Compounds for the inhibition of angiogenesis and use thereof

1. A compound of the formula (I)

wherein

D is pyrrolidine,

X is a radical selected from the group consisting of C═O and (C═O)—O, wherein X is attached to the nitrogen atom of D,

Y is a radical selected from the group consisting of —OCH n —NH—(CH 2 ) n and —(CH 2 ) n -E-(CH 2 ) m -L-(CH 2 ) k

wherein E is an O radical,

k, m and n are individually and independently 0, 1, 2 and 3,

Z is an alkyl radical, wherein the alkyl is CH 2 or CH 2 CH 2 ,

A is a radical selected from the group consisting of benzyl, phenyl, and alkyl,

B is a radical having formula (II)

wherein

R 1 is H,

R 2 is selected from the group consisting of 1-methyl cyclohexyl, alkyl and, cycloalkyl, cycloalkylalkyl,

G is pyridine-2-yl, and

wherein Q and L are each and independently from each other a radical selected from the group consisting of (C═O)—NH, C═O, C═S, NH, O, S, CH 2 , NH—NH, N═N, CH═N, N═CH, NH—(C═O)—NH, NH—(C═O), O—(C═O)—NH, NH—(C═O)—O, (C═O)—O, O—(C═O), NH—(C═S), (C═S)—NH, NH—(C═S)—NH, SO 2 , NH—SO 2 , SO 2 —NH.

2. The compound according to claim 1 , wherein Z is CH 2 .

3. The compound according to claim 1 , wherein A is a phenyl group or a benzyl group having the formula (IV) or (V)

wherein R 3 , R 4 , and R 5 is each and independently a radical selected from the group consisting of H, halogen, alkyl, and alkoxy.

4. The compound according to claim 3 , wherein alkyl is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, whereby any of the residues is straight, branched, branched-linear or branched non-linear.

5. The compound according to claim 3 , wherein alkoxy is selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy.

6. The compound according to claim 3 , wherein the halogen is independently selected from the group consisting of I, Br, Cl and F.

7. The compound according to claim 1 , wherein R 2 is

8. The compound according to claim 1 , wherein Q of B is C═O.

9. The compound according to claim 1 , wherein G is 3,4,5,6-tetrahydro-pyridin-2-ylamine.

10. The compound according to claim 1 , wherein G is 4 methoxy-pyridin-2-ylamine.

11. A compound having the formula (VIII)

wherein R 10 is CO—O—R 13 or —CO—R 13 ,

wherein R 11 is pyridine-2-ylamine,

wherein R 12 is —CO—R 13 , —SO 2 —R 13 , and

wherein R 13 is a radical selected from the group consisting of alkyl, cycloalkyl, and aryl.

12. The compound according to claim 11 , whereby the compound has the formula (IX)

wherein R 14 is 3-carboxy-phenyl or 3,3-dimethyl-butyryl,

wherein R 15 is pyridin-2-ylamine or 4-methoxy-pyridin-2-ylamine,

wherein R 16 is —CO—R 17 , and

wherein R 17 1 methyl cyclohexyl.

13. A compound selected from the group consisting of

compound 91: 4-{[2-Carboxy-2-(cyclohexanecarbonyl-amino)-ethylcarbamoyl]-methoxy}-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester

compound 101: 4-({2-Carboxy-2-[(1-methyl-cyclohexanecarbonyl)-amino]-ethylcarbamoyl}-methoxy)-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester

compound 105: 4-({2-Carboxy-2-[(2-methyl-cyclohexanecarbonyl)-amino]-ethylcarbamoyl}-methoxy)-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester

compound 119: 4-{[2-Carboxy-2-(cyclopropanecarbonyl-amino)-ethylcarbamoyl]-methoxy}-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester

compound 120: 4-{[2-Carboxy-2-(2-cyclopentyl-acetylamino)-ethylcarbamoyl]-methoxy}-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester

compound 121: 4-[(2-Carboxy-2-isobutyrylamino-ethylcarbamoyl)-methoxy]-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester

compound 122: 4-{[2-Carboxy-2-(2-cyclohexyl-acetylamino)-ethylcarbamoyl]-methoxy}-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester

compound 123: 4-{[2-Carboxy-2-(2-propyl-pentanoylamino)-ethylcarbamoyl]-methoxy}-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester

compound 124: 4-{[2-Carboxy-2-(4-methyl-pentanoylamino)-ethylcarbamoyl]-methoxy}-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester

compound 125: 4-{[2-Carboxy-2-(2-cycloheptyl-acetylamino)-ethylcarbamoyl]-methoxy}-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester

compound 147: 4-({2-Carboxy-2-[(1-methyl-cyclohexanecarbonyl)-amino]-ethylcarbamoyl}-methoxy)-2-[(4-methoxy-pyridin-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acid benzyl ester

compound 148: 3-(2-{1-(3,3-Dimethyl-butyryl)-5-[(4-methoxy-pyridin-2-ylamino)-methyl]-pyrrolidin-3-yloxy}-acetylamino)-2-[(1-methyl-cyclohexanecarbonyl)-amino]-propionic acid.

14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

15. The pharmaceutical composition according to claim 14 , wherein the compound is present as a pharmaceutically acceptable salt.

16. The compound according to claim 1 , wherein n is 0, E is 0, m is 1, L is (C═O)—NH and k is 0.

17. A compound of the formula (I)

wherein

D is pyrrolidine,

X is a C═O radical, wherein X is attached to the nitrogen atom of D,

Y is a —(CH 2 ) n -E-(CH 2 ) m -L-(CH 2 ) k radical,

wherein E is an O radical, n is 0, m is 1, k is 0,

Z is an alkyl radical, wherein the alkyl is CH 2 ,

A is an alkyl radical,

B is a radical having formula (II)

wherein

R 1 is H,

R 2 is

G is 4-methoxy-pyridin-2-ylamine, and

wherein Q and L are each and independently from each other a radical selected from the group consisting of (C═O)—NH, NH and NH—(C═O), or a pharmaceutically acceptable salt thereof.

18. A compound of the formula:

or a pharmacologically acceptable salt thereof.

19. The compound according to claim 18 , wherein the compound is 3-(2-{1-(3,3-Dimethyl-butyryl)-2-[(4-methoxy-pyridin-2-ylamino)-methyl]-pyrrolidin-3-yloxy}-acetylamino)-2-[(1-methyl-cyclohexanecarbonyl)-amino]-propionic acid.

20. A pharmaceutical composition comprising a compound according to claim 18 or claim 19 and a pharmaceutically acceptable carrier, diluent or excipient.

21. A compound of the formula

or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 21 , wherein the compound is compound 148: 3-(2-{1-(3,3-Dimethyl-butyryl)-5-[(4-methoxy-pyridin-2-ylamino)-methyl]-pyrrolidin-3-yloxy}-acetylamino)-2-[(1-methyl-cyclohexanecarbonyl)-amino]-propionic acid.

23. A pharmaceutical composition comprising a compound according to claim 21 or claim 22 and a pharmaceutically acceptable carrier, diluent or excipient.