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 compound according to Formula (II):
wherein:
A is N;
R 1 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 -cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl, heterocycloalkyl C 1 -C 6 alkyl, heteroaryl C 1 -C 6 alkyl, amino or 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, heterocycloalkyl, alkoxy, aryl or heteroaryl;
R 3 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or 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 or 6; and
PG 1 is H or a protecting group selected from benzyl, t-butyl, THP, TMS or TBS.
2. The compound according to claim 1 , wherein said compound is selected from:
(2S)—N-(benzyloxy)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methyl pentan-1-amine ; or
(2S)—N-(benzyloxy)-2-[(4-biphenyl-4-ylpiperazin-1-yl)carbonyl]-4-methylpentan-1-amine.
3. A N-hydroxyamide derivative selected from the group consisting of:
hydroxy((2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methylpentyl)formamide: and
{(2S)-2-[(4-biphenyl-4-ylpiperazin-1-yl)carbonyl]-4-methylpentyl}hydroxyformamide.
4. The N-hydroxyamide derivative according to claim 3 , wherein said derivative is hydroxy((2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methylpentyl) formamide.
5. The N-hydroxyamide derivative according to claim 3 , wherein said derivative is {(2S)-2-[(4-biphenyl-4-ylpiperazin-1-yl)carbonyl]-4-methylpentyl}hydroxyformamide.
6. A method of treating arthritis, emphysema, multiple sclerosis or pre-term labor comprising the administration of a compound of Formula (I) to a subject having arthritis, emphysema, multiple sclerosis or pre-term labor,
wherein:
A is N;
R 1 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 -cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl, heterocycloalkyl C 1 -C 6 alkyl, heteroaryl C 1 -C 6 alkyl, amino or 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, heterocycloalkyl, alkoxy, aryl or heteroaryl;
R 3 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or 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; and
n is an integer selected from 1, 2, 3, 4, 5 or 6;
or pharmaceutically acceptable salts thereof,
wherein carbons (2) and (3) are two chiral centers, chiral center (2) has a configuration selected from “S” and “R” and chiral center (3) has a “S” configuration.
7. The method according to claim 6 , wherein said subject has multiple sclerosis.
8. The method according to claim 6 , wherein said subject has arthritis.
9. The method according to claim 6 , wherein said subject has emphysema.
10. The method according to claim 6 , wherein R 1 is selected from aryl or heteroaryl.
11. The method according to claim 6 , wherein R 2 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl.
12. The method according to claim 6 , wherein R 3 is H.
13. The method according to claim 6 , wherein R 4 , R 5 and R 7 are H.
14. The method according to claim 6 , wherein R 1 is selected from aryl or heteroaryl; 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, heterocycloalkyl or alkoxy; R 3 , R 4 , R 5 and R 7 are H; R 6 is selected from H or methyl; and n is an integer selected from 1, 2 or 3.
15. The method according to claim 6 , wherein R 2 is selected from H, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 -cycloalkyl, heterocycloalkyl or alkoxy.
16. The method according to claim 6 , wherein said subject has pre-term labor.
17. The method according to claim 6 , wherein said method comprises the administration of a compound according to Formula (I) in combination with pegylated or non-pegylated interferon beta, glatiramer, mitoxantrone, methotrexate, azathioprine, cyclophosphamide, methylprednisolone, prednisone, dexamethasone or cladribine to a patient having multiple sclerosis.
18. A pharmaceutical composition comprising at least one N-hydroxyamide derivative according to claim 3 and a pharmaceutically acceptable carrier, diluent or excipient.
19. A process for the preparation of a N-hydroxyamide derivative, comprising reacting a compound of Formula (II) with a formylating agent of formula (FA):
wherein:
A is N;
R 1 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 -cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl, heterocycloalkyl C 1 -C 6 alkyl, heteroaryl C 1 -C 6 alkyl, amino or 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, heterocycloalkyl, alkoxy, aryl or heteroaryl;
R 3 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or 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 or 6; and
PG 1 is H or a protecting group selected from benzyl, t-butyl, THP, TMS or TBS; LG 1 is a leaving group selected from —OH, —OAc, —OPiv, —OCH 2 CN, —OCH 2 CF 3 , —OPh or —OPfp.