CS205026B2 - Method of producing glocosamine 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 provides a process for the preparation of novel glucosamine derivatives, in particular glucosamine-3-alkanoyl dipeptides, in particular compounds of formula 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,

R2 is hydrogen or (C1 -C5) alkyl,

R 1 and R a represent hydrogen or an acyl radical with and 2. up to 18 carbon atoms,

R? is hydrogen, (C 1 -C 5) alkyl, hydroxymethyl, or phenyl;

R1 represents an optionally esterified or amidated carboxyl group and R5 represents an optionally esterified or amidated carboxyl group, provided that the alkyl radical R is more than 1 carbon atom when X is carbonyl and R2 is methyl, or when X represents a carbonyl group, the radical R2 represents hydrogen and Ra and R9 represent a carbonyl group, as well as their pharmaceutically usable acid addition salts.

In the following, the term "lower" for radicals, radicals or compounds means, unless otherwise indicated, preferably radicals 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, and in particular methyl, ethyl or n-propyl.

The optionally esterified or amidated carboxyl group is preferably a carboxyl group itself or a carboxyl group esterified with a lower alkanol such as methanol or ethanol or also a carbamoyl group which is unsubstituted or monosubstituted or disubstituted with an alkyl group, especially a lower alkyl group, an aryl group. phenyl or aralkyl, such as benzyl.

The carbamoyl group may also contain an alkylidene group such as a butylidene group or a pentylidene group. The carbamoyl group Re may also contain 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 of 2 to 18 carbon atoms, such as an acetyl or propionyl group, or also an aroyl group such as 1-naphthoyl, 2-naphthoyl and especially benzoyl or halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or a lower alkanoyloxy substituted benzoyl or naphthoyl group, or also an acyl radical of an organic sulfonic acid, for example an alkanesulfonic acid, in particular a lower alkanesulfonic acid such as methanesulfonic acid or ethanesulfonic acid, or an arylsulfonic acid, especially phenylsulfonic acid optionally substituted by lower alkyl. or p-toluenesulfonic acid.

In the above compounds in which R2 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. If R 7 is not hydrogen, R 7 -aminoacetic acid is present in the L-form.

Depending on the nature of their substituents, the novel compounds according to the invention are 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 or 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 especially pharmaceutically usable, nontoxic acid addition salts such as inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acids, or with organic acids such as organic carboxylic acids, such as acetic acid. acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic 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, 2-h ydroxyethanesulfonic 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 of free compounds or for the production of other salts as well as for characterization purposes such as, for example, salts with picric acid, picrolonic acid, flavianic acid, phosphotungstic acid, fosfomolybdic acid, chloroplatinic acid, Reinecke salt or perchloric acid salt.

The compounds of 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 adjuvant and antigen into both hind paws. Four weeks later, a skin reaction is induced by intracutaneous injection of 100 ovalbumin in 0.1 ml of buffered saline, and a quantitative evaluation is made after 24 hours based on the reaction volume calculated by 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 with incomplete Freund's adjuvant (10 parts of a 0valbumin solution 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 complete adjuvant to which mycobacteria (5 mg killed and lyophilized M. butyricum per 10 ml Bayol F / Arlacel A) were added for effective immunization. of evidence of activity in potentiating the immunity of test substances, these may be admixed with mycobacteria in doses ranging from 10 to 100 pg to the antigen-in-oil mixture.

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 compounds of the type described. to the antigen-in-oil mixture, but administered subcutaneously at doses of 10 to 100 pg per animal within a few days after immunization (for example, at 0, 1, 2, 5, 6 and 7) in chloride solution sodium.

Thus, it is shown that compounds of the type described are capable of substantially enhancing cellular immunity, both when mixed with the antigen alone (adjuvant effect in the strict sense) and with a time and locally separate delivery from the antigen injection (systemic potentiation of immunity).

2. Potentiation of humoral immunity in vivo · Increased production of antibodies against bovine serum albumin in mice

Mice (NMRI strain) are immunized by intraperitoneal (i.p) injection of 10 µg clot-free bovine serum albumin on day 0. Serum samples were collected at 9, 15 and 29 days and assayed for anti-bovine serum albumin antibodies by passive hemagglutination. At the dose used, the soluble bovine serum albumin is subimmunogenic to the animals to which it is administered, i.e., it is unable to elicit any, or induce only very low production of antibodies. Additional administration of certain immunopotentiating agents to mice before or after antigen administration results in an increase in serum antibody titer. The effect of this administration is expressed by the value of the degree achieved, ie the sum of the log2 titer differences on the three days of blood collection.

The compounds of the invention are capable of increasing statistically significant production of antibodies against bovine serum albumin when administered intraperitoneally or subcutaneously at a dose of 100-300 mg / kg animal weight for five consecutive days (i.e., days 0-4) after immunization with bovine serum albumin. .

The immunostimulatory effect of these compounds is antigen-dependent in contrast to other bacterial immunoleptics (e.g. LPS from Escherichia coli). 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 not dependent on whether the stimulus is administered in the same way as the antigen or Whether they must be co-administered with antigen, as is the case with classical adjuvants.

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

3. · Potentiating · Humal immunity in vitro. erythrocyte-mediating effect of T-cells in response to antibodies in mouse spleen cells. sheep (SE)

In many cases, thymus lymphocytes (so-called T cells) are required to induce antibody responses. These cells interact with emerging lymphocytes forming antibody (B cells) and. they help them to respond to stimulation by so-called T-dependent antigens while simultaneously proliferating, differentiating and synthesizing antibodies. . Suspension. spleen cells congenitally · athymic nu / nu mice do not contain any. functional T cells and cannot, for example, form in vitro. presence of sheep erythrocytes no antibodies against sheep erythrocytes. Surprisingly, the compounds of the invention are able to functionally replace T cells. v. such cultures. . thus allowing the formation of antibodies. responses against sheep erythrocytes. . Addition of these substances to the cultures of spleen cells in the presence. sheep erythrocytes lead · during 4 '. days to substantially increase the number of antibody-forming cells. The results show that said. The compounds are able to increase the production of humoral antibodies in vitro and compensate. lack of T-cells in the system.

4- Selective · mitogenicity ·. for B-cells:

effect on stimulation of proliferation in B- cultures. -lymphocytes

Suspension of highly enriched B-lymphocytes (lymph node cells of congenital athymic nu / nu mice), as well. also from largely pure immature or mature T-lymphocytes (thymus or thymus cells from cortisone-resistant Balb / c mice, i.e., cells persistent at 43 hours after cortisone injection) are 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 a measure of proliferative activity.

The compounds of the invention are mitogenic to B cells (i.e., pre-205026 pedestrians of antibody-forming cells) but not to T cells.

Thus, they are able to promote the proliferation of lymphocytes involved in humoral immunological responses.

5. Tolerance '

Although the compounds of the described type show potentiating 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, they were not observed in mice even at five doses. after 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 immunological reactivity when administered systemically. treated organism. In doing so, the compounds are capable of promoting both cellular and humoral immunity and activate the lymphocytes that make up the antibodies.

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

Furthermore, the compounds are useful in admixture with a 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 populations.

In addition, the novel compounds can be used without concomitant 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 as they may be encountered in old age, during more severe primary diseases, and in particular after 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 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 a and R g 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.

Stress should be particularly · a compound of formula II _from OH CH

DD ⁰ - * ¹

CO-NH-CH-CONH-CH- (CH ₂ ) g R ₉ (II) wherein

R is lower alkyl or phenyl,

R 1 is hydrogen or lower alkyl,

R2 is hydrogen or methyl,

R 7 represents hydrogen, lower alkyl 'or hydroxymethyl',

Ra represents a carbamoyl group and

R 9 is' carboxyl, provided that the lower alkyl radical R contains more than 1 carbon atom when R 2 is methyl, and salts thereof.

In particular, compounds of formula (ii) in which:

R represents a lower alkyl group or a phenyl group,

R 1 is hydrogen,

R 5 is hydrogen or methyl,

R 7 is hydrogen, methyl or hydroxymethyl,

Ra represents a carbamoyl group and

R 9 is a carboxyl group, provided that the lower alkyl moiety of R has more than 1 carbon atom when R a is a methyl group, and salts thereof.

According to the invention, the novel glucosamine derivatives of the formula 'i' are prepared by producing a compound of the formula V

CfeORI ^K- i ^C d ??

CONH-CH-COOH (v) wherein

R and R 2 are as defined above,

R1 °, Rd ° and R6 ° have the meaning of R1, R4 and R6, or are an easily cleavable capping group,

R ⁷⁰ is as R 7 or, when R 7 contains a free hydroxy group, this hydroxy group is protected by an easily cleavable protecting group, condenses with a compound of formula VI

Rf °

AND

H 2 N-CH- (CH 2) 2 -R 9 ^o (VI) wherein

R 8 ° and R 9 ° have the meaning of R 8 and R 8 or, if R 8 and R 9 contain free carboxyl groups, these groups are protected by readily cleavable cap groups, provided that the carboxyl groups present in residues R ⁷⁰ , R 8 and R 8 are present; the free hydroxyl groups are protected by readily cleavable capping groups, whereupon the optionally present capping groups are cleaved and optionally the salts obtained are converted into the free compounds or the obtained salts are converted into their physiologically acceptable acid addition salts.

The condensation is carried out, for example, by reacting a compound of formula V with an amino derivative of formula VI in the form of an activated carboxylic acid or reacting an acid of formula V with a compound of formula VI whose amino group is present in the activated form. The activated carboxyl group may be, for example, an acid anhydride, preferably a mixed acid anhydride such as an acid azide, an acid amide such as an imidazolide, isoxazolid or an activated ester. Activated esters include, but are not limited to: cyanomethyl ester, carboxymethyl ester, p-nitrophenylthioester, p-nitrophenyl ester,

2,4,5-trichlorophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 8-hydroxyquinolinester, 2-hydroxy-1,2-dihydro-1-ethoxycarbonylquinolinester, N-hydroxypiperidinester or enol esters obtained with N-ethyl- 5-phenylisoxazolium-3'-sulfonate. Activated esters may also be obtained optionally by treatment with carbodiimide with the addition of N-hydroxysuccinimide or unsubstituted or, for example, halogen, methyl or methoxy-substituted 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydrobenzo [d] -1,2,3 -triazine.

The amino group is activated, for example, by reaction with phosphitamide.

Among the methods of reaction with activated esters, mention may be made in particular of reaction with N-ethyl-5-phenylisoxazolium-3‘-sulfonate (Woodward's reagent Kj or with 2-ethoxy-1,2-dihydro-1-ethoxycarbonylquinoline or carbodiimide).

Easily cleavable capping groups are those known from peptide chemistry or sugar chemistry. For carboxyl groups, mention may be made in particular of tert-butyl, benzyl or benzhydryl and, for hydroxyl groups, in particular acyl groups, for example lower alkanoyl groups such as acetyl, aroyl groups such as benzyl and in particular residues derived from carbonic acid such as benzyloxycarbonyl or lower alkoxycarbonyl, or alkyl, in particular tert-butyl, optionally nitro, lower alkoxy or halogen substituted benzyl or tetrahydropyranyl or optionally substituted alkylidene radicals, which are bonded to the oxygen atoms at the 4 and 6 positions. Such alkylidene radicals are particularly lower an alkylidene radical, in particular an ethylidene radical, an isopropylidene radical or a propylidene radical or also optionally substituted, preferably p-polozo-substituted benzylidene radical.

These capping groups can be removed in a manner known per se. Thus, they can be removed by hydrogenolysis, for example with hydrogen in the presence of a noble metal catalyst, such as a palladium or platinum catalyst, or by acid hydrolysis.

Starting materials can be obtained in a manner known per se. Thus, for example, the corresponding unsubstituted sugar at the 3-position can be reacted with halo-R 2 -acetamido-R ⁷⁰ -acetic acid or a compound of formula III with amine-R 7 -acetic acid whose carboxyl group is protected as described above and cleaved. cover group.

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

The processes 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 heating, under elevated pressure and / or under an inert gas atmosphere such as nitrogen.

In this connection, particularly gentle reaction conditions such as short reaction times, mild acidic or basic reagents in lower concentrations, stoichiometric ratios can be used, taking into account all substituents present in the molecule, optionally, particularly in the presence of readily hydrolyzable O-acyl residues. , 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 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 which have been described as being of particular value.

The invention also relates to pharmaceutical compositions containing the compounds of formula I. The pharmaceutical compositions according to the invention are for enteral, oral or rectal, as well as for parenteral administration to warm-blooded animals, which contain a pharmacologically active substance 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 novel pharmaceutical preparations contain about 10% to about 95%, preferably from about 20% to about 90%, of the active ingredient. For example, the pharmaceutical compositions of the invention may be presented in unit dosage form such as dragees, tablets, capsules, suppositories, or ampoules.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing 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 compound with solid carriers, the resulting mixture optionally granulated and the mixture or granulate, optionally after the addition of suitable excipients. for 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 calcium phosphate, binders such as greasy starch using, for example, corn starch, wheat starch, rice starch or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or optionally disintegrating tablets such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginate or its salt sodium, excipients which are primarily flow regulators and lubricating agents such as silicic acid, talc, stearic acid or its salts such as magnesium or calcium stearate, and / or polyethylene englykol.

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 manufacture of gastric juice-resistant coatings, solutions of suitable cellulose derivatives such as acetylcellulose phthalate or hydroxypropylmethylcellulose 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

9.14 g of benzyl-2-acetamido-4,6-benzylidene-3-O-carboxymethyl-2-deoxy-α-D-glucopyranoside, 2.9 g of tert-butyl L-alanine ester and 5.94 g of 2-ethoxy-N -ethoxycarbonyl-1,2-dihydroquinoline is dissolved in 80 ml of dimethylformamide and the reaction solution is allowed to stand at room temperature for 20 hours. The reaction solution is freed from dimethylformamide in a high vacuum at room temperature, the residue is triturated cold with petroleum ether and the excess petroleum ether is separated off by decantation (this procedure is repeated 2 to 3 times). The semi-solid was partitioned between water and chloroform and the organic phase was washed once with water, once with cold 1 N hydrochloric acid solution, then with water, saturated sodium bicarbonate solution and again with water. After drying with sodium sulfate and evaporation, 10.5 g (90 percent) of benzyl 2-acetamido-4,6-O-benzylidene-3-O- (1-carboxyethyl-11-carbamoylmethyl) -2-deoxy- α-D-glucopyranoside in the form of a slightly yellowish foam.

8.77 g of benzyl-2-acetamido-4,6-O-benzylidene-3-O- (1-carboxyethyl-11-carbamoylmethyl) -2-deoxy-α-D-glucofuranoside tert-butyl ester is poured into 80 ml pre-cooled 205028 % trifluoroacetic acid and stirred for 1 hour in an ice bath. The clear, yellowish solution was evaporated on a rotary evaporator at room temperature to half its original volume, 10 volumes of water were added and lyophilized. The residue thus obtained is triturated three times with absolute diethyl ether and the product is precipitated from a mixture of methanol, diethyl ester and petroleum ether. Benzyl-2-acetamido-3-O- (1-carboxyethyl) -L-1-carbamoylmethyl-2-deoxy-α-D-glucose precipitated as a pale yellow, hygroscopic powder (6.21 g; 94%).

5.95 g of this compound, 2.73 g of D-isoglutamine γ-tert-butyl ester, and 4.01 g of 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline are dissolved in 60 ml of dimethylformamide while stirring. 15 hours at room temperature. Dimethylformamide is removed at room temperature under high vacuum, the residue is triturated in the cold several times with petroleum ether, excess petroleum ether is removed by decantation and the residue is precipitated twice from a mixture of methanol, ether and petroleum ether. Benzyl 2-acetamido-3-O- [[L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylmethyl] carbamoylmethyl] -2-deoxy-α-D-glucopyranoside is obtained as a colorless powder.

In an analogous manner, 1-.alpha.-benzyl-2-acetamido-3-O- [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoyl ethyl] carbamoylmethyl] -2-deoxy-D-glucose is obtained.

5.69 g of 1-benzyl-2-acetamido-3-O - [[1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-D-glucose, which is dissolved in 100 ml 80% of the methanol was hydrogenated with hydrogen in the presence of 1 g of 10 ° / d palladium on carbon at atmospheric pressure and at room temperature until hydrogen uptake ceased. Then the catalyst is filtered off, the mixture is washed and the filtrate is evaporated to dryness. The obtained 2-acetamido-3-O - [[1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-D-glucose is taken up in twice the amount of distilled water and lyophilized. [.alpha.] D @ ²⁰ = 10 DEG + 1 DEG (water, c 0.930).

The following compounds can be obtained in an analogous manner:

(a) benzyl-3-O- [D1- (L1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl) carbamoyl] -1,2-propionylamino-2-deoxy-α-D-glucopyranoside, m.p. 155-160 ° C ( decomposition), [α] _D ²⁰ -? -105 ° + 1 ° (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- i -ethyl-D-glucofuranoside, m.p. 215-217 ° C, [ _.alpha. ] _D @ 20 = -22 DEG (degrees N @ 2; c = 0.97);

d) 3-ethyl-2-benzamido-2-deoxy-3-O-

- [L1- (D1,3-bis-N-methylcarbamoylpropyl) carbamoylmethyl] carbamoylmethyl-D-glucopyranoside, m.p. 233-240 ° C, [ _.alpha. ] _D @ 20 = -20 DEG (SD, c = 0.937),

e) 2-benzamido-2-deoxy-3-0- [Ll- (Dl, 3-bis-N-methylcarbamoylpropyl) carbamoylmethyl] carbonyl bamoylmethyl-D-glucopyranose, m.p. 125-132 ° C, [ «Jr> ² [Alpha ^] = + 24 [deg.] (H2O, c = 0.93),

f) 2-benzamido-2-deoxy-3-O- [L-1- (D-1,3-bis-methoxycarbonylpropyl) carbamoylethyl] carbamoyl Imethyl-D-glucopyranosate as a hydrate, m.p. 80-90 ° C, _{[a] D} 20 -. = -j_25 ° (СНзОН, c = 1.017)

(g) ethyl-2-benzamido-2-deoxy-3-O-

- [L1- (D1,3-Bis-methoxycarbamoylpropyl) carbamoylethyl] carbamoylmethyl- SD-glucopyranoside, m.p. 127-135 ° C. Celsius, [α] _D ²⁰ = -17 ° (СНзОН, c = 1,024),

(h) 2-benzamido-2-deoxy-3-O- [L-1- (D-1-N-benzylcarbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl-D-glucopyranose;

(i) 2-benzamido-2-deoxy-3-O- [L-1- (D-1-N-carbamoylmethylcarbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl-D-glucopyranose;

(k) 2-benzamido-2-deoxy-3-O- [L-1-carbamoyl-3-carboxypropyl) carbamoylbutyl] carbamoylmethyl-D-glucopyrrose;

(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-carbamoy-1-3-carboxypropyl) carbamoy-2-methylpropyl] -1-carbamoylmethyl-D-glucopyranose,

n) 2-acetamido-3-O- [D 1 -carbamoyl-3-carboxypropyl) carbamoylmethylcarbamoylmethyl] -2-deoxy-D-glucose [α] _D ²⁰ = = -1-27 ° + Г (water, c = 0.944) ,

o) methyl-2-acetamido-3-O - [[1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-α-D-glucopyranoside o [α] _D ²⁰ = 4-49 ° + 1 ° (water, c = 0.939),

p) methyl-2-acetarnido-3-O - [[1- (D-car205026 bamoy 1-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-6-O-stearoyl-o-D-glucopyranoside o [[[d] ²⁰ = - (- 50 ° + 1 ° (Ν, Ν-dimethylformamide, c = 0.921),

q) 2-Acetamido-3-O7 [L 1 - (Dl, 3-0ikarbamoylpr PROPYL) carbamoylethyl] karbamoylmethyll-2 / deoxy-D / glucose, [a] - = + ⁰ + 7c ± 1 ° (water, c = 0.514),

r) 2-3 (β-31 β ((0-3--0-1- [D-1-carbamoyl-3-carboxypropyl) carbamoylmethyl] carbamoylpropyl) -2-deoxy-D-glucose, [a] - - ⁰ = H-46 ^O 4. - (water, c = 0.630),

(s) - acetamido-O-L-1- (D-1-carbamoyl-3-carboxypoly) carbamoylethyl] carbamoylmethyl-2-ethoxy-D-glucose;

t) 2-Acetoimido-.alpha.] -1L-1- (D1,3-carbonylpyridyl) carbamoylethyl] carbamylmethyl] -2-decxy-D-glucose dimethyl ester [α] -? - = -) - 23 ° + 1 ° (voa, c = 0.814),

u) 3-O - [[L-1- (D-1-carbamoyl-3-carbonylpropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-2-propionamido-D-glucose,

(v) 3-O-11-l- [D-g-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl-2-caprinoylamido-2-deoxy-D-glucose,

(w) 2-acetamino (γ-goocχ-3-O - / - L-1- (D-1,3-bis-methylcarbamoyl-propyl) carbamoylethyl] carbamoylmethyl) -D-glucose;

(x) 2-acetamidocg - [[L-1- (D-carbamyl-3-carboxypropyl) carbamyl-2-hydroxyethyl] carbamyl] methyl] -2-deoxy-D] -glucose;

y) 2-acetallindo-g-g [[--- (D-1-carbamoyl-3-carbonylpropyl) carbamoylbutyl] carbamoylmethyl] -2-deoxy-D-glucose,

z) 3-O-1L-1- (D-carbamyl-3-carbonyloxy) carbamoyl ethyl) carbamoylmethyl / -2-oxo-2-stearyl-amido-D-glucose, aa) 2-acetamino-3- g - [L-1- (DL-3-karbamcyl karbcxypropyl) carbamoyl b - ^ - methylpropyl] carbamoyl 1lnethy1, ^/ -2-decxy-D-glucose, bb) acetamiOc 2-3-O /. [L -1- (D1-carbamoyl-1-3-carboxypropyl) carbamyl-3-methylbutyl] carbamylmethyl-2-O-oxy-D-glucose, cc) 2-acetamido-3-O- / [L-1- (D1-carbamcyl-3-carboxypropyl) carbamoylpropyl] carbamoylmethyl / -2-decxy-D-glucose,

-o) 2-acetylamino-3-O - [L-1- (D1-carbamcyl-3-carb (-oxypropyl) carbamoylphenylmethyl] carbamyl) methyl] -2-deoxy-D-glucose, ee ) benzyl-2-acetamido-3-O- [L-1- (D-1,3-bis-carbamoylpropyl) carbamoylethyl] carbamoylmethyl-2-deoxy-β-D-glucosyranoside, [a] - ⁰ - —44 ° + 1 ° (Ν, Ν-Dimethyl-crmam10, c = 0,989),

-) Benzyl (2) acetamyl [3] -O - [[1- (D-1,3-bis-carboxypropyl) carbamoyl-ethyl] carbamoylmethyl] -2-acetyl- (3-D-glucopyrancside, gg) 2- acetamido-3-O- [[L-1- (D1-carbamoylmethylcarbamcyl-3-carbonylpropyl) carbamoylethyl] carbamethylmethyl] -2-Oeoxy-D-glucose, white powder, alcohol) 3-O- / [L-1- ( D1-carbamoyl-3-carbonyl (xypropylcarbamoylethyl) carbamoylmethyl] -2-O-oxy-2-p-tolylsulfonylamino-D-glucose, white powder, ii) 2- (acetaminomethylcarbonylamino) -2-deoxy-3,0- [Ll- (dl-3-carbamoyl-kaгbcxy propyl) -1-methylethyl carbamoyl yl Jkarbamoylmet ^b / -α ', ₁ ^6-D-gluc-O per kK) 2 trimetbylacetam-to-2-deoxy-3,0 - / [L-1- (D-1-carbonyl-3-carboxypropyl) -1-carbamethylethyl] carbamoyl-2-carboxy-α, β-D-glucose,

11) benzyl-2-acetamino-3-O- [L-1- (D1-carbamoyl-3-carbonylpropyl) carbamoylethyl] carbamoylmethyl-2-leoxy-6-O-stearoyl-α-D-glucopyranoside, [α] d ²⁰ - - (- ⁰ + 33 1 ° (chloroform, c = 1.046) mm) benzocУamino 2-3-O - D-ll1L-L1 (D-llkarbamoyll3 karboxypгopyl) -1-karbamcylethy1] karbamoylethy / - 2dieoxy / c tЗ-D-glucose, mp 140 ° C (decomposition) nn) 2-benzoyl-1 aminc-3-O-/Dl- (L-1- (D-llkarbaln (-yll3- _to arboxypropyl) carbamoylethyl] karbamoylpr [.alpha.] - 2-deoxy-.alpha., 3 &apos; / D-glucose, m.p. 114 DEG-14 DEG C., [.alpha.] D @ 20 = + 17 DEG (in methanol). O-1- (D1-carbamoyl-3-carboxypropyl) -1-carbamoylethyl] carbamoylmethyl-2-deoxy-.alpha., D-glucose, m.p. 175 DEG-177 DEG C. (as hydrate),

p) 2-benzami0c-2-deoxy-3 / O- [1-L- (3-ld Oikar boxypr opyy) carbamate-yl-ethyl] -D-karbamoylmetlly1 g1ukcpyrancsa, [a] - ²⁰ = + 25 ° (HO c = 0.997), qq) 2-benzamino-2-O-oxy-3-10- (1-L- (1-D-carbamcyl-13-carboxypropyl) carbamoyl-4-hydroxyethyl] carbamethylmethyl-D-glucopyranose, m.p. 100 up to 115 ° C, [α] 20 _D -4-23 ° (H 2 O, c = 0.886), [eta] &lt; 2 > -benzamido-2-deoxy-3-O- [1-J] (1-DNn-propylcarbamoyl- 3-carboxypropyl) -carbamoylethyl] -carbamoyl-methyl-D-glucopyranose, m.p. 65-140 ° C, _[a] 20 _D == _ | _28 ° (water, c = 1.03), SS) -2-benzamido-2-deoxy- -3-O- [1-methyl-1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl-D-glycopyranose, m.p. 110 DEG-120 DEG C., [ _.alpha. ] _{D @} ²⁰ ₌ (H2 O, c = 0, 88), mp) 2-benzamido-2-deoxy-3-O - [(D1-carbamoyl-3-carboxypropyl) carbamoylmethyl] carbamoylmethyl-D-glucose, mp 115-155 ° C, [α] _D ²⁰ = + 34 ° (water, c = 0.81), µu) 2-Benzamido-2-deoxy-3-O- [L1- (D-1,3-dicarbamoylpropyl) carbamoylethyl] carbamoylmethyl-D-glu 82 DEG-143 DEG C., [.alpha.] D @ ²⁰ = + 24 DEG (H2 O, c = 0.98).

Claims (2)

the subject of the invention A process for the preparation of glucosamine derivatives of the general formula I CH _i or _e R-C-H phyl CO-NH-CH-CONH-CH (D) (I) wherein 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, R4 and R6 are hydrogen or an acyl radical having 2 to 18 carbon atoms, R 7 is hydrogen, C 1 -C 7 alkyl, hydroxymethyl or phenyl, R e represents an optionally esterified or amidated carboxyl group and R 8 is an optionally esterified or amidated carboxyl group, provided that the alkyl moiety R has more than 1 carbon atom when X is carbonyl and R 2 is methyl or when X is carbonyl, R 2 is hydrogen and Ra and R 9 represent a carboxyl group, as well as a pharmaceutically acceptable acid addition salt thereof, characterized in that the compound of formula (V): RfCH \ CONH-CH-COOH _й - ^(V) in which R1 and R2 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, R ⁷⁰ is as R 7 or, when R 7 contains a free hydroxy group, the hydroxy group is protected by an easily cleavable protecting group, condenses with a compound of the general formula се VI R8 ° h ₂ n- -CH- (CH 2) 2 -R 9 ^o (VI), in which R ⁰ and R 9 ⁰ have the meanings of the symbols R and R 9, or R and R9 contain free carboxylic acid groups, these groups are protected with easily cleavable protective groups, with the proviso that in the radicals R 7 ⁰ R & and R9 ⁰ present carboxyl groups and optionally the free hydroxyl groups are protected by readily cleavable capping groups, whereupon the optionally present capping groups are cleaved and optionally the salts obtained are converted into the free compounds or the obtained salts are converted into their physiologically acceptable acid addition salts. 2. A process according to claim 1, wherein the acids of formula V are reacted in the form of an anhydride or reactive ester with an amino derivative of formula VI, or the acid of formula V is reacted with a compound of formula VI whose amino group is activated by phosphitamide.