Substituted benzoylamino-indan-2-carboxylic acids and related compounds
View Patent ↗The present invention relates to novel compounds of the formula Ia: in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, wherein the substituents are as described herein. The inventive compounds have CXCR5 inhibitory activity, and are particularly useful in treating or preventing various inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, lupus, Crohn's Disease, associated with the modulation of the human CXCR5 receptor.
1. A compound of the formula Ia
wherein:
A is CH═CH;
R 23 is hydrogen, halogen, (C 1 -C 4 )-alkyl, or (C 1 -C 4 )-alkyloxy;
R 24 is hydrogen or halogen;
X is N(H)C═O;
Y is C(R 12 )═C(R 13 );
R 12 is (C 1 -C 6 )-alkyl, (C 3 -C 6 )-alkenyl, (C 4 -C 6 )-cycloalkyloxy, (C 5 -C 6 )-cycloalkyl, (C 5 -C 6 )-cycloalkenyl, (C 3 )-cycloalkyl[(C 2 )-alkyl or (C 2 )-alkenyl], (C 3 )-cycloalkyl(C 1 )-alkyloxy, (C 3 -C 4 )-alkyloxy, (C 3 )-alkenyloxy, (C 1 -C 3 )-alkyl-S—, or (C 3 )-alkylcarbonyl;
R 13 is hydrogen, halogen, or (C 1 )-alkyl;
R 21 is hydrogen;
R 22 is hydrogen, halogen, or (C 1 )-alkyl; and
R 51 is COOH;
wherein all alkyl groups herein can independently of each other be optionally substituted by one or more fluorine atoms; or
a pharmaceutically acceptable ester thereof, a stereoisomeric form thereof, mixture of stereoisomeric forms thereof in any ratio, or a physiologically acceptable salt thereof.
2. The compound according to claim 1 wherein
R 23 is hydrogen or halogen.
3. The compound according to claim 1 wherein
R 12 is (C 4 -C 6 )-alkyl.
4. The compound according to claim 1 wherein
R 12 is (C 4 )-alkenyl.
5. The compound according to claim 1 wherein
R 12 is (C 4 )-cycloalkyloxy.
6. The compound according to claim 1 wherein
R 12 is (C 5 -C 6 )-cycloalkyl.
7. The compound according to claim 1 wherein
R 12 is (C 5 -C 6 )-cycloalkenyl.
8. The compound according to claim 1 wherein
R 12 is (C 3- )-cycloalkyl[(C 2 )-alkyl or (C 2 )-alkenyl].
9. The compound according to claim 1 wherein
R 12 is (C 3 )-cycloalkyl(C 1 )-alkyloxy.
10. The compound according to claim 1 wherein
R 12 is (C 3 -C 4 )-alkyloxy.
11. The compound according to claim 1 wherein
R 12 is (C 3 )-alkenyloxy.
12. The compound according to claim 1 wherein
R 13 is halogen or (C 1 )-alkyl.
13. The compound according to claim 1 wherein
R 13 is (C 1 )-alkyl wherein the alkyl is optionally substituted by 1-3 fluorine atoms.
14. The compound according to claim 1 wherein
R 13 is unsubstituted (C 1 )-alkyl.
15. The compound according to claim 1 wherein
R 13 is (C 1 )-alkyl that is substituted by 2-3 fluorine atoms.
16. The compound according to claim 1 wherein
R 13 is halogen.
17. The compound (with Example number indicated parenthetically) according to claim 1 selected from:
2-(2-Allyloxy-3-methyl-benzoylamino)-indan-2-carboxylic acid (5),
2-(2-Isopropoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid (7),
2-(2-Cyclobutoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid (9),
2-(2-Cyclopropylmethoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid (11),
2-(2-sec-Butoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid (13),
2-(3-Chloro-2-isopropoxy-benzoylamino)-indan-2-carboxylic acid (16),
2-(2-Allyloxy-3-chloro-benzoylamino)-indan-2-carboxylic acid (18),
2-(3,5-Dichloro-2-cyclobutoxy-benzoylamino)-5-fluoro-indan-2-carboxylic acid (21),
2-(2-Isopropoxy-3-methyl-benzoylamino)-5-methoxy-indan-2-carboxylic acid (93),
2-(2-Isopropoxy-3-methyl-benzoylamino)-5-trifluoromethyl-indan-2-carboxylic acid (95),
5-Fluoro-2-(2-isopropoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid (97),
2-(2-Cyclobutoxy-3-methyl-benzoylamino)-5-trifluoro-indan-2-carboxylic acid (99),
5-Bromo-2-(2-cyclobutoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid (101),
2-(2-Cyclobutoxy-3-methyl-benzoylamino)-5-fluoro-indan-2-carboxylic acid (103),
2-(2-Cyclobutoxy-3-methyl-benzoylamino)-5,6-difluoro-indan-2-carboxylic acid (105),
2-[3-Methyl-2-((Z)-pent-1-enyl)-benzoylamino]-indan-2-carboxylic acid (125),
2-(3-Methyl-2-pentyl-benzoylamino)-indan-2-carboxylic acid (127),
2-[2-(-1-Ethyl-but-1-enyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid (129),
2-[2-(1-Ethyl-butyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid (130),
2-(2-Cyclopent-1-enyl-3-methyl-benzoylamino)-indan-2-carboxylic acid (132),
2-(2-Cyclopentyl-3-methyl-benzoylamino)-indan-2-carboxylic acid (133),
2-[3-Methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (135),
2-(2-Isobutyl-3-methyl-benzoylamino)-indan-2-carboxylic acid (136),
2-[2-(-2-Cyclopropyl-vinyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid (138),
2-[2-(2-Cyclopropyl-ethyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid (139),
2-(2-Cyclohex-1-enyl-3-methyl-benzoylamino)-indan-2-carboxylic acid (141),
2-[3-Methyl-2-(1-propenyl)-benzoylamino]-indan-2-carboxylic acid (143),
2-(3-Methyl-2-propyl-benzoylamino)-indan-2-carboxylic acid (144),
2-[3-Methyl-2-((E)-pent-1-enyl)-benzoylamino]-indan-2-carboxylic acid (146),
5-Fluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (149),
5-Fluoro-2-(2-isobutyl-3-methyl-benzoylamino)-indan-2-carboxylic acid (150, 155),
2-(2-Cyclopent-1-enyl-3-methyl-benzoylamino)-5-fluoro-indan-2-carboxylic acid (152),
5-Fluoro-2-[3-methyl-2-((E)-propenyl)-benzoylamino]-indan-2-carboxylic acid (154),
5,6-Difluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (158),
5,6-Difluoro-2-(2-isobutyl-3-methyl-benzoylamino)-indan-2-carboxylic acid (159),
5,6-Difluoro-2-(3-methyl-2-propenyl-benzoylamino)-indan-2-carboxylic acid (160),
5,6-Difluoro-2-(3-methyl-2-propyl-benzoylamino)-indan-2-carboxylic acid (161),
5-Bromo-2-[3-methyl-2-((E)-propenyl)-benzoylamino]-indan-2-carboxylic acid (163),
2-(5-Chloro-2-cyclobutoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid (212),
2-(2-Isobutyryl-3-methyl-benzoylamino)-indan-2-carboxylic acid (229),
2-[2-(1,1-Dimethyl-propyl)-benzoylamino]-indan-2-carboxylic acid (248),
2-(2-Cyclobutoxy-3-methyl-benzoylamino)-4,5-dichloro-indan-2-carboxylic acid (256),
2-(2-Cyclobutoxy-3-methyl-benzoylamino)-5-chloro-indan-2-carboxylic acid (262),
2-(2-Cyclobutoxy-3-methyl-benzoylamino)-4-fluoro-indan-2-carboxylic acid (267),
2-(5-Bromo-2-cyclobutoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid (319),
2-(2-Isopropylsulfanyl-benzoylamino)-indan-2-carboxylic acid (327),
2-(5-Chloro-2-cyclobutoxy-3-methyl-benzoylamino)-5-fluoro-indan-2-carboxylic acid (329),
4,5-Difluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (388),
4,5-Difluoro-2-(2-isobutyl-3-methyl-benzoylamino)-indan-2-carboxylic acid (389),
4,7-Difluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (392),
4,7-Difluoro-2-(2-isobutyl-3-methyl-benzoylamino)-indan-2-carboxylic acid (393),
5-Chloro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (395), and
2-[2-(2-Methyl-propenyl)-3-trifluoromethyl-benzoylamino]-indan-2-carboxylic acid (397), or
a pharmaceutically acceptable ester thereof, a stereoisomeric form thereof, mixture of stereoisomeric forms thereof in any ratio, or a physiologically acceptable salt thereof.
18. The compound according to claim 1 of the following structure
19. The compound according to claim 1 of the following structure
20. A pharmaceutical composition comprising a pharmaceutically acceptable amount of a compound according to claim 1 and at least one of a pharmaceutically acceptable excipient and pharmaceutically acceptable carrier.