JPS6219419B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 4′ and 5 represented by the following general formula []
-Disubstituted-3-biphenylylacetic acid derivatives. However, R ¹ represents hydrogen, lower alkoxy or halogen, R ² represents hydrogen, halogen or acetylamino group, and R ³ represents hydrogen or methyl group. The compound of the present invention is a novel substance that has not been described in any literature, and has excellent anti-inflammatory and analgesic effects, as well as platelet aggregation inhibiting effects, and is useful as a pharmaceutical. The pharmacological actions of the compounds of the present invention will be shown below to clarify their usefulness.

[Table] The compound of the present invention is an asymmetrically substituted biphenyl derivative having a substituent at the meta-position of the acetate group of phenylacetic acid, and has a seemingly simple structure. However, this type of compound has been difficult to obtain because there is no simple manufacturing method, and its usefulness has not been clearly understood. The present inventors converted methyl 5-(4-substituted phenyl)-3-oxocyclohexen-1-yl acetate, which is easily available by the method previously developed (Japanese Patent Publication No. 51-26433), into an oxime by a known method, When the obtained oxime is reacted with an acetylating agent, R ¹ is hydrogen, methoxy group or chlorine, R ² is an acetylamino group, and R ³ is a We found that hydrogen, R ⁴ , can be easily derived into methyl group compounds in high yield. (R ¹ , R ² , and R ³ are the same as above. ^{R 4} is lower alkyl.) Moreover, other compounds represented by the general formula [ ] can also be prepared using known methods using them as starting materials.
It could be manufactured in ~2 steps. As a result, it was possible to produce a new compound represented by the general formula [] by a simple method of reacting the compound represented by the general formula [] with caustic alkali, and the usefulness of these compounds as pharmaceuticals was discovered through pharmacological tests, and the present invention has been achieved. It was completed. The compound of the present invention is a typical asymmetrically substituted biphenyl, and is a compound that is extremely difficult to manufacture using conventional ideas. To explain further, the two biggest problems in the production of such biphenyl compounds are (i) formation of a biphenyl skeleton and (ii) efficient introduction of necessary substituents to desired positions. First, various methods are known for forming a biphenyl skeleton, but none of them can be effectively used to form an asymmetrically substituted biphenyl skeleton. Furthermore, introduction of necessary substituents into desired positions generally requires electrophilic or nucleophilic reactions on the biphenyl skeleton, as well as various subsequent conversion reactions. Electrophilic or nucleophilic reactions on biphenyl skeletons generally produce by-products such as positional isomers, depending on the type of existing substituents, and are not practical because separation of the products requires great effort. The present inventors solved the above-mentioned problems in the production of asymmetrically substituted biphenyl by easily producing an alicyclic compound having the necessary substituents in advance, and aromatizing it to form a biphenyl skeleton. overcoming the points and expressed by the general formula []
A simple production route for 4',5-disubstituted-3-biphenylylacetic acid derivatives was established. That is, by heating the compound represented by the general formula [] in a caustic alkali, preferably an aqueous solution of sodium hydroxide or potassium hydroxide, or a mixed solution of these and an alcohol, preferably methanol, the compound represented by the general formula [] is prepared. 4′・5-disubstitution
A 3-biphenylylacetic acid derivative is produced. The preferred reaction temperature for this conversion is between 50° and 100°C. Examples related to the manufacturing method are given below to further clarify the present invention. Example 1 A solution of methyl 5-acetylamino-3-biphenylylacetate (5.0 g), sodium hydroxide (0.78 g) and water (10 ml) and methanol (50
ml) and reflux for 1 hour. Methanol is distilled off, the residue is dissolved in water (25 ml) and washed with ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid under ice cooling, and the resulting reddish brown crystals were recrystallized from methanol to obtain 5-acetylamino-3-biphenylylacetic acid (2.829 g, yield 60%), melting point 166-168°C. Elemental analysis value C ₁₆ H ₁₅ NO ₃ Calculated value C: 71.36, H: 5.61, N: 5.20 Experimental value C: 71.32, H: 5.71, N: 5.08 Similarly, general formula

The following compound represented by the formula (in which R ¹ , R ² and R ³ are the same as before) was prepared.

[Table] Example 2 A solution of methyl 5-amino-3-biphenylylacetate hydrochloride (3.0 g) and sodium hydroxide (0.95 g) in water (5 ml) and methanol (30 ml)
Add to the mixed solution and heat under reflux for 1 hour. Methanol was distilled off, the residue was diluted with water (15 ml), and washed with ethyl acetate. The aqueous solution is made acidic under ice cooling (2 ml) and the precipitated crystals are collected. After washing with water and drying, the product was recrystallized from methanol to obtain 5-amino-3-biphenylylacetic acid (1.54 g, yield 63%), melting point 158° to 160°C. Elemental analysis value C ₁₄ H ₁₃ O ₂ N Calculated value C: 73.99, H: 5.77, N: 6.16 Experimental value C: 74.00, H: 5.74, N: 6.19 Similarly, the following compounds represented by the general formula [] Can be manufactured.

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Claims (1)

[Claims] 1. A 4',5-disubstituted-3-biphenylylacetic acid derivative represented by the following general formula []. However, R ¹ represents hydrogen, lower alkoxy or halogen, R ² represents hydrogen, halogen or an acetylamino group, and R ³ represents hydrogen or a methyl group.