6 aralkyl with CI-C 6 aikyl and 06-Cloaryl; or 0 8-Clearalkenyl with 02-Cealkenyl and C 6 -Cloaryl, and n is 2 or 1. A compound according to claim 34, wherein R 8 is unsubstituted CI-C 12 alkyl; Cl-C 4 alkyl 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-Cl2cycloalkyl; C3-Cl 2 cycloalkyI which is substituted by one or more OH, unsubstituted C6-Cloaryl; C 6 -Cloaryl which is substi- tuted by one or more substituents selected from the group consisting of halogen, -C(O)OH, C(O)ONa, CI-C 6 alkyl, CI-C 6 alkoxy, -SO 3 H, SO 3 Na, OSO 3 Na, NHSO 3 Na, nitro and cyano; or unsubstituted C7-Cl 6 aralkyl with Cj-C 6 alkyI and 06-Cloaryl, and R 9 is H, Cl-C 4 alkyl, phenyl- OH 2 phenyl-CH 2 CH 2 phenyl-(CH 2 3 or phenyl-CH=CH-CH 2 and n is 2 or 1. 36. A compound according to claim 32, wherein R 4 is an amino alkyl R 8 *R 9 ,NCH 2 in which R 8 and R 9 are, independently of one another, hydrogen; Cl-C 8 alkyl, cyclopentyl, cyclohexyl, or C6cycloal kyl methyl, phenyl-C 1 -C 4 alkyl or phenyl-C 2 -C 4 alkenyl. 37. A compound according to claim 32, wherein R 4 is an amine R8,R 9 ,NCH 2 where R 8 and R 9 are, independently of one another, H, Cl-C 6 alkyl, phenyl-Cl- or -C 2 alkyl. 38. A compound according to claim 26, wherein R 4 is C 7 -Cl 1 aralkyI, C:3-Cl 2 cycloalkyl or CI-C 12 alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of NH 2 C3-C1 2 cycloalkyl, primary amino, secondary amino, sulfonamide and carbamide and aminocarbonylamido. 39. A compound according to claim 38, wherein the substituents for Cl-Cl 2 alkyl are selected from the group consisting of NH 2 cyclohexyl, C6-Cloaryl, RBC(O)N(R 9 R 8 S(O) 2 N(R 9 R 8 NHC(O)NR 9 and R 8 .R 9 in which R13 and R 9 are, independently of one another, hydro- gen, Cl-C 12 alkyI, C3-Cl 2 cycloalkyl, 02-01 iheterocycloalkyl, OG-Cloaryl, C 7 -C 11 aralkyI or C6-Cloheteroaralkyl and R 8 and R 9 are, independently of one another, hydrogen, OH, Cl-Cl 2 alkyl, C3-C12cycloalkyl, C2-Cllheterocycloalkyl, C6.Cloaryl, Cs-Cghetero- aryl, C7-Cliaralkyl or 06-Cloheteroaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs 1 OC(O)RS 4 C(O)R, 52 nitro, NH 2 cyano, SONY~, OSO 3 My, NR 20 SO 3 MY, CI-C 12 alkyl, C2-Cl 2 alkenyl, Cl-Cl 2 alkoxy, C3-Cl 2 cycloalkyl, C3-Cl2cycloalkenyl, 1 Clheterocycloalkyl, WO 97/01569 PCT/EP96/02785
10. 125- 1 Clheterocycloalkenyl, C6-Cloaryl, 06-Cloaryloxy, C5-Cgheteroaryl, 07-011 aralkyl, 07-Cl 1 aralkyloxy, C6-Cloheteroaralkyl, 08-Cl iaralkenyl, C7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamnate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where is hydrogen, My, Cl-Cl 2 alkyl, 0 2 -Cl 2 alkenyl, C3-Cl 2 cycloalkyl, C2-011 heterocycloalkyl, C6-ClOaryl, C5-Cgheteroaryl, Cr-Cliaralkyi or 0 6-Cloheteroaralkyl, R14 is hydrogen, Cl -Cl 2 alkyl, C 2 -C 12 alkenyl, C3-Cl 2 CYCloalkyl, C2-C1 iheterocycloalkyl, OB-Cloaryl, aryl, 07-Cllaralkyl or C 6 -Cloheteroaralkyl and RS 2 and R 2 0 are hydrogen, Cl-Cl 2 alkyl, 02-Cl 2 alkenyl, C3-Cl2CYCloalkyl, C3-Cl2cycloalkenyl, C2-Cl iheterocycloalkyl, 02-01 1 hetero- cycloalkenyl, O6-0,oaryl, 05-Cgheteroaryl, 07-Cl 1 aralkyl, C6-Cloheteroaralkyl, C8-C1 1 -aralkenyl or C7-Cloheteroaralkenyl, 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; 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 R 9 together are tetramethylene, pentamethylene, -(CH 2 2 -O-(CH 2 2 -(CH 2 2 -S-(CH 2 2 or -(CH 2 2 -NR 7 -(0H 2 2 and R 7 is H, Cl-C 6 alkyl, C7-Cl 1 ar- alkyl, C(O)RS 2 or sulfonyl. A compound according to claim 39, wherein R 4 is CH 2 -0 6 H 5 (0H 2 2 -C 6 H 5 cyclohexyl, methyl, ethyl or isopropyl which are unsubstituted or substituted by one or more substitu- ents selected from the group consisting of NH- 2 cyclohexyl, OB-Cloaryl, R 8 0(O)N(R 9 R8S(O) 2 N(R 9 R 8 NHC(O)NR 9 NR 9 C(O)NHR 8 and R 8 ,R 9 in which R 8 R 9 R13, and R 9 are, independently of one another, hydrogen, CI-0 12 alkyl, 03-C12CYCioalkyl, C6-ClOaryl or C7-Ollaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OMy, nitro, cyano, SO 3 My, OSQ 3 My, NHSO 3 My, Cl-Cl 2 alkyl, Cl-C 12 alkoxy and C6-Cloaryl, 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 R 4 is C 6 1- 11 CH(CH 3 2 CH 2 -phenyl, (CH 2 2 -phenyl, CH2NHC(O)-phenyl, CH2NHC(O)(CH 2 3 -phenyi, CH 2 NHC(O)(CH 2 3 0H, CH 2 NHC(O)0F 3 CH 2 NHC(O)C 6 H 11 CH 2 NHC(O)C 11 H 2 3 CH 2 NHC(O)CH(C 6 H 5 2 CH 2 HNC(O)NHC 6 H 5 CH 2 NHC(O)C 2 H 4 C0 2 Na, CH 2 NHC(O)04[(1 ,3,4,5)0H1 4 H 7 CH2NHC(O)C6H 4 -P-SO 3 Na, CH 2 NHC(O)C 6 H 4 CI, CH 2 NHC(O)C 6 H 4 N0 2 CH 2 NHC(O)C 6 H 4 0CH 3 CH 2 NHC(O)C6H 4 (3,4)I 2 CH 2 NHC(O)C 6 H 4 CH 3 WO 97/01569 WO 9701569PCT/EP96/02785 -126- CH 2 NHC(O)C 6 H 4 C 6 H 5 CH 2 NHC(O)C 6 H 4 CN, CH 2 NHC(O)0 10 H 7 CH 2 NHC(O)C6H 4 000Na, CH 2 NHC(O)(CHOH) 2 C00Na, OH 2 N(CH2CH=CH-phenyl)[C(O)-phenyl], CH2N[CH 2 CH(CH 3 2 ][C(O)-phenyl], CH 2 N[OO)C61H 5 1IH 2 C 6 H- 5 CH 2 N[C(O)C 6 H 5 ](CH 2 3 C 6 H 5 CH- 2 0 6 H- 1 1 (CH 2 )0 2 C 6 H- 11 CH 2 NH 2 CH 2 NHCH 2 CH=CH-phenyl, CH 2 NHCH 2 -phenyl, CH 2 NHCH 2 OH(CH 3 2 CH 2 N(CH 2 -phenyl) 2 CH 2 N[CH 2 CH(CH 3 2 2 CH2NHSO 2 -p-nitrophenyl, CH 2 NHSO 2 -P-tolYl, CH 2 NHSO 2 CF 3 CH 2 NHC(O)NHC 6 H 5 or CH 2 N[SO 2 -p-nitrophenyl][CH 2 CH(CH 3 2 2 42. A compound according to claim 1, which corresponds to the formula la COOR 3 OH R 0 A 7 R 6 0 H OH HO in which R 3 is hydrogen or My; and R 4 is Cl -C 12 alkyl, C 2 -Cl 2 alkenyl, C 3 -C 1 2 cycloalkyl, 0 3 -Cl 2 cycloalkenyl, C2-C1 1 heterocycloalkyl, 02-011 heterocycloalkenyl, C 6 -C 10 aryl, C 5 -Cgheteroaryl, C7-Cl 1 aralkyl, 0 6 -Cloheteroaralkyl, C 8 -Cl 1 aralkenyl or C 7 -Cloheteroaralkenyl, which are unsubstituted or substituted once or several times; R 5 and R 6 are, independently of one another, hydrogen, 0 1 -C 12 alkyl, C 3 -C 1 2 CYCloalkyl, C2-C11 heterocycloalkyl, 0 6 -CloaryI, C 5 -Cgheteroaryl, C7-011 aralkyl or C 6 -CO 1 heteroaralkyl; or R 5 and R 6 are, together with the -OH-OH- group, C 3 -C 12 cycloalkylene, C 4 -CI 2 cycloalken- ylene, O 2 -Clheterocycloalkylene and C3-Cliheterocycloalkenylene with hetero atoms selected from the group of and 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 1 OC(O)Rs4, C(O)RS 2 nitro, NH- 2 cyano, SO 3 MY, OSO 3 My, NR 20 SO 3 My, C 1 -C 12 alkyI, C2-Cl 2 alkenyl, Cl-Cl 2 alkoxy, 03-C12cycloalkyl, C3-Cl2CYCloalkenyl, 02-Cl 1 hetero- WO 97/01569 PCT/EP96/02785 -127- cycloalkyl, C2-C1 iheterocycloalkenyl, C 6 -Ci()aryl, 06-Cloaryloxy, C7-Cl 1 aralkyl, 07-Cl 1 aralkyloxy, 0 6 -Cioheteroaralkyl, Ca-Cl iaralkenyl, C7- Cioheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonyl- amide, where R 51 is hydrogen, My, 0 1 -C 12 alkyl, C 2 -Cl 2 alkenyl, 03-Cl 2 cycloalkyl, C2-Cllhetero- cycloalkyl, Cs-Cloaryl, C 5 -Cgheteroaryl, 07-01 1 aralkyl or 06-Cloheteroaralkyl, R1 4 is hydrogen, Cl-Cl 2 alkyl, C2-Cl 2 alkenyl, C: 3 -C 12 cycloalkyl, 02-Cl 1 heterocycloalkyl, C 6 -Cloaryl, aryl, 07-Ollaralkyl or C 6 -Clc 0 heteroaralkyl and R,, 2 and R 20 are hydrogen, Cl-Cl 2 alkyl, 02- C 1 2 alkenyl, C3-Cl 2 cycloalkyl, 03-Cl 2 cycloalkenyl, 02-Cl iheterocycloalkyl, 0 2-Cl11- heterocycloalkenyl, C 6 -Cloaryl, 0 5 -Cgheteroaryl, 07-Cl 1 aralkyl, C6-Cloheteroaralkyl, C8-Cl 1- aralkenyl or C7-ClOheteroaralkenyl, 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 R 3 is H, K or Na; R 5 and R 6 are, together with the -OH-OH- group, C3-Cl 2 CYCloalkylene, C4-Cl2cycloalkenylene, C2-Cl iheterocyclo- alkylene and C3-Cllheterocycloalkenylene with hetero atoms selected from the group and which are unsubstituted or substituted once or several times; where the sub- stituent is selected from the group consisting of OH, halogen, C(O)ORS 1 OC(O)RI4, C(O)Rs 2 nitro, NH 2 cyano, SO 3 My, OSO 3 My, NR 20 SO 3 My, 0 1 -Cl 2 alkyl, C2-Cl 2 alkenyl, C, -Cl 2 alkoxy, C3-C 12 CYCloalkyl, C3-Cl 2 cycloal kenyl, 02-Cl lheterocycloalkyl, 02-Cl 1 hetero- cycloalkenyl, C6-Cloaryl, 06-Cloaryloxy, Cs-Cgheteroaryl, 05-Ogheteroaryloxy, 07-01 1 aralkyl, 07-Cl 1 aralkyloxy, C 6 -Cl 0 heteroaralkyl, Ca-Cl 1 aralkenyl, OCiCoheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, in which R 51 is hydrogen, My, Cl-Cl 2 alkyl, C 2 -Cl 2 alkenyl, C3-Cl 2 cycloalkyl, 02-Cl ~heterocycloalkyl, C6-Cloaryl, 07-Cl 1 aralkyl or 06-Cloheteroaralkyl, R1 4 is hydrogen, C, -C 12 alkyl, 02-01 2 alkenyl, C 3 -C 12 cycloalkyl, 02-Cl iheterocycloalkyl, C6-Cloaryl, C 5 -Cgheteroaryl, C 7 -Cl 1 aralkyl or C 6 -Cloheteroaralkyl and R1 2 and R 2 o are hydrogen, Cl-Cl 2 alkyl, 02-C 12 alkenyl, C 3 -C 12 CYCloalkyl, 03-Cl 2cycloalkenyl, 02-Cl ~heterocycloalkyI, 02-Cl 1 hetero- cycloalkenyl, OG-Cloaryl, C 5 -Cgheteroaryl, 07-Cl 1 aralkyl, 06-Cloheteroaralkyl, Ca-Cl 1 -aralkenyl or C7-Cloheteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclo- WO 9701569PCT1EP96102785 128 alkyl, heterocycloalkenyl, aryi, aryloxy, heteroaryl, heteroaryloxy, araikyl, 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; R 4 is a residue R1 2 -(CH 2 or cyclohexyl, in which n is 1 or 2 and R 12 is Cl-Cloalkyl, Cs-Cecycloalkyl, 06-Cloaryl or C8-Cl2aralkenyl, which are unsubstituted or substituted by Cj-C 4 alkyl, CI-C 4 alkoxy, F, Cl, -ON or -NO 2 or R 12 is an amino group -NR 8 ,R 9 and R 8 and R 9 are Cl-Cl 2 alkyl or unsubstituted or Cl -C4alkyl-substituted C5- or C6cycloalkyl, C 6 -Cloaryl, C7-Cl 2 aralkyl or C8-C1 2 aralkenyl; or R 12 is an amide group -N(R 9 )C(O)R 8 -N(R 9 2 R 8 -NRgC(O)NHRB or -NR 9 C(O)NHR 8 in which R 8 is 06-Cloaryl, which is unsubstituted or substituted by Cl-C 4 alkyl, Ci-C4alkoxy, F, Cl, -ON or -NO 2 or Cl-Cloalkyl which is unsubstituted or substituted by F or Cl, and R 9 is H, Cl-Cl 0 alkyl, C5- or C6CYCloalkyl, C5- or C6CYCloalkyl-Cl-Cr:akyl phenyl-Cl-C 6 alkyl or phenyl- C2-C 6 alkenyl; or R 4 is Cl-Cl 2 alkyl, C3-CI2CYCloalkyl or C7-Ollaralkyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OR. 1 OC(O)R 4, C(O)R,1 2 nitro, NH 2 cyano, SO 3 MY, OSO 3 My, NR 20 SO 3 My, CI-Cl 2 alkyl, C2-Cl2alkenyl, Cl-Cl 2 alkoxy, C3-C12cycloalkyl, C3-Cl2CYCloalkenyl, 1 Clheterocycloalkyl, C2- C11 heterocycloalkenyl, C6-Cloaryl, C6-Cloaryloxy, C5-Cgheteroaryl, C5-Cgheteroaryloxy, C7- C ilaralkyl, C7-Cl iaralkyloxy, O6-Cloheteroaralkyl, 08-Cl iaralkenyl, C7-Cloheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamnate, sul- fonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where RI is hydrogen, My, C, -C1 2 alkyl, 02-Cl 2 alkenyl, C3-Cl2CYCloalkyl, C2-Cl iheterocycloalkyl, C6-Cloaryl, C5-Cgheteroaryl, 07-Cl 1 aralkyl or C6-Oloheteroaralkyl, R14 is hydrogen, Oi-Cl 2 alkyl, C2-Cl 2 alkenyl, C3-C12CYCloalkyl, C2-Cl iheterocycloalkyl, C6-Cloaryl, Cs-Cghetero- aryl, C7-Cllaralkyl or Ce-Cioheteroaralkyl and R. 2 and R 2 o are hydrogen, CI-C 12 alkyl, C2-Cl2alkenyl, C3-C12cycloalkyl, C3-Cl2CYCloalkenyl, 02-Cl iheterocycloalkyl, 02-Cl 1 hetero- cycloalkenyl, C6-ClOaryl, Os-Cgheteroaryl, C7-Cl 1 aralkyl, C6-Olo)heteroaralkyl, 08-Cl i-aralkenyl or C7-Cloheteroaralkenyl, 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. WO 97/01569 PCTIEP96/02785
11. 129-= 44. A compound according to claim 43, wherein R 4 is C 6 H 11 C 6 H 11 -CH 2 C6HI-CH 2 CH 2 C 6 H 5 -CH 2 C 6 H 5 -CH 2 CH 2 or C6H5-CH=CH-CH 2 (ii) R 4 is C 6 H 11 C 6 H 11 -CH 2 C 6 H 11 -CH 2 CH 2 C 6 H5-CH 2 C6H 5 -CH 2 CH 2 -CH 2 -NRl 9 -S0 2 R, 8 -CH 2 -NR 19 -C(O)R 4 0, CH2NHC(O)NHR,8, -CH 2 NHR 21 or CH 2 N(R 21 2 in which R 1 8 is -C 6 H 5 phenyl which is substituted by 1 to 3 methyl or methoxy or -NO 2 or F or Cl, or Cl-C 4 alkyl, which is substituted by F; R 40 is phenyl which is unsubstituted or substituted by 1 to 3 methyl or methoxy or -NO 2 or F or Cl; Rig is H, Cl-C 6 alkyl, phenyl-(CH 2 with z equal to a number from 1 to 3, phenyl-CH=CHCH 2 -CH 2 -CH(CH 3 2 or benzyl; and R 21 is -CH 2 -CR 22 R 23 R 24 in which R 22 and R 23 methyl, ethyl or phenyl and R 24 is H, ethyl or methyl; or (iii) R 4 is C 6 H 11 CH1 2 -C 6 H 5 (CH 2 2 -C 6 H 5 methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents; selected from the group consisting of NH 2 cyclo- hexyl, C6-C 10 aryl, RBC(O)N(R 9 RBS(O) 2 N(R 9 NRgC(O)NHR 8 and R 8 ,R 9 in which R 8 R 9 R 8 and R 9 are, independently of one another, hydrogen, Cl-Cl 2 alkyl, C3-Cl2cycloalkyl, C6-Cj 0 aryl or C7-Cliaralkyl which are unsubstituted or substituted by one or more substitu- ents selected from the group consisting of OH, halogen, C(O)OMy, nitro, cyano, SO 3 MY, OSO 3 My, NR 20 SO 3 MY, Cl-Cl 2 alkyl, Ci-C 1 2 alkoxy and C6-Cloaryl, where R 20 is hydrogen, C, -Cl 2 alkyl, C2-Cl 2 alkenyl, 03-Cl 2CYCloalkyl, C3-Cl2cycloalkenyl, 02-Ciliheterocycloalkyl, C 2 -C 1 i-heterocycloalkenyl, C6-Cloaryl, Cs-Cgheteroaryl, C7-Cl 1 aralkyl, C6-Cloheteroaralkyl, C8-C1l-aralkenyl or C7-Cloheteroaralkenyl, y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. A compound according to claim 42, wherein R 4 is C 6 HI 1 CH(CH 3 2 CH 2 -phenyl, (CH2) 2 -phenyl, CH2NHC(O).phenyl, CH2NHC(O)(CH 2 3 -phenyl, CH2NHC(O)(CH1 2 3 oH, CH1 2 NHC(O)CF 3 CH 2 NHC(O)C 6 H 1 CH 2 NHC(O)0 11 H 2 3 CH2NHC(O)CH(C6H 5 2 CH2HNC(O)NHC 6 H 5 CH2NHC(O)C 2 H 4 C0 2 Na, CH 2 NHC(O)C6[(1 ,3,4,5)OH 4 H 7 CH2NHC(O)C 6 H 4 -P..SO3Na, CH 2 NHC(O)C 6 H 4 CI, CH 2 NHC(O)C 6 H 4 N0 2 CH2NHC(O)C 6 H 4 0CH 3 CH 2 NHC(O)C 6 H 4 (3,4)CI 2 CH2NHC(O)C 6 H 4 cH 3 CH 2 NHC(O)C6H 4 C 6 H 5 CH 2 NHC(O)C6H 4 CN, CH 2 NHC(O)C 0 H 7 CH2NHC(O)C6H 4 000Na, CH2NHC(O)(CHOH) 2 COONa, CH2N(CH2CH=CH..phenyl)[C(o).phenyl], CH2N[CH2CH(CH 3 2 1C(O).phenyll, CH2N[C(O)C 6 HsICH 2 C 6 H5, CH2N[C(O)C 6 H 5 ](CH 2 3 0 6 H 5 CH 2 C 6 H 11 (CH 2 2 C 6 H 11 CH 2 NH 2 CH2NHCH 2 CH=CH-phenyl, CH2NHCH 2 -phenyl, CH 2 NHCH 2 CH(CH 3 2 CH 2 N(CH 2 -phenyl) 2 CH 2 N[CH 2 CH(CH 3 2 j 2 CH2NHS0 2 -p-nitrophenyl, WO 97/01569 PCT/EP96/02785 -130- CH 2 NHSO 2 -p-tolyl, CH 2 NHSO 2 CF 3 CH 2 NHC(O)NHC 6 Hs or 2 -p-nitrophenyl][CH 2 CH(CH 3 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 3 OH HO R12 in which R 2 and X have the meanings mentioned in claim 1, R 1 2 is a protective group and R1 2 and R 12 are, independently of one another, hydrogen or a protective group, with a compound of the formula VI R 1 -R 13 (VI) in which R, has the meaning mentioned in claim 1 and R3 is a leaving group, and elimina- ting 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 HO.x O R2F O OR12 OR 12 OR 1 2 (VII), WO 97/01569 PCT/EP96/02785 131 in which R 2 and X have the meanings mentioned in claim 1, and R 12 is a protective group, with the protected galactose of the formula Vill JPR12 (Vill), I -OR OR12 12 in which R, and R 1 2 have the meanings mentioned in claim 1, Z is 0 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 X is the residue of a non-glycosidic aliphatic 1 ,2-diol; R 2 is hydrogen, Cl-Cl 2 alkyl or Cearyl; 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 1 OC(O)R,4, C(O)RS 2 nitro, NH 2 cyano, SO 3 My, OSO 3 My, NR 20 SO 3 My, C 1 -C 12 alkyl, C2-Cl 2 alkenyl, C 1 -C 12 alkoxy, C3-Ci 2 cycloalkyl, C 3 -C 1 2cycloalkenyl, 02-Cl ~heterocycloalkyl, 02-Oliheterocycloalkenyl, C6-Cloaryl, C6-Ci 0 aryloxy, C5-Ogheteroaryl, Cs-Cgheteroaryloxy, C 7 -C 1 1 aralkyl, C7-C1 1 aralkyloxy, C6-Cloheteroaralkyl, 08-Cl aralkenyl, C7-Coheteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where R~j is hydrogen, My, Cl -C 12 alkyl, 02-Cl 2 alkenyl, C3-Cl 2 cycloalkyl, C2-Cl iheterocycloalkyl, P:\OPER\MJC\63053-96.SPE 15/3/99
12. 132- or C 7 -Co 1 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteraralkenyl 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/ and M is a divalent metal; R 5 and R 6 are, together with the -CH-CH- group, C 3 -C 12 cycloalkylene, C 3 -C 12 cycloalkenylene, C 2 heterocycloalkylene and C 3 -C,,heterocycloalkenylene with hetero atoms selected from the group and where cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more of the above substituents; R 12 is a protective group and R 12 and R 12 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 15 claim 48 which comprises initially synthesizing pseudo-trisaccharide building 0 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 R into the pseudotrisaccharide and subsequently modifying the resulting compounds in the desired manner. 50. A method of treating inflammation in warm-blooded animals, including animals, comprising administration of a therapeutically effective amount of a compound according to claim 1. 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. 52. Use of a compound according to claim 1 for the preparation of a medicament SA for the treatment of inflammation. P:\OPER\MJC\63053-96.SPE 15/3/99 133 53. A compound according to claim 1 substantially as hereinbefore described with reference to any one of the examples. 54. A process according to claim 46 or claim 47 substantially as hereinbefore described with reference to any one of the examples. DATED this 15th day of March, 1999 Novartis AG By DAVIES COLLISON CAVE Patent Attorneys for the Applicant ee 0@ @0 0 6 0e 0 0 060 S 0 0 0000 00 0. 00 0 6 Ob 0 0 006 0060 0 0 @0 0 6@@0 0* 6 00 00 0 0 S 00 0 6 060. 0 000000 6 6