WO1995006655A1

WO1995006655A1 - (glycosil amide) uronic acid derivatives

Info

Publication number: WO1995006655A1
Application number: PCT/EP1994/002737
Authority: WO
Inventors: Oswald Lockhoff; Burkhard Mielke; Helmut Brunner
Original assignee: Bayer Aktiengesellschaft
Priority date: 1993-08-30
Filing date: 1994-08-17
Publication date: 1995-03-09
Also published as: DE4329094A1; AU7613894A

Abstract

The present invention relates to (glycosil amide) uronic acid derivatives of general formula (I) in which the substituents have the meaning given in the specification, process for producing them and their use in medicaments.

Description

(GΙvcosylamide) uronic acid derivatives

The invention relates to (glycosylated) uronic acids and derivatives, ner processes for their preparation and their use in medicaments.

It is known that glycosylamides from aldopyranoses or from aminosugars can increase the body's immune response (Ger. Offen. DE-OS 3 213 650 AI).

The present invention now relates to (glycosylamide) uronic acid derivatives of the general formula (I),

in which

R ^{1 represents} straight-chain or branched, saturated or unsaturated alkyl having up to 25 carbon atoms,

R ^{2 represents} straight-chain or branched, saturated or unsaturated alkyl having up to 25 carbon atoms,

R ^{3 represents} hydrogen, acetyl, benzoyl or benzyl, R ⁴ independently of one another is hydrogen, C 1 -C ₇ -alkyl, hydroxymethyl,

1-hydroxy-ethyl, mercapto-methyl, 2-methylthio-ethyl, 3-aminopropyl, 3-

Ureido-propyl, 3-guanidyl-propyl, 4-amino-butyl, carboxy-methyl,

Carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl, 4-hydroxy-benzyl, 3-indolyl-methyl or 4-imidazolyl-methyl,

R ^{5 represents} hydrogen, lower alkyl or arylalkyl and

n represents a number 1, 2 or 3,

in the event that n = 2 or 3, the individual meanings for R ⁴ may be different.

The Nerbindungen invention have several asymmetrical carbon atoms. They can therefore exist in various stereochemical forms. The invention relates both to the individual isomers and to their mixtures.

Compounds of the general formula (I) in which

R ^{1 represents} a straight-chain, saturated or monounsaturated alkyl radical having 10 to 20 carbon atoms,

R ^{2 represents} a straight-chain, saturated or monounsaturated alkyl radical having 10 to 20 carbon atoms,

R ^{3 represents} hydrogen, acetyl, benzoyl or benzyl,

R ⁴ independently of one another for hydrogen, C _r to C ₇ - alkyl, hydroxymethyl, 1-hydroxyethyl, mercapto-methyl, 2-methylthio-ethyl, 3-aminopropyl, 3- Ureido-propyl, 3-guanidyl-propyl, 4-amino-butyl, carboyxy-methyl, carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl, 4-hydroxy-benzyl, 3-indolyl-methyl or 4-imidazolyl-methyl,

R ^{5 represents} hydrogen, lower alkyl or arylalkyl and

n represents a number 1, 2 or 3,

Particular preference is given to compounds of the general formula (I) in which

R ^{1 represents} a straight-chain saturated alkyl radical having 10 to 20 carbon atoms,

R ^{2 represents} a straight-chain saturated alkyl radical having 10 to 20 carbon atoms,

R ^{3 represents} hydrogen or acetyl,

R ^{4 is} independently hydrogen, C _j - to C ₇ -alkyl, hydroxymethyl, 1-hydroxyethyl, mercapto-methyl, 2-methylthio-ethyl, 3-aminopropyl, 3-

Ureido-propyl, 3-guanidyl-propyl, 4-amino-butyl, carboxy-methyl,

R ^{5 represents} hydrogen, lower alkyl or arylalkyl and n represents a number 1, 2 or 3,

Very particular preference is given to compounds of the general formula (I) in which

R ^{3 represents} hydrogen,

R ⁴ independently of one another is hydrogen, C to C ₇ -alkyl, hydroxymethyl, 1 -hydroxy-ethyl, 3-aminopropyl, 4-aminobutyl, carboxy-methyl, carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl or 4-hydroxy-benzyl,

R ^{5 represents} hydrogen and

n represents a number 1, 2 or 3,

in the event that n = 2 or 3, the individual meanings for R ⁴ may be different. In addition, a ner process for the preparation of the inventive compounds of the general formula (I) was found, characterized in that Nerbindungen of the general formula (II)

in the

R, 1, r R> 2 and R have the meaning given above,

by applying oxidative conditions to uronic acids of the general formula (in)

in the

R, 1, τ R> 2 and R have the meaning given above,

implements. In this way, the Nerbindungen of general formula (I) are obtained in which

R, 1, 1 R52 and R have the meaning given above, and n means the number 0.

The compounds of the general formula (I) in which

R ¹ , R ² , R ³ , R ⁴ , and R ^{5 have} the meaning given above and

n represents the number 1, 2 or 3,

where n = 2 or 3, the individual meanings for R ⁴ may be different,

means are obtained by using compounds of the formula (III) in which

R ¹ , R ² and R ^{3 have} the meaning given above and

n means the number 0,

with amino acids, di- or tripeptides of the general formula (IV)

in the

R ⁴ and R ^{5 have} the meaning given above and

n represents the number 1, 2 or 3, where n = 2 or 3, the individual meanings for R ⁴ may be different,

reacted with each other under the usual conditions of peptide synthesis.

The compounds of the formula (I) unsubstituted on the hydroxyl functions and on the carboxy group, in which

R ³ and R ^{5 represent} hydrogen,

can be obtained by methods of cleavage of ester derivatives or benzyl ethers customary in protective group chemistry (ex. T. Greene, Protective Groups in Organic Chemistry, John Wiley, New York (1981)).

The starting compounds of the formula (II) in which R ^{3 represents} hydrogen are known (Ger. Offen. DE-OS 3 213 650 AI).

The oxidation of the hexopyranosyl amides of the general formula (II) to the (hexopyranosyl amide) uronic acids of the formula (III) can be carried out by various processes which are known in principle. Suitable methods are, for example, the catalytic oxidation of compounds of the formula (II) in which R ³ represents hydrogen in the presence of transition metals, for example platinum, by the action of oxygen. In this process, the primary hydroxyl group is selectively oxidized to the carboxy group. This method is known in principle (K. Heyns and H. Paulsen, Advan. Carbohydr. Chem. 17 (1962) 169, and D. Keglevic, Advan. Carbohydr. Chem. 36 (1979) 57).

In the process according to the invention, however, it has proven to be more advantageous to use such compounds of the formula (II) as starting compounds in only the primary hydroxy group is unsubstituted and the secondary hydroxy groups are blocked. Suitable compounds of the formula (II) are those in which R ^{3 is} a protective group for hydroxyl functions, for example acetyl, benzoyl or benzyl.

These compounds are obtainable from the unsubstituted compounds of the formula (II) in which R ^{3 represents} hydrogen, by selective blocking of the primary hydroxy function with a protective group reagent which, owing to its chemical behavior, reacts preferentially or exclusively with the primary hydroxy function. Suitable protecting group reagents are, for example, triphenylmethyl chloride (trityl chloride) or p-methoxyphenyl-diphenyl-methyl chloride (p-methoxytrityl chloride). In the subsequent step, the unsubstituted secondary hydroxyl groups are blocked with other protective groups. Suitable protective groups for the secondary hydroxyl functions are, for example, acetyl, benzoyl or benzyl groups, the acetyl groups being preferred in the sense of the process according to the invention. The acid-labile trityl ethers can be split off selectively to obtain the substitutions on the secondary hydroxyl groups, so that the compounds of the general formula (II) are obtained in which R ^{3 represents,} for example, acetyl, benzoyl or benzyl. For the purposes of the process according to the invention, the p-methoxy trityl ethers are preferred because, compared to the triphenyl methyl ethers, they can be split off under milder acidic conditions under which undesired migration of acetyl groups from the secondary hydroxyl groups to the primary hydroxyl group does not occur.

The oxidation of the primary hydroxyl group to the carboxy group in the compounds of the formula (II) in which R ^{3 represents} acetyl can be carried out by various methods, for example directly by the action of strong oxidizing agents such as permanganate, nitric acid or chromic acid or indirectly by oxidation of an aldehyde function, which were generated intermediate from the primary hydroxy group is. Preferred in the sense of the process according to the invention is the direct oxidation of the primary hydroxy group in the compounds of the formula (II) with chromic acid, the compounds of the formula (III) in which R ^{3 is} acetyl being obtained.

In order to obtain the compounds of the formula (I) in which R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meaning given above and n is a number 1, 2 or 3, the compounds of the general formula (III ) with amino acids, di- or tripeptides or their derivatives of the general formula (IV), in which R ⁴ and R ^{5 have} the meaning given above, reacted with one another under the conditions of peptide synthesis. Common methods of peptide chemistry are known (E. Wünsch et al .: synthesis of peptides, in: Methods of Organic Chemistry (Houben-Weyl) (E. Müller, ed.) Volume XN / I and XN / II, 4th ed. , Thieme Verlag Stuttgart (1974)).

Such methods are e.g. the condensation of the amino function in the compound of general formula (IV) with the compounds of formula (III) in the presence of dehydrating agents, e.g. Carbodumides such as dicyclohexylcarbodiimide or diisopropylcarbodiimide.

The condensation of the compounds of the formula (III) with the compounds of the formula (IV) can also be carried out when the carboxy group in the compounds of the formula (III) is activated. An activated carboxy group can be, for example, a carboxylic anhydride, preferably a mixed anhydride with alkyl carbonates, acetic acid or another carboxylic acid, or an amide of the acid, such as an imidazolide, or an activated ester such as, for example, cyanomethyl ester, pentachlorophenyl ester or Ν-hydroxyphthalimide ester. Activated esters can also be obtained from the uronic acids of the formula (III) and Ν-hydroxysuccinimide or 1-hydroxybenzotriazole in the presence of a dehydrating agent such as carbodiimide. The derivatives of the amino acids, di- or tripeptides of the general formula (IV) are known in principle.

In order to obtain the unsubstituted compounds of the formula (I) in which R ¹ , R ² and R ^{4 have} the meaning given above and in which R ³ and R ^{5 are} hydrogen, the protective groups R ³ and R ^{5 must be} split off. Conditions for splitting off the protective groups used according to the invention are known in principle. If R ^{3 is} acetyl or benzoyl, these ester functions can be eliminated under basic conditions, for example by dilute sodium hydroxide solution or potassium hydroxide solution, but also under transesterification conditions, ie the transfer of the acyl groups to other alcohols which act as solvents. Suitable conditions for the latter variant are, for example, the reaction in methanol in the presence of catalytic amounts of sodium methoxide.

The carboxy function in the compounds of the formula (I) is released by splitting off the substituent R ⁵ . This ester function can be split under basic conditions, for example by dilute sodium hydroxide solution or potassium hydroxide solution. Tert.-butyl esters are preferably cleaved off by trifluoroacetic acid in pure form or in dilute solution, for example in dichloromethane. The benzyl esters which are preferably used can be cleaved under hydrogenolytic conditions, for example by hydrogenation in the presence of palladium on carbon at atmospheric pressure or elevated pressure.

The compounds of the general formula (I) obtained in this way are isolated in the form of crystalline or amorphous solids by methods known per se and, if necessary, are purified by recrystallization, chromatography, extraction, etc.

The method can be illustrated using the following formula scheme.

1.) p-methoxy-trityl chloride / pyridine 2.) acetic anhydride / pyridine

H ⁺

Cr0 ₃ , H ₂ S0 ₄ , H ₂ 0

Dicyclohexylcarbodiimide odiimide,

N-hydroxysuccinimide imide

H ₅ C ₅ -CH ₂ -0-CO-CH ₂ -NH ₂ CH ₂ -NH ₂

The invention also relates to salts of the compounds of the formula (I). These are primarily non-toxic salts that are commonly used pharmaceutically, e.g. Ammonium salts of chlorides, acetates, lactates.

It has been found that the compounds of the general formula (I) described in more detail below stimulate and thus improve the body's own defense processes. The compounds can therefore be used as immunologically active drugs. The immune-stimulating effect was detected both in vivo in animal experiments and in vitro on cells of the immune system. This fact is confirmed by the following test results.

Female mice (CFW ^ with a weight of approx. 18 g were divided into groups according to random criteria. The animals were treated intraperitoneally, subcutaneously or intravenously with a dose of 10 mg / kg body weight of the compounds of the formula (I) according to the invention, or 24 hours later, the animals were infected intraperitoneally with the 10-fold lethal dose (LD ₅₀ ) of Escherichia coli C14, and the table below shows that survival rates in mice seven days after infection were those with the present invention Compounds of formula (I) had been treated above that of mice that had received physiological saline.

table

Example of surviving mice P *

Control 3/12 (25%) 3h 7/12 (58%) 0.11

* Fischer test pi = after infection

Output connections

Example I: General instructions for the preparation of N- (2,3,4-tri-O-acetyl-6-O-p-methoxyphenyldiphenylmethyl-β-D-hexopyranosyl) -N-alkylcarbonamides.

The solution of N- (β-D-hexopyranosyl) -N-alkyl-carbonamide (30 mmol) (preparation described in DE-OS 3 213 650 AI) in abs. Chloitriphenylmethane (16.7 g; 60 mmol) is added to pyridine (180 ml) and the mixture is left to stand at 20 ° for 72 h. Pyridine (200 ml) and acetic anhydride (150 ml) are then added. After 1 h, the mixture is poured onto ice water (1000 ml) and dichloromethane (500 ml) is added. The organic phase is washed with water (2 times 100 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue is filtered through silica gel (eluent toluene / acetone 30: 1).

Ia N- (2,3,4-Tri-O-acetyl-6-O-p-methoxyphenyldiphenylmethyl-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide. from N- (ß-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide.

Ib N- (2,3,4-tri-O-acetyl-6-O-p-methoxyphenyldiphenylmethyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide. from N- (ß-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide.

Ic N- (2,3,4-tri-O-acetyl-6-Op-methoxyphenyldiphenylmethyl-ß-D-glucopy ranosy l) -N-octadecy 1 -octad ecansäureami d. from N- (β-D-glucopyranosyl) -N-octadecyl-octadecanoic acid amide.

Id N- (2,3,4-tri-O-acetyl-6-O-p-methoxyphenyldiphenylmethyl-β-D-galactopyranosyl) -N-dodecyl-dodecanoic acid amide. from N- (ß-D-galactopyranosyl) -N-dodecyl-dodecanoic acid amide.

Ie N- (2,3,4-tri-O-acetyl-6-O-p-methoxyphenyldiphenylmethyl-β-D-galactopyranosyl) -N-octadecyl-dodecanoic acid amide. from N- (β-D-galactopyranosyl) -N-octadecyl-dodecanoic acid amide.

If N- (2,3,4-tri-O-acetyl-6-O-p-methoxyphenyldiphenylmethyl-ß-D-mannopyranosyl) -N-dodecyl-dodecanoic acid amide. from N- (ß-D-mannopyranosyl) -N-dodecyl-dodecanoic acid amide.

Ig N- (2,3,4-tri-O-acetyl-6-O-p-methoxyphenyldiphenylmethyl-β-D-mannopyranosyl) -N-octadecyl-dodecanoic acid amide. from N- (ß-D-mannopyranosyl) -N-octadecyl-dodecanoic acid amide.

Example II: General instructions for the preparation of N- (2,3,4-tri-O-acety 1-β-D-hexopyranosyl) -N-alkyl-carbonamides.

DaN- (2,3,4-tri-O-acetyl-6-O-p-methoxyphenyldiphenylmethyl-ß-D-hexopyranosyl) -

N-alkyl-carbonamide according to Example I (20 mmol) in 2-propanol (100 ml),

Glacial acetic acid (160 ml) and water (40 ml) dissolved and stirred at 50 ° for 5 h. After cooling to 20 °, the mixture is concentrated under reduced pressure and three times taken up in toluene (100 ml each) and concentrated under reduced pressure. The residue is used in the following oxidation reaction without further purification.

Ha N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide.

Ilb N- (2,3,4-tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide.

IIc N- (2,3,4-tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-octadecanoic acid amide.

Ild N- (2,3,4-tri-O-acetyl-β-D-galactopyranosyl) -N-dodecyl-dodecanoic acid amide.

He N- (2,3,4-tri-O-acetyl-β-D-galactopyranosyl) -N-octadecyl-dodecanoic acid amide.

Ilf N- (2,3,4-tri-O-acetyl-β-D-mannopyranosyl) -N-dodecyl-dodecanoic acid amide.

Hg N- (2,3,4-Tri-O-acetyl-β-D-mannopyranosyl) -N-octadecyl-dodecanoic acid amide.

Example DI: General instructions for the preparation of [N- (2,3,4-tri-O-acetyl-β-D-hexopyranosyl) -N-alkylcarbonamide] uronic acids.

The N- (2,3,4-tri-O-acetyl-β-D-hexopyranosyl) -N-alkyl-carbonamide according to Example II (15 mmol) is dissolved in acetone (150 ml) and with cooling with a solution of Chromium trioxide (15 g; 150 mmol) in water (50 ml) and concentrated sulfuric acid (18 ml) were added. The mixture is stirred at 35 ° for 1 h. The dark Sus- Pension is poured onto ice water (1000 ml) and extracted twice with dichloromethane (400 ml each). The organic phase is washed three times with water (500 ml each), dried over magnesium sulfate and concentrated under reduced pressure. The residue is filtered through silica gel (eluent dichloromethane / methanol 25: 1).

purple [N- (2,3,4-tri-O-acetyl-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide] uronic acid.

Illb [N- (2,3,4-tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronic acid. [α] _D = + 21.5 ° (c = 0.90, dichloromethane).

IIIc [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-octadecanoic acid amide] uronic acid.

Illd [N- (2,3,4-tri-O-acetyl-β-D-galactopyranosyl) -N-dodecyl-dodecanoic acid amide] uronic acid.

Ille [N- (2,3,4-tri-O-acetyl-β-D-galactopyranosyl) -N-octadecyl-dodecanoic acid amide] uronic acid.

[α] _D = + 13.5 ° (c = 1.67, dichloromethane).

Ulf [N- (2,3,4-tri-O-acetyl-β-D-mannopyranosyl) -N-dodecyl-dodecanoic acid amide] uronic acid.

Illg [N- (2,3,4-tri-O-acetyl-β-D-mannopyranosyl) -N-octadecyl-dodecanoic acid amide] uronic acid.

[α] _D = + 6.2 ° (c = 0.74, dichloromethane). Example IV: General instructions for the preparation of (N-β-D-hexopyranosyl-N-alkyl-carbonamide) -uronic acids.

The solution of the [N- (2,3,4-tri-O-acetyl-β-D-hexopyranosyl) -N-alkylcarbonamide] uronic acid according to Example III (1.0 mmol) in anhydrous methanol (50 ml) IN sodium methoxide (0.5 ml) is added and the mixture is stirred at 20 ° for 60 min. Then Lewatit SC 108 (H ^ -form) is acidified with a cation exchanger. The exchange resin is filtered off and washed with methanol. The combined methanolic phases are concentrated under reduced pressure.

IVa (N-ß-D-glucopyranosyl-N-dodecyl-dodecanoic acid amide) uronic acid.

IVb (N-ß-D-glucopyranosyl-N-octadecyl-dodecanoic acid amide) uronic acid. [α] _D = + 5.0 ° (c = 1.01, tetrahydrofuran).

IVc (N-β-D-glucopyranosyl-N-octadecyl-octadecanoic acid amide) uronic acid.

IVd (N-ß-D-galactopyranosyl-N-dodecyl-dodecanoic acid amide) uronic acid.

IVe (N-ß-D-galactopyranosyl-N-octadecyl-dodecanoic acid amide) uronic acid. [α] _D = + 19.5 ° (c = 0.57, tetrahydrofuran).

IVf (N-ß-D-mannopyranosyl-N-dodecyl-dodecanoic acid amide) uronic acid.

IVg (N-ß-D-mannopyranosyl-N-octadecyl-dodecanoic acid amide) uronic acid. R _f = 0.36 (dichloromethane methanol / glacial acetic acid = 4: 1: 0.1).

Manufacturing examples

Example 1: General instructions for the preparation of [N- (2,3,4-tri-O-acetyl-β-D-hexopyranosyl) -N-alkyl-carbonamide] -uronyl-amino acid, di- or - tripeptide esters.

The solution of the [N- (2,3,4-tri-O-acetyl-β-D-hexopyranosyl) -N-alkylcarbonamide] uronic acid according to Example III or Example IV (2.0 mmol) and N-hydroxy succinimide (461 mg; 4.0 mmol) in N, N-dimethylformamide (20 ml) is mixed at 0 ° with N, N-dicyclohexylcarbodiimide (620 mg; 3.0 mmol) and stirred at 20 ° for 2 h . The resulting suspension is then mixed with the amino acid, di- or tripeptide benzyl ester (2.0 mmol) and stirred at 20 ° for 16 h. The mixture is concentrated under reduced pressure, the residue is stirred with diethyl ether (90 ml). The precipitated urea is filtered off and washed with diethyl ether. The filtrate is concentrated under reduced pressure, the residue is purified by column chromatography on silica gel (mobile phase toluene / acetone 20: 1).

la [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide] uronyl-glycine benzyl ester. from the compound according to example purple and glycine-benzyl ester. Ib [N- (2,3,4-tri-O-acetyl-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide] - urony 1-L-al anin-b enzy 1 ester. from the compound according to example purple and L-alanine benzyl ester.

lc [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide] uronyl-D-alanine benzyl ester. from the compound according to example purple and D-alanine benzyl ester.

Id [N- (2,3,4-tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-glycine benzyl ester. from the compound according to Example Illb and glycine-benzyl ester.

1 e [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-L-alanine benzyl ester. from the compound according to Example Illb and L-alanine benzyl ester. [α] _D = + 10.8 ° (c = 0.59, dichloromethane).

lf [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-D-alanine benzyl ester. from the compound according to Example Illb and D-alanine benzyl ester. [α] _D = + 6.9 ° (c = 1.01, dichloromethane).

1 g [N- (2,3,4-tri -O-acety 1-β-D-glucopyranosy l) -N-octadecy 1 -dodecanoic acid amid] uronyl-L-leucine-benzyl ester. from the compound according to Example Illb and L-leucine-benzyl ester.

lh [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-glycyl-glycine-benzyl ester. from the compound according to Example Illb and glycyl-glycine-benzyl ester. [α] _D = + 17.1 ° (c = 0.76, dichloromethane).

li [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-D-alanyl-glycyl-glycine-benzyl ester. from the compound according to Example Illb and D-alanyl-glycyl-glycine-benzyl ester or from the compound according to Example 2f and glycyl-glycine-benzyl ester. [α] _D = + 21.3 ° (c = 0.94, dichloromethane).

lj [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-octadecanoic acid amide] uronyl-L-alanine benzyl ester. from the compound according to Example IIIc and L-alanine benzyl ester.

lk [- (2,3,4-Tri-O-acetyl-β-D-galactopyranosyl) -N-dodecyl-dodecanoic acid amide] - uronyl-L-alanine benzyl ester. from the compound according to Example Illd and L-alanine benzyl ester.

11 [N- (2,3,4-Tri-O-acetyl-β-D-galactopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-L-alanine benzyl ester. from the compound according to Example IIle and L-alanine-benzyl ester.

1 m [N- (2,3,4-Tri-O-acetyl-β-D-galactopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-D-alanine benzyl ester. from the compound according to Example IIle and D-alanine benzyl ester. [α] _D = + 19.5 ° (c = 0.94, dichloromethane).

In [N- (2,3,4-tri-O-acetyl-β-D-mannopyranosyl) -N-dodecyl-dodecanoic acid amide] uronyl-L-alanine benzyl ester. from the compound according to Example Ulf and L-alanine-benzyl ester. lo [N- (2,3,4-Tri-O-acetyl-ß-D-mannopyranosyl) -N-octadecyl-dodecanoic acid amide] - urony 1 -L-al anin-b encylester. from the compound according to Example Illg and L-alanine benzyl ester. [α] _D = + 1.1 ° (c = 0.67, dichloromethane).

1 p [N- (2,3,4-Tri-O-acetyl-β-D-mannopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-D-alanine benzyl ester. from the compound according to Example Illg and D-alanine benzyl ester. [α] _D = + 5.4 ° (c = 0.98, dichloromethane).

Example 2: General instructions for the preparation of [N- (2,3,4-tri-O-acetyl-β-D-hexopyranosyl) -N-alkyl-carbonamide] -uronyl-amino acids, -di or

-tripeptides.

The solution of the [N- (2,3,4-tri-O-acetyl-β-D-hexopyranosyl) -N-alkyl-carbonamide] uronyl-amino acid, di- or tripeptide ester according to Example 1 (1.0 mmol) in tetrahydrofuran (60 ml), glacial acetic acid (50 ml) and water (30 ml) are mixed with 10% palladium-carbon (160 mg) and hydrogenated at normal pressure. After 16 h, the palladium-carbon is suctioned off, the residue is washed with tetrahydrofuran. The combined filtrates are concentrated under reduced pressure, taken up three times in toluene (20 ml each) and concentrated in each case under reduced pressure. 2a [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide] uronyl-glycine.

2b [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide] - uronyl-L-alanine.

2c [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide] uronyl-D-alanine.

2d [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] - uronyl-glycine.

2e [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-L-alanine.

R _f = 0.59 (dichloromethane methanol / glacial acetic acid = 10: 1: 0.1).

2f [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-D-alanine. R _f = 0.10 (dichloromethane / methanol / glacial acetic acid = 20: 1: 0.1).

2g [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-L-leucine.

2h [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-glycyl-glycine. R _f = 0.06 (dichloromethane methanol = 15: 1).

2i [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-D-alanyl-glycyl-glycine. R- _f = 0.06 (dichloromethane methanol = 10: 1).

j [N- (2,3,4-Tri-O-acetyl-β-D-glucopyranosyl) -N-octadecyl-octadecanoic acid amide] uronyl-L-alanine.

k [N- (2,3,4-Tri-O-acetyl-β-D-galactopyranosyl) -N-dodecyl-dodecanoic acid amide] uronyl-L-alanine.

1 [N- (2,3,4-Tri-O-acetyl-β-D-galactopyranosyl) -N-octadecyl-dodecanoic acid amide] - uronyl-L-alanine.

m [N- (2,3,4-Tri-O-acetyl-β-D-galactopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-D-alanine. R _f = 0.41 (dichloromethane methanol / glacial acetic acid = 10: 1: 0.1).

2n [N- (2,3,4-Tri-O-acetyl-β-D-mannopyranosyl) -N-dodecyl-dodecanoic acid amide] - uronyl-L-alanine.

2o [N- (2,3,4-Tri-O-acetyl-β-D-mannopyranosyl) -N-octadecyl-dodecanoic acid amide] uronyl-L-alanine. R _f = 0.09 (dichloromethane methanol / glacial acetic acid = 20: 1: 0.1).

2p [N- (2,3,4-Tri-O-acetyl-β-D-mannopyranosyl) -N-octadecyl-dodecanoic acid amide] - uronyl-D-alanine. R _f = 0.33 (dichloromethane / methanol / glacial acetic acid = 10: 1: 0.1).

Example 3: General instructions for the preparation of (N-β-D-hexopyranosyl-N-alkyl-carbonamide) -uronyl-amino acid, di- or -tripeptides.

The solution of the [N- (2,3,4-tri-O-acetyl-β-D-hexopyranosyl) -N-alkylcarbonarnide] uronyl amino acids, di- or tripeptides according to Example 2 (0.8 mmol) in abs. Methanol (50 ml) and IN sodium methoxide (0.8 ml) are left to stand at 20 ° for 2 h. Then Lewatit SC 108 (H ^ -form) is acidified with a cation exchanger. It is filtered off from the exchange resin, and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (mobile phase dichloromethane / methanol / glacial acetic acid 8: 1: 0.1).

3a (N-ß-D-glucopyranosyl-N-dodecyl-dodecanoic acid amide) -uronyl-glycine.

3b (N-ß-D-glucopyranosyl-N-dodecyl-dodecanoic acid amide) uronyl-L-alanine.

3c (N-ß-D-glucopyranosyl-N-dodecyl-dodecanoic acid amide) uronyl-D-alanine.

3d (N-ß-D-glucopyranosyl-N-octadecyl-dodecanoic acid amide) uronyl glycine.

3e (N-ß-D-glucopyranosyl-N-octadecyl-dodecanoic acid amide) uronyl-L-alanine. [α] _D = - 4.5 ° (c = 0.66, dichloromethane).

3f (N-ß-D-glucopyranosyl-N-octadecyl-dodecanoic acid amide) uronyl-D-alanine. [α] _D = - 13.9 ° (c = 0.72, dichloromethane).

3 g (N-ß-D-glucopyranosyl-N-octadecyl-dodecanoic acid amide) -uronyl-L-leucine. 3h (N-ß-D-glucopyranosyl-N-octadecyl-dodecanoic acid amide) -uronyl-glycyl-glycine. [α] _D = + 5.6 ° (c = 0.90, dichloromethane).

3i (N-ß-D-glucopyranosyl-N-octadecyl-dodecanoic acid amide) -uronyl-D-alanyl-glycyl-glycine. [] _D = + 15.5 ° (c = 0.74, dichloromethane).

3j (N-β-D-glucopyranosyl-N-octadecyl-octadecanoic acid amide) uronyl-L-alanine.

3k (N-β-D-galactopyranosyl-N-dodecyl-dodecanoic acid amide) uronyl-L-alanine.

31 (N-β-D-galactopyranosyl-N-octadecyl-dodecanoic acid amide) uronyl-L-alanine. [α] _D = - 17.6 ° (c = 0.51, dichloromethane).

3m (N-ß-D-galactopyranosyl-N-octadecyl-dodecanoic acid amide) -uronyl-D-alanine. [α] _D = - 0.5 ° (c = 0.87, dichloromethane).

3n (N-ß-D-mannopyranosyl-N-dodecyl-dodecanoic acid amide) uronyl-L-alanine.

3o (N-β-D-mannopyranosyl-N-octadecyl-dodecanoic acid amide) uronyl-L-alanine. [α] _D = + 9.6 ° (c = 0.78, dichloromethane).

3 p (N-ß-D-mannopyranosyl-N-octadecyl-dodecanoic acid amide) uronyl-D-alanine. [ _α ] _D =. 4.0 ° (c = 0.75, dichloromethane).

Claims

claims

(Glycosylamide) uronic acid derivatives of the general formula (I),

in which

R ^{3 represents} hydrogen, acetyl, benzoyl or benzyl,

R ⁴ is independently hydrogen, C _j - to C ₇ alkyl, hydroxymethyl, 1-hydroxy-ethyl, mercapto-methyl, 2-methylthio-ethyl, 3-amino-propyl, 3-ureido-propyl, 3- Guanidyl-propyl, 4-amino-butyl, carboxy-methyl, carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl, 4-hydroxy-benzyl, 3-indolyl-methyl or 4-imidazolyl-methyl ,

R represents hydrogen, lower alkyl or arylalkyl and n represents a number 1, 2 or 3,

2. Compounds of general formula (I) according to claim 1, in which

R ^{3 represents} hydrogen, acetyl, benzoyl or benzyl,

R ⁴ independently of one another for hydrogen, C - to C ₇ -alkyl, hydroxymethyl, 1-hydroxyethyl, mercapto-methyl, 2-methylthio-ethyl, 3-aminopropyl, 3-ureido-propyl, 3-guanidyl propyl, 4-amino-butyl, carboxy-methyl, carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl, 4-hydroxy-benzyl, 3-indolyl-methyl or 4-imidazolyl-methyl,

R ^{5 represents} hydrogen, lower alkyl or arylalkyl and

n represents a number 1, 2 or 3,

in the event that n = 2 or 3, the individual meanings for R ⁴ may be different. 3. Compounds of general formula (I) according to claim 1, in which

R ^{3 represents} hydrogen or acetyl,

R ⁴ independently of one another for hydrogen, C - to C ₇ -alkyl, hydroxymethyl, 1-hydroxyethyl, mercapto-methyl, 2-methylthio-ethyl, 3-aminopropyl, 3-ureido-propyl, 3-guanidyl propyl, 4-amino-butyl, carboyxy-methyl, carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl, 4-hydroxy-benzyl,

3-indolyl-methyl or 4-imidazolyl-methyl,

R ^{5 represents} hydrogen, lower alkyl or arylalkyl and

n represents a number 1, 2 or 3,

4. Compounds of general formula (I) according to claim 1, in which

R ^{1 represents} a straight-chain saturated alkyl radical having 10 to 20 carbon atoms, R ^{2 represents} a straight-chain saturated alkyl radical having 10 to 20 carbon atoms,

R ^{3 represents} hydrogen,

R ⁴ independently of one another for hydrogen, C _j - to C ₇ - alkyl, hydroxymethyl, 1-hydroxyethyl, 3-aminopropyl, 4-aminobutyl, carboxy-methyl, carbamoyl-methyl, 2-carboxy- is ethyl, 2-carbamoyl-ethyl, benzyl or 4-hydroxy-benzyl,

R ^{5 represents} hydrogen and

n represents a number 1, 2 or 3,

5. A process for the preparation of the compounds of the general formula (I) according to Claim 1, in which n = 0 and R ^{5 is} H, characterized in that compounds of the general formula (II)

in the

R, ι, R and R have the meaning given in claims 1 to 4, by applying oxidative conditions to uronic acids of the general formula (III)

in the

R, R ^ and R have the meaning given in claims 1 to 4,

implements. In this way, the compounds of general formula (I) are obtained in which

R ¹ , R ² and R ^{3 have} the meaning given above, and

n means the number 0.

6. Process for the preparation of the compounds of the general formula

(I) according to claim 1, in which

R ¹ , R ² , R ³ , R ⁴ , and R ^{5 have} the meaning given in claims 1 to 4 and

n is the number 1, 2 or 3,

where n = 2 or 3, the individual meanings for R ⁴ may be different, means, characterized in that compounds of the formula (III) in which

R ¹ , R ² and R ^{3 have} the meaning given in Claims 1 to 4 and n represents 0,

with amino acids, di- or tripeptides of the general formula (IV)

in the

R> 4 and i τ R> 5 which have the meaning given in claims 1 to 4 and

represents the number 1, 2 or 3,

where n = 2 or 3, the individual meanings for R ⁴ may be different,

reacted with each other under the usual conditions of peptide synthesis.

Medicaments containing one or more compounds according to claims 1 to 4.

Use of compounds according to claims 1 to 4 for the manufacture of medicaments.