DE2742955A1 - 1-SUBST.-GLYCOPYRANOSIDE WITH INSULIN-LIKE ACTIVITY AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Dr.-Incj. Waller AbIt * ^

Dr. Di eic ·: · F., ν. ο rf Dipl.-Pr.ys. f, i. c., jchnsder 8 Munich 86. Pienzenauerstr. 28

23rd September 1977 15 825

MERCK & CO., INC. Rahway, New Jersey 07065, V.St.A.

1-sub-glycopyranosides with insulin-like activity and process 2u of their preparation

809813/0975

The invention relates to new 1-deoxy-glycopyranosides, preferably 1-deoxy-D-manno-pyranosides, which contain a cc- aminoalkylthio, co-aminoalkyloxy or oJ-aminoalkanoylamino substituents in the 1-position of the pyranoside ring, and new processes for Production of these i-substituted-1-deoxy-glycopyranosides using the corresponding tetra-O-acetylglycopyranosyl bromide or amine as starting material. These co-amino-Calkylthio-, -alkyloxy- or -alkanoylamino) -1-deoxy-glycopyranosides and in particular 1 - [(6'-aminohexyl) -thio- or -oxy] -1-deoxy-D-manno-pyranosides have insulin-like activity.

The invention relates generally to new 1- (co-aminoalkyl) glycopyranosides and their 1-deoxy analogs with a 1- (cO-aminoalkylthio) - or 1-Aminoalkanoylamino -Substituenten im Case of the preferred 1-substituted-D-manno-pyranosides by the following formula

can be represented in the

.Z Oxy, Thio or NHCO and
χ mean an integer from 2 to 8,

and the invention further relates to novel processes for the preparation of these compounds. These new 1- (cd-aminoalkyl) -glycopyranosides, 1 - [(a; -aminoalkyl) -thio] -1-deoxy-glycopyranoside and 1- [ (co -aminoalkanoyl) -amino] -1-deoxy-glycopyranoside have one biological activity that corresponds to the action of insulin.

These 1-substituted glycopyranosides are expediently prepared by using a tetra-O-acetyl-

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glycopyranosyl bromide in the case of 1- (cc> -aminoalkyl) -glycopyranosides, an alkali metal glycopyranosyl mercaptide (e.g. 1-thio-hexose alkali metal salt) or tetra-O-acetyl-glycopyranosyl bromide in the case of the 1 - [(o ^ -aminoalkyl) -thio] -1-deoxy-glycopyranoside, or a tetraacetyl-glycopyranosylaain in the case of the 1 - [(α; -aminoalkanoyl) -amino] -1-deoxy-glycopyranoside used.

The Λ- {co -aminoalkyl) -glycopyranosides are normally 2,3,4,6-tetra-O-acetyl-aD-mannopyranosyl bromide, 2,3,4 , 6-tetra-0-acetyl-aD-glucopyranosyl bromide, 2,3,4,6-tetra-O-acetyl-aD-galactopyranosyl bromide and others, with a <o - (benzyloxycarbonylamino) -i-alkanol, such as 5- (Benzyloxycarbonylamino) -1-pentanol, 6- (benzyloxycarbonylamino) -1-hexanol, 7- (benzyloxycarbonylamino) -1-heptanol and similar compounds, with formation of the corresponding 1- (ccJ -benzyloxycarbonylamino-alkyl) -tetra-o-acetyl glycopyranosides, such as 1- (5-benzyloxycarbonylamino-pentyl) -2,3,4,6-tetra-O-acetyl-aD-manno-pyranoside, 1- (6-benzyloxycarbonylamino-hexyl) -2,3, A, 6-tetra-O-acetyl-aD-manno-pyranoside, 1- (6-benzyloxycarbonylamino-hexyl) -2,3,4,6-tetra-O-acetyl-ß-D-gluco-pyranoside, 1- (6 -Benzyloxycarbonylamino-hexyl) -2,314,6-tetra-O-acetyl-ß-D-galacto-pyranoside, 1- (7-benzyloxycarbonylamino-heptyl) -2,3,4,6-tetra-0-acetyl-aD- manno-pyranoside et al., manufactured t. The reaction is preferably carried out by the reactants in an essentially anhydrous, polar, organic solvent such as nitromethane, or mixtures of nitromethane and benzene, among others, in the presence of a mercury (II) cyanide catalyst and a dehydrating agent such as anhydrous Calcium sulfate to ensure that anhydrous conditions exist during the reaction, and the resulting mixture is stirred at room temperature for a period of about 15 hours. The implementation is towards the end of this time

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essentially terminated. The reaction mixture is customary Evaporated to dryness manner, extracted with a water-immiscible organic solvent such as chloroform, and the material soluble in chloroform is chromatographed on silica gel to give 1- (cJ -Benzyloxycarbonylamino-alkyl) -tetra-0-acetyl-glycopyranoside obtained in essentially pure form.

This compound is then reacted in solution in a lower alkanol such as methanol with an alkali metal alkoxide such as sodium methylate at substantially room temperature for a period of about 2 hours. The acetyl groups are transesterified to the corresponding 1- (o> -Benzyloxycarbonylamino-alkyl) -glycopyranoside. The somewhat alkaline transesterification mixture is neutralized by stirring with an acidic resin, the resin is filtered off and the filtrate is evaporated. This gives Λ- (θ -Benzyloxycarbonylamino-alkyl) -glycopyranoside, such as 1- (5-benzyloxycarbonylamino-pentyl) -oc-D-manno-pyranoside, 1- (6-Benzy loxycarbony lamino-hexyl) -cc-D-mannopyranoside , 1- (6-Benzyloxycarbonylamino-hexylJ-ß-D-glucopyranoside, 1- (6-benzyloxycarbonylamino-hexyl) -ß-D-galactopyranoside, 1- (7-benzyloxycarbonylamino-heptyl) -oc-D-mannopyranoside and others

The 1- (cc> -Benzyloxycarbonylamino-alkyl) -glycopyranoside is then reacted with hydrogen to remove the benzyloxycarbonyl group. The hydrogenation reaction is conveniently carried out by dissolving the 1- (to -benzyloxycarbonylaminoalkyl) -glycopyranoside in an aqueous alkanol such as methanol, adding a palladium-on-carbon catalyst and the mixture at about 25 ° C. in contact with hydrogen Atmospheric pressure vigorously moves or stirs. Under these conditions, the hydrogenation reaction is essentially complete in about 1 hour, and the corresponding Λ- (CO- aminoalkyl) -glycopyranoside is formed. The latter is made expedient

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obtained from the hydrogenation reaction mixture by filtering the mixture through kieselguhr and chromatography of the filtered solution on a silica gel column. The 1- (α-> -aminoalkyl) -glycopyranoside, such as 1- (5-aminopentyl) -cc-D-mannopyranoside, 1- (6-aminohexyl) -oc-D-mannopyranoside, 1 is obtained essentially in pure form - (6-Aminohexyl) -β-D-glucopyranoside, 1- (6-aminohexyl) -β-D-galactopyranoside, 1- (7-aminoheptyl) -aD-mannopyranoside, among others

The 1 - [( CO -aminoalkyl) -thio] -1-deoxy-glycopyranosides are normally prepared by adding the corresponding tetra-O-acetyl-glycopyranosyl bromide, such as 2,3,4,6-tetra-O-acetyl-cc -D-mannopyranosyl bromide, 2,3,4,6-tetra-O-acetyl-cc-D-glucopyranosyl bromide, 2,3, ^, e-tetra-O-acetyl-aD-galactopyranosyl bromide and others, with thiourea in solution in one essentially anhydrous, polar organic solvent, such as anhydrous acetone, to form the corresponding tetra-0-acetyl-1-deoxy-glycopyranosyl-isothiouronium bromide. The reaction is preferably carried out by heating the anhydrous mixture of tetra-O-acetyl-glycopyranosyl bromide, thiourea and anhydrous acetone at reflux temperatures. Under these conditions, the reaction is essentially complete in 2 hours. The reaction mixture is cooled, evaporated to dryness in vacuo, and the remaining material is recrystallized from cold water or acetone. Tetra-O-acetyl-i-deoxy-glycopyranosyl-isothiouronium bromide, such as 2,3,4,6-tetra-O-acetyl-1-deoxy-aD-mannopyranosyl-isothiouronium bromide, 2,3,4,6-tetra, are obtained -O-acetyl-1-deoxy-ß-glucopyranosyl-isothiouronium bromide, 2,3,4,6-tetra-O-acetyl-i-deoxy-ß-D-galactopyranosyl-isothiouronium bromide and others

The tetra-O-acetyl-1-deoxy-glycopyranosyl-iso thiouronium bromide is with 1-iodine-CO-trifluoroacetylamino-alkane, such as 1-iodo-5-trifluoroacetylamino-pentane, i-iodine-6-trifluoroacetylamino-

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hexane, i-iodine ^ -trifluoroacetylamino-heptane, etc., implemented. The reaction is conveniently carried out by incorporating an aqueous solution of tetra-O-acetyl-i-deoxy-glycopyranosylisothiouroniumbromid, potassium carbonate and potassium metabisulfite, and an acetone solution, such as 1-iodo OJ -trifluoracetylamino alkanoic contains, bringing together and the resulting mixture is vigorously agitated or stirred at about 25 ° C. Under these conditions, the reaction is usually complete in about 30 minutes. The acetone is then evaporated, the remaining aqueous mixture is extracted with a water-immiscible organic solvent such as chloroform, and the chloroform extract is evaporated to dryness. The remaining material is recrystallized from a lower alkenol such as ethanol; the corresponding 1 - [(6J -trifluoroacetylaminoalkylJ-thioJ-tetra-O-acetyl-i-deoxy-glycopyranoside, such as 1 - [(5-trifluoroacetylamino-pentyl) -thio] -2,3,4,6-tetra is obtained -O-acetyl-i -deoxy-aD-mannopyranoside, 1 - [(6-trifluoroacetylamino-hexyl) -thio] -2,3,4,6-tetra-O-acetyl-1-deoxy-aD-mannopyranoside, 1 - [(6-Trifluoroacetylamino-hexyl) -thio] -2,3,4,6-tetra-0-acetyl-1-deoxy-ß-D-glucopyranoside, 1 - [(6-trifluoroacetylamino-hexyl) -thio] -2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranoside, 1 - [(7-trifluoroacetylaminoheptyl) -thio] -2,3,4,6-tetra-0-acetyl -1-deoxy-aD-mannopyranoside et al

Alternatively, a mixture of the 1-thiohexose salt, for example an alkali metal glycopyranosyl mercaptide, such as 1-thio-aD-mannose sodium salt, 1-thio-ß-D-mannose sodium salt, 1-thio-D-galactose sodium salt or 1 thio-ß-D-glucose-sodium salt, an aqueous alkenol, such as aqueous ethanol and a 1-iodo <*> -trifluoracetylamino-alkane, such as 1-iodo-5-trifluoroacetylamino-pentane, i-iodo-6-trifluoroacetylamino -hexane or i-iodo-7-trifluoroacetylamino-heptane, with stirring at a temperature of about 50 ° C. At these conditions the reaction is essentially in about 1 hour

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quit. The reaction mixture is evaporated to dryness, the remaining material is treated with acetic anhydride and pyridine acetylated, and the acetylated mixture becomes co-distilled with toluene. Thereby the pyridine, unreacted Acetic anhydride and acetic acid as a by-product removed. The remaining material is between Dichloromethane and water divided; you get the corresponding 1 - [(o-> -Trifluoroacetylamino-alkyl) -thio] -tetra-0-acetyl-1-deoxy-glycopyranoside.

The 1 - [(6-> -Trifluoroacetylamino-alkyl) -thio] -tetra-0-acetyl-1-deoxy-glycopyranoside is then in aqueous ethanol solution with a strongly basic anion exchange resin in the Hydroxyl cycle implemented. The resin contains quaternary ammonium groups, bound to a styrene-divinylbenzene copolymer. The reaction mixture becomes violent at a temperature stirred from about 25 ° C. Under these conditions hydrolysis of the acetyl and trifluoroacetyl groups is normal finished in about 15 hours. The insoluble resin is filtered off from the reaction mixture with an organic solvent, such as methanol, and the solvents are evaporated from the combined filtrate and washings. A syrup is obtained which normally crystallizes on standing and the corresponding 1 - [(cO -aminoalkyl) -thio] -1-deoxy-glycopyranoside gives how 1 - [(5-aminopentyl) thio] -1-deoxy-oc-D-mannopyranoside, 1 - [(6-Aminohexyl) -thio] -1-deoxy-cc-D-mannopyranoside, 1 - [(6-Aminohexyl) -thio] -1-deoxy-ß-D-mannopyranoside, 1 - [(6-Aminohexyl) -thio] -1-deoxy-ß-D-glucopyranoside, 1 - [(6-Aminohexyl) -thio] -1-deoxy-ß-D-galactopyranoside, 1 - [(7-Aminoheptyl) -thio] -1-deoxy-ß-D-mannopyranoside et al.

If desired, the tetra-O-acetyl-i-deoxy-glycopyranosyl-isothiouronium bromide with a <* ^ - iodine-1-alkanol, like 5-iodo-i-pentanol, 6-iodo-1-hexanol and others. In this implementation, done in an analogous way to the previous one

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reaction described is carried out, 1-iodo-c ^ trifluoroacetylamino-alkane is used instead of cu-iodine-1-alkanol. The corresponding 1 - [( co- hydroxyalkyl) -thio] -tetra-0-acetyl-1-deoxy-glycopyranoside, such as 1 - [(5-hydroxypentyl) -thio] -2,3,4,6-tetra, is obtained -0-acetyl-1-deoxya-D-mannopyranoside, 1 - [(6-hydroxyhexyl) -thio] -2,3,4,6-tetra-0-acetyl-1-deoxy-aD-mannopyranoside, 1- [ (6-Hydroxyhexyl) -thio] -2.3 ^, ö-tetra-O-acetyl-i-deoxy-ß-D-glucopyranoside, 1 - [(6-hydroxyhexyl) -thio] -2.3, 4,6-tetra-0-acetyl-1-deoxyß-D-galactopyranoside et al

The 1 - [( CO -hydroxyalkyl) -thio] -tetra-O-acetyl-1-deoxy-glycopyranoside is then reacted with p-toluenesulfonyl chloride in the presence of a base such as pyridine to form the corresponding p-toluenesulfonate. The reaction is expediently carried out by dissolving the 1 - [(<U -hydroxyalkyl) -thio] -tetra-0-acetyl-1-deoxy-glycopyranoside in dry pyridine, to this solution a solution of an equivalent amount of p-toluenesulfonyl chloride in an organic solvent such as chloroform and stir the resulting mixture at a temperature of about OOC. Under these conditions, the esterification reaction is usually complete in about 4 hours. The reaction mixture is then poured onto ice-water. The aqueous mixture is extracted with a water-immiscible organic solvent such as dichloromethane. The combined dichloromethane extracts are washed with an aqueous bicarbonate solution to remove the acidic materials, and the organic layer is dried and vacuum co-distillation with toluene to remove Subjected to pyridine. The remaining material is purified by chromatography. The corresponding 1 - [( co -p-toluenesulfonyloxy-alkylJ-thioj-tetra-0-acetyl-1-deoxy-glycopyranoside, such as 1 - [(5-p-toluenesulfonyloxy-pentyl) -thio] -2.3) is obtained »4,6-tetra-0-acetyl-1-deoxy-aD-mannopyranoside, 1 - [(6-p-toluenesulfonyloxy-hexyl) -thio] -2,3,4,6-

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tetra-O-acetyl-1-deoxy-a-D-mannopyranoside, 1 - [(6-p-toluenesulfonyloxy-hexyl) -thio] -2.3 > 4,6-tetra-O-acetyl-1-deoxy-ß-D-glucopyranoside, 1 - [(6-p-Toluenesulfonyloxy-hexyl) -thio] -2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranoside i.a.

A mixture of this 1 - [( co -p-toluenesulfonyloxy-alkyl) -thio] -tetra-O-acetyl-1-deoxy-glycopyranoside, one equivalent of sodium cyanide and an amount of dimethylformamide about 10 times the combined weight of these reactants is heated with stirring at a temperature of about 45 ° C while the mixture is maintained under substantially anhydrous conditions. The replacement of the p-toluenesulfonyloxy substituent with the cyano group is normally complete in about 4 hours. The reaction mixture is poured onto ice-water, the aqueous mixture is extracted with a water-immiscible organic solvent such as dichloromethane, and the dichloromethane extracts are washed with water, dried and evaporated to dryness. The remaining material is acetylated with an excess of acetic anhydride-pyridine and the acetylated product is purified by chromatography. The corresponding 1 - [( CO- cyanohexyl) -thio] -tetra-0-acetyl-1-deoxy-glycopyranoside, such as 1 - [(5-cyanopentyl) -thio] -2,3,4,6-tetra, is obtained -O-acetyl-1 -deoxy-cc-D-mannopyranoside, 1 - [(6-cyanohexyl) -thio] -2,3,4,6-tetra-0-acetyl-1-deoxy-cc-D-mannopyranoside , 1 - [(6-cyanohexyl) -thio] -2,3,4,6-tetra-0-acetyl-1-deoxy-β-D-glucopyranoside, 1 - [(6-cyanohexyl) -thio] -2 , 3,4,6-tetra-0-acetyl-1-deoxy-β-D-galactopyranoside, among others

A solution of this 1 - [(co-cyanohexylJ-thioJ-tetra-O-acetyl-1-deoxy-glycopyranoside in dry methanol at a temperature of 25 ° C with a catalytic amount of sodium methylate implemented. Under these conditions, the deacetylation reaction is usually complete in about 2 hours. The reaction solution is made by stirring with an acidic resin

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neutralized, the resin is filtered off and the filtrate is evaporated; the corresponding 1 - [(a> -Cyanohexyl) -thio] -1-deoxy-glycopyranoside is obtained, such as 1 - [(5-cyanopentyl) thio] -1-deoxy-a-D-mannopyranoside, 1 - [(6-cyanohexyl) thio] -1-deoxya-D-mannopyranoside, 1 - [(6-cyanohexyl) thio] -1-deoxy-ß-D-glucopyranoside, 1 - [(6-cyanohexyl) thio] -1-deoxy-β-D-galactopyranoside i.a.

A solution of 1 - [( oJ -cyanoalkyl) -thio] -1-deoxy-glycopyranoside in ethanolic ammonia is vigorously in contact with hydrogen at a pressure of about 2.81 kg / cm (40 psi) in the presence of a Raney nickel -Catalyst and a temperature of about 25 ° C. Under these conditions, the hydrogenation reaction is usually complete in about 8 hours. The hydrogenation mixture is filtered through kieselguhr, the filtered solution is evaporated in vacuo and the remaining material is chromatographed; the corresponding 1 - [(^ -aminoalkyl) thio] -1-deoxy-glycopyranoside is obtained, such as 1 - [(6-aminohexyl) thio] -1-deoxy-aD-mannopyranoside, 1 - [(7-aminoheptyl ) -tMo] -1-deoxy-α-D-mannopyranoside, 1 - [(7-aminoheptyl) -thio Ji-deoxy-β-D-glucopyranoside, 1 - [(7-aminoheptyl) -thio] -1-deoxy-β -D-galactopyranoside et al

The 1 - [(iL) -Aminoalkanoyl) -amino] -1-deoxy-glycopyranoside are usually prepared by adding a solution of an organic solvent such as methylene chloride, a hexose pentaacetate such as D-mannose pentaacetate, D-glucose pentaacetate, b-galactose pentaacetate inter alia, tin (IV) chloride and trimethylsilyl azide and the resulting mixture is vigorously agitated ^{at a temperature of about 25 ° C.} Under these conditions, the reaction is usually complete in about 6 hours. The methylene chloride reaction solution is washed with water, aqueous sodium bicarbonate solution, dried and then evaporated in vacuo to a syrup which normally crystallizes on standing and the corresponding Tetra-O-

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acetyl-glycopyranosyl azide, such as 2,3,4,6-tetra-O-acetyl-cc-D-mannopyranosyl azide, 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl azide, 2,3,4 , 6-tetra-O-acetyl-ß-D-galactopyranosyl azide and the like. _f results.

This Tetra-0-acetyl-glycopyranosyl azide is in an organic Solvent, such as ethyl acetate, dissolved, a Raney nickel catalyst is added and the mixture is agitated vigorously with hydrogen at about 25 ° C. With these conditions is the hydrogenation reaction, with its accompanying inversion, is essentially completed in about 6 hours. The hydrogenation mixture is filtered through kieselguhr and the filtered one Solution is evaporated to a syrup, which normally occurs when standing in the cold with the formation of the corresponding Tetra-O-acetyl-glycopyranosylamine, such as 2,3,4,6-Tetra-O-acetyl-ß-D-mannopyranosylamine, 2,3,4,6-Tetra-O-acety1-ß-D-glucopyranosylamine, 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosylamine et al., crystallized.

This tetra-O-acetyl-glycopyranosylamine is treated with a benzyloxycarbonylamino-alkanoylating agent, such as the halide, the anhydride or the acid, in the presence of a condensing agent, such as dicyclohexylcarbodiimide, for example 5-benzyloxycarbonylamino-pentanoyl chloride, 6-benzyloxycarbonylaminoyl chloride, 6-benzyloxycarbonylaminoyl chloride -Benzyloxycarbonylamino-heptanoylchlorid inter alia, implemented. The reaction is conveniently carried out by bringing the reactants together in solution in an organic solvent such as methylene chloride, in the presence of 4-dimethylaminopyridine and the mixture is stirred at a temperature of about 25 ⁰ C vigorously. Under these conditions, the reaction is generally complete after about 1 hour. The methylene chloride reaction mixture, which can be diluted with further methylene chloride, is washed with aqueous hydrochloric acid solution, with aqueous sodium bicarbonate solution and with water. The methylene

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The chloride solution is then evaporated to a small volume and the resulting solution is dried over silica gel, preferably using a 1: 1 mixture of ethyl acetate: chloroform as eluent, chromatographed; you get that corresponding 1 - [(oJ-Benzyloxycarbonylamino-alkanoyl) -amino] -tetra-O-acetyl-i-deoxy-glycopyranoside, such as 1 - [(5-benzyloxycarbonylamino-pentanoyl) -amino] -2,3,4, ö-tetra-O-acetyl-1-deoxy-ß-D-mannopyranoside, 1 - [(6-Benzyloxycarbonylaminohexanoyl) -amino] -2,3,4,6-tetra-O-acetyl-i-deoxy-ß-D-mannopyranoside, 1 - [(7-Benzyloxycarbonylamino-heptanoyl) -amino] -2,3,4, ö-tetra-O-acetyl-1-deoxy-ß-D-mannopyranoside, 1 - [(7-Benzyloxycarbonylamino-heptanoyl) -amino] -2,3,4,6-tetra-O-acetyl-1-deoxy-ß-D-glucopyranoside, 1 - [(7-Benzyloxycarbonylamino-heptanoyl) -amino] -2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranoside i.a.

A solution of the 1 - [(<* ■> -Benzyloxycarbonylamino-alkanoyl) -amino] -tetra-O-acetyl-i-deoxv-glycopyranosides in dry methanol is at a temperature of 25 ° C with a catalytic Amount of sodium methylate implemented. Under these conditions, the diacetylation reaction is usually in about 2 hours quit. The reaction solution is neutralized by stirring with an acidic resin. The resin is filtered off and that The filtrate is evaporated; the corresponding 1 - [(o> Benzyloxycarbonylamino-alkanoyl) -amino] -1-deoxy-glycopyranoside is obtained, like 1 - [(5-Benzyloxycarbonylamino-pentanoyl) -amino] -1-deoxy-ß-D-mannopyranoside, 1 - [(6-Benzyloxycarbonylaminohexanoy1) -amino] -1-deoxy-ß-D-mannopyranoside, 1 - [(7-Benzyloxycarbonylamino-heptanoyl) -amino] -1-deoxy-ß-D-mannopyranoside, 1 - [(7-Benzyloxycarbonylamino-heptanoyl) -amino] -1-deoxy-β-D-glucopyranoside , 1 - [(7-Benzyloxycarbonylamino-heptanoyl) -amino] -1-deoxy-β-D-galactopyranoside etc.

A mixture of a solution of 1 - [(iO -Benzyloxycarbonylamino-alkanoyl) -amino] -1-deoxy-glycopyranoside in aqueous

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Methanol and a catalytic amount of a palladium on carbon catalyst becomes violently in contact with a hydrogen atmosphere at atmospheric pressure and temperature moved or stirred from about 25 ° C. Under these conditions, the hydrogenation reaction is usually complete in about 1 hour. The hydrogenation mixture is filtered through kieselguhr and the filtered solution is evaporated in vacuo. You get the corresponding 1 - [(o; -aminoalkanoyl) -amino] -1-deoxy-glycopyranoside, such as 1 - [(5-amino-pentanoyl) -amino] -1-deoxyβ-D-mannopyrano s id, 1 - [(6-Amino-hexanoyl) -amino] -1-deoxy-ß-D-mannopyranoside, 1 - [(7-Amino-heptanoyl) -amino-1-deoxy-ß-D-mannopyranoside, 1 - [(7-Amino-heptanoyl) -amino] -1-deoxy-ß-D-glucopyranoside, 1 - [(7-Amino-heptanoyl) -amino] -1-deoxy-β-D-galactopyranoside i.a.

The following examples illustrate the present invention.

example 1

A mixture of about 35 g of 2,3,4,6-tetra-O-acetyl-oc-D-mannopyranosyl bromide, 6.7 g of thiourea and 40 ml of anhydrous acetone is at reflux temperature with stirring and under essentially anhydrous conditions during heated for a time of about 2 h. The reaction mixture is cooled and evaporated to dryness in vacuo. The remaining material is dissolved in about 50 ml of water, the aqueous solution is ^{washed with 2 U} ml of ether, and the aqueous layer is separated off, ^{cooled to 0} ° C. and can crystallize at this temperature for about 15 h. The crystalline material is filtered off, recrystallized from water and dried. About 25 g of 2,3,4,6-tetra-O-acetyl-i-deoxy-aD-mannopyranosyl-isothiouronium bromide monohydrate are obtained; Mp 125 to 128 ° C; [α] {" ⁵ = + 103 ° (c 1, acetone).

To a mixture of about 4.8 g of 2,3,4,6-tetra-0-acetyl-1-deoxy-a-D-mannopyranosyl-isothiouronium bromide monohydrate.

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1.5 g of potassium carbonate, 2.1 g of potassium metabisulphite and about 10 ml of water are added with stirring to a solution of about 2.5 g of i-iodo-6-trifluoroacetylamino-hexane in 10 ml of acetone. The mixture is stirred at a temperature of about 25 ° C for about 30 minutes and the acetone is evaporated from the reaction mixture. The remaining aqueous mixture is extracted with chloroform and the chloroform extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The remaining material is recrystallized from ethanol; about 4.0 g of 1 - [(6-trifluoroacetylamino-hexyl) -thio] -2,3,4,6-tetra-O-acetyl-i-deoxy-aD-mannopyranoside, melting point 113.5 to 115, are obtained ° C; [a] ^ ⁵ = + 77.1 ° (c 1, CHCl ₃ ).

A mixture of about 2.0 g of 1 - [(6-trifluoroacetylamino-hexyl) -thio] -2,3,4,6-tetra-O-acetyl-1-deoxy-aD-mannopyranoside, 75 ml of 50% aqueous Ethanol and 40 meq. a strongly basic anion exchange resin in the hydroxyl cycle containing quaternary ammonium groups attached to the styrene-divinylbenzene copolymer is vigorously stirred at a temperature of about 25 ° C for about 15 hours. The reaction mixture is filtered, the insoluble resin is washed well with methanol, and the combined filtrate and washings are evaporated to a syrup which slowly crystallizes on standing. To obtain about 960 mg of substantially pure 1 -. [(6-aminohexyl) thio] -1-deoxy-aD-mannopyranoside, mp 93 to 95 ⁰ C, [a] ^ ⁵ = + 188 ° (c 1, MeOH ).

Example 2

A mixture of about 600 mg of 1-thio-ß-D-mannose sodium salt, 888 mg of 1-iodo-6-trifluoroacetylamino-hexane and 25 ml of 40 # aqueous ethanol is stirred for about 1 hour at a temperature of 50 ° C heated. The reaction mixture is cooled and evaporated to dryness in vacuo. The remaining material is at about 25 ⁰ C with excess

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Acetic anhydride and pyridine reacted. The reaction mixture is distilled in vacuo, then co-distilled in vacuo with toluene, essentially all of the pyridine, unreacted acetic anhydride and acetic acid being evaporated as by-products. The remaining material is distributed between dichloromethane and water. The dichloromethane layer is washed with aqueous sodium thiosulfate and then with cold water, dried and evaporated to dryness in vacuo. The remaining material is recrystallized from ethanol; about 1.4 g of 1 - [(6-trifluoroacetylamino-hexyl) thio] -2,3,4,6-tetra-0-acetyl-1-deoxy-β-D-mannopyranoside are obtained; Mp. 121 to 122 ^° C; [oc] ^ = -47.6 ° (c 1, chloroform).

A mixture of about 0.9 g of 1 - [(6-trifluoroacetylamino-hexyl) -thio] -2,3,4,6-tetra-O-acetyl-i-deoxy-ß-D-mannopyranoside, 46 ml of 50% aqueous Ethanol, 20 meq. A strongly basic anion exchange resin in the hydroxyl cycle, which contains quaternary ammonium groups bound to a styrene-divinylbenzene copolymer, is stirred ^{vigorously at a temperature of about 25 ° C. for about 15 hours.} The reaction mixture is filtered. The insoluble resin is washed well with methanol. The combined filtrate and washing solutions are evaporated to dryness. The remaining solid material is recrystallized from ethanol; about 422 mg of essentially pure 1 - [(6-aminohexyl) thio] -1-deoxy-β-D-mannopyranoside are obtained, melting point 161.8 to 163.8 ° C .; [a] jp = -83.1 ° (c 1, methanol).

Example 3

To a mixture of about 10.5 g of 2,3,4,6-tetra-0-acetyl-1-deoxy-a-D-mannopyranosyl-isothiouronium bromide monohydrate, 3.3 g potassium carbonate, 4.6 g potassium metabisulfite and about A solution of about 20.8 mmol of 6-iodo-1-hexanol in 20 ml of acetone is added to 20 ml of water while stirring. The mixture will

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about 30 min at a temperature of about 25 ⁰ C stirred. The acetone is evaporated from the reaction mixture. The remaining aqueous mixture is extracted with dichloromethane and the dichloromethane extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The remaining material is dissolved in chloroform. The solution is chromatographed on a silica gel column using a 10: 1 mixture of chloroform-ethyl acetate as the eluent. The chromatographed product is crystallized from ethanol; about 6.8 g of essentially pure 1 - [(6-hydroxyhexyl) thio] -2,3 ^ »6-tetra-0-acetyl-1-deoxy-aD-mannopyranoside are obtained; Mp 91-92 ° C; [a] jp = + 93.6 ° (c 1, chloroform).

A solution of about 3.0 g of 1 - [(6-hydroxyhexyl) thio] -2,3,4,6-tetra-0-acetyl-1-deoxy-aD-mannopyranoside in 6 ml of dry pyridine is added Solution of about 1.4 g of p-toluenesulfonyl chloride in 3 »0 ml of chloroform. The mixture is stirred at a temperature of about ^{0 ° C. for about 4 hours.} The reaction mixture is poured into ice-water. The aqueous mixture is extracted with three 30 ml portions of dichloromethane. The combined dichloromethane extracts are washed with aqueous sodium bicarbonate solution and with cold water and dried over anhydrous sodium sulfate. The dried dichloromethane solution is evaporated in vacuo, then co-distilled in vacuo with toluene, the pyridine being substantially completely evaporated. The remaining material is dissolved in dichloromethane. The solution is chromatographed on a silica gel column using a 2: 1 mixture of ether: petroleum ether as the eluent. The chromatographed product is recrystallized from ethanol; about 1.8 g of 1 - [(6-p-toluenesulfonyloxy-hexyl) -thio] -2,3,4 »6-tetra-0-acetyl-1-deoxy-aD-mannopyranoside are obtained; M.p. 73.8 to 74.4 ° C; [a] jp = + 104 ° (c 1, chloroform).

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15 825 ^C *

A mixture of about 0.82 g of 1 - [(6-p-toluenesulfonyloxyhexyl) -thio] -2,3,4,6-tetra-O-acetyl-i-deoxy-aD-mannopyranoside, 0.23 g of sodium cyanide and 10 ml of dry dimethylformamide is heated with stirring at about 45 ° C. under essentially anhydrous conditions for about 4 hours. The reaction mixture is poured into 50 ml of ice-water. The aqueous mixture is extracted with three 25 ml portions of dichloromethane. The combined dichloromethane extracts are washed with ice-water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The remaining material is reacted with excess acetic anhydride and pyridine at a temperature of 25 ° C. for about 15 hours. The reaction mixture is distilled in vacuo and then co-distilled with toluene in vacuo. The resulting syrup is dissolved in chloroform. The solution is chromatographed on silica gel using a 9: 1 mixture of chloroform-ethyl acetate as the eluent; about 0.5 g of 1 - [(6-cyanohexyl) thio] -2,3,4,6-tetra-O-acetyl-1-deoxy-aD-mannopyranoside is obtained; M.p. 88 to 89.2 ° C; [cc] q ⁵ = + 91.7 ° (c.1, chloroform).

A mixture of about 1 g of 1 - [(6-cyanohexyl) thio] -2,3,4,6-tetra-O-acetyl-i-deoxy-cc-D-mannopyranoside, 5 ml of dry methanol and a catalytic amount of sodium methylate is stirred at about 25 ° C. for about 15 hours. About 0.1 g of a strongly acidic cationic exchange resin made from sulfonated styrene-divinylbenzene copolymer in the hydrogen cycle is added to the reaction solution. The mixture is stirred. The sodium cation is adsorbed on the resin. The resulting mixture is filtered through kieselguhr. The filtered reaction solution is evaporated in vacuo to a syrup which crystallizes from ethyl acetate-ethyl ether. The crystalline material is filtered off and dried; 1 - [(6-cyanohexyl) thio] -1-deoxy-aD-mannopyranoside is obtained in essentially quantitative yield; M.p. 82 to 83 ^° C; [a] _D = + 181 ° (£ 1, methanol).

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A mixture of about 200 mg of 1 - [(6-cyanohexyl) -thio] -1-deoxya-D-mannopyranoside, 200 mg of Raney nickel catalyst and 10 ml of ethanolic ammonia containing 3 g of ammonia is vigorously stirred with hydrogen at an initial pressure of about 2.81 kg / cm (40 lb / in) for about 8 hours at about 25 ° C. The reaction mixture is filtered through kieselguhr and the filtered solution is evaporated to dryness. The leftover Material is dissolved in methanol-chloroform (1: 1). The solution is put on a silica gel column using a 3: 3: 1 Chromatography mixture of chloroform / methanol: ammonia as eluent; about 120 mg of 1 - [(7-aminoheptyl) thio] -1-deoxy-a-D-mannopyranoside are obtained.

Example 4

A solution of 10 g of 2,3,4,6-tetra-O-acetyl-a-D-mannopyranosyl bromide in 50 ml of dry benzene is a solution of 5.0 1 g of 6- (Benzy loxycarbony lamino) -1-hexanol in 250 ml Nitromethane containing 5.3 g of mercury (II) cyanide and 5 g Calcium sulfate, added. The mixture is about 15 h at a Stirred at a temperature of about 25 ° C. The reaction mixture is filtered and the filtered solution is in vacuo to Evaporated dry. The remaining material is dissolved in chloroform. The chloroform solution is sequentially with water, aqueous sodium bicarbonate solution and again with Washed water, dried and the dry chloroform solution is evaporated to a smaller volume. That I separating material, about 2 g of unreacted 6- (benzyloxycarbonylamino) -1-hexanol, is filtered off. The filtered solution is put on a silica gel column using 15 # ethyl acetate in chloroform as eluent chromatography rt; about 3.6 g of 1- (6-benzyloxycarbonylamino-hexyl) are obtained -2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside as Syrup.

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15 825

A solution of about 3 g of 1- (6-benzyloxycarbonylamino-hexyl) -2,3,4,6-tetra-O-acetyl-aD-mannopyranoside and 200 mg of sodium methylate in 20 ml of dry methanol is about 2 h at a temperature of held about 25 ⁰ C. The solution is then neutralized by stirring with an acidic resin and filtered. The filtrate is evaporated in vacuo; about 2 g of i-CO-benzyloxycarbonylamino-hexylJ-aD-mannopyranoside are obtained in the form of a crystalline product; Mp 80 ° C; [cc] ² ) ⁵ = + 46 ° (£ 1, methanol).

A mixture of 700 mg of 1- (6-benzyloxycarbonylamino-hexyl) -Ad-mannopyranoside, 20 ml of aqueous methanol and 200 mg of a 1Obigen palladium-on-carbon catalyst is stirred vigorously h with hydrogen at atmospheric pressure and about 25 ⁰ C for about 1 or moves. The reaction mixture is filtered through kieselguhr. The filtered solution is chromatographed on a silica gel column using a 60:40:10 mixture of chloroform: methanol: 5096 ammonium hydroxide as the eluent; about 450 mg of 1- (6-aminohexyl) -aD-mannopyranoside are obtained, R _f = 0.2.

Example 5

About 2 ml of tin (IV) chloride are added to a solution of 8 g of D-mannose pentaacetate and 2.6 ml of trimethylsilyl azide in 180 ml of methylene chloride. The resulting mixture is stirred at about 25 ° C for about 6 hours. The reaction solution is diluted with a further 100 ml of methylene chloride. The resulting methylene chloride solution is washed successively with water, an aqueous sodium bicarbonate solution and again with water and dried over anhydrous sodium sulfate. The dry methylene chloride solution is evaporated in vacuo to a syrup which crystallizes on standing; about 7.6 g of 2,3,4,6-tetra-O-acetyl-aD-mannopyranosyl azide are obtained; Mp. 52 to 53 ° C (after recrystallization from 2-propanol); [ccjjp = 116 ° (c 1.02, C _h loroform).

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A mixture of about 3.0 g of 2,3,4,6-tetra-O-acetyl-cc-D-mannopyranosyl azide, 0.5 g of Raney nickel catalyst and 40 ml of ethyl acetate is violently with hydrogen at atmospheric pressure about 6, Stirred at about 25 ^° C. for 5 h. The reaction mixture is filtered through kieselguhr. The filtered solution is evaporated in vacuo to a syrup which crystallizes after standing at a temperature of about 5 ° C. The crystalline product is recrystallized from 2-propanol; about 1.7 g of 2,3,4,6-tetra-O-acetyl-β-D-mannopyranosylamine are obtained; M.p. 145 to 147 ° C; [cc] * ⁵ = -9.8 ° (c 1.02, methanol).

A mixture of about 0.87 g of 2,3,4,6-tetra-O-acetyl-ß-D-mannopyranosylamine, 0.75 g of 7-benzyloxycarbonylamino-heptanoyl chloride, 62 mg of 4-dimethylaminopyridine and 20 ml of methylene chloride is about 1 Stirred at about 25 ° C. for h. The reaction mixture is diluted with a further 20 ml of methylene chloride. The resulting mixture is washed successively with 1N aqueous hydrogen chloride acid solution, aqueous sodium bicarbonate solution and then with water / water. The methylene chloride solution is evaporated to a small volume. It is chromatographed on silica gel using a 1: 1 mixture of ethyl acetate: chloroform as the eluent; about 0.9 g of 1 - [(7-benzyloxycarbonylamino-heptanoyl) -amino] -2,3,4,6-tetra-O-acetyl-i-deoxy-β-D-mannopyranoside are obtained; [ _{α] β} = -7.6 + 0.6 (c 1.58, chloroform).

A solution of about 50 mg of sodium methylate, 1.13 g of 1 - [(7-benzyloxycarbonylamino-heptanoyl) -amino] -2,3,4,6-tetra-0-acetyl-1-deoxy-β-D-mannopyranoside and 25 ml of dry methanol is kept at a temperature of about 25 ^° C. for about 2 hours. The reaction solution is neutralized with an acidic resin while stirring, filtered and the filtrate is evaporated in vacuo; a crystalline material is obtained which, after recrystallization from methanol, contains about 0.76 g of 1 - [(7-benzyloxycarbonylamino-heptanoyl) -amino] -1-deoxy-β-D-mannopyrano s id;

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Mp 169 to 172 ⁰ C, [cc] _D = -7.4 + 0.3 (c 1.0, methanol) concerns..

A mixture of about 200 mg of 1 - [(7-benzyloxycarbonylaminoheptanoyl) -amino] -1-deoxy-ß-D-mannopyranoside, 10 ml of aqueous methanol and 80 mg of 1Obigem palladium-on-carbon catalyst is vigorously with hydrogen at atmospheric pressure and about 25 ° C for about 1 h stirred or agitated. The reaction mixture is filtered through kieselguhr. The filtered solution is evaporated in vacuo to a crystalline material which is triturated with ethanol, filtered off and dried; about 125 mg of 1 - [(7-aminoheptanoyl) -amino] -1-deoxyß-D-mannopyranoside are obtained; M.p. 162 ° C (dec.), [Α] _β = -19.4 ° + 0.5 (<: 1.59, water).

End of description.

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Claims (17)

Merck & Co., Inc. 15,825 claims 1. A process for the preparation of 1 - [( oj -aminoalkyl) -glycopyranosides, characterized in that nan a tetra-O-acetyl-glycopyranosyl bromide with a cd- (benzyloxycarbonylamino) -1-alkanol to form the corresponding 1- ( Cu converts benzyloxycarbonylamino-alkyl) tetra-0-acetyl-glycopyranoside; the latter compound with an alkali metal alkoxide in solution in a lower alkanol to form
of the corresponding 1- ( CO -benzyloxycarbonylamino-alkyl) -glycopyranosids; and this Λ- ^ cO -Benzyloxycarbonylamino-alkyl) -glycopyranoside with hydrogen in the presence
a palladium-on-carbon catalyst to form the
corresponding 1- ( CO -aminoalkyl) -glycopyranosids. 2. The method according to claim 1, characterized in that 2,3,4,6-tetra-O-acetyl-a-D-mannopyranosyl bromide with 6- (Benzyloxycarbonylamino) -1-hexanol with formation of 1- (6-Benzyloxycarbonylamino-hexyl) -2,3,4,6-tetra-O-acetyl-a-D- . converts mannopyranoside; the latter compound is reacted with sodium methylate in methane solution to form 1- (6-benzyloxycarbonylamino-hexyl) -aD-mannopyraniside; and this
1- (6-Benzyloxycarbonylamino-hexyl) -2,3,4,6-tetra-0-acetyl-aD-mannopyranoside with hydrogen in the presence of a
Palladium-on-carbon catalyst converts to form 1- (6-aminohexyl) -cc-D-mannopyranoside. . 3. Process for the preparation of 1 - [( CO -aminoalkyl) -thio] -1-deoxy-glycopyranoside, characterized in that one (a) a 1-thio-hexose alkali metal salt with 1-iodine
Cl? -trifluoroacetylaminoalkane is converted and then acetylated; or (b) Tetra-O-acetyl-glycopyranosyl bromide with thiourea in solution in an essentially anhydrous, - 1 809813/0975 ORIGINAL INSPECTED 15 825 polar, organic solvent to form the corresponding Tetra-O-acetyl-1-deoxy-glycopyranosyl-isothiouronium bromide implements, and the latter connection with a Metabisülfit and then 1-iodo- io-trifluoroacetylamino-alkane implements, whereby the corresponding 1 - [(cj-trifluoroacetylamino-alkyl) -thio] -tetra-0-acetyl-1-deoxy-glycopyranoside is formed; and reacting the latter compound with a strongly basic anion exchange resin in the hydroxyl cycle with hydrolysis of the acetyl and trifluoroacetyl groups and formation of the corresponding 1 - [( Cu- aminoalkyl) -thio] -1-deoxy-glycopyranoside. 4. The method according to claim 3> characterized in that 1-thio-ß-D-mannose sodium salt with 1-iodine-6-trifluoroacetylamino-hexane reacted and the resulting product with acetic anhydride to form 1 - [(6-trifluoroacetylamino-hexyl) -thio] -2,3,4,6-tetra-O-acetyl-i-deoxy-ß-D-mannopyranoside reacts, and the latter compound with a strongly basic anion exchange resin in the hydroxyl cycle to form of 1 - [(6-aminohexyl) thio] -1-deoxy-ß-D-mannopyranoside converts. 5. The method according to claim 3 »characterized in that that 2,3,4,6-tetra-O-acetyl-a-D-mannopyranosyl bromide with Thiourea in anhydrous acetone solution to form 2,3,4,6-tetra-O-acetyl-1-deoxy-a-D-mannopyranosyl-isothiouronium bromide implements; the latter compound with potassium metabisulphite and then with i-iodo-6-trifluoroacetylaminohexane with formation of 1 - [(6-trifluoroacetylamino-hexyI) -thio] -2,3,4,6-tetra-0-acetyl-1-deoxy-a-D-mannopyranoside implements; and this 1 - [(6-trifluoroacetylamino-hexyl) -thio] -2,3,4,6-tetra-O-acetyl-1 -deoxy-cc-D-mannopyranoside with a strongly basic anion exchange resin with formation of 1 - [(6-aminohexyl) -thio] -1-deoxy-a-D-mannopyranoside implements. - 2- 809813/0975 15 825 "* 6. A process for the preparation of 1 - [( co -aminoalkyl) thio] -1-deoxy-glycopyranoside, characterized in that tetra-O-acetyl-i-deoxy-glycopyranosyl-isothiouronium bromide with a u2-iodine-1- alkanol converts to form 1 - [( ci> -hydroxyalkyl) -thio] -tetra-O-acetyl-i-deoxy-glycopyranoside; reacting the latter compound with p-toluenesulfonyl chloride in the presence of a base to form the corresponding p-toluenesulfonate; the p-toluenesulfonate is reacted with sodium cyanide in dimethylformamide solution to form the corresponding 1 - [(oj -cyanohexyl) -thio] -tetra-0-acetyl-1-deoxy-glycopyranoside; this 1 - [( CJ -Cyanohexyl) -thio] -tetra-O-acetyl-1-deoxy-glycopyranoside with a catalytic amount of an alkali metal alkoxide in solution in a lower alkanol with removal of the acetyl groups and with formation of the 1 - [( u> -Cyanohexyl) thioj-i-deoxy-glycopyranoside converts; and this deacetylated product is reacted with hydrogen in the presence of a Raney nickel catalyst to form 1 - [(iO-aminoalkyl) -thio] -1-deoxy-glycopyranoside. 7. The method according to claim 6, characterized in that 2,3,4,6-tetra-O-acetyl-i-deoxy-cc-D-mannopyranosylisothiouronium bromide with 6-iodo-1-hexanol to form 1 - [(6-hydroxyhexyl) thio] -2,3,4,6-tetra-0-acetyl-1-deoxy-a-D-mannopyranoside implements; the latter compound with p-toluenesulfonyl chloride reacted in pyridine to form the corresponding p-toluenesulfonate; the p-toluenesulfonate with sodium cyanide in dimethylformamide solution with formation of 1 - [(6-cyanohexyl) thio] -2.3 »4» 6-tetra-O-acetyl-i-deoxy-a-D-mannopyranoside implements; the 1 - [(6-cyanohexyl) thio] -2,3,4,6-tetra-0-acetyl-1-deoxy-a-D-mannopyranoside with a catalytic amount of sodium methylate in dry methanol to form of 1 - [(6-cyanohexyl) thio] -1-deoxy-a-D-mannopyranoside; and this 1 - [(6-cyanohexyl) thio] -1-deoxy-α-D-mannopyranoside in ethanolic ammonia solution with hydrogen in the presence of a Raney nickel catalyst with formation 809813/0975 15 825 t of 1 - [(7-aminoheptyl) thio] -1-deoxy-a-D-mannopyranoside. 8. A process for the preparation of 1 - [( <*> -Aminoalkanoyl)} · 1-deoxy-glycopyranosides, characterized in that a hexose-pentaacetate with Zlnn (IV) chloride and trimethylsilyl azide to form the corresponding tetra-O- acetylglycopyranosylazids converts; this azide is reacted with hydrogen in the presence of a Raney nickel catalyst to form the corresponding tetra-O-acetyl-glycopyranosylamine; this tetra-O-acetyl-glycopyranosylamine is reacted with an α-benzyloxycarbonylamino-alkanoylating agent to form the corresponding 1 - [( O) -benzyloxycarbonylamino-alkanoyl) -amino] -tetra-O-acetyl-i-deoxy-glycopyranoside; the latter compound is reacted with an alkali metal alkoxide in solution in a lower alkanol to form the corresponding 1 - [( <o -Benzyloxycarbonylamino-alkanoyl) -amino] -1-deoxy-glycopyranoside; and this 1 - [( co -benzyloxycarbonylamino-alkanoyl) -amino] -1-deoxy-glycopyranoside with hydrogen in the presence of a palladium-on-carbon catalyst to form the corresponding 1 - [( CO -aminoalkanoyl) -amino] -1 -deoxy-glycopyranosids. 9. The method according to claim 8, characterized in that D-mannose-pentaacetate is reacted with tin (IV) chloride and trimethylsilyl azide in methylene chloride solution to form the 2,314 »o-tetra-O-acetyl-aD-mannopyranosyl azide; this 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl-azide with hydrogen in the presence of a Raney nickel catalyst to form 2,3,4,6-tetra-O-acetyl-β-D -mannopyranosylamine converts; the latter compound with 7-benzyloxycarbonylamino-heptanoyl chloride in the presence of 4-dimethylaminopyridine with formation of 1 - [(7-benzyloxycarbonylamino) -heptanoyl) -amino] -2,3 »4 _f 6-tetra-O-acetyl-i-deoxy -ß-D-mannopyranoside converts; the 1 - [(7-Benzyloxycarbonylamino-heptanoyl) - -A-609613/0975 15 825 amino] -2,3,4,6-tetra-O-acetyl-i-deoxy-ß-D-mannopyranoside with Sodium methylate in dry methanol to give 1 - [(7-benzyloxycarbonylamino-heptanoyl) -amino] -1-deoxy-ß-D-mannopyranoside implements; and the 1 - [(7-benzyloxycarbonylaminoheptanoyl) -amino] -1-deoxy-β-D-mannopyranoside with hydrogen in the presence of a palladium-on-carbon catalyst Formation of 1 - [(7-Aminoheptanoyl) -amino] -1-deoxy-ß-D-mannopyranoside converts. 10. Compound with insulin-like activity, selected from the group 1 - [( co -aminoalkyl) -glycopyranoside, 1 - [( OO -aminoalkylJ-thioJ-i-deoxy-glycopyranoside and 1 - [(&? Aminoalkanoyl) -amino] - 1-deoxy-glycopyranoside. 11. A compound according to claim 10, namely 1- (6-aminohexyl) -a-D-mannopyranoside. 12. Compound according to claim 10, namely 1 - [(6-aminohexyl) - thio] -1 -deoxy- oc-D-mannopyrano s id. 13. A compound according to claim 10, namely 1 - [(6-aminohexyl) thio] -1-deoxy-β-D-mannopyranoside. 14. A compound according to claim 10, namely 1 - [(7-aminoheptyl) thio] -1-deoxy-a-D-mannopyranoside. 15. A compound according to claim 10, namely 1 - [(7-aminoheptanoyl) -amino] -1-deoxy-ß-D-mannopyranoside. 809813/0975 16. A pharmaceutical preparation, characterized in that it contains at least one 1- ( co- aminoalkyl) -glycopyranoside, 1 - [(t <J-aminoalkyl) thio] -1-deoxy-glycopyranoside and / or 1 - [(tO- Aminoalkanoyl) -aminoj-1-deoxy-glycopyranoside and optionally inert additives. 17. Pharmaceutical preparation, characterized in that it contains 1- (6-aminohexyl) -a-D-mannopyranoside and / or 1 - [(6-aminohexyl) -thio] -1-deoxy-a-D-mannopyranoside and / or 1 - [(6-Aminohexyl) -thio] -1-deoxy-β-D-mannopyranoside and / or 1 - [(7-Axninoheptyl) -thio] -1-deoxy-α-D-mannopyranoside and / or 1 - [(7-Aminoheptanoyl) -amino] -1-deoxy-ß-D-mannopyranoside, optionally together with an inert carrier or diluent. - 6 -809813/0975