CS204997B2 - Method of producing indane derivatives - Google Patents

Description

eiSKOSfaOVBMBKASOCIALISTREPUBLIC A (19) DESCRIPTION OF PATENT 204997 (11) (B2) (22) Registered 07 02 75 (21} (PV 2826-78} (51) Int. Cl.1 * 3 C 07 C 13/465 (32 } (31) (33) Priority from 16 12 74 (54292/74) United Kingdom (40) Published 31 07 80 ORAD FOR EXPLOSIONS AND DISCOVERIES (45) Published 15 12 83 (72) Author of the Invention TEULON JEAN-MARIE ing. , LA CELLE SAINT-CLOUD (France) (73) Proprietor of HEXACHIMIE, RUEIL-MALMAISON (France) (54) Method of producing indane derivatives 1

The invention relates to a process for the preparation of a derivative

of an indane of formula I

wherein X represents a hydrogen atom or a halo group and

R 1 and R 2, which may be the same or different, are C 1 -C 5 alkyl or C 3 -C 7 cycloalkyl, at least one of R 1 and R 2 may also be hydrogen.

The compounds of formula I are distinguished by significant pharmacological properties and can be used as medicaments, in particular as analgesics and anti-inflammatory agents. In particular, the compounds of formula I prepared by the process of the invention can be used, for example, as medicaments against rheumatic inflammations. The subject of the invention is a production method

indane derivatives of formula I (()) wherein X is hydrogen or halo-a

R 1 and R 2, which are identical or different, represent an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, wherein at least one of R 1 and R 2 may be hydrogen,

the essence of which is to formulate a general formula X

204997,204997 wherein R 1 and R 2 and X are as defined above, reacting Willgerodt with a primary or secondary amine of the formula NHR 5 R 5 where

R 5 and R 6 are leaving groups, preferably alkyl groups having 1 to 5 carbon atoms, or R 5 and R 6 together with the nitrogen atom to which they are attached form an N-heterocyclic group of 5 to 7 members to obtain a thioamide of general formula of Formula XI

[(2-Isopropyl) -5-indanyl] acetic acid morpholine thioamide

Formula XI wherein R 1 = hydrogen, R 2 = isopropyl

whereupon the thioamide is subjected to acid hydrolysis to provide a compound of formula I wherein R1, R2 and X are as defined above.

The compounds of formula (I) prepared by the process of the invention may be used for the preparation of medicaments useful in particular for the treatment of inflammation and recurring pain and pain syndromes. Or at least one non-toxic salt of the compound of formula (1) is a suitable physiologically acceptable excipient.

The compounds of formula (I) can be administered in the form of pills containing 50 to 250 mg of active ingredient, in a total daily dosage of 2 to 6 pills; the compounds may also be administered in the form of suppositories containing 100 to 500 mg of active ingredient, in a total daily dose of 2 to 5 suppositories, in the form of drinking suspensions containing 25 mg of the active ingredient in 5 ml of suspension, at a total daily dose of 10 to 40 ml of suspension or in the form of injectable solutions containing 50 mg of the active ingredient in 2 ml of injection solution, in a total daily dose of 2-4 injections.

The compounds of formula (I) for oral rats have a DL50 lethal dose of approximately 250 mg / kg; these compounds have only a negligible ulcerative effect and also have a higher pharmaceutical efficacy / toxicity ratio than previously known compounds having analogue pharmacological properties.

The process for the preparation of the compounds of the general formula (I) according to the invention will be further illustrated by way of example.

BLOCK

A mixture of 100 g of [(2-isopropyl) -5-indanyl] methyl ketone, 22.2 g of sulfur and 75 g of morpholine heats for 12 hours at 140 ° C. The reaction mixture was concentrated under reduced pressure and 200 ml of 95% ethanol was added. The resulting crystals are filtered off with suction and washed with cold 55% ethanol. 95 g of morpholinothioamide of [(2-isopropyl) -5-indanyl] acetic acid are thus obtained in the form of pale yellow crystals having a melting point of 120 ° C. Example 2

[(2-Isopropyl) -5-indanyl] acetic acid

Formula I in which

R 1 = H, R 2 - isopropyl and X = H.

A solution of 95 g of morpholinothioamide [(2-isopropyl) -5-indanyl] acetic acid in 125 ml of acetic acid and 175 ml of hydrochloric acid (D = 1.18) was refluxed for 18 hours.

The reaction mixture was poured onto ice and the organics were extracted with ether. The ether extract was washed thoroughly with water and dried over sodium sulfate, and the ether was evaporated under reduced pressure. Recrystallization of the residue from petroleum ether gave 63 g of [(2-isopropyl) -5-indanyl] acetic acid as white crystals, m.p. 80-81 ° C.

The pharmacological properties of the compounds of formula I prepared according to the invention are exemplified by the following tests. A) Anti-inflammatory activity

Groups of 12 male SPF rats of OFA strain weighing 120-130 g were orally dosed with test substances 2.5 hours (half of the dose each time) prior to subcutaneous injection of 0.05 ml 1% carrageenan solution into the paw. In PRA-

Claims (1)

204997 visible intervals were measured for the volume of the back paw into which the carrageenan solution was injected. The effective dose of DE 50 is determined by the control of inflammation in control animals. The results of these experiments are shown in Table I, where the percentage reduction in inflammation is reported. Table I mg / kg oral Compound of Example 2 4 - 8 - 16 - 32 10 64 19 128 47 256 63 DE 50 fmg / kg, oral) 120 DE 50 = effective dose BJ Analgesic potency Groups of 6 male mice (SPFi strain FiI) of unit weight 19-20 g of the test substances are administered orally. The invention relates to a method for producing indane derivatives of general formula (I) wherein X is hydrogen or halo and R1 and R2, which are identical or different, are alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein at least one of R1 is and R 2 may be a hydrogen atom, characterized in that the ketone of formula X is One hour thereafter, 0.3 ml of a 0.02% phenylbenzoquinone solution is injected intraperitoneally into each mouse and the number of painful reactions (ab-dominant torsion) is counted from the fifth to the tenth minute after injection of this solution. The results are shown in Table II below, which shows the percent inhibition of these re-actions. Table 2 mg / kg, orally The compound of Example 2 2 - 4 - 8 - 18 6 32 33 64 70 128 99 256 - DE 50, orally 40 DE 50 - the active ingredient ynAf of which R 1, R 2 and X are as defined above, in the Willgerodt reaction with the primary or secondary amine of the general formula NHR 5 R 6, where R 5 and R 6 represent leaving groups, preferably alkyl groups having 1 to 5 carbon atoms, or R 5 and R 6 together with the nitrogen atom to which they are attached form N a 5-7 membered heterocyclic group to give the thioamide of formula XI whereupon the thioamide is subjected to acid hydrolysis to give a compound of formula I wherein R 1, R 2 and X are as defined above. Severografia, n. P., Plant 7, Most