Acid additive salts derived hydropyridine

 

(57) Abstract:

The present invention relates to an acid additive salt is the hydrochloride and maleate 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine. Described how they receive the drug on the basis of salts and application. An acid additive salt tetrahydrocannabinolic derivatives demonstrate excellent oral absorption, metabolism in active connection and inhibit aggregation of platelets, low toxicity, excellent stability during storage and use. They are suitable as therapeutic or prophylactic agents (preferably therapeutic agents in thrombosis or embolism. 9 c. and 19 C.p. f-crystals, 4 PL.

The present invention relates to an acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (preferably the hydrochloride or maleate), which have excellent oral absorption, metabolism in active connection and activity in the inhibition of platelet aggregation and are useful as therapeutic or preventive agents for diseases, grounded is ethoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and its derivatives, which are antagonists of adenosine receptors (hereinafter referred to here denoted ADP), have excellent activity in the inhibition of platelet aggregation and are useful as antithrombotic or protivoastmaticheskih agents.

For many years the applicants actively investigated the pharmacological activity of various derivatives of hydropyridine to detect compounds having superior activity in the inhibition of platelet aggregation. Applicants have found that the acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (preferably hydrochloride or maleate) possess excellent oral absorption, metabolism in active connection, activity in the inhibition of platelet aggregation, low toxicity and excellent stability during storage and use, and suitable for the quality of medicines (preferably suitable as therapeutic or prophylactic agents, preferably therapeutic agents for diseases caused by thrombus formation or caused by embolism (preferably thrombosis or embolism).

This izopet is prohibited[3,2-c]pyridine (preferably hydrochloride or maleate), which have excellent activity in the inhibition of platelet aggregation; methods for their preparation and medicines based on them, which are suitable for therapeutic or prophylactic agents (preferably therapeutic) for diseases caused by caused by thrombosis or embolism, and preferably suitable as therapeutic or prophylactic agents (preferably therapeutic agents in thrombosis or embolism.

Description of the invention

The present invention relates to an acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (hydrochloride or maleate) and applies to medicines containing acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (hydrochloride or maleate) as the active ingredient.

Acid fragment acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine is, for example, inorganic acid, such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, or organic acid, such doctitle hydrochloric acid or maleic acid.

2-Acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride according to the present invention has the following formula:

2-Acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine maleate has the following formula:

Acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine have in the molecule asymmetric carbon atom and each connection can be two isomers having the R and S configuration. The present invention covers the individual isomers and mixtures of these isomers in any ratio. Optically active isomer of the acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of the present invention can be obtained by using optically active starting material or isolated from the racemic mixture of synthetically derived acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine conventional optical division.

In some cases, when the acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-t the th water or can absorb water to form hydrate. The present invention includes these hydrates.

Acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine get in the presence or absence of an inert solvent (preferably in an inert solvent) addition of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, which are synthesized by the method described in EP 542411 to the acid (preferably by hydrochloric acid, hydrogen chloride (gas) or maleic acid, more preferably by concentrated hydrochloric acid or maleic acid, most preferably by concentrated hydrochloric acid) or in the presence or absence of an inert solvent (preferably in an inert solvent) precapitalism or the addition of acid (preferably hydrochloric acid, hydrogen chloride (gas) or maleic acid, preferably concentrated hydrochloric acid or maleic acid, most preferably concentrated hydrochloric acid) one or more times to 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine. In this way, if necessary, can be added seed crystals of the decree is moved so so it does not adversely affect the reaction and could to some extent dissolve the starting material. Examples of such solvents include aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; derivatives ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylethylenediamine ether; a ketone derivative such as acetone, methyl ethyl ketone or diethylketone; ester derivatives such as ethyl acetate, propyl or butyl acetate; derivatives of carboxylic acids, such as acetic acid or propionic acid, or nitrile derivatives, such as acetonitrile or propionitrile. To obtain the hydrochloride preferred solvents are derivatives ethers, derivatives of ketones, derivatives of esters, derivatives of carboxylic acid or nitrile derivatives; more preferred solvents are tetrahydrofuran, dioxane, Aceto are tetrahydrofuran, dioxane, acetic acid or acetone. The most preferred acetone. On the other hand, to obtain the maleate preferred solvents are derived ethers, derivatives of ketones, derivatives of esters or derivatives of NITRILES; the preferred solvents are tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, or acetonitrile; even more preferred solvents are tetrahydrofuran, dioxane or acetone. Most preferred is acetone.

The reaction temperature varies depending on the reagent, solvent, etc. and usually varies from -20 to 100C, preferably from 0 to 70 ° C. In the case of the hydrochloride, the reaction temperature is preferably from 30 to 60 SECONDS and more preferably from 40 to 55C.

The reaction time varies depending on the reagent, solvent, reaction temperature, etc. and usually ranges from 5 minutes to 10 hours, preferably from 10 minutes to 5 hours.

In the case of obtaining maleate reaction is preferably carried out by adding 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to a solution of maleic acid in acetone at a temperature of interest in the case of obtaining hydrochloride the reaction is preferably carried out by adding or addition of the required quantity of concentrated hydrochloric acid (usually equimolar with respect to thienopyridines derived) to a solution of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in acetone at a temperature in the range from 0 to 70 C (preferably from 35 to 60 S), followed by maintaining at the same temperature over a period of time from 30 minutes to 3 hours.

More preferably the reaction is carried out by adding precapitalism half the required quantity of concentrated hydrochloric acid (usually equimolar with respect to thienopyridines derived) to the solution thienopyridine derivative in acetone at a temperature in the range from 35 to 60, preferably from 40 to 55C) during the period of time from 2 minutes to 10 minutes with the addition if necessary of the seed crystals of the specified salt, followed by maintaining at the same temperature over a period of time from 30 minutes to 2 hours and then further adding precapitalism remaining required quantity of concentrated hydrochloric acid to the reaction mixture over a period of time from 30 minutes to 2 hours, followed by keeping the same temperature for from 1 hour to 3 hours.

After the reaction of the acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine can be isolated from the reaction mixture by conventional means. For example, after the reaction, the obtained crystals are separated by filtration to obtain the specified product or evaporated the solvent of the reaction mixture to obtain the specified product. The SS="ptx2">Acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of the present invention exhibit excellent oral absorption, metabolism in active connection and activity in the inhibition of platelet aggregation, low toxicity and, in addition, stable during storage and use, thus, they are useful as preventive or therapeutic agents (preferably therapeutic agents) for diseases caused by thrombosis or embolism, more preferable as a prophylactic or therapeutic agents (preferably therapeutics) when thrombosis or embolism. Drugs described above are preferably used for warm-blooded animals, preferably humans.

When the acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of the present invention are used as therapeutic or prophylactic agents for the above diseases, they may be administered alone or in a mixture with a pharmaceutically suitable excipients, diluents, etc., in various forms of the AI, suppositories etc. for parenteral purposes.

Each of the above formulations may be obtained by well known methods using additives to compositions, such as excipients, lubricants, binders, disintegrating agents, emulsifiers, stabilizers, taste enhancers (Karagandy) and thinners.

Examples of excipients include organic excipients, for example derivatives of sugars, such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, a-starch or dextrin; cellulose derivatives such as crystalline cellulose; gum Arabic; dextran; pullulan, and inorganic excipients such as silicate derivatives such as silicic acid anhydride, synthetic aluminum silicate, calcium silicate or aluminate of metasilicate magnesium; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives, such as calcium sulfate, etc.

Examples of lubricants include stearic acid; metal derivatives of stearates such as calcium stearate or magnesium stearate; talc; waxes, such as beeswax and Umarova acid; sodium benzoate; DL-leucine; derived lauryl sulphate, such as sodium lauryl sulfate or lauryl sulfate, magnesium; derivatives of silicic acids such as silicic acid anhydride or silicic acid hydrate, and described above excipients starch derivatives.

Examples of the binder include hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, macrogol (trade mark) or excipients, as described above excipients.

Examples of disintegrating agents include cellulose derivatives such as hydroxypropylcellulose with a low degree of substitution, carboxymethylcellulose, calcixerollic or stitched natrocarbonatite; chemically modified starch or cellulose derivatives, such as carboximetilkrahmal or natrocarbonatite; stitched polyvinylpyrrolidine and derivatives of starch, as described above.

Examples of emulsifying agents include colloidal clays such as bentonite or veegum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzal the Fira of polyoxyethylenesorbitan and fatty acids or esters of sucrose and fatty acids.

Examples of stabilizers include derivatives of esters of para-hydroxybenzoic acid, such as methylparaben or propylparaben; derivatives of alcohols, such as chlorobutanol, benzyl alcohol or finitely alcohol; benzylaniline; derivatives of phenol such as phenol or cresol; thimerosal; dehydroacetic acid or sorbic acid.

Examples corrigentov include sweeteners, acidifying agents, fragrances, etc. that are commonly used.

The specific dose of a compound of the present invention varies depending on the severity of the patient's symptoms, age, etc. For oral destination number of the active ingredient in a unit dosage may be from 0.1 mg (preferably 1 mg to 1000 mg (preferably 500 mg). A unit dosage for intravenous destination may be in the range from 0.01 mg (preferably 0.1 mg) to 500 mg, preferably 250 mg) of the compound of the present invention.

The unit dosage may be administered adult from 1 to 7 times a day for 1 to 7 days depending on the severity of the patient's symptoms.

The following examples, reference examples, examples, test examples and compositions, p. the particular steps of the invention.

Example 1

2-Acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (crystal A)

To a solution of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10 g) obtained according to reference example 1 in acetone (150 ml) is added precapitalism concentrated hydrochloric acid (36%, 2,71 g) under stirring at room temperature (25C). A small amount of seed crystals of a given product (crystal And obtained by another method) are added to the solution and the mixture is then stirred for 90 minutes at the same temperature. The resulting crystals are separated by filtration, the crystals washed with a small amount of acetone and then dried at 50 ° C under reduced pressure for 4 hours to obtain the connection specified in the header, in the form of white crystals (8.1 g, yield 74%) (crystal A), so pl. 133-S.

1H NMR (CDCl3) memorial plaques: 0.92-0.99 (1H, m), 1.05-1.16 (2H, m), 1.23-1.34 (1H, m), 1.84-1.95 (1H, m), 2.26 (3H, s), 3.07-3.23 (2H, m), 3.57-4.39 (4H, m), 6.04 (1H, s), 6.45 (1H, ush.C.), 7.37 - 7.57 (3H, m), 7.66-7.75 (1H, m).

Mass spectrum (CI, m/z): 374 (M++1).

IR (KBr),maxcm-1: 1762, 1720.

Example 2

2-Acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]ylcarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (15.0 g), obtained according to reference example 1, the mixture is then stirred at room temperature (25about(C) within 2 hours. The resulting crystals are separated by filtration, washed with a small amount of acetone and then dried at 50 ° C under reduced pressure for 4 hours to obtain the connection specified in the header, in the form of white crystals (17.1 g, yield 92%), so pl. 171-172C.

1H NMR (CD3OD) M. D.: of 0.89 to 0.97 (1H, m), 1,02-of 1.09 (2H, m), 1,14-of 1.23 (1H, m), 1,94-2,03 (1H, m), of 2.25 (3H, s), 3.00 and-to 3.09 (2H, m), 3.33 and-a 3.50 (2H, m), 3,88 (1H, d, J=14,9 Hz), 4.05 (1H, d, J=14,9 Hz), 5,70 (1H, s), of 6.25 (2H, s) 6,40 (1H, s), 7,30-7,42 (2H, m), 7,45-7,52 (1H, m), 7,56-7,66 (1H, m).

Mass spectrum (CI, m/z): 374 (M++1).

IR (KBr),maxcm-1: 1782, 1713.

Example 3

2-Acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (crystal B1)

To a solution of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10 g) obtained according to reference example 1 in acetone (100 ml) add precapitalism concentrated hydrochloric acid (36%, 2,71 g) under stirring for 1 min at 40C. The reaction mixture is stirred for 60 minutes at the same temperature (the crystals begin to precipitate after 10 minutes after dobavleniem dried at 60C under reduced pressure for 2 hours to obtain compound, specified in the header, in the form of white crystals (9,72 g, yield 89%) (crystal B1), which are more stable during storage than the crystal And, so pl. 166-S.

Mass spectrum (CI, m/z): 374 (M++1).

IR (KBr),maxcm-1: 1758, 1690.

Example 4

2-Acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (crystal B2)

To a solution of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (50 g) obtained according to reference example 1 in acetone (750 ml) add precapitalism concentrated hydrochloric acid (36%, of 6.78 g) under stirring for 5 minutes at 40C. Crystals B1 (0.1 g) obtained in example 3, is added to the reaction mixture as the seed crystals and the resulting mixture was stirred at the same temperature for 60 minutes. To the resulting mixture, optionally add precapitalism concentrated hydrochloric acid (36%, 6,10 g) for 60 minutes and the mixture is stirred at the same temperature for 120 minutes. The resulting crystals are separated by filtration, washed with acetone (100 ml) and then dried at 70 C under reduced pressure for 3 hours to obtain the connection specified in the header, in the form of white crystals (47,8 military in example 3, so pl. 165-S.

Mass spectrum (CI, m/z): 374 (M++1).

IR (KBr), maxcm-1: 1758, 1690.

Example 5

2-Acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine maleate

To a solution of maleic acid (932 g) in acetone (15 l), heated to 40C, add 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3000 g) obtained according to reference example 1. The mixture is stirred at room temperature for 2 hours. The resulting crystals are separated by filtration and washed with acetone (4 l) and then dried at 60C under reduced pressure for 8 hours to obtain the connection specified in the header, in the form of white crystals (3538 g, yield 90%), so pl. 172-173C.

Mass spectrum (CI, m/z): 374 (M++1).

IR (KBr),maxcm-1: 1782, 1713.

Example 6

2-Acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (crystal B2)

To a solution of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (50 g) obtained according to reference example 1 in acetone (750 ml) add precapitalism concentrated hydrochloric acid (36%, of 6.78 g) under stirring for 5 minutes and the resulting mixture was stirred at the same temperature for 60 minutes. To the resulting mixture, optionally add precapitalism concentrated hydrochloric acid (36%, between 6.08 g) for 60 minutes and the mixture is stirred at the same temperature for 120 minutes. The resulting crystals are separated by filtration, washed with acetone (100 ml) and then dried at 70 C under reduced pressure for 3 hours to obtain the connection specified in the header, in the form of white crystals (46.2 g, yield 89%) (crystal B2), so pl. 164-S.

Mass spectrum (CI, m/z): 374 (M++1).

IR (KBr),maxcm-1: 1758, 1690.

Reference example

2-Acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

(a) Cyclopropyl-2-forbindelsen

To a suspension of powdered magnesium (7.2 g) in anhydrous diethyl simple ether add a solution of 2-ftorangidridy (30 ml) in diethyl ether (30 ml), the mixture is then stirred at room temperature for 1 hour. The reaction mixture was added precapitalism to a solution of cyclopropylamine (18.2 ml) in diethyl ether (120 ml) for 100 minutes. After stirring for 30 minutes at room temperature, stir the mixture heated to boiling under reflux for 1 hour. After the reaction, the reaction mixtures is washed with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue purified by chromatography on silikagelevye column using toluene as eluent to obtain the specified product (23 g, solvent) as a yellow liquid.

1H NMR (CDCl3) memorial plaques: 0,82-0,98 (2H, m), 1,03-1,17 (2H, m), 1,92 e 2.06 (1H, m), 3,86 (2H, s), 7,10-7,30 (4H, m).

Mass spectrum (CI, m/z): 179 (M++1).

(b) 5-(-Cyclopropanecarbonyl-2-terbisil)-2-oxo-2,4,5,6,7,7 and-hexahydrofuro[3,2-c]pyridine

To a solution of cyclopropyl-2-forbindelsen (8.7 g) obtained in reference example 1(a), tetrachloride methane (80 ml) is added N-bromosuccinimide (9.6 g) and benzoyl peroxide (0.5 g), the mixture is then heated to boiling under reflux for 6 hours. After the reaction, to the reaction mixture are added toluene, and the obtained solid is filtered off. The filtrate was concentrated under reduced pressure. The residue is purified by chromatography on silikagelevye column using toluene as eluent to obtain cyclopropanecarbonyl-2-ftorangidridy (8.5 g) as a yellow oil.

To dissolve the 2,4,5,6,7,7 and-hexahydrofuro[3,2-c]pyridine hydrochloride (4.8 g), which is obtained according to the method described in EP 192535 (publication of Japanese patent application No. Sho 61-246186), and potassium bicarbonate (7.0 g). After stirring the mixture at room temperature for 2 hours, the reaction mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After purification of the residue by chromatography on silikagelevye column using as eluent toluene/ethyl acetate=3/1 product is crystallized from diisopropyl simple ether to obtain the desired product (2.6 g, yield 35%) as light brown crystals, so pl. 123-125C.

1H NMR (CDCl3) memorial plaques: of 0.75 to 0.96 (2H, m), 0,99-to 1.14 (2H, m), 1,83 is 2.01 (1H, m), 2,02-2,17 (1H, m), 2,25-2,45 and 2,47-2,62 (all 2H, each m), 2,85, and 3,10 (all 2H, each d, J=12.0 Hz), 3,88-4,01 and a 4.03-4,16 (all 2H, each m), 4,85 and 4,89 (all 1H, each s), 6,03 and 6.06 (all 1H, each s), 7,10 was 7.45 (4H, m).

Mass spectrum (CI, m/z): 332 (M++1), 262.

Analytically calculated for C18H18FNO2S, %: C 65,23; H 5,48; N TO 4.23.

Found, %: C 65,09; H Of 5.55; N 4,20.

(C) 2-Acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

To a solution of 5-(-cyclopropa the form of a mixture with dimethylformamide (10 ml) and acetic anhydride (5 ml), chilled in an ice bath, add sodium hydride (60% dispersion in mineral oil, 0.35 g), then the mixture is stirred at the same temperature for 30 minutes and further at room temperature for 3 hours. After the reaction, the mixture is extracted with ethyl acetate and the extract washed with saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. After purification of the residue by chromatography on silikagelevye column using toluene/ethyl acetate=3/1 as eluent, the product is crystallized from diisopropyl simple ether to obtain the desired compound (1.88 g, yield 65%) as white crystals, so pl. 120-122C.

1H NMR (CDCl3) memorial plaques: to 0.80-0.95 (2H, m), 0,99-of 1.16 (2H, m), and 2.27 (3H, s), 2.21 are of 2.34 (1H, m), 2,70-2,95 (4H, m), 3,47 (1H, d, J=15,0 Hz), 3,57 (1H, d, J=15,0 Hz), a 4.83 (1H, s), 6,27 (1H, s), 7,10-of 7.55 (4H, m).

IR (KBr),maxcm-1: 1758, 1704.

Mass spectrum (CI, m/z): 374 (M++1), 304.

Analytically calculated for C20H20FNO3S, %: C 64,32; H OF 5.40; N 3,75.

Found, %: C 64,46; H 5,39; N To 3.73.

The test example 1

The concentration of the metabolite in the plasma of dogs

After oral administration of the test compound to the males of the breed Beagle (the weight of the body is the eye is of IMT-2-terbisil]-4-methylthio-3-piperidinylidene]acetic acid (hereinafter referred to here denoted as “S-methyl form) used as a reference metabolite. This S-methyl form is the main metabolite 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in the plasma of humans, dogs and rats. Earlier it was reported that S-methyl form is a measure of the amount of the active metabolite of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine as it is formed during the subsequent metabolism of the active metabolite [Annu. Rep. Sankyo Res. Lab., 51, 1 (1999)].

Thirty minutes after feeding dogs with special food for dogs, each test compound (10 mg/kg), Packed in gelatin capsules, oral was administered to each of the dogs. Took a blood sample volume of 3 ml syringe treated with heparin, braccialini saphenous vein of each dog after 15, 30, 45, 60, 90 and 120 minutes after injection. Immediately after sampling whole blood was centrifuged to obtain plasma. Plasma samples were stored until analysis at-30C. To 0.5 ml of thawed plasma add 0.25 ml of 2-hydroxyacetophenone (1 µg/ml as an internal standard substance), 0.25 ml of 10 mm potassium phosphate buffer (pH 4.5) and 0.5 ml of methanol. The mixture was stirred at S.

After adding 8 ml of a mixture of isopropyl alcohol/chloroform (1/9) mixture vstra the t is separated into an aqueous phase and a phase of the solvent when using low-speed centrifugation (1500g for 15 minutes). A suitable aliquot of the basic phase of the solvent is dried to dryness using nitrogen gas and then re-dissolved in 0.25 ml of the mobile phase WAHI. Separately, a known amount of S-methyl form is added to control plasma of dogs with subsequent similar extraction. The calibration curve is obtained by applying the ratio of the peak areas of S-methyl form and connection of the internal standard on the Y-axis opposite the appropriate concentration of the added S-methyl form along the axis X. the Concentration of S-methyl form in the sample is calculated based on the calibration curve.

Conditions VEHI

Column: YMC A302 (4,6150 mm).

Mobile phase: acetonitrile/isopropyl alcohol/water/ triperoxonane acid (10/12/78/0,01).

The flow rate of 1.0 ml/min

Registration: UV 220 nm.

The injected amount of 30 μl.

The results are shown in table 1. In this table, the area under the plasma concentration curve based on time, which is a measure of the number obtained in vivo, and the maximum concentration in plasma, which are pharmokinetics parameters are abbreviations AUC and Cmax, respectively. In this table, the term “hydrochloride” means 2-acetoxy-5-(cyclo is the free form” means 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.

The results show that as the values of AUC and Cmax increased by conversion of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in its hydrochloride.

The test example 2

Inhibitory effect on platelet aggregation (feeding)

For this test have used a dog breed Beagle (body weight about 10 kg, sold Kasho Co., Ltd. and Nippon Nosan Kogyo K. K.). One group consisted of 5 or 6 dogs. Platelet aggregation was measured using an automatic aggregometry platelets (“PAM-6C”, trade name; product Mebanix Corporation) in accordance with the method of Born et al. (J. Physiol., 168, 178 (1963)) with slight modifications.

Every 2.5 hours and 4.5 hours after feeding were selected to 5.4 ml of blood from the head vein of each dog using sodium citrate (0.6 ml, 3.8 percent (weight/about.) as an anticoagulant. Blood with the addition of citrate was centrifuged (240 g, 20 minutes) to separate the plasma, platelet-rich (hereafter referred to as PRP), and plasma, with a low platelet (hereinafter referred to here referred to as PPP). After counting of platelets in PRP auto Hematology analyzer (“K-1000”, trade name; product of Sysmex Corporation) dobavlyayutsya aggregometer platelets. After pre-heating (when C) for 1 minute, add 10 μl of ADP (final concentration 20 μm) for platelet aggregation. Within 10 minutes was measured platelet aggregation and maximal platelet aggregation was determined to get the value before the introduction.

The next day, 30 minutes after feeding, the test compound in the form of gelatin capsules is administered orally to dogs. The blood was collected every 2 and 4 hours after injection. We measured platelet aggregation PRP, whereby determine the maximum aggregation. Inhibition (%) platelet aggregation test compound was calculated by comparing it with the value before the introduction. The results are presented in tables 2 and 3.

In these tables, the term “hydrochloride” means 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, obtained in example 1, while the “free form” means 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and “maleate” means 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine maleate obtained in example 2.

The test example 3

Inhibit the Beagle (body weight about 10 kg, sold Kasho Co., Ltd. and Nippon Nosan, Kogyo K. K.). One group consisted of 3 dogs. Platelet aggregation was measured using an automatic aggregometry platelets (“PAM-6C”, trade name; product Mebanix Corporation) in accordance with the method of Born et al. (J. Physiol., 168, 178 (1963)) with slight modifications.

From head vein of each dog which has received no food during the night, were selected to 5.4 ml of blood using sodium citrate (0.6 ml, 3.8 percent (weight/about.)) as an anticoagulant. Received blood with the addition of citrate was centrifuged (240 g, 20 minutes) to separate the plasma, platelet-rich (hereafter referred to as PRP), and plasma with a low platelet (hereinafter referred to here referred to as PPP). After counting of platelets in PRP auto Hematology analyzer (“K-1000”, trade name; product of Sysmex Corporation) add PPP to establish the number of platelets to 3108/ml PRP (240 μl), dispergirovannoyj in a ditch, was placed in automatic aggregometer platelets. After pre-heating (when C) for 1 minute, add 10 μl of ADP (final concentration 20 μm) for platelet aggregation. Within 10 minutes was measured platelet aggregation and maximum platelet aggregation on the Oh capsule is administered orally to dogs. The blood was collected every 2 and 4 hours after injection. We measured platelet aggregation PRP, whereby determine the maximum aggregation. Inhibition (%) platelet aggregation test compound was calculated by comparing it with the value before the introduction. The results are presented in table 4.

In this table, the term “maleate” means 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine maleate obtained in example 2, while the term “free form” means 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.

The results of tests 2 and 3 show that the inhibitory effect of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and maleate on ADP-induced platelet aggregation is stronger than for 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, and 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and maleate both exhibit excellent pharmacological activity compared with 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.

Example idrogeno[3,2-c]pyridine hydrochloride (50 mg), lactose (128,7 mg), cellulose (70 mg) and start magnesium (1.3 mg) are blended, passed through a sieve (60 mesh) and fill hard gelatin capsule (No. 3, 250 mg).

Example composition 2

Pill

Powder 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (50 mg), lactose (124 mg), cellulose (25 mg) and start magnesium (1 mg) are mixed and pressed in a tablet press machine to obtain a tablet weight of 200 mg, which may optionally have a coating.

Example of compound 3

Solid capsule

Powder 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine maleate (50 mg), lactose (128,7 mg), cellulose (70 mg) and start magnesium (1.3 mg) are blended, passed through a sieve (60 mesh) and fill hard gelatin capsule (No. 3, 250 mg).

Example of compound 4

Pill

Powder 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Maleta (50 mg), lactose (124 mg), cellulose (25 mg) and start magnesium (1 mg) are mixed and pressed in a tablet press machine to obtain a tablet weight of 200 mg, which may optionally have a coating.

1. Acid additive salts of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6, salt p. 1, in which the specified salt is a 2-acetoxy-5-(and-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine hydrochloride.

3. An acid additive salt under item 1, in which the specified salt is a 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine maleate.

4. An acid additive salt PP.1-3, suitable for obtaining a medicinal product for preventing or treating diseases caused by the formation of a blood clot or caused by embolism of warm-blooded animals.

5. An acid additive salt p. 4, wherein said medicinal product is intended for the prevention or treatment of thrombosis or embolism in humans.

6. An acid additive salt p. 4, wherein said drug is intended for treatment of thrombosis or embolism in humans.

7. Drug with activity in the inhibition of platelet aggregation, containing as the active ingredient salt according to any one of paragraphs.1-3.

8. Drug under item 7, wherein said medicinal product is intended for the prevention or treatment of diseases caused by blood clot or caused by the hydrated product is intended for the prevention or treatment of thrombosis or embolism in humans.

10. Drug under item 7, wherein said drug is intended for treatment of thrombosis or embolism in humans.

11. A method of preventing or treating diseases caused by the formation of a blood clot or caused by embolism of warm-blooded animals, which comprises introducing an effective amount of salt according to any one of paragraphs.1-3.

12. A method of preventing or treating thrombosis or embolism in humans, which includes the introduction of an effective amount of salt according to any one of paragraphs.1-3.

13. A method of treating thrombosis or embolism in humans, which includes the introduction of an effective amount of salt according to any one of paragraphs.1-3.

14. Drug for prevention or treatment of diseases caused by blood clot or caused by embolism of warm-blooded animals, representing salt according to any one of paragraphs.1-3.

15. Medicinal product for preventing or treating thrombosis or embolism in humans, representing a salt according to any one of paragraphs.1-3.

16. Drug for the treatment of thrombosis or embolism in humans, representing a salt according to any one of paragraphs.1-3.

17. The method of obtaining the acid additive salts of 2-acetoxy - 5-(-cyclopropanecarbonyl-2-FNL-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine with an acid in an inert solvent, if necessary with the addition of seed crystals.

18. The method of obtaining the acid additive salts under item 17, characterized in that it includes the addition of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine to a solution of the acid in an inert solvent, if necessary with the addition of seed crystals.

19. The method of obtaining the acid additive salts under item 18, wherein the specified inert solvent is acetone and the specified acid is a maleic acid.

20. The method of obtaining the acid additive salts under item 17, characterized in that it includes adding precapitalism acid in one or more doses to a solution of 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine in an inert solvent, if necessary with the addition of seed crystals.

21. The method of obtaining an acid additive salt on p. 20, wherein the specified inert solvent is acetone and the specified acid is a concentrated hydrochloric acid.

22. The method of obtaining the acid additive salts under item 17, wherein the specified salt is a 2-acetoxy-5-(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine hydrochloride, what olaney acid to a solution of 2-acetoxy-5(-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno [3,2-C]pyridine in an inert solvent at elevated temperature, if necessary with the addition of seed crystals, additional add-precapitalism remaining required quantity of concentrated hydrochloric acid at the same temperature.

23. The method of obtaining the specified hydrochloride p. 22, which specified elevated temperature is in the range from 35 to 60 SECONDS.

24. The method of obtaining the specified hydrochloride p. 22, which specified elevated temperature is in the range from 40 to 55C.

25. The method of obtaining the specified hydrochloride according to any one of paragraphs.21-23, at which time the specified add-precapitalism half the required quantity of concentrated hydrochloric acid is from 2 to 10 minutes

26. The method of obtaining the specified hydrochloride according to any one of paragraphs.21-24, at which time the specified add-precapitalism half the required quantity of concentrated hydrochloric acid is from 30 minutes to 2 hours

27. The method of obtaining the specified hydrochloride according to any one of paragraphs.21-25, at which time the specified add-precapitalism remaining required quantity of concentrated hydrochloric acid is from 30 minutes to 2 hours

28. The method of obtaining the specified hydrochloride according to any one of paragraphs.21-26, at which time the specified add p

 

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in which

R1, R2in each case, independently of one another represent H, A, HE, OA or Hal,

X is R4, R5or R6, monosubstituted R7,

R4is unbranched or branched alkylene with 1-10 atoms, in which one or two CH2groups can be substituted by a group-CH=CH-,

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