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 either R1means chain-CH(Ra)-NON-NON-CH2HE and R2means chain-CH2-NON-NON-CH2HE, or R1means chain-CH2-NON-NON-CH2HE and R2means chain-CH2-NON-NON-CH2HE, or R1and R2the same and each one represents a chain -- (SNON)n-CH2HE, where n is 1, 2, 3, or 4 Ra means CNS radical with 1-6 carbon atoms in a straight or branched chain, with the exception of the compounds of formulas II and III. Also described is a method of obtaining compounds of formula I. Compounds exhibit hypoglycemic activity and therapy are of interest for the prevention and treatment of diabetes. 3 S. and 3 C.p. f-crystals.

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The invention concerns pharmaceutical preparations containing as active principle at least one compound of the formula

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or one of its stereoisomers or their salts with mineral or organic acid, and also new compounds of the formula (I) and their poluchaeca-CH2-NON-NON-CH2HE

or R1means chain-SNON-CHF-CHOH-CH2OH and R2means chain-CH2-F-SNON-CH2HE

or R1means chain-CHOH-CHOH-CHOH-Rb and R2means chain-CH2-NON-NON-Rb

or R1means chain-CH2-CHOH-CHOH-CH2OH and R2means chain-CH2-NON-NON-CH2HE

or R1and R2the same and each one represents a chain -- (SNON)n-CH2HE, where n is 1, 2, 3, or 4

Ra means CNS radical (with 1-6 carbon atoms in a straight axis or branched chain) or fluorine atom,

Rb means a carboxyl radical, -CO-NH2or-CH2-NH2.

The compounds of formula (I), contain several asymmetric carbon atoms have the form of stereoisomers. Such different stereoisomers are included in the invention.

The connection formulas

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described in Nippon Shokuhin Kogyo Gakkaishi 37(2), 154 (1990), Agric. Biol. Chem. 44(5), 1189 (1980), Carbohydr. Res. 67(2), 549 (1978).

The connection formulas

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

For data derived no pharmacological activity has not been described.

Other compounds of formula (I) are new and this is mi are those in which the active agent contains at least one of the following connections:

- 4-[6-(2,3,4-trihydroxyphenyl)-pyrazin-2-yl] -4-methods-sebutan-1,2,3-triol,

- 4-[6-(2,3,4-trihydroxyphenyl)-pyrazin-2-yl]-4-verboten-1,2,3-triol,

- 1-[6-(2-fluoro-3,4-dihydroxybutyl)-pyrazin-2-yl] -2-verboten-1,3,4-triol,

- 1-[6-(2,3-dihydroxy-4-aminobutyl)-pyrazin-2-yl] -4-aminobutane-1,2,3,4-triol,

- 4-[6-(2,3-dihydroxy-4-carboxypropyl)-pyrazin-2-yl] -2,3,4-trihydroxybutane acid,

- 4-[6-(2,3-dihydroxy-4-carbamoylmethyl)-pyrazin-2-yl] -2,3,4-trihydroxybutane,

- 4-[6-(2,3,4-trihydroxyphenyl)-pyrazin-2-yl]-butane-1,2,3-triol,

- 1-[6-(1,2-dihydroxyethyl)-pyrazin-2-yl]-ethane-1,2-diol,

- 1-[6-(1,2,3-trihydroxypropane)-pyrazin-2-yl]-propane-1,2,3-triol,

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

- 1-[6-(1,2,3,4,5-pentahydroxy)-pyrazin-2-yl] -pentane-1,2,3,4 S, 5-pentol,

as well as their stereoisomers and their salts with mineral or organic, pharmacologically compatible acid.

Particularly preferred drugs are those which contain a compound selected from the following compounds:

- 4-[6-(2S, 3R, 4-trihydroxysilyl)-pyrazin-2-yl]-4R-methoxybutan-1,2 R, 3S-triol,

- 4-[6-(2S, 3R,4-trihydroxysilyl)-pyrazin-2-yl]-4R-verboten-1,2 R,3R-triol,

- 1-[6-(2S-fluoro-3R,4-dihydroxybutyl)-pyrazin-2-yl]-2S-verboten-1R,3R, 4-triol,

- 4-[6-(2R, 3R,4-trihydroxysilyl)-pyrazin-2-yl]-4S-verboten-1,2 R,3R-triol,

- 1-[6-(2S,3R-dihydroxy-4-aminobutyl)-pyrazin-2-yl]-4-aminobutane-1R,2R, 3R-triol,

- 1-[6-(2S,3S-dihydroxy-4-aminobutyl)-pyrazin-2-yl]-4-aminobutane-1,2 R, 3S-triol,

- 4-[6-(2S, 3S-dihydroxy-4-carboxypropyl)-pyrazin-2-yl] - 2S,3S,4R-trihydroxybutane acid,

- 4-[6-(2R, 3S-dihydroxy-4-carboxypropyl)-pyrazin-2-yl]-2S,3R,4R-trihydroxybutane acid,

- 4-[6-(2S,3S-dihydroxy-4-carbamoylmethyl)-pyrazin-2-yl]-23,3 S,4R-trihydroxybutane,

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

- 4-[6-(2R,3R,4-trihydroxysilyl)-pyrazin-2-yl]-butane-1,2 R,3R-triol,

- 1-[6-(1R,2-dihydroxyethyl)-pyrazin-2-yl]-ethane-1R,2-diol,

- 1-[6-(1S,2-dihydroxyethyl)-pyrazin-2-yl]-ethane-1,2-diol,

- 1-[6-(1R,2S,3-trihydroxypropane)-pyrazin-2-yl]-propane-1R,2S,3-triol,

- 1-[6-(1S,2R,3-trihydroxypropane)-pyrazin-2-yl]-propane-13,2 R,3-triol,

- 1-[6-(IS,2S,3-trihydroxypropane)-pyrazin-2-yl]-propane-1S,2S,3-triol,

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

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

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

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

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

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

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

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

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

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

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

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

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

and their salts with mineral or organic, pharmaceutically compatible acid.

Even more preferred drugs are those which contain a compound selected from the following compounds:

- 4-[6-(2S, 3R, 4-trihydroxysilyl)-pyrazin-2-yl]-4R-methoxybutan-1,2 R, 3S-triol,

- 4-[6-(2R, 3R, 4-trihydroxysilyl)-pyrazin-2-yl]-4S-methoxybutan-1,2 R, 3R)-pyrazin-2-yl]-4R-verboten-1,2 R,3R-triol,

- 1-[6-(2S-fluoro-3R,4-dihydroxybutyl)-pyrazin-2-yl]-2S-verboten-1R,3R, 4-triol,

- 4-[6-(2R, 3R,4-trihydroxysilyl)-pyrazin-2-yl]-4S-verboten-1,2 R,3R-triol,

- 1-[6-(2S,3R-dihydroxy-4-aminobutyl)-pyrazin-2-yl]-4-aminobutane-1R,2R, 3R-triol,

- 1-[6-(2S,3S-dihydroxy-4-aminobutyl)-pyrazin-2-yl]-4-aminobutane-1R,2R, 3S-triol,

- 4-[6-(2S, 3S-dihydroxy-4-carboxypropyl)-pyrazin-2-yl]-2S,3S,4R-trihydroxybutane acid,

- 4-[6-(2R, 3S-dihydroxy-4-carboxypropyl)-pyrazin-2-yl]-2S,3R,4R-trihydroxybutane acid,

- 4-(6-(2S,3S-dihydroxy-4-carbamoylmethyl)-pyrazin-2-yl]-2S,3S,4R-trihydroxybutane,

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

- 4-[6-(2R,3R,4-trihydroxysilyl)-pyrazin-2-yl]-butane-1,2 R,3R-triol,

and their salts with mineral or organic acid.

The compounds of formula (I) can be obtained by the action of ammonium formate at one or two derivatives of the formula

OHC-CHOH-Rc (II)

in which RC means chain-CH(Ra)-CHOH-CHOH-CH2HE, -CHOH-CHF-CHOH-CH2HE IS NON-NON-NON-Rb, -CH2-NON-NON-CH2OH or -(SNON)n-CH2HE, where n is 1, 2, 3, or 4 Ra CNS means the radical (1 to 6 carbon atoms in a straight or branched chain) or a fluorine atom, Rb denotes a carboxyl radical, -CO-NH is about, in the aquatic environment at a temperature of from 20 to 100oC.

Derivatives of the formula (II) and their stereoisomers are commercially available or can be obtained from:

a) commercially available of aldos:

- epimerization reactions carried out using the methods described in Adv. Carbohydr. Chem., 13, 63, (1958), and their adapted versions, in particular in the basic environment using dilute aqueous sodium hydroxide solution (0,03-0,05%) at a temperature of from 20 to 40oWITH,

- reactions of elongation of the chain by using the methods described in "The Carbohydrates", publishers W. Pigwan and D. Horton, Academic Press, New-York, T. IA, 133 (1972), and their adapted versions, in particular, with the formation of cyanhydrin source an aldose (for example, the influence of sodium cyanide in aqueous solution at temperatures from 10 to 30oIn the presence of sodium hydroxide and at a pH of about 9), followed by hydrolysis of the obtained nitrile function to the corresponding acid, carried out by the methods described in Organic Synthesis, volume I, S. 436, and volume III, S. 85 and their variants (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), then restore functions carboxylic acid with whom and with alkali metal borohydride (e.g., sodium borohydride), in aqueous solution at a temperature of 20oC to the boiling point of the reaction medium,

- reactions shortening chains using the methods described in "The Carbohydrates", editors: W. Pigman and D. rton. Academic Press, New-York, volume IB, 1980, S. 929 or Chem. Ber., 83, 559 (1950), and their adapted versions, in particular the conversion of the aldehyde functions of an aldose to the corresponding hydroxylamine by using the methods described in Organic Synthesis, volume II, page 314 (for example, with hydroxylamine hydrochloride in aqueous solution and in the presence of a base such as sodium carbonate, at a temperature of from 20 to 50oC), and their adapted versions, then the influence of 3,4-dinitrofluorobenzene in the presence of carbon dioxide and a base such as sodium bicarbonate in aqueous solution, as well as aliphatic alcohol (e.g. isopropyl alcohol) at a temperature of from 50 to 80oWITH,

b) the corresponding allyl alcohols using the methods described in Science, 220, 949 (1983), and their adapted versions, in particular, using the gidroperekisi tert-butyl in the presence of titanium complex (IV), such as complex isopropylate titanium (IV), and tartrate optically pure dialkyl (e.g., diethyltartrate) with further posledn Diisopropylamine.

Derivatives of the formula (II) can also be obtained using the methods described in J. Am. Chem. Soc., 113(21), 8137 (1991), Chem. Pharm. Bull., 35(7), 2894 (1987), Carbohydr. Res. , 154, 127 (1986), Sen i Gakkaihi, 35(12), 525 (1979), Chem. Ber., 101(7), 2294 (1968), J. Carbohydr. Chem., 3(2) 219 (1984) and Tetrahedron, 40(12), 2233 (1984) and in patents WO 9310137, WO 89-US51089029 and their adapted versions.

Different stereoisomers of the compounds of formula (I) is obtained on the basis of the corresponding stereoisomers of the intermediate product (II). Of these stereoisomers, preferably using 3-methoxy-D-glucopyranose, 3-fluoro-3-deoxy-D-glucose, 4-fluoro-4-deoxy-D-glucose, 6-amino-6-deoxy-D-glucose, D-glucuronic acid, D-galacturonic acid, D-glucuronamide and 3-deoxy-D-glucose.

For professionals it is obvious that when using the above methods according to the invention may require the introduction of protective groups for functions: amino, hydroxy and carboxy, to prevent secondary reactions. Such groups are those that can be removed without touching the rest of the molecule. As examples of protective groups for the function amino, you can specify carbamates, tert-butyl or methyl, which can be played using attributively. As examples, illustrious. As protective groups for carboxyl functions, you can specify esters (for example, a complex methoxymethyl, tetrahydropyranyl, benzyl esters), oksazolov and 2-alkyl-1,3-oxazoline. Other protective groups used in the above methods, are also described in K. GREEN and al., Protective Groups in Organic Synthesis (Protective groups in organic synthesis, 2nd edition, 1991, Jhon Wiley & Sons and P. J. KOCIENSKI, Protecting Groups, ed. Thieme Verlag (1994).

The reaction mixture obtained in various ways, described above, traditional physical (e.g., evaporation, extraction, distillation, chromatography, crystallization) or chemical (for example, salt formation) methods.

If necessary, the compounds of formula (I) can be transformed into additive salts with a mineral or organic acid by exposure to this acid in a medium of an organic solvent, such as alcohol, ketone, simple ether or a chlorinated solvent.

Such salts are also part of the invention.

As examples of the pharmacologically compatible salts can specify additive salts with mineral or organic acids, such as acetate, propionate, succinate, benzoate, fumarate, maleate, is t, nitrate and phosphate.

Preferred compounds of formula (I) are the compounds listed above as the active principle in the preferred medications, except for known products.

The following examples illustrate the invention.

EXAMPLE 1

In a solution consisting of 2 g of 3-methoxy-D-glucopyranose 3.4 cm3distilled water, add 3.2 g of ammonium formate. The reaction mixture is heated under reflux with stirring and at a temperature of 100oC for 2 hours, After cooling the mixture to a temperature of about 25oWith its diluted to 25 cm3ethyl acetate and defend. The aqueous phase is washed with 25 cm3ethyl acetate, then concentrated under reduced pressure (2.7 kPa) at a temperature of approximately 70oC. the Residue collect 100 cm3absolute ethanol and stirred for 24 h resulting precipitate is filtered through sintered glass, washed several times with absolute ethanol, the filtrate is concentrated under reduced pressure (2.7 kPa) at a temperature of approximately 45o(Operation is repeated once). The residual oil is subjected to chromatography on a column with 160 g of silica (0.02 to 0.05 mm), diluted with a mixture of water . The fractions containing the desired product are pooled and concentrated under reduced pressure (2.7 kPa) at a temperature of approximately 55oC. thus obtain 4-[6-(2S, 3R,4-trihydroxysilyl)-pyrazin-2-yl]-4R-methoxybutan-1,2 R,3S-triol [NMR spectrum1H (400 MHz, (CD3)2SO d6in'clock N. m): 2,73 and 3,09 (2 DD, respectively J= 14 and 9.5 Hz, J=14 and 3 Hz, each 1H:CH26); to 3.34 (s, 3H: co3in position 2); 3,30-3,55 and 3,55-3,70 (2 MTS:7H match: CH 2 - CH 2 - CH2About 2 - CH 6 and CH26); 3,79 (MT, 1H:CH 6); 4,00-5,00 (several distributed MFS:HE); br4.61 (broad s, 1H:CH 2); 8,39 (s, 1H:= CH in position 5); 8,42 (s, 1H:=CH in position 3).

EXAMPLE 2

In a solution of 10 g L-gulose 28 cm3distilled water is added 21 g of ammonium formate. The reaction mixture is heated under reflux with stirring and at a temperature of about 100oC for 30 minutes After cooling to a temperature of about 25oThe mixture is concentrated under reduced pressure (2.7 kPa) and at a temperature of about 50oC. the remainder of the 5 five-dissolved in ethanol, then concentrate under the same conditions, and finally dissolved in ethanol and stirred for 3 hours the resulting precipitate is filtered through sintered glass, washed with diethyl afroamerican in the column with 800 g of silica (0.02 to 0.05 mm), elwira a mixture of water-ethanol in a ratio of 1:19 in volume at atmospheric pressure and collect fractions of 30 cm3. The fractions containing the desired product are pooled and concentrated under reduced pressure (2.7 kPa) and a temperature of approximately 40oC. the resulting product will recrystallized in a mixture of water-ethanol, and then dried under reduced pressure (2.7 kPa) at a temperature of approximately 25oC. Get l-[6-(1R,2S,3S,4-tetrahydroquinolin)-pyrazin-2-yl]-butane-1R,2S,3S,4-tetraol. The compounds of formula (I) possess interesting pharmacological properties. They are hypoglycemic agents.

Hypoglycemic effect of compounds of formula (I) was determined by the hyperglycemic response to oral glucose to mice with normal blood sugar level in accordance with the following Protocol.

Swiss albino mice (Swiss albinos) weighing from 22 to 26 g were kept without food for 2 hours At the end of this period was determined by the sugar content in the blood and immediately orally introduced them a dose of glucose (2 g/kg). After 30 min again determined the content of sugar in the blood. Mouse, a reaction which resulted in hyperglycemia, greater than 170 mg/DL, were processed and used opredelennosti at least 10 animals in each. Different groups were given once daily by introduced into the stomach tube a solution of the test product in an amount of from 3 to 50 mg/kg in a medium such as water or a mixture of methylcellulose/tween and water or media. This regime lasted 4 days. On the fourth day, after the last treatment, animals received a dose of glucose (2 g/kg), and after 20-40 min was determined by the sugar content in the blood. The percentage of suppression of the hyperglycemic response to glucose was calculated relative to the response measured in the group that received media.

In this test, the compounds according to the invention demonstrate the suppression of the development of hyperglycemia by 10% or more.

Compounds of General formula (I) according to the invention are of low toxicity. The rate LD50 for mice during oral introduction of more than 2000 mg/kg

In human therapy, these products are useful for the prevention and treatment of diabetes, particularly type II diabetes (diabetes NID), diabetes, fat, diabetes, midlife, metapleural diabetes, senile diabetes and diabetes in an easy manner. They can be used later on in insulin insulin-dependent diabetes, in which they pozwolenie to hypoglycemic sulfonamides, when last did not sufficiently reduce the sugar content in the blood. Also, such products can be used in diabetic complications, such as hyperlipemia, lipid metabolism, dyslipemia, obesity. It is useful to apply them also in the prevention and treatment of atherosclerotic lesions and their complications (colonopathy, myocardial infarction, cardiomyopathy, the development of these three types of complications in the failure of the left ventricle, various arteriopathy, arteritis of the lower limbs with lameness and progression in the direction of ulcers and gangrene, cerebral vascular insufficiency and its complications, impotence of vascular origin), diabetic retinopathy and all its manifestations (increased capillary permeability, expansion and pulmonary capillary microaneurysms, arteriovenous collateral, varicose veins, dotty and spotty hemorrhages, exudates, spotted swelling, symptoms of proliferative retinopathy: the tumor vessels, scars proliferative retinitis, vitreous hemorrhage, retinal detachment), diabetic cataract, diabetic neuropathy in different forms (peripheral polyneuropathy and their manifestations, such as Paris diabeticheskih manifestations feet (ulcers on the lower limbs and feet), diabetic nephropathy in two forms: diffuse and nodular, atheromatosis (increased levels of high density lipoprotein (HDL), facilitates the removal of cholesterol from plaques of atheroma, reducing low-density lipoprotein (LDL), decrease of the ratio LDL/HDL, the slow oxidation of low-density lipoproteins, decreased adhesion plaques), hyperlipemia and dyslipemia (hypercholesterolemia, hypertriglyceridemia, normalization of the levels of fatty acids, normalization of uricemia, normalization of apoproteins a and b), cataracts, high blood pressure and its consequences.

Medicinal product according to the invention consist of one of the compounds according to the invention or a combination of these products in pure form or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which is inert or physiologically active. Medicinal product according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration may be tablets, pills, powders (gelatin capsules, pills or granules. In such compositions, the active principle according to the image is over or silicon dioxide, in a stream of argon. Such compositions can in addition thinners contain other substances, for example one or more lubricants such as magnesium stearate or talc, a colorant, a shell (pills) or icing.

As liquid compositions for oral administration can be used pharmaceutically compatible solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable or paraffin oil. Such compositions may contain in addition to the solvents and other substances, for example wetting, sweetening, thickening, flavouring or stabilizing products.

Sterile compositions for parenteral administration can preferably be aqueous or nonaqueous solutions, suspensions or emulsions. As a solvent or carrier, you can use water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, complex organic esters for injection, for example etiloleat or other suitable organic solvents. Such compositions may also contain additives, in particular wetting, isotonic, emulsifying, dispersing and stabilizatio sterilizing substances, irradiation or heating. They can be prepared in the form of sterile solid compositions, which at the time of application can be dissolved in sterile water or any other sterile environment for injection.

Compositions for rectal injection are suppositories or capsules for rectal use, containing in addition to the active substance indifferent substances, such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for external use can be, for example, creams, lotions, eye drops, gargle for mouth, nasal drops or aerosols.

The dose depends on the desired effect, the duration of treatment and the route of administration: usually, it ranges from 150 to 600 mg per day for oral introduction to the adult, with single dose of 50 mg to 200 mg of active substance.

Typically, the required dosage is prescribed by a physician taking into account age, weight and all other factors relating to the patient.

The following examples illustrate compositions according to the invention.

EXAMPLE A.

According to the traditional technology prepare gelatin capsules containing 50 mg of active the Naya silicon dioxide - 1

Sodium carboxymethylate starch - 10

Talc - 10

Magnesium stearate - 1

EXAMPLE Century.

According to the traditional technology to prepare tablets containing 50 mg of active substance, of the following composition, mg:

Active substance - 50

Lactose - 104

Cellulose - 40

Polyvidone - 10

Sodium carboxymethylate starch - 22

Talc - 10

Magnesium stearate - 2

Colloidal silicon dioxide - 2

A mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3,5-24,5) - enough for 1 ready, film-coated, tablets weighing 245 mg - 245

EXAMPLE C.

Prepare a solution for injection containing 50 mg of active substance, of the following composition:

Active substance 50 mg

Benzoic acid 80 mg

Benzyl alcohol - 0.06 ml

Sodium benzoate - 80 mg

Ethanol 95% - 0.4 ml

Sodium hydroxide - 24 mg

Propylene glycol - 1,6 ml

Water In sufficient quantity to 4 ml

The invention also concerns the use of compounds of General formula (I) to obtain a pharmaceutically effective compositions for the treatment or prevention of diabetes and its complications.

1. Medicinal products containing as active is HE-CH2HE and R2means chain-CH2-NON-NON-CH2HE

or R1means chain-CH2-NON-NON-CH2HE and R2means chain-CH2-NON-NON-CH2HE

or R1and R2the same and each one represents a chain -- (SNON)n-CH2HE, where n is 1, 2, 3, or 4

Ra means CNS radical (with 1-6 carbon atoms in a straight or branched chain), their stereoisomers and their salts with mineral or organic acid.

2. Drug under item 1, characterized in that the compound of formula (I) under item 1 is-1-[6-(1R, 2S, 3S, 4-tetrahydroquinolin)pyrazin-2-yl] butane-1R, 2S, 3S, 4-tetraol.

3. Drug under item 1, characterized in that the compound of formula (I) p. 1 represents-4-[6-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -4R-methoxybutan-1,2 R, 3S-triol.

4. Derivatives polyhydroxyalkanoates formula (I)

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where either R1means chain-CH(Ra)-NON-NON-CH2HE and R2means chain-CH2-NON-NON-CH2HE

or R1means chain-CH2-NON-NON-CH2HE and R2means chain-CH2-NON-NON-CH2HE

or R
Ra means CNS radical (with 1-6 carbon atoms in a straight or branched chain), except for compounds of the formula

< / BR>
< / BR>
their stereoisomers and their salts with mineral or organic acid.

5. The compound of formula (I) under item 4 or one of its stereoisomers or one of its salts with a mineral or organic acid, intended for production of pharmaceutical compositions suitable for the treatment or prevention of diabetes and its complications.

6. The method of obtaining compounds of formula (I) under item 4, which consists in the fact that they are carrying out the reaction between the ammonium formate and one or two derivatives of the formula

OHC-CHOH-Rc (II)

where RC denotes the chain-CH(Ra)-CHOH-CHOH-CH2OH, -CH2-NON-NON-CH2HE or -(SNON)n-CH2HE, where n is 1, 2, 3, or 4 Ra means CNS radical (with 1-6 carbon atoms in a straight or branched chain) or one of its stereoisomers,

highlight the product and, if necessary, turn it into a salt with a mineral or organic acid.

Priority points and features:

17.07.1997 on PP. 1, 3-6 - all values radicals, except for R1= R2(SNON)n-CH2HE is the compounds of formula 1;

 

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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
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

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein n = 1 or 2; R1 represents chlorine, fluorine, bromine atom, methyl or methoxy-group; R2 is taken among of one the following groups: (i) halogen atom, nitro-, hydroxy- amino- or cyano-group; (ii) -X1-R5 wherein X1 represents -O-, -S-, -SO-, -SO2-, NR6-, -CO-, -CONR6-, -NR6CO- wherein R6 represents hydrogen atom and R5 is taken among (C1-C6)-alkyl optionally substituted with one or some A, and so on; (iii) 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom and so on; R3 represents (C1-C6)-alkyl optionally substituted with one or some A and so on; A is taken among hydroxy-, amino-group, halogen atom, carboxy-, N-(C1-C4-alkyl)-amino-, N,N-di-(C1-C4-alkyl)-amino-group, carbamoyl and (C1-C6)-alkoxy-group; D is taken among: (i) -Xa-Rc wherein Xa represents -SO2, -CO-, -NRdCO-, -NRd- or -CONRd-; (iv) cyano-group or halogen atom; (v) -XcRf wherein Xc represents -C(O)- and Rf represents 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom with optionally additional heteroatom taken independently among oxygen atom (O), optionally substituted at ring carbon atom by the hydroxy-group, halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or cyano-group; G represents (C1-C6)-alkanoyl; R4 represents hydrogen or fluorine atom; or to its pharmaceutically acceptable salt or its ester hydrolyzed in vivo. Also, invention proposes a method for preparing compound of the formula (I). Also, invention proposes pharmaceutical composition enhancing activity of pyruvate dehydrogenase comprising substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I) or its pharmaceutically acceptable salt or ester hydrolyzed in vivo in combination with pharmaceutically acceptable vehicle or carrier. Invention provides preparing derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 1 tbl, 85 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I with PGl2 receptor agonist activity. In formula R1 and R2 represent independently optionally substituted phenyl; Y represents N, N-O or CR5; Z represents N or CR6; A represents NR7; D represents alkylene or alkenylene; or A and D may together form divalent group; E represents phenylene or direct bond, or D and E may together form divalent group; G represents O, S, SO, SO2; R3 and R4 represent hydrogen atom or alkyl; Q represents carboxyl, alkoxycarboxyl, tetrazolyl, carbamoyl or -CONH-SO-R10 group. Prostaglandin I2(PGl2) is potent inhibitor of platelet aggregation and may be effectively used in treatment of vascular diseases, arteriosclerosis, hypertension, etc.

EFFECT: new compounds and drugs for platelet aggregation inhibition and treatment of vascular and other diseases.

15 cl, 3 tbl, 109 ex

FIELD: organic chemistry, chemical technology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to novel chemical compounds, namely, to complexes of palladium with heterocyclic ligands of the general formula (I): wherein R1 means-NH, oxygen atom (O), -CH2; R2 means two hydrogen atoms (2H), O; R3 means hydrogen atom H, CH3, CH2-CH2-NH2,-(CO)-CH3; X means chlorine (Cl), bromine (Br) atom; n = 1; m = 1 if R1 means -NH, O; R2 means 2H; R3 means H, CH3, CH2-CH2-NH2, -(CO)-CH3; n = 2; m = 1 if R1 means O, -CH2; R2 means O, 2H; R3 means H, CH3, -(CO)-CH3; n = 2; m = 3 if R1 means -NH; R2 means 2H; R3 means CH2-CH2-NH2 eliciting pharmacological, in particular, anti-tumor activity. Proposed compounds possess high activity and characterized by reduced toxicity as compared with anti-tumor preparations with platinum complexes.

EFFECT: valuable medicinal properties of complexes.

4 cl, 2 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): or its pharmaceutically acceptable salt, solvate or hydrolyzed ester wherein R1 and R2 represent independently hydrogen atom or (C1-C3)-alkyl; X represents oxygen atom (O); one of radicals R3 and R4 represents independently hydrogen atom and another represents (C1-C3)-alkyl; X1 represents -CH2 or -SO2; R5 represents (C1-C6)-alkyl (possibly substituted with (C1-C6)-alkoxy- or (C1-C6)-alkylthio-group), (C2-C6)-alkenyl, (C0-C6)-alkylphenyl (wherein phenyl is substituted possibly with one or more -CF3 group, halogen atom, (C1-C3)-alkyl, (C1-C3)-alkoxy-group), -CO-(C1-C6)-alkyl, -SO2-(C1-C6)-alkyl; R6 represents phenyl or 6-membered heteroaryl group comprising 1 or 2 nitrogen atom (N) and wherein phenyl or heteroaryl group are substituted possibly with 1, 2 or 3 groups chosen from group consisting of (C1-C6)-alkyl, phenyl (possibly substituted with one or more group chosen from halogen atom, -CF3, (C1-C3)-alkyl, O-(C1-C3)-alkyl, -CN). Compound of the formula (I) is designated for using as activator of human receptors activated by peroxisomal proliferators (hPPAR). Invention provides derivatives of propionic acids activating human receptors activated by peroxisomal proliferators (hPPAR).

EFFECT: valuable medicinal properties of derivatives.

14 cl, 58 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of aniline of the general formula (I): and their pharmaceutically acceptable salts and isomeric forms possessing properties of phosphodiesterase-4 inhibitors. Compounds can be used, fore example, for enhancing cognitive ability. In compounds of the general formula (I) R1 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more halogen atoms; R2 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkoxy or their combinations, (C3-C10)-cycloalkyl, (C4-C16)-cycloalkylalkyl wherein alkyl fragment comprises from 1 to 4 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and alkyl fragment that can be linear or branched and comprises from 1 to 5 carbon atoms and wherein radical arylalkyl can be unsubstituted or substituted in aryl fragment with one or more substitutes of the following order: halogen atom, alkoxy group comprising from 1 to 4 carbon atoms or their combinations, and in alkyl fragment one group -CH2CH2- is optionally replaced for group -CH=CH-, and one group -CH2- is optionally replaced for -O- for -NH-, partially unsaturated carbocyclic group comprising from 5 to 9 carbon atoms that can comprise condensed benzene ring, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including one atom chosen from oxygen (O), or heterocyclylalkyl group wherein heterocyclic fragment can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including 1-2 atoms chosen from nitrogen (N) or sulfur (S) atoms, and alkyl fragment that can be linear or branched comprises from 1 to 5 carbon atoms; R3 means partially unsaturated carbocyclylalkyl group wherein carbocyclic fragment comprises from 5 to 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein arylalkyl radical can be linear or substituted in aryl fragment with one or more substitutes of the following group: trifluoromethyl, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations, heterocyclylalkyl group wherein heterocyclic fragment can be aromatic, partially or completely saturated and comprises from 5 to 10 atoms in cycle including 1-2 atoms chosen from N, O or S, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein heterocyclylalkyl group can be linear or substituted in heterocyclic fragment with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations; R4 means (C6-C12)-aryl that can be linear or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C2-C4)-alkenyl, hydroxy, (C1-C4)-alkoxy, (C2-C4)-alkoxyalkoxy, nitro, trifluoromethyl, -OCF3, amino group, aminoalkyl, aminoalkoxy, hydroxy-(C1-C4)-alkyl, hydroxamic acid, tetrazol-5-yl, 2-(heterocyclyl)-tetrazol-5-yl, carboxy, alkoxycarbonyl, cyano, acyl, alkylsulfonyl, phenoxy, trialkyloxy, R5-L or their combinations, or heteroaryl comprising from 5 to 10 atoms in cycle including 1-2 atoms chosen from N wherein heteroaryl can be linear or substituted with one or more substitutes of the following order: (C1-C4)-alkyl, (C1-C4)-alkoxy, carboxy, alkoxycarbonyl or their combinations; R5 means hydrogen atom, (C1-C8)-alkyl, (C3-C10)-cycloalkyl, C6-aryl, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 10 atoms in cycle from which at least atom means N or O, and wherein heterocyclic group can be linear or substituted with one or more (C1-C4)-alkyls, or group heterocyclylalkyl, and others. Also, invention relates to intermediates compounds and to a method for enhancing the cognitive ability.

EFFECT: valuable biological and biochemical property of compounds.

49 cl, 8 sch, 26 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of aniline of the general formula (I): and their pharmaceutically acceptable salts and isomeric forms possessing properties of phosphodiesterase-4 inhibitors. Compounds can be used, fore example, for enhancing cognitive ability. In compounds of the general formula (I) R1 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more halogen atoms; R2 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkoxy or their combinations, (C3-C10)-cycloalkyl, (C4-C16)-cycloalkylalkyl wherein alkyl fragment comprises from 1 to 4 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and alkyl fragment that can be linear or branched and comprises from 1 to 5 carbon atoms and wherein radical arylalkyl can be unsubstituted or substituted in aryl fragment with one or more substitutes of the following order: halogen atom, alkoxy group comprising from 1 to 4 carbon atoms or their combinations, and in alkyl fragment one group -CH2CH2- is optionally replaced for group -CH=CH-, and one group -CH2- is optionally replaced for -O- for -NH-, partially unsaturated carbocyclic group comprising from 5 to 9 carbon atoms that can comprise condensed benzene ring, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including one atom chosen from oxygen (O), or heterocyclylalkyl group wherein heterocyclic fragment can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including 1-2 atoms chosen from nitrogen (N) or sulfur (S) atoms, and alkyl fragment that can be linear or branched comprises from 1 to 5 carbon atoms; R3 means partially unsaturated carbocyclylalkyl group wherein carbocyclic fragment comprises from 5 to 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein arylalkyl radical can be linear or substituted in aryl fragment with one or more substitutes of the following group: trifluoromethyl, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations, heterocyclylalkyl group wherein heterocyclic fragment can be aromatic, partially or completely saturated and comprises from 5 to 10 atoms in cycle including 1-2 atoms chosen from N, O or S, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein heterocyclylalkyl group can be linear or substituted in heterocyclic fragment with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations; R4 means (C6-C12)-aryl that can be linear or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C2-C4)-alkenyl, hydroxy, (C1-C4)-alkoxy, (C2-C4)-alkoxyalkoxy, nitro, trifluoromethyl, -OCF3, amino group, aminoalkyl, aminoalkoxy, hydroxy-(C1-C4)-alkyl, hydroxamic acid, tetrazol-5-yl, 2-(heterocyclyl)-tetrazol-5-yl, carboxy, alkoxycarbonyl, cyano, acyl, alkylsulfonyl, phenoxy, trialkyloxy, R5-L or their combinations, or heteroaryl comprising from 5 to 10 atoms in cycle including 1-2 atoms chosen from N wherein heteroaryl can be linear or substituted with one or more substitutes of the following order: (C1-C4)-alkyl, (C1-C4)-alkoxy, carboxy, alkoxycarbonyl or their combinations; R5 means hydrogen atom, (C1-C8)-alkyl, (C3-C10)-cycloalkyl, C6-aryl, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 10 atoms in cycle from which at least atom means N or O, and wherein heterocyclic group can be linear or substituted with one or more (C1-C4)-alkyls, or group heterocyclylalkyl, and others. Also, invention relates to intermediates compounds and to a method for enhancing the cognitive ability.

EFFECT: valuable biological and biochemical property of compounds.

49 cl, 8 sch, 26 ex

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