FI61865C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBAR 2-ETYL-5-INDANAETTIKYYRA - Google Patents

Description

61865

Process for the preparation of therapeutically useful 2-ethyl-5'-indaneacetic acid

Divided by application EN 3073/74 5

The invention relates to a process for the preparation of a new 2-ethyl-5-indaneacetic acid of the formula I.

(ΧΗς. // ¾¾. / CH „COOH

10 TT 1 2-Ethyl-5-indaneacetic acid has anti-inflammatory effect.

U.S. Patent No. 3,452,085 discloses compounds that are structurally similar to the presently prepared compound. However, these known compounds have no substituent at the 2-position of the indan ring. The unsubstituted compounds in question do not have an anti-inflammatory effect.

The effect depends mainly on the 2-substitution, in which case the potency increases in the order: CH 2 <C 2 H, - <i-prop. Thus, the essential factors for the effect are the substitution and the nature of the substituent at the 2-position. The 1-spiro-substituted compounds described in U.S. Patent No. 3,682,964 are also unsatisfactory.

2-Ethyl-5-indaneacetic acid can be prepared by forming a CN group in a compound of the formula c2h5.

30 xQ II

converted to the COOH group by hydrolysis.

The reaction may be carried out by heating the compound of formula II vigorously in the presence of a basic catalyst, for example an alkali metal hydroxide such as sodium or potassium hydroxide, at a temperature of 20 to 150 ° C.

61865 2 2-Ethyl-5-indaneacetic acid can be isolated from the reaction mixture and purified in a manner known per se.

The starting material of formula II can be prepared, for example, by reacting a compound of formula 5 C2H5 \ / ^ ^ ^.CH2-Cl

\\ ^ | III

10 to react with metal cyanide. Preferably, alkali metal cyanides such as sodium or potassium cyanide or copper I cyanide are used. The reaction may be carried out, for example, in an inert solvent such as water, acetone, a lower alcohol or dimethylformamide, or in a mixture of water and such an organic solvent, optionally with the addition of a metal iodide such as sodium or potassium iodide. The reaction temperature is 10 to 150 ° C, preferably 50 to 120 ° C.

2-Ethyl-5-indaneacetic acid has not been previously described in the literature. It has interesting pharmacodynamic properties that allow it to be used as a drug. 2-ethyl-5-indaneacetic acid has an anti-inflammatory (anti-inflammatory) effect which has been shown in animal experiments. Thus, it prevents the formation of edema in rats in the Carrageenan anterior paw test at a dose of about 20-100 mg / kg body weight.

When 2-ethyl-5-indaneacetic acid is used as the drug, the dosage will, of course, vary with the mode of administration and the condition of the patient being treated. In general, however, satisfactory results are obtained at a dosage of 20 to 100 mg / kg body weight.

In addition, 2-ethyl-5-indaneacetic acid has an anti-arthritic effect. Thus, for example, in a Freund's adjuvant-arthritis latency test in rats, it has an anti-edematous effect at a dose of about 30-100 mg / kg body weight.

Due to its anti-arthritic activity, compound 35 can be used for the prophylaxis and treatment of arthritis and rheumatic diseases. The dosage employed will, of course, vary with the mode of administration and the condition of the patient being treated.

3,61865

In general, however, satisfactory results are obtained at a dosage of 30 to 100 mg / kg of body weight.

2-Ethyl-5-indaneacetic acid can be administered as a medicament either alone or in the form of a pharmaceutical composition with excipients.

Example 2-Ethyl-5-indaneacetic acid 12.8 g of 2-ethyl-5-indaneacetonitrile are dissolved in 350 ml of ethanol, a solution of 26.7 g of potassium hydroxide in 45 ml of water is added and the mixture is refluxed for 20 hours. . The solution is concentrated to 50 ml, diluted with water and extracted with ether and the ether phase is discarded. The aqueous phase is then acidified with 2N hydrochloric acid and extracted with ether. The crude 2-ethyl-5-indaneacetic acid obtained after concentrating the ether extract is purified by chromatography on 50 times of silica gel using chloroform containing 1.5% methanol as eluent. After recrystallization from hexane, 2-ethyl-5-indaneacetic acid is obtained, melting at 44-46 ° C.

The starting material can be obtained as follows: a) A mixture of 10.0 g of 2-ethylindan in 7.12 ml of a 40% aqueous formaldehyde solution and 14.2 ml of concentrated hydrochloric acid is stirred at 70 ° C. 9.8 ml of concentrated sulfuric acid are added dropwise over 6 hours and the mixture is further stirred for two days at 70 ° C. After cooling, water is added to the reaction mixture and extracted with ether. The extract is washed twice with 8% sodium bicarbonate solution and once with water, dried over sodium sulfate and the solvent is evaporated, the crude 2-ethyl-5-30 chloromethylindan obtained as an oily crude product is further worked up directly.

b) 12.0 g of the oily crude product described above are dissolved in 350 ml of acetone, boiled with stirring, and a solution of 17.6 g of sodium cyanide in 35 ml of water is added dropwise. The reaction mixture is refluxed for 20 hours, cooled to 25 ml. ° C and evaporated in vacuo. The residue is diluted with water and extracted with ether. The extract is washed with water, dried over sodium sulfate and evaporated to give crude 2-ethyl-5-indaneacetonitrile as an oil which is purified by distillation, mp = 131-135 ° C.