Anti-inflammatory carboxamide derivatives
A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or isomer thereof. Pharmaceutical compositions comprising the compounds of formula (I) as well as their use in therapy, particularly in the treatment of inflammatory conditions. Advantageously, the compounds show a broad and robust anti-inflammatory effect, and are therapeutically safe.
1 . A compound of formula (I):
or a pharmaceutically acceptable salt, hydrate, or isomer thereof,
wherein:
R 1 represents halogen; —OR 4 ; (C 1 -C 10 )alkyl; or (C 1 -C 10 )alkyl substituted with one or more substituents, the same or different, selected from OH, halogen, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, nitro, cyano, and halogen; or, alternatively,
R 1 together with X 2 forms an aromatic, saturated or partially saturated known ring, the ring having 5 or 6 members selected from the group consisting of: —C(R x ) 2 —, —CR x —, —N—, —NR x —, S, and O;
represents a single bond or a double bond;
R 2 represents —OH; halogen; (C 1 -C 10 )alkyl; (C 1 -C 10 )alkyl substituted with one or more substituents, the same or different, selected from OH, halogen, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, nitro, cyano, and halogen; —S(O) 2 R 4 ; an aromatic known ring system comprising 5 or 6 members selected from —CR a —, and —N—;
R 3 represents —NR 5 R 6 , being R 5 and R 6 the same or different and being selected from —H, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, and an aromatic known ring system comprising 5 or 6 members selected from —CR b —, and —N—; or, alternatively,
R 2 together with R 3 form an aromatic, saturated or partially saturated known ring, the ring having 5 or 6 members selected from —C(R y ) 2 —, —CR y —, —N—, —NR y , —S—, and —O—;
A is a known ring system having from 1 to 3 rings and comprising from 4 to 14 members, each one of the members being selected from, —C(R z ) 2 —, —CR z —, —N—, —NR′ z —, —S—, —Se—, —SO 2 , —SeO 2 , and —O—; the rings being saturated, partially unsaturated, or aromatic; and being fused or isolated; or, alternatively,
A represents —NR c -A′, wherein
R c represents —H or (C 1 -C 10 )alkyl, and
A′ is a known ring system having from 1 to 3 rings and comprising from 4 to 14 members, each one of the members being selected from, —C(R z ) 2 —, —CR z —, —N—, —NR z —, —S—, —Se—, —SO 2 , —SeO 2 , and —O—; the rings being saturated, partially unsaturated, or aromatic; and being fused or isolated;
n represents a enter value comprised from 1 to 7;
X 1 and X 2 are the same or different and represent C or N atom;
R 4 represents —H; (C 1 -C 10 ) alkyl; or (C 1 -C 10 ) alkyl substituted with one or more substituents, the same or different, selected from OH, halogen, (C 1 -C 6 )alkyl, —O—(C 1 -C 5 )alkyl, nitro, cyano, and halogen;
the term “(C 3 -C 10 )cycloalkyl” refers to a saturated carbocyclic ring containing from 3 to 10 carbon atoms;
each one of R a is independently selected from the group consisting of —H, —OH, halogen, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkyl substituted with one or more substituents, the same or different, selected from: OH, halogen, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, nitro, cyano, and halogen;
each one of R b is independently selected from the group consisting of —H, —OH, halogen, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkyl substituted with one or more substituents, the same or different, selected from: OH, halogen, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, nitro, cyano, and halogen;
R t represents (C 1 -C 10 ) alkyl;
each one of the Rx is independently selected from the group consisting of —H, —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O—(C 1 -C 6 )alkyl, nitro, —NR 7— , —NR 8 R 9 , and halogen;
each one of the Ry is independently selected from the group consisting of —H, —OH, (C 1 -C 6 )alkyl, (C 1 -C 5 )haloalkyl, —O—(C 1 -C 6 )alkyl, nitro, —NR 10 —, —NR 11 R 12 , and halogen;
each one of the Rz is independently selected from the group consisting of —H, —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O—(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )haloalkyl, nitro, —NR 13 —, —NR 12 R 15 , and halogen;
R′ z is selected from the group consisting of (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl; and
each one of R 7 to R 15 is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and —O—(C 1 -C 6 )alkyl.
2 . The compound of claim 1 which is one of formula (Ia):
3 . The compound of claim 1 , wherein
R 1 is selected from —OH, —O—(C 1 -C 10 )alkyl, and halogen; or alternatively,
R 1 together with X 2 forms a partially saturated or aromatic known ring having 5 or 6 members, the members being as defined above.
4 . The compound of claim 1 , wherein
R 2 represents halogen or —S(O) 2 R t .
5 . The compound of claim 1 , wherein
R 3 represents —NR 6 R 7 , R 6 and R 7 being the same, alternatively
R 3 together with R 2 form an aromatic or partially saturated known ring, the ring having 5 or 6 members as defined above.
6 . The compound of claim 1 , wherein A is selected from:
an aryl ring comprising 5 or 6 members,
a saturated ring comprising from 4 to 8 members, and
—NH-A′, wherein A′ is an aryl ring comprising 5 or 6 members.
7 . The compound of claim 6 , wherein A is selected from:
a known 6-membered aryl wherein one of the members is —N—, and the other members forming the 6-membered ring are —CR z —, each one of the R z being independently selected from: H, (C 1 -C 6 )haloalkyl, and halogen;
a known 6-membered aryl ring having 6 —CR z — members, each one of the R z being independently selected from: H, (C 1 -C 6 )haloalkyl, —NR 7 —, and halogen;
a saturated known 6-membered ring, wherein one or two of the members are selected from —NR′ z —, —S—, and —O— and the other members forming part of the ring represent —C(R z ) 2 —, each one of the R z being independently selected from: H, (C 1 -C 6 )alkyl, and halogen; and R′ z representing (C 1 -C 6 )alkyl; and
—NH-A′, wherein A′ is a known 6-membered aryl ring having 6 —CR z — members, each one of the R z being independently selected from: H, (C 1 -C 6 )haloalkyl, halogen and —O—(C 1 -C 6 )haloalkyl.
8 . The compound of claim 1 , which is selected from the group consisting of:
4-amino-5-chloro-2-methoxy-N-((1-morpholinocycloheptyl)methyl)benzamide;
4-amino-5-(ethylsulfonyl)-2-methoxy-N-((1-morpholinocycloheptyl)methyl)benzamide;
4-amino-5-fluoro-2-methoxy-N-((1-morpholinocycloheptyl)methyl)benzamide;
4-amino-2,5-difluoro-N-((1-morpholinocycloheptyl)methyl)benzamide;
6-amino-5-chloro-2-methoxy-N-((1-morpholinocycloheptyl)methyl)nicotinamide;
6-chloro-N-((1-morpholinocycloheptyl)methyl)imidazo[1,2-a]pyridine-8-carboxamide;
N-((1-morpholinocycloheptyl)methyl)quinoxaline-2-carboxamide;
4-amino-5-chloro-2-hydroxy-N-((1-morpholinocycloheptyl)methyl)benzamide;
4-amino-5-chloro-2-methoxy-N-((1-thiomorpholinocycloheptyl)methyl)benzamide;
4-amino-5-chloro-2-methoxy-N-((1-(4-methylpiperazin-1-yl)cycloheptyl)methyl)benzamide;
4-amino-5-chloro-N-((1-(4-fluoropiperidin-1-yl)cyclohexyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(4,4-difluoropiperidin-1-yl)cyclohexyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(4-chlorophenyl)cyclopropyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(4-chlorophenyl)cyclobutyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(4-chlorophenyl)cyclopentyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(4-chlorophenyl)cyclohexyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(4-chlorophenyl)cycloheptyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-((4-chlorophenyl)amino)cycloheptyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(3,4-dichlorophenyl)cycloheptyl)methyl)-2-methoxybenzamide;
6-amino-5-chloro-N-((1-(4-chlorophenyl)cycloheptyl)methyl)-2-methoxynicotinamide;
5-amino-6-chloro-N-((1-(4-chlorophenyl)cycloheptyl)methyl)chroman-8-carboxamide;
4-amino-5-chloro-N-((1-(4-fluorophenyl)cycloheptyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(2-chloro-4-fluorophenyl)cycloheptyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-((1-(4-(trifluoromethyl)phenyl)cycloheptyl)methyl) benzamide;
4-amino-5-chloro-2-methoxy-N-((1-(5-(trifluoromethyl)pyridin-2-yl)cycloheptyl)methyl) benzamide;
4-amino-5-chloro-2-methoxy-N-((1-(pyridin-3-yl)cycloheptyl)methyl)benzamide;
4-amino-5-chloro-N-((1-((2-chloro-4-fluorophenyl)amino)cycloheptyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-((1-((3-(trifluoromethoxy)phenyl)amino) cycloheptyl)methyl)benzamide;
and any pharmaceutically acceptable salt, hydrate, and isomer thereof.
9 . The compound of formula (I) according to claim 7 , which is selected from:
4-amino-5-chloro-2-methoxy-N-((1-thiomorpholinocycloheptyl)methyl)benzamide;
4-amino-5-chloro-N-((1-(4-chlorophenyl)cyclohexyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(4-chlorophenyl)cycloheptyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-((4-chlorophenyl)amino)cycloheptyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(3,4-dichlorophenyl)cycloheptyl)methyl)-2-methoxybenzamide;
6-amino-5-chloro-N-((1-(4-chlorophenyl)cycloheptyl)methyl)-2-methoxynicotinamide;
4-amino-5-chloro-N-((1-(4-fluorophenyl)cycloheptyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-(2-chloro-4-fluorophenyl)cycloheptyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-N-((1-((2-chloro-4-fluorophenyl)amino)cycloheptyl)methyl)-2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-((1-((3-(trifluoromethoxy)phenyl)amino) cycloheptyl)methyl)benzamide; and
any pharmaceutically acceptable salt, hydrate, and isomer thereof.
10 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined in claim 1 , together with one or more pharmaceutically acceptable excipients or carriers.
11 . The compound of claim 1 , wherein R 2 represents halogen or —S(O) 2 R t .
12 . The compound of claim 2 , wherein A is selected from:
an aryl ring comprising 5 or 6 members,
a saturated ring comprising from 4 to 8 members, and
—NH-A′, wherein A′ is an aryl ring comprising 5 or 6 members.
13 . The compound of claim 12 , wherein A is selected from:
a known 6-membered aryl wherein one of the members is —N—, and the other members forming the 6-membered ring are —CR z —, each one of the R z being independently selected from: H, (C 1 -C 6 )haloalkyl, and halogen;
a known 6-membered aryl ring having 6 —CR z — members, each one of the R z being independently selected from: H, (C 1 -C 6 )haloalkyl, —NR 7 —, and halogen;
a saturated known 6-membered ring, wherein one or two of the members are selected from —NR′ z —, —S—, and —O— and the other members forming part of the ring represent —C(R z ) 2 —, each one of the R z being independently selected from: H, (C 1 -C 6 )alkyl, and halogen; and R′ z representing (C 1 -C 6 )alkyl; and
—NH-A′, wherein A′ is a known 6-membered aryl ring having 6 —CR z — members, each one of the R z being independently selected from: H, (C 1 -C 5 )haloalkyl, halogen and —O—(C 1 -C 5 )haloalkyl.
14 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined in claim 2 , together with one or more pharmaceutically acceptable excipients or carriers.