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. An N-hydroxyamide derivative according to Formula (I),
wherein:
A is N;
R 1 is aryl, optionally substituted with halogen or —O—R;
R is C 1 -C 6 alkyl, optionally substituted with halogen,
R 2 is H;
R 3 is H;
R 4 is selected from H and unsubstituted C 1 -C 6 alkyl; and
R 5 , R 6 and R 7 are H;
or an enantiomer, diastereomer, racemate, or a pharmaceutically acceptable salt thereof.
2. An N-hydroxyamide derivative according to claim 1 wherein R 1 is phenyl.
3. An N-hydroxyamide derivative according to claim 1 , selected from the group consisting of:
(2R)-4-[4-(4-fluorophenyl)piperazin-1-yl]-N,2-dihydroxy-4-oxobutanamide;
(2S)-4-[4-(4-fluorophenyl)piperazin-1-yl]-N,2-dihydroxy-4-oxobutanamide;
(2S)—N,2-dihydroxy-4-{(2R)-2-methyl-4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}-4-oxobutanamide; and
(2S)-4-[(2R)-4-biphenyl-4-yl-2-methylpiperazin-1-yl]-N,2-dihydroxy-4-oxo butanamide;
or a pharmaceutically acceptable salt thereof.
4. A method of treating a subject with a matrix metalloproteinase (MMP) associated disease or disorder, wherein the metalloproteinase is selected from the group consisting of MMP-9, MMP-2 and MMP-12, and the disease or disorder is associated with MMP activity and/or expression, and the matrix metalloproteinase (MMP) associated disease or disorder is multiple sclerosis or chronic obstructive pulmonary disorders, comprising administering to the subject an effective amount of a compound according to claim 1 .
5. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
6. 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 aryl, optionally substituted with halogen or —O—R;
R is C 1 -C 6 alkyl, optionally substituted with halogen;
R 2 is H;
R 4 is selected from H and unsubstituted C 1 -C 6 alkyl;
R 5 , R 6 and R 7 are H; and
R 8 is selected from H, t-butyl, benzyl, trialkylsilyl, and tetrahydropyranyl.
7. The process according to claim 6 , further comprising a deprotection step, wherein the deprotection step is occurring at R 8 , when R 8 is not H.
8. A compound according to Formula (IV):
wherein
A is N;
R 1 is aryl, optionally substituted with halogen or —O—R;
R is C 1 -C 6 alkyl, optionally substituted with halogen;
R 2 is H; and
R 4 is selected from H and unsubstituted C 1 -C 6 alkyl; and
R 5 , R 6 and R 7 are H;
or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 8 selected from the group:
(5R)-5-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-2,2-dimethyl-1,3-dioxolan-4-one;
(5S)-5-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-2,2-dimethyl-1,3-dioxolan-4-one;
(5S)-2,2-dimethyl-5-[2-[((2R)-2-methyl-4-{4-[(trifluoromethyl)oxy]phenyl}piperazin-1-yl)-2-oxoethyl]-1,3-dioxolan-4-one; and
(5S)-5-{2-[(2R)-4-biphenyl-4-yl-2-methylpiperazin-1-yl]-2-oxoethyl}-2,2-dimethyl-1,3-dioxolan-4-one;
or a pharmaceutically acceptable salt thereof.