MXPA01006975A - Novel polyhydroxypyrazine derivatives, preparation and pharmaceutical compositions containing same - Google Patents

Abstract

The invention concerns novel derivatives of formula (I) wherein:R1 represents the stereoisomerical forms of the chain -(CHOH)3-CH2-O-COR (II) and either R2 represents a hydrogen atom and R3 represents the stereoisomerical forms of the chain -CH2-(CHOH)2-CH2-O-COR (III) or R2 represents the stereoisomerical forms of the chains -(CHOH)3-CH2-O-COR (II) or -CH2-(CHOH)2-CH2-O-COR (III) and R3 represents a hydrogen atom and R represents -(Alk)i-(Cycloalk) radical;i is equal to 0 or 1;Alk represents an alkyl radical, Cycloalk represents a cycloalkyl radical, and their salts with a mineral or organic acid, their preparation and the medicines containing as active principle at least a product of general formula (I) or its salts with a mineral or organic acid.

Description

NOVEDOSOS DERIVED FROM POLYHYDROXYPYRAZINES, ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM DESCRIPTION OF THE INVENTION The present invention relates to the novel products of the general formula (I), as well as its salts with a mineral or organic acid, its preparation, the pharmaceutical compositions containing them, and its use as an antidiabetic agent. The products that have hypoglycemic properties, of the general formula: REF: 131060 in which either Rx represents a hydrogen atom and R2 represents a chain of the formula: -CH2-CHOH-CHOH-CH2OH (A) -CHOH-CHOH-CHOH-CH2OH (B) or Rx represents a chain of the formula (A) y. R2 represents a hydrogen atom, as described in the application WO 97/28813. However, there is nothing to foresee in the prior art that, due to the fact of their structural modifications in relation to these products, the products of the general formula (I) according to the invention would have considerably improved properties, both in terms of anti-glycemic activity as in terms of bioavailability and / or toxicity. The present invention relates to the products of the general formula (I), wherein Rx represents the stereoisomeric forms of the chain - (CHOH) 3-CH2-0-COR (II) and either R2 represents a hydrogen atom and R3 represents the stereoisomeric forms of the chain -CH2- (CHOH) 2-CH2-0-COR (III) or R2 represents the stereoisomeric forms of the chains - (CHOH) 3-CH2-0-COR (II) • CH2- (CHOH) 2-CH2-0-COR (III) and R3 represents a hydrogen atom and R represents a radical - (Alk) i- (Cycloalk), for which: Alk designates an alkyl radical, Cycloalk designates a cycloalkyl radical, i is equal to 0 or 1; as well as their stereoisomeric forms, and their salts with a mineral or organic acid.

The term "alkyl" means: a straight or branched chain saturated hydrocarbon radical containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl, - cycloalkyl: a saturated cyclic hydrocarbon radical containing 5 or 6 carbon atoms such as cyclopentyl, cyclohexyl. The present invention relates to the products of the general formulas (VI) in which R represents a radical - (Alk) i- (Cycloalk), for which: Alk represents an alkyl radical, Cycloalk represents a cycloalkyl radical, i is equal to 0 or 1; as well as their stereoisomeric forms, or the salts of such products with an organic or mineral acid. According to the present invention, the products having the following general formulas are preferred: OH in which R represents a radical - (Alk) i- (Cycloalk), for which: Alk represents an alkyl radical, Cycloalk represents a cycloalkyl radical, i is equal to 0 1 1; as well as the salts of such products with an organic or mineral acid. Even more preferably, the present invention relates to the products of the general formula (IX) wherein: R represents a radical - (Alk) i- (Cycloalk), for which: Alk represents an alkyl radical, Cycloalk represents a cycloalkyl radical, i is equal to 0 or 1; as well as the salts of such products with an organic or mineral acid. According to an even more advantageous aspect, the present invention relates to the products of the general formula (IX) in which: R represents a radical - (Alk) i- (Cycloalk), for which: Alk represents a radical methyl, Cycloalk represents a cyclohexyl radical, i is equal to 0 or 1; as well as its salts with an organic or mineral acid. More advantageously, the products according to the present invention can be chosen individually from: 4,4 '-0,0-dicyclohexyl-2 - [(1R, 2S, 3R) (1,2,3,4-tetrahydroxybutyl)] -5 - [(2'S, 3'R) (2 ', 3', 4 # - trihydroxybutyl) Jpyrazine 4,4 '-0, 0-di (cyclohexyl-acetyl) -2- [(IR, 2S, 3R) (1,2,3,4-tetrahydroxybutyl)] - 5 - [(2'S, 3'R) (2 ', 3', 4'-trihydroxybutyl) Jpyrazine as well as its salts with a mineral or organic acid. In particular: 4,4'-0,0-dicyclohexyl-2 - [(1R, 2S, 3R) (1,2,3,4-tetrahydroxybutyl)] - 5 - [(2'S, 3'R) (2 ' , 3 ', 4' - trihydroxybutyl) Jpyrazine as well as its salts with mineral or organic acid.

According to the present invention, the products of the general formula (I), in which R is defined as above, can be obtained from the products of the general formula: in which: Rii represents the stereoisomeric forms of the chain - (CHOH) 3-CH2OH (XI) and either Ri2 represents a hydrogen atom and Ri3 represents the stereoisomeric forms -CH2- (CHOH) 2-CH2OH (XII) or Ri2 represents the stereoisomeric forms of the chains - (CHOH) 3-CH2OH (XI) or -CH2- (CHOH) 2-CH2OH (XII) and R3 represents a hydrogen atom, by the action of a corresponding acyl halide , of the formula R-COX, in which R is as defined above and X represents a halogen atom such as chlorine. This reaction is carried out in the presence of an organic or mineral base, preferably pyridine, at temperatures between 0 and 40 ° C. In acyl halide of the formula R-COX in which R is as defined above and X represents a halogen atom, such as chlorine, it can be commercially available or optionally prepared from the corresponding acid R-COOH, according to usual methods, especially acyl chloride can be prepared from the corresponding acid, by the action of oxalyl chloride, in a solvent such as dichloromethane, N, N-dimethylformamide, or a mixture of these two solvents. Advantageously, the acyl halide can be prepared in situ. The products of the general formula (X) can be prepared in the following manner: The stereoisomeric forms of the products of the general formula (X) are obtained from the stereoisomeric forms of the reagents mentioned below, used by the process of Preparation according to the invention. The stereoisomers of the products of the formula (X) for which Rii represents the stereoisomeric forms of the chain - (CHOH) 3-CH2OH (XI), Ri2 represents a hydrogen atom and Ri3 represents the stereoisomeric forms of the -CH2 chain - (CHOH) 2-CH2OH (XII) can be obtained by reaction of the ammonium formate on an aldose, or a mixture of 2 aldoses, dextrorotatory or levorotatory series of the general formula: in which Rii has the same meaning as in the formula (X). This reaction can be carried out preferably at a temperature comprised between 15 ° C and 100 ° C, preferably in an aqueous medium. Aldoses are marketed or can be obtained from: a) commercially available aldoses: - by epimerization reactions by application or adaptation of the methods described in Adv. Carbohydr.

Chem., 13, 63, (1958) mainly in basic medium by means of a dilute aqueous solution of soda (0.03 to 0.05%) at a temperature comprised between 20 and 40 ° C, by means of chain elongation reactions by application or adaptation of the methods described in "The Carbohydrats", editors: W. Pigman and D. Horton, Academic Press, New York, Volume IA, 133 (1972) and mainly forming the cyanohydrin of the starting aldose (for example by the action of the sodium cyanide in aqueous solution, at a temperature comprised between 10 and 30 ° C and in the presence of soda, at a pH close to 9) after hydrolysis of the functional group nitrile, thus formed, in the corresponding acid by means of the application or adaptation of the methods described in Organic Synthesis volume I page 436 and volume III page 85 (for example with the help of hydrochloric acid or concentrated sulfuric acid, in aqueous solution, at a temperature between 20 ° C and the temp reflux erature of the reaction medium), then reduction of the carboxylic acid functional group in the corresponding aldehyde by application or adaptation of the methods described in J. Am. Chem. Soc. 71, 122 (1949) mainly with the aid of a borohydride of an alkali metal (sodium borohydride for example), in aqueous solution at a temperature between 20 ° C and the boiling temperature of the reaction medium, - by chain shortening reactions by application or adaptation of the methods described in "The Carbohydrates", editors: W. Pigman and D. Horton, Academix Press, New-York, Volume IB, 1980, page 929 or Chem. See ., 83 ,. 559 (1950) and mainly transforming the aldehyde functional group of the aldose into corresponding hydroxylamine by applying or adapting the methods described in Organic Synthesis volume II page 314 (for example with the help of hydroxylamine hydrochloride, in aqueous solution and in the presence of a base such as sodium carbonate, at a temperature comprised between 20 and 50 ° C), then the action of 3,4-dinitrofluorobenzene in the presence of carbon dioxide and of a base such as sodium hydrogen carbonate in aqueous solution and of an aliphatic alcohol (isopropyl alcohol for example), at a temperature between 50 and 80 ° C, b) corresponding allylic alcohols by applying or adapting the methods described in Science, 220, 949 (1983) and mainly with the aid of terbutyl hydroxyperoxide in the presence of a titanium (IV) complex such as the titanium (IV) isopropylate complex and dialkyl optic tartrate pure mind (diethyl tartrate for example), followed by the successive action of thiophenolate sodium, parachloroperbenzoic acid in acetic anhydride and in diisopropylaluminum hydride. The stereoisomers of sugar of the formula (XIII) can be those of the aldoses with 6 carbon atoms; those used preferably are D-glucose, D-gulose, D-mannose, D-galactose, D-allose, D-altrose, D-idosa, D-talose, L-glucose, L-mannose, L-galactose, L-alose, L-altrose, L-idosa, L-talose, L-gulose. The stereoisomers of the products of the formula (X) for which Rii represents the stereoisomeric forms of the chain - (CHOH) 3-CH2OH (XI), Ri2 represents the stereoisomeric forms of the chain (CHOH) 3-CH2OH (XI) and Ri3 represents a hydrogen atom, can be obtained by treatment in basic medium of an amino-aldose, or of a mixture of 2 amino-aldoses of the general formula: optionally in the form of addition salt, such as the hydrochloride, in which Rix has the same meaning as the general formula (X). Preferably, it is operated at a temperature close to 20 ° C and a solution of ammonia, and more particularly a 28% solution, is preferably used.

The amino-aldoses of the formula (XIV) are marketed or can be prepared by applying or adapting the methods described for example in: (a) Methods Carbohydr. Chem., 7, 29 (1976) which consist of transforming the aldehyde functional group of the corresponding aldose into a nitroethylene group with the help of nitromethane in basic medium (sodium ethylate for example) then treating the product obtained successively by means of a solution saturated with ammonia, at a temperature between 20 ° C and 30 ° C, by Ba (OH) 2 in aqueous solution, at a temperature between 20 ° C and 30 ° C, and finally diluted sulfuric acid (10 to 15%) ), at a temperature between 20 ° C and 30 ° C, (b) "The Amino Sugar", editor: RW Jeanloz, Academic Press, New York, 1969, page 1 or "The Carbohydrates", editors: W. Pigman and D. Horton, Academic Press, New York, volume IB, 1980, page 664, which consists of transforming the aldehyde functional group of the corresponding aldose in an imino group from a primary aromatic amine (aniline for example), then reacting successively hydrocyanic acid, at a temperature between 0 ° C and 20 ° C and hydrogen in the presence of palladium in a solvent such as ether (tetrahydrofuran for example) or an aliphatic alcohol (ethanol or methanol for example) at a temperature comprised between 20 ° C and 50 ° C.

The stereoisomers of the amino-aldose of the formula (XIV) can be those of the amino-aldoses with 6 carbon atoms, such as D-glucosamine, D-galactosamine, L-glucosamine, L-galactosamine; those used preferentially are D-glucosamine, D-galactosamine and mainly D-glucosamine, optionally in the form of an addition salt such as the hydrochloride. The stereoisomers of the products of the formula (X) for which Rii represents the stereoisomeric forms of the chain - (CHOH) 3-CH2OH (XI), Ri2 represents the stereoisomeric forms of the -CH2- (CHOH) 2-CH2OH chains (XII) and Ri3 represents a hydrogen atom, can be obtained either from an aminoaldosa, or from a mixture of two aminoaldoses, of the general formula: CHO-CH (NH2) Ri? (XIV) In which Rii has the same meaning as in the general formula (I) in acid medium, and more particularly in acetic acid medium and preferably operating at a temperature comprised between 15 ° C and 100 ° C. or from a ketose, or a mixture of 2 ketoses of the general formula: HOCH2-CO-RÍ! (XV) wherein Rix has the same meaning as the formula (X), by the action of the ammonium formate and preferably operating at a temperature comprised between 15 ° C and 100 ° C, and preferably in an aqueous medium. The ketoses of the formula (XV) are marketed or can be prepared by applying or adapting the methods described for example in: a) Adv. Carbohydr. Che., 13, 63 (1958) which consists in reacting the corresponding aldose with either a base such as calcium hydroxide, soda, pyridine, quinoline, or with an acid such as a sulfuric acid, in aqueous solution or in pure phase, at a temperature between 20 and 50 ° C. b) Tetrahedron Asymmetry, 7 (8), 2185, (1996), J. Am. Chem; Soc, 118 (33), 7653 (1996), J. Org. Chem., 60 (13), 4294 (1995), Tetrahedron Lett., 33 (36), 5157 (1992), J. Am. Chem. Soc., 113 (17), 6678 (1991), Angew. Chem, 100 (5), 737, (1988), J. Org. Chem., 57, 5899 (1992) consisting, for example, of condensing either hydroxypuiruvaldehyde, 1,3-dihydroxyacetone, 1,3-dihydroxyacetone monophosphate or hydroxypyrubic acid onto a 2-hydroxy-substituted acetaldehyde in the 2-position. , optionally optically pure, in the presence optionally of an enzyme such as a transketolase. This reaction is generally carried out in an aqueous solution, at a temperature comprised between 20 and 50 ° C, optionally in the presence of a base (soda for example), barium chloride, magnesium chloride or zinc chloride. Derivatives that possess a 2-hydroxy-acetaldehyde group are commercialized or can be prepared from aldoses by applying or adapting the methods described in P. Collins, R. Ferrier, Monosaccharides, their Chemistry and their roles in Natural Products, editors J. Wiley (1995) M. Bols, Carbohydrate Building Blocks, editor J. Wiley (1996). The amino-aldoses of the formula (XIV) can be those of the aminoaldoses with 6 carbon atoms, such as D-glucosamine, D-galactosamine, L-glucosamine, L-galactosamine; those used preferentially are D-glucosamine, D-galactosamine, and especially D-glucosamine, optionally in the form of addition salt such as hydrochloride. The stereoisomers of the products of the formula (XV) can be those of the ketone with 6 carbon atoms; those used preferably are D-psychosa, D-fructose, D-sorbose, D-galactose, L-psycosa, L-fructose, L-sorbose, L-tagatose. The reaction mixtures obtained by the various methods described above are treated according to the classical physical methods (evaporation, extraction, distillation, chromatography, crystallization for example) or chemical (formation of salts for example). The products of the formula (I) can optionally be converted into addition salts, such as a mineral or organic acid, by the action of an acid of this type, in a solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. These salts also form part of the invention. As an example of pharmaceutically acceptable salts, the addition salts with the mineral or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophylline acetate, salicylate, methylene-bis-b- can be cited. oxinaftoato, hydrochloride, sulfate, nitrate and phosphate. The products of the formula (I) present interesting pharmacological properties. These are hypoglycemic. The hypoglycemic activity of the products of the formula (I) has been determined on the hypoglycemic response to glucose administration orally, in normoglycemic mice, according to the protocol described in example 3.

The products of the general formula (I) according to the invention have low toxicity. Its LD50 is higher than 2000 mg / kg orally in the mouse. In human therapy, these products are useful in the prevention and treatment of diabetes and mainly of type II diabetes (diabetes NID), diabetes of the obese, diabetes of the fifties, metapletoric diabetes, diabetes of the subject of advanced age and light diabetes These can be used as an adjunct to insulin therapy, in insulin-dependent diabetes, where they allow to progressively decrease the dose of insulin, unstable diabetes, insulin-resistant diabetes, in addition to hypoglycemic sulphonamides when these do not determine a sufficient lowering of blood glucose . These products can also be used in complications of diabetes such as hyperlipidemias, lipid metabolism problems, dyslipidemias, obesity. These are also useful in the prevention and treatment of atherosclerotic lesions and their complications (coronopathies, myocardial infarctions, cadiomyopathies, evolution of these three complications towards left ventricular failure, diverse arteriopathies, arteritis of the lower limbs with claudication or lameness, and evolution towards ulcers and gangrene, cerebral vascular insufficiency and its complications, vascular impotence of vascular origin), diabetic retinopathy and all its manifestations (increased capillary permeability, dilatation and capillary thrombosis, microaneurysms, aretriovenous deviation, venous dilatation, punctate hemorrhages and macular, exudates, macular edema, manifestations of proliferating retinopathy: neovessels, proliferative retinitis scars, hemorrhage of the vitreous body, detachment of the retina), diabetic cataracts, diabetic neuropathy in its different forms (peripheral polyneuropathies and their atherosclerosis, hyperesthesias and pains, mononeuropathies, radiculopathies, autonomic neuropathies, diabetic amyotrophies), diabetic foot manifestations (ulcers of the lower extremities and foot), diabetic nephropathy in its two forms, diffuse and modular, atheromatosis (elevation of HDL lipoprotein that favors the elimination of cholesterol from atherosclerotic plaques, decreased LDL lipoproteins, decreased LDL / HDL ratio, inhibition of LDL oxidation, decreased platelet adhesiveness), hyperlipemia and dyslipidemia (hypercholesterolemia, hypertriglyceridemia, normalization of the proportion of fatty acids, normalization of uricemia, normalization of apoproteins A and B), cataracts, high blood pressure and its consequences. The medicaments according to the invention are constituted by a product according to the invention or a combination of those products, in pure form or in the form of a composition in which this is associated with any other pharmaceutically compatible product, and may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically. As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, sacks) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or several inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (fillers) or a varnish. As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol can be used., vegetable oils or paraffin oil. These compositions may comprise substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers. Sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or different suitable organic solvents can be used. These compositions may also contain adjuvants, in particular wetting agents, isotonizing agents, emulsifiers, dispersants and stabilizers. The sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. These can also be prepared in the form of sterile solid compositions which can be dissolved at the time of their use in sterile water or in any other sterile injectable medium. Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols. The compositions for topical administration can be for example creams, lotions, collides, mouthwashes, nasal drops or aerosols. Doses depend on the effect sought, the duration of treatment and the route of administration used; these are generally between 150 mg and 600 mg per day, by the oral route for an adult with unit doses ranging from 50 mg to 200 mg of active substance. In general, the doctor will determine the appropriate physiology according to age, weight and all other factors specific to the subject to be treated. The following example 4 illustrates the compositions according to the invention. The invention also relates to the use of the products of the general formula (I) for the preparation of the pharmaceutical compositions, useful for the treatment and / or prevention of diabetes and the complications of diabetes. The following examples illustrate more particularly and not in a limiting manner the preparation method used according to the invention. This forms part of the general knowledge of the expert in the field to apply or adapt these methods in order to implement the invention.

Example 1 4 / 4'-0,0-dicyclohexyl-2 - [(1R, 2S, 3R) (1,2,3,4-tetrahydroxybutyl)] - 5 - [(2'S 3'R) (2 ', 3, 4 '-trihydroxybutyl) Jpyrazine To 300 mg of -2- [(IR, 2S, 3R) (1,2,3,4-tetrahydroxybutyl) J-5 - [(2'S, 3'R) (2 ', 3', 4 '-trihydroxybutyl) Jpirazin in suspension, in 7.5 cm3 of pyridine dried on molecular sieve of 4Á is added, drop by drop, at a temperature close to 20 ° C under an argon atmosphere, 0.328 cm3 of cyclohexanoyl chloride. The white reaction suspension is stirred for 15 hours at a temperature close to 20 ° C. The reaction medium is diluted with 30 cm3 of ethyl acetate and 30 cm3 of distilled water. After decanting, the organic phase is washed with 20 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered on sintered glass and then concentrated to dryness under reduced pressure (0.2 kPa) at room temperature. temperature close to 40 ° C. A yellow oil is obtained which is purified by preparative chromatography on 4 plates of 60F254 silica gel from Merck (thickness = 0.5 mm, 20x20 cm) eluting with a mixture of dichloromethane-methane (90-10 by volume). The fractions that do not contain the desired products are extracted by a mixture of dichloromethane-methanol (80-20 by volume), filtered on sintered glass and then concentrated to dryness under reduced pressure (0.5 kPa) at a temperature close to 40 ° C. They are obtained in this way 23.3. 4,4'-O, O-dicyclohexyloyl-2 - [(1R, 2S, 3R) (1,2,3,4-tetrahydroxybutyl) J 5- [(2 'S, 3'R) (2') mg , 3 ', 4' -trihydroxybutyl) Jpyrazine in the form of a white solid. The obtained product possesses the following characteristics: Spectrum of R.M.N. XH (400 MHz, (CD3) 2SO D6, d in ppm): from 1.10 to 1.95 (mt, 20H in total: CH2 cyclohexyl); 2.34 (mt, 2H: OCOCH); 2.76 and 3.12 (2 dd, respectively J = 14 and 10 Hz and J = 14 and 3 Hz, 1H each: CH2 5a); from 3.50 to 3.65 (mt, 1H: CH 5?); 3.60 (broad t, J = 8.5 Hz, 1H: CH 2ß); 3.78 (mt, 1H: CH 5β); 3.86 (mt, 1H: CH 2?); from 3.95 to 4.05 (mt, 2H: 1H of CH20 5d and 1H of CH20 2d); 4.24 (dd, J = 11 and 3 Hz, 1H: the other H of CH205d); 4.30 (dd, J = 12 and 2.5 Hz, 1H: the other H of CH202d); 4.63 (d, J = 8.5 Hz, 1H: OH in 2β); 4.86 (d, J = 7 Hz, 1H: OH in 5β); 4.97 '(broad d, J = 6.5 Hz, 1H: CH 2a); 5.05 (d, J = 6 Hz, 1H: OH in 2y); 5.11 (d, = 6 Hz, 1H: OH in 5); 5.40 (d, J = 6.5 Hz, 1H: OH in 2a): 8.43 (broad s, 1H: = CH in 6); 8.67 (broad s, 1H: = CH in 3). The 2 - [(1R, 2S, R) (1, 2, 3, 4-tetrahydroxybutyl)] -5 - [(2'S, 3'R) (2 ', 3', '-trihydroxybutyl) Jpyrazine can be prepared to Starting from D-glucosamine, in the presence of an acetic acid, or even by applying or adapting the methods described in Advances in Carbohydrate Chemistry and Biochemistry, Academic Press, New York, vol. 25, 1970, 311-349.

Example 2 4, '-O, O-di (cyclohexylacetyl) -2- [(IR, 2S, 3R) (1,2,3,4-tetrahydroxybutyl)] 5 - [(2'S, 3'R) (2' , 3 ', 4'-trihydroxybutyl) Jpyrazine To 350 mg of cyclohexane-acetic acid in 2 cm 3 of dry dichloromethane on molecular sieve of 4 A are added, dropwise, at a temperature close to 20 ° C under an argon atmosphere, 0.26 cm 3 of oxalyl chloride. The reaction mixture is stirred at a temperature close to 20 ° C for 1 hour, around which time the initial gas evolution is triggered. To 300 mg of 2- [(IR, 2S, 3R) (1,2,3,4-tetrahydroxybutyl)] 5 - [(2'S, 3'R) (2 ', 3', 4'-trihydroxybutyl) Jpyrazine in suspension, in 7.5 cm3 of dry pyridine on molecular sieve of 4A, the acid chloride solution previously prepared is added dropwise at a temperature close to 20 ° C under argon atmosphere. The white reaction suspension is stirred for 17 hours at a temperature close to 20 ° C. The reaction medium is partially concentrated under air flow at a temperature close to 20 ° C, then purified by preparative chromatography on 4 plates of 60F254 Merck silica gel (thickness = 0.5 mm, 20x20 cm) eluting with a dichloromethane mixture -methanol (20-10 in volumes). The fractions that do not contain the desired products are extracted with a mixture of dichloromethane-methanol (80-20 volumes), filtered on sintered glass, then concentrated to dryness under reduced pressure (0.5 kPa) at a temperature close to 40 ° C. 31.5 mg of 4,4 '-0,0-di (cyclohexyl-acetyl) -2 - [(1R, 2S, 3R) (1,2,3,4-tetrahydroxybutyl)] - 5- [ (2'S, 3'R) (2 ', 3', 4 '-trihydroxybutyl) Jpyrazine in the form of a white solid. The obtained product possesses the following characteristics: Spectrum of R.M.N. XH (400 MHz, (CD3) 2SO D6, d in ppm): from 0.85 to 1.80 (mt, 22H in total: CH in CH2 cyclohexyl); 2.20 (mt, 4H: OCOCH2); 2.76 and 3.13 (2 dd, respectively J = 14 and 10 Hz and J = 14 and 3 Hz, 1H each: CH2 5a); from 3.50 to 3.65 (mt, 1H: CH 5?); 3.60 (broad t, J = 8.5 Hz, 1H: CH 2ß); 3.78 (mt, 1H: CH 5β); 3.86 (mt, 1H: CH 2?); from 3.95 to 4.10 (mt, 2H: 1H of CH20 5d and 1H of CH20 2d); 4.25 (dd, J = 11 and 3 Hz, 1H: the other H of CH20 5d); 4.30 (dd, J = 12 and 2.5 Hz, 1H: the other H CH20 2d); 4.62 (dd J = 8.5 Hz, 1H: OH in 2β); 4.62 (d, J = 8.5 Hz, 1H: OH2 in 2β); 4.86 (d, J = 7 Hz, 1H: CH 5β); 4.96 (broad d, J = 6.5 Hz, 1H: OH 2a); 5.05 (d J = 6 Hz, 1H: OH in 2?); 5.11 (d, J = 6.5 Hz, 1H: OH in 5?): 5.41 (d, J = 6.5 Hz, 1H: OH 2a); 8.43 (d, J = 1 Hz, 1H: = CH in 6); 8.67 (broad s, 1H: = CH in 3). The 2 - [(1R, 2S, 3R) (1, 2, 3, 4-tetrahydroxybutyl)] 5 - [(2'S, 3 'R) (2', 3 ', 4' -trihydroxybutyl) J-pyrazine can be prepared from D-glucosamine, in the presence of acetic acid, or even by application or adaptation of the methods described in Advances in Carbohydrate Chemistry and Biochemistry, Academic Press, New York, vol. 25, 1970, 311-349.

Example 3 Swiss albino mice weighing between 22 and 26 grams are fasted for 2 hours. At the end of this period, the blood glucose is measured, and immediately afterwards, a dose of glucose (2 g / kg) is administered orally. 30 minutes later, the glycemia is measured once more. Mice responding to a hyperglycemia greater than 170 mg / dL are selected and used to detect the hypoglycaemic activity of the products according to the invention. The mice thus chosen are divided into groups of at least 10 animals. The different groups receive doses of 3 to 50 mg / kg of product, in a vehicle such as water or a mixture of methylcellulose / tween and water, once a day by gastric intubation. The treatment lasts 4 days. On the fourth day, after the last treatment, the animals receive a dose of glucose (2 g / kg) and the blood glucose is measured 20 to 40 minutes later. The percentage of inhibition of the hyperglycemic response to glucose administration is calculated in relation to the response measured in the group treated by the vehicle. In this test, the products according to the invention have a percentage of inhibition of glycemia greater than or equal to 10%.

A comparative test according to the protocol described above has been tested with the product of example 1 according to the present invention and the reference product 2- (1, 2, 3, 4-tetrahydroxybutyl) -5- (2 ', 3 ', 4' -trihydroxybutyl) J-pyrazine whose antidiabetic activity has been described in the application WO 97/28813: The results obtained after an administration of 3 mg / kg demonstrate the relative activity of 149% of the product of example 1 in relation to to the reference product.

Example 4 EXAMPLE 4A Capsules dosed to 50 mg of active compound having the following composition are prepared according to the usual technique: - Active product 50 mg Cellulose 18 mg Lactose 55 mg Colloidal silica 1 mg Carboxymethylstarch sodium 10 mg - Talc 10 mg Magnesium stearate 1 mg EXAMPLE 4B They are prepared according to the usual technique, tablets dosed to 50 mg of active product having the following composition: Active product 50 mg - Lactose 104mg Cellulose 40 mg Polividona 10 mg Carboxymethylstarch sodium 22 mg - Talc 10 mg - Magnesium stearate 2 mg Colloidal silica 2 mg Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3.5-24.5) c.b.p. 1 tablet in finished film at 245 mg EXAMPLE 4C An injectable solution containing 50 mg of active compound is prepared, having the following composition: Active product 50 mg - Benzoic acid 80 mg - Benzyl alcohol 0.06 ml Sodium Benzoate 80 mg - 95% Ethanol 0.4 ml Sodium hydroxide 24 mg Propylene glycol 1.6 ml - Water c.b.p. 4 ml It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (11)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The products of the general formula in which: Ri represents the stereoisomeric forms of the chain

- (CHOH) 3-CH2-0-COR (II) or R2 represents a hydrogen atom and R3 represents the stereoisomeric forms of the chain

-CH2- (CHOH) 2-CH2-0-COR (IIi; or R2 represents the stereoisomeric forms of the chains

- (CHOH) 3-CH2-0-COR (II) or -CH2- (CHOH) 2-CH2-0-COR (III) and R3 represents a hydrogen atom and R represents a radical - (Alk) ± - (Cycloalk), for which: Alk designates an alkyl radical, Cycloalk designates a cycloalkyl radical, i is equal to 0 or 1; as well as their stereoisomeric forms, and their salts with a mineral or organic acid. 2. The products according to claim 1, of the general formulas: characterized in that R represents a radical - (Alk) - (Cycloalk), for which: Alk represents an alkyl radical, Cycloalk represents a cycloalkyl radical, i is equal to 0 or 1; as well as their stereoisomeric forms, or the salts of such products with an organic or mineral acid. 3. The products according to any of the preceding claims of the general formula: characterized in that R represents a radical - (Alk) x- (Cicloalk), for which: Alk represents an alkyl radical, Cycloalk represents a cycloalkyl radical, i is equal to 0 or 1; as well as the salts of such products as an organic or mineral acid. 4. The products according to any of the preceding claims of the general formula: characterized in that R represents a radical - (Alk), - (Cycloalk), for which: Alk represents an alkyl radical, Cycloalk represents a cycloalkyl radical, i is equal to 0 1 1; as well as its salts with an organic or mineral acid.

5. The products according to any of the preceding claims characterized in that: R represents a radical - (Alk)! - (Cycloalk), for which: Alk represents a methyl radical Cycloalk represents a cyclohexyl radical, i is equal to 0 1; as well as its salts with an organic or mineral acid.

6. The products according to any of the preceding claims, chosen individually from: 4, 4'-0,0-dicyclohexyl-2 - [(1R, 2S, 3R) (1,2,3,4-tetrahydroxylbutyl)] -5 - [(2'S, 3'R) (2 ', 3', 4'-trihydroxybutyl) J-pyrazine 4,4'-0,0-di (cyclohexyl-acetyl) -2 - [(1R, 2S, 3R) (1,2,3,4-tetrahydroxylbutyl) J-5 - [(2'S, 3'R) (2 ', 3', 4'-trihydroxybutyl) Jpyrazine as well as their salts with a mineral or organic acid.

7. 4,4'-0,0-Dicyclohexyl-2 - [(1R, 2S, 3R) (1, 2,3,4-tetrahydroxybutyl)] - 5 - [(2'S, 3'R) (2 ', 3 ', 4'-trihydroxybutyl) J-pyrazine as well as its salts with a mineral or organic acid.

8. The process for preparing the products according to any of the preceding claims, characterized in that the products of the general formula are obtained: in which: Rii represents the stereoisomeric forms of the chain - (CHOH) 3-CH2OH (XI or Ri2 represents a hydrogen atom and Ri3 represents the stereoisomeric forms -CH2- (CHOH) 2-CH2OH (???: or Ri2 represents the stereoisomeric forms of the chains - (CHOH) 3-CH2OH (XI) or -CH2- (CHOH) 2-CH2OH (XII) and R3 represents a hydrogen atom, by the action of a corresponding acyl halide, of the formula R-COX, in which R is as defined in claims 1 to 7 and X represents a halogen atom.

9. The process according to claim 8, characterized in that the reaction is carried out in the presence of pyridine, temperatures comprised between 0 and 40 ° C.

10. Medicaments, characterized in that they contain as active principle one or several active products according to any of claims 1 to 7 and one or more excipients.

11. The use of the products according to any of claims 1 to 7, for the preparation of a medicament for the prevention and / or treatment of diabetes and the complications of diabetes. NOVEDOSOS DERIVED FROM POLYHYDROXYPYRAZINES, ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM SUMMARY OF THE INVENTION The novel derivatives of the formula (I) are described, in which: Ri represents the stereoisomeric forms of the chain - (CHOH) 3-CH2-0-COR (II) and whether R2 represents a hydrogen atom and R3 represents the stereoisomeric forms of the chain -CH2- (CHOH); - CH2-0-COR (III) or R2 represents the stereoisomeric forms of the chain - (CHOH) 3-CH2-0-COR (II) or -CH2- (CHOH) 2-CH2-0-COR (III) and R represents a hydrogen atom, - i- * and R represents a radical - (Alk) - (Cycloalk); i is equal to 0 or 1; Alk represents an alkyl radical, Cycloalk represents a cycloalkyl radical, and / or its salts with a mineral or organic acid, its preparation and the medicaments containing as active principle at least one product of the general formula (I) or its salts with a mineral or organic acid. 10