4-phenyl-5-OXO-1,4,5,6,7,8-hexahydroquinoline derivatives as medicaments for the treatment of infertility
View Patent ↗The invention relates to a 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to Formula (I), wherein the substituents are defined as in the description, or a pharmaceutically salt thereof. The compounds of this invention are potent FSH receptor activators and may be used for treating fertility disorders in e.g. controlled ovarian hyperstimulation and IVF procedures.
1. A 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to Formula I,
wherein
R 1 is (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl;
R 2 is halogen, (1-4C)alkoxy, fluorinated (1-4C)alkoxy, (1-4C)alkyl, or fluorinated (1-4C)alkyl; or R 2 may be H when R 3 is R 9 ,R 10 -aminosulfonyl;
R 3 is OH, NO 2 , CN, fluorinated (1-4C)alkoxy, (1-4C)alkoxy(2-4C)alkoxy, hydroxy(2-4C)alkoxy, (1-4C)alkoxycarbonyl, (3-4C)alkenyloxycarbonyl, (1-4C)alkoxycarbonyloxy, (3-4C)alkenyloxycarbonyloxy, R 7 ,R 8 -amino, R 9 ,R 10 -amino, R 9 ,R 10 -aminocarbonyl, R 9 ,R 10 -aminosulfonyl or phenyl(1-4C)alkoxy, wherein the phenyl ring is optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (di)(1-4C)alkylamino;
R 4 is R 11 -phenyl or R 11 -(2-5C)heteroaryl, wherein the phenyl or heteroaryl group is optionally further substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluromethyl, cyano, (1-4C)alkyl, (1-4C)alkylthio, (1-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl;
R 7 is H, (1-4C)alkyl;
R 8 is (1-4C)alkylsulfonyl, (1-4C)alkylcarbonyl, (2-4C)alkenylcarbonyl, (3-6C)cycloalkylcarbonyl, (1-4C)alkoxycarbonyl, (3-4C)alkenyloxycarbonyl, (1-4C)alkoxy(1-4C)alkylcarbonyl, (3-4C)alkenyloxy(1-4C)alkylcarbonyl phenylcarbonyl, (2-5C)heteroarylcarbonyl, phenyl(1-4C)alkylcarbonyl, (2-5C)heteroaryl(1-4C)alkylcarbonyl, wherein the phenyl ring or the heteroaromatic ring is optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (di)(1-4C)alkylamino;
R 9 and R 10 are independently selected from H, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl and (1-4C)alkoxy(2-4C)alkyl;
or R 9 and R 10 may be joined in a (4-6C)heterocycloalkenyl ring or a (2-6C)heterocycloalkyl ring, optionally substituted with one or more (1-4C)alkyl substituents;
R 11 is H, (1-6C)alkoxycarbonyl, R 12 ,R 13 -amino, (1-6C)alkylcarbonyl, (1-6C)alkylsulfonyl, R 14 -oxy, R 14 ,R 15 -amino, R 14 ,R 15 -aminocarbonyl, R 14 ,R 15 -aminosulfonyl;
R 12 is H, (1-4C)alkyl;
R 13 is (1-4C)alkylsulfonyl, (1-4C)alkylcarbonyl, (3-6C)cycloalkylcarbonyl, (1-4C)alkoxycarbonyl, (3-4C)alkenyloxycarbonyl, (di)(1-4C)alkylamino-(1-4C)alkylcarbonyl, (2-6C)heterocycloalkyl(1-4C)alkylcarbonyl, (4-6C)heterocyclo-alkenyl(1-4C)alkylcarbonyl or (1-4C)alkoxy(1-4C)alkylcarbonyl;
R 14 and R 15 are independently selected from H, (1-6C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, hydroxy(2-4C)alkyl, amino(2-4C)alkyl, (1-4C)alkoxy(2-4C)alkyl, (di)(1-4C)alkylamino(2-4C)alkyl, (2-6C)heterocycloalkyl(2-4C)alkyl, (4-6C)heterocycloalkenyl(2-4C)alkyl, phenyl(1-4C)alkyl and (2-5C)heteroaryl(1-4C)alkyl;
X is O or R 16 —N;
Y is CH 2 , C(O) or SO 2 ;
Z is CN or NO 2 ;
R 16 is H, (1-4C)alkyl, (1-4C)alkylcarbonyl;
or a pharmaceutically acceptable salt thereof.
2. The 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to claim 1 , wherein R 1 is (1-6C)alkyl.
3. The 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to claim 1 , wherein R 2 is halogen.
4. The 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to claim 1 , wherein R 3 is R 9 ,R 10 -aminosulfonyl.
5. The 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to claim 4 , wherein R 9 and R 10 are independently (1-6C)alkyl.
6. The 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to claim 1 , wherein R 4 is R 11 -phenyl or R 11 -(2-5C)heteroaryl, wherein the phenyl or heteroaryl group is optionally further substituted with one (1-4C)alkoxy.
7. The 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to claim 6 , wherein R 11 is H or R 12 ,R 13 -amino.
8. The 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to claim 1 , wherein Z is CN.
9. The 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to claim 1 , wherein X is O.
10. The 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to claim 1 , wherein Y is CH 2 .
11. A pharmaceutical composition comprising a 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1 , and pharmaceutically suitable auxiliaries.