PL112672B1 - Process for preparing novel derivatives of glycosamine - Google Patents

Description

The patent description was published: April 30, 1982 112672 Int. 01. ^ C07H 15/12 Inventor Proprietor of the patent: Ciba-Geigy AG., Basel (Switzerland) Method for the production of new glycosamine derivatives The method of producing new sub-derivative glycosoanins with general visor 1, in which X is a carbonyl group, R is an alkyl radical of 1-18 carbon atoms or a phenyl radical, Ri is a hydrogen atom or an alkyl radical of 1-3 carbon atoms, R2 is a hydrogen atom or an allkyl radical with 1- <3 carbon atoms, R4 is hydrogen, Re is hydrogen, R7 is aphtho hydrogen, alkyl group with 1-5 carbon atoms, hydroxymethyl or phenyl group, Rs is carboxyl, alkoxycarbohydrate nyoyl with 1-3 carbon aitomes in the alkoxy part, group up toaanbamoyl, group N ^ aiLkylcarbamoyl with 1-4 carbon atoms in the alkyl part, group N ^ benEylcarbamoyl or carbamoylmethylphenbamoyl group, R9deyl group, arboxylic group, alkoxycarbonyl group with 1-3 carbon atoms in the allkoxy part, benzyloxycarbonyl group, carbaimino group, N-alkylcarbamoyl group with 1-4 carbon atoms in the alkyl part, provided that the alkyl radical R contains more than 1 carbon atom when X is carbonyl and R2 is methyl, or when X is kairibonyl, R2 is hydrogen and Rs and R9 are carboxyl groups, and their salts.

In the above-discussed compounds, in which R2 is an alkyl radical, the t1 * -ne at the -3 position of the glycosamine group and the acetamid bond group of R2 is optically active, that is, it is present in a condensation inD. In case R7 is not hydrogen, the amino acetic acid R7 is in the L-configuration.

The new compounds produced by the method according to the invention are, depending on their substituents, neutral, acidic or basic compounds. When excess acid groups are present, they form salts with bases such as ammonium salts, or salts with alkali metals or alkaline earth metals, for example sodium, potassium, calcium or magnesium. If excess basic groups are present, they form acid addition salts.

Acid addition salts include, in particular, pharmacologically acceptable non-toxic acid addition salts such as salts with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids, or organic acids. such as organic carboxylic acids, for example with acetic, propionic, glycolic, succinic, maleic, hydroxymaleic, mintmaleic, fumaric, apple, tartaric, citric, benzoic, cinnamic, mandelic, salicylic, 4-aminosalicylic acids , 2-phenoxyibenzoic, 2-hydroxybenzoic, embonic, nicotinic or isonicotinic, or with such as organic sulfonic acids, for example with methanesulfanic acid, atanesulfonic acid, 2-ihydroxinate, ethaininic acid, ethaininic acid, ethaininic acid , benzenosulfonic acid, p-toluenesulfonic acid or naphthaenesulfonic acid and H2, and also other acid addition salts which can be adjusted to for example as intermediates, for example for the purification of free compounds or for the formation of other salts and for their characterization, such as salts with pilcricic acid, pyicrodonic acid, flavanic acid, phosphoixolylamic acid, phosphorolybdic acid, perchloric acid and Reine acid. cke.

Relationships, made up. according to the invention, they exhibit valuable pharmacological properties, especially excellent immunity-enhancing activity. This can be evidenced from the following study system 1–5 1. In vitro cell-mediated immunity: growth of late-type supernatural worms to hen egg albumin in guinea pigs.

Moirsfcie pigs, cv. Piribrdigihfa, on day 0, are immunized with 10 mg of ovalbumin in complete Ereumd's adjuvant by means of a ribbon 0.1 ml of amityigen mixture in both hind legs. After 4 weeks, skin reactions are evoked by intradermal injection of 100 [Mg of ovalbumin in 0.1 ml of buffered saline solution and quantified on the basis of the volume of the reaction, calculated after 24 hours from the surface of erythema and the thickness of the skin. After 24 hours (late type reaction), the observed amtigene-specific increase in the volume of the reaction serves as the cellular mediator of transmitted immunity. Egg albumin is too much of an imaruuinogen to be incomplete by itself or in an incomplete water-oil emulsion. Freund's adjuvant (10 parts of the aJibumdny egg solution at 0.9 * / t Above mixed with 8.5 parts of Bayol F and 1.5 parts of the agent called Arlacel A) induced late type reactions, but for the immunization to be effective, the immunization must be applied in complete adjuvant, to which is added the washes [5 mg of killed and lyophilized - buttyoum powder has 10 ml of Bayol F / Anlacel A system]. In order to determine the resistance-promoting effect of the test substances, these substances can be added to the anti-corrosive-oil mixture instead of the powders in doses of 10 to 100 pg.

The glycosamine peptides prepared according to the invention are capable of mimicking the effect of these fractions in the test system described and quantitatively surpassing it.

A clear increase in the reactivity of the late type to hen egg albumin can also be achieved by the fact that the compounds of this type are not incorporated in an amitygene-oil mixture, but are administered subcutaneously in a kitchen solution in doses of 10 to 10 pg per experimental animal within days 20 25 after immunization (one example on days 0, 1, 2, & s 6 and 7).

Thus, it has been proved that the compounds of the type in question are capable of seriously increasing the cellular immunity, both in mfeishanias with the antigen itself (adjuvant affect in the strict sense) and when applied temporarily and locally separate from the antigen injection ( systemic proofing of immunity). ao 2. The suppression of liquid immunity in vivo: increased production of antibodies to bovine serum albumin (BSA) in mice.

Day 0 NMU mice are immunized by an intraperitoneal (i.p.) injection of 10 µg of sedimented bovine serum albumin (BSA). After 9, 15 and 29 days, serum samples are taken and tested for anti-BSA antibodies by a haemagglutinating technique.

At the dosages used, soluble albumin BSA is for animals that consume subiimmunogenin, that is, it is not capable or only capable of eliciting very little antibody production.

Additional treatment of the mice with certain immune-enhancing substances before or after the antigen dose increases the serum antibody titer. The effect of this treatment is the write loss achieved, ie the sum log 2 of the difference in titers over the three days of bleeding.

The compounds according to the invention are able to increase the production of 100-300 mg / kg / 35% of an animal in the five consecutive days (day 0 to 4) after immunization with BSA albumin when administered intraperitoneally or subcutaneously (SC). opposed to BSA.

The immunity-stimulating effect of these 40 compounds is antigen-dependent, unlike other bacterial immunoleptics (e.g. E. coli IiPS): injection of new compounds only in BSA-inimmunized and never in unimmunized mice 45 causes a titer increase. am / you-BSA. It is noteworthy that the subcutaneous administration of the compounds in question is as effective as the intraperitoneal administration, that is to say, the observed immune-promoting effect is systemic and does not depend on the stimulator being like amltygen or being mixed with the antigen in the same way. way, as is the case with the classical adjuvamites.

Thanks to the described tests, it was found that compounds of the type in question are also capable of specifically increasing the liquid resistance, that they improve the immune response to the child, and that their immune-promoting effect is based on the systemic activation of the immune apparatus. 3. The enhancement of liquid immunity in vitro: the effect of thymic cells (T) on the response of mouse spleen cell antibodies to ovine erythrocytes (SE). «S For the induction of antibody responses, in many cases, lymphocytes (T-cells) of thymic origin are necessary. These cells interact with the antibody-forming predecessors of the lymphocytes (B-cells) and help them respond to purgation with the help of so-called T-dependent antigens through cell proliferation, differentiation and antibody synthesis. The cell suspensions of the siledizdones of virodized anthymic mu / nu mice do not contain any functional T cells and are unable, for example, to form any anti-SE antibodies in vit.

The self-produced compounds according to the invention are unexpectedly able to functionally replace T cells in these cultures and allow antibodies to respond to the SE erythrocytes. The addition of these substances to the culture of n / o cells followed by the presence of SE erythrocytes leads to within 4 days for a significant increase in the number of cells forming the antibody.20 The results show that these compounds are able to increase liquid antibody production in Viitro and compensate for the defect in the -T-cellular component. 25 4. Selective myithogenicity for B-cells: e - the effect favoring the proliferation of cells in cultures of B-lymphocytes.

Suspensions of highly enriched iymphocytes-B (cells of the lymph nodes of nu / nu mice with thymus deficiency), and the amusingly purest, immature and milking iimffoicytes-T [thymic cells relatively resistant to cortisone, i.e. 48 hours after injection * of coirtisone, the graisicize cells of the Ballb / c mice are cultured in the presence of the test substances for three days .. Incorporations of Hs-thymidine in these lymphocytes during an approximately 16 hour cultivation period serve as a measure of cell proliferation activity.

The compounds prepared by the method of the invention are mitogenic for B-lymphocytes (that is, for the ancestors of antibody-producing cells) and non-myitogenic for T-lymphocytes. Thus, these compounds are able to induce a differentiation of the lymphocytes involved in the liquid response (immune response) / £ 4 3 tolerance. Although the compounds of the type in question exert their potentiating effect on guinea pigs, for example, after a single subcutaneous dose of 0.05 mg / kg, and in mice, after subcutaneous administration of a 5-fold dose of 10 mg / kg, even after No toxic effects were observed after intraperitoneal application of 300 mg / kg to mice 5 times. The substances in question therefore also have an excellent therapeutic range.

The compounds prepared by the method according to the invention show the ability, firstly, in a mixture with an antigen to increase its immunogenicity, and secondly, when administered systemically, to increase the immunological reactivity of the treated organism. Moreover, the discussed satatants are able to promote both cellular and liquid immunosuppression and activate lymphocytes responsible for the production of antibodies, but the new compounds can therefore be used as adjuvants in a mixture with vaccines. to improve the vaccination result and also to increase the anti-infective protection against bacterial infections, viral parasitic bacteria, caused by fluid resistance antibodies and / or cellular immunity.

Finally, the compounds in question will be suitable in a mixture with a variety of antigens as adjuvants in the experimental and industrial preparation of antiserum for therapy and diagnosis, and in the induction of immunologically activated lymphocyte populations for the purpose of cell donation.

Moreover, the new compounds can be used even without the addition of an antigen to promote already subliminal immune responses in humans and animals. These compounds are therefore particularly suitable for stimulating the body's own defense, for example in the case of chronic and acute infections, or with selective (antigen-specific) immunological deficiencies, and with congenital but also acquired general (i.e. is not antigen-specific) immune deficiency states, such as those occurring in old age, in the course of severe main diseases and, above all, after therapy with ionizing radiation of the limb with hormones that suppress immunity. The substances in question may therefore be administered advantageously also in conjunction with anti-infectious antibiotics, chemotherapeutic agents, or other therapeutic treatments to counteract immune damage. Finally, the substances in question are suitable for general prevention of infectious diseases in humans and animals.

In J. Med. Ohem. 9 (1966), pages 971-072, describe compounds of formula I wherein X is a carbonyl group, R is a methyl radical, R2 is a hydrogen atom or b a methyl radical, R7 is a methyl radical, and Rs and H9 denote carboxylic groups, the action of these compounds not being shown. Own studies have shown that, unexpectedly, these substances are not immunologically active.

In Biochem. and Biophys. Res. Com on pages 1316– (1322, inter alia, describe compounds of formula 1 in which X is carbonyl, R and R2 are methyl, R7 is methyl, Rs is carbamoyl and R9 is. the carboxyl group, the compounds having an adjuvant effect The novel compounds of the formula I prepared according to the invention are at least as effective as the recently reported known compounds, but are also surprisingly much less toxic.

Particularly valuable are compounds of the formula 1 in which X represents a carbonyl group, R 2 0- represents a hydrogen atom, and the other symbols have the above meanings, and their salts.

In particular, compounds of the general formula II are to be distinguished in which Rr is a lower alkyl or phenyl radical, Ri is a hydrogen atom or a lower alkyl radical, R2 is a hydrogen atom or a methyl radical, R7 is a hydrogen atom, a lower alkyl radical or a group of hydroxyethyl, R8 is a Rerbamoail group and Rq is an isinic group is a carboxyl group, with vairumlk, with the lower alkyl radical R having more than 1 carbon atom in the case where R2 is a methylene radical, and their salts. First of all, it is necessary to mention the compounds pvisoTize 2, in which R is a lower alkyl radical or a phenyl radical, Ri is a hydrogen atom, R2 is a hydrogen atom or a methyl radical, R7 is a hydrogen atom, a methyl group or a hydroiximethyl group. , Rs is carbamoyl and R9 is carboxy, with the proviso that the lower alkyl radical R has more than 1 carbon in the case where R2 is methyl, and their salts. According to the invention, the method for producing the new compounds consists in the fact that in the compound of formula III, in which R and R2 have the meaning given above, R70, R8 ° and R "have the meanings given for the symbols R7, Rs and R9. and wherein the hydroxyl groups are protected easily by cleavable ethers or estyrium radicals and R5 is an alkylidene or cycloalkylMdenum radical, cleaved under acidic conditions in the oxazoline and dioxolane rings in the presence of a compound of the formula R1-OH. wherein Ri is as defined above and any protecting groups present are cleaved off.

The alkylidene radical is especially a lower alkylidene radical, such as the isopropylidene radical, and a cycloalkylidene radical, such as the cyclopenitylidene or cyclohexylidene radical.

This cleavage probably follows the scheme shown in the figure, in which the compounds placed in the large double clamp are hypothetical transients, indistinguishable. West - no x ^ p. with an acidic ionite, especially ionite containing sulfo groups, such as Ambeiilite HW20 (polystyrene resin with strongly acid saalphyl groups) or Dowex 50 (polystyrene sulfomic acids), or with a strong acid an inorganic, inorganic or organic acid such as hydrochloric, hydroformic, sulfuric or sulphonic acid, for example methanesulphonic acid, or an optionally aromatically substituted phenylsulphonic acid such as pHtOluenesulphonic acid or trifluoroacetic acid. In an aqueous environment, then in the position ^ 1 there is a free hydroxyl group, if the naiton is tapped in the presence of alcohol with the amount of HO-Ri, in which. Ri is an even-unsubstituted alkyl radical, this yields a compound containing in position-1! group - ^ O — R1 # If one of the kailboxyl groups Rg and / or R $ is esterified with an alcohol, especially with a lower alteano, it can be saponified especially at an elevated temperature of 65 S with an aqueous solution of sulfonate.

In the compounds obtained, the protecting groups on the peptide radical can be subsequently cleaved, especially by hydrogenation, for example by means of catalytically activated hydrogen, or by hydrolysis.

(The starting compounds used in this case can be obtained, for example, when the radical R2- - is introduced into the appropriate oxysoline, containing a free hydroxyl group in the -3 position of the sugar residue, in one or two stages! ^ acetaihiiidopepitide.

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

The above-described methods of the process are carried out by known methods, without the presence or preferably in the presence of rheumatants or solvents, and if necessary by cooling the lulb by heating, under elevated pressure and / or in an inert gas atmosphere, such as afcot.

Taking into account all the substituents present in the molecule, it is necessary, if necessary, especially in the presence of easily hydrolyzable O-acyl radicals, to use mild reactions, such as short reaction times, introduction of mild acid agents and low concentration, quantitative steohiometric ratios, selection of the appropriate catalyst, solvent, temperature and / or pressure.

The process according to the invention can also be carried out by such routes, where the starting material is orbated compounds are used as an intermediate product at any stage of the process and the missing process steps are performed, or the process is interrupted at any stage, or the starting materials are produced under the reaction conditions or used in the form of a reactive derivative or salt. Preference is given to using as starting subsidies such substrates which, according to the method according to the invention, lead to the preservation of the compounds defined above as particularly valuable.

The compounds of the formula I can be included in pharmaceutical preparations. These pharmaceutical preparations are preparations for enteral administration, such as oral or rectal administration, and for parenteral administration by heat therapy, containing pharmacologically active substances alone or in combination with with a pharmacologically acceptable carrier.

The dosage of this active ingredient depends on the kind of steel-blooded species, the age and the individual condition of the patient, and the method of administration. These pharmaceutical preparations contain from about 10 to 90%, preferably from about 20 to 40% of this active ingredient. They can be, for example, in the form of single-bridge doses, such as dragees, tablets, capsules, ozop or ampoules. 112,672 * 10 Pharmaceutical preparations are made in a known manner, for example, by means of conventional mixing, granulating methods. , drazing, dissolving or lyophilizing. In addition to the aforementioned types of application, it is also possible to prepare a formula for oral use by combining the active ingredient with naso-sieves, possibly granulating the resulting mixture, and by translating the mixture relatively, granules, if necessary or necessary, by adding suitable excipients to form tablets or dragee cores.

Suitable noisndfcaimides are, in particular, fillers such as culcrs, for example lactose, saccharide, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, binders, binders, etc. starch cartridges using corn, wheat, rice or potato starch, gelatin, tragalcanth, methylcellulose, hyoxymethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if necessary shaving, taffeta, such as the above-mentioned starches, further carboxymethyl starches, cross-linked polyvinylpyrrolidone, agar, alginic acid or its salt, such as sodium stinate.

Auxiliaries are mainly fluid regulators and lubricants, for example krizemic acid, talc, stearic acid or its salts, taffeta, such as magnesium or calcium stearate and / or polyethylene glycol. Dragee cores are provided with suitable coatings, which are very resistant to gastric softness, whereby concentrated sugar solutions are used, and the fctire may contain Arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or dianitami of varnishes in suitable organic solvents or solvent mixtures, or to form gastro-resistant coatings, solutions of suitable cellulose acetyl phthalate or hydroxypropyl methylcellulose phthalate are used. Dyes or pigments can be incorporated into the coatings of the tablets or dragees, for example for the purpose of identification or for the labeling of different doses (k active ingredient.

The following examples explain the method according to the invention in more detail. The temperatures in the examples are given in degrees Celsius.

Example I. 3.77 g of 2-phenyl-4; 5H [3-O- (DH1- carboxyethyl) -5.6 [beta] -isopropyllidienoHDHglylkyurano] -z12-oxazolline in 60 ml of acetomyithric and 15 ml of dimethylformamide It is mixed with 1.4 ml of triethylamine and 2.55 g of 3'-sulfionylamine-3'-ethyl-5-phenyl-isoxazoM- for 1.5 hours at 09, whereby almost all of it is dissolved .

Then, 3.44 g of L-alanyl-Dngluitamic acid γ-benzyl ester hydrochloride are added and 1.4 ml of triethyl alcohol is added to the mixture and stirred for 24 hours at room temperature and then evaporated in an oil vacuum. to a syrup and chromatographed on silica gel with a mixture of cMorophore and acetomy (8: i2). A colorless solid syrup is obtained, which crystallizes when mixed with ether, showing a melting point of 96: 99 ° and a condensability [a] J = + 13 ° (in chloroform).

The crystalline benzyl ester is hydrogenated with a 5 ° / "palliliad catalyst" on a carbon carrier in diotassing at room temperature under normal pressure and obtained after evaporation under a vacuum, we find acid in the form of a syrup.

This acid is mixed in water with W and H of an ionite named Dowex ^ O-H + at room temperature for 15 hours.

* After filtering and defrosting, a colorless powder is obtained with a decomposition temperature of 140 °. The obtained 2-benzoylamil-3-O- {D-1-CL-1- / D-1 -cairbamoyl-3-carboxypropyl / -il-1-carlbam-20 ylethyl] -carbamoylethyl} H2-desdxy-a, depending on depending on the drying conditions, a variable amount of crystal water, and in the above case, after drying at 60 ° under the pressure of 0.01 mm Hg for 1.5 hours, it contains 1/3 of the water.

Example II. 6.0 g of 2-phenyl-4H [[3-O- (D-ylHcarboxypropyl / H5,6-.04-isoiproipylidene-D- @ lilkJotfura ^ - ^ opcazoin, 4.08 g of N-ethyl 3'HSulfbnlate) The -5-phenyl-isoxazolium and 2.25 ml of triethyl amine are mixed in 100 ml of acetonitrile and 25 ml of dimatyl-phoTmamide for 1 hour at a temperature of 0-6 °, whereby. the whole thing will change. Subsequently, 5.5 g of L-alanyl-DHgluitaminic acid benzyl ester and amino acid hydrochloride 85 ml are added with a further 2.35 ml of triethylamine and stirred for 48 hours at room temperature.

The whole is concentrated under an oil vacuum and chromatographed on silica gel in a mixture of chloro tofoil and ethanol (19.1). 9 g of the colorless syrup thus obtained are hydrogenated in dioxane with a 5% carbon catalyst pallllaid catalyst, the catalytic converter is desalted, the solution is concentrated under vacuum and hydrolyzed at room temperature in a mixture of 40 ml of tetrahydrofuran and 30 ml of water with 1.5 md of trifluoroiotic acid.

Then it is evaporated to dryness four times in a vacuum, dissolved in water and lyophilized. O- retained 24> enzoylamino -3 ^ 0- {D-yl- | [iL ^ l- (IDHl-carbamioylH3 ^ cairboxyproipyl) -lcarbamoyl ethylHair- bamoylpropylol ^^ deoIxy ^ a ^ Hgilicose crystalline from 0.5 molar water, showing a melting temperature of 114-152 ° and a skewness [a] ™ = + 17 ° (in the metal).

IP r z y / k l a d III. 3.63 g of 2-phenyoyl-4.5i ['34) -carboxynyl-isotropopyMdeno-DHglycofuran-oixazoline, 3.43 g of γ-eisiter-ohlorohydride benzyl-1-amide L-aJanyl-1-amide Vitaminium, 60 1.21 g of N-hydroxyxylkymine, 2 to 16 g of dicyclohexylcarboidimidium and 1.45 ml of triethylamine are dissolved in 40 ml of di-nylphorimamide and stirred for 24 hours at room temperature. Then it is evaporated under an oil vacuum, dissolved in bicyclohexylurea and water, the lost dicyclohexylurea is filtered off under reduced glare, the organism layer is shaken twice with water and the water layer is shaken twice with water. dwudhloiroeitaneim.

After drying and evaporating the organic layer, a solid syrup is obtained, which is chromatographed on silica gel in a mixture of chloroform (ethanol / 9: 1). The obtained peptide, which crystallizes on rubbing with ether, has a melting point of 167-168 [deg.] And a resilience [a] q ° = -15 ° (in chloroform). 4.5 g of the aforementioned esiter is visualized in dioxane with the aid of a 5% palladium catalyst on a carbon carrier, the catalyst is filtered off and additionally. it is extracted with ethanol. The combined filtrates are evaporated and the remainder is tethistorized from isopropyl alcohol. The acid obtained has a melting point of 200-207 °. 2.85 g of this acid is mixed in a mixture of 30 B0 ml of water and 15 ml of tetrahydrofuran with 5 ml of an ion exchanger called DowexH50.H + for 15 hours, at room temperature, filtered through a hard filter and evaporated under vacuum to dryness. . After trituration with ether, a colorless powder is obtained, which is 2-benzoylan-3-O - {[IL-1- (D-yl-, carbamoyl-, 3HkaiiboixypropylM-carboanoylethyl] - (kairbamoylmethyl} ^ 2H-desolxy-) [alpha] -D-g'liJkose, m.p. 175- (177 [deg.] (in the form of ttta -dziaou) - ..., transforming the method described in Acta Chem.

Scand. 18, 185 (1964), the suibstrate can be prepared as discussed below. 100 g of 2-phenyl-4,545,6-0-; isopropylidene-DHglycofuran] -z12JOixazoline, access excluded. of moisture and carbon dioxide, dissolved in 1 liter of acetonitrile, and with vigorous stirring, 15.2 g of a 55% sodium hydride suspension in mineral oil are added in portions, and stirring is continued for an hour at room temperature. 40 milliols of ethyl chloroacitate are deposited steplessly at a temperature of 0 ° 42 and after 1.5 hours in the liquid a further portion of 4) 2 than of ethyl dichloroacetate is deposited. After 1.5 hours, 11.4 g of the sodium hydride suspension are added again, the mixture is stirred for 45 hours and a further 42 ml of ethyl chloroacetate are added dropwise at 0 °.

After a further 2 hours, everything is left under vacuum - at the end of the procedure under an oil vacuum - to the consistency of a syrup. The syrup 50 is dissolved in eityl ether, shaken three times with water, the ethereal layer is dried over sodium sulphate and after evaporation, 155 g of brown oil are obtained. It is dissolved in 150 ml of methanol and mixed with a solution of 30 g of potassium hydroxide in 150 ml of water, extracted twice with ether, and the ether layer is washed once with water. The ether is stripped from the aqueous layer under vacuum and the pH is brought to the value of & H with the help of In hydrochloric acid. = 4.60 measured with a pH meter.

The precipitated, crystalline 2-dtenyl-4,5- [3-N (carboxymethyl) -5.6-0-isopyrapylidene-2-oxazoline is filtered off under reduced pressure, washed with water and dried. I get. per 12,107 g (93% of theoretical yield) of this product with a melting point of 106-188 °, with a curvature of [a \ n 1 = ^ -9 ° (c = 0.9 in chloroform) and [a] d = —23p (c = 3 in chloroform).

Example IV. 6.33 g of 2-Ehyl-4,5- (3-O-carboxymethyl-5,6-O-isopropylidene-olylkyl) (morning) - N-2-oxazoline, 5.75 g of 2-ethoxy-N4-carbo-etholxy- 1,2,2-dihydroquinoline (KEDQ) and 9.3 ml of triethylamine are added to a solution of Lnalanyl-D-glultammic dibenzyl ester trifiroocitate (prepared from 8.3 g of N-tertiary n-butyloxycarbonyl-L dibenzyl -alanyl-D 4 glutamate with 5.1 ml of trifluoroacetic acid and 2.6 ml of di-chloroethane by hydrolysis for 4 hours at 40 ° C in 70 ml of dichloroethane.

The mixture is reacted for 15 hours at the temperature of ° C, diluted with chloroform, shaken twice with water and the aqueous layer shaken once with dhloroform. After drying over sodium sulphate and evaporating the chloroform solution, 19.9 g of an oil is obtained, which is purified on 400 g of silica gel (Merck product) by elution with ether and then with chloroform system: acetone = 17 : 3. Pure 2-n-phenyl-4.5M [8-O- (11L- {il-D, 3HdivuibenJzylyokisyfca; ribonylopropyl} 4carbamoyloylO] carbamoylmethyl-5,6-O-isopropylide eno-D-glycOfiurano] is obtained. - Jf - oxazoline, melting point 113M1160 and k, with a condensability [a] q = —47 ° (c = 1.57 in chloroform). 7 g of the above compound are hydrogenated with 1.8 g of palladium kaitallizitor on a carbon carrier in a mixture of 80 ml of tetrahydrofuran and 20 ml of water until the reaction is complete, the catalyst is filtered off under reduced pressure, the filtrate is evaporated under a vacuum and the residue was triturated with ether to give 4.9 g of the dicarboxylic acid as a colorless powder. 4.4 g of the above dicarboxylic acid are mixed with 1 ml of Dowex-50IWx4 ion exchanger in a mixture of 45 ml of tetrahydrofuran and 20 ml of water for 20 hours at 40 ° C.

After filtering and clarifying with charcoal (named Darco G 60), the solution freeze-dried, giving a colorless, amorphous 2-benzamide-OH-2-deoxy-3-O- [11-yilHD, 3H-ducar! -Boxy-propyl) -CaTibamolylyelty-dhgilcopylbine with optical precision [a] ™ = + i25 ° (c = 0.907 in water).

Example 5 By analogy with Example IV, 5.7 g of 2H-phenyoyl-4.5 ^ 3'OHcarboxymethyl ^ ^ HOHisolpropopyliidene-D-glyicofiuralnol-zl * -oxazoline are condensed with 4.9 g of γ-ester of the III-sol. - n-butyl α-amide of L ^seryl-D ^ glultaimine acid with the addition of 2.3 ml of triethylamline and 5.2 g of 2 ^-toxic 44caiiboetoikisyHl, 2H-dihydro and Clhinoline in 45 ml of dichloroitam.

After 18 hours at 40 °, a crystalline form is formed. These crystals are added to a further portion of 50 ml of dichloroethane, cooled in ice, 112 672 13 14 filtered, under reduced pressure! and washed with cold dichloroethene.

Pure for analysis, colorless crystals of 2-pheinyl-, 5- [3-O- / l- - {l-Hkaiibaimoyl-13-III-riz.Hbuityio-xyikairboinylpripylol- kaiiitamoyl-hyidiroxyethyl) / kairbaimoylimethyl-5 The 6, O-isopropyliideine-Dnglycofuranol - 1 - oxazolines show a melting point of 187-188 ° and a friction [α] ™ = + 7 ° (c = 1.125 in methanol). 2 g of this compound is hydrolyzed at room temperature for 20 hours with a mixture of 15 ml of methylene chloride and 5 ml of trifluoroacetic acid. All is evaporated under an oil vacuum, the residue is triturated with ether to give 2-benza1m, andoH2MdeiZOJxy-3-0 - [! LL- / lD-Hcarbamoyl-3-icairboixypropyl] -l; rbamiolyl-2-yl-hydroxyethylmethyl- D ^ gfliilkopirainotze in the form of a meringue-colored powder with a melting point of 100-416 ° and a curvature of [a] ^ ° - = + 23 ° (c = 0.886 in water), which crystallizes with 2 moles of water and 1 mole of trifluoroacetic acid . The product has an Rf value of 0.28 in the system CHO13: CH3OH = 1: 1 (thin layers of silica gel, product from Merck).

Example VI. Analogously to Example IV, 5.25 g of 2-phenya-4.5n [3.0- (carboxymethyl-5.6-0 4'-isopropylidene-DHgflyfuram] - ^ 8-olkisizole are compensated trifluoroacetate with L-alanyl-DH-glutanic acid [alpha] -nn-propylamide benzyl ester (prepared from 6.2 g of N-III-irzHbultyloxyicarbonyl [alpha] l-alanyl y-benzyl ester of [alpha] -n-propylamido [alpha] of ultra-amine and 4.2 g. of trifluoroethane acid in 2.5 ml of divuichloroethane for 6 hours at 40 ° C) in 60 ml of difchyloroethane with addition of 7.75 ml of triethylamine and 4.8 g of 2-ethok. After 20 hours at 40 °, 50 ml of chloroform is diluted, shaken twice with water, and the water is shaken twice with chloroform.

After drying and concentration of the chloroform layer, 15 g of an oil is obtained, which is purified over 200 g of silica gel (Merck product) by elution with ethyl ether and then with chloroform: aiceiton = -7: 3. 6.4 g of a colorless, amorphous substance with an Rf value of 0.35 are obtained in the form of CHO3: acetone = 7: 3 (thin layers of silica gel, Merck product).

These substances were hydrogenated with 1.8 g of a 5% palladium catalyst on a carbon carrier in 80 ml of tetraidorofuran and 20 ml of water until the reaction ceased, the catalyst was absorbed and the filtrate was concentrated. K (this band shows Rf = 0.58 in the system CHJCl3: CH3OH = 3: 1) (thin layers of silica gel, Merck product).

It is then mixed with 10 ml of the ionite Dowex 50-Wx4, 50 ml of tetrahydrofuran and 25 ml of water for 15 hours at room temperature and for 1.2 hours at 40 °.

After aspirating, clarifying (named Darco G 60), re-sipping and lyophilization, the result is a barren, amorphous 2-benisamid--2-deoxy-3-OH [1-D1711 ^ D ^ N'HnHpropyQocarbamoyl- - S, kaiithiokisypropyl (arbaimoyliethiol, kairbamolylmethyl-D, gaiikopyranize), melting point 65 140 ° C, Md = + 28 ° (€ = 1.03 in water) and Rf value = 0.48 in CHCl3 system : H3OH = 1: 1 (thin layers of silica gel, Merck product). ao- Example VII. 7.3 g of 2-phenyl-4,3-l [3-O-carboxymethyl-5,6-O-icoproipylidene-D 4 -glycofurain] 2 -oxazolim, 6.5 g of y-eister hydrochloride of the tertiary L-alphaiminozobultyryl-D-glutamic acid -butyl α-amide and 2.9 g of butyl chloronisate are dissolved in E5 ml of dimethylformimide and 50 ml of dichloroethane. For this purpose, a solution of 6.1 ml of triethylamine in 20 imd of dichloroetam is added dropwise at a temperature ranging from -1115 ° to -40 ° over a period of 30 minutes. 20 'It is then allowed to warm to room temperature and the mixture is stirred for another 15 hours at room temperature. The whole is diluted with 50 ml of dichloromethane, shaken with water, twice with 0.5 N NaOH and three times with (water and 25 water layers are shaken twice with dichlorethane, the organic layers are dried and obtained after evaporation 116, 5 g of oil. This oil is purified on silica gel: (MerCk's product) by elution with CH1OI3: 30: Cs4OH 1 = 19: 1. 9.7 g of colorless, amorphous 2-phenyl are obtained. -4,! 5- (3-O-l [lnmeityl-lVI-iDHcarbamoyl-3- -III-, t.-bultylixycarbonylpropyl / carboimoyloyl] &lt; 5,6-0-isopropyllidene-D-gliylkofurano} -ZP Oxa-35 'zolines with optical rotation [α, β = + 6 ° (c = 1.027 in • chloroform), melting point 75-89 ° and Rf = 0.35 in ul Mada OHCl3: C2H5OH = 9.11 (thin layers of silicon ionic gel, a product of Merck). 8.3 g of the above: the compound is kept for 15 hours at room temperature in the name of 20 nul of trifluoroethylene icwais, 60 ml of meltyle chilomide nu and 2 ml of water. Then it drops off under a vacuum and the remainder rubs with the ether. The formed, differently colored proisizek is dissolved in 200 ml of water and clarified with 0.55 (a carbon named Dairco ^ G ^ 60.

After filtering and evaporation, a colorless, amorphous 24> entomido ^ 2Hdezoc! Sy-3-O-i [1Hmeityl-1- (EMl-ika; rbamoylO-3Hka> rbamoylO-3Hka> rboixypropyl-1o) -carbimoyl ethylthylthylcarbamolylimeter D ^ glycopyranose with a temperature of 110'-IIIZ1O0, with completeness [a] ^, 0 = + i310 (c - 0.88 in water) and 55 values of Rf = 0.52 in 'ufcflaidysis' acetone: ethanol = = 1: 1 (thin layers of silica gel, product from Merdk), which material crystallizes out of 0.6 moles of trifluoroacetic acid and 1.7 moles of water. 60 Prizyklad VIII. Analogously to jpremis IV and with 2 ^ benizamido-2-deo: kisy-3-OHkanboixymethyloyl - ^ - ethyl-D-iglycopyranizyid 'and iso'lia kjwa & u trifluoroiroofctigo with ynesitr IH-iriz.-buityllo ct ^ Iqwaisu L ^ alanyl-D ^ gCl'Uitarinium 65 and with 2-, ethoxy-N, ^ a'rboetokisy ^ l, \ 2Hdw'U Hydrogenolchinoil "40 45112 672 15 16 ny the appropriate glycopeptide with completeness [a] ^ is obtained = —F23 ° (c = 1.107 in methanol) and the value of Rf - 0.47 in the CH2C12 system: C2H5OH = 8: 2, and after hydrogenation with a palladium catalyst 5% by weight, it has a carbon carrier in the system of etohydrofuran (water is obtained 2-benzam-2-ezofcsy-3-0- (L-li- (D-11-Cairo-bamoyl-3-carbofcsypyropyio) rarbanoylethylHcarbamoylmethyl-N-ethyl-Digliycopyranoside. mp 215-217 °, with a condensability of [α] ≤ ° = -? 22 ° = 0.36 in the CHO1 ^: CH3OH system = neither (thin layers of silica gel, Merck product). sulbstrate used 2nbenzaimiido ^ 2-deizoJkisy- -3-0-! Cairo! bbiks> ymety lo-i /? ^ o- is kept as discussed below. 2-phenylo, 5413-OHcarbokisymejtya6, 6-04! Z (propyldene-D-glyicotfuran) -It-oixazoyline is dissolved in 0.1 N HOl in ethanol and allowed to stand for 6 hours at room temperature. The solution is dried with sodium ethoxide in ethanol, evaporated to dryness and dissolved in acetone. The solution is filtered and dripped through a layer of silica-tool gel ((Iprodiulfet from Merk), the elualt is evaporated to dryness and the residue is extracted. is sown twice with diethyl ether at room temperature. After recrystallization from ethyl acetate, 2-tbenzimido-2H-deoxy-3-0-30-carboxymethyl-1-ethyl-D-tg is obtained (lycypyraniside, melting point 186-1188 ° II with a specificity of [α] β = - ≤35 ° 9.4 g of this ester is washed with a solution of 1.7 g of potassium hydroxide in 250 ml of ethanol and 25 35 ml of water within 2 hours (at room temperature). The reaction is then brought to the value of ipH = 3.5 after the Itn of hydrochloric acid and concentrated under vacuum. in ether and then three times with 20 ml. of ice water each time and filtered under reduced pressure. [Yes, crystals of 2'-benjzami- toH2'-deokisy-34) -caribo-xymethylethylOHD-gilylcopyranzide with a melting point of 205-2H0 ° and a microscale (a] gj, = -40 °) are obtained.

Example IX. 24> enzaimddo «2Hdezofcsy-3-0 ^ [D- -lncarbamoyl ^^ carboxypropyl] Hcarbamoylmethyl4DHgldose is obtained from - 3 g 2-phenyl ^ y543-0 - {/ l> HlJkairbaimoylO'-3 ^ isopropyllidene- Digest] i! Kofurano] - 2-oxazoline by hydrolysis and with 1.5 sun Itrijifiluoroacetic acid in a mixture of 15 ml of dimethoxyelthane and 15 ml of water at 40 ° for 3 hours. The whole thing is concentrated under the praxis to dryness and the rest is extracted and re-elter.

The resulting powder is dissolved in water and (treated with charcoal called Darco-G-60, sucked and freeze-dried. Obtained and amorphous sulbsltanlqje with a melting point of 11-155 °, condensation [a] ™; = + 34 ° (c = 0.81 in water) and with an RF value of 0.28 in the CHGlj: CH3ÓH system. (= 1: ii (thin layers of emery gel, Merck product). & Sutetrat is prepared according to the method is discussed below 8.0 g of N-III-z acid benzyl α-amide, Hbutyiloxycarbinylglycyllglycilone D-gluitam: in a mixture of 6.3 ml of trifluoroacetic acid and 7 ml of dichloromethane, It gives a reaction for 2 days at room temperature and for 13 hours at 45 ° C. While cooling, 12 ml of triacylamide, 7.0 g of 2-ethoxy-N-carboethoxyHl, 2% dihydroquinoline are added. (EEDQ), -8 [mu] g 2-phenyl- (1.5H [3-O-6-carboxymethyl-5.6 [beta] -Hisopropylidene-D-glycofan] -Z12JOxazoline and 20 ml of dimethylformanide.

After 20 hours at 40 ° C it all collapses under an oil vacuum and the residue is separated between the layers of methylene chloride and water. After drying to concentrate the methylene chloride layer, a solid residue is obtained, which is extracted twice with ethyl ether and recrystallized from toluene to give 8.25 g of a product with a melting point of 1157 °, optical crevity (D = + 110 ° and (c = 1.48 in chloroform) and with an RF value of 0.35 in the system chloroform: ethanol = 0: 1 (thin layers of silica gel, Merck product). The benzyl ester thus obtained is hydrogenated. with 1 g of a 5% carbon-supported palladium catalyst in 100 ml of tetrahydrofuran and 25 ml of water until the reaction ceased.

After filtering off the catalyst and evaporation, the substances are chromatographed on 250 g of silica gel (Merck product in the CHOI3. CH2OH = 4: 1 system. 5.8 g of colorless, amorphous 2-phenyl) are obtained. 4,5H [3-0 - {/ Dl- Hcarba.moi! Lo-.3Hcarboxyipropyl) -ycaribamoylmethyl-carbamoylmelltylOHS ^ eO-isopropyliidene-D-glycofuran] -z12-oxazoline with Rf value = 0, 53 in the CHCl3 system: CH2OH = 3: i2 ((thin layers of silica gel, product from Merck).

Example X. Similarly as in example IV, 9.5 g of 2-phenyl ^ 5 ^ 3-OH-carboxy-methyl-5,6-O-isotpropyladenone-D ^ glycofuran] - ^ -O-xazoline are compensated with 6.25 g of a, y- hydrochloride L-aianyl-D-luteamic acid diamide in the presence of 3.4 ml of triethylamine and 7.95 g of 2-ephthoxy-N-carboethoxyHl, 2-dihydroquinoline (EEDQ) in mixture of 50 ml of dichloroethane and 160 ml divumethylformamiide. While stirring, the entire reaction is completed for 2 days at room temperature and for 4 hours at 40 °.

Then it is concentrated under an oil vacuum and the remainder is extracted first twice with ether, then twice with ice water. After drying, the Klvuchlorethane proid is recrystallized, giving colorless crystals with a melting point of 170-1184 °, a skewness [d \ ™ = + 3 ° D) and a Rf = 0-4 wu | clause CH1Cl3: : CH3OH = 3: 1 (thin layers of silica gel, product from Merck). 6.1 g of this compound is hydrolyzed with 113.5 ml of Dowex'50 ion exchanger in a mixture of 60 mils of dimitoxyethane and 60 µm! water in a run of iittai ii Md - 15 hours in (room. After siphoning and watering), the residue dissolves in water, (clarifies with carbon "Darco-G-60, drains under low pressure) and the permeate is lyophilized to obtain ibezibarvin, amyl 2-benziamido-2-deoxy-3-0H [Li-yl- / DHl, 3'-dicarbaineyliprop (lo / -! kar, baimoylethyl] Hcarbamc) Dilomethyl-D ^ giliicopyrainosis with a melting point of 82—143 °, a sikreci ^ lnOisci M ^ 0 = + 04 ° (c = 0.98 in water) and Rf = 0.4) 5 in the CHOI3 system: CH $ OH = il: d (thin layers of silica gel, a product from Mencik), this is crystallized from 1.23 moles of irisite water.

Similarly, the following compounds are obtained, marked with letters a .- ^ z. a) 3-0 - {! [L-il- / Dnl-4cairbainoyl-3Hkairiboiksyipropy-lo / ^ a ^ bamoiiloeitylo] ^ carbaimoiMome (tylo} -2 ^ aceita- mido-2Hdeaoikisy-Dn9liJko: for o twist = —il0 ° 4l ° iflwater, c = (0 ^ 930); b) 3 ^) - {(Pwl / D-14catrbaimoto ikaiiibaonooyimiethyl] ^ kainbamoylpropyl} -42-aiceltajmi- to ^ ndazic ^ y-DiglJilkoza o .s | kirecalinoiscii Md = = + 46 ° ± il ° (water, c = 0.63); c) 3-04L-1- / D-1 ^ kainbaimoyl-3-icarbolxyipro (pyio / - ^ kairbamoiioeityilJHkatfbamoyl ^ -2Hdesoxy -, /? - eityyl- D> g> Lycoyl: anoside (mp 21-15-217 ° and sikrecailine Md = -22 ° (methanol; d) 1-ethyl? 2-beinza [mcooH2-idezokisy-34) H [ILH1-) D- -1,4 -Ibis-N-methylcarbaminoipropyl (arbaimoyl-ethyl] -fcarbamoyl-methyl-DigylLcoipyraniOiside with a melting point of 233-240 ° and condensability Md ° = -20 ° (methanol, c = 0.937); e ) 2'beinizamidoH2-idezoixy ^ 3HOH [iL-yl- / D-yl, 3yl | (is-N-methylcarbanioiiylpropyl / Hkairbaimoylethyl] carbamoylmethyl-Diglycoipyranois with a melting point of 125 ° Hli320 and = Mdiccalnic + 24 ° (water, c - 0.93) ;; f) 2-benzamim! ido-2H-deoxyM3-OH-L-yl- (D-', 3-methoxycarbonyl-pipyl) -aribaimiloylethiol-aribarnooylmethyl-D-glycilicipiraaiose in the form of a hydrate with a melting point of 80 ° -90 ° and a sulfur Md = + 25 ° i (meitano! Lr c = '1.017); g) Ethyl-2-benzimido-2-deoxy-3-O - ([l-l-yi-dnl, 3-buis-metho-aorbaimoyl-methyl-l-dngiyl-pipyriniside (mp 127-1315 °, mp. ° = → = → 17 ° (methanol, c = 1.024); h) 2 → bein, zamiid9 → HdezaxyH3-0- {LH1- / DH1HNHkiarbamoylmethyl-icaribamoyl-3-carboxypropyl / → carbamoyloeitylJ-carbarndilimethyl → D- igiliikoipyranoisis (melting temperature 163M1700 and islkrecailinoisci MD ° = + 21 ° (water, c = il, 08); i) 2-fbenizamiido ^ 2-deoxy ^ 3HOi [L.-11- / DHl-lcaribamoyl ^ 3Hcarbolxyproipyio / ^ kao1bamoilloproipy'lo] Hcarbamoylmethyl ^ D ^ glycopyranysis (melting point 11-14-1155 ° and sparkling Md = + 34 ° (water, c = 0.83); j) 2-lbenizaimildo-3 ^ desoiki6y- (3H0 - {Ld- / Dd-icasbaimoyl-SHkainboJxyproipyl / HkaTibaimoyl ^ 2-methylcopyropylolHlncarbimoylimethylOHDHgilicopyranose with SiC 10 15 20 25 30 35 40 45 50 55 60, 20 total Md = 32 ° '(water, c = 0.78); 05 k) 2-aceamide ^ H () ^ [/ DH1- carbamodl-3-carboxy-propyl-2-carbamodlmethyl- dehyde oxy-D-igilycosis with 'Md = + 27 ° ± 1 ° (water, c = 0.944); i) Methyl-2-acetaimido-3-O - {(L-yl- (D-phl) ka; ribaimoyl-3-carboxypropyl) -ika-baimoylethyl] 4-cartolomethyl-i-deoxy-αD-glylcoipiirainoiside with skrecalase, [a] D ° = + 49 ° ± 11 ° (water, c = 0.913 * 9); 1) 2-acetamido-3-0 - {[Lnln / Dnl, 3-idwulka, r! baimoylpropyl / ^ caa &quot; Baimoyloyloyl / Hkaribaimoylanethyl} &quot; Deokisy-D-glylkylysis with sikrecalinoiscd Md 1 = + 7 &lt; 0 > m) 2 ^ ce'1aimido-3- {D-1-i [DH1Hkar! bamoyl-3-carboxypropyl) [beta] arbamoylioniethylol-kairibarnoiylpropyl} n2-deoikisy-D ^ g | lyilkoysis of .sikrecalinity Mr? = = + 46 ° ± 1 ° (water, c = 0.630); n) 2 ^ aiceitamiido-3 ^ OJ [L-: 1VD-d-flcarbaimoyl-3-carboxypropopyio / 4carbafmoylethyl] ^ kairbaimioiilomeltyio- ^ desoixy-D- (gl! ilkose with Md = + I10 ° ± 1 ° (water, c = 0.812); o) 2-acetamido-3-0 - {{iLHl- (lD- -1,3-diikaxbolxyproipyl) [beta] aribanTodJloeityllo] -ikar-bamoylanethyl} H2-deo-oxy- (DHglylkoxy with a friction 't'] D0 = '+ 23 ° ± 1 ° (water, c> = 0.814); p) 3-0- {fLc-Jln / PnlHkanbamoyl-3- (karoxypropyl / ~ caribamothiyleptyl] -to ^ xy ^ 2-fpropioinamide <> - iD-iglylcoysis with Md = + «° ± il ° (water, c = 1.46); q) 3-iÓ- {l [Lil- / D-tl- | carlbaimoyl ^ 3-ikairibok; sypropy- lo / ikairibamoyoylethyllolncaribamoylmethoe} -2-kaipiy-noiiloa (midon2- (deoxy ^ D-iglycase with akrejoailnoscii Md = + ia ° ±) l ° (water, c = 1.0523); r) 2 -acetairnddoH2 ^ deisoixy-3H0- {i [L-yl- / Dl, 3-ibi3- Hmethylcaribaimoylpropyl / Jkarbaimoiaoethylol ^ carbamoi'loaTiiethyl} ^ I> igiliicysis with sulfur Md ^ ° = + 3il ° c = i0.410); is) 2-aceto! mido-3 ^ 0- {and [Lnl- / DMlncarbaimo! il ^ 3-Cairo-boiksyipropy.lo / -ikairibamodilH2Hhydirolkisyejtyllo] Hkarto ^ moylmethyl ^ Hdezoixy-Dnglycosis with abnormality ° ± MD ° = + H0 ° MD ° = + 1 °, (water, and c = il, 053); rt) 2 &lt; 2 &gt; ce ^ imddo-3-O- {and [L1- (DH1Hkai] &lt; baimo, il-3-carboxypropyl) &lt; carbaimoyiolbutyl] Hcarbaimoylimeityl } -2 ^ deoixy-DHglylkoylysis with a slope of Md = * = + .12 ° ± 1 ° (water, c = 0.722); u) 3-0 - ([L-.l- / Dl-ika'rbaniooy ^ 3 ^ kairboixypropyl / -carbaimoiylet3 ^ 1oJcarbaimoliylaiieityilo} -2-deokisy- »20 -2-iateairoiloaimddo-Diglycase with slk-calcified Md ^ = + 24 ° 6 µl ° (id-dimethidophonamamide, c = 0.6 × 3; v) 2-a (cetaimiido-3-0 - {[mi-ZD-d-icaribamoyl-S- arbo (xypropyl / Hka; rbamoylone-2Hmethyl; pro (pylo] -kaT-baimoylimethyl} -2ndezoixo-iD-iglilko! for o ^ krecal + il0 ± µl ° (water, c = mp, 096); w) 2Hacataimiido ^ 3-0 - {[L-yl - / DnUkairibamoyl-3-boxypropyQo / nkarbaimodil- (3-imethylibuityl] -jka: rba moiiioimeityil} -2-deisoixo-D- (silicosis with Md = + <16 ° ± 1 ° (water, ^ c = il, 0i60 ); x) 2-aceitamido ^ 3 ^ 0- {i [Lnl- (Dd- (caribaimoyl ^ 3-carboxypropyl) - (kaiibamoi) loipropyl] -lcaribaimoylmethyl} n2-deo (xy-Digilicose o skrecainoisci = + (lil ° ± il ° (water, c = (1.0il'9); y) 2 ^ aceitamido ^ 3-0 - {[LH-ZD- ^ l-featribaimoyl-S ^ kaT * mL0 Md ~ - Id lys m boxyproipyl (kiairbiamoyl phenyl) Hmeityiol - carbamolylimethyl] -2-deoxy-Dnglycose with sicreality [a] g = + 12 ° ± 1 ° (water, c ¦ = 0.706); and ) 2-aicata'miido ^ 3 ^ 0- {and [Ll- / D ^ 1Hkair [bamoylmethyl-carifoylamoyl-34-carboxypropylM-carboainoyloeity- -carbamoylmethyl} n2idiezo, x-diglycose ealnose ([a] £ °, =. + il0 ± 1 ° (rw, c = 0.76); z) 2ntTÓ'jmety (loaceitamiido-n2Hd € isoifcsy-3-0- {[L ^ l-kairbaimoyl-3 ^ calibixyproipyl / - (carbaim) o, iloeityl] - Io] Hcarbam'oylom'ethyl} -a, ^ - Digliiiko, for a spark M 20 = -7 ° (methanol, c = 0.6).

IZ a; polyethylene glycol, A method for the preparation of new glyrosomime derivatives, of the general formula '1, in which X stands for an icarbonyl group, R stands for an alkyl radical with 1 to 18 carbon atoms, or a phenyyl roidmilk, Rj is an atomic acid (hydrogen). ilu and b aMpl rhodium with 1-3 carbon atoms, R2 is a hydrogen atom or an alkyl radical of 2-3 carbon atoms, R4 is a hydrogen atom, R6 is a hydrogen atom, R7 is a hydrogen atom, an alkyl radical of 2-5 atoms Rg is a carboxyl group, an alkoxylcarbinyl group, p 1 h ^ 3 carbon atoms, 10 15 20 25 carbon atoms, a carbamoyl group, an N-alkylcarbamoyl group with 1 to 4 carbon atoms in the alkyl part, coarse N-benzylcarbamoyl group or (carbamiiomeitylcarbamoyl group, R9 densifies the carboxyl group, aflJkolxylcarbonyl group with 1-3 carbon atoms in the alkoxy part, coarse [benzyl | xylcarfoonyl, Nimoyl-carbamoyl) group from -4 atoms of carbon and in the alkyl part, with (variuinic, that the alkyl radical R contains more than 1 carbon atom and in the case where X is a carbonyl group and R2 is an imethile iodine, or and in the case where X represents a carbonyl group, R2 is a hydrogen atom and Rg and R9 are carboxy groups or their salts, characterized in that in (compound of formula III, above (where R and R2 are as defined above, R70, Rg ° and R90) have the meanings given for the symbols R7, R, A, and R9, and wherein the ihydroxyyl groups contained are readily protected with indissimilable ethereal radicals. In esters, and 1R5 is an alkylidene and polycimalikilidene radical, cleaves under acidic conditions the oxazoline and dioixolate ring in the presence of (a compound of formula Ri— —OH, in which R5 is as defined above, and any protecting groups present are cleaved. 112 672 CHOR Rfl ^ °> M / NHXR RiC-H ^ 7 Re tO-NH-ChhCONH-CH (CH2) 2-R9 Formula 1 f D) CH? OH f? 8 H ^ O-R, 7 NH-CO- R Ra-CH ^ XCO-NH-CH-CONHi5H- | CH2) 2-R9 Formula ZRC °] .0 R, -CH O NCR 78 CONH-CH-CONH-CH-tHtRl Formula 3112 672 R5 ^ noon ril N = CR R2-CH R ° p | ^ 3XC0NHCH-C0NH-CH- (CH ^ R H + I HOR! R, -CH r; tONHCH - C0NH-CH- (CH ^ 2-R9 ° HO- tf HOR1, 0, -ORi R2-CH HN-CR Rz O • ?: CONHCH-CONH-CH- (CH ^ R (I Setami 4 CH2OR6 * fto-xR CO-NH-CH-CONH-CHfH ^ -Rg c.fif- Scheme i (DN-i3, izaim 35 / 82 Price: PLN 45