RU2034831C1 - Diphenylethylene derivatives - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: the product includes diphenylethylene derivatives of the formula I wherein R is hydrogen or C₁-C₆-alkyl; n is 1-3. Reagent 1: a compound of the formula 2. Reagent 2: a compound of the formula 3 wherein Hal is halogen. Reaction conditions: reagent 1 and 2 are reacted, e. g. in the presence of zinc in tetrahydrofuran to obtain a compound of the formula 4 in a solvent (tetrahydrofuran or benzene) followed by hydration and recovery of the desired product. EFFECT: improved of compounds of the formulae 1,2,3, and 4.

Description

 The invention relates to diphenylethylene derivatives. These derivatives may be useful as pharmaceuticals for inhibiting blood agglomeration.

 Serious diseases that humanity is currently suffering from include vascular diseases such as myocardial infarction, cerebral thrombosis, cerebral thrombosis, cerebral infarction, pulmonary embolus, deep phlebothrombosis and peripheral arteriothrombosis.

 Recently, much attention has been paid to antiplatelet agents and they are clinically used to treat these diseases. However, their application has been implemented only recently. Thus, the development of better drugs is expected in the future.

где R водород, С₂ С₆-алкил; n 1, 3.The present invention is directed to substituted diphenylethylene derivatives of the general formula I

where R is hydrogen, C ₂ C ₆ -alkyl; n 1, 3.

 In this definition, said alkyl includes straight or branched alkyl groups containing from one to six carbon atoms, for example methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, and n-hexyl.

OCH₃
(Ia) вводят в контакт с галогенидом общей формулы
H-

CH₂)_n-COOR где Наl представляет собой атом галогена, и n и R имеют значения, определенные выше, например, в присутствии цинка в тетрагидрофуране по известной методике, с получением гидроксильного соединения формулы III (реакция Реформатского)

Примерами растворителя, пригодного для указанной реакции, являются тетрагидрофуран, бензол и эфир. Кроме того, можно использовать растворимую смесь, содержащую, например, триметилборат или триэтилборат с тетрагидрофураном.The target compounds of formula I can be obtained as follows. Ketone of the general formula
CH ₃ O

Och ₃
(Ia) is contacted with a halide of the general formula
H-

CH ₂ ) _n -COOR where Hal is a halogen atom, and n and R are as defined above, for example, in the presence of zinc in tetrahydrofuran according to a known method, to obtain a hydroxyl compound of formula III (Reformed)

Examples of a solvent suitable for this reaction are tetrahydrofuran, benzene and ether. In addition, you can use a soluble mixture containing, for example, trimethyl borate or triethyl borate with tetrahydrofuran.

This reaction can usually be carried out at a temperature of from about 70 to 150 ^about C.

Примерами растворителей, пригодных для этой реакции, являются бензол, толуол, тетрагидрофуран, эфир и диоксан, в то время как примерами катализаторов для них являются п-толуолсульфокислота, хлористый тионил, пятиокись фосфора, йод и хлористоводородная кислота. Эту реакцию можно проводить при температуре примерно от 70 до 150^оС.The hydroxyl compound (III) thus obtained can be dehydrated in the usual manner to give compound 1, which is a compound of the present invention.

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

 Typical examples of the compounds of the invention will be given to illustrate the invention, but not to limit it. Each connection will be shown in free form.

4-cyano-5,5-bis (4-methoxyphenyl) -4-pentenoic acid ethyl ester, 4-cyano-5,5-bis (4-methoxyphenyl) -4-pentenoic acid, 5-cyano-6 methyl ester, 6-bis (4-methoxyphenyl) -5-hexenoic acid, 3-cyano-4,4-bis (4-methoxyphenyl) -3-butenoic acid ethyl ester, 3-cyano-4,4-bis (4- methoxyphenyl) -3-butenoic acid, 4-cyano-5,5-bis (4-methoxyphenyl) -4-pentenoic acid ethyl ester
The diphenylethylene derivative of the invention exhibits excellent pharmacological efficacy. It effectively suppresses platelet agglutination, and therefore, it is useful as an anti-platelet or antithrombotic agent. In particular, it is useful for the treatment and / or prevention of cerebrovascular diseases, such as transient ischemic attack, cerebral infarction (thrombus and embolus) and cerebral arteriosclerosis, postoperative thrombus, embolus and circulatory disorders associated with vascular surgery and extracorporeal circulation, chronic arterial disorders such as Burger disease, obstructive arteriosclerosis, peripheral arteriosclerosis, SLE and Raynaud's disease, and coronary diseases such as angina pectoris and myocardial infarction. In addition, it is useful for preventing the recurrence of these diseases and for improving the prognosis of their course.

 The effect of the product according to the invention will be supported by the following pharmacological tests, first for the diphenylethylene derivative.

Test example
1. The effect of inhibition of platelet agglutination (in vitro).

Blood was collected from the human ulnar vein and a solution was prepared so that it contained a 3.8% solution of sodium citrate in an amount of 1.10 relative to the blood volume. Then, platelet-rich plasma was prepared from it according to the method described by Raskham et al, (Packham, MA et al, J. Exp. Med, 126, 171-189 (1967). 25 microliter was added to 0.2 ml of the obtained platelet-rich plasma portions of solutions of each compound according to the invention (from 1 to 3) at various concentrations, and they were incubated at 37 ^about C for 3 minutes, then platelets were agglutinated using arachidonic acid, collagen, ADP, and PAF.

 Platelet agglutination was evaluated according to the method described by Mustart et al. (Mustard, JF et al. J. Lab. Clin. Med. 64, 548-559 (1964) using an aggregometer (aggregation meter, approx. Translation) supplied by Schenko or Nico Bioscience Co. In other words, this test is carried out to to investigate the effect of the substance on platelet aggregation (in vitro).

 The results are shown in table. 1.

 The effect of inhibiting platelet agglutination (ex vivo).

 Compounds 1-3, which were representative examples of the compounds of the invention, were orally administered to guinea pigs. After 2 hours, the blood of each animal was collected from its abdominal aorta during etherification. The effect of each compound on platelet agglutination caused by collagen (3 mg / ml) and arachidonic acid (50 μmol / L) was then examined. In the table. 2 shows 50% effective doses determined from the ratios of the solvent introduced. In other words, this test was carried out in order to investigate the effect of the compounds on platelet aggregation (ex vivo).

 Acute toxicity

The acute toxicity of the compounds from C and E, which were typical examples of the compounds of the invention, was investigated by introducing these compounds into male Wistar rats having a body weight of 300-400 g. As a result, it was found that the LD _{50 of} each compound is over 500 mg per kg of live weight.

 When a compound of the invention is used as an anti-platelet and antithrombotic agent, it can be administered orally or parenterally, for example, intramuscularly, subcutaneously or intravenously. Its dose can be changed depending on, for example, the disease, the condition and the age of the patient. Unless specifically stated, it can be administered in a dose of 0.1-300 mg, preferably 0.1-60 mg, particularly preferably 0.3-30 mg, and even more preferably 0.6-10 mg for an adult per day.

 A compound of the invention may be formulated, for example, in tablets, granules, powders, capsules, injections or suppositories using known methods used in the art.

 If it needs to be included in the formulation of solid preparations for oral administration, then a filler and, if necessary, other additives, such as binders, disintegrants, lubricants, dyes and improvers, are added to the base, and the resulting mixture is then molded by known methods, for example in tablets, coated tablets, granules, powders or capsules.

 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 polyvinyl pyrrolidone. Examples of disintegrants are starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, calcium bicarbonate, calcium citrate, dextrin and pectin. Examples of lubricants are magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. Examples of dyes are those that are taken as additives or for drugs. Examples of improvers are cocoa powder, methol, aromatic acids, peppermint oil, Bornean camphor, and cinnamon powder. These tablets and granules, if necessary, can undoubtedly be coated with, for example, sugar or gelatin.

 When it is necessary to prepare a preparation for injection, the composition includes various additives, such as pH regulators, buffers, stabilizers and antioxidants, and the resulting mixture is formed into a preparation for subcutaneous, intramuscular or intravenous injection.

 The following are examples of the preparation of representative representatives of the compounds according to the invention.

 PRI me R 1. Ethyl 4-cyano-5,5-bis (4-methoxyphenyl) -4-pentenoic acid.

 2.42 g (0.01 mol) of 4,4'-dimethoxybenzophenone, 1 g of zinc and 2.1 g of trimethyl borate were suspended in 15 ml of tetrahydrofuran. To the resulting suspension, 2.2 g of ethyl 4-bromocyanobutyric acid ethyl ester and a catalytic amount of iodine were added, and the mixture was allowed to react at room temperature for 5 hours. After completion of the reaction, 10 ml of a saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was stirred for 1 h. After zinc was filtered off, the filtrate was extracted with ethyl acetate. The resulting crude product was extracted with ethyl acetate. The resulting crude product was purified by silica gel chromatography to give 1.5 crystals. The crystals were dissolved in 10 ml of benzene and 1 ml of thionyl chloride was added to the resulting solution. After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo and dispersed in ice-water. The mixture was then extracted with benzene, washed with water and concentrated. Thus, 1.3 g of the title compound are obtained as a colorless oily product.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ 6.7-7.3 (8H), 4.1 (2H), 3.8 (6H), 2.7 (4H) and 1.3 (3H).

PRI me R 2. 4-Cyano-5,5- (4-methoxyphenyl) -4-pentenoic acid
3.6 g of 4-cyano-5,5-dis (4-methoxyphenyl) -4-pentenoic acid ethyl ester was dissolved in 10 ml of dioxane, and 3 ml of 5N aqueous was added thereto. NaOH solution. The resulting mixture was stirred at ⁶⁰ ° C for 5 hours. After completion of the reaction, the reaction mixture was acidified and extracted with ethyl acetate.

Thus, 3.2 g of the title compound are obtained having the following physicochemical properties. This product can then be purified by recrystallization from ethyl acetate / hexane. Mp 124-125 ^C. NMR _(CDCl3) δ 9,5 (1H), 6.8-7.4 (8H), 3.8 (6H), 2.7 (4H).

 PRI me R 3. Methyl ester of 5-cyano-6,6-bis (4-methoxyphenyl) -5-hexenoic acid.

The procedure of Example 1 was followed with the exception that instead of 4-bromo-4-cyanobutyric acid ethyl ester, 2.2 g of 5-bromo-5-cyanopentanoic acid methyl ester was used. Thus, the title compound was obtained having the following physicochemical properties. NMR spectrum (CDCl ₃ ) δ 6.7-7.3 (8H), 3.8 (6H), 3.6 (3H) and 1.8-2.6 (6H).

 PRI me R 4. 5-Cyano-6,6-bis (4-methoxyphenyl) -5-hexenoic acid.

 260 mg of the ester obtained in Example 3 were treated in the same manner as shown in Example 2 to obtain 250 mg of the title compound.

The data of the NMR spectrum analysis of this compound are given below. The analysis was performed with CDCl ₃ δ. 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).

Claims (1)

DIPHENYLETHYLENE DERIVATIVES of the general formula

where R is hydrogen, C ₁ -C ₆ alkyl;
n is 1.3.

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