JPH05170696A - Bis(4-alkoxyphenyl)ethylene derivative - Google Patents

Abstract

PURPOSE:To provide the subject new ethylene derivative having bis(4- alkoxyphenyl) ethylene structure, exhibiting platelet agglutination activity and anti-inflammatory and analgesic actions and useful as an agent for preventing and treating thrombosis and anti-inflammatory agent. CONSTITUTION:A Grignard reagent prepared from 4-bromoanisole, magnesium and dried ether by conventional method is made to react with 4-(4- methoxybenzoyl)butyric acid methyl ester to obtain 5,5-bis(4-methoxyphenyl)-4- pentenoic acid. The product is dissolved in methanol, thionyl chloride is dropped into the solution and the system is refluxed by heating for 1hr to effect the methyl esterification. The produced ester is made to react with phosphorus oxychloride in N,N-dimethylformamide at 60 deg.C for 20hr. After completing the reaction, the reaction liquid is incorporated with water, alkalized with potassium carbonate and extracted with ether. The extract is purified by column chromatography after distilling out the solvent to obtain the compound of formula (R<1> is lower alkyl; R<2> is formyl, etc.; R<3> is H or lower alkyl; (n) is 1-4).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel bis (4-alkoxyphenyl) ethylene derivative and a pharmacologically acceptable salt thereof, and an object of the present invention is to obtain excellent platelet aggregation inhibitory action and anti-inflammatory analgesia. It is intended to provide a compound having an action and useful as an antithrombotic agent or an anti-inflammatory agent.

[0002]

2. Description of the Related Art As a compound having a bis (4-alkoxyphenyl) ethylene group, for example, JP-A 64-85 is available.
The compound described in Japanese Patent No. 963 is used as a PAF antagonist, and is disclosed in Japanese Patent Application Laid-Open No.
The compound described in 3-10743 is known as an antiplatelet agent.

[0003]

The ischemic diseases of the circulatory system represented by myocardial infarction and cerebral thrombosis have become a large proportion of adult diseases in recent years. The causes of these are
The formation of blood clots due to arteriosclerosis is raised, and its prevention and treatment will become a major issue for future medical care.

Antiplatelet therapy for lowering platelet function is considered to be one of the effective means for preventing thrombus, and in recent years, ticlopidine [Merck Index (The Merck In
dex), 11th edition, 9361] and cilostazol [The Merck Index, 11th edition, 2277], although a small number of drugs having an inhibitory effect on platelet aggregation have been clinically used, but they are still insufficient. The advent of more effective and more effective antiplatelet agents is strongly desired.

[0005]

DISCLOSURE OF THE INVENTION As a result of intensive studies conducted by the present inventors in view of the above-mentioned circumstances, the novel bis (4-alkoxyphenyl) ethylene derivative according to the present invention has excellent platelet aggregation inhibitory action and anti-inflammatory analgesia. The effect was found and the present invention was completed.

That is, the present invention has the following general formula (I):

[Chemical 2] (In the formula, R ¹ is a lower alkyl group, R ² is a formyl group,
A hydroxyiminomethyl group or a lower alkoxyiminomethyl group, R ³ represents a hydrogen atom or a lower alkyl group,
n represents an integer of 1 to 4. ) New bis (4
-Alkoxyphenyl) ethylene derivatives and pharmaceutically acceptable salts thereof.

In the general formula (I) of the present invention, R ¹ and R
Examples of the lower alkyl group represented by ³ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group, and R ² As the lower alkoxyiminomethyl group represented by, for example, methoxyiminomethyl group, ethoxyiminomethyl group, n-propoxyiminomethyl group, isopropoxyiminomethyl group, n-butoxyiminomethyl group, isobutoxyiminomethyl group, tert Examples include butoxyiminomethyl group.

Preferred compounds of the present invention include the following compounds. 3-formyl-4,4-bis (4-methoxyphenyl)
Methyl-3-butenoate 3-formyl-4,4-bis (4-methoxyphenyl)
-3-Butenoic acid 4-formyl-5,5-bis (4-methoxyphenyl)
-4-Methyl-4-pentenoate 4-formyl-5,5-bis (4-methoxyphenyl)
-4-Pentenoic acid 5-formyl-6,6-bis (4-methoxyphenyl)
-5-Hexenoic acid methyl 5-formyl-6,6-bis (4-methoxyphenyl)
-5-hexenoic acid 6-formyl-7,7-bis (4-methoxyphenyl)
Methyl-6-heptenate 6-formyl-7,7-bis (4-methoxyphenyl)
-6-Heptenoic acid 3-hydroxyiminomethyl-4,4-bis (4-methoxyphenyl) -3-butenoic acid methyl 3-hydroxyiminomethyl-4,4-bis (4-methoxyphenyl) -3-butenoic acid 4-hydroxyiminomethyl-5,5-bis (4-methoxyphenyl) -4-pentenoic acid methyl 4-hydroxyiminomethyl-5,5-bis (4-methoxyphenyl) -4-pentenoic acid 5-hydroxyiminomethyl Methyl-6,6-bis (4-methoxyphenyl) -5-hexenoate 5-Hydroxyiminomethyl-6,6-bis (4-methoxyphenyl) -5-hexenoic acid 6-Hydroxyiminomethyl-7,7- Methyl bis (4-methoxyphenyl) -6-heptenoate 6-hydroxyiminomethyl-7,7-bis (4-methoxyphenyl) 6-Heptenoic acid 3-methoxyiminomethyl-4,4-bis (4-methoxyphenyl) -3-butenoic acid methyl 3-methoxyiminomethyl-4,4-bis (4-methoxyphenyl) -3-butenoic acid 4 -Methoxyiminomethyl-5,5-bis (4-methoxyphenyl) -4-pentenoic acid methyl 4-methoxyiminomethyl-5,5-bis (4-methoxyphenyl) -4-pentenoic acid 5-methoxyiminomethyl- Methyl 6,6-bis (4-methoxyphenyl) -5-hexenoate 5-methoxyiminomethyl-6,6-bis (4-methoxyphenyl) -5-hexenoic acid 6-methoxyiminomethyl-7,7-bis Methyl (4-methoxyphenyl) -6-heptenoate 6-methoxyiminomethyl-7,7-bis (4-methoxyphenyl) -6-heptenoic acid

Among the compounds represented by the above general formula (I) of the present invention, those in which R ³ is a hydrogen atom can be converted into a pharmacologically acceptable salt, if desired, or the formed salt. Can also be converted to the free acid.

Examples of the pharmacologically acceptable salt of the compound represented by the general formula (I) of the present invention include alkali addition salts, for example, inorganic alkali salts such as sodium, potassium, calcium and ammonium, Alternatively, salts of organic bases such as trimethylamine, triethylamine, pyrrolidine, piperidine, piperazine, N-methylmorpholine and the like can be mentioned.

The novel bis (4-alkoxyphenyl) ethylene derivative represented by the general formula (I) of the present invention is
It can be manufactured by various methods.

According to the first mode of the method for producing a compound of the present invention, among the compounds represented by the general formula (I), those in which R ² is a formyl group are compounds in which R ² is a hydrogen atom. In addition, it can be produced by a so-called Vilsmeier reaction in which N, N-disubstituted formamide is reacted with phosphorus oxychloride or phosgene. N,
Examples of the N-disubstituted formamide include N, N-dimethylformamide, N-methylformanilide and the like,
The reaction is carried out in the range of 0 ° C to 150 ° C.

According to the second mode of the method for producing a compound according to the present invention, among the compounds represented by the general formula (I), those in which R ² is a hydroxyiminomethyl group or a lower alkoxyiminomethyl group are: It can be produced by reacting a compound in which R ² is a formyl group with hydroxylamine hydrochloride or lower alkoxyamine hydrochloride in the presence of a base in a solvent. Any solvent may be used as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and the like. Aprotic polar solvent of
Examples thereof include aromatic solvents such as benzene, toluene and pyridine, examples of the base used include triethylamine, pyridine, sodium carbonate, potassium carbonate and the like, and the reaction is carried out in the range of 0 ° C to 150 ° C. Done.

According to the third mode of the method for producing a compound of the present invention, among the compounds represented by the above general formula (I), R ³ is a hydrogen atom, and R ³ is a lower alkyl group. The compound can be produced by performing a hydrolysis reaction with a base or an acid in a water-containing solvent. The water-containing solvent used may be water alone, but it is preferable to mix it with a solvent such as methanol, ethanol, acetone, or tetrahydrofuran. As the base used,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Examples thereof include potassium carbonate and the like, and examples of the acid include hydrochloric acid, hydrobromic acid, sulfuric acid and the like, and the reaction is carried out in the range of 0 ° C. to the reflux temperature of the solvent.

The above-mentioned general formula (I) produced in this manner
The pharmaceuticals containing the novel bis (4-alkoxyphenyl) ethylene derivative and the pharmacologically acceptable salt thereof as the active ingredient are usually oral preparations such as capsules, tablets, fine granules, powders and syrups. It is administered as an administration agent or an injection. These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, in the case of oral agents, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.), disintegrants (carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), binders (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.) Solubilizers or solubilizers that can form the mold (distilled water for injection, physiological saline, propylene glycol, etc.), pH adjusters (inorganic or organic acids or bases), isotonic agents (salt, glucose, glycerin, etc.) ), Stabilizers and other formulation components are used.

The dose of the compound of the present invention to a treated patient depends on the symptoms of the patient, but in the case of an adult, the daily dose is usually 1 to 500 mg orally and 1 to 300 mg parenterally.
It is a degree.

[0017]

The present invention will be described below with reference to reference examples and examples, but the present invention is not limited to the specific details of these examples.

Reference Example 1 5,5-bis (4-methoxyphenyl) -4-pentenoic acid 4-bromoanisole 20.3 g, magnesium 2.4
The Grignard reagent prepared from 7 g and 70 ml of dry ether by a conventional method was added dropwise at room temperature to a solution of 16.0 g of methyl 4- (4-methoxybenzoyl) butyrate in 100 ml of dry ether over about 40 minutes. The reaction mixture was ice-cooled, 3
After dropping 200 ml of a sulfuric acid aqueous solution of 100%, the ether layer was separated. The ether layer was back-extracted with aqueous sodium hydroxide solution, then the aqueous layer was acidified with dilute hydrochloric acid and extracted with ether. The ether layer was washed with water and dehydrated, and the solvent was distilled off to give light brown crystals.
12 g was obtained. Recrystallized from hydrous ethanol, melting point 1
Colorless needle crystals of 12 to 113 ° C were obtained. Elemental analysis value C ₁₉ H ₂₀ O ₄ theoretical value C _, 73.06; H, 6.45 experimental value C _, 72.96; H, 6.50

Reference Example 2 Methyl 5,5-bis (4-methoxyphenyl) -4-pentenoate 5,5-bis (4-methoxyphenyl) -4-pentenoic acid 2.50 g of methanol was added to a solution of thionyl chloride in 40 ml of methanol. 0.57 ml was added dropwise, and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with an aqueous potassium carbonate solution, washed with water and dehydrated, and then the solvent was distilled off to obtain 2.58 g of a pale yellow liquid. IR spectrum ν (liq) cm ^-1 : 1738 Mass spectrum m / z: 326 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 2.35-2.50 (4H,
m), 3.65 (3H, s), 3.77 (3H, s), 3.82 (3H, s), 5.80-5.95 (1H,
m), 6.79 (2H, d, J = 9Hz), 6.90 (2H, d, J = 9Hz), 7.08 (2H, d, J = 9
Hz), 7.13 (2H, d, J = 9Hz)

Example 1 4-Formyl-5,5-bis (4-methoxyphenyl)
Methyl-4-pentenoate N, N-dimethylformamide (30 ml) was added dropwise with phosphorus oxychloride (5.07 ml) under ice-cooling and the mixture was stirred for 10 minutes. A solution of 6.00 g of methyl 5,5-bis (4-methoxyphenyl) -4-pentenoate in 20 ml of N, N-dimethylformamide was added thereto, and the mixture was stirred at 60 ° C. for 20 hours. Water was added to the reaction solution, which was made alkaline with potassium carbonate and extracted with ether. The ether layer was washed with water, dehydrated, and then the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel, methylene chloride) to give 5.52 g of pale yellow crystals.
Got Recrystallized from isopropyl ether, melting point 94
Yellow crystals of ˜95 ° C. were obtained. Elemental analysis value C ₂₁ H ₂₂ O ₅ theoretical value C _, 71.17; H, 6.26 experimental value C _, 71.40; H, 6.18

Example 2 4-Formyl-5,5-bis (4-methoxyphenyl)
-4-Pentenoic acid 4-formyl-5,5-bis (4-methoxyphenyl)
To a solution of methyl 4-pentenoate (80 mg) in methanol (0.5 ml) was added 2N aqueous sodium hydroxide solution (0.2 ml).
Stir for 15 minutes at ° C. The solvent was evaporated under reduced pressure, water was added to the residue, the mixture was acidified with diluted hydrochloric acid, and the mixture was extracted with ether. The ether layer was washed with water, dehydrated and the solvent was distilled off to obtain 50 mg of a pale yellow viscous liquid. IR spectrum ν (liq) cm ^-1 : 1712, 1658 Mass spectrum m / z: 340 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 2.50-2.60 (2H,
m), 2.70-2.80 (2H, m), 3.83 (6H, s), 6.87 (2H, d, J = 9Hz), 6.8
9 (2H, d, J = 9Hz), 7.06 (2H, d, J = 9Hz), 7.08 (2H, d, J = 9Hz), 9.
46 (1H, s)

Example 3 Methyl 4- (E) -hydroxyiminomethyl-5,5-bis (4-methoxyphenyl) -4-pentenoate 4-formyl-5,5-bis (4-methoxyphenyl)
A solution of 3.00 g of 4-pentenoic acid, 0.71 g of hydroxylamine hydrochloride and 1.02 g of triethylamine in 20 ml of methanol was heated under reflux for 3 hours. Water was added to the reaction solution and extracted with ether. Wash the ether layer with dilute hydrochloric acid,
After washing with water and dehydration, the solvent was distilled off. Column chromatography of the residue (silica gel, methylene chloride-methanol
Purification with 100: 1) gave 2.39 g of pale yellow crystals. Recrystallized from isopropyl ether and melting point 101-
A colorless plate crystal at 102 ° C. was obtained. Elemental analysis value C ₂₁ H ₂₃ NO ₅ theoretical value C _, 68.28; H, 6.28; N, 3.79 experimental value C _, 68.43; H, 6.18; N, 3.75

Example 4 4- (E) -Hydroxyiminomethyl-5,5-bis (4-methoxyphenyl) -4-pentenoic acid 4- (E) -Hydroxyiminomethyl-5,5-bis (4-) Methoxyphenyl) -4-pentenoate methyl.
To 80 g of methanol (3 ml) was added 2N aqueous sodium hydroxide solution (2.2 ml), and the mixture was heated under reflux for 1 hr. The solvent was distilled off under reduced pressure, water was added to the residue, acidified with diluted hydrochloric acid and extracted with ether. The ether layer was washed with water, dehydrated and then the solvent was distilled off to obtain 0.68 g of colorless crystals. Recrystallization from water-containing methanol gave colorless crystals with a melting point of 142-144 ° C. Elemental analysis value C ₂₀ H ₂₁ NO ₅ theoretical value C _, 67.59; H, 5.96; N, 3.94 experimental value C _, 67.58; H, 5.91; N, 3.91

Example 5 4- (E) -methoxyiminomethyl-5,5-bis (4
-Methoxyphenyl) -4-pentenoate methyl 4-formyl-5,5-bis (4-methoxyphenyl)
A mixture of 1.06 g of methyl-4-pentenoate, 0.38 g of O-methylhydroxylamine hydrochloride and 4 ml of pyridine was heated under reflux at 50 ° C. for 1 hour. Add water to the reaction mixture,
It was acidified with dilute hydrochloric acid and extracted with ether. The ether layer was washed with water, dehydrated, and the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel, methylene chloride) to obtain 1.14 g of a pale yellow viscous liquid. IR spectrum ν (liq) cm ^-1 : 1738 Mass spectrum m / z: 383 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 2.55-2.70 (2H,
m), 2.75-2.85 (2H, m), 3.62 (3H, s), 3.79 (3H, s), 3.80 (3H,
s), 3.86 (3H, s), 6.81 (2H, d, J = 9Hz), 6.85 (2H, d, J = 9Hz), 6.
99 (2H, d, J = 9Hz), 7.04 (2H, d, J = 9Hz), 7.77 (1H, s)

Example 6 4- (E) -Methoxyiminomethyl-5,5-bis (4
-Methoxyphenyl) -4-pentenoic acid 4- (E) -methoxyiminomethyl-5,5-bis (4
-Methoxyphenyl) -4-pentenoate methyl 1.18
3.1 ml of 2N aqueous sodium hydroxide solution was added to a solution of 5 g of methanol in 5 ml, and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, acidified with diluted hydrochloric acid and extracted with ether. After washing the ether layer with water and dehydration, the solvent is distilled off,
0.95 g of pale yellow crystals were obtained. Recrystallization from hydrous ethanol gave colorless plate crystals having a melting point of 127 to 128 ° C. Elemental analysis value C ₂₁ H ₂₃ NO ₅ theoretical value C _, 68.28; H, 6.28; N, 3.79 experimental value C _, 68.41; H, 6.38; N, 3.72

[0026]

INDUSTRIAL APPLICABILITY The novel bis (4-alkoxyphenyl) ethylene derivative represented by the above general formula (I) and the pharmacologically acceptable salt thereof thus produced have an excellent inhibitory effect on platelet aggregation. It also has an anti-inflammatory and analgesic effect and is extremely useful as a preventive and therapeutic agent for various thrombosis caused by platelet aggregation or an anti-inflammatory agent.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shunichiro Sakurai 12-6-2 Inogeya, Katsuyama City, Fukui Prefecture

Claims (1)

[Claims] 1. The following general formula: (In the formula, R ¹ is a lower alkyl group, R ² is a formyl group,
A hydroxyiminomethyl group or a lower alkoxyiminomethyl group, R ³ represents a hydrogen atom or a lower alkyl group,
n represents an integer of 1 to 4. ) And a pharmaceutically acceptable salt thereof.