JPS5835519B2 - Isodoridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R1 and R2 each represent hydrogen, lower alkyl,
Xl represents hydrogen or lower alkyl, X2 represents hydrogen or halogen, and Y represents nitrile, carbamoyl, lower alkoxycarbonyl, or carboxyl.

).

In each definition, lower alkyl refers to methyl, ethyl, etc., halogen refers to chlorine, fluorine, etc., and lower alkoxycarbonyl refers to methoxycarbonyl, ethoxycarbonyl, etc.

The compound of general formula CI) has analgesic, antipyretic, and antiinflammatory effects,
It is useful as a medicine and as an intermediate thereof.

According to the invention, compounds of general formula CI) are prepared by the following method.

[In the formula, X is halogen (chlorine, vinegar.

) is reacted with a compound represented by the general formula bromine, etc.) in an appropriate solvent, and the resulting pyridinium salt represented by the general formula is reacted in the presence of an appropriate deoxidizing agent without isolating the pyridinium salt represented by the general formula. It is produced by heating to

As the solvent used, any solvent that does not inhibit the reaction can be used, such as alcohol solvents such as methanol, ethanol, and isopropyl alcohol, and aromatic hydrocarbon solvents such as benzene, toluene, and xylene.

In addition, as a deoxidizing agent, sodium carbonate, potassium carbonate,
Carbonates such as sodium bicarbonate, alkali hydroxides such as sodium hydroxide, potassium hydroxide, etc. are suitable.

The reaction was maintained at reflux of the solvent used for 5 to 50 hours, then after distilling off the solvent, an aqueous solution of an appropriate deoxidizing agent was added, and the mixture was heated on a water bath for 30 hours.
Heat for minutes to 2 hours.

(In the formula, 2 represents nitrile, carbamoyl, or lower alkoxycarbonyl.

) is hydrolyzed in the presence of an acid or a base by a conventional method to produce a compound represented by the general formula.

Suitable acids used include hydrochloric acid, hydrobromic acid, sulfuric acid, and acetic acid, and suitable bases include alkali hydroxides such as sodium hydroxide and potassium hydroxide.

Next, the pharmacological action of the compound of general formula CI) will be shown along with experimental methods.

Experimental method 1 Analgesic effect (phenylquinone method) Henderschot et al.'s method (J, Pharm
acol, exp.

Ther, Vol. 125, p. 237 (1957)].

The test compound was orally administered to female dd mice (6 mice per group) weighing around 20S', and 1 hour later, 0.02% phenylquinone solution was administered intraperitoneally to 0.211L7/20P, and the frequency of stretch symptoms was measured for 20 minutes. The ED5o value was determined by the probit method from the inhibition rate relative to the control group.

Experimental method 2 Anti-inflammatory effect (ultraviolet erythema method) Winder et al.'s method CArch, int, Ph
armacodyn.

Volume 116, page 261 (1958)].

Weight 250-450? Using a guinea pig, a rubber plate with three holes of 7 mm in diameter was placed on the flank, which had been previously depilated, and irradiated with a 600 W mercury lamp from a distance of 15 mm for 80 seconds.

After 2 hours, the degree of erythema formation was scored according to the scoring method of Winder et al., and a total score of 1.5 or less was considered effective, and the effectiveness rate was determined.

In addition, half the test compound solution was added one hour before and immediately after irradiation (
The total amount was 10 ml/kg) orally.

Experimental method 3 Anti-edema effect (carrageenin method) Winter et al.'s method (Proc, Soc, Ex
ptl, B iol.

Med, Vol. 111, p. 544 (1971)].

The test compound solution was orally administered (25 rul/kg) to Donryn rats (5 rats per group) weighing around 150 P, and 1 hour later, 0.05 rrLl of 1% carrageenan was subcutaneously injected into the right hind paw, and after a certain period of time, the paw volume was The percentage of increase in the paw volume before carrageenan administration was calculated, and the inhibition rate was determined relative to the control group.

This inhibition rate was shown as the average value of 2 to 3 repeated experiments.

The results of the above experiments are shown in Table 1.

Test compounds A and B in Table 1 are as follows.

A: 2-(4-(2-intridinyl)phenyl)propionic acid B: 2-(3-fluoro-4-(2-intridinyl)
The compound of the general formula CI) of phenyl]furopionic acid can be prepared by itself or mixed with an appropriate pharmacologically acceptable carrier, excipient, or diluent to form a powder,
It can be administered orally or parenterally in the form of granules, tablets, capsules, injections, and the like.

The dosage may be, for example, 1,100 W1 at a time, three times a day, but it goes without saying that these are differentiated depending on symptoms, body weight, and the like.

Next, the present invention will be specifically explained using examples.

Example 1 8.31.5.61 2-methylpyridine of 2-(4-(ω-chloro)acetylphenyl)propionitrile is added to 1OOrILl of alcohol and refluxed on a water bath for 20 hours.

Concentrate under reduced pressure, add 5.0 parts of sodium bicarbonate and 50 TrL of water to the residue, and heat on a water bath for 2 hours.

The generated crystals were collected, washed with water, and recrystallized from alcohol to obtain 2-[4(2-intridinyl)phenyl]propionitrile 6.31, which is a pale yellow scale-like crystal with a melting point of 219-220°C (decomposition). It will be done.

Example 2 6.31 of 27(4-(2-intridinyl)phenyl)propionitrile was added to 501 rL of concentrated hydrochloric acid, heated to reflux overnight, and adjusted to pH 6~ with 10% aqueous sodium hydroxide solution.
7, the resulting crystals are collected and recrystallized from methanol to give colorless powdery crystals with a melting point of 253-254°C (
4.52 of 2-(4-(2intridinyl)phenyl)propionic acid is obtained.

Compounds produced in the same manner are listed below.

◎4-(2-Intridinyl)phenylacetic acid ethyl ester Melting point: 159-160℃ ◎2-(4-(2-Intridinyl)phenyl]propionamide Melting point: 250-253℃ (decomposition) ◎2-(4-(7-Methyl) Indolizin-2-yl)phenyl]propionamide Melting point 240-241'C
(Decomposition) ◎2-[3-fluoro-4-(2-intridinyl)phenyl]propionamide Melting point 193-195°C ◎2-[3-fluoro-4-(2-intridinyl)phenyl]propion [melting point i63°G (Disassembly)

Claims (1)

[Claims] 1 General formula (wherein R1 and R2 each represent hydrogen, lower alkyl,
xI represents hydrogen or lower alkyl, X2 represents hydrogen or halogen, and Y represents nitrile, carbamoyl, 1-alkoxycarbonyl, or carboxyl. ) Indolizine derivatives represented by