WO1995006653A1

WO1995006653A1 - Glycosyl amides of 6-amino-6-deoxy sugars

Info

Publication number: WO1995006653A1
Application number: PCT/EP1994/002733
Authority: WO
Inventors: Oswald Lockhoff; Yutaka Hayauchi; Burkhard Mielke; Helmut Brunner; Klaus STÜNKEL; Michael Sperzel; Klaus Schaller
Original assignee: Bayer Aktiengesellschaft
Priority date: 1993-08-30
Filing date: 1994-08-17
Publication date: 1995-03-09
Also published as: AU7613694A

Abstract

The present invention relates to substituted (6-amino-6-deoxy glycosyl) amides of general formula (I), processes for producing them and their use in medicaments.

Description

Glycosylamides of 6-amino-6-deoxy sugars

The invention relates to substituted (6-amino-6-deoxy-glycosyl) amides, processes for their preparation and their use in medicaments.

It is known that glycosylamides from aldopyranoses or from amino sugars can increase the body's immune response (DE-OS 3 213 650). It is also known that amino acids substituted (2-amino-2-deoxy-glycosyl) amides can cause both an increase in the specific and non-specific immune response (DE-OS 3 521 994).

The present invention now relates to substituted (6-amino-6-deoxy-glycosyl) amides 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} hydroxy or acetylamino and

R ⁴ for a radical of the formula

R ⁶ - NH - CH (R ⁵ ) - CO - in which

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

R ^{6 represents} hydrogen or a radical of the formula

R ⁸ - (NH - CH (R ⁷ ) - CO) _n -

stands in which

R ^{7 has} the meaning of R ⁵ given above and is the same or different with it,

R ^{8 stands} for hydrogen or a protective group customary in peptide chemistry (cf. A. Hubbuch, contacts (Darmstadt) 1979. 14; EE Bullesbach, contacts (Darmstadt) 1980. 23),

and in what

n represents a number 0, 1 or 2,

in the event that n = 2, the two meanings of R ⁷ may be different.

The compounds according to the invention have several asymmetric 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) are preferred

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} hydroxy or acetylamino and

R ⁴ for a radical of the formula

R ⁶ - NH - CH (R ⁵ ) - CO -

in which

R ⁵ 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 ^{6 represents} hydrogen or a radical of the formula

R ⁸ - (NH - CH (R ⁷ ) - CO) _n -

stands in which

R ^{8 represents} hydrogen, acetyl, benzoyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or fluorenylmethyoxycarbonyl,

and in what

n represents a number 0, 1 or 2, in the event that n = 2, the two meanings of R ⁷ may be different.

Compounds of the general formula (I) are particularly preferred

in which

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

R ^{3 represents} hydroxy or acetylamino and

R ⁴ for a radical of the formula

R ⁶ - NH - CH (R ⁵ ) - CO -

in which

R ^{3 represents} hydrogen, C _j - to C ₇ -alkyl, hydroxymethyl, 1-hydroxyethyl,

Mercapto-methyl, 2-methylthio-ethyl, 3-amino-propyl, 3-ureido-propyl, 3-guanidyl-propyl, 4-amino-butyl, carboxy-methyl, carbamoyl-methyl, 2-

R ^{6 represents} hydrogen or a radical of the formula

R ⁸ - (NH - CH (R ⁷ ) - CO) _n -

stands in which

R ^{7 has} the meaning of R ⁵ given above and is the same or different with it, R ^{8 represents} hydrogen, benzyloxycarbonyl or tert-butyloxycarbonyl,

and in what

n represents a number 0, 1 or 2,

in the event that n = 2, the two meanings of R ⁷ may be different.

In addition, a process for the preparation of the compounds of the general formula (I) according to the invention was found, characterized in that

Compounds of the general formula (II)

in which

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

with derivatives of amino acids, di- or oligopeptides of the general formula (HI),

(|||)

in which

R ⁵ , R ⁷ and n have the meaning given above,

R ^{9 represents} a protective group for the nitrogen atom of amino acids which is customary in peptide chemistry and which can be split off again selectively while maintaining the peptide bond R 10 represents a hydroxyl group or an escape group customary in peptide chemistry for the activation of amino acids,

and in what

n denotes a number 0, 1 or 2, _β - → where, when n = 2, the two meanings of R can react with one another, an amidic bond being formed and compounds of the general formula ( VI) can be obtained.

In a second reaction step, the N-terminal protective group R ⁹ in the compounds of the formula (VI) is split off, the compounds of the general formula (VTI) having a free amino group being obtained.

The starting compounds of the general formula (II) can be prepared from the corresponding hexopyranosyl amides, which are known in principle and whose preparation is described in DE-OD 3 521 994.

For the selective introduction of the amino group into the 6-position of the sugar residues, the 6-hydroxy function can be selectively introduced into a sulfonic acid ester of the general formula (IV)

in which

R ^{11 represents,} for example, methyl, triflourmethyl or p-tolyl,

be transferred. The preparation of the 6-O-sulfonates (IV) is known in principle and is described in DE-OD 3 508 025.

By nucleophilic substitution of the 6-O-sulfonate groups in the compounds of formula (IV) with nitrogen nucleophiles, an optionally blocked amino function can be introduced into the sugar residues. Preferred nitrogen nucleophiles are azide anions which are used to form the 6-azido-6-deoxy-hexopyranosyl-amides of the formula (V)

to lead. Azido functions are blocked amino groups and can be converted into the amino groups under reducing conditions.

The 6-O-sulfonates (IV) are converted into the 6-azido-6-deoxy compounds (V) in an inert solvent, preferably N, N-dimethylformamide, with alkali azides, for example lithium azide or sodium azide, if appropriate elevated temperature. The 6-O-methanesulfonates or the 6-O-toluenesulfonates are reacted with azide ions at temperatures of 50-150 °, preferably at 80-120 °. The corresponding more reactive 6-O-trifluoromethanesulfonates are preferably reacted with azide ions at 40-80 °. The conversion of the azido function into the amino function can take place under reductive conditions (see S. Patai (ed.): The Chemistry of the Azido Group, Interscience Publishers, 1971). Preferred methods of the present application are the use of hydrogen in the presence of transition metals, preferably palladium / carbon. This process is preferably used to prepare the compounds of the general formula (II) with saturated alkyl radicals R ¹ and R ² . In the case of unsaturated alkyl radicals R ¹ and / or R ² in compounds of the general formula (II), the azido group is reduced by using reducing agents in which the unsaturated alkyl radicals are not reduced to the saturated alkyl radicals, for example by using the Staudinger Reaction. In the Staudinger reaction, the azido group is reduced by using phosphines, preferably triphenylphosphine, in the presence of organic nitrogen bases (cf. H. Paulsen et al., Chem. Ber. 114 (1981) 3242). However, it is also possible to convert the azido group to the unsaturated alkyl radicals R ¹ and / or R ² using hydrazine hydrate in the presence of Raney nickel in ethanol as solvent (cf. R. Goutarel et al., Tetrahedron 24 (1968) 7013).

Suitable protective groups R ⁹ for the amino function in compounds of the formula (III) are, for example, acyl groups such as trifluoroacetyl or trichloroacetyl, o-nitrophenylsulfenyl, 2,4-dinitrophenylsulfenyl or optionally substituted lower alkoxycarbonyl such as methoxycarbonyl, tert.-butyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, fluorenylmethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl.

Preferred amino protective groups R ⁹ are the tert-butyloxycarbonyl group or the benzyloxycarbonyl group.

The 6-amino-6-deoxy-glycosylamides of the general formula (II) can be linked to the amino acids or the di- or oligopeptides of the general formula (III) by conventional methods of peptide chemistry (E. Wünsch et al .: synthesis von Peptiden, in: Methods of Organic Chemistry (Houben-Weyl) (E. Müller, ed.) Volume XV / I and XV / II, 4th edition, Thieme Verlag Stuttgart (1974)). Common methods are, for example, the condensation of the amino function in the compound of the general formula (II) with an N-protected amino acid derivative of the general formula (III) in the presence of dehydrating agents, for example carbodiimides such as dicyclohexylcarbodiimide or diisopropylcarbodiimide.

The condensation of the compounds of formula (II) with the compounds of formula (III) can also be carried out when the carboxy group 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 N-hydroxyphthalimide ester. Activated esters can also be obtained from the amino acid derivatives of the formula (III) in which R ^{10 is} OH and N-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 (III) are known in principle.

In the second process step to prepare the compounds of the general formula (I), the protective group R ^{8 is} split off.

The protective groups R ⁸ used with preference in the compounds of the general formula (I), the N-carbobenzoxy group and the N-tert-butyloxycarbonyl group, can be eliminated to give the amidic groups present in the compounds. Such methods are known in principle.

The carbobenzoxy group can be selected by hydrogenolysis in the presence of transition metals, such as palladium on carbon, in a suitable solvent such as methanol, ethanol, glacial acetic acid or tetrahydrofuran, either in pure form or in a combination of the solvents with one another, or also water split off, which can be carried out both at normal pressure and at elevated pressure. The tert-butyloxycarbonyl group in the compounds of the formula (I) can be split off by means of acidolytic processes. Suitable conditions include the use of hydrogen chloride or trifluoroacetic acid, either in pure form or diluted in suitable solvents such as glacial acetic acid, dichloromethane, diethyl ether, dioxane or ethyl acetate.

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.

Scheme 1: Preparation of the starting compounds.

Scheme 2: Preparation of the compounds of general formula (VII) or (I) according to the invention.

R - SO ₂ -O-CH 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. own defense processes. The compounds can therefore be used as immunologically active drugs. The immunostimulating effect was demonstrated 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 _j ) weighing approx. 18 g were randomly divided into groups. The animals then became intraperitoneal, subcutaneous. or treated intravenously with a dose of 10 mg / kg body weight of the compounds of the formula (I) according to the invention, or received physiological saline solution. Twenty-four hours later, the animals were infected intraperitoneally with the 10-fold lethal dose (LD ₅₀ ) of Escherichia coli C14. The following table shows that the survival rates seven days after infection in mice which had been treated with the compounds of the formula (I) according to the invention were significantly higher than that of mice which had received physiological saline solution.

table

Example surviving mice on day 7 p.i. (Difference to control)

21a 12/16 (75%) <0.001 21b 12/16 (75%) <0.001

21d 13/16 (81%) <0.001

21g 10/16 (63%) <0.001 21h 7/16 (44%) <0.05 21i 10/16 (63%) <0.001 21j 9/16 (56%) <0.01 21k 11/16 (69 %) <0.001 211 7/16 (44%) <0.05 21m 6/16 (38%) <0.05 Example of surviving mice on day 7 pi P * (difference to control)

21n 7/16 (44%) <0.01

21p 13/16 (81%) <0.001 21q 7/12 (58%) <0.01

21r 6/16 (38%) <0.05

* Fisher Test p.i. = after infection

It has been found that glycosylamides of 6-amino-6-deoxy sugars have good activity as immunomodulator stimulators, in particular also as adjuvants for TNF formation.

Cells of the retico-endothelial system (RES) play an important role in inflammatory processes. They synthesize and release a number of mediators that not only result in a systemic change in homeostasis, but also locally activate cell systems, e.g. in lymphocytes, granulocytes, endothelial cells, etc. In this context, the so-called pro-inflammatory cytokine TNF-α plays a major role in inflammatory processes. As has been shown in the past, this cytokine, like the closely related TNF-ß (lymphotoxin), is part of various biological processes such as immune regulation, inflammation, cachexia, angiogenesis and septic shock. TNF-α is triggered, for example, by stimuli such as bacterial endotoxins / lipopolysaccharides (LPS) (B. Beutler et al. 1985 Nature 316: 562). Under certain conditions, TNF can play a critical role, ie overproduction or chronic production of TNF leads to Pathological changes in symptoms such as malaria or other diseases of mycobacterial origin The relationship between TNF-dependent, pathological changes under the conditions of bacterial sepsis with transition to lethal shock is well documented - at least in experimental animal models.

On the other hand, there are clear examples of an essential, protective role of TNF in immunological defense processes in the case of mycobacterial and other infections (B. Echternacher et al. 1990 J. Immunol. 145: 3762). In the following, substances from the substance class of glycosylamides are described in their immunomodulatory, adjuvant effect with regard to TNF-free setting.

The in-vivo experiments to induce an endotoxin-induced shock as an indirect parameter for TNF release in vivo were carried out on female inbred mice (F _j [B ₆ D ₂ ]). Endotoxin / LPS from Salmonella abortus equi (5 ng / mouse) was administered in combination with D-galactosamine hydrochloride (D-GalN; 60 mg / kg body weight) intraperitoneally or intravenously based on information from Galamos et al. (1979, Proc. Natl. Acad. Sci. USA 76: 5939; V. Lehmann et al. 1987, J. Exp. Med. 165: 657). The substances (dose: 10; 30; 60 mg / kg) were administered intraperitoneally six hours or one hour before the endotoxemic shock was triggered. The observation period was 48 hours.

If a substance has adjuvant properties, the rate of death is higher than that of the LPS control. Animals that received GalN plus one of the substances mentioned in the absence of a triggering stimulus (in this test example is the TNF-inducing noxa LPS) do not die in any case. These findings make it clear that the substances per se do not induce activation and thus TNF release, but only work in conjunction with an activating stimulus.

The use of a murine TNF-neutralizing, monoclonal antibody from the rat has demonstrated that the immunomodulating property of glycosylamides leads to an increase in TNF release and thus to an increased death rate (B. Echternacher et al. 1990. J Immunol. 145: 3762). No animal died using this antibody (100 μg antibody per mouse, ip or IV, simultaneous with LPS application). Table 1 Immunomodulating property of glycosylamides:

Increase in TNF synthesis in the sense of adjuvant therapy using the example of selected substances.

Substances survival rate (%)

21 1> 50

21 y> 50

21 i> 50

21 k> 50

21 p> 50

21 q> 50

21 m> 50

Control <20

The stem cell number in the bone marrow of C57BL / 6 mice was reduced by fluorouracil (FU) and its regeneration was then examined under the influence of the GLAs (30 mg / kg sc). As shown in Fig. 1, the reconstitution of the damaged bone marrow is accelerated by the GLAs, the hematopoietic activity is increased.

Along with IL-1 and IL-6, TNF is an important mediator of septic shock. It could be shown that glycolipids significantly reduce the E. coli-mediated TNF activity in the serum of mice (preventive). Glycolipids thus inhibit an important mediator of septic shock. NMRI mice were pretreated once with 30 mg / kg glycolipid subcutaneously, one hour later with a lethal dose (10 x LD ₅₀ ) E. coli. TNF activity was determined 1.5 hours after infection.

Protective screening in the neutropenic Candida infection model The aim of this experimental model is to find substances that stimulate the body's defense in nutropeni see mice.

methodology

At -96 h, the mice are treated intra peritoneally with 0.2 ml of endoxane at a dose of 200 mg / kg per animal. At times - 72, -48 and - 24 h, the mice are treated intra peritoneally with 0.2 ml of the screening substance. Alternatively, treatments with screening substances are also carried out with 0.2 ml s.c. and i.V., as well as with 0.5 ml per os. Two groups with 10 animals each are used per preparation. One group is routinely treated with 10 mg / kg, the other with 30 mg / kg body weight. Much lower dosages are also used for in-depth tests.

At the time of 0 h, the mice are treated with 0.2 ml of a lethal germ suspension i.v. infected in the tail vein.

Observation and assessment

The mice are observed until 4 h after treatment for possible

To be able to record drug intolerance.

From 1 day to 14 days after infection, the mice are assessed once a day in the morning. The state of health is recorded in 5 levels. (- good - slightly ill - sick - seriously ill - dead -) The critically ill mice are killed after the assessment, they should not suffer.

Result

As a result, the consideration rate and / or a delay in the clinical picture is documented. Both compared to the control mice treated with Endoxan. techniques

Applications i.p., s.c. and i.v. we carry out with a 1 ml disposable syringe and an injection syringe No. 18. The per os application is carried out with a 5 ml disposable syringe and the injection syringe No. 12 with olive. For i.p. and the os mice are fixed in the hand. With the s.c application, the mice are fixed on the cage lid. The mice are at the i.v. -Application and i.v. -Infection fixed in a mouse cage. In addition, the mice are placed under red light for approximately 10 minutes before IV treatment and infection in order to dilate the tail veins.

parameter

Mouse: B ₆ O ₂ ¥ - 20 g, female germ: Candida albicans, (Hl 2) 5 x 10 ⁵ germs per mouse

Substance: Endocan is water soluble.

If possible, the screening substances are also dissolved in sterile water. If this is not possible, an attempt is made to solve them as follows: dissolve in pure DMSO (final DMSO concentration in the application solution = 2%). Then Cremophor was added (final Cremophor concentration in the application solution = 8%). Make up to the final volume with sterile water.

Animal husbandry: The animals are kept in Type II Makrolon cages. All animals receive food and water ad libitum.

The compound from Example 21 k shows the protective effect in neutropeni see mice in the Candida infection model. Compound 21 p shows a protective effect in the same model. Output connections

Example I

General instructions for the conversion of the 6-O-sulfonates of the formula (IV) to the 6-azido-6-deoxy compounds of the formula (V).

The mixture of the 6-O-sulfonate (10 mmol) of the general formula (IV), sodium azide (0.98 g; 15 mmol) and N, N-dimethylformamide (40 ml) is heated to 110 °. The course of the reaction is followed by thin layer chromatography (mobile phase dichloromethane / methanol 15: 1). After the reaction is cooled to 20 ° and concentrated in a high vacuum. The residue is taken up in dichloromethane, washed twice with water, dried over magnesium sulfate and purified by column chromatography (mobile phase dichloromethane / methanol 15: 1).

Ia N- (6-azido-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide. Yield 62%. Rf value 0.35 (dichloromethane / methanol 15: 1)

Ib N- (6-Azido-6-deoxy-β-D-glucopyranosyl) -N-tetradecyl-octadecanoic acid amide.

Yield 70%. Rf value 0.28 (dichloromethane / methanol 15: 1)

Ic N- (6-azido-6-deoxy-β-D-galactopyranosyl) -N-dodecyl-octadecanoic acid amide. Yield 79%. R ^ value 0.30 (dichloromethane / methanol 15: 1)

Id N- (6-azido-6-deoxy-β-D-mannopyranosyl) -N-tetradecyl-dodecanoic acid amide. Yield 70%. R _f value 0.27 (dichloromethane / methanol 15: 1)

Ie N- (2-acetamido-6-azido-2,6-dideoxy-ß-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amid. Yield 80%. R _j value 0.17 (dichloromethane / methanol 15: 1)

If N- (6-azido-6-deoxy-β-D-glucopyranosyl) -N-dodecyl oleic acid amide. Yield 55%. Rf value 0.29 (dichloromethane / methanol 15: 1) Example II

A) General instructions for converting the 6-azido-6-deoxy compounds of the formula V to the 6-amino-6-deoxy compounds of the formula (VI).

The mixture of the 6-azido-6-deoxy compound according to Example (I) (15 mmol), tetrahydrofuran (300 ml), methanol (300 ml) and 1N hydrochloric acid (30 ml) is mixed with 10% palladium-carbon (1.0 g) were added and hydrogenated under hydrogen at atmospheric pressure. The course of the reaction is followed by thin layer chromatography (mobile phase dichloromethane / methanol 7: 1). After the reaction has ended, the mixture is filtered off with suction and the filtrate is concentrated under reduced pressure. The residue is taken up several times in methanol and concentrated in each case under reduced pressure. The residue is dissolved in tetrahydrofuran (50 ml), water (300 ml) and 1N hydrochloric acid (15 ml) and freeze-dried.

Ha N- (6-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride. Yield 90%. Rf value 0.16 (dichloromethane / methanol 5: 1)

Ilb N- (6-amino-6-deoxy-β-D-glucopyranosyl) -N-tetradecyl-octadecanoic acid amide hydrochloride.

Yield 95%. Rf value 0.14 (dichloromethane methanol 5: 1). 166-167 °

IIc N- (6-amino-6-deoxy-β-D-galactopyranosyl) -N-dodecyloctadecanoic acid amide hydrochloride. Yield 89%. R ^ value 0.18 (dichloromethane / methanol 5: 1)

Ild N- (6-amino-6-deoxy-β-D-mannopyranosyl) -N-tetradecyl-dodecanoic acid amide hydrochloride. Yield 68%. R _j value 0.17 (dichloromethane / methanol 5: 1)

Ile N- (2-acetamido-6-amino-2,6-dideoxy-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide hydrochloride. Yield 90%. Rf value 0.05 (dichloromethane / methanol 5: 1) B) General instructions for converting the 6-azido-6-deoxy compounds of the formula (V) to the 6-amino-6-deoxy compounds of the formula (VI).

The mixture of the 6-azido-6-deoxy compound according to Example I (5 mmol) is dissolved in tetrahydrofuran (50 ml) and methanolic ammonia (with ammonia at 20 ° semi-saturated methanol, 200 ml) and with triphenylphosphine (3.57 g) added. The thin-layer chromatogram (dichloromethane / methanol 5: 1) initially shows the formation of a compound (phosphinimine) which occurs in the meantime and slowly reacts further to the free amine under the reaction conditions. The reaction is complete after about 20 hours. The mixture is evaporated to dryness. The residue is chromatographed on silica gel (mobile phase dichloromethane / methanol 7: 1). The residue is dissolved in tetrahydrofuran (15 ml), water (150 ml) and 1N hydrochloric acid (4 ml) and freeze-dried.

Ilf N- (6-amino-6-deoxy-β-D-glucopyranosyl) -N-dodecyl oleic acid hydrochloride. Yield 78%. Rf value 0.06 (dichloromethane / methanol 5: 1)

Manufacturing examples

example 1

General instructions for the implementation of the 6-amino-6-deoxy compounds of the formula (II) with N-protected amino acids, di- or tripeptides of the general formula (III) to give the N-protected, amino-substituted 6-aminoacylamino 6-deoxy compounds of the formula (VI):

The mixture of the N-protected α-amino acid, or the di- or oligopeptide (7.7 mmol), N-hydroxysuccinimide (1.77 g, 15.4 mmol) and N, N-dimethylformamide (70 ml) N.N'-dicyclohexylcarbodiimide (1.88 g, 8.4 mmol) is added and the mixture is stirred at 20 ° for 30 min. Ethyl diisopropylamine (8.0 mmol) and the 6-amino-6-deoxy compound according to Example II (7.0 mmol) are added and the mixture is stirred for 16 h. The mixture is mixed with water (3 ml), stirred for 30 min and concentrated to a syrup under reduced pressure. The residue is stirred with diethyl ether (100 ml), the urea which has precipitated is filtered off with suction, and the filtrate is concentrated in a high vacuum. The residue is taken up in diethyl ether (150 ml), washed three times with water (70 ml each), dried over magnesium sulfate and concentrated to a syrup under reduced pressure. The residue is filtered through silica gel (mobile phase dichloromethane / methanol / concentrated ammonia water 25: 1: 0.05).

11a N- [6- (N-carbobenzoxy-glycyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide. Educ. 67%. R _f value: 0.28 (toluene / ethanol 5: 1)

11b N- [6- (N-carbobenzoxy-L-alanyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide. Educ. 82%. R _r value: 0.35 (toluene / ethanol 5: 1)

11 c N- [6- (N-carbobenzoxy-L-valyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecy 1-dodecanoic acid amid. Educ. 73%. R _r value: 0.40 (toluene / ethanol 5: 1) ldd N- [6- (N-carbobenzoxy-L-leucyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide. Educ. 74%. Rf value: 0.38 (toluene / ethanol 5: 1)

l le N- [6- (N-carbobenzoxy-L-phenylalanyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide.

Educ. 98%. R _j value: 0.38 (toluene / ethanol 5: 1)

lf N- [6- (N-carbobenzoxy-L-prolyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecy 1 -dodecanoic acid amide. Educ. 80%. Rf value: 0.38 (toluene / ethanol 5: 1)

1 µg of N- [6- (N-carbobenzoxy-L-seryl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide.

Educ. 48%. Rr value: 0.68 (dichloromethane / methanol / concentrated ammonia 10: 3: 0.1)

11h N- [6- (N-carbobenzoxy-glycyl-glycyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide.

Educ. 82%. Rr value: 0.48 (dichloromethane / methanol / concentrated ammonia 10: 1.5: 0.1)

l li N- [6- (N-carbobenzoxy-L-alanyl-glycyl) amino-6-deoxy-ß-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide. Educ. 77%. R _f value: 0.35 (dichloromethane / methanol / concentrated ammonia

10: 1.5: 0.1)

l lj N- [6- (N-carbobenzoxy-L-leucyl-glycyl) amino-6-deoxy-ß-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide.

Educ. 81%. Rf value: 0.46 (dichloromethane / methanol / concentrated ammonia 10: 1.5: 0.1)

11k N- [6- (N-carbobenzoxy-L-phenylalanyl-glycyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide.

Educ. 83%. R _f value: 0.39 (dichloromethane / methanol / concentrated ammonia 10: 1.5: 0.1) 1 11 N- [6- (N-carbobenzoxy-L-alanyl-L-alanyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide.

Educ. 77%. Rr value: 0.50 (dichloromethane / methanol / concentrated ammonia 10: 1.5: 0.1)

l in N- [6- (N-carbobenzoxy-D-alanyl-L-alanyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide.

Educ. 84%. R _j value: 0.66 (dichloromethane methanol / concentrated ammonia 10: 1.5: 0.1)

l In N- [6- (tri-N-carbobenzoxy-L-arginyl-L-alanyl) amino-6-deoxy-β-D-glycopyranosyl] -N-octadecyl-dodecanoic acid amide.

Educ. 86%. Rf value: 0.63 (dichloromethane / methanol / concentrated ammonia 10: 1.5: 0.1)

l lo N- [6- (N-carbobenzoxy-L-asparaginyl-L-alanyl) amino-6-deoxy-β-D-glycopyranosyl] -N-octadecyl-dodecanoic acid amide. Educ. 43%. Rf value: 0.08 (dichloromethane / methanol / concentrated ammonia

20: 1.5: 0.1)

11p N- [6- (N-carbobenzoxy-L-leucyl-L-leucyl) amino-6-deoxy-ß-D-glucopy ranosy 1] -N-octadecy 1-dodecanoic acid ami.

Educ. 73%. R _f value: 0.45 (dichloromethane / methanol / concentrated ammonia 10: 1.5: 0.1)

lq N- [6- (N-carbobenzoxy-D-alanyl-L-leucyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide.

Educ. 69%. R _f value: 0.46 (dichloromethane / methanol / concentrated ammonia 10: 1.5: 0.1)

1 lr N- [6- (N-carbobenzoxy-glycyl-glycyl-glycyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide.

Educ. 51%. Rf value: 0.27 (dichloromethane / methanol / concentrated ammonia 10: 1.5: 0.1) 12a N- [6- (N-carbobenzoxy-glycyl) amino-6-deoxy-β-D-glucopyranosyl] -N-tetradecyl-octadecanoic acid amide. Educ. 69%. R _f value: 0.28 (toluene / ethanol 5: 1)

12b N- [6- (N-carbobenzoxy-L-alanyl) amino-6-deoxy-β-D-glucopyranosyl] -N-tetradecyloctadecanoic acid amide.

Educ. 72%. R _f value: 0.38 (toluene / ethanol 5: 1)

12c N- [6- (N-carbobenzoxy-L-valyl) amino-6-deoxy-β-D-glucopyranosyl] -N-tetradecyl-octadecanoic acid ami. Educ. 55%. R _f value: 0.43 (toluene / ethanol 5: 1)

12d N- [6- (N-carbobenzoxy-L-leucyl) amino-6-deoxy-β-D-glucopyranosyl] -N-tetradecy 1-octadecanoic acid amid. Educ. 52%. R _f value: 0.37 (toluene / ethanol 5: 1)

12e N- [6- (N-carbobenzoxy-L-phenylalanyl) amino-6-deoxy-β-D-glucopyranosyl] -N-tetradecyloctadecanoic acid amide. Educ. 52%. R _f value: 0.49 (toluene / ethanol 5: 1)

12f N- [6- (N-carbobenzoxy-L-prolyl) amino-6-deoxy-β-D-glucopyranosyl] -N-tetradecyl-octadecanoic acid amide. Educ. 62%. R _r value: 0.44 (toluene / ethanol 5: 1)

12g N- [6- (N-carbobenzoxy-L-seryl) amino-6-deoxy-β-D-glucopyranosyl] -N-tetradecyl-octadecanoic acid amide.

12h N- [6- (N- C arb ob enzoxy-glycyl-glycyl) amino-6-deoxy-ß-D-glucopyranosyl] -N-tetradecyl-octadecanoic acid amide.

12i N- [6- (N-carbobenzoxy-glycyl-glycyl-glycyl) amino-6-deoxy-β-D-glucopyranosyl] -N-tetradecyl-octadecanoic acid amide.

13a N- [6- (N-carbobenzoxyglycyl) amino-6-deoxy-β-D-galactopyranosyl] -N-dodecyloctadecanoic acid amide. Educ. 58%. R _r value: 0.29 (toluene / ethanol 5: 1) 13b N- [6- (N-carbobenzoxy-L-alanyl) amino-6-deoxy-β-D-galactopyranosyl] -N-dodecyl-octadecanoic acid amide. Educ. 57%. R _f value: 0.26 (toluene / ethanol 5: 1)

13c N- [6- (N-carbobenzoxy-L-valyl) amino-6-deoxy-β-D-galactopyranosyl] -N-dodecyl-octadecanoic acid amide.

Educ. 30%. R _f value: 0.40 (toluene / ethanol 5: 1)

13d N- [6- (N-carbobenzoxy-L-leucyl) amino-6-deoxy-β-D-galactopyranosyl] -N-dodecyloctadecanoic acid amide. Educ. 69%. R _f value: 0.42 (toluene / ethanol 5: 1)

13e N- [6- (N-carbobenzoxy-L-phenylalanyl) amino-6-deoxy-β-D-galactopyranosyl] -N-dodecyloctadecanoic acid amide. Educ. 53%. R _f value: 0.53 (toluene / ethanol 5: 1)

13f N- [6- (N-carbobenzoxy-L-prolyl) amino-6-deoxy-β-D-galactopyranosyl] -N-dodecyl-octadecanoic acid amide. Educ. 49%. R _f value: 0.47 (toluene / ethanol 5: 1)

13g N- [6- (N-carbob enzoxy-glycyl-glycyl) amino-6-deoxy-β-D-galactopyranosyl] -N-dodecyl octadecanoic acid amide.

13h N- [6- (N-carbobenzoxy-glycyl-glycyl-glycyl) amino-6-deoxy-β-D-galactopyranosyl] -N-dodecyl-octadecanoic acid amide.

14a N- [6- (N-carbobenzoxy-glycyl) amino-6-deoxy-β-D-mannopyranosyl] -N-tetradecyl-dodecanoic acid amide.

14b N- [6- (N-carbobenzoxy-L-alanyl) amino-6-deoxy-β-D-mannopyranosyl] -N-tetradecyl-dodecanoic acid amide.

15a N- [2-acetamido-6- (N-carbobenzoxy-glycyl) amino-2,6-dideoxy-β-D-glucopyranosyl] -N-dodecyl-dodecanoic acid amide. 15b N- [2-acetamido-6- (N-carbobenzoxy-L-alanyl) amino-2,6-dideoxy-β-D-glucopyranosyl] -N-dodecyl-dodecanoic acid amide.

16a N- [6- (N-tert-butyloxycarbonyl-glycyl) amino-6-deoxy-β-D-glucopyranosyl] -N-dodecyl oleic acid amide.

16b N- [6- (N-tert-butyloxycarbonyl-L-alanyl) amino-6-deoxy-β-D-glucopyranosyl] -N-dodecyl oleic acid amide.

Example 2

General instructions for converting the N-protected 6-aminoacylamino-6-deoxy compounds of the formula (VI) substituted with amino acids to the N-unsubstituted 6-aminoacylamino-6-deoxy compounds of the formula (VII):

The N-carbobenzoxy-protected compound of the general formula (VI) (1.0 mmol) is dissolved in tetrahydrofuran (10 ml), methanol (5 ml) and 1N hydrochloric acid (1 ml) and mixed with 10% palladium-carbon ( 0.2 g) added. The mixture is hydrogenated for 16 h at normal pressure in a hydrogen atmosphere. It is then suctioned off through a Celite filter layer and the residue is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (mobile phase dichloromethane-methanol-concentrated ammonia 10: 1: 0.1). The residue is dissolved in tetrahydrofuran (5 ml), water (30 ml) and 1N hydrochloric acid (1.5 ml) and freeze-dried.

21a N- (6-glycylamino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride. Educ. 90%. [α] _D = + 8.2 ° (c = 1.02; methanol)

21b N- (6-L-Alanyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride. Educ. 95%. [α] _D = + 0.8 ° (c = 1.19; methanol)

21c N- (6-L-valylamino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide-Hy drochloride. Educ. 85%. [α] _D = + 0.7 ° (c = 1.67; methanol) 21d N- (6-L-leucylamino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride. Educ. 74%. [α] _D = - 0.3 ° (c = 0.97; methanol)

21e N- (6-L-phenylalanyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride.

Educ. 59%. [α] _D = + 7.6 ° (c = 0.97; methanol)

21f N- (6-L-prolyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride. Educ. 55%. [α] _D = -12.8 ° (c = 1.08; methanol)

21g N- (6-L-Seryl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride. Educ. 68%. [α] _D = - 0.4 ° (c = 0.85; methanol)

21h N- (6-glycyl-glycyl-amino-6-deoxy-ß-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide hydrochloride. Yield 71%. [Α] _D = 0.0 ° (c = 1, 0; methanol)

21i N- (6-L-Alanyl-glycyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride. Educ. 64%. [α] _D = - 9.4 ° (c = 0.86; methanol)

21j N- (6-L-leucylglycyl) amino-6-deoxy-β-D-glucopyranosyl] -N-octadecyl-dodecanoic acid amide hydrochloride.

Educ. 67%. [α] _D = -17.3 ° (c = 0.98; methanol)

21k N- (6-L-phenylalanyl-glycyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride. Educ. 69%. [α] _D = -31.1 ° (c = 0.90; methanol)

211 N- (6-L-Alanyl-L-alanyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride. Educ. 84%. [α] _D = -19.0 ° (c = 0.96; methanol) 21m N- (6-D-alanyl-L-alanyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide-hydrochloride. Educ. 86%. [α] _D = -16.7 ° (c = 0.95; methanol)

21 n N- (6-L-Arginyl-L-alanyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride.

Educ. 70%. [α] _D = + 0.7 ° (c = 1.09; methanol)

21o N- (6-L-Asparaginyl-L-alanyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride. Educ. 43%. [α] _D = -15.3 ° (c = 0.95; methanol)

21p N- (6-L-leucyl-L-leucyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride.

Educ. 61%. R _f value: 0.66 (dichloromethane methanol / concentrated ammonia 10: 1.5: 0.1)

21 q N- (6-D-alanyl-L-leucyl-amino-6-deoxy-β-D-glucopyranosyl) -N-octadecyl-dodecanoic acid amide hydrochloride.

Educ. 82%. [α] _D = -27.5 ° (c = 0.85; methanol)

21r N- (6-Glycyl-glycyl-glycyl-amino-6-deoxy-ß-D-glucopyranosyl] -N-octadeyl-dodecanoic acid amide hydrochloride. Yield 69%. [Α] _D = + 1.1 ° (c = 0.89; methanol)

22a N- (6-glycylamino-6-deoxy-β-D-glucopyranosyl) -N-tetradecyloctadecanoic acid hydrochloride. Educ. 31%. [α] _D = + 5.2 ° (c = 0.86; methanol)

22b N- (6-L-Alanyl-amino-6-deoxy-β-D-glucopyranosyl) -N-tetradecyl-octadecanoic acid amide hydrochloride. Educ. 79%. [α] _D * = + 1.2 ° (c = 1.08; methanol)

22c N- (6-L-valylamino-6-deoxy-β-D-glucopyranosyl) -N-tetradecyloctadecanoic acid hydrochloride. Educ. 84%. [α] _D = + 2.7 ° (c = 0.92; methanol)

22d N- (6-L-leucylamino-6-deoxy-β-D-glucopyranosyl) -N-tetradecyl-octadecanoic acid amide hydrochloride. Educ. 71%. [α] _D = + 1.7 ° (c = 0.79; methanol)

22e N- (6-L-phenylalanyl-amino-6-deoxy-β-D-glucopyranosyl) -N-tetradecyl-octadecanoic acid amide hydrochloride. Educ. 94%. [α] _D = + 8.7 ° (c = 0.86; methanol)

22f N- (6-L-prolyl-amino-6-deoxy-β-D-glucopyranosyl) -N-tetradecyloctadecanoic acid amide hydrochloride. Educ. 82%. [α] _D = -10.4 ° (c = 1.00; methanol)

22g N- (6-L-serylamino-6-deoxy-β-D-glucopyranosyl) -N-tetradecyloctadecanoic acid hydrochloride.

22h N- (6-glycyl-glycyl) amino-6-deoxy-β-D-glucopyranosyl] -N-tetradecyl-octadecanoic acid amide hydrochloride.

22i N- (6-glycyl-glycyl-glycyl) amino-6-deoxy-β-D-glucopyranosyl] -N-tetradecyl-octadecanoic acid amide hydrochloride.

23a N- (6-glycylamino-6-deoxy-β-D-galactopyranosyl) -N-dodecyloctadecanoic acid amide hydrochloride. Educ. 52%. [α] _D = + 8.7 ° (c = 0.86; methanol)

23b N- (6-L-Alanyl-amino-6-deoxy-β-D-galactopyranosyl) -N-dodecyloctadecanoic acid hydrochloride. Educ. 80%. [α] _D = + 14.5 ° (c = 0.93; methanol)

23c N- (6-L-Valylamino-6-deoxy-β-D-galactopyranosyl) -N-dodecyloctadecanoic acid amide hydrochloride. Educ. 62%. [α] _D = + 23.5 ° (c = 0.98; methanol) 23d N- (6-L-leucylamino-6-deoxy-β-D-galactopyranosyl) -N-dodecyloctadecanoic acid amid-Hy drochl ori d. Educ. 83%. [α] _D = - 0.4 ° (c = 0.93; tetrahydrofuran)

23e N- (6-L-phenylalanyl-amino-6-deoxy-β-D-galactopyranosyl) -N-dodecyloctadecanoic acid amide-Hy drochl ori d.

Educ. 81%. [α] _D = + 33.2 ° (c = 1.04; methanol)

23f N- (6-L-prolylamino-6-deoxy-β-D-galactopyranosyl) -N-dodecyloctadecanoic acid hydrochloride. Educ. 39%. [α] _D = + 10.3 ° (c ^■ = 0.79; methanol)

23g of N- (6-glycyl-glycyl-amino-6-deoxy-β-D-galactopyranosyl) -N-dodecyl-octadecanoic acid amide hydrochloride.

23h N- (6-glycyl-glycyl-glycyl-amino-6-deoxy-β-D-galactopyranosyl) -N-dodecyl-octadecanoic acid amide hydrochloride.

24a N- (6-glycylamino-6-deoxy-β-D-mannopyranosyl) -N-tetradecyl-dodecanoic acid amide hydrochloride.

24b N- (6-L-alanyl-amino-6-deoxy-β-D-mannopyranosyl) -N-tetradecyl-dodecanoic acid amide-Hy drochl orid.

25a N- (2-acetamido-6-glycylamino-2,6-dideoxy-β-D-glucopyranosyl) -N-dodecyl-dodecanoic acid amide hydrochloride.

25b N- (2-acetamido-6-L-alanyl-amino-2,6-dideoxy-β-D-glucopyranosyl] -N-dodecyl-dodecanoic acid amide hydrochloride.

General instructions for splitting off the tert-butyloxycarbonyl groups in the compounds of the formula (VI) to give the amines of the formula (VII):

The compound of the general formula (VI) (1.0 mmol) substituted with the tert-butyloxycarbonyl group is dissolved in dichloromethane (10 ml) at 0 ° and trifluoroacetic acid (10 ml) is added. After 2 h at 0 ° with toluene (50 ml) diluted and concentrated under reduced pressure. The residue obtained is taken up three times in toluene (50 ml each) and concentrated in each case under reduced pressure. The residue obtained is purified by column chromatography on silica gel (gradient dichloromethane-methanol-concentrated ammonia 20: 1: 0.1 → 10: 1: 0.1 → 10: 3: 0.1). The residue is dissolved in tetrahydrofuran (5 ml), water (30 ml) and 1N hydrochloric acid (1.5 ml) and freeze-dried.

26a N- (6-glycylamino-6-deoxy-β-D-glucopyranosyl) -N-dodecyl oleic acid hydrochloride.

26b N- (6-L-alanyl-amino-6-deoxy-β-D-glucopyranosyl) -N-dodecyl-oleic acid-hydrochloride.

Claims

claims

1. Substituted 6-amino-6-deoxy-glycosyl) amides of the general formula (I),

in which

R ^{3 represents} hydroxy or acetylamino and

R ⁴ for a radical of the formula

R ⁶ - NH - CH (R ⁵ ) - CO -

in which

R ⁵ 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, carboxy-methyl, carbamoyl-methyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl, benzyl, 4-hydroxy-benzyl, 3-indolyl-methyl or 4-imidazolylmethyl,

R ^{6 represents} hydrogen or a radical of the formula

R ⁸ - (NH - CH (R ⁷ ) - CO) _n - stands in which

R ^{8 represents} hydrogen or a protective group customary in peptide chemistry

and in what

n represents a number 0, 1 or 2,

in the event that n = 2, the two meanings of R ⁷ may be different.

Compounds of the general formula (I) according to Claim 1

in which

R ^{3 represents} hydroxy or acetylamino and

R ⁴ for a radical of the formula

R ⁶ - NH - CH (R ⁵ ) - CO -

in which

R ⁵ 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 ^{6 represents} hydrogen or a radical of the formula

R ⁸ - (NH - CH (R ⁷ ) - CO) _n -

stands in which

R ^{8 represents} hydrogen, acetyl, benzoyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or fluorenylmethoxycarbonyl,

and in what

n represents a number 0, 1 or 2,

in the event that n = 2, the two meanings of R ⁷ may be different.

3. Compounds of general formula (I) according to claim 1

in which

R ^{3 represents} hydroxy or acetylamino and R ⁴ for a radical of the formula

R ⁶ - NH - CH (R ⁵ ) - CO -

in which

R ⁵ for hydrogen, C _j - to C ₇ -alkyl, hydroxymethyl, 1-hydroxyethyl, mercapto-methyl, 2-methylthio-ethyl, 3-aminopropyl, 3-

R ^{6 represents} hydrogen or a radical of the formula

R ⁸ - (NH - CH (R ⁷ ) - CO) _n -

stands in which

R ⁸ for hydrogen, acetyl, benzoyl, trichloroacetyl, trifluoroacetyl,

Methoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or fluorenylmethyoxycarbonyl,

and in what

n represents a number 0, 1 or 2,

in the event that n = 2, the two meanings of R ⁷ may be different.

4. A process for the preparation of the compounds of general formula (I) according to claim 1, characterized in that a) compounds of the general formula (II)

in which

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

with derivatives of amino acids, di- or oligopeptides of the general formula (III),

10

R ⁹ - NH-CH-COH-NH-CH-CO-R

I (III)

R 'n RT

in which

R ⁵ , R ⁷ and n have the meaning given in Claims 1 to 3,

R ^{9 represents} a protective group for the nitrogen atom of amino acids which is customary in peptide chemistry and which can be split off again selectively while maintaining the peptide bond

R ^{10 represents} a hydroxy group or an escape group customary in peptide chemistry for the activation of amino acids,

and in what

n represents a number 0, 1 or 2, in the event that n = 2, the two meanings of R ⁷ can react with one another, an amidic bond being formed and compounds of the general formula (NI)

be preserved and

b) in a second reaction step, the Ν-terminal protective group R ⁹ in the compounds of the formula (VI) is split off, the compounds of the general formula (I) having a free amino group being obtained.

5. Medicament containing one or more compounds from claims 1 to 3.

Use of compounds from claims 1 to 3 for the manufacture of medicaments.