Quinoline derivatives for the treatment of inflammatory diseases

1. A method of treating an inflammatory disease comprising at least administering a compound of formula (I) to a patient in need thereof:

wherein:

Z is C or N,

V is C or N,

means an aromatic ring wherein V is C or N and when V is N, V is in ortho, meta or para of Z, i.e. forms respectively a pyridine, a pyridazine, a pyrimidine or a pyrazine group,

R independently represent a hydrogen atom, a halogen atom or a group chosen among a —CN group, a hydroxyl group, a (C 1 -C 3 )fluoroalkyl group, a (C 1 -C 3 )fluoroalkoxy group, a (C 3 -C 6 )cycloalkyl group, a —NO 2 group, a —NR 1 R 2 group, a (C 1 -C 4 )alkoxy group, a phenoxy group, a —NR 1- SO 2- NR 1 R 2 group, a —NR 1- SO 2_ R 1 group, a —NR 1 —C(═O)—R 1 group, a —NR 1 —C(═O)—NR 1 R 2 group, a —SO 2_ NR 1 R 2 group, a —SO 3 H group, a —O—SO 2 —OR 3 group, a —O—P(═O)—(OR 3 )(OR 4 ) group, a —O—CH 2 —COOR 3 group and a (C 1 -C 3 )alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group,

Q is N or O, provided that R″ does not exist when Q is O,

R 1 and R 2 are independently a hydrogen atom or a (C 1 -C 3 )alkyl group,

R 3 and R 4 independently represent a hydrogen atom, Li + , Na + , K + , N + (Ra) 4 or a benzyl group,

n is 1, 2 or 3,

n′ is 1, 2 or 3,

R′ independently represent a hydrogen atom or a group chosen among a (C 1 -C 3 )alkyl group, a halogen atom, a —NO 2 group, a —NR 1 R 2 group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (C 1 -C 3 )fluoroalkyl group, a —O—P(═O)—(OR 3 )(OR 4 ) group and a —CN group, and can further be a group chosen among:

A is a covalent bond, an oxygen atom or NH,

B is a covalent bond or NH,

m is 1, 2, 3, 4 or 5,

p is 1, 2 or 3,

Ra and Rb independently represent a hydrogen atom, a (C 1- C 5 )alkyl group or a (C 3 -C 6 )cycloalkyl group,

Ra and Rb can further form together with the nitrogen atom to which they are attached a saturated 5- or 6-membered heterocycle optionally containing a further heteroatom chosen among N, O and S, said heterocycle being optionally substituted by one or more Ra, provided that when R′ is a group (IIa) or (IIIa), n′ may be 2 or 3 only if other R′ groups are different from said group (IIa) or (IIIa),

R″ is a hydrogen atom, a (C 1 -C 4 )alkyl group or is a group (IIa) as defined above,

or any one of its pharmaceutically acceptable salt; wherein

said inflammatory disease being treated by the administration of the compound of formula (I) is at least one member selected from the group consisting of: Inflammatory Bowel Disease, Crohn's disease, Ulcerative Colitis, arthritis, Rheumatoid Arthritis and Osteoarthritis.

2. The method according to claim 1 , wherein R″ is a hydrogen atom, a (C 1 -C 4 )alkyl group or a group

wherein m is 2 or 3 and X 1 is O, CH 2 or N—CH 3 .

3. The method according to claim 1 , wherein R independently represent a hydrogen atom, a methyl group, a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, an amino group, a halogen atom and a —O—P(═O)—(OR 3 )(OR 4 ) group.

4. The method according to claim 1 , wherein R′ independently represent a hydrogen atom, a halogen atom, an amino group, a methyl group, a —O—P(═O)—(OR 3 )(OR 4 ) group or a group

wherein A is O or NH, m is 2 or 3 and X 1 is O, CH 2 or N—CH 3 , provided that when R′ is such a group, n′ is 1 or 2, and when n′ is 2, the other R′ group is different from said group or alternatively R′ independently represent a hydrogen atom, a halogen atom, a methyl group or a group

wherein A is O or NH, m is 2 and X 1 is O, CH 2 or N—CH 3 , provided that when R′ is such a group, n′ is 1 or 2, and when n′ is 2, the other R′ group is different from said group.

5. The method according to claim 1 , wherein Q is N.

6. The method according to claim 1 , wherein the compound of formula (I) is selected from

7. The method according to claim 1 , wherein the compound of formula (I) is selected from compounds of formula (Id) and (Ie):

wherein R, R′, n and n′ are as defined in claim 1 .

8. A compound selected from a group consisting of:

(8) 8-chloro-5-(3-(piperidin-1-yl)propoxy)-N-(4-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

(9) 8-chloro-N 4 -(3-(piperidin-1-yl)propyl)-N 2 -(4-(trifluoromethyl)pyridin-2-yl)quinoline-2,4-diamine

(10) 8-chloro-N-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

(11) 8-chloro-N 4 -(2-morpholinoethyl)-N 2 -(4-(trifluoromethyl)pyridin-2-yl)quinoline-2,4-diamine

(13) 4,8-dichloro-N-(4-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

(14) 8-chloro-N-(3-morpholinopropyl)-N-(4-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

(15) 8-chloro-6-(2-morpholinoethoxy)-N-(3-morpholinopropyl)-N-(4-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

(16) 8-chloro-5-(2-morpholinoethoxy)-N-(3-morpholinopropyl)-N-(4-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

(17) 8-chloro-6-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(4-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

(18) 8-chloro-6-(2-(piperidin-1-yl)ethoxy)-N-(4-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

(19) 8-chloro-6-(3-(piperidin-1-yl)propoxy)-N-(4-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

(20) 8-chloro-N-(3-fluoro-4-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

(21) N-(5-bromo-4-(trifluoromethyl)pyridin-2-yl)-8-chloroquinolin-2-amine

(22) N 2 -(8-chloroquinolin-2-yl)-N 5 -(3-(4-methylpiperazin-1-yl)propyl)-4-(trifluoromethyl)pyridine-2,5-diamine

(28) 8-chloro-N-methyl-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(29) 8-chloro-5-(3-(piperidin-1-yl)propoxy)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(30) 8-chloro-N-(3-(piperidin-1-yl)propyl)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(31) 8-chloro-N-(2-morpholinoethyl)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(32) 8-chloro-N-(2-(pyrrolidin-1-yl)ethyl)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(33) 8-chloro-N-(4-morpholinobutyl)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(34) 8-chloro-N 4 -(3-(piperidin-1-yl)propyl)-N 2 -(4-(trifluoromethoxy)phenyl)quinoline-2,4-diamine

(35) 4,8-dichloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(36) 8-chloro-5-(2-morpholinoethoxy)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(37) N 1 -(4,8-dichloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine

(38) 4,8-dichloro-N-(2-morpholinoethyl)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(39) 8-chloro-6-(2-morpholinoethoxy)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(40) 8-chloro-N 2 -(2-morpholinoethyl)-N 4 -(3-(piperidin-1-yl)propyl)-N 2 -(4-(trifluoromethoxy)phenyl)quinoline-2,4-diamine

(41) 8-chloro-N-(2-morpholinoethyl)-N-(2-nitro-4-(trifluoromethoxy)phenyl)quinolin-2-amine

(42) N 1 -(8-chloroquinolin-2-yl)-M-(2-morpholinoethyl)-4-(trifluoromethoxy)benzene-1,2-diamine

(43) 8-chloro-5-(2-morpholinoethoxy)-N-(2-morpholinoethyl)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

(44) N 1 -(8-chloro-5-(2-morpholinoethoxy)quinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine

(46) 8-chloro-2-((4-(trifluoromethyl)pyridin-2-yl)oxy)quinoline

(47) 4-(2-((8-chloro-2-((4-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-6-yl)oxy)ethyl)morpholine

(48) 8-chloro-2-(4-(trifluoromethoxy)phenoxy)quinoline

(49) 4-(2-((8-chloro-2-(4-(trifluoromethoxy)phenoxy)quinolin-6-yl)oxy)ethyl)morpholine

(50) 4-(2-((8-chloro-2-(4-(trifluoromethoxy)phenoxy)quinolin-5-yl)oxy)ethyl)morpholine

(51) phosphoric acid mono-[8-chloro-2-(4-trifluoromethyl-pyridin-2-ylamino)-quinolin-6-yl] ester

(52) phosphoric acid mono-[2-(8-chloro-quinolin-2-ylamino)-5-trifluoromethoxy-phenyl] ester

(53) phosphoric acid mono-[8-chloro-2-(4-trifluoromethoxy-phenylamino)-quinolin-6-yl] ester

and their pharmaceutically acceptable salts.

9. The method as claimed in claim 1 , wherein said inflammatory disease is at least one member selected from the group consisting of: Inflammatory Bowel Disease, Crohn's disease, and Ulcerative Colitis.

10. A pharmaceutical composition comprising at least one compound as claimed in claim 8 .

11. A compound of formula (Id) or (le):

wherein:

R represents a (C 1 -C 3 )fluoroalkoxy group,

n is 1, 2 or 3,

n′ is 1, 2 or 3, and

R′ independently represent a hydrogen atom or a group chosen among a (C 1 -C 3 )alkyl group, a halogen atom, a —NO 2 group, a —NR 1 R 2 group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (C 1 -C 3 )fluoroalkyl group, a —O—P(═O)—(OR 3 )(OR 4 ) group and a —CN group, and can further be a group chosen among:

A is a covalent bond, an oxygen atom or NH,

B is a covalent bond or NH,

m is 1, 2, 3, 4 or 5,

p is 1, 2 or 3,

Ra and Rb independently represent a hydrogen atom, a (C 1- C 5 )alkyl group or a (C 3 -C 6 )cycloalkyl group,

Ra and Rb can further form together with the nitrogen atom to which they are attached a saturated 5- or 6-membered heterocycle optionally containing a further heteroatom chosen among N, O and S, said heterocycle being optionally substituted by one or more Ra, provided that when R′ is a group (IIa) or (IIIa), n′ may be 2 or 3 only if other R′ groups are different from said group (IIa) or (IIIa).

12. The compound of claim 11 , wherein the compound is a compound of formula (Id).

13. The compound of claim 11 , wherein the compound is a compound of formula (Ie).

14. The method according to claim 1 , wherein the compound of formula (I) is 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine.

15. The method as claimed in claim 1 , wherein said inflammatory disease is at least one member selected from the group consisting of: arthritis, Rheumatoid Arthritis and Osteoarthritis.

16. The method as claimed in claim 1 , wherein said inflammatory disease is Inflammatory Bowel Disease.

17. The method as claimed in claim 1 , wherein said inflammatory disease is arthritis.

18. The method as claimed in claim 1 , wherein said inflammatory disease is Rheumatoid arthritis.

19. The method as claimed in claim 1 , wherein said inflammatory disease is Osteoarthritis.

20. The method as claimed in claim 1 , wherein said inflammatory disease is Crohn's disease.

21. The method as claimed in claim 1 , wherein said inflammatory disease is Ulcerative Colitis.

22. A method of reducing inflammation comprising at least administering a compound of formula (I) to a patient having an inflammatory disease to reduce inflammation associated with the inflammatory disease:

wherein:

Z is C or N,

V is C or N,

means an aromatic ring wherein V is C or N and when V is N, V is in ortho, meta or para of Z, i.e. forms respectively a pyridine, a pyridazine, a pyrimidine or a pyrazine group,

R independently represent a hydrogen atom, a halogen atom or a group chosen among a —CN group, a hydroxyl group, a (C 1 -C 3 )fluoroalkyl group, a (C 1 -C 3 )fluoroalkoxy group, a (C 3 -C 6 )cycloalkyl group, a —NO 2 group, a —NR 1 R 2 group, a (C 1 -C 4 )alkoxy group, a phenoxy group, a —NR 1- SO 2- NR 1 R 2 group, a —NR 1- SO 2- R 1 group, a —NR 1 —C(═O)—R 1 group, a —NR 1 —C(═O)—NR 1 R 2 group, a —SO 2_ NR 1 R 2 group, a —SO 3 H group, a —O—SO 2 —OR 3 group, a —O—P(═O)—(OR 3 )(OR 4 ) group, a —O—CH 2 —COOR 3 group and a (C 1 -C 3 )alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group,

Q is N or O, provided that R″ does not exist when Q is O,

R 1 and R 2 are independently a hydrogen atom or a (C 1 -C 3 )alkyl group,

R 3 and R 4 independently represent a hydrogen atom, Li + , Na + , K + , N + (Ra) 4 or a benzyl group,

n is 1, 2 or 3,

n′ is 1, 2 or 3,

R′ independently represent a hydrogen atom or a group chosen among a (C 1 -C 3 )alkyl group, a halogen atom, a —NO 2 group, a —NR 1 R 2 group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (C 1 -C 3 )fluoroalkyl group, a —O—P(═O)—(OR 3 )(OR 4 ) group and a —CN group, and can further be a group chosen among:

A is a covalent bond, an oxygen atom or NH,

B is a covalent bond or NH,

m is 1, 2, 3, 4 or 5,

p is 1, 2 or 3,

Ra and Rb independently represent a hydrogen atom, a (C 1- C 5 )alkyl group or a (C 3 -C 6 )cycloalkyl group,

Ra and Rb can further form together with the nitrogen atom to which they are attached a saturated 5- or 6-membered heterocycle optionally containing a further heteroatom chosen among N, O and S, said heterocycle being optionally substituted by one or more Ra, provided that when R′ is a group (IIa) or (IIIa), n′ may be 2 or 3 only if other R′ groups are different from said group (IIa) or (IIIa),

R″ is a hydrogen atom, a (C 1 -C 4 )alkyl group or is a group (IIa) as defined above,

or any one of its pharmaceutically acceptable salt.