Derivatives polyhydroxyalkanoates, receipt and medicines containing them

 

(57) Abstract:

The invention relates to the derivatives of polyhydroxyalkanoates formula I used as active principle in medicine, in which R1means stereoisomeric forms chain (II): -(SNON)3-CH2HE, R2denotes a hydrogen atom and R3denotes the stereoisomeric forms of the circuit (III): -CH2(SNON)2-CH2HE or R2means stereoisomeric forms chains (II): -(SNON)3-CH2HE or (III): CH2(SNON)2-CH2HE and R3denotes a hydrogen atom. Also described methods for producing compounds of formula I based on them. The compounds exhibit hypoglycemic activity and therapy are of interest for the prevention and treatment of diabetes. 5 C. and 7 C.p. f-crystals.

The invention relates to medicinal products containing as active principle at least one compound of General formula

< / BR>
in the form of stereoisomeric forms and their salts with mineral or organic acids, and to new compounds of the formula I, their salts with mineral or organic acids and the way they are received.

In the General Formula I:

R1oboznachaya, and R3means stereoisomeric forms chain

-CH2(SNON)2-CH2HE (III),

or R2means stereoisomeric forms chain

(SNON)3-CH2HE (II)

or

-CH2(SNON)2-CH2OH (III),

a R3denotes a hydrogen atom,

except

- fructosamine formula

< / BR>
- deoxyglucosone formula

< / BR>
and the compounds of formula

< / BR>
Medicinal product according to the invention contain, therefore, at least one stereoisomer of the following compounds:

< / BR>
< / BR>
< / BR>
or salt of one of these compounds with an organic or mineral acid except fructosamine, deoxyinosine and the compounds of formula VI.

Preferred drugs according to the invention are those which contain as active principle at least one compound of formula I, selected from the following compounds:

1-[5-(1R, 2R, 3R, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1R,2R,3R, 4-tetraol,

1-[5-(1R, 2R, 3S,4-tetrahydroquinolin)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol,

1-[5-(1R, 2S, 3S,4-tetrahydroquinolin)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol,

1-[5-(1S, 2R, 3R,4-tetrahydroquinolin)pyrazin-2-yl]butane is oxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol,

1-[5-(1S, 2S, 3S,4-tetrahydroquinolin)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol,

1-[5-(2R,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol,

1-[5-(2R,3S,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol,

1-[5-(2S,3S,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol,

1-[5-(2R,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol,

1-[5-(2R,3S,4-trihydroxybutane)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol,

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol,

1-[5-(2S,3S,4-trihydroxybutane)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol,

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

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

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

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

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

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

or salts of these compounds with an organic or mineral acid,

and even more preferred drugs are those which contain as active principle at least one compound of formula I, selected from the following compounds:

1-[5-(1R, 2R, 3R,4-tet is Aol,

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol,

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

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

or salts of these compounds with organic or mineral acids.

Known are the following connections:

- fructoses, deoxyglucosone and the compound of formula VI, as described in patent JP 43-13469; Ann., 644, 122-127 (1961); Agr. Biol. Chem., 39 (5), 1143-1148 (1975);

- stereoisomers following General formulas VIa, VIb, VIc and VId:

< / BR>
< / BR>
< / BR>
< / BR>
described in the patent JP 43-13469; Carbohyd. Res., 26 (2), 377-384 (1973); J. Anal. Appl. Pyrolysis, 13, 191-198 (1988);

compounds of General formula VII, VIII and IX, which is the derivative of glucose, fructose, mannose, galactose, as described in Japanese patent JP 53-90401.

However, the use of these compounds as medicines have not been reported, and such application is the subject of the present invention.

The compounds of formula I or their salts with mineral or organic acids, with the exception of the following compounds:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
are new compounds and as such are part of hydroxybutyl) pyrazin-2-yl]butane-1R,2R,3S,4-tetraol, 1-[5-(1S,2R,3R,4-tetrahydroquinolin)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol, 1-[5-(1S,2S,3R,4-tetrahydroquinolin)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol, 1-[5-(1S,2S,3S,4-tetrahydroquinolin)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol, 1-[5-(2R, 3S,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol, 1-[5-(2S, 3S, 4-trihydroxybutane)pyrazin-2-yl] butane-1R,2S,3S,4-tetraol, 1-[5-(2R, 3R, 4-trihydroxybutane)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol, 1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol, 1-[6-(2R, 3S, 4-trihydroxybutane)pyrazin-2-yl} butane-1R, 2R,3S,4-tetraol, 1-[6-(2R,3R, 4-trihydroxybutane)pyrazin-2-yl] butane-1S, 2R, 3R,4-tetraol, 1-[6-(2S,3R,4-trihydroxybutane)pyrazin-2-yl] butane-1S, 2S, 3R,4-tetraol and salts of these compounds with mineral or organic acids.

Of the above compounds are preferred:

1-[5-(2S, 3S, 4-trihydroxybutane)pyrazin-2-yl] butane-1R,2S,3S,4-tetraol, 1-[5-(2R, 3R, 4-trihydroxybutane)pyrazin-2-yl] butane-1S,2R,3R,4-tetraol, 1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] butane-1S,2S,3R,4-tetraol and salts of these compounds with mineral or organic acids, the most preferred compound is 1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl] butane-lS,2S,3R,4-tetraol or salt of this compound with a mineral or organic acid.

Stereoisomeric forms of soy is receiving according to the invention.

The stereoisomers of compounds of the formula I, in which R1means stereoisomeric forms chain -(SNON)3-CH2HE (II), R2denotes a hydrogen atom and R3means stereoisomeric forms chain-CH2(SNON)2-CH2HE (III), i.e. compounds denoted by formula VII can be obtained by the action of ammonium formate to aldose or a mixture of two algos of programalso or levogyrate number of General formula

SNO-SNO-R1(X)

in which R1has the same meaning as in formula I.

This reaction can be advantageously carried out at a temperature of from 15 to 100oWith and preferably in the aquatic environment.

An aldose can be purchased ready-made or received from:

a) commercially available algos:

- epimerization reactions with the use or adaptation of the methods described in Adv. Carbonydr. Chem., 13, 63 (1958), in particular, in an alkaline medium using a diluted aqueous solution of caustic soda (0,03-0,05%) at a temperature of from 20 to 40oC;

- reactions of chain elongation by the application or adaptation of the methods described in "The Carbohydrates", publishers W. Pigman and D. Horton, Academic Press, New-York, Volume IA, 133 (1972), and in particular, through education cyanhydrin outstay sodium alkali at pH close to 9) followed by hydrolysis of the resulting nitrile function to the corresponding acid function by application or adaptation of the methods described in Organic Synthesis, volume I, pages 436 and volume III, page 85 (for example, using concentrated hydrochloric or sulfuric acid in an aqueous solution at a temperature of 20oC to the boiling temperature of the reaction medium under reflux) and restoration of the carboxyl function to the corresponding aldehyde using or adapting methods described in J. Amer. Chem. Soc. 71, 122 (1949), in particular, by using an alkali metal borohydride (e.g. sodium borohydride) in an aqueous solution at a temperature of 20oC to the boiling temperature of the reaction medium;

- reactions of the shortening of the chain with the application or adaptation of the methods described in "The Carbohydrates", publishers W. Pigman and D. Horton, Academic Press, New-York, Volume IB, 1980, page 929, or hm. Ber., 83, 559 (1950), and in particular by conversion of the aldehyde functions of an aldose to the corresponding hydroxylamine by application or adaptation of the methods described in Organic Synthesis, volume II, page 314 (e.g., using hydroxylaminopurine in aqueous solution in the presence of a base such as sodium carbonate, at a temperature Akogo as sodium bicarbonate, in aqueous solution and aliphatic alcohol (e.g. isopropyl alcohol) at a temperature of from 50 to 80oC;

(b) the corresponding allyl alcohols by application or adaptation of the methods described in Science 220, 949 (1983), and in particular using tert-butylhydroperoxide in the presence of a complex of titanium (IV), such as isopropyl titanium (IV), and optically pure dialkylamino (for example, diethyltartrate) followed by successive action thiophenolate sodium p-chloroperbenzoic acid in acetic anhydride and hydride Diisopropylamine.

The sugar stereoisomers of formula X can be stereoisomers of aldos to 6 carbon atoms, which are preferably used D-gulose, D-galactose, D-allose, D-altrose, D-idose, D-taleea, L-pucssa, L-mannose, L-galactose, L-allose, L-altrose, L-idose, L-talose, L-gulose.

The stereoisomers of compounds of the formula I, in which R1means stereoisomeric forms chain -(SNON)3-CH2HE (II), R2means stereoisomeric forms chain -(SNON)3-CH2HE (II) and R3is a hydrogen atom, i.e. compounds denoted by formula VIII can be obtained by treatment in an alkaline environment aminoacids or a mixture of two aminovaleric, where R1has the same meaning as in General formula I.

The process is conducted mainly at a temperature close to 20oWith using preferably ammonium, preferably 28% solution.

Aminoacidos formula XI can be purchased ready-made or obtained by the application or adaptation of the methods described, for example, in:

a) Methods Carbohyd. Chem., 7, 29 (1976), consisting in the transformation of the aldehyde function corresponding to the aldose in nitroethylene group with nitromethane in an alkaline environment (for example, sodium ethylate), followed by processing the resulting product is consistently saturated ammonia solution at a temperature of from 20 to 30oWith, an aqueous solution of Ba(OH)2at 20-30oAnd finally diluted (10-15%) sulfuric acid at 20-30oWITH,

b) The Amino Sugar", publisher R. W. Jeanioz, Academic Press, New York, 1969, page 1, or "The Carbohydrates", publishers W. Pigman and D. Horton, Academic Press, New-York, Volume IB, 1980, page 664, consisting in the transformation of the aldehyde function corresponding to the aldose in aminogroup on the basis of a primary aromatic amine (e.g., aniline), followed by reaction with hydrocyanic acid at a temperature of from 0 to 20oAnd then with hydrogen in the presence of palladium in a solvent such nature from 20 to 50oC.

Stereoisomers aminoacidos formula XI can be aminoindazole to 6 carbon atoms, preferably used D-galactosamine, which can also be used in the form of a salt adduct, for example the hydrochloride.

The stereoisomers of compounds of the formula I, in which R1means stereoisomeric forms chain -(SNON)3-CH2HE (II), R2means stereoisomeric forms chain-CH2(SNON)2-CH2HE (III) and R3is a hydrogen atom, i.e. compounds denoted by the formula IX can be obtained

any of aminoacids or a mixture of two aminoacids General formula

CHO-CH(NH2)-R1(XI)

in which R1has the same meaning as in General formula I, in an acidic environment, mainly in the medium of acetic acid, and preferably at a temperature of from 15 to 100oWITH,

either ketosis or a mixture of two ketosis General formula

HOCH2-CO-R1(XII)

in which R1has the same meaning as in General formula I, acting by ammonium formate and carrying out the reaction preferentially at a temperature of from 15 to 100oWith and preferably in the aquatic environment.

Ketosis formula XII can be purchased as is or is sootvetstvujushej an aldose or base, such as calcium hydroxide, sodium hydroxide, pyridine or quinoline, or an acid, such as sulfuric acid, in aqueous solution or pure phase at a temperature of from 20 to 50oC;

b) Tetrahedron Asymmetry, 7 (8), 2185 (1966), J. Amer. Chem. Sc., 118 (33), 7653 (1966), J. Org. Chem., 60 (13), 4294 (1995), Tetrahedron Lett., 33 (36), 5157 (1992), J. Amer. Chem. Soc., 113 (17), 6678 (1991), Angew. Chem., 100 (5), 737 (1988), J. Org. Chem., 57, 5899 (1992), consisting, for example, condensation or hydroxybenzaldehyde, 1,3-dihydroxyacetone, 1,3-dihydroxyacetone-monophosphate or hydroxyisovalerate acid substituted in position 2 2-hydroxyacetaldehyde (including optically pure), possibly in the presence of the enzyme, for example transketolase. This reaction is carried out mainly in aqueous solution at a temperature of from 20 to 50oWith, possibly, in the presence of a base (e.g., caustic soda), barium chloride, magnesium chloride or zinc chloride. Derivatives containing 2-hydroxyacetaldehyde group, can be purchased ready-made or received from aldos with the application or adaptation of the methods described in R. Collins, R. Ferrier, Monosaccharides. Their Chemistry and their roles in Natural Products, publisher J. Wiley (1995), and M. Bols, Carbohydrate Building Blocks, publisher J. Wiley (1996).

Mainly used by stereoisomer aminoacidos formula XI t the volumes of carbon of which are preferably used are D-psicose, D-sorbose, D-tagatose, L-psicose, L-fructose, L-sorbose and L-tagatose.

The reaction mixture obtained these various above-described methods, processes using traditional physical (e.g., evaporation, extraction, distillation, chromatography, crystallization) or chemical (for example, obtaining salts) methods.

The compounds of formula I can be converted into a salt adducts with mineral or organic acid by the action of these acids in organic solvents, such as alcohols, ketones, ethers, and chlorinated solvents. These salts also form part of the invention.

As examples of pharmaceutically acceptable salts include a salt adducts with mineral and organic acids: acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isothionate, theophyllinate, salicylate, methylene-bis-b-xinafoate, hydrochloride, sulfate, nitrate and phosphate.

The following examples illustrate in more detail used in accordance with the invention, a method of receiving the products.

EXAMPLE 1.

A solution of 1.0 g D-SOR is proven to cool to room temperature. The mixture is then concentrated under reduced pressure (2.7 kPa) at a temperature close to the 40oC. Brown residue is taken sequentially with ethyl ether and toluene and evaporated to dryness. New balance take ethanol and filtered. The filtrate is evaporated, getting a reddish-brown oil. Operation is repeated several times until, until there is no further precipitate. The resulting residue purified by chromatography on a column of silica gel (0,063-0,200 mm), elwira a mixture of ethanol/n-butanol/28% aqueous ammonia/water in a volume ratio of 8/2/2/1. The fractions containing the desired product are pooled and concentrated under reduced pressure (2.7 kPa) at a temperature close to the 40oC. the yellow sticky solid product take a mixture of ethanol/methanol in a quantity sufficient to obtain a solution, to which you then add ethyl ester prior to the appearance of the precipitate, which is filtered off. After crystallization of the product is obtained 0.15 g of 1-[5-(2R,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1S, 2R,3R,4-tetraol in the form of a beige solid with so pl. 90oC.

An NMR spectrum1H (400 MHz, (CD3)2SO d6in M. D.): 2,85 and 2.93 (DD respectively, J = 13 and 9 Hz and J = 13 and 4 Hz, 2H: CH25); O2 - HE 2 HE 5 HE 5 HE 5); 4,78 (t, J = 4.5 Hz, 1H: CH 2) ; of 5.39 (d, J = 4.5 Hz, 1H: 2); 8,43 (s, 1H: =CH 6); 8, 61 (s, 1H: = CH 3).

20D= +71,31,3 (C = 0.5% of the Meon).

EXAMPLE 2.

A suspension containing 1.0 g of D-galactosaminidase and 0.73 cm3diethylamine, stirred for 1 hour and filtered. The filtrate is evaporated, the residue is dissolved in 10 cm328% aqueous ammonia and stirred at room temperature for 3 weeks. The mixture is then concentrated under reduced pressure (2.7 kPa) at a temperature close to the 40oC receives a yellow oil, which was taken with methanol and filtered. The filtrate is evaporated with the formation of an orange oil, which was purified by chromatography on a column of silica gel (0.04 to 0,063 mm), elwira a mixture of ethanol/n-butanol/28% ammonia/water in a volume ratio of 8/2/2/1. The fractions containing the desired product are pooled and concentrated under reduced pressure (2.7 kPa) at a temperature close to the 40oWith getting yellow-orange sticky solid product. The latter is crystallized from methanol, filtering the solid product to obtain 0.12 g of 1-[5-(1R,2R,3R,4-tetrahydroquinolin)pyrazin-2-yl] butane-1R,2R,3R,4-tetraol in the form of a beige powder with so pl. 109oC.

An NMR spectrumH - 2 CH 2 CH 5 and CH 5) ; 4,24 (d, J = 8 Hz, 2H: 2 and HE 5); to 4.41 (d, J = 6,5 Hz, 2H: 2 and HE 5) ; 4,50 (t broadened, J = 6 Hz, 2H: 2 and HE 5); with 4.64 (DD, J = 7 and 6 Hz, 2H: CH 2 and CH 5); of 5.48 (d, J = 6 Hz, 2N: 2 and HE 5) ; 8,56 (s, 2H: = CH 3 =CH 6).

EXAMPLE 3.

A solution of 1.0 g of D-galactose and 3.5 g of ammonium formate in 4 cm3water boiled for 0.5 hour under reflux and then allowed to cool to room temperature. The mixture is filtered and the residue concentrated under reduced pressure (2.7 kPa) at a temperature close to the 40oWith getting red-brown residue, which consistently take ethanol and ethyl ether and then evaporated to dryness. The residue is triturated in ethyl ether, filtered and dissolved the resulting brown solid in ethanol. To the solution add sodium hydroxide to pH 12 and stirred for 40 hours, watching the sediment. The reaction mixture is filtered, and concentrate the filtrate under reduced pressure (2.7 kPa) at a temperature close to the 40oC receives a yellow solid, which take a mixture of methanol/ethyl ether and filtered. The filtrate is evaporated, the residue is dissolved in methanol and add alcohol solution of Hcl to pH 2. The resulting precipitate of attilla a mixture of ethanol/n-butanol/aqueous ammonia/water in a volume ratio of 8/2/1/1. The fractions containing the desired product are pooled and concentrated under reduced pressure (2.7 kPa) at a temperature close to the 40oC. the Obtained white solid product is recrystallized from methanol, receiving 90 mg 1-[5-(2R, 3R,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol

white solid crystals with so pl. 146oC.

An NMR spectrum1H (400 MHz, (CD3)2SO d6, M. D.): 2,86 (DD, J = 14 and 9 Hz, 1H: 1H of CH25; 2,9,2 (DD, J = 14 and 3.5 Hz, 1H: the other H of CH25 ; from 3,30 to 3.60 (m, 5H: CH2ABOUT 2 - CH2O 5 and CH 5); from 3.70 to 3.85 (m, 2H: CH 2 and CH 2); 3,90 (m, 1H: CH 5); 4,22 (d, J = 7 Hz, 1H: 2); to 4.38 (d, J = 6,5 Hz, 1H: 2); 4,43 (d, J = 7 Hz, 1H: HE 5); from 4,40 up 4,55 (m, 2H: 2 and HE 5); from 4,55 to 4.70 (m, 2H: CH 2 and HE 5); 5,44 (d, J = 6 Hz, 1H: 2); 8,43 (s, 1H: = CH 6); 8,54 (s, 1H: = CH 3).

20D= -14,61,13 (C = 0,2% water).

EXAMPLE 4.

A solution of 10.0 g L-sorbose and 7.0 g of ammonium formate in 28 cm3water boiled for 2.5 hours under reflux and allowed to cool to room temperature. The mixture is then concentrated under reduced pressure (2.7 kPa) at a temperature close to the 50oC. the Red-brown pasty residue is purified by chromatography on a column of silica gel (0,020-0,045 mm is oduct, combine and concentrate under reduced pressure (2.7 kPa) at a temperature close to the 50oC. the Obtained red-brown oil (9.1 g) take a mixture of 100 cm3ethanol and 10 cm3water. The mixture is brought to boiling, treated with 0.9 g of animal charcoal and filtered through a paper filter. The filtrate is concentrated under reduced pressure (2.7 kPa) at a temperature close to the 50oWith getting a red-brown oil (6.2 g). The last take a mixture of 50 cm3ethanol and 1.5 cm3water and recrystallized. The resulting crystals are filtered, to remove moisture and washed with the same mixture. After drying to constant weight get 0,86 g of 1-[5-(2S,3S,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol in the form of a beige crystalline substance with so pl. 116oC.

An NMR spectrum1H (400 MHz, (CD3)2SO-d6in M. D.): 2,87 (AB limit, 2H: CH25); from 3,30 to 3.60 (m, 6N: CH 2 - CH2About 2 - CH 5 and CH25); 3,76 (m, 1H: CH 2); 3,90 (m, 1H: CH 5); of 4.77 (d, J = 5.5 Hz, 1H: CH 2) ; 8,43 (with extended, 1H: = CH 6); 8,61 (with extended, 1H: = CH 3).

20D= -62,41, 2 (=0.5% of water).

EXAMPLE 5.

A solution of 5.0 g L-glucose and 5.2 g of ammonium formate in 20 cm3water is boiled for 2 hours with the reverse you can see the (2.7 kPa) at a temperature close to 50oC. Black pasty residue is taken methanol, triturated, filtered off the insoluble fraction and washed it with methanol. The filtrate is concentrated under reduced pressure (2.7 kPa) at a temperature close to the 50oWith, obtaining 7.5 g of red-brown oil, which was purified by chromatography on a column of silica gel (0,020-0,045 mm), elwira a mixture of ethanol/n-butanol/aqueous ammonia/water in a volume ratio of 8/2/2/1. The fractions containing the desired product are pooled and concentrated under reduced pressure (2.7 kPa) at a temperature close to the 50oC. the Residue is successively picked up by ztenolol and ether, then concentrated. Resulting oil (0.6 g) take 5 cm3water and lyophilized, thus receiving of 0.47 g of 1-[6-(2S,3S,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol in the form of brown lyophilisate.

An NMR spectrum1H (400 MHz, (CD3)2SO-d6the temperature of 383 K, in M. D.): 2,94 and 3,03 (d respectively, J = 14 and 9 Hz and J = 14 and 4 Hz, 1H each: CH26); from 3.40 in to 3.70 (m, 6N: CH 2 - CH2About 2 - CH 6 and CH26); 3,88 (t, J = 4 Hz, 1H: CH 2); 4,01 (m, 1H: CH 6); 4,84 (d, J = 4 Hz, 1H: CH 2); 8,42 (s, 1H: = CH 5); to 8.57 (s, 1H: = CH 3).

20D= -65,91,4 (C = 0.5% of water).

Putnam fridge and leave to cool to room temperature. The mixture is then concentrated under reduced pressure (2.7 kPa) at a temperature close to 65oC. the Red-brown pasty residue is taken methanol, triturated, filtered off the insoluble fraction and washed it with methanol. The filtrate is concentrated under reduced pressure (2.1 kPa) at a temperature close to the 50oC. Repeat this operation with ethanol, obtaining 6.2 g of red-brown oil. Last purify by chromatography on a column of silica gel (0,020-0,045 mm), elwira a mixture of ethanol/n-butanol/aqueous ammonia in the volume ratio of 8/2/1. The fractions containing the desired product are pooled and concentrated under reduced pressure (2.7 kPa) at a temperature close to 60oC. the resulting oil (0.5 g) take 14 cm3ethanol, filtered hot and crystallized. After drying to constant weight at a temperature close to the 40oTo receive 0.35 g of 1-[6-(2R,3S,4-trihydroxybutane)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol in the form of beige crystals with so pl. 114oC.

Rf = 0.3, when chromatographicaliy in a thin layer of silica gel with elution with a mixture of ethanol/n-butanol/aqueous ammonia/water in a volume ratio of 8/2/2/1.

EXAMPLE 7.

A solution of 2.0 g D-psicose and 3.2 g of ammonium formate 3.4 km sgry. The mixture is then diluted with 25 cm3ethyl acetate and decanted. The aqueous phase is washed with 25 cm3ethyl acetate and concentrated under reduced pressure (2.7 kPa) at a temperature close to 70oC. the Red-brown oily residue is taken 100 cm3ethanol, triturated, filtered off the insoluble fraction and washed it with ethanol. The filtrate is concentrated under reduced pressure (2.7 kPa) at a temperature close to 45oC, getting red-brown pasty substance (1.6 g). Last purify by chromatography on a column of silica gel (0,020-0,045 mm), elwira a mixture of ethanol/water in a volume ratio of 199/1, and then on a column of silica gel (0,020-0,045 mm), elwira a mixture of ethyl acetate/acetic acid/water in a volume ratio of 30/12/10, and, finally, on a column of silica gel (0,020-0,045 mm) under a pressure of approximately 1,5xl05PA, elwira a mixture of ethanol/n-butanol/aqueous ammonia in the volume ratio of 8/2/1. The fractions containing the desired product are pooled and concentrated under reduced pressure (2.7 kPa) at a temperature close to the 50oC. the Obtained solid amber color (0,22 g) take a mixture of 5 cm3ethanol and 0.25 cm3water, filtered while hot and then recrystallized. Education is widely 65,5 mg 1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol in the form of crystalline powder buff with so pl. 141oC.

An NMR spectrum1H (400 MHz, (CD3)2SO-d6in M. D.): 2,75 and is 3.08 (DD respectively, J = 14 and 10 Hz and J = 14 and 2.5 Hz, 1H each: - CH25; from 3,30 to 3.50 (m, 4H: CH 2 CH 5 - 1H of CH2About 2 and 1H of CH2O 5); of 3.60 (m, 2H: the other H of CH2O 2 and the other N of CH25); with 3.79 (m, 2H: CH 2 and CH 5); 4,36 and 4.45 (2T, J = 5.5 Hz, 1H each: 2 and HE 5); 4,58 with 4.64 - 4,71 and 4,78 (4D, respectively, J = 4.5 Hz, J = 6,5 Hz, J = 5 Hz and J = 5.5 Hz, 4H: HE); 4,82 (t, J = 5.5 Hz, 1H: CH 2); of 5.53 (d, J = 5.5 Hz, 1H: 2); to 8.41 (with extended, 1H: = CH 6); at 8.60 (with extended, 1H: = CH 3).

EXAMPLE 8.

A solution of 5.0 g of D-galactose and 8.8 g of ammonium formate in 14 cm3water boiled for 45 min under reflux and allowed to cool to room temperature. The mixture is then diluted with 50 cm3ethyl acetate and decanted. The aqueous phase is twice washed with 50 cm3ethyl acetate and concentrated under reduced pressure (2.7 kPa) at a temperature close to 65oC. the Red-brown pasty residue is taken 100 cm3ethanol and pound. The supernatant concentrated under reduced pressure (2.7 kPa) at a temperature close to 45oWith (one repeat). Red-brown solid residue consistently taken methanol, ethanol and ZAT isoC. the Residue is purified by chromatography on a column of silica gel (0,020-0,045 mm) under a pressure of 1,5x105PA, elwira a mixture of ethanol/n-butanol/aqueous ammonia in the volume ratio of 8/2/1. The fractions containing the desired product are pooled and concentrated under reduced pressure (2.7 kPa) at a temperature close to the 40oC. the Obtained yellow solid (0.26 g) take a mixture of 3 cm3ethanol and 0.25 cm3water, filtered while hot and then recrystallized. The obtained solid product is filtered off and remove moisture. After drying under reduced pressure (2.7 kPa) at a temperature close to the 25oTo receive 119 kg of 1-[6-(2R,3R,4-trihydroxybutane)pyrazin-2-yl] butane-1R, 2R, 3R,4-tetraol in the form of a pasty product amber color, melting at 90-130o(Paste).

An NMR spectrum1H (400 MHz, (CD3)2SO d6in M. D.): 2,89 (AB limit, 2H: CH26; from 3,30 to 3,55 (m, 5H: CH2ABOUT 2 - CH2O 6 and CH 6); from 3.70 to 3.85 (m, 2H: CH 2 and CH 2); to 3.92 (m, 1H: CH 6); with 4.64 (d, J = 8.5 Hz, 1H: CH 2); scored 8.38 (s, 1H: = CH 5); to 8.45 (s, 1H: = CH 3).

The compounds of formula I possess useful pharmacological properties, showing hypoglycemic activity.

The hypoglycemic activity of the compounds of the formula I defined the eat glucose according to the following procedure.

Mice Swiss albino weighing from 22 to 26 g survive without food for 2 hours. At the end of this period, measure the glucose level and directly after that, the mice administered oral glucose in a dose of 2 g/kg After 30 min again measure the glucose level. Selected mice with glucose levels above 170 mg/DL to define them hypoglycemic activity of the compounds according to the invention.

Selected mice are divided into groups consisting of at least 10 animals each. In different groups of animals receive a dose of from 3 to 50 mg/kg of product in the media, such as water or a mixture of methylcellulose/twin room, with water once a day using a gastric tube. Treatment continued for 4 days. On the fourth day, after the last injection, the animals receive a dose of glucose (2 g/kg) and after 20-40 min measured glucose level. Degree (%) of inhibition of the hyperglycemic response to the reception of glucose calculated from comparison with hyperglycemic response, measured in the group receiving only the media.

In this test, compounds according to the invention exhibit inhibition of hyperglycemia by 10% or more.

Compounds of General formula I according to the invention obl>In human therapy, these compounds are of interest for the prevention and treatment of diabetes, particularly type II diabetes (diabetes NID), diabetes, obese diabetes fifty years, metalurgicheskogo diabetes (plethora), diabetes, elderly and mild diabetes. The compounds can be used as an adjunct to insulin therapy in insulin-dependent diabetes, and in this case they allow you to gradually reduce the dose of insulin; unstable diabetes; non-insulin-dependent diabetes, complementing the sulfonamides-hypoglycemiant, when the latter does not provide sufficient lowering of blood sugar levels. Connections can also be used when complications of diabetes, such as hyperlipemia, disorders of lipid metabolism, dyslipemia, obesity. They can also be used for the prevention and treatment of atherosclerotic disorders and their complications (colonopathy, myocardial infarction, cardiomyopathy, the transition of these three complications in the failure of the left ventricle of the heart, various arteriopathy, arteritis of the lower limbs with a limp and going to ulcers and gangrene, cerebrovascular insufficiency and its complications, impotence due to vascular disorders), diabetic retinopathy and arteriovenous shunt, varicose veins, spotted and spot bleeding, exudate, spotted swelling, symptoms proliferate retinopathy: a new tumor blood vessels, scars proliferative retinitis, vitreous hemorrhage, retinal detachment), diabetic cataract, various forms of diabetic neuropathy (peripheral polyneuropathy and their symptoms, such as paresthesia, giperstesia and pain, mononeuropathy, radiculopathy, Autonomous neuropathy, diabetic disease), symptoms of diabetic foot (ulcers of the lower limbs and feet), diabetic nephropathy in its diffuse and nodular forms, atheromatosis (increased levels of high density lipoprotein (HDL), promote the removal of cholesterol from atomnykh plaque, lowering low-density lipoprotein (LDL), lower relationship LDL/HDL, inhibition of oxidation of low-density lipoprotein, reducing the stickiness of platelets), hyperlipemia and dyslipemia (prolactinemia, hyperglyceridemia, normalization of the levels of fatty acids, normalization of uricemia, the normalization of the level of apoproteins a and b), cataracts, high blood pressure and its consequences.

Medicinal product according to the invention consists of compounds for imaging efticiency compatible product which may be inert or physiologically active. Medicinal product according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration can be used in tablets, pills, powders (gelatin capsules, pills or granules. In these compositions, the active principle according to the invention is mixed in a stream of argon with one go several inert diluents, such as starch, cellulose, sucrose, lactose or silica. These compositions can also contain other non-solvent substances, for example one or more lubricating agents such as magnesium stearate or talc, a colorant, shell (pills) or lacquer.

As liquid compositions for oral administration can be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions can also contain other non-solvent substances, such as moisturizing agents, sweeteners, thickeners, flavorings and stabilizers.

the AMI suspensions or emulsions. As a solvent or carrier can be used water, propylene glycol, polyethylene glycol, vegetable oils (especially olive oil), injectable esters of organic acids, for example etiloleat, or other suitable organic solvents. These compositions can also contain additives, in particular moisturizers, isotonic agents, emulgator, dispersants and stabilizers. Sterilization compositions can be produced in several ways, such as aseptic filtration, by the introduction of sterilizing agents, by irradiation or by heating. The composition can also be prepared in a sterile solid form for dissolved immediately before use in sterile water or any other suitable for injection sterile environment.

Compositions for rectal injection are suppositories or rectal capsules which contain, besides the active substance, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The composition for external use may constitute, for example, creams, lotions, eye drops (ointment, liquid for rinsing, nasal drops or AEST from 150 to 600 mg per day by oral administration for adults with single doses ranging from 50 to 200 mg per active substance.

Typically, the physician determines the appropriate dose depending on the age, weight and other factors related to the patient.

The composition according to the invention is illustrated by the following examples.

EXAMPLE A.

Prepare in the usual way gelatin capsules containing 50 mg of active substance and is characterized by the following composition, mg:

Active substance - 50

Cellulose - 18

Lactose - 55

Colloidal silica is 1

Sodium carboximetilkrahmal - 10

Talc - 10

Magnesium stearate - 1

EXAMPLE Century.

Prepare in the usual way tablets containing 50 mg of active substance, characterized by the following composition, mg:

Active substance - 50

Lactose - 104

Cellulose - 40

Polyvidone - 10

Sodium carboximetilkrahmal - 22

Talc - 10

Magnesium stearate - 2

Colloidal silica - 2

A mixture of hydroxymethylcellulose, glycerin, titanium oxide (72/3,5/24,5) in a quantity sufficient to make 1 tablet weighing 245 mg

EXAMPLE C.

Prepare in the usual way solution for injection containing 50 mg of active substance and is characterized by the following composition:

Active substances is th ethanol, ml - 0,4

Sodium hydroxide, mg - 24

Propylene glycol, ml - 1,6

Water in sufficient quantity, ml - 4

The invention relates also to the use of compounds of General formula I to obtain pharmaceutical compositions suitable for the treatment and prevention of diabetes and complications of diabetes.

1. Medicinal products containing as active principle at least one compound of General formula

< / BR>
in which R1means stereoisomeric forms chain

(SNON)3-CH2HE (II)

and either R2denotes a hydrogen atom, and R3means stereoisomeric forms chain

-CH2(SNON)2-CH2HE (III)

or R2means stereoisomeric forms chain

(SNON)3-CH2HE (II)

or

-CH2(SNON)2-CH2OH (III)

a R3denotes a hydrogen atom, except

fructosamine formula

< / BR>
deoxyglucosone formula

< / BR>
and the compounds of formula

< / BR>
or a salt of these compounds with organic or mineral acids.

2. Drug under item 1, in which the compound of formula I selected from the following compounds:

1-[5-(1R, 2R, 3R, 4-tet 2R, 3S, 4-tetraol,

1-[5-(1R, 2S, 3S, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1R, 2S, 3S, 4-tetraol,

1-[5-(1S, 2R, 3R, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1S, 2R, 3R, 4-tetraol,

1-[5-(1S, 2R, 3S, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1S, 2R, 3S, 4-tetraol,

1-[5-(1S, 2S, 3R, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1S, 2S, 3R, 4-tetraol,

1-[5-(1S, 2S, 3S, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1S, 2S, 3S, 4-tetraol,

1-[5-(2R, 3R, 4-trihydroxybutane)pyrazin-2-yl] butane-1R, 2R, 3R, 4-tetraol,

1-[5-(2R, 3S, 4-trihydroxybutane)pyrazin-2-yl] butane-1R, 2R, 3S, 4-tetraol,

1-[5-(2S, 3S, 4-trihydroxybutane)pyrazin-2-yl] butane-1R, 2S, 3S, 4-tetraol,

1-[5-(2R, 3R, 4-trihydroxybutane)pyrazin-2-yl] butane-1S, 2R, 3R, 4-tetraol,

1-[5-(2R, 3S, 4-trihydroxybutane)pyrazin-2-yl] butane-1S, 2R, 3S, 4-tetraol,

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] butane-1S, 2S, 3R, 4-tetraol,

1-[5-(2S, 3S, 4-trihydroxybutane)pyrazin-2-yl] butane-1S, 2S, 3S, 4-tetraol,

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

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

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

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

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

1-[6-(2S, 3S, 4-Tr is Linyi acids.

3. The compounds of formula

< / BR>
in which R1means stereoisomeric forms chain

(SNON)3-CH2HE (II)

or R2denotes a hydrogen atom, and R3means stereoisomeric forms chain

-CH2(SNON)2-CH2HE (III)

or R2means stereoisomeric forms chain

(SNON)3-CH2HE (II)

or

-CH2(SNON)2-CH2OH (III)

R3denotes a hydrogen atom,

or their salts with mineral or organic acids, with the exception of the compounds of formulas (see graphic part).

4. Connection on p. 3, representing the following connections:

1-[5-(1R, 2R, 3S, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1R, 2R, 3S, 4-tetraol,

1-[5-(1S, 2R, 3R, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1S, 2R, 3R, 4-tetraol,

1-[5-(1S, 2S, 3R, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1S, 2S, 3R, 4-tetraol,

1-[5-(1S, 2S, 3S, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1S, 2S, 3S, 4-tetraol,

1-[5-(2R, 3S, 4-trihydroxybutane)pyrazin-2-yl] butane-1R, 2R, 3S, 4-tetraol,

1-[5-(2S, 3S, 4-trihydroxybutane)pyrazin-2-yl] butane-1R, 2S, 3S, 4-tetraol,

1-[5-(2R, 3R, 4-trihydroxybutane)pyrazin-2-yl] butane-1S, 2R, 3R, 4-tetraol,

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] butane-butil)pyrazin-2-yl] butane-1S, 2R, 3R, 4-tetraol,

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

and salts of these compounds with mineral or organic acids.

5. The compounds of formula 1 on p. 3, representing the following connections:

1-[5-(2S, 3S, 4-trihydroxybutane)pyrazin-2-yl] butane-1R, 2S, 3S, 4-tetraol,

1-[5-(2R, 3R, 4-trihydroxybutane)pyrazin-2-yl] butane-1S, 2R, 3R, 4-tetraol,

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] butane-1S, 2S, 3R, 4-tetraol

and salts of these compounds with mineral or organic acids.

6. The compounds of formula (I) under item 3, to obtain pharmaceutical compositions used for the treatment and prevention of diabetes and complications of diabetes.

7. The method of obtaining compounds of formula 1 on p. 3 in which R1means stereoisomeric forms chain -(SNON)3-CH2OH (II), R2denotes a hydrogen atom, and R3means stereoisomeric forms chain-CH2-(CHOH)2-CH2OH (III), characterized in that the ammonium formate is introduced into the reaction Aldatu or a mixture of two algos of programalso or levogyrate number of General formula

CHO-CHOH-R1(X)

in which R1has the same meaning as in paragraph 3,

produce the product and make actose, D-allose, D-altrose, D-idose, D-talose, L-glucose, L-mannose, L-galactose, L-allose, L-altrose, L-idose, L-talose, L-gulose.

9. The method of obtaining compounds of formula I on p. 3 in which R1means stereoisomeric forms chain -(SNON)3-CH2HE (II), R2means stereoisomeric forms chain -(SNON)3-CH2HE (II), and R3is a hydrogen atom, characterized in that aminoacids or a mixture of two aminoacids General formula SNO-CH(NH2)-R1(XI) in which R1has the same meaning as in paragraph 3, are alkaline environment, produce the product and make it optionally in salt with a mineral or organic acid.

10. The method according to p. 9, which is used by aminoalcohol formula XI is D-galactosamine.

11. The method of obtaining compounds of formula I on p. 3 in which R1means stereoisomeric forms chain -(SNON)3-CH2HE (II), R2means stereoisomeric forms chain-CH2(SNON)2-CH2HE (III), and R3is a hydrogen atom, characterized in that the ketosis or a mixture of two ketosis General formula HOCH2-CO-R1(XII) in which R1has the same meaning as in paragraph 3, is introduced into reaction with formate Ammon 12. The method according to p. 11, in which a derivative of formula XII is D-psicose, D-corbea, D-tagatose, L-psicose, L-fructose, L-sorbose or L-tagatose.

 

Same patents:

The invention relates to applicable in medicine new derived aminotriazole or its hydrate and its pharmaceutically acceptable salts

The invention relates to new aminoven derivatives, processes for their production and insecticide containing as selective compounds listed derivatives

The invention relates to medicine, in particular to diabetology and gastroenterology, and can be used in the treatment of diabetes mellitus type II with exacerbation of chronic gastroduodenal ulcers

The invention relates to new amide derivatives of General formula (I) or their salts, where a means thiazolidin, imidazoline, triazoline, benzimidazolyl, benzothiazolyl, thiadiazolyl, imidazopyridine or imidazothiazole; X is a bond, -NR5-, -NR5CO-, -NR5CONH-, NR5SO2-, -NR5C(= NH)NH-; R1means H, lower alkyl, aryl, pyridyl, thienyl, furyl, thiazolyl, benzimidazolyl, imidazopyridine, triazolyl, thiadiazolyl, imidazolyl, imidazothiazoles, benzothiazolyl, cyclohexyl, which may be optionally substituted with halogen, lower alkyl, -OH, -CN, -NO2, -CF3, -NH2, -O-lower alkyl, and the Deputy of the lower alkyl may be substituted by phenyl, naphthyl, fullam, tanila or pyridium;2a, R2bmean H or lower alkyl; R3means hydrogen or lower alkyl; R4a, R4bmean H or HE, or taken together form a group =O or =N-O-lower alkyl; R5means H or lower alkyl

The invention relates to medicine, namely to the creation of new biologically active food additives on the basis of bis(L-malate)oxovanadate (IV) having insulin-like action and providing preventive and therapeutic effect on diabetes

The invention relates to the field of medicine may be used for the treatment of late diabetic complications, namely diabetic polyneuropathy

The invention relates to medicine, in particular to endocrinology, and for the treatment of non-insulin dependent diabetes mellitus (NIDDM)

The invention relates to amide derivatives of formula (I), where a is a monocyclic heteroaryl group, X is a bond or alkilinity group, R is hydrogen, halogen, alkyl, amino, arylalkyl group or halogen(aryl)alkyl group
The invention relates to medicine, specifically to a pharmaceutical composition having antimicrobial activity comprising as active principle an effective amount sulfalena and targeted supplements, which are used potato starch and/or corn, oxypropylation, magnesium stearate and/or calcium

The invention relates to new derivatives of 4-(1-piperazinil)benzoic acid of formula I in which Ar represents a mono-, di - or tricyclic aryl having from 6 to 14 carbon atoms, while Ar may have from 1 to 3 substituents selected from the group comprising (C1-C8)alkyl, (C1-C8)alkoxy, halogen, trifluoromethyl; R1selected from the group comprising a hydrogen atom, cycloalkyl containing from 3 to 8 carbon atoms, (C6-C14)aryl, heteroaryl(C1-C6)alkyl, and heteroaryl selected from the group comprising furyl; R2and R3is hydrogen, a solvate and a pharmaceutically acceptable salt

The invention relates to arylalkylamines formula I, where In - unsubstituted pyridyl, pyrazinyl, isoxazolyl or thienyl; Q - CH2; X - CH2or S; R1and R2each - H; and R3- OR5; R4OA; R5- Or cycloalkyl with 4-6 C atoms; And the alkyl with 1-6 C-atoms, and their physiologically acceptable salts
The invention relates to the field of medicine and relates to a pharmaceutical composition having anti-TB activity

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides composite therapeutical agent exhibiting antituberculous effect and made in the form of solid dosage form containing as active principle combination of lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus auxiliaries.

EFFECT: increased assortment of antituberculous drugs.

4 cl, 1 tbl, 4 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides high-activity antituberculous formulation made in the form of solid dosage form containing as active principle combination of lomefloxacin, protionamide, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus pharmaceutically acceptable auxiliaries.

EFFECT: increased assortment of antituberculous drugs.

4 cl, 1 tbl, 4 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides antituberculous formulation made in the form of solid dosage form containing as active principle combination of isoniazid, rifampicin, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus pharmaceutically acceptable auxiliaries: starch, lubricant, and optionally microcrystalline cellulose. Composition is characterized by storage stability and high therapeutical efficiency.

EFFECT: increased assortment of antituberculous drugs.

6 cl, 2 tbl, 3 ex

Up!