FR2766186A1 - Treatment of diabetes, diabetic complications and related disorders - Google Patents

Abstract

Novel medicaments contain, as active agent, one or more of 2,6-di-(polyhydroxyalkyl)-pyrazine derivatives of formula (I) (or their stereoisomers or salts with mineral or organic acids). (i) R1 = -CH(Ra)-CHOH-CHOH-CH2OH and R2 = -CH2-CHOH-CHOH-CH2OH; (ii) R1 = -CHOH-CHF-CHOH-CH2OH and R2 = -CH2-CHF-CHOH-CH2OH; (iii) R1 = -CHOH-CHOH-CHOH-Rb and R2 = -CH2-CHOH-CHOH-Rb; (iv) R1 = -CH2-CHOH-CHOH-CH2OH and R2 = -CH2-CHOH-CHOH-CH2OH; or (v) R1,R2 = the same -(CHOH)n-CH2OH; n = 1-4; Ra = 1-6C alkoxy or F; Rb = -COOH, -CONH2 or -CH2NH2. Compounds (I) (including salts and stereoisomers) are new, apart from the compound of formula (I') and (I; R1,R2 = 1,2,3,4-tetrahydroxybutyl).

Description

DRUGS CONTAINING DERIVATIVES OF

  POLYHYDROXYALKYLPYRAZINE, THE NEW DERIVATIVES OF

  POLYHYDROXYALKYLPYRAZINE AND THEIR PREPARATION

  The present invention relates to medicaments containing as active principle at least one compound of formula:

R2 N R

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

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

  In the formula (I) R1 and R2 represent a chain - (CHOH) n-CH2OH in which n is equal to 1, 2, 3 or 4, The compounds of formula (I) comprising several asymmetric carbons, present stereoisomeric forms. These different stereoisomers make

part of the invention.

  In other words, the medicaments according to the invention contain at least one of the following compounds: 1- [6- (1,2-dihydroxy-ethyl) -pyrazin-2-yl] -ethane-1, 2-diol, 1- [ 6- (1,2,3-trihydroxy-propyl) -pyrazin-2-yl] -propane-1,2,3-triol, 1- [6- (1,2,3,4-tetrahydroxy-butyl) - pyrazin-2-yl] -butane-1,2,3,4- tetraol, 1- [6- (1,2,3,4,5-pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 , 2, 3,4,5-pentaol, or one of their stereoisomers or one of their salts with a mineral or organic acid. The preferred medicaments according to the invention are those which contain, as active ingredient, at least one compound of formula (I) chosen from: 1 - [6- (1 R, 2-Dihydroxy-ethyl) -pyrazin-2-yl] ethane- 1 R, 2-diol, 1 - [6- (1 S, 2-Dihydroxy-ethyl) -pyrazin-2-yl] -ethane-1 S, 2-diol, 1- [6- (1 R, 2R, 3-Trihydroxy-propyl) -pyrazin-2-yl] -propane-1 R, 2R, 3-triol, 1 - [6- (1 R, 2S, 3- Trihydroxy-propyl) -pyrazin-2-yl] - propane-1 R, 2S, 3-triol, 1- [6- (1 S, 2R, 3- Trihydroxy-propyl) -pyrazin-2-yl] -propane- 1S, 2R, 3-triol, 1- [6 - (1 S, 2S, 3-Trihydroxy-propyl) -pyrazin-2-yl] -propane-1 S, 2S, 3-triol,

  1- [6- (1 R, 2R, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2R, 3R, 4-

tetraol,

  i1- [6- (1 R, 2R, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2R, 3S, 4-

tetraol,

  1 - [6- (1 R, 2S, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2S, 3R, 4-

tetraol,

  1- [6- (1 R, 2S, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2S, 3S, 4-

tetraol,

  1- [6- (1 S, 2R, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2R, 3R, 4-

tetraol,

  1 - [6- (1 S, 2R, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2R, 3S, 4-

tôtral

  1 - [6- (1 S, 2S, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2S, 3R, 4-

tetraol,

  1- [6- (1 S, 2S, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2S, 3S, 4-

  tetraol, 1- [6- (1 R, 2R, 3R, 4S, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] - pentane1 R, 2R, 3R, 4S, 5-pentaol,

  1- [6- (1 R, 2S, 3S, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

1 R, 2S, 3S, 4R, 5-pentaol,

  1- [6- (1 R, 2S, 3R, 4S, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

1 R, 2S, 3R, 4S, 5-pentaol,

  1 - [6- (1 R, 2R, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

i R, 2R, 3R, 4R, 5-pentaol,

  i1- [6- (1 R, 2S, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

1 R, 2S, 3R, 4R, 5-pentaol,

  1- [6- (1 S, 2R, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

1 S, 2R, 3R, 4R, 5-pentaol,

  1- [6- (1 S, 2R, 3S, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

1 S, 2R, 3S, 4R, 5-pentaol,

  or one of their salts with a mineral or organic acid.

The compound of formula:

QH OH

WE

HO OH

OH N OH

  is described in Nippon Shokuhin Kogyo Gakkaishi 37 (2), 154 (1990), Agric.

  Biol. Chem. 44 (5), 1189 (1980), Carbohydr. Res. 67 (2), 549 (1978).

The compound of formula:

OHOH OH OH OH

HO ,,, Nz - OH toH N

OH - '^ OH

  is described in Dev. Food Sci. 13, 85 (1986).

  No pharmacological activity is described for these derivatives.

  The compounds of formula (I), their stereoisomers and their salts with a mineral or organic acid with the exception of those mentioned above are

  new and are also part of the invention.

  0 The preferred compounds of formula (I) are the following compounds: 1- [6 (1 R, 2-Dihydroxy-ethyl) -pyrazin-2-yl] -ethane-1 R, 2-diol, 1 - [6- (1 S, 2Dihydroxy-ethyl) -pyrazin-2-yl] -ethane-1 S, 2-diol, 1- [6- (1 R, 2S, 3 Trihydroxy-propyl) -pyrazin-2-yl] -propane- 1 R, 2S, 3-triol, 1 - [6- (1 S, 2R, 3 Trihydroxy-propyl) -pyrazin-2-yl] -propane- 1 S, 2R, 3-triol, 1 - [6- (1 S, 2S, 3-Trihydroxy-propyl) -pyrazin-2-yl] -propane-1 S, 2S, 3-triol,

  1 - [6- (1 R, 2R, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2R, 3R, 4-

tetraol,

  1- [6- (1 R, 2R, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2R, 3S, 4-

tetraol,

  1- [6- (1 R, 2S, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2S, 3S, 4-

tetraol,

  1 - [6- (1 S, 2R, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2R, 3R, 4-

  tetraol, 1 - [6- (1 S, 2R, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane- 1 S, 2R, 3S, 4-tetraol,

  1- [6- (1 S, 2S, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2S, 3R, 4-

tetraol,

  1- [6- (1 S, 2S, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2S, 3S, 4-

tetraol,

  1- [6- (1 R, 2R, 3R, 4S, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

1 R, 2R, 3R, 4S, 5-pentaol,

  1- [6- (1 R, 2S, 3S, 4R, 5- Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

i R, 2S, 3S, 4R, 5-pentaol,

  1 - [6- (1 R, 2S, 3R, 4S, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

i R, 2S, 3R, 4S, 5-pentaol,

  1- [6- (1 R, 2R, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

1 R, 2R, 3R, 4R, 5-pentaol,

  1 - [6- (1 R, 2S, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

1 R, 2S, 3R, 4R, 5-pentaol,

  1 - [6- (S, 2R, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

1 S, 2R, 3R, 4R, 5-pentaol,

  1 - [6- (1 S, 2R, 3S, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-

1 S, 2R, 3S, 4R, 5-pentaol,

  and their salts with a mineral or organic acid.

  The compounds of formula (I) can be prepared by the action of ammonium formate on an aldose of formula: R1-CHOH-CHO (II) in which R1 has the same meanings as in formula (I) or one of

its stereoisomers.

  This reaction is generally carried out in an aqueous medium, at a temperature

between 20 C and 100 C.

  The R1-CHOH-CHO aldoses and their stereoisomers are marketed or can be prepared 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 sodium hydroxide (0.03 to 0.05%), at a temperature between 20 and 40 C, -by elongation reactions by application or adaptation of the methods described in "The Carbohydrates", editors: W. Pigman and D. Horton, Academic Press, New-York, Volume IA, 133 (1972) and in particular by forming the cyanohydrin of the aldose of start (for example by action of sodium cyanide in aqueous solution, at a temperature between 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 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 between 20 C and the boiling temperature of the reaction medium), then reduction of the has a 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 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, Academic 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 hydrogen carbonate in aqueous solution and an aliphatic alcohol (isopropyl alcohol for example), at a temperature between 50 and 80 C, b) alcohols corresponding allylics 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 titanium (IV) isopropylate complex 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 reaction mixtures obtained by the various processes described above

  are also treated according to conventional physical methods (evaporation, extraction, distillation, chromatography, crystallization by

  example) or chemical (eg salt formation).

  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

chlorinated solvent.

  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, methylenebis-3-

  oxynaphtoate, hydrochloride, sulfate, nitrate and phosphate.

  The following examples illustrate the invention:

EXAMPLE 1

  To a solution of 10 g of L-gulose in 28 cm 3 of distilled water is added 21 g of ammonium formate. The reaction mixture is heated to reflux with stirring at a temperature of approximately 100 ° C. for 30 minutes. After cooling to a temperature of around 25 C, the mixture is concentrated under reduced pressure (2.7 kPa) at a temperature close to 50 C. The residue is taken up 5 times in ethanol then reconcentrated under the same conditions and finally taken up in ethanol and stirred for 3 h. The precipitate thus obtained is filtered through a sintered glass, washed with diethyl ether and drained. The filtrate is concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 50 C. The residue is chromatographed on a column of 800 g of silica (0.02-0.05 mm) eluted with a water / ethanol mixture 1:19 in volumes at atmospheric pressure and collecting fractions of cm3. The fractions containing the expected product are combined and concentrated under reduced pressure (2.7 kPa) at a temperature close to C. The product obtained is recrystallized from a water / ethanol mixture, then

  dried under reduced pressure (2.7 kPa) at a temperature in the region of 25 C.

  Is thus isolated 1- [6- (1R, 2S, 3S, 4-tetrahydroxy-butyl) -pyrazin-2-yl] butane-

  1 R, 2S, 3S, 4-tetraol. The compounds of formula (I) have pharmacological properties

  interesting. 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 fasting for 2 hours. At the end of this period, the blood sugar level is measured and, immediately after, a dose of glucose (2 g / kg) is administered orally. Thirty minutes later, the blood sugar is measured again. Mice that respond with hyperglycaemia greater than 170 mg / dl are selected and used to detect the hypoglycaemic activity of

compounds according to the invention.

  The mice thus chosen are divided into groups of at least 10 animals.

  Separate groups receive a volume of 0.4 ml of product or sound

  vehicle once a day by gastric tubing. The treatment lasts 4 days.

  On the 4th day, after the last treatment, the animals receive a dose of glucose (2 g / kg) and the glycemia is measured 20 to 40 minutes later. The percentage of inhibition of the hyperglycemic response to administration glucose is calculated based on the response measured in the treated group

by the vehicle.

  In this test, the compounds according to the invention have a percentage

  blood glucose inhibition equal to or greater than 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 IDN), 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

  in which they allow the dose of insulin to be gradually reduced, the di

  unstable beast, insulin-resistant diabetes, in addition to sulphonylureas when these do not determine a sufficient drop in blood sugar. 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 failure, 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, punctate 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 (polyn peripheral europathies 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 the LDL / HDL ratio, inhibition of LDL oxidation, decrease in platelet adhesiveness), hyperlipemias and dyslipemias (hypercholesterolaemia, hypertriglyceridaemia, normalization of fatty acid levels, normalization of uricemia, normalization of apoproteins A and B), cataracts, high blood pressure 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 by the

  oral, parenteral, rectal or topical.

  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, sack-

  charose, 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 stbarate or talc, a

  coloring, coating (dragees) or varnish.

  As liquid compositions for oral administration,

  solutions, suspensions, emulsions, syrups and pharmaceutical elixirs

  ceutically acceptable containing inert diluents such as water,

  Ethanol, glycerol, vegetable oils or paraffin oil. These com-

  positions may 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 done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by

  heater. They can also be prepared in the form of a compound.

  sterile solids 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

  than cocoa butter, semi-synthetic glycerides or polyethyl-

  leneglycols. The compositions for topical administration may, for example, be

  creams, lotions, eye drops, mouthwashes, nose 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 mg and 600 mg per day orally for an adult with doses

  units 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 ........................................ ......................... .DTD: ............. 18 mg - Lactose ..... ......................... DTD: ....................... ............................. 55 mg - Colloidal silica ................ ................................................ .DTD : ..... 1 mg - Carboxymethyl starch sodium ................................ DTD: ..... ........ 10 mg Talc ..................................... DTD: .................................................. 10 mg - Magnesium stearate ............................................ ............ 1 mg..DTD: EXAMPLEB

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

  .................................................. ...... 50 mg Lactose ......................................... .......................... .DTD: .............. 104 mg - Cellulose ... ......................... DTD: ....................... ............................ 40 mg Polyvidone ................... ............................................. .DTD: .. .......... 10 mg - Carboxymethyl starch sodium ........................ DTD: ......... ............ 22 mg Talc ................................... .... DTD: ............................................ ... 10 mg - Magnesium stearate ......................................... ............... 2 mg Colloidal silica ............................... .......................... DTD: ............. 2 mg - Mixture of hydroxymethylcellulose, glycerin , titanium oxide (72-3,5-24,5) qs 1 film-coated tablet finished at 245 mg..DTD: EXAMPLE C

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

  ........................................... 50 mg - Benzoic acid .. .. DTD: .............................................. .................. 80 mg - Benzyl alcohol ........................... ..................... DTD: .................. 0.06 ml - Sodium benzoate. ......................... DTD: ....................... ............ 80 mg - 95% ethanol ............... DTD: .............. ......................................... 0.4 ml - Sodium hydroxide. .................................................. .... .DTD: .... 24 mg - Propylene glycol .................................. .......... DTD: ........................ 1.6 ml - Water ........ .................... DTD: ............................ .................. qs 4 ml The invention also relates to the use of the compounds of general formula (I), their stereoisomers and their salts with a mineral or organic acid for the preparation of pharmaceutical compositions useful for..DTD: the treatment or prevention of diabetes and complications of diabetes.

Claims (27)

  1 - Medicines containing as active ingredient at least one compound of formula: (I) R2 "- N   N in which R1 and R2 represent a chain - (CHOH) n-CH2OH and n is equal to 1, 2, 3 or 4, 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 chosen from the following: 1- [6- (1,2-dihydroxy-ethyl) -pyrazin-2-yl] -ethane- 1,2- diol, 1- [6- (1,2,3-trihydroxy-propyl) -pyrazin-2-yl] - propane-1,2,3-triol, 1- [6- (1,2,3,4- tetrahydroxy-butyl) -pyrazin-2-yl] - butane- 1,2,3,4-tetraol, 1- [6- (1,2,3,4,5-pentahydroxy-pentyl) -pyrazin-2yl] - pentane-1,2,3,4,5-pentaol, or one of their stereoisomers or one of their salts with a mineral or organic acid. 3 - Medicines according to claim 1 containing as active ingredient at least one compound chosen from the following:  1- [6- (1 R, 2-Dihydroxy-ethyl) -pyrazin-2-yl] ethane-1 R, 2-diol, 1- [6- (1 S, 2-Dihydroxy-ethyl) -pyrazin-2 -yl] -ethane- 1 S, 2-diol, 1- [6- (1 R, 2R, 3-Trihydroxy-propyl) -pyrazin-2-yl] -propane-1 R, 2R, 3-triol, 1 - [6- (1 R, 2S, 3- Trihydroxy-propyl) -pyrazin-2-yl] -propane-1 R, 2S, 3-triol, 1- [6- (1 S, 2R, 3- Trihydroxy- propyl) -pyrazin-2-yl] -propane- iS, 2R, 3-triol, 1- [6- (1 S, 2S, 3-Trihydroxy-propyl) -pyrazin-2-yl] -propane-1 S, 2S, 3-triol, 1 - [6- (1 R, 2R, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] - butane-1 R, 2R, 3R, 4-tetraol,   1- [6- (1 R, 2R, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2R, 3S, 4- tetraol,   1- [6- (1 R, 2S, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2S, 3R, 4- tetraol,   1- [6- (1 R, 2S, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2S, 3S, 4- tetraol,   1 - [6- (1 S, 2R, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2R, 3R, 4- tetraol,   1- [6- (1 S, 2R, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2R, 3S, 4- tetraol,   1- [6- (1 S, 2S, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2S, 3R, 4- tetraol,   1 - [6- (1 S, 2S, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2S, 3S, 4- tetraol,   1 - [6- (1 R, 2R, 3R, 4S, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 R, 2R, 3R, 4S, 5-pentaol,   1 - [6- (1 R, 2S, 3S, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 R, 2S, 3S, 4R, 5-pentaol,   1 - [6- (1 R, 2S, 3R, 4S, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-   1 R, 2S, 3R, 4S, 5-pentaol, 1- [6- (1 R, 2R, 3R, 4R, 5-Pentahydroxy-pentyl) pyrazin-2-yl] -pentane- 1 R, 2R, 3R, 4R, 5-pentaol,   1- [6- (1 R, 2S, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 R, 2S, 3R, 4R, 5-pentaol,   i - [6- (1 S, 2R, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 S, 2R, 3R, 4R, 5-pentaol,   1 - [6- (1 S, 2R, 3S, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 S, 2R, 3S, 4R, 5-pentaol,   or one of their salts with a mineral or organic acid. 4 - Compounds of formula: R2 N R1   in which R1 and R2 represent a chain - (CHOH) n-CH20H and n is equal to 1, 2, 3 or 4, their stereoisomers and their salts with a mineral or organic acid with the exception of the compounds of formulas: OH OH HO N OH OH N OH OH OH OH OH HO. ILN OH   - Compounds of formula (I) according to claim 4 chosen from: 1 - [6 (1 R, 2-Dihydroxy-ethyl) -pyrazin-2-yl] -ethane-1 R, 2-diol, 1 - [6- (1 S, 2Dihydroxy-ethyl) -pyrazin-2-yl] -ethane-1 S, 2-diol, 1 - [6- (1 R, 2S, 3Trihydroxy-propyl) -pyrazin-2-yl] -propane- 1 R, 2S, 3-triol, 1- [6- (1 S, 2R, 3 Trihydroxy-propyl) -pyrazin-2-yl] -propane-1 S, 2R, 3-triol, i - [6- (1 S, 2S, 3 Trihydroxy-propyl) -pyrazin-2-yl] -propane-1 S, 2S, 3-triol,   i - [6- (1 R, 2R, 3R, 4-T6trahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2R, 3R, 4- tetraol,   1- [6- (1 R, 2R, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2R, 3S, 4- tetraol,   1- [6- (1 R, 2S, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 R, 2S, 3S, 4- tetraol,   1- [6- (1 S, 2R, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2R, 3R, 4- tetraol,   1- [6- (1 S, 2R, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2R, 3S, 4- tetraol,   1- [6- (1 S, 2S, 3R, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2S, 3R, 4- tetraol,   1- [6- (1 S, 2S, 3S, 4-Tetrahydroxy-butyl) -pyrazin-2-yl] -butane-1 S, 2S, 3S, 4- tftraoll   1- [6- (1 R, 2R, 3R, 4S, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 R, 2R, 3R, 4S, 5-pentaol,   1- [6- (1 R, 2S, 3S, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane-   1 R, 2S, 3S, 4R, 5-pentaol, 1- [6- (1 R, 2S, 3R, 4S, 5-Pentahydroxy-pentyl) pyrazin-2-yl] -pentane- 1 R, 2S, 3R, 4S, 5-pentaol,   1- [6- (1 R, 2R, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 R, 2R, 3R, 4R, 5-pentaol,   1- [6- (1 R, 2S, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 R, 2S, 3R, 4R, 5-pentaol,   i - [6- (1 S, 2R, 3R, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 S, 2R, 3R, 4R, 5-pentaol,   i - [6- (1 S, 2R, 3S, 4R, 5-Pentahydroxy-pentyl) -pyrazin-2-yl] -pentane- 1 S, 2R, 3S, 4R, 5-pentaol,   and their salts with a mineral or organic acid.   6 - Process for preparing the compounds of formula (I) according to claim 1 ceractérisé in that one reacts ammonium formate on an aldose of formula: R1-CHOH-CHO (II) in which Ri has the same meanings that in claim 1 or one of its stereoisomers, isolate the product and optionally transform it into   salt with a mineral or organic acid.   7 - Use of the compounds of formula: (I) R2 ′ N - 1 in which R1 and R2 represent a chain - (CHOH) n-CH20H and n is equal to 1, 2, 3 or 4 or one of their stereoisomers or one of their salts with a mineral or organic acid for the preparation of pharmaceutical compositions useful for the treatment or prevention of diabetes and the complications of diabetes.