Benzophenone oxime derivatives, pharmaceutical compositions and use

Abstract: A new diphenyl-methane derivative is useful to inhibit agglomeration of blood and is defined by the formula, including a diphenylethylene derivative and a benzophenone oxime ether derivative. in which R1 and R2 each are hydrogen, hydroxyl or a lower alkoxy, U is =CXY or =N-O-W, X is hydrogen, cyano or -COR6, R6 being hydroxyl or an amino, Y is -R10-COOR3, R3 being hydrogen or a lower alkoxy, R10 being an alkylene having 1 to 3 carbon atoms, straight or branched, -CO-NR4R5, R4 and R5 each being hydrogen, a lower alkyl or a lower arylalkyl, -CH2-NHSO2-C6H5 or -C(R8)=NR7, R7 being a lower alkoxy or an aryl, R8 is -VR9, V being oxygen, sulfur or nitrogen, R9 being an alkyl or an aryl, W is -CH2-CO-CH2-COOR13, R13 being hydrogen or a lower alkyl, -CH2-C(=NOR14)-CH2-COOR15, R15 being hydrogen or a lower alkyl, R14 being a lower alkyl, -CH(CN)-(CH2)q-COOR16, R16 being hydrogen or a lower alkyl, q being an integer of 1 to 3, or -(CH2)p-Z, Z being -SH, -SCN or a monovalent group derived from a five- or six-membered ring which may be substituted by a ring having one or more sulfur atoms in the ring, p being 1 or 2. A pharmaceutical composition containing compounds of formula (XX) or their pharmaceutically acceptable salts as active ingredients, and the use of compounds of formula (XX) or their pharmaceutically acceptable salts in the preparation of a medicament for treatment of diseases caused by blood stream disorders are also disclosed.

Description: The invention relates to diphenylethylene derivatives, a process for preparing the same and the pharmaceutical use thereof. The most serious diseases for mankind at present include acute vascular diseases such as myocardial infarction, cerebral apoplexy, cerebral thrombosis, cerebral infarction, pulmonary embolus, deep phlebothrombosis and peripheral arteriothrombosis. Recently antiplatelet agents have attracted public attention and been clinically employed for treating these diseases. However their application has been only lately realized. Thus it is expected to develop better drugs in future. GB-999,613 includes diphenyl acrylic acid derivatives being useful to impart to organic materials superior resistance to degradation and deterioration when they are exposed to ultraviolet radiation. The above document is especially concerned with α-cyano-β,β-diphenyl acrylic acid derivatives. CH-455,676 refers to the use of compounds of the formula (I): wherein Ar₁ and Ar₂ represent aromatic carbocyclic residues not including primary, secondary or tertiary amino groups as substituents, and wherein Z is represented by -OY or wherein Y, Y₁ and Y₂ are hydrogen atoms or organic residues, for the protection of non-textile, organic materials against ultraviolet radiation. The present invention provides a diphenylethylene derivative of the general formula (I) or a pharmaceutically acceptable salt thereof: wherein R¹ and R² may be the same or different from each other and each represents hydrogen, hydroxyl or a C₁-C₆ alkoxy group; X represents a cyano group; and Y represents a group of the formula (wherein R⁴ and R⁵ may be the same or different from each other and each represents a group selected from benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, phenethyl, 2-picolyl, 3-picolyl and 4-picolyl); or a group of the formula -CH₂-NHSO₂-C₆H₅ or -C(R⁸)=NR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, R⁸ is -VR⁹, V being oxygen, sulfur or nitrogen, R⁹ being an alkyl or an aryl, or a pharmaceutically acceptable salt thereof. In the above definition, a C₁-C₆ alkyl group as mentioned with regard to R⁴ and R⁵ includes straight-chain or branched alkyl groups carrying one to six carbon atoms, e.g. methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups. An alkoxy group as mentioned with regard to R¹ and R² includes any lower alkoxy group derived from the lower alkyl groups as cited above. Among these groups, methyl and ethyl groups are the most desirable lower alkyl groups while a methoxy group is the most desirable lower alkoxy group. In addition, the invention provides a plurality of processes for preparing the above defined diphenylethylene derivative. Each process is explained below in detail. Moreover the invention provides a pharmaceutical composition which comprises a pharmacologically effective amount of a diphenylethylene derivative of the formula: wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a C₁-C₆ alkoxy group, X is cyano, Y is -CO-NR⁴R⁵, R⁴ and R⁵ each being hydrogen, a C₁-C₆ alkyl or a group selected from benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, phenethyl, 2-picolyl, 3-picolyl and 4-picolyl; -CH₂-NHSO₂-C₆H₅ or -C(R⁸)=NR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, R⁸ is -VR⁹, V being oxygen, sulfur or nitrogen, R⁹ being an alkyl or an aryl, or a pharmaceutically acceptable salt thereof, and a pharmacologically acceptable carrier. The invention also provides the use of a diphenylethylene derivative of the formula: wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a C₁-C₆ alkoxy group, X is cyano, Y is -CO-NR⁴R⁵, R⁴ and R⁵ each being hydrogen, a C₁-C₆ alkyl or a group selected from benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, phenethyl, 2-picolyl, 3-picolyl and 4-picolyl; -CH₂-NHSO₂-C₆H₅ or -C(R⁸)=NR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, R⁸ is -VR⁹, V being oxygen, sulfur or nitrogen, R⁹ being an alkyl or an aryl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of diseases caused by blood stream disorders. The invention compound will be explained in more detail in line with the above shown embodiments. Process for Preparation There may be various processes for preparing the compound (I) of the present invention. Typical examples thereof are as follows. (1) The aimed compound of the formula (I), wherein Y is a group of the formula (wherein R⁴ and R⁵ are as defined above). A carboxylic acid of the general formula (II): wherein R¹, R² and X are as defined above, or a reactive acid derivative thereof is converted into an amide by reacting with an amine of the general formula: wherein R⁴ and R⁵ are as defined above, to give a compound (I') which is one of the aimed compounds of the present invention: wherein R¹, R², X, R⁴ and R⁵ are as defined above. A reactive acid derivative of the compound (III) includes, for example, a halide, an anhydride or a mixture of acid anhydrides of the compound (III). This reaction may be carried out in the presence of dehydrating agent(s) such as N,N'=dicyclohexylcarbodiimide, N,N'-diethylcarbodiimide, trialkyl phosphates, polyphosphate or tosyl chloride, if required. When a halide is used as a reactive derivative, base(s) may be added to the reaction mixture to bind the hydrogen halide formed during the reaction, thus accelerating the reaction. Examples of the bases are inorganic salts such as potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate and tertiary amines such as pyridine and triethylamine. This reaction may be usually carried out in a solvent. Any solvent may be employed so long as it exhibits no adverse effect on the reaction. Examples of such a solvent are dimethyl sulfoxide, tetrahydrofuran, dioxane, ethanol and mixtures thereof. The reaction may be usually carried out at a temperature of -50 to 200°C unless particularly limited. After the completion of the reaction, the aimed compound may be isolated in a conventional manner. (2) The aimed compound of the formula (I), wherein Y is a group of the formula An amine of the general formula (IV): wherein R¹, R² and X are as defined above, is reacted with a sulfonyl halide of the general formula (V): wherein Hal represents a halogen atom, in a conventional manner to thereby readily give the aimed compound (I'') in the form of a sulfonamide: This reaction may be usually carried out in a solvent. Any solvent may be employed so long as it exhibits no adverse effect on the reaction. Examples of such a solvent are chloroform, 1,2-dichloroethane, ethyl ether, pyridine, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, benzene, toluene and mixtures thereof. The temperature at which this reaction is carried out is not particularly limited. Usually a temperature of -50 to 150°C is preferable. After the completion of the reaction, the aimed compound may be isolated in a conventional manner. The invention compound is defined to include a compound having the formula (I) in which Y is -C(R⁸)=NR⁷, that is, -C(VR⁹)=NR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, V being oxygen, sulfur or nitrogen, R⁹ being an alkyl or an aryl. The compound is prepared by the below given procedures. (3) A compound having the formula (I) in which Y is -CONHR⁷ is reacted with a compound having the formula of HVR⁹ by a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride and thionyl chloride to obtain a compound having the formula (I) in which Y is -C(VR⁹)=NR⁷, in a solvent such as benzene, toluene and chloroform. The reaction may be effected in the presence of an organic base such as dimethylaniline, triethylamine and pyridine or an inorganic base such as potassium carbonate and sodium carbonate. (4) The same starting compound as used in the preparation (3) is reacted with a sulfurizing agent such as phosphorus pentasulfide in a solvent such as benzene and toluene to obtain a corresponding thioamide having the formula (I) in which Y is -C(=S)-NH-R⁷. Then the thioamide is reacted with a halide having the formula of R⁹-hal to obtain a compound having the formula (I) in which Y is -C(SR⁹)=NR⁷. A solvent and. a base may be used in the same was as shown in the preparation (3). (5) A compound having the formula (I) in which Y is -C(VR⁹)=NR⁷, R⁹ is an alkyl and R⁷ is a C₁-C₆ alkoxy is obtained below. A compound having the formula (I) in which Y is -CO-VR⁹ is reacted with H₂N-R⁷ to obtain the above intended compound. The above shown procedures are illustrated below. The diphenyl ethylene derivative of the invention exhibits an excellent effect in the pharmacological point of view. It effectively inhibits the aggulutination of platelets and eventually is useful for a remedy of an antiplatelet and antithrombotic agent. In particular, it is useful for treating and/or preventing cerebrovascular diseases such as transient ischemic attack (TIA), cerebral infarction (thrombus and embolus) and cerebral arteriosclerosis; postoperative thrombus, embolus and blood stream disorders accompanying vascular operation and extracorporeal circulation; chronic arterial obstructions such as Buerger's disease, obstructive arteriosclerosis, peripheral arteriosclerosis, SLE and Raynaud's disease; and ischemic cardial diseases such as stenocardia and myocardial infarction. It is further useful for preventing recurrence of these diseases and for improving prognosis thereof. When the compound of the present invention is used as an antiplatelet and antithrombotic agent, it may be orally or parenterally, for example, intramuscularly, subcutaneously or intravenously administered. The dose thereof may vary depending on, for example, the disease, the condition and the age of each patient. Unless particularly limited, it may be administered in a dose of 0.1 to 300 mg, preferably 0.1 to 60 mg, particularly preferably 0.3 to 30 mg, further particularly preferably 0.6 to 10 mg to an adult per day. The compound of the present invention may be formulated into, for example, tablets, granules, powders, capsules, injections or suppositories in conventional manners known in the art. When it is to be formulated into solid preparations for oral administration, excipients and, if required, other additives such as binders, disintegrants, lubricants, colorants and corrigents are added to the base and the obtained mixture is then formulated into, for example, tablets, coated tablets, granules, powders or capsules in conventional manners. Examples of the excipients are lactose, corn starch, white sugar, glucose, sorbitol and crystalline cellulose. Examples of the binders are polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylstarch and polyvinylpyrrolidone Examples of the disintegrants are starch, agar, powdery gelatin, crystalline cellulose, calcium carbonate, calcium hydrogencarbonate, calcium citrate, dextrin and pectin. Examples of the lubricants are magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. Examples of the colorants are those approved as additives for drugs. Examples of the corrigents are cocoa powder, methol, aromatic acids, peppermint oil, Borneo camphor and cinnamon powder. These tablets and granules may be, as a matter of course, coated with, for example, sugar or gelatin if required. When an injection is to be prepared, various additives such as pH adjustors, buffers, stabilizers and preservatives are added to the base and the obtained mixture is formulated into an injection for subcutaneous, intramuscular or intravenous administration.

Claims: Claims for the following Contrating States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A pharmaceutical composition which comprises a pharmacologically effective amount of a diphenyl ethylene derivative of the formula; wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a C₁-C₆ alkoxy group, X is cyano, Y is -CO-NR⁴R⁵, R⁴ and R⁵ each being hydrogen, a C₁-C₆ alkyl or a group selected from benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, phenethyl, 2-picolyl, 3-picolyl and 4-picolyl; -CH₂-NHSO₂-C₆H₅ or -C(R⁸)=NR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, R⁸ is -VR⁹, V being oxygen, sulfur or nitrogen, R⁹ being an alkyl or an aryl, or a pharmaceutically acceptable salt thereof, and a pharmacologically acceptable carrier. A pharmaceutical composition as claimed in claim 1, wherein in the formula (I) both of R¹ and R² are C₁-C₆ alkoxy groups. A pharmaceutical composition as claimed in claim 2, wherein in the formula (I) both of R¹ and R² are methoxy groups. Use of a diphenyl ethylene derivative of the formula: wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a C₁-C₆ alkoxy group, X is cyano, Y is -CO-NR⁴R⁵, R⁴ and R⁵ each being hydrogen, a C₁-C₆ alkyl or a group selected from benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, phenethyl, 2-picolyl, 3-picolyl and 4-picolyl; -CH₂-NHSO₂-C₆H₅ or -C(R⁸)=NR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, R⁸ is -VR⁹, V being oxygen, sulfur or nitrogen, R⁹ being an alkyl or an aryl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of diseases caused by blood stream disorders. The use as claimed in claim 4, wherein in the formula (I) both of R¹ and R² are C₁-C₆ alkoxy groups. The use as claimed in claim 5, wherein in the formula (I) both of R¹ and R² are methoxy groups. A diphenyl ethylene derivative of the formula: wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a C₁-C₆ alkoxy group, X is cyano, Y is -CO-NR⁴R⁵, R⁴ and R⁵ each being a group selected from benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, phenethyl, 2-picolyl, 3-picolyl and 4-picolyl; -CH₂-NHSO₂-C₆H₅ or -C(R⁸)=NR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, R⁸ is -VR⁹, V being oxygen, sulfur or nitrogen, R⁹ being an alkyl or an aryl, or a pharmaceutically acceptable salt thereof. A diphenyl ethylene derivative as claimed in claim 7, wherein both of R¹ and R² are C₁-C₆ alkoxy groups, or a pharmaceutically acceptable salt thereof. A diphenyl ethylene derivative as claimed in claim 8, wherein both of R¹ and R² are methoxy groups, or a pharmaceutically acceptable salt thereof. A process for preparing a diphenyl ethylene derivative of the general formula (I) as given by claim 7, wherein R¹, R² and X are as defined above, Y is -CO-NR⁴R⁵, R⁴ and R⁵ are each as defined above, or a pharmaceutically acceptable salt thereof, which comprises reacting a carboxylic acid of the general formula (II): wherein R¹, R² and X are as defined above, or a reactive acid derivative thereof with an amine of the general formula (III): wherein R⁴ and R⁵ are as defined above, and if necessary, converting the product to a pharmaceutically acceptable salt. A process for preparing a diphenyl ethylene derivative of the general formula (I) as given by claim 7, wherein R¹, R² and X are as defined above, Y is -CH₂NHSO₂-C₆H₅, or a pharmaceutically acceptable salt thereof, which comprises reacting an amine of the general formula (IV): wherein R¹, R² and X are as defined above with a sulfonyl halide of the general formula (V): wherein Haℓ represents a halogen atom, and if necessary, converting the product to a pharmaceutically acceptable salt. A process for preparing a diphenyl ethylene derivative of the general formula (I) as given by claim 7, wherein R¹, R² and X are as defined above, Y is -C(R⁸)=NR⁷, R⁷, R⁸, V and R⁹ being as defined above, or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the general formula (I) as given by claim 7 wherein R¹, R² and X are as defined above and Y is -CONHR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, with a compound of the formula HVR⁹, wherein V and R⁹ are as defined above, in the presence of a halogenating agent and, if necessary, converting the product to a pharmacaeutically acceptable salt thereof. Claims for the following Contracting States : AT, ES, GR Use of a diphenyl ethylene derivative of the formula: wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a C₁-C₆ alkoxy group, X is cyano, Y is -CO-NR⁴R⁵, R⁴ and R⁵ each being hydrogen, a C₁-C₆ alkyl or a group selected from benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, phenethyl, 2-picolyl, 3-picolyl and 4-picolyl; -CH₂-NHSO₂-C₆H₅ or -C(R⁸)=NR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, R⁸ is -VR⁹, V being oxygen, sulfur or nitrogen, R⁹ being an alkyl or an aryl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of diseases caused by blood stream disorders. The use as claimed in claim 1, wherein in the formula (I) both of R¹ and R² are C₁-C₆ alkoxy groups. The use as claimed in claim 2, wherein in the formula (I) both of R¹ and R² are methoxy groups. A process for preparing a diphenyl ethylene derivative with the formula (I): wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a C₁-C₆ alkoxy group, X is cyano, Y is -CO-NR⁴R⁵, R⁴ and R⁵ each being a group selected from benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, phenethyl, 2-picolyl, 3-picolyl and 4-picolyl, or a pharmaceutically acceptable salt thereof, which comprises reacting a carboxylic acid of the general formula (II): wherein R¹, R² and X are as defined above, or a reactive acid derivative thereof with an amine of the general formula (III): wherein R⁴ and R⁵ are as defined above, and if necessary, converting the product to a pharmaceutically acceptable salt. A process for preparing a diphenyl ethylene derivative of the formula (I): wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a C₁-C₆ alkoxy group, X is cyano, Y is -CH₂-NHSO₂-C₆H₅, or a pharmaceutically acceptable salt thereof, which comprises reacting an amine of the general formula (IV): wherein R¹, R² and X are as defined above, with a sulfonyl halide of the general formula (V): wherein Haℓ represents a halogen atom, and if necessary, converting the product to a pharmaceutically acceptable salt. A process for preparing a diphenyl ethylene derivative of the formula (I): wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a C₁-C₆ alkoxy group, X is cyano, Y is -C(R⁸)=NR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, R⁸ is -VR⁹, V being oxygen, sulfur or nitrogen, R⁹ being an alkyl or an aryl, or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the general formula (I) as given above, wherein R¹, R² and X are as defined above and Y is -CONHR⁷, R⁷ being a C₁-C₆ alkoxy or an aryl, with a compound of the formula HVR⁹, wherein V and R⁹ are as defined above, in the presence of a halogenating agent and, if necessary, converting the product to a pharmaceutically acceptable salt thereof.

Inventors: ABE SHINYA, AKASAKA KOZO, FUJIMORI TOHRU, HARADA KOUKICHI, HAYASHI KENJI, IKUTA HIRONORI, MIYAMOTO MITSUAKI, NAKAMOTO KOUJI, OKANO KAZUO, SUZUKI TAKESHI, YAMAGISHI YOUJI, YAMATSU ISAO, YOSHIMURA HIROYUKI, ABE, SHINYA, AKASAKA, KOZO, FUJIMORI, TOHRU, HARADA, KOUKICHI, HAYASHI, KENJI, IKUTA, HIRONORI, MIYAMOTO, MITSUAKI, NAKAMOTO, KOUJI, OKANO, KAZUO, SUZUKI, TAKESHI, YAMAGISHI, YOUJI, YAMATSU, ISAO, YOSHIMURA, HIROYUKI
Applicants: EISAI CO LTD, EISAI CO., LTD.
Application year: 1987
Main classification: C07C251
IPC codes: C07C235, C07D213, C07C257, C07C327, C07C59, C07C251, C07C311, C07C255