CS205027B2 - 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 (CH 2 -R 4 ^(D) (I) wherein

X represents a carbonyl group or a sulfonyl group,

R represents 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 1 and R 3 are hydrogen or an acyl radical having 2 to 18 carbon atoms,

R 2 represents hydrogen, C 1 -C 5 alkyl, hydroxymethyl or phenyl,

R b is an optionally esterified or amidated carboxyl group and

R9 is an optionally esterified or amidated carboxyl group, with the alkyl moiety R being more than 1 hydrogen when X is carbonyl and R-2 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.

In the following, the term "lower" for radical or compound radicals 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 carboxylic group esterified with a lower alkanol such as methanol or ethanol or a carbamoyl group which is unsubstituted or disubstituted on an nitrogen atom by an alkyl group, especially a lower alkyl group, an aryl group, especially phenyl or an aralkyl group such as a benzyl group. !

The carbamoyl group may contain an alkylidene group such as a butylidene group or a pentylidene group. The carbamoyl group R 5 may contain such a carbamoylmethyl group on the nitrogen atom.

In particular, the acyl group is an organic acid acyl group, in particular an organic carboxylic acid. Thus, the acyl group is especially an alkanoyl group, in particular of 2 to 12 carbon atoms, such as an acetyl or propionyl group, or 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 such 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 arylsulfonic acid, in particular a phenylsulfonic acid which is optionally substituted; 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. If R7 is not hydrogen, R7-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-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid; and other acid addition salts, for example those which can be used as intermediates, e.g. for the purification of the free compounds or for the production of other salts, as well as for characterization such as 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 pronounced potency in potentiating immunity. This effect can be demonstrated by the following experiments:

1. Potentiation of cellular immunity in vivo:

Increased delayed type hypersensitivity to ovalbumin in guinea pigs

Guinea pigs (Pirbrightj are immunized on day 0 with 10 mg of ovalbumin in complete Freund's adjuvant by injecting a 0.1 inl mixture containing adjuvant and antigen into both hindpaws. After 4 weeks, a skin reaction is induced by intracutaneous injection of 100 µg ovalbumin in 0.1 ml buffered. saline and quantitative evaluation is made 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. immunogen in order to induce a response delay of either ^one alone as such or in · water-in-oil emulsion together with incomplete Freund's adjuvant (10 parts of a solution of ovalbumin in ^0.9%: sodnáho chloride solution are mixed with 8.5 parts of Bayol F (mineral oil) and 1.5 parts of 'Arlacel A' (mannitol monooleate), and for active imu Addition should be added in complete adjuvant to which mycobacteria (5 mg killed and lyophilized M-butyric per 10 ml Bayol F / Arlacel A) were added. To demonstrate efficacy in boosting the immunity of test substances, these may be admixed with the antigen-in-oil mixture instead of mycobacteria at doses of 10 to 100 μξ.

The glucosaminopeptides 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 ranging from 10 to 100 μ &lt; -1 &gt; 2, 5, 6 and 7) in sodium chloride solution.

Thus, it is shown that compounds of the type described are capable of substantially enhancing cellular immunity, both when mixed with the antigen itself (adjuvant effect in the strict sense of the word), and when temporally and locally separated. supply from antigen injection (systemic potentiation of immunity).

2. Potentiation · Humoral immunity in vivo: Increase in production of antibodies against bovine serum albumin in mice

Mice (NMRI strain) are immunized. by intraperitoneal (i.p.) injection of 10 µg of bovine serum albumin free from clots at zero. day. Samples are taken at 9, 15 and 29 days. serum and the content of antibodies against bovine serum albumin was determined by passive hemagglutination. At the dose used, the soluble bovine serum albumin is sub-immunogenic to the animals to which it is administered, i.e., it is unable to elicit any, or indeed, very little antibody production. Additional submission of certain. immunopotentiating agents to mice before. administration of the antigen or following administration of the antigen results in an increase in the antibody titer in the serum. The effect of this administration is expressed by the value of the degree achieved, ie the sum of the log2 titer differences over the three days of collection. blood.

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

Unlike other bacterial immunoleptics (for example LPS from Escherichia coli), the immunostimulatory effect of these compounds is dependent on. antigen. 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. in admixture with an antigen, as is the case with classical adjuvants.

The above experiments have shown that compounds of the type described are capable of specifically enhancing humoral immunity, improving the immunological response to irritation, and their immunopotentiating effects. they rest on. systemic activation of the immunological system.

3. Potentiation of humoral immunity in. vitro: Effect of T-cell effect on antibody response in mouse mouse cells. to erythrocytes. sheep (SE)

To induce a response. Antibodies are required in many cases by thymus lymphocytes (called T-cells). These cells interact with emerging lymphocytes producing antibody (B-cells) and help them to respond to. stimulating 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 cannot, for example, form in. in vitro. presence of erythrocytes from sheep no antibodies. against sheep erythrocytes.

Surprisingly, the compounds of the invention are able to functionally replace T cells in such cultures. . thus allowing antibody response against sheep erythrocytes by antibody production. Addition of these substances. nu / nu leads to spleen cell cultures in the presence of sheep erythrocytes. within 4 days to substantial. an increase in the number of antibody-forming cells. The results show. that said compounds are. able to raise. production of humoral antibodies in vitro and compensate for the lack of T-cells in the system.

4. Selective B-cell mitogenicity:

Effect on stimulation of proliferation in B cell cultures

Suspensions of highly enriched B-lymphocytes (lymph node cells, congenital athymic nu / nu mice), as well as. even from the big. rates of pure immature or mature. T-lymphocytes (thymus cells or thymus cells from cortisone-resistant Balb / c mice, i.e., cells persistent 48 hours after cortisone injection) were administered. Incubate for 3 days in the presence of test compounds. Incorporation. 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., precursors to 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 have a potent effect in guinea pigs, for example, after a single dose of 0.05 mg per kg by subcutaneous administration, and in mice after five doses of 10. mg per kg subcutaneously, no toxic effects were observed in mice even at five doses of 300 mg / kg intraperitoneally. Listed. the compounds therefore have an excellent therapeutic breadth.

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 humoral immunity and activate the lymphocytes that make up the antibodies.

Accordingly, the novel compounds may 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 bacteria. 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 inducing immunologically activated lymphocyte populations in cell transfer.

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 suitable 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) immunologically defective conditions as may be encountered in old age, during more severe primary diseases, and especially 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 injectable 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 1, R 6, R 7, R 6 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.

Stress should be particularly a compound of formula II 0becného сн ^ он _"0 Z> ^{0 'R} <

NH-CO-R

R ^CdHHнC _& \-NHCH- CONH-CH- ( ^CH _Z ) _; ^- R ^g di.) Wherein

R is lower. an alkyl group or a phenyl group,

R1 is hydrogen or lower alkyl,

R2 is hydrogen or methyl,

R7. represents hydrogen, lower alkyl or hydroxymethyl,

Ra - represents a carbamoyl group and

R 5 is a carboxyl group, provided that the lower alkyl moiety R 8 is lower. contains more than 1 carbon atom when R2 'is' methyl,' and salts thereof.

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

R 'represents a lower alkyl group or a phenyl group,

R 1 is hydrogen,

R2 is hydrogen or methyl,

R 7 is hydrogen, methyl or hydroxymethyl,

R 5 represents a carbamoyl group α

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

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

R1 and R2 are as defined above,

R7 °, Rs ⁰ and R9 ° have the meaning of R7, Rs and R9 or, when they contain free carboxyl and optionally free hydroxy groups, these groups are protected by readily cleavable capping groups, and

R 5 represents an alkylidene or cycloalkylidene group, cleaves the oxazoline and dioxolane ring under acidic conditions, the optionally present capping groups are cleaved, and the optionally-free amino group at the 2-position of the sugar molecule is introduced with a -X-R residue where X and R are as defined above; whereupon the optionally obtained salts are converted into the free compounds or the obtained salts are converted into their physiologically acceptable acid salts.

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 the action of acidic ion exchangers, in particular those containing sulfo groups, such as "Amber Lite IR-120" (styrene resin with strongly acidic sulfo groups) or "Dowex 50" (polystyrene sulfonic acids) ) or by treatment with strong inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or sulfonic acids, for example methanesulfonic acid, or optionally substituted aromatic ring phenylsulfonic acid, such as p-toluenesulfonic 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, a 1-O-R 1 derivative is obtained. If one of the carboxyl groups R @ 5 and / or R @ 8 is also esterified with an alcohol, in particular a lower alkanol, this group can be saponified, in particular at a higher temperature, by treatment with an aqueous acid solution.

However, it is also possible that at the cleavage of u10, the amino group at the 2-position of the sugar molecule is liberated, in which case the residue -X-R, in which X and R are as defined above, must additionally be introduced. This introduction is carried out in a conventional manner by acylation or sulfonation.

In the compounds obtained, the hiding groups on the peptide residue can be 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 R 2 -acetamidopeptide residue in one or more stages into the corresponding oxazoline having a free hydroxy group at the 3-position of the sugar residue.

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 at 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 the pharmacacellular steps of starting with a compound obtained as an intermediate at any stage of the process and carrying out the missing steps, or interrupting the process at any stage, or forming the starting material under reaction conditions or using 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, pharmaceutical preparations can be formulated. They 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 being granulated and the mixture or the granulate, optionally after adding suitable excipients, 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, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or. where appropriate, substances allowing. disintegration of tablets such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate; are primarily flow regulators. and lubricating agents such as silicic acid, talc, stearic acid or salts thereof such as magnesium salt or stearic calcium salt and / or polyethylene glycol.

Kernels. dragees are provided with suitable coatings which are optionally resistant to action. gastric juices, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol. and / or titanium dioxide, furthermore paint solutions in suitable organic solvents or solvent mixtures, or k. production 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 ones. doses of 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 1

3,77 g. 2-phenyl-4,5- [3-O- (D-1-carboxyethyl) -5,6-O-isopropylidene-D-glucofurano] -N- ^2- oxazoline in 60 ml of acetonitrile and 15 ml of dimethylformamide are stirred together with 1, 4 ml of triethylamine and 2.55 g of N-ethyl-5-phenylisoxazolium-3 &apos; -sulfonate at 0 DEG C. ^for 1.5 hours, almost. all components will go into solution. 3.44 g of L-alanyl-D-glutamic acid 1-amido-γ-benzyl ester hydrochloride and an additional 1.4 ml of triethylamine were added and the reaction mixture was allowed to stir for 24 hours at room temperature. Then the reaction mixture is evaporated in a syrup oil pump vacuum and this syrup-like product is chromatographed on silica gel using chloroform / acetone (8/2). A colorless syrup is obtained which crystallizes on trituration with ether. Temperature. mp 96-99 ° C, [α] _D 20 = + 13 ° (in chloroform).

The crystalline benzyl ester is hydrogenated in the presence of 5% palladium on carbon in dioxane at room temperature and atmospheric pressure to give the appropriate acid as a syrup after evaporation in vacuo.

This syrup is stirred in water with 10 ml of "Dowex-50" in an H + -cycle at room temperature for 15 hours. After filtration and freeze-drying. gives a colorless powder with a decomposition temperature of 140 ° C. The obtained 2-benzoylamino-3-O- [D] - [L1- (D1-carbamoyl-3-carboxypropyl) -1-carbamoylethyl] carbamoylethyl] -2-deoxy-1,3,3-D-glucose contains, depending on the drying conditions, varying amounts of crystalline water, in the above case after drying at 60 ° C, 1.3 Pa, at 15 hours: 1/3 mol. crystalline water.

Example 2

6.0 g of 2-phenyl-1-4,5- (3-O- (D-1-carboxypropyl) -5,6-O-isopropylidene-D-glucofurano-N-oxazoline), 4.03 g of N-ethyl- 5-phenyl-isoxazol-3'-sulfonate and 2.25 ml of triethylamine are stirred in 100 ml of acetonitrile and 25 ml of dimethylformamide for 1 hour at 0-5 [deg.] C. and the solution is then added. 55 g of L-alanyl-D-glutamic acid 1-amido-γ-benzyl ester hydrochloride and an additional 2.35 ml of triethylamine are added and the reaction mixture is stirred at room temperature for 48 hours. 9 g of the thus obtained colorless syrup are hydrogenated in dioxane using 5% palladium on carbon, the catalyst is filtered off, the filtrate is evaporated in vacuo and the residue is hydrolyzed in a mixture of 40 ml. tetrahydrofuran and 30 ml of water using 1.5 ml of trifluoroacetic acid at room temperature, then the water is evaporated in vacuo four times. The residue was dissolved in water and lyophilized to give 2-benzoylamino-3-O- [D-1- [1H- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylpropyl] -2-deoxy- [alpha], 11D-glucose crystallizes with 0.5 mol of water, m.p. 114-152 ° C, [α] _D ²⁰ -) - 17 ((in methanol)).

Example 3

3.63 g of 2-phenyl-4,5- [3O-carboxymethyl-5,6-O-isopropylidene-D-glucofurane] -A- ² -oxazoline, 3.43 g of 1-amido-γ-benzyl ester hydrochloride L-alanyl-D-glutamic acid,

1.21 g of N-hydroxysuccinimide, 2.16 g of dicyclohexylcarbodiimide and 1.45 ml of triethylamine are dissolved in 40 ml of dimethylformamide and the mixture is stirred at room temperature for 24 hours. The reaction mixture is then evaporated in an oil pump vacuum, the residue is taken up in dichloroethane and water, the precipitated dicyclohexylurea is filtered off and the organic phase is extracted twice with water and the aqueous phase is extracted twice with dichloroethane. After drying and evaporation of the organic phase, a syrup is obtained which is chromatographed on silica gel using chloroform / ethanol (9: 1) as eluent. The obtained peptide ester, which crystallizes upon trituration with ether, melts at 167-168 ° C, [α] D = -5 ° (chloroform).

4.5 g of the above ester were hydrogenated in dioxane using 5% palladium on carbon, then the catalyst was filtered off and extracted again with ethanol. The combined filtrates were evaporated and the residue was recrystallized from isopropyl alcohol. The acid obtained melts at 200-207 ° C.

2.85 g of this acid are stirred in a mixture consisting of 30 ml of water and 15 ml of tetrahydrofuran and 5 ml of "Dowex-50" in an H + -cycle for 15 hours at room temperature, then the mixture is filtered and the filtrate is evaporated to dryness in vacuo. On trituration with ether, a colorless powder is obtained which is 2-benzylamino-3-O - [{1- 1- (D-1-carbamoyl-3-carboxypropyl) -1-carbamoylethyl] carbamoyl] ethyl] -2-deoxy- α, β-D-glucose having a melting point of 175-177 ° C (as a hydrate).

By a variation of the method described in Acta Chem. Scand. 18, 185 (1964), the starting material can be prepared as follows:

100 g of 2-phenyl-4,5- (5,6, -O-isopropylidene-D-glucofurano] - ² -oxazoline are dissolved in 1 liter of acetonitrile, excluding moisture and carbon dioxide, and added in portions to this solution. 15.2 g of a 55% dispersion of sodium hydride in mineral oil with good stirring and the reaction mixture is further stirred at room temperature for 1 hour, then 42 ml of ethyl chloroacetate are added dropwise at 0 ° C and after a further 1.5 hours After 1.5 hours 11.4 g of sodium hydride dispersion were added dropwise, the mixture was stirred for half an hour, and an additional 42 ml of ethyl chloroacetate were added dropwise at 0 ° C. The syrup is taken up in ether, the ether solution is shaken three times with water, the ether phase is dried over sodium sulphate and evaporated to give 155 g of a brown solid. This oil is dissolved in 150 ml of methanol and then a solution of 3D g of potassium hydroxide in 150 ml of water is added, extracted twice with ether and the ether phase is washed once with water. The aqueous phases are freed from ether in vacuo and adjusted to pH 4 by addition of 1 N hydrochloric acid solution (monitoring by pH meter).

The precipitated crystalline 2-phenyl-4,5- [3-O- (cyanomethyl-5,6-O-propylidene-D-glucofurano) -A 2 -oxazoline is filtered off, washed with water and dried to give 107 g. g, i.e. 93% of theory · of product, mp 186-188 ° C, _[a] 20 d = -9 ° (chloroform, c = 0.9), and [c ² d 0 = -23 ° (CHCl , c = 3).

Example 4

6.33 g of 2-ftnyli4,5i (3iOikarboxymtthyl-5,6iO isopropylldtn-D-glukofuran (l) -Δ ² oxazoline, 5.75 g of 2 - methoxy ^^ N - ^^ hoxykarbonyl 12-dihydroquinoline 9.3 ml of triethylamine is added to a solution of L-alanyl-D-glutamic acid dibenzyl ester trifluoroacetate (obtained from 8.3 g of N-tert-butyloxycarbonyl-L-alanyl-D-glutamic acid dibenzyl ester with 5.1 ml of trifluoroacetic acid and 2 ml). (6 ml of dichloroethane by 4 hours hydrolysis at 40 DEG C.) in 70 ml of dichloroethane The reaction mixture is allowed to react for 15 hours at 40 DEG C., diluted with chloroform, shaken twice with water and the aqueous phases are shaken once with chloroform. evaporation of the chloroform solution gave 19.9 g of an oil which was purified over 400 g of silica gel (gauge) eluting with ether and then with a 17: 3 mixture of chloroform and acetone. O-il-L- (1D, 3- (dibenzoyloxycarbonylpropyl) carbamoylethyl) carbamoylmethyl-5,15-O-2-s-2-oxylcarbonyl (5H-2-carboxylic acid) i ^ - ^ ll ^ U ^ (^ jiUгano] -Δ ² oxazoline of melting point 113-116 ° C, [?] D20 = -47 · (CHC15, c = 1.54).

g of the above compound. The mixture is hydrogenated in the presence of 1.8 g of 5% palladium on carbon in a mixture of 80 ml of tetrahydrofuran and 20 ml of water until the consumption of hydrogen ceases, the catalyst is filtered off, the filtrate is evaporated in vacuo and the residue triturated with ether. Like this. 4.9 g of dicarboxylic acid are obtained in the form of a colorless powder.

4.4 g of the above dicarboxylic acid are stirred for 20 hours at 40 DEG C. with 1 ml of Dowix-50 W ion exchange resin. X 4 'in a mixture consisting of 45 ml of tetrahydrofuran and 20 ml of water. Filtration and clarification with activated charcoal (Darco G 60), freeze-drying of the solution gives colorless, am (N, 2-benzamido-deeoy-3-O- [11L- (1D, 4-dicarboxypropyl) carbamoy]. Lethyl] carbamoylmethyl-D-glucopyranose with optical rotation [α] _D 20 = + -25 ° (H 2 O, c = 0.997).

Example 5

In an analogous manner to that described in Example 5, 5.7 g of 2-phthyl-4,5- [30-carb205027 oxymethyl-5,6-O-isopropylidene-D-gluco- were condensed. furano] -? ² -oxazoline with 4.9 g of L-seryl-D-glutamic acid α-amide tert -butyl ester hydrochloride with the addition of 2.3 ml of triethylamine and 5.2 g of 2-ethoxy-N-ethoxycarbonyl- Of 1,2-dihydroquinoline in 45 ml of dichloroethane. After 18 hours at 40 ° C a crystallizate is formed. An additional 50 ml of dichloroethane is then added, the mixture is cooled in ice, filtered and the crystals are washed with cold dichloroethane. Analytically pure, colorless crystals of 2-phenyl-4,5- [3-O- (1-L- / 1-D-carbamoyl-3-tert-butyloxycarbonylpropyl) carbamoyl-2-hydroxyethyl] carbamoylmethyl-5,6-O- isopropylidene-D-glucofurano] -? - oxazoline have a melting point of 187-188 ° C and λ = + 7 ° (CH 3 OH, c = 1.125).

g of this compound are hydrolyzed at room temperature for 20 hours with a mixture of 15 ml of methylene chloride and 5 ml of trifluoroacetic acid. The mixture was evaporated in an oil pump vacuum, the residue was triturated with ether to give 2-benzamido-2-deoxy-3-O- [1-L- (1-D-carbamoyl-3-carboxypropyl) carbamoyl-2-hydroxyethyl] carbamoylmethyl-D-glucopyranose in the form of a beige powder, m.p. 100 DEG-115 DEG C., [ _.alpha. ] _D @ 20 = + 213 DEG (H2 O, c = 0.886), which crystallizes with 2 moles of water and 1 mol of trichloride. Acidic acid. Rf value = 0.28 (1: 1 chloroform / methanol, thin layer chromatography).

Example

In an analogous manner to Example 4, 5.25 g of 2-phenyl-4,5- [3-O-carboxymethyl-5,6-O-sopropylidene-D-glucurfurano] -A2-oxazoline were condensed with the salt (1). - L-alanyl-D-glutamic acid α-n-propylamide with trifluoroacetic acid, obtained from 6.2 g of N-tert-butyloxycarbonyl-L-alanyl-D-glutamic acid β-benzyl ester and 4, 2 ml of trifluoroacetic acid in 2.5 ml of dichloroethane over 6 hours at 40 ° C, in 60 ml of dichloroethane with the addition of 7.75 ml of triethylamine and

4.8 g of 2-e] 10-oxy-N-e-oxo-carbonyl-1,2-dihydroquinoline. After 20 hours at 40 ° C, the reaction mixture is diluted with 50 ml of chloroform, shaken twice with water, and the water is then extracted twice with chloroform. After drying and concentration of the chloroform phases, 15 g of an oil are obtained, which is purified over 200 g of silica gel using ether and then a 7: 3 mixture of chloroform and acetone. 6.4 g of a colorless amorphous substance having an Rf value of 0.35 and a 7: 3 mixture of chloroform and acetone (thin layer chromatography, silica gel, Gauge) are obtained.

This substance is then treated. It is hydrogenated in the presence of 1.2 g of 5% palladium on carbon in 80 ml of tetrahydrofuran and 20 ml of water until the consumption of hydrogen ceases, the catalyst is filtered off and the filtrate is concentrated. The acid has an Rf value of - 0.58 (chloroform / methanol 3: 1, silica gel thin layer chromatography, Gauge). It is then stirred with 10 ml of the "Dowex 50-W x 4" ion exchanger, 50 ml of tetrahydrofuran and 25 ml of water for 15 hours at room temperature and 12 hours at 40 ° C. Filtration, clarification with activated carbon (Darco-G-60), re-filtration and freeze-drying gave colorless amorphous 2-benzamido-2-deoxy-3-O- [1-L- (1-DNopropylcarbamoyl-3-carboxypropyl) (carbamoylethyl) carbamoylmethyl-D-glucopyranose, m.p. 65 DEG-140 DEG C. [.alpha.] D = 28 DEG (water, c = 1.03), Rf = 0.48 (1: 1 chloroform / methanol, chromatography). on a thin layer of silica gel, Merek).

Example 7

7.3 g of 2-phenyl-4,5- [3-O-carboxymethyl-5,6-O-isopropylidene-D-glucofurano] -2-oxazoline, 6.5 g of α-amide α-tert-butyl ester hydrochloride, of aminoisobutyroyl-D-glutamic acid and 2.9 g of isobutyl chloroformate were dissolved in 25 ml of dimethylformamide and 50 ml of dichloroethane. A solution of 6.1 ml of triethylamine in 20 ml of dichloroethane is added dropwise at -15 to -10 ° C over 30 minutes. The mixture was then allowed to warm to room temperature and stirred at room temperature for 15 hours. The reaction mixture is diluted with 50 ml of dichloroethane, then shaken with water, twice with 0.5 N sodium hydroxide solution and three times with water, the aqueous phases are extracted twice with dichloroethane, the organic phases are dried and evaporated to give 16.6 g. oils. This oil was purified on silica gel, gauge, eluting with a 19: 1 mixture of chloroform and ethanol. 9.7 g of colorless amorphous 2-phenyl-1,5,5- [3-O- [(eta) &lt; 6 &gt; - (1-D-carbamoyl-3-tert-butyloxycarbonylpropyl) carbamoylethyl] -5 are obtained, 6-O-propylidene-D-glucofuran-4-oxazoline with optical rotation [α] D 20 = + -6 ^O (chloroform, c = 1.027), melting point = 75-89 ° C, Rf value = 0, 35, chloroform / ethanol 9: 1 (silica gel thin layer chromatography, Merek).

8.3 g of the above compound are left at room temperature for 15 hours in a mixture of 20 ml of trifluoroacetic acid, 60 ml of methylene chloride and 2 ml of water. The mixture was evaporated in vacuo and the residue triturated with ether. The resulting pink powder was dissolved in 200 mL of water and clarified with 0.5 g of activated carbon (Darco-G-60). Filtration and evaporation gave a colorless, amorphous 2-benzamido-2-deoxy-3-O- [Т-теШуМ-

- (D1- [alpha] -bamoyl-3-carboxypeptide) carbamoylethyl] carbamoylmethyl-D-glucopyranose, m.p. 110 DEG-120 DEG C., [ _.alpha. ] _D @ ²⁰ = -31 DEG ⁽ H2 O, c = 0.88. ^Rf = 0.52 (acetone / ethanol 1: 1, silica gel thin layer chromatography, Merek) which crystallizes with 0.6 mol of trifluoroacetic acid and 1.7 mol of water.

Example d8

In an analogous manner to that described in Example 4, from 2-benzamido-2-deoxy-3-O-carboxymethyl-4-methyl-1-D-glucopyranoside and α-amide L-amide salt of α-tert-butyl ester. alanyl-D-glutamic acid with trifluoroacetic acid and with 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline to give the corresponding glycopeptide with (α) _D 20-23 ° (methanol, c = 1.107) and R 1 = 0, 47 (methylene chloride: ethanol · 8: 2) and hydrogenation in the presence of · 5% palladium on carbon in tetrahydrofuran / water gave 2-benzamido-2-deoxy-3-O- [L-1- (D1-carbamoyl) 215 DEG-217 DEG C., [.alpha.] _D @ ²⁰ = -22 DEG (methanol, c = 0.97), Rf -3-carboxypropyl) carbamoylethyl] carbamoylmethyl 1- [3-ethylbeta] -glucopyranoside Melting point = 0.36 (1: 1 chloroform: methanol, silica gel thin layer chromatography, Merck).

The 2-benzamido-2-deoxy-3-O-carboxymethyl-1-ethyl-D-glucopyranoside used as starting material is obtained as follows:

2-phenyl-1-4,5- [3-0-carboxymethyl-5,6-0-isopropylidene-D-glukof Urano] - A ² oxazoline were dissolved in 0.1 N sodium eth-anolického chloride and the mixture allowed 6 hours at room temperature. It is then neutralized with sodium ethoxide in ethanol, evaporated to dryness and the residue is dissolved in acetone. The solution obtained is filtered through a pad of silica gel, the eluate is evaporated to dryness and the residue is extracted twice with ether at room temperature. Recrystallization from ethyl acetate gave 2-benzamido-2-deoxy-3-O-methoxycarbonylmethyl-4- (4-iodo-4-yl) -D-glucopyranoside, m.p. 185-188 ° C. C and [a] ² 0 = -35 ° (methanol, c = - 1.121).

9.4 g of this ester were saponified with a solution of 1.7 g of potassium hydroxide in 250 ml of ethanol and 25 ml of water for 2 hours at room temperature. The pH was then adjusted to 3.5 by the addition of 1 N hydrochloric acid and the solution was concentrated in vacuo. The residue is triturated first with ether, then three times with 20 ml of ice-water each time and the product is filtered off. Thus, crystals of 2-benza.mido-2-de oxy-3-O-carboxymethyl-.beta.-eehyl D-glucopyranoside, melting point 205-210 ° C, [ «) ²⁰ _D - 40 ° (methanol, c - 1.04).

Example 9

2-Benzamido-2-deoxy-3-O - [(D1-carbamoyl-3-carboxypropyl) carbamoylmethyl] carbamoylmethyl-D-glucose is obtained from 3 g of 2-phenyl-4,5- [3-O - / ( D 1 -carbamoyl-3-carboxypropyl) carbamoylmethyl / carbamoylmethyl-5,6-O-isopropylidene-D-glucofurano] - N 2 -oxazoline by hydrolysis with 1.5 ml. of acid in a mixture of 15 ml of dimethoxyacetate and 15 ml of water at 40 ° C for 3 hours. The mixture was then concentrated to dryness under vacuum and the residue extracted again with ether. The remaining powder was dissolved in water, the solution was clarified with activated carbon (Darco-G-60), filtered and freeze-dried. Thus, a colorless, amorphous solid, mp 115-155 ° C, _{[e] D} 20 = + 34 ° (water, c = 0.81) Rf = 0.28 (chloroform: methanol 1: 1, silica gel thin layer chromatography, Gauge).

The starting material for this purpose is obtained as follows:

8.0 g of N-tert-butyl oxycarbonylglycyl-D-glutamic acid α-amide is dissolved in a mixture of 6.3 ml of trifluoroacetic acid and 7 ml of dichloroethane and the solution is allowed to react at room temperature for 2 days. room temperature and 3 hours at 45 ° C. Then, 12.1 ml of triethylamine, 7.0 g of 2-ethoxy-N-ethoxycarbonyl, 2-dihydroquinoline and 8.1 g of 2-phenyl-4,5- [3-O-carboxymethyl] are added while cooling. -5,6-O-isopropylidene-D-glucofurano] -2-oxazoline and 20 ml of dimethylformamide. After 20 hours at 40 ° C, the mixture is concentrated in an oil pump vacuum and the residue is partitioned between methylene chloride and water. After drying and concentration of the methylene chloride phases, a solid residue is obtained which is extracted twice with ether and recrystallized from toluene. Yield 8.25 g, m.p. 157 DEG C .; Celsius, [α] β20 · = · - (- 10 ° (chloroform, c = 1.48), Rf = 0.35 (chloroform / ethanol 9: 1, silica gel thin layer chromatography, Gauges).

The benzyl ester thus obtained is hydrogenated in the presence. 5% palladium on carbon in 100 ml tetrahydrofuran and 25 ml water until hydrogen consumption ceased. After filtering off the catalyst and evaporation, the material is chromatographed on 250 g of silica gel, Mek, using chloroform and methanol 4: 1 as eluent. 5.8 g of colorless, amorphous 2-phenyl-4,5- [3-O- (D1-carbamoyl-3-carboxypropyl) carbamido] carbamoylmethyl-5,6-O-isopropylidene-D-glucofuran are obtained. R 2 = 0.43, 3: 2 chloroform / methanol (silica gel thin layer chromatography, Gauge).

Example 10

9.5 g of 2-phenyl-4,5- [3-O-carboxymethyl- (5,6-O-2-methyl-2,4-diidene-D-glucofurano) - are condensed in an analogous manner to that of Example 4. N- ² -oxazoline with 6.25 g of L-alanyl-D-glutamic acid α, γ-dlamide with the addition of 3.4 ml of triethylamine and 7.95 g of 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline in a mixture 50 ml of dichloroethane and 150 ml of dimethylformamide. The mixture was allowed to react with stirring for 2 days at room temperature and 4 hours at 40 ° C. Celsius. The mixture was concentrated in an oil pump vacuum and the residue was extracted twice with ether, then twice with ice water. After. drying of the recrystallized product 205027 is from dichloroethane. 170 DEG-184 DEG C., [ _.alpha. ] _D @ ²⁰ = + 3 DEG (dimethylsulfoxide, c ' = 1.43), Rf = 0.64 (3: 1 chloroform: methanol), thin layer silica gel, Merck).

6.1 g of this compound are hydrolyzed by treatment with 13.5 ml of ion exchange resin (Dowex 50) in a mixture of 60 ml of dimethoxyethane and 60 ml of water for 15 hours at room temperature. After filtration and concentration, the residue is taken up in water, clarified with activated carbon (Darco-G-60), filtered again and the filtrate freeze-dried. A colorless amorphous 2-benzamido-2-deoxy-3-O- (Ll- (Dl, 3-dicarboxylic bamoylpr PROPYL) -carbamoylethyl] -carbamoyl-methyl-D-glucopyranose, m.p. 82-143 Wed Celsius [ «IJD ²⁰ = + 24 ° (water, c = 0.98), Rf = 0.45 1: 1 chloroform: methanol, thin layer chromatography (Merck). The substance crystallizes with 1.23 moles of crystalline water.

The following compounds can be obtained in an analogous manner:

a) benzyl 3-O- [D1- [L1- (D1-carbamoyl-3-carboxypropyl) carbamoyl] carbamoylethyl] -2-propionylamino-2-deoxy-6-glucopyranoside, m.p. 155-160 ° C (decomposition), [ _.alpha. ] _{D @} ²⁰ = + 105 DEG + 1 DEG (dimethylformamide, c = 0.58),

b) 3-О - / [Ll- (DL-carbamoyl-1-3-carboxypropyl) carbonyl bamoylethy 1] carbamoylmethyl / acetami'do -2-2-deoxy-D-glucose, (ia] _D 20 ° ₌ 4 _io -1 ° (water, c = 0.930),

c) 3-O- [D-1- (L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylpropyl) -2-acetamino-2-deoxy-D-glucose,

d) 3-O- [11- (D1-carbamoyl-3-carboxypropyl) carbamoylmethyl] carbamoylmethyl-2-benzamido-2-deoxy- / 3-ethyl-D-glycoifuranosd, m.p. 215-217 ° C, [JoO ²⁰ ₌ -22 ° (СНзОН, c = 0.97),

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

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

(f) 2-benzamido-2-deoxy-3-O- [11- (D-1,3-bis-N-methylcarbamoylpropyl) carbamoylethyl] carbamoylmethyl-D-glucopyranose, m.p. 125 DEG-132 DEG C. [w] d ²⁰ ₌ 4-24 ° (НгО, c = 0.93),

g) 2-Benzamido-2-deoxy-3-O- [L- (D-1,3-bis-methoxycarbonylpropyl) carbamoyl ethyl] carbamoylmethyl-D-glucopyranose as a hydrate, m.p. 80-90 ° C, good ²⁰ = + 25 ° (longitude, c = 1,017),

h) ethyl-2-benzamido-2-deoxy-3-O- [L-1-

(D, 1,3-bis-methoxycarbonylpropyl) carbamoylethyl) carbamoylmethyl-13-D-glucopyranoside, m.p. 127-135 ° C; Celsius, [α] _D ²⁰ = -17 ° (СНзОН.с = 1,024),

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

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

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

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

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

o) 2-acetamido-3-O- [D-1-carbamoyl-3-carboxypropyl) carbamoylmethylcarbamoylmethyl] -2-deoxy-D-glucose,

p) of methyl 2-acetamido-3-O - / [Ll- (dl-carbamoyl-3-carboxypropyl) carbamoyl 1-ethyl] carbamoylmethyl / -2-deoxy-UF-D-glucopyranoside of [a] _D ²⁰ = -J- 49 ° + 1 ° (water, c = 0.939),

q) methyl-2-acetamido-3-O - [[1- (D1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl] -2-deoxy-6-O-stearoyl-α-D-glucopyranoside o [ ] _D ²⁰ =

- 4-50 ° + 1 ° (N, N-dimethylformamide, c = 0.921),

r) 2-Acetamido-3-O7 [Ll- (Dl, 3-dikarbamoylpropyl) carbamoylmethyl] carbamoylmethyl / -2-deoxy-D-glucose, [?] _D 20 = _ [_ ₇ ° and the fourth DEG (water, c = 0.514),

s) 2-acetamido-3- [1 - [(D1-carbamoyl-3-carboxypropyl) carbamoylmethyl] carbamoylpropyl] -2-deoxy-D-glucose, [ _.alpha. ] _D @ 20 = 4-46 DEG + 1 DEG (water) , c = 0.630)

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

u) 2-acetamido-3-O - [[L-1-] dimethyl ester]

- (D1,3-dicarboxypropyl) carbamoylethyl] carbamoylmethyl / -2-deoxy-D-glucose [α] D ²⁰ = + 23 ° ± 1 ° (water, c = 0.814),

(v) 3-O - / (L-1- (D-1-carbamoyl-3-carbo205027 xpropyl) carbamoylethyl] carbamoylmethyl / -2-deoxy-2-propionamido-D-glucose,

w) 3Ό-- [L-1- (D-1-carbamoyl-3-carboxypiperidocarbamoylethyl) carbamoylmethyl] -2-caprinoylamido-2-deoxy-D-glucose,

(x) 2-acetamido-2-deoxy-3-O- [L-1- (D-1,3-Ь15-methylcarbamoylpropyl) carbamoylethyl] carbamoylmethyl] -D-glucose,

y) 2-acetamido-3-O - [L-1- (D-carbamoyl-3-carboxypropyl) carbamoyl-2-hydroxyethyl] carbamoylmethyl-4-deoxy-D-glucose,

z) 2-acetamido-3-O- [[L-1- (J-carbamoyl-3-carboxypropyl) carbamoylbutyl] carbamoylmethyl] -2-deoxy-D-glucose, aa) 3-O- [L-1- (D-1-carbamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl 1 -2-deoxy-2-stearoylamido-D-glucose, bb) 2-acetone mido-3-O - [L-1- (D1-carbamoyl) 1-3-carboxypropylcarbamoyl-2-methylpropylcarbamoylmethyl] -2-deoxy-D-glucose, cc) 2-acetamido-3-O- [L-1- (D1-carbamoyl-3-carboxypropyl) carboxy bamoyl-3-methylbutyl] carbamoylmethyl-2-deoxy-D-glucose, dd) 2-acetamido-3-07 [L-1- (D1-carbamoyl-13-carboxy) crude] ] carramoylmethyl-2-deoxy-D-glucose, ee) 2-acetainido-3-Ol [L-1- (D1-aryrmoyl-3-carboxypropyl) carbamoylphenylmethyl] carbamylmethyl-1,2-deoxy-D -glucose, (f) trimethyl-2-arctamido-3-O- [1,1- (D1,3-ris-carbamoylpropyl) arrrnoylethyl] carramoylmethyl-3-deoxy-D-gluaopyranoside, [a] D ²⁰ May = -44 ° + 1 ° (N, N-dimethylformamide, c. = 0.989), (gg) renzyl-2-acetamido-3-O-1L-1- (D1,3-bis-aarboxyrroryl) dimethyl ester arrrrmoylethyl]. carbamoylmethyl 1 -2-deoxy-1-D-glucopyrrolidide, hh) 2-acetamido-3-O - / (L-1- (D1-aramramoyl methylaramamoyl-3-carboxypropyl) carbamoylethyl] carbamoylmethyl) -2-deoxy-D- glucose, white powder, (ii) 3-O - [[L1 ([D1 - raremoyl-3-arrboxypropyl) 1-aminoylethyl] carbamoylmethyl] -2-deoxy-2-p-tolylsulfonylamino'-D-glucose, white powder ,.

kk) 2- (acetaminomethylmethylamino) -2-deoxy-3,0 - [[L-1- (D1-aarramoyl-3-hydroxypropyl) -1-carbamoylmethyl] carbamoylmethyl] -α, | 3- D-gluaose,

11) 2-trimethylaceram-do-2-deoxy-3,0-l [L-1- (D-1-carbonyl-3-carboxyrroryl) -1-carbamoylethyl] carbamoyl -D-glucose, mm) renzyl-2-dimetamido-3-Oз [L-1- (D1-carbamoyl-3-carbamoylpropyl) carbamoylethyl] carbamoylmethyl-2-deoxy-6-O-Stearyl-α-D-glucoryrnoside.

Claims (1)

I will invent the subject Process for the preparation of glucosamine derivatives of the general formula I CO-NH-CH-CONH-CH < ^DI <11 with 1 to 5 carbon atoms or benzyl residue, R2 is hydrogen or (C1-C5) -alkyl, R 1 and R 6 are hydrogen or an acyl radical having 2 to 18 carbon atoms, R 2 represents 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 atom when X is carbonyl and R2 is methyl, or when X is carbonyl, R2 is hydrogen and R 8 and R 9 are carboxyl,. as well as their pharmaceutically usable acid addition salts, characterized in that in a compound of the general formula (IX): 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 an alkyl radical R 7 °, Re ° a. R &lt; 9 &gt; has the meaning of R &lt; 7 &gt;, R &lt; 6 &gt; and R &lt; 9 &gt; R 5 represents an alkylidene or cycloalkylldene group,. cleaves the oxazoline and dioxolane ring under acidic conditions, the optionally present capping groups are cleaved, and the optionally-free amino group at the 2-position of the sugar molecule is introduced with the —X — R moiety in which X and R are as hereinbefore defined; freely compounds or converted salts thereof into their physiologically acceptable acid addition salts. in which R1 and R2 are as defined above, Scverography, n., Plant 7, Most