IL41630A - Quinolineacetic acid derivatives,their manufacture and pharmaceutical compositions containing them - Google Patents

Claims (9)

1. WHAT WE CLAIM IS: 1. Process for the manufacture of quinolineacetic compounds of the wherein Ar denotes phenyl, thienyl or phenyl substituted by halogen, R^, and independently of one another denote hydrogen or a lower alkyl group, and esters of these carboxy- lic acids or salts of such compounds, characterised in that a) in a compound of the formula wherein X represents a radical which can be converted into an optionally esterified group of the formula -CH(R^)-C(=0)-0H, X is converted into an optionally esterified group of the formula -CH(R~) -C (=0)-0H, or b) an aniline derivative of the formula ft CH—C00H (i ) 41630-or an ester thereof relative to the carboxyl group is condensed with a compound of the formula Ar-Z? (IV), in which Z-j^ and denote radicals which together with the aniline radical can form the desired quinoline ring and, if desired, a resulting compound is converted, within the defined scope, into another compound of the invention, and/or if desired, a resulting free compound is converted into a salt or a resulting salt into the free compound and/or, if desired, a resulting isomer mixture is separated into the individual isomers.

2. Process according to Claim 1, characterised in that in a compound of the formula II, wherein X represents a radical of the formula -CH(R^)-X-L, wherein X-j_ represents a nitrile group, an optionally substituted thiocarbamoyl group, an etherified hydroxyl or mercaptoformimidoyl group, a trihalogenomethyl group or tri-lower alkoxymethyl group, X^ is hydrolysed to give an optionally esterified .--carboxyl group.

3. Process according to Claim 1, characterised in that a compound of the formula II, wherein X denotes a group of the formula -CH(R^)-X2, in which X2 denotes a metallic radical, is treated with a functional derivative of carbonic acid.

4. Process according to Claim 1, characterised in that a compound of the formula II, wherein X is a group of the formula -CH(R^)-X^, wherein X^ represents an optionally etherified hydroxyl group, is treated with carbon monoxide or with formic acid or a reactive functional derivative thereof. 41630-2

5. Process according to Claim 1, characterised in that a compound of the formula II wherein X represents a group of the formula -CH(R^)-CH0 is oxidised.

6. Process according to Claim 1, characterised in that in a compound of the formula II wherein X denotes an optionally esterified group of the formula -C (=R°) -C (=0) -OH, in which R° represents a lower alkylidene group, R^ is reduced to a lower alkyl group. Process according to Claim 1, characterised in that a compound of the formula II, wherein X is an optionally esterified group of .the formula -C(R^) (X^)-C- (=0)-0H, in which X^ denotes a carboxyl group, is decarboxylated. 8. Process according to Claim 1, characterised in that a compound of the formula II, wherein X denotes a group of the formula -CH(R^)-Xg, in which Xg represents an optionally esterified carboxycarbonyl group, is de- carbonylated. 9 Process according to Claim 1, characterised in that a compound of the formula II, wherein X represents a group of the formula -C(=0)-C(N2)-R^, is reacted with water or an alcohol. 10. Process according to Claim 1, characterised in that a compound of the formula III, wherein denotes a hydrogen atom, is condensed with a compound of the formula IV, wherein Z2 represents a radical of the formula -CH=C(R2)- C(R£)=0, in which one of the groups R and R£ denotes hydrogen and the other corresponds to the definition of R2 in Claim 1. 41630-2 ^*- Process according to Claim 1, characterised in that a compound of the formula III, wherein denotes the group of the formula -C0R£, is condensed with a compound of the formula IV, wherein ∑2 denotes the group of the formula -COCi^R^, in which one of the groups R and R denotes hydrogen and the other corresponds to the definition of R2 in Claim 1. 12.- Process according to Claim 1, characterised in that a compound of the formula III, wherein Z-^ denotes the group Cf^ ^* i-s condensed with a compound of the formula IV, wherein denotes the group in which one of the groups R and R^ denotes hydrogen and the other corresponds to the definition of R2 Jji Claim 1. 1-3. Process according to one of Claim 1-12,, characterised in that resulting esters are hydrolysed to the free acids. 14. Process according to one of Claims 1-13, characterised in that in a resulting compound with a free carboxyl group, the latter is converted into an esterified carboxyl group. 15. Process according to one of Claims 1-14, characterised in that resulting esters or salts having a hydrogen atom in the a-position are metallised and alkylated with a reactive ester of a lower alkanol. 16. Process according to one of Claims 1-14, characterised in that a compound formed as an intermediate product at any stage is used as the starting material and 41630-2 the remaining stage or stages is or are carried out therewith, or that the process is interrupted at any stage. 17T Process according to one of Claims 1-16, characterised in that starting substances are formed under the reaction conditions or are used in the form of salts or reactive derivatives. 18". Process according to one of Claims 1-17, character! sed in that compounds of the formula I, in which Ar has the meaning given in claim 1, R^, and R^ independently of one another denote hydrogen or lower alkyl with at most 4 carbon atoms and one of the groups -CH(R^)C00H and occupies the 6-position and the other 8-position and the group R? occupies the 4-position, lower alkyl esters with at most 4 carbon atoms, as well as salts of these compounds, are manufactured . 19. Process according to one of Claims 1-17, character! sed in that compounds of the formula I, wherein Ar has the meaning given in claim 1, R^ denotes hydrogen, R2 denotes hydrogen or methyl in the 4-position and R^ denotes hydrogen or methyl and wherein the -CH(R.-.)C00H group occupies the 6-position, methyl esters of these acids and their salts with bases, are manufactured. 20. Process according to one of Claims 1-13 and 15-19," characterised . in that 2-phenyl-6-quinolineacetic acid, or salts thereof, are manufactured. 41630 - 2 21. Process according to 1-19 ," ' -characterised in that a-methyl-2-phenyl-6-quinolineacetic acid, its methyl ester or salts thereof are manufactured. 22 . Process according to Claims 1-19 , characterised in that a-methyl-2-(p-chlorophenyl)-6-quinolineacetic acid, its methyl ester or salts thereof are manufactured. 23 . Process according to Claims 1-19 , recharacterised in that a-methyl-2-(p-fluorophenyl)-6-quinolineacetic acid, its methyl ester or salts thereof are manufactured. 24 ; Process according to Claims 1-19 , characterised in that a-methyl-2-(2-thienyl)-6-quinoline-acetic acid, its methyl ester or salts thereof are manufactured. 25. Process according to Claims 1-13 and 15-19 , characterised in that 2-(p-chlorophenyl)-6-quinolineacetic acid or salts thereof are manufactured. 6: Process according to Claims 1- 13 and 15-19 , characterised in that 2-(p-fluorophenyl)-6-quinolineacetic acid or. salts thereof are manufactured. 2

7. Process according to Claims 1- 13 anχ_ 15- 19 , characterised in that 2-(2-thienyl)-6-quinolineacetic acid or salts thereof are manufactured. 2

8 . Process according to Claims 1- 13 and 15-19 , characterised in that 4, a-dimethyl-2-(2-thienyl)-6-quinolineacetic acid is manufactured. ■"29-. The compounds obtainable according to the process of Claims 1-28 _ ··· .'·- Quinolineacetic acid compounds of the formula wherein Ar denotes phenyl, thienyl or phenyl substituted by halogen, R^, R2 and R^ independently of one another denote hydrogen or a lower alkyl group, and esters of these carboxylic acids and salts of these compounds. 31. Compounds of the formula I, according to Claim 30, in which Ar has the meaning given in claim 30, R^, an R^ independently of one another denote hydrogen or lower alkyl with at most 4 carbon atoms, and wherein one of the groups -CHCR^COOH and R^ occupies the 6-position and the other the 8-position and and the group R occupies the 4-position, lower alkyl esters with at most 4 carbon atoms, as well as salts of these compounds. 32. Compounds of the formula I, according to Claim 30, wherein Ar has the meaning given in claim 30, R^ denotes hydrogen, R2 denotes hydrogen or methyl in the 4-position and R^ denotes hydrogen or methyl, and wherein the -CH(R.j)C00H group occupies the 6-position, methyl esters of these acids and their salts with bases. 33. a-Methyl-2-phenyl-6-quinolineacetic acid methyl ester -aooording to 9no-ea£__Claimc 30-32. 34.- -Methyl-2~(p-chlorophenyl)-6-quinolineacetic acid methyl ester. 35. α-Kethyl-2-(p-fluorophenyl)-6-quinollneacetic acid methyl ester. 36. a-Methyl-2-(2-thienyl)-6-quinolineacetie acid methyl ester. 37. 2-Phenyl-6-quinolineacetie acid. 38. 2-(p-Chlorophenyl)-6-quinolineacetic acid. 3

9. 2-(p-Fluorophenyl)-6-quinolineacetic acid. 40. 2-(2-Thieny1)-6-quinolineacetic acid. 41. a-Methyl-2-phenyl-6-quinolineacetic acid. 4 . a-Methyl-2-(p-chlorophenyl)-6-quinolineacetic acid. 43· a-Methyl-2-(p- luorophenyl)-6-quinolineacetie acid. 44. α-Μβthy1-2-(2-t enyl)-6-quinolineacetic acid. 45. 4 ,a-Dimethyl-2-(2-thien l)-6-quinolineacetic acid. 46. Salts of the compounds of Claims 37 to 45· 47. Pharmaceutically usable salts of compounds of Claims 3¾ to 45. 48. Pharmaceutical preparations characterised ^i that they contain one of the compounds indicated in Claims PARTKERS