SI9620099A - 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

Diglycosylated 1,2-diols as mimetics of sialyl-Lewis X and sialyl-Lewis A

The present invention relates to mimetics sialyl-Lewis X and sialyl-Lewis A, in which in natural tetrasaccharide the neuramic acid residue is replaced by S-configured methyl substituted with one carboxyl residue and one other substituent and is N-acetylglucosamine residue with of 1,2-diol residues, to processes for the preparation of these compounds and to the use of these mimetics in therapeutic methods.

A complex process of inflammation, which takes place in various stages, is a natural reaction of the body to injuries, for example. also invasion of infectious agents. Under the influence of cytokines, it expresses the endothelium that covers blood vessels, adhesion proteins to its surface. P and E selectins are induced by protein-carbohydrate interaction with glycolipids and glycoproteins on the leukocyte membrane i.e. leukocyte rolling. The latter are slowed down by this process and there is activation of certain proteins (integrins) on their surface, which ensures firm adhesion of leukocytes to the endothelium. This is followed by migration of leukocytes into the damaged tissue.

When this procedure is performed in a controlled manner, the injury is eliminated after a certain period of time without leaving any major adverse effects. This is true in the case of certain acute and chronic inflammatory procedures in which the migration of leukocytes occurs in an uncontrolled manner, leading to serious injury to the body. This is in the case of disorders 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)].

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In various ways, attempts have already been made to develop drugs to mediate at different points in these adverse procedures [Dasgupta, F., Rao, B.N.N., Exp. Opin. Invest. Drugs 3: 709-724 (1994)]. The purpose of one method is to prevent the interaction between P and E selectins and their receptors on the leukocyte membrane and thus to roll, with mimetics of appropriate epitopes. This also results in suppression of later procedures. One of the smallest carbohydrate epitopes as a ligand for E selectin is sialyl-Lewis X [neuramic acid - a - (2 -> 3) - galactose - β (1 - »4) fucose - α (1 -> 3) - N acetylglucosamine ( sLe *)].

EP-A-0 579 196 proposes as compounds that compete with natural ligands for binding to the E selectin mMetics sLe * in which the neuramic acid residue is replaced by the lactic acid residue. WO 93/10796 describes compounds which comprise α-hydroxy acid residue instead of neuramic acid. WO 93/23031 describes mimetics in which the N-acetylglucosamine residue (GlcNAc residue) is replaced by R, R-1,2cyclohexanedioxy. However, it is common for all these compounds to have a binding affinity between

X increases them and E selectively only slightly, compared to that for sLe, whether it is actually worse and not sufficient for therapeutic effect.

It has now been surprisingly found that the simultaneous replacement of neuramic acid residue with S-configured methyl substituted with one carboxylic residue and one other substituent and N-acetylglucosamine residue with a non-glycosidic residue of aliphatic diol results in an unexpectedly high affinity of binding. The new compounds additionally imply structural and chemical simplification, have a lower molecular weight and can be obtained in greater quantities by processes of lower synthetic complexity.

The present invention relates to compounds of formula I:

where it is

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

R1 is S-configured methyl substituted with one carboxyl residue and one other substituent; and

R ₂ is hydrogen, C 1 -C 6 alkyl or C ₆ aryl; wherein alkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR j, OC (O) OR ₄ , C (O) R ₂ , nitro, NH ₂ , cyano, SO ₃ M _y OSO ₃ M _y, NR _2Q SO ₃ M _y C-C _p alkyl, C ₂ -C ₁₂ alkenyl, C ^ C ^ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ C _n heterocycloalkyl, C 1 -C 4 heterocycloalkenyl, C ₆ -C _1Q aryl, C ₆ -C _{1 ()} 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, Cg-C ^ aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino, seconds amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonamide wherein R is _E is hydrogen, M, C-C ^ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ C ₁₂ cycloalkyl, C ₂ -C ₁₁ heterocycloalkyl, C ₆ -C, ₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ C _1Q heteroaralkyl, R ₄ is hydrogen, C 1 -C ₁₂ alkyl, C _? -C ₁₂ alkenyl, C ₃ -C ₁ cycloalkyl, C ₂ C 3-6 cycloalkyl, C ₆ -C ₁₀ aryl, C-C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C ₁₀ heteroaralkyl, and R _p and R _{7Q are} hydrogen, C 1 -C 6 alkyl, C 1 -C _p alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ C _p cycloalkenyl, C ₉ -C _H heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C _{1 ()} aryl, CC ₉ heteroaryl, C ₇ -C _{) 1} aralkyl, C ₆ -C _{1 ()} heteroaralkyl, C ₈ -C _H aralkenyl, or C _? C 1 _{- (} heteroaralkenyl ₎ , and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl being unsubstituted or substituted by the above or unsubstituted substituents, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, including their physiologically acceptable salts.

Preferred aliphatic residues X are linear or branched C ₂ -C _2Q -, preferably C ₂ -C _p - and particularly preferably C _2-6 alkylene and -alkenylene, C ₃ -C ₁₂ -, preferably C ₃ -C _g - and especially preferably C ₅ -C _? cycloalkylene and cycloalkenylene and C ₃ -C _H -, preferably C ₃ -C _? - and especially preferably C ₃ -C ₅ heterocycloalkylene and heterocycloalkylene with heteroatoms selected from the group -O-, -S- and -N-.

The residue X may contain substituents such as OH, halogen, C (O) OR _sl , OC (O) OR _s4 , C (O) R _s2 , nitro, NH ₂ , cyano, SO ₃ M _y , 0S0 ₃ M _y , NR _2Q SO ₃ M _y , C 1 -C _p alkyl, C ₂ -C ₁₂ alkenyl, C _t -C ₂ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ C _1-6 heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₆ -C _w aryloxy, C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C _? -C j _t aralkyl, C ₇ -C _n aralkyloxy, C ₆ -C _I0 heteroaralkyl, C _g -C _n aralkenyl, _C? C ₁₀ heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and amidokarbonilamid, wherein R _E is hydrogen, M _y, Cl-C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₁ -C ₁₃ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, CJ-C 1, aralkyl or C _fi C ₁₀ heteroaralkyl, R ₄ is hydrogen, C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C _t jhe and o cycloalkyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _n aralkyl or C ₆ -C _w heteroaralkyl, and R _p and hydrogen, C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C _p cycloalkenyl, C ₁ -C ₄ heterocycloalkyl, CJ-C 4 heterocycloalkenyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C _? C aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _H aralkenyl or C ₇ -C ₁₀ heteroaralkenyl, and are alkyl, alkenyl. alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl, in turn, are unsubstituted or substituted with one of the above substituents, and y is monovalent and y is monovalent and y 1/2 and M divalent metal.

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

H

= H

H where are they

R ₅ and R ₆ independently of one another are hydrogen, C 1 -C 6 alkyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C 6, heterocycloalkyl, C 1 -C. _n aryl, C-C _n heteroaryl, C-C, aralkyl or C, -C ... heteroaralkyl, or R ₅ and R ₆ together with the group -CH-CH-, C ₃ -C ₁₂ cycloalkylene, C ₃ -C ₁₂ cycloalkenylene, C ₂ -C _H heterocycloalkylene and C ₃ -C ₁₁ heterocycloalkenylene with heteroatoms selected from the group -O-, -S- and -N-, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2 , nitro, NH ₂ , cyano, SO ₃ M _y , OSO ₃ M _y , NR 1 SO 4 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 ₁ [heterocycloalkyl, C ₂ -C ₁₁ heterocycloalkenyl, C ₆ -C _{1 ()} aryl, C ₆ C _{] 0} aryloxy, C ₅ -C ₉ heteroaryl, C ₁ -C ₄ heteroaryloxy-C 4 - Cnaralkyl, C ₇ -C _n aralkyloxy, C ₆ C heteroaralkyl, C -CLaralkenyl, C.-C. _n heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M, C, C _p alkyl, C, -C ,, alkenyl, C _3-C ,, cycloalkyl, C ₂ -C, heterocycloalkyl, C _{6 -C] O} aryl, _Ci-C9 heteroaryl, C ^ C ^ aralkyl, or C ₆ -C _1Q heteroaralkyl, R ^ is hydrogen, C, - C _p alkyl, C ₂ -C, ₂ alkenyl, C ₃ C _p cycloalkyl, C ₉ -C _H heterocycloalkyl, C ₆ -C _{] ()} aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ 6

C _{1Q is} heteroaralkyl, and R ₂ and R _{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 _H heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C-aryl, CC ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _H aralkenyl, or C ₇ C ₁₀ heteroaralkenyl, and are alkyl, alkenyl , alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are in turn unsubstituted or substituted with one of the above substituents and monovalent, and monovalent and y is 1/2 and M is a divalent metal.

The second substituent in R 1 preferably has 1 to 20, more preferably 1 to 16, especially preferably 1 to 12 and especially preferably 1 to 8 atoms of C. The second substituent is preferably selected from the group consisting of unsubstituted and substituted C 1 -C ₁₂ alkyl, C ₂ -C, ₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C _n heterocycloalkyl, C ₂ C _1-6 heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ - C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C 1 aralkenyl and C ₇ -C ₁₀ heteroaralkenyl. The other substituent is particularly preferably substituted methyl or 2-substituted ethyl or cyclohexyl. Examples of suitable substituents are those mentioned above in the definition of R ₂ , especially OH, halogen (F, Cl or Br), carboxyl, -SO ₃ H, C (O) OM _y , SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y where R _{20 is} hydrogen, C 1 -C 6 alkyl, C _f C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ C _n heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _n aralkenyl or C ₇ -C _w heteroaralkenyl, or C 1 -C 4 alkyl, C 1 -C 1 alkoxy, nitro, -NH ₂ , primary amino with 1 to 20 C atoms, seconds amino with 2 to 30 C atoms, cyano, C ₃ C ₈ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, C ₆ - C _10-10 aryl, C ₃ -C ₉ heteroaryl, C ₇ -C ₁₆ heteroaralkyl, wherein the heteroatoms are selected from the group of O, S and N atoms, and carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide or aminocarbonylamide whose N atoms are unsubstituted or substituted by a hydrocarbon group or a hydroxy hydrocarbon group of 1 to 20 atoms C. Hydrocarbon groups e and r

heterocarbon groups are, in turn, unsubstituted or substituted, e.g.

with C ₍ -C ₄ alkylotin, C ₁ -C ₄ alkoxy, carboxyl, halogen, (F, Cl or Br), -OH, -CN or no ₂ .

In a particular embodiment, compounds of formula IR _] correspond to a group of formula III:

COOR, (1H), ^R 4 c ₅ c ₇ where

R _{3 is} hydrogen or M _y ; and _R4 is Cj-C ^ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C _J2 cycloalkyl, C ₃ C ₁₂ cycloalkenyl, C ₂ -C, heterocycloalkyl, C _2-c heterocycloalkenyl, C ₆ -C _1Q aryl, C 1-6 heteroaryl, C 1-6 aralkyl, CC,. Heteroaralkyl, C 1-6 aralkenyl, or

C ₁₀ heteroaralkenyl unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R ₄ . C (O) R _s , nitro, NH ₂ , cyano, SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y , C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₁ C ₁₂ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C, -C _H heterocycloalkyl, C ₂ -Cheterocycloalkenyl, C ₆ -C _1Q aryl, C ₆ -C ₁₀ aryloxy, C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C _? -C j _t aralkyl, _C? -C _n aralkyloxy, C ₆ -C ₁₀ heteroaralkyl, C _g -C _H aralkenyl, C _? C _{l ()} heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, _M, C, C _p alkyl, C, -C _p alkenyl, C ₃ -CpCycloalkyl, C 1 -C _H heterocycloalkyl, C ₆ -C _{1 ()} aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _{1 t} aralkyl or C ₆ C ₀ heteroaralkyl, R ₄ is hydrogen, C 1 -C ₁₂ alkyl, C 1 -C _p alkenyl, C ₃ -C ₁ cycloalkyl. C, C ,, heterocycloalkyl, C _A -C ₁₀ aryl, C 1-4 heteroaryl, C ₇ -C _tl aralkyl or C _fi -C _and heteroaralkyl, io and R and R are hydrogen, s 2 20

C 1 -C ₁₂ alkyl, C ₂ -C ₂ alkenyl, C ₃ -C ₁₂ cycloalkyl. C ₃ CpCycloalkenyl, © -Cp heterocycloalkyl, © -Cpheterocycloalkenyl, © -Cmaril, © 8

C ₉ heteroaryl, C ₇ -C _H aralkyl, C ₆ -C ₁₀ heteroaralkyl, C ₈ -C _H aralkenyl, or C _? C 1 _{H is} heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are unsubstituted, unsubstituted, unsubstituted, substituted and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

For the purposes of the present invention, it is to be understood that the metal is an alkali metal [e.g. lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs)], 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 should be understood to mean, in particular, alkali and alkaline earth metal salts, e.g. sodium, potassium, magnesium and calcium salts. Sodium and potassium ions and their salts are preferred.

Halogen must be understood to mean a group consisting of fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred, especially fluorine and chlorine.

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

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

Cycloalkyl and cycloalkenyl may preferably contain 5 to 8 and especially preferably 5 or 6 ring carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclooundecyl and cyclododecyl. Cyclohexyl is a particularly preferred cycloalkyl group. Examples of cycloalkenyl are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, cyclooundecenyl and cyclododecenyl. Cyclohexenyl is a particularly preferred cycloalkenyl group.

Examples of alkylene are ethylene, 1,2-propylene, 1,2- or 2,3-butylene, 1,2- or 2,3-pentylene, 1,22,3- or 3,4-hexylene. Examples of cycloalkylene are 1,2-cyclopropylene, 1,2-cyclobutylene, 1,2-cyclopentylene, 1,2-cyclohexylene, 1,2-cycloheptylene and 1,2-cyclooctylene. Examples of heterocycloalkylene are pyrrolidinylene, piperidinylene, tetrahydrofuranylene, di- and tetrahydropyranylene.

Examples of heterocycloalkyl are derived from pyrrolidine, imidazolidine, oxazolidine, pyrazolidine, piperidine, piperazine and morpholine. Examples of heterocycloalkenyl are derived from 2- and 3-pyrrolines, oxazoline, 2- and 4-imidazoline, and 2- and 3-pyrazoline.

For the purposes of the present invention, an aryl or heteroaryl is a five or six membered ring or a double ring consisting of two fused five or six membered rings or one six membered or one five membered ring and in the case of heteroaryl may be one or more C atoms replaced, independently of one another, by an atom selected from the group consisting of oxygen, nitrogen and sulfur. Examples are derived from benzene, naphthalene, indene, furan, pyrrole, pyrazole, imidazole, isoxazole, oxazole, furazane, thiadiazole, thiophene, thiazole, oxadiazole, triazole, indole, indazole, purine, benzimidazole, benzoxazole, benzothiazole, benzothiazole pyridazine, triazine, pyrimidine, pyrazine, isoquinoline, cinnoline, phthalazine, quinoline, quinazoline, pterdin, benzotriazine or quinoxaline. Aryl is preferably naphthyl and phenyl. Phenyl is particularly preferred. Heteroaryl is preferably furanyl, pyridinyl and pyrimidinyl.

Aralkyl preferably has 7 to 12 C atoms and may be phenyl-C _n -H _2n - zn equal to the number from 1 to 6. Examples are benzyl, phenylethyl or phenylpropyl. Benzyl and 2-phenylethyl are preferred. Aralkenyl is preferably unsubstituted phenyl-CH = CH-CH ₂ (cinnamyl), and cinnamyl r

is substituted on the phenyl with a substituent selected from the group consisting of

OH, halogen, COOH, C (O) OM _y , C, -C _{] 2} alkyl, C, -C ₆ alkoxy, C ₆ -C, ₀ aryl, SO ₃ M _v , OSO ₃ M _y , NR _2Q SO ₃ M _y where R _{20 is} hydrogen, C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C _1? cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C _H heterocycloalkyl, C, -C _H hetero cycloalkenyl, C ₆ -C _[0 aryl, CC ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C _w heteroaralkyl , C ₈ -C _H aralkenyl or C _? C ₁₀ heteroaralkenyl and NO ₂ , C ₁ -C ₄ primates amino, C ₂ -C _{2 ()} seconds amino, amino and CN.

Heteroaralkyl and heteroaralkenyl are preferably C ₄ -C ₅ heteroarylmethyl and C ₄ C ₅ heteroarylethenyl with one or two O and N group heteroatoms, and heteroaryl may comprise the above heteroaryl residues.

The alkoxy may be unbranched or branched, preferably branched once or twice in position a. Some examples of alkoxy, preferably containing 1-12 C atoms, are methoxy, ethoxy and isomers of propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy and dodecoxy. Preferred alkoxy groups are methoxy and ethoxy.

Examples of aryloxy and araloxy are phenoxy and benzyloxy. Heteroaryloxy is preferably furanyloxy, pyridinyloxy and pyrimidinyloxy.

The primary amino preferably contains 1 to 12, especially preferably 1 to 6, C atoms. Some examples are methyl-, ethyl-, hydroxyethyl-, n- or i-propyl-, n-, i- or t-butyl-, pentyl-, hexyl-, cyclopentyl-, cyclohexyl-, phenyl-, methylphenyl-, benzyl- and methyl-benzylamino. Secondarily, amino preferably contains 2 to 14, especially preferably 2 to 8, C atoms. Some examples are dimethyl-, diethyl-, methylethyl-, di-n-propyl-, di-i-propyl-, di-n-butyl-, diphenyl -, Dibenzylamino, morpholino, piperidine and pyrrolidine.

NH ₂ , primary amino, seconds amino, carbamide, carbamate, carbhydrazide, sul * phonamide, sulfonhydrazide and aminocarbonylamide preferably correspond to the group

R ₈ C (O) (NH) N (R,) -, C (O) (NH) NR _with R, R, OC (OXNH) N (R,>.

RAo ^NC (° X ^NH ) p ^N ) ^R 9- '-OC (O) (NH) NRA -N (R ₄₀ ) C (O) (NH) NR ₈ R _9J R ₈ S (O) ₂ (NH) _p N (R ₉ ) -; -S (O) ₂ (NH) NR ₈ R ₉ ; R ₈ R _4Q NS (O) ₂ N (R ₉ ) - or -NR ₄₀ S (O) ₂ NR ₈ R ₉ , where R ₈ , R ₉ and R _{40 are} independently hydrogen, OH, C-C ₁₂ alkyl, C ₁ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C _p cycloalkenyl, C ₂ -C _H ether cycloalkyl, C ₂ C _H heterocycloalkenyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ -C, ₆ aralkyl, C ₈ -C, ₆ aralkenyl with C ₂ C.alkenylene and CC, aryl, C-C. .heteroaralkyl, CC, .heteroaralkenyl, or di-C C ₁₀ aryl-C ₁ -C _f. alkyl or R _g , R ₉ , N where R _gl and R ₉ are independently hydrogen, OH, SO M , OSO, M, C.-C, .alkyl, CC..cycloalkyl, CC. .heterocycloalkyl, C-C .. aryl, CC _n heteroaryl, CL-C, .alkyl, C, -C,. heteroaralkyl, C.-C., aralkenyl with C.-C.alkenylene and / 11 OlU olo 2 o

CC, _n aryl, or di-C-C-aryl-C.-Calkyl, unsubstituted or substituted by one 6 10 '6 10 16' or more substituents selected from the group consisting of OH, halogen, C ( O) OR _sl , OC (O) R ₄ , C (O) R ₂ , nitro, NH ₂ , cyano, SO ₃ M _y , OSO ₃ M _v , NR _2Q SO ₃ M _y , C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ^ C ^ alkoxy, C ₃ -C _S cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ C ,, heterocycloalkyl, CC, .heterocikloalkenil C, -C..aril C, - C ,, aryloxy, C, CJieteroaryl, C.-C.heteroaryloxy, CC ,, aralkyl, C.-C. .aralkyloxy, CC..heteroaralkyl,

5 9 ⁷ 7 11 ⁷ 711 ⁷ o IU

C ₈ -C _H aralkenyl, C ₇ -C _{1 ()} heteroaralkenyl, primary amino, amino seconds, amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where R _{sJ is} hydrogen, M, C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ C ₁₂ cycloalkyl, C ₂ -C _H heterocycloalkyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _n aralkyl or C ₆ C _{1 ()} heteroaralkyl, R ₄ is hydrogen, C 1 -C 6 alkyl, C ₂ -C _p alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C ₁ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C _1Q heteroaralkyl, and R _s? is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C _p cycloalkenyl, C, C _H heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? C _1-6 aralkyl, C ₆ -C _{] ()} heteroaralkyl, C _g -C ₁ aralkyl, or C ₇ -C ₁₀ heteroaralkenyl, and are alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl , heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are, in turn, 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, or R ₈ and R ₉ or R ₈ , and R _(/ or R _g and R ₄₀ in the case of NR _g R ₉ or NR ₈ , R ₉ , or R ₈ R ₄₀ N- together are tetramethylene, pentamethylene, - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -, - (CH ₂ ) ₂ S (CH ₂ ) ₂ - or - (CH ₂ ) ₂ NR ₇ - (CH ₂ ) ₂ , and R _? H, C _f C ₆ alkyl, C ₇ -C _n aralkyl, C (O) R ₂ or sulfonyl.

The sulfonyl substituent is suitable, e.g. of the formula R ₁₀ -SO ₂ - wherein R is C 1 -C alkyl, C ₃ C, ~ cycloalkyl, CC, heterocycloalkyl, C, -C _and aryl, C.-C _Q heteroaryl, C.-C, aralkyl, or C, C _w he and o ar alkyl, unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2, nitro, NH., cyano, SO "M OSO.M, NR .. BMSC, CC, -alkyl, C, -C..alkenil, C, C ₁₂ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C I ₂ cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ C, heterocycloalkenyl, CC 'aryl, CC..aryloxy, CC.heteroaryl, C. -Cheteroaryloxy C ₇ -C [aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _H aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M _y , C ₁ -C ₄ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C ₁₁ heterocycloalkyl, C ₆ -C _1Q aryl, C ₅ C ₉ heteroaryl, C ₇ -C _n aralkyl or C ₆ -C ₁₀ heteroaralk il, R ₄ is hydrogen, C 1 -C 4 alkyl, C ₂ C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C _H heterocycloalkyl, C ₆ -C _{1 ()} aryl, C ₅ -C ₉ heteroaryl, C _? C _H aralkyl or C ₆ -C _{1 ()} heteroaralkyl, and R _{2 is} and R _{20 is} hydrogen, C ₁ -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C _1? cycloalkyl, C ₃ -C _1? cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, Cg-C 4 _] aralkenyl , or C _? C _{10 is} heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl are in turn substituted or substituted by one of the foregoing y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

r

Preferred compounds of formula I are those in which X corresponds to a group of formula II in which R. and R.

> o (a) unsubstituted or substituted with C 1 -C ₁₂ alkyl, such as e.g. methyl, ethyl, or (JC ₁₂ alkoxy, e.g. methoxy, ethoxy;

(b) together with the group -CH-CH- a 5- to 8-membered carbocyclic ring and a particularly preferred 5- to 6-membered carbocyclic ring, and particularly particularly R, R-1,2-cyclohexylene;

(c) together with the group -CH-CH- a 5- to 8-membered heterocarbocyclic ring and a particularly preferably a 5- or 6-membered heterocarbocyclic ring with nitrogen as a heteroatom and particularly particularly preferably R, R-3,4-piperidylene;

(d) independently of one another, hydrogen, unsubstituted C ₍ -Calkyl or C ₁ -C ₁₂ alkyl, which is substituted by a substituent selected from the group consisting of -C (O) OR _sl , -OC (O) R _s4 , -C (O) ONa or -C (O) OK, primary amino, amino seconds, C ₃ C, 'cycloalkyl, C, -C, alkoxy, phenyloxy and benzyloxy; unsubstituted CC, _n cycloalkyl or

1 D j 12

C ₃ -C ₁₂ cycloalkyl which is substituted with a substituent selected from the group consisting of -C (O) OR _E, OC (O) R _s4, -C (O) ONa or -C (O) OK, primary amino, seconds amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyloxy and benzyloxy; C ₆ -C ₁₀ aryl, which is unsubstituted or substituted by -C (O) OR _sl , -OC (O) R ₄ , -C (O) ONa, or -C (O) OK, primary amino, secondary amino, C _t- C ₆ alkyl or C 1 -C ₆ alkoxy; C ₃ -C ₉ heteroaryl having 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen atoms, or C ₇ -C ₁₂ aralkyl unsubstituted or substituted by -C (O) OR _sl , -OC (O) R ₄ , -C (O) ONa or -C (O) OK, primary amino, secondary amino, C 1 -C ₆ alkyl or C 1 -C ₆ alkoxy;

(e) together with the group -CH-CH- a 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 atoms; or (f) together with the group -CH-CH-C ₃ -C, ₂ cycloalkylene, C ₄ -C ₁₂ cycloalkenylene, C ₂ C _n heterocycloalkylene and C ₃ -C, ₁ heterocycloalkenylene with heteroatoms selected from the group -O-, -S- and -N-; wherein the cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted with one or more substituents selected from the group consisting of OH, halogen, C (O) O R _sl , O C (O) R _s4 , C (O) R _s2 , nitro, NH., cyano, SO, M, OSO.M, NR..S0.M, CC ,, alkyl, C, -C, .alkenyl, C, '2''3 y 3 y' 20 3 y ' 1 12 '2 12' 1

C _p alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C ₁ heterocycloalkyl, C ₂ C ₁₁ heterocycloalkenyl, C ₆ -C _{1 ()} aryl, C ₆ -C ₁₀ aryloxy, C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ -C _H aralkyl, C _? -C ₁₁ aralkyloxy, C ₆ -C ₁₀ heteroaralkyl, C _g -C ar alkenyl, C _? C ₁₀ heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M _y, Cj-C ^ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C _H heterocycloalkyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _n aralkyl or C ₆ C..heteroaralkyl, R. is hydrogen, CC., Alkyl , C, -C..alkenyl, C, -C..cycloalkyl, C, C ₁ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C ₁₀ heteroaralkyl , and R ₂ and R _{20 are} hydrogen, C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ C ₁₂ cycloalkenyl, C ₂ -Cheterocycloalkyl, C ₁ -C ₆ heterocycloalkenyl, C ₆ -C _1Q aryl, C ₅ C ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C _w heteroaralkyl, Cg-C 1-6 alkenyl, or C _? C _(O heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl being unsubstituted or substituted with the above-substituted , and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Particularly preferred compounds are those in which X corresponds to a group of formula II in which R and R _f together with a group -CH-CH-C ₃ -C _{p is} cycloalkylene or C, -C 1 heterocycloalkylene with nitrogen as a heteroatom, where cycloalkylene and heterocycloalkylene unsubstituted or substituted by one or more of the above substituents.

Particularly preferred compounds are those wherein R ₅ and R ₆ together with the group -CH-CHC ₃ -C _{12 are} cycloalkylene or C ₂ -C _H heterocycloalkylene with nitrogen as a heteroatom; wherein the cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR _sl , OC (O) R ₄ ,

C ₂ -C _H heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? C., aralkyl, C _o -C., Aralkenyl with CC, alkenylene and C, -C, _n aryl, C, -C., Heteroaralkyl, C-C, .heteroaralkenyl, or di-C-C _and aryl-CC , alkyl unsubstituted or oo JU lo substituted with one or more substituents selected from the group consisting of OH,

C, cycloalkenyl, C-C ,, heter o cycloalkyl, C-C. .heterocycloalkenyl, CC _and aryl, CC _{1 ()} aryloxy, C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, (J-C ₁ aralkyl, C ₇ -C _in aralkyloxy, C ₆ C ₁₀ heteroaralkyl, C ₈ -C _n aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino, amino seconds, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide; R _sl is hydrogen, M, C 1 -C 4 alkyl, C ₂ C ₁₂ alkyl, C ₂ C ₁₂ alkyl, C ₂ C ₁₂ alkenyl , C ₃ -C ₁₂ cycloalkyl, C ₂ -C _H heterocycloalkyl, C ₆ -C ₁₀ aryl, C.-C ₉ heteroaryl, C _? C _H aralkyl, or C ₆ -C ₁₀ heteroaralkyl, R ^ is hydrogen, Cj-C _p alkyl, C ₂ -C ₁₇ alkenyl, C ₃ C ₁₂ cycloalkyl, C ₂ -C _H heterocycloalkyl, C ₆ -C _{1 () aryl,} C ₅ -C ₉ heteroaryl, CJ-CJaralkil or C _fi C ₁₀ heteroaralkyl, R _s2 is hydrogen, Cj-C ^ alkyl, C ₂ -C _J7 alkenyl, C _{3 C] 2} cycloalkyl, C ₃ C ₁₂ cycloalkenyl, C ₂ -C, heterocycloalkyl, C ₂ -C ₁ [heterocycloalkenyl, C ₆ -C, _O aryl, C ₅ C ₉ heteroaryl, C ₁ -C ₆ aralkyl, C ₆ -C _{1 ()} heteroaralkyl, C ₈ -C _n aralkenyl, or C _? C _{10 is} heteroaralkenyl, and are alkyl, alkenyl, alkoxy. cycloalkyl, cycloalkenyl, *

heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl as substituents in turn unsubstituted or substituted with one of the above substituents, p is 0 or 1, and y is 1 and M is monovalent y 1/2 and M divalent metal.

R _g and R ₉ are, in particular, independently of one another hydrogen, C ₁ -C 6 alkyl, C ₃ -C _p cycloalkyl, CC 1 ₍₎ aryl, C 1 - _? -C ₁₆ aralkyl of 1 to 6 C atoms in the alkylene group and C ₆ -C _1Q aryl, CgCHaralkenyl with CC.alkenylene and C-CLaryl, or di-C, -C, _n aryl-C.-C, alkyl, e.g. .diphenylmethyl or 2,2-diphenylethyl, wherein R _g and R _{9 are} unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH,

C (O) OM _y , C 1 -C 6 alkyl, C 1 -C ₆ alkoxy, C ₆ -C _1Q aryl, C ₆ -C _1Q aryloxy, SO _g M _y , OSO ₃ M _y ,

NR 2 _O SO ₃ M _y , NO ₂ , amino, primary amino, amino and CN seconds, R 4 is hydrogen, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C 1-6 heterocycloalkyl,

C ₂ -C ₁₁ heterocycloalkenyl, C ₆ -C _w aryl, C ₅ -C ₉ heteroaryl, C ₇ -C ₁ aralkyl, C ₆ C _and heteroaralkyl, CC 1 aralkenyl or C-C 1-3 heteroaralkenyl, and y is 1 and M 10 8 11 7 10 ^J J is a monovalent metal or y is 1/2 and M is a divalent metal.

R. _n corresponds to the particular CC _1o alkyl, ..cikloalkil CC u, CC. _n aryl, C.-C. .alkyl having from 1 to 6 C atoms in the alkylene group and C ₆ -C _{1 ()} aryl, C _g -C ₁₆ aralkenyl with C ₂ -C ₆ alkenylene and CC _ir aryl, or di-C, -C _and aryl-C .-C, alkyl, e.g. diphenylmethyl or 2,2-diphenylethyl which are

1U ⁷ 6 IO 16 ¹ unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C (O) OM _y , C 1 -C 6 alkyl, C 1 -C ₆ alkoxy, C ₆ - C _1Q aryl, SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y , NO ₂ , amino, primary amino, seconds amino and CN, where R _{20 is} hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C, C _H heterocycloalkyl, C ₁ -C ₆ heterocycloalkenyl, C ₆ -C _w aryl, C ₅ -C ₉ heteroaryl, C _? C 1, aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _H 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.

Furthermore, R ₁₀ is preferably C ^ C ^ alkyl, C ₃ -C _S cycloalkyl, C _{6 -C) 0} aryl, C ₇ -C _LF aralkyl with 1 to 6 C atoms in the alkylene group and the C-C _{fi] ()} aryl , which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH,

amino, primary amino, seconds amino and cyano, or C ₈ -C ₁₆ aralkenyl with C ₂ C ₆ alkenylene and C ₆ -C ₁₀ aryl, or di-C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl, e.g. diphenylmethyl or 2,2diphenylethyl.

In a preferred subgroup of compounds, R ₅ and R _{f are} taken together with the group -CH-CH-C ₃ C, _n cycloalkylene or C-C, heterocycloalkylene with nitrogen as a heteroatom, where 12 2 11 ^J cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2 ,

unsubstituted or substituted by one or more C 1 -C 16 alkoxy, R is C 1 -C 6 alkyl, C _g C _{1 ()} aryl or C _? -C _n aralkyl unsubstituted or substituted by one or more C _t -

C ₃ C ₁₂ cycloalkyl or C ₆ -C 1 ₍₎ aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl being, in turn, unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O ) OR _sl , and OC (O) R _s4 'where R is _sl , M _y or C 1 -C ₁₂ alkyl, and R s ₄ , C _1-12 alkyl, and y is 1 and M is a monovalent metal or y is 1/2 and M divalent metal.

Particularly preferred compounds in this group are those in which R ₅ and R _{f are} taken together with the group -CH-CH cyclohexylene.

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

Particularly preferred compounds are those wherein R _s and R _{fi are} together with the group -CH-CH piperidylene, wherein the heteroatom is unsubstituted or substituted with a substituent selected

C 1 _t heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C, ₀ aryl, C ₆ -C, _O aryloxy, C ₅ C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ -C _n aralkyl, C ₇ -C _n aralkyloxy, C ₆ -C ₁₀ heteroaralkyl, C ₁ -C ₁₀ aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino, amino seconds, sulfonyl, sulfonamide, sulfonhydrazide, and one or more C atoms in the ring unsubstituted or substituted with one or more substituents selected from the group consisting of OH, OC (O) R ₄ , NH ₂ , OSO ₃ M _y , NR _{2 ()} SO ₃ M _y , C, -C ₁₂ alkoxy, C ₆ -C ₁₀ aryloxy, C ₅ C ₉ heteroaryloxy, C ₇ -C [aralkyloxy, primary amino, secondary amino, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M _y C-C ^ alkyl , C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl,

C.-C ,, heterocycloalkyl, C, -C. _n aryl, C - C _Q heteroaryl, CC. .alkyl or C, C ₁₀ heteroaralkyl, R ₄ is hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C ₁ heterocycloalkyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ -C ₁₁ aralkyl or C ₆ -C _w heteroaralkyl, R _g and R 4 are independently hydrogen, OH, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C _n heterocycloalkyl, C ₆ - C _1Q aryl, C ₅ -C _g heteroaryl, C ₇ -C _I6 aralkyl, C ₆ -C ₁₅ heteroaralkyl, C _g C ₁₆ arilaralkenil with a C ₂ -C ₆ alkenylene and C ₆ -C _{1 ()} aryl, or di- C ₆ -C ₁₀ aryl-C ₁ -C ₆ -alkyl, or R _g and R _(J together are tetramethylene, pentamethylene, - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -, - (CH ₂ ), -S- (CH _{2) 2} or - (CH _{2) 2} -NR ₇ - (CH _{2) 2} -, and _R? is H, C, -C ₆ alkyl, C ₇ -C _n aralkyl, C (O) R ₂ or sulfonyl, and R _{2 is} and R 2 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 1 heterocycloalkyl, C ₂ -C _n heterocycloalkenyl, C ₆ -C _{1 ()} aryl, C ₅ -C ₉ heteroaryl, _C? C j aralkyl, C _{6 -C] 0} heteroaralkyl, C ₈ -C _H aralkenyl or C ₇ -C ₁₀ heteroaryl lkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroarylalkyl, aralkenyl and heteroaralkenyl are unsubstituted or substituted, or substituted y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Particularly preferred compounds are those in which R. and R _{ft are} together with the group -CH-CHpiperidylene, wherein the heteroatom is unsubstituted or substituted with a substituent selected from the group consisting of C (O) OR _sl , C (O) R _{s 2} , -C (O) NR _r R ₉ and R ₁₀ -SO ₉ -, and is one or more C atoms in the ring unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH ₂ , R _g S (O) ₂ N (R ₉ ) -, R _g C (O) N (R ₉ ) -, and R _g OC (O) N (R ₉ ) -, where R _{9 is} hydrogen, and R _{g is} C, -C _J2 alkyl, C _{6 -C] 0} aryl or C ₇ -C _H aralkyl, wherein the alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C-C alkoxy, R is C ^ C ^ alkyl C _fi -C ₁₀ aryl or C ₇ -C _S aralkyl, wherein the alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C, -C "alkyl, R is C, -C, _o alkyl, and R _{s 2} is C ₁ -C ₄ alkyl, C ₃ -C ₁₂ cycloalkenyl, C ₃ -C ₁₂ cycloalkyl or C ₆ -C ₁₀ aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl being the substituents on their side are unsubstituted tuated or substituted with one or more substituents selected from the group consisting of OH, C (O) OR _sl , and OCfOjR ^ .. wherein R _{r is} M _y or C _r C _{12 is} alkyl and R s is ₄ , C, - C ₁₂ alkyl, y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Another sub-group of preferred groups are those in which R _$ and R ₆ together with the -CH-CH- group, piperidylene which is unsubstituted or substituted with one or more substituents selected from the group consisting of OH, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2 , NH ₂ , C ₁ -C ₁₂ alkyl, R ₈ C (O) N (R ₉ ) -, -C (O) NR _g R ₉ , R _g S ( O) ₂ N (R ₉ ) -; R _g OC (O) N (R ₉ ) -, R _g R ₄₀ NC (O) N (R ₉ ) -, -OC (O) NR _g R ₉ and R ₁₀ -SO ₂ -, where R ₉ is hydrogen , and R _{g is} C _r C ₁₂ alkyl, CC, 'aryl or CC ,, aralkyl, wherein alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C 1 -C 4 alkoxy or C ₇ -C _n aralkyloxy, R ₁₀ C ₁ -C ₄ alkyl, C ₆ -C _1Q aryl or C ₇ C _n aralkyl, which are unsubstituted or substituted by one or more C ₁ -C ₆ alkyl, R ₄₀ is hydrogen, OH, C 1 -C ₁₂ alkyl, C ₁ - C ^ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C _p cycloalkenyl, C ₁ -C ₁ heterocycloalkyl, C ₇ -C _n heterocycloalkenyl, C ₆ -C, _O aiyl, C.-C ₉ heteroaryl, C _? C ₁₆ aralkyl, C _g -C ₁₆ aralkenyl with C ₂ -C ₆ alkenylene and C ₆ -C ₁₀ aryl, C ₆ -C, heteroaralkyl, CC.-heteroaralkenyl, or diC, -C _and aryl-C.-C , -alkyl, R. and R CC -alkyl, and R ,, Cj-C ^ alkyl, C ₃ -C _S cycloalkyl, C ₃ -C ₁₂ cycloalkyl or C ₆ -C _H) aryl, and alkyl, cycloalkenyl, cycloalkyl and aryl, as substituents on their part unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR _sl , and

OC (O) R ₄ "wherein R _s], and _Y, or C, -C ₁₂ alkyl, and R _s4, C, _{-C] 2} alkyl, y is 1 and M is a monovalent metal or y is 1/2 and M 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 _? , -C (O) CH ₃ , -C (O) C ₆ H ₅ ,

-C (O) (CH ₂ ) ₈ C (O) OCH ₃ , -C (O) [CH (OH)] ₂ C (O) ONa, C (O) -C _fi H ₈ (OH) ₃ , - C (O) C ₆ H _n , -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 ₆ H ₃ (OCH ₃ ) ₂ , -S (O) ₂ -C ₄ H ₉ , -NHC (O) NHC ₆ H ₅ , -S (O) ₂ -C ₆ H ₄ CH ₃ -S (O) ₂ -CH ₂ C ₆ H ₅ and -S (O) ₂ - (CH) ₂ C ₁₀ H ₇ .

Preferred compounds of formula I are those in which R corresponds to a group of the formula III, in which R ₃ is hydrogen or M, and R ₄ (a) unsubstituted d-C ₁₂ alkyl; C-C alkyl substituted with one or more substituents selected from the group consisting of -NH ₂ , primary amino, amino seconds, C ₁ -C ₁₂ sulfonyl, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide, aminocarbonylamido, C ₃ -C ₁₂ cycloalkyl, C 1 -C ₆ alkoxy, phenyloxy and benzyloxy, unsubstituted C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkyl substituted with one or more substituents selected from the group consisting of C ₃ -C ₁₂ cycloalkyl, C1-C8alkyl, C1-C4alkoxy, CC., Sulfonyl, phenyloxy and benzyloxy; CC, .aryl; CC, .heteroaryl having 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen atoms; C _? C, _r ar alkyl with C, - (l · alkyl and C-C, _n aryl; CT-C, .heteroaralkyl with CC.alkyl and CC ₁₀ heteroaryl with 1 or 2 heteroatoms selected from the group consisting of oxygen atoms and nitrogen and a total of 3 to 5 carbon atoms, C ₆ -C _{1 ()} aryl, C ₃ -C ₉ heteroaryl having 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen atoms, _C? C 'ar alkyl with C, -C.alkyl and C.-C .. aryl, CC..heteroaralkyl with CC.alkyl and CC, ₀ heteroaryl with 1 or 2 heteroatoms, selected fz a group consisting of oxygen and nitrogen atoms and a total of 3 to 5 carbon atoms which are substituted by one or more substituents selected from the group consisting of OH, halogen, C, -C _p -sulfonyl, carboxyl, C (O) OM _y , C 1 -C ₍₂ alkyl, C, - C ₆ alkoxy, C ₆ -C _[O aryl, SO ₃ M _y , OSO ₃ M _y , NR ₂₀ SO ₃ M _y , where R _{20 is} hydrogen, C ₁ -C ₄ alkyl, C ₂ -C _{] 2} alkenyl, C ₃ -C _p cycloalkyl, C ₃ C ₁₂ cycloalkenyl, C ₂ -C ₁₁ heterocycloalkyl, C ₂ -C ₁₁ heterocycloalkenyl, C ₆ -C aryl, C ₅ C _Q heteroaryl, C ₇ - C _H aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _H aralkenyl or C _? C _{1 ()} heteroaralkenyl and nitro, NH ₂ , primary amino, amino, carbamide, carbamate, sulfonamide and cyano in seconds, where y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, or (b) C, -C ₁₂ alkyl or C ₇ -C _n aralkyl unsubstituted or substituted by one or more substituents selected from the group consisting of: OH, halogen, C (O) OR _sl , OC (O) R ₄ ,

C (O) R ₂ , nitro, NH ₂ , cyano, SO ₃ M, OSO ₃ M, NR _2Q SO ₃ M _in , C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkeml, (JC ^ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ C ₆ heterocycloalkenyl, C ₆ -C _w aryl, C ₆ -C _1Q aryloxy, C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy , GC ,, aralkyl, C-C ,, aralkyloxy, CC, .heteroaralkyl. CC ,, aralkenyl, C, C ₁₀ heteroaralkenyl, primary amino, seconds amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where R _E is hydrogen, M _y, Cj-C ^ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, GC..heterocikloalkil, CC..aril, CC.heteroaril, CC..aralkil or GC ₁₀ heteroaralkyl, R ₄ is hydrogen, C 1 -C ₁₂ alkyl, C ₂ -C _p alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₇ C _H heterocycloalkyl, C ₆ -C _{1 ()} aryl, C ₅ -C ₉ heteroaryl C ₇ -C _H aralkyl, or C ₆ -C _{1 ()} heteroaralkyl, and R _s? and R ₂₀ is hydrogen, Cj-C ^ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ - C _p cycloalkenyl, C ₉ -C _H hetero cycloalkyl, GC ^ heter o cycloalkenyl, C ₆ -C _{] ()} aryl, C ₅ -C ₉ heteroaryl, C ₇ C _H aralkyl, C ₆ -C ₁₀ heteroaralkyl, C ₈ -C _H aralkenyl or C _? -C _{1 ()} heteroaralkemyl, and are alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroarylalkyl, aralkenyl and heteroaralkenyl having, by themselves, or heteroaralkenyl with one or more substituents thereof of said substituents, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

Κ ₃ in Formula III is preferably hydrogen, K or Na.

The following preferences apply to group (a) for the meanings of R ₄ :

R ₄ is alkyl, preferably methyl, ethyl, n- or i-propyl and n-, i- or t-butyl. In the case of substituted alkyl, the alkylene group is preferably ethylene and in particular methylene. A particularly preferred cycloalkyl group is cyclohexyl. Preferred as aryl and aralkyl are naphthyl and phenyl, particularly preferably phenyl and phenyl-C _n -H _2n - zn equal to the number from 1 to 6, in particular benzyl and 2-phenylethyl. When R _{4 is} heteroaryl, preferably C ₄ -C _{5 is} heteroaryl with one or two heteroatoms of group O and N. Furanyl, pyridinyl and pyrimidinyl are preferred. R ₄ as heteroaralkyl is preferably C ₄ -C ₅ heteroarylmethyl having one or two heteroatoms and groups O and N, preferably heteroaryl comprising the above heteroaryl groups.

Further preferred compounds are those wherein R ₄ in Formula III is C ₃ -C ₁₂ cycloalkyl, especially preferably cyclohexyl, substituted C ₁ -C ₄ alkyl, especially methyl or ethyl with C ₃ C ₁₂ cycloalkyl or C ₁ -C ₄ alkyl and in particular cyclohexyl or methyl, C ₆ -C _{1 ()} aryl and especially particularly phenyl or R ₄ C ₇ -C ₁₂ aralkyl with C ₁ -C ₆ alkyl and C ₆ -C ₁₀ aryl. Particularly preferred groups for R ₄ in this species are benzyl, naphthylmethyl, 2-phenylethyl,

3-phenylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclohexyl and isopropyl.

Carbamido, carbhydrazido, sulfonamido, sulfonhydrazido, aminocarbonylamide and carbamate, as substituents for R _4, preferably represent groups of the formulas R ₈ NHC (O) N (R ₉ ) -, R ₈ OC (O) N (R ₉ ) -, R _g C (O) (NH) _p N (R ₉ ) - m R _g S (O) ₂ (NH) N (R ₉ ) - where R _{8 is} preferably H, C, -C _I? alkyl, C ₅ - or C ₆ cycloalkyl, C ₅ - or C ₆ cycloalkylmethyl, or -ethyl-, C- or C / heterocycloalkyl, C - or C heterocycloalkylethyl or -ethyl-, phenyl, naphthyl, benzyl, 2-phenylethyl , di-phenylmethyl, unsubstituted or substituted by one or more t

substituents from the group consisting of OH, NH _? , C [- (^ primary amino, C, C _{] for 4} seconds amino, NO ₂ , -CN, -F, -Cl, - C (O) OH, -C (O) ONa, -SO ₃ H, -OSO ₃ Na,

NR _2Q SO ₃ Na, where R _{20 is} hydrogen, C ₍ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ C ₉ cycloalkenyl, C ₂ -C] heterocycloalkyl, C ₂ - C _n hetero cycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ C ₉ heteroaryl, C ₇ -C _H aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _H aralkenyl or C _? C ₁₀ heteroaralkenyl and -SO ₃ Na, C 1 -C ₄ alkyl, C 1 -C ₄ alkoxy and phenyl, and R _{9 is} H, C ₍ C ₁₀ alkyl, phenyl, naphthyl, benzyl, 2-phenylethyl or phenyl-CH = CH-CH ₂ , and p is 0 or 1.

In the group (a) the carbamido substituted alkyl substituent for R ₄ particularly preferably represents R _g -C (O) NR ₉ - (CH ₂ ) _n -, where n is 1 or 2, R _g is hydrogen; C 1 -C 6 alkyl, C ₃ C ₁₂ cycloalkyl, C ₆ -C _1Q aryl or C ₇ -C ₁₆ aralkyl with C 1 -C ₆ alkyl and C ₆ -C ₁₀ aryl, where alkyl, cycloalkyl, aryl and aralkyl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C (O) OM _y , C 1 -C 6 alkyl, ς-ς-alkoxy, C ₆ -C _w aryl, SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y , C (O) OR ,, OC (O) R _s4 , nitro, amino and cyano; or C ₀ -C., aralkenyl with C-Clalkenyl and C, -C _and aryl or C, -C, _n arylC 1 -C ₆ alkyl; and R ₉ is H, straight or branched chain Cj-C ^ alkyl, C ₅ - or C ₆ cycloalkyl, C ₅ - or CgCikloalkilmetil or -ethyl, phenyl, naphthyl or benzyl, 2-phenylethyl or phenyl-CH = CH-CH ₂ -; y is 1 and M is an alkali metal or y is 1/2 and M is an alkaline earth metal, R ₂₀ is hydrogen, C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl , C, C 1 heterocycloalkyl, C ₂ -C 1 _H heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? C _H aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C, ^ alkenyl or C ₇ -C ₁₀ heteroaralkenyl, R _sl is hydrogen, M _y , C ₁ -C ₁₂ alkyl, C ₂ -C, ₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C _t heterocycloalkyl, C ₆ -C _1Q aryl, CC ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C ₁₀ heteroaralkyl, and R ₄ is hydrogen, C 1 -C ₁₂ alkyl, C , C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₁ -C ₆ heterocycloalkyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C _? C 1-6 aralkyl or CC, _n heteroaralkyl. The sulfonamide substituted alkyl substituent for R. particularly preferably represents R _g -SO ₉ NR ₉ - (CH ₂ ) _n -, wherein R _g , R ₉ and n have the meanings given above for the urea. Aminocarbonylamide or carbamate-substituted alkyl substituent for R 1 particularly preferably represents R ₉ NHC (O) NH (CH ₇ ) _n or R ₉ OC (O) NH (CH ₂ ) _n , wherein R _{9 has the} meanings given herein before carbamido, and additionally phenyl and n are as previously stated in connection with the carbamide.

Carbhydrazido substituted alkyl substituent for R _[ especially preferably represents R ₈ C (O) NHNR _Q (CH ₂ ) _n , wherein R _g , R _y and n have the meanings previously mentioned in connection with the carbamide. The sulfonhydrazido substituted alkyl substituent for R ₄ particularly preferably represents R _g -SO ₂ -NHNR ₉ - (CH ₂ ) _n , wherein R _g , R ₉ and n have the meanings previously mentioned in connection with the urea.

Further particularly preferred compounds are those wherein R ₄ in Formula III is an amide of R _g C (O) N (R ₉ ) (CH ₂ ) _n - or R 2 Oj ^ R ^ CH ^ -, where R _g and R ₉ independently of one another, hydrogen, unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkyl, which is substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C (O) ONa, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C ₆ -C _1Q aryl, SO ₃ H, OSO ₃ Na, NR _2Q SO ₃ Na, SO ₃ Na, nitro and cyano; unsubstituted C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkyl substituted with one or more OH, unsubstituted CC, _n aryl, unsubstituted C.-C 1, aralkyl with C 1 - (/ alkyl and CkC, or aryl, CC, .aryl or CC ,, aralkyl with C, -C, alkyl and C, -C. _N aryl substituted with one or more substituents selected from the group consisting of OH, halogen, carboxyl, C (O ) ONa, -C (O) OK, C ^ C ^ alkyl, C ^ C ^ alkoxy, C ₆ -C _1Q aryl, SO ₃ Na, OSO ₃ Na, NR ₂₀ SO ₃ Na, C (O) OR _sl . OC (O) R ₄ , nitro, amino and cyano, R ₂₀ 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 _{( 1} heterocycloalkyl, C ₁ -C ₁₁ heterocycloalkenyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ C aralkyl, C ₆ -C _1Q heteroaralkyl, Cg-C _n aralkenyl or C ₇ -C _{1 ()} heteroaralkenyl , R _s] is hydrogen, M, C, -C1, alkyl, C.-C., alkenyl, C, -C1, cycloalkyl, C, -C..heterocycloalkyl, C-C3aryl, C, C ₉ heteroaryl, C ₇ -C _H aralkyl, or C ₆ -C _w heteroaralkyl, and R _s4 is hydrogen, C, -C _p alkyl, C ₂ C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkanes kil, C ₂ -C _n heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C, C 1-6 alkyl or C-C 1 heteroaralkyl, and n is 2 or 1.

Particularly preferred compounds are those wherein R ₄ of formula III is an amide

RgC (O) N (R ₉ ) (CH ₂ ) _n - or R ₈ S (O) ₂ N (R ₉ ) (CH ₂ ) _n - wherein R _{g is} unsubstituted C ₁ -C ₁ alkyl;

C 1 -C ₈ alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) ONa and C ₆ -C _[O aryl; unsubstituted C ₃ -C _p cycloalkyl; C ₃ C _g cycloalkyl substituted with one or more OH, unsubstituted C ₆ -C _w aryl or C _? C ₁₂ aralkyl, C _t -C ₆ alkyl; C ₆ -C, ₀ aryl, C ₇ -C ₁₂ aralkyl with C ₁ -C ₆ alkyl and C ₆ -C _1Q aryl, or C _g -C ₁₆ aralkenyl with C ₂ -C ₆ alkenyl and C ₆ -C ₁₀ aryl, which is substituted by 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 ₈ alkoxy, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NR _2Q SO ₃ Na, where R _{20 is} hydrogen, C ₁ -C ₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C 1 -C _n heterocycloalkyl, CC, heterocycloalkenyl, C, -C _1ft aryl, C-CJeteroaryl, CC..aralkyl, C, C _w heteroaralkyl, C _? -C _n aralkyl, C ₆ -C _w heteroaralkyl, C ₈ -C _H aralkenyl or C _? C _{1 ()} heteroaralkenyl, and nitro and cyano; and R _{(} is} hydrogen; unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C, _n aryl, unsubstituted C 1 -C 6, aralkyl with C ₁ -C ₈ alkyl and CC, _n aryl; or C ₈ -C ₁₆ aralkenyl with C ₂ -C ₆ alkenyl and C ₆ -C ₁₀ aryl, and n is 2 and preferably 1.

Particularly preferred compounds are also those in which R ₄ in Formula III is an amide R _g C (O) N (R ₉ ) (CH ₂ ) _n -, where R _{g is} unsubstituted C ₁ -C ₁₂ alkyl, C ₁ -C ₄ alkyl which is substituted by one or more substituents selected from the group consisting of cyclohexyl, OH, halogen, -C (O) OH, -C (O) ONa and phenyl; unsubstituted C ₃ -C ₁₂ cycloalkyl; C ₃ C ₁₂ cycloalkyl substituted with one or more OH; unsubstituted C ₆ -C _1Q aryl; C ₆ C _1Q aryl which is substituted by one or more substituents selected from the group consisting of halogen, C (O) ONa, -C (O) OH, _C] -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 C _? -C ₁₆ aralkyl with C ₁ -C ₈ alkyl and C ₆ -C ₁₀ aryl, and R _{9 is} hydrogen; unsubstituted C1-C6 alkyl; unsubstituted C ₇ -C ₁₆ aralkyl with C ₁ -C ₆ alkyl and C ₆ -C _1Q aryl; or C _g -C ₁₆ aralkenyl with C ₂ -C ₆ alkenyl and C ₆ -C _{I ()} aryl, and n is 2 and preferably 1.

Further particularly preferred compounds are those wherein R ₄ in Formula III is an amide

R _g is C (O) N (R ₉₎ (CH _{9) n} -, where R _g is unsubstituted Cj-C _p alkyl, C, -C ₄ alkyl which is substituted by one or more substituents selected from the group it is composed of OH, halogen, -C (O) OH, -C (O) ONa and phenyl; unsubstituted © - © ₂ cycloalkyl, especially C ₆ H _h ; © - ©, cycloalkyl substituted with one or more OH, unsubstituted C ₆ -C ₁₀ aryl, in particular C _fi -H _s or C _{] 0} ©; © -Caryl which is substituted by one or more substituents selected from the group consisting of halogen, -C (O) OH, -C (O) ONa, © - © alkyl, ©ktop alkoxy, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NHSO ₃ Na, nitro and cyano, especially © H ₄ C1, C ₆ H ₄ (3,4) C1 ₂ , © LTD COONa, © SPORT C ©, © SPORT OC ©, © SPOT SO ₃ Na © © NO ₂ or ©bour CN; or unsubstituted © - © ₆ aralkyl with © - © alkyl and © -C _{1 ()} aryl, in particular (CH © spokestival, and © is H, © - © alkyl, phenyl-C © -, phenyl-C © CH ₂ , phenyl- (C ©) ₃ - or phenylCH = CH-C © -, and n is 2 and preferably 1.

Particularly preferred compounds are also those in which R in Formula III amide, R ₈ C (O) N (R ₉₎ (C ©) _n -, where R _g is unsubstituted or substituted © - © ₂ alkyl, cyclohexyl, naphthyl, biphenyl, phenyl, benzyl, phenylethyl or diphenylmethyl, and © is © - © alkyl, phenyl- ©\\\\\\\\\\\\ alkyl alkyl, in particular C ©\\\\\\\\\\\\\\\\\ or (CH \\\\\\\\\\\\\\\\ or (CH \\\\\\\\\\\\\\\ "; or phenyl-C ₂ - © - alkenyl, especially ©ktop -CH = CH-CH ₂ , and n is 2 and preferably 1.

Further particularly preferred compounds are those in which R ₄ in Formula III is sulfonamido R ₈ S (O) ₂ N (R ₉ ) (CH ©, where R _{g is} - © ₂ alkyl, especially © - © alkyl which is unsubstituted or substituted by one or more halogen atoms (e.g. Cl and especially F), in particular CF ₃ ; or C 1 -Caryl, in particular phenyl or naphthyl, which is substituted by one or more C 1-6 alkyl (e.g. methyl or ethyl), © - © alkoxy (e.g. methoxy or ethoxy), halogens,

-CN or -NO ₂ , and R _g is hydrogen or isobutyl, and n is 2 and preferably 1.

Further particularly preferred compounds are those in which R ₄ in Formula III is an aminocarbonyl radical of formula R _g -NH-C (O) NH (CH © -, where R _{g is} -C ^ aUdl or © Cmaril, especially Cj- C ₆ alkyl unsubstituted or substituted by halogen, -CN, -NO, z

C, -C, alkyl or C 1-6 alkoxy, or C - or Ccycloalkyl, CC, _n aryl such as phenyl or

14 '5 6 6 10' ⁱⁿ naphthyl, but C _? -C aralkyl, such as benzyl, phenylethyl, phenylpropyl or phenylpropenyl, and n is 2 and preferably 1.

Particularly preferred compounds are further those wherein R ₄ in formula II is aminoalkyl, preferably R _g , R ₉ , N (CH ₂ ) _n , where R _g , and R _y , independently of one another, are hydrogen, unsubstituted C 1 -C ^ alkyl, C 1 -C ₁₂ alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR _sJ , OC (O) R _s4 , C (O) NR _H R ₁₂ , C _f C ₁₂ alkyl, C _f C ₆ alkoxy, C ₆ -C, _O aryl, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NR _2Q SO ₃ Na, nitro, amino and cyano; unsubstituted C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkyl substituted with one or more OH, C ₆ -C ₁₀ aryl; C ₇ -C ₁₆ aralkyl with C 1 -C ₆ alkyl and C _fi C _and aryl; or CC _{1 <;} aralkenyl with C <C _r alkenyl, and CC _1rt aryl, wherein the aryl and the aryl in the aralkyl and aralkenilu unsubstituted or substituted with one or more substituents selected from the group consisting of OH, halogen, C (O) OR _E, OC ( O) R _s4 , -C (O) ONa, -C (O) OK, -C (O) -NR _h R ₁₂ , C _r C ₁₂ alkyl, C, -C ₆ alkoxy, C ₆ -C ₁₀ aryl, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NR _2Q SO ₃ Na, nitro, amino and cyano, wherein n is 2 and preferably 1, and R is _sl hydrogen, K or Na, Cj-C ^ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C _n heterocycloalkyl, C 1 -C. _n aryl, CC _Q heteroaryl, CC ,, aralkyl or CC,. heteroaralkyl, R, is hydrogen, C, C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₁ -C ₆ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C _{1 ()} heteroaralkyl, R _u is H, C ₁ -C ₄ alkyl, C _? C _{4 is} hydroxyalkyl, phenyl or benzyl, and R _{12 has an} independent meaning for R _n , or R _n and R _p together are tetramethylene, pentamethylene or CH ₂ CH ₂ -O-CH ₂ CH ₂ and R _{2 () is} hydrogen. C, -C _p alkyl, C ₂ -C _p alkenyl, C ₃ -C _p cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C, -C, heterocycloalkyl, C, C _1-6 heterocycloalkenyl, C ₆ -C _1Q aryl, C ₅ - C ₉ heteroaryl, C ₇ -C _{1 [} aralkyl or CC _[() heteroaralkyl, C ₈ -C ₁₀ aralkenyl or C ₇ -C ₁₀ heteroaralkenyl.

Particularly preferred compounds are further those wherein R ₄ in Formula III is aminoalkyl *

R ₈ , R ₉ , NCH ₇ -, where R _g , and R _(/ independently of one another are hydrogen; C 1 -C ₈ alkyl, cyc28 lopentyl, cyclohexyl, C- or C ₆ cycloalkylmethyl, phenyl-C, - C ₄ alkyl, especially -CH ₂ C ₆ H ₅ , or phenyl-C ₂ -C ₄ alkenyl, especially -CH ₂ CH = CHC ₆ H ₅ .

Particularly preferred compounds are further those wherein R ₄ in Formula III is an amine Rg.Rg.NCHp wherein R _g and R ₉ are independently H, C 1 -C 4 alkyl, phenyl-C _{1 -} or C ₂ independently of one another alkyl, especially CH ₂ C ₆ H ₅ .

Preferred compounds of group (b) for the meanings of R ₄ are those in which R _{4 is} C ₇ -C _H aralkyl, especially -CH ₂ C ₆ H ₅ and (CH ₂ ) ₂ -C ₆ H ₅ , C ₃ -C ₁₂ cycloalkyl or C 1 -C 6 alkyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of NH ₂ , C ₃ -C ₁₂ cycloalkyl, primary amino, amino, sulfonamide, urea and aminocarbonylamido. Particularly preferred substituents for C 1 -C ₁₂ alkyl are NH ₂ , cyclohexyl, C ₆ -C ₁₀ aryl, R ₈ C (O) N (R ₉ ) -, R _g S (O ₂ ) N (R ₉ ) -, R _g NHC (O) NR _g -, NR ₉ C (O) NHR _g and Rg.Rg.N-, where R _g and Rg are independently hydrogen, C ₁ -C ₁₂ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C _to heterocycloalkyl, C ₆ -C _{1 ()} aryl, C ₅ -C ₉ heteroaryl, C _? C _n aralkyl or C ₆ -C ₁₀ heteroaralkyl and R 8 and R ₉ are independently hydrogen, OH, C 1 -C ₁₂ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C _n hetero cycloalkyl, C ₆ - C _1Q aryl, C ₅ -C ₉ heteroaryl,

C _? -C _H aralkyl or C ₆ -C ₁₀ heteroaralkyl unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R s ₄ , C ( O) OR ₂ , nitro, NH ₂ , cyano, -SO ₃ M _y , OSO ₃ M _v , NR _2Q SO ₃ M _y , C _r C ₁₂ alkyl,

C ₂ -C _p alkenyl, C ₁ -C ₆ , alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ C _H heterocycloalkyl, C, -C 1 heterocycloalkenyl, C _fi -C ₁₀ aryl, C ₆ - C _1Q aryloxy, CC _n heteroaryl, CL-C, .heteroaryloxy, C-C..alkyl, C, -C..alkyloxy, CC..heteroaralkyl, CC ,, aralkenyl, C, -C..heteroaralkenyl, primary amino, secondary amino, sulfonyl, about 1 I / 1 with a sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M, C-C ^ alkyl, C ₂ -C ₁₂ alkenyl, C , *

C _p cycloalkyl, C _{2 -C]} heterocycloalkyl, C ₆ -C _1Q aryl, C-C ₉ heteroaryl, C ₇ -C _H aralkyl, or C _{6 C] ()} heteroaralkyl, R _s4 is hydrogen, C, -C , ₂ alkyl, C 1 -C _p alkenyl, C ₃ -C ₁ cycloalkyl, C, 29

Cj j heterocycloalkyl, C ₆ -C, _o aryl, C ₅ -C ₉ heteroaryl, C _7-c [aralkyl or C, _fi -C ₁₀ heteroaralkyl, and R _s2 and _R20 are hydrogen, Cl-C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C, ₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C 1 [heterocycloalkyl, C ₂ -C [[heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? C 1-3 alkyl, C ₆ -C ₁₀ heteroalkyl, C _g -C [[aralkenyl or C ₇ -C ₁₀ heteroaralkenyl, and are alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl , aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl, in turn, 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; or R _g , and R _y , together are tetramethylene, pentamethylene, - (CH ₂ ) -0 (CH ₂ ) ₂ -, - (CH ₂ ) ₂ -S- (CH ₂ ) ₂ - or - (ΟΗ ₂ ) ₂ ^ - (εΗ ₂ ) ₂ -, and is R _? H, C 1-6 alkyl, C _? C 1-3 alkyl, C (O) R ₂ or sulfonyl.

Particularly preferred compounds in this group are those in which R _{4 is} CH ₂ -C ₆ H ₅ , (CH ₂ ) ₂ C ₆ H ₅ , cyclohexyl, methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of NH ₂ , cyclohexyl, C ₆ -C, _O 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 _g and Rg.Rg.N-, where R _g , R _g , R _g , and R ₉ are independently hydrogen, C 1 -C _p alkyl , C ₃ -C ₁₂ cycloalkyl, C ₆ C _{1 ()} aryl or C ₇ -C _n aralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (0) 0M , nitro, cyano, SO _q M, 0S0, M, NHS0..M, C.-CCalkyl, CC, .alkoxy and CC, _n aryl, where y is 1 and M is a monovalent metal or y is 1/2 and M is divalent metal. Particularly preferred compounds are those in which R _g , R ₉ , R _g , and Rg are independently hydrogen, C 1 -C [ ₇ alkyl, cyclohexyl, phenyl, naphthyl or C ₇ -C _H aralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, F, Cl, C (O) ONa, nitro, cyano, SO ₃ Na, C ₍ -C ₆ alkyl, methoxy and phenyl.

In a preferred group of compounds of formula I, R _{t is} formula III in which R _{4 is} C ₆ H,

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 ₆ H „, CH ₂ NHC (O) C„ H ₂₃ ,

CH ₂ NHC (O) CH (C ₆ H ₅ ) ₂ , CH ₂ HNC (O) NHC ₆ H _s , CH ₂ NHC (O) C ₂ H ₄ CO ₂ Na,

CH ₂ NHC (O) C ₆ [(1,3,4,5) OH] ₄ H ₇ CH ₂ NHC (O) C ₆ H ₄ -p-SO ₃ Na, CH ₂ NHC (O) C ₆ H4C1, CH ₂ NHC (O) C ₆ H ₄ NO ₂ , CH ₂ NHC (O) C ₆ H ₄ OCH ₃ , CH ₂ NHC (O) C ₆ H ₄ (3,4) C1 ₂ ,

CH ₂ NHC (O) C ₆ H ₄ CH ₃ , CH ₂ NHC (O) C ₆ H4C ₆ H ₅ , CH ₂ NHC (O) C ₆ H ₄ CN,

CH ₂ NHC (O) C ₁₀ H ₇ CH ₂ NHC (O) C ₆ H 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 ₆ H ₅ ] CH ₂ C ₆ H ₅ , CH ₂ N [C (O) C ₆ H ₅ ] (CH ₂ ) ₃ C ₆ H ₅ , CH ₂ C ₆ H _lb ( CH ₂ ) ₂ C ₆ H _lb 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 -ptolyl, CH ₂ NHSO ₂ CF ₃ , CH ₂ NHC (O) NHC ₆ H ₅ or CH ₂ N [SO ₂ -pnitrophenyl] [CH ₂ CH (CH ₃ ) ₂ ] ₂ .

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

In the case of halogen as a substituent on R ₂ , it may preferably be F, Cl and Br; in the case of -C (O) OM _y is preferably -C (O) ONa or -C (O) OK; in the case of alkyl, preferably C 1 -C ₆ - and particularly preferably C 1 -C ₄ alkyl, such as e.g. methyl, ethyl, n- or i-propyl and n-, i- or t-butyl; in the case of alkoxy, preferably C 1 -C 6 alkoxy, e.g. methoxy and ethoxy; in the case of aryl, preferably phenyl or naphthyl; in the case of -SO M is preferably -SO Na or -SO ₃ K; in the case of a primary amine C 1 -C ₁₂ primates an amino such as e.g. methyl-, ethyl-, n- or i-propyl-, n-, i- or t-butyl, pentyl, hexyl, cyclohexyl, phenyl or benzylamino; in the case of a secondary amine, C ₂ -C is ₂₀ seconds amino, such as e.g. dimethyl-, diethyl-, methylethyl-, di-n-propyl-, di-i-propyl-, di-n-butyl-, diphenyl-, dibenzylamino, morpholino, thiomorpholino, piperidino and pyrrolidino; -SO ₂ -NR _g R ₉ ; and -C (O) -NR _g R ₉ , wherein R _g and R _{9 are} independently H, C 1 -C ₄ alkyl, C ₂ -C ₄ hydroxyalkyl, phenyl or benzyl, or R _g and R _{9 are} together with the N atom morpholino, thiomorpholino, pyrrolidino or piperidino.

R _g and R ₉ as alkyl preferably contain 1 to 6 and especially preferably 1 to 4 C atoms and may be e.g. methyl, ethyl, n- or i-propyl or n-, i- or t-butyl. R _g and R ₉ as hydroxyalkyl preferably contain 1 to 6 and especially preferably 1 to 4 C atoms and may be e.g. hydroxymethyl or 2-hydroxyethyl. R _g and R ₉ as cycloalkyl are preferably cyclopentyl or cyclohexyl. Substituents for R g and R _g as phenyl and benzyl are preferably F, Cl, methyl, ethyl, methoxy and ethoxy.

A preferred subset of the compounds of formula I is one in which R _{2 is} hydrogen, unsubstituted C ₁ -C ₈ alkyl, especially preferably C ₁ -C ₄ alkyl, especially methyl or ethyl, which is substituted by C (O) OH, -C (O) ONa, -C (O) OK, -OH, -C (O) -NR _g R ₉ or -SO ₂ -NR _g R ₉ where Rg is H, C, C ₄ alkyl, C ₂ -C ₄ hydroxyalkyl, phenyl or benzyl, and R _g independently represents Rg, or Rg and together are tetramethylene, pentamethylene or -CH ₂ CH ₂ -O-CH, CH ₂ -. Particularly preferred compounds are those 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 -, and R _g and R _g independently of one another are H, C 1 -C ₆ alkyl, C ₂ -C ₄ hydroxyalkyl, phenyl, benzyl, or together morpholino.

A particularly preferred embodiment of the invention comprises compounds of formula Ia:

where it is

R _{3 is} hydrogen or M _y ; and R ₄ a C-C _p alkyl, C, -C _p alkenyl, C ₃ -C _r cycloalkyl, C ₃ C _p cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C _{6 -C] 0} aryl, C 9

C ₉ heteroaryl, C ₇ -C ₍₁ aralkyl, C _{6 -C] 0} heteroaralkyl, C _g -C ₁₁ aralkenyl or _{C? C) ()} heteroaralkenyl, which are unsubstituted or substituted one or more times;

R ₅ and R ₆ independently of one another are hydrogen, C, -C _I2 alkyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C [heterocycloalkyl, C, _{fi-C 1 ()} aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _n aralkyl, or C ₆ -C, _O heteroaralkyl, or R ₅ and R _{ft are} together with the group -CH-CH-, C ₃ -C _{] 2} cycloalkylene, C ₄ -C ₁₂ cycloalkenylene, C ₂ -C _{H is} heterocycloalkylene and C ₃ -C ₁₁ heterocycloalkylene with heteroatoms selected from the group -O-, -S- and -N-; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted one or more times, where the substituent is selected from the group consisting of OH, halogen, C (0) 0r _sl OCjOjR ^, C (O) R _s2 , nitro, NH ₂ , cyano, -S0 ₃ M _y , 0S0 ₃ M _y , NR ^ SO ^, where R ^ is hydrogen, C 1 -C 6 alkyl, C ₂ C ₁₂ alkenyl , C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C [[heterocycloalkyl, C ₂ C 1 heterocycloalkenyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C _{1 ()} heteroalkyl, C _g Cnaralkenyl or C ₇ -C ₁₀ heteroaralkenyl, and C ₁ -C 6 alkyl, C ₂ -C 4 alkenyl, C 1 -C 6 alkoxy, C ₃ C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C, [heterocycloalkyl, C ₂ -C [[heterocycloalkenyl, CC _{] n} aryl, CC, aryloxy, CC.heteroaryl, C ₅ -C _n heteroaryloxy, CC ,, aralkyl, C, C [[aralkyloxy , C ₆ -C ₁₀ heteroaralkyl, C ₈ -C ₁₈ aralkenyl, C ₇ -C _1Q heteroaralkenyl, primary amino, amino seconds, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where R is hydrogen, M, sl y

C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C ₁ [heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ C ₉ heteroaryl, C ₇ -C _n aralkyl or C ₆ C _{1 ()} heteroaralkyl, R _j4 is hydrogen, C [-C ₁₂ alkyl, C ₂ C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C _2-c [heterocycloalkyl, C ^ C ^ aryl, C ₅ -C _g heteroaryl, C _? C _{1 - 6} aralkyl or C ₆ -C _{1 ()} heteroaralkyl, and R _{2 is} hydrogen, C ₁ -C ₆ , alkyl, C ₂ -C ₁₂ alkenyl, C ₃ C 6 cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C, [heterocycloalkyl, C 1 -C ₆ [heterocycloalkenyl, C ₆ C _[() aryl, C ₅ -C ₉ heteroaryl, C _? -C [aralkyl, C _{6 -C) 0} heteroaralkyl, C _g-C [[aralkenyl or _C? C 1 _{O is} heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are substituted with unsubstituted or substituted unsubstituted or substituted substituted; and y 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 wherein Rg is H, K or Na; R «. and R _f are taken together with the group -CH-CH-C ₃ -C _p cycloalkylene, C ₄ -C, ₂ cycloalkenylene, C ₂ C _H heterocycloalkylene and C ₃ -C ₁ heterocycloalkylene with heteroatoms selected from the group -O-, -S- and -N-; which are unsubstituted or substituted once or more, where the substituent is selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2 , nitro, NH ₂ , cyano, -S0 ₃ M _y OSO ₃ M _y, NR _2Q SO ₃ M _y, where R ₂₀ is hydrogen, C? _{-C) 2} alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C ₁ H heterocycloalkyl,

C.-C. .heterocycloalkenyl, CC, .aryl, CC.heteroaryl, C.-C, .alkyl, CC ₁₀ heteroaralkyl, C _g -C ₁ , aralkenyl or C ₇ -C ₁₀ heteroaralkenyl, and C 1 -C ₂ alkyl, C ₂ C ₁₂ alkenyl. , C _t -C ₁₂ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ C _n ether cycloalkyl, 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 _n aralkyl, C ₇ -C _n aralkyloxy, C ₆ -C ₁₀ heteroaralkyl, C _g -C ₁ Aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino , secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M _y, Cj-C ^ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ C "cycloalkyl, CC, .heterocycloalkyl, C, -C .. aryl, C «. -C. Heteroaryl, C, -C ,, aralkyl or C, 12 2 11 o 10 5 9 ⁷ 7 11 o

C .. heteroaralkyl, R. is hydrogen, CC, .alkyl, C.-C, .alkenyl, C.-C,. cycloalkyl, C _1-6 heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C ₁₀ heteroaralkyl, and is R. hydrogen, CC., alkyl, C.-C, .alkenyl , CC .. cycloalkyl, CC .. cycloalkenyl, CC _H heterocycloalkyl, C ₂ -C ₁ heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? C ₁ -C ₁₀ alkyl, C ₆ -C ₁₀ heteroaralkyl, C ₈ -C ₆ aralkenyl or C ₇ -C ₁₀ heteroaralkenyl, and are alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxyalkylalkyl , aralkenyl and heteroaralkenyl are 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) R ₄ is a residue of R ₁₂ - (CH ₂ ) _n - or cyclohexyl, where n is 1 or 2, and R _{1 is 2} C, -C _w alkyl, C ₅ C _g cycloalkyl, especially cyclohexyl, C ₆ - C _1Q aryl, preferably phenyl, or C _g -C ₁₂ aralkenyl, preferably phenyl-C ₂ -C ₄ alkenyl, which are unsubstituted or substituted by C, -C ₄ alkyl, Cj-C ^ alkoxy, F, Cl, -CN, or - NO ₂ ; or R _J2 is an amino group -NR _g R _g ', R _g, and R g, CC..alkil or unsubstituted or C -C.alkilno substituted C? - or C cycloalkyl, C anus, C ₇ -C ₁₂ aralkyl or C _g -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 ₆ H ₅ CH = CH-CH ₂ -, or R _{12 is} an amide group-N (R ₉ ) C (O ) R _g , -N (R ₉ ) S (O) ₂ R _g , -NR ₉ C (O) NHR _g - or -NR ₉ C (O) NHR _g , where R _g C ₆ -C ₁₀ aryl, preferably phenyl which is unsubstituted or substituted with C 1 -C 6 alkyl, in particular methyl, C 1 -Calkoxy, in particular methoxy, F, Cl, -CN or -NO ₂ , or C 1 -C 6 alkyl which is unsubstituted or substituted with F or Cl, and R is H, Cj-C ^ alkyl, C ₅ - or C ₆ cycloalkyl, C ₅ - or CgCikloalkil-C-NHR phenyl-Cj- ^ alkyl or phenyl-C ₂ -C ₆ alkenyl, especially H, C 1 -C ₆ alkyl, cyclohexyl, cyclohexylCH ₂ , cyclohexyl-CH ₂ CH ₂ -, cyclohexyl-CH ₂ CH ₉ CH ₂ , C ₆ H ₅ CH ₂ , C ₆ H ₅ CH ₂ CH ₂ -, C, H_CH CH.CH - and C H.CHCHCH-,

R ₉ is in particular hydrogen, unbranched and preferably branched C 1 -C 6 alkyl, phenyl or phenyl (CH ₂ ) _z having z equal to 1 to 4, e.g., methyl, ethyl, n- or i-propyl, n-, i - or t-butyl, pentyl, isopentyl, hexyl, benzyl, phenylethyl, phenylpropyl and phenyl-CH = CH-CH ₂ , particularly particularly CH ₂ -CH (CH ₃ ) ₂ , benzyl, 2-phenylethyl and 3-phenylpropyl; or (b) R ₄ is C ₁ -C ₄ alkyl, C ₃ -C, ₂ cycloalkyl or C ₇ -C _H aralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2 , nitro, NH ₂ , cyano, -SO ₃ M _y , OSO ₃ M _y , NR ₂₀ SO _a M _y , where R _{? ()} hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ C _p cycloalkenyl, C 1 -C heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C, ₀ aryl , C ₅ Cgheteroaryl, C _? -C aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C 1 _] aralkenyl or C _? C, _n heteroaralkenyl, and CC, .alkyl, C-C .. alkenyl, C-C ... alkoxy, CC..cycloalkyl, C, C ^ cycloalkenyl, C-C heterocycloalkyl, C, -C ^ heterocycloalkenyl , C ₆ -C ₁₀ aryl, C ₆ C _{1 ()} aryloxy, C ₅ -C _y heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ -C ₁ jaralkyl, C ₇ -C _n aralkyloxy, C ₆ 35

C [ _O heteroaralkyl, C _g -C _n aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino, seconds amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where R, hydrogen, M C, -C, alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C, ₂ cycloalkyl, C ₂ -C [[heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? C 1, aralkyl or C ₆ -C ₁₀ heteroaralkyl, R _s) is hydrogen, C 1 -C [ ₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ C ₁₂ cycloalkyl, C ₂ -C n heterocycloalkyl, C ₆ -C, _O aryl, C ₅ -C ₉ heteroaryl, C ₇ -C 'aralkyl or C ₆ C 1 _O heteroaralkyl, and R _{2 is} hydrogen, C 1 -C ₁₂ alkyl, C ₂ -C _{] 2} alkenyl, C ₃ -C 4 cycloalkyl , C ₃ C ₁₂ cycloalkenyl, C ₂ -C [[heterocycloalkyl, C ₂ -C [[heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ C ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, C ₈ -C aralkenyl or C _? C _{10 is} heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are substituted or unsubstituted, substituted or unsubstituted, substituted or unsubstituted and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal.

A preferred subgroup of compounds of group (a) is one in which (i) R ₄ is C ₆ H _n , C ₆ H _n -CH ₂ , C ₆ H [[- CH ₂ CH ₂ -, C ₆ H.CH ₂ - , C ₆ H ₅ CH ₂ CH ₂ - or c ₆ h ₅ -ch = ch-ch ₂ -, (ii) R ₄ stands for C ₆ H _n , C ₆ H, _f CH ₂ , C ₆ H _n -CH ₂ CH ₂ -, C ₆ H ₅ CH ₂ -, C ₆ H ₅ CH ₂ CH _f , CH ₂ nr, ₉ -so ₂ r ₁₈ , -ch ₂ -nr ₁₉ -c (O) r ₄₀ , ch ₂ nhc ( O) nhr, ₈ , ch ₂ nhr ₂₁ or ch ₂ n (r ₂₁ ) ₂ , wherein R _{1 is} -C ₆ H ₅ , phenyl substituted with 1 to 3 methyl or methoxy or -NO ₂ or F or Cl , in particular p-CH ₃ C ₆ H ₄ -, p-CH ₃ OC ₆ H ₄ - or 2,3,5-CH ₃ -C ₆ H ₂ - or pO ₂ NC ₆ H ₄ -, or C _r C ₄ alkyl substituted with F, in particular -CF ₃ ; R ₄₀ is phenyl which is unsubstituted or substituted with 1 to 3 methyl or methoxy or -NO ₂ or F or Cl; R ₉ is H, C-C ₆ alkyl, phenyl- (CH,) _z, where z is a number from 1 to 3, phenyl-CH = CH-CH _2, and particularly _-CH? CH (CH ₃ ) or benzyl; and R 1 is -CH ₂ -CR ₂₇ R ₂₃ R ₂₄ wherein R 1 and R _{73 are} methyl, ethyl or phenyl and R _{4 is} hydrogen, ethyl or methyl, particularly preferably R 1 and R _{23 are} methyl , and R is ₄ hydrogen.

A preferred subgroup of compounds of group (b) consists of those in which R ₄ © H, C © spoketu, (CH © - © spok, methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from the group , consisting of N ©, cyclohexyl, ©ktop _o aryl, © C (O) N (©) -, © S (O) ₂ N (©) -, N © C (O) NH ©, and © spok, N , wherein ©, ©, © and © are independently hydrogen, © - © ₂ alkyl, © - © ₂ cycloalkyl, © -Cmaril or © - © jaralkyl, which are unsubstituted or substituted by one or more substituents selected from groups consisting of OH, halogen, C (O) OM, nitro, cyano, -SO, M, OSO ₃ M _y , N © ₀ SO ₃ M _y , where © _{0 is} hydrogen, © - © ₂ alkyl, © - © ₂ alkenyl, © - © ₂ cycloalkyl, © - © ₂ cycloalkenyl, © -Cheterocycloalkyl, © -Cheterocycloalkenyl, © -Cmaril, ©ktop heteroaryl, CC ,, aralkyl, CC, .hetero alkyl, © -C ,, aralkenyl or C 9/11 oIU oll 7 © _O heteroaralkenyl, and C ₁ -C ₁₂ alkyl, © -C ₁₂ alkoxy and © -Cmaril, wherein y is 1 and M is a monovalent metal or y is 1/2 and M is di Especially preferred compounds are those in which R _g , ©, ©, and R ₉ are independently hydrogen, C ₁ -C ₁₂ alkyl, cyclohexyl, phenyl, naphthyl or C ₁ -C ₆ aralkyl, which are unsubstituted or substituted with one or more substituents selected from the group consisting of OH, F, Cl, C (O) ONa, nitro, cyano, SO ₃ Na, C 1-6 alkyl, methoxy and phenyl.

In a preferred group of compounds of formula la R ₄ © H, CH (C ©) _2, C © -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 ₆ Hi ,, CH ₂ NHC (O) C ₁₁ H ₂ 3, CH ₂ NHC (O ) CH (C ₆ H ₅ ) ₂ , CH ₂ HNC (O) NHC ₆ H ₅ , CH ₂ NHC (O) C ₂ H ₄ CO ₂ Na, CH ₂ NHC (O) C ₆ [(1,3,4 , 5) OH] ₄ H ₇

CH ₂ NHC (O) C ₆ H ₄ -p-SO ₃ Na,

CH ₂ NHC (O) C ₆ H ₄ OCH ₃ ,

CH ₂ NHC (O) C ₆ H ₄ C ₆ H ₅ ,

CH ₂ NHC (O) C ₆ H ₄ COONa,

CH ₂ NHC (O) C ₆ H ₄ NO ₂ ,

CH ₂ NHC (O) C ₆ H ₄ CH ₃ ,

CH ₂ NHC (O) C ₁₀ H ₇

CH ₂ NHC (O) C ₆ H ₄ C1,

CH ₂ NHC (O) C ₆ H ₄ (3,4) C1 ₂ ,

CH ₂ NHC (O) C ₆ H ₄ CN,

CH ₂ NHC (O) (CHOH) ₂ COONa, CH ₂ N (CH ₂ CH = CHphenyl) [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 6H _S, CH ₂ N [C (O) C ₆ H _5] (CH ₂₎ 3 C ₆ H5, CH ₂ C ₆ H !, (CH ₂ ) ₂ C ₆ H ,,, 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 37 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 .

The present invention further relates to a process for the preparation of compounds of formula I comprising the etherification of a 3-OH group of a compound of formula V:

in which R ₂ and X have the above meanings, R ₁₂ is a protecting group and R 'and R are independently hydrogen or a protecting group, with a compound of formula VI:

R 1 -R ₁₃ (VI) wherein R 1 has the above meaning and R _{J 3 is a} leaving group, and eliminating protecting groups.

The leaving groups may be: halides such as chloride, bromide and iodide, and sulfonic acids, e.g. trifluoromethanesulfonate, aliphatic, cycloaliphatic or aromatic sulfonic acids, which are unsubstituted or substituted by CC, alkyl, CC, alkoxy, nitro, cyano or halogen (chlorine, bromine). Some examples of acids are: methanesulfonic, mono-, di- or trifluoromethanesulfonic or p-nitrobenzenesulfonic. CF ₃ -S0, -0 (which is also referred to as triflate) is particularly preferred. The leaving group is preferably selected from the group consisting of halogen and unsubstituted and halogenated R-SO ₂ -, where R is C 1 -C alkyl, especially C-C ₆ alkyl, C ₅ -C ₆ cycloalkyl, phenyl, benzyl, C - C alkylphenyl, especially C ₁ -C ₄ alkylphenyl or C ₁ -C ₄ alkylbenzyl, especially C, 38

C ₄ alkylbenzyl, e.g. methane, ethane, propane, butane, benzene, benzyl and pmethylbenzenesulfonyl. Preferred leaving groups are: Cl, Br, J, -SO ₂ CF ₃ (triflate) and p-nitrobenzenesulfonyl; -SO ₂ CF ₃ is particularly preferred.

The compounds of formula VI are known in some cases or can be obtained by known methods as described by Degerbeck et al. [Abstract] [Degerbeck, F., Fransson, B., Grehn, L., Ragnarsson, U., J. Chem. Soc. Perkin Trans. 1: 11-14 (1993) and Dureault et al. [Dureault, A., Tranchepain, I., Depezay, J.C., Synthesis 491-493 (1987)]. Optically pure compounds can be obtained using optically pure starting compounds (e.g. amino acids, α-hydroxyl acids) or by chromatographic separation processes, 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 processes based on known fucosyl and galactosyl donors and diols of the formula ΗΟ-Χ-ΟΗ. The stepwise introduction of galactose and fucose or vice versa is preferred.

For the preparation of compounds of formula V, pseudotrisaccharide-forming blocks are first synthesized. The pseudotrisaccharide is assembled either by glycosidic binding of activated and protected galactose to the fucose-O-X-OH-forming block or by glycosidic binding of suitably protected and activated fucose to the galactose-O-X-OH-forming block. Glycosylation reactions are very well known and have been described in specific literature.

It is then possible to introduce the R group ₍ into a pseudotrisaccharide. The compounds of formula I obtained can then be modified. This modification may involve the hydrogenation of aromatic compounds into cycloaliphatic groups, which takes place, for example, at the same time as the hydrogenolytic elimination of protecting groups. It is further possible that the amino group acylated and / or alkylated and / or sulfonated The preparation of secondary and tertiary amines can be carried out by reductive amination.

It has been shown that it is preferable to activate the 3-OH group of the galactose residue by etherification. Particularly suitable for these purposes are dialkyltin oxides, dialkyltin alkoxylates and bis (trialkyl) tin oxides. Some examples are dibutyltin oxide, dibutyltin (O-methyl) ₂ and (tributyltin) ₂ O. Activation agents are preferably used in stoichiometric amounts. In this case, the reaction is carried out in two steps, namely a) activation and b) coupling with compounds of formula VI.

The activation process can be carried out at a temperature of from 40 to 200 ° C, preferably from 60 to 120 ° C.

The compounds of formulas V and VI can be used in equimolar amounts. However, it has proved more advantageous to use compounds of formula VI in excess, e.g. in an amount up to 10 times, preferably 5 times the amount of the compound of formula V.

Furthermore, it is more advantageous to carry out the reactions in both reaction steps in the presence of an inert solvent or solvent mixture. Reactive protic solvents such as alkanols and further acid amides are unsuitable in reaction step b). It is possible to use non-semi-aprotic and semi-aprotic or semi-protic solvents. These may be aliphatic or aromatic hydrocarbons such as: pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene or xylene, halogenated hydrocarbons such as e.g. methylene chloride, chloroform, tetrachloromethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane and chlorobenzene, linear or cyclic ethers such as e.g. diethyl ether, dibutyl ether, ethylene glycol dimethyl or diethyl ether, tetrahydrofuran and dioxane, Ν, dial-dialkylated carboxamides, such as e.g. dimethylformamide, N-alkylated lactams such as e.g. N-methylpyrrolidone, ketones, e.g. acetone and methyl isobutyl ketone, carboxyl esters such as e.g. methyl or ethyl acetate, or alkanols, such as e.g. methanol, ethanol, propanol, butanol and ethylene glycol monoethyl ether. Particularly preferred solvents are methanol, ethanol, benzene and toluene.

Protective groups and methods for derivatizing hydroxyl groups with such protecting groups are generally known in the chemistry of sugars and nucleotides and are described e.g.

Beaucage, SL Iyer, R .. Tetrahedron 48: 2223-2311 (1992). Examples of such protecting groups are benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, dimethoxybenzyl, bromobenzyl, 2,4-dichlorobenzyl; diphenylmethyl, di (methylphenyl) methyl, di (dimethylphenyl) methyl, di (methoxyphenyl) methyl, di (dimethoxyphenyl) methyl, triphenylmethyl, tris-4,4 ', 4terc.butylphenylmethyl, di-p-anisylphenylmethyl, tri (methylphenyl) methyl , three (dimethylphenyl) methyl, methoxyphenyl (diphenyl) methyl, di (methoxyphenyl) phenylmethyl, three (methoxyphenyl) methyl, three (dimethoxyphenyl) methyl; triphenylsilyl, alkyldiphenylsilyl, dialkylphenylsilyl and trialkylsilyl of 1 to 20, preferably 1 to 12 and especially preferably 1 to 8 C atoms in alkyl groups, e.g. triethylsilyl, tri-n-propylsilyl, i-propyl-dimethylsilyl, t-butyl-dimethylsilyl, t-butyldiphenylsilyl, n-octyl-dimethylsilyl, (1,1, 2,2, -tetramethylethyl) dimethylsilyl; C ₂ -C I ₂ -, especially C ₂ -C _g acyl, such as e.g. acetyl, propanyl, butanoyl, pentanoyl, hexanoyl, benzoyl, methylbenzoyl, methoxybenzoyl, chlorobenzoyl and bromobenzoyl. The protecting groups may be identical or different. Preferred protecting groups are selected from the group consisting of linear and branched C 1 -C ₈ alkyl, especially C 1 -C ₄ alkyl, e.g. methyl, ethyl, n- and ipropyl, n-, i- and t-butyl; C ₇ -C ₁₂ aralkyl, e.g. benzyl; trialkylsilyl of 3 to 20 C atoms and especially 3 to 12 C atoms, e.g. triethylsilyl, tri-n-propylsilyl, tri-i-propylsilyl, i-propyldimethylsilyl, t-butyl-dimethylsilyl, t-butyl-diphenylsilyl, n-octyl-dimethylsilyl, (1,1,2,2tetramethylethyl dimethylsilyl; substituted methylidene groups they can be obtained by the formation of acetals or ketals from adjacent hydroxyl groups of sugars or sugar derivatives with aldehydes and ketones, preferably containing 2 to 12 or 3 to 12 C atoms, e.g., C 1 -C 4 alkylidene, preferably C 1 -C 4 alkylidene, and in particular C ₁ -C ₄ alkylidene, such as ethylidene, 1,1- and 2,2-propylidene, 1,1- and 2,2-butylidene, benzylidene; unsubstituted and halogenated C ₂ -C ₁₂ acyl, in particular C ₂ -C ₈ acyl, such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, pivaloyl and benzoyl.

The synthesis preferably takes place with the protecting groups of R _p 'and R ₁₂ , which together form an alkylidene group, preferably of 1 to 12 and more preferably of 1 to 8 atoms C. In this connection, those protecting groups in which R _p is particularly preferred and R ₁₂ together is an alkylidene group, in particular of 1 to 12 C atoms, wherein the alkylidene group is acetal or ketal forming with oxygen atoms. These protecting groups are those that can be eliminated under neutral or weakly acidic conditions. Particularly suitable protecting groups are acyl, benzyl, substituted benzyl, benzyloxymethyl, alkyl and silyl. R ₁₂ 'and R _p are particularly preferably together alkylidene, e.g. alkyl- or alkoxy-substituted benzylidene. R ₂ and _{R] 2} may also be hydrogen or one of R 'and R ₁₂ may be a protecting group such as benzyl, and the other of R ₁₂ and R _L2' may be hydrogen.

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

The reaction to eliminate the protecting groups is preferably carried out at a temperature of from 0 ° C to 50 ° C and especially at room temperature.

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

An alternative synthesis route comprises glycosidic binding of protected fucose hydroxy ether of formula VII:

(VII) in which R ₂ , R _p and X have the meanings indicated above, with protected galactose of the formula

VIII:

(Vlil) in which R! the above meaning, Z is O or S, R _p is a protecting group and R is a leaving group, and then removing the protecting groups from the resulting compound.

It is possible to choose reaction conditions similar to those used in the process described previously. The leaving group R may be e.g. -C (= NH) -CCl ₃ or 4pentenyl. The compounds of formula VII can be obtained easily by glycosidic coupling of a suitably protected fucose with a compound of formula ΗΟ-Χ-mon which is mono-protected where appropriate. Compounds of formula VIII can be obtained by etherification of compounds of formula RjOH with galactose, which is protected where appropriate.

The compounds of the present invention have anti-inflammatory properties and can accordingly be used as medicaments. They can be especially mitigated by disorders such as cardiogenic shock, myocardial infarction, thrombosis, rheumatism, psoriasis, dermatitis, acute respiratory distress syndrome, asthma, arthritis and metastatic cancer. The present invention further relates to the compounds of the invention for use in therapeutic methods for the treatment of disorders in warm-blooded animals, including humans. Dosages for administration to warm-blooded animals weighing approximately 70 kg may be e.g. 0.01 to 1000 mg per day. The administration preferably takes the form of pharmaceutical compositions parenterally, e.g. intravenously or intraperitoneally.

The invention further relates to a pharmaceutical composition comprising an active amount of a compound of the invention alone or together with other substances, a pharmaceutical carrier, preferably in a labeled amount, and where administered with excipients.

The pharmacologically active compounds of the invention can be used in the form of compositions that can be administered parenterally or as infusion solutions. Solutions of this type are preferably isotonic aqueous solutions or suspensions, which may preferably be prepared later, e.g. in the case of lyophilized compositions comprising the active substance alone or together with the carrier, e.g. mannitol, before use. The pharmaceutical compositions may be sterilized and / or comprise excipients, e.g. safeners, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for controlling osmotic pressure and / or buffers. Pharmaceutical compositions which, if necessary, may comprise other pharmacologically active substances, such as antibiotics, may be prepared in a manner known per se, e.g. by conventional dissolution or lyophilization processes, and comprise from about 0.1% to 90%, in particular from about 0.5% to about 30%, e.g. 1% to 5% of active substance.

The following examples illustrate the present invention.

The following abbreviations are used:

Bz: benzoyl; Bn = benzyl; DMTST: dimethyl (methylthio) sulfonium triflate; FAB: mass spectroscopy with ionization of molecules in an ion source with fast atoms; 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; BS A: bovine serum albumin; PAA: polyacrylic amide; SA: streptavidin

Unbound hyphen in formulas means methyl.

Sieve molecules are activated at 300 ° C under high vacuum for 12 hours before use.

They are used in powder form.

A: Preparation of starting compounds

Example Al: Preparation of compound no. Al

Benzyl chloride (660 ml, 5.72 mmol) was added at room temperature to a mixture of R-3-azido-2hydroxypropionic acid 28 [Dureault, A., Tranchepain, I., Depezay, JC, Synthesis 491-493 (1987)], triethylamine (850 ml, 6.1 mmol) and DMF (7.0 ml). The mixture was stirred for 16 hours and then further triethylamine (850 μΐ, 6.1 mmol) and benzyl chloride (660 μΐ,

5.72 mmol). The reaction mixture was stirred for 2 days and concentrated under high vacuum. The residue was taken up in water and the mixture was extracted several times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried (Na ₂ SOJ, filtered and concentrated in vacuo. The crude product (1 g) was purified by flash chromatography on silica gel (ethyl acetate / hexane 1: 4) to give benzyl R-3 -Azido-2hydroxypropionate 29 (0.717 g, 85%) as an oil NMR (250 MHz, CDCl 3 δ 7.36 (m,

5H), 5.25 (s, 2H), 4.39 (q, J = 4.2 Hz, 1H), 3.65 (dd, J = 3.3, 12.9 Hz, 1H), 3. 51 (dd, J = 4.3, 12.9 Hz, 1H), 3.20 (d, J = 4.0 Hz, 1H).

o

OTf

A1

Trifluoromethanesulfonic acid anhydride (770 ml, 4.41 mmol) was added at -20 ° C while stirring 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 dry CH ₂ Cl ₂ (11.0 ml). Heat the clear colorless solution to

0 ° C for 40 minutes and stirred at this temperature for a further 2 hours. The mixture was diluted with CH ₂ C1 ₂ (40 ml) and 1 M aqueous KH ₂ PO ₄ (30 ml) was added with vigorous stirring. The organic phase was separated and the aqueous phase was extracted twice with CH ₇ C 1 _second The combined organic phases were washed with H ₂ O (30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The oily residue (2.3 g) was purified by flash column chromatography on silica gel (ethyl acetate / hexane 1: 7) to give benzyl R-3-azido2-trifluoromethanesulfonyloxypropionate Al (1.16 g, 85%) as a yellowish oil . 1 H NMR (250 MHz, CDCl ₃ ) δ 7.38 (br s, 5H), 5.32 (d, J = 12.1 Hz, 1H), 5.27 (d, J = 12, 1 Hz. 1H), 5.4 (dd, J = 4.2, 5.5 Hz, 1H), 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. A2

Benzyl (R) -4-phenyl-2-trifluoromethanesulfonyloxybutyrate (Α2):

To a solution of (R) -2-hydroxy-4-phenylbutyric acid 26 (0.2 g, 1.11 mmol) in MeOH / H, O (9: 1, 1.3 ml) was adjusted to pH 8 with a 20% solution of Cs ₂ CO ₃ . The solution was concentrated in vacuo and azeotroped first with ethanol and then with hexane, then dried under high vacuum to remove the remaining H ₂ O. The residue was mixed with N, Ndimethylforamide (1.3 ml) and benzyl bromide (132 μΐ, 1.11 mmol). and the mixture was stirred at room temperature for 75 minutes. Further benzyl bromide (20 μΐ, 0.168 mmol) was then added and the mixture was stirred for a further 50 minutes. The white suspension was diluted with CH, C1, (5 ml), filtered through HyfloSuperCel® and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel (eluent: ethyl acetate / hexane 4: 1) gave benzyl (R) -2-hydroxy-4-phenylbutyrate 27 (0.21 g, 70%). Product (0.3 g,

1.11 mmol) was dissolved in CH ₂ C1 ₂ (4.5 ml), 2,6-di-tert-butylpyridine (323 μΐ was added,

1.44 mmol) and the mixture was cooled to -20 ° C. Then trifluoromethanesulfonanhydride (222 μΐ, 1.27 mmol) was added dropwise over 3 minutes and the solution warmed to 0 ° C for 45 minutes. After 75 minutes at 0 ° C, the mixture is diluted with CH ₂ Cl _? (20 ml) and washed with 1 molar aqueous solution of KH ₂ PO ₄ (15 ml). The aqueous phase was extracted with CH ₂ Cl ₂ (2 x 10 mL) and the combined organic phases with H ₂ O (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was roughly purified by column filtration on silica gel (eluent: ethyl acetate / hexane 1: 9) to give crude triflate A2 (0.311 g, 70%) as an oil. Use the product immediately in the 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, 11.0 Hz, 1H), 2.82 (m, 2H), 2.41 (m, 2H).

Example A3: Preparation of compound no. A3

The R-hydrochloric acid was converted to triflate A3 according to Example A2.

Example A4: Preparation of compound no. A4

R-2-hydroxy-3-methylbutyric acid was converted to triflate A4 according to Example A2.

ExampleA5: Preparation of Compound no. A5

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

B Preparation of mimetics

Example BI: Preparation of compound no. B 1.1

A mixture of thioglycoside 1 (5.38 g, 8.40 mmol) [Biessen, E. A. L., Beuting, D. M., Roelen,

H.C.P.F., van de Marel, G.A., van Boom, J.H., van Berkel, T.J.C., J.Med.Chem. 38: 1538-1546 (1995)] and acceptor 2 (3.44 g, 6.46 mmol) were dried under high vacuum for one hour. Then activated 0.4 nm activated sieve molecules (20 g) and DMTST (4.17 g,

16.14 mmol) under a nitrogen atmosphere, and then CH, C1 ₂ (70 ml). The yellow suspension was dried at room temperature and after 3 hours 5 ml of the suspension consisting of DMTST (5.84 g, 22.61 mmol), 0.4 nm molecular sieves (4.0 g) and CH ₂ C1 _{2 were added.} (35 ml). A further 5 ml portion of this DMTST suspension was added at 30, 45, respectively. 90 minutes. The brown reaction mixture was then stirred for 15 hours and then filtered through Hyflo Super Cel® (filtered auxiliary), washed with CH ₂ Cl ₂ (300 ml). The filtrate was extracted by shaking first with 10% aqueous NaHCO ₃ solution and then with saturated NaCl solution and the organic phase was dried with Na ₂ SO ₄ , filtered and concentrated in a vacuum rotary evaporator. The remaining brown foam was purified 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%) to be used immediately.

A solution of tetrabenzoate 3 (3.38 g, 3.04 mmol) and sodium methoxide (0.165 g, 3.05 mmol) in dry methanol (32 ml) was stirred at room temperature for 3 hours. The mixture was neutralized by the addition of a strong acid ion exchanger (Amberlyst 15) and then filtered through Hyflo Super Cel® by washing with CH ₂ C1 ₇ . The filtrate was concentrated in vacuo and the remaining yellow oil was purified by flash chromatography on silica gel (elution CH ₂ Cl ₂ / methanol 19: 1) to give pure tetrol 4 (1.95 g, 92%).

OH

A solution of tetrol 4 (1.0 g, 1.44 mmol) of dimethyl acetal benzaldehyde (430 ml, 2.86 mmol) and camphrasulfonic acid (0.1 g, 0.43 mmol) in acetonitrile (20 ml) was stirred at room temperature. . After 4 hours, further camphrasulfonic acid (0.15 g, 0.65 mmol) was added and the mixture was stirred for a further 6 hours at room temperature and then heated at 35 ° C for a further 6 hours. Further camphrasulfonic acid (0.06 g, 0.26 mmol) was then added and the solution was stirred at room temperature for 6 hours. The reaction mixture was filtered through Hyflo Super Cel® by washing with ethyl acetate. The filtrate was extracted by shaking first with saturated aqueous NaHCO ₃ solution and then with saturated NaCl solution and the organic phase dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo 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) gave, in addition to the required benzylidene acetal 5 (0.475 g), a mixture of less polar by-products (0.4 g). They were treated again under the reaction conditions described above and purified, yielding a further 0.08 g of benzylidene acetal 5. The total yield of 5 was: 0.555 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, 1 H), 4.77 (d, J = 12.1 Hz, 1 H), 4.71 (d, J = 1 1 .5 Hz, 1 H), 4.70 (m, 1 H). 4.66 (d, J = 12.0 Hz, 1 H), 4.62 (d, J = 1 1 .5 Hz, 1 H), 4.51 (d,> 11.1 Hz, 1 H),

4.36 - 4.31 (m, 2H), 4.22 (br d,> 2.8 Hz, 1 H), 4.06 (dd> 1.7, 12.3 Hz, 1 H), 3.97 (dd,> 2.9, 10.2 Hz, 1 H), 3.92 (d,> 12.0 Hz, 1 H), J.90 (dd,> 3.8, 10.2 Hz, 1 H).

3.76 - 3.68 (m, 3H), 3.53 (ddd,> 4.9, 9.0, 1 1 .0 Hz. 1 H), 3.43 (br s, 1 H), 3.37 (d.> 2.5 Hz, 1 H), 2.57 (d,> 8.0 Hz, 1 H), 2.51 (s, 1 H), 2.08 (m, 2H), 1 .73 (br d.> 9.5

Hz, 2H), 1 .42 - 1 .25 (m, 2H), 1.20 (br t, J = 1 1 .2 Hz, 2H), 1 .07 (d, J = 6.3 Hz, 3H); MS (FAB, THG) 800 (M + NH ₄ ), 783 (M + H).

A mixture of diol 5 (0.098 g, 0.125 mmol), di-n-butyltin oxide (0.062 g, 0.25 mmol) and methanol (5 ml) was refluxed under argon for 2 hours. The reaction mixture was concentrated in vacuo and pentane was added to the residue, and then concentrated again. Dry CsF (dried under high vacuum at 300 ° C, 0.068 g, 0.45 mmol) was added under an argon atmosphere and the mixture was further dried under high vacuum (30 minutes). After the addition of anhydrous 1,2-dimethoxyethane (1.5 ml), a solution of benzyl R-3-phenyl-2-trifluoromethanesulfonyloxypropionate was added [Degerbeck, F., Fransson, B., Grehn, L., Ragnarsson, U., J.Chem .Soc. Perkin Trans. 1: 11-14 (1993)] (0.24 g, 0.62 mmol) in dry 1,2-dimethoxyethane (1.5 ml). The mixture was first thoroughly stirred at room temperature for 4 hours and then at 40 ° C for a further 2 hours. After addition of 1 M aqueous solution of KH ₂ PO _{4, the} mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were extracted by shaking with dilute aqueous KF solution and then with saturated NaCl solution. The organic phase was dried (Na, SO ₄ ), 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) afforded ether 6 (0.045 g, 35%) and more semi-precursor 5 (0.043 g, 44%): 1 h NMR (250 MHz, CDCl ₃ ) δ 7.49 (br d, J = 6.9 Hz, 2H),

7.37 - 7.05 (m, 28H), 5.36 (s, 1 H), 5.04 (d, J = 12.0 Hz, 1 H), 4.98 (d, J = 1.2.0 Hz, 1 *

H), 4.72 - 4.63 (m, 3H), 4.62 - 4.48 (m, 4H), 4.31 (d, J = 1 1 .2 Hz, 1 H), 4.16 (m, 1 H).

4.1 1 (d, J = 7.9 Hz, 1 H), 4.07 (d, J = 3.4 Hz, 1 H), 3.88 - 3.79 (m, 2H), 3.76 (dd, J = 3.4,

10.3 Hz, 1 H), 3.66 (d, J = 1 l, 3 Hz, 1 H), 3.62 - 3.47 (m, 2H), 3.44 - 3.35 (m, 1 H),

3.36 (dd, J = 3.5, 9.6 Hz, 1 H), 3.16 - 3.06 (m, 2H), 3.12 (br s, 1 H), 3.01 (dd, J = 8.4, 13.9 Hz, 1 H), 2.03 - 1 .86 (m, 2H), 1 .93 (d, J = 2.0 Hz, 1 H), 1 .71 - 1 .55 (m, 2H).

1.36-1 .00 (m, 4H), 0.99 (d, J = 7.1 Hz, 3H).

? OONa

-►

e) coc

And OH

HO OH ^ 52-0 «

HO ⁰

B1.1

Dioxane (2.5 ml), water (1.2 ml) and glacial acetate (0.1 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.03 g) and protected compounds 6 (0.03 g, 0.029 mmol). Evacuate and rinse the flask several times with argon. This was then rinsed with hydrogen and the black reaction mixture was hydrogenated at slightly elevated hydrogen pressure at room temperature for 13 hours and then filtered through a cellulose filter (pore size 45 pm). The filtrate was concentrated in vacuo and the residue was taken up in water and concentrated again several times to remove excess acetic acid.

The residue solution in water is lowered through a Dowex50 + ion exchange column

(Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The clear filtrate was concentrated and purified by reverse phase chromatography (RP18 silica gel, column 1.4 cm in diameter, length 7.0 cm, gradient elution: 40% MeOH / H ₂ O over 45% MeOH / H ₂ O to 50% MeOH / H ₂ O) to give the target molecule Bl.l (0.015 g, 78%) as a colorless solid: * H NMR (500 MHz, D ₂ O) δ 7.38 - 7.30 (m, 4H), 7.29 - 7.23 ( m, 1 H), 4.92 (d, J = 4.0 Hz, 1 H), 4.55 (q, J = 6.7 Hz, 1 H), 4.35 (d, J = 7.8 Hz, 1 H), 4.1 1 (dd, J = 4.8, 8.5 Hz, 1 H), 3.86 (d, J = 3.6 Hz, 1 H), 3.84 (dd, J = 3.3, 10.5 Hz, 1 H), 3.74 (d, J = 3.5 Hz, 1 H) ), 3.71 (dd, J = 3.9, 10.5 Hz, 1 H), 3.69 - 3.62 (m, 3H), 3.50 (ddd, J = 1 .0, 4.5, 7.1 Hz, 1 H), 3.48 3.41 (m. 1 H), 3.43 (dd, J = 8.0, 9.7 Hz, 1 H), 3.24 (dd, J = 3.5, 9.7 Hz, 1 H), 3.09 (dd, J = 4.6, 14.0 Hz, 1 H), 2.92 (dd, J = 8.8, 14.0 Hz, 1H), 2.06 - 1.97 (m, 2H), 1 .63 (br s, 2H), 1 .24 - 1 .14 (m, 4H), 1. 13 (d, J = 7.0 Hz, 3H); ¹³ C NMR (100.6 MHz, APT, D ₂ O) d 139.5 (C _q ), 130.7 (2 CH), 129.9 (2 CH), 128.0 (CH), 100.8 (CH), 96.8 (CH), 84.0 (CH ), 83.3 (CH), 79.6 (CH), 78.4 (CH), 75.6 (CH), 73.3 (CH), 71.4 (CH), 70.9 (CH), 69.2 (CH), 67.7 (CH), 67.4 (CH) ), 62.8 (CH ₂ ), 40.6 (CH ₂ ), 30.9 (CH ₂ ), 30.4 (CH ₂ ), 24.4 (2 CH ₂ ), 16.6 (CH ₃ ); MS (FAB, THG) 595 (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 dry methanol (2.0 ml) was refluxed under argon. After 2.25 hours, the clear colorless solution was concentrated in vacuo and the residue was mixed with benzene and concentrated several times to remove excess MeOH. This was then dried under high vacuum for 30 minutes and the residue was stirred under an argon atmosphere with CsF (dried under high vacuum at 300 ° C, 0.03 g, 0.197 mmol) and dry 1,2dimethoxyethane (0.4 ml). The mixture was cooled to 0 ° C and a solution of benzyl R-3phenyl-2-trifluoromethanesulfonyloxypropionate was added [Degerbeck, F., Fransson, B., Grehn, L., Ragnarsson, U., J.Chem.Soc. Perkin Trans. 1: 11-14 (1993)] (0.085 g, 0.219 mmol) in dry 1,2-dimethoxyethane (0.4 ml) with a syringe. The reaction mixture was then warmed to room temperature and stirred for 1 hour, then stirred at 40 ° C for a further 2 hours. After addition of IM aqueous KH ₂ PO ₄ solution, the mixture was diluted with water and extracted three times with CH, Cl,. The combined organic phases were washed with aqueous KF solution and then dried (Na _? SO ₄ ), filtered and concentrated in vacuo. Purification of the residue was carried out by flash chromatography twice 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%): * H NMR ( 250 MHz, CDCI ₃ ) δ 7.40 - 7.00 (m, 25H), 5.15 (d,> 1 1 .6 Hz, 1 H), 5.09 (d,> 1 1 .6 Hz, 1 H), 4.89 (d. > 1 1 .8 Hz, 1 H), 4.86 (d,> 3.2 Hz, 1 H), 4.77 (d,> 1 1, 6 Hz, 1 H), 4.69 (d,> 12.0 Hz, 2H), 4.57 (d,> 12.0 Hz, 1 H), 4.56 (d,> 1 1 .8 Hz, 1 H), 4.35 (q,> 6.5 Hz, 1 H), 4.28 (dd,> 4.0, 9.5 Hz, 1 H ), 4.1 1 (d,> 7.6 Hz, 1 H), 4.02 - 3.88 (m, 2H), 3.79 (dd,> 7.3, 1 1.9 Hz, 1 H),

3.66 (br s, 1 H), 3.63 - 3.40 (m, 5H), 3.22 (m, 1 H), 3.10 (dd,> 4.0, 14.0 Hz, 1 H), 3.09 (br s, 1 H), 3.03 (dd,> 3.5, 9.3 Hz, 1 H), 2.90 (dd,> 9.5, 14.0 Hz, 1 H), 1.97 1 .84 (m, 2H), 1 .75 (d,> 1.9 Hz , 1 H), 1 .59 (br s, 2H), 1 .29 - 1 .07 (m, 4H), 1.01 (d,> 6.4 Hz, 3H).

1,4-dioxane / water (2.0 ml of 4: 1 mixture) was added to the protected carbohydrate 8 (0.03 g, 0.032 mmol) and Pd / C (0.03 g, Pd content 10%) and then glacial acetic acid (0.1 ml) was added. Evacuate the flask and rinse repeatedly with argon. Repeat this process with hydrogen. The mixture was hydrogenated at slightly elevated hydrogen pressure with vigorous stirring until a thin-layer chromatography test (n-BuOH silica gel plates: H ₂ O: acetone: glacial acetic acid: NH ₄ OH 70: 60: 50: 18: 1.5) revealed the absence of a precursor and intermediates (approximately 3.5 hours). The black suspension was filtered twice through a cellulose filter (pore size 45 μιη) and the filtrate was concentrated in vacuo. The residue is taken up in water and the solution is passed through an ion exchange column (Dowex 50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The filtrate was concentrated and purified by reverse phase chromatography (RP18 silica gel, column diameter 1.4 cm, length 7.0 cm, gradient elution: 40% MeOH / H ₂ O over 45%

MeOH / H ₉ O to 50% MeOH / H ₂ O) to give the target molecule Bl.l (0.015 g, 78%) as a colorless solid.

Example B2: Preparation of Compound No. BI.2

B1.1

The aromatic compound Bl.l (0.152 g, 0.256 mmol) and 5% Rh / Al ₂ O ₃ (0.2 g) was taken up in H ₂ O (5.5 ml), dioxane (3.5 ml) and acetic acid ( 1.0 ml). Replace the air with multiple evacuations first with argon and then with hydrogen. The black suspension was hydrogenated at slightly elevated hydrogen pressure with vigorous stirring for 2 days and then filtered through a cellulose filter (pore size 45 pm). The clear colorless solution was concentrated in vacuo and the residue was taken up in water and concentrated several times to remove excess acetic acid. The solution of the crude product in water was filtered through a Dowex 50 ion exchange column (Na-shape, length: 9 cm, diameter: 1.3 cm) and the column was washed with water. The filtrate was concentrated in vacuo and the residue (0.16 g) was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.55 ml / min , detection at 215 nm) followed by reverse phase chromatography (Merck silica gel RP18, elution: 55% MeOH / H ₉ O) to give the target molecule BI.2 (0.11 g, 73%) as a hairy white solid (after lyophilization). H NMR (500 MHz, D ₂ O) δ 4.93 (d, J = 3.8 Hz, 1 H), 4.58 (q, J = 6.4 Hz, 1 H), 4.43 (d, J = 7.5 Hz, 1 H). 3.91 (dd, J = 3.5, 9.0 Hz, 1 H), 3.88 - 3.83 (m, 2H), 3.75 (d, J = 3.3 Hz, 1 H), 3.73 - 3.64 (m, 4H), 3.57 3.53 (m , 1 H), 3.49 (dd, J = 7.3, 9.0 Hz, 1 H), 3.50 - 3.43 (m. 1 H), 3.33 (dd, J = 3.2, 9.2

Hz, 1 H), 2.10-1 .99 (m, 2H), 1 .73 (br d, J = 12.0 Hz, 1 H), 1 .69 - 1 .44 (m, 9H), 1 .29 - 1 .07 (m, 7H), 1 .14 (d, J = 6.5 Hz, 3H), 0.96 - 0.80 (m, 2H); MS (FAB, THG) 623 (M + Na), 601 (M + H).

Example B3: Preparation of compound no. BI.3

a)

Suspension consisting of benzylidene acetal 9 (0.5 g, 1.60 mmol) (EP 671,406), sodium cyanoborohydride (0.9 g, 14.3 mmol), activated 0.4 nm molecular sieves (1.0 g ) and dry tetrahydrofuran (30 ml) were cooled to 0 ° C under a nitrogen atmosphere. The pH of the mixture was adjusted to 1 by the careful addition of saturated HCl gas solution in dry diethyl ether. The suspension was stirred at 0 ° C and the pH was maintained at 1 by occasional addition of an ethereal HCl solution. After 10 hours, cold saturated aqueous NaHCO ₃ solution (30 ml) was added. The organic phase was decided and the aqueous phase was extracted twice with ethyl acetate (70 ml each). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 1.3 g of the crude product. Purification was carried out by flash chromatography on silica gel (CHCl ₃ / isopropanol 19: 1) to give the required 6-benzyl ether 10 (0.3 g, 60%) and slightly less polar by-product (0.045 g): * H NMR ( 250 MHz, CDCI ₃ ) δ 7.47 - 7.33 (m, 5H),

4.64 (s, 2H), 4.37 (d, J = 9.3 Hz, 1 H), 4.13 (br d, J = 3.0 Hz, 1 H), 3.89 - 3.69 (m, 4H).

3.64 (dd, J = 3.1, 9.0 Hz, 1H), 2.89 - 2.70 (m, 2H), 1.38 (t, J = 7.3 Hz, 3H).

b)>

BzO

Pyridine (0.045 ml, 5.56 mmol) and benzoyl chloride (0.49 ml, 4.22 mmol) were added to a solution of triol 10 (0.296 g, 0.941 mmol) in CH ₂ Cl ₂ (3.0 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 3.5 hours and then a 1 M aqueous solution of KH ₂ PO _{4 was added} and the mixture was extracted three times with CH ₂ Cl ₂ . The combined organic phases were washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 1.0 g of the crude product. Purification by flash chromatography on silica gel (hexane / ethyl acetate 4: 1) gave tribenzoate 11 as yellowish crystals (0.517 g, 88%). 1 H 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 = 7.5 Hz, 2H), 7.68 (t , J = 7.4 Hz, 1 H), 7.63 - 7.39 (m, 7H), 7.38 - 7.23 (m, 6H), 6.06 (d, J = 3.3 Hz, 1 H),

5.85 (t, J = 10.0 Hz, 1 H), 5.66 (dd, J = 3.5, 10.0 Hz, 1 H), 4.88 (d, J = 10.0 Hz, 1 H),

4.60 (d, J = 1 1 .9 Hz, 1 H), 4.49 (d, J = 1 1.9 Hz, 1 H), 4.23 (t, J = 6.3 Hz, 1 H), 3.84 3.64 (m, 2H) , 3.02 - 2.80 (m, 2H), 1.38 (t, J = 7.5 Hz, 3H).

OBz

Dry CH _? Cl ₇ (0.8 ml) was added 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 0.4 nm- of molecular sieves (2.5 g) under an argon atmosphere. A suspension of DMTST (0 * 39 g, 1.51 mmol) and activated 0.4 nm molecular sieves (0.8 g) in dry CH ₂ C1 ₂ (5.0 ml) was prepared in a second round bottom flask. The two suspensions were stirred at room temperature for 3.5 hours. Then, 3 portions of 1 ml DMTST suspension in one hour are added to the glycosyl donor / acceptor mixture. The yellowish reaction mixture was stirred at room temperature for a further 1.5 hours and then filtered through Hyflo Super Cel® by washing with CH ₂ Cl ₂ . The filtrates were extracted by shaking with aqueous NaHCO ₃ and then with water. The aqueous phases were re-extracted with CH ₂ Cl ₂ and the combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 0.67 g of crude product. Purification was carried out by flash chromatography twice on silica gel (first chromatography: toluene / ethyl acetate 14: 1; second chromatography: hexane / ethyl acetate 4: 1) to give product 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 was then neutralized by the addition of an acid ion exchanger (Amberlyst 15) and the suspension filtered through Hyflo Super Cel®. The filtrate was concentrated in vacuo and the remaining 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, 1 H),

4.95 (d, J = 1 1.2 Hz, 1 H), 4.83 (d, J = 1 1 .2 Hz, 1 H), 4.77 (d, J = l 1 .3 Hz, 1 H), 4.69 (d. J = 1 1 .3 Hz, 1 H), 4.68 (d, J = 1 1 .5 Hz, 1 H), 4.61 (d, J = 1 1 .5 Hz, 1 H), 4.53 (s, 2H) , 4.34 (d, J = 7.0 Hz, 1 H), 4.33 (m, 1 H), 4.04 (dd „J = 3.7, 10.1 Hz, 1 H), 4.02 (m, 1 H), 3.97 (dd, J = 2.9, 10.0 Hz, 1 H), 3.81 - 3.77 (m, 1 H), 3.77 (dd, J = 6.0, 9.4 Hz, 1 H),

3.70 (dd, J = 5.0, 9.6 Hz, 1 H), 3.65 (d, J = 2.0 Hz, 1 H), 3.63 - 3.54 (m, 4H), 2.95 (br s.

Η), 2.60 (br d,> 2.0 Hz, 2H), 2.07 (m, 1 H), 2.01 (m, 1 H), 1.69 (m, 2H), 1.45 - 1 .30 (m, 2H) , 1 .29 - 1 .18 (m, 2H), 1 .10 (d,> 6.5 Hz, 3H); MS (FAB, THG) 783 (ΜΗ), 693 (M-PhCH _2).

e)

OH II

HO OBn

Al ^ HioBn I (Mn

COOBn

A mixture of triol 13 (0.515 g, 0.656 mmol) and di-n-butyltin oxide (0.245 g, 0.984 mmol) in dry methanol (15 ml) was refluxed under nitrogen for 2 hours. The clear solution was concentrated in vacuo and taken up in benzene and concentrated three times to remove excess MeOH. The residue was dried in high vacuum and then dried CsF (dried in high vacuum at 300 ° C, 0.5 g,

3.29 mmol) under an argon atmosphere followed by dry 1,2-dimethoxyethane (4.0 ml) and a solution of benzyl R-3-azido-2-trifluoromethanesulfonyloxypropionate Al (1.16 g, 3.28 mmol) in dry 1 , 2-dimethoxyethane (8.0 ml). The reaction mixture was stirred at room temperature for 6 hours and then a 1 M aqueous solution of KH ₂ PO ₄ (60 ml) was added. The mixture was extracted three times with ethyl acetate and the combined organic phases were washed first with aqueous NaHCO ₃ solution and then with NaCl solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. 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 CH ₂ Cl ₇ / MeOH 19: 1) to give ether 14 (0.488 g. 75%) as a colorless foam and precursor 13 (0.075 g, 15%). 14: * H NMR (500 MHz, CDCl ₃ ) δ 7.40 - 7.22 (m, 25H), 5.25 (d,> 1 1.7 Hz, 1 H), 5.16 (d,> 1 1.8 Hz, 1 H). 4.96 (d,> 10.9 Hz, 1 H),

4.95 (d,> 3.1 Hz, 1 H), 4.82 (d,> 10.8 Hz, 1 H), 4.76 (d,> 1 1.1 Hz, 1 H), 4.72 4.66 (m, 2H), 4.62 (d,> 1 1 .0 Hz, 1 H), 4.57 (dd,> 3.2, 6.0 Hz, 1 H), 4.53 (d,> 1 1 .3 Hz, 1 H), 4.50 (d,> 1 1 .3 Hz. 1 H), 4.39 (q,> 6.2 Hz, 1 H), 4.31 (d,> 7.4 Hz, 1 H), 4.04 (br s, 1 H), 4.02 (dd,> 3.0, 9.5 Hz, 1 H) , 3.99 (dd,> 2.4, 9.5 Hz, 1 H), 3.82 (ddd,> 1 .9, 7.3, 8.9 Hz, 1 H), 3.77 (dd,> 6.0, 9.2 Hz, 1 H), 3.78 - 3.74 (m, 1H),

3.70 - 3.65 (m, 2H), 3.63 (dd,> 3.0, 12.3 Hz, 1 H), 3.58 (ddd,> 4.2, 8.0, 9.5 Hz, 1 H), 3.53 (dd,> 6.0, 12.5 Hz, 1 H), 3.55 - 3.51 (m, 1 H), 3.44 (dd,> 3.1, 9.0 Hz, 1 H), 2.90 (dd,> 1 .2, 1.8 Hz, 1 OH), 2.86 (d, 2.0 Hz, 1 OH), 2.09-1.196 (m, 2H), 1.68 (m, 2H), 1.44-1.18 (m, 4H), 1.11 (d,> 6.3 Hz, 3H); MS (FAB, THG) 1010 (M + Na), 984 (M + Na + 2H-N ₂ ), 962 (M + 3H-N ₂ ).

Pt / BaSO ₄ (0.35 g, Pt content: 5%) was added to a solution of azide 14 (0.11 g, 0.111 mmol) in ethyl acetate (12 ml). Evacuate the flask and rinse repeatedly with argon. It is then flushed with hydrogen and the mixture is hydrogenated under atmospheric pressure with vigorous stirring. Hydrogenation was stopped after 2.5 hours, the suspension was filtered through a cellulose filter (pore size 45 pm) and the filtrate was concentrated in vacuo. 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 required amine 16 (0.055 g, 51%) but also less precursor precursor 14 (0.042 g, 38 %). Amin 16 is unstable and is used immediately for subsequent experiments.

COOBn

HO OB «

B1.3 (i) Preparation of benzamide intermediate 17: Diisopropylethylamine (3.5 ml, 0.02 mmol) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.012 g, 0.0271 mmol) were added at 0 ° C to a solution of β -amino acid derivative 16 (0.013 g, 0.0135 mmol) and benzoic acid (0.0033 g, 0.027 mmol) in dry THF (0.5 ml). The reaction mixture was stirred for 45 minutes, then a saturated aqueous NaHCO ₃ solution was added. The mixture was extracted three times with CH ₂ C1 ₂ and the combined organic phases were 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 in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: 35% ethyl acetate / toluene to 40% ethyl acetate / toluene) to give benzamide 17 (0.0098 g, 68%).

(ii) Deprotection 17: dioxane (1.5 ml), water (0.7 ml) and glacial acetic acid (0.1 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.011 g) and benzyl ether 17 (0.0097 g, 0.0091 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black mixture was hydrogenated at slightly elevated pressure with vigorous stirring for 14 hours. The mixture was filtered through a cellulose filter (pore size 45 μτη) and the filtrate was concentrated in vacuo. The residue is taken up in water and concentrated several times to remove excess acetic acid. The solution of the crude product with + · little water is then passed through an ion exchange column (Dowex 50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The filtrate was concentrated in vacuo and the residue (0.007 g) was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.59 ml / min, detection at 230 nm) followed by reverse phase chromatography (Merck RP18 silica gel, gradient elution: 37% MeOH / H, O to 45% MeOH / H ₂ O) to give the target molecule B1.3 (3.3 mg, 58 %) as a hairy white solid (after lyophilization). 1 H NMR (500 MHz, D ₂ O) δ 7.74 (d,> 7.5 Hz, 2H), 7.57 (t,> 7.2 Hz, 1 H), 7.48 (t,> 7.6 Hz, 2H), 4.92 (d. > 4.0 Hz „1 H), 4.57 (q,> 6.7 Hz, l H),

4.44 (d,> 7.8 Hz, 1 H), 4.17 (dd,> 3.9, 8.1 Hz, 1 H), 3.94 (d,> 3.0 Hz, 1 H), 3.86 (d,> 3.5 Hz, 1 H). 3.84 (t,> 4.0 Hz, l H), 3.74 (d,> 3.5 Hz, 1 H), 3.75 - 3.65 (m,

4Η), 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 (br s , 2H), 1 .26-1.13 (m, 4H), 1 .1 1 (d, J = 6.5 Hz, 3H); MS (FAB, THG) 660 (M + Na), 638 (M + H).

Example B4: Preparation of compound no. B1.4

(a) Preparation of amide intermediate 19: Diisopropylcarbodiimide (20 ml, 0.129 mmol) was added at room temperature to a solution of amine 16 (0.032 g, 0.033 mmol) dihydrocyclic acid (0.015 g, 0.1 mmol), 1-hydroxybenzotriazole (0.025 g, 0.185 mmol) in dry THF (1.0 ml). The reaction mixture was stirred for 30 minutes and then concentrated in vacuo. The residue (0.09 g) was purified by flash chromatography twice on silica gel (eluent for the first chromatography: CH ₂ Cl / MeOH 39: 1; for the second chromatography: CH ₂ Cl ₂ / isopropanol 39: 1) to give the pure amide 19 (0.031 g, 86%).

(b) Deprotection 19: dioxane (2.0 ml), water (1.0 ml) and glacial acetic acid (0.5 ml) were added to a mixture of Pd (OH), / C (Pearlman catalyst, Pd content of 20%, 0.035 g). and benzyl ether 19 (0.031 g, 0.0283 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black mixture was hydrogenated at slightly elevated hydrogen pressure with vigorous stirring for 18 hours. The mixture was filtered through a cellulose filter (pore size 45 µm) and the filtrate was concentrated in vacuo. The residue was mixed 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 little water was then passed through an ion exchange +

column (Dowex 50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The filtrate was concentrated in vacuo and the residue (0.02 g) was purified by reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent 60% MeOH / H ₂ O) and then gel filtration on Bio- Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml / min, detection at 215 nm) to give the target molecule BI.4 (0.014 g, 74% ) as a hairless colorless solid (after lyophilization). 1 H NMR (500 MHz, D ₂ O) δ 7.32 (m, 2H), 7.24 (m, 3H), 4.93 (d, J = 4.1 Hz, 1 H), 4.57 (q, J = 6.7 Hz). 1 H), 4.40 (d, J = 8.0 Hz, 1 H), 3.9 3.84 (m, 3H), 3.75 - 3.66 (m, 5H), 3.63 (dd, J = 3.8, 14.0 Hz, 1 H), 3.53 (br dd,> 4.5, 7.5 Hz, 1 H), 3.49 (dd,> 7.9, 9.6 Hz, 1 H), 3.50 - 3.44 (m, 1 H), 3.23 (dd,> 7.8, 14.0 Hz, 1 H ), 3.15 (dd,> 3.2, 9.8 Hz, 1H), 2.88 (br t, J = 7.3 Hz, 2H),

2.59-2.45 (m, 2H), 2.09 (m, 1H), 2.03 (m, 1H), 1 .67 (br s, 2H), 1 .30 - 1 .15 (m, 4H), 1. 13 (d, > 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: Diisopropylcarbodiimide (16 ml, 0.103 mmol) was added with stirring at room temperature to a solution of amine 16 (0.026 g, 0.027 mmol), sodium 4-hydroxybutyrate (0.010 g, 0.079 mmol), 1 -hydroxybenzotriazole (0.020 g, 0.148 mmol) in a mixture of dry THF (1.0 ml) and DMF (0.2 ml). After 4 hours, further DMF (dimethylformamide) (0.2 ml) was added and the mixture was stirred for a further 13 hours. After the volatiles (including DMF) were distilled off under high vacuum, the residue (0.09

g) was purified by flash chromatography twice on silica gel (CH ₂ Cl ₂ / MeOH 29: 1) to give amide 21 (0.02 g, 71%).

(b) Deprotection 21: Dioxane (2.0 ml), water (1.0 ml) and glacial acetate (0.5 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0, 04 g) and benzyl ether 21 (0.036 g, 0.034 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black mixture was hydrogenated at slightly elevated hydrogen pressure with vigorous stirring for 18 hours. The mixture was filtered through a cellulose filter (pore size 45 µm) and the filtrate was concentrated in vacuo. The residue was mixed 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 little water was then passed through an ion exchange column (Dowex 50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The filtrate was concentrated in vacuo and the residue (0.02 g) was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, 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 RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH / H ₂ O 1: 4) to give the target molecule B1.5 (0.015 g, 70%) as a hairless colorless solid (after lyophilization). 1 H NMR (500 MHz, D ₂ O) δ 4.93 (d, J = 3.9 Hz, 1 H), 4.59 (q, J = 6.7 Hz, 1 H), 4.47 (d, J = 7.5 Hz, 1 H) , 4.04 (dd, J = 3.8,

7.3 Hz, 1 H), 3.92 (d, J = 3.2 Hz, 1 H), 3.86 (dd, J = 3.4, 10.2 Hz, 1 H), 3.75 (d, J = 3.5 Hz, 1 H), 3.74 - 3.65 (m, 4H), 3.62 (dd, J = 3.9, 14.0 Hz, 1H), 3.59 - 3.51 (m, 2H),

3.55 (t, J = 6.3 Hz, 2H), 3.50 - 3.44 (m, 1 H), 3.43 (dd, J = 3.5, 9.8 Hz, 1 H), 3.38 (dd, J = 7.5, 14.0 Hz, 1 H) ), 2.27 (t, J = 7.4 Hz, 2H), 2.1 1 - 2.00 (m, 2H), 1 .77 (p, J = 7.1 Hz, 2H), 1 .65 (br s, 2H), 1. 29-1.13 (m, 4H), 1 .15 (d, J = 6.8 Hz, 3H). MS (FAB) 643 (M + H-Na), 620 (M + H), 598 (M + 2H-Na).

Example B6: Preparation of compound no. B1.6

Dioxane (2.0 ml), water (1.0 ml) and glacial acetate (0.5 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.03 g) and azide 14 (0.03 g, 0.03 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black mixture was hydrogenated at slightly elevated hydrogen pressure with vigorous stirring for 16 hours. The mixture was filtered through a cellulose filter (pore size 45 µm) and the filtrate was concentrated in vacuo. The residue was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, water, flow rate 0.55 ml / min, detection at 215 nm) and then by reverse phase chromatography ( Merck RP18 silica gel, column diameter 1.2 cm, length 7 cm, eluent: 25% MeOH / H ₂ O) to give the target molecule BI.6 (0.011 g, 70%) as a hairless colorless solid (after lyophilization) . 1 H NMR (500 MHz, D ₂ O) δ 4.93 (d,> 3.9 Hz, 1 H), 4.58 (q,> 6.7 Hz, 1 H), 4.48 (d,> 7.9 Hz, 1 H), 4.22 ( dd,> 3.7, 8.4 Hz, 1 H), 3.99 (d,> 3.1 Hz, 1 H),

3.86 (dd,> 3.3, 9.9 Hz, 1 H), 3.75 (d,> 3.3 Hz, 1 H), 3.74 - 3.65 (m, 4H), 3.61 - 3.55 (m, 2H), 3.50 (dd,> 3.0) , 9.3 Hz, 1 H), 3.48 (m, 1 H), 3.35 (dd,> 3.7, 12.9 Hz, 1 H),

3.16 (dd,> 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,> 6.5 Hz, 3H); MS (FAB, THG) 510 (M-H).

Example B7: Preparation of compound no. B1.7

B1.6

B1.7

Amin BI.6 (0.09 g, 0.176 mmol) was dissolved in dry MeOH (1.5 ml) and CH ₂ C1 ₂ (1.8

m) and activated with 0.3 nm sieve molecules (approximately 0.2 g), cinnamaldehyde (24 µl, 0.19 mmol) and acetic acid (9 μΐ) were added. The yellow suspension was stirred for 2 minutes and then NaBH ₃ (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 was washed with MeOH / CH ₂ Cl ₂ 1: 1 and the filtrate was concentrated in vacuo. The glassy residue was taken up in water (5 ml) and the solution acidified (pH about 1-2) with 1 M hydrochloric acid (0.7 ml). The cloudy solution was again filtered through a cellulose filter (pore size 45 pm) and the filtrate adjusted to pH 7 with a 1 M sodium hydroxide solution (approximately 1 ml) and then concentrated. The residue was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.6 ml / min, detection at 215 nm) and then reverse phase chromatography (Merck RP18 silica gel, gradient elution: 50% MeOH / H, O) to 70% MeOH / Η, Ο to give the target molecule BI.7 (0.03 g, 27%) as a hairy white solid (after lyophilization). 1 H NMR (500 MHz, D ₂ O) δ 7.48 (d,> 8.0 Hz, 2H), 7.41 - 7.31 (m, 3H), 6.83 (d,> 15.4 Hz, 1 H),

6.26 (dt,> 15.4, 7.0 Hz, 1 H), 4.92 (d,> 3.8 Hz, 1 H), 4.56 (q,> 6.3 Hz, 1 H), 4.43 (d,> 7.6 Hz, 1 H). 4.31 (dd,> 3.5, 8.2 Hz, 1 H), 3.98 (d,> 3.0 Hz, 1 H), 3.88 - 3.81 (m, 2H), 3.84 (d,> 6.0 Hz, 1 H), 3.76 - 3.63 (m, 5H), 3.60 - 3.51 (m, 2H), 3.49 (dd,> 3.0, 10.4 Hz, 1H), 3.49-3.41 (m, 1H), 3.41 (dd,> 3.5, 13.2 Hz, 1 H), 3.26 (dd,> 8.5, 13.2 Hz, 1 H), 2.02 (m, 2H), 1 .64 (br s, 2H), 1 .27 - 1.12 (m, 4H), 1 .12 (d ,> 6.3 Hz, 3H); MS (FAB, THG) 650 (M + Na), 628 (M + H).

Example B8: Preparation of compound no. BI.8

A solution of the amino acid B1.7 (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 was added with vigorous stirring). μϊ). After 40 minutes, a further 8.0 μϊ of benzoyl chloride solution was added, after 130 minutes a further 3.0 μϊ and after a total of 3.5 hours a further 1.0 pl. 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 was concentrated in vacuo and the residue was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.49 ml / min, detection at 215 nm ) and then by reverse phase chromatography (Merck RP18 silica gel, gradient elution: 60% MeOH / H ₂ O to 70% MeOH / H ₂ O, yielding the target molecule B1.8 (7.9 mg, 66%) as a hairy white solid (after lyophilization) NMR (500 MHz, D ₂ O): 1.4: 1 mixture of rotamers, characteristic signals: δ 7.52 - 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, 1 H, Fuc-1 H), 1 .16 (d, J = 7.0 Hz, 1.26H, Fuc-6H). 1.11 (d. J = 6.8 Hz, 1.74H, Fuc-6H); MS (FAB, THG) 776 (M + Na), 754 (M + H).

Example B9: Preparation of Compounds no. BI.9 and no. WOULD. 10

CH ₂ Cl _{2 -} solution of freshly distilled benzaldehyde (0.083 g in 1.0 ml CH ₂ Cl ₂ , 0.1 ml,

0.078 mmol), activated by 0.3 nm sieve molecules (0.1 g) and glacial acetate (5 pl, 0.087 mmol) was added to a solution of amino acid BI.6 (0.04 g, 0.078 mmol) in MeOH / CH ₂ Cl ₂ (1: 1, 1.0 ml). The suspension was stirred at room temperature and NaBH ₃ (CN) (0.008 g, 0.129 mmol) was added after 2 minutes. After 2.5 hours, a further 15 μΐ of benzaldehyde solution was added and the mixture was stirred for an additional hour. The reaction mixture was diluted with water, acidified with dilute acetic acid and filtered through a cellulose filter (pore size 45 µm) and the filtrate adjusted to pH 8-9 with 1 M aqueous NaHCO ₃ solution and then concentrated. The residue was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm) and then reversed phase chromatography (Merck RP18 silica gel, gradient elution: 35% MeOH / H ₂ O to 60% MeOH / H ₂ O) eluting first with monobenzylamine B1.9 (0.020 g, 41%) followed by dibenzylamine B1.10 (0.005 g, 9 %). Monobenzylamine BI.9: * H NMR (500 MHz, D ₂ O) δ 7.45 (s, 5H), 4.93 (d,> 4.0 Hz, 1 H), 4.57 (q,> 6.7 Hz, 1 H), 4.45 ( d,> 7.6 Hz, 1 H), 4.33 (dd,> 3.8, 8.8 Hz, 1 H), 4.28 (d,> 13.3 Hz, 1 H), 4.24 (d,> 13.3 Hz, 1 H), 3.99 ( d,> 3.1 Hz, 1 H), 3.85 (dd,> 3.5, 10.2 Hz, 1 H), 3.74 - 3.65 (m, 5H), 3.59 - 3.54 (m. 2H), 3.49 (dd,> 3.2, 9.7 Hz, 1 H), 3.48 - 3.44 (m, 1 H), 3.42 (dd,> 3.7, 13.2 Hz, 1 H), 3.26 (dd,> 8.9, 13.2 t

Hz, 1H), 2.04 (m, 2H), 1.65 (br s, 2H), 1.28 1.14 (m, 4H), 1.12 (d,> 6.7 Hz, 3H);

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

Dibenzylamine BI. 10: 1 h NMR (500 MHz, D ₂ O): 6 H a for N signals are very wide at room temperature (d 4.10 - 3.60, 4H and 3.12 - 2.67, 2H) δ 7.38 (s, 10H), 4.93 ( d, J = 4.0 Hz, 1 H), 4.60 (q, J = 6.6 Hz, 1 H), 4.43 (d, J = 8.0 Hz, 1 H), 4.23 (dd, J = 3.6, 8.5 Hz, 1 H) ) 3.88 - 3.83 (m, 2H), 3.75 - 3.63 (m, 5H), 3.56 (dd, J = 8.0, 9.3 Hz, 1H), 3.53 - 3.44 (m, 2H), 3.32 (dd, J = 3.0) , 9.5 Hz, 1 H), 2.13-1 .98 (m, 2H), 1 .66 (br s, 2H), 1 .31 1.10 (m, 4H), 1 .14 (d, J = 6.6 Hz. 3H); MS (FAB, THG) 714 (M + Na), 692 (M + H).

Example B10: Preparation of Compounds no. B1.11 and no. B1.12

M CH ₂ Cl ₂ -isobutyraldehyde solution (0.156 ml), activated with 0.3 nm sieve molecules (0.2 g) and glacial acetic acid (10 μΐ, 0.17 mmol) were added to amino acid solution B1.6 (0.08 g, 0.156 mmol) in MeOH / CH ₂ Cl ₂ (1: 1, 2.0 ml). The suspension was stirred at room temperature and NaBH ₃ (CN) (0.016 g, 0.258 mmol) was added after 1 minute. After 60 minutes, the reaction mixture was diluted with water and filtered through a cellulose filter (pore size 45 µm) and the filtrate adjusted to pH 8-9 with a 1 M aqueous NaHCO ₃ solution and then concentrated.

The residue was purified by gel filtration on Bio-Gel P2 (particle size 65 μιη, column diameter 2.5 cm, length 35 cm, eluent. Water, flow rate 0.5 ml / min, detection at 215 nm) and then reverse phase chromatography (Merck RP18 silica gel, gradient elution: 35% MeOH / H, O to 50% MeOH / Η, Ο) eluting first with monoisobutylamine BI. 11 (0.041 g, 46%) followed by diisobutylamine B1.12 (0.01 g, 10%).

Monoisobutylamine BI. 11: * H NMR (500 MHz, D ₂ O) δ 4.92 (d, J = 4.0 Hz, 1H), 4.59 (q, J = 6.7 Hz, 1 H), 4.47 (d, J = 7.6 Hz, 1 H) ), 4.29 (dd, J = 4.0, 9.0 Hz, 1 H), 3.98 (d, J = 3.5 Hz, 1 H), 3.85 (dd, J = 3.3, 10.0 Hz, 1 H), 3.76 - 3.65 (m , 5H), 3.56 (dd, J = 7.5,

9.3 Hz, 1 H), 3.59 - 3.54 (m, 1 H), 3.50 (dd, J = 3.0, 9.7 Hz, 1 H), 3.50 - 3.43 (m, 1 H),

3.34 (dd, J = 3.9, 13.0 Hz, 1 H), 3.20 (dd, J = 9.2, 13.2 Hz, 1 H), 2.90 (dd, J = 7.6, 12.0 Hz, 1 H), 2.86 (dd, J = 7.3, 12.0 Hz, 1 H), 2.11 1 .99 (m, 2H), 1 .96 (none, J = 6.9 Hz, 1 H), 1 .65 (m, 2H), 1.28 - 1 .1 1 (m, 4H), 1 .14 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 6H); MS (FAB, THG) 590 (M + Na), 568 (M + H).

Diisobutylamine BI. 12: * H NMR (500 MHz, D ₂ O): δ 4.92 (d, J = 4.1 Hz, 1 H), 4.59 (q,

J = 6.7 Hz, 1 H), 4.46 (d, J = 7.1 Hz, 1 H), 4.36 (t, J = 6.6 Hz, 1 H), 4.02 (br s, 1 H), 3.85 (dd, J = 3.3, 10.3 Hz, 1 H), 3.76 - 3.66 (m, (m, 5H), 3.57 (dd, J = 4.7, 7.5 Hz, 1 H), 3.55 - 3.50 (m, 2H), 3.49 - 3.39 (m , 3H), 3.07 (br s, 4H), 2.12 (ni, J = 6.8 Hz, 2H), 2.12-1 .99 (m, 2H), 1 .65 (br s, 2H), 1 .28 1.11 ( m, 4H), 1.13 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.8 Hz, 12H); MS (FAB, THG) 646 (M + Na), 624 (M + H) .

Example Bil: Preparation of compounds no. B1.13

M solution of benzoyl chloride in toluene (41 μΐ) was added at room temperature to a solution of amino acid Bl.l 1 (0.020 g, 0.0339 mmol) in 1 M aqueous NaHCO ₃ (100 μΐ).

The mixture was stirred thoroughly and further benzoyl chloride (41 μΐ 1 M solution) was added after 1 hour. After completion of the reaction, the volatile components were removed under high vacuum and the residue was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck silica gel RP18, elution: 45% MeOH / © O) and then lyophilized to give benzamide BI. 13 as a fluffy powder, (0.014 g, 59%). H NMR (500 MHz, D ₂ O): 1: 1 rotomeme mixture: δ 7.5 - 7.37 (m, 5H), 4.93 (d, J = 4.0 Hz, 0.5H), 4.92 (d, J = 4.0 Hz, 0.5H), 4.60 (q, J = 6.4 Hz, 1 H),

4.48 (d, J = 8.0 Hz, 0.5H), 4.37 (d, J = 8.0 Hz, 0.5H), 4.32 (dd, J = 4.5, 8.0 Hz, 0.5H), 4.02 (dd, J = 4.3, 8.7 Hz, 0.5H), 3.94 (d, J = 3.2 Hz, 0.5H), 3.89 - 3.83 (m, 1, 5H), 3.82 3.61 (m, 7H), 3.60 - 3.52 (m, 1, 5H), 3.51 - 3.43 (m, 2.5H), 3.25 (dd, J = 7.9, 14.2 Hz, 0.5H), 3.20 (dd, J = 7.9, 14.2 Hz, 0.5H), 3.17 - 3.10 (m, 1 H), 2.16 - 1.97 (m, 2.5H), 1.86 (ni, J = 6.9 Hz, 0.5H), 1 .65 (br s, 2H), 1 .29 - 1 .14 (m, 4H), 1 .17 (d, J = 6.4 Hz, 1, 5H), 1.1 1 (d, J = 6.6 Hz, 1, 5H), 0.95 (d, J = 6.5 Hz, 1.5H), 0.92 (d, J = 6.6 Hz. 1.5H), 0.65 (d, J = 6.4 Hz, 1.5H), 0.65 (d, J = 6.5 Hz, 1.5H); MS (FAB, THG) 716 (M + Na), 694 (M + H).

Example B12: Preparation of Compounds no. WOULD. 14

B1.14 A molar solution of p-nitrobenzenesulfonyl chloride in toluene (43 pl) was added with vigorous stirring to a solution of amino acid BI.6 (0.02 g, 0.039 mmol) in 1 molar aqueous NaHCO ₃ solution (0.2 ml). The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was taken up in water (0.3 ml) and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm). The crude product (0.025 g) was further purified by reverse phase chromatography (Merck RP18 silica gel, first chromatography: elution with 50% MeOH / H ₂ O; second chromatography, elution with 40% MeOH / H ₂ O) and then lyophilized to give the target compound as a fluffy powder (0.0105 g, 39%). ^! H NMR (400 MHz, D ₂ O) δ 8.39 (m, 2H), 8.07 (m, 2H), 4.93 (d,> 4.0 Hz, 1 H), 4.56 (q,> 6.6 Hz, 1 H), 4.43 (d,> 7.9 Hz, 1 H), 3.96 (dd,> 3.5, 7.1 Hz, 1 H), 3.88 - 3.83 (m, 2H), 3.76 - 3.64 (m, 5H), 3.54 - 3.44 (m, 3H ), 3.38 (dd,> 3.5, 13.7 Hz, 1 H), 3.33 (dd,> 3.2, 9.6 Hz, 1 H), 3.19 (dd,> 7.3,

13.7 Hz, 1 H), 2.05 (br t,> 13.4 Hz, 2H), 1 .66 (br s, 2H), 1 .30 - 1 .12 (m, 4H), 1.14 (d,> 6.6 Hz. 3H); MS (FAB, THG) 719 (M + Na), 697 (M + H).

Example B13: Preparation of compound no. WOULD. 15

B1.15 molar solution of p-toluenesulfonyl chloride in toluene (22 pl) was added at 0 ° C with vigorous stirring to a solution of amino acid BI.6 (0.01 g, 0.02 mmol) in 1 molar aqueous NaHCO ₃ solution (0 , 1 ml). The reaction mixture was stirred at 0 ° C for 90 minutes, then further p-toluenesulfonyl chloride (10 μϊ 1 M solution) was added. The reaction mixture was then warmed to room temperature, stirred for 18 hours and then concentrated in vacuo. The residue was taken up in water and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm) and then by reverse phase chromatography (Merck silica gel RP18, elution with 45% MeOH / H _? O) and then lyophilized to give the target compound as a hairy powder (0.004 g, 30%). 1 H NMR (400 MHz, D ₂ O) δ 7.69 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 4.88 (d, J = 3.9 Hz, 1 H), 4.52 (q, J = 6.6 Hz, 1 H), 4.35 (d, J = 7.9 Hz, 1 H), 3.85 - 3.78 (m, 2H), 3.74 (d, J = 2.8 Hz, 1 H), 3.71 - 3.56 (m, 5H), 3.50 3.39 (m, 3H), 3.29 (dd, J = 3.4, 13.8 Hz, 1 H), 3.10 (dd, J = 3.1, 9.6 Hz, 1 H), 3.03 (dd, J = 8.0, 13.8 Hz, 1 H), 2.34 (s, 3H), 2.08 - 1 .93 (m, 2H), 1 .61 (br s, 2H), 1 .26 - 1 .07 (m, 4H) ), 1 .09 (d, J = 6.6 Hz, 3H).

Example BI4: Preparation of compound no. WOULD. 16

Pentafluorophenyl trifluoroacetate (4.5 ml, 0.026 mmol) was added at room temperature by stirring 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). After 15 minutes, further pentafluorophenyl trifluoroacetate (2.5 ml, 0.015 mmol) was added. 30 minutes later, further triethylamine (2.8 mL, 0.02 mmol) and pentafluorophenyl trifluoroacetate (4.5 mL, 0.026 mmol) were added. The same amount of the latter reagent was added again 20 minutes later. The mixture was stirred for a further 45 minutes and then a saturated aqueous solution of 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 ₇ SO ₄ ), filtered and concentrated in vacuo. The crude product (0.04 g) was purified by flash chromatography on silica gel with eluent: ethyl acetate / toluene 1: 3 to give trifluoroacetamide 24 (0.022 g, 83%)

Ί3

Deprotection 24: dioxane (1.4 ml), water (0.7 ml) and glacial acetic acid (0.35 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.02 g) and benzyl ether .24 (0.021 g, 0.021 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black mixture was hydrogenated at slightly elevated pressure for 3.5 hours. The reaction mixture was filtered through a cellulose filter (pore size 45 µm) and the filtrate was concentrated in vacuo. Dissolve the residue solution in a little water through an ionic _t + exchange column (Dowex 50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The filtrate was concentrated in vacuo and the residue was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml / min, detection at 215 nm) and then by reverse phase chromatography (Merck RP18 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 title molecule BI. 16 (0.0085 g, 68%) as a hairless colorless solid (after lyophilization). 1 h NMR (500 MHz, D ₂ O) δ 4.93 (d, J = 3.9 Hz, 1 H), 4.59 (q, J = 6.5 Hz, 1 H), 4.45 (d, J = 8.2 Hz, 1 H) , 4.08 (dd, J = 3.4, 8.2 Hz, 1 H), 3.91 (d, J = 3.1 Hz, 1 H),

3.86 (dd, J = 3.1, 10.0 Hz, 1 H), 3.75 (d, J = 3.1 Hz, 1 H), 3.72 (dd, J = 3.9, 10.0 Hz, 1 H), 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, 1H), 2.10 - 2.00 (m, 2H), 1.65 (m. 2H), 1.28-1.15 (m, 4H), 1.14 (d, J = 6.5 Hz, 3H); MS (FAB, THG) 652 (M + Na), 630 (M + H), 608 (M + 2H-Na).

Example B15: Preparation of Compounds no. B1.17

B1.17 (a) Preparation of amide 26: Diisopropylcarbodiimide (17 ml, 0.11 mmol) was added with stirring at room temperature to a mixture of amine 16 (0.027 g, 0.028 mmol), cyclohexane carboxylic acid (0.011 g, 0.086 mmol), 1 -hydroxybenzotriazole (0.021 g, 0.155 mmol) and dry THF (0.9 ml). After 20 minutes, dry DMF (0.4 ml) was added and the mixture was stirred for an additional hour. The reaction mixture was concentrated in vacuo and the remaining DMF removed in 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) Deprotection 26: Dioxane (2.0 ml), water (1.0 ml) and glacial acetate (0.5 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0, 03 g) and benzyl ether 26 (0.024 g, 0.022 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the Black mixture was hydrogenated at slightly elevated pressure for 18 hours. The reaction mixture was filtered through a cellulose filter (pore size 45 µm) and the filtrate was concentrated in vacuo. Dissolve the residue solution in a little water through ionic +

exchange column (Dowex 50, Na shape, column diameter 0.9 cm, length 3.5 cm), with rinsing with deionized water. The filtrate was concentrated in vacuo and the residue was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, water, flow rate 0.5 ml / min, detection at 215 nm) and then by reverse phase chromatography (Merck RP18 silica gel, column diameter 1.2 cm, length 6 cm, eluent: MeOH / H _? O 3: 2) to give the target BI molecule. 17 (0.008 g, 56%) as a hairless colorless solid (after lyophilization). * H NMR (500 MHz, D ₂ O) δ 4.93 (d,> 4.0 Hz, 1 H), 4.60 (q, J = 6.7 Hz, 1 H), 4.47 (d,> 8.0 Hz, 1 H), 4.04 (dd,> 3.8, 7.5 Hz, 1 H), 3.92 (d,> 2.8 Hz, 1 H), 3.86 (dd,> 3.2, 10.3 Hz, 1 H), 3.75 (d,> 3.3 Hz, 1 H) , 3.74 3.64 (m, 4H), 3.61 (dd,> 3.8, 13.8 Hz, 1 H), 3.59 - 3.52 (m, 2H), 3.50 - 3.44 (m, 1 H), 3.42 (dd,> 3.3, 9.8 Hz, 1 H), 3.35 (dd,> 7.7, 14.0 Hz, 1 H), 2.19 (tt,> 3.3, 1 1 .5 Hz, 1 H), 2.1 1 2.00 (m, 2H), 1.78 - 1 .57 (m, 7H), 1 .34 1.08 (m. 9H), 1.15 (d,> 6.5 Hz, 3H); MS (FAB, THG) 644 (M + H), 622 (M + 2H Na).

Example B16: Preparation of Compound B1.18

A solution of triol 13 (0.129, 0.17 mmol) in dry MeOH (4.0 ml) and di-n-butyl tin oxide (0.064 g, 0.258 mmol) was refluxed under argon for 2 hours. The clear solution was concentrated in vacuo and the residue was mixed with pentane (2 ml), re-concentrated and then dried under high vacuum for 30 minutes to remove residual MeOH. The residue was mixed under an argon atmosphere with dry CsF (0.131 g, 0.86 mmol; weighed under argon) and dry 1,2-dimethoxyethane (0.5 ml) followed by a solution of benzyl (R) -4-phenyl-2-trifluoromethanesulfonyloxybutyrate (A2) (0.3 g, 0.861 mmol) in dry 1,2-dimethoxyethane (1.0 ml). The reaction mixture was stirred at room temperature for 75 minutes and 1 M aqueous KH, PO _{4 was added} and the mixture was diluted with water and extracted with ethyl acetate (phase separation was accelerated by the addition of a little aqueous KF solution). The organic extracts were combined, dried with Na ₂ SO ₄ , filtered and concentrated in vacuo 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 = 12.1 Hz, 1 H), 5.03 (d, J = 12.1 Hz, 1 H), 4.88 (d, J = 1 1.4 Hz, 1 H),

4.87 (d, J = 2.0 Hz, 1 H), 4.78 - 4.50 (m, 5H), 4.46 (d, J = 12.5 Hz, 1 H), 4.40 (d, J = 12.5 Hz, 1 H). 4.33 (q, J = 6.5 Hz, 1 H), 4.24 (d, J = 7.8 Hz, 1 H), 4.09 (dd, J = 4.0, 8.5 Hz, 1 H), 3.93 (br s, 2H), 3.80 - 3.38 (m, 7H), 3.26 - 3.17 (m, 2H), 2.86 - 2.62 (m, 2H), 2.59 (d,> 2.0 Hz, 1 OH), 2.29 (br s, 1 OH), 2.11 - 1 .85 (m, 4H), 1.67-1.52 (m, 2H), 1 .40 - 1 .06 (m, 4H), 1 .03 (d.> 6.5 Hz, 3H).

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. Replace the air in the reaction vessel first with argon by evacuation and rinsing repeatedly, followed by hydrogen. The black reaction mixture was hydrogenated at slightly elevated hydrogen pressure for 90 minutes and then filtered through a cellulose filter (pore size 45 µm) by washing with water. The filtrate was concentrated and the residue was taken up in toluene and concentrated several times to remove the remaining acetic acid. The crude product (0.095 g) was dissolved in a little 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 silica gel RP18, elution 40% MeOH / H ₂ O) and then gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm. length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm) and then lyophilized to give the target compound BI. 18 as a fluffy powder (0.045 g, 55%). 1 H NMR (500 MHz, D ₂ O) δ 7.35 - 7.27 (m, 4H),

7.22 (tt,> 1 .5, 7.0 Hz, 1 H), 4.93 (d,> 4.0 Hz, 1 H), 4.60 (q,> 6.7 Hz, 1 H), 4.47 (d,> 7.8 Hz, 1 H ), 3.89 - 3.82 (m, 3H), 3.76 (d,> 3.5 Hz, 1 H), 3.74 - 3.63 (m, 4H), 3.59 - 3.52 (m, 2H), 3.51 - 3.45 (m, 1 H) , 3.37 (dd,> 3.5, 9.8 Hz, 1 H), 2.80 - 2.68 (m, 2H), 2.12 - 1.99 (m, 3H), 1 .98 - 1 .89 (m, 1 H), 1.65 (br s, 2H), 1 .30 - 1 .13 (m, 4H), 1 .15 (d,> 6.6 Hz, 3H); MS (FAB, THG) 609 (M + Na), 587 (M + H).

Example BI7: Preparation of Compound no. B1.19

Aromatic compound BI. 18 (0.02 g, 0.033 mmol) was dissolved in water (1.8 ml), dioxane (1.2 ml), glacial acetic acid (0.3 ml) and 5% Rh / Al ₂ O ₃ (0.04 g) was added. ). The air in the reaction vessel is replaced with hydrogen by evacuation and repeated rinsing, and the mixture is hydrogenated at slightly elevated hydrogen pressure with vigorous stirring for 1.5 days. It was then filtered through a cellulose filter (pore size 45 μιη) and washed with water, the filtrate was concentrated and the residue was taken up in toluene and concentrated several times to remove the remaining acetic acid. The crude product was purified by gel filtration on BioGel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm) and then hydrogenated again at the above conditions for 2 days. The reaction mixture was then filtered through a cellulose filter (pore size 45 µm) and washed with water and the filtrate was concentrated, then the residue was taken up in toluene and concentrated several times. The crude product was purified by gel filtration on BioGel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm) and then by reverse phase chromatography (Merck RP18 silica gel, elution with 50% MeOH / H ₂ O) and then lyophilized to give the target compound BI. 19 as a fluffy powder (0.01 g, 50%). 1 H NMR (250 MHz, D ₂ O) δ 4.83 (d,> 4.0 Hz, 1 H), 4.48 (q,> 6.7 Hz, 1 H), 4.35 (d,> 7.8 Hz, 1 H), 3.81 - 3.69 (m, 3H), 3.67 - 3.53 (m, 5H), 3.49 r 3.31 (m, 3H), 3.25 (dd,> 3.1,

9.7 Hz, 1 H), 2.03 - 1.87 (m, 2H), 1 .72 - 1 .38 (m, 9H), 1 .24 - 0.97 (m, 10H), 1 .04 (d,> 6.6 Hz, 3H), 0.75 (br s, 2H); MS (FAB, THG) 615 (M + Na), 593 (M + H).

Example B18: Preparation of Compound BI.38

A solution of p-nitrobenzenesulfonyl chloride in toluene (1 M, 150 μΐ) was added to the BI amino acid solution. 11 (0.035 g, 0.0617 mmol) in 1 molar aqueous NaHCO ₃ solution (315 μΐ). The mixture was stirred thoroughly at room temperature and a further solution of p-nitrobenzenesulfonyl chloride (120 μΐ) was added after 17 hours. The reaction mixture was stirred for a further 24 hours, then diluted with water and washed twice with ethyl acetate. Concentrate the aqueous phase to a volume of 0.5 ml in vacuo and purify this solution by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 100 cm, eluent: water, flow rate 0.5 ml / min, detection at 215 nm). The crude product (0.06 g) was further purified three times by reverse phase chromatography (Merck RP18 silica gel, elution 40% MeOH / H ₂ O) and then lyophilized to give sulfonamide

B1.38 (0.013 g, 27%) as a colorless flake 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, 1 H), 4.53 (q, J = 6.5 Hz, 1 H), 4.38 (d, J = 7.9 Hz, 1 H) 4.06 (dd, J = 3.9, 8.2 Hz, 1 H) 3.84-3.79 (m, 2H), 3.70 (d, J = 3.0 Hz, 1 H), 3.67 (dd, J = 3.9, 10.4 Hz, 1 H), 3.69 - 3.58 (m, 3H), 3.57 - 3.38 (m, 5H) 3.25 (dd, J = 3.2, 9.5 Hz, 1 H) 3.10 (dd, J = 7.7, 14.1 Hz, 1 H) 3.05 ( dd, J = 7.7, 14.1 Hz, 1 H), 2.07-1.94 (m, 2H) 1 .89 (hep, J = 6.7 Hz, 1 H), 1.61 (br s, 2H), 1.25 - 1.07 (m, 4H), 1.10 (d, J = 6.6 Hz, 3H) 0.70 (d, J = 6.6 Hz, 3H), 0.63 (d, J = 6.6Hz, 3H).

The compounds below are prepared analogously to the above examples:

Preparation in in accordance with case no. Compound no. Ra R4 FAB-MS THG B15 B1.20 On CH ₂ NHC (O) C 1 H 23 7WKRJ- 738 (M + Na) B15 B1.21 On CH ₂ NHC (O) CH (C _e H _s ) ₂ 728 (M + H) 750 (M + Na) B12 ⁽¹⁾ B1.22 On CH ₂ NHC (O) C ₂ H ₄ CO ₂ Na 656 (M + H) 678 <M + Na) B15 B1.23 On CH ₂ NHC (O) C _e [(1,3,4,5) OH] ₄ H ₇ quinamide 708 (M + H) 730 <M + Na) B15 B1.24 On CH ₂ NHC (O) CeH ₄ -p-SO ₃ Na 740 (M + H) 762 (M + Na) B12 B1.25 On CH ₂ NHC (O) C _e H ₄ CI 672 (M + H) 694 (M + Na) B12 B1.26 On CH ₂ NHC (O) C _e H ₄ NO ₂ 683 (M + H) 705 (M + Na) B12 B1.27 On CH ₂ NHC (O) C _e H ₄ OCH ₃ 66fl (M + H) 690 (M + Ni) B12 B1.28 On CH ₂ NHC (O) C _e H ₄ (3,4) CI ₂ 706 (M * H) 728 <M + N 1) B12 B1.29 On CH ₂ NHC (O) C _e H ₄ CH ₃ 652 (M + H) 674 (M + Na) B12 ^<2) B1.30 On CH ₂ NHC (O) C _e H ₄ C _e H ₅ 714 (M + H) 736 <M + Na)

Continued Table 1:

Preparation in compliance with case no. Compound no. r ₃ R, FAB-MS THG B12 ⁽³⁾ B1.31 On CH _Z NHC (O) C «H ₄ CN S63 (M + H) 636 <ΜΗ · Νβ) B12 B1.32 On CH ₂ NHC (O) C, oH ₇ eaa (MtH) 710 (M ^ Na) B12 ^W 61.33 On CH ₂ NHC (O) CeH ₄ COONa 7O4 (M + H) 726 <M »Na) B12 ^(S) B1.34 On CH ₂ NHC (O) (CHOH) ₂ COONa 688 (M »H) 710 (kUNa) Bill B1.35 On CH ₂ N [C (O) C _e H ₅ ] CH ₂ C _e H _s 72S (M * K) 7S0 (M + Na) Bi 1 B1.36 On CH ₂ NiC (O) C ₆ H _s ] (CH ₂ ) ₃ C _e H _s 756 (M «H) 77B (M.N4) B15 ^W B1.37 On CH ₂ NHSO ₂ CF ₃ βββ (Μ + Η) βββ (Μ + ΝΗ)

using a solution of succinic acid anhydride in DMF as a reagent (2) using a solution of pentafluorophenyl biphenylcarboxylate in dioxane as a reagent (3) using a solution of pentafluorophenyl p-cyanobenzoate in dioxane as a reagent (4) using a solution of methyl pentafluorophenyl dioxane reagent. After the formation of the amide is completed, 1 M aqueous NaOH is added to the reaction mixture, which is heated at 65 ° C until the hydrolysis of the methyl ester is complete.

^(} 1 M NaOH is used instead of 1 M NaHCO _r A solution of (+) - di-O-acetylL-tartaric acid anhydride in dioxane is used as a reagent.

(6)

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

Example BI9: Preparation of compound no. B1.39

A suspension of 13 (0.086 g, 0.11 mmol) and di-n-butyltin oxide (0.05 g, 0.19 mmol) in dry benzene (3.3 ml) was refluxed under argon for 12 hours. The reaction mixture was concentrated in vacuo and dried under high vacuum for one hour. Then CsF (dried under high vacuum at 300 ° C for several hours, 0.042 g, 0.274 mmol) was added under argon, followed by dry 1,2-dimethoxyethane (0.6 ml) and triflate A3 solution (0.25 g, 0 , 66 mmol) in dry 1,2-dimethoxyethane (0.4 ml). The reaction mixture was heated to 35-40 ° C and stirred at this temperature for 5 hours. Then a solution of 15% KF in IM aqueous KH ₂ PO ₄ (30 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 in vacuo.

The oily residue (0.16 g) was purified by column chromatography on silica gel (gradient elution: toluene / ethyl acetate 80:20 to 75:25, then CH ₇ Cl ₂ / MeOH 19: 1) to give ether 31 (0.049 g , 44%) as a colorless foam and precursor 13 (0.035 g, 40%).

Dioxane (2.0 ml), water (1.0 ml) and glacial acetate (0.5 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.028 g) and benzyl ether 31 ( 0.048 g, 0.047 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black reaction mixture was hydrogenated at slightly elevated hydrogen pressure at room temperature for 17 hours and then filtered through a cellulose filter (pore size 45 pm). The filtrate was concentrated in vacuo and the residue was taken up in water and again concentrated several times to remove excess acetic acid. A solution of residue in water

4Look through an ion exchange column (Dowex 50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The clear filtrate was concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, elunet: water, flow rate 0.45 ml / min, detection at 230 nm) and then by reverse phase chromatography (Merck RP18 silica gel, elution with 7: 3 H ₂ O / methanol) to give the target molecule BI.39 (0.014 g,

51%) as a hairy white solid (after lyophilization): * H NMR (400 MHz, D ₂ O) δ

4.83 (d,> 4.0 Hz, 1 H), 4.49 (q,> 6.6 Hz, 1 H), 4.33 (d,> 7.7 Hz, 1 H), 3.74 (d,> 3.1 Hz, 1 H), 3.22 ( dd,> 2.6, 9.5 Hz, 1H); ¹³ C NMR (100.6 MHz, D ₂ O) δ 181 .5 (C _q ), 100.2 (CH), 95.7 (CH); MS (FAB, THG) 609 (M + Na), 587 (M + H).

Example B20: Preparation of Compound B1.40

Coupling of alcohol 13 with A4 triflate was carried out in accordance with Example B19 (preparation of compound 31).

Hydrogenation of benzyl ether and then purification was performed according to Example B19 (Preparation of Compound BI.39): * H NMR (400 MHz, D ₂ O) δ 4.88 (d, J = 4.1 Hz, 1 H), 4.53 (q, J = 6.7 Hz, 1 H), 4.39 (d, J = 7.7 Hz, 1 H), 3.29 (dd, J = 2.9, 9.8 Hz, 1 H), 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 BI.41

34

Hydroxypiperidine (6.0 g, 34.6 mmol, prepared from D - (-) - laxose according to Ichikawa and Igarashi [Ichikawa, Y., Igarashi, Y., Tetrahedron Letters 36: 4585-4586 (1995)] and triethylamine (18.1 ml, 130 mmol) was dissolved in dry tetrahydrofuran (100 ml) and the solution cooled to -10 ° C under an argon atmosphere. Slowly added allyl chloroformate (3.87 ml, 36.4 mmol) over one hour at thereby to form a white suspension. the reaction mixture was stirred at -10 ° C for a further hour, then was added IM aqueous solution of KH ₂ PO ₄ (150 mL) and the mixture was extracted three times with CH ₇ C1 _2. the combined organic phases were dried (Na ₇ SOJ and concentrated in vacuo to give a yellow oil (9 g) Purification by silica gel column chromatography (hexane / ethyl acetate 1: 1) gave allyl carbamate 34 (7.66 g, 86%).

0.4 nm sieve molecules (dried in high vacuum at 300 ° C, 15 g) were added to a solution of acceptor 34 (7.66 g, 29.8 mmol) in dry CH, Cl ₂ (150 ml) under an argon atmosphere and the suspension was stirred at room temperature for one hour. In parallel, prepare a suspension of DMTST (15.4 g, 59.6 mmol) and 0.4 nm molecular sieves (15 g) in dry CH ₂ C1 ₂ (150 ml) under an argon atmosphere in a second round bottom flask and stirred for 1 hour. DMTST was then added in 4 portions over a further hour to the acceptor solution, and the mixture was then stirred for 1 hour. The reaction mixture was filtered through Hyflo Super Cel® by rinsing thoroughly with CH ₂ Cl ₂ . The filtrate is extracted by shaking with 10% aqueous NaHCO ₃ solution, the aqueous phase is extracted three times with CH, C1 ₂ and the combined organic phases are dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The remaining yellow oil (36 g) was purified by column chromatography on silica gel (gradient elution: hexane / ethyl acetate 3: 1 to 3: 2) to give glycoside 35 (13.1 g, 54%).

Acetonide 35 (13.1 g, 15.94 mmol) was dissolved in dioxane (140 ml) and 50% aqueous trifluoroacetic acid (25 (f ml) was added at room temperature. After 2 hours the reaction mixture was concentrated in high vacuum and the residue was purified silica gel column chromatography (ethyl acetate / hexane 2: 1) to give diol 36 (11.23 g, 90%).

ο

A mixture of diol 36 (11.63 g, 14.88 mmol), tetra-n-butylammonium bromide (12.7 g, 39.4 mmol) and 0.4 nm molecular sieves (dried in high vacuum at 300 ° C, 22 g) is dried under high vacuum for 30 minutes and then dry CH ₂ Cl ₂ (62 ml) and dimethylformamide (36 ml) are added under argon. The gray suspension was stirred at room temperature for 30 minutes. A solution of ethyl-2,3,4-tri-O-benzyl-1-thioL-fucopyranoside (7.48 g, 15.62 mmol, prepared by the Lonna process [Lonn, H. Carbohydr. Res. 139: 105-113 (1985)]) in dry CH ₂ C1 ₂ (49 ml) under an argon atmosphere in a second round bottom flask and a solution of bromine (2.85 g Br ₂ , 17.84 mmol) in CH is added at 0 ° C. ₂ C1 ₂ (25 ml). The red solution was stirred at 0 ° C for 30 minutes and the bromine excess was decomposed by the addition of a few drops of cyclohexene. This solution is then added with a needle to the acceptor solution and the reaction mixture is stirred at room temperature for 40 hours. The reaction mixture was then filtered through Hyflo Super Cel® and washed thoroughly with CH ₇ C1 ₇ and the filtrate washed with 10% aqueous NaHCO ₃ . The aqueous phase was re-extracted three times with CH ₇ C1 ₇ and the combined organic phases were dried (Na ₇ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 35:65) to afford 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 was then neutralized by the addition of a strong acid ion exchanger (Amberlyst 15), then filtered through Hyflo Super Cel and concentrated in vacuo. 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%).

A suspension of 38 (1.0 g, 1.13 mmol) and di-n-butyltin oxide (0.49 g, 1.98 mmol) in dry benzene (33 ml) was refluxed under argon for 5 hours. The reaction mixture was concentrated in vacuo and dried under high vacuum for one hour. Then CsF (dried under high vacuum at 300 ° C for several hours, 0.43 g, 2.82 mmol) was added under argon, followed by dry 1,2-dimethoxyethane (7.4 ml), and benzyl R-3 solution. -phenyl-2-trifluoromethanesulfonyloxypropionate (2.6 g, 6.77 mmol) in dry 1,2-dimethoxyethane (4.9 ml). The reaction mixture was heated to 35-40 ° C and stirred at this temperature for 3 hours. Then a solution of 15% KF in IM 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 in vacuo. 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.

Dioxane (3.5 ml), water (1.7 ml) and glacial acetate (0.25 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.035 g) and benzyl ether 39 ( 0.038 g, 0.034 mmol). Evacuate the flask and rinse repeatedly with argon. This is then rinsed with hydrogen and the black reaction mixture is hydrogenated at slightly elevated hydrogen pressure at room temperature for 24 hours and then filtered through a cellulose filter (pore size 45 pm). The filtrate was concentrated in vacuo and the residue was taken up in water and again concentrated several times to remove excess acetic acid. Residue solution in water +

run through an ion exchange column (Dowex 50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The clear filtrate was concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and then by reverse phase chromatography (Merck RP18 silica gel, gradient elution: H ₇ O / methanol 65:35 to 55:45) to give the target molecule BI.41 (0.014 g, 59%) as a hairy white solid (after lyophilization): 1 H NMR (500 MHz, D ₂ O, + 50 ° C) δ 7.58-7.53 (m, 4H), 7.51-7. ^ 6 (m, 1H), 5.22 (d, J = 4.0 Hz) , 1 H), 4.57 (d, J = 7.6 Hz. 1 H), 4.56 (q, J = 6.4 Hz, 1 H), 4.33 (dd, J = 4.2, 8.6 Hz, 1 H),

4.30 (dt, J = 6.3, 3.2 Hz. 1 H), 3.66 (dd, J = 8.0, 9.4 Hz, 1 H), 3.59 (dd, J = 3.0, 13.8 Hz,

Η), 3.33 (dd,> 4.2, 14.0 Hz, 1 H), 3.13 (dd,> 9.0, 14.0 Hz, 1 H), 1 .82 (sex,> 6.9 Hz, 2H), 1 .36 (d. > 6.4 Hz, 3H), 1.10 (t,> 7.5 Hz, 3H); MS (FAB, NBA) 720 (M + Na), 698 (M + H).

Example B22: Preparation of Compound BI.42

A suspension of 38 (0.65 g, 0.73 mmol) and di-n-butyltin oxide (0.32 g, 1.28 mmol) in dry benzene (22 ml) was refluxed under argon for 16 hours. The reaction mixture was concentrated in vacuo and dried under high vacuum for one hour. Then CsF (dried under high vacuum at 300 ° C for several hours, 0.28 g, 1.83 mmol) was added under argon, followed by dry 1,2-dimethoxyethane (4.0 ml) and triflate A5 solution (1, 74 g, 4.4 mmol) in dry 1,2-dimethoxyethane (2.7 ml). The reaction mixture was heated to 35-40 ° C and stirred at this temperature for 3 hours. Then a solution of 15% KF in IM 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 in vacuo. The oily residue (2.6 g) was purified by column chromatography on silica gel (elution: toluene / ethyl acetate 3: 1, then CH _{2 Cl?} / Methanol 19: 1), resulting in the ether 40 (0.33 g, 40% ) as a colorless foam and partial recovery of precursor 38 (0.167 g, 26%) was achieved.

Dioxane (1.2 ml), water (0.6 ml) and glacial acetate (0.3 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.025 g) and benzyl ether 40 (0.036 g) ,

0.032 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black reaction mixture was hydrogenated at slightly elevated hydrogen pressure at room temperature for 8 hours and then filtered through a cellulose filter (pore size 45 pm). The filtrate was concentrated in vacuo and the residue was taken up in water and again concentrated several times to remove the excess acetic acid.

Dissolve the residue solution in water through an ion exchange column (Dowex 50, +

On -form, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The clear filtrate was concentrated in vacuo and purified by gel filtration on BioGel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and then by reverse phase chromatography (Merck RP18 silica gel, elution: H ₂ O / methanol 1: 1) to give the target molecule B1.42 (0.009 g, 41%) as a hairy white solid (after lyophilization): ¹ H NMR ( 400 MHz, D2O) δ 5.09 (d, J = 3.7 Hz, 1 H), 4.58 - 4.46 (m, 2H), 3.94 (d, J = 2.2 Hz, 1 H), 3.58 (t, J = 8.4 Hz. 1 H), 3.43 (dd, J = 1 .8, 9.5 Hz, 1 H), 1.83 (d, J = 12.2 Hz, 1 H), 1.23 (d, J = 6.7 Hz, 3H), 0.95 ( t, J = 7.6 Hz, 3H); ¹³ C NMR (100.6 MHz, D 2 O) δ 183.0 (C _q ), 101.6 (CH), 98.0 (CH); MS (FAB, THG) 704 (M + H).

Example B23: Preparation of Compounds no. B1.43.

46

Morpholine (1.1 ml) and Pd (PPh ₃ ) ₄ (0.071 g, 0.062 mmol) were added to a solution of allyl carbamate 39 (0.695 g, 0.618 mmol) in tetrahydrofuran (8.5 ml). After exactly 15 minutes, the solution was concentrated and the residue was dried under high vacuum for one hour. Purification of the residue by column chromatography on silica gel (eluent: CH _? Cl ₂ ^{/ m} ethanol 98: 2, containing 0.3% concentrated aqueous ammonia solution) yielded less polar allylamine 46 (0.24 g, 36%) and then more polar piperidine 41 (0.39 g, 60%).

Pyridine (5 pl, 0.06 mmol) and acetanhydride (1.8 pl, 0.04 mmol) were added under argon atmosphere to a solution of piperidine derivative 41 (0.035 g, 0.0336 mmol) in dry CH ₂ C1 ₂ (0, 6 ml) at 0 ° C. The solution was stirred at 0 ° C for 45 minutes and then washed with 5% aqueous NaHCO solution and extracted again three times with CH.CL. The combined organic phases were dried with Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue (0.05 g) was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane 4: 1) to give acetyl piperidine 42 (0.033 g, 91%) as a colorless foam.

Dioxane (1.4 ml), water (0.7 ml) and glacial acetate (0.35 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.03 g) and benzyl ether 42 (0.04 g, 0.037 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black reaction mixture was hydrogenated at slightly elevated hydrogen pressure at room temperature for 48 hours and then filtered through a cellulose filter (pore size 45 pm). The filtrate was concentrated in vacuo and the residue was taken up in water and again concentrated several times to remove excess acetic acid. Residue solution in water +

run through an ion exchange column (Dowex 50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The clear filtrate was concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and then by reverse phase chromatography (silica gel)

Merck RP18, gradient elution: methanol / H ₂ O 2: 3 over 1: 1 to 3: 2) to give the target molecule BI.43 (0.014 g, 64%) as a hairy white solid (after lyophilization); 1 H NMR (400 MHz, D ₂ O) δ 7.22 7.06 (m, 5H), 4.86 (m, 1 H), 1.95 (s, 3H), 0.98 (d, J = 6.7 Hz, 3H); MS (FAB, THG) 654 (M + H), 632 (M + 2H-Na).

Example B24: Preparation of Compound BI.44

Compound 43 was prepared from piperidine 41 (0.02 g, 0.019 mmol) and benzoyl chloride (2.5 μΐ, 0.021 mmol), analogous to the procedure for acetylpiperidine 42 (Example B23). The yield was 0.02 g (90%).

The target compound B1.44 was prepared by hydrogenation of benzyl ether 43 (0.042 g, 0.0367 mmol) and then purified by analogy as the acetyl derivative of BI.43. After lyophilization, the product is obtained as a hairy white solid. Yield: 0.015 g (57%): MS (FAB, THG) 716 (M + H), 694 (M + 2H-Na).

Example B25: Preparation of Compound B1.45

The target compound BI.45 was prepared analogously to example 23 (preparation of compound B1.43) from piperidine derivative 41: Ή NMR (400 MHz, D ₂ O) δ 7.28 - 7.13 (m, 5H), 4.95 (m, 1 H), 4.37 - 4.23 (m, 2H), 3.56 (s, 3H), 3.04 (m, 1H), 2.84 (m, 1H), 2.26 (t, J = 7.6 Hz, 2H), 1.08 (d, J = 7.4 Hz, 3H); MS (FAB, THG) 810 (M + H).

Example B26: Preparation of Compound B1.46

45

Pyridine (4 pl, 0.05 mmol) and cyclohexanecarbonyl chloride (7.2 pl, 0.05 mmol) were added at 0 ° C to a solution of piperidine derivative 41 (0.04 g, 0.038 mmol) in dry CH ₂ C1 ₂ ( 0.7 ml). After 20 minutes, the reaction mixture was washed with 10% aqueous NaHCO ₃ solution and the aqueous phase was extracted three more times with CH ₂ Cl _? . The combined organic phases were dried (Na ₇ SO ₄ ), filtered and concentrated in vacuo. Purification by column chromatography as a crude product (0.09 g) on silica gel (eluent: hexane / ethyl acetate

1: 1) gave amide 45 (0.03 g, 68%).

.41.46

Dioxane (1.1 ml), water (0.55 ml) and glacial acetate (0.27 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.05 g) and benzyl ether 45 (0.029 g, 0.025 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black reaction mixture was hydrogenated at 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 the hydrogenation was continued for 24 hours. The reaction mixture was then filtered through a cellulose filter (pore size 45 µm), the filtrate was concentrated in vacuo, and the residue was taken up in water and concentrated again several times to remove excess acetic acid. The solution of the residue in water is passed through an ion exchange column +

(Dowex 50, Na shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The clear filtrate was concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP18 silica gel, elution: methanol / H _? 0 60:40) to give the target molecule B1.46 (0.012 g, 64%) as a hairy white solid (after lyophilization): ¹ H NMR (400 MHz, D ₂ O) δ 5.04 (m, 1 H), 4.48 (m, 1 H), 4.45 - 4.32 (m, 1 H), 2.72 (m, 1 H), 1.17 (d, J = 5.8 Hz, 3H); MS (FAB, THG) 728 (M + H), 706 (M + 2H-Na).

Example B27: Preparation of Compound BI.47

B1.47

Dioxane (1.4 ml), water (0.7 ml) and glacial acetate (0.35 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.03 g) and benzyl ether 46 (0.042 g, 0.039 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black reaction mixture was hydrogenated at slightly elevated hydrogen pressure at room temperature for 16 hours and then filtered through a cellulose filter (pore size 45 pm). The filtrate was concentrated in vacuo and the residue was taken up in water and again 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 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and then by reverse phase chromatography (Merck RP18 silica gel, elution: methanol / H ₂ O 1: 3), yielding the target compound B1.47 (0.009 g, 36%) as a fluffy white solid (after ^{lyophilization):!} H NMR (400 MHz, D ₂ O) δ 7.10 - 7.02 (m, 4H), 7.01 - 6.94 (m, 1 H), 4.80 (br s, 1 H), 4.10 (d,> 7.0 Hz, 1 H) , 3.84 (dd,> 4.7, 8.5 Hz, 1 H), 3.20 (t,> 8.7 Hz, 1 H), 2.97 (dd,> 3.3, 9.7 Hz, 1 H), 2.83 (dd,> 4.7, 13.1 Hz , 1H), 2.63 (dd,> 8.5, 13.1 Hz, 1H), 0.87 (d,> 7.0 Hz, 3H), 0.63 (t,> 7.3 Hz, 3H); MS (FAB, THG) 654 (M + Na), 632 (M + H).

Example B28: Preparation of Compound B1.48

Triethylamine (7 μΐ, 0.05 mmol) and n-butanesulfonyl chloride (3.7 μΐ, 0.029 mmol) were added at 0 ° C to a solution of piperidine 41 (0.025 g, 0.024 mmol) in CH ₂ C1 ₂ (0.3 ml ). After 45 minutes, the reaction mixture was washed with 10% aqueous NaHCO ₃ solution and the aqueous phase was extracted three more times with CH ₂ Cl ₂ . The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: hexane / ethyl acetate 60:40) to give sulfonamide 47 (0.022 g, 79%).

B1.48

Dioxane (1.0 ml), water (0.5 ml) and glacial acetate (0.25 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.013 g) and benzyl ether 47 ( 0.027 g, 0.023 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black reaction mixture was hydrogenated at slightly elevated hydrogen pressure at room temperature for 24 hours and then filtered through a cellulose filter (pore size 45 μπι). The filtrate was concentrated in vacuo and the residue was taken up in water and again concentrated several times to remove excess acetic acid. The solution of the residue in water is passed through an ion exchange column (Dowex50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The clear filtrate was concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and then by reverse phase chromatography (Merck RP18 silica gel, gradient elution: methanol / H ₂ O 35:65 to 45:55) to give the target molecule B1.48 (0.011 g, 65%) as a hairy white solid (after lyophilization): 1 H NMR (400 MHz, D ₂ O) δ 7.51 - 7.35 (m, 5H), 5.15 (d,> 3.4 Hz, 1 H), 4.54 (q,> 6.2 Hz, 1 H), 4.51 ( d,> 8.0 Hz, 1 H) 4.03 (dd,> 2.8, 10.4 Hz, 1 H), 3.59 (t,> 8.9 Hz, 1 H), 3.23 (dd,> 4.8, 13.4 Hz, 1 H), 3.05 (dd,> 8.6, 13.4 Hz, 1 H), 1 .84 (pen,> 7.6 Hz, 2H), 1.54 (sex,> 7.3 Hz, 2H), 1 .27 (d,> 6.6 Hz, 3H). 1 .02 (t, J = 7.5 Hz, 3H); MS (FAB, THG) 732 (M + H).

Example B29: Preparation of Compound BI.49

The target compound BI.49 was prepared analogously to example B28 (preparation of compound B1.48) starting from the piperidine derivative 41 and p-toluenesulfonyl chloride: 'NMR (400 MHz, D ₂ O) δ 7.56 (d,> 7.2 Hz, 2H), 7.33 (d,> 7.2 Hz, 2H), 7.28 - 7.1 1 (m, 5H), 4.81 (d,> 3.4 Hz, 1 H), 4.22 (d,> 7.9 Hz, 1 H), 3.75 (d. > 2.4 Hz, 1 H), 3.65 (dd,> 2.4, 10.2 Hz, 1 H), 3.41 (t,> 5.7 Hz, 1 H), 3.32 (t,> 8.7 Hz, 1 H), 3.13 (dd, > 2.5, 9.3 Hz, 1 H), 3.00 (dd,> 4.0, 13.6 Hz, 1 H), 2.81 (dd,> 8.9 / 13.6 Hz, 1 H), 2.67 (br s, 1 H), 2.29 (s , 3H), 0.95 (d, J = 7.1 Hz, 3H); MS (FAB, THG) 788 (M + Na), 766 (M + H).

Example B30: Preparation of Compound B1.50

B1.50

Dioxane (1.5 ml), water (0.75 ml) and glacial acetate (0.38 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.02 g) and benzyl ether 47 (0.041 g, 0.035 mmol). Evacuate the flask and rinse repeatedly with argon. This is then rinsed with hydrogen and the hydrogenated reaction mixture is hydrogenated at slightly elevated hydrogen pressure at room temperature for 16 hours. Then 5% Rh / C (0.025 g) was added to hydrogenate the aromatic ring and the hydrogenation was continued for 16 hours. The reaction mixture was filtered through a cellulose filter (pore size 45 µm), the filtrate was concentrated in vacuo, and the residue was taken up in water and concentrated again several times to remove excess acetic acid. Dissolve the residue solution in water through ionic +

exchange column (Dowex 50, Na shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The clear filtrate was concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter

2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP18 silica gel, gradient elution: methanol / H ₂ O 40:60 to 50:50) to give the target molecule BI.50 (0.021 g, 82%) as a hairy white solid (after lyophilization): 'HNMR (400 MHz, D ₂ O) δ 4.97 (d,> 3.7 Hz, 1 H), 4.41 (d,> 7.7 Hz, 1 H), 4.36 (q,> 6.7 Hz, 1 H), 3.81 (d,> 2.6 Hz. 1 H), 3.76 (dd,> 2.4, 7.3 Hz, 1 H), 3.55 (dd,> 4.4, 7.2 Hz, 1 H), 3.30 (dd,> 2.7. 9.7 Hz, 1 H), 1.34 (sex,>'7.4 Hz, 2H), 1 .10 (d,> 6.7 Hz, 3H), 0.81 (t,> 7.5 Hz, 3H); MS (FAB, THG) 738 (M + H), 716 (M + 2H-Na).

Example B31: Preparation of Compound B1.51

49

Morpholine (0.37 ml) and Pd (PPh ₃ ) ₄ (0.025 g, 0.021 mmol) were added to a solution of allyl carbamate 40 (0.24 g, 0.212 mmol) in tetrahydrofuran (2.9 ml). After exactly 15 minutes, the solution was concentrated and the residue was dried under high vacuum for one 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) gave piperidine derivative 49 (0.17 g, 76%) .

Phenyl isocyanate (4.6 pl, 0.042 mmol) and diisopropylethylamine (8.5 pl, 0.05 mmol) were added at 0 ° C to a solution of piperidine derivative 49 (0.04 g, 0.038 mmol) in CH ₂ C1, (0 , 6 ml). After 90 minutes, the reaction mixture was washed with IM aqueous _ΚΗ Ί ΡΟ ₄ and the aqueous phase re-extracted three times with CFfCl ,. The combined organic phases are dried (Na, SOJ, filtered and concentrated in vacuo. Purification of the crude product

100 (0.047 g) by silica gel column chromatography (eluent: hexane / ethyl acetate 58:42) yielded urea derivative 50 (0.035 g, 78%).

B1.51

Dioxane (1.3 ml), water (0.65 ml) and glacial acetate (0.33 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.018 g) and benzyl ether 50 ( 0.036 g, 0.031 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black reaction mixture was hydrogenated at slightly elevated hydrogen pressure at room temperature for 16 hours and then filtered through a cellulose filter (pore size 45 pm). The filtrate was concentrated in vacuo and the residue was taken up in water and again concentrated several times to remove excess acetic acid. Dissolve the residue solution in water + through an ion exchange column (Dowex 50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by washing with deionized water. The clear filtrate was concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck RP18 silica gel, elution: methanol / H ₂ O 1: 1) to give the target molecule BI.51 (0.018 g, 80%) as a hairy white solid (after lyophilization): * H NMR (400 MHz, D ₂ O) δ 7.14 (t,> 7.9 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 6.95 (t,> 7.7 Hz, 1 H), 4.87 (d,> 4.0 Hz, 1

H), 4.30 (d,> 7.4 Hz, 1 H), 4.23 (q,> 6.6 Hz, 1 H), 3.66 (d,> 2.8 Hz, 1 H), 3.42 (dd,> 4.4, 7.7 Hz, 1 H), 3.16 (dd,> 2.6, 9.5 Hz, 1H), 1 .00 (d,> 6.6 Hz, 3H); MS (FAB,

THG) 737 (M + H), 715 (M + 2H-Na).

101

Example B32: Preparation of Compound B1.52

COOBn

OH

NH

COOBn

KI OH

O o

_In J OBn

BnO

BnO

O O

Piperidine derivative 49 was converted analogously to Example B28 (preparation of compound B1.48) using phenylmethanesulfonyl chloride as the reagent into target compound BI.52: 1 H NMR (400 MHz, D ₂ O) δ 7.50 (m, 5H), 5.02 (d. > 3.5 Hz, 1 H), 4.61 (d,> 13.7 Hz, 1 H),

4.54 (d,> 13.7 Hz, 1 H), 4.32 (d,> 8.0 Hz, 1 H), 3.62 (t,> 6.0 Hz, 1 H), 3.52 (dd,> 7.7, 8.4 Hz, 1 H). 3.36 (dd,> 3.2, 9.6 Hz, 1H), 3.22 (br d,> 12.6 Hz, 1H), 1 .17 (d,> 6.5 Hz, 3H); MS (FAB, THG) 772 (M + H), 750 (M + 2H-Na).

102

Example B33: Preparation of Compound B1.53

Dioxane (3.7 ml), water (1.8 ml) and glacial acetate (0.9 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.05 g) and benzyl ether 49 (0.09 g, 0.086 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black reaction mixture was hydrogenated at slightly elevated hydrogen pressure at room temperature for 48 hours and then filtered through a cellulose filter (pore size 45 pm). The filtrate was concentrated in vacuo and the residue was taken up in water and again 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 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and then by reverse phase chromatography (Merck RP18 silica gel, gradient elution: methanol / H ₂ O 30:70 to 50:50) to give the target molecule B1.53 (0.04 g, 78%) as a hairy white solid (after lyophilization): 'ΗΝΜΙΙ (400 MHz, D ₂ O) δ 5.04 (d, J = 4.2 Hz, 1 H), 4.43 (d. J = 7.6 Hz, 1 H), 4.27 (m, 2H), 4.20 (q, J = 6.5 Hz, 1 H), 4.02 (dd, J = 2.6, 6.6 Hz, 1 H). 3.51 (dd, J = 7.8, 9.5 Hz, 1H), 1.12 (d, J = 6.2 Hz, 3H); MS (FAB, THG) 618 (M + Na), 596 (M + H).

103

Example B34: Preparation of compound BI.54

An M solution of 2- (1-naphthyl) ethanesulfonyl chloride in toluene (46 μΐ) was added at room temperature to a solution of the piperidine derivative BI.53 (0.025 g, 0.042 mmol) in 1N aqueous NaHCO ₃ solution (0.22 ml). The mixture was stirred thoroughly for 22 hours, then concentrated in vacuo and dried under high vacuum for 15 minutes. The crude product was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and then reversed. phase chromatography (Merck RP18 silica gel, elution: methanol / H ₂ O 7: 3) to give the target molecule B1.54 (0.011 g, 31%) as a hairy white solid (after lyophilization): NMR (400 MHz, D ₂ O) δ 7.72 (d, J = 8.8 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1

H), 7.44 (d, J = 8.6 Hz, 1 H), 7.28 (t, J = 7.2 Hz, 1 H), 7.22 (t, J = 7.2 Hz, 1 H), 7.14 (t, J = 7.2 Hz) , 1 H), 7.08 (d, J = 8.7 Hz, 1 H), 4.91 (d, J = 4.1 Hz, 1 H), 4.20 (d, J = 7.0 Hz, 1 H), 3.99 (br s, 1 H) 3.90 (br s, 1 H), 1.09 (d, J = 6.3 Hz, 3H); MS (FAB, THG) 858 (M + Na), 836 (M + H).

104

Example B35: Preparation of Compound B1.55

B1.53 B1.55

A 0.5 M solution of acetanhydride in toluene was added in small portions (50 to 100 pl) at room temperature to a solution of the piperidine derivative BI.53 (0.035 g, 0.059 mmol) in IM aqueous NaHCO ₃ solution (0.5 ml) until consumed. whole precursor (thin layer chromatography test: silica gel TLC plates, mobile phase: nbutanol / water / acetone / glacial acetate / NH ₄ OH 70: 60: 50: 18: 1,5). The reaction is complete after about 1 hour and the mixture is concentrated in vacuo and dried under high vacuum for 15 minutes. The crude product was purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and then reversed. phase chromatography (Merck RP18 silica gel, elution: methanol / H ₂ O 3: 7) to give the target molecule B1.55 (0.026 g, 67%) as a hairy white solid (after lyophilization): * H NMR (400 MHz , D ₂ O) δ 5.01 (d,> 4.2 Hz, 0.5H), 4.99 (d,> 4.2 Hz, 0.5H), 4.44 (d,> 7.3 Hz, 1 H), 4.32 (q,> 6.6 Hz, 0.5H), 3.14 (dd,> 8.0, 12.9 Hz, 0.5H), 2.10 (s, 1.5H), 2.08 (s, 1.5H), 1.13 (d,> 6.6 Hz, 3H).

105

Example B36: Preparation of compound BI.56

A 1.5 M solution of (+) - di-O-acetyl-L-tartaric anhydride in 1,4-dioxane was added in small portions (50 to 100 μΐ) at room temperature to a solution of the piperidine derivative BI.53 (0.03 g, 0.05 mmol) in IM aqueous NaOH solution (0.15 ml) until all precursor is consumed (thin layer chromatography assay: TLC silica gel, mobile phase: n-butanol / water / acetone / glacial / NH ₄ OH 70: 60: 50: 18: 1.5). The mixture was maintained basic throughout the reaction by periodically adding an IM solution of NaOH. The starting material is consumed after about 2 hours and then a further 1 M sodium hydroxide solution (0.13 ml) is added and the mixture is heated to 40 ° C to hydrolyze the ester groups. After 1 hour the mixture was concentrated in vacuo and dried under high vacuum for 15 minutes. The crude product was 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) and then reversed. phase chromatography (Merck RP18 silica gel, elution: methanol / H ₂ O 1: 9) to give the target molecule B1.56 (0.020 g, 52%) as a hairy white solid (after lyophilization); MS (FAB, THG) 794 (M + Na), 772 (M + H), 750 (m + 2H-Na).

106

Example B37: Preparation of Compound B 1.57

N, N-diisoproylcarbodiimide (11.7 μΐ, 0.075 mmol) was added at 0 ° C to a solution of shikimic acid (0.013 g, 0.075 mmol) and 1-hydroxybenzotriazole (0.01 g, 0.075 mmol) in dry N, N-dimethylformamide (0.37 ml) and the mixture was then stirred for 30 minutes. The mixture was then warmed to room temperature and piperidine derivative B1.53 (0.015 g, 0.025 mmol) was added. After 3 hours, a 10% aqueous solution of NaHCO ₃ (0.15 ml) was added and the reaction mixture was stirred for a further 20 minutes and then concentrated in high vacuum. The residue is taken up in water, filtered through a cellulose filter (pore size +

pm) and then passed through an ion exchange column (Dowex 50, Na-shape, column diameter 0.9 cm, length 3.5 cm) by rinsing with deionized water. The filtrate was concentrated in vacuo and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) and then by reverse phase chromatography (Merck RP18 silica gel, elution: methanol / FL, O 1: 9) to give the target molecule BI.57 (0.007 g, 33%) as a hairy white solid (after lyophilization): 1 H NMR (400 MHz, D ₂ O) δ 5.8 (br s, 1 H), 4.94 (m, 1 H), 2.55 (m, 1 H), 2.10 (m, 1 H), 1.07 (d, J = 6.0 Hz) , 3H); MS (FAB, THG) 796 (M + Na), 774 (M + H).

107

Example B38: Preparation of Compound BI.58

N, N-dimethylaminopyridine (1.03 g, 8.44 mmol) and p-nitrobenzenesulfonyl chloride (1.65 g,

7.44 mmol) was added at room temperature to a solution of alcohol 37 (6.11 g, 5.1 mmol) in CH ₂ Cl ₂ (35 ml). After 52 hours, the reaction mixture was washed with 10% aqueous NaHCO ₃ and the aqueous phase was re-extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Raw product (10

g) was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane 35:65) to give nosylate 52 (6.58 g, 93%).

A solution of nozilate 52 (7.78 g, 5.62 mmol) and dry LiN ₃ (0.99 g, 20.21 mmol) in dry N, N-dimethylforamide (50 ml) was heated to 50-60 ° C under an argon atmosphere . After hours, the solvent was removed under high vacuum and the residue was taken up in CH ₂ Cl ₂ and washed with 10% aqueous NaHCO ₃ solution. The aqueous phase is re-extracted three times with

108

CH ₂ Cl ₂ and the combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / hexane 30:70), eluting first with the required 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 reaction mixture was then adjusted to a neutral pH by the addition of strong acidic +

ion exchanger (Amberlyst15, H-form), the suspension is filtered and the filtrate is concentrated in vacuo. The crude product (4.5 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / methanol 19: 1) to give triol 54 (2.89 g, 92%).

A suspension of 54 (2.89 g, 3.17 mmol) and di-n-butyltin oxide (1.56 g, 6.27 mmol) in dry benzene (95 ml) was refluxed under argon for 16 hours. The reaction mixture was concentrated in vacuo and dried under high vacuum for one hour. Then we add

109

CsF (dried under high vacuum at 300 ° C for several hours, 1.2 g, 7.9 mmol) under an argon atmosphere followed by dry 1,2-dimethoxyethane (80 ml) and A5 triflate solution (6.3 g, 15 , 97 mmol) in dry 1,2-dimethoxyethane (50 ml). The reaction mixture was heated to 35-40 ° C and stirred at this temperature for 3 hours. The mixture was then washed with a solution of 15% KF in IM aqueous KH ₂ PO ₄ (150 ml) and the aqueous phase extracted three times with CH ₂ Cl ₂ and the combined organic phases dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo.

The oily residue (10.9 g) was purified by silica gel column chromatography (elution: toluene / ethyl acetate 4: 1 then CH ₂ Cl ₂ / methanol 19: 1) to recover the precursor to give ether 55 (1.94 g, 53%) as a colorless foam and partially recovered precursor (1.1 g, 26%).

Morpholine (215 μΐ) and Pd (PPh ₃ ) ₄ (0.015 g, 0.013 mmol) were added under an argon atmosphere to a solution of allyl carbamate 55 (0.15 g, 0.13 mmol) in tetrahydrofuran (1.7 ml). After exactly 15 minutes, the solution was concentrated and the residue was dried under high vacuum for one hour. The crude product was purified on a short column of silica gel (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 was then taken up in dry CH ₂ Cl ₂ (1.7 ml), the solution cooled to 0 ° C and triethylamine (43 μΐ, 0.31 mmol) and n-butane-sulfonyl chloride (18 pil, 0.14 mmol) added. After 15 minutes, the reaction mixture was warmed to room temperature and washed with 10% aqueous NaHCO 3 solution _. The aqueous phase was re-extracted three times with CH ₇ Cl _? and the organic phases are combined, dried (Na ₇ SO ₄ ), filtered and

110 was concentrated in vacuo. Purification of the crude product by column chromatography on silica gel (eluent: ethyl acetate / hexane 30:70) gave sulfonamide 56 (0.12 g, 77%).

Dioxane (1.2 ml), water (0.6 ml) and glacial acetate (0.25 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.035 g) and benzyl ether 56 ( 0.027 g, 0.023 mmol). Evacuate the flask and rinse repeatedly with argon. This was then rinsed with hydrogen and the black reaction mixture was hydrogenated at slightly elevated hydrogen pressure at room temperature for 12 hours and then filtered through a cellulose filter (pore size 45 pm). The filtrate was concentrated in vacuo and the residue was taken up in water and again concentrated several times to remove excess acetic acid. The crude intermediate (0.017 g, lyophilized) was taken up in 1 M aqueous NaHCO ₃ solution (0.3 ml) and after 5 hours several smaller portions (30 to 50 pl) of approximately 1 M solution of 3,4dimethoxybenzoyl chloride in toluene were added until the test Thin-layer chromatography (silica gel TLC plates, mobile phase: nbutanol / water / acetone / glacial acetate / NH ₄ OH 70: 60: 50: 18: 1.5) does not detect complete conversion of the intermediate. The pH of the solution was maintained basic during this reaction by adding several portions of solid NaHCO ₃ (approximately 0.025 g total). The reaction mixture was then concentrated in vacuo and the residue taken up in little water and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck silica gel RP18, elution: methanol / H ₂ O 65:35) to give the target molecule B1.58 (0.008 g, 39%) as a hairy white solid (after lyophilization): * H NMR (400 MHz, D ₂ O) δ 7.41 (br d, J = 8.3 Hz, 1 H), 7.32

111 (br s, 1 H), 7.04 (d,> 8.3 Hz, 1 H), 5.05 (d,> 3.9 Hz, 1 H), 4.51 (d,> 7.8 Hz, 1 H),

4.14 (q,> 6.7 Hz, 1 H), 4.09 (t,> 4.1 Hz, 1 H), 3.82 (s, 6H), 3.33 (dd,> 3.1, 9.6 Ηζ, Ι H), 1 .13 (d ,> 6.3 Hz, 3H), 0.68 (t,> 7.6 Hz, 3H); MS (FAB, THG) 923 (M + Na), 901 (M + H), 879 (M + 2H-Na).

Example B39: Preparation of Compound B1.59

Dioxane (5.3 ml), water (2.6 ml) and acetic acid (1.1 ml) were added to a mixture of Pd (OH) ₂ / C (Pearlman catalyst, Pd content of 20%, 0.13 g) and benzyl ether 56 (0.12 g, 0.1 mmol). Evacuate the flask and rinse repeatedly with argon. This is then rinsed with hydrogen and the hydrogenated reaction mixture is hydrogenated at slightly elevated hydrogen pressure at room temperature for 24 hours and then filtered through a cellulose filter (pore size 45 pm). The filtrate was concentrated in vacuo and the residue was taken up in water and again concentrated several times to remove excess acetic acid. The crude amine (0.074 g) was taken up in a little water and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck silica gel RP18, elution: methanol / Η, Ο 1: 1) to give the target molecule B1.59 (0.052 g, 73%) as a hairy white solid (after lyophilization): 'HNMR (400 MHz, D ₂ O) 5 5.00 (d,> 3.6 Hz, 1 H), 4.41 (d,> 7.7 Hz, 1 H), 4.28 (q,> 6.5 Hz, 1 H ), 3.83 (d,> 3.1 Hz, 1 H), 3.79 (dd,> 3.1,9.7 Hz, 1 H), 3.32 (dd,> 3.2, 9.6 Hz, 1 H), 1 .12 (d,> 6.1 Hz, 3H), 0.83 (t,> 7.9 Hz, 3H); MS (FAB, THG) 737 (M + Na), 713 (M + H).

112

Amine BI.59 (0.027 g, 0.038 mmol) was taken up in 1 M aqueous NaHCO ₃ solution (0.35 ml) and after 4 hours several smaller portions (30 to 50 μϊ) of about 0.5 M benzoyl chloride solution in toluene were added. until complete conversion was detected by thin layer chromatography (silica gel TLC plates, mobile phase: n-butanol / water / acetone / glacial acetate / NH ₄ OH 70: 60: 50: 18: 1,5). The pH of the solution was maintained basic throughout the reaction by adding several portions of solid NaHCO ₃ (approximately 0.01 g total). The reaction mixture was then concentrated in vacuo and the residue taken up in little water and purified by gel filtration on Bio-Gel P2 (particle size 65 pm, column diameter 2.5 cm, length 35 cm, eluent: water, flow rate 0.45 ml / min, detection at 215 nm) followed by reverse phase chromatography (Merck silica gel RP18, elution: methanol / H ₂ O 1: 1) to give the target molecule BI.60 (0.027 g, 85%) as a hairy 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, 1 H), 7.44 (t, J = 7.5Hz , 2H), 5.05 (d, J = 3.8 Hz, 1 H), 4.50 (d, J = 8.1 Hz, 1 H), 4.17 (q, J = 6.6 Hz, 1 H), 3.92 (br d, J = 10.4 Hz, 1 H), 3.85 (d, J = 2.8 Hz, 1 H), 3.80 (dd, J = 3.1, 10.4 Hz, 1 H), 3.33 (dd, J = 2.8, 9.8 Hz, 1 H), 1.12 (d, J = 7.1 Hz, 3H), 0.70 (t, J = 8.2 Hz, 3H); MS (FAB, THG) 863 (M + Na), 841 (M + H).

113

Example B41: Preparation of Compound BI.61

B1.59 B1.61

Carbamate B1.61 was prepared starting from amine BI.59 (0.027 g, 0.038 mmol) using benzyl chloroformate as a reagent analogous to Example B40 (preparation of compound BI. 60). The yield is 0.007 g (21%) : ^! H NMR (400 MHz, D ₂ O) δ 7.31 (m, 5H), 5.06 (d, J = 12.0 Hz, 1 H), 4.97 (d,> 12.0 Hz, 1 H), 4.96 (d,> 4.0 Hz , 1 H), 4.42 (d,> 7.7 Hz, 1 H), 4.19 (q,> 6.6 Hz, 1 H), 3.96 (br s, 1 H), 3.80 (d,> 2.9 Hz, 1 H). 3.50 (dd,> 8.2, 9.4 Hz, 1 H), 3.29 (dd,> 2.9, 9.7 Hz, 1 H), 3.20 (br d,> 12.2 Hz, 1 H), 1 .06 (d,> 6.5 Hz , 3H), 0.77 (t,> 8.0 Hz, 3H); MS (FAB, THG) 871 (M + H), 849 (M + 2HNa).

The following compounds are prepared analogously to the above examples:

Compound no. r ₃ Rha B1.64 On C (O) -3,4- (OH) ₂ -C _e H _s B1.65 On C (O) CH (C, H ₅ ) ₂ B1.68 On C (O) -3,4- (OCH2C _e H ₅ ) 2-CeH ₅

114

Compound no. r ₃ Rha B1.70 On C (O) -3,4,5- (OH) ₃ -CeH _e B1.72 On C (O) [CH (OH)] ₂ C (O) ONa B1.73 On C (O) CH ₃ B1.77 On S (O) ₂ (CH ₂ ) ₂ C ₁₀ H ₇ B1.78 H H B1.80 On S (O) ₂ CH ₂ C _e H ₅ B1.81 On C (O) NHCeH ₅ B1.82 On C (O) C _e H " B1.83 On S (O) ₂ (CH ₂ ) 3CH ₃ B1.84 On C (O) O (CH ₂ ) ₂ CH ₃

Compound no. r ₃ Rha Rca B1.62 On C (O) CH ₃ NHC (O) C ₁₀ H ₇ B1.63 On C (O) CH ₃ NHC (O) OCH ₂ C _e H ₅ B1.66 On C (O) CH ₃ NHC (O) CH ₂ C _e H ₅ B1.67 On C (O) CH ₃ NHC (O) CH ₂ OC _e H ₅ B1.69 On C (O) CH ₃ NHC (O) CH ₂ NHC (O) OCH ₂ C _e H ₅ B1.71 On C (O) O (CH ₂ ) ₂ CH ₃ NHS (O) ₂ CH ₂ C _e H ₅ B1.74 On S (O) ₂ (CH ₂ ) ₃ CH ₃ NHC (O) OCH ₂ C _e H ₅ B1.75 On S (O) ₂ (CH ₂ ) ₃ CH ₃ NHC (O) C ₆ H ₅ B1.76 H S (O) ₂ (CH ₂ ) ₃ CH ₃ 'NH ₂ B1.79 On S (O) ₂ (CH ₂ ) ₃ CH ₃ NHC (O) -3,4- (OCH ₃ ) ₂ C _e H ₃

115

Compound no. Ra Rha B1.85 On S (O) r4-CH3-C _is H4 B1.86 On C (O) (CH ₂ ) eC (O) OCH ₃ B1.87 On S (O) ₂ (CH ₂ ) ₃ CH ₃ B1.88 H (CH ₂ ) ₂ CH ₃ B1.89 On C (O) C _e H ₅ B1.90 On C (O) CH ₃ B1.91 On C (O) O (CH ₂ ) ₂ CH ₃

C. Ligand binding assay to determine IC. ₍₎ values - canned use of positive controls

E-selectin / human IgG chimeras (cloned and expressed according to Kolbinger et TM al. Biochemistry 35: 6385-6392 (1996)) were incubated on a Falcon probind microtiter plate (plate 1) at a concentration of 200 ng / well in 0.01 M Tris, 0.15 M NaCl, 1 mM + 4CaCl ₂ , pH 7.4 (Tris-Ca buffer). The seed solution is distributed as 100 μΙ / well 2 μg / ml E-chimera. Leave line 12 blank; just a buffer. Plate 1 was incubated coated at 37 ° C for 2 hours. After incubation, 100 μΙ / well of 2% BS A v is added

Tris Ca buffered and incubated at room temperature for 1 hour. During incubation, the compound (2x + + serial dilution) was titrated in 1% BS A in Tris Ca using U-shaped low-binding microtiter plates (plate 2). The species are serially diluted to type 9. Species

116

10, 11 and 12 are buffer only. The final volume is 60 μΐ / well and the first well

X contains 10 mM compounds except 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.

in a

The PolySle SA-HRP conjugate was prepared in advance by incubating Sialyl Le -PAA-biotin (cat. # 01-044, GlycoTech Corp., Rockville, MD) with Streptavidin-HRP in a 1: 2 molar ratio. 60 μΐ / well 1 ng / μΐ polySle ^d SA-HRP conjugate in 1% BSA in TrisCa was added to each well except row 11 in plate 2. Wash plate 1 four times ++ with Tris-Ca in an automatic plate washer. Transfer 100 μΐ / well from plate 2 to plate 1 based on the lowest concentration of the compound. Discard plate 2. The plate was incubated during shaking at room temperature for 2 hours. The plate was washed four times with Tris ++

Ca using an automatic plate washer. 100 μΙ / well of the substrate [Mix 3,3 ', 5,5'-tetramethylbenzidine reagent and H ₂ O ₂ at a ratio of 1: 1] was added with an 8-channel pipette from right to left. The plate was incubated at room temperature for 2 minutes. The reaction was stopped by adding 100 μΐ / well IM H ₃ PO ₄ using a 8-channel pipette device from right to left. The light absorbance at 450 nm was measured on a microtiter plate reader.

Control compound A:

117

Control compound B:

IC _{50 was} calculated by determining the concentration of a compound required to inhibit the maximal binding of the polySialylLe HRP conjugate to immobilize E-selectin / human IgG chimeras by 50%. The relative IC _{50 is} calculated by determining the ratio of IC _{50 of the} internal control compound to IC _{50 of the} test compound.

IC ₅₀ (test compound)

In the following tables, RIC ₅₀ means: -------------------------------- IC ₅₀ (control compound)

118

Table 2:

Compound no. r ₃ Rt RIC50 B1.1 On -CH2C6H5 0.35 B1.2 On CH ₂ C _e Hu 0.08 B1.3 On -CH ₂ NHC (O) C ₆ H ₅ 1.11 B1.4 On -CH ₂ NHC (O) (CH ₂ ) ₂ CeH _s 1.85 B1.5 On -CH ₂ NHC (O) (CH ₂ ) ₃ OH 1.23 B1.6 H -ch ₂ nh ₂ 0.96 B1.7 H -CH ₂ NHCH ₂ (CH) ₂ C ₆ H ₅ 1.15 B1.8 On -CH ₂ N [C (O) C _e H ₅ ] CH ₂ (CH) ₂ CeH ₅ 0.90 B1.9 H CH ₂ NHCH ₂ C _e H ₅ 0.61 B1.1O On -CH ₂ N (CH ₂ C _e H ₅ ) ₂ 0.60 B1.11 H -CH ₂ NH [CH ₂ CH (CH ₃ ) ₂ 0.74 B1.12 H -CH ₂ N [CH ₂ CH (CH ₃ ) ₂ ] ₂ 0.32 B1.13 On -CH ₂ N [C (O) C ₆ H _s ] [CH ₂ CH (CH ₃ ) ₂ ] 0.21 B1.14 On -CH ₂ NH [SO ₂ (C ₆ H ₄ ) NO ₂ ] 0.12 B1.15 On -ch ₂ nhso ₂ c ₆ h ₄ ch ₃ 0.13 B1.16 On -CH ₂ NHC (O) CF ₃ 0.64 B1.17 On -CH ₂ NHC (O) C _e Hn 1.33 B1.18 On -ch ₂ ch ₂ c ₆ h ₅ 0.14 B1.19 On -ch ₂ ch ₂ c ₆ h " 0.17

119

Continued Table 2:

Compound no. r ₃ R4 RICjo B1.20 On -CH ₂ NHC (O) C „H23 1.76 B1.21 On -CH ₂ NHC (O) CH (C ₆ H ₅ ) 2 0.71 B1.22 On -CH ₂ NHC (O) C ₂ H ₄ CO ₂ Na 1.05 B1.23 On -CH ₂ NHC (O) Ce [(1,3,4,5) 01 ^ 7 0.79 B1.24 On -CH ₂ NHC (0) C _e H ₄ S0 ₃ Na 0.93 B1.25 On -CH ₂ NHC (O) CeH ₄ CI 1.29 B1.26 On -CH ₂ NHC (O) CeH ₄ NO ₂ 1.21 B1.27 On -CH ₂ NHC (O) C _e H ₄ OCH ₃ 1.15 B1.28 On -CH ₂ NHC (O) C ₆ H ₄ (3,4) CI ₂ 2.04 B1.29 On -CH ₂ NHC (O) C ₆ H ₄ CH ₃ 1.30 B1.30 On -CH ₂ NHC (O) CeH ₄ C _e H ₅ 1.65 B1.31 On -CH ₂ NHC (O) C _e H ₄ CN 1.04 B1.32 On -CH ₂ NHC (O) C _w H ₇ 1.44 B1.9 On -ch ₂ nhch ₂ c ₆ h ₅ 0.61 B1.33 On -CH ₂ NHC (O) C _e H ₄ COONa 0.96 B1.34 On -CH ₂ NHC (O) (CHOH) ₂ COONa 0.78 BI.35 On -CH ₂ N [C (O) C _e H ₅ ] CH ₂ C _e H ₅ 0.44 B1.36 On -CH ₂ N [C (O) C _e H ₅ ] (CH ₂ ) ₃ C _e H ₅ 0.57 B1.37 On -CH ₂ NHSO ₂ CF ₃ 0.26 B1.38 On -CH ₂ N [CH ₂ CH (CH ₃ )] SO ₂ C _e H ₄ NO ₂ 0.32

120

Table 2a:

Compound no. RIC ₅₀

Compound no. RIC50

B1.62 0.949 B1.77 0.618 B1.64 0.287 B1.78 0.304 B1.65 0.862 B1.79 0.196 B1.66 1.112 B1.80 0.203 B1.67 0.564 B1.81 0.216 B1.68 0.696 B1.82 0.195 B1.69 2.661 B1.83 0.176 B1.70 0.199 B1.84 0.169 B1.71 0.414 B1.85 1.28 BI.72 0.186 BI.86 2.733 B1.73 0.249 B1.87 0.520 B1.74 0.134 B1.88 1.257 B1.75 0.102 B1.89 0.696 B1.76 0.451 B1.90 0.569 B1.63 0.087

For

NOVARTIS AG:

ΡΜΕγΓΠ

LJUSU,> r> r, 75 T1 „d

MA, CHOPOVA

121

Claims (51)

Patent claims A compound of formula I: X | OH OH (0 where X is the residue of the non-glycosidic aliphatic 1,2-diol; R _t is S-configured methyl substituted with one carboxyl moiety and one other substituent; and R ₂ is hydrogen, C 1 -C ₁₂ alkyl or C ₆ aryl; wherein alkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C _n heterocycloalkyl, C ₂ -C _n heterocycloalkenyl, C ₆ -C _1Q aryl, C ₆ -C ₁₀ aryloxy, C ₅ C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ -C _n aralkyl, C ₇ -C _n aralkyloxy, C ₆ -C ₁₀ heteroaralkyl, C ₈ -C _H aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R is _sl hydrogen, M _y , C 1 -C _p alkyl, C ₂ -C ₁₂ alkenyl, C ₃ C ₁₂ cycloalkyl, C ₂ -C _t heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C _g heteroaryl, C ₇ -C _n aralkyl, or C _{6 C-1 (),} heteroaralkyl, R _s4 is hydrogen, Cj-stations, C ₂ -C ₁₂ alkenyl, C ₃ -C _J2 cycloalkyl, C ₇ C _H heterocycloalkyl, C ₆ -C _{1 ()} aryl, C -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C _1Q heteroaralkyl, and R ₇ and R _{7Q are} hydrogen, C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁ cycloalkyl, C ₃ C ₁₂ cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ -C ₁₁ heterocycloalkenyl, C ₆ -C, ₀ aryl, C ₅ C ₉ heteroaryl, C ₇ -C _to aralkyl, C ₆ -C _{1 ()} heteroar lkyl, Cg-C ,, aralkenyl, or C ₇ 122 C ₁₀ heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are unsubstituted or substituted with the above substituted , and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, including its physiologically acceptable salts. Compound according to claim 1, characterized in that (a) NH ₂ , primary amino, seconds amino, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide and aminocarbonylamide are representatives selected from the group consisting of R, R _M NC (O) (NH) _p N (iy-, -OC (O) (NH) NR, R, -N (R ₄₀ ) C (O) (NH) NR, ?, ,, where R 8, R _g and R _{4Q are} independently hydrogen, OH, C 1 -C 6 alkyl, C ₁ C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₁ -C ₃ heterocycloalkyl, C ₉ C ₁ heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ -C ₁₆ aralkyl, C _g -C ₁₆ aralkenyl with C ₂ CLalkenylene and C-CLaryl, C, -C .. heteroaralkyl, CC, .heteroaralkenyl or di- C, C _{1 () an} -C 1 -C ₆ alkyl or R _g , R ₉ , N, where R _g , and R g, independently of one another, are hydrogen, OH, SO ₃ M _y , OSO ₃ M _y , Cj- C ₁₂ alkyl, C ₃ -C ₁₂ cycloalkyl, (^ - (^ heterocycloalkyl, C ₆ -C _1Q aryl, C ₅ Cgheteroaril, _C? -C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C ₁₆ aralkenyl with C ₂ -C ₆ alkenylene and C-CLaryl, or di-C _with -C, _n aryl-C-C-alkyl which are unsubstituted or substituted by one or more substituents, or R _g and R _y or R _g , and R _g , or R _g and R ₄₀ in the case of NR _g R ₉ or NR _gt R ₉ , or R _g R _4Q N- together tetramethylene, pentamethylene, - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -, - (CH ₂ ) ₂ S-sulfonyl; and (b) is a sulfonyl representative of the formula R ₁₀ -SO ₇ wherein R _{10 is} C 1 -C ₁₂ alkyl, C ₃ C _p cycloalkyl, C ₂ -C _n heterocycloalkyl, C ₆ -C _{1 ()} aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ C ₍₍₎ heteroaralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R _s4 , C (O) R.,. 123 C _p alkoxy, C ₃ -C _p cycloalkyl, C ₃ -C ₍₂ cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ C], heterocycloalkenyl, C ₆ -C _1Q aryl, C ₆ -C _(O aryloxy, C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C _7-c j aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _n aralkenyl, _C? -C ₁₀ heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where R is hydrogen, M, si y 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 ₁ -C ₄ heteroaryl, C ₁ -C ₆ alkyl or CC .- heteroaralkyl, R is hydrogen, C₁₋₄alkyl, C-C, C _[2 alkenyl, C ₃ -C _J2 cycloalkyl, C ₂ -C _n heterocycloalkyl, C _{6 -C) 0} aryl, C ₅ -C ₉ heteroaryl , C _? C ,, aralkyl or CC,. heteroaralkyl, and R and R 'are hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₈ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? -C ₁₁ aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _H aralkenyl, or C _? J C ₁₀ heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl are in turn substituted or substituted with one of the above; p is 0 or 1, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. 3. A compound according to claim 1, characterized in that X is a linear or branched C ₂ -C _2Q alkylene, -alkenylene, C ₃ -C _I2 -cikloalkilen, -cycloalkenylene, C ₃ -C ₁₁ -heterocikloalkilen or heterocycloalkenylene with hetero atoms, selected from the group -O-, -S- and -N-. Compound according to claim 1, characterized in that X is substituted by a substituent selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2 , nitro, NH ₂ , cyano, SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y , C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₁ C, ₂ alkoxy, C ₃ -C, ₂ cycloalkyl, C ₃ -C _{) 2} cycloalkenyl, C 1 -C 4 heterocycloalkyl, C ₂ C ₁ -heterocycloalkenyl, C ₆ -C _1Q aryl, C ₆ -C _1Q aryloxy, C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ - C _n aralkyl, C ₇ -C _H aralkyloxy, C ₆ -C _1Q heteroaralkyl, C _g -C _n aralkenyl, C _; C _{] ()} heteroaralkenyl, primary amino, amino seconds, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and 124 aminocarbonylamide, wherein R. hydrogen, M, CC, alkyl, CC / alkenyl, C-C cycloalkyl, C ₂ -C [[heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _t [aralkyl or C ₆ C, ₀ heteroaralkyl, R _u is hydrogen, C, -C _{| 2} alkyl, C ₂ -C _I2 alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C [[heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? -C [[aralkyl or C ₆ -C ₁₀ heteroaralkyl, and R ₂ and R _{2 () 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 [[heterocycloalkyl, C ₂ -C [[heterocycloalkenyl, C ₆ -C _{1 ()} aryl, C ₅ C ₉ heteroaryl, C ₇ -C] aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g - C [aralkenyl, or C _? C ₁₀ heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl being unsubstituted, substituted or substituted and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. Compound according to claim 1, characterized in that X is a 1,2-diol residue corresponding to formula II: H H H where are they R _s and R ₆ independently of one another are hydrogen, C ₁ -C ₁₂ alkyl, C ₃ -C, ₂ cycloalkyl, C ₂ C, [heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ - C 'aralkyl or C ₆ -C, _O heteroaralkyl, or R and R ₆ together with the group -CH-CH-, C ₃ -C ₁₂ cycloalkylene, C ₃ -C _{] 7} cycloalkenylene, C ₇ -C j [heterocycloalkylene and C ₃ -C [[heterocycloalkenylene with heteroatoms selected from the group -O-, -S- and -N-; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted with one or more substituents, 125 selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2 , nitro, NH ₂ , cyano, SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y , C 1 -C ₁₂ alkyl, C ₇ -C ₁₂ alkenyl, O ₍ C ₍₂ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C, [heterocycloalkyl, CCj [heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₆ -C _] aryloxy, C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ -C _to aralkyl, C ₇ -C [[aralkyloxy, C ₆ - C ₁₀ heteroaralkyl, C _8-c [aralkenyl, _C? Cjheteroaralkenil, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M, C [-C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, CC..heterocikloalkil, CC. _n aryl, C -C heteroaryl, _Q, CC..aralkil or C and C _{1 ()} lieteroaralkil, R is hydrogen , C ₁ -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C _1-6 heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroanl, C ₇ -C ₁ jaralkyl or C ₆ - C ₁₀ hetero ar alkyl, and st a R _{s 2} and R 4 hydrogen, C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ C ₁₂ cycloalkenyl, C ₂ -C ₁ [heterocycloalkyl, C ₂ -C ₁ [heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ C ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, Cg-CJ aralkenyl, or C _? C ₁₀ heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl being unsubstituted, substituted or substituted and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. Compound according to claim 5, characterized in that R ₅ and R _{f 1} (a) are unsubstituted or substituted by C 1 -C 6 alkyl or C 1 -C ₁₂ alkoxy (b) together with the group -CH-CH-5- to The 8-membered carbocyclic ring (c) together with the group -CH-CH- 5- to 8-membered heterocarbocyclic ring (d) independently of one another hydrogen, unsubstituted C 1 -C 6 alkyl or C 1 -C ₂ alkyl which is substituted with a substituent selected from the group consisting of -C (O) OR _sl , -OC (O) R _s4 , -C (O) ONa or -C (O) OK, primary 'amino, amino seconds, C ₃ -C ₃ cycloalkyl , C 1 -C ₆ alkoxy, phenyloxy and benzyloxy; unsubstituted C ₃ -C _]? cycloalkyl or 126 C ₃ -C ₁₂ cycloalkyl which is substituted with a substituent selected from the group consisting of -C (O) OR _E, OC (O) R _s4, -C (O) ONa or -C (O) OK, primary amino, amino seconds, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, phenyloxy and benzyloxy; C ₆ -C _{1 ()} aryl, which is unsubstituted or substituted by -C (O) OR _sl , -OC (O) R ₄ , -C (O) ONa or -C (O) OK, the primary amino, the secondary amino , C 1 -C ₆ alkyl or C ₁ -C ₆ alkoxy; C ₃ -C ₉ heteroaryl having 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen atoms, or C _? -C ₁₂ aralkyl, which is unsubstituted or substituted by -C (O) OR _E, OC (O) R _s4, -C (O) ONa or -C (O) OK, primary amino, secondary amino, _C₁-6 alkyl or C? -C ₆ alkoxy; (e) together with the group -CH-CH- a 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 atoms; or (f) together with the group -CH-CH-C ₃ -C ₁₂ cycloalkylene, C ₄ -C ₁₂ cycloalkenylene, C ₂ -Cheterocycloalkylene and C ₃ -C ₁ [heterocycloalkenylene with heteroatoms selected from -O-, -S- and -N-; wherein the 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 _gl , 0C (O) R _s4 , C (O) R _s2 , nitro, NH ₂ , cyano, S0 ₃ M _y , OSO ₃ M _y , NR 4 SO 4, C ₁ -C ₄ alkyl, C ₂ -C ₁₂ alkenyl, C, C ₁₂ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C ₁₁ heterocycloalkyl, C ₂ -Cheterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy, C ₅ -C ₉ heteroaryl, C _g -C ₉ heteroaryloxy, C 1 -C 6 aralkyl , C ₇ -C _H aralkyloxy. C ₆ -C ₁₀ heteroaralkyl, C _g -C _n aralkenyl, C ₇ C ₁₀ heteroaralkenyl, primary amino, seconds amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where R _{sl is} hydrogen. M, C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₉ -C _t [heterocycloalkyl, C ₆ -C _(O aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _J j aralkyl or C ₆ C _{1 ()} heteroaralkyl, R 4 is hydrogen, C 1 -C ₁₂ alkyl, C ₁ -C ₁₂ alkenyl, C ₃ -C _p cycloalkyl, C ₇ C [[heterocycloalkyl, C ₆ -C, _o aryl, C ₅ -C ₉ heteroaryl, C / C ₆ aralkyl or C ₆ -C ₁₀ heteroaralkyl, and R _p and R _{20 are} hydrogen, C 1 -C ₁₂ alkyl, C 1 -C ₁₂ alkenyl, C ₃ -C _{] 2} cycloalkyl, C ₃ 127 C ₂ cycloalkenyl, C ₉ -C, [heterocycloalkyl, C ₂ -C, [heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ C ₉ heteroaryl, C ₇ -C _H aralkyl, C _r -C _{] 0} heteroaralkyl, C _x -C _H aralkenyl or C _? C _{1 ()} heteroaralkemyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl being unsubstituted or substituted by the above or unsubstituted substituents, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. I A compound according to claim 6, wherein R ₅ and R _{f are} taken together with the group -CH-CHC ₃ -C ₁₂ cycloalkylene or C ₂ -C [[heterocycloalkylene with nitrogen as a heteroatom; wherein the cycloalkylene and heterocycloalkylene 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 group -CH-CHC ₃ -C _{12 are} cycloalkylene or C ₂ -C ₁ heterocycloalkylene with nitrogen as a heteroatom; wherein the cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR _sl , OC (O) R ₄ , C (O) R ₂ , NR ₈ R ₉ , Cj -C ^ alkyl, R _g C (O) (NH) NCR,) -, -C (O) (NH) N ^ R ,, R ₈ S (O) ₂ (NH) N (R ₉ ) -; ^ _4θ Ν0 (Ο) (ΝΗ) N (R ₉ ) -, R _g OC (O) (NH) N (R ₉ ) -, -OC (O) (NH) _p NR _g R ₉ and R, ₀ - SO ₂ - wherein R _g , R 1, R ₁₀ and R _{40 are} independently hydrogen, OH, C 1 -C 6 alkyl, C ₁ -C ₄ alkenyl, C ₃ -C _p cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C [h ^{eterocycloalkyl} , C ₂ -C [[heterocycloalkenyl, C ₆ -C _{) ()} aryl, C ₅ -C ₉ heteroaryl, C _? C ₁₆ aralkyl, C _g -C ₁₆ aralkenyl with C ₂ -C ₆ alkenylene and C ₆ -C ₁₀ aryl, C ₆ -C ₁₅ heteroaralkyl, CC, &quot; heteroaralkenyl or di-CC. _n aryl-C 1 -C _A alkyl which are unsubstituted or substituted 6 15 o 10 loz one or more substituents selected from the group consisting of OH, halogen, C (O) OR,, OC (O) R. ₄ , C (O) R ₂ , nitro, NH ₂ , cyano, SO ₃ M _in . OSO ₃ M _y , NR _2Q SO ₃ M _y , 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 ₉ C , [heterocycloalkyl, C ₉ -C | [heterocycloalkenyl, C ₆ -C, _O aryl, C ₆ -C _{1 ()} aryloxy, CC _y heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ -C [[aralkyl, C _? -C [[aralkyloxy, C ₆ -C, _O heteroaralkyl, 128 C, -C, aralkenyl, C _{7 -C] 0} heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide; R. is hydrogen, M, C-C, alkyl, C, -C, alkenyl, C, C ₁₂ cycloalkyl, C ₂ -C _H heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ C ₁₀ heteroaralkyl, R ₄ is hydrogen, C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C _H heterocycloalkyl, C ₆ -C _1Q aryl , C ₅ -C ₉ heteroaryl, C ₇ -C _n aralkyl or C ₆ -C ₁₀ heteroaralkyl, R _{s 2} and are hydrogen, C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C 1 heterocycloalkyl, C ₂ -C ₁ [heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? C _1-6 alkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C ₁ aralkenyl, or C ₇ -C ₁₀ heteroaralkenyl, and are alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy , aralkyl, heteroaralkyl, aralkenyl and heteroaralkenyl as substituents are in turn 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 _g and R _{9 are} independently hydrogen, C 1 -C ₁₂ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₆ -C ₁₀ aryl, C ₇ -C ₁₆ aralkyl having from 1 to 6 atoms of C in the alkylene group and C ₆ -C ₁₀ aryl, C _g -C ₁₆ aralkenyl with C ₂ -C ₆ alkenylene and C ₆ C ₁₀ aryl, or di-C ₆ -C ₁₀ aryl-C [ -C ₆ alkyl, wherein R _g and R g are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, COOH, C (O) OM _y , C 1 -C 6 alkyl, C 1 -C ₆ alkoxy, C ₆ -C _{1 ()} aryl, C ₆ -C ₁₀ aryloxy, SO ₃ M _y , OSO ₃ M _y? NR _2Q SO ₃ M _y , NO ₂ , amino, primary amino, amino and CN seconds, R ₂₀ is hydrogen, C 1 -C ₁₇ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₇ C [[heterocycloalkyl, C ₂ -C ₁ [heterocycloalkenyl, C 1 -C 6 aryl, C ₅ -C ₉ heteroaryl, C ₇ C, [aralkyl, C ₆ -C, ₀ heteroaralkyl, C _g -C. , aralkenyl or C ₇ -C _l0 heteroaralkenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. 10. A compound according to claim 8, characterized in that _{R] 0} C [C ₍₇ alkyl, C ₃ -C ₁₇ cycloalkyl, C ₆ C, _o aryl, C _{7 -C) 6} aralkyl having from 1 to 6 carbon atoms, in the alkylene group and C ₆ -C, _O aryl, C _g 129 C ,, aralkenyl with C ₇ -C, alkenylene and C - ©, .aryl, or di-C 1-6 alkyl 1-6 6 610 '610 16' unsubstituted or substituted by one or more substituents selected from the group that C 1 is heterocycloalkyl, © - © j heterocyclo alkenyl, C ₆ -C _1Q aryl, © - © heteroaryl, © C _1-6 alkyl, © - ©ktop etheroalkyl, © - ©, aralkenyl or C ₇ -C, ₀ heteroarakenyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. Compound according to claim 10, characterized in that R is C ₁ - ₂ alkyl, C ₁ -C ₁₂ cycloalkyl, C ₁ -C ₁₀ aryl, C ₇ - ₆ aralkyl of 1 to 6 C atoms in the alkylene group and C ₆ - C ₁₀ aryl unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, carboxyl, C (O) 0M _y , C ₁ -C ₂ alkyl, C ₁ -C 6 alkoxy, C 1 -Caryl, SO ₃ M _y , nitro, amino, primary amino, seconds amino and cyano; or © - © ₆ aralkenyl with C- © alkenylene and CC, _n aryl, or di-CC, _aryl-C- © alkyl. A compound according to claim 8, characterized in that R ₅ and R ₆ together with the group -CH-CH 1 -C, cycloalkylene or CC, heterocycloalkylene with nitrogen as a heteroatom, wherein 3 12 2 13 ^{J are} cycloalkylene and heterocycloalkylene unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2 , unsubstituted or substituted by one or more © -C ₁₂ alkoxy, R ₁₀ is C 1 -C 6, alkyl, C ₁ -C ₁₀ aryl or C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more C 1 -, cycloalkyl cycloalkyl or C 1 -Caryl, and are alkyl, cycloalkenyl, cycloalkyl and aryl as * substituents in turn unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR _with j, and OC (O) R _s4 'wherein R is _sl , M _y or 130 C ₍ -C ₁₂ alkyl, and R 2 is C 1 -C 4 alkyl, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. Compound according to claim 12, characterized in that R ₅ and R _{g are} together with the group -CH-CHcyclohexylene. 14. A compound according to claim 8, characterized in that R ₅ and R _fi, together with the group -CH-CHpiperidilen. 15. A compound according to claim 14, characterized in that R ₅ and R ₆ together with the -CH-CH- group, piperidylene, wherein the heteroatom is unsubstituted or substituted with a substituent selected from the group consisting of C (O) OR _E , C (O) R _{s 2} , C (O) NR _g R ₉ , NH ₂ , SO ₃ M _y , C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₁ -C ₄ alkoxy, C ₃ -C ₁₂ cycloalkyl , C ₃ -C ₁₂ cycloalkenyl, CC, heterocycloalkyl, CC. .heterocycloalkenyl, C, -C, aryl, C, -C. aryloxy, CC ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ -C _n aralkyl, C ₇ -C aralkyloxy, C ₆ -C ₁₀ heteroaralkyl, C _g -C _H aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino, amino seconds, sulfonyl, sulfonamide, sulfonhydrazide, and one or more C atoms in the ring are unsubstituted or substituted by one or more substituents selected from the group consisting of consists of OH, OC (O) R ₄ , NH ₂ , OSO ₃ M _y , NR ₂₀ SO ₃ M _y , C 1 -C 4 alkoxy, C ₆ -C _w aryloxy, C ₅ C ₉ heteroaryloxy, C ₇ -C _H aralkyloxy , primary amino, secondary amino, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M, C-C ^ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C _S cycloalkyl, C ₂ -C _n heterocycloalkyl, C _fi -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _n aralkyl or C ₆ C ₁₀ heteroaralkyl, R ₄ is hydrogen, C 1 -C 6 alkyl, C ₇ -C _{] 2} alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C _H heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ het eroaryl, C ₇ -C _H aralkyl or C ₆ -C ₁₀ heteroaralkyl, R _g and R ₉ are independently hydrogen, OH, C ₁ -C 6 alkyl, C ₃ -C _p cycloalkyl, C ₇ C ₁ heterocycloalkyl, C ₆ - C _{1 ()} aryl, C-C ₉ heteroaryl, C ₇ -C ₁₆ aralkyl, C ₆ -C ₁₅ heteroaralkyl, C _g C ₁₆ arylalkenyl with C ₂ -C ₆ alkenylene and C ₆ -C ₁₀ aryl, or di- C ₍ .-C ₁₀ aryl-C ₁ -C ₆ -alkyl, or R _g and R ₉ together are tetramethylene, pentamethylene, - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -, - (CH ₇ ) ₇ -S- (CH ₂ ) ₂ 131 c ₂ -c, j heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C, _O aryl, C ₅ -C ₉ heteroaryl, C _? C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, C-C 1-4 alkenyl or C ₇ -C ₁₀ heteroaralkenyl, and are alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroarylalkyl, 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. 16. A compound according to claim 15, characterized in that R ₅ and R ₆ together with the group -CHCH- piperidylene, wherein the hetero atom is unsubstituted or substituted with a substituent selected from the group consisting of C (O) OR _E, C (O) R _{s 2} , -C (O) NR _g R ₉ and R _1Q -SO ₂ -, and one or more C atoms in the ring is unsubstituted or substituted by one or more substituents selected from the group consisting of OH, NH ₂ , R _g S (O) ₂ N (R ₉ ) -, C ₇ -C _n aralkyl, where alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C 1 -C 6 alkoxy, R 11 _and i.e. CC, miki 1, CC, _n aryl or C 1 -C 6 aralkyl, which are unsubstituted or substituted with one or more Cj-C ^ alkyl, R _E is C-C ₁₂ alkyl, and R _s2 is a Cj-C ^ alkyl, C ₃ C ₁₂ cycloalkenyl, C ₃ -C ₁₂ cycloalkyl or C ₆ -C ₁₀ aryl, and the alkyl, cycloalkenyl, cycloalkyl and aryl as substituents are in turn unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR _sl , and OC (O) R _s4 'where R is _sl, M _y, or Cj-C ^ alkyl, and R ^, Cj-C ^ alkyl, 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 1 is. and R _(i together with the group -CH-CHpiperidylene which is unsubstituted or substituted by one or more substituents selected from 132 OC (O) NR _g R ₉ and R _{10 O} -SO ₂ -, where R _{9 is} hydrogen, and R _{g is} C, -C, ₂ alkyl, C ₆ -C _w aryl or C _? Cj j aralkyl, wherein the alkyl, aryl and aralkyl are unsubstituted or substituted by one or more C, -C ₁₂ alkoxy or C ^ C ,, aralkyloxy, R, _on the C-C ^ alkyl, C ₆ -C _1Q aryl or C ₇ -C _n aralkyl are unsubstituted or substituted by one or more C, -C "alkyl, _{R, and} U is hydrogen, C, C, _{J 2} alkyl, C _{3 -C] 2} cycloalkyl, C ₂ -C _n heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? C 1-6 alkyl or C 1 -C 8 heteroaralkyl; R. and R. are CC,., alkyl, and R is, CC .. alkyl. C, C ₁₂ cycloalkenyl, C ₃ -C ₁₂ cycloalkyl or C ₆ -C _1Q aryl, and the alkyl, cycloalkenyl, cycloalkyl and aryl as substituents are in turn unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C (O) OR _sl , and OC (O) R _s4 'where R is _sl , M _y or C 1 -C 6 alkyl and R ₄ is C ₄ , C 1 -C 6 alkyl, y is 1 and M is a monovalent metal or is y 1/2 and M 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 _? , -C (O) CH ₃ , -C (O) C ₆ H ₅ , -C (O) (CH ₂ ) _g C (O) OCH ₃ , -C (O) [CH (OH)] ₂ C ( O) ONa, C (O) -C ₆ H _g (OH) ₃ , -C (O) C ₆ H _n , -C (O) OC ₃ H _? , -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 ₆ H ₃ (OCH ₃ ) ₂ , -S (O) ₂ -C ₄ H ₉ , -NHC (O) NHC ₆ H ₅ , -S (O) ₂ -C ₆ H ₄ CH _3> -S (O) ₂ -CH ₂ C ₆ H _s and -S (O) ₂ (CH) ₂ C _{] O} H,. A compound according to claim 1 wherein R _{7 is} C ₁ -C ₆ alkyl. A compound according to claim 1, characterized in that the substituents for R _{2 are} selected from halogen, -C (O) OM _y , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, phenyl, naphthyl, -SO ₃ M _y , C, C _{12 of the} prime amino, C, -C ₂₀ second amino, -SO ₂ -NR _g R ₉ and -C (O) -NR _g R ₉ , where R _g and R _{9 are} independently of one another H, C C ₁ -C ₄ alkyl, C ₇ -C ₄ hydroxyalkyl, phenyl or benzyl, or R _g and R _Q together with the N atom are morpholino, thiomorpholine, pyrrolidino or piperidino. 133 21. A compound according to claim 1, characterized in that R ₉ is hydrogen, unsubstituted C ₁ -C _fi alkyl or Cl-C ₆ alkyl substituted with C (O) OH, -C (O) ONa, -C (O ) OK, -OH, -C (O) -NR _g R ₉ or -SO ₂ -NR _g R ₉ where R _{g is} H, C 1 -C ₄ alkyl, C ₂ -C ₄ hydroxyalkyl, phenyl or benzyl, and R _g independently has the meaning of R _g , whether R _g and R ₉ together are tetramethylene, pentamethylene or -CH ₂ CH ₂ o-ch ₂ ch ₂ -. A compound according to claim 21, wherein R, hydrogen, methyl, ethyl, HO (O) CCH ₂ CH ₂ -, NaOC (O) CH ₂ CH ₂ - or R _g R ₉ NC (O) CH ₂ CH ₂ -, and R _g and R _{9 are} independently H, C ₁ -C ₄ alkyl, C ₂ -C ₄ hydroxyalkyl, phenyl, benzyl, or together morpholino. A compound according to claim 1, characterized in that the second substituent in R 1 has from 1 to 20 C atoms. Compound according to claim 23, characterized in that the second substituent is selected from the group consisting of unsubstituted and substituted C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C _n heterocycloalkyl, C ₁ -C 6 heterocycloalkenyl, C _fi C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _n aralkenyl and C _? C ₁₀ heteroaralkenyl. A compound according to claim 24, wherein the second substituent is substituted methyl or 2-substituted ethyl or cyclohexyl. A compound according to claim 1, wherein R 1 corresponds to a group of formula III: (HI). 134 where it is R _{3 is} hydrogen or M _y ; and R ₄ is C ₁ -C ₄ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ C ₁₂ cycloalkenyl, C ₂ -C, [heterocycloalkyl, C ₂ -C ₁ [heterocycloalkenyl, C ₆ -C, _O aryl, C _{5 9} heteroaryl, C ₇ -C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, C ₈ -C _n aralkenyl or C _? C is heteroaralkenyl unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2 , nitro, NH ₂ , cyano, SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y , C 1 -C 6 alkyl, C _? -C [ ₂ alkenyl, C ₁ -C ₁₂ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C, -Cj [heterocycloalkyl, C ₂ Cj [heterocycloalkenyl, C ₆ -C _w aryl, C ₆ -C ₁₀ aryloxy , C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ -C [[aralkyl, C ₇ -C _n aralkyloxy, C ₆ -C _{I ()} heteroaralkyl, C _g -C [[aralkenyl, C _? C [heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M _y, Cl-C ₁₂ alkyl, _C? -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C [[heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? -C [aralkyl or CCjheteroaralkil, R _s4 is hydrogen, Cj-C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C j [heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? -C ₁ -alkyl or C ₆ -C ₁₀ heteroaralkyl, and R _{2 is 2} and R 4 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 ₁ [heterocycloalkyl, C ₂ -C ₁ [heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? C 1-3 alkyl, C ₈ -C 6 heteroaralkyl, C ₈ -C _H aralkenyl or C ₇ -C ₆ heteroaralkenyl, and are alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxyalkyl, arylalkyl, arylalkyl and heteroaralkenyl in turn unsubstituted or substituted with 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 compound according to claim 26 wherein R _? hydrogen or M, and R ₄ (a) is 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, amino seconds, C, 135 _C12 sulfonyl, carbamide, carbamate, carbhydrazide, sulfonamide, sulfonhydrazide, aminocarbonylamido, C ₃ -C ₁₂ cycloalkyl, C ^ -C ^ alkoxy, phenyloxy and benzyloxy, unsubstituted C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkyl, which is substituted with one or more substituents selected from the group consisting of C ₃ -C ₁₂ cycloalkyl, C ₁ -C _fi alkyl, C _t C _fi alkoxy, C -C ₁₂ sulfonyl, phenyloxy and benzyloxy; C ₆ -C _1Q aryl; C ₃ -C ₉ heteroaryl having 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen atoms; C _? C 1-6 aralkyl with C 1-8 alkyl and C-C _and aryl; C 1 -C ₆ heteroaryl with CC 1 alkyl and CC ₁₀ heteroaryl having 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to 5 carbon atoms; C ₆ -C, aryl, C ₃ -C ₉ heteroaryl with 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen atoms, C _? C ,, aralkyl with CC.alkyl and C, -C. _n aryl, CC, .heteroaralkyl with CC.alkyl and CC ₁₀ heteroaryl with 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen atoms and a total of 3 to 5 carbon atoms which are substituted by one or more substituents selected from the group consisting of OH, halogen, _{C₁-p-sulfonyl,} carboxyl, C (O) OM _y, Cl-C ₁₂ alkyl, C _{1-C g} alkoxy, C _{g-C 10} aryl, SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y , nitro, NH ₂ , primary amino, seconds amino, carbamide, carbamate, sulfonamide and cyano, where y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal , or (b) C 1 -C ₁₂ alkyl or C ₇ -C _n aralkyl unsubstituted or substituted with one or more substituents selected from the group consisting of: OH, halogen, C (O) OR _sl , OC (O ) R _s4 , C (O) R ₂ , nitro, NH ₂ , cyano, SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y , C ₁ -C ₄ alkyl, C ₂ -C, ₂ alchel, C , -C ₁₂ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C _{] 2} cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ C _H heterocycloalkemyl, C ₆ -C, ₀ aryl , C ₆ -C ₁₀ aryloxy, C-C ₉ heteroaryl, C _g -C ₉ heteroaryloxy, C ₇ -C _H aralkyl, C ₇ -C ₁₀ aralkyloxy, C ₆ -C ₁₀ heteroaralkyl, C ₈ -C _n aralkenyl , C _? C ₁₀ heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, MC, -C ₁₂ alkyl, C, -C ₁₂ alkenyl, C ₃ - C _p cycloalkyl, C ₂ -C _H heterocycloalkyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C _{7 -C]]} aralkyl, or C _g 136 C ₁₀ heteroaralkyl, R ₄ is hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C, C [[heterocycloalkyl, C ₆ -C, ₀ aryl, C ₅ -C ₉ heteroaryl , C _? -C [jaralkyl or C ₆ -C ₁₀ heteroaralkyl, and R _{2 is 2} and R 4 is hydrogen, C 1 -C ₁₇ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C 4 cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C [[heterocycloalkyl, C ₂ -C ₁ [heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ C _1-6 alkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C [[aralkenyl or C ₇ - C ₁₀ heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroarylalkyl, aralkenyl and heteroaralkenyl are unsubstituted, unsubstituted, unsubstituted, substituted and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. 28. The compound of claim 27 wherein R. is hydrogen, K or Na. A compound according to claim 27, wherein R _{4 is} methyl, ethyl, n- or i-propyl and n-, or t-butyl, cyclohexyl, naphthyl, phenyl, benzyl, naphthylmethyl, 2-phenylethyl, 3-phenylpropyl , cyclohexylmethyl, 2-cyclohexylethyl, furanyl, pyridinyl or pyrimidinyl. A compound according to claim 27, characterized in that carbamido, carbhydrazido, sulfonamido, sulfonhydrazido, aminocarbonylamide and carbamate as substituents for R ₄ represent groups of the formulas R _g NHC (O) N (R ₉ ) -, R _g OC (O ) N (R ₉ ) -, R _g C (O) (NH) _p N (R ₉ ) - and R _g S (O) ₂ (NH) N (R ₉ ) -, where R _{g is} preferably H, C [-C ₁₂ alkyl, C ₅ or C ₆ cycloalkyl, C ₅ - or C ₆ cycloalkylmethyl, or -ethyl-, C ₅ - or C ₆ heterocycloalkyl, C ₅ - or C ₆ heterocycloalkylmethyl or-ethyl-, phenyl, naphthyl, benzyl, 2-phenylethyl, di-phenylmethyl, which are unsubstituted or substituted by one or more substituents in the group consisting of OH, NH ,, C [-C _g primamino, C ₂ -C ₁₄ seconds amino, NO ,, -CN, -F, -Cl, C (O) OH, -C (O) ONa, -SO ₃ H, -OSO ₃ Na, NR _2Q SO ₃ Na, where R _{20 is} hydrogen, C, -C ,, alkyl, C ₂ -C _1? alkenyl, C ₃ -C, cycloalkyl, C ₃ -C, cycloalkenyl, C, -C [[heterocycloalkyl, C, C 1 [heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? -C ,, aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C ₁ [aralkenyl or C ₇ -C ₁₀ heteroaralkenyl and -SO ₃ Na, C 1 -C ₄ alkyl, C 1 -C ₄ alkoxy and phenyl, 137 and R _{y is} H, C 1 -C ₁₀ alkyl, phenyl, naphthyl, benzyl, 2-phenylethyl or phenyl-CH = CH-CH ₂ , and p is O or 1. A compound according to claim 27, wherein R ₄ (a) is a urea substituted alkyl group R _g -C (O) NR _y - (CH ₂ ) _n - where n is 1 or 2, R _g is hydrogen; C -C. »Alkyl, C, -C. "Cycloalkyl, CC." Aryl or CC, .alkyl with C, -C. Alkyl and C ₆ -C ₁₀ aryl, wherein alkyl, cycloalkyl, aryl and aralkyl are unsubstituted or substituted with one or more substituents selected from the group consisting of it consists of OH, halogen, carboxyl, C (O) OM _y , C 1 -C ₁₂ alkyl, C ₁ -C ₈ alkoxy, C ₆ -C ₁₀ aryl, SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y , C (O) OR _sl , OC (O) R ₄ , nitro, amino and cyano; or C _g -C _H aralkenyl with C ₂ C ₆ alkenyl and C ₆ -C ₁₀ aryl, or di-C 1 -C 4 aryl-C 1 -C 6 alkyl; and R _{y is} H, unbranched or branched C ₁ -C ₁₀ alkyl, C ₅ - or C ₆ cycloalkyl, C ₅ - or C ₆ cycloalkylmethyl, or -ethyl, phenyl, naphthyl or benzyl, 2-phenylethyl or phenyl-CH = CH-CH ₂ -; y is 1 and M is an alkali metal or y is 1/2 and M is an alkaline earth metal, R ₂₀ is hydrogen, alkyl, C ₂ -C _p alkenyl, C ₃ C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C 1 -C Heterocycloalkyl, C 1 -C 6 heterocycloalkenyl, C _g C 6 aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, Cg-CHaralkenyl or C ₇ C. »heteroaralkenyl, R, is hydrogen , M, C.-C. "Alkyl, C-C ,, alkenyl, CC," cyloalkyl, C "C" heterocycloalkyl, C-C, "aryl, C, -C" heteroaryl, CC ,, aralkyl or CC, "heteroaralkyl and R. is hydrogen, CC. "Alkyl, CC." Alkenyl, C "-C." Cycloalkyl, C "-C. Heterocycloalkyl, C, Cmaryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C ₁₀ heteroaralkyl; (b) a sulfonamide substituted alkyl group R _g -SO ₂ NR ₉ - (CH ₂ ) _n -, wherein R _g , R ₉ and n have the meanings given in (a); (c) an aminocarbonylamide or carbamate substituted alkyl group R ₉ NHC (O) NH (CH ₂ ) _n or R ₉ OC (O) NH (CH ₂ ) _n , where R _{y has the} meanings indicated in (a) and additionally phenyl and n are as indicated in (a); (d) a carbhydrazido substituted alkyl group R _g C (O) NHNR ₉ (CH,) _n , wherein R _g , R ₉ and n have the meanings indicated in (a); or 138 (e) a sulfonhydrazido substituted alkyl group R _g -SO ₂ -NHNR ₉ - (CH ₂ ) _n , wherein R _g , R ₉ and n have the meanings given in (a). A compound according to claim 27, wherein R ₄ (a) is an amide R _g C (O) N (R ₉ ) (CH ₂ ) _n - or R _g S (O) ₂ N (R ₉ ) (CH ₂ ) _n - wherein R _g and R _(J independently of one another are hydrogen, unsubstituted C 1 -C ₁₂ alkyl, C 1 -C ₁₂ alkyl substituted with one or more substituents selected from the group consisting of OH, halogen , carboxyl, C (O) ONa, C 1 -C 6 alkyl, C ₁ -C ₈ alkoxy, C ₆ -C _1Q aryl, SO ₃ H, OSO ₃ Na, NR _2Q SO ₃ Na, SO ₃ Na, nitro and cyano; unsubstituted C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkyl substituted with one or more OH, unsubstituted C ₆ -C _1Q aryl, unsubstituted C ₇ -C ₁₂ aralkyl with C, -C alkyl and C-C _and aryl, CC _1A aryl or CC, .alkyl with CC, alkyl and CC _w aryl substituted with one or more substituents selected from the group consisting of OH, halogen, carboxyl, C (O) ONa, -C (O) OK , C-C ^ alkyl, C _{[-C 6} alkoxy, C ₆ -C _1Q aryl, SO ₃ Na, OSO ₃ Na, NR ^ SC ^ to C (O) OR _E, OC (O) R _s4, nitro, , amino and cyano, R ₂₀ is hydrogen, C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C 1 heterocycloalkyl, C ₂ -C _n heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₅ -C _g heteroaryl, C ₇ C ₁ aralkyl, C ₆ -C _1Q heteroaralkyl, C _g -C _n aralkenyl or C ₇ -C ₁₀ heteroaralkenyl, R _E is hydrogen, M, C.-C ,, alkyl, CC..alkenil C -C..cikloalkil, CC. .heterocikloalkil, CC aryl, C Cnheteroaril, C ₇ -C _H aralkyl, or C ₆ -C ₁₀ heteroaralkyl, and R _s4 is hydrogen, Cj-C ^ alkyl, C ₇ C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C ₁ heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C _? C _n aralkyl or C ₆ -C ₁₀ heteroaryl, and n is 2 or 1; or (b) sulfonamide R _g S (O) ₂ N (R ₉ ) (CH ₂ ) _n , wherein R _{g is} C 1 -C ₁₂ alkyl which is unsubstituted or substituted by one or more halogen atoms; or C ₆ -C _1Q aryl substituted with one or more C-C ₄ alkyl, C 1 -C ₄ alkoxy, halogens, -CN or -NO ₇ , and R ₉ is hydrogen or isobutyl, and n is 2 or 1 ; or (c) aminocarbonylamide R _g -NH-C (O) NH (CH ₂ ) _n -, where R _{g is} C 1 -C 6 alkyl or C ₆ -C _{) ()} aryl which is unsubstituted or substituted by halogen, - CN, -NO _{2, C]} -C ₄ alkyl, C? -C _'4 alkoxy, C ₅ - or C ₆ cycloalkyl, C ₆ -C, ₀ aryl or C _{7 -C) 7} aralkyl, and n is 2 or 1; or 139 (d) aminoalkyl R _gI R ₉ , N (CH ₂ ) _n , wherein R _gl and R ₉ , independently of one another, are hydrogen, unsubstituted C 1 -C alkyl; C 1 -C ₁₂ alkyl which is substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R ₄ , C (O) NR _h R ₁₂ , C 1 -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C, _O aryl, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NR 4 SO Na, nitro, amino and cyano; unsubstituted C ₃ -C ₁ cycloalkyl, C ₃ -C _1? cycloalkyl substituted with one or more OH, C-C, aryl; C.-C, .aralkil with a C -C alkyl, and C, C, _n aryl; or CC, .alkenyl with C.-C.alkenyl and CC, .aryl, wherein aryl and aryl in aralkyl and aralkenyl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O ) OR _sl , OC (O) R _s4 , -C (O) ONa, -C (O) OK, -C (O) -NR _n R ₁₂ , C, -C ₁₂ alkyl, C 1 -C ₆ alkoxy, C _{6-C, o} aryl, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NR _2Q SO ₃ Na, nitro, amino and cyano, wherein n is 2 and preferably 1, and R is _sl hydrogen, K or Na, C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C _H hetero cycloalkyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C ₁₀ heteroaralkyl, R ₄ is hydrogen, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C ₁ [heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ C ₉ heteroaryl, C ₇ -C _1-6 alkyl or C ₆ -C ₁₀ heteroaralkyl, R _u is H, C 1 -C ₄ alkyl, C ₂ C ₄ hydroxyalkyl, phenyl, or benzyl, and R _{12 has an} independent meaning for R _n , or R _n and R ₁₂ together tetramethylene, pentamethylene or CH ₂ CH ₂ -O-CH ₂ CH ₂ , and R _{20 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 [[heterocycloalkyl, C ₂ C [[heterocycloalkenyl, C ₆ -C ₁₀ aryl, C _with -C ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C _{1 ()} heteroaralkyl, C _g -C [[aralkenyl or C ₇ -C [ ₀ heteroaralkenyl]. A compound according to claim 32, wherein R _{4 is an} amide R _g C (O) N (R ₉ ) (CH,) _n - or R _g S (O), N (R ₉ ) (CH ₂ ) _n - wherein R _{g is} unsubstituted C 1 -C ₁₇ alkyl; C [C _g alkyl, which is substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) ONa and C _{6 -C] 0} aryl; unsubstituted C ₃ -C _1? cycloalkyl; C ₃ -C _g cycloalkyl substituted with one or more OH, unsubstituted C ₆ -C, _O aryl or C ₇ -C ₇ aralkyl with C 1 -C alkyl; CC, aryl, CC ₁₇ aralkyl with CC _r alkyl and CC _and aryl or CC. Aralkenyl with C ₇ -C ₆ alkenyl and C ₆ -C ₁₀ aryl substituted with one or more substituents, 140 selected from the group consisting of halogen, -C (O) OH, C (O) ONa, C, -C _p alkyl, ©ktop alkoxy, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NF © S (© Na, where © _{θ is} hydrogen, © - © ₂ alkyl, © spok ₂ alkenyl, © - © ₂ cycloalkyl, © -C, ₂ cycloalkenyl, © - © jheterocycloalkyl, © Cjjheterocycloalkenyl, © - © _o aryl, © - © heteroaryl, © - © jaralkyl, © - © _O heteroaralkyl, © -C 1 aralkenyl or © - © _O heteroaralkenyl, and nitro and cyano; and is hydrogen; unsubstituted C1-C6 alkyl, unsubstituted C-Caryl, unsubstituted C-C, aralkyl with C, 16 6 10/12 1 alkyl and C-Caryl; or C-C ,, aralkenyl with © - © alkenyl and C - © .anions, and n o o 10 o Io 2 6 6 10 is 2 or 1. 34. A compound according to claim 32, characterized in that the amide © © C (O) N (©) (CH _{2) n} -, wherein © unsubstituted © - © ₂ alkyl; C 1 -C alkyl which is substituted by one or more substituents selected from the group consisting of cyclohexyl, OH, halogen, -C (O) OH, -C (O) ONa and phenyl; unsubstituted © - © ₂ cycloalkyl; © - © ₂ cycloalkyl substituted with one or more OH; unsubstituted © - © _o aryl; © - © _{on the} aryl which is substituted by one or more substituents selected from the group consisting of halogen, C (O) ONa, C (O) OH, © - © alkyl, © - © alkoxy, phenyl, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NHSO ₃ Na, nitro and cyano; or © -C ,, aralkyl with © - © alkyl and © - © .arilom, and R _o is hydrogen; unsubstituted C 1-6 alkyl; unsubstituted © - ©. aralkyl with CC.alkyl and C, -C .. aryl; or © 16 7 16 16 6 10 o C _1-6 aralkenyl with C _1-6 alkenyl and C ₁ -C ₁₀ aryl, and n or 2 or 1. A compound according to claim 34, characterized in that © is unsubstituted C ₁ -C ₁₂ alkyl, C 1-6 alkyl substituted with one or more substituents selected from the group consisting of OH, halogen, -C (O) OH , -C (O) ONa and phenyl; unsubstituted C ₁ -C ₂ cycloalkyl; © - © ₂ cycloalkyl which is substituted by one or more OH, unsubstituted © C, _o aryl; © -C ₁₀ aryl, which is substituted by one or more substituents selected from the group consisting of halogen, -C (O) OH, -C (O) ONa, © - © alkyl, © - © alkoxy, -SO ₃ H, SO ₃ Na, OSO ₃ Na, NHSO ₃ Na, nitro and cyano; or unsubstituted © -C, ₆ aralkyl with C, 141 C ₆ alkyl and C ₆ -C ₁₀ aryl, and R _(J H, C ₁ -C ₄ alkyl, phenyl-CH ₂ -, phenyl-CH, 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} aminoalkyl R ₈ , R ₉ , NCH ₂ - wherein R _g and R 4 are independently hydrogen; Cl-C _g alkyl, cyclopentyl, cyclohexyl, C ₅ - or C ₆ cycloalkylmethyl, phenyl-C ₁ -C ₄ alkyl or phenyl-C ₂ -C ₄ alkenyl. A compound according to claim 32, wherein R _{4 is an} amine R _g , R ₉ , NCH ₂ -, where R _g , and R g, independently of one another, are H, C 1 -C ₆ alkyl, phenyl-C ₁ - or -C ₂ alkyl. A compound according to claim 26, wherein R _{4 is} C ₇ -C _n aralkyl, C ₃ -C ₁₂ cycloalkyl or C 1 -C 6 alkyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of it is composed of NH ₂ , C ₃ -C ₁ cycloalkyl, the primary amino, amino seconds, sulfonamide, urea and aminocarbonylamido. A compound according to claim 38, characterized in that the substituents for C 1 -C 6 alkyl are selected from the group consisting of NH ₂ , cyclohexyl, C ₆ -C _1Q aryl, R _g C (O) N (R ₉ ) -, R ^ OJN ^) -, R _g NHC (O) NR ₉ - and R _g , R ₉ , N-, where R _g and R _{y are} independently hydrogen, C ₁ -C _{J 2} alkyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C [[heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C ₁₀ heteroaralkyl, and R _g and R ₉ are independently from each other hydrogen, OH, C ₁ -C ₄ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C [[heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₁₀ heteroaryl, C ₁ -C ₁₀ aralkyl or C , -C. "Heteroaralkyl 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) OR _s2 , nitro, NH ,, cyano, -SO ₃ M _y , OSO ₃ M _y , NR, ₀ SO ₃ M _y , C [-C _{] 2} alkyl, C, -C _{] 7} alkenyl, C | -C [, alkoxy , C ₃ -C 4 cycloalkyl, C ₃ C [ ₂ cycloalkenyl, C ₂ -C, [heterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₆ t C, aryloxy, CC.heteroaryl, C -Cheteroaryloxy, C ₇ -C..alkyl, CC..alkyloxy, CC ₁₀ heteroaralkyl, C _g -C [[aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino, sec. 142, amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M, C-C ₁₂ alkyl, C _1Q heteroaralkyl, and R _s2 and R ₍₎ is hydrogen, C ₁ -C _J2 alkyl, C ₂ -C _[2 alkenyl, C ₃ -C ₁₂ cycloalkyl, C, -C, _n cycloalkenyl, CC, .heterocikloalkil, CC, .heterocycloalkenyl, CC, 'aryl, C C heteroaryl, C _? -C _n aralkyl, C ₆ -C, _O heteroalkyl, C _g -C _n aralkenyl or C _? C _{10 is} heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl are unsubstituted or substituted substituted; 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 _gl and R ₉ , taken together A compound according to claim 39, wherein R _{4 is} CH ₂ -C ₆ H ₅ , (CH ₂ ) ₂ -C ₆ H _g , cyclohexyl, methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or several substituents selected from the group consisting of NH ₂ , cyclohexyl, C ₆ -C ₁₀ aryl, R _g , R ₉ , R _g , and R 4, independently of one another, are hydrogen, C ₁ -C _p alkyl, C ₃ -C ₁₂ cycloalkyl, C ₆ C _1Q aryl or C _? -C _n aralkyl unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OM _y , nitro, cyano, monovalent metal or y 1/2 and M is divalent metal . 143 A compound according to claim 26, wherein R ₄ C ₆ H _n , 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 ₆ H „, CH ₂ NHC (O ) C _n H23, CH ₂ NHC (O) CH (C ₆ H ₅ ) ₂ , CH ₂ HNC (O) NHC ₆ H ₅ , CH ₂ NHC (O) C ₂ H4CO ₂ Na, CH ₂ NHC (O) C ₆ [(1,3,4,5) OH] ₄ H ₇ CH ₂ NHC (O) C ₆ H 4 -p-SO ₃ Na, CH ₂ NHC (O) C ₆ H ₄ OCH ₃ , CHjNHCCO ^ HiCfiHs, CH ₂ NHC (O) C ₆ H ₄ COONa, CH ₂ NHC (O) C ₆ H ₄ NO _2> CH ₂ NHC (O) C ₆ H ₄ CH ₃ , CH ₂ NHC (O) C ₁₀ H ₇ CH ₂ NHC (O) C ₆ H ₄ C1, CH ₂ NHC (O) C ₆ H 4 (3,4) C1 ₂ , CH ₂ NHC (O) C ₆ H ₄ CN, CH ₂ NHC (O) (CHOH) ₂ COONa, CH ₂ N (CH ₂ CH = CHphenyl) [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 ₆ H ₅ , CH ₂ N [C (O) C ₆ H ₅ ] (CH ₂ ) ₃ C ₆ H ₅ , CH ₂ C ₆ H ', (CH ₂ ) ₂ C ₆ H _1b 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 _{0 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 . A compound according to claim 1, characterized in that it corresponds to the formula la: where it is R8 is hydrogen or M _y ; 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 _H heterocycloalkyl, Cg-C 4 heterocycloalkemyl, C ₆ -C ₁₀ aryl, C ₅ C ₉ heteroaryl, C _? -C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, C ₈ -C _H aralkenyl or C _? C, _n heteroaralkenyl unsubstituted or substituted one or more times; R, and R, independently of one another are hydrogen, C, -C ₁₂ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₂ C _H heterocycloalkyl, C ₆ -C ₍₀ aryl, C ₃ -C ₉ heteroaryl, _C? - C ₁ [aralkyl or C ₆ -C ₁₀ heteroaralkyl, or R ₅ and R ₆ together with the group -CH-CH-, C ₃ -C _p cycloalkylene, C ₄ -C ₁₂ cycloalkenylene, C, -C _tl heterocycloalkylene and C ₃ -C [[heterocycloalkenylene with heteroatoms selected from 144 groups -Ο-, -S- and -N-; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted once or more; wherein the substituent is selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R _s4 , C (O) R _s2 , nitro, NH ,, cyano, -SO, M, OSO, M, NR, _n SO, M, CC..alkyl, C.-C 1-6 alkenyl, C, C ₁₂ alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ -Cheterocycloalkenyl , C ₆ -C ₁₀ aryl, C ₆ -C _w aryloxy, C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ -C _H aralkyl, C ₇ -C _n aralkyloxy, C ₆ -C _w heteroaralkyl, C _g -C _n aralkenyl, C ₇ C _1Q h ether o ar alkenyl, primary amino, amino seconds, amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where R _{sl is} hydrogen, M _y , Cj -C ^ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ^ C 1 heterocycloalkyl, C ₆ -C _{1 ()} aryl, C.-C ₉ heteroaryl, C ₇ -C ₁₁ aralkyl or C ₆ C _{1 () is} heteroaralkyl, R ₄ is hydrogen, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -Cheterocycloalkyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ -C ₀ heter oaralkyl, and R _{2 is} and R 2 is hydrogen, C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C 1 heterocycloalkyl, C ₂ -C _n heterocycloalkenyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C _? C _n aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _n aralkenyl or C ₇ -C ₁₀ heteroaralkenyl, and are alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl; , aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl, 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 compound according to claim 42, wherein R _{3 is} H, K or Na; R ₅ and R ₆ together with the group -CH-CH-C ₃ -C ₁₂ cycloalkylene, C ₄ -C ₁₂ cycloalkenylene, C ₂ -C _H heterocycloalkylene and C ₃ 'C 1j heterocycloalkylene with heteroatoms selected from the group -O- , -S- and -N-; which are unsubstituted or substituted one or more times; wherein the substituent is selected from the group consisting of OH, halogen, C (O) OR _sl , OC (O) R _s4 , C (O) R _p , nitro, NH ,, cyano, SO ₃ M _v , OSO ₃ M _y , NR ₂₀ SO ₃ M _v , C _f C ₁₂ alkyl, C ₂ -C, ₂ alkenyl, C, -C ₁₂ alkoxy, C ₃ 145 C, ₂ cycloalkyl, C ₃ -C, ₉ cycloalkenyl, C, -C ₁ [heterocycloalkyl, C ₂ -C [[heterocycloalkenyl, CC, aryl, CC, aryloxy, C-C.heteroaryl, CC.heteroaryloxy, CC. , aralkyl, C „olU olU jy ⁷ j 9 7 11 ⁷ 7 C [[aralkyloxy, C ₆ -C ether o aralkyl, C ₈ -C _n aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino, seconds amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonyl acid; where R is hydrogen, M, si y C, -C, .alkyl, CC, .alkenyl, C, -C, .cycloalkyl, CC ,, heterocycloalkyl, C, -C, .aryl, C1 12 ⁷ 2 12 ⁷ 3 12 ⁷ 2 II ⁷ 6 1U 5 C.heteroaryl, CC., Aralkyl or C, -C..heteroaralkyl, R. is hydrogen, C. -C..alkyl, CC ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C [heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₅ -C ₉ heteroaryl, C ₇ C ₆ aralkyl or C ₁ -C ₆ heteroaralkyl, and R 1 and R 4 are. hydrogen, C, -C, .alkyl, CC,. alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -C ₁ [heterocycloalkyl, C ₂ -C ₆ [heterocycloalkenyl, C-C, _r aryl, C _e -C 'heteroaryl, CC ,, aralkyl, CC, heteroaralkyl, CC ,, aralkenyl or C_O lu j 9/11 ^with o 1U o 11 / C ₁₀ heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl being unsubstituted, substituted or substituted and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. (a) R ₄ is a radical R ₁₂ - (CH _{2) n} - or cyclohexyl, in which n is 1 or 2, and R _J2 C-C ₁₀ alkyl, C ₅ C ₈ cycloalkyl, C ₆ -C ₁₀ aryl, or C _g -C ₁₂ aralkenyl, which are unsubstituted or substituted with a C, C ₄ alkyl, C [-C ₄ alkoxy, F, Cl, -CN or -NO _2; or R _{12 is an} amino group -NR _g , R ₉ 'and R _g and R ₉ are C 1 -C ₂ alkyl or unsubstituted or C 1 -C ₄ alkyl substituted C ₅ - or C ₆ cycloalkyl, C ₆ -C _1Q aryl, C ₇ -C ₁₂ aralkyl or C _g -C ₁₂ aralkenyl; or R _J2 is an amide group -N (R ₉₎ C (O) R _g, -N (R ₉₎ S (O) ₂ R _g, -NR ₉ C (O) NHR _g - or -NR ₉ C (O ) NHR _g , in which R _{g is} C ₆ -C ₁₀ aryl, which is unsubstituted or substituted by C 1 -C ₄ alkyl, C [-C ₄ alkoxy, F, Cl, -CN or -NO ₂ , or C [-C ₁₀ alkyl, unsubstituted or substituted by F or Cl, and R _{9 is} H, C [-C ₁₀ alkyl, C ₅ or C, cycloalkyl, C - or C-cycloalkyl-C-C 1-4 alkyl, phenyl- CC alkyl or phenyl-C-C alkenyl; 6 '5 6 16 16 26 t or is it 146 (b) R ₄ C, -C, ₂ alkyl, C ₃ -C ₁₂ cycloalkyl or C ₇ -C _H aralkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR _sl , OCCOjR ^, C (O) R _s2 , nitro, NH ₂ , cyano, -SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _y , 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 _H heterocycloalkyl, C ₂ -C _in heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₆ C _{1 ( )} aryloxy, C ₅ -C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C _? -C _n aralkyl, C ₇ -C _n aralkyloxy, C ₆ C _{1 ()} heteroaralkyl, C _g -C _n aralkenyl, C ₇ -C ₁₀ heteroaralkenyl, primary amino, seconds amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, karbohidroksamska acid and aminocarbonylamide, where R _E is hydrogen, M _y, C, -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₂ -C _n heterocycloalkyl, C ₆ -C ₁₀ aryl , C ₅ -C ₉ heteroaryl, C _? C 1 _H aralkyl or C ₆ -C ₁₀ heteroaralkyl, R 4 is hydrogen, C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ C ₁₂ cycloalkyl, C ₂ -C _n heterocycloalkyl, C ₆ -C _1Q aryl, C ₅ -C ₉ heteroaryl, C ₇ -C _H aralkyl or C ₆ C _{1 ()} heteroaralkyl, and R _{2 is} hydrogen and C 1 -C 6 alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ -Cheterocycloalkyl, C ₂ -C _H heterocycloalkenyl, C ₆ -C _1Q aryl, C ₅ C ₉ heteroaryl, C _? -C aralkyl, C ₆ -C ₁₀ heteroaralkyl, C _g -C _H ar alkenyl or C ₇ C ₁₀ heteroaralkenyl, and are alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, 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 compound according to claim 43, wherein (i) R ₄ is C ₆ H _n , C ₆ H _n -CH ₂ , C ₆ H _n -CH ₂ CH ₂ -, C ₆ H ₅ CH ₂ -, C ₆ H ₅ CH ₂ CH ₂ - or C ₆ H ₅ -CH = CH-CH ₂ -; (ii) R ₄ is C ₆ H _n , C ₆ H _n -CH ₂ , C ₆ H _n -CH ₂ CH ₂ -, C ₆ H ₅ CH ₂ -, C ₆ H ₅ CH ₂ CH ₂ -, CH, NR ₁₉ -SO ₂ R, ₈ , -CH ₂ -NR ₁₉ -C (O) R ₄₀ , CH ₂ NHC (O) NHR ₁₈ , CH ₂ HR ^ or CH ₂ N (R ₂₁ ) ₂ , where R - C ₆ H ₅ , phenyl substituted with 1 to 3 methyl or methoxy or -NO ₂ or F or Cl or C 1 -C ₄ alkyl substituted with F; R ₄₀ is phenyl which is unsubstituted or substituted 147 with 1 to 3 methyl or methoxy or -NO ₂ or F or Cl; R ₉ is H, C 1 -C ₆ alkyl, phenyl- (CH ₂ ) _z , where z is 1 to 3, phenyl-CH = CH-CH ₂ , -CH ₂ -CH (CH ₃ ) ₂ or benzyl; and -CH ₂ -CR ₂₂ R ₂₃ R ₂₄ wherein R 1 and R _{23 are} methyl, ethyl or phenyl, and R _{4 is} hydrogen, ethyl or methyl; or (iii) R ₄ C ₆ H _h , CH ₂ -C ₆ H ₅ , (CH ₂ ) ₂ -C ₆ H ₅ , methyl, ethyl or isopropyl, which are unsubstituted or substituted by one or more substituents selected from groups consisting of NH ₂ , cyclohexyl, C ₆ -C ₁₀ aryl, R _g C (O) N (R ₉ ) -, R _g S (O) ₂ N (R ₉ ) -, NR ₉ C (O) NHR _g and R _g , R ₉ , N where Rg, R ₉ , R _g , and Rg are independently hydrogen, C-C ₁₂ alkyl, C ₃ -C ₁₂ cycloalkyl, C-Caryl or C-C ,, aralkyl unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OM _y , nitro, cyano, -SO ₃ M _y , OSO ₃ M _y , NR _2Q SO ₃ M _s, C-stations, Cj -C ₁₂ alkoxy and C ₆ -C ₁₀ aryl, wherein hydrogen, Cl-C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, C ₂ C 'heterocycloalkyl, CC ,, heterocycloalkenyl, C.-C, _n aryl, CC _Q heteroaryl, C, C, aralkyl, C, -C. Jeteroalkyl, CC.aralkenyl or C.-C, _n heteroaralkenyl; y 1 and M 11 O 10 oll / iv j is a monovalent metal or y is 1/2 and M is a divalent metal. A compound according to claim 42, wherein R ₄ C ₆ H is _p CH (CH ₃ ) ₂ , CH, -phenyl, 3'2 '(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) C6H _n , CH ₂ NHC (O) CnH ₂₃ , CH ₂ NHC (O) CH (C ₆ H ₅ ) ₂ , CH ₂ HNC (O) NHC ₆ H ₅ , CH ₂ NHC (O) C ₂ H ₄ CO ₂ Na, CH ₂ NHC (O) C ₆ [(1,3,4,5) OH] ₄ H ₇ CH ₂ NHC (O) C ₆ H ₄ -p-SO ₃ Na, CH ₂ NHC (O) C ₆ H ₄ OCH ₃ , CH ₂ NHC (O) C ₆ H ₄ C ₆ H ₅ , CH ₂ NHC (O) C ₆ H ₄ COONa, CH ₂ NHC (O) C ₆ H ₄ NO ₂ , CH ₂ NHC (O) C ₆ H ₄ CH ₃ , CH ₂ NHC (O) C ₁₀ H ₇ CH ₂ NHC (O) C ₆ H ₄ Cl, CH ₂ NHC (O) C ₆ H 4 (3,4) C1 ₂ , CH ₂ NHC (O) C ₆ H ₄ CN, CH ₂ NHC (O) (CHOH) ₂ COONa, CH ₂ N (CH ₂ CH = CHphenyl) [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 ₆ H ₅ , CH ₂ N [C (O) C ₆ H ₅ ] (CH ₂ ) ₃ C ₆ H ₅ , CH ₂ C ₆ H ,, (CH ₂ ) ₂ C ₆ H „, 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, CH ₂ NHSO ₂ CF ₃ , CH ₂ NHC (O) NHC ₆ H ₅ or CH ₂ N [SO ₂ rp-metrophenyl] [ CH ₂ CH (CH ₃ ) ₂ ] ₂ . 148 A process for the preparation of compounds of formula I according to claim 1, characterized in that it comprises the etherification of a 3-OH group of a compound of formula V: in which and X have the meanings indicated in claim 1, R ₁₂ is a protecting group and R 'and R ₁₂ ' are independently hydrogen or a protecting group, with a compound of formula VI: R _r R ₁₃ (VI) in which R 1 has the meaning given in claim 1 and R _{13 is a} leaving group and eliminating the protecting groups. A process for the preparation of compounds of formula I according to claim 1, characterized in that it comprises glycosidic binding of protected fucose hydroxy ether of formula VII: (VII) wherein R ₂ and X have the meanings given in claim 1 and R _{p is a} protecting group having protected galactose of formula VIII: 149 in which R _t and R ₁₂ have the meanings given in claim 1, Z is O or S, and R is a leaving group and then removing the protecting groups from the resulting compound. 48. A compound of formula V: where it is R ₂ is hydrogen, C 1 -C ₁₂ alkyl or C ₆ aryl; wherein alkyl and aryl are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C (O) OR j, OCCOjOR ^, C (O) R ₂ , nitro, NH ₂ , cyano, SO ₃ M _y OSO ₃ M _y, NR _2Q SO ₃ M _y, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₁ -C _J2 alkoxy, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, , C ₂ C 1- [heterocycloalkyl, C ₂ -C [[heterocycloalkenyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy, C ₅ C ₉ heteroaryl, C ₅ -C ₉ heteroaryloxy, C ₇ -C _H aralkyl, C ₇ -C _n aralkyloxy, C ₆ -C ₁₀ heteroaralkyl, C ₈ -C [aralkenyl, C ₇ -Cioheteroaralkenyl, primary amino, seconds amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonyl acid, and aminocarbonylamide R _E is hydrogen, M, C [-C ₁₂ alkyl, C ₂ -C _[2 alkenyl, C ₃ C? cycloalkyl, CL-C..heterocycloalkyl, CC, _n aryl, C -Cheteroaryl, CC..aralkyl or C, C [ _O heteroaralkyl, R ^ is hydrogen, C [-C _{] 2} alkyl, C ₂ -C [ ₇ alkenyl , C ₃ -C _p cycloalkyl, C, C, heterocycloalkyl, C 1 -C. _n aryl, C.-C _n heteroaryl, C, -C., aralkyl or C, -C, heteroaralkyl, 11 o IU 3 9/11 o IU 150 and R _{2 is} hydrogen and C 1 -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₃ -C ₁₂ cycloalkyl, C, C _{] 2} cycloalkenyl, C ₂ -C _H heterocycloalkyl, C ₂ -C _n heterocycloalkenyl, C -Caryl, C ₅ C ₉ heteroaryl, C ₇ -C _n aralkyl, C ₆ -C _{1 ()} heteroaralkyl, C _g - C _n aralkenyl, or C _? C _{1 ()} heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl being unsubstituted or substituted by the above substituents, and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal; R _g and R _g together with the group -CH-CH-, C ₃ C ₁₂ cycloalkylene, C ₃ -C ₁₂ cycloalkenylene, C ₂ -C ₁₁ heterocycloalkylene and C ₃ C ₁ -heterocycloalkenylene with heteroatoms selected from the group -O-, -S - and -N-; wherein the cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more of the above substituents; R ₁₂ is a protecting group and R _{J 2} '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 it first comprises synthesizing pseudotrisaccharide-forming blocks by glycosidic binding of activated and protected galactose to a fucose-0-X-OH-forming block or glycosidically binding and activated fucose to galactose-OX-OH-forming block, then introducing the Rj group into the pseudotrisaccharide and then modifying the resulting compounds in the desired manner. A compound according to claim 1 for use in a therapeutic method for the treatment of disorders in warm-blooded beings, including humans. 51. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 alone or together with other active substances, a pharmaceutical carrier and, where appropriate, excipients.