DD263233A5 - PROCESS FOR PREPARING A SUBSTITUTED DIPHENYLTHYLENE DERIVATIVE - Google Patents

Abstract

The invention relates to a process for the preparation of a substituted Diphenylethylenderivats. According to the invention, a diphenylethylene derivative and a benzophenone oxime ether derivative are prepared which are encompassed by the general formula wherein R1 and R2 are each hydrogen, hydroxy or lower alkoxy, U is CXY or NOW, X is hydrogen, cyano or COR6, R6 is hydroxy or amino, Y R10 is -COOR3, R3 is hydrogen or lower alkoxy, R10 is alkylene of 1 to 3 carbon atoms, straight or branched, CONR4R5, R4 and R5 are each hydrogen, lower alkyl or lower aralkyl, CH2NHSO2C6H5 or C (R8) NR7, R7 is lower alkoxy or aryl , R8 is VR9, V is oxygen, sulfur or nitrogen, R9 is alkyl or aryl, W is CH2COCH2COOR13, R13 is hydrogen or lower alkyl, CH2C (NOR14) CH2COOR15, R15, is hydrogen or lower alkyl, R14 is lower alkyl, CH (CN) (CH 2) q COOR 16, R 16 is hydrogen or lower alkyl, q is an integer from 1 to 3, or (CH 2) p Z, Z is SH, SCN or a monovalent group derived from a five- or six-membered ring may be substituted by a ring containing one or more sulfur atoms in the ring, p is 1 or 2. Formula

Description

HO

CH- (CH ₀₎ -COOR ⁴

2'-

(wherein R ¹ , R ² , η and R ^{4 are} as defined above) is dehydrated to form a substituted diphenylethylene derivative represented by the above general formula and optionally forming said substituted diphenylethylene derivative represented by the above general formula Formula is reproduced, and optionally, said substituted Diphenylethylenderivat is converted into a pharmaceutically acceptable salt thereof.

Field of application of the invention

The invention relates to a process for the preparation of a substituted Diphenylethylenderivats with valuable pharmacological properties, in particular with inhibiting effect on the agglutination of platelets. The compounds according to the invention are used pharmaceutically as medicaments, for example for the treatment of cerebrovascular diseases

 In particular, the invention relates to a diphenylethylene derivative and a benzophenone oxime ether derivative.

Characteristic of the known state of the art

Presently, the most numerous human diseases present are acute vascular diseases such as myocardial infarction, cerebral apoplexy, cerebral thrombosis, cerebral infarction, pulmonary embolism, deep vein thrombosis, and peripheral arterial thrombosis.

New antithrombocytic agents have aroused public interest and have been used clinically for the treatment of these diseases. However, their application has only recently been realized. It is therefore expected to develop better medicines in the future.

Object of the invention

The aim of the invention is the provision of new compounds with a strong inhibiting effect on the agglutination of platelets.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, a diphenylmethane derivative of the formula (XX) and a pharmacologically acceptable salt of this compound

(XX)

manufactured,

wherein R ¹ and R ² each represent hydrogen, hydroxyl or lower alkoxy and U is = CXY or = NOW; X is hydrogen, cyano or CÖR ⁶ , wherein R ^{6 is} hydroxyl or amino; Y is -R ¹⁰ -COOR ³ wherein R ^{3 is} hydrogen or lower alkoxy and R ¹⁰ is alkylene of 1 to 3 carbon atoms, straight or branched, -CO-NR ⁴ R ⁵ where R ⁴ and R ^{s are} each hydrogen, Lower alkyl or lower alkyl, -CH ₂ -NHSO ₂ -C ₆ H ₅ or -C (R ⁸ ) = NR ⁷ , wherein R ^{7 is} lower alkoxy or aryl, R ^{8 is} VR ⁹ , V is oxygen, sulfur or nitrogen and R ^{9 is} alkyl or aryl.

W is -CH ₂ -CO-CH ₂ -COOR ¹³ , wherein R ¹ - ^{3 is} hydrogen or lower alkyl, -CH ₂ Cl = NOR ¹⁴ ) -CH ₂ -COOR ^TS , wherein R ^{15 is} hydrogen or lower alkyl and R ¹⁴ is lower alkyl , -CH (CN) - (CH ₂ ) _q -COOR ¹⁶ , wherein R ^{16 is} hydrogen or lower alkyl and q is an integer from 1 to 3, or - (CH ₂ ) _p -Z, wherein Z is -SH ₁ -SCN or a monovalent group derived from a five- or six-membered ring which may be substituted by a ring which may have one or more sulfur atoms in the ring, and ρ is 1 or 2.

In the formula (XX), R ¹⁰ can be defined by - (CH ₂ J _n -, wherein η is one, two or three.

The above-defined diphenylmethane derivative has two embodiments. One of them is a diphenylmethane derivative of the formula (XX) in which U has the meaning = CXY, also referred to as diphenylethylene derivative. The other is a diphenylmethane of the formula (XX), wherein U has the meaning = N-O-W, also referred to as Benzophenonoximetherderivat. The invention will now be described in detail with respect to these two embodiments. In addition, the invention provides a variety of methods of preparation of the diphenylmethane derivatives defined above. Each method is explained in detail below.

Furthermore, the invention relates to a pharmaceutical composition consisting of a pharmacologically effective amount of a diphenylmethane derivative as defined above or a pharmacologically acceptable salt thereof

and a pharmacologically acceptable carrier.

In this connection, the invention relates to a method of treating a disease caused by bloodstream irregularities by administering the diphenylmethane derivative as defined above or a pharmacologically acceptable salt thereof.

The compound of the present invention will now be described in more detail according to the above embodiments.

The object compound of the present invention is a substituted diphenylethylene derivative of the general formula (I) or a

pharmaceutically acceptable salt thereof,. ,

(I)

wherein R ¹ and R ^{2 are the} same or different and each represents hydrogen or lower alkoxy; X is a hydrogen atom or a cyano group; and Y is a group of the formula - (CH ₂ J _n -COOR ³ (wherein R ^{3 is} a hydrogen atom or a lower alkoxy group and η is an integer of 1 to 3), a group of the formula

-G-E

(wherein R ⁴ and R ^{5 may be the} same or different and each represents a hydrogen atom, lower alkyl or arylalkyl) or a group of the formula ₍

-CH ₂ -CHSO ₂ -

.a

(wherein R ^{6 is} a hydrogen atom or a lower alkyl group, and Y may further be-C (R ⁸ ) = NR ⁷ .

In the above definition, the term lower alkyl group as mentioned for R ³ , R ⁴ and R ⁵ includes straight or branched chain alkyl groups of one to six carbon atoms, e.g. For example, methyl, ethyl, n-propyl, η-butyl, isobutyl, isopropyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl. An alkoxy group as mentioned for R ¹ and R ² detects any lower alkoxy group derived from the above lower alkyl groups. 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.

An arylalkyl group as mentioned with respect to R ⁴ and R ⁵ is benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl , 4-methoxybenzyl and phenethyl groups, as well as heteroaryl groups such as 2-picolyl, 3-picolyl and 4-picolyl. Pharmaceutically acceptable salts of the object compound wherein R ^{3 is} hydrogen include metal salts such as Na, K, Ca and Mg salts.

There are various methods of preparation of the compound (I) according to the invention. Typical examples are the following.

(1) The compound of the formula (I) wherein Y is a group of the formula -CO-NR ⁴ R ⁶ (wherein R ⁴ and R ^{5 may be the} same or different and each represents a hydrogen atom or a lower alkyl or arylalkyl group).

A carboxylic acid of the general formula (II):

COOH

wherein R ¹ , R ² 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

(III)

in which R ⁴ and R ^{5 have} the abovementioned meaning. There was thus obtained a compound (Γ) which is one of the objective compounds of the present invention:

d ')

wherein R ¹ , R ² , X, R ⁴ and R ^{5 have} the above meaning.

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). If necessary, this reaction may be carried out in the presence of dehydrating agents such as N, N'-dicyclohexylcarbodiimide, Ν, Ν'-diethylcarbodiimide, trialkyl phosphates, polyphosphate or tosyl chloride.

When a halide is used as the reactive derivative, base (s) may be added to the reaction mixture to bind the hydrogen halide formed during the reaction to thereby accelerate the reaction. Examples of these 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 can usually be carried out in a solvent. Any solvent may be used as long as it shows no adverse effect on the reaction. Examples of such a solvent are dimethyl sulfoxide, tetrahydrofuran, dioxane, ethyl alcohol and mixtures thereof.

The reaction may be carried out usually at a temperature of -50 ⁰ C to 200 ⁰ C, if it is not limited due to peculiarities. After completion of the reaction, the target compound can be isolated in a conventional manner. (2) The object compound of the formula (I) wherein Y is a group of the formula

-CH ₂ -ISHSO ₂

is.

An amine of the general formula (IV)

E ¹

(IV),

Σ -C-GH ₂ - ₂

wherein R ¹ , R ² and X have the abovementioned meaning, is reacted with a sulfonyl halide of the general formula (V) in customary.

Shark - SO,

wherein Hal represents a halogen atom, which easily gives the object compound (I ") in the form of the sulfonamide

R ²

XC-CH ₂ -ITH-SO ₂

This reaction can usually be carried out in a solvent. Any solvent may be used as long as it shows no adverse effect on the reaction. Examples of such solvents are chloroform, 1,2-dichloroethane, ethyl ether, pyridine, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, benzene, toluene and

their mixtures.

The temperature at which this reaction is carried out is not particularly limited. Usually, a temperature of -50 ° C to 15O ⁰ C is preferred. After complete reaction, the target compound can usually be isolated.

(3) The object compound of the formula (I) wherein Y is a group of the formula - (CH ₂ ) _n -COOR ³ (wherein η and R ³ are as defined above

Have meaning).

A ketone of the general formula (VI):

,1

C η

(Vl),

wherein R ¹ and R ^{2 are} as defined above, with a halide of the general formula (VII)

"" Hai

ι.

HC- (CH ₀ J _n -COOR ³

1 c- Xl

(VII)

, -5- ZÖ3Z33

wherein Hal is a halogen atom and η and R ^{3 have} the above meaning, for example, in the presence of zinc in tetrahydrofuran in usually reacted to obtain a hydroxy compound of formula (VIII) (Reformatsky's reaction)

(VIII)

CH - (

Examples of solvents which can be used for the above reaction are tetrahydrofuran, benzene and ether. It is also possible to use a solvent mixture which comprises, for example, trimethyl borate or triethyl borate with metrahydrofuran. This reaction can usually be carried out at a temperature between -7O ⁰ C to 15O ⁰ C. The hydroxy compound (VIII) thus obtained can be dehydrated in a conventional manner to give a compound of the formula (Γ ") which is one of the objective compounds of the present invention.

(CH ₂ ) _n - COOR-

Examples of solvents usable for this reaction are benzene, toluene, tetrahydrofuran, ether and dioxane, while examples of catalysts usable therefor are p-toluenesulfonic acid, thionyl chloride, phosphorus pentoxide, iodine and hydrochloric acid. This reaction can be carried out at a temperature between about -70 ⁰ C and 150 ⁰ C.

The compound of the invention is to be defined as including a compound of the formula (I) in which Y has the meaning -C (R ⁸ J = NR ⁷ , ie - (VR ⁹ I = NR ⁷ ) which is within the scope of the R ⁹ is an alkyl radical, substituted alkyl, alkenyl or aryl.

The compound is prepared by the methods given below.

(7) A compound of the formula (I) in which Y is -CONHR ⁷ is reacted with a compound having the formula HVR ⁹ by means of a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride and thionyl chloride. to obtain a compound of the formula (I) in which Y has the meaning-C (VR ⁹ J = NR ⁷ ) The reaction is carried out in a solvent such as benzene, toluene and chloroform and can be carried out in the presence of an organic base such as dimethylaniline, triethylamine and pyridine or an inorganic base such as potassium carbonate and sodium carbonate.

(8) The crude starting compound as in Preparation (7) is reacted with a sulfonating agent such as phosphorus pentasulfide in a solvent such as benzene and toluene to give a corresponding thioamide of formula (I) wherein Y is' -C (= S) -NH-R ⁷ 'has. Subsequently, the thioamide is reacted with a halide of the formula R ⁹ -Hal to obtain a compound of the formula (I) in which Y has the meaning-C (SR ⁹ ) = NR ⁷ . A solvent and a base can be used in the same manner as in the preparation (7).

(9) A compound of the formula (I) in which Y has the meaning-C (VR ⁹ ) = NR ⁷ , in which R ^{9 is} alkyl or substituted alkyl and R ⁷ is lower alkoxy, is obtained below. A compound of the formula (I) wherein Y is -CO-VR ⁹ is reacted with H ₂ NR ⁷ to obtain the above-desired compound.

The above methods are explained below. '(see page 11, following, and equation:

C O

Q CA.

-7- Z53Z33

ΝίΗ- <Ρ

MH (O

"HF

CH 3 0,

Chio

dimetn / i amine / CHCl

To further elucidate the present invention, but not to limit it, typical examples of the compounds of the invention now follow. Each connection is given in its free form.

N-Benzyl-3,3-bis (4-methoxyphenyl) acrylamide N- (2-chlorobenzyl) -3,3-bis (4-methoxyphenyl) acrylamide NO-chlorobenzyD-SS-bis-W-methoxyphenyldacrylamide 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 ethyl 4-cyano-5,5-bis (4-methoxyphenyl) -4-pentenoate 4-cyano-5,5-bis (4-) methoxyphenyl) -4-pentenoic acid methyl 5-cyano-6,6-bis (4-methoxyphenyl) -5-hexenoate ethyl 3-cyano-4,4-bis (4-methoxyphenyl) -3-butenoate ethyl-4- cyano-5,5-bis (4-ethoxyphenyl) -4-p entenoate methyl 4-cyano-5,5-bis (4-ethoxyphenyl) -4-pentenoate 4-cyano-5,5-bis (4-ethoxyphenyl) -4-pentenoic acid 5-cyano-6,6-bis (4 -ethoxyphenyl) -5-hexenoic acid and 3-cyano-4,4-bis (4-ethoxyphenyl) -3-butenoic acid In addition to the types of compounds and compounds obtained in Examples for the first embodiment of the invention, the following compounds are within the scope of the invention ,

N-phenyl-3,3-bis (4-methoxyphenyl) acrylamide, wherein the phenyl radical in the 2,3 or 4-position may be substituted 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, wherein alkyl is methyl or ethyl.

N- (3- (N, N-dialkylamino) propyl-3,3-bis (4-methoxyphenyl) acrylamide, wherein alkyl is methyl or ethyl.

N, N-bis (2- (N, N-dimethylamino) ethyl) -3,3-bis (4-methoxyphenyl) acrylamide.

N- (2- (N, N-diethylamino) ethyl) -N-benzyl-3,3-bis (4-methoxyphenyl) acrylamide N-phenyl-3,3-bis (4-ethoxyphenyl) acrylamide, wherein the phenyl radical is represented by 2-chlorophenyl, 3-pyridyl, benzyl, 2-chlorobenzyl or (3-pyridyl) methyl may be substituted.

N-phenyl-N-methyl-3,3-bis (4-ethoxyphenyl) acrylamide, wherein the phenyl radical 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) acrylamide N-Benzyl-3- (4-methoxyphenyl) -3- (4-ethoxyphenyl) acrylamide N-Benzyl-N-methyl-3- (4-methoxyphenyl) -3- (4-ethoxyphenyl) acrylamide N- (2- (N, N-Dimethylamino) ethyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -3- (4-methoxyphenyl) -3- (4-ethoxyphenyl) acrylamide 3,3-bis (4-methoxy, 4-ethoxy or 4-hydroxyphenyl) -N-phenylacryliminoacid ethyl ester 3- (4-Methoxyphenyl) -3- (4-ethoxyphenyl) -N-phenylacryliminoacid ethyl ester SS-bis-IA-methoxyphenyll-N-benzyl-acryliminoacid ethyl ester 3,3 bis (4-methoxyphenyl) -N- (3-pyridyl) -acryliminic acid methyl ester 3,3-bis (4-methoxy, 4-ethoxy or 4-hydroxyphenyl) -N, N'-diphenylacrylamidine 3- ( 4-methoxyphenyl) -3- (4-ethoxyphenyl) -N, N'-diphenylacrylamidine 3,3-bis (4-methyl-oxy or 4-ethoxyphenyl) -N, N'-dibenzyl-acrylamine 3,3-bis ( 4-Metho xyphenyl) -N-phenyl-N'-benzylacrylamidin 3,3-bis (4-methoxy, 4-ethoxy or 4-hydroxy-phenyl) -N-phenylacrylothioiminoic acid allyl ester 3- (4-methoxyphenyl) -3- (4 3-bis (4-methoxyphenyl) -N-benzylacrylothioiminoic acid allyl ester 3,3-bis (4-methoxyphenyl) -N- (3-pyridyl) -acrylothioiminoic acid ethyl ester methyl-3. -ethoxyphenyl) -N-phenylacrylthioiminoic acid allyl ester -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-hydroxyphenyl) allyl) -methanesulfonamide N- (3- (4-methoxyphenyl) -3 - (4-ethoxyphenyl) allyl) -methanesulfonamide N- (3,3-bis (4-ethoxy or 4-hydroxyphenyl) allyl) -benzenesulfonamide N- (3- (4-methoxyphenyl) -3- (4-ethoxyphenyl ) allyl) -benzenesulfonamide N- (3,3-bis (4-ethoxy- or 4-hydroxyphenyl) allyl) -beta-toluenesulfonamide N- (3- (4-methoxyphenyl) -3- (4-ethoxyphenyl) allyl) beta-toluenesulfonamide

N-ß ^ -bisW-ethoxy-ode ^ -hydroxy-phenyDallylM-carboxybenzenesulfonamide N-fS-W-methoxyphenyD-S - ^ - ethoxyphenylyallylM-carboxybenzenesulfonamide Ethyl 3-cyano-4,4-bis (4-ethoxy- or 4-bis) hydroxy-phenyl) -3-butenoate

Ethyl 3-cyano-4- (4-methoxyphenyl-4- (4-ethoxyphenyl) -3-butenoate

3-cyano-4,4-bis (4-methoxyphenyl) -3-butenoic acid

3-cyano-4,4-bis (4-hydroxyphenyl) -3-butenoic acid

3-cyano-4- (4-methoxyphenyl) -4- (4-ethoxyphenyl) -3-butenoic acid

Ethyl 4-cyano-5,5-bis (4-methoxyphenyl) -4-pentenoate

Ethyl 4-cyano-5,5-bis (4-hydroxyphenyl) -4-pentenoate

Ethyl 4-cyano-5- (4-methoxyphenyl) -5- (4-ethoxyphenyl) -4-pentenoate

Ethyl 4-cyano-5- (4-hydroxyphenyl) - (Z) -or- (E) -5- (4-methoxyphenyl) -4-pentenoate ethyl-4-cyano-5- (4-hydroxyphenyl) - ( Z) -or- (e) -5- (4-ethoxyphenyl) -4-pentenoat4-cyano-5- (4-methoxyphenyl) -5- (4-ethoxyphenyl) -4-pentenoic acid

Ethyl 4-cyano-2-methyl-5,5-bis (4-methoxy, 4-ethoxy or 4-hydroxyphenyl) -4-pentenoate ethyl 4-cyano-2-methyl-5- (4- methoxyphenyl) -5- (4-ethoxyphenyl) -4-pentenoate 4-cyano-2-methyl-5,5-bis (4-ethoxy- or 4-hydroxyphenyl) -4-pentenoic acid

4-cyano-2-methyl-5- (4-methoxyphenyl) -5- (4-ethoxyphenyl) -4-pentenoic acid

Methyl 5-cyano-6,6-bis (4-ethoxy- or 4-hydroxyphenyl) -5-hexenoate

Methyl-5-cyano-6- (4-methoxyphenyl) -6- (4-ethoxyphenyl) -5-hexenoate

5-cyano-6,6-bis (4-methoxy- or 4-hydroxyphenyl) -5-hexenoic acid

5-cyano-6- (4-methoxyphenyl) -6- (4-ethoxyphenyl) -5-hexenoic acid

Ethyl 4-ethoxycarbonyl-5,5-bis (4-methoxy-phenyl) -4-pentenoate

4-carboxy-5,5-bis (4-ethoxy-or 4-hydroxy-phenyl) -4-pentenoic acid

4-carboxy-5- (4-methoxy-phenyl) -5- (4-ethoxy-phenyl) -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 object compound of the present invention is a substituted benzophenone oxime ether derivative of the general formula (XI) or its pharmaceutically acceptable salt

(XI)

wherein R ¹ and R ^{2 are the} same or different and each represents a hydrogen atom or a lower alkoxy group; and W represents a group of the formula

-CH-CH ₀ -C ₀ -COOR ¹³

(wherein R ^{13 is} a hydrogen atom or a lower alkyl group), a group of the formula

-CH-CH ₀ -C ₀ -COOR ¹⁵ Jl N-OR ¹⁴

(wherein R ^{15 is} a hydrogen atom or a lower alkyl group and R ^{14 is} a lower alkyl group), a group of the formula

-CH- (CH ₂ J-COOR ¹⁶

CN

(wherein R ^{16 represents} a hydrogen atom or a lower alkyl group and g is an integer of 1 to 3) or a group of the formula - (CH ₂ ) _P -Z (wherein Z is a group of the formula -SH, a group of the formula - SCN or a monovalent group derived from a five- or six-membered ring, which may optionally be substituted by a ring having one or more sulfur atoms in the ring, and ρ is an integer 1 or 2). In the above definition, a lower alkyl group as mentioned with respect to R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ include straight-chain or branched alkyl groups having 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, for example R ¹ and R ² include any lower alkoxy group derived from the above-cited lower alkyl groups Among these groups, methyl and ethyl groups are the most preferable lower alkyl groups, while the methoxy group is the most preferable lower alkoxy group.

By the monovalent group derived from a five- or six-membered ring optionally substituted by a ring containing one or more sulfur atoms in the ring as defined for YZ of the compound (XI) of the invention, for example, 1-pyrrolyl, 1 (1,2,3,4-tetrazolyl), 1-pyrrolidinyl, 1,3-dithianyl and S-allylmercapto-i ^^ - triazolyl.

A pharmaceutically acceptable salt of the target compound of formula (XI) wherein R ¹³ , R ¹⁵ and / or R ^{16 are} hydrogen atoms,

detects metal salts such as Na, K, Ca and Mg salts. · '

Further, some of the target compounds can be converted to acid addition salts by reacting them with a pharmaceutically acceptable inorganic or organic acid. Examples of such inorganic acids are hydrochloric acid, hydrogen bromide, hydrogen iodide and sulfuric acid. Examples of such organic acids are maleic, fumaric, succinic, acetic, malonic, citric, benzoic, oxalic and methanesulfonic acid.

There are various processes for the preparation of the compound (XI) according to the invention. Typical examples are the following.

Production process 4

R ¹

(XIL).

(Step 1)

(XlIl)

(Level 2)

Hal-W

(XIV)

R '

ti

H- 0 - W

(XI)

wherein R ¹ , R ² and W have the abovementioned meaning and Hai is a halogen atom.

A benzophenone compound of the formula (XII) is reacted with a hydroxylamine to obtain a benzophenone oxime of the formula (XIII) (Step 1). Then, the compound of the formula (XIII) is condensed with a halide of the formula (XIV) to obtain the objective compound of the formula (XV) (Step 2). The resulting product may be converted into a pharmaceutically acceptable salt, if necessary, if necessary.

The step I can be carried out usually at temperatures of approximately 0 to 200 ° C, preferably at room temperature to 100 ⁰ C using a solvent such as methanol, ethanol, propanol, benzene, toluene or

Water. ,

Step 2 can usually be carried out at a temperature of approximately 0 to 100 ^° C. by means of a solvent such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methanol, ethanol, propanol, benzene or toluene. The reaction may be carried out in the presence of a base such as sodium hydride (NaH), triethylamine, dimethylaniline, potassium hydroxide, methoxysodium (NaOMe), ethoxy sodium (NaOEt) or tert-butoxy-potassium to give a preferable result. ,

manufacturing process

A target compound of the formula (XI) in which R ¹³ , R ¹⁵ and R ¹⁶ in the radical W represent hydrogen atoms.

An ester of the formula

JST-OW ¹

wherein W has the same meaning as W in the general formula (XI) except that R ¹³ , R ¹⁵ and R ^{16 are} hydrogen atoms, ie, lower alkyl groups, in general, for example, with an alkali such as caustic. Soda, hydrolyzed to reach the target compound.

Production process 6

A target compound of the general formula (XI), wherein W is a group of the formula

-CHO-C -OHp-COOR

wherein R ^{14 is} a lower alkyl group and R ^{15 is} a hydrogen atom or a lower alkyl group.

-'OR

CH ₅ --C - CH ₀ 0

- COOR

15

(XVlI)

(XVIII)

-Ό - CH ₀ -C ^;

CH ₂ - COOR

15

U-OR

wherein R), R ² , R ¹⁴ and R ^{15 have} the abovementioned meaning.

A compound of the general formula (XVI) is reacted with an amine of the general formula (XVII) to give a compound of the formula (XVIII) which is one of the target compounds. This reaction may preferably be carried out at a temperature of about -20 ⁰ C to 200 ⁰ C in a solvent such as methanol, ethanol, propanol, benzene, toluene.

In order to further illustrate the present invention, but not to limit it, typical examples of compounds according to the invention are given below. Each connection is given in its free form.

4,4'-dimethoxy-0- (3-methoxycarbonyl-2-oxopropyl) oxime,

4,4'-dimethoxy-0- (3-ethoxycarbonyl-2-oxopropyl) oxime,

4,4'-Dimethoxybenzophenone-O- (3-methoxycarbonyl-2-methoxyiminopropyl) oxime, 4,4'-dimethoxybenzophenone-O- (3-ethoxycarbonyl-2-methoxyiminopropyl) oxime, 4,4'-dimethoxybenzophenone-0- 3-carboxy-2-methoxyiminopropyl) oxime,

4,4'-dimethoxy-0- (1-cyano-3-methoxycarbonylpropyl) oxime,

4,4'-dimethoxy-0- (1-cyano-3-ethoxycarbonylpropyl) oxime,

4,4'-dimethoxy-0- (1-cyano-3-carboxypropyl) oxime,

4,4'-dimethoxy-0- (1-cyano-4-methoxycarbonylbutyl) oxime,

4,4'-dimethoxybenzophenone O- (1-cyano-4-carboxybutyl) oxime,

4,4'-dimethoxybenzophenone-o- {2- [3-allylmercapto-1,2,4-triazolyl)] ethyl} oxime, 4,4'-dimethoxybenzophenone-0- {2- [1- (1,2, 3,4-tetrazolyl)] ethyl} oxime,

4,4'-dimethoxy-0- {2- [2- (1,3-dithianyl)] ethyl} oxime,

4,4'-dimethoxy-0- [2- (1-pyrrolidinyl) ethyl] oxime,

4,4'-dimethoxy-0- (2-thiocyänatethyl) oxime,

4,4'-dimethoxy-0- (2-mercaptoethyl) oxime,

4,4'-dimethoxy-0- [2- (1-pyrrolyl) ethyl] oxime,

4,4'-Diethoxybenzophenon-0- (3-ethoxycarbonyl-2-oxopropyl) oxime,

4,4'-Diethoxybenzophenone-O- (3-ethoxycarbonyl-2-methoxyiminopropyl) oxime, 4,4'-diethoxybenzophenone-O- (3-carboxy-2-methoxyiminopropyl) oxime,

4,4'-Diethoxybenzophenon-0- (1-cyano-3-ethoxycarbonylpropyl) oxime,

4,4'-Diethoxybenzophenon-0- (1-cyano-3-carboxypropyl) oxime,

4-methoxybenzophenone-0- (3-ethoxycarbonyl-2-oxopropyl) oxime,

4-methoxybenzophenone-O- (3-ethoxycarbonyl-2-methoxyiminopropyl) oxime, 4-methoxybenzophenone-O- (3-carboxy-2-methoxyiminopropyl) oxime,

4-methoxybenzophenone-O- (1-cyano-3-ethoxycarbonylpropyl) oxime and

4-methoxybenzophenone-0- (1-cyano-3-carboxypropyl) oxime.

The diphenylmethane derivatives of the invention, both the diphenylene derivatives and the benzophenone oxime ether derivatives, show a pharmacologically excellent effect. They effectively inhibit agglutination of platelets and are eventually useful for a drug in the form of an anti-platelet agent and anti-thrombotic agent. In particular, such agent is useful in the treatment and / or prevention of cerebrovascular diseases, such as transient ischemic attacks (TlA), myocardial infarction (thrombus and embolus) and cerebral arteriosclerosis; postoperative thrombus, embolus, and blood flow irregularities in vascular surgery and extracorporeal circulation; chronic arterial occlusions such as Buerger's disease, obstructive atherosclerosis, peripheral arteriosclerosis, SLE and Raynaud's disease; and ischemic cardinal diseases such as stenocardia and myocardial infarction.

It is also useful for preventing the recurrence of these diseases and for improving their prognosis.

The effect of the product according to the invention is underlined by the pharmacological tests listed below, starting with the diphenylethylene derivative.

experimental example

1. Inhibiting effect on agglutination of platelets (in vitro)

The blood was collected from a human elbow vein to contain a 3.8% solution of sodium citrate in an amount of 1.10 times the blood volume. From this, the platelet-rich plasma (PRP) was subsequently obtained by the method of Packham (Packham, MA et al., J. Exp. Med., 126, 171-189 [1967]). To 0.2 ml of the obtained PRP, 25-microliter portions of solutions of each compound of the present invention (A to E) were added at various concentrations and incubated at 37 ^° C. for three minutes. Then, agglutination of the platelets was induced by arachidonic acid, collagen, ADP and PAF. Platelet agglutination was assessed by the method described by Mustard et al. (Mustard, JF, et al., J. Lab. Clin. Med., 64, 548-559 [1964]) using an aggregometer. In other words, the test was performed to check for platelet aggregation (in vitro). Table 1 shows the result.

Table 1 Inhibierungs- Inhibitory effect of agglutination by ADP PAF testvér effect of binding collagen arachidonic IC ₅₀ (μΜ) IC ₅₀ (MM) agglutination acid IC ₅₀ (μΜ) IC ₅₀ (MM) 5 15 Vdbg.A 20 5 2.0 2.5 (Ex.1) Vbdg. B 1.4 0.9 0.2 1.8 (Example 2) Vbdg. C 0.2 0.07 1.9 2.8 (Example 3) Vdd. D 1.7 0.8 0.2 1.3 (Example 4) Vbdg. E 0.15 0.06 (Example 5)

Note: The compounds A to E listed above correspond to the target compounds obtained in Examples 1 to 5 (A = Ex. 1, etc.).

2. Inhibitory effect on platelet agglutination (ex vivo)

The compounds of designations A to E, which are typical examples of compounds of the invention, were orally administered to Guinea pigs. After two hours, the blood of each animal was removed from its abdominal aorta under ether. Thereafter, the effect of each compound on collagen (3 μg / ml) and arachidonic acid (50 μΜ) -induced platelet agglutination was examined. Table 2 shows the 50% effective doses determined from the administration ratios of the solvent. In other words, the test was carried out to check platelet aggregation (ex vivo).

Table 2

Testver inhibiting effect of agglutination by

binding collagen arachidonic acid

ED ₅₀ (mg / kg) ED ₅₀ (mg / kg)

Connection A - '

(Example 1) 100 100

Compound B

(Example) 20 20

Compound C

(Example 3) 0.05 0.03

Connection D

(Example ^ 0.05 0.03

Connection E

(Example 5) 1 0.3

Ticlopidine S 200 150

3. Acute toxicity

The acute toxicities of compounds A to E, which are typical examples of compounds of the invention, were tested by administering these compounds to male Wistar rats at 300 to 400 g body mass. The result was that the LD _{50 of} each compound was higher than 500 mk per kg.

The effect of the invention is also supported by the test results listed below for the benzophenone oxime ether derivatives.

The test compounds L to Rent Talk to the respective products of Examples 11 to The tests were carried out in the same manner as previously shown for the Diphenyiethylenderivate. Results for the inhibition of agglutination are given in Table 3 for the in vitro test and in Table 4 for the ex vivo test. The acute toxicity test showed the same results as obtained for the diphenylethylene derivatives.

Table 3

Testver inhibiting effect of agglutination by

binding collagen arachidon-ADP PAF

acid

(each IC ₅₀ in μΜ)

Connect. L

(Ex. 11) 0.5

Connect. M

(Ex. 12) 14.0

Connect. N

(Ex. 13) 2,8

0.1 0.8 1.2 12.5 13.2 20.0 0.7 5.0 4.1

Continuation of Table 3

Testver inhibiting effect of agglutination by

binding collagen arachidon-ADP PAF

acid

(each IC ₅₀ in μΜ)

Connect. O

(Ex. 14) 14.0

Connect. P

(Ex. 15) 1,1

Connect. Q

(Ex. 16) 36,0

Connect. R

(Ex. 17) 80.0

7.0 20.0 14.5 0.4 2.7 1.5 12.0 35.0 37.0 50.0 85.0 79.0

Table 4

Test-inhibiting effect of agglutination by binding collagen arachidonic acid ED ₅₀ (mg / kg) ED ₅₀ (mg / kg)

Connection L

(Example 11) 30 30

Connection M

(Example 12) 55 55

Connection N

(Example 13) 1.3 0.3

Compound O

(Example 14) 1.0 0.3

Connection P

(Example 15) 1.1 0.3

Connection Q

(Example 16) 88 50

Ticlopidine & 200-150

Connection R

(Example 17) S100 ^ 100

When the compound of the present invention is used as an antiplatelet agent and as an antithrombotic agent, it may be administered orally or parenterally, for example, intramuscularly, subcutaneously or intravenously. The dosage levels may be, for example, dependent on the disease, the condition and the age of each patient. Unless specifically limited, it may be administered in a dose of 0.1 to 300 mg, preferably 0.1 to 60 mg, more preferably 0.3 to 30 mg, and particularly preferably 0.6 to 10 mg per adult and per day , The compound according to the invention can be formulated, for example, into tablets, granules, powders, capsules, injectable liquids or suppositories by known technical methods.

When it is to be formulated into solid preparations for oral administration, carriers and, if necessary, other additives such as binders, spreading agents, lubricants, dyes and corrigents are to be added to the base, and the resulting mixture is then, for example, tablets, granules, powders or capsules formulated in the usual way. Examples of excipients are lactose, corn starch, white sugar / glucose, sorbitol and crystalline cellulose. Examples of binders are polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch and polyvinylpyrrolidone. Examples of distributing agents are starch, agar, powdered gelatin, crystalline cellulose, calcium carbonate, calcium hydrogencarbonate, CaCO ₃ , CaHCO ₃ , calcium citrate, dextrin and pectin. Examples of lubricants are magnesium stearate, talc, polyethylene glycol, silica and hydrogenated vegetable oils. Examples of dyes are those used as additives for pharmaceuticals. Examples of corrigents are cocoa powder, methanol, aromatic acids, peppermint oil, borneo-camphor and cinnamon powder. Of course, these tablets and granules may be coated with, for example, sugar or gelatin if necessary. When an injectable liquid is to be prepared, various additives such as pH adjuster, buffers, stabilizers and protective agents are added to the base, and the resulting mixture is formulated into an injectable liquid for subcutaneous, intramuscular or intravenous administration.

embodiment

The invention is explained in more detail below with reference to some examples

 The examples given are not intended to limit the invention.

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 were added 1.2 g (0.012 M) of triethylamine and 1.2 g of ethyl chlorocarbonate under ice cooling. After one hour were 1.2g

Benzylamine was added, and the mixture was stirred at room temperature for one hour. After completion of the reaction, the reaction mixture was dissolved in 50 ml of ethyl acetate, washed successively with 10% hydrochloric acid, a saturated NaHCO ₃ aqueous solution and a brine, and dried over magnesium sulfate. Silica gel column chromatography followed, to give 3.3 g of the title compound having the following physicochemical properties:

Schmelzpunkt99bis100 ° C

NMR (CDCl ₃ ) 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] benzenesulfonamide

2.69 g of 3,3-bis [4-methoxyphenyl] allylamine were dissolved in 5 ml of pyridine. To the obtained solution, 1.9 g of benzenesulfonyl chloride was added under ice-cooling, and the mixture was stirred for 5 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate and washed with 5% hydrochloric acid and saturated brine successively. The crude product thus obtained was purified by silica gel chromatography in a usual manner. In this way, 3.6 g of the title compound were obtained in the form of a colorless, oily product.

NMR (CDCl ₃ ) O: 7.8 (2H), 7.5 (3H), 6.7-7.1 (8H), 5.8 (1H), 4.4 (1H), 3, 8 (6), 3.7 (2H).

Example 3

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 were added 2.2 g of ethyl 4-bromo-4-cyano butyrate and a catalytic amount of IOD, and then the mixture was allowed to stand at room temperature for 5 hours. After 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 off the zinc, the filtrate was filtered with ethyl acetate. The obtained crude product was purified by silica gel chromatography to obtain 1.5 g of crystals. The obtained 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 in ice / water. Then it was extracted with benzene, washed with water and concentrated. In this way, 1.3 g of the title compound were obtained in the form of a colorless oily product

NMR (CDCl ₃ ) δ: 6.7-7.3 (8H), 4.1 (2H), 3.8 (6H), 2.7 (4H) and 1.3 (3H).

Example 4

4-cyano-5,5-bis (4-methoxy-phenyl) -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 NaOH aqueous solution was added thereto. The resulting mixture was stirred at 60 ^° C. for five hours. After completion of the reaction, the reaction mixture was made acid and extracted with ethyl acetate. In this way, 3.2 g of the title compound having the following physicochemical properties were obtained. This product could be further purified by recrystallization from ethyl acetate / hexane.

Melting point 124-125 ° C

NMR (CDCl ₃ ) δ: 9.5 (1H), 6.8-7.4 (8H), 3.8 (6H), 2.7 (4H).

Example 5

Methyl-5-cyano-6,6-bis (4-methoxyphenyl) -5-hexenoate

The procedure of Example 3 was repeated except that the ethyl 4-bromo-4-cyano butyrate was replaced by 2.2 g of methyl 5-bromo-5-cyanopentane. Thus, the title compound having the following physicochemical properties was obtained.

NMR (CDCl ₃ ) O: 6.7-7.3 (8H), 3.8 (6H), 3.6 (3H) and 1.8-2.6 (6H).

Example 6 to 13

6. N-phenyl-3,3-bis (4-methoxyphenyl) acrylamide

7. N- (3-pyridyl) -3,3-bis (4-methoxyphenyl) acrylamide

8. N- (4-pyridyl) -3,3-bis (4-methoxyphenyl) acrylamide

9. N- (2-chlorobenzyl) -3,3-bis (4-methoxyphenyl) acrylamide

10. N- (3-pyridyl) methyl-3,3-bis (4-methoxyphenyl) acrylamide

11. N-Benzyl-N-methyl-3,3-bis (4-methoxyphenyl) acrylamide

12. N-Benzyl-N-isopropyl-3,3-bis (4-methoxyphenyl) acrylamide

13. N- (2- (N, N-Di-ethylamino) ethyl) -N- (2- (3,4-dimethoxyphenyl) ethyl) -3,3bis (4-methoxyphenyl) acrylamide

Each of the compounds listed above is obtained in the same manner as in Example 1, with the exception that benzylamine has been replaced by the corresponding compound listed below.

6. aniline; 7. 3-aminopyridine; 8. 4-aminopyridine; 9. 2-chlorobenzylamine; 10. 3-aminomethylpyridine; 11. N-methylbenzylamine; 12. N-isopropylbenzylamine; and 13. N, N-dimethyl-N '- (2- (3,4-dimethoxyphenyl) ethyl) ethylenediamine.

Example 14

Ethyl 3,3-bis (4-methoxyphenyl) -N-phenyl-acrylimide

One gram (2.8 mmol) Example 6 disinfected amide obtained was reacted with 10ml of phosphorus oxychloride at 60 ⁰ C for 2 hours. The product mixture was condensed and with 50 ml of chloroform, 5 ml ethanol and 5 ml of N, N-dimethylaniline mixed, followed by further reaction at 6O ⁰ C for 2 hours joined. 0.2 g of the abovementioned compound was obtained.

Example 15

3,3-bis (4-methoxyphenyl) - "N, N'-diphenylacrylamidine This compound was prepared by reaction between 1 g of the amide obtained in Example 6 and 0.3 ml of aniline with 0.3 ml of phosphorus oxychloride in 20 ml of toluene over 3 hours formed under reflux, giving 80 mg.

Example 16

Allyl-3,3-bis (4-methoxyphenyl) -N-phenyl-acrylthioimid One gram of the amide 6erhaltenen in Example was reacted with 1.2 g of phosphorus pentasulfide in 50 ml of benzene at 50 ⁰ C for one hour. The product mixture was condensed and dissolved in chloroform and then washed with water. 0.6 g of the thioamide from the product mixture was purified by silica gel chromatography. 0.06 g (1.6 mmol) of the thioamide was mixed with 2.0 g (16 mmol) of allyl bromide with 0.5 g of potassium carbonate in 50 ml of tetrahydrofuran at room temperature implemented one night. The reaction product mixture was condensed and dissolved in chloroform and then washed in water. 0.45 g of the title compound was obtained by chromatography on silica gel.

Example 17

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 used 2.0 g (24, OmMoI) of the hydrochloric acid salt of methoxyamine in 50 ml of pyridine at 6O ⁰ C for 2 hours. 3.2 g of the intended compound were obtained.

Example 18

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 in Example 4 from the ester obtained from Example.

Example 19

N- (3,3-bis (4-methoxyphenyl) allyl) -methanesulfonamide

Example 20

N- (3,3-bis (4-methoxyphenyl) allyl-4-carboxybenzenesulfonamide '

These compounds were obtained by the same reaction as in Example 2 except that methanesulfonyl chloride and 4- (chlorosulfonyl) benzoic acid were used instead of benzenesulfonyl chloride.

Example 21

4-cyano-5,5-bis (4-ethoxyphenyl) -4-pentenoic acid Example 3 was repeated except that 4,4'-diethoxybenzophenone and tetrahydrofuran were used as the solvent. The product mixture was dehydrated with thionyl chloride and hydrolyzed in the same manner as in Example 4.

Example 22

4-cyano-5- (4-hydroxyphenyl) - (Z) -5- (4-methoxyphenyl) -4-pentenoic acid and its (E) -compound The procedure of Example 3 was followed, with the exception that 4-methoxy-4 '-methoxymethoxybenzophenone was used.

The product mixture was treated with hydrochloric acid and hydrolyzed in the same manner as in Example 4. The elution of the product mixture with a 5:95 mixture of methanol and chloroform from chromatography using silica gel gave the (Z) compound. Elution with the mixture at a ratio of 10:90 gave the (E) compound.

Example 23

(4-Cyano-5- (4-hydroxyphenyl) - (Z) -5- (4-ethoxy-phenyl) -4-pentenoic Acid and the (E) Compounds Thereof The procedure of Example 22 was followed except that 4-Ethoxy-4'-methoxymethoxybenzophenone was used.

Example 24

4-cyano-5,5-bis (4-hydroxyphenyl) -4-pentenoic acid

Example 25

4-Cyano-2-methyl-5,5-bis (4-methoxyphenyl) -4-pentenoic acid The procedure of Example 22 was followed except that 4,4'-dimethoxymethoxybenzophenone and 4,4'-dimethoxybenzophenone were used. The hydrolysis product was the compound intended above.

Example 26

4-carboxy-5,5-bis (4-methoxyphenyl) -4-pentenoic acid The procedure of Example 3 was followed except that diethyl 2-bromoglutarate was used for ethyl 4-bromo-4-cyano butyrate. The hydrolysis was carried out in the same manner as in Example 4.

Example 27

4-carbamoyl-5,5-bis (4- (methoxyphenyl) -4-pentenoic acid.

Two grams of the acid obtained in Example 4 was heated with 10 ml of a 5N aqueous solution of NaOH in 50 ml ethylene glycol at 15O ⁰ C for 12 hours. The product mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was purified by silica gel chromatography, to give 0.5 g of the compound intended above.

Example 28 '

5-cyano-6,6-bis (4-methoxyphenyl) -5-hexenoic acid

260 mg of the ester obtained in Example 5 was treated in the same manner as in Example 4 to obtain 250 mg of the above-intended compound. · .. ·. '

The data of the NMR analysis for the compounds of the products obtained in Examples 6 to 28 are listed below. The analysis was performed with CDCl ₃ , δ.

Example analysis

6 6.8-7.4 (14H); 6.4 (1H), 3.9 (6H)

7 7.9-8.4 (3H), 6.8-7.4 (10H), 6.4 (1H), 3.8 (6H)

8,8,3 (3H), 6,7-7,3 (10H), 6,3 (1H), 3,8 (6H) ·.

9,7, O-7,3 (8H), 6,7-6,9 (4H), 6,3 (1H), 5,7 (1H), 4,4 (2H), 3,8 (6H)

10 8.5 (1H), 8.3 (1H), 7.0-7.5 (6H), 6.8 (4H), 6.3 (1H), 5.6 (1H)

11 6.7-7.4 (13H), 6.3 (1H), 4.5 (2H), 3.8 (6H), 2.7 (3H)

12 6.6-7.5 (13H), 6.4 (1H), 4.8 (1H), 4.5 (2H), 3.8 (6H), 1.0 (6H)

13 6.6-7.4 (11H), 6.2 (1H), 3.8 (12H), 3.2-3.7 (4H), 2.1-2.8 (10H) 14 · · 6.5-7.6 (13H), 5.9 (1H), 4.0 (2H), 3.8 (6H), 0.9 (3H)

15 x 6.6-7.4 (19H), 6.1 (1H), 3.8 (6H)

16 6.5-7.3 (13H), 6.2 (1H), 5.8 (1H), 5.1 (2H), 3.5-3.8 (8H)

17 6.7-7.3 (8H), 6.6 (1H), 4.0 (2H), 3.9 (3H), 3.8 (6H), 2.9 (2H), 1.2 (3H)

18 10.0 (1H), 6.7-7.3 (9H), 3.9 (3H), 3.8 (6H), 2.9 (2H) *.

19 6.6-7.4 (8H), 5.9 (1H), 4.4 (1H), 3.8 (8H), 2.9 (3H)

20 10.0 (1H), 7.6-8.2 (4H), 6.5-7.1 (8H), 5.7 (1H), 4.4 (1H), 3.4-3 , 9 (8H)

21 9.5 (1H), 6.6-7.2 (8H), 4.0 (4H), 2.6 (4H), 1.4 (6H)

22 8.0-9.5 (2Η), 7.1-7.5 (2Η), 6.7-7.0 (6Η), 3 _; 8 (3Η), 2.7 (4Η)

23 7.5-9.5 (2H), 7.0-7.3 (2H), 6.6-6.9 (6H), 4.0 (2H), 2.6 (4H ), 1.4 (3 H)

24 8.5-10.0 (3H), 6.7-7.4 (8H), 2.6 (4H),

25 9.0 (1H), 7.1-7.3 (3H), 6.6-7.0 (6H), 3.8 (6H), 2.3-3.1 (3H), 1, 2 (3H),

26 8.0-9.5 (2H), 6.7-7.4 (8H), 3.8 (6H), 2.7 (4H)

27 8.2 (1H), 6.6-7.2 (10H), 3.7 (6H), 2.3 (4H)

28 8.0-9.0 (1H) 7.1-7.3 (2H), 6.7-7.0 (6H), 3.8 (6H), 2.2-2.5 (4H ), 1.8-2.2 (2H)

The examples given above relate to the first group of the invention. The second embodiment will be explained below.

Example 29. , '.

4,4'-dimethoxy-0- (3-ethoxycarbonyl-2-oxopropyl) oxime

(1) Synthesis of 4,4'-dimethoxybenzophenone oxime

242 g (1 mol) of 4,4'-dimethoxybenophenone were suspended in 2000 ml of ethanol, and 210 g (3 mol) of hydroxylamine hydrochloride and 300 ml (3 mols) of a 10N aqueous solution of NaOH were added. Thereafter, the resulting mixture was heated to reflux. After two or three hours, the ethanol was distilled off in vacuo and then brine was added thereto, followed by extraction with chloroform. The chloroform phase was washed with water and dried over Magnesiumfulfat. After distilling off the chloroform, the residue was recrystallized from ethanol. In this way, 240 g of the title compound were obtained in the form of colorless needles. Melting point 131-132 ° C NMR (CDCl ₃ ) O: 9.60 (bs, 1H), 7.50 (m, 8H), 3.83 (s, 3H), 3.80 (s, 3H)

(2) Synthesis of 4,4'-dimethoxybenzophenone-O - (- ethoxycarbonyl-2-oxopropyl) oxime

2.57 g (0.01 mol) of the 4,4'-dimethoxybenzophenone oxime obtained in Step 1 was dissolved in 5 ml of dimethylformamide, to which was added 1.2 g of potassium tert-butoxide under ice-cooling. The resulting mixture was stirred for 10 minutes. Subsequently, 1.8 g of ethyl 1-chloroacetoacetate was added and the resulting mixture was stirred at room temperature. After two hours, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethanol. The crude product thus obtained was purified by silica gel chromatography to obtain 3.1 g of the title compound. NMR (CDCl ₃ ) δ: 6.7-7.4 (8H), 4.6 (2H), 3.9-4.4 (2H), 3.8 (6H), 3.5 (2H), 1,2 (3H)

Example 30

4,4'-P'methoxybenzophenone-O- (3-ethoxycarbonyl-2-methoxy-in-trinopropyl) oxime 3.85g of the 4,4'-dimethoxybenzophenone-O- (3-ethoxycarbonyl-2-oxopropyl) oxime of Example 1 was dissolved in 5ml Pyridine was dissolved and 1 g of methoxylamine hydrochloride was added. Then, the resulting mixture was stirred at room temperature.

After two hours, the reaction mixture was poured into ethyl acetate, washed with dilute hydrochloric acid and then purified with saturated brine and then by silica gel chromatography. In this way, 4 g of the title compound was obtained as a colorless oily product.

NMR (CDCl ₃ ) O: 6.7-7.4 (8H), 5.0.4.7 (2H), 3.8-4.2 (2H), 3.8 (9H), 3, 3,3,4 (2H), 1,0-1,2 (3H)

Example 31

4,4'-dimethoxy-0- (3-carboxy-2-methoxyiminopropyl) oxime

4.14 g of the 4,4'-dimethoxybenzophenone-O- (3-ethoxycarbonyl-2-methoxyiminopropyl) oxime obtained in Example 30 were dissolved in 20 ml of methanol, and 3 ml of a 5N aqueous solution of caustic soda was added. The resulting mixture was stirred at room temperature for five hours. After completion of the reaction, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. There was thus obtained 3.8 g of the title compound as a colorless oily product.

NMR (CDCl ₃ ) O: 9.50 (1H), 6; 8-7.5 (8H), 5.0, 6.8 (2H), 3.8-3.9 (9H), 3, 5,3,3 (2H)

- IS- <£ OO £ .00

Example 32

 M 'dimethoxy-O-O-cyano-S-ethoxycarbonylpropylJoxim

The procedure of Example 29 was repeated, except that the 4-chloroacetoacetate was replaced by 2.2 g of ethyl 4-bromo-4-cyano butyrate. There was thus obtained 3.6 g of the title compound having the following properties NMR (CDCl ₃ ) S: 6.5-7.5 J8H), 5.0 (1H), 4.0-4.3 (2H), 3.8 (6H), 2.2-2.6 (4H), 1.2J3H)

Example 33

4,4'-dimethoxy-0- (1-cyano-3-carboxypropyl) oxime

3.96 g of 4,4'-dimethoxybenzophenone-O- (1-cyano-3-ethoxycarbonylpropyl) oxime was dissolved in 20 ml of dioxane and 3 ml of a 5 N aqueous solution of caustic soda was added. Then the mixture was allowed to react at 60 ^° C. for five hours.

After completion of the reaction, the reaction mixture was acidified and extracted with ethyl acetate. In this way, 3.6 g of the title compound were obtained in the form of a colorless oily product.

NMR (CDCl ₃ ) O: 6.7-7.5 (8H), 5.0 (1H), 3.8 (6H), 2.1-2.7 (4H),

Example 34

4,4'-dimethoxy-0- (1-cyano-4-methoxycarbonylbutyl) oxime

, The procedure of Example 29 was repeated except that the ethyl 4-chloroacetoacetate was replaced by 2.2 g of methyl 5-bromo-5-cyanopentanoate. In this way, 3.7 g of the title compound having the following properties were obtained. NMR (CDCl ₃ ) δ: 6.8-7.6 (8H), 4.9 (1H), 3.8 (6H), 3.6 (3H), 2.4 (2H), 1.6 -2.2 (4H)

Example 35

4,4'-dimethoxy-0- (1-cyano-4-carboxybutyl) oxime

The title compound with the following properties was obtained by the procedure of Example 33: NMR (CDCl ₃ ) δ: 6.7-7.5 (8H), 4.9 (1H), 3.8 (6H), 2.4 (2H), 1.6-2.2 (4H)

Claims (1)

Process for the preparation of a substituted diphenylethylene derivative of the general formula _t R ¹ (CH ₂ ) _n -COOR ⁴ (wherein R ¹ and R ^{2 may be the} same or different and each may be a hydrogen atom, a hydroxy group or a lower alkoxy group, R ^{4 is} a hydrogen atom or a lower alkyl group and η is an integer of 1 to 3), or a pharmaceutically acceptable one Salt thereof, characterized in that a compound of general formula