5-substituted quinoline and isoquinoline derivatives, a process for their production and their use as anti-inflammatory agents

1. A compound of formula (IIa) or (IIb)

in which

R 1 and R 2 , independently of one another, mean a hydrogen atom, a C 1-3 -alkyl group, a halogen atom, a cyano group, a C 1-3 -alkoxy group or a hydroxy group, or a racemate or a separately present stereoisomer thereof or a physiologically compatible salt thereof.

2. A compound of formula (IIa) or (IIb)

in which

R 1 and R 2 , independently of one another, mean a hydrogen atom, a C 1-3 -alkyl group, a halogen atom, a cyano, a C 1-3 -alkoxy or a hydroxy group, or a racemate or a separately present stereoisomer thereof or a physiologically compatible salt or prodrug thereof.

3. The compound according to claim 1 , which is 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-2-methylquinoline.

4. The compound according to claim 1 , which is 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-1-methylisoquinoline.

5. The compound according to claim 1 , which is 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]isoquinol-1(2H)-one.

6. The compound according to claim 1 , which is 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-2,6-dimethylquinoline.

7. The compound according to claim 1 , which is 5-[4-(5-fluoro-2,3-dihydrohenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluorolnethyl-pentylamino]-6-chloro-2-methylquinoline.

8. The compound according to claim 1 , which is 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]isoquinoline.

9. The compound according to claim 1 , which is 5-[4-(5-fluoro-2,3-dihydrohenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]quinoline.

10. The compound according to claim 1 , which is 5-[4-(2,3-dihydro-5-fluoro-7-benzofuranyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]quinolin-2[1H]-one.

11. The compound according to claim 1 , which is 6-fluoro-5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-2-methylquinoline.

12. The compound according to claim 1 , which is 8-fluoro-5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-2-methylquinoline.

13. The compound according to claim 1 , which is 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-2-methylisoquinol-1(2H)-one.

14. The (+)-enantiomer of the compound according to claim 3 .

15. The (−)-enantiomer of the compound according to claim 3 .

16. A process for preparing a compound of formula IIa or IIb according to claim 1 comprising reacting isobutene in the presence of a Lewis acid catalyst with trifluoroalkyl pyruvate to form a compound of formula XII

wherein R 3 means C 1 -C 5 -alkyl, the compound of formula XII is optionally subjected to an enantiomer separation and then is reacted as a chiral compound or as a racemate with 5-fluoro-2,3-dihydrobenzofuran

in a Friedel Crafts alkylation reaction to form a compound of formula X

which is optionally subjected to an enantiomer separation,

the compound of formula X— as a chiral compound or as a racemate—is either

reduced to form the alcohol of formula XI

and then oxidized to form the aldehyde of formula III

or

compound X is reduced directly to form the aldehyde of formula III and then reacted to form the compound of formula IIa or IIb under conditions of reductive amination, optionally in two stages, with a 5-aminoquinoline derivative or with a 5-aminoisoquinoline derivative of one of the following formulae

17. The process according to claim 16 , wherein the enantiomer separation is carried out by column chromatography on a chiral phase.

18. The process according to claim 16 , wherein a racemic intermediate stage from the synthesis is converted using a chiral adjuvant either into a diastereomer salt or into a diastereomer, then the diastereomer separation is performed, and a chiral auxiliary reagent is cleaved again.

19. The process according to claim 16 , wherein an enantiomer separation is carried out at a stage of a compound of formula III, IV, V, VI, VII, VIII, IX, X or XI

20. The process according to claim 18 , wherein the chiral adjuvant is a chiral base, chiral diol, chiral alcohol or chiral acid.

21. A process for preparing a compound of formula IIa and or IIb according to claim 1 , comprising reacting an aldehyde of formula III

under conditions of reductive amination, optionally in two stages, with a 5-aminoquinoline derivative or with a 5-aminoisoquinoline derivative of one of the following formulae

in which

R 1 and R 2 , independently of one another, mean a hydrogen atom, a C 1-3 -alkyl group, a halogen atom, a cyano group, a C 1-3 -alkoxy group or a hydroxy group.

22. The process according to claim 21 , wherein the compound of formula III is obtained either

by reduction of a compound of formula X—used as a chiral compound or as a racemate—

in which R 3 means C 1 -C 5 -alkyl, to form the alcohol of formula XI

and subsequent oxidation to form the aldehyde of formula III

or

by reduction of compound X—used as a chiral compound or as a racemate—directly to form the aldehyde of formula III

23. The process according to claim 22 , wherein the compound of formula X is obtained from a compound of formula XII

wherein R 3 means C 1 -C 5 -alkyl, the compound of formula XII is optionally subjected to an enantiomer separation, then reacted as a chiral compound or as a racemate with 5-fluoro-2,3-dihydrobenzofuran

in a Friedel-Crafts alkylation reaction to form a compound of formula X

which is optionally subjected to an enantiomer separation.

24. The process according to claim 23 , wherein the compound of formula XII is obtained by reacting isobutene in the presence of a Lewis acid catalyst with trifluoroalkyl pyruvate to form the compound of formula XII

wherein R 3 means C 1 -C 5 -alkyl,

the compound of formula XII is optionally subjected to an enantiomer separation.

25. The process according to claim 16 , wherein the Lewis acid catalyst is chiral.

26. The process according to claim 14 , wherein the starting materials are used in a chiral manner.

27. The process according to claim 22 , wherein the intermediate products that are obtained in each case are subjected to an enantiomer separation or, after reaction with chiral adjuvants, to a diastereomer separation.

28. A method for treating an inflammatory disease comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

29. A method according to claim 28 , wherein the compound is administered locally.

30. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition according to claim 30 , which is suitable for local administration.

32. A compound according to claim 1 , which is a salt of a compound of formula IIa or IIb.