2-aryl-propionic acids and derivatives and pharmaceutical compositions containing them

1. A compound of formula (I),

wherein:

R 1 is selected from:

H and CH 3 ;

R 2 is selected from:

H and linear C 1 -C 4 -alkyl;

X is OH or a residue of formula NHR 3 :

wherein:

R 3 is selected from:

H, OH, C 1 -C 5 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 5 -alkenyl, C 1 -C 5 -alkoxy;

straight or branched C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, C 1 -C 6 -phenylalkyl, each of which is substituted with a carboxy (COOH) group; and

a residue of formula SO 2 R 4 wherein R 4 is C 1 -C 2 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 3 -haloalkyl;

Y is a heteroatom selected from:

S, O and N;

Z is a residue selected from:

halogen, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -alkoxy, hydroxy, carboxyl, C 1 -C 4 -acyloxy, phenoxy, cyano, nitro, amino, C 1 -C 4 -acylamino, halo-C 1 -C 3 -alkyl, halo-C 1 -C 3 -alkoxy, benzoyl, linear or branched C 1 -C 8 -alkanesulfonate, linear or branched C 1 -C 8 -alkanesulfonamides, and linear or branched C 1 -C 8 alkyl sulfonylmethyl;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein the carbon atom bound to the phenyl ring is in RS configuration.

3. The compound according to claim 1 ,

wherein

R 1 is CH 3 ;

R 2 is selected from

H and CH 3 ;

X is OH;

Y is selected from

S and O;

Z is selected from

halogen, C 2 -C 4 -alkenyl, C 1 -C 4 -acyloxy, phenoxy, cyano, nitro, halo-C 1 -C 3 -alkyl, benzoyl, linear or branched C 1 -C 8 -alkanesulfonate, and linear or branched C 1 -C 8 -alkanesulfonamides.

4. The compound according to claim 1 selected from:

2-[4-(4-trifluoromethylthiazol-2-yl)aminophenyl]propionic acid;

2-methyl-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid;

(2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid;

(2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid sodium salt;

2-(4-{methyl[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid;

(2S)-2-(4-{methyl[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid;

(2S)—N-hydroxy-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl) propanamide;

(2S)—N-(methylsulfonyl)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanamide;

(2S)—N-[(trifluoromethyl)sulfonyl]-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl) propanamide;

(2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl propanamide;

(2S)-2-(4-{methyl[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl) propanamide;

(2S)-2-{[(2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl) propanoyl]amino}propanoic acid;

(2S)-3-methyl-2-{[(2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoyl]amino}butanoic acid;

2-{4-[(4-trifluoromethyl)-oxazol-2-yl]amino}phenyl propionic;

(2R)-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanoic acid;

(2S)-2-(4-{methyl[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanoic acid;

(2S)—N-(methylsulfonyl)-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanamide;

(2S)-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanamide;

(2S)-2-(4-{methyl-[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanamide; and

(2S)-2-{[(2S)-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl) propanoyl]amino}propanoic acid.

5. The compound according to claim 1 which is (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid.

6. A pharmaceutical composition comprising a compound according to claim 1 in admixture with a suitable carrier thereof.

7. A method for inhibiting CXCL8 induced human PMNs chemotaxis comprising administering to a subject a pharmaceutically effective amount of a compound according to claim 1 .

8. A method for treating transient cerebral ischemia, damages caused by ischemia and reperfusion, bullous pemphigo, rheumatoid arthritis, idiopathic fibrosis or glomerulonephritis comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound according to claim 1 .

9. A process for the preparation of the compound of claim 1 comprising the steps of: converting (R,S) or (S) methyl 2-[4-(carbamothioylamino)phenyl]propanoate or (R,S) or (S) methyl 2-[4-carbamoylamino]phenyl]propanoate into the related 4-heterocycle derivative; subsequently hydrolyzing the compound obtained in the previous step to the carboxylic acid of formula (I) wherein X is OH, and reacting this carboxylic acid with sulfonamides or amines, thereby affording the compound of formula (I) when X is NHR 3 .

10. The compound according to claim 1 wherein Z is —CF 3 .

11. A compound of formula:

wherein

R 2 is selected from

H and linear C 1 -C 4 -alkyl;

X is OH or a residue of formula NHR 3

wherein

R 3 is selected from

H, OH, C 1 -C 5 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 5 -alkenyl, C 1 -C 5 -alkoxy;

straight or branched C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, C 1 -C 6 -phenylalkyl, each of which is substituted with a carboxy (COOH) group; and

a residue of formula SO 2 R 4 wherein R 4 is C 1 -C 2 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 3 -haloalkyl;

Y is a heteroatom selected from:

S, O and N;

Z is a residue selected from:

halogen, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -alkoxy, hydroxy, carboxyl, C 1 -C 4 -acyloxy, phenoxy, cyano, nitro, amino, C 1 -C 4 -acylamino, halo-C 1 -C 3 -alkyl, halo-C 1 -C 3 -alkoxy, benzoyl, linear or branched C 1 -C 8 -alkanesulfonate, linear or branched C 1 -C 8 -alkanesulfonamides, and linear or branched C 1 -C 8 alkyl sulfonylmethyl;

or a pharmaceutically acceptable salt thereof.

12. A compound, the compound being:

(2S)—N-[(1S)-2-amino-1-methyl-2-oxoethyl]-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanamide.