JP2547207B2 - Substituted diphenyl ethylene derivative - Google Patents

Description

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

2. Description of the Related Art Presently, as one of the diseases that cause a serious health risk for humankind, acute vascular disease such as myocardial infarction, stroke, cerebral thrombosis, cerebral infarction, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion. and so on.

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.

OBJECT OF THE INVENTION It is an object of the present invention to provide a substituted diphenylethylene derivative and a pharmacologically acceptable salt thereof which have excellent effects as pharmaceuticals, and further, the substituted diphenylethylene derivative and a pharmacologically acceptable salt thereof. Another object of the present invention is to provide a method for producing a possible salt, and further to provide a medicine comprising the substituted diphenylethylene derivative and a pharmacologically acceptable salt thereof as an active ingredient.

Structure and Effect of the Invention 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.

{In the formula, R ¹ and R ² mean the same or different hydroxyl groups or lower alkoxy groups. X means a cyano group.

Y is formula -Alk-COOR ³ [wherein Alk has the formula - (CH ₂₎ 2 _- group, or represented by And R ³ means a hydrogen atom or a lower alkyl group].に お い て In the above definition, a lower alkyl group found in R ³ 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-
It means butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl and the like, and the lower alkoxy group found in R ¹ and R ² means all lower alkoxy groups derived from the above lower alkyl groups. To do. 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 present invention, a pharmacologically acceptable salt means, when R ³ is a hydrogen atom in the structural formula of the target substance, for example,
Metal salts such as Na, K, Ca and Mg can be cited.

Production Method There are various possible methods for producing the compound (I) of the present invention. Typical methods among these are as follows.

That is, a ketone body represented by the general formula (II) and a halogenated body represented by the general formula (III) are reacted by a conventional method in a tetrahydrofuran solvent in the presence of, for example, zinc to give a hydroxy body (IV ) Is obtained (Reformatsky reaction).

As the solvent, for example, tetrahydrofuran, benzene, ether and the like can be used, but if necessary, the reaction can be carried out in a mixed solvent with trimethyl borate, triethyl borate and the like.

 This reaction is usually performed at a temperature of about -70 to 150 ° C.

From the obtained hydroxy form (IV), the target compound (V) can be obtained by a usual dehydration method.

In this reaction, benzene, toluene, tetrahydrofuran, ether, dioxane or the like can be used as a solvent, and p-toluenesulfonic acid, thionyl chloride, phosphorus pentoxide, iodine, hydrochloric acid or the like can be used as a catalyst. The reaction temperature is about -70 to 150 ° C.

The case where Y is a group represented by the formula — (CH ₂ ) ₂ —COOR ³ (wherein R ³ has the above meaning) is specifically described as follows.

The representative compounds of the present invention will be listed below, but the purpose thereof is to facilitate the understanding of the present invention.
It goes without saying that the scope of the present invention is not limited thereby. In addition, all the following descriptions are described in a free form.

・ 4-Cyano-5,5-bis (4-methoxyphenyl)-
4-Pentenoic acid methyl ester 4-cyano-5,5-bis (4-methoxyphenyl)-
4-Pentenoic acid ethyl ester 4-cyano-5,5-bis (4-ethoxyphenyl)-
4-Pentenoic acid ethyl ester 4-cyano-5,5-bis (4-hydroxyphenyl)
-4-Pentenoic acid ethyl ester 4-cyano-5- (4-methoxyphenyl) -5-
(4-Ethoxyphenyl) -4-pentenoic acid ethyl ester 4-cyano-5- (4-hydroxyphenyl)-
(Z) -5- (4-Methoxyphenyl) -4-pentenoic acid ethyl ester 4-cyano-5- (4-hydroxyphenyl)-
(E) -5- (4-Methoxyphenyl) -4-pentenoic acid ethyl ester 4-cyano-5- (4-hydroxyphenyl)-
(Z) -5- (4-ethoxyphenyl) -4-pentenoic acid ethyl ester 4-cyano-5- (4-hydroxyphenyl)-
(E) -5- (4-Ethoxyphenyl) -4-pentenoic acid ethyl ester 4-cyano-5,5-bis (4-methoxyphenyl)-
4-Pentenoic acid 4-cyano-5,5-bis (4-ethoxyphenyl)-
4-Pentenoic acid 4-cyano-5,5-bis (4-hydroxyphenyl)
-4-Pentenoic acid 4-cyano-5- (4-methoxyphenyl) -5-
(4-Ethoxyphenyl) -4-pentenoic acid 4-cyano-5- (4-hydroxyphenyl)-
(Z) -5- (4-methoxyphenyl) -4-pentenoic acid 4-cyano-5- (4-hydroxyphenyl)-
(E) -5- (4-Methoxyphenyl) -4-pentenoic acid 4-cyano-5- (4-hydroxyphenyl)-
(Z) -5- (4-Ethoxyphenyl) -4-pentenoic acid 4-cyano-5- (4-hydroxyphenyl)-
(E) -5- (4-Ethoxyphenyl) -4-pentenoic acid 4-cyano-2-methyl-5,5-bis (4-methoxyphenyl) -4-pentenoic acid ethyl ester 4-cyano-2 -Methyl-5,5-bis (4-ethoxyphenyl) -4-pentenoic acid ethyl ester-4-Cyano-2-methyl-5,5-bis (4-hydroxyphenyl) -4-pentenoic acid ethyl ester-4 -Cyano-2-methyl-5- (4-methoxyphenyl) -5- (4-ethoxyphenyl) -4-pentenoic acid ethyl ester 4-cyano-2-methyl-5,5-bis (4-methoxyphenyl) ) -4-Pentenoic acid 4-cyano-2-methyl-5,5-bis (4-ethoxyphenyl) -4-pentenoic acid 4-cyano-2-methyl-5,5-bis (4-hydroxyphenyl) ) -4-Pentenoic acid-4 Cyano-2-methyl-5- (4-methoxyphenyl) -5- (4-ethoxyphenyl) -4-pentenoic acid The substituted diphenylethylene derivative provided by the present invention has an excellent platelet aggregation inhibitory action, It is useful as a therapeutic agent based on this action, that is, an antiplatelet agent and an antithrombotic agent. Specifically, cerebrovascular disorders such as TLA (transient cerebral ischemic attack), deep infarction (thrombosis, infarction) cerebral arteriosclerosis, postoperative thrombosis and embolism and blood flow associated with vascular surgery and extracorporeal blood circulation. Treatment / prevention of chronic arterial occlusion such as disorders, Buerger's disease, arteriosclerosis obliterans, peripheral arteriosclerosis, SLE, white fistula, angina pectoris, ischemic heart disease such as myocardial infarction, etc. It is useful for preventing disease recurrence and improving prognosis.

Next, pharmacological experiments will be presented in order to explain the effects of the compounds of the present invention in detail.

Experimental example 1. Inhibition of platelet aggregation (in vitro) From human cubital vein, 3.8% sodium citrate solution was added 1/1
Blood was collected so as to contain 0 amount, and the method of Packham et al. [Packham,
MA et al, J. Exp. Med. 126 , 171-189 (1967)], to prepare platelet floating plasma (PRP ... Platelet Rich Plasma). 0.2 ml of this human PRP was added to various concentrations of the compound of the present invention.
A, B and 25 μl of the solution were added and incubated at 37 ° C. for 3 minutes to induce platelet aggregation with arachidonic acid, collagen, ADP and PAF. Platelet aggregation was performed by using a method of Mustard et al. [Mustard, JF, et al, J.Lab Cli manufactured by Schenko or Nikko Bioscience.
n.Med. 64 , 548-559 (1964)].

 Table 1 shows the results.

Compounds A and B in Table 1 above mean the target substances obtained in Examples 1 and 2, respectively.

2. Platelet aggregation inhibitory effect (ex vivo) Compounds A and B, which are representative compounds of the present invention, are orally administered to guinea pigs, and after 2 hours, blood is collected from abdominal aorta under ether anesthesia and collagen (3 μg / ml) The inhibitory effect on platelet aggregation by arachidonic acid (50 μM) was examined. The solvent administration rate was determined, and the 50% effective dose is shown in Table 2.

3. Acute toxicity Regarding the representative compounds (compounds A and B) of the compound of the present invention,
When an acute toxicity test was performed using rats (body weight: 300-400 g Wistar system), 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 by oral administration or non-oral administration (intramuscular, subcutaneous, intravenous, etc.). The dose varies depending on the difference in disease, the degree of symptoms, age, etc., but is not particularly limited, but in the case of an adult, it is usually 0.1 to 300 mg, preferably 0.1 to 60 mg, more preferably 0.3 to 30 mg, further preferably 0.6 per day. ~ 10 mg.

In order to formulate the compound of the present invention, tablets, granules, powders, capsules, injections, suppositories and the like are formed into a dosage form by a conventional method in the technical field of preparation.

That is, in the case of producing a solid preparation for oral cavity, an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, and then a tablet is prepared by a conventional method. Coated tablets, granules, powders, capsules, etc.

Examples of excipients include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and the like, and examples of binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose. , Hydroxypropyl starch, polyvinylpyrrolidone and the like, as disintegrants, for example, starch, agar, powdered gelatin, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin and the like, lubricants, for example, Magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oils, etc., which are allowed to be added to pharmaceuticals as coloring agents, are used as flavoring agents in cocoa. , Menthol, aromatic acid, peppermint oil, borneol, cinnamon powder and the like are used. These tablets and granules can of course be sugar-coated, gelatin-coated and optionally coated as needed.

When preparing an injection, a pH adjusting agent, a buffering agent, a stabilizer, a preservative, etc. are added to the main drug as necessary, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.

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

Example 1 4-Cyano-5,5-bis (4-methoxyphenyl) -4
- In pentenoic acid ethyl ester [Formula (1), X = CN, Y = - (CH 2) 2 -COOC
₂ H ₅ ] 4,4'-dimethoxybenzophenone 2.42 g (0.01 mo
l), zinc 1 g, trimethylborate, 2.1 g are suspended in tetrahydrofuran 15 ml, and then 4-bromo-
2.2 g of 4-cyanobutyric acid ethyl ester and a catalytic amount of iodine are added, and the mixture is reacted at room temperature for 5 hours. 10 ml after the reaction
Saturated aqueous ammonium chloride solution is added, and the mixture is stirred for 1 hour, zinc is removed by filtration, and the filtrate is extracted with ethyl acetate. The crude product was purified by silica gel chromatography, white crystals 1.
Get 5g. This is dissolved in 10 ml of benzene, 1 ml of thionyl chloride is added, and the mixture is 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) 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) -
3.6 g of 4-pentenoic acid ethyl ester was dissolved in 10 ml of dioxane, 3 ml of 5N NaOH aqueous solution was added thereto, and the mixture was heated at 60 ° C.
Stir for 5 hours. After completion of the reaction, the reaction solution was acidified and extracted with ethyl acetate to give the title compound having the following physical properties.3.
Get 2g. This was recrystallized from ethyl acetate-hexane,
It can be purified.

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) Example 3 4-cyano-5,5-bis (4-ethoxyphenyl) -4
- [In formula (I), X = CN, Y = - (CH 2) 2 -COOH ] pentenoic acid Example 1 Similarly 4,4'-diethoxy benzophenone and 2.7 g (0.01 mol) of zinc 1 g trimethyl borate 2.1 g 4-Brom-4-cyanobutyric acid ethyl ester 2.2 g Iodine A catalytic amount was reacted in 15 ml of tetrahydrofuran, dehydrated with thionyl chloride, and then hydrolyzed in the same manner as in Example 2 to give the title compound 1.
Get 1g.

・ NMR (CDCl ₃ ) δ: 9.5 (1H), 6.6 to 7.2 (8H), 4.0 (4H), 2.6 (4H), 1.4
(6H) Example 4 4-cyano-5- (4-hydroxyphenyl)-(Z)
-5- (4-Methoxyphenyl) -4-pentenoic acid and 4-cyano-5- (4-hydroxyphenyl)-
(E) -5- (4-Methoxyphenyl) -4-pentenoic acid As in Example 1, 4-methoxy-4'-methoxymethoxybenzophenone 12.2 g (0.045 mol) zinc 4.4 g trimethylborate 10.2 ml 4-bromo- 4-Cyanobutyric acid ethyl ester 9.9 g Iodine catalytic amount was reacted in 25 ml of tetrahydrofuran, treated with hydrochloric acid, and then hydrolyzed in the same manner as in Example 2.

Silica gel chromatography eluting with methanol-chloroform (5:95) gave 1.9 g of the (Z) -form.

・ NMR (CDCl ₃ ) δ: 8.0 to 9.5 (2H), 6.7 to 7.2 (8H), 3.8 (3H), 2.6 (4
H) Elute with methanol-chloroform (10:90),
(E) -2.2 g of the product was obtained.

・ NMR (CDCl ₃ ) δ: 8.0 to 9.5 (2H), 7.1 to 7.5 (2H), 6.7 to 7.0 (6H), 3.8
(3H), 2.7 (4H) Example 5 4-cyano-5- (4-hydroxyphenyl)-(Z)
-5- (4-ethoxyphenyl) -4-pentenoic acid and 4-cyano-5- (4-hydroxyphenyl)-
(E) -5- (4-Ethoxyphenyl) -4-pentenoic acid As in Example 1, 4-ethoxy-4'-methoxy methoxybenzophenone 7.2 g (0.025 mol) zinc 2.5 g trimethylborate 5.7 ml 4-bromo- 4-Cyanobutyric acid ethyl ester 5.5 g Iodine catalytic amount was reacted in 15 ml of tetrahydrofuran, treated with hydrochloric acid, and then hydrolyzed in the same manner as in Example 2.

Silica gel chromatography eluting with methanol-chloroform (5:95) gave 0.9 g of (Z) -form.

・ NMR (CDCl ₃ ) δ: 8.0 to 10.0 (2H), 6.6 to 7.2 (8H), 4.0 (2H), 2.6 (4
H), 1.4 (3H) Methanol-chloroform (10:90) was eluted,
(E) -body 0.8g was obtained.

・ NMR (CDCl ₃ ) δ: 7.5 to 9.5 (2H), 7.0 to 7.3 (2H), 6.6 to 6.9 (6H), 4.0
(2H), 2.6 (4H), 1.4 (3H) Example 6 4-Cyano-5,5-bis (4-hydroxyphenyl)-
4-Pentenoic acid 15.1 g (0.05 mol) zinc 4.9 g trimethylborate 11.4 ml 4-bromo-4-cyanobutyric acid ethyl ester 11.0 g 4,4'-dimethoxy methoxybenzophenone 15.1 g (0.05 mol) same as in Example 1 Iodine catalyst amount tetrahydrofuran 12.5 ml The reaction was carried out in a medium, treated with hydrochloric acid, and then hydrolyzed in the same manner as in Example 2 to obtain 4.6 g of the title compound.

_{· NMR (CDCl 3) δ:} 8.5~10.0 (3H), 6.7~7.4 (8H), 2.6 (4H) Example 7 4-cyano-2-methyl-5,5-bis (4-methoxyphenyl) -4 -Pentenoic acid As in Example 1, 4,4'-dimethoxybenzophenone 2.42 g (0.01 mol) zinc 1 g trimethylborate 2.3 ml 4-bromo-2-methyl-4-cyanobutyric acid ethyl ester 2.3 g iodo Catalytic amount in tetrahydrofuran 15 ml Was treated with hydrochloric acid and treated with hydrochloric acid, and then hydrolyzed in the same manner as in Example 2 to obtain 1.1 g of the title compound.

・ NMR (CDCl ₃ ) δ: 9.0 (1H), 7.1 to 7.3 (2H), 6.6 to 7.0 (6H), 3.8 (6
H), 2.3 ~ 3.1 (3H), 1.2 (3H)

Front page continued (72) Inventor Koji Nakamoto 712-91 Nakanuki, Tsuchiura City (72) Inventor Kazuo Okano 4-19-13 Kasuga Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture Eisai Shiyama Dormitory (72) Inventor Shinya Abe Ushiku-shi Mekamachi 1083-44 (72) Inventor Hironori Ikuta 2-35-12 Sakaemachi, Ushiku-shi (72) Kenji Hayashi 3-7-1 Ninomiya, Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture (72) Hiroyuki Yoshimura Tsukuba, Ibaraki Prefecture 4-19-13 Kasuga, Gunyabe Town Eisai Dormitory (72) Toru Fujimori 2-9 Tokodai, Toyosato-cho, Tsukuba-gun, Ibaraki Prefecture (72) Kokichi Harada 4-19-13 Kasuga Yatabe-cho, Tsukuba-gun, Ibaraki Eisai Shiyama Dormitory (72) Inventor Isao Yamazu 3605-669, Kashiwa-cho, Ushiku City (56) References Japanese Patent Publication No. 49-48316 (JP, B1) Bull. Soc. Chim. Fr. (12), 3895-3900, 1966.

Claims (9)

(57) [Claims] 1. A general formula {In the formula, R ¹ and R ² mean the same or different hydroxyl groups or lower alkoxy groups. X means a cyano group. Y is formula -Alk-COOR ³ [wherein Alk has the formula - (CH ₂₎ 2 _- group, or represented by And R ³ means a hydrogen atom or a lower alkyl group]. } The substituted diphenyl ethylene derivative represented by these, or its pharmacologically acceptable salt. 2. The substituted diphenylethylene derivative according to claim 1, wherein R ¹ and R ² are both lower alkoxy groups, or a pharmaceutically acceptable salt thereof. 3. The substituted diphenylethylene derivative according to claim 1, wherein R ¹ and R ² are both methoxy groups, or a pharmaceutically acceptable salt thereof. 4. A substituted diphenylethylene derivative according to claim 1, wherein Y is a group represented by the formula:-(CH ₂ ) ₂ --COOR ³ (wherein R ³ has the above meaning) or a derivative thereof. A pharmacologically acceptable salt. 5. R ¹ and R ² are both lower alkoxy groups, and Y is a group represented by the formula — (CH ₂ ) ₂ —COOR ³ (wherein R ³ has the above meaning). Claims No. 1
The substituted diphenylethylene derivative according to the item or a pharmaceutically acceptable salt thereof. 6. The substituted diphenylethylene derivative according to claim 5, wherein R ¹ and R ² are both methoxy groups, or a pharmaceutically acceptable salt thereof. 7. The compound is 4-cyano-5,5-bis- (4-
A substituted diphenylethylene derivative according to claim 1, which is methoxyphenyl) -4-pentenoic acid, or a pharmaceutically acceptable salt thereof. 8. The compound is 4-cyano-5,5-bis- (4-
The substituted diphenylethylene derivative according to claim 1, which is methoxyphenyl) -4-pentenoic acid ethyl ester, or a pharmaceutically acceptable salt thereof. 9. General formula {In the formula, R ¹ and R ² mean the same or different hydroxyl groups or lower alkoxy groups. X means a cyano group. Y is formula -Alk-COOR ³ [wherein Alk has the formula - (CH ₂₎ 2 _- group, or represented by And R ³ means a hydrogen atom or a lower alkyl group]. } An antiplatelet / antithrombotic agent comprising a substituted diphenylethylene derivative represented by or a pharmacologically acceptable salt thereof as an active ingredient.