CS205028B2 - Method of producing glucosamine derivatives - Google Patents

Abstract

Glucosamine derivatives of the formula <IMAGE> (X, R, R1, R2, R4, R6-R9 have the meaning stated in Claim 1) are prepared by condensation of corresponding 3-O-carboxymethylglucopyranosides with corresponding dipeptides. These glucosamine derivatives have the ability to increase the immunogenicity of an antigen on admixture therewith and, on systemic administration, to enhance the immunological reactivity of the treated organism. They can thus be used as adjuvants to increase the vaccine protection from bacterial, viral or parasitic pathogens.

Description

The present invention relates to a process for the preparation of novel glucosamine derivatives, in particular glucosamine-3-alkanoyl dipeptides, in particular compounds of formula I

CO-NH-CH-CONH-CH

R 2 is hydrogen or C 1 -C 5 alkyl,

R1 and R6 are hydrogen or an acyl radical having 2 to 18 carbon atoms,

R 7 is hydrogen, C 1 -C 5 alkyl, hydroxymethyl or phenyl,

R 5 represents an optionally esterified or amidated carboxyl group and

R9 is an optionally esterified or amidated carboxyl group provided that the alkyl moiety of R is more than 1 carbon atoms when X is carbonyl and R2 is methyl, or when X is carbonyl, R2 is hydrogen and and R 9 represent a carboxyl group, as well as pharmaceutically acceptable acid addition salts thereof.

In the following, the term "lower" refers to radicals, radicals or compounds, unless otherwise indicated, preferably radicals, radicals or compounds containing up to 7, in particular up to 4, carbon atoms.

Alkyl is, for example, isopropyl, straight or branched, bonded in any position with butyl, pentyl, hexyl or heptyl,

X represents a carbonyl group or a sulfonyl group,

R is a C 1 -C 18 alkyl radical or a phenyl radical,

R 1 is hydrogen or C 1 -C 5 alkyl or benzyl, all methyl, ethyl. or n-propyl.

The optionally esterified or -amylated carboxyl group is preferably a carboxyl group itself or a carboxylic acid group esterified with a lower alkanol such as methanol or ethanol or a carbamoyl group which is unsubstituted or monosubstituted or disubstituted with an alkyl group, in particular a lower alkyl group, with a nitrogen atom. especially a phenyl group or an aralkyl group such as a benzyl group.

The carbamoyl group may contain an alkylidene group such as butylidene or pentylidene. The carbamoyl group Re may contain such a carbamoylmethyl group on the nitrogen atom.

In particular, the acyl group is an acyl group of an organic acid, in particular an organic carboxylic acid. Thus, the acyl group is in particular an alkanoyl group, in particular -with 2 to 18 carbon atoms, such as acetyl or propionyl, or also aroyl, such as 1-naphthoyl, 2-naphthoyl and especially benzoyl or halogen, lower alkyl, lower-alkoxy, trifluoromethyl, hydroxy. - or such an acyl radical of an organic sulfonic acid, for example an alkanesulfonic acid, especially a lower alkanesulfonic acid, such as methanesulfonic acid or ethanesulfonic acid, or an arylsulfonic acid, especially phenylsulfonic acid, which is optionally substituted by a lower one alkyl such as benzenesulfonic acid or p-toluenesulfonic acid.

In the above compounds in which -R 2 is an alkyl group, the R2-acetic acid amide moiety attached to the - oxygen atom - at the 3-position of the glucosamine moiety is optically active, i.e., occurs in the D-form. . When R2 is not hydrogen, R2-aminoacetic acid is present in the L-form.

The novel compounds of this invention are, depending on the nature of their substituents, neutral, acidic or basic compounds. When excess acid groups are present in these compounds, these compounds form salts with bases such as ammonium or alkali metal salts or with alkaline earth metal salts, for example sodium, potassium, calcium or magnesium. However, if excess basic groups are present, such compounds form acid addition salts.

Acid addition salts are, in particular, pharmaceutically usable, non-toxic acid addition salts such as inorganic acids, for example with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acids, or with organic acids, such as organic carboxylic acids , for example with acetic acid, -propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleinic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosallicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid, or isonicotinic acid or with organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid k 2-hydroxyethanesulfonic acid ethane-1,2-disulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid, as well as other acid addition salts, for example those which can be used as intermediates, for example for purification free salts or for the preparation of other salts as well as for characterization, such as, for example, salts with picric acid, picrolonic acid, flavianic acid, phosphotungstic acid, phosphomolybdic acid, chloroplatinic acid, Reinecke salt or perchloric acid salt. The compounds according to the invention have valuable pharmacological properties, in particular they have a marked effect in potentiating immunity. This effect can be demonstrated by the following experiments:

1. In vivo potentiation of cellular immunity: Increased delayed type hypersensitivity to ovalbumin in guinea pigs

Guinea pigs (Pirbright) are immunized on day 0 with 10 mg of ovalbumin in complete Freund's adjuvant by injecting 0.1 ml of the mixture containing the adjuvant and antigen into both hind paws. Four weeks later, a skin reaction is induced by intracutaneous injection of 100 µg ovalbumin in 0.1 ml buffered. saline sodium chloride solution and quantitative evaluation is performed after 24 hours - based on the reaction volume calculated using the area of erythema and the increase in skin thickness.

The antigen-specific increase in reaction volume observed after 24 hours (delayed reaction) is a measure of cellular immunity Ovalbumin is too weak - an immunogen to induce a delayed reaction either alone or in a water-in-oil emulsion together with incomplete Freund - adjuvant (10 parts of a solution of ovalbumin in 0.9% sodium chloride solution) is mixed with 8.5 parts of Bayol F (mineral oil) and 1.5 parts of Arlacel A (mannitol monooleate), and must be added in an effective immunization complete adjuvant to which 205028 ny mycobacteria (5 mg killed and lyophilized M. butyricum per 10 ml Bayol F / Arlaceia A) were added. To demonstrate efficacy in potentiating the immunity of test substances, these may be admixed with mycobacteria in doses ranging from 10 to 100. g to a mixture of antigen in oil.

The glucosamine peptides of this invention have the ability to perfectly mimic the effect of mycobacteria in the described experimental setup and quantitatively exceed it.

Statistically significant potentiation of the delayed response to ovalbumin can also be achieved by not adding the compounds of the described type to the antigen-in-oil mixture, but administering subcutaneously at doses of 10 to 100 μξ per animal within a few days after immunization (e.g. On days 2, 5, 6 and 7 in sodium chloride solution.

Thus, it is shown that compounds of the described type are capable of - substantially enhancing cellular immunity - both in admixture with an antigen (adjuvant effect in the strict sense) as well as in time and locally separated delivery from antigen injection. (systemic potentiation of immunity).

2. Enhancing humoral immunity in vivo: Increasing the production of antibodies against bovine serum albumin in mice

Mice (NMRI 1 strain are immunized by intraperitoneal (ip) injection of 10 µg bovine serum albumin, clot-free on day zero) Serum samples are collected at 9, 15 and 29 days and assayed for anti-bovine serum albumin by passive hemagglutination. The dose of soluble bovine serum albumin is sub-immunogenic to the animals to which it is administered, i.e. it is unable to elicit or induce only a slight production of antibodies. The effect of this administration is expressed by the value of the degree achieved, i.e. the sum of the log2 titer differences on the three blood collection days mentioned above.

The compounds of the invention are capable of intraperitoneal or subcutaneous administration of a dose of 100-300 mg / kg animal weight for five consecutive days (i.e., days 0-4) after albumin immunization bovine serum to increase statistically significantly the production of antibodies for bovine serum albumin.

The immunostimulatory effect of these compounds is, in contrast to other bacterial immunosuppressants (e.g. LPS from Escherichia cdi), antigen-dependent. Injection of the new compounds causes an increase in antibody titer against bovine serum albumin only in mice that have been immunized with bovine serum albumin, but not in mice that have not been immunized. It is noteworthy that the subcutaneous dose of the compounds is as effective as the intraperitoneal dose, i.e. the observed immunopotentiating effect is systemic and is not dependent on whether the stimulant is administered in the same way as the antigen, or whether it must be administered. together with the antigen, as in the case of classical adjuvants.

Experiments have shown that compounds of the type described are capable of specifically enhancing humoral immunity, that it has improved the immunological response to irritation, and that their immunopotentiating effects are based on systemic activation of the immune system.

3. In vitro potentiation of humural immunity: Effect of T-cell effect on antibody response in mouse spleen cells to sheep erythrocytes (SE)

In many cases, thymus lymphocytes (so-called T-cells) are required to induce antibody responses. These cells interact with emerging antibody-forming lymphocytes (B-cells) and help them to respond to stimulation by so-called T-dependent antigens while simultaneously proliferating, differentiating, and synthesizing antibodies. Spleen cell suspensions of congenitally athymic nu / nu mice contain no -functional T cells and, for example, cannot produce any antibodies against sheep erythrocytes in vitro in the presence of sheep erythrocytes.

Surprisingly, the compounds of the present invention are able to replace functionally T cells in such cultures and thereby allow the production of antibodies against the erythrocytes from sheep. The addition of these substances to nu / nu cultures of spleen cells in the presence of sheep erythrocytes leads to a substantial increase in the number of antibody-forming cells within 4 days. The results show that the compounds are able to increase the production of humoral antibodies in vitro and compensate for the lack of - T-cells in the system.

4. Selective - mitogenicity for B-cells:

Effect on stimulation of proliferation in B cell cultures

Suspension of highly enriched B cells (lymph node cells - congenitally athymic nu / nu mice), as well as largely pure immature or mature T cells (thymus cells or thymus cells from cortisone resistant Balb / c mice, i.e. cells persistent 48 hours after cortisone injection) were incubated for 3 days in the presence of test compounds. Incorporation of H3-thymidine into lymphocytes during the last 18 hours of culture is considered as a measure of proliferative activity.

The compounds of the invention are mitogenic to B cells (i.e., precursors to antibody-forming cells), but not to T cells.

Thus, they are capable of promoting the proliferation of lymphocytes involved in luminal immunological responses.

5. Tolerance

Although compounds of the described type appear to potentiate the effect in guinea pigs, for example, after a single dose of 0.05 mg per kg by subcutaneous administration, and in mice given five doses of 10 mg per kg subcutaneously, 300 mg / kg intraperitoneally no toxic effects. They therefore have an excellent therapeutic range.

The compounds of the present invention are capable of enhancing immunogenicity in admixture with an antigen and, on the other hand, increasing the immunological reactivity of the treated organism when administered systemically. In doing so, the compounds are capable of promoting both cellular and munoral immunity and activate the lymphocytes that make up the antibodies.

Accordingly, the novel compounds can be used as adjuvants in admixture with vaccines; in order to improve the vaccination result and thus the protection against infection mediated by humoral and / or cellular immunity against bacteria, viruses or parasites.

Furthermore, the compounds are useful in admixture with a wide variety of antigens as adjuvants in the experimental and industrial production of antisera for therapy and diagnosis and for the induction of immunologically activated lymphocyte cell mediations.

In addition, the novel compounds can be used without the simultaneous antigen delivery to support already weak immunological reactions in humans and animals. Accordingly, these compounds are particularly useful for stimulating the body's own defense, for example in chronic and acute infections or in selective (antigen-specific) immunological defects, as well as in congenital but also later acquired general (i.e. not antigen-specific) immunological defects. conditions such as may be encountered in old age, during more severe primary diseases, and in particular for ionizing radiation therapy or hormones that act to suppress immunity. Accordingly, the compounds may also be advantageously administered in combination with anti-infective antibiotics, chemotherapeutic agents, or other therapies to counteract immunological damage.

Finally, the compounds are also useful in the general prophylaxis of infectious diseases in humans and animals.

In particular, the invention relates to a process for the preparation of compounds of the formula I in which:

X is a carbonyl group,

R is lower alkyl or phenyl and

R 1, R 2, R d, R 6, R 7, R e and R 9 are as defined above, and salts thereof.

Of particular interest are also compounds in which R 2 is hydrogen and the other radicals are as defined above, and salts thereof.

Particular emphasis should be placed on the compounds of formula II

NH-CQ-R 'Ir' CO-NH-CH-CONhl · (II)

In particular, the compounds of formula (II) in which:

R is lower alkyl or phenyl,

R 1 is hydrogen,

R2 is hydrogen or methyl,

R 7 is hydrogen, methyl or hydroxymethyl,

Re represents a carbamoyl group and

R 9 represents a carboxyl group, with the lower alkyl radical as defined

R contains more than 1 carbon atom if

R 2 represents a methyl group, and salts thereof.

in which

R is lower alkyl or phenyl,

R 1 is hydrogen or lower alkyl,

R2 is hydrogen or methyl,

R 7 is hydrogen, lower alkyl or hydroxymethyl,

R 5 represents a carbamoyl group α

R 8 represents a carboxyl group, provided that the lower alkyl radical R contains more than 1 carbon atom when R 2 represents a methyl group, and salts thereof.

According to the invention, the compounds of formula (I) are prepared by reacting a compound of formula (VII)

CHORUS

STEED

NH-X-R.

wherein X and R are as defined above,

R 1 °, R 4 and R ⁰ DEG They have a meaning of the symbols Ri, R4 and R6 represent, or a readily removable cover 'groups, where optionally present hydroxy groups are protected .snadno cleavable protective group, with a compound of formula VIII (VID

R7 ^U R8 ^O

Z — CH — O) NHCH — CONH — CH— (CH2) 2 —Ra 'I'

Rz in which

Z is a reactive esterified hydroxy group and

R70, Re0 and R90 have the meanings of R7, Ra and R9 and, when these radicals contain a free carboxy or hydroxy group, these groups are protected by readily removable capping groups, whereupon any capping groups present are removed and any salts obtained are removed. optionally converting them into the free compounds or converting the obtained salts into their physiologically acceptable acid addition salts.

The reactively esterified hydroxy group is in particular a hydroxy group which is esterified with a strong inorganic or organic acid, in particular a hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid.

The readily cleavable capping groups correspond to the abovementioned capping groups. These groups can be cleaved in a manner known per se, for example by hydrogenolysis with hydrogen in the presence of a noble metal catalyst such as a palladium or platinum catalyst or by acid hydrolysis.

Starting materials used for this. procedure are known.

Alkylidene is especially lower alkylidene, such as isopropylidene, and cycloalkylidene is primarily cyclopentylidene or cyclohexylidene.

This cleavage is also carried out in a manner known per se, for example by treatment with acidic ion exchangers, in particular those containing sulfo groups, such as "Amberlite IR 120" (styrene resin with strongly acidic sulio groups) or "Dowex 50" (polystyrenesulfonic acid), or strong inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid (VIII), acetic or sulfonic acid, for example methanesulfonic acid, or optionally. phenylsulfonic acid substituted in the aromatic ring; as p-toluenesulfonic acid. acid or trifluoroacetic acid. When working in the presence of water, a free hydroxy group is obtained at the 1-position; if, on the other hand, the reaction is carried out in the presence of an alcohol of the formula HO-R 1, in which R 1 is an optionally substituted alkyl radical, then it is preferred. to give the 1-O-R1 derivative. Even if one of the carboxyl groups R @ 5 and / or R @ 8 is esterified with an alcohol, in particular a lower alkanol, this group can be saponified in particular. at a higher temperature. with an aqueous acid solution.

However, it is also possible that this cleavage releases the amino group at the 2-position of the sugar molecule. In this case . the rest must be introduced. —X — R, wherein X and R are as defined above. This introduction is carried out in a conventional manner by acylation or sulfonation.

Covering groups are obtained in the compounds obtained. at the peptide residue additionally cleaved, for example by hydrogenolysis, such as catalytically activated hydrogen or hydrolysis.

The starting materials used in this process can be obtained, for example, by introducing the Rž-acetamidopeptide residue in one into the corresponding oxazoline having a free hydroxy group at the 3-position of the sugar residue. or in several stages.

The compounds obtained can be converted into their salts in a manner known per se, for example by reaction of the acid compounds obtained with alkali metal hydroxides or with alkali metal hydroxides. alkaline earth metal hydroxides or by reaction of the obtained basic compounds with acids.

The procedures described above. are carried out by methods known per se, in the absence or preferably in the presence of a diluent or solvent, optionally with cooling or with heating,. at elevated pressure and / or at 205028 inert atmosphere. gas as in a nitrogen atmosphere.

In doing so, it is possible to take into account:. all substituents present in the molecule, optionally, especially in the presence of readily hydrolyzable O-acyl radicals, use particularly gentle reaction conditions such as short reaction times, use mild acidic or basic reagents in lower concentration, use stoichiometric ratios, select suitable catalysts , solvents, temperatures and / or pressure conditions.

The invention also relates to those embodiments of the process wherein the starting material is a compound obtained as an intermediate at any stage of the process and the missing steps are performed, or the process is interrupted at any stage, or the starting material is formed under the reaction conditions or · Is used in the form of a reactive derivative or a salt. Preference is given here to starting materials which, according to the invention, lead to the compounds described above as being particularly valuable.

The invention also relates to pharmaceutical compositions comprising compounds of formula I. The pharmaceutical compositions of the invention are enteral preparations. as oral or rectal, as well as for parenteral administration to a warm-blooded animal, comprising a pharmacologically active agent alone or together with a pharmaceutically acceptable carrier. The dose of the active ingredient is dependent on the species of warm-blooded individual, age and individual condition as well as the mode of administration.

The new pharmaceutical preparations contain from about 10 · -ο / about ¹ to about 95%, 'preferably from about 20% to about 90% active ingredient ·. The pharmaceutical compositions of the invention may be present, for example, in unit dose form, such as dragees, tablets, capsules, suppositories, or ampoules.

The pharmaceutical preparations according to the present invention are produced in a manner known per se, for example by means of conventional mixing, granulating, dragee, etc. dissolution or lyophilization processes. In addition to the methods of administration mentioned above, the pharmaceutical preparations can also be prepared in a form suitable, in particular, for oral administration by mixing the active ingredient with solid carriers, the resulting mixture optionally granulated and the mixture optionally granulate, optionally after adding suitable excipients is processed into tablets or dragee cores.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium phosphate or middle calcium phosphate, binders such as greasy starch using for example corn starch, wheat starch, rice starch or potato starch, gelatin, tragacanth, methylcellulose,. hydroxy12 propylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or optionally disintegrants such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate, excipients which are primarily flow regulators and lubricating agents such as silicic acid, talc, stearic acid or its salts such as magnesium or calcium stearic acid, and / or polyethylene glycol.

Dragee cores are provided with suitable coatings which are optionally resistant to gastric juice, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, and lacquer solutions in suitable organic solvents. or solvent mixtures, or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose derivatives such as acetylcellulose phthalate or hydroxypropylcellulose phthalate. The tablets or dragee cores may contain the addition of dyes or pigments, for example to distinguish or identify different doses of the active ingredient.

The following examples illustrate the invention described above. These examples are not intended to limit the scope of the invention in any way. Temperatures are given in degrees Celsius.

Example

4.1 g of benzyl-2-acetamido-2-deoxy-4,6-benzylidene-α-D-glucopyranoside are dissolved in 30 ml of Ν, Ν-dimethylformamide and this solution is stirred at room temperature up to 40 °. Celsius is mixed with a dispersion of sodium hydride in mineral oil while avoiding moisture until a homogeneous solution is obtained. 0.5 g of a sodium hydride dispersion in a mineral oil is used. A solution of 4.76 g of N-iodacyl-L-anilyl-D-isoglutamine χ-benzyl ester in 15 ml of Ν, Ν-dimethylformamide is then added dropwise at 10 ° C and the mixture is stirred at room temperature for 24 hours. The reaction mixture was then evaporated in vacuo to give a syrup.

A solution of 8 g of this compound in 400 ml of 60% acetic acid was kept at 80 ° C for 1 hour. After cooling, the solution is evaporated to dryness, 50 ml of water are added twice more to the residue and evaporated to dryness in each case. . The crystalline residue obtained is stirred with a small amount of water, the crystals are filtered off and dried. Benzyl 2-acetamido-3-O - [[1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-2-D-glucopyranoside benzyl ester, m.p. [.Alpha.] _D @ 20 = -77 DEG. + -. 1 DEG (dimethylformamide, c = 0.599).

A solution of 4 g of benzyl 2-acetamido-3-O - [[1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoyl] -50- [methyl] -2-deoxy-α-D-glucopyranoside benzyl ester in 80 ml of methanol is hydrogenated in the presence of 0, 4 g of 5% palladium on carbon catalyst at atmospheric pressure and at room temperature until no more hydrogen is consumed. The catalyst is then filtered off, washed with a small amount of methanol and the filtrate is evaporated to dryness in a water pump vacuum. The residue was dissolved in 50 ml of distilled water and further hydrogenated in the presence of 1 g of 5% palladium on carbon catalyst at atmospheric pressure and at room temperature until hydrogen uptake ceased. The catalyst is filtered off, washed with a small amount of water and then the filtrate is evaporated to dryness. The obtained 2-acetamido-3-O - [[1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-D-glucose is dried under high vacuum with phosphorus pentoxide, [&lt; ²⁰ &gt; 10 ° (water, c = 0.930).

The following compounds can be obtained in an analogous manner:

(a) benzyl 3-O- [D 1 - [L 1 - (D 1 -carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylethyl] -2-propionylamino-2-deoxy-α-glucopyranoside, m.p. 155-160 ° C (decomposition) [.alpha.] _{D @} ²⁰ = + 105 DEG + 1 DEG (dimethylformamide, c = 0.58);

b) 3-O- [D-1- [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylpropyl] -2-acetamido-2-deoxy-D-glucose;

c) 3-O- [11- (D1-carbamoyl-3-carboxypropyl) -1-carbamoylethyl] carbamoylmethyl-2-benzamido-2-deoxy-3-ethyl-D-glucofuranoside, m.p. 215-217 ° C, ( [alpha] D &lt; ²⁰ &gt; = -22 [deg.] (СNзОН; c = 0.97);

(d) 3-ethyl-2-benzamido-2-deoxy-3-O- (L- (D1,3-bis-N-methylcarbamoylpropyl) carbamoylethyl] carbamoylmethyl-D-glucopyranoside, m.p. 233-240 ° C; [α] ²⁰ = -20 ° (Н ° C), c = 0.937);

e) 2-benzamido-2-deoxy-3-O- [Ll- [D-1,3-bis-N-methylcarbamoylpropyl) karbamoylethylJkarbamoylmethyl-D-glucopyranose, m.p. 125-132 ° C, [ ^«20 Jo = 4 24 ° (H 2 O, c = 0.93);

f) 2-Benzamido-2-deoxy-3-O- [L-1-

- (D1,3-bis-methoxycarbonylpropyl) carbamoylethyl] carbamoylmethyl 1-D-glucopyranose as a hydrate, m.p. 80 DEG-90 DEG C., [.alpha.] D @ ²⁰ = = 4-25 DEG ([deg.] C., c = 1.017);

(g) ethyl 2-benzamido-2-deoxy-3-O- [L1- (D1,3-bis-methoxycarbamoyl-propyl) carbamoylethyl] carbamoylmethyl-3-D-glucopyranoside, melting point 127-135 ° C; ] _D ²⁰ = -17 ° (degrees N, c = 1.024);

h) 2-Benzamido-2-deoxy-3-D-

- (D-1-N-benzylcarbamoy 1-3-carboxypropyl) carbamoylethyl] carbamoylmethyl-D-glucopyranose;

1) 2-Benzamido-2-deoxy-3-O- [L-1-

- (D-1-N-carbamoylmethylcarbamoyl-3-carboxypropyl) carbamoylethyl) carbamoyl; methyl-D-glucopyranose;

k) 2-benzamido-2-deoxy-3-O- [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylbutyl] carbamoy Imethyl-D-glucopyranose;

l) 2-benzamido-2-deoxy-3-O- [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylpropyl] carbamoylmethyl-D-glucopyranose;

m) 2-benzamido-3-deoxy-3-O- [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoyl-2-methylpropyl] -2-carbamoylmethyl-D-glucopyranose;

n) 2-acetamido-3-O- [Dl-carbamoyl-3-carboxypropyl) karbamoylmethylkarbamoylmethyl] -2-deoxy-D-glucose _{[a] D} 20 ₌ _ | _27 + 1 ° (water, c = 0.944);

o) methyl-2-acetamido-3-O7 [11- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-αD-glucopyranoside o [α] _D ⁰² - + 49 ° + 1 ° (water) c = 0.939);

p) methyl-2-acetamido-3-O - [[1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-6-O-stearoyl-α-D-glucopyranoside o [a] ? ²⁰ - + 50 ° +? (N, N-dimethylformamide, c = 0.921);

q) 2-acetamido-3-O - [[1- (D1,3-dicarbamoylpropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-D-glucose, [α] _D 20 ₌ -] - 7 ° + 1 ° (water) c = 0.514);

(r) 2-acetamido-3- [D1- [D1-carbamoyl-3-carboxypropyl) carbamoylmethyl] carbamoylpropyl] -2-deoxy-D-glucose, [α] _ο 20 = ψ ₄₆ ο-f-г (water, c = 0.630);

s) 2-acetamido-3-O- [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl-2-deoxy-D-glucose;

t) 2-acetamido-3-O7 [L1- (D1,3-dicarboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-D-glucose dimethyl ester [α] _D 20 ₌ 4-23 ⁰ + 1 ° (water, c = 0.814);

u) 3-O - [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-2-proplonamido-D-glucose;

v) 3-O - [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-caprinoylamido-2-deoxy-D-glucose;

w) 2-acetamido-2-deoxy-3-O7 [L-1- (D-1,3-bis-methylcarbamoylpropyl) carbamoylethyl] carbamoylmethyl] -D-glucose;

x) 2-acetamido-3-O - [L-1- (D-carbamoyl-3-carboxypropyl) carbamoyl-2-hydroxyethyl] carbamoylmethyl] -2-deoxy-D-glucose;

y) 2-acetamido-3-O - [[L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylbutyl] carbamoylmethyl] -2-deoxy-D-glucose;

z) 3-07 (L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl) -2-deoxy-2-stearoylamido-D-glucose;

aa) 2-acetamido-3-O - [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoyl-2-methylpropyl] carbamoylmethyl] -2-deoxy-D-glucose;

bb) 2-acetamido-3-O - [[L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoyl-3-methylbutyl] carbamoylmethyl] -2-deoxy-D-glucose;

cc) 2-acetamido-3-O - [[L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylpropyl] carbamoylmethyl] -2-deoxy-D-glucose;

dd) 2-acetamido-3-O - [[L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylphenylmethyl] carbamoylmethyl] -2-deoxy-D-glucose;

ее) benzyl-2-acetamido-3-O- [[1- (D-1,3-bis-carbamoylpropyl) carbamoyl] carbamoylmethyl] -2-deoxy- | SD-glucopyranoside, [«] _n ²⁰ = - 44 ° + 1 ° (Ν, Ν-dimethylformamide, c = 0.989);

ff) benzyl-2-acetamido-3-O - [(L-1- (D-1,3-bis-carboxypropyl) carbamoylethyl) carbamoylmethyl] -1,2-deoxy- [beta] -D-glucopyranoside dimethyl ester;

gg) 2-acetamido-3-O - [(L-1- (D-1-carbamoy] methylcarbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl) -2-deoxy-D-glucose, white powder;

hh) 3- [N- [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-2-p-tolylsulfonylamino-D-glucose, white powder;

ii) 2- (acetaminomethylcarbonylamino) -2-deoxy-3,0 - [[L-1- (D-1-carbamoyl-3-carboxypropyl) -1-carbamoylethyl] carbamoylmethyl + and β-D-glucose;

kk] 2-trimethylacetamido-2-deoxy-3,0,7 (L-1- (D-1-carbamoyl-3-carboxypropyl) -1-carbamoylethyl] carbamoylmethyl-β-α, β-D-glucose;

11) benzyl-2-acetamido-3-O- [L1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl-2-deoxy-6-O-stearoyl-α-D-glucopyranoside, [α] o ²⁰ = + 33 ° + 1 ° (chloroform, c = 1.046);

mm) 2-benzoylamino-3-07D-1- [L1- (D1-carbamoyl-3-carboxypropyl) -1-carbamoylethyl] carbamoylethyl] -2-deoxy- [beta] -D-glucose, m.p. 140 [deg.] C (decomposition);

nn) 2-benzoylamino-3-O- [D-1- [L-1-

- (D 1 -carbamoyl-1-carboxypropyl) carbamoylethyl] carbamoylpropyl] -2-deoxy-α, (3-D-glucose, mp 114-142 ° C, [α] _D ²⁰ = + 17 ° ( in methanol);

oo) 2-benzoylamino-3-O- [L- (D1-carbamoyl-3-carboxypropyl) -1-carbamoyl] -carbamoylmethyl] -2-deoxy-α, β-D-glucose, temperature mp 175-177 ° C (as hydrate);

pp) 2-benzamido-2-deoxy-3-O- [1-L- (1D-3-dicarboxypropyl) carbamoylethyl] carbamoylmethyl-D-glucopyranose, [α] _D 20 ₌ - [- 25 ° (H ₂ O, c = 0.997);

qq) 2-benzamido-2-deoxy-3-O- [1-L- (1-D-carbamoyl-3-carboxypropyl) carbamoyl-2-hydroxyethyl] -carboylmethyl-D-glucopyranose, m.p. 100-115 ° C, [α] D ²⁰ = ^{23 O} (H 2 O, c = 0.886);

(rr) 2-Benzamido-2-deoxy-3-O- [1-L-

- (1D-n-propylcarbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl-D-glucopyranose, m.p. 65-140 ° [α] D ²⁰ = - | -28 ° (water, c = 1.03);

ss) 2-benzamido-2-deoxy-3-O- [1-methyl-1- (D 1 -carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl-D-glucopyranose, m.p. 110-120 ° C; (a] _D ²⁰ = + 31 ° (H 2 O, c = 0.88);

tt) 2-Benzamido-2-deoxy-3-O - [(D1-carbamoyl-3-carboxypropyl) carbamoylmethyl] carbamoylmethyl-D-glucose, m.p. 115 DEG C., [ _.alpha. ] _D @ ²⁰ = + 34 DEG (water) c = 0.81);

uu] 2-Benzamido-2-deoxy-3-O- [11- (D1,3-dicarbamoylpropyl) carbamoylethyl] carbamoylmethyl-D-glucopyranose, m.p. 82-143 ° C, [α] _D ²⁰ = + 24 ° (H ₂ O, c = 0.98).

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of glucosamine derivatives of the general formula I CO-NH-CH-CONH-CH (CH, -R. ID) ^{Z Я} (I) in which X represents a carbonyl group or a sulfonyl group, R is a C 1 -C 18 alkyl radical or a phenyl radical, R 1 is hydrogen or (C 1 -C 5) -alkyl or benzyl, R 2 is hydrogen or C 1 -C 5 alkyl, R a and R e are hydrogen or an acyl radical having 2 to 18 carbon atoms, R 7 is hydrogen, C 1 -C 5 alkyl, hydroxymethyl or phenyl, R a represents an optionally esterified or amidated carboxyl group and R9 is an optionally esterified or amidated carboxyl group, provided that the alkyl moiety of R is more than 1 carbon atom when X is carbonyl and R2 is methyl, or when X is carbonyl, R2 is hydrogen and R 8 and R 9 represent a carboxyl group as well as their pharmaceutically usable acid addition salts, characterized in that the compounds of the general formula VII (VII) in which: X and R are as defined above, R 1, R ^4, and R 6 are as defined by R 1, R 4 and R 6, or are readily cleavable capping groups, wherein any hydroxy groups present are protected by a readily cleavable capping group, acting as a compound of formula VIII R7 ⁰ R9 ⁰ I i Z-CH-CONH CONHCH - CH- _(CH2) 2-R " AND R2 (VIII), whereupon the optionally present capping groups are cleaved and the optionally obtained salts are optionally converted into the free compounds or converted into their physiologically acceptable acid addition salts. in which Z is a reactive esterified hydroxy group, R7 °, Ro ° and R9 ⁰ have the meanings of the symbols R7, Ro and R9, and when these residues contain a free carboxy or hydroxy group, these groups are protected by readily cleavable protecting groups,