Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-12-26
2004-02-17
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S114000
Reexamination Certificate
active
06693115
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (preferably the hydrochloride or maleate) which exhibit excellent oral absorption, metabolization into the active compound, and activity in inhibition of platelet aggregation, and are useful as therapeutic or prophylactic agents for thrombus formation-induced or embolization-induced diseases.
2. Background Information
In EP-542411 (Japanese Patent Application Publication No. Hei 6-411239) it is described that 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and derivatives thereof, which are antagonists of receptors of adenosine diphosphate (hereinafter referred to as “ADP”), exhibit excellent activity in inhibition of platelet aggregation and are useful as antithrombotic or antiembolic agents.
SUMMARY OF THE INVENTION
For many years the present inventors have earnestly studied the pharmacological activity of various hydropyridine derivatives in order to discover compounds having excellent activity in inhibition of platelet aggregation. The present inventors have found that acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (preferably the hydrochloride or maleate) exhibit excellent oral absorption, metabolization into the active compound, activity in inhibition of platelet aggregation, low toxicity, and excellent storage and handling stability, and are useful as medicaments (preferably useful as therapeutic or prophylactic agents (preferably therapeutic agents)) for thrombus formation-induced or embolization-induced diseases (preferably thrombosis or embolism).
The present invention provides acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (preferably the hydrochloride or maleate), which exhibit excellent activity in inhibition of platelet aggregation; processes for the preparation thereof; and medicaments containing them which are useful as therapeutic or prophylactic agents (preferably therapeutic) for thrombus formation-induced or embolization-induced diseases, and are preferably useful as therapeutic or prophylactic agents (preferably therapeutic agents) for thrombosis or embolism.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (hydrochloride or maleate) and relates to medicaments containing acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (hydrochloride or maleate) as an active ingredient.
The acid moiety of acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine is, for example, an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid; or an organic acid such as trifluoroacetic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, and preferably hydrochloric acid or maleic acid.
2-Acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride of the present invention has the following formula:
2-Acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine maleate has the following formula:
Acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine have an asymmetric carbon in their molecule and in each compound two isomers having R and S configurations can exist. The present invention encompasses the individual isomers and mixtures of these isomers in optional proportions. An optically active isomer of acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of the present invention can be prepared using an optically active starting material or is isolated from a racemic mixture of synthetically prepared acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine by a conventional optical resolution.
In some cases, when acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine are allowed to stand in contact with the atmosphere or are recrystallized, they may absorb water or may take up water to form a hydrate. The present invention encompasses these hydrates.
Acid addition salts of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine are prepared in the presence or absence of an inert solvent (preferably in an inert solvent) by addition of 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, which is synthesized by a method described in EP-542411, to an acid (preferably hydrochloric acid, hydrogen chloride (gas), or maleic acid; more preferably concentrated hydrochloric acid or maleic acid; most preferably concentrated hydrochloric acid); or in the presence or absence of an inert solvent (preferably in an inert solvent) by dropwise addition or addition of an acid (preferably hydrochloric acid, hydrogen chloride (gas), or maleic acid; more preferably concentrated hydrochloric acid or maleic acid; most preferably concentrated hydrochloric acid) at one or more times to 2-acetoxy-5-(&agr;-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine. In this procedure, if necessary, seed crystals of said salt can be added.
The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction and it can dissolve the starting material to some extent. 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; ether derivatives such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethyleneglycol)dimethyl ether; ketone derivatives such as acetone, methyl ethyl ketone or diethyl ketone; ester derivatives such as ethyl acetate, propyl acetate or butyl acetate; carboxylic acid derivatives such as acetic acid or propionic acid; or nitrile derivatives such as acetonitrile or propionitrile. For the preparation of the hydrochloride, the preferred solvents are ether derivatives, ketone derivatives, ester derivatives, carboxylic acid derivatives or nitrile derivatives; more preferred solvents are tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetic acid or acetonitrile; still more preferred solvents are tetrahydrofuran, dioxane, acetic acid or acetone. Acetone is the most preferred. On the other hand for the preparation of the maleate, the preferred solvents are ether derivatives, ketone derivatives, ester derivatives or nitrile derivatives; more preferred solvents are tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, or acetonitrile; still more preferred solvents are tetrahydrofuran, dioxane or acetone. Acetone is the most preferred.
The reaction temperature will vary depending on the reagent, the solvent and the like, and usually is from −20° C. to 100° C., preferably from 0° C. to 70° C. With respect to the hydrochloride, the reaction temperature is preferably from 30° C. to 60° C. and more preferably from 40° C. to 55° C.
The reaction time will vary depending on the reagent, the solvent, the reaction temperature and the like, and usually is from 5 minutes to 10 hours, preferably 10 minutes to 5 hours.
With respect to the preparation
Asai Fumitoshi
Inoue Teruhiko
Naganuma Hideo
Nakamura Kazuyoshi
Ogawa Taketoshi
Huang Evelyn Mei
Sankyo Company Limited
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