N-hydroxyamide derivatives and use thereof
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. An N-hydroxyamide derivative according to Formula (I),
wherein:
A is N;
R 1 is selected from pyridinyl, pyrazinyl, thiadiazolyl, pyrimidinyl, oxadiazolyl, quinolinyl, thienyl and benzofuranyl;
R 2 is H;
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, wherein R l and R 3 -R 7 are unsubstituted or substituted with 1 to 5 substituents selected from C 1 -C 6 alkyl, amino, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto or nitro;
or an enantiomer, diastereomer, racemate, or a pharmaceutically acceptable salt thereof.
2. An N-hydroxyamide derivative according to claim 1 , wherein R 3 is H.
3. An N-hydroxyamide derivative according to claim 1 wherein R 5 , R 6 and R 7 are H.
4. An N-hydroxyamide derivative according to claim 1 wherein R 4 is selected from H and methyl.
5. An N-hydroxyamide derivative according to claim 1 wherein R 2 , R 3 , R 5 , R 6 and R 7 are H; and R 4 is selected from H and methyl.
6. A method of treating a subject with a matrix metalloproteinase (MMP) associated disease or disorder, comprising administering to the subject an effective amount of a compound according to claim 1 , wherein the metalloproteinase is MMP-9, MMP-2 or MMP-12, and the matrix metalloproteinase (MMP) associated disease or disorder is multiple sclerosis or chronic obstructive pulmonary disorders.
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
8. A process for the manufacture of a compound of Formula I:
said process comprising the step of reacting a compound of Formula (IV):
with a hydroxylamine, H 2 NO—R 8 , and thereby forming the compound according to Formula I;
wherein
A is N;
R 1 is selected from pyridinyl, pyrazinyl, thiadiazolyl, pyrimidinyl, oxadiazolyl, quinolinyl, thienyl and benzofuranyl;
R 2 is H;
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, wherein R 1 and R 3 -R 7 are unsubstituted or substituted with 1 to 5 substituents selected from C 1 -C 6 alkyl, amino, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto or nitro; and
R 8 is selected from H, t-butyl, benzyl, trialkylsilyl and tetrahydropyranyl.
9. The process according to claim 8 , further comprising a deprotection step at R 8 , when R 8 is not H.
10. A compound according to Formula (IV):
wherein
A is N;
R 1 is selected from pyridinyl, pyrazinyl, thiadiazolyl, pyrimidinyl, oxadiazolyl, quinolinyl, thienyl and benzofuranyl;
R 2 is H;
R 3 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl; and
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, wherein R 1 and R 3 -R 7 are unsubstituted or substituted with 1 to 5 substituents selected from C 1 -C 6 alkyl, amino, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto or nitro; or a pharmaceutically acceptable salt thereof.