JPS6361940B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel 1-substituted-4-phenyl-isonicopetic acid esters, more specifically, the following general formula () having excellent analgesic, anti-inflammatory and anesthetic effects: (In the formula, R ₁ is a lower alkyl group, and R ₂ is an acetonyl group or a 3-piperidino-2-hydroxypropyl group.) It has been known that many isonicopetic acid derivatives have medicinal effects.
In view of this situation, the present inventor synthesized many such derivatives and investigated their physiological activities, and found that the compound represented by the above general formula () has excellent analgesic, anti-inflammatory, and anesthetic effects. , completed the invention. Therefore, the present invention provides 1-acetonyl-4-phenyl-isonicopetic acid ester or 1-(3'-piperidino-2'-hydroxypropyl)-4-phenyl-isonicopetic acid ester represented by the general formula (). This is what we provide. The 1-substituted-4-phenyl-isonicopetic acid ester of the present invention is produced by reacting 4-phenyl-isonicopetic acid ester () with monohalogenoacetone () according to the following reaction formula. -Method for obtaining isonicopetate ester (a), or 4-phenyl-
1-(3'-piperidino-2' -hydroxypropyl)-4-phenyl-isonicopetic acid ester (b). ( _Wherein , It is easily produced by condensation with a compound followed by decarbobenzylation after alcoholysis. The reaction between 4-phenyl-isonicopetic acid ester () and compounds () to () is carried out by heating the reaction at a temperature of 50 to 100°C in the presence or absence of a solvent according to a method known per se. It is done by folding. In addition, when the compounds () and () are reacted, it is preferable to carry out the reaction in the presence of a deoxidizing agent such as trialkylamine or pyridine. The pharmacological effects of the compound of the present invention thus obtained are as follows. Note that 1-acetonyl-4-phenyl-isonicopetic acid ethyl ester/hydrochloride is compound a, and 1-(3'-piperidino-2'-hydroxypropyl)-4-phenyl-isonicopetic acid ethyl ester/hydrochloride is compound b. It was shown as (i) Analgesic effect Table 1 shows the analgesic effect measured by the acetic acid lighting method.

[Table] (ii) Anti-inflammatory effect 100 mg/Kg of the test drug was orally administered to Sprogne-Dawley male rats (body weight 200-250 g, 5 rats per group), and after 60 minutes, histamine diphthalamic acid dissolved in physiological saline was administered. Osphate (100 μg/0.1 ml) was injected into the back skin at two locations each. After 15 minutes, sacrifice the skin, peel off the skin, and measure the area of the inner stained area (longitude x short length, cm ² ).
were measured and compared with the control. The results are shown in Table 2.

[Table] (iii) Local anesthetic effect 0.2 ml of a 1% aqueous solution of the test drug was dropped onto the cornea of a rabbit, and the presence or absence of a blink reaction was tested using stimulated bristles, and the time when there was no blink reaction was determined as the duration of surface anesthesia. And so. Also,
0.1 ml of a 0.3% aqueous solution of the test drug was injected into the eyelids, the blink response was similarly assayed, and the duration of infiltration anesthesia was measured. The results are shown in Table 3.

[Table] Next, examples will be given and explained. Example 1 3 g of ethyl 4-phenyl-isonicopetate was dissolved in 10 ml of benzene, and triethylamine was added to the solution.
1.44g, add 1.34g of monochloroacetone, 50-70
Stirred at ℃ for 2 hours. After cooling, 10 ml of 10% hydrochloric acid was added and shaken, the aqueous layer was separated, made alkaline, and extracted with ether. The ether layer was washed with water, unreacted raw materials were removed as carbonates by passing carbon dioxide gas, hydrogen chloride was passed through the ether layer, the precipitate was collected, and the precipitate was recrystallized twice with anhydrous acetone to give a melting point of 176°C.
2.6 g of 1-acetonyl-4-phenyl-isonicopetic acid ethyl ester hydrochloride was obtained. Elemental analysis value C ₁₇ H ₂₇ O ₃ NCl Calculated value (%): C62.57, H7.4, N4.3 Experimental value (%): C62.19, H7.8, N4.15 Example 2 (i) Epichlorohydrin 13g, piperidine 11g,
A mixture of 0.5 ml of water was stirred at 30°C for 6 hours. Add a solution of 7.5 g of sodium hydroxide and 14 ml of water to this at 25°C.
The mixture was stirred for 40 minutes, added with 15 ml of water, and extracted with ether. After drying the extract, the solvent was distilled off,
Distillation under reduced pressure yielded 15 g of 3-piperidino-1,2-epoxypropene having a boiling point of 132°C/5 mmHg. (ii) 2.5 g of ethyl 4-phenyl-isonicopetate
0.6 g of 3-piperidino-1,2-epoxypropene obtained above was added to the mixture, and the mixture was stirred at 100°C for 8 hours.
After extraction with ether, the ether layer was dried and distilled under reduced pressure. The residue was dissolved in ether and hydrogen chloride was passed through it to remove the precipitate. This was recrystallized from an ether-ethanol mixture to obtain a melting point of
2.1 g of 1-(3'-piperidino-2'-hydroxypropyl)-4-phenyl-isonicopetic acid ethyl ester hydrochloride at 172°C was obtained. Elemental analysis value C ₂₂ H ₃₉ O ₃ N ₂ Cl Calculated value (%): C63.61, H9.65, N6.77 Experimental value (%): C63.28, H9.23, N6.42

Claims (1)

[Claims] First-order general formula (), (In the formula, R ₁ is a lower alkyl group, and R ₂ is an acetonyl group or a 3-piperidino-2-hydroxypropyl group.)