JP2608382B2 - Substituted diphenylethylene derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a substituted diphenylethylene derivative having excellent action as a medicament, a pharmaceutically acceptable salt thereof, a method for producing the same, and a medicament containing the same.

[0002]

2. Description of the Related Art At present, one of the serious health risks for human beings is acute vascular disease such as myocardial infarction, stroke, cerebral thrombosis, cerebral infarction, pulmonary embolism, deep vein thrombosis, peripheral artery. Obstruction and the like. In recent years, antiplatelet agents have attracted clinical attention and are being widely used as one of the therapeutic agents for these diseases, but the history of antiplatelet agents is relatively new, and the development of better drugs is expected in the future. I have.

[0003]

An object of the present invention is to provide a substituted diphenylethylene derivative having excellent action as a pharmaceutical and a pharmacologically acceptable salt thereof, and further provide the substituted diphenylethylene derivative and a pharmacologically acceptable salt thereof. It is an object of the present invention to provide a method for producing a salt which is acceptable to the public, and to provide a medicament comprising the substituted diphenylethylene derivative and a pharmaceutically acceptable salt thereof as an active ingredient.

[0004]

The object compound of the present invention is a substituted diphenylethylene derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0005]

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In the formula, R ¹ and R ² represent the same or different hydrogen atoms, hydroxyl groups or lower alkoxy groups.

[0007]

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(Wherein R ³ represents a hydroxyl group or an amino group). Y is the formula ^{_{-CH 2 -NH-SO 2 -R 7}} (
Wherein R ⁷ represents a lower alkyl group or an aryl group)
A group represented by, or

[0009]

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Wherein R ⁸ represents a lower alkoxy group or an aryl group; R ⁹ represents a group represented by the formula —ZR ¹⁰ [wherein Z is a group represented by the formula —O—, a group represented by the formula —S—, or

[0011]

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And R ¹⁰ represents a lower alkyl group, a lower alkenyl group or an aryl group.
A group represented by or

[0013]

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Wherein alk represents a straight-chain or branched alkylene group having 1 to 3 carbon atoms, and R ¹² represents a hydrogen atom or a lower alkyl group. Means a group.に お い て In the above definition,
The lower alkyl group found in R ⁷ , R ¹⁰ , R ¹¹ and R ¹² is a linear or branched alkyl group having 1 to 6 carbon atoms,
For example, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-
Butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl, etc., and the lower alkoxy groups found in R ¹ , R ² and R ⁸ are all lower alkoxy groups derived from the above lower alkyl groups. Means a group. Of these, the most preferred are a methyl group and an ethyl group for a lower alkyl group, and a methoxy group for a lower alkoxy group.

In the definition of Y, the branched alkylene group in alk is an alkylene group having 1 to 3 carbon atoms, and a lower alkyl group such as a methyl group or an ethyl group is bonded to any one of carbon atoms. Say the case. A good example would be

[0016]

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And the like. The aryl group found in the definition of R ⁷ can be a substituted or unsubstituted phenyl group, and preferred examples of the substituted phenyl group include

[0018]

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The aryl group found in the definitions of R ⁸ and R ¹⁰ includes, similarly to R ⁷ , a substituted or unsubstituted phenyl group. The lower alkenyl group preferably has 1 to 5 carbon atoms. And refers to a group having a double bond at any position.

In the present invention, pharmacologically acceptable salts include, for example, metal salts such as Na, K, Ca, and Mg.

[0021] Although are various method for producing the manufacturing method of the present invention compound (I), it is as follows Stated representative methods of these.

(1) In the formula (I), Y is a group represented by the formula —CH ₂ —NH
When it is a group represented by —SO ₂ —R ⁷ , it can be produced according to the following reaction formula.

[0023]

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That is, the amine compound represented by the general formula (V) and the sulfonyl halide represented by the general formula (VI) are reacted by a conventional method to give a target substance (V
II) can be easily obtained.

The reaction is usually performed in a solvent, and any solvent can be used as long as it does not adversely affect the reaction. Examples include solvents such as chloroform, 1,2-dichloroethane, ethyl ether, pyridine, tetrahydrofuran, dioxane, ethylene glycol, dimethyl ether, benzene, and toluene, or a mixture of two or more of these solvents. The reaction temperature is not particularly limited, but is usually -50 to 15
After the reaction is completed, the target substance is isolated by a conventional method.

[0026]

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In this reaction, the amide represented by the general formula (VIII) is reacted with a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, and then the compound represented by the general formula (IX) The compound (X) which is one of the target substances is obtained by reacting the compound to be obtained. At this time, as the solvent, no solvent or benzene, toluene,
A solvent that does not participate in the reaction, which is appropriately selected from chloroform or the like, is used. The reaction can be performed in the presence of an organic base such as dimethylaniline, triethylamine and pyridine or an inorganic base such as potassium carbonate and sodium carbonate.

[0028]

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That is, in this reaction, the amide represented by the general formula (VIII) is reacted with a sulfurizing agent such as phosphorus pentasulfide to obtain a thioamide (XI), which is then reacted with the general formula (XII). The compound represented by the general formula (XIII), which is one of the target substances, is obtained by reacting the halide represented by the conventional method.
At this time, as the solvent, a solvent which does not participate in the reaction, which is appropriately selected from benzene, toluene, chloroform and the like, is used without a solvent. The reaction can be performed in the presence of an organic base such as dimethylaniline, triethylamine and pyridine or an inorganic base such as potassium carbonate and sodium carbonate.

[0030]

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That is, in this reaction, a ketone compound represented by the general formula (XIV) is reacted with an amine compound represented by the general formula (XV) or a salt thereof (for example, an acid addition salt such as hydrochloride), By an ordinary method, an oxime compound represented by the general formula (XVI), which is one of the target substances, can be obtained.

Next, typical compounds of the present invention will be listed, but the purpose is to make the present invention easier to understand, and it is meant that the scope of the present invention is not limited thereby. Not even. In addition, all the following descriptions are described in a free form.

3,3-bis (4-methoxyphenyl)-
N-phenyl-acrylimidic acid ethyl ester • 3,3-bis (4-ethoxyphenyl) -N-phenyl-acrylimidic acid ethyl ester • 3,3-bis (4-hydroxyphenyl) -N-phenyl-acrylimide Ethyl acid ester ・ 3- (4-methoxyphenyl) -3- (4-ethoxyphenyl) -N-phenyl-acrylimidic acid ethyl ester ・ 3,3-bis (4-methoxyphenyl) -N-benzyl-acrylimide Ethyl acid ester · 3,3-bis (4-methoxyphenyl) -N- (3-pyridyl) -acrylimidic acid methyl ester · 3,3-bis (4-methoxyphenyl) -N, N′-diphenyl-acrylic acid Amidine ・ 3,3-bis (4-ethoxyphenyl) -N, N′-diphenyl-acrylamidine ・ 3,3-bis (4-hydroxy Eniru) -N, N '
-Diphenyl-acrylamidine -3- (4-methoxyphenyl) -3- (4-ethoxyphenyl) -N, N'-diphenyl-acrylamidine -3,3-bis (4-methoxyphenyl) -N, N ' -Dibenzyl-acrylamidine -3,3-bis (4-ethoxyphenyl) -N, N'-dibenzyl-acrylamidine -3,3-bis (4-methoxyphenyl) -N-phenyl-N'-benzyl-acryl Amidine ・ 3,3-bis (4-methoxyphenyl) -N-phenyl-acrylthioimidic acid allyl ester ・ 3,3-bis (4-ethoxyphenyl) -N-phenyl-acrylthioimidic acid allyl ester ・ 3, 3-bis (4-hydroxyphenyl) -N-phenyl-acrylthioimidic acid allyl ester · 3- (4-methoxyphenyl) -3- (4-ethoate (Ciphenyl) -N-phenyl-acrylthioimidic acid allyl ester · 3,3-bis (4-methoxyphenyl) -N-benzyl-acrylthioimidic acid allyl ester · 3,3-bis (4-methoxyphenyl) -N -(3-pyridyl) -acrylthioimidic acid ethyl ester • 3-methoxyimino-5,5-bis (4-methoxyphenyl) -4-pentenoic acid ethyl ester • 3-methoxyimino-5,5-bis (4 -Ethoxyphenyl) -4-pentenoic acid methyl ester • 3-methoxyimino-5,5-bis (4-methoxyphenyl) -4-pentenoic acid • 3-methoxyimino-5,5-bis (4-ethoxyphenyl) 4-pentenoic acid 3-methoxyimino-5,5-bis (4-hydroxyphenyl) -4-pentenoic acid 3-methoxyimino-5- (4-meth Kishifeniru)
-5- (4-ethoxyphenyl) -4-pentenoic acid N- [3,3-bis (4-methoxyphenyl) allyl]
-Methanesulfonic acid amide N- [3,3-bis (4-ethoxyphenyl) allyl]
-Methanesulfonic acid amide N- [3,3-bis (4-hydroxyphenyl) allyl] -methanesulfonic acid amide N- [3- (4-methoxyphenyl) -3- (4-ethoxyphenyl) allyl] -Methanesulfonic acid amide N- [3,3-bis (4-methoxyphenyl) allyl]
-Benzenesulfonamide-N- [3,3-bis (4-ethoxyphenyl) allyl]
-Benzenesulfonic acid amide N- [3,3-bis (4-hydroxyphenyl) allyl] -benzenesulfonic acid amide N- [3- (4-methoxyphenyl) -3- (4-ethoxyphenyl) allyl] -Benzenesulfonic acid amide N- [3,3-bis (4-methoxyphenyl) allyl]
-P-toluenesulfonic acid amide N- [3,3-bis (4-ethoxyphenyl) allyl]
-P-toluenesulfonic acid amide N- [3,3-bis (4-hydroxyphenyl) allyl] -p-toluenesulfonic acid amide N- [3- (4-methoxyphenyl) -3- (4-ethoxy) Phenyl) allyl] -p-toluenesulfonic acid amide N- [3,3-bis (4-methoxyphenyl) allyl]
-4-Carboxybenzenesulfonic acid amide N- [3,3-bis (4-ethoxyphenyl) allyl]
-4-carboxybenzenesulfonic acid amide N- [3,3-bis (4-hydroxyphenyl) allyl] -4-carboxybenzenesulfonic acid amide N- [3- (4-methoxyphenyl) -3- (4 -Ethoxyphenyl) allyl] -4-carboxybenzenesulfonic acid amide The substituted diphenylethylene derivative provided by the present invention has an excellent inhibitory action on platelet aggregation, and a therapeutic agent based on this action, that is, an antiplatelet agent, Useful as a thrombotic agent. Specifically, cerebrovascular disorders such as TLA (transient cerebral ischemic attack), cerebral infarction (thrombosis, embolism), cerebral arteriosclerosis, thrombus and emboli after vascular surgery and postoperative blood associated with extracorporeal blood circulation, and blood Treatment, prevention of chronic arterial occlusion such as blood flow disorder, Buerger's disease, atherosclerosis obliterans, peripheral arteriosclerosis, SLE, leukoderma, angina pectoris, myocardial infarction, etc.
Furthermore, it is useful for preventing recurrence of these diseases and improving prognosis.

Next, pharmacological experimental examples will be given in order to explain the effects of the compounds of the present invention in detail. Experimental Example 1. Platelet aggregation inhibitory action (in vitro) Blood was collected from human elbow vein so as to contain a 1/10 volume of 3.8% sodium citrate solution [Packham, M .;
A. et al, J. Exp. Med. 126, 171-189 (1967)], platelet floating plasma (PRP... Platelet Rich Plasma) was prepared. To 0.2 ml of this human PRP, 25 μl of the compound A of the present invention at various concentrations was added and incubated at 37 ° C. for 3 minutes to induce platelet aggregation with arachidonic acid, collagen, ADP and PAF. Platelet aggregation was performed using Aggregometor from Schenko or Nikko Biosciences.
Using the method of Mustard et al. [Mustard, JF, et al, J. La
bClin. Med. 64 , 548-559 (1964)].
Table 1 shows the results.

[0035]

[Table 1]

In Table 1, compound A means the target substance obtained in Example 1. 2. Inhibition of platelet aggregation (ex vivo) Compound A, a representative compound of the present invention, was orally administered to guinea pigs. Two hours later, blood was collected from the abdominal aorta under ether anesthesia, and collagen (3 μg / ml) and arachidonic acid were collected. (50 μM) was examined for its inhibitory effect on platelet aggregation.
The solvent administration rate was determined, and the 50% effective dose is shown in Table 2.

[0037]

[Table 2]

3. Acute toxicity An acute toxicity test was conducted on a representative compound of the present invention (compound A) using rats (body weight: 300 to 400 g, Wistar system II), and the LD ₅₀ was 500 mg / kg or more. .

When the compound of the present invention is used as an antiplatelet agent or an antithrombotic agent, it is administered orally or parenterally (intramuscularly, subcutaneously, intravenously, etc.). The dose is
It varies according to the difference of disease, degree of symptoms, age, etc., and is not particularly limited. In the case of an adult, it is usually 0.1 to 300 m per day.
g, preferably 0.1-60 mg, more preferably 0.3-30 m
g, more preferably 0.6 to 10 mg.

In order to formulate the compound of the present invention, tablets, granules, powders, capsules, injections, suppositories and the like are prepared by a usual method in the technical field of preparation. That is,
When an oral solid preparation is manufactured, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, and the like are added to the main drug, if necessary, and then tablets, coated tablets, and the like are obtained in a conventional manner. Granules, powders, capsules, etc.

As excipients, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, etc., and as binders, for example, polyvinyl alcohol,
Polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc. Sodium, calcium citrate, dextrin, pectin, etc., as lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., and as coloring agents, those which are allowed to be added to pharmaceuticals However, cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder and the like are used as flavoring agents. These tablets and granules can of course be sugar-coated, gelatin-coated and optionally coated as needed.
When preparing an injection, a pH adjuster, a buffer, a stabilizer, a preservative, and the like are added to the main drug, if necessary, to give a subcutaneous, intramuscular, or intravenous injection according to a conventional method.

Next, examples of the present invention will be described, but it goes without saying that the present invention is not limited to these.

Reference Example 1 4-cyano-5,5-bis (4-methoxyphenyl) -4
- [In formula (I), X = CN, Y = - (CH 2) 2 -COOC 2 H 5 ] pentenoic acid ethyl ester 4,4'-dimethoxy benzophenone 2.42 g (0.01 mol), zinc 1g, trimethyl borate 2.1 g was suspended in 15 ml of tetrahydrofuran, and 2.2 g of 4-bromo-4-cyanobutyric acid ethyl ester and a catalytic amount of iodine were added thereto, followed by reaction at room temperature for 5 hours. After completion of the reaction, 10 ml of a saturated aqueous ammonium chloride solution was added, and after stirring for 1 hour, zinc was removed by filtration and the filtrate was extracted with ethyl acetate. The crude product was purified by silica gel chromatography to give 1.5 g of white crystals.
Get. This was dissolved in benzene (10 ml), thionyl chloride (1 ml) was added, and the mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and dispersed in ice water. Then, it was extracted with benzene, washed with water and concentrated. Then, the residue was purified by silica gel column chromatography to obtain 1.3 g of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ: 6.7 to 7.3 (8H), 4.1 (2H), 3.8 (6H), 2.7 (4H), 1.3 (3H) Reference Example 2 4-cyano-5,5-bis ( 4-methoxyphenyl) -4
- [In formula (I), X = CN, Y = - (CH 2) 2 -COOH ] pentenoic acid 4-cyano-5,5 - bis (4-methoxyphenyl) -4
-3.6 g of pentenoic acid ethyl ester was dissolved in 10 ml of dioxane, and 3 ml of 5N NaOH aqueous solution was added thereto.
Stir at C for 5 hours. After the reaction is completed, the reaction solution is made acidic,
Extract with ethyl acetate to give the title compound having the following physical properties
3.2 g are obtained. This can be further recrystallized and purified with ethyl acetate-hexane.

Melting point (° C.): 124 to 125 NMR (CDCl ₃ ) δ: 9.5 (1H), 6.8 to 7.4 (8H), 3.8 (6H), 2.7 (4H) Reference Example 3 N-benzyl-3, 3-bis (4-methoxyphenyl) a
2.84 g of acrylamide 3,3-bis (4-methoxyphenyl) acrylic acid
(0.01 mol) was dissolved in 10 ml of dimethylformamide, and 1.2 g (0.012 mol) of triethylamine and 1.2 g of ethyl chlorocarbonate were added thereto under ice cooling. After one hour, 1.2
g of benzylamine is added and the mixture is stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution was dissolved in 50 ml of ethyl acetate, washed with 10% hydrochloric acid, saturated aqueous NaHCO ₃ and brine, dried over magnesium sulfate, and purified by silica gel column chromatography. Title compound with physical properties
3.3 g is obtained.

Melting point (° C.): 99 to 100 NMR (CDCl ₃ ) δ: 6.7 to 7.3 (13H), 6.3 (1H), 5.5 (1H), 4.3 (2H), 3.8 (6H) Reference Example 4 N -Phenyl-3,3-bis (4-methoxyphenyl) a
Like the acrylic acid amide Reference Example 3, 3,3 - bis (4-methoxyphenyl) acrylic acid 15 g (0.05 mol), triethylamine 8.0
g (0.08 mol), ethyl chlorocarbonate 6.9 g (0.064 mol), aniline 6.3 g (0.068 mol), dimethylformamide 200 ml
Was used to obtain 10.8 g of the title compound.

NMR (CDCl ₃ ) δ: 6.8 to 7.4 (14H), 6.4 (1H), 3.9 (6H) Example 1 N- [3,3-bis (4-methoxyphenyl) allyl]-
Benzenesulfonic acid amide 3,3-bis (4-methoxyphenyl) allylamine 2.69
g was dissolved in 5 ml of pyridine, and 1.9 g of benzenesulfonyl chloride was added under ice cooling, followed by stirring for 5 hours.
After completion of the reaction, the reaction solution is dissolved in ethyl acetate, washed with 5% hydrochloric acid and saturated saline, and purified by silica gel chromatography using a crude product in a conventional manner to obtain 3.6 g of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ: 7.8 (2H), 7.5 (3H), 6.7 to 7.1 (8H), 5.8 (1H), 4.4 (1H),
3.8 (6H) 3.7 (2H) Example 2 3,3-bis (4-methoxyphenyl) -N-phenyla
Crylimidic acid ethyl ester 1.0 g ( 2.8 mmol) of the amide obtained in Reference Example 4 and phosphorus oxychloride (10 ml) were reacted at 60 ° C. for 2 hours, concentrated and concentrated, and chloroform (50 ml), ethanol (5 ml) and N, N-dimethylaniline (5 ml) were added. In addition, react at 60 ° C for 2 hours.
I got

NMR (CDCl ₃ ) δ: 6.5 to 7.6 (13H), 5.9 (1H), 4.0 (2H), 3.8 (6H), 0.9 (3H) Example 3 3,3-bis (4-methoxyphenyl) ) -N, N'-jifu
E sulfonyl acrylic amidine Reference Example 4 obtained in amide 1.0 g (2.8 mmol), phosphorus oxychloride 0.3ml, and aniline 0.3ml was refluxed for 3 h in toluene 20ml to give the title compound 80 mg.

NMR (CDCl ₃ ) δ: 6.6 to 7.4 (19H), 6.1 (1H), 3.8 (6H) Example 4 3,3-bis (4-methoxyphenyl) -N-phenyla
Chestnut Lucio imidate ants glycol ester

[0051]

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1.0 g (2.8 mm) of the amide compound obtained in Reference Example 4
ol) and 1.2 g of phosphorus pentasulfide were reacted in 50 ml of benzene at 50 ° C. for 1 hour, concentrated, dissolved in chloroform and washed with water.
Silica gel chromatography was performed to obtain a thioamide derivative (0.6 g).
Thioamide derivative 0.6 g (1.6 mmol), allyl bromide 2.0 g (16 m
mol) and 0.5 g of potassium carbonate were reacted in 50 ml of tetrahydrofuran at room temperature overnight, concentrated, dissolved in chloroform, and washed with water. Perform silica gel chromatography to give the title compound (0.45 g).
I got

NMR (CDCl ₃ ) δ: 6.5 to 7.3 (13H), 6.2 (1H), 5.8 (1H), 5.1 (2H), 3.5 to 3.8
(8H) Example 5 3-methoxyimino-5,5-bis (4-methoxyphenyl
E) 4-Pentenoic acid ethyl ester

[0054]

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Ethyl 3-oxo-5,5-bis (4-methoxyphenyl) -4-pentenoate 4.0 g (11.3 m
mol) and 2.0 g (24.0 mmol) of methoxyamine hydrochloride in 50 ml of pyridine at 60 ° C. for 2 hours to obtain 3.2 g of the title compound.

NMR (CDCl ₃ ) δ: 6.7 to 7.3 (8H), 6.6 (1H), 4.0 (2H), 3.9 (3H), 3.8 (6H),
2.9 (2H), 1.2 (3H) Example 6 3-methoxyimino-5,5-bis (4-methoxyphenyl
Ru) -4-pentenoic acid

[0057]

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The 3-methoxyimino- obtained in Example 5
2.5 g of 5,5-bis (4-methoxyphenyl) -4-pentenoic acid ethyl ester was treated in the same manner as in Reference Example 2 to obtain 2.0 g of the title compound.

NMR (CDCl ₃ ) δ: 10.0 (1H), 6.7 to 7.3 (9H), 3.9 (3H), 3.8 (6H), 2.9 (2H) Example 7 N- [3,3-bis (4 -Methoxyphenyl) allyl]-
[In the formula _{(I), Y = -CH 2} -NH-SO 2 -CH 3 ] methane sulfonamide in the same manner as in Example 1 3,3 - bis (4-methoxyphenyl) allylamine 540 mg (2.0 mmol) methanesulfonamide Using 1.0 ml (13 mmol) of pyridine and 5 ml of pyridine, 350 mg of the title compound is obtained.

NMR (CDCl ₃ ) δ: 6.6 to 7.4 (8H), 5.9 (1H), 4.4 (1H), 3.8 (8H), 2.9 (3H) Example 8 N- [3,3-bis (4 -Methoxyphenyl) allyl]-
4-Carboxybenzenesulfonic acid amide As in Example 1, 1.1 g (4.1 mmol) of 3,3-bis (4-methoxyphenyl) allylamine 0.9 g (4.1 mmol) of 4- (chlorosulfonyl) benzoic acid 25 ml of pyridine was used. To give 0.3 g of the title compound.

NMR (CDCl ₃ ) δ: 10.0 (1H), 7.6 to 8.2 (4H), 6.5 to 7.1 (8H), 5.7 (1H), 4.4
(1H), 3.4-3.9 (8H)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/215 A61K 31/215 C07C 59/48 C07C 59/48 59/68 59/68 233/11 233/11 235/34 235/34 255/41 255/41 255/42 255/42 255/61 255/61 311/02 311/02 311/16 7419-4H 311/16 (72) Inventor Koji Nakamoto 712-91 Nakanuki, Oaza, Tsuchiura-shi, Ibaraki (72) Inventor Kazuo Okano 4-19-13 Kasuga, Yatabe-cho, Tsukuba-gun, Ibaraki Pref.Eisai Shizan Ryokan (72) Inventor Shinya Abe 1083-44 (72) Inventor Hironori Ikuta 2-35-12, Sakaecho, Ushiku-shi, Ibaraki (72) Inventor Kenji Hayashi 3-7-1, Ninomiya, Yatabe, Tsukuba, Ibaraki (72) Inventor Hiroyuki Yoshimura 4-, Kasuga, Yatabe, Tsukuba, Ibaraki 19-13 Eisai Shizan Dormitory (72) Inventor Tohru Fujimori Toko, Toyosato-cho, Tsukuba-gun, Ibaraki Pref. 2-9-9 (72) Inventor Kokichi Harada 4-19-13 Kasuga, Yatabe-cho, Tsukuba-gun, Ibaraki Pref.Eisai Shizan Ryo (72) Inventor Isao Yamazu 3605-669, Kashiwada-cho, Ushiku-shi, Ibaraki Pref. JP-A-59-231058 (JP, A) JP-A-59-167550 (JP, A) JP-B-49-48316 (JP, B1) JP-B-42-3938 (JP, B1)

Claims (7)

(57) [Claims] 1. A substituted diphenylethylene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image In the formula, R ¹ and R ² represent the same or different hydrogen atoms, hydroxyl groups or lower alkoxy groups. Embedded image (Wherein R ³ represents a hydroxyl group or an amino group). Y is a group represented by the formula —CH ₂ —NH—SO ₂ —R ⁷ (wherein R ⁷ represents a lower alkyl group or an aryl group), or Wherein R ⁸ represents a lower alkoxy group or an aryl group, R ⁹ is a group represented by the formula -ZR ¹⁰ [wherein Z is a group represented by the formula -O-, a formula-
A group represented by S-, or Wherein R ¹⁰ represents a lower alkyl group, a lower alkenyl group or an aryl group] or a group represented by the following formula: Wherein alk represents a straight-chain or branched alkylene group having 1 to 3 carbon atoms, and R ¹² represents a hydrogen atom or a lower alkyl group. I do. ｝ 2. The substituted diphenylethylene derivative according to claim 1, wherein Y is a group represented by the formula —CH ₂ —NH—SO ₂ —R ⁷ (wherein R ⁷ has the above-mentioned meaning) or its pharmacology. Acceptable salts. (3) Y is The substituted diphenylethylene derivative according to claim 1, which is a group represented by the formula (wherein R ⁸ and R ⁹ have the above-mentioned meanings) or a pharmaceutically acceptable salt thereof. 4. The substituted diphenylethylene derivative according to claim 1, wherein R ¹ and R ² are both methoxy groups, or a pharmaceutically acceptable salt thereof. 5. The substituted diphenylethylene derivative according to claim 1, wherein the compound is N- [3,3-bis- (4-methoxyphenyl) allyl] -benzenesulfonic acid amide, or a pharmaceutically acceptable salt thereof. . 6. A compound of the general formula (V) Wherein R ¹ and R ² represent the same or different hydrogen atoms, hydroxyl groups or lower alkoxy groups, and X represents a hydrogen atom, a cyano group, or An amine compound represented by｝, which represents a group represented by the formula, is represented by the general formula (VI) Hal-SO ₂ -R ⁷ (VI) (wherein Hal represents a halogen atom, R ⁷ is a lower alkyl group or Characterized by reacting with a sulfonyl halide represented by an aryl group)
I) (Wherein R ¹ , R ² , X and R ⁷ have the above-mentioned meanings). 7. An antiplatelet / antithrombotic agent comprising a substituted diphenylethylene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Embedded image In the formula, R ¹ and R ² represent the same or different hydrogen atoms, hydroxyl groups or lower alkoxy groups. Embedded image (Wherein R ³ represents a hydroxyl group or an amino group). Y is a group represented by the formula —CH ₂ —NH—SO ₂ —R ⁷ (wherein R ⁷ represents a lower alkyl group or an aryl group), or Wherein R ⁸ represents a lower alkoxy group or an aryl group, R ⁹ is a group represented by the formula -ZR ¹⁰ [wherein Z is a group represented by the formula -O-, a formula-
A group represented by S-, or And R ¹⁰ represents a lower alkyl group, a lower alkenyl group or an aryl group.] Or a group represented by the following formula: Wherein alk represents a straight-chain or branched alkylene group having 1 to 3 carbon atoms, and R ¹² represents a hydrogen atom or a lower alkyl group. I do. ｝