Diphenyl-methane derivative, pharmaceutical composition 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 a diphenyl-methane derivative, a process for preparing the same and the pharmaceutical use thereof. In particular, it relates to a diphenylethylene derivative. 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. Chem. Abstr., vol. 78, abstract no. 124159p, 1973, discloses the synthesis of 1,1-diarylallenes having the formula RR¹C=C=CH₂ (R = R¹ = Ph, p-MeC₆H₄, p-MeOC₆H₄). EP-A-0 120 321 includes diphenyl-methane derivatives including an amide group. EP-A-0 124 791 includes compounds with a similar structure as given in EP-A-0 120 321. GB-A-1 257 266 and Chem. Abstr., vol. 77, abstract no. 101001w, 1972, disclose compounds of the formula wherein U = CXY, X = hydrogen or COOH, Y = -R₁₀-COOR₃, R₃ being hydrogen, and R₁₀ being an alkylene having 1 to 3 carbon atoms. The invention provides a diphenyl-methane derivative having the formula (XX) and a phamacologically acceptable salt thereof: in which R1 and R2 each are hydrogen, hydroxyl or a C₁-C₆ alkoxy, U is =CXY, X is hydrogen or -COR6, R6 being hydroxyl or an amino, Y is -R10-COOR3, R3 being hydrogen or a C₁-C₆ alkyl, R10 being an alkylene having 1 to 3 carbon atoms, straight or branched, -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, under the proviso that compounds of the formula (XX) fulfilling simultaneously the requirements of Y = -R¹⁰-COOR³, R³ = -H and X = -H or -COOH are excluded. In the formula (XX), R10 may also be defined as -(CH2)n-in which n is 1, 2 or 3. The diphenyl-methane derivative as defined above may also called a diphenylethylene derivative. In addition, the invention provides a plurality of processes for preparing the above defined diphenyl-methane derivative. Each process is explained below in detail. Moreover the invention provides a pharmaceutical composition which comprises a a pharmacologically effective amount of the diphenyl-methane derivative as defined above or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier. In this connection, the invention also includes the use of the diphenyl-methane derivative for the preperation of a medicament for treating a disease caused by the blood stream disorder. The invention compound will be explained in more detail in line with the above shown embodiments. The aimed compound of the present invention is a substituted diphenylethylene derivative. In the above definition of the formula (XX), a C₁-C₆ alkyl group as mentioned with regard to R³ 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 C₁-C₆ alkoxy group derived from the C₁-C₆ alkyl groups as cited above. Among these groups, methyl and ethyl groups are the most desirable C₁-C₆ alkyl groups while a methoxy group is the most desirable C₁-C₆ alkoxy group. A pharmaceutically acceptable salt of the aimed compound wherein R³ is a hydrogen atom includes metals salts such as Na, K, Ca and Mg salts. Process for Preparation There may be various processes for preparing the compound (XX) of the present invention. Typical examples thereof are as follows. (1) The aimed compound of the formula (XX), 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, which falls within the scope of the first embodiment. R9 is an alkyl, a substituted alkyl, an alkenyl or an aryl. The compound is prepared by the below given procedures. (2) A compound having the formula (XX) 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 (XX) 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. (3) The same starting compound as used in the preparation (2) 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 (XX) 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 (XX) in which Y is -C(SR9)=NR7. A solvent and a base nay be used in the same was as shown in the preparation (2). (4) A compound having the formula (XX) in which Y is -C(VR9)=NR7, R9 is an alkyl or a substituted alkyl and R7 is a lower alkoxy is obtained below. A compound having the formula (XX)in which Y is -CO-VR9 is reacted with H2N-R7 to obtain the above intended compound. The above shown procedures are illustrated below. In order to further illustrate the present invention, and not by way of limitation, typical examples of the compound of the present invention will be given. Each compound will be shown in free form. N-benzyl-3,3-bis(4-methoxyphenyl)acrylamide, N-(2-chlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(3-chlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(4-chlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(2-methylbenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(3-methylbenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(4-methylbenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(2-methoxyphenyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(3-methoxybenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(4-methoxybenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(2-picolyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(3-picolyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(4-picolyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-[3,3-bis(4-methoxyphenyl)allyl]benzenesulfonamide, N-[3,3-bis(4-methoxyphenyl)allyl -p-toluenesulfonamide, N-phenyl-3,3-bis(4-methoxyphenyl)acrylamide in which the phenyl may be substituted at 2, 3 or 4 position by chlorine. N-(2-, 3- or 4-pyridyl)-3,3-bis(4-methoxyphenyl)acrylamide N-(2-, 3- or 4-pyridyl)methyl-3,3-bis(4-methoxyphenyl)acrylamide N-phenyl-N-methyl or isopropyl-3,3-bis(4-methoxyphenyl)acrylamide N-(2-, 3- or 4-pyridyl)-N-methyl-3,3-bis(4-methoxyphenyl)acrylamide N-(2-, 3- or 4-pyridyl)-N-isopropyl-3,3-bis(4-methoxyphenyl) acrylamide N-(2-(N,N-dialkylamino)ethyl-3,3-bis(4-methoxyphenyl)acrylamide. the alkyl being methyl or ethyl. N-(3-(N,N-dialkylamino)propyl-3,3-bis(4-methoxyphenyl) acrylamide, the alkyl being methyl or ethyl. N,N-bis(2-(N,N-dimethylamino)ethyl)-3,3-bis(4-methoxyphenyl)acrylamide N-(2-(N,N-dimethylamino)ethyl)-N-benzyl-3,3-bis(4-methoxyphenyl)acrylamide N-phenyl-3,3-bis(4-ethoxyphenyl)acrylamide in which the phenyl may be replaced by 2-chlorophenyl, 3-pyridyl, benzyl, 2-chlorobenzyl or (3-pyridyl)methyl. N-phenyl-N-methyl-3,3-bis(4-ethoxyphenyl)acrylamide in which the phenyl may be replaced by 3-pyridyl or benzyl. N-benzyl-N-isopropyl-3,3-bis(4-ethoxyphenyl)acrylamide N-(2-(N,N-dimethylamino)ethyl)-3,3-bis(4-ethoxyphenyl)acrylamide N-(2-(N,N-diethylamino))ethyl)-N-(2-(3,4-dimethoxyphenyl)ethyl)-3,3-bis(4-ethoxyphenyl)acrylamide N-benzyl-3,3-bis(4-hydroxyphenyl)acrylic amide N-benzyl-3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)acrylic amide N-benzyl-N-methyl-3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)acrylic amide N-(2-(N,N-dimethylamino)ethyl)-N-(2-(3,4-dimethoxyphenyl)ethyl)-3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)acryl amide 3,3-bis(4-methoxy, 4-ethoxy or 4-hydroxyphenyl)-N-phenyl-acrylic imino acid ethyl ester 3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)-N-phenyl-acrylic imino acid ethyl ester 3,3-bis(4-methoxyphenyl)-N-benzyl-acrylic imino acid ethyl ester 3,3-bis(4-methoxyphenyl)-N-(3-pyridyl)-acrylic imino acid methyl ester 3,3-bis(4-methoxy-, 4-ethoxy- or 4-hydroxy-phenyl)-N,N'-diphenylacrylic amidine 3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)-N,N'-diphenylacrylic amidine 3,3-bis(4-methoxy- or 4-ethoxy-phenyl )-N,N'-dibenzylacylic amidine 3,3-bis(4-methoxyphenyl)-N-phenyl-N'-benzylacrylic amidine 3,3-bis(4-methoxy-, 4-ethoxy- or 4-hydroxy-phenyl)-N-phenyl-acrylic thioimino acid allyl ester 3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)-N-phenyl-acrylic thioimino acid allyl ester 3,3-bis(4-methoxyphenyl)-N-benzyl-acrylic thioimino acid allyl ester 3,3-bis(4-methoxyphenyl)-N-(3-pyridyl)-acrylic thioimino acid ethyl ester methyl 3-methoxyimino-5,5-bis(4-ethoxyphenyl)-4-pentenoate 3-methoxyimino-5,5-bis(4-methoxy- or 4-ethoxy-phenyl)-4-pentenoic acid 3-methoxyimino-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoic acid N-(3,3-bis(4-ethoxy- or 4-hydroxy-phenyl)allyl)-methanesulfonic amide N-(3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)allyl)-methanesulfonic amide N-(3,3-bis(4-ethoxy- or 4-hydroxy-phenyl)allyl)-benzenesulfonic amide N-(3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)allyl)-benzenesulfonic amide N-(3,3-bis(4-ethoxy- or 4-hydroxy-phenyl)allyl)-beta-toluenesulfonic amide N-(3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)allyl)-beta-toluenesulfonic amide N-(3,3-bis(4-ethoxy- or 4-hydroxy-phenyl)allyl)-4-carboxybenzenesulfonic amide N-(3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)allyl)-4-carboxybenzenesulfonic amide ethyl 4-ethoxycarbonyl-5,5-bis(4-methoxyphenyl)-4-pentenoate 4-carboxy-5,5-bis(4-ethoxy- or 4-hydroxy-phenyl)-4-pentenoic acid 4-carboxy-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoic acid ethyl 4-carbamoyl-5,5-bis(4-methoxyphenyl)-4-pentenoate 4-carbamoyl-5,5-bis(4-ethoxy- or 4-hydroxy-phenyl)-4-pentenoic acid 4-carbamoyl-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoic acid The diphenyl-methane derivative of the invention, exhibits an excellent effect in the pharmacological point of view. It effectively inhibits the agglutination 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. The effect of the invention product will be supported by the below given pharmacological tests, first about the diphenylethylene derivative. Test Example 1. Effect of inhibiting aggulutination of platelets (in vitro) The blood was collected from a human cubital vein in such a manner as to contain a 3.8% solution of sodium citrate in an amount 1.10 time by volume as much as the blood. Then platelet-rich plasma (PRP) was prepared therefrom according to the method reported by Packham et al. (cf. Packham, M.A., et al, J. Exp. Med., 126 , 171 - 189 (1967)). To 0.2 ml of the obtained PRP, 25 µl portions of solutions of each compound of the present invention (A to E) at various concentrations were added and incubated at 37°C for three minutes. Then the aggultination of platelets was induced with arachidonic acid, collagen, ADP and PAF. The aggulutination of platelets was evaluated according to the method reported by Mustard et al. (cf. Mustard, J.F., et al., J. Lab. Clin. Med., 64 , 548 - 559 (1964) with the use of an aggregometer available from Schenko or Niko Bioscience Co. In other words, this test is carried out to examine the effect on platelet aggregation (in vitro). Table 1 shows the result. Test Cpd. Effect of inhibiting collagen aggultination I C₅₀(µM) Effect of inhibiting arachidonic acid aggultination I C₅₀(µM) Effect of inhibiting ADP aggultination I C₅₀(µM) Effect of inhibiting PAF aggultination I C₅₀(µM) Cpd. A (Ex. 1) 20 5 5 15 Cpd. B (Ex. 2) 1.4 0.9 2.0 2.5 Note: The compounds A and B as shown above corresponds to the aimed compounds obtained in Examples 1 and 2 respectively. 2. Effect of inhibiting aggultination of platelets (ex vivo) The compounds A and B, which were typical examples of the compound of the present invention, were orally administered to guinea pigs. After two hours, the blood of each animal was collected from the abdominal aorta thereof under etherization. Then the effect of each compound on the aggultination of platelets induced by collagen (3 µg/ml) and arachidonic acid (50 µM) was examined. Table 2 shows the 50% effective doses determined from the solvent administration ratios. In other words, this test is conducted to examine the effect on platelet aggregation (ex vivo). Test Cpd. Effect of inhibiting collagen aggultination ED₅₀(mg/kg) Effect of inhibiting arachidonic acid aggultination ED₅₀(mg/kg) Cpd. A (Ex. 1) 100 100 Cpd. B (Ex. 2) 20 20 Ticlopidine ≦200 150 3. Acute toxicity The acute toxicities of the compounds A and B, which were typical examples of the compound of the present invention, were examined by administering these compounds to male Wistar rats of 300 to 400 g in body weight. As a result, the LD₅₀ of each compound was higher than 500 mg per kg. The effect of the invention will be supported also with the test compounds L to R corresponding to the products of Examples 8 to 14, respectively. The tests were conducted in the same way as shown. Results for inhibition of aggulutination are shown in Table 3. for the in-vitro test and in Table 4 for the ex-vivo test. Test cpd. Effect of inhibiting collagen agglutination IC₅₀(µM) Effect of inhibiting arachidonic agglutination IC₅₀(µM) Effect of inhibiting ADP agglutination IC₅₀(µM) Effect of inhibiting PAF agglutination IC₅₀ (µM) Cpd.L (Ex.8) 0.5 0.1 0.8 1.2 Cpd. M (Ex.9) 14.0 12.5 13.2 20.0 Cpd. N (Ex.10) 2.8 0.7 5.0 4.1 Cpd. O (Ex.11) 14.0 7.0 20.0 14.5 Cpd. P (Ex.12) 1.1 0.4 2.7 1.5 Cpd. Q (Ex.13) 36.0 12.0 35.0 37.0 Cpd. R (Ex.14) 80.0 50.0 85.0 79.0 Test cpd. Effect of inhibiting collagen agglutination ED₅₀(mg/kg) Effect of inhibiting arachidonic acid agglutination ED₅₀(mg/kg) Cpd. L (Ex.8) 30 30 Cpd. M (Ex.9) 55 55 Cpd. N (Ex.10) 1.3 0.3 Cpd. O (Ex.11) 1.0 0.3 Cpd. P (EX.12) 1.1 0.3 Cpd. Q (Ex.13) 88 50 Cpd. R (Ex.14) ≦100 ≦100 Ticlopidine ≦200 150 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. To further illustrate the present invention, and not by way of limitation, the following Examples will be given. Example 1: N-Benzyl-3,3-bis(4-methoxyphenyl)acrylamide 2.84 g (0.01 M) of 3,3-bis(4-methoxyphenyl)acrylic acid was dissolved in 10 ml of dimethylformamide. To the obtained solution, 1.2 g (0.012 M) of triethylamine and 1.2 g of ethyl chlorocarbonate were added under icecooling. After one hour, 1.2 g of benzylamine was added thereto and the mixture was stirred at room temperature for one hour. After the completion of the reaction, the reaction mixture was dissolved in 50 ml of ethyl acetate, washed with 10% hydrochloric acid, a saturated aqueous solution of NaHCO₃ and a saline solution successively and dried over magnesium sulfate followed by purifying by silica gel column chromategraphy. Thus 3.3 g of the title compound having the following physicochemical properties was obtained. m.p.: 99 - 100°C. NMR (CDCl₃)δ : 6.7 - 7.3(13H), 6.3(1H), 5.5(1H) , 4.3 (2H) and 3.8(6H). Example 2: N-[3,3-Bis(4-methoxyphenyl)allyl]benzensulfonamide 2.69 g of 3,3-bis-(4-methoxyphenyl)allylamine was dissolved in 5 ml of pyridine. To the obtained solution, 1.9 g of benzenesulfonyl chloride was added under icecooling and the mixture was stirred for five hours. After the completion of the reaction, the reaction mixture was dissolved in ethyl acetate and washed with 5% hydrochloric acid and a saturated saline solution successively. The crude product thus obtained was purified by silica gel chromatography in a conventional manner. Thus 3.6 g of the title compound was obtained in the form of a colorless oily product. NMR (CDCl₃)δ : 7.8 (2H), 7.5(3H), 6.7 - 7.1(8H), 5.8(1H), 4.4(1H), 3.8(6H), 3.7(2H) Reference Example 1: Ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate 2.42 g (0.01 M) of 4,4'-dimethoxybenzophenone, 1 g of zinc and 2.1 g of trimethyl borate were suspended in 15 ml of tetrahydrofuran. To the obtained suspension, 2.2 g of ethyl 4-bromo-4-cyanobutyrate and a catalytic amount of iodine were added and the mixture was allowed to react at room temperature for five hours. After the completion of the reaction, 10 ml of a saturated aqueous solution of ammonium chloride was added thereto and the mixture was stirred for one hour. After filtering the zinc off, the filtrate was extracted with ethyl acetate. The obtained crude product was purified by silica gel chromatography to give 1.5 g of crystals. The crystals were dissolved in 10 ml of benzene and 1 ml of thionyl chloride was added to the obtained solution. After stirring at room temperature for one hour, the reaction mixture was concentrated in vacuo and dispersed into ice/water. Then it was extracted with benzene, washed with water and concentrated. Thus 1.3 g of the title compound was obtained in the form of a colorless oily product. NMR (CDCl₃)δ : 6.7 - 7.3(8H), 4.1(2H), 3.8(6H), 2.7(4H) and 1.3(3H). Reference Example 2: 4-Cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid 3.6 g of ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate was dissolved in 10 ml of dioxane and 3 ml of a 5N aqueous solution of NaOH was added thereto. The obtained mixture was stirred at 60°C for five hours. After the completion of the reaction, the reaction mixture was acidified and extracted with ethyl acetate. Thus 3.2 g of the title compound having the following physicochemical properties was obtained. This product could be further purified by recrystallizing from ethyl acetate/hexane. m.p.: 124 - 125°C. NMR (CDCl₃)δ : 9.5 (1H), 6.8-7.4(8H), 3.8(6H), 2.7(4H) Examples 3 to 10 3. N-phenyl-3,3-bis(4-methoxyphenyl)acrylamide 4. N-(3-pyridyl)-3,3-bis(4-methoxyphenyl)acrylamide 5. N-(4-pyridyl)-3,3-bis(4-methoxyphenyl)acrylamide 6. N-(2-chlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide 7. N-(3-pyridyl)methyl-3,3-bis(4-methoxyphenyl)acrylamide 8. N-benzyl-N-methyl-3,3-bis(4-methoxyphenyl)acrylamide 9. N-benzyl-N-isopropyl-3,3-bis(4-methoxyphenyl)acrylamide 10. N-(2-(N,N-dimethylamino)ethyl)-N-(2-(3,4-dimethoxyphenyl)ethyl)-3,3-bis(4-methoxyphenyl)acrylamide Each of the above listed compounds was obtained in the same way as shown in Example 1, except benzylamine was replaced by the respective, below listed compounds. 3. aniline, 4. 3-aminopyridine, 5. 4-aminopyridine, 6. 2-chlorobenzylamine, 7. 3-aminomethylpyridine, 8. N-methylbenzylamine, 9. N-isopropylbenzylamine, and 10. N,N-dimethyl-N'-(2-(3,4-dimethoxyphenyl)ethyl)ethylenediamine. Example 11 ethyl 3,3-bis(4-methoxyphenyl)-N-phenyl-acrylic imide One gram ( 2.8 mmol) of the amide obtained in Example 3 was reacted with 10 ml of phosphorus oxychloride at 60°c for 2 hours. The product mixture was condensed and mixed with 50 ml of chloroform, 5 ml of ethanol and 5 ml of N,N-dimethylaniline, followed by further reaction at 60°c for 2 hours, to obtain 0.2 g of the above named compound. Example 12 3,3-bis(4-methoxyphenyl)-N,N'-diphenylacrylic amidine This was obtained by reaction between 1 g of the amide obtained in Example 3 and 0.3 ml of aniline with 0.3 ml of phosphorus oxychloride in 20 ml of toluene for 3 hours while refluxed. The amount was 80 mg. Example 13 allyl 3,3-bis(4-methoxyphenyl)-N-phenyl-acrylic thioimide One gram of the amide obtained in Example 3 was reacted with 1.2 g of phosphorus pentasulfide in 50 ml of benzene at 50°c for 1 hour. The product mixture was condensed and dissolved in chloroform, followed by washing with water. 0.6 g of the thioamide was obtained from the product mixture with the chromatography using silicagel. 0.6 g (1.6 mmol) of the thioamide was reacted with 2.0 g (16 mmol) of allyl bromide with 0.5 g of potassium carbonate in 50 ml of tetrafurane at the room temperature over one night. The reaction product mixture was condensed and dissolved in chloroform, followed by washing with water. 0.45 g of the above intended compound was obtained with the chromatography of silicagel. Example 14 ethyl 3-methoxyimino-5,5-bis(4-methoxyphenyl)-4-pentenoate 4.0 g (11.3 mmol) of ethyl 3-oxy-5,5-bis(4-methoxyphenyl)-4-pentenoate was reacted with 2.0g(24.0 mmol) of hydrochloric acid salt of methoxyamine in 50 ml of pyridine at 60°c for 2 hours. 3.2 g of the above intended compound was obtained. Example 15 3-methoxyimino-5,5-bis(4-methoxyphenyl)-4-pentenoic acid 2.0 g of the above intended compound was obtained by the same reaction as shown in Reference Example 2 from the ester obtained in Example 14. Example 16 N-(3,3-bis(4-methoxyphenyl)allyl)-methanesulfonic amide Examples 17 N-(3,3-bis(4-methoxyphenyl)allyl)-4-carboxybenzenesulfonic amide These were obtained by the same reaction as shown in Example 2, except that methanesulfonic chloride and 4-(chlorosulfonyl)benzoic acid were respectively used instead of benzenesulfonic chloride. Example 18 4-carboxy-5,5-bis(4-methoxyphenyl)-4-pentenoic acid Reference Example 1 was followed except that diethyl 2-bromoglutarate was used for ethyl 4-bromo-4-cyanobutyrate and the hydrolysis was conducted in the same way as shown in Reference Example 2. Example 19 4-carbamoyl-5,5-bis(4-methoxyphenyl)-4-pentenoic acid Two grams of the acid obtained in Reference Example 2 was heated with 10 ml of a 5N aqueous solution of NaOH in 50 ml of ethylene glycol at 150°c for 12 hours. The product mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was treated with the chromatography of silicagel to obtain 0.5 g of the above intended compound. The data of the NMR analysis about the compounds obtained in Examples 3 to 19 is listed below. The analysis was conducted with CDCl₃, δ examples analysis 3 6.8-7.4(14H), 6.4(1H), 3.9(6H) 4 7.9-8.4(3H), 6.8-7.4(10H), 6.4(1H), 3.8(6H) 5 8.3(3H), 6.7-7.3(10H), 6.3(1H), 3.8(6H) 6 7.0-7.3(8H), 6.7-6.9(4H), 6.3(1H), 5.7(1H), 4.4(2H), 3.8(6H) 7 8.5(1H), 8.3(1H), 7.0-7.5(6H), 6.8(4H), 6.3(1H), 5.6(1H), 4.3(2H), 3.8(6H) 8 6.7-7.4(13H), 6.3(1H), 4.5(2H), 3.8(6H), 2.7(3H) 9 6.6-7.5(13H), 6.4(1H), 4.8(1H), 4.5(2H), 3.8(6H), 1.0(6H) 10 6.6-7.4(11H), 6.2(1H), 3.8(12H), 3.2-3.7(4H), 2.1-2.8(10H) 11 6.5-7.6(13H), 5.9(1H), 4.0(2H), 3.8(6H), 0.9(3H) 12 6.6-7.4(19H), 6.1(1H), 3.8(6H) 13 6.5-7.3(13H), 6.2(1H), 5.8(1H), 5.1(2H), 3.5-3.8(8H) 14 6.7-7.3(8H), 6.6(1H) , 4.0(2H) 3.9(3H), 3.8(6H), 2.9(2H), 1.2(3H) 15 10.0(1H), 6.7-7.3(9H), 3.9(3H), 3.8(6H), 2.9(2H) 16 6.6-7.4(8H), 5.9(1H), 4.4(1H), 3.8(8H), 2.9(3H) 17 10.0(1H), 7.6-8.2(4H), 6.5-7.1(8H), 5.7(1H), 4.4(1H), 3.4-3.9(8H) 18 8.0-9.5(2H), 6.7-7.4(8H), 3.8(6H), 2.7(4H) 19 8.2(1H), 6.6-7.2(10H), 3.7(6H), 2.3(4H)

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A diphenyl-methane derivative having the formula (XX) and a pharmacologically acceptable salt thereof: in which R¹ and R² each are hydrogen, hydroxyl or a C₁-C₆ alkoxy group, U is =CXY, X is hydrogen or -COR⁶, R⁶ being hydroxyl or an amino, Y is -R¹⁰-COOR³, R³ being hydrogen or a C₁-C₆ alkyl, R¹⁰ being an alkylene having 1 to 3 carbon atoms, straight or branched, -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, under the proviso that compounds of the formula (XX) fulfilling simultaneously the requirements of Y=-R¹⁰-COOR³, R³=-H and X=-H or -COOH are excluded. A diphenyl-methane derivative as claimed in claim 1, wherein both of R¹ and R² are C₁-C₆ alkoxy groups or a pharmaceutically acceptable salt thereof. A diphenyl-methane derivative as claimed in claim 1, wherein Y is -R¹⁰-COOR³ (wherein R³ and R¹⁰ are as defined in claim 1), or a pharmaceutically acceptable salt thereof. A diphenyl-methane derivative as claimed in claim 1, wherein Y is a group of the formula and a pharmaceutically acceptable salt thereof. A diphenyl-methane derivative as claimed in claim 1, wherein both of R¹ and R² are methoxy groups or a pharmaceutically acceptable salt thereof. A diphenyl-methane derivative as claimed in claim 1, wherein the compound is N-[3,3-bis(4-methoxyphenyl)-allyl]-benzensulfonamide, and a pharmaceutically acceptable salt thereof. A pharmaceutical composition which comprises a pharmacologically effective amount of the diphenyl-methane derivative as defined in any of claims 1 to 6 or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier. Use of the compounds of any of claims 1 to 6 in the preparation of a medicament for the treatment of diseases caused by blood stream disorders. Claims for the following Contracting States : AT, ES, GR A process for preparing a diphenyl-methane derivative having the formula (XX) and a pharmacologicallY acceptable salt thereof: in which R¹ and R² each are hydrogen, hydroxyl or a C₁-C₆ alkoxy group, U is =CXY, X is hydrogen or -COR⁶, R⁶ being hydroxyl or an amino, Y is -R¹⁰ -COOR³, R³ being hydrogen or a C₁-C₆ alkyl, R¹⁰ being an alkylene having 1 to 3 carbon atoms, straight or branched, wherein compounds of the formula (XX) fulfilling simultaneously the requirements of R³ = -H and X = -H or -COOH are excluded, which comprises reacting a ketone of the general formula (VI) wherein R¹ and R² are as defined above, with a halide of the general formula (VII) wherein Hal represents a halogen atom, and R³ and R¹⁰ are as defined above, to give a hydroxy compound of the formula (VIII), which is then dehydrated to give the compound of the formula (XX), and, if necessary, converting the product to a pharmaceutically acceptable salt. A process for preparing a diphenyl-methane derivative having the formula (XX) and a pharmacologically acceptable salt thereof: in which R¹ and R² each are hydrogen, hydroxyl or C₁-C₆ alkoxy group, U is =CXY, X is hydrogen or -COR⁶, R⁶ being hydroxyl or an amino, Y is -CH₂-NHSO₂-C₆H₅, 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 obtained product of the formula (XX) to a pharmaceutically acceptable salt. A process for preparing a diphenyl-methane derivative having the formula (XX) and a pharmacologically acceptable salt thereof: in which R¹ and R² each are hydrogen, hydroxyl or a C₁-C₆ alkoxy group, U is =CXY, X is hydrogen or -COR⁶ , R⁶ being hydroxyl or an amino, 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, which comprises reacting a compound of the formula (XX), in which R¹, R², U and X are as defined above and Y is -CONHR⁷, R⁷ being as defined above, with a compound having the formula of HVR⁹, where V and R⁹ are as defined above, in the presence of a halogenating agent, and, if necessary, converting the resulting product of the formula (XX) to a pharmaceutically acceptable salt. A process for preparing a diphenyl-methane derivative having the formula (XX) and a pharmacologically acceptable salt thereof: in which R¹ and R² each are hydrogen, hydroxyl or a C₁-C₆ alkoxy group, U is =CXY, X is hydrogen or -COR⁶, R⁶ being hydroxyl or an amino, 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, which comprises reacting a compound of the formula (XX), in which R¹, R², U and X are as defined above, and Y is -CO-VR⁹, where V and R⁹ are as defined above, with an amine of the formula H₂N-R⁷, where R⁷ is as defined above, and, if necessary, converting the resulting product of the formula (XX) to a pharmaceutically acceptable salt. A process as defined in any of the preceding claims, wherein both of R¹ and R² are C₁-C₆ alkoxy groups. A process as defined in claim 5, wherein both of R¹ and R² are methoxy groups. A process for preparing a pharmaceutical composition which comprises the mixing of a pharmacologically effective amount of a diphenyl-methane derivative as defined in any of the preceding claims 1 to 6 or a pharmacologically acceptable salt thereof with a pharmacologically acceptable carrier. Use of a diphenyl-methane derivative as prepared according to any of the claims 1 to 6, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diseases caused by blood stream disorders.

Inventors: ABE SHINYA, AKASAKA KOZO, FUJIMORI TOHRU, HARADA KOUKICHI, HAYASHI KENJI, IKUTA HIRONORI, MIYAMATO 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, MIYAMATO, 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: C07C235
IPC codes: C07C59, C07C327, C07D213, C07C235, C07C251, C07C255, C07C257, C07C311