Cyclohexyl(alkyl)propanolamines, preparation method and pharmaceutical compositions containing same
View Patent ↗The present invention relates to the compounds of formula (I): in which A is a group of formula (a) or (b) in which R represents a hydrogen or halogen atom, an —S(O) z (C 1 -C 4 )alkyl group, an —NHSO 2 (C 1 -C 4 )alkyl group, an —SO 2 NH(C 1 -C 4 )alkyl group, an —NHSO 2 phenyl-(C 1 -C 4 )alkyl group or an —NHSO 2 phenyl group, said phenyl possibly being substituted with a halogen atom, with a (C 1 -C 4 )alkyl group or with a (C 1 -C 4 )alkoxy group; R 1 represents a hydrogen atom or a (C 1 -C 4 )alkyl group, a —CO(C 1 -C 4 )alkyl group, a phenyl-(C 1 -C 4 )alkyl group or a —COphenyl group, said phenyl also possibly being substituted with a halogen atom or with a (C 1 -C 4 )alkoxy group; R 2 is a hydrogen atom or an —SO 2 (C 1 -C 4 )alkyl group, an —SO 2 phenyl-(C 1 -C 4 )alkyl group or an —SO 2 phenyl group; X completes a ring of 5 to 8 atoms, said ring being saturated or unsaturated, possibly being substituted with one or two (C 1 -C 4 )alkyl groups and bearing one or two carbonyl groups; n, m and z are, independently, 0, 1 or 2; R 3 represents a hydrogen or halogen atom, a (C 1 -C 6 )alkyl group, a (C 1 -C 4 )alkoxy group, a —COO(C 1 -C 4 )alkyl group, a —CO(C 1 -C 4 )alkyl group, an —NHSO 2 (C 1 -C 4 )alkyl group, an —NHSO 2 phenyl-(C 1 -C 4 )alkyl groups, —NO 2 , —CN, —CONR 4 R 5 , —COOH, or a 4,5-dihydro-1,3-oxazol-2-yl or 4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl group; R 4 and R 5 represent, independently, a hydrogen atom, a phenyl, a (C 1 -C 4 )alkyl group or a phenyl-(C 1 -C 4 )alkyl group or R 4 and R 5 with the nitrogen atom to which they are attached, may form a ring of 5 to 7 atoms in total; and to the salts or solvates thereof, to the pharmaceutical compositions containing them, to a process for the preparation thereof and to intermediates in this process.
1. A compound of formula (I):
wherein
A is a group of formula (a) or (b)
R is a hydrogen or halogen atom, an —S(O) z (C 1 -C 4 )alkyl group, an —NHSO 2 (C 1 -C 4 )alkyl group, an —SO 2 NH(C 1 -C 4 )alkyl group, an —NHSO 2 phenyl-(C 1 -C 4 )alkyl group or an —NHSO 2 phenyl group, wherein the phenyl moiety is optionally substituted with a halogen atom, a (C 1 -C 4 )alkyl group or a (C 1 -C 4 )alkoxy group;
R 1 is a hydrogen atom, a (C 1 -C 4 )alkyl group, a —CO(C 1 -C 4 )alkyl group, a phenyl-(C 1 -C 4 )alkyl group or a —COphenyl group, wherein the phenyl moiety is optionally substituted with a halogen atom or a (C 1 -C 4 )alkoxy group;
R 2 is a hydrogen atom, an —SO 2 (C 1 -C 4 )alkyl group, an —SO 2 phenyl-(C 1 -C 4 )alkyl group or an —SO 2 phenyl group;
X taken together with the O and N atoms to which it is attached and the carbon atoms of the phenyl moiety to which the O and N atoms are attached form a 5 to 8 membered ring, wherein the 5 to 8 membered ring is saturated or unsaturated, and is optionally substituted with one or two (C 1 -C 4 )alkyl groups or one or two oxo groups;
n, m and z are, independently 0, 1 or 2;
R 3 is a hydrogen or halogen atom, a (C 1 -C 6 )alkyl group, a (C 1 -C 4 )alkoxy group, a —COO(C 1 -C 4 )alkyl group, a —CO(C 1 -C 4 )alkyl group, an —NHSO 2 (C 1 -C 4 )alkyl group, an —NHSO 2 phenyl-(C 1 -C 4 )alkyl group, —NO 2 , —CN, —CONR 4 R 5 , —COOH, or a 4,5-dihydro-1,3-oxazol-2-yl or 4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl group; and
R 4 and R 5 are, independently, a hydrogen atom, a phenyl, a (C 1 -C 4 )alkyl group or a phenyl -(C 1 -C 4 )alkyl group; or
R 4 and R 5 together with the nitrogen atom to which they are attached, form a 5 to 7 membered ring;
or a salt thereof.
2. The compound according to claim 1 , in which n and m are each 0.
3. The compound according to claim 1 , in which R 1 is a hydrogen atom.
4. The compound according to claim 1 , in which R is chosen from an —NHSO 2 (C 1 -C 4 )alkyl group, an —NHSO 2 phenyl-(C 1 -C 4 )alkyl group or an —NHSO 2 phenyl group.
5. The compound according to claim 1 , in which R 3 is —CN, —COOH, —COO(C 1 -C 4 )alkyl or —CO(C 1 -C 4 )alkyl.
6. The compound according to claim 1 , in which z is 2.
7. The compound according to claim 1 , wherein X is methylene, ethylene or propylene, or a salt thereof.
8. The compound according to claim 1 , wherein X is carbonyl, —CO—CO—, —CO—C((C 1 -C 4 )alkyl) 2 —CO—, —CO—CH 2 —, or a methylene monosubstituted or disubstituted with (C 1 -C 4 )alkyl, or a salt thereof.
9. The compound according to claim 1 , which is ethyl 4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(phenylsulphonylamino)-phenoxy)propylamino)cyclohexyl]benzoate or a salt thereof.
10. The compound according to claim 1 , which is 4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)phenoxy)propylamino)cyclohexyl]benzoic acid or a salt thereof.
11. The compound according to claim 1 , which is:
ethyl 4-[4-((2S)-3-(4-benzyloxy-3-(methylsulphonylamino)phenoxy)-2-hydroxypropylamino)cyclohexyl]benzoate,
ethyl 4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(n-butylsulphonyl-amino)phenoxy)propylamino)cyclohexyl]benzoate,
ethyl 4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(benzylsulphonyl-amino)phenoxy)propylamino)cyclohexyl]benzoate,
ethyl 4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonyl)-phenoxy)propylamino)cyclohexyl]benzoate,
N-[5-[[(2S)-3-((4-(4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-phenyl)cyclohexyl)amino)-2-hydroxypropyl]oxy]-2-hydroxyphenyl]-methanesulphonamide,
4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)-phenoxy)propylamino)cyclohexyl]-N,N-diethylbenzamide,
4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)-phenoxy)propylamino)cyclohexyl]-N-n-butylbenzamide,
4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)-phenoxy)propylamino)cyclohexyl]benzene,
4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)-phenoxy)propylamino)cyclohexyl]benzonitrile,
4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino-phenoxy)propylamino)cyclohexyl]benzamide,
ethyl 4-[4-((2S)-2-hydroxy-3-(4-methoxy-3-(methylsulphonyl-amino)phenoxy)propylamino)cyclohexyl]benzoate,
ethyl 4-[4-(((2S)-2-hydroxy-3-[(3-(methylsulphonyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]oxy)propyl)amino)cyclohexyl]benzoate,
ethyl 4-[4-((2S)-2-hydroxy-3-((5-methylsulphonyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-7-yl)oxy)propylamino)cyclohexyl]benzoate,
ethyl 4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-chlorophenoxy)-propylamino)cyclohexyl]benzoate,
N-[4-[4-((2S)-2-Hydroxy-3-(4-hydroxy-3-methylsulphonylamino-phenoxy)propylamino)cyclohexyl]benzoyl]pyrrolidine,
ethyl 4-[4-((2S)-2-hydroxy-3-(4-hydroxyphenoxy)propylamino)-cyclohexyl]benzoate,
4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)-phenoxy)propylamino)cyclohexyl]-1-ethylcarbonylbenzene,
tert-butyl 4-[4-((2S)-2-hydroxy-3-(4-hydroxy-3-(methylsulphonylamino)-phenoxy)propylamino)cyclohexyl]benzoate, or
4-[4-(((2S)-2-hydroxy-3-[(3-(methylsulphonyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-oxy)propylamino)cyclohexyl]benzamide,
or a salt thereof.
12. A process for preparing a compound of claim 1 , wherein
(a) a compound of formula (II):
wherein A is as indicated in claim 1 , is reacted with an amine of formula (III):
wherein n, m and R 3 are as defined in claim 1 , and optionally, the compound of formula (I) thus obtained is transformed into a salt thereof.
13. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutical excipient.
14. A pharmaceutical composition comprising a compound of formula (I) according to claim 9 or a pharmaceutically acceptable salt thereof, together with a pharmaceutical excipient.
15. A pharmaceutical composition comprising a compound of formula (I) according to claim 10 or a pharmaceutically acceptable salt thereof, together with a pharmaceutical excipient.
16. A pharmaceutical composition comprising a compound of formula (I) according to claim 11 or a pharmaceutically acceptable salt thereof, together with a pharmaceutical excipient.
17. A method for delaying preterm birth in a patient in need thereof comprising administering to the patient an effective amount of the compound according to claim 1 or a salt thereof.
18. A method for delaying preterm birth in a patient in need thereof comprising administering to the patient an effective amount of the compound according to claim 9 or a salt thereof.
19. A method for delaying preterm birth in a patient in need thereof comprising administering to the patient an effective amount of the compound according to claim 10 or a salt thereof.
20. A method for delaying preterm birth in a patient in need thereof comprising administering to the patient an effective amount of the compound according to claim 11 or a salt thereof.