Medicine comprising acid addition salt of hydropyridine derivative

Description: TECHNICAL FIELD [Detailed description of the invention]

【0001】

[Technical field to which the invention belongs]

The present invention relates to acid addition salts of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine (particularly hydrochloric acid or With respect to drugs containing (maleate) (particularly therapeutic or prophylactic agents for diseases caused by thrombosis or embolism).

【0002】

[Conventional technology]

2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4, which is an adenosine diphosphate (hereinafter abbreviated as ADP) receptor antagonist, is a hydropyridine derivative having an inhibitory effect on platelet aggregation. , 5,6,7-Tetrahydrothieno [3,2-c] Pyridine and its analogs are known to have excellent platelet aggregation inhibitory activity and are useful as antithrombotic agents or anti-embolic agents. (See, for example, Patent Document 1).

【0003】

[Patent Document 1]

European Patent Application Publication No. 542411 (Japanese Patent Application Laid-Open No. 6-411239) [0004]

[Problems to be Solved by the Invention]

The present inventors have conducted intensive studies on the pharmacological activities of various hydropyridine derivatives with the aim of developing compounds having an excellent platelet aggregation inhibitory effect over many years, and as a result, 2-acetoxy-5- (α-). Cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] Platelet acid addition salt (particularly hydrochloric acid or maleate) has excellent oral absorbability and metabolic activation. And because it has an inhibitory effect on platelet aggregation, is weakly toxic, and has excellent storage and handling stability, it is a drug [preferably a disease caused by thrombosis or embolism (more preferably, thrombosis or embolism). )] As a prophylactic or therapeutic agent (particularly, a therapeutic agent)], and completed the present invention.

【0005】

The present invention has 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, which has an excellent inhibitory effect on platelet aggregation. Drugs containing acid addition salts (particularly hydrochloric acid or maleate) [preferably prophylactic or therapeutic agents (particularly therapeutic agents) for diseases caused by thrombosis or embolism, more preferably thrombosis or Prophylactic or therapeutic agents for embolism (particularly therapeutic agents)].

【0006】

[Means for solving problems]

The medicament of the present invention contains an acid addition of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine as an active ingredient. Contains salt (hydrochloric acid or maleate).

【0007】

Acid addition of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, which is the active ingredient of the medicament of the present invention. The acid moiety of the salt can be, for example, an inorganic acid such as sulfuric acid, hydrochloric acid, nitrate, phosphoric acid or an organic acid such as trifluoroacetic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, which is preferred. Is hydrochloric acid or maleic acid.

【0008】

Hydrochloride of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, which is the active ingredient of the medicament of the present invention. Is a compound having the following structure.

【0009】

[Chemical 1]

<img file="JP2003246735A_D0001.tif" />【0010】

In addition, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine maleine, which is the active ingredient of the medicament of the present invention. The acid salt is a compound having the following structure.

【0011】

[Chemical 2]

<img file="JP2003246735A_D0002.tif" />【0012】

Acid addition of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, which is the active ingredient of the medicament of the present invention. The salt has an asymmetric carbon atom in the molecule and has R- and S-coordinated steric isomers, and each of them or any ratio of compounds thereof is included in the present invention. Will be done. Such stereoisomers are, for example, synthesized or synthesized using optically resolution raw material compounds 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6, The acid addition salt of 7-tetrahydrothieno [3,2-c] pyridine can be optically resolved using conventional optical resolution or separation method, if desired.

【0013】

Acid addition of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, which is the active ingredient of the medicament of the present invention. The salt may absorb water and become adsorbed water or become a hydrate when left in the air or recrystallized. An acid addition salt containing such water is also present in the present invention. Included in.

【0014】

BEST MODE FOR CARRYING OUT THE INVENTION

The acid addition salt of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine of the present invention is published in EP 542411. 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3] synthesized according to the method described in JP-A-6-411239. , 2-c] Pyridine in solvent or in the absence of solvent (preferably in solvent), acid [preferably hydrochloric acid, hydrogen chloride (gas) or maleic acid, more preferably concentrated hydrochloric acid or maleine. Acid, most preferably concentrated hydrochloric acid] or acid [preferably hydrochloric acid, hydrogen chloride (gas) or maleic acid, more preferably concentrated hydrochloric acid or maleic acid, most preferably concentrated Hydrochloric acid] in a solvent or in the absence of a solvent (preferably in a solvent), 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [ It is produced by dropping or adding to 3,2-c] pyridine at one time or in two to several degrees and reacting. In this method, seed crystals can be added as needed.

【0015】

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene. , Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone or diethyl ketone; esters such as ethyl acetate, propyl acetate or butyl acetate; carboxylic acids such as acetic acid or propionic acid; or acetonitrile Alternatively, it can be a nitrile such as propionitrile, and in the case of hydrochloride, it is preferably ethers, ketones, esters, carboxylic acids or nitriles, and more preferably tetrahydrofuran, dioxane, acetone, It is methyl ethyl ketone, ethyl acetate, acetic acid or acetonitrile, particularly preferably tetrahydrofuran, dioxane, acetic acid or acetone, and most preferably acetone. On the other hand, in the case of maleate, it is preferably ethers, ketones, esters or nitriles, more preferably tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate or acetonitrile, and particularly preferably. , Tetrahydrofuran, dioxane or acetone, most preferably acetone.

【0016】

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

【0017】

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

【0018】

In a method for producing maleate, a preferred embodiment is to dissolve maleic acid in acetone and at 0 to 70 ° C, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5. , 6,7-Tetrahydrothieno [3,2-c] pyridine is added and reacted at the same temperature for 1 to 3 hours.

【0019】

Further, in the method for producing a hydrochloride, a preferred embodiment is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c]. Dissolve pyridine in acetone and at 0-70 ° C (preferably 35 ° C-60 ° C) half of the required amount of concentrated hydrochloric acid (usually equimolar to thienopyridine) for 2 minutes- Dropped over 10 minutes, if necessary, seed crystals were added, reacted at the same temperature for 30 minutes to 2 hours, and the remaining required amount of concentrated hydrochloric acid was added dropwise over 30 minutes to 2 hours. It is a method of reacting at the same temperature for 1 to 3 hours.

【0020】

After completion of the reaction, the acid addition salt of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine of the present invention was added. Collected from the reaction mixture according to conventional methods. For example, after the reaction is completed, the precipitated crystals are collected by filtration, or after the reaction is completed, the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

【0021】

The acid addition salt of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine of the present invention provides excellent oral absorption. It has sex, metabolic activation and platelet aggregation inhibitory effects, is weakly toxic, and has excellent storage and handling stability. Therefore, it is a drug [preferably a prophylactic or therapeutic agent for diseases caused by thrombosis or embolism. (In particular, a therapeutic agent), more preferably a prophylactic or therapeutic agent for thrombosis or embolism (particularly a therapeutic agent)]. Further, the above-mentioned medicine is preferably for warm-blooded animals, and more preferably for humans.

【0022】

The acid addition salt of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine of the present invention is used to treat the above diseases. When used as a drug or prophylactic, it may be mixed with excipients, diluents, etc., which are itself or appropriately pharmacologically acceptable, and orally in tablets, capsules, granules, powders, syrups, etc. It can be administered parenterally or by injection or suppository.

【0023】

Examples include cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, and sucrose fatty acid esters. ), Stabilizers (eg, parahydroxybenzoic acid esters such as methylparaben, propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalconium chloride; phenols such as phenol, cresol; Timerosal; dehydroacetic acid; and sorbic acid can be mentioned), flavoring agents (eg, commonly used sweeteners, acidulants, fragrances, etc.), diluents (eg, usually). Used, lactose, mannitol, glucose, sculose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium aluminometasilicate or these. It is produced by a well-known method using additives such as (the mixture of) and the like. And sorbic acid can be mentioned. ), Flavoring agents (eg, commonly used sweeteners, acidulants, fragrances, etc.), diluents (eg, commonly used lactose, mannitol, glucose, sucrose, calcium sulfate, etc.), With additives such as calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium aluminometasilicate or a mixture thereof) Manufactured by a well-known method. And sorbic acid can be mentioned. ), Flavoring agents (eg, commonly used sweeteners, acidulants, fragrances, etc.), diluents (eg, commonly used lactose, mannitol, glucose, sucrose, calcium sulfate, etc.), With additives such as calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium aluminometasilicate or a mixture thereof) Manufactured by a well-known method.

【0024】

The amount used varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit of 0.1 mg (preferably 1 mg) and the upper limit of 1000 mg (preferably 500 mg) are administered intravenously. Can administer a lower limit of 0.01 mg (preferably 0.1 mg) and an upper limit of 500 mg (preferably 250 mg) per dose to an adult 1 to 7 times per day depending on the symptoms.

【0025】

[Example]

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto.

【0026】

Example 1 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (A crystal) 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine (10 g) obtained in Reference Example 1 ) Is dissolved in acetone (150 ml), stirred at room temperature (25 ° C), 36% concentrated hydrochloric acid (2.71 g) is added dropwise, a small amount of seed crystal (separately manufactured A crystal) is added, and then the same. Stir at room temperature for 90 minutes. The precipitated crystals were collected by filtration, washed with a small amount of acetone, and then dried under reduced pressure at 50 ° C. for 4 hours to obtain the title compound (8.1 g, yield 74%) as white crystals (A crystals). Melting point: 133 --136 ° C;¹1 NMR spectrum, δppm (CDCl₃): 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, brs), 7.37 --7.57 (3H, m), 7.66 --7.75 (1H, m); Mass spectrum, (CI, m / z): 374 (M⁺+1); IR spectrum, ν_maxcm^-1(KBr): 1762, 1720. [0027]

Example 2 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine maleate Maleic acid (4.43 g) was dissolved in acetone (60 ml) and then 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7 obtained in Reference Example 1 -Tetrahydrothieno [3,2-c] pyridine (15.0 g) was added, and the mixture was stirred at room temperature (25 ° C) for 2 hours. The precipitated crystals were collected by filtration, washed with a small amount of acetone, and then dried under reduced pressure at 50 ° C. for 4 hours to obtain the title compound (17.1 g, yield 92%) as white crystals. Melting point: 171-172 ° C;¹1 NMR spectrum, δppm (CD₃OD): 0.89 --0.97 (1H, m), 1.02 --1.09 (2H, m), 1.14 --1.23 (1H, m), 1.94 --2.03 (1H, m), 2.25 (3H, s), 3.00 --3.09 ( 2H, m), 3.33 --3.50 (2H, m), 3.88 (1H, d, J = 14.9Hz), 4.05 (1H, d, J = 14.9Hz), 5.70 (1H, s), 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 spectrum, ν_maxcm^-1(KBr): 1782, 1713. [0028]

Example 3 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (B1 crystal) 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine (10 g) obtained in Reference Example 1 ) Was dissolved in acetone (100 ml), and 36% concentrated hydrochloric acid (2.71 g) was added dropwise over 1 minute under stirring at 40 ° C., and the mixture was stirred at the same temperature for 60 minutes (from about 10 minutes after the addition of concentrated hydrochloric acid). Crystals began to precipitate.). The precipitated crystals were collected by filtration, washed with acetone (20 ml), and dried under reduced pressure at 60 ° C. for 2 hours to obtain the title compound (9.72 g, yield 89%) as white crystals (B1 crystals). .. This B1 crystal showed even better storage stability than the A crystal obtained in Example 1. Melting point: 166-174 ° C; Mass spectrum, (CI, m / z): 374 (M⁺+1); IR spectrum, ν_maxcm^-1(KBr): 1758, 1690. [0029]

Example 4 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (B2 crystal) 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine (50 g) obtained in Reference Example 1 ) Was dissolved in acetone (750 ml), and 36% concentrated hydrochloric acid (6.78 g) was added dropwise over 5 minutes under stirring at 40 ° C., and the B1 crystal (0.1 g) obtained in Example 3 was used as a seed crystal. In addition, the mixture was stirred at the same temperature for 60 minutes. Further, 36% concentrated hydrochloric acid (6.10 g) was added dropwise over 60 minutes, and the mixture was stirred at the same temperature for 120 minutes. The precipitated crystals were collected by filtration, washed with acetone (100 ml), and dried under reduced pressure at 70 ° C. for 3 hours to give the title compound (47.8 g, yield 92%) as white crystals (B2 crystals). .. This B2 crystal showed even better storage stability than the B1 crystal obtained in Example 3. Melting point: 165-178 ° C; Mass spectrum, (CI, m / z): 374 (M⁺+1); IR spectrum, ν_maxcm^-1(KBr): 1758, 1690. [0030]

Example 5 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine maleate Maleic acid (932 g) was dissolved in acetone (15 L) and then heated to 40 ° C. Next, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine (3000 g) obtained in Reference Example 1 was added. In addition, it was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed with acetone (4 L), and dried under reduced pressure at 60 ° C. for 8 hours to give the title compound (3538 g, yield 90%) as white crystals. Melting point: 172 --173 ° C; Mass spectrum, (CI, m / z): 374 (M⁺+1); IR spectrum, ν_maxcm^-1(KBr): 1782, 1713. [0031]

Example 6 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (B2 crystal) 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine (50 g) obtained in Reference Example 1 ) Was dissolved in acetone (750 ml), and 36% concentrated hydrochloric acid (6.78 g) was added dropwise over 5 minutes under stirring at 55 ° C., and the B1 crystal (0.1 g) obtained in Example 3 was used as a seed crystal. In addition, the mixture was stirred at the same temperature for 60 minutes. Further, 36% concentrated hydrochloric acid (6.08 g) was added dropwise over 60 minutes, and the mixture was stirred at the same temperature for 120 minutes. The precipitated crystals were collected by filtration, washed with acetone (100 ml), and dried under reduced pressure at 70 ° C. for 3 hours to give the title compound (46.2 g, yield 89%) as white crystals (B2 crystals). .. Melting point: 164-178 ° C; Mass spectrum, (CI, m / z): 374 (M⁺+1); IR spectrum, ν_maxcm^-1(KBr): 1758, 1690. [0032]

Reference example 1 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine [0033]

(a) Cyclopropyl 2-fluorobenzyl ketone Anhydrous diethyl ether (60 ml) was added to metallic magnesium (7.2 g), a solution of 2-fluorobenzyl bromide (30 ml) in diethyl ether (30 ml) was added dropwise with stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a solution of cyclopropyl cyanide (18.2 ml) in diethyl ether (120 ml) over 100 minutes, stirred at room temperature for 30 minutes, and then further stirred under reflux for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride solution is added to the reaction solution, extracted with ethyl acetate, the extract is washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer is washed with anhydrous sodium sulfate. It was dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: toluene) to obtain the title compound (23 g, including solvent) as a yellow liquid.¹1 NMR spectrum, δppm (CDCl₃): 0.82 --0.98 (2H, m), 1.03 --1.17 (2H, m), 1.92 --2.06 (1H, m), 3.86 (2H, s), 7.10 --7.30 (4H, m); Mass spectrum, (CI, m / z): 179 (M⁺+1). 【0034】

(b) 5- (α-Cyclopropylcarbonyl-2-fluorobenzyl) -2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine Cyclopropyl 2-fluorobenzyl obtained in (a) above Ketone (8.7 g) was dissolved in carbon tetrachloride (80 ml), N-bromsuccinate imide (9.6 g) and benzoyl peroxide (0.5 g) were added, and the mixture was stirred under reflux for 6 hours. After completion of the reaction, toluene was added to the reaction solution, the precipitated solid was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: toluene). -Cyclopropylcarbonyl-2-fluorobenzyl bromide (8.5 g) was obtained as a yellow liquid. Next, the obtained α-cyclopropylcarbonyl-2-fluorobenzyl bromide (6.0 g) was dissolved in dimethylformamide (20 ml), and the method described in EP-192535 (Japanese Patent Laid-Open No. 61-246186). 2-Oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine hydrochloride (4.8 g) and potassium hydrogen carbonate (7.0 g) synthesized according to the above were added and at room temperature. Stirred for 2 hours. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: toluene / ethyl acetate = 3/1) and then crystallized from diisopropyl ether to give the title compound. (2.6 g, yield 35%) was obtained as light brown crystals. Melting point: 123-125 ° C;¹1 NMR spectrum, δppm (CDCl₃): 0.75 --0.96 (2H, m), 0.99 --1.14 (2H, m), 1.83 --2.01 (1H, m), 2.02 --2.17 (1H, m), 2.25 --2.45 and 2.47 --2.62 (2H in total, each) m), 2.85 and 3.10 (total 2H, each d, J = 12.0Hz), 3.88 --4.01 and 4.03- 4.16 (total 2H, each m), 4.85 and 4.89 (total 1H, each s), 6.03 and 6.06 (total) 1H, each s), 7.10 --7.45 (4H, m); Mass spectrum, (CI, m / z): 332 (M⁺+1), 262; Elemental analysis, C₁₈H₁₈FNO₂As S, the calculated value: C, 65.23; H, 5.48; N, 4.23; Measured value: C, 65.09; H, 5.55; N, 4.20. [0035]

(c) 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine 5-obtained in (b) above (Α-Cyclopropylcarbonyl-2-fluorobenzyl) -2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] Pyridine (2.6 g), dimethylformamide (10 ml) ) And anhydrous acetic acid (5 ml), sodium hydride (60% mineral oil dispersion, 0.35 g) was added under ice-cooled stirring, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 3 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: toluene / ethyl acetate = 3/1) and then crystallized from diisopropyl ether to give the title compound (1.88). g, yield 65%) was obtained as white crystals. Melting point: 120-122 ° C.¹1 NMR spectrum, δppm (CDCl₃): 0.80 --0.95 (2H, m), 0.99 --1.16 (2H, m), 2.27 (3H, s), 2.21 --2.34 (1H, m), 2.70 --2.95 (4H, m), 3.47 (1H, d) , J = 15.0Hz), 3.57 (1H, d, J = 15.0Hz), 4.83 (1H, s), 6.27 (1H, s), 7.10 -7.55 (4H, m); IR spectrum, ν_maxcm^-1(KBr): 1758, 1704; Mass spectrum, (CI, m / z): 374 (M⁺+1), 304; Elemental analysis, C₂₀H₂₀FNO₃As S, the calculated value: C, 64.32; H, 5.40; N, 3.75; Measured value: C, 64.46; H, 5.39; N, 3.73. [0036]

Test example 1 Canine plasma metabolite concentration The test compound was orally administered to a male beagle dog (body weight about 10 kg, Kasho and Nippon Agricultural Industry Co., Ltd.), and then the plasma metabolite concentration was measured. The metabolite for comparison is (2Z)-[1- [α-cyclopropylcarbonyl-2-fluorobenzyl] -4-methylthio-3-piperidinilidene] acetic acid (hereinafter abbreviated as S-methyl form). And said. The S-methyl form of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine in humans, dogs and rats It is the main metabolite in plasma and is a pharmacologically active metabolite of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine. It has already been reported that it is an index of the amount of active metabolites produced because it is produced by undergoing further one-process metabolism from [Sankyo Research Institute Annual Report, Vol. 51, Page 1 (1999) [Annu. Rep. . Sankyo Res. Lab., 51, 1 (1999)]]. Thirty minutes after feeding the dogs, the test compound (10 mg / kg) packed in gelatin capsules was orally administered. At 15, 30, 45, 60, 90 and 120 minutes after administration, 3 ml of blood was collected from the saphenous vein of the brachial arm using a heparin-treated injection tube. The whole blood obtained was immediately centrifuged to obtain plasma, and the obtained plasma was cryopreserved at -30 ° C until measurement. To the thawed plasma (0.5 ml), 1 μg / ml concentration of 2-hydroxyacetophenone (0.25 ml), 10 mM potassium phosphate buffer (pH 4.5, 0.25 ml) and methanol (0.5 ml) were added as internal standard substances. Stirred at 20 ± 3 ° C. An isopropyl alcohol / chloroform (1/9) mixed solution (8 ml) was added thereto, and the mixture was shaken to extract the S-methyl compound and the internal standard substance into the solvent phase. The extract was separated into an aqueous phase and a solvent phase by low-speed centrifugation (1500 g, 15 minutes), and an appropriate amount of the solvent phase in the lower layer was dried with nitrogen gas. This was redissolved in an HPLC mobile phase (0.25 ml). Separately, a known amount of S-methyl was added to canine control plasma, and the extraction operation was performed in the same manner. A calibration curve was prepared with the area ratio of the S-methyl compound and the internal standard substance in this sample on the y-axis and the concentration of the added S-methyl compound on the x-axis. The S-methyl compound concentration in the sample was calculated from this calibration curve and quantified. HPLC conditions Column: YMC A302 (4.6 x 150 mm) Mobile phase: acetonitrile / isopropyl alcohol / water / trifluoroacetic acid (10/12/78 / 0.01) Flow velocity: 1.0 ml / min Detection: UV 220nm Injection volume: 30 μl The results are shown in Table 1. In the table, as drug kinetic parameters, the area under the plasma concentration-time curve, which is an index of the amount produced in vivo, is omitted as AUC, and the maximum plasma concentration is omitted as Cmax. In the table, "hydrochloride" refers to 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] of Example 1. ] Pyridine Hydrochloride, the "free form" is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine Is shown.

【0037】

[table 1]

Drug kinetic parameters of plasma S-methyl form after oral administration to dogs (Mean ± standard deviation) Test compound n AUC (μg min / ml) Cmax (μg / ml) Hydrochloride 4 74.1 ± 25.8 1.09 ± 0.26 -------------------------------------------------- ------------ Free body 3 36.4 ± 8.2 0.615 ± 0.141 [0038]

The above results are obtained by using 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine as a hydrochloride salt. And Cmax are both improved.

【0039】

Test example 2 Platelet aggregation inhibitory effect (feeding) In the test, male beagle dogs (weighing about 10 kg, Kasho and Nosan Corporation) were used as 5 or 6 dogs in one group. Platelet aggregation is described in The Journal of Physiology, Vol. 168, p. 178 (1963) [J. Physiol., 168, 178 (1963)], the method of Born et al. Was partially modified, and the measurement was performed using an automatic platelet aggregation measuring device (PAM-6C, Mevanics Co., Ltd.). After 2.5 and 4.5 hours of feeding, 5.4 ml of blood was collected from the cephalic vein of the dog, and 3.8% (w / v) sodium citrate (0.6 ml) was collected as an anticoagulant. The resulting citrate-added blood is centrifuged (240 g, 20 minutes) and platelet-rich plasma (platelet-rich). Plasma, hereinafter abbreviated as PRP. ) And platelet-rich plasma (platelet-poor plasma, hereinafter abbreviated as PPP) were separated. The platelet count in PRP was measured with an automatic blood cell measuring device (K-1000, Sysmex Corporation), and then adjusted to 3x108 / ml by adding PPP. PRP (240 μl) dispensed into the cuvette was set in an automatic platelet measuring device, and after 1 minute of preheating (37 ° C), 10 μl of ADP (final concentration 20 μM) was added to induce platelet aggregation. Platelet aggregation was measured for 10 minutes to determine the maximum aggregation rate, which was used as the pre-administration value. The next day, 30 minutes after feeding, the test compound packed in gelatin capsules was orally administered to dogs. Blood was collected 2 and 4 hours after administration, and platelet aggregation was measured using PRP to determine the maximum aggregation rate. The aggregation inhibition rate (%) of the test compound was calculated by comparison with the value before administration. The results are shown in Tables 2 and 3. In the table, "hydrochloride" refers to 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] of Example 1. ] Pyridine Indicates hydrochloride, "free" indicates 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine , "Maleate" is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridin maleate of Example 2. Indicates a acid salt.

【0040】

[Table 2]

Platelet aggregation inhibitory effect after oral administration to dogs (mean ± standard error) Test compound Dosage (mg / kg) n Agglutination inhibition rate (%) -------------------------- 2 hours 4 hours Hydrochloride 0.3 5 49.0 ± 18.7 48.5 ± 18.3 -------------------------------------------------- -------------- Free body 0.3 5 25.8 ± 10.9 28.6 ± 14.2 [0041]

[Table 3]

Platelet aggregation inhibitory effect after oral administration to dogs (mean ± standard error) Test compound Dosage (mg / kg) n Agglutination inhibition rate (%) -------------------------- 2 hours 4 hours Maleate 0.3 6 50.9 ± 14.5 58.6 ± 15.7 -------------------------------------------------- -------------- Free body 0.3 6 21.7 ± 9.8 23.8 ± 12.6 [0042]

Test example 3 Platelet aggregation inhibitory effect (fasting) In the test, male beagle dogs (weighing about 10 kg, Kasho and Nosan Corporation) were used as 3 dogs in 1 group. Platelet aggregation is described in The Journal of Physiology, Vol. 168, p. 178 (1963) [J. Physiol., 168, 178 (1963)], the method of Born et al. Was partially modified, and the measurement was performed using an automatic platelet aggregation measuring device (PAM-6C, Mevanics Co., Ltd.). Blood was collected from the cephalic vein of dogs fasted overnight using 5.4 ml of blood and 3.8% (w / v) sodium citrate (0.6 ml) as an anticoagulant. The obtained citrate-added blood is centrifuged (240 g, 20 minutes), and platelet-rich plasma (hereinafter abbreviated as PRP) and platelet-rich plasma (platelet-poor) are collected. plasma, hereinafter abbreviated as PPP. ) Was separated. The platelet count in PRP was measured with an automatic blood cell measuring device (K-1000, Sysmex Corporation), and then adjusted to 3x108 / ml by adding PPP. PRP (240 μl) dispensed into the cuvette was set in an automatic platelet measuring device, and after 1 minute of preheating (37 ° C), 10 μl of ADP (final concentration 20 μM) was added to induce platelet aggregation. Platelet aggregation was measured for 10 minutes to determine the maximum aggregation rate, which was used as the pre-administration value. The next day, the test compound packed in gelatin capsules was orally administered to dogs. Blood was collected 2 hours and 4 hours after administration, and platelet aggregation was measured using PRP to determine the maximum aggregation rate. The aggregation inhibition rate (%) of the test compound was calculated by comparison with the value before administration. The results are shown in Table 4. In the table, "maleate" is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-" of Example 2. c] Pyridine Representing maleate, the "free form" is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine. Shown.

【0043】

[Table 4]

Platelet aggregation inhibitory effect after oral administration to dogs (mean ± standard error) Test compound Dosage (mg / kg) n Agglutination inhibition rate (%) -------------------------- 2 hours 4 hours Maleate 1.0 3 63.4 ± 22.9 88.5 ± 5.7 -------------------------------------------------- -------------- Free body 1.0 3 27.9 ± 24.8 28.7 ± 24.4 [0044]

The results of Test Example 2 and Test Example 3 show that the inhibitory effect on ADP-induced platelet aggregation is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [ 3,2-c] Pyridine hydrochloride and maleate are more 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2] Stronger than -c] pyridine, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride and maleic acid The salt has even better pharmacological activity than 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine. It is shown that.

【0045】

Preparation example 1 Hard capsule 50 mg powdered 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride, 128.7 mg lactose, After mixing 70 mg of cellulose and 1.3 mg of magnesium stearate and passing through a 60 mesh sieve, this powder is placed in 250 mg of No. 3 gelatin capsule to make a capsule.

【0046】

Preparation example 2 tablet 50 mg powdered 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride, 124 mg lactose, 25 mg 1 mg of cellulose and 1 mg of magnesium stearate are mixed and tableted with a tableting machine to obtain 1 tablet of 200 mg of tablet. This tablet can be coated if desired.

【0047】

Preparation example 3 Hard capsule 50 mg powdered 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine maleate, 128.7 mg lactose , 70 mg of cellulose and 1.3 mg of magnesium stearate are mixed and passed through a 60 mesh sieve, and then this powder is placed in 250 mg of No. 3 gelatin capsule to make a capsule.

【0048】

Formulation example 4 tablet 50 mg powdered 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine maleate, 124 mg lactose, Mix 25 mg of cellulose and 1 mg of magnesium stearate and tablet with a tableting machine to make 1 tablet of 200 mg. This tablet can be coated if desired.

【0049】

[Effect of the invention]

The pyridine acid addition salt of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine of the present invention (particularly, hydrochloric acid). Alternatively, a pharmaceutical composition containing (maleate) has excellent oral absorbability, metabolic activation and platelet aggregation inhibitory action, is weakly toxic, and has excellent storage and handling stability. Preferably, it is useful as a prophylactic or therapeutic agent (particularly, a therapeutic agent) for a disease caused by thrombosis or embolism (more preferably, thrombosis or embolism).