WO1999003838A1

WO1999003838A1 - 2-(1,2,3,4-tetrahydroxybutyl)pyrazine derivatives, preparation and medicines containing them

Info

Publication number: WO1999003838A1
Application number: PCT/FR1998/001539
Authority: WO
Inventors: Georges Bashiardes; Jean-Christophe Carry; Michel Evers; Bruno Filoche; Serge Mignani
Original assignee: Rhone-Poulenc Rorer S.A.
Priority date: 1997-07-17
Filing date: 1998-07-15
Publication date: 1999-01-28
Also published as: FR2766180A1; ZA986328B; AU8735898A

Abstract

The invention concerns medicines containing as active principle at least one 2-(1,2,3,4-tetrahydroxybutyl)pyrazine derivative of formula (I) in which: R1 and R2, identical or different, represent (a) a hydrogen atom, (b) an alkyl radical, (c) a phenyl radical, (d) a phenyl radical substituted by one or several substituents selected among hydroxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, (e) a phenylalkyl radical or (f) a phenylalkyl radical whereof the phenyl is substituted by one or several substituents selected among hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino or one of its stereoisomers or one of its salts, the novel compounds of formula (I), their stereoisomers and the salts and the method for preparing them.

Description

DERIVATIVES OF 2- (1,2,3,4-TETRAHYDR0XYBUTYL) PYRAZINE, THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM

The present invention relates to medicaments containing as active ingredient at least one 2-0, 2,3,4-tetrahydroxybutyDpyrazine derivative of formula:

or one of its stereoisomers or one of its salts with a mineral or organic acid, the new compounds of formula (I), their stereoisomers and their salts with a mineral or organic acid and their preparation.

In formula (I), Ri and R ₂ , identical or different, represent (a) a hydrogen atom, (b) an alkyl radical, (c) a phenyl radical, (d) a phenyl radical substituted by one or several substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, (e) a phenylalkyl radical or (f) a phenylalkyl radical in which the phenyl is substituted by one or more substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl , amino, monoalkylamino and dialkylamino.

In the definitions above and those which follow, the alkyl and alkoxy radicals and portions contain 1 to 6 carbon atoms in a straight or branched chain.

The preferred compounds of formula (I) serving as active ingredient in the medicaments according to the invention are the following: - (1,2,3,4-tetrahydroxy-butyl) -pyrazin-2-yl, - (1, 2 , 3 ₎ 4-tetrahydroxy-butyl) -2,3-dimethylpyrazin-5-yl, - (1,2,3,4-tetrahydroxy-butyl) -2-methylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -3-methylpyrazin-5-yl,

- (1, 2 ₎ 3,4-tetrahydroxy-butyl) -2,3-diphenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2-phenylpyrazin-5-yl, - (1,2,3,4-tetrahydroxy-butyl) -3-phenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2,3-dibenzylpyrazin-5-yle ₍

- (1,2,3,4-tetrahydroxy-butyl) -2-benzylpyrazin-5-yle _J

- (1,2,3,4-tetrahydroxy-butyl) -3-benzyipyrazin-5-yle,

- (1,2,3,4-tetrahydroxy-butyl) -2-methyl-3-phenylpyrazin-5-yl, - (1,2,3,4-tetrahydroxy-butyl) -3-methyl-2-phenylpyrazin- 5-yle,

- (1,2,3,4-tetrahydroxy-butyl) -2-methyl-3-benzylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -3-methyl-2-benzylpyrazin-5-yl, their stereoisomers and their salts with a mineral or organic acid.

More particularly preferred, the compounds of formula (I) serving as active ingredient in the medicaments according to the invention are the following:

- (1 R, 2R, 3R, 4-tetrahydroxy-butyl) -pyrazin-2-yle,

- (1 R, 2R, 3S, 4-tetrahydroxy-butyl) -pyrazin-2-yle,

- (1 R, 2S, 3R, 4-tetrahydroxy-butyl) -pyrazin-2-yle,

- (1 R, 2S, 3S, 4-tetrahydroxy-butyl) -pyrazin-2-yle, - OS, 2R _I 3R, 4-tetrahydroxy-butyl) -pyrazin-2-yle _I

- (1 S, 2R, 3S ₎ 4-tetrahydroxy-butyl) -pyrazin-2-yle,

- (1 S, 2S, 3R, 4-tetrahydroxy-butyl) -pyrazin-2-yle,

- (1 S, 2S, 3S, 4-tetrahydroxy-butyl) -pyrazin-2-yl and their salts with a mineral or organic acid.

The compounds of formula (I) for which Ri and R ₂ each represent a hydrogen atom or else Ri represents a methyl radical and R ₂ represents a hydrogen atom or else R ₂ represents a methyl radical and R _T represents an atom of hydrogen are known (J. Org. Chem., 34, 3842 (1969); J. Org. Chem., 37, 2635 (1972); Nippon Shokuhin Kogyo Gakkaishi, 37, 154-161 (1990)) but no pharmacological properties are described for these.

The compounds of formula (I) for which Ri and R ₂ , identical or different, represent (a) a hydrogen atom, (b) an alkyl radical, (c) a phenyl radical, (d) a phenyl radical substituted by one or more substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, (e) a phenylalkyl radical or (f) a phenylalkyl radical in which the phenyl is substituted by one or more substituents chosen from hydroxy, alkoxy, carboxy , alkoxycarbonyl, amino, monoalkylamino and dialkylamino, with the exception of those for which Ri and R ₂ each represent a hydrogen atom or else Ri represents a methyl radical and R ₂ represents a hydrogen atom or else R ₂ represents a methyl radical and R 1 represents a hydrogen atom, their stereoisomers and their salts with a mineral or organic acid are new and form part of the invention as such.

The compounds of formula (I) have asymmetric carbon atoms and have stereoisomeric forms. These are part of the invention.

The compounds of formula (I) can be prepared by reduction of a derivative of formula:

or one of its stereoisomers in which Ri and R ₂ have the same meanings as above. This reduction is generally carried out by means of hydrogen, in the presence of a hydrogenation catalyst (palladium on carbon for example), in an inert solvent such as an aliphatic alcohol (methanol for example), at a temperature between 0 ° C and 80 ° C. The derivatives of formula (II) for which R- _\ and R ₂ , identical or different, represent (a) a hydrogen atom, (b) an alkyl radical, (c) a phenyl radical, (d) a phenyl radical substituted by one or more substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, (e) a phenylalkyl radical or (f) a phenylalkyl radical in which the phenyl is substituted by one or more substituents chosen from hydroxy, alkoxy , carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, with the exception of those for which Ri and R ₂ each represent a hydrogen atom or a methyl or phenyl radical or else Ri represents a methyl or phenyl radical and R ₂ represents a hydrogen atom or else R ₂ represents a methyl or phenyl radical and Ri represents a hydrogen atom and their stereoisomers are new and as such form part of the invention.

The derivatives of formula (II) and their stereoisomers can be obtained by the action of a derivative of formula HON = CH-CH (NH ₂ ) - (CHOH) ₃ -CH ₂ OH or one of its stereoisomers on a derivative R ₁ - CO-CO-R ₂ for which Ri and R ₂ have the same meanings as in formula (I).

This reaction is generally carried out in an inert solvent such as water, or an aliphatic alcohol (methanol for example) or a mixture of the two, at a temperature between 5 ° C. and the boiling point of reaction medium.

The derivatives of formula R ₁ CO-CO-R ₂ are marketed or can be obtained by application or adaptation of the methods described by F. Weygand et al., Chem. Ber., 90, 1230 (1957); H. Gopal et al., Tetrahedron Lett., 2941 (1971); H. Mόhrle et al., Chem. Ber., 104, 2475 (1971), E. Biehl et al., J. Org. Chem., 37, 135N 0972); Nudelman et al., J. Org. Chem., 47, 4347 (1982); Leyendecker et al., Tetrahedron Lett., 24, 2375 (1983); J. Souppe et al., Tetrahedron Lett., 25, 2869 (1984); MC Carre et al., Tetrahedron Lett., 26, 3103 (1985); K. Shudo et al., J. Am. Chem. Soc, 110, 1862 (1988); R. Zibuck et al., Helv. Chim. Acta, 71, 237P (1988); Bulman Page et al., Tetrahedron Lett., 48, 7265 (1992). Preferably, they are obtained by oxidation of the corresponding alkyne, by means of ruthenium oxide, in an inert solvent such as carbon tetrachloride, or else by oxidation of methylated ketones such as alkyl methyl ketones and aryl methyl ketones. using selenium dioxide, in an inert solvent such as dioxane, or else by condensation of arylaldehydes in the presence of alkaline cyanide, in a solvent such as dimethylformamide then action of an acid followed by an oxidation reaction for example with thallium nitrate or else by alkylation of the anion deriving from a dithiane for example a 2-alkyl-1, 3-dithiane or a 2-aryl-1, 3-dithiane by a alkyl- or aryl-aldehyde then treatment with N-bromosuccinimide in solution in aqueous acetone.

The derivative of formula HON = CH-CH (NH ₂ ) - (CHOH) ₃ -CH ₂ OH and its stereoisomers can be obtained by the action of hydroxylamine on a derivative of formula O = CH-CH (NH ₂ ) - (CHOH ) ₃ -CH ₂ OH or one of its stereoisomers.

This reaction is generally carried out in an inert solvent such as water, an alcohol (methanol for example), pyridine or a mixture of these solvents, at a temperature between 0 ° C. and the temperature of boiling of the reaction medium. The amino aldose O = CH-CH (NH ₂ ) - (CHOH) ₃ -CH ₂ OH and its stereoisomers are commercially available or can be prepared by application or adaptation of the methods described for example in:

(a) Methods Carbohydr. Chem., 7, 29 (1976) which consist in transforming the aldehyde function of the corresponding aldose into a nitroethylenic group using nitromethane in basic medium (sodium ethylate for example) and then treating the product obtained successively with a saturated ammonia solution, at a temperature between 20 ° C and 30 ° C, with Ba (OH) ₂ in aqueous solution, at a temperature between 20 ° C and 30 ° C and finally dilute sulfuric acid (10 to 15%), at a temperature between 20 ° C and 30 ° C,

(b) "The Amino Sugar", editor: RW Jeanloz, Académie Press, New York, 1969, page 1 or "The Carbohydrates", editors: W. Pigman and D. Horton, Académie Press, New York, Volume IB , 1980, page 664 which consist in transforming the aldehyde function of the corresponding aldose into an imino group starting from an aromatic primary amine (aniline for example), then successively reacting hydrocyanic acid, at a temperature between 0 ° C and 20 ° C and hydrogen in the presence of palladium in a solvent such as an ether (tetrahydrofuran for example) or an aliphatic alcohol (ethanol or methanol for example), at a temperature between 20 ° C and 50 ° C.

Among the stereoisomers of the derivative O = CH-CH (NH ₂ ) - (CHOH) ₃ -CH ₂ OH, use is preferably made of D-allosamine, D-altrosamine, D-glucosamine, D-mannosamine, D-gulosamine and DHdosamine, D-galactosamine and D-talosamine.

The aldoses O = CH-CHOH- (CHOH) ₃ -CH ₂ OH and their stereoisomers 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) in particular in basic medium by means of a dilute aqueous solution of soda (0.03 to 0.05%), at a temperature between 20 and 40 ° C,

-by chain lengthening reactions by application or adaptation of the methods described in "The Carbohydrates", editors: W. Pigman and D. Horion, Académie Press, New York, Volume IA, 133 (1972) and in particular by forming the cyanohydrin of the starting aldose (for example by the action of sodium cyanide in aqueous solution, at a temperature between 10 and 30 ° C and in the presence of soda, at a pH close to 9) then hydrolysis of the nitrile function thus formed into the corresponding acid by application or adaptation of the methods described in Organic Synthesis volume I page 436 and volume III page 85 (for example using hydrochloric acid or concentrated sulfuric acid, in aqueous solution, at a temperature included between 20 ° C and the boiling temperature of the reaction medium), then reduction of the carboxylic acid function to the corresponding aldehyde by application or adaptation of the methods described in J. Am. Chem. Soc. 71, 122 (1949) in particular using an alkali metal borohydride (sodium borohydride for example), in aqueous solution at a temperature between 20 ° C. and the boiling point 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, Académie Press, New York, Volume IB, 1980, page 929 or Chem. Ber., 83, 559 (1950) and in particular by transforming the aldehyde function of the aldose into the corresponding hydroxylamine by application or adaptation of the methods described in Organic Synthesis volume II page 314 (for example using hydroxylamine hydrochloride, in aqueous solution and in the presence of a base such as sodium carbonate at a temperature between 20 and 50 ° C), then action of 3,4-dinitro - fluorobenzene in the presence of carbon dioxide and a base such as sodium hydrogencarbonate in aqueous solution and an aliphatic alcohol (isopropyl alcohol for example), at a temperature between 50 and 80 ° C,

b) corresponding allylic alcohols by application or adaptation of the methods described in Science, 220, 949 (1983) and in particular using terbutyl hydroperoxide in the presence of a titanium (IV) complex such as the isopropylate complex of titanium (IV) and optically pure dialkyl tartrate (diethyl tartrate for example), followed by the successive action of sodium thiophenolate, para-chloroperbenzoic acid in acetic anhydride and diisopropylaluminum hydride.

The stereoisomers of the compounds of formula (I) are prepared from the corresponding stereoisomers of the intermediates.

The reaction mixtures obtained by the various processes described above are treated according to conventional physical (evaporation, extraction, distillation, chromatography, crystallization, for example) or chemical (formation of salts, for example) methods.

The compounds of formula (I) can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, an ether or a solvent chlorine. These salts are also part of the invention.

As examples of pharmaceutically acceptable salts, there may be mentioned the addition salts with mineral or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, me- thanesulfonate, isethionate, theophyllinacetate, salicylate, methylene-bis-β- oxynaphtoate, hydrochloride, sulfate, nitrate and phosphate.

The preferred compounds of formula (I) are the following:

- (1,2,3,4-tetrahydroxy-butyl) -2,3-dimethylpyrazin-5-yl, - (1,2,3,4-tetrahydroxy-butyl) -2,3-diphenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2-phenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -3-phenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2,3-dibenzylpyrazin-5-yle,

- (1,2,3,4-tetrahydroxy-butyl) -2-benzylpyrazin-5-yle, - (1,2,3,4-tetrahydroxy-butyl) -3-benzylpyrazin-5-yl, their stereoisomers and their salts with a mineral or organic acid.

The following examples illustrate the invention:

Example 1:

To a suspension of 700 mg of palladium on carbon at 10% in 30 cm ³ of methanol, 2.7 g of (1 R, 2R, 3R, 4-tetrahydroxy-butyl) -4- oxidopyrazin-2-yl are added. . The reaction mixture is placed under a hydrogen atmosphere (190 kPa) and stirred for 60 hours, at a temperature in the region of 20 ° C. The reaction medium is filtered, then the filtrate is concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The yellow solid residue (1.2 g) is chromatographed on a silica column (0.02-0.045 mm), 3.5 cm in diameter, eluted with a 20% chloroform-methanol-ammonia mixture (24: 6 : 1 by volume) by collecting fractions of 50 cm ³ . The fractions containing the product are concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 120 mg of (1 R, 2R, 3R, 4-tetrahydroxy-butyl) -pyrazin-2-yl are thus obtained in the form of a white solid melting at a temperature of 168 ° C. [NMR spectrum ^" Η (250 MHz , (CD ₃ ) ₂ SO d6, δ in ppm): from 3.30 to 3.55 (mt, 1 H of CH ₂ 3δ); 3.63 (mt, 3H: the other H of CH ₂ 3δ - CH 3β and CH 3γ); 4.45 (wide t, J = 6 Hz, 1 H: OH in 3δ); 4.51 (d, J = 7.5 Hz, 1 H: OH); 4.78 ( d wide, J = 3.5 Hz, 1 H: OH); 5.00 (d, J = 6 Hz, 1 H: CH 3α); 5.48 (d, J = 6 Hz, 1 H: OH) ; 8.49 (d, J = 2.5 Hz, 1 H: = CH in 5); 8.55 (mt, 1 H: = CH in 6); 8.76 (s wide, 1 H: = CH in 2). La (1 R, 2R, 3R, 4-tétrahydroxy-butyl) -4-oxidopyrazin-2-yl can be prepared as follows: to a solution of 11 g of 2-amino-2-deoxy-D- glucose oxime in 21 cm ³ of distilled water, 6.40 cm ³ of a 40% aqueous solution of glyoxal in water are added in approximately 15 minutes. The reaction mixture is stirred for 20 h at a temperature in the region of 5 ° C. The solid formed is filtered and then dried under atmospheric pressure at a temperature in the region of 30 ° C. 2.7 g of (1 R, 2R, 3R, 4-tetrahydroxy-butyl) -4-oxidopyrazin-2-yl are thus obtained in the form of an orange solid [H NMR spectrum (400 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 3.45 (mt, 1 H: 1H of CH ₂ 3δ); 3.50 to 3.70 (mt, 3H: the other H of CH ₂ 3δ - CH 3β and CH 3γ); 4.40 (broad t, 1 H: OH in 3δ); 4.54 (d, J = 5.5 Hz, 1 H: OH); 4.70 (br s, 1H: OH); 4.92 (d, J = 4 Hz, 1 H: CH 3a); 5.48 (d, J = 5.5 Hz, 1 H: OH); 8.20 (mt, 2H: = CH in 6 and = CH in 2); 8.46 (d, J = 4 Hz, 1H: = CH in 5).

2-amino-2-deoxy-D-glucose oxime can be prepared as described by S. Fujii et al., J. Org. Chem. 34, 3842 (1969).

Example 2

By operating as in Example 1, but replacing the glyoxal with 4.80 g of 2,3-butanedione, we obtain the (1 R, 2R, 3R, 4-tetrahydroxy-butyl) -2 ₎ 3-dimethylpyrazin- 5-yle.

The compounds of formula (I) have interesting pharmacological properties. They are hypoglycemic agents.

The hypoglycaemic activity of the compounds of formula (I) was determined on the hyperglycemic response to the administration of glucose by the oral route in normoglycemic mice, according to the following protocol:

Swiss albino mice weighing between 22 and 26 g are left on an empty stomach for 2 hours. At the end of this period, blood sugar is measured and, immediately after, a dose of glucose (2 g / kg) is administered orally. Thirty minutes later, the blood sugar is measured again. The mice which respond with a hyperglycaemia greater than 170 mg / dl are selected and used to detect the hypoglycaemic activity of the compounds according to the invention.

The mice thus chosen are divided into groups of at least 10 animals. Separate groups receive a solution of 3 to 50 mg / kg of the test product in a vehicle such as water or a mixture of methylcellulose / tween and water or from the vehicle once a day by gastric tubing. The treatment lasts 4 days. The 4 ^th day after the last treatment, the animals receive a dose of glucose (2 g / kg) and the glycaemia is measured 20 to 40 minutes later. The percentage inhibition of the hyperglycemic response to glucose administration is calculated relative to the response measured in the group treated by the vehicle.

In this test, the compounds according to the invention have a percentage inhibition of blood sugar greater than or equal to 10%.

The compounds of general formula (I) according to the invention have low toxicity. Their LD50 is greater than 2000 mg / kg orally in mice.

In human therapy, these products are useful in the prevention and treatment of diabetes, and in particular of type II diabetes (diabetes PID), obese diabetes, fiftieth diabetes, metaplethoric diabetes, diabetes in the elderly. and mild diabetes. They can be used in addition to insulin therapy in insulin-dependent diabetes, where they make it possible to gradually decrease the dose of insulin, unstable diabetes, insulin-resistant diabetes, in addition to sulphonylureas when these do not determine sufficient drop of glycemia. These products can also be used in the complications of diabetes such as hyperlipemias, lipid metabolism disorders, dyslipemias, obesity. They are also useful in the prevention and treatment of atherosclerotic lesions and their complications (coronopathies, myocardial infarction, cardiomyopathies, evolution of these three complications towards left ventricular insufficiency, various arteriopathies, arteritis of the lower limbs with lameness and evolution towards ulcers and gangrene, cerebrovascular insufficiency and its complications, sexual impotence of vascular origin), diabetic retinopathy and all its manifestations (increase in capillary permeability, dilation and capillary thrombosis, microaneurysms, arteriovenous shunt, venous dilation, punctual and macular hemorrhages, exudates, macular edemas, manifestations of proliferative retinopathy: neovessels, proliferative retinitis scars, vitreous hemorrhages, retinal detachment), diabetic cataracts, diabetic neuropathy in its various forms (poly peripheral neuropathies and its manifestations such as paraesthesia, hyperesthesia and pain, mononeuropathies, radiculopathies, autonomic neuropathies, diabetic amyotrophies), manifestations of diabetic foot (ulcers of the lower extremities and foot), diabetic nephropathy in its diffuse and nodular forms, atheromatosis (elevation of HDL lipoproteins favoring the elimination of cholesterol from atheroma plaques, decrease in LDL lipoproteins, decrease in LDIJHDL ratio, inhibition of LDL oxidation, decrease in platelet adhesiveness), hyperlipemia and dyslipemias (hypercholesterolemia, hypertriglyceridemia, normalization of fatty acid levels, normalization of uricemia, normalization of apoproteins A and B), cataracts, hypertension and its consequences. The medicaments according to the invention consist of a compound according to the invention or a combination of these products, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which 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, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or the like, can be used. suitable organic solvents. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be do this in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The 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, eye drops, mouthwashes, nasal drops or aerosols.

The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 150 mg and 600 mg per day orally for an adult with unit doses ranging from 50 mg to 200 mg of active substance.

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.

The following examples illustrate compositions according to the invention:

EXAMPLE A

Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:

- Active product 50 mg

- Cellulose 18 mg - Lactose 55 mg

- Colloidal silica 1 mg

- Carboxymethyl starch sodium 10 mg - Talc 10 mg

- Magnesium stearate 1 mg

EXAMPLE B

Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:

- Active product 50 mg

- Lactose 104 mg

- Cellulose 40 mg

- Polyvidone 10 mg - Carboxymethyl starch 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) q.s.p. 1 film-coated tablet finished at 245 mg

EXAMPLE C

A solution for injection containing 50 mg of active product having the following composition is prepared:

- 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 q.s.p. 4 ml

The invention also relates to the use of the compounds of general formula (I) for the preparation of pharmaceutical compositions useful for the treatment or prevention of diabetes and the complications of diabetes.

Claims

1 - Drug containing as active ingredient at least one derivative of 2-0, 2,3,4-tetrahydrobutyOpyrazine of formula:

in which Ri and R ₂ , identical or different, represent (a) a hydrogen atom, (b) an alkyl radical, (c) a phenyl radical, (d) a phenyl radical substituted by one or more substituents chosen from hydroxy , alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, (e) a phenylalkyl radical or (f) a phenylalkyl radical in which the phenyl is substituted by one or more substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino it being understood that the radicals and alkyl and alkoxy portions contain 1 to 6 carbon atoms in a straight or branched chain or one of its stereoisomers or one of its salts with a mineral or organic acid.

2 - Medicines according to claim 1 containing as active ingredient at least one compound of formula (I) chosen from the following compounds:

- (1,2,3,4-tetrahydroxy-butyl) -pyrazin-2-yle,

- (1,2,3,4-tetrahydroxy-butyl) -2,3-dimethylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2-methylpyrazin-5-yl, - (1,2,3,4-tetrahydroxy-butyl) -3-methylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2,3-diphenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2-phenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -3-phenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2,3-dibenzylpyrazin-5-yle, - (1,2,3,4-tetrahydroxy-butyl) -2-benzylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -3-benzylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2-methyl-3-phenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -3-methyl-2-phenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2-methyl-3-benzylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -3-methyl-2-benzylpyrazin-5-yl,

or one of its stereoisomers or one of its salts with a mineral or organic acid.

3 - Medicines according to claim 1 containing as active ingredient a compound of formula (I) chosen i from the following compounds:

- (1 R, 2R, 3R, 4-tetrahydroxy-buty l) -pyrazin-2-yle,

- 0 R, 2R, 3S, 4-tetrahydroxy-buty l) -pyrazin-2-yle,

- (1R, 2S, 3R, 4-tetrahydroxy-butyl l) -pyrazin-2-yle,

- (1 R, 2S, 3S, 4-tetrahydroxy-buty l) -pyrazin-2-yle, - (1S, 2R, 3R, 4-tetrahydroxy-buty l) -pyrazin-2-yle,

- (1S, 2R, 3S, 4-tetrahydroxy-buty l) -pyrazin-2-yle,

- (1S, 2S, 3R, 4-tetrahydroxy-buty l) -pyrazin-2-yle,

- (1 S, 2S, 3S, 4-tetrahydroxy-butyl l) -pyrazin-2-yle

and one of its salts with a mineral or organic acid.

4 - Compounds of formula:

in which Ri and R ₂ , identical or different, represent (a) a hydrogen atom, (b) an alkyl radical, (c) a phenyl radical, (d) a radical phenyl substituted by one or more substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, (e) a phenylalkyl radical or (f) a phenylalkyl radical in which the phenyl is substituted by one or more substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, with the exception of those for which Ri and R ₂ each represent a hydrogen atom or else Ri represents a methyl radical and R ₂ represents a hydrogen atom or else R ₂ represents a methyl radical and Ri represents a hydrogen atom, their stereoisomers and their salts with a mineral or organic acid.

5 - Compounds according to claim 4 chosen from the following compounds:

- (1,2,3,4-tetrahydroxy-butyl) -2,3-dimethylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2,3-diphenylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -2,3-dibenzylpyrazin-5-yle,

- (1,2,3,4-tetrahydroxy-butyl) -2-benzylpyrazin-5-yl,

- (1,2,3,4-tetrahydroxy-butyl) -3-benzylpyrazin-5-yl,

their stereoisomers and their salts with a mineral or organic acid.

6- A process for preparing the compounds of formula (I) according to claim 4 characterized in that a derivative of formula is reduced:

or one of its stereoisomers in which Ri and R ₂ , identical or different, represent (a) a hydrogen atom, (b) an alkyl radical, (c) a phenyl radical, (d) a phenyl radical substituted by one or several substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, (e) a phenylalkyl radical or (f) a phenylalkyl radical in which the phenyl is substituted by one or more substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl , amino, monoalkylamino and dialkylamino, with the exception of those for which Ri and R ₂ each represent a hydrogen atom or else Ri represents a methyl radical and R ₂ represents a hydrogen atom or else R ₂ represents a methyl radical and R 1 represents a hydrogen atom, isolates the product and optionally transforms it into a salt with a mineral or organic acid.

7 - Compounds of formula:

in which Ri and R ₂ , identical or different, represent (a) a hydrogen atom, (b) an alkyl radical, (c) a phenyl radical, (d) a phenyl radical substituted by one or more substituents chosen from hydroxy , alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, (e) a phenylalkyl radical or (f) a phenylalkyl radical in which the phenyl is substituted by one or more substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, with the exception of those for which Ri and R ₂ each represent a hydrogen atom or a methyl or phenyl radical or else Ri represents a methyl or phenyl radical and R ₂ represents a hydrogen atom or else R ₂ represents a methyl or phenyl radical and Ri represents a hydrogen atom and their stereoisomers.

8 - Use of a compound of formula:

in which Ri and R ₂ , identical or different, represent (a) a hydrogen atom, (b) an alkyl radical, (c) a phenyl radical, (d) a phenyl radical substituted by one or more substituents chosen from hydroxy , alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, (e) a phenylalkyl radical or (f) a phenylalkyl radical in which the phenyl is substituted by one or more substituents chosen from hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino and dialkylamino, it being understood that the alkyl and alkoxy radicals and portions contain 1 to 6 carbon atoms in a straight or branched chain or one of its stereoisomers or one of its salts with a mineral or organic acid, for the preparation of pharmaceutical compositions useful for the treatment or diabetes prevention and diabetes complications.