N-hydroxyamide derivatives and use thereof
View Patent ↗The present invention is related to N-hydroxyamide derivatives of Formula (I) and use thereof in particular for the treatment and/or prophylaxis of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, cancer, respiratory diseases and fibrosis, including multiple sclerosis, arthritis, emphysema, chronic obstructive pulmonary disease, liver and pulmonary fibrosis.
1. A N-hydroxyamide according to Formula (I),
wherein:
A is —C(B)—;
B is B forms a bond with either R 5 or R 7 ;
R 1 is selected from C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, aryl, pyridinyl, pyrazinyl, thiadiazolyl, pyrimidinyl, oxadiazolyl, quinolinyl, thienyl, benzofuranyl, amino and alkoxy;
R 2 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 -cycloalkyl, and aryl;
R 3 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl;
R 4 , R 5 , R 6 and R 7 are independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; or R 4 and R 7 form together a —CH 2 — linkage;
n is an integer selected from 1, 2, 3, 4, 5 and 6;
wherein R 1 -R 7 may be substituted by from 1 to 5 substituents selected from the group consisting of C 1 -C 6 -alkyl, amino, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro;
Carbons (2) and (3) are two chiral centers, wherein chiral center (2) has a configuration selected from “S” and “R” and wherein chiral center (3) has a “S” configuration as well as pharmaceutically acceptable salts thereof.
2. A N-hydroxyamide according to claim 1 , wherein R 1 is selected from aryl, pyridinyl, pyrazinyl, thiadiazolyl, pyrimidinyl, oxadiazolyl, quinolinyl, thienyl, and benzofuranyl.
3. A N-hydroxyamide according to claim 1 wherein R 2 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl.
4. A N-hydroxyamide according to claim 1 wherein R 2 is aryl.
5. A N-hydroxyamide according to claim 1 wherein R 2 is selected from optionally substituted C 3 -C 8 -cycloalkyl.
6. A N-hydroxyamide according to claim 1 wherein R 3 is H.
7. A N-hydroxyamide according to claim 1 wherein R 4 , R 5 and R 7 are H.
8. A N-hydroxyamide according to claim 1 wherein R 6 is selected from H and C 1 -C 6 alkyl.
9. A N-hydroxyamide according to claim 1 wherein R 5 and R 6 are H and R 4 and R 7 can form together a —CH 2 — linkage.
10. A N-hydroxyamide according to claim 1 wherein the configuration of the chiral carbons is (2S), (3S).
11. A N-hydroxyamide according to claim 1 wherein the configuration of the chiral carbons is (2R), (3S).
12. A N-hydroxyamide according to claim 1 having a Formula (Ib):
wherein A is a carbon atom;
R 1 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, pyridinyl, pyrazinyl, thiadiazolyl, pyrimidinyl, oxadiazolyl, quinolinyl, thienyl, benzofuranyl, amino and alkoxy;
R 2 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 -cycloalkyl, and aryl;
R 3 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl;
R 4 , R 6 and R 7 are independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; or R 4 and R 7 form together a —CH 2 — linkage;
n is an integer selected from 1, 2, 3, 4, 5 and 6;
Carbons (2) and (3) are two chiral centers, wherein chiral center (2) has a configuration selected from “S” and “R” and wherein chiral center (3) has a “S” configuration as well as pharmaceutically acceptable salts thereof.
13. A N-hydroxyamide according to claim 12 wherein R 1 is selected from aryl and R 3 , R 4 , R 5 , R 6 and R 7 are H.
14. A pharmaceutical composition comprising at least one N-hydroxyamide according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
15. A process for the preparation of a N-hydroxyamide according to claim 1 , comprising reacting a compound of Formula (IV) with H 2 N—O—R 8 :
wherein A, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and n are as defined in claim 1 and R 8 is selected from H and a protective group selected from t-butyl, benzyl, trialkylsilyl, tetrahydropyranyl.
16. A process for the preparation of a N-hydroxyamide according to claim 1 , comprising reacting a compound of Formula (V) with H 2 N—O—R 8 :
wherein A, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and n are as defined in claim 1 and R 8 is selected from H and a protective group.
17. A process according to claim 15 , further comprising removing the protecting group of R 8 when R 8 is a protective group.
18. A process for the preparation of a N-hydroxyamide according to claim 15 , further comprising reacting a compound of Formula (II) with an amine of Formula (III) to form the intermediate of Formula (IV), optionally in presence of a coupling agent selected from DIC, EDC, TBTU, DCC, HATU, PyBOP®, Isobutyl chloroformate and 1-methyl-2-chloropyridinium iodide
wherein A, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and n are as defined in claim 15 ; G is a group selected from OH and Cl.
19. A compound according to Formula (IV):
wherein A is —C(B)—;
B forms a bond with either R 5 or R 7 ;
R 1 is selected from C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, aryl, pyridinyl, pyrazinyl, thiadiazolyl, pyrimidinyl, oxadiazolyl, quinolinyl, thienyl, benzofuranyl, amino and alkoxy;
R 2 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 -cycloalkyl, and aryl;
R 4 , R 5 , R 6 and Rare independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; or R 4 and R 7 form together a —CH 2 — linkage;
n is an integer selected from 1, 2, 3, 4, 5 and 6;
wherein R 2 , R 4 , R 5 , R 6 and R 7 may be substituted by from 1 to 5 substituents selected from the group consisting of C 1 -C 6 -alkyl, amino, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro.
20. A compound according to Formula (V):
wherein
A is —C(B)—;
B forms a bond with either R 5 or R 7 ;
R 1 is selected from C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, aryl, pyridinyl, pyrazinyl, thiadiazolyl, pyrimidinyl, oxadiazolyl, quinolinyl, thienyl, benzofuranyl, amino and alkoxy;
R 2 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 -cycloalkyl, and aryl;
R 4 , R 5 , R 6 and R 7 are independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; or R 4 and R 7 form together a —CH 2 — linkage;
n is an integer selected from 1, 2, 3, 4, 5 and 6;
wherein R 2 , R 4 , R 5 , R 6 and R 7 may be substituted by from 1 to 5 substituents selected from the group consisting of C 1 -C 6 -alkyl, amino, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro.