SK177897A3 - Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a - Google Patents

Abstract

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

Description

Technical field

The invention relates to sialyl-Lewis X and sialyl-Lewis A mimetics, in which in the natural tetrasaccharide the neuraminic acid residue is replaced by a methyl group in the S-configuration substituted by one carboxyl residue and one additional substituent and the N-acetylglucosamine residue is replaced by a non-glycoside residue 1,2 -diol, methods for their preparation and their use as mimetics in therapeutic methods.

BACKGROUND OF THE INVENTION

The complex inflammatory process, which takes place in several stages, is the body's natural response to injuries, which also infect substances, for example. As a result of cytokines, the endothelium, which loses blood vessels, pushes adhesion proteins to its surface. P and E selectins act by interacting with protein-saccharide with glycolipids and glycoproteins on the leukocyte membrane, i. winding of leukocytes. This is retarded by this procedure and activates certain proteins (integrins) on their surface, which provides for a firm adhesion of the leukocytes to the endothelium. This is followed by the migration of leukocytes into the damaged tissue.

If this process is controlled, the damage is eliminated after a certain period of time without major persistent adverse effects. This is otherwise the case for certain acute and chronic inflammatory processes in which leukocyte migration occurs in an uncontrolled manner, leading to severe body damage. This is the case in diseases such as cardiogenic shock, myocardial infarction, thrombosis, rheumatism, psoriasis, dermatitis, acute respiratory distress syndrome and metastatic cancer [Dasgupta F., Rao B.N.N., Exp. Opin. Invest.Drugs 3: 709-724 (1994)].

Several attempts to develop drugs that interfere at different stages of these adverse processes have been performed [Dasgupta F., Rao B.N.N., Exp.Opin.Invest.Drugs 3: 709-724 (1994)]. The aim of one of these methods is to prevent the interaction between P and E selectins and their receptors on the leukocyte membrane and thus prevent coiling by mimetics of the corresponding epitopes. It also leads to suppression of subsequent processes. One of the smallest carbohydrate epitopes as ligand for E selectin is sialyl-Lewis X [neuraminic acid-α (2-> 3) -galactose-β- (1-> 4) - (fucose-α- (1-> 3)) -N-acetylglucosamine (sLe)].

EP-A-0 579 196 proposes mimetics of sLe * in which the neuraminic acid residue is replaced by a lactic acid residue as compounds competing with the natural ligand for binding to E selectin. WO 93/10 796 discloses compounds which contain an α-hydroxy acid residue instead of a neuraminic acid residue. WO 93/23 031 discloses mimetics in which the N-acetylglucosamine residue (GlcNAc residue) is replaced by R, R-1,2-cyclohexanedioxy. However, all of these compounds have in common that the binding affinity between them and E selectin increases only marginally compared to the binding affinity with sLe * or is in fact worse and is therefore unsatisfactory for the therapeutic effect.

SUMMARY OF THE INVENTION

It has now been found that the simultaneous replacement of a neuraminic acid residue with an S-configuration methyl group substituted with one carboxyl residue and one other substituent and a N-acetylglucosamine residue with a non-glycoside residue of an aliphatic diol causes an unexpected high affinity binding of the mimetic formed. Moreover, these novel compounds represent structural and chemical simplification, have a lower molecular weight and can be obtained in larger quantities by less complicated synthesis methods.

The present invention provides compounds of formula I

X is the residue of a non-glycoside aliphatic 1,2-diol,

R ¹ is a methyl group in the S-configuration substituted by one carboxyl residue and one other substituent, and

R ² is H, alkyl of 1 to 12 carbon atoms or aryl of 6 carbon atoms, wherein the alkyl and aryl are unsubstituted or substituted by one or more subscituencami selected from a OK, flavorings halogen, C (O) OR ^d1 , OC (0) ^R ", C (C) R ^{s 2,} nizroskupinu, NH 2, CN, SO ^ .M, OSO3M ^, NR ²⁰ SO2 Me, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 C C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 aryl up to 10 carbon atoms, aryloxy of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, heteroarloxy of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, aralkyloxy (C až-C ar) heteroaryl, (C až-C hetero) heteroarylalkyl, (C až-C ar ar) aralkenyl, (C až-C hetero hetero) heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamoyl, carbamate, sulfonhydrazide, carbohydrazide, carbohydroxamic acid and aminocarbonylamide, wherein R is hydrogen, My, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 alkenyl, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms or heteroaralkyl of 6 to 10 carbon atoms, R is hydrogen, C1 -C12 alkyl, C2 -C12 alkenyl; 10-carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms or heteroaralkyl (C až-C R) group and R ^{s a2} and R a ^sú are hydrogen, (C až-C alkyl) alkyl, (C až-C alk) alkenyl, (C až-C cyk) cycloalkyl, (C cyk-C 12) cycloalkenyl group carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl (C 6 -C 10), (C 8 -C 11) aralkenyl or (C 7 -C 10) heteroaralkenyl carbon, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, or aralkenyl, and aralkenyl; substituted with one of the above substituents, ay is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, including physiologically acceptable salts thereof.

Preferred aliphatic radicals X are straight or branched alkylene and alkenylene groups having 2 to 20, preferably 2 to 12 and particularly preferably 2 to 6 carbon atoms, cycloalkylene and cycloalkenylene groups having 3 to 12, preferably 3 to 8, and particularly preferably And 5 to 7 carbon atoms, and heterocycloalkylene and heterocycloalkenylene groups having 3 to 11, preferably 3 to 7, and particularly preferably 3 to 5 carbon atoms, with heteroatoms selected from the group consisting of -O-, -S- and -N-.

The residue X may comprise; substituents such as OH, halogen, C (O) OR ^S, OC (O) R ^S, C (O) R ^s2 , nitro, NH 2, cyano, SO- ^ My, OSO- ^ My, NR ²⁰ SO 3 My, (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 1 -C 12) alkoxy, (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, aryloxy of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, heteroaryloxy of 5 to 9 carbon atoms, aralkyl of 7 C 1 -C 11 aralkyloxy, C 7 -C 10 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl, C 7 -C 10 heteroaralkenyl, primary amino, secondary amino upina, sulfonyl, sulfonamido, carbamoyl, carbamate, sulfonhydrazine, carbohydrazide, carbohydroxamic acid and aminocarbonylamide ¢ -, 1, wherein R is hydrogen, My, C 1 -C 12 alkyl, C 2 alkenyl C 1 -C 12 cycloalkyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or (C 6 -C 10) heteroaralkyl, R is hydrogen, (C 1 -C 12) alkyl, (C 2 -C 10) alkenyl, (C 3 -C 12) cycloalkyl, (C 2 -C 11) heterocycloalkyl, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, aralkyl group pina having 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 and R ²⁰ are H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 3 carbon atoms, aralkyl sc with 7 to 11 carbon atoms, heteroaralkyl of 5 to 10 carbon atoms, aralkenyl of 8 to 11 carbon atoms or heteroaralkenyl of 7 to 10 carbon atoms, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl group, heterocycloalkenyl, aryl, arylcyclo, heteroaryl, heteroar yloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are, in turn, unsubstituted or substituted by one of the above 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 invention, it corresponds to the general formula II

X a residue of 1,2-diol

and R 6 are independently hydrogen, C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, heteroaryl C 5 -C 9 aralkyl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl, or R ⁵ and R 0 together with the -CH-CH- group form a C 3 -C 12 cycloalkylene group, a cyclcalkenylene group C 3 -C 12 heterocycloalkylene, C 2 -C 11 heterocycloalkylene and C 3 -C 11 heterocycloalkenylene, heteroatoms selected from the group consisting of -O-, -S- and -N-, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylene, cycloalkenylene, heterocyclo the alkylene group and the heterocycloalkenylene group are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR ^S, O (O) R ^S , C (O) R ^{s 2} , nitro, NH 2, cyano, We SO ^, ^ OSO- My, ^NR20 _SO3 My, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms , (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, (C 6 -C 10) aryloxy, (C 5 -C 5) heteroaryl (C hetero-C hetero) heteroaryloxy (C až-C 9) heteroaryloxy, (C až-C ar) aralkyl (Cal-C ar), (C až-C n) aralkyloxy (C až-C 10) ka, C 8 -C 11 aralkenyl, C 7 -C 10 heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamido, carbamoyl, carbamate, sulphonhydrazide, carbohydrazide, carbohydrazide, carbohydrazide, R is hydrogen, My, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycioalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 atoms carbon, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms or heteroaralkyl of 6 to 10 carbon atoms, R is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 10 atoms C 3 -C 12 cycloalkyl, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and ^R ^ and R C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 5 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cyclo alkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted with one of the aforementioned substituents; the metal or y is 1/2 and M is a divalent metal.

The other substituents in R ¹ preferably have 1 to 20, more preferably 1 to 16, particularly preferably 1 to 12 and particularly preferably 1 to 8 carbon atoms. These other substituents are preferably selected from the group consisting of alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 12 carbon atoms C 11 -C 10 heterocycloalkenyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, aralkenyl (C až-C 11) and C 7-C hetero hetero (C až-C hetero) heteroaralkenyl, which are unsubstituted or substituted. Another substituent is preferably selected in particular from the group consisting of substituted methyl, or 2-substituted ethyl or cyclohexyl. Examples of suitable substituents are the substituents for R ^z , in particular 0-4, possibly the higher halogen atom (fluorine,

C (0) 0M

SO ₃ M _y , OSO ₃ M _y , chloro or bromo), carboxy, -SO ₃ H, [R ²⁰ SO ₃ M _y , where R ²⁰ is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 (C až-C ac) cycloalkyl, (C až-C ac) cycloalkyl, (C až-C až) cycloalkenyl, (C až-C heteroc) heterocycloalkyl, (C až-C heteroc) heterocycloalkenyl, (C až-Cry) aryl group, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, or C 1 alkyl -C 12 alkyl, C 1 -C 12 alkyl, nitro, _-NH2, primary amino with 1 to 20 carbon atoms, secondary amino with 2 to 30 carbon atoms, cyano, cycloalkyl (C 8-C 8) group, (C až-C heteroc heteroc) heterocycloalkyl, (C až-C 9 hetero) aryl, (C až-C hetero hetero) heteroarryl, (C 7-C 16 heter) heteroaralkyl group, wherein the heteroatoms are selected from the group consisting of C skupiny-C 16 16; comprising 0, S and N atoms, and a carbamoyl group, carbamate group, carbohyarazide group, sulfonamide group, sulfonhydrazide group or aminocarbonylamide group, whose N atoms are unsubstituted or substituted by a hydrocarbon group or a hydroxy-hydrocarbon group having 1 to 20 carbon atoms. Hydrocarbon groups and heterocarbons are, in turn, unsubstituted or substituted by, for example, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, carboxy, halogen (fluorine, chlorine or bromine), -OH, -CN or -NO ₂ .

Particularly preferred are compounds of formula I wherein R * is a group of formula III (III)

where

R ³ is hydrogen or My, and

R ⁴ is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, heterocycloalkenyl C 2 -C 11 aryl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or a C7 -C10 heteroaralkenyl group which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) ^OR11 , OC (O) R. ^s4, C (O) R ^s2, nitro, NH 2, CN, SO 3 M, OSO3My, NR ²⁰ SO 3 M _y, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, (C 5 -C 10) aryloxy group C 5 -C 9 heteroaryl, C 5 -C 9 heteroaryloxy, C 7 -C 11 aralkyl, C 7 -C 11 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 aralkenyl C7 -C10 heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamoyl a carbamate group, a sulfonhydrazide group, a carbohydrazide group, a carbohydroxamic acid and an aminocarbonylamide group wherein R ^s1 is a hydrogen atom, M, an alkyl group having 1 to carbon atoms, an alkenyl group having 2 to 12 carbon atoms, a cycloalkyl group having 3 to 12 atoms atoms, the heterocycloalkyl group having 2 to 11 carbon atoms, aryl of up to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, R ^s4 · a a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, a heterocycloalkyl group having 2 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group C 5 -C 9, aralkyl C 7 -C 11, or heteroaralkyl having 6 to 10 carbon atoms, and R ^s2 and R ²⁰ are H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl (C 6 -C 10) aralkyl, (C 8 -C 11) aralkenyl, or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy , heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralk the alkyl group, the aralkenyl group and the heteroaralkenyl group are again unsubstituted or substituted by one of the above substituents, ay is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

By metal for the purposes of the present invention is meant an alkali metal (e.g. lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs)), an alkaline earth metal [e.g. magnesium (Mg), calcium (Ca) ) and strontium (Sr)] or manganese (Mn), iron (Fe), zinc (Zn) or silver (Ag). Physiologically acceptable salts are in particular alkali metal salts and alkaline earth metal salts, for example sodium, potassium, magnesium and calcium salts. Sodium and potassium ions and salts thereof are preferred.

By halogen is meant a representative group consisting of fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred, especially fluorine and chlorine.

The alkyl group may be straight or branched, preferably branched once or twice in the c-position. Examples of alkyl groups, preferably having 1 to 12 carbon atoms, include methyl, ethyl, and isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Preferred alkyl groups are methyl, ethyl, n- and isopropyl, n-, iso- and tert-butyl.

Examples of alkenyl groups include allyl, but-1-en-3-yl or -4-yl, pent-3- or -4-en-1-yl or -2-yl, hex-3- or -4 - or -5-en-1-yl or -2-yl and a group of formula (C 1 -C 4 alkyl) CH = CH-CH 2 -.

The cycloalkyl and cycloalkenyl group may preferably contain 5 to 8 and particularly preferably 5 or 6 ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Cyclohexyl is particularly preferred. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, cycloundecenyl and cyclododecenyl. Cyclohexenyl is particularly preferred.

Examples of alkylene groups include ethylene,

1,2-propylene, 1,2- or 2,3-butylene, 1,2- or 2,3-pentylene,

1,2-, 2,3- or 3,4-hexylene. Examples of cycloalkylene groups include 1,2-cyclopropylene, 1,2-cyclobutylene,

1,2-cyclopentylene, 1,2-cyclohexylene, 1,2-cycloheptylene and 1,2-cyclooctylene. Examples of heterocycloalkylene groups include pyrrolidinylene, piperidinylene, tetrahydrofuranylene, di- and tetrahydropyranylene.

As examples of heterocycloalkyl groups, the groups are derived from pyrrolidine, imidazolidine, oxazolidine, pyrazolidine, piperidine, piperazine and morpholine. As examples of heterocycloalkenyl groups, the groups are derived from 2- and 3-pyroline, oxazoline, 2- and 4-imidazoline and 2- and 3-pyrazoline.

For the purposes of the present invention, an aryl or heteroaryl group refers to a five- or six-membered ring or a bicyclic ring consisting of two fused six- or five-membered rings or one six-membered and one-membered ring and in the case of a heteroaryl group one or more carbon atoms may be independently replaced by an atom selected. from the group consisting of oxygen, nitrogen and sulfur. Examples include benzene, naphthalene, indene, furan, pyrrole, pyrazole, imidazole, isoxazole, oxazole, furazan, thiadiazole, thiophene, thiazole, oxadiazole, triazole, indole, indazole, purine, benzimidazole, benzoxazole, benzothiazole, benzothiazole, pyran, pyridine, pyridazine, triazine, pyrimidine, pyrazine, isoquinoline, cinoline, phthalazine, quinoline, quinazoline, pteridine, benzotriazine or quinoxaline. The aryl group is preferably naphthyl or phenyl. Phenyl is particularly preferred. The heteroaryl group is preferably furanyl, pyridinyl and pyrimidinyl.

The aralkyl group preferably has 7 to 12 carbon atoms and may be phenyl-C _n H _2n -, where n is 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 - (cinamyl) and cinamyl substituted on the phenyl with a substituent selected from the group consisting of OH, halogen, COOH, C (O) OMy, C 1 -C 12 alkyl, (C 1 -C 6) alkoxy, (C 6 -C 10) aryl, SO 4 My, OSO ₃ M _y , NR ²⁰ SO ₃ My, wherein R ²⁰ is hydrogen, C 1 -C 12 alkyl, alkenyl (C 2 -C 12) cycloalkyl, (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl (C 6 -C 10) aryl group carbon atoms, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or heteroaralk C 7 -C 10 enyl, furthermore NC> 2, C 1 -C 12 primary amino, C 2 -C 20 secondary amino, amino and CN.

The heteroaralkyl and heteroaralkenyl groups are preferably heteroarylmethyl and heteroaryletenyl having from 4 to 5 carbon atoms in the heteroaryl having one or two heteroatoms selected from the group consisting of O and N, and the heteroaryl group may be the aforementioned heteroaryl radicals.

The alkoxy group may be straight or branched, preferably one or two branches in the α-position. Examples which may be mentioned are alkoxy groups having 1 to 12 carbon atoms, such as methoxy, ethoxy and isomers of propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy and dodecoxy groups and dodecoxy groups. Preferred are methoxy and ethoxy.

Examples of aryloxy and aralkoxy include phenoxy and benzyloxy. Heteroaryloxy is preferably furanyloxy, pyridinyloxy and pyrimidinyloxy.

The primary amino group preferably contains 1 to 12, particularly preferably 1 to 6 carbon atoms. Examples are methylamino, ethylamino, hydroxyethylamino, n- or isopropylamino, n-, iso- or tert-butylamino, pentylamino, hexylamino, cyclopentylamino, cyclohexylamino, phenylamino, methylphenylamino, methylphenylamino and methylphenylamino. The secondary amino group preferably contains 2 to 14, particularly preferably 2 to 8, carbon atoms. Examples which may be mentioned are dimethylamino, diethylamino, methylethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diphenylamino, dibenzylamino, morpholino, piperidino and pyrrolidino.

NH 2, primary amino, secondary amino, carbamoyl, carbamate, carbohydrazide, sulfonamide, sulfonhydrazide, and aminocarbonylamide preferably correspond to R ⁸ C (O) (NH) p N (R ⁹ ) -, -C (O) ( NH) pNR ⁸ R ⁹ , R ⁸ OC (O) (NH) p N (R ⁹ ) -, R ⁸ R ⁴⁰ NC (O) (NH) p N (R ⁹ ) -, - 0C (0) (NH) NR ⁸ R ⁹ , -N (R ⁴⁰ ) C (O) (NH) p NR ⁸ R ⁹ , R ⁸ S (O) 2 (NH) p N (R ⁹ ) -, -S (O) 2 (NH) p NR ⁸ R ⁹ , R ⁸ R ⁴ NS (O) 2 N (R ⁹ ) - or -NR ⁴⁰ S (O) 2 NR ⁸ R ⁹ , wherein R ⁸ , R ⁹ and R ⁴⁰ independently of one another are hydrogen, OH, alkyl C 1 -C 12 alkenyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 10 carbon atoms C 15 -C 16 aralkenyl, C 2 -C 6 alkenylene and C 6 -C 10 aryl, C 6 -C 15 heteroaralkyl, C 6 -C 15 heteroaralkenyl, or diarylalkyl having 6 to 10 carbon atoms in the aryl moiety and having 1 to 6 carbon atoms in the aryl moiety

Q ¹ QIQIQI alkyl, or R R N, wherein R and R are independently H, OH, SO ^ We, OSO3M, alkyl of 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 atómamiuhlíka, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 8 aralkenyl (C s-C alk alk) alkenylene (C až-C alk alk) aryl or Clal-Cry di (C až-C di di) aryl and C až-C di di (Clal-C di di) diarylalkyl group which are unsubstituted or substituted by one or a plurality of substituents selected from the group consisting of OH, halogen, C (O) OR ^s , OC (O) R ^s4 , C (O) R ^s2 , nitro, NH ₂ , cyano, SO ₃ M, OSOnM, NR ²⁰ SOnM, alk C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 1 -C 12 -alkoxy, C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 2 -C 11 -heterocycloalkyl carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, aryloxy of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, heteroaryloxy of 5 to 9 carbon atoms, aralkyl of 7 (C-C,), (C až-Cal) aralkyloxy, (C až-C hetero) heteroaralkyl, (C až-C ar) aralkenyl, (C až-C hetero) heteroaralkenyl, primary amino, secondary amino, sulphonyl, sulphonamido carbamoyl group, carbamate group, sulfone hydrazide group, carbohydrazide group Upin, carbohylamino-aminocarbonylamide and aminocarbonylamide, wherein R is hydrogen, M, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, heterocycloalkyl (C 2 -C 11), (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl or C 6 -C 10 heteroaralkyl, R is hydrogen, alkyl C 1 -C 12 alkenyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl , aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms and R ^s2 is hydrogen, alkyl of 1 to 12 carbon atoms, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl, or C 7 -C 8 heteroaralkenyl group 10 carbon atoms, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, aralkyl, and aralkyl, heteroaralkyl, and aralkyl; nesub substituted or substituted with one of the above 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 R ⁸ R ⁴⁰ N- together form a tetramethylene group, pentamethylene group, - (CH 2) 2 ( ^CH 22 '- (CH ₂ ) ₂ - S- (CH ₂ ) ₂ - or - (CH ₂ ) ₂ -NR ⁷ - (CH ₂ ) ₂ -, and R ⁷ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 7 to 11 carbon atoms , C (O) R or sulfonyl.

Sulfonyl substituent 10

R ¹⁰ -SO ₂ -, wherein R ^{± u} is an alkyl carbon, a 3-rocycloalkyl group having 2 to 6 carbon atoms, or, for example, a formula of 1 to 12 carbon atoms to 12 carbon atoms, hete 11 carbon atoms, aryl of up to 10 carbon atoms, heteroaryl of 5 carbon, aralkyl of 7 to 11 atoms heteroaralkyl of 6 to 10 carbon atoms which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) ^s4 OR, OC (O) R ^s4, C (O) R ^s2, nitro, NH 2, CN, SO ^ We, we OSO- ^, NR ²⁰ SO 3 M, an alkyl group of 1 to 12 carbon atoms, alkenyl of 2 C 1 -C 12 alkoxy, C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, heterocycloalkenyl 8 nu of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, aryloxy of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, heteroaryloxy of 5 to 9 carbon atoms, aralkyl of 7 to 11 atoms carbon, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl, C 7 -C 10 heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamoyl, carbamide, carbohydrazide, sulfonhydrazide, sulfonhydrazide a carbohydroxamic acid and an aminocarbonylamide group wherein R is a hydrogen atom, a C 1 -C 12 alkyl group, a C 2 -C 12 alkenyl group, a C 3 -C 12 cycloalkyl group, a C 2 -C 11 heterocycloalkyl group C, a a a ary ary a a aryryry a a ary a ary a (Cδ až a a a a a hetero aryry a) (C1-C6) -alkyl, (C1-C6) -alkyl, (C1-C6) -alkyl, or (heteroaralkyl) -carbon, R (4) is hydrogen, carbon, (C2-C12) alkenyl, (C3-C12) cycloalkyl; , the heterocycloalkyl group having 2 to 11 carbon atoms., an aryl group having 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and ^R R 6 and R 6 O are hydrogen, alkyl having 2-6 carbon atoms;

C 1 to C 12 alkenyl, C 2 to C 12 alkenyl, C 3 to C 12 cycloalkyl, C 3 to C 12 cycloalkenyl, C 2 to C 11 heterocycloalkyl, C 2 to C 11 heterocycloalkenyl , (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 8 aralkenyl

II carbon atoms or C7 -C10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heteroalkyl, aralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted by one of the above substituents, ayjel and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Preferred compounds of formula I are those in which X corresponds to the group of formula II, wherein R ⁵ and R ⁶ is (a) unsubstituted or substituted alkyl of 1 to 12 carbon atoms, e.g., methyl or ethyl, or alkoxy of 1 to 12 (b) together with the -CH-CH- group, a 5- to 8-membered carbocyclic ring, and preferably a 5- or 6-membered carbocyclic ring, and especially preferably R, R1, 2-cyclohexylene, (c) together with a - group; CH-CH- a 5- to 8-membered heterocarbocyclic ring and particularly preferably a 5- or 6-membered heterocarbocyclic ring with a nitrogen atom as the heteroatom and particularly preferably R, R-3,4-piperidylene, (d) independently of one another a hydrogen atom, an unsubstituted 1 to C 12 -alkyl or C 1 -C 12 -alkyl substituted with a substituent selected from C 1 -C 12 the group consisting of -C (O) OR ^s1 , -OC (O) R ^s4 , -C (O) ONa or -C (O) OK, a primary amino group, a secondary amino group, a C 3 -C 12 cycloalkyl group, an alkoxy group C 1 -C 6, phenyloxy and benzyloxy, unsubstituted C 3 -C 12 cycloalkyl, or C 3 -C 12 cycloalkyl substituted with a substituent selected from -C (O) OR ^S 1, -OC (O) R ^ ^s, C (O) ONa or -C (O) OK, primary amino, secondary amino, C 1 -C 6 alkyl, C 1 -C 6 alkyl, phenyloxy and benzyloxy, aryl, C 6 -C 10 unsubstituted or substituted with a substituent selected from the group consisting of -C (O) OR ^s1 , -OC (O) R ^s4 , -C (O) ONa, or -C (O) OK, a primary amino group , a secondary amino group, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group a C 1 -C 6 group, a C 3 -C 9 heteroaryl group having 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen, or an C 7 -C 12 aralkyl group which is unsubstituted or substituted with a substituent selected from the group including the groups -C (O) OR ^s1 , -OC (O) R ^s4 , -C (O) ONa or -C (O) OK, a primary amino group, a secondary amino group, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms; (e) together with a -CH-CH- group of 5- to 12-membered carbocyclic ring or a 5- or 6-membered heterocarbocyclic ring with a heteroatom selected from the group consisting of oxygen and nitrogen, or (f) together with -CH-CH - cycloalkylene of 3 to 12 carbon atoms, cycloalkenylene of 4 to 12 carbon atoms, heterocycloalkylene of 2 to 11 carbon atoms and heterocycloalkene (C až-C 11) heteroarylene selected from the group consisting of -O-, -S- and -N-, wherein the cycloalkylene, cycloalkenylene, heterocycloalkylene, and heterocycloalkenylene are unsubstituted or substituted with one or more substituents selected from the group OH, halogen, C (O) OR ^sl, 0C (0) R ^s4, C (0) R ^{s 2,} nitro, NH _2, CN, SO ^ We, OSO-INJURY, NR ²⁰ SO INJURY, C C 1 -C 12 alkenyl, C 2 -C 12 alkenyl, C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 5 -C 9 heteroaryl, h (C 5 -C 9) aeroaryloxy, (C 7 -C 11) aralkyl, (C 7 -C 11) aralkyloxy, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl, (C 7 -C 10) heteroaralkenyl , a primary amino group, a secondary amino group, a sulfonyl group, a sulfonamide group, a carbamoyl group, a carbamate group, a sulfonhydrazide group, a carbohydrazide group, a carbohydroxamic acid and an aminocarbonylamide group wherein R ⁵ · ¹ · is hydrogen, My, , C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 aralkyl or heteroaralkyl having from 6 to 10 carbon atoms R is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and ^R ^ and R ^ _p U is H, alkyl of 1 to 12 carbon atoms , C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 aryl up to 10 carbon atoms, 5 to 9 carbon heteroaryl, 7 to 11 carbon aralkyl, 6 to 10 heteroaralkyl carbon, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, , aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted by one of the above substituents, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Particular preference is given to those compounds in which X corresponds to a group of the formula II in which R ⁸ and R ⁸ together with the -CH-CH- group form a C 3 -C 12 cycloalkylene or a C 2 -C 11 heterocycloalkylene group such as nitrogen as heteroatom wherein the cycloalkylene group and heterocycloalkylene group are unsubstituted or substituted with one or more of the above substituents.

Particularly preferred are those wherein R ⁵ and R ⁶ together with the -CH-CH- group form a C 3 -C 12 cycloalkylene group or a C 2 -C 11 heterocycloalkylene group with a nitrogen atom as the heteroatom, wherein the cycloalkylene group and the heterocycloalkylene group are unsubstituted or substituted with one or more 1 substituents selected from OH, C (O) oR G, -OC (O) R ^s4, C (O) ^R 2, NR ⁸ R ^9, alkyl of 1 to 12 carbon atoms , R ⁸ C (O) (NH) N (R ⁹ ) -, - C (O) (NH) p NR ⁸ R ⁹ , R ⁸ S (O) 2 (NH) _p N (R ⁹ ) -, R ⁸ R ⁴⁰ NC (O) (NH) pN (R ⁹ ) -, R ⁸ C (O) (NH) N (R ⁹ ) -, -OC (O) (NH) p NR ⁸ R ⁹ and R ¹⁰ -SO ² - wherein R ⁸ , R ⁹ , R ¹⁰ and R ⁴⁰ are each independently hydrogen, OH, (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 3 -C 12) cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl; C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 16 aralkyl, C 8 -C 16 aralkenyl with alkenylene moiety (C 2 -C 6) -alkyl, (C 6 -C 10) -aryl, (C 6 -C 15) heteroaralkyl, (C 6 -C 15) heteroaralkenyl, or (C 6 -C 10) diarylalkyl (C 1 -C 6) aryl alkyl, unsubstituted or substituted by one or more substituents selected from OH, halogen, C (O) oR ^bs, OC (O) R ^s4, C (O) R ^s2, nitro, NH _2, CN C 1 -C 12 alkyl, C 1 -C 12 alkyl, C 1 -C 12 alkyl, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 1 -C 12 alkoxy, cyclic (C 3 -C 12) alkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, (C 6 -C 10) aryloxy group carbon atoms, C 5 -C 9 heteroaryl, C 5 -C 9 heteroaryloxy, C 7 -C 11 aralkyl, C 7 -C 11 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 aralkenyl up to 11 carbon atoms, 7 to 10 carbon heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamido, carbamoyl, carbamate, sulfonhydrazide, carbohydrazide, carbohydroxamic acid, and aminocarbonylamide, where R is, C 1 -C 12 alkyl; C 1 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 5 -C 9 aralkyl C 7 -C 11 heteroaralkyl or C 6 -C 10 heteroaralkyl, R is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, heterocycloalkyl 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 is hydrogen, C C 1 -C 12 alkenyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, cycloalkenyl (C 3 -C 12) group, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl group carbon atoms, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl , aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl as substituents are again unsubstituted or substituted by one of the above substituents, p is 0 or 1 and y is 1 and M is a monovalent metal or y is 1/2 and M is divalent metal.

R (a) are, in particular, independently of one another, a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 1 to 12 carbon atoms up to 6 carbon atoms in the alkylene moiety and 6 to 10 carbon atoms in the aryl moiety, an aralkenyl group of 8 to 16 carbon atoms with 2 to 6 carbon atoms in the alkenylene moiety and 6 to 10 carbon atoms in the aryl moiety, or a diarylalkyl group having (C až-C 10) aryl group and (C až-C,) alkyl group, for example diphenylmethyl or

Q Q

2,2-diphenylethyl, wherein R and R are unsubstituted or substituted by one or more substituents selected from the group consisting of OK, halogen, COOH, C (O) OMy, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 6 atoms C 6 -C 10 aryl, C 6 -C 10 aryloxy, SO 4 M, OSO 4 M,

NR ²⁰ SO ₃ M, NO 2, amino, primary amino, secondary * 9 nu n amino and CN, R is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms C 12 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 6 aryl, C 5 -C 9 heteroaryl, aralkyl (C 7 -C 11), (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl or (C 7 -C 10) heteroaralkenyl group, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

R is in particular an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 16 carbon atoms having 1 to 6 carbon atoms in the alkylene moiety and 6 up to 10 carbon atoms in the aryl part, an aralkenyl group of 8 to 16 carbon atoms with 2 to 6 carbon atoms in the alkenyl moiety and 6 to 10 carbon atoms in the aryl moiety, or a diarylalkyl group with 6 to 10 carbon atoms in the aryl moiety and 1 -C 6 alkyl, for example diphenylmethyl or 2,2-diphenylethyl, which are unsubstituted or substituted by one or more substituents selected from OH, halogen, COOH, C (O) OM _yl, alkyl radical of 1 to 12 carbon atoms, C 1 -C 6 alkoxy, C 6 -C 10 aryl, SO 4 My, OSO 4 My, NR 5 SO 4 My, NO ₂ amino, primary amino, seconds amine and CN, wherein R is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of C 2 -C 11, C 2 -C 5 heterocycloalkenyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Further, · R ^1-0 is preferably an alkyl group having 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl having 7 to 16 carbon atoms having 1 to 6 carbon atoms in the alkylene having 6 to 10 carbon atoms in the aryl portion which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxy, C (O) OMy, alkyl of 1 to 12 carbon atoms, alkoxy of 1 C 6 -C 10 aryl, C 6 -C 10 aryl, SO 4 My, nitro, amino, primary amino, secondary amino and cyano, or C 8 -C 16 aralkenyl having 2 to 6 carbon atoms in the alkenylene moiety (C 6 -C 10) -aryl or diarylalkyl (C 6 -C 10 -aryl) and (C 1 -C 6) -alkyl parts such as diphenylmethyl or 2,2-diphenylethyl.

In a preferred subgroup of compounds R ³ and R ^8, together with the -CH-CH- group, form a C 3 -C 12 cycloalkylene group or a C 2 -C 11 heterocycloalkylene group with nitrogen as the heteroatom, wherein the cycloalkylene group and the heterocycloalkylene group are unsubstituted or substituted. by one or more substituents selected from OH, C (O) oR ^bs, OC (O) R ^s4, C (O) R ^{s 2,} NH 2, alkyl having 1 to 12 carbon atoms, R ⁸ C (O) N ( R ⁹ ) -, -C (O) NR ⁸ R ⁹ , R ⁸ S (O) 2 N (R ⁹ ) -, R ⁸ S (O) N (R ⁹ ) - and R ¹⁰ -SO ₂ -, where R ⁹ is hydrogen and R ⁸ is C 1 -C 12 alkyl, C 6 -C 10 aryl or C 7 -C 11 aralkyl which is unsubstituted or substituted by one or more C 1 -C 12 alkoxy groups , R ¹⁰ is an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, or aral (C až-C) alkyl group which is unsubstituted or substituted by one or more C až-C, alkyl groups, R ^{sl a} and R ^s4 are C až až alkyl alkyl groups and R R2 ^s is (C až až až) alkyl group carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms or aryl of 6 to 10 carbon atoms, and alkyl, cyclo27 alkenyl, cycloalkyl and aryl as substituents are in turn unsubstituted or substituted by one or more substituents selected from OH, C (O) oR ^sl and 0C (0) R ^s4, wherein R ^sl is M or CZL ^{1 2} alkyl of 1 to 12 carbon atoms and R is alkyl of 1 to 12 carbon atoms, y is I and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Particularly preferred compounds of this group are those wherein R 1 and R 2 together with the -CH-CH- group form cyclohexylene.

Another preferred subgroup of compounds are those wherein R 1 and R 2 together with the -CH-CH- group form piperidylene.

Particularly preferred are those wherein R 1 and R 2 together with the -CH-CH- group form piperidylene, wherein the non-heteroatom is unsubstituted or substituted with a substituent selected from the group consisting of C (O) OR ^S, C (O) R ^S , C (O) NR 4 R 6, NH 2, SO 4 M, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, (C 6 -C 10) aryloxy, (C 5 -C 5) heteroaryl (C uhlí-C hetero) heteroaryloxy, (C až-C hetero) heteroaryloxy, (C až-C ar) aralkyl (C až-C ar), (C až-C ar) aralkyloxy (C až-C hetero) heteroaralkyl, 1 carbon atoms, C7 -C10 heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, sulfonhydrazide, and one or more ring carbon atoms are unsubstituted or substituted by one or more substituents selected from OH, OC (O) ^R 4, NH 2, OSO ₃ M _y, NR SO ^ M, alkoxy of 1 to 12 carbon atoms, aryloxy of 6 to 10 carbon atoms, heteroaryloxy having 5 to 9 carbon atoms, aralkyloxyskupi28 is a hydrogen atom, We, a C 1 -C 12 alkyl group, a C 7 -C 11 hetene, a primary amino group, a secondary amino group, a sulfonamide group, a carbamoyl group, a carbamate group, a sulfonhydrazide group, a carbohydrazide group, a carbohydroxamic acid and an aminocarbamic acid a group wherein R ^with carbon atoms, alkenyl carbons, cycloalkyl groups; a 3-rocycloalkyl group having 2 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 5 to 9 carbon atoms, an aralkyl group having 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, R s4 up to 12 carbon atoms, carbon, cycloalkyl up to 12 carbon atoms, hete11 carbon atoms, aryl is hydrogen, alkyl of 1 to 2 alkenyl groups of 3 to 12 carbon atoms, heterocycioalkyl of 2 to 11 carbon atoms, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl or C 6 -C 10 heteroaralkyl, R and R are each independently hydrogen, OH, alkyl (C 1 -C 12) -cycloalkyl, (C 3 -C 6 -cycloalkyl) cycloalkyl, (C 5 -C 9) heteroaryl or (C až-C ar) aralkyl, (C až-C ar ar) aralkyl, (C až-C hetero hetero) heteroaralkyl, (C až-C ar ar) aralkenyl, (C až-C 6 v), or (C až-C 10 alk) aryl group, or (C 6 -C 10) aryl and C 1 -C 6 -alkylalkyl group, or R and R together form tetramethylene, pentamethylene, - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -, - (CH ₂ ) ₂ -S- (CH ₂ ) ₂ - or

- (CH ₂ ) 2 -NR 2 - (CH ₂ ) ₂ - ^and R ₂ - d ^e is H, alkyl of 1 to 6 carbon atoms, aralkyl of 7 to 11 carbon atoms, C (O) R ^s2, or sulfonyl, and R ^s2 and R ²⁰ are H, alkyl of 1 to 12 carbon carbon, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycioalkyl of 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl 29 C 6 -C 10 heteroaryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl carbon, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted with one of the above substituents, ay is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Especially preferred are those compounds, wherein R ^b and R ^b, together with the -CH-CH- form a piperidylene, wherein the hetero atom is unsubstituted or substituted by a substituent selected from C (O) OR ^sl, C (O) R ^s2, - C (O) NR ⁸ R ⁹ and R ¹⁰ -SO ₂ and one or more ring atoms or substituted by one or selected from the group consisting of carbon are unsubstituted by multiple substituents

OH, NH _2,

R ⁸ S (O) ₂ N (R ⁹⁾

R ⁸ C (O) N (R ⁹ ) - and R ⁸ OC (O) N (R ⁹ ) -, wherein R ⁹ is a hydrogen atom and R ^{8 is a} C 1 -C 12 alkyl group, a 6 to 10 aryl group or C 7 -C 11 aralkyl, wherein the alkyl, aryl and aralkyl group are unsubstituted or substituted by one or more C 1 -C 12 alkoxy groups, R ^1-8 is an C 1 -C 12 alkyl group , (C 6 -C 10) aryl or (C 7 -C 11) aralkyl group which are unsubstituted or substituted by one or more C 1 -C 12 alkyl groups, R is C 1 -C 12 alkyl and R is alkyl of 1 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, or aryl of 6 to 10 carbon atoms, and alkyl, cycloalkenyl, cycloalkyl alkyl group and aryl are in turn unsubstituted or substituted by one or more substituents selected from OH, C (O) OR ^s4 and OC (O) R ^s4, wherein R ^S 1 is M or alkyl of 1 to 12 carbon atoms, and R ⁴ 'is an alkyl group having 1 to 12 carbon atoms, y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

SZ C

Another preferred sub-group consists of compounds wherein R and R 1 together with the -CH-CH- group form piperidylene which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR ⁴ , OC (O) R ^s4, C (O) R ^{s 2,} NH 2, alkyl having 1 to 12 carbon atoms, R ⁸ C (O) N (R ⁹⁾ -, -C (O) NR ⁸ R ^9, R ⁸ s (O) 2 N (R ⁹ ) -, R ⁸ OC (O) N (R ⁹ ) -,

R ⁸ R ⁴⁰ NC (O) N (R ⁹ ) -OC (O) NR ⁸ R ⁹ and R ¹⁰ -SO ₂ -, wherein R ⁹ is hydrogen and R is alkyl of 1 to 12 carbon atoms, aryl (C 6 -C 10) or (C 7 -C 11) aralkyl group wherein the alkyl, aryl and aralkyl group are unsubstituted or substituted by one or more (C 1 -C 12) alkoxy or (C 7 -C 11) aralkyloxy groups; ¹⁰ is an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms or an aralkyl group having 7 to 11 carbon atoms which are unsubstituted or substituted by one or more alkyl groups having 1 to 12 carbon atoms, R ⁴⁰ is an atom hydrogen, OH, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 heterocycloalkyl C 1 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 16 aralkyl, C 8 -C 16 aralkenyl (C 2 -C 6) alkenylene and (C 6 -C 10) aryl, (C 6 -C 15) heteroaralkyl, (C 6 -C 15) heteroaralkenyl, or (C 6 -C 10) diarylalkyl group. 1 -C 6 alkyl, R ³ · * · and R ^s4 are alkyl of 1 to 12 carbon atoms, and R ^s2 is alkylo31 Scales of 1 to 12 carbon atoms, cycloalkenyl having 3 to 12 carbon atoms, a cycloalkyl C 3 -C 12 or C 6 -C 10 aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl such as the substituents are again unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR ^s1 and OC (O) R ^s4 , wherein R ^s1 'is M or an alkyl group having 1 to 12 carbon atoms and R is an alkyl group having 1 to 12 carbon atoms, y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Particularly preferred compounds of formula I are those 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 h ₅ , -c (o) (ch ₂ ) ₈ c (o) and ₃ ,

-C (O) [CH (OH)] ₂ C (O) ONa, C (O) -C ₈ H ₈ (OH) ₃ , -C 10 O-C ₈ H ₇ -, -C (O) OC ₃ H ₇ ,

-C (O) NHC ₆ H _5, -NHS (O) ₂ CH ₂ C ₆ H _5, -NHC (O) OCH ₂ C ₆ H _5,

-NHC (O) C 8 H ₃ (OCH ₃ ) ₂ , -S (O) ₂ -C ₄ H ₉ , -NHC (O) NHC ₉ H ₈ , - S (O) ₂ -C _g H ₄ CH ₃ -S (0) ₂ -CH ₂ C ₆ H ₅ and -S (O) ₂ - (CH) ₂ C ₁₀ H ₇ .

Preferred compounds of formula I are those wherein R ¹ is a group of formula III wherein R ² is hydrogen or My and R ⁴ is a sulfonyl group with a carbamate (a) unsubstituted C 1 -C 12 alkyl group, an alkyl group C 1 -C 12 substituted with one or more substituents selected from the group consisting of -NH ₂ , primary amino, secondary amino, C 1 -C 12, carbamoyl, carbonydrazide, sulfonamido, sulfonhydrazide, aminocarbonylamide, cycloalkyl C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, phenyloxy and benzyloxy, furthermore unsubstituted C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkyl substituted with one or more substituents selected from cycloalkylo C 3 -C 12 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 12 sulfonyl, phenyloxy and benzyloxy, C 6 -C 10 aryl, heteroaryl (C až-C 9) group having 1 or 2 heteroatoms selected from oxygen and nitrogen, (C až-C ar) aralkyl (C ar-C 6) alkyl group and (C až-C 10) aryl group; (C až-C) heteroaralkyl group having 1 to 6 carbon atoms in the alkyl moiety and 3 to 10 carbon atoms in the heteroaryl moiety having 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen atoms and having a total of 3 to 5 carbon atoms; (C 6 -C 10) aryl, (C 3 -C 9) heteroaryl group having 1 or 2 heteroatoms selected from the group consisting of comprising an oxygen atom and a nitrogen atom, an aralkyl group having from 7 to 16 carbon atoms having from 1 to 6 carbon atoms in the alkyl moiety and from 6 to 10 carbon atoms in the aryl moiety, a heteroaralkyl group having from 3 to 16 carbon atoms with 1 to 6 carbon atoms in an alkyl moiety and 4 to 10 carbon atoms in the heteroaryl moiety with 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen, and a total of 3 to 5 carbon atoms substituted with one or more substituents selected from OH, halogen , (C 1 -C 12) sulfonyl, carboxy, C (O) OM, (C 1 -C 12) alkyl, (C 1 -C 6) alkoxy, (C 6 -C 10) aryl, SO- ^Me, OSO -JMy, NR ²⁰ SO ₃ My, wherein R ²⁰ is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms C 12 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, aralkyl (C 7 -C 11) heteroaryl, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl or C 7 -C 10 heteroaralkenyl, and nitro, NH ₂ , primary amino, secondary amino, carbamoyl, carbamate, sulfonamido and cyano, ay is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, or (b) an alkyl of 1 to 12 carbon atoms or an aralkyl of 7 to 11 carbon atoms, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) ^Sl OR, OC (O) R ^s4, C (O) R ^s2, nitro, NH 2, CN, SO ^ We, OSO3My, NR ²⁰ SO 3 M, an alkyl group of 1 to 12 carbon atoms, alkenyl of 2 to 12 C C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 aryl (C-Cry) heteroaryl, (C až-C hetero) heteroaryl, (C až-C hetero) heteroaryloxy, (C až-C ar) aralkyl (C hetero-C 11), (C až-C 11) aralkyloxy, (C až-C 11) aralkyloxy C 6 -C 10 aralkenyl, C 8 -C 11 aralkenyl, C 7 -C 10 heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide couplings, carbamoyl, carbamate, sulfonhydrazide, carbohydrazide, carbohydroxamic acid, and aminocarbonylamide, wherein R is hydrogen, M, (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, C 3 cycloalkyl C 12 -C 12 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl, R ( ⁴⁾ is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or h heteroaralkyl group having 6 to 10 carbon atoms, and ^R ^ and R ^ are H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 C 12 -C 12 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl group , aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyls the alkoxy group, the heteroaralkyl group, the aralkenyl group and the heteroaralkenyl group are again unsubstituted or substituted by one of the aforementioned substituents, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

R @ 1 in formula III is preferably hydrogen, K or Na.

The following preferences apply to the group.

(a) the meanings for R

R is an alkyl group, preferably methyl, ethyl, n- or isopropyl and n-, iso- or tert-butyl. In the case of a substituted alkyl group, the alkylene group is preferably ethylene, and the cycloalkyl group and aralkyl groups are particularly preferably phenyl, and especially methylene. Cyclohexyl is particularly preferred. Preferred aryl groups are naphthyl and phenyl, phenyl-H _2n -, wherein n is a number from 1 to 6, especially benzyl and 2-phenylethyl. When R ^{4 is a} heteroaryl group, it is preferably a heteroaryl group having 4 to 5 carbon atoms with 1 or 2 heteroatoms selected from the group consisting of O and N. Furanyl, pyridinyl and pyrimidinyl are preferred. When R ^{4 is a} heteroaralkyl group, it is preferably a heteroarylmethyl group having 4 to 5 carbon atoms in the heteroaryl moiety with 1 or 2 heteroatoms selected from the group consisting of O and N, wherein the heteroaryl moiety may have the meaning given above for heteroaryl groups.

Further preferred compounds are those in which R ⁴ of formula III is a C 3 -C 12 cycloalkyl group, particularly preferably Cyclohexyl, a C 1 -C 4 alkyl group, especially methyl or ethyl, substituted with a C 3 -C 12 cycloalkyl group alkyl or alkyl of 1 to 4 carbon atoms, in particular cyclohexyl or methyl, aryl of 6 to 10 carbon atoms, in particular phenyl, or R ⁴ is an aralkyl group having 7 to 12 carbon atoms C 1 -C 6 alkyl and C 6 -C 10 aryl. Particularly preferred groups for R ⁴ are benzyl, naphthylmethyl, 2-phenylethyl, 3-phenylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclohexyl and isopropyl.

Carbamoyl, carbohydrazide, sulfonamide, sulfonhydrazide, aminocarbonylamide and carbamate as substituents for R ⁴ qq preferably represent groups of the general formulas R NHC (O) N (R) -,

R ⁸ OC (O) N (R ⁹ ) -, R ⁸ C (O) (NH) - J ⁹ - and R ⁸ S (O) n (NH) N (R ⁹ ) -, in which R is preferably a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 5 or 6 carbon atoms, a cycloalkylmethyl or cycloalkylethyl group having 5 or 6 carbon atoms in the cycloalkyl moieties, a heterocycloalkyl group having 5 or 6 carbon atoms, heterocycloalkylmethyl or heterocycloalkylethyl having 5 or 6 carbon atoms in the heterocycloalkyl moieties, benzyl, 2-phenylethyl, diphenylmethyl which are or substituted by one or more phenyl, naphthyl, unsubstituted by substituents selected from the group consisting of -OH,

NH

2, a primary amino group having 1 to 8 carbon atoms, a secondary amino group having 2 to 14 carbon atoms, > 20,

-NO-CN, -F, .20

-Cl, -C (O) OH, -C (O) ONa, -SO 4 H, -OSO 4 Na, NR 4 SO 4 Na, where R ^z is hydrogen, C 1 -C 12 alkyl, alkenyl (C 2 -C 12) cycloalkyl, (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl group carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl of 8 to 11 carbon atoms or heteroaralkenyl of 7 to 10 carbon atoms, and - SO4Na, (C1-C4) -alkyl, (C1-C4) alkoxy;

Q is C and phenyl, and R is hydrogen, C 1 -C 10 alkyl, phenyl, naphthyl, benzyl, 2-phenylethyl or phenyl-CH = CH-C ₂ -, and p is 0 or 1.

In (a) a carbamoyl-substituted alkyl group as a substituent for R ⁴ particularly preferably represents a group R ⁸ -C (O) NR 4 - (CH 2) n - wherein n is 1 or 2, R ⁸ is a hydrogen atom, an alkyl group (C až-C 12) cycloalkyl, (C až-C 12 cyk) cycloalkyl, (C až-C a a) aryl or (C až-C ar ar) aralkyl group (C až-C ar); an aryl moiety wherein the alkyl, cycloalkyl, aryl and aralkyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxy, -C (O) OM, (C 1 -C 12) alkyl, (C 1 -C 6) alkoxy, (C 6 -C 10) aryl, SO ₃ My, OSO ₃ My, NR ²⁰ SO ₃ My, C (O) OR ^s , OC (O) R ^s4 , nitro, amino and cyano, or aralkenyl s C 8 -C 16 C 2 -C 6 alkenyl and C 6 -C 10 aryl, or C 6 -C 10 aryl aryl and C 1 -C 6 diarylalkyl; and R ⁹ is a hydrogen atom, a straight or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 5 or 6 carbon atoms, a cycloalkylmethyl or cycloalkylethyl having 5 or 6 carbon atoms in the cycloalkyl moieties, 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 2 f)

M is an alkaline earth metal, R is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, heterocycloalkyl 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heceroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms , C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, R is hydrogen, M, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 atoms and R is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms; C 2 -C 11 heterocycloalkyl, C 1 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl. Suifonamide substituted alkyl as substituent for R ⁴ is preferably R -SO 2 NR - (CH 2) n -, where R, R and n are as defined above for the carbamoyl group. Aminocarbonylamide and carbamate-substituted alkyl substituent for ^R1 is particularly preferably the group R ^9, NHC (0) NH (CH 2) or R OC (O) NH (CH _{2) n,} wherein R is as defined above for the carbamoyl group, and also means phenyl and is as defined above for the carbamoyl group. A carbohydrazide substituted alkyl group as a substituent for R ⁴ is preferably R ⁸ C (O) NHNR ⁹ (CH ₂ ) _n , wherein R ⁸ , R ^8a and n are as defined above for the carbamoyl group. The sulfonhydrazide substituted alkyl group as a substituent for R ⁴ is preferably R ⁸ -SO 2 -NHNR ⁹ - (CH 2) _n - wherein R 0, R ²⁷ and n are as defined above for the carbamoyl group.

Other particularly preferred compounds are those wherein R ⁴ in formula III is an amide R ⁸ C (O) N (R ⁹ ) (CH 2) or R ⁸ S (O) 2 N (R ⁹ ) (CH ₂ ) _n -, wherein R ⁸ and R ⁹ are each independently hydrogen, unsubstituted C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted with 1 aryl moiety that is selected from 2 moiety or more of OH, halogen, carboxy, C (O) ONa, C 1 -C 12 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, -SO 4 H, OSO-; Na, NR ²⁸ SO ₃ Na, SO 4 Na, nitro and cyano, unsubstituted cycloalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms substituted with one or more OH groups, unsubstituted aryl of 6 to 10 carbon atoms , unsubstituted (C až-C) aralkyl group having 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atoms in the aryl moiety, (C 6-C až) aryl or (C alebo-C až) aralkyl group C 6 -C 10 -alkyl substituted by one or more of OH, halogen, carboxy, C (O) ONa, -C (O) OK, C 1 -C 12 alkyl, alkoxy (C 1 -C 6), (C 6 -C 10) aryl, SO ₃ Na, OSO ₃ Na, NR ^{2 (9} SO ₃ Na, C (O) OR ^S 1, OC (O) R s ⁴ , nitro, amino) and cyano, R is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of up to 11 carbon atoms, heterocycloalkenyl of up to 11 carbon atoms ka, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl of 8 to is hydrogen, My, alkyl (C 1 -C 3 -C 12), R (C ⁴ -C ⁴ ) or C 7 to C 10 heteroaralkenyl, C (C 12 -C 12) alkenyl, C 2 -cycloalkyl heterocycloalkyl (C 11-C 11) aryl, (C až-Cry) aryl, (C až-C hetero) heteroaryl, (C až-C ar) aralkyl (Calkyl-C hetero) heteroaralkyl (C až-C atóm) is hydrogen, (C až-C alkyl) alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, aryl a C 6 -C 10 group, a C 5 -C 9 heteroaryl group, a C 7 -C 11 aralkyl group or a C 6 -C 10 heteroaralkyl group, and n is 2 or 1.

Particularly preferred compounds are those in which R ⁴

QQ in formula III is an RC (O) N (R) (CK ₂ ) _n - or amide amide

Q Q O

RS (O) ₂ (R) (CH ₂ ) _n -, wherein R is unsubstituted C 1 -C 12 alkyl, C 1 -C 8 alkyl substituted with one or more substituents selected from OH, halogen, C (O) 0Na and aryl of 6 to 10 carbon atoms, unsubstituted cycloalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted with one or more OH groups, unsubstituted aryl of 6 to 10 carbon atoms, or (C až-C) aralkyl group, (C až-C v a) aryl group, (C až-C ar ar) aralkyl group (C až-C a) aryl atoms of the aryl moiety or aralkenyl group having 2 to 6 carbon atoms in the alkenyl moiety and having 6 to 10 carbon atoms in the aryl moiety which are substituted one or more substituents selected from the group consisting of halogen, -C (O) OH, C (O) ONa, (C 1 -C 12) alkyl, (C 1 -C 6) alkoxy, -SO ₃ H, SO ₃ Na, OSO-Na, NR ²⁰ SO ₃ Na,

Where R is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl C8-C11 heteroaralkenyl or C7-C10 heteroaralkenyl

Q is carbon and nitro and cyano, and R is hydrogen, unsubstituted (C 1 -C 6) alkyl, unsubstituted (C 6 -C 10) aryl, (C 1 -C 6) unsubstituted (C 1 -C 6) aralkyl or a C 6 -C 10 aryl moiety, or an C 8 -C 16 aralkenyl group having 2 to 6 carbon atoms in the alkenyl moiety having 6 to 10 carbon atoms in the aryl moiety, and n is 2 and preferably 1.

Particularly preferred compounds are those in which R ⁴ in formula III is an amide R ⁸ C (O) N (R ⁹ ) (CH 2) _n -, wherein R ⁸ is an unsubstituted C 1 -C 12 alkyl group; C 1 -C 12 substituted with one or more substituents selected from the group consisting of cyclohexyl, OH, halogen, -C (O) OH, -C (O) ONa and phenyl, unsubstituted C 3 -C 12 cycloalkyl, cycloalkyl C 3 -C 12 substituted by one or more OH groups, unsubstituted C 6 -C 10 aryl, C 6 -C 10 aryl substituted by one or more substituents selected from halogen, C (O) ONa, -C (O) OH, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, phenyl, -SO 4 H, δ ,βΝθ, OSO 4 Na, NHSO 4 Na, nitro and cyano or a (C 1 -C 6) -alkyl aralkyl group having from 6 to 10 carbon atoms in the aryl portion and R ⁹ is a hydrogen atom, an unsubstituted (C 1 -C 6) alkyl group, an unsubstituted aralkyl group. (C 7-C 16) C 1-C a 10 (C a-C časti alebo) aryl group, or C až 8-C ar ar (C až-C ar) aralkenyl group (C až-C alk alk) the carbon atoms in the aryl moiety, and n is 2 and preferably 1.

Another preferred group of compounds are those wherein R ⁴ of formula III is an amide R ⁸ C (O) N (R ⁹ ) (CH ₂ ) _n Q wherein R is unsubstituted C 1 -C 12 alkyl, C 1 -C 12 alkyl C 1-4 substituted by one or more substituents selected from OH, halogen, C (O) OH, C (O) ONa and phenyl, unsubstituted C 3 -C 12 cycloalkyl, especially C 8 H ₄₁ , cycloalkyl C 3 -C 12 substituted by one or more OH groups, unsubstituted C 6 -C 10 aryl, especially C ₆ H 6 or C 6 -C 6 aryl, C 6 -C 10 aryl substituted by one or more substituents selected from the group consisting of: halogen, -C (O) OH, C (O) ONa, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, -SO 4 H, SO 4 Na, OSO 4 Na, NHSO ₃ Na, nitro group ak yanoskupinu, in particular C _g H ₄ Cl, C ₆ H ₄ (3.4) C 1 _2, C ₆ H ₄ COONa, C _g H ₄ CH _3, C _g H ₄ OCH _{3, 4} CGH _SO3 Na, C _g H ₄ NO ₂ or C _g H ₄ CN, or unsubstituted aralkyl group having 7 to 16 carbon atoms having 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atoms in the aryl moiety, in particular (CH _{2) 2} C _g Hg R is H, alkyl of 1 to 4 carbon atoms, _phenyl-CH2 -, phenyl-CH ₂ CH ₂ -, phenyl- (CH _{2) 3} - or phenyl-CH = CH-CH ₂ and n is preferably 2, and first

Particularly preferred are also those compounds wherein R ⁴ of formula III is an amide R ⁸ C (O) N (R 6) (CH 2) n -, wherein R ⁸ is an unsubstituted or substituted C 1 -C 12 alkyl group, cyclohexyl, naphthyl, biphenylyl, phenyl, benzyl, phenylethyl or diphenylmethyl; and R 6 is C 1 -C 4 alkyl, C 1 -C 6 phenylalkyl, especially CH ₂ C _g Hg, (CH ₂ ) ₂ C _g Or _g (CH ₂ ) ₃ C ₈ H ₈ or a phenylalkenyl group having 2 to 6 carbon atoms in the alkenyl moiety, in particular C 8 H 8 -CH = CH-CH ₂ , and n is 2 and preferably 1.

Other particularly preferred compounds are those in which

R ⁴ in formula III is a sulfonamido group

R ⁸ S (O) 2N (R ⁹ ) (CH 2) _n -, wherein R ⁸ is an alkyl group having 1 to 12 carbon atoms, in particular an alkyl group having 1 to 6 carbon atoms which is unsubstituted or substituted by one or more halogen atoms (e.g. Cl and especially F), in particular CF ₃ , or an aryl group having 6 to 10 carbon atoms, in particular phenyl or naphthyl, which is unsubstituted or substituted by one or more alkyl groups having 1 to 4 carbon atoms (e.g. methyl or ethyl), (C 1 -C 4) alkoxy groups (e.g., methoxy group g or ethoxy group), halogen atoms, -CN or -NO ₂ , and R is hydrogen or isobutyl, and n is 2 and preferably 1.

Further particularly preferred are those compounds of formula III is aminocarbonyl wherein R ⁴ in the group of formula I is 1

R ⁸ is

R ⁸ -NH-C (O) -NH (CH ₂ ) _n -, wherein alkyl of up to 12 carbon atoms or aryl of 6 to 10 carbon atoms, especially alkyl of 1 to 6 carbon atoms which is unsubstituted or substituted by an atom halogen, -CN, -NO ₂ , (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy or C (C 5 -C 6) cycloalkyl, (C 6 -C 10) aryl group such as phenyl or naphthyl, or a (C7 -C12) aralkyl group such as benzyl, phenylethyl, phenylpropyl or phenylpropenyl, and n is 2 and preferably 1.

Further particularly preferred are those compounds wherein R ⁴ of formula III is an aminoalkyl group, preferably R ⁸ 'R ⁹ ' N (CH 2) n, wherein R ⁸ 'and R ⁹ ' are independently hydrogen, unsubstituted alkyl of 1 to 12 carbon atoms, alkyl of 1 to 12 carbon atoms substituted by one or more substituents selected from OH, halogen, C (O) oR ^bs, OC (O) R ^s4, C (O) NR ¹¹ R ¹² , (C 1 -C 12) alkyl, (C 1 -C 6) alkoxy, (C 6 -C 10) aryl, -SO 3 H, SO 4 Na, OSO 2 Na, NR ²⁰ SO ₃ Na, nitro, amino43 and cyano, unsubstituted C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkyl substituted by one or more OH groups, C 6 -C 10 aryl, C 1 -C 6 aralkyl carbon in the alkyl moiety; and (C 6 -C 10) aryl or C 8 -C 16 aralkenyl (C 2 -C 6) alkenyl and (C 6 -C 10) aryl group, wherein the aryl group and the aryl group in the aralkyl group and the aralkenyl group group is unsubstituted or substituted by one or more substituents selected from OH, halogen, C (O) oR ^bs, OC (O) R ^s4, -C (O) ONa, -C (O) OK, -C (O -NR ¹¹ R ¹² , C 1 -C 12 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, -SO 4 H, SO 3 Na, OSO-Na, NR ²⁰ SO 3 Na, nitro , amino and cyano, wherein n is 2 and preferably 1, and R ^s1 is hydrogen, K or Na, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms , heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms carbon atoms, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl, R ⁴ is hydrogen, C 1 -C 12 alkyl, C 2 -C 10 alkenyl C 12 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or heteroaralkyl (C 6 -C 10), R ¹¹ is hydrogen, (C 1 -C 4) alkyl, (C 2 -C 4) hydroxyalkyl, phenyl or benzyl, and R is independently R, or R and R together are tetramethylene a group, pentamethylene or -CH ₂ CH ₂ -O-CH ₂ CH ₂ - and R ²⁰ is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl (C 2 -C 12), (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl group C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl.

Particularly preferred compounds are also those wherein R ^{4 * * *} in formula III is an aminoalkyl group R ⁸ 'r ⁹ ' nch 2 -, wherein R ⁸ 'and R ⁹ ' are each independently hydrogen, alkyl having 1 to 2 carbon atoms; to 8 carbon atoms, cyclopentyl, cyclohexyl, cycloalkylmethyl having 5 or 6 carbon atoms in the cycloalkyl, phenylC 1 -C 4 alkyl, especially -CH 2 C _g H _5, or phenyl- 2 to 4 carbon atoms in the alkenyl parts, especially -CH ₂ CH = CHC _g H ₅ .

Particularly preferred compounds are further those compounds in which in formula ⁴ + 11 is an aminoalkyl group of ⁸ 'and R ⁹ ' independently of one another are hydrogen, 1 to 6 carbon atoms, phenylalkyl carbon atoms in the alkyl moiety, in particular RR ⁸ 'R ⁹ 'NCH ₂ -, where

R ^{c is an} alkyl group having a group of 1 or 2 ch ₂ c ₆ h ₅ .

4Výhodnými compound from (b) with values for R include those wherein R ⁴ is an aralkyl group having 7 to 11 carbon atoms, in particular CH ₂ -C _g H _g, and (CH _{2) 2} -C ₅ H _g, cycloalkyl C 1 -C 12 alkyl or C 1 -C 12 alkyl unsubstituted or substituted by one or more substituents selected from the group consisting of NH ₂ , C 3 -C 12 cycloalkyl, primary amino, secondary amino, sulfonamido, carbamoyl and aminocarbonylamido. Particularly preferred substituents for the C 1 -C 12 alkyl group are NH ₂ , cyclohexyl, C 6 -C 10 aryl, R ⁸ C (O) N (R ⁹ ) -, R ⁸ S (O) ₂ N (R ⁸ ) ⁹ ) -, R ⁸ NHC (O) NR ⁹ -, NR ⁹ C (O) NHR ⁸ and R ⁸ R ⁹ N-, wherein R ⁸ and R ⁹ are independently hydrogen, C 1 -C 12 alkyl C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 5 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or heteroaralkyl The 6 to 10 carbon atoms and R ⁸ 'and R ⁹ ' are each independently hydrogen, OH, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl (C 6 -C 10) group, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl group C 6 -C 10 heteroaralkyl groups which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR ^S 1, OC (O) R ^S 4, C (O) R ^s2, nitro, NH 2, CN, SO 3 M, OSO3My, NR ²⁰ SO 3 M _y, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, cycloalkyl of 3 to 12 C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, heteroaryl C 5 -C 9 heteroaryloxy, C 5 -C 9 heteroaryloxy, C 7 -C 11 aralkyl, C 7 -C 11 aralkyloxy, heteroaralkyl (C 6 -C 10) pin, C 8 -C 11 aralkenyl, C 7 -C 10 heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamido, carbamoyl, carbamate, sulfonhydrazide, carbohydrazide, carbohydrazide, carbohydrazide, carbohydrazide acid and aminocarbonylamido wherein R is hydrogen, M _?, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, aryl (C 6 -C 10), (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl, or (C 6 -C 10) heteroaralkyl, R ⁴ is hydrogen, C 1 -C 12 alkyl, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 atoms C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl, and R ^s2 and ^R28 are hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl (C 8 -C 11) or C 7 -C 11 heteroaralkenyl, and alkyl, alkenyl, alkoxy upina, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl, and heteroaralkenyl, the above-mentioned, or substituted with one or more substituents, is unsubstituted or substituted; 0 or lay is 1 and M is a monovalent metal or y is 1/2 and M is

QIQI divalent metal, or R and R together form a tetramethylene group, pentamethylene group, - (CH ₂ ) 2 "°" (¾½ ^- ') groups

- (CH ₂ ) ₂ S- (CH ₂ ) 2 or - (CH ₂ ) ₂ -NR ⁷ - (CH ₂ ) ₂ -, and R ⁷ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 2 a group having 7 to 11 carbon atoms, a C (O) R or a sulfonyl group.

Particularly preferred are compounds wherein R ⁴ is CH ₂ -C ₈ H ₅ , (CH ₂ ) ₂ -C 8 H 4, cyclohexyl, methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH ₂ , cyclo47 hexyl, (C 6 -C 10) aryl, R ⁸ C (O) N (R ⁹ ) -, R ⁸ S (O) ₂ N (R ⁹ ) -, R ⁸ NHC (O) NR ⁹ -, NR ⁹ C (O) NHR ⁸ and R ⁸ 'r ⁹ ' n-, where R ⁸ ,

Q Q I

R, R and R are each independently hydrogen, C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl or C 7 -C 11 aralkyl unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OMy, nitro, cyano, SO-jMy, OSO ₃ My, NHSO 4 My, alkyl of 1 to 12 carbon atoms, alkoxy of 1 and Y is 1/2 and M is divalent metal. Particularly preferred are those compounds wherein R ⁸ , R ⁹ , R ⁸ 'and R ⁹ ' are independently hydrogen, C 1 -C 12 alkyl, cyclohexyl, phenyl, naphthyl or aralkyl 7 to 11 carbon atoms which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, Cl, C (O) Na, nitro, cyano, SO-Na, alkyl of 1 to 6 carbon atoms, methoxy and phenyl.

In a preferred class of compounds of formula I, R ^{1 is a} group of formula III wherein R ⁴ is C 8 H ₄₁ , CH (CH ₃ ) ₂ , CH ₂ -phenyl, (CH ₂ ) ₂ -phenyl, CH ₂ NHC (O) -phenyl .

CH ₂ NHC (O) (CH ₂ ) ₃ -phenyl, CH ₂ NHC (O) (CH ₂ ) ₃ OH, CH ₂ NHC (0) CF ₃ , CH ₂ NHC (O) C ₆ H ₁₁ , CH ₂ NHC (O) C ₁₁ H ₂₃ , CH ₂ NHC (O) CH (C ₆ H ₅ ) ₂ ,

CH ₂ NHC (0) NHC _with H ₅ , CH ₂ NHC (0) C ₂ H ₄ CO ₂ Na,

CH ₂ NHC (O) C ₆ [(1,3,4,5) OH] ₄ H ₇ , CH ₂ NHC (O) C _g H ₄ -p-SO ₃ Na,

CH ₂ NHC (O) C ₆ H ₄ O, CH ₂ NHC (0) c ₆ h ₄ no ₂ , CH ₂ NHC (O) C ₆ H ₄ OCH ₃ ,

CH ₂ NHC (0) C ₆ H ₄ (3,4) _{Cl2, CH2} NKC (0) ₄ CH ₃ CGH, CH ₂ NHC (0) ₄ CGH CGH _5, CH ₂ NHC (O) CGH ₄ CN, CH ₂ NHC (0) C ₁₀ H ₇ , CH ₂ NHC (0) C 8 H ₄ COONa,

CH ₂ NHC (O) (CHOH) ₂ COO Na, CH ₂ N (CH ₂ CH = CH-phenyl) [C (O) -phenyl], CH ₂ N [CH ₂ CH (CH ₃ ) ₂ ] [C (0 ) phenyl], CH ₂ N [C (0) C _g H _{5] CH2} C _g H _5,

CH ₂ N [C (O) C ₈ H ₈ ] (CH ₂ ) ₃ C ₈ H ₅ , CH ₂ C ₉ H ₁₁ , (CH ₂ ) ₂ C ₈ H _{, L} , CH ₂ NH ₂ , 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 (CH ₃ ) ₂ ] ₂ , CH ₂ NHSO 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 .

As an alkyl group, R ² may preferably contain from 1 to 6 carbon atoms and particularly preferably from 1 to 4 carbon atoms. Methyl and ethyl are particularly preferred.

The substituents for R ^z may be: in the case of halogen atoms F, Cl and Br, in the case of -C (O) OM preferably -C (O) ONa or -C (O) OK, in the case of an alkyl group preferably an alkyl group of 1 to 2 C 1 -C 4 alkyl and especially preferably C 1 -C 4 alkyl, such as methyl, ethyl, n- or isopropyl and n-, iso- or tert -butyl, in the case of alkoxy, preferably C 1 -C 4 alkoxy, for example methoxy and ethoxy in the case of an aryl group preferably phenyl or naphthyl, in the case of -SO2 My, preferably -SO2Na or -SO3K, in the case of a primary amino group, a primary amino group having 1 to 12 carbon atoms, such as methylamino, ethylamino, n- or isopropylamino, n- , iso- or tert-butylamino, pentylamino, hexylamino, cyclohexylamino, phenylamino or benzylamino, in the case of a secondary amino group a secondary amino group having 2 to 20 carbon atoms, such as dimethylamino group, diethylamino group , Methylethylamino, di-n-propylamino, diisopropylamino, di-n-butyl-, diphenyl-, dibenzylamino, morpholino, thiomorpholino, piperidino and pyrrolidino, -SO ₂ -NR ⁸ R ⁹ and -C (O) -NR ⁸ R ^9, wherein R and R are each independently hydrogen, (C 1 -C 4) alkyl, (C 2 -C 4) hydroxyalkyl, phenyl or benzyl, or R and R together with the nitrogen atom form a morpholino, thiomorpholino, pyrrolidino or piperidino group .

p Q

R and R as alkyl groups contain 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms and may be, for example, methyl, ethyl, n- or isopropyl or n-, iso- or tert-butyl. R ^J and R as a hydroxyalkyl group containing 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms and may be, e.g., hydroxymethyl or 2-hydroxyethyl. R and R as cycloalkyl groups are preferably cyclopentyl or cyclohexyl. When R and R are phenyl and benzyl, the substituents on them may be advantageous

Cl, methyl, ethyl, methoxy and ethoxy.

A preferred subgroup of compounds of formula (I) are those wherein R is hydrogen, unsubstituted (C 1 -C 6) alkyl, particularly preferably (C 1 -C 4) alkyl, especially methyl or ethyl, or (C 1 -C 6) alkyl especially C 1 -C 4 alkyl, especially methyl or ethyl, substituted with C (O) OH, -C (O) ONa, -C (O) OK, -OH, -C (O) -NR ⁸ R ⁹ or -SO ₂ -NR ⁸ R ⁹ wherein R ⁸ is hydrogen, C 1 -C 4 alkyl, hydroxyalkyl

Q is C 2 -C 4, phenyl or benzyl, and R has

QOQ independently of the meaning of R, or R and R together form a tetramethylene group, pentamecylene group or -CH ₂ CH ₂ -O-CH ₉ CH ₂ -.

Particularly preferred are methyl, ethyl, 18 _π 9 _τ compounds wherein R ² is hydrogen, HO (O) CCH ₂ CH ₂ -, NaOC (O) CH ₂ CH ₂ - or

QQ ^Ό · = ^D are each independently hydrogen, 1 to δ carbon atoms, hydroxyaalkyl carbon atoms, phenyl, benzyl or together

RRNC (O) CH ₂ CH ₂ -, and an R and R alkyl group having a 2-4 moiety group.

Particularly preferred compounds of formula Ia according to the invention are compounds

ABOUT

R is hydrogen or M, and

R ⁴ is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, heterocycloalkenyl C 2 -C 11 aryl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl a C 7 -C 10 heteroaralkenyl group which is unsubstituted or mono- or polysubstituted,

Cľ z:

R and R are each independently hydrogen, C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 heteroaryl C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl or C 6 -C 10 heteroaralkyl, or R and R together with the -CH-CH- group form a C 3 -C 12 cycloalkylene group, a C 3 -C 12 cycloalkenylene group C 12 -C 11 heterocycloalkylene and C 3 -C 11 heterocycloalkenylene with heteroatoms selected from the group consisting of -O-, -S- and -N-, wherein alkyl, cycloalkyl, heterocycloalkyl , aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylene, cycloalkenylene, hetero the cycloalkylene group and the heterocycloalkenylene group are unsubstituted or mono- or polysubstituted, wherein the substituents are selected from the group consisting of OH, halogen, C (O) OR ^1- , OC (O) R ^s4 , C (O) R ^s2 , nitro, NH2, cyano, SO 3 M, OSO3My, NR ²⁰ SO 3 M _y, wherein R ²⁰ is H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to C 12 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, heteroaralkyl (C 6 -C 10) group, (C 8 -C 11) aralkenyl or (C 7 -C 10) heteroaralkenyl, and C 1 -C 12 alkyl group carbon atoms, C 2 -C 12 alkenyl, C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, heterocycloalkenyl (C 2 -C 11), (C 6 -C 10) aryl, (C 6 -C 10) aryloxy, (C 5 -C 9) heteroaryl, (C 5 -C 9) heteroaryloxy, (C 7 -C 11) aralkyl group , (C 7 -C 11) aralkyloxy, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl, (C 7 -C 10) heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carboylamide , carbamate group, sulfone hydrazide group, carbohydrazide group, carbohyd rox movu acid and aminocarbonylamide radical, in which R ^s3 · represents hydrogen, My, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, the heterocycloalkyl group having 2 to 11 carbon C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl, R ⁴ is hydrogen, C 1 -C 12 alkyl carbon atoms, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, aralkyl (C až-C 11) heteroaralkyl or (C hetero-C je) heteroaralkyl group and R is hydrogen, (C až-C uhlí) alkyl group ka, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl group of 3 to 12 carbon atoms C 6 -C 10 heteroaryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 8 aralkenyl or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxyalkalkenyl, heteroaralkyl, and aralkyl. unsubstituted or substituted by one of the above substituents, ay is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Preferred compounds of formula Ia are those in which

R ⁸ is hydrogen, K or Na,

R ⁵ and R ⁶ together with the -CH-CH- group represent a C 3 -C 12 cycloalkylene group, a C 4 -C 12 cycloalkenylene group, a C 2 -C 11 heterocycloalkylene group and a C 3 -C 11 heterocycloalkenylene group heteroatoms selected from the group consisting of -O-, -S- and -N-, which are unsubstituted or mono- or polysubstituted, wherein the substituents are selected from the group consisting of OH, halogen, C (O) OR ^s , OC (O) R ^s4, C (O) R ^s2, nitro, NH 3, CN, SO 3 M, OSO3My, NR ²⁰ SO 3 M _y, wherein R ²⁰ is H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, a cycloalkyl (C 3 -C 12) cycloalkenyl (C 3 -C 12), (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, heteroaryl (C 5 -C 9) alkyl, (C 7 -C 11) aralkyl, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl or C 7 -C 11 heteroalkenyl, and C 7 -C 11 aralkyl group; (C 1 -C 12) alkenyl, (C 2 -C 12) alkenyl, (C 1 -C 12) alkoxy, (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, (C 6 -C 10) aryloxy, (C 5 -C 9) heteroaryl, (C 5 -C 9) heteroaryloxy, (C 7 -C 11) aralkyl group C 7 -C 11 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 aralkenyl C 1 -C 11 heteroaralkenyl, C 7 -C 10 heteroaralkenyl, primary amino, secondary amino, sulphonyl, sulphonamide, carbamoyl, carbamate, sulphonhydrazide, carbohydrazide, carbohydroxamic acid, and aminocarbonylamide, where R is, We, (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 3 -C 12) cycloalkyl, (C 2 -C 11) heterocycloalkyl, (C 6 -C 10) aryl, heteroaryl (s) C 5 -C 9 aralkyl, C 7 -C 11 aralkyl or C 5 -C 10 heteroaralkyl, R is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, cycloalkyl C 3 -C 12 heterocycioalkyl having 2 to 11 atoms amino alkyl, aryl of 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 is hydrogen, alkyl of 1 (C 12-C 12) alkenyl, (C až-C alk) alkenyl, (C až-C cyk) cycloalkyl, (C 3-C až) cycloalkenyl, (C až-C heteroc) heterocycloalkyl, (C až-C heteroc) heterocycloalkenyl, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl, or C 7 -C 8 heteroaralkenyl group 10 carbon atoms, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocy kloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl, and heteroaralkenyl are again unsubstituted or substituted with one of the aforementioned substituents; (2) and M is a divalent metal, (a) R ⁴ is a radical of R ¹² - (CH ₂ ) _n - or cyclohexyl, wherein n is 1 or 2 and R is an alkyl group of 1 to 10 carbon atoms, C-C najmä,, especially cyclohexyl, C 6-C a a aryl, preferably phenyl, or C až-C ar 12 aralkenyl, preferably Ceny-Ceny-phenylalkenyl in the alkenyl moiety which are unsubstituted or substituted by C alky-C alky alkyl (C 1 -C 4), (C 1 -C 4) alkoxy, F, Cl, -CN or -NO ₂ , or

R is an amino group -NRR, and R and R are alkyl of 1 to 12 carbon atoms or unsubstituted or alkyl of 1 to 4 carbon atoms substituted cycloalkyl of 5 or 6 carbon atoms, aryl of 6 to 10 carbon atoms, (C 7 -C 12) aralkyl or C 8 -C 12 aralkenyl, 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 CH ₂ -, C ₆ H ₅ CH ₂ CH ₂ -, C ₆ H ₅ -CH ₂ -CH ₂ -CH ₂ - or C ₈ H ₅ CH = CH-CH ₂ -, or

R ¹² is an amide group -N (R ⁹ ) C (O) R ⁸ , -N (R ⁹ ) S (O) 2 R ⁸ , -NR ⁹ C (O) NHR ⁸ or -NR ⁹ C (O) NHR ⁸ wherein R ⁸ is an aryl group having 6 to 10 carbon atoms, preferably phenyl, which is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms, in particular methyl, C 1 -C 4 alkoxy, in particular methoxy, F, Cl, - CN or -NO 2, or an alkyl group having 1 to 10 carbon atoms which is

Q is unsubstituted or substituted by F or Cl, and R is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 5 or 6 carbon atoms, cycloalkylalkyl of 5 or 6 carbon atoms in the cycloalkyl moiety and 1 to 6 carbon atoms in Q alkyl, C 1 -C 6 phenylalkyl or C 2 -C 6 phenylalkenyl, in particular hydrogen, C 1 -C 6 alkyl, cyclohexyl, cyclohexyl-CH ₂ -, cyclohexyl- CH ₂ CH ₂ -, cyclohexyl-CH ₂ CH ₂ CH ₂ -, C ₈ H ₅ CH ₂ -, C ₉ H ₅ CH ₂ CH ₂ -, C ₉ H ₅ CH ₂ CH ₂ CH ₂ - and C ₉ H ₅ CH = CHCH ₂ -, R ⁹ is especially hydrogen, straight and branched-chain alkyl group preferably having 1 to 6 carbon atoms, phenyl or phenyl- (CH ₂₎ -, wherein z is 1-4, such as methyl, ethyl, n- or isopropyl, n- , iso- or tert-butyl, pentyl, isopentyl, hexyl, benzyl, phenylethyl, phenylpropyl and phenyl-CH = CH-CH ₂ -, especially preferably CH ₂ -CH (CH-j) ₂ , benzyl, 2-phenylethyl and

Or (b) R ⁴ is C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, or C 7 -C 11 aralkyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of: OH, halogen, C (O) OR ^sl, 0C (0) R ^s4, C (O) R ^s2, nitro, NH 2, CN, SO 3 M, OSO3My, ^NR2 ®SO3M _yl, wherein R ² is H ® , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 heterocycloalkenyl C 1 -C 11 aryl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, aralkenyl a C 8 -C 11 group or a C 7 -C 11 heteroaralkenyl group and a C 1 -C 12 alkyl group, a C 2 -C 12 alkenyl group, a C 1 -C 12 alkoxy group, a C 3 -C 12 cycloalkyl group C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, heteroaryl C 5 -C 9 heteroaryloxy, C 5 -C 5 heteroaryloxy, C 7 -C 11 aralkyl, C 7 -C 11 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl, (C 7 -C 10) heteroaralkenyl, primary amino, secondary amino, sulfonyl, s ulphonamide, carbamoyl, carbamate, sulfonhydrazide, carbohydrazide, carbohydroxamic acid and aminocarbonylamide, wherein R is hydrogen, M, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, cycloalkyl C 3 -C 12 heterocycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or C 5 -C 11 heteroaralkyl

And 4 carbon atoms, R is hydrogen, alkyl of up to 10, 1 to 2 to 12 to 12 carbon atoms, hete11, aryl, aryl, alkenyl, 3-cycloalkyl, 2 to 6 C 1 -C 10 heteroaryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl, and R is hydrogen, C 1 -C 12 alkyl, alkenyl (C 2 -C 12) cycloalkyl, (C 3 -C 12) cycloalkyl, (C 12 -C 12) cycloalkyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl, and t or a C7 -C10 heteroaralkenyl group, and an alkyl, alkenyl, 3- to 2-11 alkoxy group, a cycloalkyl group, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an aryl group, an aryloxy group, a heteroaryl group , heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are in turn unsubstituted or substituted by one of the above substituents, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

A preferred sub-group of compounds of group (a) are those wherein (1) R ⁴ is C 8 H 8,

C ₆ H ₅ -CH ₂ CH ₂ - or C ₆ H ₅ -CH = CH-CH ₂ -,

C ₉ H ₅ -CH (2) R ⁴ is _{C 8} H _{11 -C 8} H ₁₁ -CH ₂ -, C 8 H 4 -CH ₂ CH ₂ -, C ₈ H ₅ -CH ₂ -,

C 8 H ₅ -CH ₂ CH ₂ -, -CH ₂ -NR ¹⁹ -SO ₂ R ¹⁸ , -CH 2 -NR ¹⁹ -C (O) R ⁴⁰ ,

-CH ₂ NHC (O) NHR ¹⁸ , -CH ₂ NHC (O) NHR ¹⁸ , -CH 2 NHHR ²¹ or -CH 2 N (R ²¹ ) 2 wherein R is -C ₈ H ₅ , phenyl substituted with 1 to 3 methyl or methoxy groups or -NO ₂ or F or Cl, in particular p-CH ₃ -C ₆ K ₄ -, p-CH ₃ OC ₆ H ₄ - or 2,3,5-CH ₃ -C ₈ H ₂ - or pO ₂ N-C 8 H ₄ - or an alkyl group C 1-4 substituted with F, in particular CF ₃ , R ⁴⁸ is phenyl unsubstituted or substituted with 1 to 3 methyl or methoxy groups or -NO 2 or F or Cl, R is hydrogen, C 1 -C 6 alkyl, f enyl - (CH 2) 7 wherein z is a number from 1 to 3, phenyl-CH = CH-CH 2 -, and in particular -CH 2 -CH (CH 3) 2 or benzyl, and R ² is -CH 2 -CR ²² R ²³ R ²⁴ wherein R ²² and R ²² is a methyl, ethyl or phenyl, and R is H, ethyl or methyl, particularly preferably R ²² and R ²³ are methyl and R ²⁴ is a hydrogen atom.

A preferred sub-group of compounds of group (b) are those wherein R ⁴ is CH 2 -C 8 H 5, (CH 2) 2 -C 8 H 5, methyl, ethyl or isopropyl which are unsubstituted or substituted with one or more substituents selected from NH 2, cyclohexyl, aryl (C 6 -C 10), R ⁸ C (O) N (R ⁹ ) -, R ⁸ S (O) 2 N (R ⁹ ) -, NR ⁹ C (O) NHR ⁸ and R ⁸ 'r ⁹ ' n - wherein R, R, R and R are each independently hydrogen, C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl or 7-11 aralkyl carbon atoms, which is unsubstituted or substituted by one or more substituents selected from OH, halogen, C (O) OM, nitro, cyano, SO ₃ M _y OSO ₃ M _y, NR ²⁰ SO 3 M, wherein R ²⁰ represents hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl (C 12-C 12) cycloalkenyl, (C až-C,) heterocycloalkyl, (C až-C heteroc) heterocycloalkenyl (C až-C 10) aryl, (C až-C hetero) heteroaryl C 9 -C 7 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, and C 1 -C 12 alkyl, (C 1 -C 12) alkoxy and (C 6 -C 10) aryl group wherein y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. Particularly preferred are those wherein R ⁸ , R ⁹ , R ⁸ 'and R ⁹ ' are independently hydrogen, C 1 -C 12 alkyl, cyclohexyl, phenyl, naphthyl, or C 7 -C 11 aralkyl carbon which is unsubstituted or substituted 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 formula Ia, R ^{4 C} 6 ^H LL ^{'CH (CH3)} _{2, CH2-phenyl, (CH2) 2-phenyl,} CH ₂ NHC (O) -, phenyl, CH ₂ NHC (O) ( CH ₂ ) ₃ -phenyl, CH ₂ NHC (O) (CH ₂ ) ₃ OH, CH ₂ NHC (O) CF ₃ , CH ₂ NHC (O) C 9 H _11; CH ₂ NHC (O) C _{1; L} H ₂₃ , CH ₂ NHC (O) CH (C 8 H ₅ ) ₂ ,

CH ₂ NHC (O) NHCgHg, CH ₂ NHC (0) C ₂ H ₄ CO ₂ Na,

CH ₂ NHC (O) C 8 [1,3,4,5) OH] ₄ H _? , CH ₂ NHC (O) C 8 H ₄ -p-SO ₃ Na,

CH ₂ NHC (0) C ₈ H ₄ Cl, CH ₂ NHC (0) C 8 H ₄ NO ₂ , CH ₂ NHC (0) C 8 H ₄ OCH ₃ ,

CH ₂ NHC (0) C 9 H ₄ (3,4) Cl ₂ , CH ₂ NHC (0) C ₉ H ₄ CH ₃ , CH ₂ NHC (0) C 9 H _{4 C 8} H ₅ , CH ₂ NHC (O) C 9 H ₄ CN, CH ₂ NHC (O) C ₁₀ H ₇ , CH ₂ NHC (O) C ₈ H ₄ C00Na,

CH ₂ NHC (O) (CHOH) ₂ COONa, CH ₂ N (CH ₂ CH = CK-phenyl) [C (O) -phenyl], CH ₂ N [CH ₂ CH (CH ₃ ) ₂ ] [C (O ) -phenyl], CH ₂ N [C (O) C ₆ H ₅ ] CH ₂ C _g H ₅ , CH ₂ N [C (O) C ₆ K ₅ ] (CH ₂ ) ₃ C ₆ H ₅ , CH ₂ C ₆ H _11f (CE ^ CgH 4, (¾¾, CH ₂ NHCH ₂ CH = CH-phenyl, CH ₂ NECH ₂ -phenyl), CH ₂ NHCH ₂ CH (CK ₃ ) ₂ , CH ₂ N (CH ₂ -phenyl) ₂ , CK ₂ N [CH ₂ CH (CH ₃ ) ₂ ] ₂ , CH ₂ NHSO ₂ -p-nitrophenyl, CH ₂ NHSO ₂ -p-folyl, CE ₂ NHSO _{2 C} 7 ₃ , CH ₂ NEC (O) NHCgH 4 or CH ₂ N [SO ₂ -p-nitrophenyl] [CE ₂ CH (CH ₃ ) ₂ ] 2 ·

The present invention further provides a process for the preparation of compounds of formula (I) by etherification

A 3-OH group in a compound of formula V

n IO in which R and X have the meanings given above, R 19 '1 9 ^{1 1} x and and R are independently a protecting group, the compound of formula VI is a protecting hydrogen or

R ¹ -R ¹³ (VI) wherein R ¹ is as defined above and R ¹³ is a leaving group, then deprotecting.

The leaving groups may be halides such as chloride, bromide and iodide, sulfonic acids, for example trifluoromethanosulfonate, aliphatic, cycloaliphatic or aromatic sulfonic acids, which are unsubstituted or substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, cyano or halogen (chlorine or bromine). Some examples of such acids include methanesulfonic acid, mono-, di- or trifluoromethanesulfonic acid or p-nitrobenzenesulfonic acid. Use is particularly preferred

CF 3 -SC 3 -o '(also referred to as triflate). The leaving group is preferably selected from the group consisting of halogen and unsubstituted and halogenated R-SO ₂ -, wherein R is an alkyl group having 1 to 12 carbon atoms, especially an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 or 6 carbon atoms, phenyl, benzyl, alkylphenyl of 1 to 12 carbon atoms in the alkyl moiety, especially alkylphenyl of 1 to 4 carbon atoms in the alkyl moiety, or alkylbenzyl of 1 to 12 carbon atoms in the alkyl moiety, especially alkylbenzyl of 1 to 4 atoms carbon in the alkyl moiety, for example, methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, benzenesulfonyl, benzylsulfonyl and p-methylbenzenesulfonyl. Preferred leaving groups are Cl, Br, I, -SO ₂ CF ₃ (triflate) and p-nitrobenzenesulfonyl, and -SO ₂ CF ₂ is a particularly preferred group.

Compounds of formula (VI) are known in some cases or can be prepared by known methods as described by Degerbeck et al. [J. Degerbeck, B. Fransson, L. Grehn, and U. Ragnarsson, J. Chem. Soc. Perkin trans. 1:11-14 (1993)] and Dureault et al. [A. Dureault, I. Tranchepain, J.C. Depezay, Synthesis 491-493 (1987)]. Optically pure compounds can be obtained using optically pure starting compounds (e.g., amino acids, α-hydroxy acids) or chromatographic separation procedures, e.g., with chiral solid phases.

The compounds of formula V are novel and the present invention also relates to them. They can be obtained by known glycosylation methods from known fucosyl and galactosyl donors and diols of the general formula HO-X-OH. Gradual introduction of galactose and fucose or vice versa is preferred.

In order to prepare the compounds of formula V, pseudo-trisaccharide building blocks are first synthesized. The pseudotrisaccharide is attached either by the glycoside linkage of activated and protected galactose to the fucose-O-X-OH building block or by the glycoside linkage of suitably protected and activated fucose to the galactose-O-X-OH building block. Glycosylation reactions are known to a large extent and are described in the specialized literature.

R ¹ may then be introduced into the pseudotrisaccharide. The resulting compounds of formula I can be subsequently modified. The modification may consist in the hydrogenation of the aromatic compounds to the cycloaliphatic groups, which may take place, for example, at the same time as the hydrogenolytic deprotection. Furthermore, the amino group can be acylated and / or alkylated and / or sulfonated. The preparation of secondary and tertiary amines can be accomplished by reductive amination.

Activation of the 3-OH group of the galactose residue by etherification has proven advantageous. Dialkyl tin oxides, dialkyl tin alkoxylates and bis (trialkyl) tin oxides are particularly suitable for this purpose. Examples include 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 steps, a) activation and b) coupling with compounds of formula VI.

The activation can be carried out at temperatures from 40 to 200 ° C, preferably from 60 to 120 ° C.

Compounds of formula V and formula VI may be used in equimolar amounts. However, it is expedient to use the compounds of the formula VI in excess, for example in an amount of 10 times, preferably up to five times, relative to the compound of the formula V.

It is further preferred to carry out the reaction in both reaction steps in the presence of an inert solvent or a mixture of solvents. Reactive protic solvents such as alkanols and acid amides are unsuitable for reaction step b). Non-polar aprotic and polar aprotic and polar protic solvents may be used. They may be aliphatic or aromatic hydrocarbons such as pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene or xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 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 ether or ethylene glycol diethyl ether, tetrahydrofuran and dioxane, N, N-dialkylated carboxamides such as dimethylformamide, N-alkylated lactams, such as N-methyl lactams, such as N-methyl lactam acetone and methyl isobutyl ketone, carboxylic acid esters such as methyl acetate or ethyl acetate, or alkanols such as methanol, ethanol, propanol, butanol and ethylene glycol monoethyl ether. Particularly preferred solvents are methanol, ethanol, benzene and toluene.

Protecting groups and procedures for derivatizing hydroxyl groups with these protecting groups are generally known from the chemistry of carbohydrates and nucleotides and are described, for example, in

SLBeaucage, R. Iyer, Tetrahedron 48: 2223-2311 (1992). Examples of such protecting groups include: benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, dimethoxybenzyl, bromobenzyl, 2,4-dichlorobenzyl, methyl, di (dimethylphenyl) methyl, toxyphenyl) methyl, triphenylmethyl, methyl, di-p-anisylphenylmethyl, diphenylmethyl, di (methylphenyl) di (methoxyphenyl) methyl, di (dimetre-4,4 ', 4 ^1' -t-butylfenyltri (methylphenyl) methyl, tri (dimethylphenyl) methyl, methoxyphenyl (diphenyl) methyl, di (methoxyphenyl) phenylmethyl tri (methoxyphenyl) methyl, tri (dimethoxyphenyl) methyl, triphenylsilyl, alkyldiphenylsilyl, dialkylphenylsilyl and trialkylsilyl having 1 to 20, preferably 1 to 12 and particularly preferably 1 to 8 carbon atoms in alkyl groups, for example triethylsilyl, tri-n-propylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, n-octyldimethylsilyl, (1,1,2,2-tetramethylethyl) dimethylsilyl, an acyl group having 2 to 12, in particular 2 to 8 carbon atoms such as acetyl, propanoyl, butanoyl, butane, butanoyl, , hexanoyl, benzoyl, methylbenzoyl, methoxybenzoyl, chlorobenzo The protecting groups may be the same or different. Preferred protecting groups are selected from the group consisting of a linear and branched alkyl group having 1 to 8 carbon atoms, in particular an alkyl group having 1 to 4 carbon atoms, for example methyl, ethyl, n- and isopropyl, n-, iso- and tert-butyl, (C až-C 12) aralkyl group, for example benzyl, Cs-C trial trial trialkylsilyl, especially C až-C 12,, for example triethylsilyl, tri-n-propylsilyl, triisopropylsilyl, isopropyldimecylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyl, tercyl n-octyldimethylsilyl, (1,1,2,2-tetramethylethyl) dimethylsilyl, substituted methylidene groups obtainable by formation of acetal or ketal from adjacent hydroxy groups of saccharides or saccharide derivatives with aldehydes and ketones, preferably containing 2 to 12 or 3 to 3 12 carbon atoms, for example an alkylidene group having 1 to 12 carbon atoms, preferably an alkylidene group having 1 to 6 carbon atoms, and in particular an alkylidene (C1-C4) -ene such as ethylidene, 1,1- and 2,2-propylidene, 1,1- and 2,2-butylidene, benzylidene, further unsubstituted and halogenated acyl group with 2 to 12 carbon atoms, especially acyl having 2 to 8 carbon atoms such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, pivaloyl and benzoyl.

The synthesis is preferably carried out with protecting groups, 12, 12 for R ¹ and R 2, which together form an alkylidene group preferably having 1 to 12 and even more preferably having 1 to 8 carbon atoms. In this context, particularly preferred protecting groups are those in which R and R together form an alkylidene group having in particular 1 to 12 carbon atoms, with an alkylidene group forming an acetal or a ketal with oxygen atoms. These protecting groups may be removed under neutral or weakly acidic conditions. Particularly preferred protecting groups are acyl, benzyl, substituted benzyl, benzyloxymethyl, alkyl and silyl. R @ 1 and R @ 2 are preferably an alkylidene group, for example benzylidene substituted by an alkyl or alkoxy group. However, R and R may also be hydrogen or one of R ¹² 'and R ¹² ''may be a protecting group,

Ί O such as benzyl, and the other of the R groups hydrogen.

may be an atom

Examples of protecting carboxylate groups include alkoxycarbonyl and aralkoxycarbonyl groups, preferably -CO ₂ Bn, -CO ₂ CH ₃ .

The deprotection is preferably carried out at a temperature of from 0 ° C to 50 ° C and in particular at room temperature.

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

An alternative synthetic procedure involves forming a glycosia bond with the hydroxyether protected fucose of formula VII

wherein R ² , R ¹² and X are as defined above, with a protected galactose of formula VIII

wherein R ¹ is as defined above, Z is O or S, R ¹² is a protecting group and R is a leaving group, then deprotecting the resulting compound.

The reaction conditions can be selected similarly to those described above. The leaving group R can be, for example, -C (= NH) -CCl ₃ or 4-pentenyl. Compounds of formula (VI) may be obtained in a simple manner by glycoside coupling of an appropriately protected fucose with a compound of formula (HO-X-OH), which is protected once if necessary. Compounds of formula VIII may be obtained by etherification of compounds of formula R 1 OH with galactose, which is optionally protected.

The compounds of the invention have anti-inflammatory properties and can be used as medicaments. They can control diseases such as cardiogenic shock, myocardial infarction, thrombosis, rheumatism, psoriasis, dermatitis, acute respiratory distress syndrome, asthma, arthritis and metastatic cancer. Furthermore, the invention relates to compounds of the invention for use in the treatment of diseases of warm-blooded animals, including humans. For example, a daily dose for warm-blooded animals having a body weight of about 70 kg may be 0.01 to 1000 mg. Administration is preferably in the form of pharmaceutical compositions, parenterally, for example intravenously or intraperitoneally.

The present invention further provides a pharmaceutical composition comprising an effective amount of a compound of the invention, either alone or together with other active ingredients, and a pharmaceutical carrier, preferably in a significant amount, and, if desired, excipients.

The pharmaceutically active compounds of the invention may be used in the form of compositions which can be administered parenterally or in the form of infusion solutions. Solutions of this type are preferably isotonic aqueous solutions or suspensions which may be prepared, for example, in the case of lyophilized compositions which contain the active ingredient alone or together with a carrier, for example mannitol, before use. These pharmaceutical compositions may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for controlling osmotic pressure and / or buffers. These pharmaceutical compositions, which may optionally contain other pharmaceutical active compounds such as antibiotics, are prepared in a conventional manner, for example by conventional dissolution or lyophilization processes, and contain from about 0.1% to 90%, in particular from about 0.5% up to about 30%, for example 1% to 5%, of the active agent or agents.

The following examples illustrate the invention in more detail. The following abbreviations are used:

Bz = benzoyl, Bn = benzyl, DMTST = dimethyl (methylthio) sulfonium triflate, FAB = fast atom bombardment mass spectrometry, 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 = horseradish peroxidase, BSA = bovine serum albumin, PAA = polyacrylamide, SA = streptavidin. An unattached link in the formulas means methyl. Molecular sieves were activated at 300 ° C and under high vacuum for 12 hours before use. They are used in powder form.

DETAILED DESCRIPTION OF THE INVENTION

A: Preparation of the starting compounds

Example A1: Preparation of Compound No. 1 Al

To a mixture of R-3-azido-2-hydroxypropionic acid 28 [A. Dureault, I. Tranchepain, JCDepezay, Synthesis 491-493 (1987) 1, triethylamine (850 mL, 6.1 mmol) and DMF (7.0 mL) are added benzyl chloride (660 mL, 5.72 mmol) at room temperature. . The mixture is stirred for 16 hours, then additional triethylamine (850 μΐ, 6.1 mmol) and benzyl chloride (660 μΐ, 5.72 mmol) are added. The reaction mixture was stirred for two days and then concentrated under high vacuum. The residue is taken up in water and the mixture is extracted several times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product (1 g) was purified by flash chromatography on silica gel (ethyl acetate / hexane 1: 4) to give benzyl R-3-azido-2-hydroxypropionate 29 (0.717 g, 85%) as an oil. ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.36 (m, 5H), 5.25 (s, 2H), 4.39 (q, J = 4.2 Ηζ, ΙΗ), 3.65 (dd) J = 3.3, 12.9 Hz, 1H), 3.51 (dd, J = 4.3, 12.9 Hz, 1H), 3.20 (d, J = 4.0 Hz, 1H) .

A1

To a solution of alcohol 29 (0.85 g, 3.84 mmol) and 2,6-di-tert-butylpyridine (1.12 mL, 4.99 mmol) in anhydrous CK ₂ Cl ₂ (11.0 mL) at - Trifluoromethanesulfonic anhydride (770 mL, 4.41 mmol) was added with stirring at 20 ° C. The clear colorless red is heated to 0 ° C for 40 minutes and stirred at this temperature for a further 2 hours. The mixture was diluted with CH ₂ Cl ₂ (40 mL) and 1 M aqueous solution of KK ₂ PO ₄ (30 mL) was added with vigorous stirring. The organic phase was separated and the aqueous phase was extracted twice with CH ₂ Cl _2nd The combined organic phases were washed with H ₂ O (30 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The oily residue (2.3 g) was purified by short silica gel flash column chromatography (ethyl acetate / hexane 1: 7) to give benzyl R-3-azido-2-trifluoromethanesulfonyloxypropionate Al (1.16 g, 85%) in in the form of a yellowish oil. ⁴ H NMR (250 MHz, CDCl 3) δ 7.38 (broad s, 5H), 5.32 (d, J = 12.1 Hz, 1H), 5.27 (d, J = 12.1 Hz, 1H ), 5.24 (dd, J = 4.2, 5.5 Ηζ, ΙΗ), 3.90-3.75 (m, 2H), ¹³ C NMR (63 MHz, CDCl 3) δ 164.4, 133 , 9, 129.1, 128.8, 128.6, 120.9, 81.0, 69.0, 51.5.

Example A2: Preparation of Compound No. 1 A2

OH

OH *

OBn

Benzyl (R) -4-phenyl-2-trifluoromethanesulfonyloxybutyrate (A2):

(R) -2-hydroxy-4-phenylbutanoic acid solution 26 (0.2 g,

1.11 mmol) in MeOH / H ₂ O (9: 1, 1.3 mL) was adjusted to pH 8 with 20% Cs ₂ CO _{3 solution} . The solution was concentrated under reduced pressure and azeotroped first with ethanol and then with hexane, then dried under high vacuum to remove residual H ₂ O. The residue was treated with N, N-dimethylformamide (1.3 mL) and benzyl bromide ( 132 μΐ, 1.11 mmol) and the mixture is stirred at room temperature for 75 minutes. Additional benzyl bromide (20 μΐ, 0.168 mmol) was then added and the mixture was stirred for an additional 50 minutes. The white suspension was diluted with CH ₂ Cl ₂ (5 mL), filtered through Hyflo Super Cel 4, and concentrated under reduced pressure. Purification of the crude product by flash chromatography on silica gel (eluent: ethyl acetate / hexane 4: 1) afforded benzyl (R) -2-hydroxy-4-phenylbutyrate 27 (0.21 g, 70%). The product (0.3 g, 1.11 mmol) is dissolved in CH ₂ C1 ₂ (4.5 ml) was added 2,6-di-tert-butylpyridine (323 μΐ, 1.44 mmol) and the mixture was cooled to temperature -20 ° C. Trifluoromethanesulfonic anhydride (222 μΐ, 1.27 mmol) is then added dropwise over 3 minutes and the solution is warmed to temperature. 0 ° C over 45 minutes. After 75 minutes at 0 ° C, the mixture was diluted with CH ₂ Cl ₂ (20 mL) and washed with 1 molar aqueous KH ₂ PO ₄ (15 mL). The aqueous phase is extracted with CH ₂ Cl ₂ (2 x 10 mL) and the combined organic phases are washed with H ₂ O (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by preliminary filtration on silica gel column (eluent: ethyl acetate / hexane 1: 9) to give crude triflate A2 (0.311 g, 70%) as an oil The product was used directly for next step (preparation BI.18 ¹ H NMR) (250 MHz, CDCl ₃ ) δ 7.50-7.17 (m, 10H), 5.31 (s, 2H 5.28 (dd, J = 5.5, 11.0Hz, 1H), 2.82 (m, 2H), 2.41 (m, 2H).

Example A3: Preparation of compound no. A3

The R-hydrobromic acid is converted to the triflate A3 according to the procedure of Example A2.

Example A4: Preparation of compound no. A4

R-2-hydroxy-3-methylbutanoic triflate A4 according to the procedure of Example A2.

is converted n

Example A5: Preparation of Compound No. 1 A5

R-2-hydroxy-3-cyclohexylpropionic acid to the triflate A5 according to Example A2.

is transferred

B: Preparation of mimetics

Example B1: Preparation of Compound No. 1 BI. 1

BzO ^ CBz

BzO

a)

BzO

BnO

A mixture of thioglycoside 1 (5.38 g, 8.40 mmol) [E.A.L.Biessen, D.M.Beuting, H.C.P.F.Roelen, G.A. van de Marel, J.H. van Boom,

TJC van Berkel, J. Med. Chem., 38: 1538-1546 (1995)] and acceptor 2 (3.44 g, 6.46 mmol) was dried under high vacuum for 1 hour. Activated molecular sieves 4A (20 g) and DMTST (4.17 g, 16.14 mmol) were then added under a nitrogen atmosphere, followed by CH ₂ Cl ₂ (70 ml). The suspension was dried at room temperature and after 3 hours 5 ml of a suspension consisting of DMTST (5.84 g, 22.61 mmol), molecular sieve 4A (4.0 g) and the CH ₂ C1 ₂ (35 ml). After 30, 45 and 90 minutes, additional 5 ml portions of DMTST are added. The brown reaction mixture was stirred for 15 hours and then filtered through a Hyflo aid), washed with CH ₂ Cl ₂ (300 mL). shake first with 10 saturated NaCl solution, filter and concentrate p

Super Cel (filter The filtrate is extracted with aqueous NaHCO ^, and the organic phase was dried over Na ₂ SO _d, the vacuum rotary evaporator. The residual brown foam was purified twice by silica gel column chromatography (eluent for the first chromatography: ethyl acetate / hexane 1: 4, for the second chromatography: ethyl acetate / toluene 1: 9) to give pure product 3 as a colorless solid (4.28 g, 60%), which was used immediately.

b)

A solution of tetrabenzoate 3 (3.38 g, 3.04 mmol) and sodium methoxide (0.165 g, 3.05 mmol) in anhydrous methanol (32 mL) was stirred at room temperature for 3 hours. The mixture was neutralized by the addition of a strongly acidic ion exchanger (Amberlyst 15) and then filtered through Hyflo Super Cel and washed with CH 2 Cl 2. The filtrate was concentrated under reduced pressure and the residual yellow oil purified by flash chromatography on silica gel (elution: CH ₂ Cl ₂ / methanol 19: 1) to give pure tetrol 4 (1.95 g, 92%).

A solution of tetrol 4 (1.0 g, 1.44 mmol), benzaldehyde dimethyl acetal (430 mL, 2.86 mmol) and camphrosulfonic acid (0.1 g, 0.43 mmol) in acetonitrile (20 mL) was stirred at room temperature. temperature. After 4 hours, additional camphrosulfonic acid (0.15 g, 0.65 mmol) was added and the mixture was stirred at room temperature for 6 hours, then heated at 35 ° C for 6 hours. Additional camphrosulfonic acid (0.06 g 0.26 mmol) was added and the solution was stirred at room temperature for 6 hours. The reaction mixture was filtered through Hyflo Super Cel ® and washed with ethyl acetate. The filtrate is extracted by shaking first with a saturated aqueous solution of NaHCO ₃ and then with a saturated aqueous solution of NaCl and the organic phase is dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 1.5 g of crude product. Purification of the crude product by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH 39: 1) afforded, in addition to the desired benzylideneacetal 5 (0.475 g), a mixture of less polar by-products (0.4 g). These were reprocessed under the above reaction conditions and purified to yield an additional 0.08 g of benzylideneacetal 5. Total yield 5%, 555 g (49%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.53-7.51 (m, 2H)

7.38-7.19 (m, 18H), 5.62 (s, 1H), 4.83 (d, J = 3.8 Hz, 1H), 4.77 (d, J = 12.1 Hz) (1H), 4.71 (d, J = 11.5 Hz, 1H), 4.70 (m, 1H), 4.66 (d, J = 12.0 Hz, 1H), 4.62 (d) J = 11.5 Hz, 1H) 4.51 (d, J =

= 11.1 Hz, 1H) 4.36-4.31 (m, 2H), 4.22 (broad d, 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 (D, J = 12.0 Hz, 1 H), 3.90 (dd, J = 3.8, 10.2 Hz, 1H) 3.76-3.68 (M, 3H), 3.53 (ddd, J = 4.9, 9.0, 11.0 Hz, 1H), 3.43 (wide with, 1H ), 3.37 (d, J = 2, 5 Hz, 1H), 2.57 (d, J = 8.0Hz, 1H), 2.51 (with, 1H), 2.08 (m, 2K) , 1.73 (broad d, J = 9.5 Hz, 2H) 1.42-1.25 (M, 2H), 1.20 (broad t, J = 11.2 Hz, 2H), 1.07 (d,

J = 6.3 Hz, 3 H), MS (FAB, THG) 800 (M + NH ₄ ), 783 (M + H)

d)

A mixture of diol 5 (0.098 g, 0.125 mmol), di-n-butyicin oxide (0.062 g, 0.25 mmol) and methanol (5 mL) was refluxed under argon for 2 hours. The reaction mixture was concentrated under reduced pressure and pentane was added to the residue, then concentrated again. Anhydrous CsF (dried under high vacuum at 300 ° C, 0.068 g, 0.45 mmol) was added under argon and the mixture was further dried under high vacuum (30 minutes). After addition of anhydrous 1,2-dimethoxyethane (1.5 mL), a solution of benzyl-R-3-phenyl-2-trifluoromethanesulfonyloxypropionate [F.Degerbeck, B.Fransson, L.Grehn, U.Ragnarsson, J. Chem. Soc. Perkin Trans. 1:11-14 (1993)] (0.24 g,

0.62 mmol) in anhydrous 1,2-dimethoxyethane (1.5 mL). The mixture is stirred vigorously at room temperature for 4 hours and then at 40 ° C for a further 2 hours. After addition of 1 M 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 dilute aqueous KF and then with saturated aqueous NaCl. The organic phase is dried (Na ₂ SO ₄ ), for 73

prodrug 5 (0.043 g, 44%) (wide d, J = 6.9 Hz, 2H), 7, (d, J = 12.0) Hz, 1H) 4.98 (d, 4.62 to 4.48 (m, 4H) 4.31 (d, (d, J = 7.9) Hz, 1H) 4.07 (d, 3.76 (dd, J = 3.4, 10.3 Hz, 1H -3.47 (m, 2H), 3.44 -3.35 (m,

filtered and concentrated in a vacuum rotary evaporator to give the crude product. Purification by flash chromatography on silica gel (gradient elution: ethyl acetate / toluene 1: 4 to 100% ethyl acetate) gave ether 6 (0.045 g, 35%) and less polar. ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.49 37-7.05 (m, 28H), 5.36 (s, 1H), 5.04

J = 12.0 Hz, 1H), 4.72-4.63 (m, 3H),

J = 11.2Hz, 1H), 4.16 (m, 1H), 4.11 J = 3.4Hz, 1H), 3.88-3.79 (m, 2H), 3.66 (d, J = 11.3 Hz, 1H), 3.621E), 3.3 δ (dd, J = 3.5, 9.6 Ηζ, ΙΗ), 3.16-3.06 (m, 2H) 3.12 (broad s, 1H), 3.01 (dd, J = 8.4,

13.9 Hz, 1H), 2.03-1.86 (m, 2H), 1.93 (d, J = 2.0 Hz, 1H), 1.71-1.55 (m, 2H), 1.36-1.00 (m, 4H), 0.99 (d, J = 7.1 Hz, 3H).

e)

31.1

To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.03 g) and protected compound 6 (0.03 g, 0.029 mmol) was added dioxane (2.5 mL), water (1 mL), 2 ml) and glacial acetic acid (0.1 ml). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated hydrogen pressure at room temperature for 13 hours and then filtered through a cellulose filter (pore size 45 gm). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated again several times to remove excess acetic acid. Pass the solution of the residue in water through a Dowex 50 ion exchange column (Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and wash with deionized water. The clear filtrate was concentrated and purified by reverse phase chromatography (RP 18 silica gel, column diameter)

1.4 cm, length 7.0 cm, gradient elution: 40% MeOH / _H2O through 45% MeOH / _H2O to 50% MeOH / _H2O) to give the target molecule BI. 1 (0.015 g, 78%) as a colorless solid ¹ H NMR (500 MHz, D ₂ O) δ 7.38-7.30 (m, 4H), 7.29-7.23 (m, 1H) 4.92 (d, J = 4.0Hz, 1H), 4.55 (q, J = 6.7Hz, 1H), 4.35 (d, J = 7.8Hz,

1H), 4.11 (dd, J = 4.8, 8.5 Hz, 1K), 3.86 (d, J = 3.6 Hz, 1H),

3.84 (dd, J = 3.3, 10.5 Hz, 1H), 3.74 (d, J = 3.5 Hz, 1H), 3.71 (dd, J = 3.9, 10, 5 Hz, 1H), 3.69-3.62 (m, 3Η), 3.50 (ddd,

J = 1.0, 4.5, 7.1 Hz, 1H), 3.48-3.41 (m, 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 (m,

2H), 1.63 (broad s, 2H), 1.24-1.14 (m, 4H), 1.13 (d,

J = 7.0 Hz, 3H) ¹³ C NMR (100.6 MHz, APT, D ₂ O) d 139.5 (Cq),

130.7 (2CH), 129.9 (2CH), 128.0 (CH), 100.8 (CH), 96.8 (CH),

84.0 (CH), 83.3 (CH), 79.6 (CH) 78.4 (CH), 75.6 (CH), 73.3 (CH), 71.4 (CH), 70.9 (CH), 69.2 (CH), 67.7 (CH), 67.4 (CH), 62.8 _(CH2), 40.6 (CH ₂ ), 30.9 (CH ₂ ), 30.4 (CH ₂ ), 24, 4 (2 ch ₂ ), 16.6 (CK ₃ ), MS (FAB, THG) 595; (M + Na) 573 (M + H).

COOBn

A mixture of tetrol 4 (0.038 g, 0.055 mmol) and di-n-butyltin oxide (0.029 g, 0.117 mmol) in anhydrous methanol (2.0 mL) was heated to reflux under an argon atmosphere. After 2.25 hours, the clear colorless solution was concentrated under reduced pressure and the residue was treated with benzene and concentrated several times to remove excess MeOH. This was then dried under high vacuum for 30 minutes, and the residue was mixed under argon with CsF (high vacuum dried at 300 ° C, 0.03 g, 0.197 mmol) and anhydrous 1,2-dimethoxyethane (0.4 mL). ). The mixture is cooled to 0 [deg.] C. and a solution of benzyl R-3-phenyl-2-trifluoromethanesulfonyloxypro75 pionate [F.Degerbeck, B.Fransson, L. Grrehn, U. Ragnarsson, J. Chem. Soc. Perkin Trans. 1:11-14 (1993)] (0.085 g, 0.219 mmol) in anhydrous 1,2-dimethoxyethane (0.4 mL). The reaction mixture was then warmed to room temperature and stirred for an hour, then stirred at 40 ° C for an additional hour. After addition of aqueous 1 M KH ₂ PO ₄ solution, the mixture is diluted with water and extracted three times with CH ₂ Cl ₂ . The combined organic phases are washed with aqueous KF solution and then dried (Na ₂ SO _a), filtered and concentrated under reduced pressure. Purification of the residue was carried out twice by flash chromatography on silica gel (first chromatography: 2% MeOH / CHCl 3, second chromatography 45% ethyl acetate / toluene) to give ether 8 as an oil (0.013 g, 25%). ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.40-7.00 (m, 25H), 5.15 (d, J = 11.6 Hz, 1H), 5.09 (d, J = 11, 6 Hz, 1H), 4.89 (d, J = 11.8 Ηζ, ΙΗ), 4.86 (d, J = 3.2 Hz, 1H), 4.77 (d, J = 11.6) Ηζ, ΙΗ), 4.69 (d, J = 12.0 Hz, 2H), 4.57 (d, J = 12.0 Hz, 1H), 4.56 (d, J = 11.8 Hz) (1H), 4.35 (q, J = 6.5 Hz, 1H), 4.28 (dd, J = 4.0, 9.5 Hz, 1H), 4.11 (d, J = 7, 6 Hz, 1H), 4.02-3.88 (m, 2H), 3.79 (dd, J = 7.3, 11.9 Hz, 1H), 3.66 (broad s, 1H), 3 63-3.40 (m, 5H), 3.22 (m, 1H), 3.10 (dd, J = 4.0, 14.0 Hz, 1H), 3.09 (broad 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 (m (2H), 1.75 (d, J = 1.9 Hz, 1H), 1.59 (broad s, 2H), 1.29-1.07 (m, 4H), 1.01 (d, J) = 6.4 Hz, 3H).

g)

COONa

To the protected saccharide 8 (0.03 g, 0.032 mmol) and Pd / C (0.03 g, 10% Pd content) was added 1,4-dioxane / water (2.0 mL 4: 1) and then glacial acetic acid (0.1 mL). The flask was evacuated and purged several times with argon. This procedure was repeated with hydrogen. The mixture was hydrogenated under a slightly elevated hydrogen pressure with vigorous stirring until thin layer chromatography (n-BuOK: H ₂ O: acetone-glacial acetic acid: NH ₄ OH 70: 60: 50: 18: 1.5) indicated by thin layer chromatography. in the absence of precursor and intermediates (about 3.5 hours). The black suspension is filtered twice through a cellulose filter (pore size 45 gm) and the filtrate is concentrated under reduced pressure. The residue is taken up in water and the solution is poured into an ion exchange column (Dowex 50 Na ⁺ form, column diameter 0.9 cm, length

3.5 cm) and washed with deionized water. The filtrate is concentrated and purified by reverse phase chromatography (RP 18 silica gel, column diameter 1.4 cm, length 7.0 cm, gradient elution: 40% ΜθΟΗ / Η ₂ Ο over 45% MeOH / H ₂ O to 50% MeOH (H ₂ O) to give the target molecule B1.1 (0.015 g, 78%) as a colorless solid.

Example B2: Preparation of Compound No. 1 BI.2

COONa

The aromatic compound B1.1 (0.152 g, 0.256 mmol) and 5% Rh / Al ₂ O ₂ (0.2 g) was taken up in H ₂ O (5.5 mL), dioxane (3.5 mL) and acetic acid. (1.0 mL). The air is exchanged for argon and then hydrogen several times by evacuation. The black suspension is hydrogenated under a slightly elevated hydrogen pressure with vigorous stirring for 2 days and then filtered through a cellulose filter (pore size 45 μπι). The clear colorless solution is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to remove excess acetic acid. The solution of the crude product in water is filtered through a Dowex 50 ion exchange column (Na ⁺ form, length 9 cm, diameter 1.3 cm) and the column is washed with water. The filtrate was concentrated under reduced pressure and the residue (0.16 g) was purified by gel filtration on Bio-Gel P2 (65 µm particle size, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.55 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, eluent: 55% MeOH / H ₂ O) to give the target molecule BI.2 (0.11 g, 73%). in the form of a loose white solid (after lyophilization). ¹ H NMR (500 MHz, D ₂ O) δ 4.93 (d, J = 3.8 Hz, 1H), 4.58 (q, J = 6.4 Hz, 1H), 4.43 (d, J = 7.5 Hz, 1H), 3.91 (dd, J = 3.5, 9.0 Hz, 1H), 3.88-3.83 (m, 2H), 3.75 (d, J = 3.3 Hz, 1H), 3.73-3.64 (m, 4H), 3.57-3.53 (m, 1H), 3.49 (dd, J = 7.3, 9, 0 Hz, 1H), 3.50-3.43 (m, 1H), 3.33 (dd, J = 3.2, 9.2 Hz, 1H), 2.10-1.99 (m, 2H), 1.73 (broad d, J = 12.0 Hz, 1H), 1.69-1.44 (m, 9H), 1.29-1.07 (m, 7H), 1.14 ( d, J = 6.5 Hz, 3H), 0.96-0.80 (m, 2H), MS (FAB, THG) 623 (M + Na), 601 (M + H).

Example B3: Preparation of compound no. BI.3

A suspension consisting of benzylideneacetal 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 anhydrous tetrahydrofuran (30 ml) were cooled to 0 ° C under nitrogen. The pH of the mixture was adjusted to 1 by carefully adding a saturated solution of HCl gas in anhydrous diethyl ether. The suspension is stirred at 0 ° C and the pH is maintained at 1 by occasional addition of ethereal HCl. After 10 hours, cold saturated aqueous NaHCO ₃ solution (30 mL) was added. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate (70 ml each). The combined organic phases are dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give

1.3 g of crude product. Purification was carried out by flash chromatography on silica gel (CHCl 3 / isopropanol 19: 1) to give the desired benzyl ether 10 (0.3 g, 60%) and a polar by-product (0.045 g). - ^ H

CDCl ₃ ) δ 7.47-7.33 (m, 5H), 4.64 (s, 2H), 4.37

1H), 4.13 (broad d, J = 3.0 Hz, 1H), 3.89-3.69 (dd, J = 3.1, 9.0 Hz, 1H), 2.89-2, 70 (m, 2H), 1.38 3H).

slightly less NMR (250 MHz, (d, J = 9.3 Hz, (m, 4H)), 3.64 (t, J = 7.3 Hz,

b) ^Βζ θ-ΟΒη

EfW

To a solution of triol 10 (0.296 g, 0.941 mmol) in CH ₂ C1 ₂ (3.0 mL) at 0 was added pyridine (0.45 mi, 5.56 mmol) and benzoyl chloride (0.49 mL, 4 , 22 mmol). The reaction mixture was stirred at 0 ° C for 3.5 hours and then 1 M aqueous KH ₂ PO _{4 was added} and the mixture was extracted three times with CH ₂ Cl ₂ . The combined organics were washed with water, dried (Na ₂ so _D), filtered and concentrated under reduced pressure to give 1.0 g-rove product are. Purification by flash chromatography on silica gel (hexane / ethyl acetate 4: 1) afforded tribenzoate 11 as yellowish crystals (0.517 g, 88%). NMR (250 MHz, CDCl ₃ ) δ 8.09 (d, J = 7.5 Hz, 2H), 8.02 (d, J = 7.5 Hz, 2H), 7.85 (d, J = 7) 1.5 Hz, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.63-7.39 (m, 7H), 7.38-7.23 (m, 6H), 6 06 (d, J = 3.3 Hz, 1H), 5.85 (t, J = 10.0 Hz, 1H), 5.66 (dd, J = 3.5, 10.0 Hz, 1H) 4.88 (d, J = 10.0 Hz, 1H), 4.60 (d, J = 11.9 Hz, 1K), 4.49 (d, J = 11.9 Hz, 1H), 4 23 (t, J = 6.3 Hz, 1H), 3.84-3.64 (m, 2H), 3.02-2.80 (m, 2K), 1.38 (t, J = 7.5 Hz, 3H).

To a mixture of thioglycoside 11 (0.377 g, 0.60 mmol), glycosyl acceptor 2 (0.32 g, 0.60 mmol) (EP 671 409) and activated molecular sieves 4A (2.5 g) is added anhydrous under argon. CH 2 Cl 2 (8.0 mL). In a second round-bottom flask, a suspension of DMTST (0.39 g, 1.51 mmol) and activated molecular sieves 4A (0.8 g) in anhydrous ΟΗ ₂ Ο ₁₂ (5.0 mL) was prepared. The two suspensions were stirred at room temperature for 3.5 hours. Then, 3 portions of 1 ml of DMTST suspension are added to the glycosyldonor / acceptor mixture over 1 hour. The yellowish reaction mixture was stirred at room temperature for another

1.5 hours and then filtered through Hyflo Super Cel ^R and washed with CH 2 Cl 2. The filtrate was extracted by shaking with aqueous NaHCO ₃ and then water was added. The aqueous phases are re-extracted with CH 2 Cl 2 and the combined organic phases are dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give 0.67 g of crude product. Purification was carried out twice by flash chromatography on silica gel (first chromatography: toluene / ethyl acetate 14: 1, second chromatography: hexane / ethyl acetate 4: 1) to give 12 (0.404 g, 61%) as a colorless foam.

A solution of tribenzoate 12 (3.42 g, 3.12 mmol) and sodium methoxide (0.169 g, 3.12 mmol) in methanol (65 mL) was stirred at room temperature for 6 hours. The base is then neutralized by addition of an acidic ion exchanger (Amberlyst 15) and the suspension is filtered through Hyflo Super Cel ^R. The filtrate was concentrated under reduced pressure and the residual yellow oil (3.35 g) was purified by flash chromatography on silica gel (CH 2 Cl 2 / MeOH 19: 1) to give triol 13 (2.15 g, 88%) as a colorless foam. ¹ H NMR (500 MHz, CDCl 3) δ 7.41-7.24 (m, 20H), 4.99 (d, J = 3.6 Hz, 1H), 4.95 (d, J = 11.2) Hz, 1H), 4.83 (d, J = 11.2 Hz, 1H), 4.77 (d, J =

= 11.3 Hz, 1H), 4.69 (d, J = 11.3 Hz (1H), 4.68 (D, J = l, 5 Hz, 1H), 4.61 (d, J = 11.5 Hz, 1H), 4.53 (s, 2K), 4.34 (d, J = 7.0 Hz, 1H), 4.33 (m, 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 (M, 1K), 3.77 (Dd, J = 6.0, (9.4 Hz, 1H), 3.70 (dd, J = 5.0, 9.6) Hz, 1H), 3.65 (D, u = 2.0 Hz, 1H), 3.63 -3.54 (m, 4H), 2.95 (wide with, 1H), 2.60 (broad d, J = 2.0 Hz, 2H), 2.07 (m, 1H), 2.01 (M, 1H), 1.69 (m, 2H), 1.45-1.30 (m, 2H), 1.29-1.18 (m, 2H) 2H) , 1.10 (D,

J = 6.5 Hz, 3H), MS (FAB, THG) 783 (MH +), 693 (M-PhCH ₂₎

BnO

OTI

A1

O3n

COOSn

under reduced pressure and thereby removed

A mixture of triol 13 (0.515 g, 0.656 mmol) and di-n-butyltin oxide (0.245 g, 0.984 mmol) in anhydrous methanol (15 mL) was heated to reflux under nitrogen for 2 hours. The clear solution was concentrated when taken up in benzene and concentrated three times, excess MeOH. The residue was dried under high vacuum, then anhydrous CsF (dried under high vacuum at 300 ° C, 0.5 g, 3.29 mmol) was added under argon, followed by anhydrous 1,2-dimethoxyethane (4.0 mL). and a solution of benzyl R-3-azido-2-trifluoromethanesulfonyloxypropionate Al (1.16 g, 3.28 mmol) in anhydrous

1,2-dimethoxyethane (8.0 mL). The reaction mixture was stirred at room temperature for 6 hours and then 1 M aqueous KH ₂ PO ₄ (60 mL) was 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 NaCl solution, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The oily residue (1.15 g) was purified by flash chromatography on silica gel (eluting the product with toluene / ethyl acetate 4: 1 then eluting the precursor with a mixture of CH ₂ Cl ₂ and MeOH 19: 1) to give ether 14 (0.488 g,

%) as a colorless foam and precursor 13 (0.075 g,

%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.40-7.22 (m, 25H), 5.25 (d,

J = 11.7 Hz, 1H), 5.16 (d, J = 11.8 Hz, 1H), 4.96 (d, J = 10.9 Hz,

1H), 4.95 (d, J = 3.1 Hz, 1H), 4.82 (d, J = 10.8 Hz, 1H), 4.76 (d,

J = 11.1 Hz, 1H), 4.72-4.66 (m,

4.57 (dd, J = 3.2, 6.0 Hz, 1H), (d, J = 11, 30 Hz, 1K), 4.39 (q,

Hz, 1H), 4.04 (broad s, 1H),

3.99 (dd, J = 2.4, 9.5 Hz, 1H), 3.82 (ddd,

2H), 4.62 (d, J = 11.0 Hz, 1H),

4.53 (d, J = 11.3Hz, 1H), 4.50 J = 6.2Hz, 1H), 4.31 (d, J = 7.4

4.02 (dd, J = 3.0, 9.5 Hz, 1H),

J = 1.9, 7.3, 8.9 Hz,

1H), 3.77 (dd, J = 6.0, 9.2 Hz, IH), 3.78-3.74 (m, IH), 3.70-3.65 (m, 2H), 3 63 (dd, J = 3.0, 12.3 Hz, IH), 3.58 (ddd, J = 4.2, 8.0, 9.5 Hz, IH), 3.53 (dd, J = 6.0, 12.5 Hz, 1H), 3.55-3.51 (m, IH), 3.44 (dd, J = 3.1, 9.0 Hz, IH), 2.90 (dd, J = 1,2,

1.8 Hz, 1 OH), 2.86 (d, 2.0 Hz, 1 OH), 2.09-1.96 (m, 2H), 1.68 (m, 2H), 1.44- 1.18 (m, 4H), 1.11 (d, u = 6.3 Hz, 3H), MS (FAB,

THG) 1010 (M + Na), 984 (M + Na + _2H-N2), 962 (M + _3H-N2).

To a solution of azide 14 (0.11 g, 0.111 mmol) in ethyl acetate (12 mL) was added Pt / BaSO ₄ (0.35 g, Pt content 5%). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the mixture is hydrogenated at atmospheric pressure with vigorous stirring. Hydrogenation is stopped after

2.5 hours, filter the suspension through a cellulose filter (pore size 45 μπι) and concentrate the filtrate under reduced pressure. The residue (0.115 g) was purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH 19: 1) to give not only the desired amine 16 (0.055 g, 51%) but also the less polar precursor 14 (0.042 g, 38%). ). Amine 16 is unstable and is used immediately for further experiments.

g)

COOBn

COONa

B1.3 (1) Preparation of benzamide intermediate 17: To a solution of the β-amino acid derivative 16 (0.013 g, 0.0135 mmol) and benzoic acid (0.0033 g, 0.027 mmol) in anhydrous THF (0.5 mL) at diisopropylethylamine (3.5 mL, 0.02 mmol) and benztriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.012 g, 0.0271 mmol) were added at 0 ° C. The reaction mixture was stirred for 45 minutes, then saturated aqueous NaHCO 3 was added. The mixture is extracted three times with CH ₂ Cl ₂ and the combined organic phases are washed first with 1 M aqueous KH ₂ PO ₄ (pH 1-2 adjusted with 1 M aqueous HCl) and then with aqueous NaHCO 3, dried (Na ₂ SO 4). , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution: 35% ethyl acetate / toluene to 40% ethyl acetate / toluene) to give benzamide 17 (0.0098 g, 68%).

(2) Removal of protecting groups from compound 17: To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, 20% Pd content, 0.011 g) and benzyl ether 17 (0.0097 g, 0.0091 mmol) was added dioxane (1). , 5 mL), water (0.7 mL) and glacial acetic acid (0.1 mL). The flask was evacuated and purged several times with argon. It is then purged 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 µm) and the filtrate is concentrated under reduced pressure. The residue was taken up in water and concentrated several times to remove excess acetic acid. The crude product solution with a small amount of water was passed through an ion exchange column (Dowex 50, Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and washed with deionized water. The filtrate was concentrated under reduced pressure and the residue (0.007 g) was purified by gel filtration on Bio-Gel P2 (65 µm particle size, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.59 ml / min, detection at 230 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, gradient elution: 37% MeOH / H ₂ O to 45% MeOH / H ₂ O) to give the target molecule BI.3 (3, 3 mg, 58%) as a loose white solid (after lyophilization). NMR (500 MHz, D ₂ O) δ 7.74 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.48 ( t, J = 7.6 Hz, 2H), 4.92 (d, J = 4.0 Hz, 1H), 4.57 (q, J = 6.7 Hz,

1H), 4.44 (d, J = 7.8Hz,

3.94 (d, J = 3.0Hz, 1H), = 4.0Hz, 1H), 3.74 (d,

1H), 4.17 (dd, J = 3.9, 8.1 Hz, 1H), 3.86 (d, J = 3.5 Hz, 1H), 3.84 (t, J =

J = 3.5 Hz, 1H), 3.75-3.65 (m, 4H),

3.60-3.52 (m, 3H), 3.49-3.44 (m, 1H), 3.45 (dd, J = 3.5, 9.3 Hz, 1H), 2.03 ( m, 2H), 1.64 (broad s, 2H), 1.26-1.13 (m, 4H),

1.11 (d, J = 6.5Hz, 3H), MS (FAB, THG) 660 (M + Na), 638 (M + K).

Example B4: Preparation of compound no. BI.4

COOBn

OH

NH

(a) Preparation of amide intermediate 19: To a solution of 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 anhydrous THF (1.0 mL) Diisopropylcarbodiimide (20 mL, 0.129 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes and then concentrated under reduced pressure. The residue (0.09 g) was purified twice by flash chromatography on silica gel (eluent for the first chromatography: CH ₂ Cl ₂ / MeOH 39: 1, for the second chromatography: CH ₂ Cl ₂ / isopropanol 39: 1) to give pure amide 19 (0.031 g, 86%).

(b) Deprotection of compound 19: To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.035 g) and benzyl ether 19 (0.031 g, 0.0283 mmol) was added dioxane (2.0 mL). ml), water (1.0 ml) and glacial acetic acid (0.5 ml). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black mixture is hydrogenated under slightly increased pressure with vigorous stirring for 18 hours. The mixture is filtered through a cellulose filter (pore size 45 gm) and the filtrate is concentrated under reduced pressure. The residue was treated with toluene (about 2 mL) and concentrated several times to remove excess acetic acid. A solution of the crude product (0.021 g) in a small amount of water was then passed through an ion exchange column (Dowex 50, Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and washed with deionized water. The filtrate was concentrated under reduced pressure and the residue (0.02 g) purified by reverse phase chromatography (Merck RP 18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: 60% MeOH / MeOH) followed by gel filtration on Bio-Gel P2 (65 gm particle size, column diameter)

2.5 cm, length 35 cm, water, flow rate 0.5 ml / min, detection at 215 nm) to give the target molecule 31.4 (0.014 g, 74%) as a clear colorless solid (after lyophilization). ⁴ HNMR (500 MHz, D 2 O) δ 7.32 (m, 2H), 7.24 (m, 3H), 4.93 (d, J = 4.1 Hz, 1H), 4.57 (q, J) = 6.7 Hz, 1H), 4.40 (d, J = 8.0 Hz, 1H), 3.9-3.84 (m, 3H), 3.75-3.66 (m, 5H) 3.63 (dd, J = 3.8, 14.0 Hz, 1H), 3.53 (broad dd, J = 4.5, 7.5 Hz, 1H), 3.49 (dd, J = 7.9, 9.6 Hz, 1H), 3.50-3.44 (m, 1H), 3.23 (dd, J = 7.8, 14.0 Hz, 1H), 3.15 (dd J = 3.2, 9.8 Hz, 1H), 2.88 (broad t, J = 7.3 Hz, 2K), 2.59-2.45 (m, 2H), 2.09 (m 1H, 2.03 (m, 1H), 1.67 (broad s, 2H), 1.30-1.15 (m, 4H), 1.13 (d, J = 6.6 Hz, 3H) MS (FAB) 666 (M + H), 643 (M + H-Na).

Example B5: Preparation of compound no. BI.5

B1.5 (a) Preparation of amide intermediate 21: To a solution of amine 16 (0.026 g, 0.027 mmol), sodium 4-hydroxybutyrate (0.010 g,

1-hydroxybenzotriazole (0.020 g, 0.148 mmol) in a mixture of anhydrous THF (1.0 mL) and DMF (0.2 mL) was added with stirring at room temperature diisopropylcarbodiimide (16 mL, 0.103 mmol). After 4 hours, additional DMF (dimethylformamide) (0.2 mL) was added and the mixture was stirred for an additional 13 hours. After the volatiles (including DMF) were distilled off under high vacuum, the residue (0.09 g) was purified by flash chromatography on silica gel (CH 2 Cl 2 / MeOH 29: 1) to give amide 21 (0.02 g, 71%).

(b) Removal of protecting groups from compound 21: To the mixture

Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.04 g) and benzyl ether 21 (0.036 g, 0.034 mmol) were added dioxane (2.0 mL), water (1.0 mL) and ice. acetic acid (0.5 mL). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black mixture is hydrogenated under a slightly elevated hydrogen pressure with vigorous stirring for 18 hours. The mixture is filtered through a cellulose filter (pore size 45 gm) and the filtrate is concentrated under reduced pressure. The residue was treated with toluene (about 2 mL) and concentrated several times to remove excess acetic acid. The solution of the crude product (0.022 g) in a small amount of water was then passed through an ion exchange column (Dowex 50, Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and washed with deionized water. The filtrate was concentrated under reduced pressure and the residue (0.02 g) was purified by gel filtration on Bio-Gel P2 (65 gm particle size, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml / min). , detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH / H ₂ O 1: 4) to give the target molecule BI.5 (0.015 g, 70%) as a clear colorless solid (after lyophilization). ^{Σ Η} NMR (500 MHz, D ₂ O) δ 4.93 (d, J = 3.9 Hz, IH), 4.59 (q, J = 6.7 Hz, IH), 4.47 (d, J = 7.5 Hz, 1H), 4.04 (dd,

J = 3.8, 7.3 Hz, 1H), 3.92 (d, J = 3.2 Hz, IH), 3.86 (dd, J = 3.4,

10.2 Hz, 1H), 3.75 (d, J = 3.5) Hz, IH), 3.47-3.65 (m, 4H) , 3.62 (Dd, J = 3, 9, 14.0 Hz, IH) 3,59- 3.51 (m, 2H), 3.55 (T, J = 6.3 Hz, 2H), 3.50 to 3.44 (m, 1H) 3.43 (Dd, J = 3.5, 9.8 Hz, H) , 3.38

(dd, J = 7.5, 14.0 Hz, (m, 2H), 1.77 (p,

1.29-1.13 (m, 4H), (M + H-Na), 620 (M + H),

1H), 2.27 (t, J = 7.4 Hz, 2H), 2.11-2.00

J = 7.1 Hz, 2H), 1.65 (broad s, 2H),

1.15 (d, J = 6.8 Hz, 3H); MS (FAB) 643

598 (M + 2H-Na).

Example 36: Preparation of compound no. BI.6

To a mixture of Pd (OH) ₂ / C (Pearlman's catalyst, Pd content 20%, 0.03 g) and azide 14 (0.03 g, 0.03 mmol) was added dioxane (2.0 mL), water (1 mL), , 0 mL) and glacial acetic acid (0.5 mL). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black mixture is hydrogenated under a slightly elevated hydrogen pressure with vigorous stirring for 16 hours. The mixture is filtered through a cellulose filter (pore size 45 gm) and the filtrate is concentrated under reduced pressure. The residue was purified by goal filtration on Bio-Gel P2 (particle size 65 µm, column diameter 2.5 cm, length 35 cm, water, flow rate 0.55 ml / min, detection at 215 nm) followed by reverse phase chromatography ( Merck RP 18 silica gel, column diameter

1.2 cm, length 7 cm, eluent: 25% MeOH / H ₂ O) to give the target molecule B1. 6 (0.011 g, 70%) as a clear colorless solid (after lyophilization). ¹ H NMR (500 MHz D ₂ O) δ 4.93 (d, J = 3.9 Hz, 1H), 4.58 (q, J = 6.7 Hz, 1H), 4.48 (d, J = 7.9 Hz, 1H), 4.22 (dd, J = 3.7, 8.4 Hz, 1H), 3.99 (d, J = 3.1 Hz, 1H), 3.86 ( dd, J = 3.3, 9.9 Hz, 1H), 3.75 (d, J = 3.3 Hz, 1H), 3.74-3.65 (m, 4H), 3.61-3 55 (m, 2H); 3.50 (dd, J = 3.0)

9.3 Hz, 1H), 3.48 (m, 1H), 3.35 (dd, J = 3.7, 12.9 Hz, 1H), 3.16 (dd, J = 8.5, 13.5 Hz, 1H), 2.10-2.00 (m, 2H), 1.65 (m, 2H), 1.29-1.15 (m, 4H), 1.14 (d, J = 6, 5 Hz, 3H), MS (FAB, THG) 510 ([delta] -).

Example Β7: Preparation of compound no. BI.7

B1.6

B1.7

BI.6 amine (0.09 g, 0.176 mmol) is dissolved in dry MEOE (1.5 mL) and CH ₂ C1 ₂ (1.8 ml) and added with activated 3A molecular sieves (about 0.2 g). cinnamic aldehyde (24 μΐ, 0,19 mmol) and acetic acid (9 μΐ). The yellowish suspension was stirred for 2 minutes and then NaBH 4 (CN) (0.018 g, 0.286 mmol) was added. After 1.5 hours the mixture was filtered through a cellulose filter (pore size 45 μπι), the filter is washed with MeOH and CH ₂ C1 ₂ 1: 1 and the filtrate concentrated under reduced pressure. The glassy residue is taken up in water (5 ml) and the solution is acidified (about pH 1-2) with 1M hydrochloric acid (0.7 ml). The cloudy solution is filtered again through a cellulose filter (pore size 45 μπι) and the filtrate is adjusted to pH 7 with 1M sodium hydroxide solution (about 1 ml) and then concentrated. The residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μπι, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.6 ml / min, detection at 215 nm) and subsequent chromatography on reverse phase (Merck RP 18 silica gel, gradient elution: 50% MeOH / H ₂ O to 70% MeOH / H ₂ O) to give the target molecule B1. 7 (0.03 g, 27%) as a loose white solid (after lyophilization). ¹ H NMR (500 MHz D ₂ O) δ 7.48 (d, J = 8.0 Hz, 2H), 7.41-7.31 (m, 3H), 6.83 (d, J = 15) 4 Hz, 1H), 6.26 (dt, J = 15.4, 7.0 Hz, 1H), 4.92 (d, J = 3.8 Hz, 1H), 4.56 (q, J = 6.3 Hz, 1H), 4.43 (d, J = 7.6 Hz, 1H), 4.31 (dd, J = 3.5, 8.2 Hz, 1H), 3.98 (d, J = 3.0Hz, 1H), 3.88-3.81 (m, 2H), 3.84 (d, J = 6.0Hz, 1K), 3.76-3.63 (m, 5H), 3.60-3.51 (m, 2H), 3.49 (dd,

J = 3.0, 10.4 Hz, 1H), 3.49-3.41 (M, 1H), 3.41 (dd, J = 3.5, 13.2 Hz, 1H), 3.26 (dd, J = 8.5, 13.2) Hz, 1H), 2.02 (m, 2H). 1.64 (broad s, 2H), 1.27-1.12 (m, 4H) ) 1.12 (d, J = 6.3 Hz, 3 H) , MS (FAB, THG) 650 (M + Na), 628 (M + H). Example B8: Preparation of compound no . BI . 8

BI.9

A solution of amino acid BI.7 (0.01 g, 0.0159 mmol) in 1 M aqueous NaHCO 3 (0.1 mL) was cooled to 0 ° C and a 1 M solution of benzoyl chloride in benzene (16, 0 gl). After 40 minutes, an additional 8.0 g of benzoyl chloride solution is added, after 130 minutes an additional 3.0 g, and a total of

3.5 hours additional 1.0 gl. After a total of 4 hours, the reaction mixture was diluted with water and extracted with CH 2 Cl 2 to remove excess reagent. The aqueous phase is concentrated under reduced pressure 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 0.49 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, gradient elution: 60% MeOH / H ₂ O to 70% MeOH / K ₂ O) to give the target molecule BI.8 (7.9 mg, 66%) as a loose white solid (after lyophilization). ¹ H NMR (500 MHz D ₂ 0) 1.4: 1 mixture of rotamers, characteristic signals: δ 7.52 to 7.24 (m, 10H, 2xPh), 6.71 (d, J = 15.5 Hz 0.42H, PhCH = CH), 6.42 (dt, J = 15.5, 6.1 Hz, 0.42H, PhCH = CH), 6.39 (d, J = 15.5 Hz, 0) 58H, PhCH = CH), 6.13 (dt, J = 15.5, 5.6 Hz, 0.58H, PhCH = CH), 4.92 (d, J = 4.0 Hz, 1H, Fuk) -IH), 1.16 (d, J = 7.0 Hz, 1.26H, Fuk-6H), 1.11 (d, J = 6.8 Hz, 1.74H, Fuk-6H), MS (FAB, THG) 776 (M + Na) 754 (M + H).

Example B9: Preparation of compound no. BI. 9 and BI. 10

B1.6

co.hu

NH

To the amino acid solution B1. 6 (0.04 g, 0.078 mmol) in a mixture of MeOH and CH ₂ Cl ₂ (1: 1, 1.0 mL) was added CH ₂ Cl ₂ solution of freshly distilled benzaldehyde (0.083 g in 1.0 ml CH ₂ C1 _2. 0.1 ml, 0.078 mmol), activated 3Ä molecular sieves (0.1 g) and glacial acetic acid (5 μΐ, 0.087 mmol). The suspension was stirred at room temperature and after 2 minutes NaBH 4 (CN) (0.008 g, 0.129 mmol) was added. After 2.5 hours an additional 15 μΐ of benzaldehyde solution is added and the mixture is stirred for an additional hour. The reaction mixture is diluted with water, acidified with dilute acetic acid and filtered through a cellulose filter (pore size 45 μπι), and the filtrate is adjusted to pH 8-9 with NaHCO 3 solution and then concentrated. The residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μπι, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm) and subsequent chromatography with reverse phase (Merck RP 18 silica gel, gradient elution: 35% MeOH / H ₂ O to 60% MeOH / H ₂ O) eluting first with monobenzylamine BI.9 (0.020 g, 41%) and then with dibenzylamine 31.10 (0.005 g) , 9%). Monobenzylamine BI.9: ¹ H NMR (500 MHz D ₂ O) δ 7.45 (s, 5H), 4.93 (d, J-4.0 Hz, 1H), 4.57 (q, J = 6) 7 Hz, 1H), 4.45 (d, J = 7.6 Hz, 1H), 4.33 (dd, J = 3.8, 8.8 Hz, 1H), 4.28 (d, J = 13.3 Hz, 1 H),

4.24 (d, J = 13.3) Hz, 1H), 3.99 (d, J = 3.1) Hz, 1H) 3.85 (Dd, J = 3.5, 10.2 Hz, 1H) , 3.74 -3.65 (m, 5H); 3.59 to 3, 54 (m, 2H), 3.49 (dd, J = 3.2) , 9, 7 Hz, 1H), 3.48-3.44 (m, 1 H) , 3.42 (Dd, J = 3.7, 13.2 Hz, 1H), 3.26 (dd, J = 8.9, 13.2 Hz, 1H 2.04 (M,

2H), 1.65 (broad s, 2H), 1.28-1.14 (m, 4H), 1.12 (d, J = 6.7 Hz)

MS (FAB, THG) 624 (M + Na), 602 (M + H).

Dibenzylamine ΒΙ.ΙΟΙΟ Η NMR (500 MHz D ₂ O): 6 H and N signals are very broad at room temperature (d 4,10-3,60, 4H and 3,12-2,67, 12H) δ 7 38 (s, 10H), 4.93 (d, J = 4.0Hz, 1H), 4.60 (q, J = 6.6Hz, 1H), 4.43 (d, J = 8, 0 Hz, 1H), 4.23 (dd, J = 3.6,

8.5 Hz, 1H), 3.88-3.83 (m, 2H), 3.75-3.63 (m, 5H), 3.56 (dd,

J = 8.0, 9.3 Hz, 1H), 3.53-3.44 (m, 2H), 3.32 (dd, J = 3.0, 9.5)

Hz, 1H), 2.13-1.98 (m, 2H), 1.66 (wide s, 2H), 1.31-1.10 (m,

4H), 1.14 (d, J = 6.6Hz, 3H), MS (FAB, THG) 714 (M + Na), 692 (M + H).

Example B10: Preparation of compounds

no. BI.11 and BI.12

To a solution of amino acid BI.6 (0.08 g, 0.156 mmol) in a mixture of MeOH and CH ₂ Cl ₂ (1: 1, 2.0 mL) was added 1 M CH ₂ Cl ₂ solution of isobutyraldehyde (0.156 mL), activated molecular 3A sieves (0.2 g) and glacial acetic acid (10 μΐ, 0.017 mmol). The suspension was stirred at room temperature and after 1 minute NaBH4 (CN) (0.016 g, 0.258 mmol) was added. After 60 minutes the reaction was complete

dilute the mixture with water and filtered through cellulose filter (size, pore size 45 μιη) a . filtrate the adjusts to pH 8 to 9 IM aqueous NaHCO 3 solution and then the concentrated. The rest . Cisna gel filtration on Bio-Gel P2 (Size; particles 6 5 μπι, column diameter 2,5 cm, length 35 cm, elution agent: Water,

flow rate. 0.5 ml / min, detection at 215 nm), followed by reverse phase chromatography (Merck RP 18 silica gel, gradient elution: 35% MeOH / H ₂ O to 50% MeOH / H ₂ O), eluting first with monoisobutylamine BI.11 (0.041 g, 46%) followed by diisobutylamine BI.12 (0.01 g, 10%).

Monoisobutylamine BI.11: ¹ H NMR (500 MHz D ₂ O) δ 4.92 (d, J = 4.0

Hz, 1H), 3.59-3.54 (m, 1H), 3.50-3.43 (m, 1H), 3.34 (dd, J = 9.2, 13.2 Hz, 1H), 2.90 (dd, J = 7.6, 12.0 Hz, 1H), 2.11-1.99 (m,

(d, J = 7.6Hz, 1H), 4.29 (Hz, 1H), 3.85 (Dd, , 3.56 (dd, J = 7.5, 9.3 J = 3.0, 9.7 Hz, 1H), 3.0 Hz, 1H) 3.20 (Dd, 12.0 Hz, 1 H), 2.86 (Dd, , 1.96 (non, J = 6.9 Hz, 1.14 (d, J = 6) 6 Hz, 3H),

0.94 (d, J = 6.6Hz, 6H), MS (FAB, THG) 590 (M + Na), 568 (M + H).

Diisobutylamine 31.12: ¹ H NMR (500 MHz D ₂ O) δ 4.92 (d, J = 4.1

Hz, 1H), 4.59 (q, J = 6.7 Hz, 1H), 4.46 (d, J = 7.1 Hz, 1H), 4.36 (t, J = 6.6 Hz, 1H), 4.02 (broad s, 1H), 3.85 (dd, J = 3.3, 10.3 Hz, 1H), 3.76-3.66 (m, 5H), 3.57 ( dd, J = 4.7,

3.55-3.50 (m, 2H), 3.49-3.39 (m, 3H), 3.07

2.12 (m, J = 6.8 Hz, 2H), 2.12-1.99 (m, 2H),

2H), 1.28-1.11 (m, 4H), 1.13 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.8)

Hz, 12H), MS (FAB, THG) 646 (M + Na), 624 (M + H).

7.5 Hz, 1H), (broad s, 4H), 1.65 (broad s,

Example B11: Preparation of compound no. BI. 13

To a solution of amino acid BI.11 (0.020 g, 0.0339 mmol) in 1 M aqueous NaHCO 3 (100 μ 100), add a 1 M solution of benzoyl chloride in toluene (41 μΐ) at room temperature. The mixture was stirred vigorously and after 1 hour additional benzoyl chloride (41 μΐ of 1 M solution) was added. After completion of the reaction, the volatiles were removed under high vacuum and the residue purified by gel filtration on Bio-Gel P2 (particle size 65 μπι, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, eluent: 45% MeOH / H ₂ O) and then lyophilized to give benzamide BI.13 as a fluffy powder, (0.014 g). , 59

1 H NMR (500 MHz D ₂ O): 1: 1 mixture of rotamers: δ 7.50-7.37 (m, 5H), 4.93 (d, J = 4.0 Hz, 0.5H),

4.60 (q, J = 6.4Hz, 1H); 4.48 (d,

J = 8.0 Hz, 0.5H), 4.32 (dd, J = 4.5,

8.0 Hz, 0.5H), 4.02 (dd, J = 4.3, 8.7 Hz, 0.5H), 3.94 (d, J = 3.2

Hz, 0.5H), 3.89-3.83 (m, 1.5H), 3.82-3.61 (m, 7H), 3.60-3.52

1.5H), 3.51-3.43 (m, 2.5H), 3.25 (dd, J = 7.9, 14.2 Hz,

3.17-3.10 (m, 1K);

4.92 (d, J = 4.0Hz, 0.5H),

J = 8.0 Hz, 0.5H), 4.37 (d, (m,

0, 5H) 3.20 (dd, J = 7.9) 14.2 Hz, 0.5H), 2,16- 1.97 (m, 2.5H), 1.86 (Non, J = 6.9 Hz, S, 2H 1.29-1.14 (m, 4H). 1.17 (d, J = 6.4 J = 6.6 Hz, 1.5H), 0.95 (d, J = 6.5 Hz, 1.5H) 1.5 H) 0.65 (d, J = 6.4 Hz) 1.5 H) 0.65 (d, (FAB, THG) 716 (M + Na), 694 (M + H) Example B12: Preparation of compound BI. 14

B1.14

To a solution of amino acid B1.6 (0.02 g, 0.039 mmol) in 1 molar aqueous NaHCO3 (0.2 mL) with vigorous stirring was added a 1 molar solution of p-nitrobenzenesulfonyl chloride in toluene (43 μΐ). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue is taken up in water (0.3 ml) and purified by gel filtration on Bio-Gel P2 (65 gm particle size, column diameter).

2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm). The crude product (0.025 g) was further purified twice by reverse phase chromatography (Merck RP 18 silica gel, first chromatography: elution with 50% MeOH / H ₂ O, second chromatography: elution with 40% MeOH / H ₂ O) followed by lyophilization to give the title compound. compound as a loose powder (0.0105 σ, 39%). ¹ H NMR (400 MHz D ₂ O) δ 8.39 (m, 2H), 8.07 (m, 2H), 4.93 (d, J = 4.0 Hz, 1H), 4.56 (q , J = 6.6 Hz, 1H), 4.43

(D, J = 7.9 Hz, 1H), 3.96 (dd, J = 3.5, 7.1 Hz, 1H), 3.88-3, 83 (Dd, J = 3.2, 9.6 Hz, 1H) 3.19 (dd, J = 7.3, 13.7 Hz, 1H), 2 05 (wide t, J = 13, (Hz, 2H), 1.66 (wide s, 2H), 1,30-1,12 ( m.

4H), 1.14 (d, J = 6.6Hz, 3H), MS (FAB, THG) 719 (M + Na), 697 (M + H).

Example B13: Preparation of Compound No. 1 BI.15

B1.15

To a solution of amino acid B1.6 (0.01 g, 0.02 mmol) in 1 molar aqueous NaHCO ₃ (0.1 mL) with vigorous stirring at 0 ° C was added 1 molar solution of p-toluenesulfonyl chloride in toluene (22 mL). μΐ). The reaction mixture was stirred at 0 ° C for 90 minutes, then additional p-toluenesulfonyl chloride (10 µM of solution) was added. The reaction mixture is then warmed to room temperature, stirred for 18 hours and then concentrated under reduced pressure. The residue is taken up in water and purified by goal filtration on Bio-Gel P2 (particle size 65 μτη, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm ) followed by reverse phase chromatography (Merck RP18 silica gel, 45% MeOH / H ₂ O) followed by lyophilization gave the title compound as a fluffy powder (0.004 g, ^30%); H NMR (400 MHz D ₂ 0 δ 7.69 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 4.88 (d, J = 3.9 Hz, 1H), 4.52 (q, J = 6.6Hz, 1H), 4.35 (d, J = 7.9Hz, 1H), 3.85-3.78 (m, 2H), 3.74 (d J = 2.8 Hz, 1H), 3.71-3.56 (m, 5H), 3.50-3.39 (m, 3H), 3.29 (dd, J = 3.4,

13.8 Hz, 1H), 3.10 (dd, J = 3.1, 9.6 Hz, 1H), 3.03 (dd, J = 8.0,

13.8 Hz, 1H), 2.34 (s, 3H), 2.08-1.93 (m, 2H), 1.61 (broad s,

2H), 1.26-1.07 (m, 4H), 1.09 (d, J = 6.6 Hz, 3H).

Example B14: Preparation of Compound No. 1 BI.16

B1.16

To a solution of isoserine derivative 16 (0.025 g, 0.026 mmol) and triethylamine (0.7 mL, 0.005 mmol) in DMF (100 mL) was added pentafluorophenyltrifluoroacetate (4.5 mL, 0.026 mmol) at room temperature with stirring. After 15 minutes, additional pentafluorophenyltrifluoroacetate (2.5 mL, 0.015 mmol) was added. After a further 30 minutes, additional triethylamine (2.8 mL, 0.02 mmol) and pentafluorophenyltrifluoroacetate (4.5 mL, 0.026 mmol) were added. The same amount of the latter is added again after 20 minutes. The mixture was stirred for an additional 45 minutes and then saturated aqueous NaHCO 3 (0.2 mL) was added and the mixture was diluted with water and extracted several times with ethyl acetate. The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product (0.04 g) was purified by flash chromatography on silica gel using 1: 3 ethyl acetate / toluene as eluent to give trifluoroacetamide 24 (0.022 g, 83%).

Removal of protecting groups from compound 24: To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.02 g) and benzyl ether 24 (0.021 g, 0.021 mmol) was added dioxane (1.4 mL), water (0.7 mL) and glacial acetic acid (0.35 mL). The flask was evacuated and purged several times with argon. It is then purged 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 μτη) and the filtrate is concentrated.

under reduced pressure. A solution of the residue in a small amount of water is passed through an ion exchange column (Dowex 50, Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and washed with deionized water. The filtrate is concentrated under reduced pressure and the residue is purified by full filtration on Bio-Gel P2 (particle size 65 μπι, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, column diameter 1.2 cm, length 7 cm, gradient elution: 30% MeOH / H 2 O to 40% MeOH / H 2 O to give the target molecule BI.16 (0, 0085 g, 68%) as a clear colorless solid (after lyophilization) ¹ H NMR (500 MHz, D 2 O) δ 4.93 (d, J = 3.9 Hz, 1H), 4.59 (q, J = 6.5 Hz, 1H), 4.45 (d, J = 8.2 Hz, 1H), 4.08 (dd, J = 3.4, 8.2 Hz, 1H), 3.91 (d 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 (m, 4H), 3.61-3.50 (m, 3H), 3.50-3.44 (m, 1H), 3.42 (dd, J = 3.1, 9.6 Hz, 1K), 2.10-2.00 (m, 2K), 1.65 (m, 2H), 1, 28-1.15 (m, 4H), 1.14 (d, J = 6.5Hz, 3H), MS (FAB, THC -) 652 (M + Na), 630 (M + H), 608 ( M + 2H-Na).

Example B15: Addition of compound no. BI.17

(a) Preparation of amide 26: To a stirred mixture of amide 16 (0.027 g, 0.028 mmol), cyclohexanecarboxylic acid (0.011 g, 0.086 mmol), 1-hydroxybenzotriazole (0.021 g, 0.155 mmol) and anhydrous THF (0.9 mL) was added. diisopropylcarbodiimide (17 mL, 0.11 mmol) was added at room temperature. After 20 minutes, anhydrous DMF (0.4 mL) was added and the mixture was stirred for an additional 1 hour.

The reaction mixture was concentrated under reduced pressure and the remaining DMF was removed under high vacuum. The residue was purified by flash chromatography on silica gel (CH ₂ Cl ₂ / isopropanol 39: 1) to give amide 26 (0.024 g, 80%).

(b) Removal of protecting groups from compound 26: To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.03 g) and benzyl ether 26 (0.024 g, 0.022 mmol) was added dioxane (2.0 mL). ml), water (1.0 ml) and glacial acetic acid (0.35 ml). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black mixture is hydrogenated under slightly elevated pressure for 18 hours. Filter the reaction mixture through a cellulose filter (pore size 45 μπι) and concentrate the filtrate under reduced pressure. A solution of the residue in a small amount of water is passed through an ion exchange column (Dowex 50, Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and washed with deionized water. The filtrate is concentrated under reduced pressure and the residue is purified by gel filtration on Bio-Gel P2 (particle size 65 μπι, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH / H 2 O 3: 2) to give the target molecule BI.17 (0.008 g, 56%) in as a clear colorless solid (after lyophilization). ⁴ H NMR (500 MHz, D 2 O) δ 4.93 (d, J = 4.0 Hz, 1H), 4.60 (q, J = 6.7 Hz, 1H), 4.47 (d, J = 8.0 Hz, 1H), 4.04 (dd, J = 3.8, 7.5 Hz, 1H), 3.92 (d, J = 2.8 Hz, 1H), 3.86 (dd, J = 3.2, 10.3 Hz, 1H), 3.75 (d, J = 3.3 Hz, 1H), 3.74-3.64 (m, 4H), 3.61 (dd, J) = 3.8, 13.8 Hz, 1H), 3.59-3.52 (m, 2H), 3.50-3.44 (m, 1H), 3.42 (dd, J = 3.3) 9.8 Hz, 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 (m, 2H), 1.78-1.57 (m, 7H), 1.34-1.08 (m, 9H), 1.15 (d, J = 6.5 Hz) 3H), MS (FAB, THG) 644 (M + H), 622 (M + 2 H-Na)

Example B16: Preparation of Compound No. 1 BI.18

A solution of triol 13 (0.129 g, 0.17 mmol) in anhydrous MeOH (4.0 mL) and di-n-butyltin oxide (0.064 g, 0.258 mmol) was heated to reflux under argon for 2 hours. The clear solution was concentrated under reduced pressure and the residue was treated with pentane (2 mL), concentrated again, and then dried under high vacuum for 30 minutes to remove MeOH. The residue was mixed under an argon atmosphere with anhydrous CsF (0.131 g, 0.86 mmol, weighed under an argon atmosphere) and anhydrous 1,2-dimethoxyethane (0.5 mL), then a solution of benzyl- (R) -4-phenyl was added. -2-trifluoromethanesulfonyloxybutyrate (A2) (0.3 g, 0.861 mmol) in anhydrous 1,2-dimethoxyethane (1.0 mL). The reaction mixture is stirred at room temperature for 75 minutes and 1 M aqueous KK ₂ PO _{4 is added} and the mixture is diluted with water and extracted with ethyl acetate (phase separation is facilitated by the addition of a small amount of aqueous KF solution). The organic extracts were combined, dried over Na ₂ SO _d, filtered and concentrated under reduced pressure to give the crude product as an oil (0.39 g). Purification by flash chromatography on silica gel (eluent: toluene / ethyl acetate 5: 1) gave pure ether 30 (0.143 g, 81%). ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.35-7.05 (m, 30H), 5.13 (d, J = 12, 1H, ΙΗ), 5.03 (d, J = 12, 1 Hz, 1H), 4.88 (d, J = 11.4 Hz, 1H), 4.87 (d, J = 2.0 Hz, 1H), 4.78-4.50 (m, 5H) 4.46 (d, J = 12.5 Hz, 1H), 4.40 (d, J = 12.5 Hz, 1H), 4.33 (q, J = 6.5 Hz, 1K), 4 24 (d, J = 7.8 Hz, 1H), 4.09 (dd, J = 4.0, 8.5 Hz, 1H), 3.93 (broad s, 2H), 3.80-3 38 (m, 7H), 3.26-3.17 (m, 2H), 2.86-2.62 (m, 2H), 2.59 (d, J = 2.0 Hz, 10H) 2.29 (broad s, 10H), 2.11-1.85 (m, 4H), 1.67-1.52 (m, 2H), 1.40-1.06 (m, 4H) , 1.03 (d, J = 6.5 Hz, 3H).

b)

B1.18

Benzyl ether 30 (0.14 g, 0.135 mmol) was dissolved in dioxane (4 mL) and water (2 mL), glacial acetic acid (1 mL) and 20% Pd (OH) ₂ / C (0.14 g) were added. ). The air in the reaction vessel is first replaced by evacuation and multiple flushing with argon and then hydrogen. The black reaction mixture was hydrogenated under a slightly elevated hydrogen pressure for 90 minutes and 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 to remove residual acetic acid. The crude product (0.095 g) was dissolved in a small amount of water and filtered through a Dowex 50 (Na ⁺ ) ion exchange column. The filtrate was lyophilized and the residue (0.085 g) was purified by reverse phase chromatography (Merck R? 18 silica gel, elution: 40% MeOH / H 2 O) followed 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 then lyophilization to give the target molecule BI.18 as a fluffy powder (0.045 g, 55%). ^± H NMR (500 MHz, D2 O) δ 7.35-7.27 (m, 4H), 7.22 (tt, J = 5, 7.0 Hz, 1H), 4.93 (d, J = 4.0 Hz, 1H), 4.60 (q, J = 6.7 Hz, 1H), 4.47 (d, J = 7.8 Hz, 1H), 3.89-3.82 (m 3H), 3.76 (d, J = 3.5Hz, 1H), 3.74-3.63 (m, 4H), 3.59-3.52 (m, 2H), 3.51- 3.45 (m, 1H), 3.37 (dd, J = 3.5, 9.8 Hz, 1H), 2.80-2.68 (m, 2H), 2.12-1.99 ( m, 3H), 1.98-1.89 (m, 1H), 1.65 (broad s, 2H), 1.30-1.13 (m, 4H), 1.15 (d, J = 6) 6 Hz, 3H), MS (FAB, THG) 609 (M + Na), 587 (M + K).

Example B17: preparation of compound no. BI.19

B1.18

B1.19

Aromatic compound BI.18 (0.02 g, 0.033 mmol) was dissolved in water (1.8 mL) and dioxane (1.2 mL), glacial acetic acid (0.3 mL) and 5% Rh / A were added. 40% (0.04 g). The air in the reaction vessel was replaced with hydrogen by evacuation and multiple flushing, and the mixture was hydrogenated under a slightly elevated hydrogen pressure with vigorous stirring for 1.5 days. Then the mixture is 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 to remove residual acetic acid. 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 then hydrogenate 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, the filtrate is concentrated, then taken up in toluene and concentrated several times. The crude product was 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) followed by chromatography reversed phase (Merck RP 18 silica gel, elution: 50% MeOH / H ₂ O) followed by lyophilization to provide the target molecule BI.19 as a fluffy powder (0.01 g, 50%). ¹ H NMR (250 MHz, D ₂ O) δ 4.83 (d, J = 4.0 Hz, 1H), 4.48 (q, J = 6.7 Hz, 1H), 4.35 (J = 7.8 Hz, 1H), 3.81-3.69 (m, 3H),

3.67-3.53 (m, 5H), 3.49-3.31 (m, 3H), 3.25 (dd, J = 3.1, 9.7 Hz),

1H), 2.03-1.87 (m, 2H), 1.72-1.38 (m, 9H), 1.24-0.97 (m, 10H),

100

1.04 (d, J = 6.6 Hz, 3H), 0.75 (br s, 2H), MS (FAB, THG) 615 (M + Na), 593 (M + H).

Example B18: Preparation of Compound No. 1 BI.38

B1.11

B1.38

To a solution of amino acid BI.11 (0.035 g, 0.0617 mmol) in 1 molar aqueous NaHCO ₃ (315 μΐ) was added a solution of p-nitrobenzenesulfonyl chloride in toluene (1 M, 150 μΐ). The mixture was stirred vigorously at room temperature and after 17 hours additional p-nitrobenzenesulfonyl chloride solution (120 μΐ) was added. The reaction mixture was stirred for an additional 24 hours, then diluted with leader and washed twice with ethyl acetate. The aqueous phase is concentrated under reduced pressure to a volume of 0.5 ml and this solution is purified by gel filtration on Gelίο-Gel P2 (particle size 65 μπι, column diameter)

2.5 cm, length 100 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm). The crude product (0.06 g) was then further purified three times by reverse phase chromatography (Merck RP 18 silica gel, elution: 40% MeOH / H ₂ O) and then lyophilized to give sulfonamide BI.38 (0.013 g, 27%). %) in the form of a colorless fluffy powder. 1 H NMR (400 MHz, d ₂ O δ 8.34 (m, 2H), 8.05 (m, 2H), 4.88 (d, J = 4.0 Hz, 1H), 4.53 (q J = 6.5 Hz, 1H), 4.38 (d, J = 7.9 Hz, 1H), 4.06 (dd, J = 3.9, 8.2 Hz, 1H), 3.84 -3.79 (m, 2H), 3.70 (d, 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 (m, 5H), 3.25 (dd, J = 3.2, 9.5 Hz, 1H), 3.10 (dd, J = 7.7, 14, /

Hz, 1H), 3.05 (dd, J = 7.7, 14.1 Hz, 1H), 2.07-1.94 (m, 2H)

1.89 (hep, J = 6.7 Hz, 1H), 1.61 (broad s, 2H), 1.25-1.07 (m, 4H), 1.10 (d, J = 6.6) Hz, 3H), 0.70 (d, J = 6.6 Hz, 3H), 0.63 (no

J = 6.6 Hz, 3H).

101

The following compounds were prepared according to the above examples:

prípr. according to pr. no. bile. no. R ³ R ⁴ FAB-P1S THG 515 BI.20 On the CE.NEC (0) C, ₂ H ₂₂ 716 (M + E) < + > 738 (M + Na) 5 ÍL 5 EL. 21 On the en, nec (C) CE (c ₄ e _{5) 2} 723 (M + H) + 750 (M.-NaN! 312 ^; BI.22 On the CH ₂ NKC (0) CH ₂ CO ₂ Na 655 (Μτ-π). 678 (M-Nai j BIS ARE U. 23 iNs and CH.NHC (O) C ₄ [(1,3,4,5) OE] ₄ E. quinamide 703 (M + H) 730 (M + Na) Ξ15 51.24 On the CE.NEC (0) C _with H, -p-SO3Na 740 (M + E) < + > 762 (M + Na) i '312 and 51.25 On the CE.NEC (0) C _e E ₄ Cl 672 (M-E) 554 (M + Na) < + > E12 and 31.2S LMS. CEjNEC (0) E C _4, NO ₂ 633 (M + H) < + > 705 (M + Na). E12 Ei.27 On the CE.NEC (0) C ₅ K, OCEj 663 (M + E) i 650 (M + Na) + 312 51.2 3 On the CE ₂ NEC (O) C ₄ E. (3,4) C1 _; 706 (M + E) 723 (M + Na) B12 SI .29 On the CE.NEC (0) c, e ₄ ce ₃ 652 (M-E) i £ 74 (M + Na) S12 ' ^{: 1} 51.30 On the CE.NEC (0) C ₄ H ₄ C ₄ E = 714 (M + E) ' 735 (M + Na) i E12 ' ³ ' 51.31 On the CH.NHC (0) E _N E, CN 653 (M + E) 635 (M + Na) 512 and 31.32 On the CH.NHC (0) C _l0 H 633 (M + E) 710 (M + Na) E12 ⁽ “ BI.33 On the CE.NEC (0) C ₄ E, C00Na 704 (M + E) 726 (M + Na) E12 ^'51 31.34 On the CE.NEC (0) (CHOH) ₂ C00Na ! 652 (M + E) 710 (M + Na) Eli 51.35 On the CH ₂ N (C (0) C ₅ H _4] CE.C _p E _p 723 (M + E? 750 (M + Na) Bil BI .36 On the CH ₂ N [C (O) C ₄ H ₄ ] (CE ₂ ) ₃ c ₄ e ₅ 756 (M + H) 778 (M + Na) jB15 ^läi BI .37 On the CH ₂ NHSO ₂ CF 3 666 (M + E) 638 (M + Na)

102 a solution of succinic anhydride in DMF used as a reagent; ⁷ a solution of pentafluorophenylbiphenylcarboxylate in dioxane used as a reagent; (3) a solution of pentafluorophenyl p-cyanobenzoate in dioxane used as a reagent; , after the amide formation is complete, 1 M aqueous NaOH is added to the reaction mixture, the reaction mixture is heated to 65 ° C until hydrolysis of the methyl ester is complete, (1) 1 M NaOH is used instead of 1 M NaOH as anhydride solution as reagent. (+) - di-0-acetyl-L-tartaric acid in dioxane / Zr \ ^"1 the amide formation is carried out in CH ₂ C1 ₂ at 0 ° C using trifluoromethanesulfonic anhydride as reagent.

Example B19: Preparation of compound no. BI. 39

A suspension of compound 13 (0.086 g, 0.11 mmol) and di-n-butyltin oxide (0.05 g, 0.19 mmol) in anhydrous benzene (3.3 mL) was heated to reflux under argon for 12 hours. hours. The reaction mixture was concentrated under reduced pressure and dried under high vacuum for 1 hour. CsF (dried under high vacuum at 300 ° C for several hours, 0.042 g, 0.274 mmol) was then added under argon, followed by anhydrous 1,2-dimethoxyethane (0.6 mL) and a solution of triflate A3 (0.25 g). , 0.66 mmol) in anhydrous 1,2-dimethoxyethane (0.4 mL). The reaction mixture is heated to 35-40 ° C and stirred at this temperature for 5 hours. A solution of 15% KF in 1M aqueous was then added

103 of KH ₂ PO ₄ solution (30 mL) and the mixture was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The oily residue (0.16 g) was purified by silica gel column chromatography (gradient elution: toluene / ethyl acetate 80:20 to 75:25 then CH ₂ Cl ₂ / MeOH 19: 1) to give ether 31 (0.049 g, 44%) as a colorless foam and precursor 13 (0.035 g, 40%).

B1.39

To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.028 g) and benzyl ether 31 (0.048 g, 0.047 mmol) was added dioxane (2.0 mL), water (1.0 mL) and ice. acetic acid (0.5 mL). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black reaction mixture is hydrogenated at a slightly elevated hydrogen pressure at room temperature for 17 hours and then filtered through a cellulose filter (pore size 45 gm). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to remove excess acetic acid. The solution of the residue in water is passed through a Dowex 50 ion exchange column (Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and washed with deionized water. The clear filtrate is concentrated under reduced pressure 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 230 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, eluting with 7: 3 H ₂ O / methanol) to give the target molecule BI.39 (0.014 g, 51%) as a cyan white solid (after freeze-drying). 1 H NMR (400 MHz, D ₂ O) δ 4.83 (d, J = 4.0 Hz, 1H), 4.49 (q, J = 6.6 Hz, 1H), 4.33 (d, J = 7.7 Hz, 1H), 3.74 (d, J = 3.1 Hz, IH), 3.22 (dd, J = 2.6, 9.5 Hz, IH), ¹³ C NMR

104 (100.6 MHz D ₂ O) δ 181.5 (C), 100.2 (CH), 95.7 (CH), MS (FAB,

THG) 609 (M + Na), 587 (M + H).

Example B20: Preparation of Compound BI.40

pr

Coupling of alcohol 13 with Example 319 (preparation of compound A4 triflate 31).

is carried out according to

The hydrogenation of the benzyl ether and subsequent purification were carried out according to Example B19 (preparation of compound BI.39): ¹ H NMR (400 MHz, D ₂ O) δ 4.88 (d, J = 4.1 Hz, 1H), 4.53 ( q, J = 6.7 Hz, 1H), 4.39 (d, J = 7.7 Hz, IH), 3.29 (dd, J = 2.9, 9.8 Hz, IH), 1, 10 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H).

Example B21: Preparation of Compound No. 1 BI.41

HO

HO

105

Hydroxypiperidine (6.0 g, 34.6 mmol) prepared from D - (-) - lyxose according to Ichikawa and Igarashi [Y. Ichikawa, Y. Igarashi, Tetrahedron Letters 36: 4585-4586 (1995)] and triethylamine (18.1 mL, 130 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled to -10 ° C under argon. Allyl chloroformate (3.87 mL, 36.4 mmol) was added slowly over 1 hour to form a white suspension. The reaction mixture was stirred at -10 ° C for an additional hour, then 1 M aqueous KH ₂ PO ₄ (150 mL) was added and the mixture was extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a yellow oil (9 g). Purification by silica gel column chromatography (hexane / ethyl acetate 1: 1) afforded allylcarbamate 34 (7.66 g, 86%).

BzO

35

To a solution of acceptor 34 (7.66 g, 29.8 mmol) in anhydrous CH ₂ Cl ₂ (150 mL) was added molecular sieves 4A (high vacuum dried at 300 ° C, 15 g) under an argon atmosphere and the suspension was stirred at room temperature. Stir at room temperature for 1 hour. In parallel, a suspension of DMTST (15.4 g, 59.6 mmol) and 4Å molecular sieves (15 g) in anhydrous CH ₂ Cl ₂ (150 mL) was prepared in a second round-bottom flask under argon atmosphere and stirred for 1 h. hours. DMTST is then added in four portions to the acceptor solution over a further hour and the mixture is stirred for 1 hour. The reaction mixture was filtered through Hyflo Super

D

Cel and washed with CH ₂ Cl ₂ . The filtrate was extracted by shaking with a 10% aqueous NaHCO 3 solution, the aqueous phase was extracted three times with CH ₂ Cl _2, and the combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residual yellow oil (36 g) was purified by silica gel column chromatography (gradient elution: hexane / ethyl acetate 3: 1 to 3: 2) to give

106 glycoside 35 (13.1 g, 54%).

8zO

BzO

BzO

OBzl

Z— OBn

Acetoneide 35 (13.1 g, 15.94 mmol) was dissolved in dioxane (140 mL) and 50% aqueous trifluoroacetic acid (250 mL) was added at room temperature. After 2 hours, the reaction mixture was concentrated under high vacuum and the residue was purified by silica gel column chromatography (ethyl acetate / hexane 2: 1) to give diol 36 (11.23 g, 90%).

ABOUT

BnO

A mixture of dioiu 36 (11.63 g, 14.88 mmol), tetra-n-butylammonium bromide (12.7 g, 39.4 mmol) and 4Å molecular sieves (dried under high vacuum at 300 ° C, 22 g) dried under high vacuum for 30 minutes and then anhydrous CH ₂ Cl ₂ (62 mL) and dimethylformamide (36 mL) were added under an argon atmosphere. The gray suspension is stirred at room temperature for 30 minutes. In parallel, a solution of ethyl-2,3,4-tri-O-benzyl-1-thio-L-fucopy107 ranoside (7.48 g, 15.62 mmol) was prepared in a second round-bottom flask under argon atmosphere. according to the procedure of H. Lonn, Carbohydr. Res. 139: 105-113 (1985)] in anhydrous CH ₂ Cl ₂ (49 mL) and a solution of bromine (2.85 g Br ₂ , 17.84 mmol) in CH 2 Cl 2 (25 mL) was added at 0 ° C. The red solution was stirred at 0 ° C for 30 minutes and the excess bromine was quenched by the addition of a few drops of cyclohexane. The solution was then added via needle to the acceptor solution and the reaction mixture was stirred at room temperature for 40 hours. The reaction mixture was p

filter through Hyflo Super Cel and wash with CH ₂ Cl ₂ and wash the filtrate with 10% aqueous NaKCO ₃ . The aqueous phase is extracted three times with CH ₂ Cl ₂ and the combined organic phases are dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 35:65), eluting with the desired product 37 (7.85 g, 44%).

A solution of ester 37 (2.4 g, 2.0 mmol) and sodium methoxide (0.11 g, 2.0 mmol) in methanol (48 mL) was stirred at room temperature for 8 hours. The clear colorless solution is then neutralized by the addition of a strongly acidic ion exchanger (Amberlyst 15), then filtered through Hyflo Super Cel ^R and concentrated under reduced pressure. The oily residue was purified by silica gel column chromatography (gradient elution: CH ₂ Cl ₂ / methanol 98: 2 to 95: 5) to give triol 38 (1.72 g, 97%).

108

A suspension of compound 38 (1.0 g, 1.13 mmol) and di-n-butyltin oxide (0.49 g, 1.98 mmol) in anhydrous benzene (33 mL) was heated to reflux for 5 hours under argon. hours. The reaction mixture was concentrated under reduced pressure and dried under high vacuum for 1 hour. CsF (dried under high vacuum at 300 ° C for several hours, 0.43 g, 2.82 mmol) was then added under argon, followed by anhydrous 1,2-dimethoxyethane (7.4 mL) and benzyl-R solution. Of 3-phenyl-2-trifluoromethanesulfonoyloxypropionate (2.6 g, 6.77 mmol) in anhydrous 1,2-dimethoxyethane (4.9 mL). The reaction mixture is heated to 35-40 ° C and stirred at this temperature for 3 hours. A solution of 15% KF in 1 M aqueous solution of KH _2? O _and the mixture was exrrahuje three times with CH ₂ C1 ₂ and the combined organic phases were dried (Na ₂ S0 _4), filtered and concentrated under reduced pressure. The oily residue (3.2 g) was purified by silica gel column chromatography (elution: toluene / ethyl acetate 70:30) to give ether 39 (0.98 g, 78%) as a colorless foam.

To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.035 g) and benzyl ether 39 (0.038 g, 0.034 mmol) was added dioxane (3.5 mL), water (1.7 mL) and ice. acetic acid (0.25 mL). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated hydrogen pressure at room temperature for 24 hours and filtered through a cellulose filter (pore size 45 µm). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to remove excess acetic acid. The solution of residue in c is poured onto a Dowex 50 ion exchange column (Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and washed with deionized water.

109

The clear filtrate is concentrated under reduced pressure and purified by gel filtration on Bio-Gel P2 (particle size 65 μπι, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, gradient elution:

s ^ O / methanol 1 65:35 until 55 : 45),, BI.41 (0.0 14 g, 59 %) within a lyophilization ii). ¹ H NMR . (5 00 MHz 4H), 7,51- 7.46 (m, 1H) , 5 , 22 (d Hz, 1H), 4 , 56 (q, J = 6, 4 H z, 1H) 4.30 (dt, J = 6.3, 3.2 Hz, 1H), 3.59 (dd, J = 3.0, 1 3.8 Hz, 1H), 3.13 (dd, J = 9.0, 1 4.0 Hz, 1H), (d, J = 6.4 Hz, 3H) , 1, 10 (t, J =

(M + Na) 698 (M + H).

they obtain a target molecule of a white solid (po

d ₂ ° + 50 ° C) δ 7.58 -7.53 (M, J = 4, 0 Hz, 1H), 4.57 (d, J = 7.6 4.33 (Dd, J = 4.2, 8.6 Hz, 1H), 3, 66 (Dd, J = 8.0, 9.4 Hz, 1H), 3, 33 (Dd, J = 4.2, 14.0 Hz, 1H), 1.82 (Sex, J = 6.9 Hz, 2H), 1.36 , 5 Hz , 3H) , MS (FAB, NBA) 720

Example B22

Preparation of compound no

BI.42

A suspension of compound 38 (0.65 g, 0.73 mmol) and di-n-butyltin oxide (0.32 g, 1.28 mmol) in anhydrous benzene (22 mL) was heated to reflux for 16 hours under argon. hours. The reaction mixture was concentrated under reduced pressure and dried under high vacuum for 1 hour. CsF (dried under high vacuum at 300 ° C for several hours, 0.28 g, 1.83 mmol) and anhydrous 1,2-dimethoxyethane (4.0 mL) and A5 triflate solution (1 mL) were added under argon. , 74 g, 4.4 mmol) in anhydrous 1,2-dimethoxyethane (2.7 mL). The reaction mixture is warmed to 35-40 ° C and stirred at this temperature for

110 hours. A solution of 15% KF in 1M aqueous KH ₂ PO ₄ (100 mL) was added and the mixture was extracted three times with CH ₂ Cl ₂ and the combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The oily residue (2.6 g) was purified by silica gel column chromatography (elution: toluene / ethyl acetate 3: 1 then CH ₂ Cl ₂ / methanol 19: 1) to give ether 40 (0.33 g, 40%). ) as a colorless foam and in part precursor 38 (0.167 g, 26%).

B1.42

To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.025 g) and benzyl ether 40 (0.036 g, 0.032 mmol) was added dioxane (1.2 mL), water (0.6 mL) and ice. acetic acid (0.3 mL). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated hydrogen pressure at room temperature for 8 hours and filtered through a cellulose filter (pore size 45 gm). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to remove excess acetic acid. Pour the solution of the residue in water into a Dowex 50 ion exchange column (Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and wash with deionized water. The clear filtrate is concentrated under reduced pressure and purified by gel filtration on Bio-Gel P2 (65 gm particle size, column diameter)

2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, elution: H ₂ O / methanol 1: 1 ) to give the target molecule BI.42 (0.009 g, 41%) as a loose white solid (after lyophilization). ¹ H NMR

111 (400 MHz, D ₂ O) δ 5.09 (d, J = 3.7 Hz, 1H),

3.94 (d, J = 2.2 Hz, 1H); 3.58 (t, J = 8.4)

J = 1.8, 9.5 Hz, 1H), 1.83 (d, J = 12.2 Hz, 1H),

3 H), 0.95 (t, J = 7.6 Hz, 3 H), ¹³ C NMR (100, (C), 101.6 (CH), 98.0 (CH), MS (FAB, THG)

9i

4.58-4.46 (m, 2H), Hz, 1 H), 3.43 (dd,

1.23 (d, J = 6.7 Hz, 6 MHz, D ₂ O) δ 183.0 704 (M + H).

BnO

To a solution of tetrahydrofuran Pd (PPh ₃ ) ₄ (0.071 allyl carbamate (8.5 mL)) (0.695 g, 0.618 mmol) in morpholine (1.1 mL) was added and

0.062 mmol). Exactly after 15 minutes, the solution is concentrated and the residue is dried under high vacuum for 1 hour. Purification of the residue by silica gel column chromatography (eluent: CH ₂ Cl ₂ / methanol 98: 2, containing 0.3% concentrated aqueous ammonia solution) gave initially less polar alylpole more polar piperidine 41 amine 46 (0.39 g, (0 , 24 g, 36%);

COOSn

OBn

BnO

OH

112

To a solution of piperidine derivative 41 (0.035 g, 0.0336 mmol) in anhydrous CH ₂ Cl ₂ (0.6 mL) at 0 ° C was added pyridine (5 μΐ, 0.06 mmol) and acetic anhydride (1 mL) at 0 ° C. , 8 μΐ, 0.04 mmol). The solution was stirred at 0 ° C for 45 minutes and then washed with 5% aqueous NaHCO 3, and the aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phases are dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue (0.05 g) was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 4: 1) to give acetylpiperidine 42 (0.033 g, 91%) as a colorless foam.

To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.03 g) and benzyl ether 42 (0.04 g, 0.037 mmol) was added dioxane (1.4 mL), water (0.7 mL). ml) and glacial acetic acid (0.35 ml). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated hydrogen pressure at room temperature for 48 hours and filtered through a cellulose filter (pore size 45 μτη). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to remove excess acetic acid. Pour the solution of the residue in water into a Dowex 50 ion exchange column (Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and wash with deionized water. The clear filtrate is concentrated under reduced pressure and purified by gel filtration on Bio-Gel P2 (particle size 65 μτη, column diameter)

2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, gradient elution: methanol / H ₂ 0 2: 3 through 1: 1 to 3: 2) to obtain a target

113 molecule BI.43 (0.014 g, 64%) as a loose white solid (after lyophilization). 1 H NMR (400 MHz, D ₂ O) δ 7.22-7.06 (m,

5H), 4.86 (m, 1H), 1.95 (s, 3H), 0.98 (d, J = 6.7Hz, 3H), MS (FAB, THG) 654 (M + H), 632 (M + 2 H-Na).

Example B24: Preparation of Compound No. 1 BI.44

Compound 43 was prepared from piperidine 41 (0.02 g, 0.019 mmol) and benzoyl chloride (2.5 µL, 0.021 mmol) analogously to the procedure for the preparation of acetylpiperidine 42 (Example B23). Yield: 0.02 g (90%).

ABOUT

9 NO

ABOUT

B1.44

The title compound BI.44 was prepared by hydrogenation of benzyl ether 43 (0.042 g, 0.0367 mmol) and subsequent purification analogously to the procedure for the acetylderivative BI.43. After freeze-drying the product is a loose white solid. Yield: 0.015 g (57%). MS (FAB, THG) 716 (M + H), 694 (M + 2 H-Na).

Example B25: Preparation of Compound BI.45

114

Target Ex adu 23 cotton wool 41. ¹ H 1H), 4.37 to 4, 1H), 2.26 (t THG) 810 (M < + >)

(preparation of compound 31.43) from piperidine derivative NMR (400 MHz, D ₂ O) δ 7.28-7.13 (m, 5H), 4.95 (m, (m, 2H), 3.56 (s, 3H) 3.04 (m, 1H), 2.84 (m, J = 7.6Hz, 2H), 1.08 (d, J = 7.4Hz, 3H), MS (FAB,

Example B26: Preparation of Compound BI.46

To a solution of the piperidine derivative 41 (0.04 g, 0.038 mmol) in dry CH ₂ C1 ₂ (0.7 mL) was added pyridine (4 μΐ, 0.05 mmol) and cyclohexanecarbonyl chloride (7.2 μΐ, 0.05 mmol ). After 20 minutes, the reaction mixture was washed with 10% aqueous NaHCO 3 solution and the aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phases are dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification of the crude product (0.09 g) by silica gel column chromatography (eluent: hexane / ethyl acetate 1: 1) afforded amide 45 (0.03 g, 68%).

115

To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.05 g) and benzyl ether 45 (0.029 g, 0.025 mmol) was added dioxane (1.1 mL), water (0.55 mL). and glacial acetic acid (0.27 mL). The flask was evacuated and purged several times with argon. The pore was purged with hydrogen and the black reaction mixture was hydrogenated at a slightly elevated hydrogen pressure at room temperature for 24 hours. 5% Rh / C (0.02 g) was then added to hydrogenate the aromatic ring and hydrogenation was continued for 24 hours. The reaction mixture is filtered through a cellulose filter (pore size 45 μπι), the filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to remove excess acetic acid. Pour the solution of the residue in water into a Dowex 50 ion exchange column (Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and wash with deionized water. The clear filtrate is concentrated under reduced pressure and purified by gel filtration on Bio-Gel P2 (65 μπι particle size, column diameter).

2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, elution: methanol / H ₂ 0 60:40 ) to give the target molecule BI.46 (0.012 g, 64%) as a loose white solid (after lyophilization). ¹ H NMR (400 MHz, D ₂ O) δ 5.04 (m, 1H), 4.48 (m, 1H), 4.45-4.32 (m, 1H), 2.72 (m, 1H) ), 1.17 (d, J = 5.8 Hz, 3H), MS (FAB, THG) 728 (M + H), 706 (M + 2H-Na).

Example 327: Preparation of Compound No. 1. BI.47

116

To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, 20% Pd content, 0.03 g) and benzyl ether 46 (0.042 g, 0.039 mmol) was added dioxar. (1.4 mL), water (0.7 mL) and glacial acetic acid (0.35 mL). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated hydrogen pressure at room temperature for 16 hours and then filtered through a cellulose filter (pore size 45 μπι). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to remove excess acetic acid. The crude product (0.014 g) was purified by gel filtration on Bio-Gel P2 (particle size 65 μτη, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 21.5 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, elution: methanol / H ₂ 0 1: 3) to give the target molecule BI.47 (0.009 g, 36%) as a cyan white solid (after lyophilization). ). ^{Σ Η} NMR (400 MHz, D ₂ O) δ 7.10-7.02 (m, 4H), 7.01-6.94 (m, 1H), 4.80 (br s, 1H), 4, 10 (d, J = 7.0 Hz, 1H), (dd, J = 4.7, 8.5 Hz, 1H), 3.20 (t, J = 8.7 Hz, 1H), 2.97

3.84 (dd,

J = 3.3, 9.7 Hz, 1H), 2.83 (dd, J = 4.7, 13.1 Hz, 1H), 2.63 (dd, J = 8.5, 13.1 Hz) 1 H, 0.87 (d, J = 7.0 Hz, 3H), 0.63 (t, J = 7.3 Hz, 3H), MS (FAB, THG) 654 (M + Na), 632 (M + H) +.

Example B28: Preparation of Compound No. 1 BI.48

117

47

To a solution of piperidine 41 (0.025 g, 0.024 mmol) in ΟΗ ₂ Ο ₁₂ (0.3 mL) at 0 ° C was added triethylamine (7 μΐ, 0.05 mmol) and n-butanesulfonyl chloride (3.7 μΐ, 0.029). mmol). After 45 minutes, the reaction mixture was washed with 10% aqueous NaHCO ₃ solution and the aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phases are dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 60:40) to give sulfonamide 47 (0.022 g, 79%).

BnO

I oÚn

OBn

B 1.48

To a mixture of Pa (OH) ₂ / C (Pearlman catalyst, 20% Pd content (0.013 g) and benzyl ether 47 (0.027 g, 0.023 mmol) was added dioxane (1.0 mL), water (0.5 mL) and glacial acetic acid (0.25 ml) The flask was evacuated and purged several times with argon, then purged with hydrogen and the black reaction mixture was hydrogenated under a slightly elevated hydrogen pressure at room temperature for 24 hours and filtered through a cellulose filter (pore size 45). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to give

118 removes excess acetic acid. Pour the solution of the residue in water into a Dowex 50 ion exchange column (Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and wash with deionized water. The clear filtrate is concentrated under reduced pressure 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) followed by phase chromatography (Merck RP 18 silica gel, elution: 35:65 to 45:55), whereby the target molecule g, 65%) is obtained in the form of a cyan white solid (after inverted methanol / H ₂ O B1.48 (0.011 lyophilization). Η ^Χ NMR (400 MHz, D ₂ O) δ 7.51-7, 35 (m, 5H), 5.15 (d, J = 3.4Hz, 1H), 4.54 (q, J = 6.2Hz, 1H), 4.51 (d, J = 8.0) Hz,

1H), 4.03 (dd, J = 2.8, 10.4 Hz, 3.23 (dd, J = 4.8, 13.4 Hz, 1H), 1.84 (pen, J = 7, 6

J = 6.6 Hz, 3 H), (M + H).

Hz, 2H), 1.54 1.02 (t, J = 7.5 Hz,

1H), 3.59 (t, J = 8.9 Hz, 1H), 3.05 (dd, J = 8.6, 13.4 Hz, 1H), (sex, J = 7.3 Hz, 2H) 1.27 (d, 3H), MS (FAB, THG) 732

Example B29: Preparation of Compound No. 1 BI.49

BI.49

The title compound BI.49 was prepared analogously to Example B28 (preparation of BI.48) starting from piperidine derivative 41 and p-toluenesulfonyl chloride. 1 H NMR (400 MHz, D ₂ O) δ 7.56 (d, J = 7.2 Hz, 2H), 7.33 (d, J = 7.2 Hz,

2H), 7.28-7.11 (m, 5H), 4.81 (d, J = 3.4 Hz, 1H), 4.22 (d, J = 7.9 Hz, 1H), 3, 75 (d, J = 2.4Hz, 1H); 3.65 (dd, J = 2.4, 10.2Hz,

1H), 3.41 (t, J = 5.7Hz, 1H), 3.32 (t, J = 8.7Hz, 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 (broad s, 1H), 2.29 (s, 3H), 0.96

119 (d, J = 7.1 Hz, 3H), MS (FAB, THG) 788 (M + Na), 766 (M + H).

Example B30: Preparation of Compound No. 1 BI.50

B1.50

To a mixture of Pd (OK) ₂ / C (Pearlman catalyst, 20% Pd content (0.02 g) and benzyl ether 47 (0.041 g, 0.035 mmol) was added dioxane (1.5 mL), water (0.75 mL). ) and glacial acetic acid (0.38 ml), evacuated and purged several times with argon, then purged with hydrogen and the black reaction mixture was hydrogenated under moderately elevated hydrogen pressure 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 μπι), the filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times, The excess water solution is poured onto a Dowex 50 ion exchange column (Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and washed with deionized water. The clear filtrate is concentrated under reduced pressure. and purified by gel filtration on Bio-Gel P2 (particle size 65 μη?., Column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and subsequent reverse phase chromatography (Merck) RP 18 silica gel, elution: methanol / H2O ₍ 40:60 to 50:50) to give the target molecule BI.50 (0.021 g, 82%) as a pale white solid (after lyophilization). 1 H NMR (400 MHz, D ₂ O) δ 4.97 (d, J = 3.7 Hz, 1H), 4.41 (d, J = 7.7 Hz, 1H), 4.36 (q, J = 6.7 Hz,

1H), 3.81 (d, 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),

120

1.34 (sex, J = 7.4 Hz, 2H), 1.10 (d, J = 6.7 Hz, 3H), 0.81 (t, J = 7.5 Hz, 3H), MS ( FAB, THG) 738 (M + H), 716 (M + 2H-Na).

Example 331: Preparation of Compound # 1. BI.51

49

To a solution of allyl carbamate 40 (0.24 g, 0.212 mmol) in tetrahydrofuran (2.9 mL) was added morpholine (0.37 mL) and Pd (PPh ₃ ) ₄ (0.025 g, 0.021 mmol). Exactly after 15 minutes, the solution is concentrated and the residue is dried under high vacuum for 1 hour. Purification of the residue (0.38 g) by silica gel column chromatography (eluent: CH ₂ Cl ₂ / methanol 19: 1, containing 0.3% concentrated aqueous ammonia solution) afforded the piperidine derivative 49 (0.17 g, 76%). .

To a solution of the piperidine derivative 49 (0.04 g, 0.038 mmol) in CH ₂ Cl 2 (0.6 mL) at 0 was added phenyl isocyanate (4.6 μΐ, 0.042 mmol) and diisopropylethylamine (8.5 μ1,0 , 05 mmol). After 90 minutes, the reaction mixture is washed with 1 M aqueous KH ₂ PO _{4 solution} and the aqueous phase is extracted three times with CH ₂ Cl ₂ · The combined organic phases are dried (Na ₂ SO ₄ ), filtered and concentrated

121 under reduced pressure, chromatography on hexane / ethyl acetate 58:42

Purification of the crude product by silica gel column (elution gave urea derivative 50 (0.047 g) reagent: (0.035 g,

%).

To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.018 g) and benzyl ether 50 (0.036 g, 0.031 mmol) was added dioxane (1.3 mL), water (0.65 mL) and ice. acetic acid (0.33 mL). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated hydrogen pressure at room temperature for 16 hours and then filtered through a cellulose filter (pore size 45 μπι). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to remove excess acetic acid. Pour the solution of the residue in water into a Dowex 50 ion exchange column (Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and wash with deionized water. The clear filtrate is concentrated under reduced pressure and purified by gel filtration on Bio-Gel P2 (particle size 65 μπι, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, elution: methanol / H 2 O 1: 1) to give the target molecule BI.51 (0.018 g, 80%) as a cyan white solid (after lyophilization) . ¹ H NMR (400 MHz, D20) & ^{7 <14} (t »J = 7.9 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 6.95 (t, J = 7.7 Hz, 1H), 4.87 (d, J = 4.0 Hz, 1H), 4.30 (d, J = 7.4 Hz, 1H), 4.23 (q, J = 6, 6 Hz, 1H), 3.66 (d, J = 2.8 Hz, 1H), 3.42 (dd, J = 4.4, 7.7 Hz, 1H), 3.16 (dd, J = 2.6, 9.5 Hz, 1H), 1.00 (d, J = 6.6 Hz, 3H), MS (FAB, THG) 737 (M + H), 715 (M + 2H-Na).

122

Example B32: Preparation of compound no. BI.52

HO

B1.52

The piperidine derivative 49 was converted in analogy to Example B28 (Preparation of Compound BI.48) using phenylmethanesulfonyl chloride as reagent to the target compound BI.52. ^{Σ Η} NMR (400 MHz, _D2 0) δ 7.50 (m, 5 H), 5.02 (d, J = 3.5

Hz, 1H), 4.61 (d, J = 13.7 Hz, 1H), 4.54 (d, J = 13.7 Hz, 1H),

4.32 (d, J = 8.0 Hz, 1H), 3.62 (t, J = 6.0 Hz, 1H), 3.52 (dd,

J = 7.7, 8.4 Hz, 1H), 3.36 (dd, J = 3.2, 9.6 Hz, 1K), 3.22 (broad d, J = 12.6 Hz, 1H) 1.17 (d, J = 6.5 Hz, 3H), MS (FAB, THG) 772 (M + H), 750 (M + 2H-Na).

Example B33: Preparation of Compound BI.53

COOBn

B1.53

123

To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.05 g) and benzyl ether 49 (0.09 g, 0.086 mmol) was added dioxane (3.7 mL), science (1.8 ml) and glacial acetic acid (0.9 ml). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated hydrogen pressure at room temperature for 48 hours and filtered through a cellulose filter (pore size 45 gm). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to remove excess acetic acid. The crude product (0.044 g) was 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 ) followed by reverse phase chromatography (Merck RP18 silica gel, gradient elution: methanol / H ₂ 0 30:70 to 50:50), resulting in the target molecule of 31.53 (0.04 g, 78%) as a fluffy white solid (after lyophilization). ³ Η NMR (400 MHz, D ₂ O) δ

5.04 (d, J = 4.2) Hz, IH) 4.43 (D, J = 7.6 Hz, 1H), 4.27 (m, 2H), 4.20 (q, J = 6.5) Hz, IH) , 4.02 (dd, J = 2.6, 6.6 Hz, 1H) 3.51 (Dd, J = 7.8, 9.5 Hz, IH) , 1.12 (D, J = 6.2 Hz, 3H), MS (FA 3, THG) 618 (M + Na) 596 (M + H).

Example B34: Preparation of compound no. BI.54

HO

B1.53

B1.54

To a solution of piperidine derivative BI.53 (0.025 g, 0.042 mmol) in 1 M aqueous NaHCO ₃ solution (0.22 mL) at room temperature was added a 1 M solution of 2- (1-naphthyl) ethanesulfonyl chloride in toluene (46 g). The mixture was stirred vigorously for 22 hours and then concentrated under reduced pressure and dried at room temperature

124 high vacuum for 15 minutes. The crude product is purified by gel filtration on Bio-Gel P2 (65 gm particle size, column diameter)

2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, elution: methanol / H ₂ 0 7: 3 ) to give the target molecule BI.54 (0.011 g 31%) as a loose white solid (after lyophilization).

¹ H NMR (400MHz, D ₂ 0) δ 7.72 (d, J = 8.8) Hz, 1H), 7.54 (D, J = 8.8 Hz, 1H) 7.44 (d, J = 8.6 Hz, 1H), 7.28 (T, J = 7.2 Hz, 1H), , 7.22 (t, J = 7) (Hz, 1H) , 7.14 (t, J = 7.2 Hz, 1H) , 7.08 (d, J = 8, , 7 Hz,

1H), 4.91 (d, J = 4.1 Hz, 1H), 4.20 (d, J = 7.0 Hz, 1H), 3.99 (broad s, 1H), 3.90 (broad s, 1H), 1.09 (d, J = 6.3 Hz, 3H), MS (FAB, THG) 858 (M + Na), 836 (M + H).

Example B35: Preparation of Compound BI.55

To a solution of piperidine derivative BI.53 (0.035 g, 0.059 mmol) in 1 M aqueous NaHCO 3 solution (0.5 mL) at room temperature is added in small portions (50 to 100 g) a 0.5 M solution of acetic anhydride in toluene until all the precursor is consumed (test by thin layer chromatography: silica gel TLC plates, mobile phase: n-butanol / water / acetone / glacial acetic acid / _d NH 0H 70: 60: 50: 18: 1.5) for 1 hour .Approximately the reaction is complete and the mixture is concentrated under reduced pressure and dried under high vacuum for 15 minutes. The crude product was 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) followed by chromatography Reversed Phase (Merck RP 18

125 silica gel, methanol / H ₂ 0 3: 7) to give the target molecule BI.55 (0.026 g, solid (after lyophilization).

J = 4.2 Hz, 0.5H), 4.99 (d,

1H), 4.32 (q, J = 6.6Hz,

0.5H), 2.10 (s, 1.5H), 2.08 (s, 1.5H), 1.13 (d, J = 6.6 Hz, 3H).

Example B36: Preparation of compound no. BI.56

%) As a fluffy white solid Torme ^T H NMR (400 MHz, D ₂ O) δ 5.01 (d,

J = 4.2 Hz, 0.5H), 4.44 (d, J = 7.3 Hz,

0.5H), 3.14 (dd, J = 8.0, 12.9 Hz,

To a solution of piperidine derivative BI.53 (0.03 g, 0.05 mmol) in 1 M aqueous NaOH (0.15 mL) at room temperature is added in small portions (50 to 100 μΐ) a 1.5 M anhydride solution. (+) - di-O-acetyl-L-tartaric acid in dioxane until all the precursor is consumed (thin layer chromatography: silica gel TLC plates, mobile phase: n-butanol / water / acetone / glacial acetic acid / NH4) OH 70:60:50:: 18: 1.5). The mixture is kept alkaline during the reaction by periodically adding 1 M NaOH solution. The starting material was consumed in about two hours and then an additional 1 M sodium hydroxide solution (0.13 mL) was added and the mixture was heated to 40 ° C to hydrolyze the ester groups. After 1 hour, the mixture was concentrated under reduced pressure and dried under high vacuum for 15 minutes. The crude product was purified by gel filtration on Bio-Gel P2 (particle size 65 μτη, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and subsequent chromatography reversed phase (Merck RP 18 silica gel, elution: methanol / H ₂ 0 1: 9) reagent to give the target molecule BI. 56 (0.020 g, 52%) as a solid.

126 cypress white solid (after lyophilization). MS (FAB, THG) 794 (M + Na), 772 (M + H), 750 (M + 2H-Na).

Example B37: Preparation of compound no. BI.57

To shikimic acid solution (0.013 g, 0.075 mmol) and

1-hydroxybenzotriazole (0.01 methylformamide (0.37 mL))

N-N-diisopropylcarbodiimide (0.075 mmol) in anhydrous N, N-disa at 0 ° C was added (11.7 μΐ, 0.075 mmol) and the mixture was stirred for 30 minutes. Then the mixture is warmed to room temperature and the piperidine derivative B1 is added. 53 (0.015 g,

0.025 mmol). After 3 hours, a 10% aqueous NaHCO 3 solution (0.15 mL) was added and the reaction mixture was stirred for an additional 20 minutes and then concentrated under high vacuum. The residue is taken up in water, filtered through a cellulose filter (pore size 45 μπι) and poured onto a Dowex 50 ion exchange column (Na ⁺ form, column diameter 0.9 cm, length 3.5 cm) and washed with deionized leader. The filtrate is concentrated under reduced pressure and purified by gel filtration on Bio-Gel P2 (particle size 65 μπι, column diameter)

2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, elution: methanol / H ₂ 0 1: 9 ) to give the target molecule BI.57 (0.007 g 33%) as a loose white solid (after lyophilization). ¹ H NMR (400 MHz, D ₂ O) δ 5.8 (broad s, 1H), 4.94 (m, 1H), 2.55 (m, 1H), 2.10 (m, 1H), 1 07 (d, J = 6.0 Hz, 3 H), MS (FAB, THG) 796 (M + Na), 774 (M + H).

127

Example B38: Preparation of Compound No. 1 BI.58

BnO

3NO

To a solution of alcohol 37 (6.11 g, 5.1 mmol) in CH ₂ C1 ₂ (35 ml) at room temperature was added N, N-dimethylaminopyridine (1.03 g, 8.44 mmol) and p-nitrobenzenesulfonyl chloride ( 1.65 g, 7.44 mmol). After 52 hours, the reaction mixture was washed with 10% aqueous NaHCO ₃ solution and the aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (Na ₂ SO ₄ ), filtered and purified by concentration under reduced pressure. Crude product (10 g) by silica gel column chromatography (eluent: ethyl acetate / hexane 35:65) to give nozylate 52 (6.58 g, 93%).

A solution of nozylate 52 (7.78 g, 5.62 mmol) and anhydrous LiN ₃ (0.99 g, 20.21 mmol) in anhydrous N, N-dimethylformamide (50 mL) was heated to 50-60 under argon. C. After 16 hours, the solvent was removed under high vacuum and the residue was taken up into CH ₂ C1 ₂ and washed with 10% aqueous NaHCO _third The aqueous phase is extracted three times with CH ₂ Cl ₂ and the combined organic phases are dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 30:70), eluting first with the desired azide 53 (4.22 g, 61%) followed by alcohol 37 (2.5 g).

A solution of 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) was stirred at room temperature for 2.5 hours . The pH of the reaction mixture was adjusted to neutral by addition of a strongly acidic ion exchanger (Amberlyst 15, H ⁺ form), the suspension was filtered and the filtrate was concentrated under reduced pressure. The crude product (4.5 g) was purified by silica gel column chromatography (eluent: CH 2 Cl 2 / methanol 19: 1) to give triol 54 (2.89 g, 92%).

o P

Fuc .q

A suspension of compound 54 (2.89 g, 3.17 mmol) and di-n-butyltin oxide (1.56 g, 6.27 mmol) in anhydrous benzene (95 mL) was heated to reflux under an argon atmosphere for 16 hours. The reaction mixture is concentrated under reduced pressure and

The 129 was dried under high vacuum for 1 hour. CsF (dried under high vacuum at 300 ° C for several hours, 1.2 g, 7.9 mmol) was then added under argon, followed by anhydrous 1,2-aimethoxyethane (80 mL) and A5 triflate (6, 3 g, 15.97 mmol) in anhydrous 1,2-dimethoxyethane (50 mL). The reaction mixture is heated to 35-40 ° C and stirred at this temperature for 3 hours. The mixture was washed with a 15% solution of KF in 1 M aqueous KH _{2 PO, and} (150 ml) and the aqueous phase was extracted three times with CH ₂ C1 _2, then the combined organic phases dried (Na ₂ SO _a), filtered and concentrated under reduced pressure. The oily residue (10.9 g) was purified by silica gel column chromatography (eluting with: toluene / ethyl acetate 4: 1 then CH ₂ Cl ₂ / methanol 19: 1 to give a precursor) to give ether 55 (1.94). g, 53%) as a colorless foam, and in part, a precursor (1.1 g, 26%) was obtained.

To a solution of allyl carbamate 55 (0.15 g, 0.13 mmol) in tetrahydrofuran (1.7 mL) was added morpholine (215 μΐ) and Pa (PPh ₃ ) ₄ (0.015 g, 0.013 mmol) under argon. Exactly after 15 minutes, the solution is concentrated and the residue is dried under high vacuum for 1 hour. The crude product is purified on a short silica gel column (eluent: CH ₂ Cl ₂ / methanol 19: 1, containing 0.3% concentrated aqueous ammonia solution) and then dried under high vacuum for 1 hour. The residue is taken up in anhydrous CK ₂ Cl ₂ (1.7 mL), the solution is cooled to 0 ° C and triethylamine (43 μ1, 0.31 mmol) and n-butanesulfonyl chloride (18 μΐ, 0.14 mmol) are added. . After 15 minutes the reaction mixture was warmed to room temperature and washed with 10% aqueous NaHCO ₃ solution. The aqueous phase is extracted three times with CH ₂ Cl ₂ and organic

The 130 phases were combined, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography (eluent: ethyl acetate / hexane 30:70) gave sulfonium 56 (0.12 g, 77%).

B1.58

To a mixture of Pd (OH) ₂ / C (Peariman catalyst, Pd content 20%, 0.035 g) and benzyl ether 56 (0.027 g, 0.023 mmol) was added dioxane (1.2 mL), water (0.6 mL) and ice. acetic acid (0.25 mL). The flask was evacuated and purged several times with argon. It is then purged with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated hydrogen pressure at room temperature for 12 hours and then filtered through a cellulose filter (pore size 45 gm). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times 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 about 1 M solution of 3,4-dimethoxybenzoyl chloride in toluene is added in several small portions (30-50 g) over 5 hours. if thin layer chromatography test (silica gel TLC plates, mobile phase: n-butanol / water / acetone / glacial acetic acid / NH ₄ OH 70:60:50:

: 18: 1,5) shows that the conversion of the pH of the solution over a basic value by the addition of an intermediate product is complete, this reaction being maintained on several portions of solid

NaHCO 3 (total about 0.025 g). The reaction mixture is then concentrated under reduced pressure and the residue is taken up in a small amount of 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) a

131, followed by reverse phase HPLC (Merck RP .18 silica gel, methanol / H ₂ 0 65:35, resulting in the target molecule BI.58 (0.008 g, 39%) as a fluffy white solid (after lyophilization). 1 H NMR (400 MHz, D ₂ O) δ 7.41 (broad d, J = 8.3 Hz, 1K), 7.32 (broad s, 1H), 7.04 (d, J = 8.3) Hz, 1H), 5.05 (d, J = 3.9 Hz, 1H), 4.51 (d, J = 7.8 Hz, 1H), 4.14 (q, J = 6.7 Hz, 1H), 4.09 (t, J = 4.1 Hz, 1H), 3.82 (s, 6H), 3.33 (dd, J = 3.1,

9.6 Hz, 1H), 1.13 (d, J = 6.3 Hz, 3H), 0.68 (t, J = 7.6 Hz, 3H),

MS (FAB, THG) 923 (M + Na), 901 (M + H), 879 (M + 2H-Na).

Example 339:

Preparation of compound no. BI.59 o

Dioxane acetic acid (1.1 mL) was added. with argon several times.

To a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content 20%, 0.13 g) and benzyl ether 56 (0.12 g, (5.3 mL), water (2.6 mL) and ice flask) was added. evacuates and flushes

It is then purged with hydrogen and the black reaction mixture is hydrogenated under a slightly elevated hydrogen pressure at room temperature for 24 hours and then filtered through a cellulose filter (pore size 45 μτη). The filtrate is concentrated under reduced pressure and the residue is taken up in water and concentrated several times to remove excess acetic acid. The crude amine (0.074 g) was taken up in a small amount of water and purified by gel filtration on Bio-Gel P2 (particle size 65 μτη, column diameter 2.5 cm, length 35 cm eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP 18 silica gel, elution:

methanol / H ₂ 0 1: 1) to give the target molecule BI.59 (0.052 g, 73%) as a loose white solid (after lyophilization).

licking). ^{τ Η} NMR (400 MHz, D ₂ 0) δ 5.00 (d, J = 3.6) Hz, 1H), 4.41 (d, J = 7.7) Hz, 1H), 4.28 (q, J = 6.5 Hz, 1H), 3.83 (D, J = 3, 1 Hz, 1H), 3.79 (dd, J = 3.1, 9.7) Hz, 1H), 3 32 (dd, J = = 3.2, - with, 6 Hz, ± H), 1.12 (d, J = 6.1 Hz, 3H) 0.83 (t, J = 7.9 Hz, 3H) , MS (FAB, THG) 737 (M + Na) 713 (M + H).

Example B40: Preparation of Compound No. 1 BI. 60 o o

The amine B1.5S (0.027 g, 0.038 mmol) is taken up in 1 M aqueous NaHCO 3 (0.35 mL) and about 0.5 M benzoyl chloride solution is added several times in small portions (30 to 50 μΐ) over 4 hours. toluene until the TLC (silica gel TLC plates, mobile phase: n-butanol / water / acetone / glacial acetic acid / NH 4 OH 70:60:50:: 18: 1.5) showed that the conversion is complete. The pH of the solution during this reaction was kept basic by adding several portions of solid NaHCO 3 (total about 0.01 g). The reaction mixture is then concentrated under reduced pressure and the residue taken up in a small amount of 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) followed by reverse phase chromatography (Merck RP 18 silica gel, elution: methanol / H ₂ 0 1: 1) to give the target molecule B1. 60 (0.027 g 85%) as a loose white solid (after lyophilization). ¹ H NMR (400 MHz, D ₂ O) δ 7.72 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 6.9 Hz, 1H), 7.44 (t, J = 7.5Hz, 2H), 5.05 (d, J = 3.8Hz, 1H), 4.50 (d, J = 8.1Hz, 1H), 4.17 (q, J = 6.6 Hz, 1H), 3.92 (broad d, J = 10.4 Hz, 1H), 3.85 (d, J = 2.8 Hz, 1H), 3.80 (dd, J = 3) , l, 10.4

133

Hz, 1H), 3.33 (dd, J = 2.8, 9.8 Hz, IH), 1.12 (d, J = 7.1 Hz, 3H), 0.70 (t, J = 8 MS (FAB, THG) 863 (M + Na), 841 (M + H).

Example B41: Preparation of Compound No. 1 BI.61 o

HO

B1.61

B1.59

The carbamate B1.61 was prepared from the starting amine BI.59 (0.027 g, 0.038 mmol) using benzyl chloroformate as a reagent analogously to Example B40 (preparation of compound BI.60). Yield: 0.007 g (21%). 1 H NMR (400 MHz, D ₂ O) δ 7.31 (m, 5H), 5.06 (d, J = 12.0 Hz, 1H), 4.97 (d, J = 12.0)

Hz, 1H), 4.96 (d, J = 4.0 Hz, IH), 4.42 (d, J = 7.7 Hz, IH), 4.19 (q, J = 6.6 Hz, 1H), 3.96 (broad s, 1H), 3.80 (d, J = 2.9 Hz,

1H), 3.50 (dd, J = 8.2, 9.4 Hz, IH), 3.29 (dd, J = 2.9, 9.7 Hz,

1H), 3.20 (broad d, J = 12.2 Hz, 1H), 1.06 (d, J = 6.5 Hz, 3H),

0.77 (t, J = 8.0Hz, 3H), MS (FAB, THG) 871 (M + H), 849 (M + 2H-Na).

The following compounds were prepared analogously to the above examples:

134

Table la

zlúč.č. R ³ _r HA R BI. S2 On the C (O) CH NEC (O). ₀ K ₇

135

BI. 63 On the C (0) CH, NHC (O) OCH ₂ C ₆ H _s B1.6 S On the C (0) CH, NHC (O) CH ₂ C ₆ H _s BI. 67 On the C (O) CK. NHC (O) CH ₂ OC _s H _s 31.69 On the c (0) CH, NHC (O) CH ₂ NHC (O) OCH ₂ C ₆ H _s B1.71 On the C (0) 0 (CH ₂ CH, NHS (0) ₂ CH ₂ C ₆ H _s 31.74 On the S (0) ₂ (CE ₂ ), CH NHC (O) OCH, C ₆ H ₅ 31.75 On the S (O) _; (CH), ch, NHC (O) _{C 5} H 31.76 T T S (O) ₂ (CH 2), CH, NH ₂ 31.79 On the S (O) ₂ (CH3), CH, NHC (C) -3,4- (OCK,) ₂ C _S H,

Table 1b

zlúč.č. R ³ _r HA Bl · 85 On the S (O) ₂ -4-CH 2 -C _s K. BI. 56 On the C (O) (CH ₂ ) ₈ C (O) OCH, 31.87 On the S (O) ₂ (CH ₂ ), CH, 31.88 H (CH ₂ ) ₂ CK, Bl. 89 On the C (0) C _{e H;} 31.90 On the C (0) CH, 31.91 On the C (O) 0 (CH ₂ ) ₂ CH,

C. Ligand Binding Assay to Determine IC ₅₀ Values - To Use Maintained Positive Control E-Selectin / Human IgG Chimera [cloned and expressed by Kolbinger et al. , Biochemistry 35: 6385-6392 (1996)] are incubated in Falcon probind ™ microtiter plates (plate 1) at a concentration of 200 ng / well in 0.01 M Tris, 0.15 M NaCl, 1 mM CaCl ₂ , pH 7, 4 (Tris-Ca ⁺⁺ buffer). The solution thus contains 2 µg / ml E-chimera at 100 µΐ / well. Row 12 is left blank containing only

136

buffer. Plate 1 is incubated covered at 37 ° C for 2 hours. After incubation, 100 μΐ / well of 2% BSA in Tris Ca ⁺⁺ buffer is added and incubated at room temperature for 1 hour. During incubation, compounds are titrated (2 x serial dilutions) in 1% BSA in Tris-Ca ⁺⁺ using U-shaped microtiter plates (plate 2). The rows are serially diluted up to row 9. Rows 10, 11 and 12 contain only a buffer. The final volume is 60 μΐ / well and the first well contains 10 mM of the compound except for the positive controls, A (SLe * -Lemieux) and B are used as positive controls for each plate and the first well contains 5 mM of these compounds. The PolySLe ^and SA-HRP conjugate was prepared by pre-incubation of Sialyl Le ^and -PAA-biotin (catft01-044, Glyco Tech Corp., Rockville, MD) with 1: 2 molar ratio Streptavidin-HRP. 60 μΐ / well of 1 ng / μΐ of polySLe ^and SA-HRP conjugate in 1% BSA in Tris-Ca ⁺⁺ are added to all wells, except for Series 11 in plate 2. Plate 1 is washed four times with Tris-Ca ⁺⁺ buffer in automatic. plate washer. 100 μΐ / well is transferred from plate 2 to plate 1 starting from the lowest compound concentration. The plate 2 is discarded. The plate is incubated with shaking at room temperature for 2 hours. The plate is washed four times with Tris-Ca ⁺ * buffer in an automatic plate washer. Add 100 μΐ / well of Substrate [mixture of 3,3 ', 5,5'-tetramethylbenzidine reagent and H ₂ O ₂ 1: 1] using an 8-channel pipette from right to left. The plate is incubated at room temperature for 2 minutes. The reaction is stopped by adding 100 μΐ / well 1 MH ₃ PO ₄ using an 8-channel pipette from right to left. The ori 450 nm light absorbance is measured in a microtiter plate reader.

137 control compound B

IC 50 is calculated by determining the concentration of compound required for 50% inhibition of maximal binding of polySialylLe ^and HRP conjugate to immobilized E-selectin / human IgG chimera. The relative IC 50 ^is calculated by determining the ratio of IC _{50 of the} internal control compound to the IC _{50 of the} test compound.

In the following table, RIC ^ q stands for

IC _5Q (test.zl.) IC ₅₀ (controls, zl. A)

Table 2

OH

OH

138

zlúč.č. R ³ R ⁴ R1C _5O 31.1 On the -CK ₂ C ₆ K ₅ 0.35 P .2 On the -ch ₂ c ₅ h ₁₂ 0.03 31.3 On the -CH 2 NHC (O) C, H ₅ 1.11 BI. 4 On the -CH ₂ NHC (O) (CH-) ₂ C, H = 1.85 Ξ l ·. 5 On the -CH-NHC (O) (CH3), OH 1.23 «* £ -CH-NH, 0.96

PI

-CH ₂ NHCH ₂ (CH) ₂ C ₅ H ₅ /

C

On the

On the

On the

On the

On the

On the

On the

On the

On the

-C-r;

- Q

-C

-C

- C.

-C

H _; N (C (O) ClKs) CH, (CH), C ₆ H = B, NHCH ₂ C, H _;

BN (CH ₂ C _; H ₅ ),

5 ₂ NH ₂ CH ₂ CH (CHJ,

HN p _CH (CH,) _2], F ₂ NrC (C) C ₅ H ₅ TS j-CH (CH,) _2-j H.NHiSO JCjHjNC'-: a nksc ₂ C ₄ H ₂ 'chloro,

H _; NHC (O) Cl,

H ₂ NHC (O) CH 3 -. ₂ H-CH-C / H, p

i c

On the

On the

On the

On the

On the

On the

On the

On the

On the

E1.2 S Na

BI. 3 0 Na

On the

31.32 Na

31. S Na £ 3. 34

On the

On the

CH ₂ CH ₂ O (O) C _; , ZZ ₂₂

CH, NKC (0) CH (C) ₂ CH, NHC (O) C ₂ ZH ₄ CO ₂ Na CH, NHC (0) C ₄ [(1,3,4,5) CH ₃ CH ₂ NHC (0) C _{IH, SC;} Na CH _; NHC (0) C _? H ₄ Cl CH, NHC (C) C _and H, NO

CH _: NHC (O) C 2 OCH 3 CH ₂ NHC (Q) C ₅ H ₄ (3,4) Cl, CH ₂ NHC (O) C ₅ H ₄ CH ₃ CH ₂ NHC (0) c ₅ h ₄ c _{5 5} of _CH2 NHC (O) C _S h, CN CH.NHC (0) C 'h ₇ CH, NHCH ₂ C _s h,

CH ₂ NHC (O) C _with K ₄ COONa CH, NKC (0) (CHOK) ₂ COONa

1.15 0.9 0.51 0.5 0.74 0.32 0.21 0.12 0.13 0.54 1.33 0, -4 0.17 1.75 0.71 1.05 0 , 79 0, 93 1.29 1.21 1, 15 2, 04 1.3 1.65 1, 04 1.44 0, βΐΟ, 96 0.78

139

31.35 On the -CH ₂ N [C (O) C _S K _S ] CH ₂ C _S H _S 0.44 Ξ1.36 On the -CH ₂ N [C (O) _C K _5] (CH _{2) 3} C ₅ H _p 0.57 31.37 On the -CH ₂ NHSO ₂ CF ₃ 0, 26 31.33 On the -CH ₂ N [CK ₂ CH (CK ₃ )] SO.C.HsNO- 0.32

Table 2a

zlúč.č. RIC, ₃ zlúč.č. RiC =, | 31.62 0.949 JB1.77 0,618 31.64 j 0.237 31.78 0,304 31.8Ξ | 0,362 31.79 0, 196 31.66 1,112 BI .30 0,203 31.87 0, 564 31.31 0,126 z ä s i r, r c z. about _ . o and u, o - o 31.32 0, 195 2,661 131.8 3 | 0,176 E1.7 0 0,199 31.84 0,169 Ei. 71 0,414 1.3 5 1.23 31.72 0.156 iSl.36 ! 1 2,733 31.73 j 0.249 31.37 0,52 P 7 i! ¾) 1 P i - 1 ^J '- - 31.83 1,257 Ε1.7Ξ I 0.102 31.35 0,696 EI.7c j 0.451 1 Bi .90 0,569 E1.S3 1 0.087 1 and

140

Claims (50)

PATENT CLAIMS A compound of formula I wherein: X is the residue of a non-glycoside aliphatic 1,2-diol, R ¹ is a methyl group in the S-configuration substituted by one carboxyl residue and one other substituent, and R ² is H, alkyl of 1 to 12 carbon atoms or aryl of 6 carbon atoms, wherein the alkyl and aryl are unsubstituted or substituted by one or more substituents selected from OH, halogen, C (O) OR ^sl , OC (O) R ^s4, C (O) R ^s2, nitro, NH 2, CN, SO 3 M, OSO3My, NR ²⁰ SO 3 M, an alkyl group of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkoxy of 1 (C-C 12) cycloalkyl, (C až-C 12) cycloalkyl, (C až-C 12) cycloalkenyl, (C až-C heteroc) heterocycloalkyl, (C až-C heteroc) heterocycloalkenyl, (C až-C 10) aryl group, (C 6 -C 10) aryloxy, (C 5 -C 9) heteroaryl, (C 5 -C 9) heteroaryloxy, (C 7 -C 11) aralkyl, Aralkyloxy (C 7 -C 11) pin, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl, (C 7 -C 10) heteroaralkenyl, primary amino, secondary amino, 141 sulfonyl, sulfonamido, carbamoyl, carbamate, sulfónhydrazidovú group, a carbohydrazide group, a carbohydroxamic acid and aminocarbonylamide radical, in which R ^sl is hydrogen, My, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms , cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms or heteroaralkyl of 6 R ¹⁰⁴ is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of C 6 -C 10 heteroaryl, C 5 -C 9 heteroaryl, aralkyl the 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 and R ²⁸ are H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl (C 7 -C 11) heteroaryl, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl, or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl , heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, hetero aryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted with one of the above substituents, ayjel and M is a monovalent metal or y is 1/2 and M is a divalent metal, including physiologically acceptable salts thereof. 142 A compound according to claim 1, wherein (a) NH ₂ , the primary amino group, the secondary amino group, the carbamoyl group, the carbamate group, the carbohydrazide group, the sulfonamide group, the sulfone hydrazide group and the aminocarbonylamide group are groups selected from groups R ⁸ C (O) (NH) n (R ⁹ ) -, -C (O) (NH) NR ⁸ R ⁹ , R ⁸ OC (O) (NH) N (R ⁹ ) -, P P P R ⁸ R ⁴⁰ NC (O) (NH) pN (R ⁹ ) -, - C (O) (NH) p NR R ^S R ⁹ , -N (R ⁴⁰ ) C (O) (NH) p NR ⁸ R ⁹ , R ⁸ S (O) 2 (NH) pN (R ⁹ ) -, -S (O) 2 (NH) p NR ⁸ R ⁹ , R ⁸ R ⁴ ° NS (0) 2N (R ⁹ ) - or -NR ⁴⁰ S (0) ₂ NR ⁸ R ⁹ , wherein R ⁸ , R ⁹ and R ⁴⁰ are each independently hydrogen, OH, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms C 12 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, aralkyl (C až-C 16 ar), (C až-C ar ar) aralkenyl, (C až-C alk) alkenylene, (C až-C a) aryl, (C až-C hetero) heteroaralkyl, (C až-C hetero) heteroaralkenyl or diarylalkyl a group having 6 to 10 carbon atoms in the aryl moiety or or R ⁸ 'R ⁹ N, wherein R ⁸ having 1 to 6 carbon atoms in the 9 and R 8 are independently an alkyl moiety, hydrogen, OH, SO 4 My, OSO 2; We, (C 1 -C 12) alkyl, (C 3 -C 12) cycloalkyl, (C 2 -C 11) heterocycloalkyl, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 5 -C 9) aralkyl (C až-C 11) heteroaralkyl, (C až-C hetero) heteroaralkyl, (C až-C ar) aralkenyl, (C až-C alk) alkenylene, (C až-C a) aryl, or (C až-C 10) diarylalkyl; of an aryl moiety having 1 to 6 carbon atoms in the alkyl moiety which are unsubstituted or substituted by one or more substituents; 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 R ⁸ R ⁴⁰ N- together form a tetramethylene group of 143 pin, pentamethylene group, - (CH) groups ₂ ) ₂ -O (CH ₂ ) ₂ -, - (CH ₂ ) ₂ -S- (CH ₂ ) ₂ - or - (CH ₂ ) ₂ -NR ³ - (CH ₂ ) ₂ -, and R ³ is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl group having 7 to 11 carbon atoms, C (O) R ^s2, or sulfonyl, and (b) a sulfonyl group has the formula -SO 2 R ⁴⁸ wherein R ¹⁸ is an alkyl group of 1 to 12 carbon atoms, cycloalkyl of 3 C 12 -C 12 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl, which are unsubstituted or substituted by one or more substituents selected from OH, halogen, C (O) oR ^bs, OC (O) R ^s4, C (O) R ^s2, nitro, NH 2, CN, SO ₃ We, OSO ₃ My, NR ²⁸ SO ₃ My, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms alkyl, C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 aryl up to 10 carbon atoms, 6 to 10 carbon aryloxy, 5 to 9 carbon heteroaryl, 5 to 9 carbon heteroaryloxy, 7 to 11 carbon aralkyl, 6 to 10 carbon heteroaralkyl, aralkenyl C 8 -C 11 heteroaralkenyl, C 7 -C 10 heteroaralkenyl, primary amino, secondary amino, sulphonyl, sulphonamido, carbamoyl, carbamate, sulphonhydrazide, carbohydrazide, carbohydroxamic acid, and aminocarbonylamino, carbamoyl, and aminocarbonyl; , My, an alkyl group having 1 to 12 atoms C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 5 heteroaryl, 144 up to 9 atoms carbon, aralkyl group so 7 to 11 carbon or heteroaralkyl group so 6 to 10 carbon, R ^s4 is hydrogen, alkyl group s 1 to 12 carbon, alkenyl group with 2 to 12 carbon and carbon cycloalkyl of 3 heterocykioalkylová group 2 group having 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 and R ²⁰ are hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 cycloalkenyl of 3 to 11 carbon atoms, aryl of up to 1 to 1 carbon atoms, carbon atoms, atoms carbon atoms, carbon atoms, heterocycloalkenyl groups having 6 to 10 carbon atoms, aryl groups having 5 to 9 carbon atoms, aralkyl groups having 7 to 11 carbon atoms, heteroaralkyl groups having 6 to 10 carbon atoms, aralkenyl groups having 5 to 9 carbon atoms (C až-C 11 alebo) or Cara-C hetero hetero heteroaraalkenyl group, and alkyl, alkenyl; the upina, alkoxy, cycloalkyl, cycloalkenyl, heterocycioalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and heteroaraikenyl radicals are, in each case, unsubstituted or substituted, the above being substituted, 0 or lay is 1M is a monovalent metal or y is 1/2 and M is a divalent metal. A compound according to claim 1, wherein X is a straight or branched alkylene or alkenylene group having 2 to 20 carbon atoms, a cycloalkylene or cycloalkenylene group having 3 to 12 carbon atoms, a heterocycloalkylene or heterocycloalkenylene group having 3 to 11 carbon atoms, with heteroatoms selected from heteroatoms. -O-, -S- and -N-. 145 The compound of claim 1, wherein X is substituted with a substituent selected from OH, halogen, C (O) OR ^s , OC (O) R s ⁴ , C (O) R ^{s 2} , nitro, NH 2, cyano, SO We ^, ^ OSO- We, NR ²⁰ SO 3 M, an alkyl group of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of C 3 -C 12 heterocycloalkyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 5 -C 9 heteroaryl, C 5 -C 9 heteroaryloxy, C 7 -C 11 aralkyl, C 7 -C 11 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl, heteroa (C až-C 10alk) alkenyl, primary amino, secondary amino, sulfonyl, sulfonamido, carbamoyl, carbamate, sulfonhydrazide, carbohydrazide, carbohydroxamic acid and aminocarbonylamide group, where R ^s is My, C 1 -C 12, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, (C 7 -C 11) aralkyl or (C 6 -C 10) heteroaralkyl, R ⁴ is hydrogen, C 1 -C 12 alkyl, C 2 -C 10 alkenyl, C 3 -C 12 cycloalkyl C 2 -C 11 heterocycloalkyl; 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 and R ²⁸ are H, alkyl of 1 to 12 carbon C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, 146 heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl of 8 up to 11 carbon atoms or 7 to 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyl, aralkyl the heteroaralkyl group, the aralkenyl group and the heteroaralkenyl group are again unsubstituted or substituted with one of the above substituents, ay is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. A compound according to claim 1, wherein X is a 1,2-diol residue corresponding to formula II H in which R ⁵ and R ⁶ are independently H, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, the heterocycloalkyl group having 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl group C 5 -C 9 aralkyl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl, or R ⁰ and R 0 together with the -CH-CH- group form a C 3 -C 12 cycloalkylene, cycloalkenylene (C až-C-), (C až-C heteroc) heterocycloalkylene and (C až-C heteroc) heterocycloalkenylene, with heteroatoms selected from the group consisting of -O-, -S- and -N-, 147 wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene groups are unsubstituted or substituted with one or more substituents selected from OH, substituents selected from OH; , C (O) OR ^s1 , OC (O) R ^s4 , C (O) R ^s2 , nitro, NH ₂ , cyano, SO 4 M, OSO 4 M, nn NR SO ₃ M, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, heterocycloalkyl (C 2 -C 11) heterocycloalkenyl (C 2 -C 11), (C 6 -C 10) aryl, (C 6 -C 10) aryloxy, (C 5 -C 9) heteroaryl, (C 5 -C 9) heteroaryloxy group , (C 7 -C 11) aralkyl, (C 7 -C 11) aralkyloxy, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl, (C 7 -C 10) heteroaralkenyl, primary amino, secondary amino , sulfonyl, sulfonamido, carbamoyl, carbamate, sulfonhydrazide, carboxy a bohydreizide group, a carbohydroxamic acid, and an aminocarbonylamide group wherein R ^8a is a hydrogen atom, My, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, a heterocycloalkyl group having 2 to 12 C je-C, a, C,-C a a a aryl, C 5-C hetero hetero heteroaryl, C 6-C ar ar aralkyl or C je-C hetero hetero heteroaralkyl, R is hydrogen, C až-C alkyl alkyl C 12 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, aralkyl a C 7 -C 11 group or a C 6 -C 10 heteroaralkyl group 148 carbon atoms, and R ^s2 and R ²⁸ are H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, cycloalkenyl having 3 to 12 carbon atoms, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl, (C 6 -C 6) heteroaralkyl C 10 -C 8 aralkenyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl, heteroaryl , heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl the group, aralkenyl, and heteroaralkenyl are again unsubstituted or substituted with one of the above substituents, ay is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. A compound according to claim 5, wherein R and R are (a) an unsubstituted or substituted C 1 -C 12 alkyl or C 1 -C 12 alkoxy group, (b) together with a -CH-CH- group of 5- to 8-membered carbocyclic groups; (c) together with the -CH-CH- group of a 5- to 8-membered heterocarbocyclic ring, (d) independently of one another a hydrogen atom, an unsubstituted alkyl group having 1 to 12 carbon atoms or an alkyl group having 1 to 12 carbon atoms which is substituted a substituent selected from the group consisting of -C (O) OR ^s1 , -OC (O) R ^s4 , -C (O) ONa or -C (O) OK, a primary amino group, a secondary amino group, a C 3 -C 12 cycloalkyl group . 149 C 1 -C 6 alkyl, phenyloxy and benzyloxy, unsubstituted cycloalkyl group having 3 to 12 carbon atoms, or cycloalkyl of 3 to 12 carbon atoms, substituted with a substituent selected from the group consisting of -C (O) OR ^sl. -OC (O) R ^s4 , -C (O) 0Na or -C (O) OK, primary amino, secondary amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, phenyloxy and benzyloxy, aryl group having 6 to 10 carbon atoms, which is unsubstituted or substituted by a radical from the group consisting of -C (O) oR ^sl, -OC (O) R ^s4, -C (0) 0 on, or -C (O) OK, primary amino, secondary amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, C 3 -C 9 heteroaryl C 1 or 2 heteroatoms selected from oxygen and du Sika, or aralkyl having 7 to 12 carbon atoms, which is unsubstituted or substituted by a radical from the group consisting of -C (O) OR ^S \ -OC (O) R ^s4, -C (0) 0 on or -C (O OK, primary amino, secondary amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, (e) together from -CH-CH-, a 5- to 12-membered carbocyclic ring or a 5- or 6-membered heteroocarbocyclic ring with selected from the group consisting of an oxygen atom and a nitrogen atom; or (f) together with a -CH-CH- cycloalkylene group having from 3 to 3 carbon atoms; C 12 -C 12 cycloalkenylene, C 2 -C 11 heterocycloalkylene and C 3 -C 11 heterocycloalkenylene with heteroatoms selected from the group consisting of -O-, -S- and -N-, wherein: 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 ^s4 , C (O) R ^s2 , nitro , NH ₂ , 150 cyano, SO ₃ M _y , OSO ₃ M _y , NR ²⁰ SO ₃ M _y , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 1 -C 12 alkoxy, C 3 cycloalkyl C 12 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, heteroaryl C 5 -C 9 heteroaryloxy, C 5 -C 9 heteroaryloxy, C 7 -C 11 aralkyl, C 7 -C 11 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl , C7 -C10 heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamido, carbamoyl, carbamas ible group, sulfónhydrazidovú group, a carbohydrazide group, a carbohydroxamic acid and aminocarbonylamide radical, in which R ^sl is H, F, an alkyl group of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms , heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms or heteroaralkyl of 6 to 10 carbon atoms, R is hydrogen , (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 3 -C 12) cycloalkyl, (C 2 -C 11) heterocycloalkyl, (C 6 -C 10) aryl, (C 5 -C 5) heteroaryl C 7 -C 11 aralkyl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl and the atoms, and R ^s2 and R ²⁰ are H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl having 3 to 12 carbon atoms, heterocycloalkyl (C 2 -C 11) group, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl group, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl group 151 carbon, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl of 8 to 11 carbon atoms or heteroaralkenyl of 7 to 10 carbon atoms, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl , aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted by one of the above substituents, ay is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. A compound according to claim 5, wherein R ⁵ and R ⁸ together with the -CH-CH- group form a C 3 -C 12 cycloalkylene group or a C 2 -C 11 heterocycloalkylene group with nitrogen as the heteroatom, wherein the cycloalkylene group and the heterocycloalkylene group are unsubstituted or substituted by one or more substituents according to claim 6. A compound according to claim 7, wherein R ⁵ and R ⁶ together with the -CH-CH- group form a C 3 -C 12 cycloalkylene group or a C 2 -C 11 heterocycloalkylene group with nitrogen as the heteroatom, wherein the cycloalkylene group and the heterocycloalkylene group are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR ^S, OC (O) R ^s4 , C (O) R ^s2 , NR ⁸ R ⁹ , alkyl of 1 to 12 carbon atoms, R ⁸ C (O) (NH) N (R ⁹ ) -, -C (O) (NH) p NR ⁸ R ⁹ , R ⁸ S (O) 2 (NH) _p N (R ⁹ ) -, R ⁸ R ⁴⁰ NC (O) (NH) pN (R ⁸ ) -, R ⁸ OC (O) (NH) p N (R ⁹ ) -, -OC (O) (NH) _p NR ⁸ R ⁹ a R ¹⁰ -SO ₂ - in which R ⁸ , R ⁹ , R ¹⁰ and R ⁴⁰ are each independently hydrogen, OH, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, cycloalkyl (C až-C až) cycloalkenyl, (C až-C heteroc) heterocycloalkyl, (C až-C heteroc) heterocycloalkenyl (C až-C2) aryl, (C až-C hetero hetero) heteroaryl group (C až-C 9) C 7 -C 16 aralkyl, C 8 -C 16 aralkenyl of C 2 -C 6 alkenylene and C 6 -C 10 aryl, C 6 -C 15 heteroaralkyl, heteroaralkenyl (C 6 -C 15) or di (C 6 -C 10) aryl (C 1 -C 6) alkyl which is unsubstituted or substituted not one or more substituents selected from OH, halogen, C (O) OR ^s4, OC (O) R ^s4, C (O) R ^s2, nitro, NH 2, CN, SO 3 M, OSO3My, NR ²⁰ SO 3 M ,, (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 1 -C 12) alkoxy, (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, aryloxy of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, heteroaryloxy of 5 to 9 carbon atoms, aralkyl of 7 (C-C 11), (C až-C ar) aralkyloxy, (Calk-C hetero) heteroaralkyl, (C až-C ar) aralkenyl, (C až-C hetero) heteroaralkenyl; carbon atoms, a primary amino group, a secondary amino group, a sulfonyl group, a sulfonamide group, a carbamoyl group, a carbamate group, a sulfonhydrazide group, a carbohydrazide group, a carbohydroxamic acid and an aminocarbonylamide group, wherein R ^s4 is H, C1-12 alkyl, (C 2 -C 12) alkenyl, (C 3 -C 12) cycloalkyl, (C 2 -C 11) heterocycloalkyl, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 8) aralkyl R ( ⁴⁾ is hydrogen, alkyl (1 to 12 carbon atoms), alkenyl (2 to 12 carbon atoms), cycloalkyl (3 to 12 carbon atoms), heterocycloalkyl (2) up to 11 carbon atoms, 153 an aryl group having 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 and R ^{9 * * * * * * * 20} are hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl carbon, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl of 5 to 9 carbon atoms From 8 to 11 carbon atoms or from 7 to 10 heteroaralkenyl, and an alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl group a group, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted by one of the above 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. A compound according to claim 8, wherein R and R are independently hydrogen, C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, C 7 aralkyl until C-C až (C-C až), C až-C 10 ar (C až-C až) aralkyl, C až až-C ar ar (C až-C ar) aralkenyl, Ceny-C 10 (C až-C 10) , or a diarylalkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 6 carbon atoms in the alkyl moiety, Q Q wherein R and R are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C (O) OMy, C 1 -C 12 alkyl, C 1 -C 6 alkoxy, aryl 154 C 6 -C 10 aryloxy, C 6 -C 10 aryloxy, SO 4 My, OSO 4 My, NR ²⁰ SO ₃ My, NO ₂ , amino, primary amino, secondary amino and CN, R ²⁸ is hydrogen, (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 12) heterocycloalkyl 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl a group having 8 to 11 carbon atoms or a heteroaralkenyl group having 7 to 10 carbon atoms, ay 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 R ¹⁰ is C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, C 1 -C 16 aralkyl. up to 6 carbon atoms in the alkylene moiety and 6 to 10 carbon atoms in the aryl moiety, an aralkenyl group of 8 to 16 carbon atoms with 2 to 6 carbon atoms in the alkenyl moiety and 6 to 10 carbon atoms in the aryl moiety, or a diarylalkyl group having From 6 to 10 carbon atoms in the aryl moiety of up to about 6 carbon atoms in the alkyl moiety which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C (O) OMy, alkyl of 1 to 12 atoms carbon, C 1 -C 6 alkoxy, C 6 -C 10 aryl, SO 4 → My, OSO 4 My, NR ²⁸ SO ₃ My, NO ₂ , amino, primary amino, secondary amines and CN, wherein R ²⁰ is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 3 cycloalkyl C 12 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, heteroaryl 155 C 5 -C 9 aralkyl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, 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 10, wherein R ³ ® is C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, C 1 -C 16 aralkyl. 6 carbon atoms in the alkylene moiety and 6 to 10 carbon atoms in the aryl moiety which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxy, C (O) OMy, alkyl of 1 to 12 carbon atoms , (C 1 -C 6) alkoxy, (C 6 -C 10) aryl group, SO-, Μ, nitro, amino, primary amino, sec-amine and cyano, or C 8 -C 16 aralkenyl of C 2 -C 6 alkenylene and C 6 -C 10 aryl, or diarylalkyl having from 6 to 10 carbon atoms in the aryl moiety and from 1 to 6 carbon atoms in the alkyl moiety. The compound of claim 8, wherein R ⁸ and R ⁸ together with the group -CH-CH- form a cycloalkylene group having 3 to 12 carbon atoms or a heterocycloalkylene group having 2 to 11 carbon atoms with nitrogen as the heteroatom, wherein the cycloalkylene group and the heterocycloalkylene group are unsubstituted or substituted by one or more substituents selected from OH, C ( O) OR ^bs, OC (O) R ^s4, C (O) R ^s2, NH _9, alkyl of 1 to 12 carbon atoms, R ⁸ C (O) N (R ⁹⁾ -, -C (O) NR ⁸ R ⁹ , R ⁸ S (O) 2 N (R ⁹ ) -, R ⁸ S (O) N (R ⁹ ) - and R ¹⁰ -SO ² -, where R ⁹ is a hydrogen atom and Q R is alkyl of 1 to 12 carbon atoms, aryl of 6 to 10 carbon atoms or aralkyl of 7 to 11 carbon atoms which are unsubstituted or substituted with one or more alkoxy groups of 1 to 12 carbon atoms, R ⁴⁸ is an alkyl group C 1 -C 12, C 6 -C 10 aryl or aralkyl 156 are C 7 -C 11 unsubstituted or substituted by one or more C 1 -C 12 alkyl, R ¹ S and R ⁴ are C 1 -C 12 alkyl, and R ^{s 2} is C 1 -C 12 alkyl carbon atoms, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkyl or C 6 -C 10 aryl, and the alkyl, cycloalkenyl, cycloalkyl and aryl groups are again unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR ^s1 'and OC (O) R ^s4 ', wherein R ^s1 'is My or an alkyl group having 1 to 12 carbon atoms and R ^s4 ' is an alkyl group having 1 to 12 atoms carbon, 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 12, wherein R ⁵ and R ⁶ together with the -CH-CH- group form cyclohexylene. A compound according to claim 8, wherein R ⁸ and R ⁸ together with the -CH-CH- group form piperidylene. [" with* 15. The compound of claim 14, wherein R and R, together with the -CH-CH- form a piperidylene, wherein the hetero atom is unsubstituted or substituted by a substituent selected from zahŕňjúcej C (O) OR ^sl, C (O) R ^s2, C (O ) NR ⁸ R ⁹ , NH ₂ , SO _{3 MY} , alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl (C 3 -C 12), (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, (C 6 -C 10) aryloxy, (C 5 -C 9) heteroaryl C 5 -C 9 heteroaryloxy, C 7 -C 11 aralkyl, C 7 -C 11 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl C 7 -C 10 heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide 157 group, sulfónhydrazidovú group, and one or more carbon atoms in the ring are unsubstituted or substituted by one or more substituents selected from OH, OC (O) R ^s4, NH2, OSO3My, NR ²⁰ SO 3 M _y, C 1 -C 12 carbon, aryloxy of 6 to 10 carbon atoms, heteroaryloxy of 5 to 9 carbon atoms, aralkyloxy of 7 to 11 carbon atoms, primary amino, secondary amino, sulfonamido, carbamoyl, carbamate, hydroxycarbamido, carbohydrazide, carbohydrazide, carbohydrate R ( ¹⁾ is hydrogen, M, (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 3 -C 12) cycloalkyl, (C 2 -C 11) heterocycloalkyl, (Cry-Cry) aryl group C 6 -C 10 heteroaryl, C 5 -C 9 heteroaryl , a C 7 -C 11 aralkyl or a C 6 heteroaralkyl group is a hydrogen atom, a C 2 -C 12 alkenyl alkyl group, a C 3 -C 12 alkyl group, a C 2 -C 11 heterocycloalkyl group, a C 6 -C 10 aryl group C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyloxy, R c and independently of one another are hydrogen, OH, C 1 -C 12 alkyl C 3 -C 6 -cycloalkyl, C 2 -C 6 -cycloalkyl, C 5 -C 9 heteroaryl, C 7 -C 16 aralkyl, C 6 -C 15 heteroaralkyl, C 6 -C 15 aralkenyl From 8 to 16 carbon atoms having 2 to 6 carbon atoms in the alkenylene moiety and having 6 to 10 carbon atoms in the aryl moiety, or a diarylalkyl group or having from 6 to 10 carbon atoms in the aryl moiety and from 1 to 6 carbon atoms in the alkyl moiety, or R and R together form tetramethylene, pentamethylene, - (CH ₉ ) ₉ -O- (CH ₉ ) ₉ -, to 10 carbon atoms, R 4 -C 12 alkyl, alkoxy, cykloalkyiová to 12 carbon atoms, hete11 carbon atoms, aryl ₂ and ₂ - on - a ¹ 2 ^{- -} (CH _{2) 2} - S - (CH2) 2 ~ 3 because 7 7 - (CH ₂ ) ₂ -NR - (CH ₂ ) ₂ - and R is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 7 to 11 atoms 158 atoms, C (O) R ^s2, or sulfonyl, and R ^s2 and R ²⁰ are H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 8) aralkyl group C 11 -C 6 heteroaralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl group, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy the y, heteroaralkyl, aralkenyl and heteroaralkenyl groups are again unsubstituted or substituted by one of the above substituents, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. 16. The compound of claim 15, wherein R ⁸ and R ⁸ together with the -CH-CH- form a piperidylene, wherein the hetero atom is unsubstituted or substituted by a substituent selected from C (O) OR ^sl, C (O) R ^s2, - C (O) NR ⁸ R ⁹ and R ¹⁰ -SO ₉ and carbon are unsubstituted by several substituents OH, NH _2, R ⁸ S (O) ₂ N (R ⁹ ) -, one or more ring atoms or substituted with one or selected from the group consisting of R ⁸ C (O) N (R ⁹ ) - and R ⁸ OC (O) N (R ⁹⁾ ) - wherein R ⁹ is a hydrogen atom and R ⁸ is an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms or an aralkyl group having 7 to 11 carbon atoms, wherein the alkyl group, aryl group and aralkyl group are unsubstituted or substituted by one or more C 1 -C 12 alkoxy groups, R ¹⁰ is C 1 -C 12 alkyl, C 6 -C 10 aryl or C 7 -C 11 aralkyl which are unsubstituted or substituted once or a plurality of alkyl groups having 1 to 12 atoms 159 atoms, and the alkyl Alkyl and alkoxy, R ^sl is an alkyl group of 1 to 12 carbon atoms and R ^{s 2} is alkyl of 1 to 12 carbon atoms, cycloalkenyl having 3 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon the carbon or C 6 -C 10 aryl group, the cycloalkenyl group, the cycloalaryl group are again unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR ^s1 'and OC (O) R ^s4 , where R ^t is M or an alkyl group having 1 to 12 carbon atoms and c ZL '* R is an alkyl group having 1 to 12 carbon atoms, y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. / S 6 17. A compound according to claim 8, wherein R and R, together with the -CH-CH- form a piperidylene which is unsubstituted or substituted by one or more substituents selected from OH, C (O) OR ^bs, OC (O) R ^s4, C (O) R ^{s 2,} NH 2, alkyl having 1 to 12 carbon atoms, R ⁸ C (O) N (R ⁹⁾ -, -C (O) NR ⁸ R ^9, R ⁸ s (O) 2 N (R ⁹ ) -, R ⁸ OC (O) N (R ⁹ ) -, R ⁸ R ⁴⁰ NC (O) N (R ⁹ ) -, -OC (O) NR ⁸ R ⁹ and R ⁴⁸ -SO ₂ -, where R ⁹ is hydrogen and R ⁸ is C 1 -C 12 alkyl, C 6 -C 10 aryl or C 7 -C 11 aralkyl, wherein the alkyl, aryl and aralkyl are unsubstituted or substituted with one or two or more; a plurality of (C 1 -C 12) alkoxy or (C 7 -C 11) aralkyloxy groups, R ¹⁰ is C 1 -C 12 alkyl, C 6 -C 10 aryl or C 7 -C 11 aralkyl are unsubstituted or substituted by one or more alkyl groups having 1 to 12 carbon atoms, R ⁴⁰ is hydrogen, alkyl groups having 1 to 12 carbon atoms, cycloalkyl groups having 3 to 12 carbon atoms, heterocycloalkyl groups having 2 to 11 carbon atoms, (C až-C) aryl, (C až-C hetero hetero) heteroaryl, (C až-C ar ar) aralkyl or (C až až-C s hetero) heteroaralkyl, R ^{sl a} and R s ^sú are (C až-C alkyl) alkyl groups and R is C 1 -C 12 alkyl, C 3 -C 12 cycloalkenyl, 160 cycloalkyl of 3 to 12 carbon atoms or aryl of 6 to 10 carbon atoms, and the alkyl, cycloalkenyl, cycloalkyl and aryl substituents are again unsubstituted or substituted by one or more substituents selected from OH, C ( O) OR ^s4 'and OC (O) R ^s4 , wherein R ^s4 ' is My or an alkyl of 1 to 12 carbon atoms and R ^s4 'is an alkyl of 1 to 12 carbon atoms, 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 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 _g H ₃ , C (O) _{(CH2) 8} C (O) _OCH3, -C (O) [CH (OH) j ₂ C (O) ONa, C (O) -C _g H _g (OH) _3, - C (O) -CgH _{i, S,} C (O) OC ₃ H _7, -C (O) NHC H _{5 g,} -NHS (O) ₂ CH ₂ C _g H _5, -NHC (O) OCH ₂ C _g H _5, -NHC (O) C _g H ₃ (OCH _{3) 2,} -S (O) ₂ C ₄ H _9, -NHC (O) NKCgHg S (O) ₂ -C _g H ₄ CH _3, -S (O) ₂ CH ₂ C _g H _5, and -S (O) ₂ - (CH) ₂ C H _{1Q 7th} A compound according to claim 1, wherein R ² is an alkyl group having 1 to 6 carbon atoms. The compound of claim 1 wherein the substituents for R ² are selected from the group consisting of halogen, -C (O) OM, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, phenyl, naphthyl, -SO 2. ₃ We, the primary amino group having 1 to 12 carbon atoms, the secondary amino group having 2 to 20 carbon atoms, -SO ₂ -NR ⁸ R ⁹ and -C (O) -NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently hydrogen, C1-C4alkyl, C2-C4hydroxyalkyl, phenyl Q Q or benzyl, or R and R together with the nitrogen atom form a thiomorpholino, pyrrolidino or piperidino group. A compound according to claim 1, wherein R ² is hydrogen, unsubstituted C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted with C (O) OH, -C (O) ONa, -C (O) OK, -OH, -C (O) -NR ⁸ R ⁹ or -SO ₂ -NR ⁸ R ⁹ wherein R ⁸ is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl carbon 161 Q is carbon, phenyl or benzyl, and R is independently R, or Q Q R and R together form a tetramethylene group, a pentamethylene group or -CH ₂ CH ₂ -O-CH ₂ CH ₂ - A compound according to claim 21, wherein R ² is hydrogen, methyl, ethyl, HO (O) CCH ₂ CH ₂ -, NaOC (O) CH ₂ CH ₂ - or R ⁸ R ⁹ NC (O) CH ₂ CH ₂ -, Q and R and R are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 4 hydroxyalkyl, phenyl, benzyl, or together morpholino. The compound of claim 1, wherein the additional substituent in R ² has 1 to 20 carbon atoms. The compound of claim 23, wherein the additional substituent is selected from the group consisting of unsubstituted or substituted alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 (C 12-C 12), (C heteroc-C heterocyk) heterocycloalkyl, (C až-C heteroc heteroc) heterocycloalkenyl, (C až-C a,) aryl, (C až-C hetero,) heteroaryl, (C až-Cky ar) aralkyl group, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl, and C 7 -C 10 heteroaralkenyl. The compound of claim 24, wherein the additional substituent is substituted methyl or 2-substituted ethyl or cyclohexyl. A compound according to claim 1, wherein it corresponds to a group of formula III in which it is hydrogen or My, and 162 R ⁴ is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, heterocycloalkenyl C 2 -C 11 aryl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl C 7 -C 10 heteroaralkenyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR ^s , O (O) R s ⁴ , C (O) R ^{s 2} , nitro, NH ₂ , cyano, SO- ^Me, OSO ^Me, NR ^SO SOM, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkoxy of C 1 -C 12 cycloalkyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl , (C 6 -C 10) aryloxy, (C 5 -C 9) heteroaryl, (C 5 -C 9) heteroaryloxy, (C 7 -C 11) aralkyl (C 7 -C 11), (C 6 -C 10) heteroaralkyl carbon, an aralkenyl group of 8 to 8 carbon atoms 11 carbon atoms, heteroaralkenyl of 7 to 10 carbon atoms, primary amino, secondary amino, sulfonyl, sulfonamido, carbamoyl, carbamate, sulfónhydrazidovú group, a carbohydrazide group, a carbohydroxamic acid and aminocarbonylamide radical, in which R ^sl is hydrogen, My , an alkyl group having from 1 to 5 C 12 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, aralkyl group having 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, R ^s4 is 163 hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, C 6 -C 10 aryl, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 and R ²⁰ are H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to C 12 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, heteroaryl (C 5 -C 9) group, (C 7 -C 11) aralkyl, C 6 -C 10 heteroaralkyl, aralkenyl (C 8 -C 11) or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heteroaryloxy the group, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted by one of the above substituents, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. □ The compound of claim 26, wherein R is hydrogen or M 4. ^y and R 1 (a) unsubstituted C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted with one or more substituents selected from the group consisting of -NH ₂ , primary amino, secondary amino, sulfonyl of 1 to 12 carbon atoms; 12 carbon atoms, carbamoyl group, carbamate group, carbohydrazide group, sulfonamido group, sulfonhydrazide group, aminocarbonylamide group, C 3 -C 12 cycloalkyl, C 1 -C 6 alkoxy, phenyloxy And is unsubstituted cycloalkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms substituted with one or more substituents selected from the group consisting of cycloalkyl of 3 to 12 carbon atoms, alkyl of 1 to 6 carbon atoms , (C 1 -C 6) alkoxy, (C 1 -C 12) sulfonyl, phenyloxy and benzyloxy, (C 6 -C 10) aryl, (C 3 -C 9) heteroaryl selected from 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen atom, a (C 1 -C 6) -alkyl aralkyl group having from 6 to 10 carbon atoms in the aryl moiety, a (C 1 -C 6) heteroaralkyl group having 1 to 6 carbon atoms in the alkyl moiety and having from 3 to 10 carbon atoms in the heteroaryl moiety having 1 or 2 heteroatoms in the heteroaryl moiety selected from the group consisting of oxygen and nitrogen and having a total of 3 to 5 carbon atoms, furthermore an aryl group of 6 to 10 carbon atoms, a heteroaryl group of 3 to 9 carbon atoms with 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen , (C 1 -C 6) -alkyl aralkyl group having from 6 to 10 carbon atoms in the aryl moiety, a (C 1 -C 6) heteroaralkyl group having from 1 to 6 carbon atoms in the alkyl moiety and having from 4 to 6 carbon atoms. 10 carbon atoms in the heteroaryl moiety with 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen and with a total of 3 to 5 carbon atoms substituted with one or more substituents selected from OH, halogen, sulfonyl of 1 to 2 12 carbon atoms, carboxy, C (O) OMy, alkyl of 1 to 12 carbon atoms, alkoxy of C 1 -C 6 aryl, C 6 -C 10 aryl, SO 4 My, OSO ₃ My, NR ²⁰ SO ₃ My, nitro, NH ₂ , primary amino, secondary amino, carbamoyl, carbamate, sulfonamido and cyano, and y is M or a b is a monovalent metal or y is 1/2 and M is a divalent metal, or (b) an alkyl group having 1 to 12 carbon atoms or an aralkyl group. 165 is a group of 7 to 11 carbon atoms which is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR ^s , OC (O) R ^s4 , C (O) R ^s2 , nitro, NH 2, cyano, SO 3 My, OSO 2 My, NR ²⁰ SO 3 My, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 1 -C 12 alkoxy, cycloalkyl carbon, C 2 heterocycloalkyl cycloalkyl a C 2 -C 3 -cycloalkenyl group having from 3 to 12 carbon atoms, 11 carbon atoms, hetero 11 carbon atoms, (C 6 -C 10) aryl, (C 6 -C 10) aryloxy, C 5 -C 9 heteroaryl, C 5 -C 9 heteroaryloxy, (C 7 -C 11) aralkyl , (C 7 -C 11) aralkyloxy, (C 6 -C 10) heteroaralkyl, (C 8 -C 11) aralkenyl, (C 7 -C 10) heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamido, carbamoyl, carbamoyl a carbamate group, a sulfone hydrazide group, a carbohydrazide group, a carbohydroxamic acid, and an aminocarbonylamide group, wherein R ³ · ¹ · is a hydrogen atom, My, an alkyl group with a carbon atom, an alkenyl group a cycloalkyl group with a 1 to 12 carbon atoms, 2 to 12 carbon atoms, up to 12 carbon atoms, up to 11 carbon atoms, an aryl heterocycloalkyl group having 6 to 10 carbon atoms, a heteroaryl group having 5 to 9 carbon atoms, an aralkyl group having a heteroaralkyl group having 6 to 10 carbon atoms Or 10 carbon atoms; 7 to 11 6 to 10 1 to 12 carbon R ⁴ is hydrogen, alkyl of 1 to 12 atoms 2 to 12 to 12 carbon atoms, carbon to 11 carbon atoms, aryl carbon, alkenyl group with 3-cycloalkyl group with 2 heterocycloalkyl group of 6 to 10 carbon atoms, heteroaryl group of 5 to 9 carbon atoms, aralkyl group of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 and R ²⁰ are H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms . 166 cycloalkenyl group with 3 until 12 carbon alkyl, hetero- cycloalkyl group with 2 until 11 carbon alkyl, hetero- cycloalkenyl group with 2 until 11 carbon alkyl, aryl C 6 -C 10 heteroaryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl carbon atoms, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroalkaralkyl, aralkyl, and aralkenyl, or substituted with one of the above substituents, ay is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. n A compound according to claim 27, wherein R 0 is hydrogen, K or Na. A compound according to claim 27, wherein R ⁴ is methyl, ethyl, n- or isopropyl, n-, iso- or tert-butyl, cyclohexyl, naphthyl, phenyl, benzyl, naphthylmethyl, 2-phenylethyl, 3-phenylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, furanyl, pyridinyl or pyrimidinyl. A compound according to claim 27, wherein the carbamoyl group, carbohydrazide group, sulfonamide group, sulfonhydrazide group, aminocarbonylamide group and carbamate group as substituents for R ^{4 are} preferably R ⁸ NHC (O) N (R ⁹ ) -, R ⁸ OC (O) N (R ⁹ ) -, R ⁸ C (O) (NH) p (R ⁹ ) and R ⁸ S (O) 2 (NH) p N (R ⁹ ) - in which R ⁸ is a hydrogen atom , (C 1 -C 12) alkyl, (C 5 -C 6) cycloalkyl, (C 5 -C 6) cycloalkylmethyl or cycloalkylethyl, C 5 -C 6 heterocycloalkyl, C 5 heterocycloalkylmethyl or C 5 heterocycloalkylethyl 167 or 6 carbon atoms in the heterocycloalkyl moieties, phenyl, naphthyl, benzyl, 2-phenylethyl, diphenylmethyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of -OH, -NH ₂ , a primary amino group having 1 to 8 carbon atoms, a C 2 -C 14 secondary amino group, -NO ₂ , -CN, -F, -Cl, -C (O) OH, -C (O) ONa, -SO ₃ H, -OSO ₃ Na, NR ²⁰ SO ₃ Na, wherein R ²⁰ is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 atoms carbon, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl group C 8 -C 11 pins or C 7 -C 10 heteroaralkenyl, and -SO 3 Na, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and phenyl and R ⁹ is hydrogen, C 1 -C 4 alkyl to 10 carbon atoms, phenyl, naphthyl, benzyl, 2-phenylethyl or phenyl-CH = CH-CH ₂ -, and p is 0 or 1. A compound according to claim 27, wherein R ⁴ is (a) a carbamoyl substituted alkyl group R ⁸ -C (O) NR ⁹ - (CH 2) n - wherein n is 1 or 2, R ⁸ is hydrogen, alkyl (C až-C uhlí) cycloalkyl, (C až-C 12 a) cycloalkyl, (C až-C a a) aryl or (C až-C ar ar) aralkyl (C uhlí-C uhlí) alkyl group having 6 to 10 carbon atoms; an aryl moiety wherein the alkyl, cycloalkyl, aryl and aralkyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxy, -C (O) OM, (C 1 -C 12) alkyl, (C 1 -C 6) alkoxy, (C 6 -C 10) aryl, SO 3 M _y , OSO ₃ M _y , NR ²⁰ SO ₃ M _y , C (O) OR ^s , OC (O) R ^s4 , nitro, amino and cyano, 168 or an aralenyl group having from 8 to 16 carbon atoms having 2 to 6 carbon atoms in the alkenyl moiety and having 6 to 10 carbon atoms in the aryl moiety or a diarylalkyl group having 6 to 10 carbon atoms in the aryl moiety and having 1 to 6 carbon atoms in the alkyl moiety and R ⁹ is hydrogen, straight or branched (C 1 -C 10) alkyl, (C 5 -C 6) cycloalkyl, (C 5 -C 6) cycloalkylmethyl or cycloalkyl, phenyl, naphthyl or benzyl; -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 a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkenyl group (C 2 -C 12) cycloalkyl, (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or heteroaryl-phenyl 7 to 10 carbon atoms, ^R ^ is hydrogen, My, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocykioalkylová group having 2 to 11 carbon atoms , (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl or C 6 -C 10 heteroaralkyl group and R is hydrogen, C 1 -C 12 alkyl carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycioalkyl of 2 to 11 carbon atoms, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl, or (C 6 -C 10) heteroaralkyl, (b) sulfonamide-substituted alkyl group R ⁸ -SO ² NR ⁹ - (CH 2) _n -, wherein R ⁸ , R ⁹ and n are as defined above 169 in paragraph (a), (c) an alkyl group R ⁹ NHC (O) NH (CH 2) n or R ⁹ OC (O) NH (CH 2) _n wherein R ⁹ has the meanings given in paragraph (a), and additionally a phenyl n is as defined in (a), (d) carbohydrazide substituted alkyl R ⁸ -C (O) NHNR ⁹ - (CH _{2) n,} wherein R ^8, R ⁹ and n are defined or (e) a sulfonhydrazide substituted alkyl group R ⁸ -SO 2 -NHNR ⁹ - (CH 2) _n - wherein R ⁸ , R ⁹ and n have the meanings given in (a). 32. The compound of claim 27, wherein R ⁴ is (a) amido R ^and C (O) N (R 'wherein R ⁸ and R ^{9 are: CH 2}} nalebo R ⁸ S (0) _2N ^(R9: ; ch 2 n 'independently hydrogen, unsubstituted 6 to 10 (C 1 -C 12) alkyl, (C 1 -C 12) alkyl substituted with one or more substituents selected from the group consisting of OH, halogen, carboxy, C (O) 0Na, (C 1 -C 12) alkyl C 1 -C 6 alkoxy, C 6 -C 10 aryl, -SO 2 H, OSO 2 Na, NR ²⁰ SO ₃ Na, SO 2 Na, nitro and cyano, unsubstituted C 3 -C 3 cycloalkyl C 12 -C 12 cycloalkyl substituted by one or more OH groups, unsubstituted C 6 -C 10 aryl, C 7 -C 12 unsubstituted C 1 -C 6 aralkyl and alkyl atoms aryl, aryl or aralkyl having 1 to 6 carbon atoms in the alkyl portion and having 6 to 10 carbon atoms in the aryl portion; or are a substituent selected from the group consisting of OH, halogen, carboxy, C (O) OK, alkyl of 1 to 12 carbon atoms, 7 to 12 of C (O) ONa, alkoxy of 1 to 6 C 6 -C 6 aryl; 170 10 carbon atoms, SO ^Na, OSO NaNa, NR ^SO SONa, C (O) OR ^S SOC (O) R ^s4 , nitro, amino and cyano, R ²⁰ je is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 12 carbon atoms 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to heteroaryl of 5 to 9 atoms, 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl of 8 to 11 carbon atoms or a heteroaralkenyl group of 7 to 7 carbon atoms 10 carbon atoms, carbon atoms, aralkyl carbon atoms, R s1 is a hydrogen atom, We, an alkyl group C 1 to C 12 atoms, C 2 to C 12 alkenyl, carbon, heterocarbon, aryl carbon C 3 to C 12 cycloalkyl C 6 to C 10 cycloalkyl, C 6 to C 10 heteroaryl C 5 -C 9 aralkyl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl CA and R are hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 atoms or (b) a sulfonamido group R ⁸ S (O) 2 N (R ⁹ ), (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl, or (C 6 -C 10) heteroaralkyl; (CH 2) _n wherein R ⁸ is an alkyl group having 1 to 12 carbon atoms which is unsubstituted or substituted by one or more halogen atoms, or an aryl group having 6 to 10 carbon atoms substituted with one or more alkyl groups having 1 to 4 carbon atoms carbon atoms, C 1 -C 4 alkoxy, atoms Q is halogen, -CN or -NO ₂ , and R is hydrogen or isobutyl and n is 2 or 1, or (c) aminocarbonylamido ^The R-NH-C (O) NH (CH _{2) n,} wherein R ⁸ is 171 alkyl having 1 to 12 carbon atoms or aryl having 6 to 10 carbon atoms which are unsubstituted or substituted by halogen, -CN, alkyl having (C 1 -C 4), (C 1 -C 4) alkoxy, (C 5 -C 6) cycloalkyl, (C 6 -C 10) aryl or (C 7 -C 12) aralkyl; or (d) aminoalkyl RRN (CH 2) _n -, wherein R and R are each independently hydrogen, unsubstituted C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted with one or more substituents selected from OH, atom halogen, C (O) OR ^s1 , OC (O) R &lt; ⁴ &gt; C (O) NR &lt; R &gt;, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, -SO 1 H, SO-Na, OSO 2 Na, NR ²⁰ SO 3 Na, nitro, amino and cyano, unsubstituted C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkyl substituted with one or more OH groups, aryl group with aryl groups 6 a C 10-C 10 ar, C 7-C ar ar (C až-C ar) aralkyl (C až-C až ar) aryl or C 8-C 16 ar (C až-C ar) aralkenyl group (C až-C 6) and having 6 to 10 carbon atoms in the aryl moiety, wherein the aryl and the aryl moiety of the aralkyl and aralkenyl are unsubstituted or substituted one or more with substituents selected from OH, halogen, C (O) oR ^bs, OC (O R ⁴ , -C (O) ONa, -C (O) OK, -C (O) -NrHr ¹² , C 1 -C 12 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl carbon atoms, -SO 3 H, SO ₃ Na, OSO ₃ Na, NR SO ₃ Na, nitro, amino and cyano, where n is 2 and preferably 1, and R ^s1 is hydrogen, K or Na, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 atoms (C až-C a a) aryl, (C až-C hetero hetero) heteroaryl, (C až-C ar ar) aralkyl group 172 carbon atoms or a C 6 -C 10 heteroaralkyl group, R ⁴ is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 heterocycloalkyl C 1 -C 11 aryl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl or C 6 -C 10 heteroaralkyl, R ¹¹ is hydrogen, C 1 -C 10 alkyl C 1 -C 4, C 2 -C 4 hydroxyalkyl, phenyl or benzyl; and R is independently R, or R and R together form a tetramethylene, pentamethylene or -CH ₂ CH ₂ -O-CH ₂ CH ₂ - and R ²⁰ is H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalk enyl heterocycloalkyl of 2 to 11 cycloalkenyl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon atoms, aralkenyl C8-C11 heteroaralkenyl or C7-C10 heteroaralkenyl. (C až-C 12), C až-C 11 (hetero-carbon), aryl (C až-C.) A compound according to claim 32, wherein R ⁴ is an amido group R ⁸ C (O) N (R ⁹ ) (CH 2) n - or R ⁸ S (O) 2 N (R ⁹ ) (CH ₂ ) _n -, wherein R ⁸ is unsubstituted C 1 -C 12 alkyl, C 1 -C 8 alkyl substituted with one or more substituents selected from OH, halogen, C (O) ONa, and C 6 -C 10 aryl, unsubstituted cycloalkyl (C 12-C 12) cycloalkyl, (C až-C jednou) cycloalkyl substituted with one or more OH groups, (C až-C 7 až) unsubstituted aryl or (C až-C ar ar) aralkyl group (C až-C atóm) (C 6 -C 10) aryl, (C 7 -C 12) aralkyl (C 6 -C 10) alkyl group 173 carbon atoms with 6 to 10 carbon atoms in the aryl moiety or an aralkenyl group having 8 to 16 carbon atoms in the alkenyl carbon moiety in the aryl moiety substituted with one or more substituents selected from the group consisting of halogen, C (O) OH, C (O) ONa, C 1 -C 12 alkyl, C 1 -C 6 alkoxy, -SO-J, SO ₃ Na, OSO ₃ Na, NR ²⁰ SO ₃ Na, where R ²⁰ is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms, a cycloalkenyl group having 3 to 12 carbon atoms, a heterocycloalkyl group having 2 to 11 carbon atoms, (C 2 -C 11) heterocycloalkenyl, (C 6 -C 5) -aryl aryl (C 7 -C 11), C 6 -C 10 heteroaralkyl, (C 8 -C 11) aralkenyl or a heteroaralkenyl group having from 7 to 7 carbon atoms Q and nitro and cyano, and R is C 1 -C 6 alkyl of 6 to 10 unsubstituted C 7 -C 12 aralkyl of 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atoms in the aryl moiety, or (C 8 -C 16) aralkenyl having 2 to 6 carbon atoms in the alkenyl moiety and having 6 to 10 carbon atoms in the aryl moiety; and n is 2 or Unsubstituted or unsubstituted aralkyl carbon atoms 10 atoms is hydrogen, carbon atoms, carbon atoms, First A compound according to claim 32, wherein R ⁴ is an amido group R ⁸ C (O) N (R ⁹ ) (CH ₂ ) _n -, wherein R ⁸ is an unsubstituted C 1 -C 12 alkyl group, a C 1 -C 12 alkyl group carbon atoms substituted with one or more substituents selected from the group consisting of cyclohexyl, OH, halogen, -C (O) OH, -C (O) ONa and phenyl, unsubstituted C 3 -C 12 cycloalkyl, C 3 cycloalkyl up to 12 carbon atoms substituted by one or more OH groups, unsubstituted aryl of 6 to 10 carbon atoms, aryl of 6 to 10 carbon atoms substituted with one or more substituents selected from the group consisting of halogen, C (O) ONa, 174 -C (O) OH, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, phenyl, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NHSO ₃ Na, nitro and cyano, or aralkyl a group having 7 to 16 carbon atoms having 1 to 6 carbon atoms in the alkyl moiety and having 6 to 10 carbon atoms Q in the aryl moiety and R is hydrogen, unsubstituted (C 1 -C 6) alkyl, (C 1 -C 6) unsubstituted (C 1 -C 6) aralkyl, C 6 -C 10 alkyl, or an aralkenyl group having 8 to 16 carbon atoms having 2 to 6 carbon atoms in the alkenyl moiety and having 6 to 10 carbon atoms in the aryl moiety, and n is 2 or 1. A compound according to claim 34, wherein R ⁸ is unsubstituted C 1 -C 12 alkyl, C 1 -C 4 alkyl substituted with one or more substituents selected from halogen, C (O) OH, C (O) ONa, and (C až-C) alkyl group having 3 to 12 groups including OH, phenyl, unsubstituted cycloatoms, cycloalkyl one or 6 carbon atoms substituted with multiple OH groups, unsubstituted aryl of up to 10 carbon atoms, aryl of 6 to 10 carbon atoms , substituted with one or more substituents selected from the group consisting of halogen, -C (O) OH, C (O) ONa, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NHSO ₃ Na, nitro and cyano or unsubstituted C 7 -C 16 aralkyl of C 1 -C 6 alkyl and of 6 to 10 carbon atoms and R ⁹ is hydrogen, C 1 -C 4 alkyl, phenyl-CH ₂ -, phenyl-CH ₂ CH ₂ -, phenyl- (CH ₂ ) ₃ or phenyl-CH = CH-CH ₂ - and n is 2 or 1. A compound according to claim 32, wherein R ⁴ is an aminoalkyl group R ⁸ R ⁹ NCH ₂ -, wherein R ⁸ and R ⁹ are each independently hydrogen, alkyl of 1 to 8 carbon atoms, cyclopentyl, cyclohexyl, cycloalkylmethyl of 5? or 6 carbon atoms in the cycloalkyl moiety, a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety or a phenylalkenyl group having 2 to 4 atoms 175 carbon in the alkenyl moiety. A compound according to claim 32, wherein R ⁴ is an aminoalkyl group R ⁸ 'r ⁹ ' n CH ₂ -, wherein R ⁸ 'and R ⁹ ' are each independently hydrogen, alkyl of 1 to 6 carbon atoms, phenylalkyl with 1 or 2 carbon atoms in the alkyl moiety. A compound according to claim 26, wherein R ⁴ is a C 7 -C 11 aralkyl group, a C 3 -C 12 cycloalkyl group or a C 1 -C 12 alkyl group which is unsubstituted or substituted by one or more substituents selected from the group including NH ₂ , C 3 -C 12 cycloalkyl, primary amino, secondary amino, sulfonamido, carbamoyl and aminocarbonylamido. The compound of claim 38, wherein the substituents for an alkyl group comprising atoms L to 12 NH ₂ , cyclohexyl, R ⁸ NHC (O) NR ⁹ carbon are selected from the group consisting of 6-10 R ⁸ C (O) N (R ⁹ ) -, R ⁸ S (O) ₂ N (R ⁹ ) -, R ⁸ and groups 3 to 6 R 8 are independently 1 to 12 carbon atoms, carbon atoms, and R ⁸ 'r ⁹ ' n-, wherein hydrogen, alkyl carbon, cycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 atoms carbon atoms, heteroaryl group of 5 to 9 carbon atoms, aralkyl group with heteroaralkyl group with Ω I are independently hydrogen, OH, 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, 7 to 11 carbon atoms, or hetero 6 to 10 carbon atoms, which are substituted by one or more carbon atoms by alkyl or R ⁸ 'and R ⁸ '; From 7 to 11 atoms of 6 to 10 atoms, an aralkyl group with an aralkyl group with unsubstituted or substituents selected from the group consisting of OH, halogen, C (O) OR ^s , O (O) R ^s4 , C (O) R ^s2 , nitro, NH2 , CN, SO ^ We, we OSO ^, NR ²⁹ SO 3 M, an alkyl group of 1 to 12 carbon atoms, alkenyl of 2 to 12 C 176 carbon atoms, C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 12 heterocycloalkyl C 11 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 5 -C 9 heteroaryl, C 5 -C 9 heteroaryloxy, aralkyl C 7 -C 11 aralkyloxy. (C až-C až) heteroaralkyl, (C až-C hetero) heteroaralkyl, (C až-C ar) aralkenyl, (C až-C hetero) heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamido, carbamoyl, carbamate , sulfónhydrazidovú group, a carbohydrazide group, a carbohydroxamic acid and aminokarbonylamidoskupinu wherein R is ^sl H, We, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms or heteroaralkyl of 6 to 10 carbon atoms, R is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 and R ²⁰ are H, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to C 12 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, 2 to 11 heterocycloalkyl and t Mom atoms, heterocycloalkenyl group having 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkyl of 6 to 10 carbon 1ΊΊ carbon, C 8 -C 11 aralkenyl or C 7 -C 11 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted by one of the above substituents, p is 0 or layjela M is a monovalent metal or y is 1/2 and M is a divalent metal, or R a R together form a tetramethylene group, pentamethylene group, - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -, ' ^CH 2 R 2 ^S ' or - (CH _{2) 2} -NR ⁷ - (CH ₂₎ 2-, and ^R7 is H, alkyl of 1 to 6 carbon atoms, aralkyl of 7 to 11 carbon atoms, C (O) R ^s2 or sulfonyl group. The compound of claim 39, wherein R ⁴ is CH ₂ -C ₈ H ₅ , (CH ₂ ) ₂ -C ₈ H ₅ , cyclohexyl, methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH ₂ , cycloQ Q hexyl, (C 6 -C 10) aryl, RC (O) N (R) -, R ⁸ S (O) ₂ N (R ⁹ ) -, R ⁸ NHC (O) NR ⁹ -, NR ⁹ C (O) NHR ⁸ and R ⁸ 'r ⁹ ' n-, where R ⁸ , Q Q I R, R and R are each independently hydrogen, (C 1 -C 12) alkyl, (C 3 -C 12) cycloalkyl, (C 6 -C 10) aryl or (C 7 -C 11) aralkyl group; unsubstituted or substituted by one or more substituents selected from OH, halogen, C (O) OM _s, nitro, cyano, SO ₃ M _y OSO ^ We, NHSO ^ We, alkyl of 1 to 12 carbon atoms, C C 1 -C 12 and C 6 -C 10 aryl wherein y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. The compound of claim 26, wherein R ⁴ is ^c 6 ^{H 11 '} CH (CH ₃ ) ₂ , CH ₂ -phenyl, (CH _{2) 2} -, phenyl, CH ₂ NHC (O) - phenyl, CH ₂ NHC (O) (CH ₂ ) ₃ -phenyl, CH ₂ NHC (O) (CH ₂ ) ₃ OH, CH ₂ NHC (O) CF ₃ , CH ₂ NHC (O) C ₉ H ₁₁ , CH ₂ NHC (O) C ₁₁ H ₂₃ , CH ₂ NHC (O) CH (C 8 H ₅ ) ₂ , 178 CH ₂ NHC (O) NHCgH ₅ , CH ₂ NHC (O) C ₂ H ₄ CO ₂ Na, CH ₂ NHC (O) Cg [(1,3,4,5) OH] ₄ H ₇ , CH ₂ NHC (O) C 8 H ₄ -p-SO ₃ Na, CH ₂ NHC (O) CgH ₄ Cl, CH ₂ NHC (O) Cg H ₄ NO ₂ , CH ₂ NHC (O) C _g H ₄ OCH ₃ , CH ₂ NHC (O) CGH ₄ (3,4) Cl _2, CH ₂ NHC (O) C _g H ₄ CH _3, CH ₂ NHC (O) ₄ CGH CGH _5, CH ₂ NHC (O) CGH ₄ CN, CH ₂ NHC (O) C ₁₀ H _7, CH ₂ NHC (O) CGH ₄ COONa, CH ₂ NHC (O) (CHOH) ₂ COONa, CH ₂ N (CH ₂ CH = CH-phenyl) [C (O) -phenyl], CH ₂ N [CH ₂ CH (CH ₃ ) ₂ ] [C (O ) phenyl], CH ₂ N [C (O) C ₅ H _{g] CH2} CGH _5, CH ₂ N [C (O) C ₅ H ₅ ] (CH ₂ ) ₃ C ₅ H ₅ , CH ₂ C ₉ H _{11 (} (CH ₂ ) ₂ C ₈ H _{1; L} , CH ₂ NH ₂ , CH ₂ NHCH ₂ CK = 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 [CK ₂ CH (CH ₃ ) ₂ ] ₂ , CH ₂ NHSO ₂ -p- nitrophenyl, CH ₂ NHSO ₂ -p-tolyl, CH ₂ NHSO ₂ CF ₃ , CH ₂ NHC (O) NHC 8 H 2 or CH ₂ N [SO ₂ -p-nitrophenyl] [CH ₂ CH (CH ₃ ) ₂ ] 2 A compound according to claim 1, which corresponds to the general formula Ia in which R ³ is hydrogen or M, and R ⁴ is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, heterocycloalkenyl C 2 -C 11 aryl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or a C7 -C10 heteroaralkenyl group which is unsubstituted or mono- or polysubstituted; R @ 1 and R @ 2 are independently hydrogen, alkyl having 1 1-9 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a C 6 -C 10 heteroaralkyl group, or R ³ and R 6 together with the -CH-CH- group form a C 3 -C 12 cycloalkylene group, a C 4 -C 12 cycloalkenylene group, a C 2 -C 11 heterocycloalkylene group and heterocycloalkenylene of 3 to 11 carbon atoms with heteroatoms selected from the group consisting of -O-, -S- and -N-, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl , cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene and are unsubstituted or mono- or polysubstituted, wherein the substituents are selected from the group consisting of OH, halogen, C (O) OR ^s1 , OC (O) R ^s4 , C (O) R ^s2 , nitro, NH ₂ , cyano, SO C 1 -C 12, C 1 -C 12 alkyl, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, cycloalkenyl (C až-C až) heterocycloalkyl, (C až-C 11) heterocycloalkyl, (C až-C heteroc) heterocycloalkenyl, (C až-Cry a) aryl, (C až-C a a) aryloxy, (C až-C 9) heteroaryl , C 5 -C 9 heteroaryloxy, C 7 -C 11 aralkyl, C 7 -C 11 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl and, heteroaralkenyl of 7 to 10 carbon atoms, primary amino, secondary amino, sulfonyl, sulfonamide, carbamoyl, carbamate, sulfónhydrazidovú group, a carbohydrazide group, a carbohydroxamic acid and aminocarbonylamide radical, in which R ^sl is H, F, C1-C12alkyl, alkenyl 180 having 6 to 10 carbon atoms, up to 9 carbon atoms, aralkyl carbon or heteroaralkyl ο λ carbon, R 3e hydrogen, 7-carbon, carbon, aralkyl or heteroaralkyl of 2 to 12 carbon atoms, cycloalkyl (C až-C až) heterocycloalkyl, (Cyk-C heteroc) heterocycloalkyl, (C až-C ažry) aryl (C až-C hetero hetero) aryl, (C až-C alkyl alkyl) alkenyl, (C až-C alk alk) alkenyl, (C 12-C 12), (C až-C heteroc heteroc) heterocycloalkyl, (C až-C hetero) heteroaryl (C až-C hetero) heteroaryl (C až-C hetero), (C skupina-C 10), and R ^s2 and R ^{20 sú} are hydrogen, (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkyl C 3 -C 12 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl , C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted by one of the above substituents, ay is 1 and M is a monovalent metal or y is 1/2 and M is divalent metal. The compound of claim 42, wherein R ³ is hydrogen, K or Cľ Z * Na, R and R together with the -CH-CH- group form a C 3 -C 12 cycloalkylene group, a C 4 -C 12 cycloalkenylene group, a C 2 -C 11 heterocycloalkylene group and a C 3 -C 11 heterocycloalkenylene group 181 carbon atoms with heteroatoms selected from the group consisting of -O-, -S- and -N-, which are unsubstituted or mono- or polysubstituted, wherein the substituents are selected from the group consisting of OH, halogen, C (O) OR ^s , OC (O) R ^s4, C (0) R ^{s 2,} nitro, _NH2 ,, CN, SO ₃ M _y M _y OSO _3, carbon atoms, NR ²⁰ SO ₃ M _y , C 1 -C 12 alkenyl, C 1 -C 12 aralkyl alkyl, C 2 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl , heterocycloalkyl of 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl of 6 to 10 carbon atoms, aryloxy of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms heteroaryloxy of 5 to 9 carbon atoms . C 7 -C 11 aralkyloxy, C 7 -C 11 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl, C 7 -C 10 heteroaralkenyl, primary amino, secondary amino, sulfonyl, a sulfonamide group, a carbamoyl group, a carbamate group, a sulfonhydrazide group, a carbohydrazide group, a carbohydroxamic acid, and an aminocarbonylamide group wherein R ^s1 is a hydrogen atom, M, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, a cycloalkyl group (C až-C až), (C až-C heteroc) heterocycioalkyl (C až-Cry) aryl group (C až-C 10) C 12 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycioalkyl, C 6 -C 10 aryl, C 5 -C 7 heteroaryl alkyl group having 6 to 10 carbon atoms, and R ^s2 and R ²⁸ are H, alkyl of 1 to 12 carbon atoms, alkenyl, alkoxy, heteroaryl having 7 group of 6 alkyl group having 1 to to to carbon atoms, alkyl , aralkyl carbons or heteroaralkyl, s4 9 carbon atoms, R is ^the hydrogen atom, C 9, aralkyl or heteroaralkyl C 2 -C 12, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl carbon atoms, C 5 -C 9 heteroaryl, C 7 -C 11 aralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, and alkyl a group, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl aralkenyl are again unsubstituted or substituted by one of the above; , Y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, an aralkyloxy group, a heterocyclic group, 12 (a) R ⁴ is a radical R ^ ^x - (CH 2) _n -, or cyclohexyl, wherein n is Or C 1 -C 10 alkyl, C 5 -C 8 cycloalkyl, C 6 -C 10 aryl or C 8 -C 12 aralkenyl which are unsubstituted or substituted by C 1 -C 4 alkyl carbon atoms, C 1 -C 4 alkoxy, F, Cl, -CN or -NO ₂ , or R is an amino group -NR R ^J, and R and R are alkyl of 1 to 12 carbon atoms or unsubstituted or C 1 -C 4 alkyl substituted cycloalkyl of 5 or 6 carbon atoms, aryl of 6 to 10 carbon atoms , an aralkyl group with a carbon or an aralkenyl group of 8 to 12 or R ¹² is an amide group -N (R ⁹ ) C (O) R ⁸ , -NR ⁹ C (O) NHR ⁸ or -NR ⁹ C (O) NHR ⁸ , wherein R ⁸ is an aryl group of 6 to 10 carbon atoms which is unsubstituted or substituted with an alkyl group of 1 to 4 carbon atoms, From 7 to 12 carbon atoms, -N (R ⁹ ) S (O) ₂ R ⁸ C 1 -C 4 alkoxy, F, Cl, -CN or -NC 2, or C 1 -C 10 alkyl which is Q is unsubstituted or substituted by F or Cl, and R ⁷ is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 5 or 6 carbon atoms, cycloalkylalkyl of 5 or 6 carbon atoms in the cycloalkyl moiety of 1 to 6 carbon atoms in the alkyl part, a phenylalkyl group having 1 to 6 carbon atoms in the alkyl part or a phenylalkenyl group having 2 to 6 carbon atoms in the alkenyl part, or (b) R ⁴ is an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms or aralkyl of 7 to 11 carbon atoms, which is unsubstituted or substituted by one or more substituents selected from OH, halogen, C (O) oR ^bs, OC (O) R ^s4, C (O) R ^s2 , nitro, NH 2, CN, SO 3 M, OSO3My / NR ² SO 3 M _y ^, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, C 1 -C 12 C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl, C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, 6-aryl aryloxy (C 10-C 10) heteroaryl, (C až-C hetero) heteroaryl, (C až-C hetero) heteroaryloxy, (C až-Cal) aralkyl (C až-C ar), (C až-C ar) aralkyloxy (C až-C 10), aralkenyl with 8 to 11 carbon atoms, heteroaralkenyl of 7 to 10 carbon atoms, primary amino, secondary amino, sulfonyl, sulfonamide, carbamoyl, carbamate, sulfónhydrazidovú group, a carbohydrazide group, a carbohydroxamic acid and aminocarbonylamide radical, in which R ^sl is a hydrogen atom, M, C 1 -C 12 alkyl, C 2 -C 12 alkenyl 12 carbon atoms, C 3 -C 12 cycloalkyl, C 2 -C 11 heterocycloalkyl, 184 aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, or heteroaralkyl of 6 to 10 carbon atoms, R ⁴ is hydrogen, alkyl of 1 to 12 atoms carbon, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, aryl group of 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 and R ²⁰ are H, alkyl of 1 to 12 carbon carbon, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkenyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms, heterocycloalkenyl of 2 to 11 carbon atoms, aryl group of 3 to 12 carbon atoms C 6 -C 10 aromatics, C 5 -C 9 heteroaryl, aralkyl C 7 -C 11 heteroaralkyl, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl , heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are again unsubstituted or substituted with one of the above substituents, and y is 1 or M is 1 or metal And M is a divalent metal. 44. The compound of claim 43, wherein (1) R ⁴ is _IIf CGH CGH ₁₁ -CH ₂ -, _{and the CGH, L-CH 2} CH ₂ -, -CH ₂ CGH ₅ -, CGH ₅ CH ₂ CH ₂ - or CGH ₅ -CH = CH-CH ₂ -, (2) R ⁴ is a CGH _{1, L,} CGH _{1; L-CH2} -, _-CH2 CGH ₁₁ CH ₂ -, CGH ₅ -CH ₂ -, c ₆ h ₅ -ch ₂ ch ₂ -, -ch ₂ -nr ¹⁹ -so2r ¹⁸ , -ch2-nr ¹⁹ -c (o) r ⁴⁰ , -CH ₂ NHC (O) NHR ¹⁸ , -CH 2 NH ²¹ or -CH 2 N (R ²¹ ) ₂ , Kde Q wherein R is -C 8 H 8, phenyl substituted with 1 to 3 methyl 185 groups or methoxy groups or -NO ₂ or F or Cl, or an alkyl group having 1 to 4 carbon atoms substituted with F, R ⁴⁸ is phenyl unsubstituted or substituted with 1 to 3 methyl groups or methoxy groups or -NO 2 or F or Cl, R ¹⁹ is is H, alkyl of 1 to 6 carbon atoms, phenyl- (CH 2) _z, wherein z is from 1 to 3, phenyl-CH = _CH-CH2 -, _-CH2 CH _{(CH3) 2,} benzyl , and R ²¹ is -CH ₂ -CR ²² R ²³ R ²⁴ , wherein R ²² and R ²³ is methyl, ethyl or phenyl and R ²⁴ is hydrogen, ethyl or methyl, or (3) R ⁴ is C 6 H 11, CH 2 - C 5 H 5, (CH 2) 2 -C 8 H 5, methyl, ethyl or isopropyl which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH 2, cyclohexyl, (C 6 -C 10) aryl, R ⁸ C (O) N (R) ⁹ ) -, R ⁸ S (O) 2 N (R ⁹ ) -, NR ⁹ C (O) NHR ⁸ and R ⁸ 'r ⁹ ' n -, qqqiqi wherein R, R, R and R are independently hydrogen C 1 -C 12 alkyl, cyclo (C 3 -C 12) alkyl, (C 6 -C 10) aryl or (C 7 -C 11) aralkyl group unsubstituted or substituted by one or more substituents selected from OH, halogen, C (O) OMy , nitro, cyano, SO ₃ My, OSO ₃ My, NR SO ₃ My, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, and C 6 -C 10 aryl, wherein R is hydrogen, (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 3 -C 12) cycloalkyl, (C 3 -C 12) cycloalkenyl, (C 2 -C 11) heterocycloalkyl, (C 2 -C 11) heterocycloalkenyl group carbon atoms, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 9 carbon atoms, aralkyl of 7 to 11 carbon atoms, heteroaralkylo C 6 -C 10 aralkyl, C 8 -C 11 aralkenyl, or C 7 -C 10 heteroaralkenyl, y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. 186 The compound of claim 42, wherein R ⁴ is C 8 H _11f CH (CH ₃ ) ₂ , CH ₂ -phenyl, (CH ₂ ) ₂ -phenyl, CH ₂ NHC (O) -phenyl, CH ₂ NHC (0) (CH ₂ ) ₃ -phenyl, CH ₂ NHC (0) (CH ₂ ) ₃ 0H, CH ₂ NHC (0) CF ₃ , CH ₂ NHC (0) C ₆ H _{11 (} CK ₂ NHC) (O) C ₁₁ H ₂₃ , CH ₂ NHC (O) CH (C ₈ H ₅ ) ₂ , CH ₂ NHC (0) NHCgH ₅ , CH ₂ NHC (0) C ₂ H ₄ CO ₂ Na, CH ₂ NHC (O) Cg [(1,3,4,5) OH] ₄ H ₇ , CH ₂ NHC (O) CgH ₄ -p-SO ₃ Na, CH ₂ NHC (0) CGH ₄ Cl, CH ₂ NHC (0) ₄ CGH NO _2, CH ₂ NHC (0) C _g H ₄ OCH _3, CH ₂ NKC (O) C 8 H ₄ (3,4) Cl ₂ , CH ₂ NHC (0) C ₉ H ₄ CH ₃ , CH ₂ NHC (O) C 9 H _{4 C 8} H ₅ , CH ₂ NHC (0) C 9 H ₄ CN, CH ₂ NHC (O) C ₁ H ₇ , CH ₂ NHC (O) C 8 H ₄ COONa, CH ₂ NHC (O) (CHOH) ₂ C 100 Na, CH ₂ N (CH ₂ CH = CH-phenyl) [C (O) -phenyl] ], CK ₂ N [CH ₂ CH (CH ₃ ) ₂ J [C (O) -phenyl], CH ₂ N [C (O) C 8 H ₈ ] CH ₂ C _g H ₅ , CH ₂ N [C (O) C ₉ H ₅ ] (CH ₂ ) ₃ CgH ₅ , CH ₂ C _g H ₁₁ , (CH ₂ ) ₂ C _g H ₁₁ , CH ₂ NH ₂ , CH ₂ NHCH 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 (CH ₃ ) ₂ ] ₂ , CH ₂ NHSO ₂ -p-nitrophenyl, CH ₂ NHSO ₂ -p- tolyl, CK ₂ NHSO ₂ CF ₃ , CH ₂ NHC (O) NHC 8 H 4 or CH ₂ N [SO ₂ -p-nitrophenyl] [CH ₂ CH (CH ₃ ) ₂ ] ₂ · A process for the preparation of compounds of formula I according to claim 1, characterized in that the 3-OH group is etherified in a compound of formula V in which R ² and X have the meanings η o 17 of a protecting group and R and R of hydrogen or a protecting group. the group mentioned in claim 1, R ¹² is R 11 is independently a compound of the formula VI R ¹ -R ¹³ (VI) wherein R ¹ is as defined in claim 1 and R ¹³ is a group, then deprotecting. step away 187 A process for the preparation of compounds of formula I according to claim 1, characterized in that a glycoside bond is formed with a hydroxyether protected fucose of formula VII wherein R ² , R ¹² and X are as defined in claim 1 and R ⁴² is a protected galactose protecting group. wherein R ¹ and R ¹² are as defined in claim 1, Z is O or S and R is a leaving group, then deprotecting the resulting compound. Compound of formula (V) R ² is H, alkyl of 1 to 12 carbon atoms or aryl of 6 carbon atoms, wherein the alkyl and aryl are unsubstituted or substituted by 188 or more substituents selected from the group consisting of OH, halogen, C (O) OR ^s , OC (O) R ^s4 , C (O) R ^s2 , nitro, NH2, cyano, SO3My, OSO3My, NR ²⁸ SO3My, alkyl C 1 -C 12 alkenyl, C 2 -C 12 alkenyl, C 1 -C 12 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 2 -C 11 heterocycloalkyl , C 2 -C 11 heterocycloalkenyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 5 -C 9 heteroaryl, C 5 -C 9 heteroaryloxy, C 7 -C 11 aralkyl C 7 -C 11 aralkyloxy, C 6 -C 10 heteroaralkyl, C 8 -C 11 aralkenyl, C 7 -C 10 heteroaralkenyl ka, primary amino, secondary amino, sulfonyl, sulfonamide, carbamoyl, carbamate, sulfonhydrazide, carbohydrazide, carbohydroxamic acid and aminocarbonylamide, wherein R is hydrogen, M, C1-C12alkyl; (C 2 -C 12) group, (C 3 -C 12) cycloalkyl, (C 2 -C 11) heterocycloalkyl, (C 6 -C 10) aryl, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl carbon atoms>vx> o Δ. or heteroaralkyl of 6 to 10 carbon atoms, R is hydrogen, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 2 to 11 carbon atoms , aryl of 6 to 10 carbon atoms, heteroaryl of 5-9 carbon atoms, aralkyl of 7 to 11 carbon atoms or a heteroaralkyl group having 6 to 10 carbon atoms, and R ^s2 and R ²⁸ are H, alkyl of 1 (C 12-C alk) alkenyl, (C až-C alk) alkenyl, (C až-C cyk) cycloalkyl, (C až-C cyk) cycloalkenyl, (C až-C heteroc) heterocycloalkyl, (C až-C heteroc) heterocycloalkenyl, (C 1 -C 10) aryl group, (C 5 -C 9) heteroaryl, (C 7 -C 11) aralkyl group, h (C 6 -C 10) ethereroalkyl, C 8 -C 11 aralkenyl or C 7 -C 10 heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl group , aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are also unsubstituted or substituted by one of the above substituents, and y is M is a monovalent metal or y is 1/2 and M is a divalent metal, R ³ and R 0 together with the -CH-CH- group form a cycloalkylene group having 3 to 12 carbon atoms, a cycloalkenylene group having 3 to 12 carbon atoms, a heterocycloalkylene group having 2 to 11 carbon atoms and a heterocycloalkenylene group having 3 to 11 carbon atoms with heteroatoms selected from the group consisting of -O-, -S- and -N-, wherein the cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted with one or more of the above substituents, R is a protecting group and R and R are independently hydrogen or a protecting group. A process for the preparation of a compound of formula V according to claim 48, characterized in that the pseudo-trisaccharide building blocks are first synthesized by glycoside linking the activated and protected galactose to the fucose-OX-OH or protected and activated galactose-OX-OH building block, then is R ⁴ and then reacted as desired. glycosidic attachment of appropriate fucose to the building block into the pseudo-trisaccharide introduces the resulting compounds The compound of claim 1 for use in the therapeutic treatment of diseases of warm-blooded animals, including humans. 190 51. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, either alone or together with other active ingredients, a pharmaceutical carrier, and optionally excipients.