IE67385B1 - Diphenyl-methane derivative pharmaceutical composition and use - Google Patents

Description

Diphenyl-Methane Derivative, Pharmaceutieai_Cpmoo.g_ijX Γ 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 arteriofchrombosis.

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. 124159ο, 1973, discloses the synthesis of 1,1-diarylallenes having the formula rrIc-C^CH? (R = R1 = Ph, O"MeCgH4, p-MeOCgHd.

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-i 257 266 and Chem. Abstr., vol. 77, abstract no. lOlOOlw, 1972, disclose compounds of the formula R‘ R1 2 C II (XX) wherein U ~ CXY, X = hydrogen or COOH, Y = -R10-COOR3, R3 being 5 hydrogen, and Rt_q being an alkylene having 1 to 3 carbon atoms.

The invention provides a diphenyl-methane derivative having the formula (XX) and a pharmacologically acceptable salt thereof: II u 7 in which R* and R" each are hydrogen, hydroxyl Or a c.-c, alkoxy group, u is «CXY, X is hydrogen or -COR , 1 o 10 3 3 R® being hydroxyl or an amino, Y is -R -COOR , R being hydrogen or a cics· R10 being an alkylene havina 1 to 3 carbon atoms, straight or branched, -CH2-NHSO2-C6HS or -C(R8) =NR7, R7 being a 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^-rIO-COOR3 * * *, R3-"H and X=-H or -COOH are excluded. 0 In the formula (XX), R may also be defined as (CH-) - in which n is 1, 2 or 3. Ζ Π The diphenyl-methane derivative as defined above may also be called a diphenylethylene derivative.

In addition, the invention provides a plurality of processes for preparing the above defined diphenylmethane 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 c a r r i e r.

In this connection, the invention also includes the use of the diphenyl-methane derivative for the preparation 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 C^-ϋθ 3 alkyl group as mentioned with regard to R 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-pentvl, 1-ethylpropyl, isoamyl and n-hexyl groups. 2 An alkoxy group as mentioned with regard to R and R" includes any C^-Cg alkoxy group derived from the C^-Cg alkyl groups as cited above.. Among these groups, methyl and ethyl groups are the most desirable C^-Cg alkvl groups while a methoxy group is the most desirable C^-Cg alkoxy group.

A pharmaceutically acceptable salt of the aimed compound wherein R^ 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. -CH^-NHSOn-^ An amine of the general formula (IV): X— C— CHj —NKj i 2 wherein R~f R -and X are as defined above, is reacted with a sulfonyl halide of the general formula (V) : (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: ii X—c—CH.-NH— SO 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 sueh a solvent are chloroform, 1,2-dichloroethane, ethyl ether, pyridine, tetrahvdrofuran, 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 5 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 1o 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 5 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 ~G (SR9) =NR7. A solvent anda base may 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. (&) di/ne-fh/f am.'ne/CHCXs Cl H 5 s ocHs 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) acrvlamide, N-{2~chlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N-(3-chlorobenzyl)-3,3-bis(4-roethoxyphenyl)acrylamide, N-(4-ehlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N- (2-methylbenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, 10 N-(3-methylbenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, N- (4-methylbenzyl)-3,3-bis(4-methoxyphenyl)acrylamide, Ν-(2-methoxyphenyl)-3,3-bis(4-methoxvphenyl)acrylemice, 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, Ν-Γ3,3-bis(4-methoxyphenyl)allylJbenzenesulfonemide, Ni3,3-bis(4-methoxyphenyl)allyl -p-toluenesulfonamiae, 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-phenyi-N-methyi or isopropyl-3,3-bis(4-methoxyphenyl)acrylamide N-(2-, 3- or 4-pyridyl)-N-methyl-3,3-bis(4methoxyphenyl)acrylamide N-(2-, 3- or 4-pyridyl)-N-isopropyl-3,3-bis (4methoxyphenyl)acrylamide N-(2-(Ν,Ν-dialkylamino)ethyl-3,3-bis(420 methoxyphenyl)acrylamide, the alkyl being methyl or ethyl.

N~(3-(Ν,Ν-dialkylamino)propyl-3,3-bis(4methoxyphenyl)acrylamide, the alkyl being methyl or ethyl, I 1 Ν,Ν-bis (2- (Ν,Μ-dimethylaraino)ethyl) -3,3-bis (4methoxyphenyl)acrylamide N- (2- (Ν,Ν-dimethylamino)ethyl)-N-benzyl-3,3-bis (4methoxyphenyl)acrylamide 5 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 J-θ benzyl.

N-henzyl-N-isopropyl-3,3-bis(4-ethoxyphenyl)acrylamide in N- (2- (Ν,Ν-dimethylamino) ethyl) -3,3-bis (4ethoxyphenyl)acrylamide N-(2-(Ν,Ν-diethylamino))ethyl)-N-(2-(3,4-dimethoxvphenyl)ethyl)15 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- (420 ethoxyphenyl)acrylic amide N-(2-(Ν,Ν-dimethylamino)ethyl)-N-(2-(3,4dimethoxyphenyl) ethyl) -3- (4-methoxyphenyl) -3- (4-ethoxyphenyl)acrylic amide ΐ 2 3.3- bis(4-methoxy, 4-ethoxy or 4--hydroxyphenyl)-Nphenyl-acrylic imino acid ethyl ester 3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)-M-phenylacrylic 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)10 N,N’-diphenylacrylic amidine 3- (4-methoxyphenyl)-3- (4-ethoxyphenyl) -Ν,Ν’1diphenvlacrylic 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-phenyl20 acrylic thioimino. acid allyl ester ΐ, 3 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)-4pentenoate 3-me thoxy imino·* 5,5-bis (4-methoxy- or 4-ethoxy-phenvl)4~pentenoic acid 3-methoxyimino-5-(4-methoxyphenyl)-5-(4-ethoxyphenvl)" 4-pentenoic acid N-(3,3-bis(4-ethoxy- or 4"hydroxy-phenyl)allyl)methanesulfonic amide N-(3-(4-methoxvphenyl)-3-(4-ethoxvphenyl)allyl)methanesulfonic amide N- (3,3-bis (4-ethoxy- or 4-hydroxy--phenyl) allyl) benzenesulfonic amide N-(3-(4-methoxyphenvl)-3-(4-ethoxyphenyl)allyl)benzenesulfonic amide N-(3,3-bis (4-ethoxy- or 4-hydroxy-phenyl)allyl)20 beta-toluenesulfonic amide 4 Ν-(3-(4-methoxyphenyl)-3-(4-ethoxyphenvl)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-carboxybensenesulfonic amide ethyl 4-ethoxycarbonyl-5,5-bis (4-methoxyphenyl)-4pentenoate 4-carboxy-5,5-bis(4-ethoxy- or 4-hydroxy-phenyl)-4pentenoic acid 4-carboxy-5- (4-methoxyphenyl)-5-(4-ethoxyphenvl)-4pentenoic acid ethyl 4-carbamoyl-5,5-bis (4-methoxyphenyl)-4-pentenoate .4-carbamoyX-S,5-bis(4-ethoxy- or 4-hydroxy-phenyl)4-pentenoic acid 4~carhamoyl-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 (TXA), cerebral infarction (thrombus and embolus) and cerebral arteriosclerosis; ft ο 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 agglutination of platelets (in vitro) The blood was collected from a human cubital vein in such a manner as to contain a 3.81 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 yl portions of solutions of each compound of the present invention (A to E) at various concentrations were added and incubated at 37GC for three minutes. Then the agglutination of platelets t 7 was induced with arachidonic acid, collagen, ADP and PAF.

The agglutination of platelets was evaluated according to the method reported hv 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.

Table 1 Test Cpd. Effect of inhibiting collagen agglutination I c5q(um) Effect of inhibiting arachidonic acid agglutination I c50(mM) Effect of inhibiting ADP agglutination i c50(wm) Effect of inhibiting j PAF aggLurination ί I c50(m) Cpd. A (Ex. 1) 20 5 5 ί 15 Cad. B (Ex. 2) 1.4 0.9 2.0 2.5 ! Note: The compounds A and B as shown above correspond to the aimed compounds obtained in Examples 1 and 2, respectively. 2. Effect of inhibiting agglutination of platelets (ex vivo) The compounds Aand 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 agglutination of platelets induced by collagen (3 pg/ml) and arachidonic acid (50 pM) 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).

Table 2 Test Cpd. Effect of inhibiting collagen agglutination ED50(mg/kg) Effect of inhibiting arachidonic acid agglutination ED30(mg/kg) Cod. A (Ex. 1) 100 100 Cpd. B (Ex. 2) '2020 Ticlcpiaine <200150 9 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 LD^q 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 agglutination are shown in Table 3 for the in-vitro test and in Table 4 for the ex-vivo test. Ο Table 3 Test cpd. ! Effect of ιinhibiting ίcollagen !agglutination i IC50(uM) Effect ox inhibiting arachidoaic agglutination ic5O0jH-) Exxect ox inhibiting ADP agglutination 1C50(mM) Exrect ox ; inhibiting pae agglutination ic5O6-m) Cpd. L (EX. 8) j 0.5 0.1 0.8 1 1.2 Cpd. M (Ex. 9) ί 14.0 12.5 13.2 20.0 Cod. N (Ex. 10) 1 2.8 0.7 5.0 4.1 Cpd. 0 (Ex. 11) 14.0 1 i | 7.0 20.0 14.5 j Cpd. P (Ex.12) ..1 0.4 2.7 j 1.5 Cpd. Q (Ex. 13) Ϊ 36.0 II 12.0 j 35.0 37.0 Cpd. R (Ex. 14) 80.0 j 50.0 |85.0 79.0 i 1 Table 4 Test cpd. ....... j Effect of I inhibiting ί collagen ! agglutination : ED-θ(mg/kg) Effect of inhibiting arachiaonic acid • agglutination ED-θ(mg/kg) Cpd. L (Ex. 8) j 30 . . 1 Cad. M (Ex. 9) j 55 j 55 j Cod. N (Ex.. 10) 1.3 0.3 | . . p Cpd. 0 (EX. ID 1.0 0.3 I 1 Cod. P (EX. 12) 1.1 0.3 Cpd. Q (Ex. 13) es ί 50 | III Cpd. B. (Ex. 14) <100 <100 I Ticlopidine I <200 150 2 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 3.Q 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, methvlcellulose, gum arable, 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 4 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 NaHCO-j and a saline solution successively and dried over magnesium sulfate followed by purifying by silica gel column chromatography. Thus 3.3 g of the title compound having the following physicochemical properties was obtained. m.p.: 99 - 100°C.

NMR (CDCl-,)6 : 6.7 - 7.3(13H), 6.3(IH), 5.5(IH), 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 benzenesulfonvl chloride was added under iceeooling 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 (CDC13)<5 : 7.8(2H), 7.5(3H), 6.7 - 7.1(8H), 5.8(1H), 4.4(IH), 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 6 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 (CDC13)6 : 6.7 - 7.3(8K), 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)-4pentenoate 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 (CDC13)o : 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 . N-(4-pyridyl)-3,3-bis(4-methoxyphenyl)acrylamide 6. N-(2-chlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide a 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 . N-(2-(N,N-dimethvlamino)ethyl)-N-(2-(3,410 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-amlnopyridine, 5. 4-aminopyridine, ' 6. 2-chlorobenzylamine, 7. 3-aminomethylpyridine, 8. N-methylbenzylamine, 9. N-isopropylbenzylamine, and 10. N,N-dimethyl-N’-(2-(3,420 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 Ν,Ν-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-raethoxyimino-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 Ν- (3,3-bis (4-methoxyphenyl)allyl)-methanesulfonic amide Example 17 N-(3,3-bis (4-methoxyphenyl)allyl)-4carboxybenzenesulfonic 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. a 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-carbamoyl5,5-bis(4-methoxyphenyl)-4~pentenoic θ 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 J·5 extracted with ethyl acetate. The extract was treated with the chromatography of silicagel to obtain 0.5 g of the above intended compound.

Claims (12)

Claims:

1. A diphenvl-methanederivative having the formula (XX) and a pharmacologically acceptable salt thereof: 1 7 m which and R each are hydrogen, hydroxyl or a C.-C, alkoxy group, ϋ is »CXY, X is hydrogen or -CQR°, θ 1 Π 1 15 r6 being hydroxyl or an amino, Y is -R -COOR , R being hydrogen or a c^Cg. alkyl, R 10 being an alkylene having 1 to 3 carbon atoms, straight or branched, -CHj-NHSOj-CgKg or -C(R 8 )=NR 7 , R 7 being a.c^-Cg alkoxy or an aryl, R 8 is =VR 9 , v being oxygen, sulfur or nitrogen, R 9 being 20 an alkyl or an aryl, under the proviso that compounds of the formula (XX) fulfilling simultaneously the requirements of Y=-R l0 -COOR 3 , R 3 --H and X«-H or -COOH are excluded.

2. A diphenyl-methane derivative as claimed in . 1 9 25 claim 1, wherein both of R” and R“ are C„-c r alkoxy 1 6 groups or a pharmaceutically acceptable salt thereof.

3. A diphenyl-methane derivative as claimed in claim 1, wherein Y is -R^-COOR 3 (wherein R 3 and _30 R 10 are as defined in claim 1), or a pharmaceutically acceptable salt thereof. 3 5

4. A diphenyl-methane derivative as claimed in claim 1, wherein Y is a group of the formula -CH 9 -nh-S0 9 and a pharmaceutically acceptable salt thereof.

5. ,, A diphenyl-methane derivative as claimed in 1 2 claim 1, wherein both of R and R are methoxy groups or a pharmaceutically acceptable salt thereof.

6. 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.

7. 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.

8. 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.

9. A compound according to claim 1, substantially as hereinbefore described and exemplified.

10. A process for preparing a compound according to claim 1, substantially as hereinbefore described and exemplified.

11. A compound according to claim 1, whenever prepared by a process claimed in claim 10.

12. A pharmaceutical composition according to claim 7, substantially as hereinbefore described.