2-aminocarbonyl-pyridine derivatives

1. A compound of formula I

wherein

R 1 represents an imidazolyl, pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl ring, which ring may be substituted by a methyl group, or also R 1 represents phenyl optionally substituted 1 to 3 times by substituents each independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl and trifluoromethoxy;

W represents a bond and R 2 represents hydrogen, halogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl or heteroaryl; or

W represents —O— or —S— and R 2 represents alkyl, cycloalkyl, aryl or heterocyclyl; or

W represents —NR 3 —, R 2 represents alkyl, hydroxyalkyl or alkoxyalkyl and R 3 represents hydrogen or alkyl; or

W represents —C≡C— and R 2 represents hydroxyalkyl or alkoxyalkyl; or

W represents —NR 3 — and R 2 and R 3 form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7 members wherein the members needed to complete said heterocyclic ring are each independently selected from —CH 2 — and —CHR x —, it being understood however that said heterocyclic ring does not contain more than one —CHR x — member, R x representing hydroxy, hydroxymethyl, alkoxymethyl or alkoxy; or also

W represents —NR 3 — and R 2 and R 3 form, together with the nitrogen that carries them, an imidazolyl, pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl ring, which ring is optionally substituted by a methyl group;

R a represents hydrogen or fluorine and R b represents hydrogen, or R a represents hydrogen and R b represents alkoxy;

each of R 4 and R 5 represents independently hydrogen or methyl;

R 6 represents alkoxy; and

Y represents alkylene or phenylalkylene, and Z represents —OH, —COOH, cyano, tetrazolyl or —COOR 7 , R 7 representing alkyl;

it being understood that:

when R a represents fluorine then: i) R 1 represents phenyl optionally substituted once by fluorine, methyl, methoxy, trifluoromethyl or trifluoromethoxy, ii) W does not represent —O— or —S—, and iii) if W is a bond, then R 2 does not represent hydrogen;

in free or salt form.

2. The compound according to formula I as defined in claim 1 , which is also a compound of formula I P

wherein

R 1 represents phenyl optionally substituted once by a substituent selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl and trifluoromethoxy;

W represents a bond and R 2 represents hydrogen, halogen, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl or heteroaryl; or

W represents —O— or —S— and R 2 represents alkyl, cycloalkyl, aryl or heterocyclyl; or

W represents —NR 3 —, R 2 represents alkyl, hydroxyalkyl or alkoxyalkyl and R 3 represents hydrogen or alkyl; or

W represents —C≡C— and R 2 represents hydroxyalkyl or alkoxyalkyl; or

W represents —NR 3 — and R 2 and R 3 form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7 members wherein the members needed to complete said heterocyclic ring are each independently selected from —CH 2 — and —CHR x —, it being understood however that said heterocyclic ring does not contain more than one —CHR x — member, R x representing hydroxy, hydroxymethyl, alkoxymethyl or alkoxy; or also

W represents —NR 3 — and R 2 and R 3 form, together with the nitrogen that carries them, an imidazolyl, pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl ring, which ring is optionally substituted by a methyl group;

each of R 4 and R 5 represents independently hydrogen or methyl;

R 6 represents alkoxy; and

Y represents alkylene or phenylalkylene, and Z represents —OH, —COOH, cyano, tetrazolyl or —COOR 7 , R 7 representing alkyl;

in free or salt form.

3. The compound according to claim 1 , wherein W represents a bond in free or salt form.

4. The compound according to claim 1 , wherein W represents —O— in free or salt form.

5. The compound according to claim 1 , wherein W represents —S— in free or salt form.

6. The compound according to claim 1 , wherein W represents —NR 3 — in free or salt form.

7. The compound according to claim 1 , wherein W represents —C≡C— in free or salt form.

8. The compound according to claim 1 , wherein R 1 represents phenyl optionally substituted once by a substituent selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl and trifluoromethoxy in free or salt form.

9. The compound according to claim 1 , wherein Y represents alkylene or phenylalkylene and Z represents —COOH in free or salt form.

10. The compound according to claim 1 , wherein R 2 represents fluorine and R b represents hydrogen in free or salt form.

11. The compound according to claim 1 , which is selected from the group consisting of:

4-{(S)-4-carboxy-2-[(4-chloro-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4-cyclopentyloxy-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-(1-hydroxy-1-methyl-ethyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4,6-diphenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(6-phenyl-4-pyrazol-1-yl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-(4-methoxy-phenyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-cyclopropyl-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-2-[(4-butyl-6-phenyl-pyridine-2-carbonyl)-amino]-4-carboxy-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-(2-fluoro-phenyl)-4-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-(4-fluoro-phenyl)-4-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4-phenyl-6-o-tolyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4-phenyl-6-p-tolyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-((R)-3-hydroxy-pyrrolidin-1-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4-hydroxy-6′-phenyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(6-phenyl-4-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-(2-hydroxy-ethylamino)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-((S)-3-methoxy-pyrrolidin-1-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4-isopropylamino-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-(2-methoxymethyl-cyclopropyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-(2-hydroxymethyl-cyclopropyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-3-cyano-2-[(4,6-diphenyl-pyridine-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4,6-diphenyl-pyridine-2-carbonyl)-amino]-butyryl}-3-methyl-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-2-[(4,6-diphenyl-pyridine-2-carbonyl)-amino]-3-hydroxy-propionyl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4-phenyl-6-pyrazol-1-yl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-(3-hydroxy-propyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-(3-hydroxy-3-methyl-but-1-ynyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-(3-hydroxy-3-methyl-butyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-(4-hydroxy-cyclohexyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(6-phenyl-4-phenylsulfanyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-(2-hydroxy-cyclohexyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(6-phenyl-4-thiophen-3-yl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4-furan-3-yl-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4-isopropylsulfanyl-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-3-(4-carboxy-phenyl)-2-{[4-(2-methoxymethyl-cyclopropyl)-6-phenyl-pyridine-2-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(4-methyl-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-phenyl-4-(tetrahydro-furan-3-yloxy)-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-carboxy-2-[(6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-O-tert-butoxycarbonyl-2-[(4-chloro-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4-cyclopentyloxy-6-phenyl-pyridine-2 carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-(1-hydroxy-1-methyl-ethyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4,6-diphenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(6-phenyl-4-pyrazol-1-yl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-(4-methoxy-phenyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-cyclopropyl-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4-butyl-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-O-tert-butoxycarbonyl-2-[(4-[(R)-3-hydroxy-pyrrolidin-1-yl]-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4-hydroxy-6′-phenyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(6-phenyl-4-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-(2-hydroxy-ethylamino)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-((S)-3-methoxy-pyrrolidin-1-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4-isopropylamino-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-(2-methoxymethyl-cyclopropyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-(2-hydroxymethyl-cyclopropyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4,6-diphenyl-pyridine-2-carbonyl)-amino]-butyryl}-3-methyl-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4-phenyl-6-pyrazol-1-yl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-(3-hydroxy-propyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-(3-hydroxy-3-methyl-but-1-ynyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-(3-hydroxy-3-methyl-butyl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(6-phenyl-4-phenylsulfanyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(6-phenyl-4-thiophen-3-yl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4-furan-3-yl-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4-isopropylsulfanyl-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-3-(4-tert-butoxycarbonyl-phenyl)-2-{[4-(2-methoxymethyl-cyclopropyl)-6-phenyl-pyridine-2-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-2-[(4,6-diphenyl-pyridine-2-carbonyl)-amino]-3-(2H-tetrazol-5-yl)-propionyl]-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[4-((S)-3-methoxy-pyrrolidin-1-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid butyl ester;

4-((S)-3-hydroxy-2-{[4-((S)-3-methoxy-pyrrolidin-1-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester;

4-((S)-2-{[4-((S)-3-methoxy-pyrrolidin-1-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-3-methyl-butyryl)-piperazine-1-carboxylic acid butyl ester;

4-((S)-4-carboxy-2-{[5-fluoro-4-((S)-3-methoxy-pyrrolidin-1-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid butyl ester;

4-{(S)-4-carboxy-2-[(4-cyclopropyl-3-methoxy-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[4-((S)-3-methoxy-pyrrolidin-1-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid butyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[5-fluoro-4-(3-methoxy-pyrrolidin-1-yl)-6-phenyl-pyridine-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid butyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4-cyclopropyl-3-methoxy-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(5)-2-[(4-butylamino-5-fluoro-6-phenyl-pyridine-2-carbonyl)-amino]-4-carboxy-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-{(5)-2-[(4-butylamino-5-fluoro-6-phenyl-pyridine-2-carbonyl)-amino]-4-carboxy-butyryl}-piperazine-1-carboxylic acid butyl ester;

4-{(S)-4-tert-butoxycarbonyl-2-[(4-chloro-5-fluoro-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester; and

4-{(S)-4-tert-butoxycarbonyl-2-[(4-chloro-5-fluoro-6-phenyl-pyridine-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester;

in free or a pharmaceutically acceptable salt form.

12. A pharmaceutical composition containing at least one compound of formula I as defined in claim 1 , in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier, diluent or excipient.

13. A method for treating myocardial infarction, arterial thrombosis, transient ischaemic attacks, peripheral vascular disease and stable or unstable angina, comprising administering to a patient in need thereof an effective amount of a compound of formula I as defined in claim 1 , in free or pharmaceutically acceptable salt form.

14. A method for treating thrombosis, comprising administering to patient in need thereof an effective amount of a compound of formula I as defined in claim 1 , in free or pharmaceutically acceptable salt form.

15. The compound according to claim 2 , wherein

R 1 represents phenyl optionally substituted once by halogen or methyl;

W represents a bond and R 2 represents hydroxyalkyl, alkoxyalkyl or cycloalkyl optionally substituted once by a member of the group consisting of hydroxy, hydroxymethyl, methoxymethyl, methoxy and ethoxy; or

W represents —O— or —S— and R 2 represents heterocyclyl; or

W represents —NR 3 —, R 2 represents hydroxyalkyl or alkoxyalkyl and R 3 represents hydrogen; or

W represents —C≡C— and R 2 represents hydroxyalkyl or alkoxyalkyl; or

W represents —NR 3 — and R 2 and R 3 form, together with the nitrogen that carries them, a heterocyclic ring of 4 to 7 members wherein the members needed to complete said heterocyclic ring are each independently selected from —CH 2 — and —CHR x —, it being understood however that said heterocyclic ring does not contain more than one —CHR x — member, R x representing hydroxy, hydroxymethyl, alkoxymethyl, methoxy or ethoxy; or also

W represents —NR 3 — and R 2 and R 3 form, together with the nitrogen that carries them, an imidazolyl, pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl ring;

one of R 4 and R 5 represents hydrogen or methyl and the other represents hydrogen;

Y represents alkylene or phenylalkylene and Z represents —COON;

in free or salt form.

16. A method for treating myocardial infarction, arterial thrombosis, transient ischaemic attacks, peripheral vascular disease and stable or unstable angina, comprising administering to a patient in need thereof an effective amount of a compound of formula I P as defined in claim 15 , in free or pharmaceutically acceptable salt form.

17. A method for treating thrombosis, comprising administering to patient in need thereof an effective amount of a compound of formula I P as defined in claim 15 , in free or pharmaceutically acceptable salt form.