Propanolaminomethyltetralines, their preparation and pharmaceutical composition comprising same
View Patent ↗The invention concerns compounds of formula (I), wherein A is a group of formula (a) or (b), wherein: R represents a hydrogen or halogen atom, a —S(O) z (C 1 –C 4 )Alk wherein z is 0, 1 or 2, a —NHSO 2 (C 1 –C 4 )Alk, —SO 2 NH(C 1 –C 4 )Alk, —NHSO 2 —(C 1 –C 4 )Alk-phenyl or —NHSO 2 -phenyl group, said phenyl capable of bearing a halogen atom, a (C 1 –C 4 )Alk group or a (C 1 –C 6 )alkoxy group; R 1 represents a hydrogen atom or a —(C 1 –C 4 )Alk, —CO(C 1 –C 4 )Alk, —(C 1 –C 4 )Alk-phenyl or —CO-phenyl group, said phenyl capable of bearing a halogen atom or a —(C 1 –C 4 )Alk or (C 1 –C 6 )alkoxy group; R 2 is a hydrogen atom, a —SO 2 (C 1 –C 4 )Alk, —SO 2 —(C 1 –C 4 )Alk-phenyl, —SO 2 -phenyl group, or a —(C 1 –C 4 )Alk group; X completes a saturated or unsaturated cycle of 5 to 8 atoms, capable of bearing one or two —(C 1 –C 4 )Alk groups and/or two carbonyl groups; R 3 and R′ 3 represent each independently a hydrogen or halogen atom, a —(C 1 –C 6 )Alk, hydroxy, —CN, —(C 1 –C 6 )alkoxy, —COR 4 or Y—CR 8 R 9 —COR 4 group; Y represents O or CH 2 ; R 4 represents a hydroxy, (C 1 –C 6 )alkoxy or —NR 5 R 6 group; R 5 and R 6 independently represent a hydrogen atom, a —(C 1 –C 4 )Alk, group, aryl or heteroaryl optionally substituted by a R 7 group, aralkyl or heteroaralkyl optionally substituted by a R 7 group; or R 5 and R 6 , with the nitrogen atom which bears them, form a saturated or unsaturated cycle of 5 to 7 atoms optionally substituted by a R 7 group; and R 7 represents a hydrogen or halogen atom, a hydroxy, —(C 1 –C 4 )Alk, —(C 1 –C 6 )alkoxy, —NH(C 1 –C 4 )Alk, —N(C 1 –C 4 )Alk 2 , —COO(C 1 –C 4 )Alk, aralkyl or heteroaryl group; R 8 and R 9 independently represent a hydrogen atom or a —(C 1 –C 4 )Alk group; their salts or solvates, the pharmaceutical compositions containing them, a method for preparing them and synthesis intermediates
1. A compound of formula (I):
in which:
A is a group of formula (a) or (b)
where
R represents a hydrogen or halogen atom, an —S(O) 2 (C 1 –C 4 )alk group where z is 0, 1 or 2, an —NHSO 2 (C 1 –C 4 )alk, —SO 2 NH(C 1 –C 4 )alk, —NHSO 2 —(C 1 –C 4 )alk-phenyl or —NHSO 2 -phenyl group, it being possible for said phenyl to carry a halogen atom, a (C 1 –C 4 )alk group or a (C 1 –C 6 )alkoxy group;
R 1 represents a hydrogen atom or a —(C 1 –C 4 )alk, —CO(C 1 –C 4 )alk, —(C 1 –C 4 )alk-phenyl or —CO-phenyl-group, it being possible for said phenyl to carry a halogen atom or a —(C 1 –C 4 )alk or (C 1 –C 6 )alkoxy group;
R 2 is a hydrogen atom, an —SO 2 (C 1 –C 4 )alk, —SO 2 —(C 1 –C 4 )alk-phenyl, —SO 2 -phenyl, or a —(C 1 –C 4 )alk group;
X completes a saturated or unsaturated 5- to 8-atom ring which can carry one or two —(C 1 –C 4 )alk groups and/or one or two carbonyl groups;
R 3 and R′ 3 each represent independently a hydrogen or halogen atom, a —(C 1 –C 6 )alk, hydroxyl, —CN, —(C 1 –C 6 )alkoxy, —COR 4 or —Y—CR 8 R 9 —COR 4 group;
Y represents O or CH 2 ;
R 4 represents a hydroxyl, (C 1 –C 6 )alkoxy or —NR 5 R 6 group;
R 5 and R 6 represent independently a hydrogen atom; a —(C 1 –C 4 )alk, aryl or heteroaryl group optionally substituted with an R 7 group, an aralkyl or heteroaralkyl group optionally substituted with an R 7 group;
or else R 5 and R 6 , with the nitrogen atom carrying them, form a saturated or unsaturated 5- to 7-atom ring optionally substituted with an R 7 group;
R 7 represents a hydrogen or halogen atom, a hydroxyl, —(C 1 –C 4 )alk, —(C 1 –C 6 )alkoxy, —NH(C 1 –C 4 )alk, —N(C 1 –C 4 )alk 2 , —COO(C 1 –C 4 )alk, aralkyl or heteroaralkyl group; and
R 8 and R 9 represent independently a hydrogen atom or a —(C 1 –C 4 )alk group; or a salt thereof.
2. A compound according to claim 1 wherein the configuration of the carbon of the propanolamine carrying the OH group is (S).
3. A compound according to claim 1 wherein A is a group of formula (a).
4. A compound according to claim 3 wherein R is an —NHSO 2 (C 1 –C 4 )alk group.
5. A compound according to claim 4 wherein R 1 is a hydrogen atom.
6. A compound according to claim 1 wherein R 3 and/or R′ 3 are a hydrogen atom, a hydroxyl, —(C 1 –C 6 )alkoxy or —Y—CR 8 R 9 —COOCH 2 —CH 3 group.
7. A compound selected from the group consisting of:
N-[2-Benzyloxy-5-({(2S)-2-hydroxy-3-[(1,2,3,4-tetrahydro-2-naphthalenylmethyl)amino]-propyl}oxy)phenyl]methane sulfonamide;
N-[2-Hydroxy-5-({(2S)-2-hydroxy-3-[(1,2,3,4-tetrahydro-2-naphthalenylmethyl)amino]propyl}oxy)phenyl]methanesulfonamide;
N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methane sulfonamide;
N-(2-Benzyloxy-5-{[(2S)-2-hydroxy-3-({[(2R)-6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]methyl}amino)propyl]oxy}phenyl)methanesulfonamide;
N-(2-Hydroxy-5-{[(2S)-2-hydroxy-3-({[(2R)-6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]methyl}amino)propyl]oxy}phenyl}methanesulfonamide;
N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(7-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(7-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(6-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(6-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methane sulfonamide;
(2S)-1-[4-Benzyloxyphenoxy]-3-{[(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}-2-propanol;
4-[((2S)-2-Hydroxy-3-{[(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]amino}propyl)oxy]phenol;
Ethyl [(6-{[((2S)-3-{4-benzyloxy-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)-amino]methyl}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]acetate;
Ethyl [(6-{[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]-phenoxy}propyl)amino]methyl}-5,6,7,8-tetrahydro-2-naphthalenyl)oxy]acetate;
N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(5-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(5-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-[2-Benzyloxy-5-({(2S)-3-[(2,3,6,7,8,9-hexahydronaphtho[2,3-b][1,4]dioxin-7-ylmethyl)amino]-2-hydroxypropyl}oxy)phenyl]methanesulfonamide;
N-[5-({(2S)-3-[(2,3,6,7,8,9-Hexahydronaphtho[2,3-b][1,4]dioxin-7-ylmethyl)amino]-2-hydroxypropyl}oxy)-2-hydroxyphenyl]methanesulfonamide;
N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Benzyloxy-5-[((2S)-2-hydroxy-3-{[(7-hydroxy-1,2,3,4-tetrahydro-1-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[(7-hydroxy-1,2,3,4-tetrahydro-1-naphthalenyl)-methyl]amino}propyl)oxy]phenyl}methanesulfonamide;
N-{2-Benzyloxy-5-[((2S)-3-{[(6,7-dimethoxy-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-amino}-2-hydroxypropyl)oxy]phenyl}methanesulfonamide; and
N-{5-[((2S)-3-{[(6,7-Dimethoxy-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]amino}-2-hydroxypropyl)oxy]-2-hydroxyphenyl}methanesulfonamide;
or a salt thereof.
8. A process for preparing a compound according to claim 1 which comprises reacting a compound of formula (II)
with an amine of formula (III)
in the form of a nonsalified base, where A, R 3 and R′ 3 are as defined in claim 1 , and optionally converting the compound thus obtained into one of its salts.
9. A compound according to claim 2 wherein A is a group of formula (a).
10. A compound according to claim 9 wherein R is an —NHSO 2 (C 1 –C 4 )alk group.
11. A compound according to claim 10 wherein R 1 is a hydrogen atom.
12. A compound according to claim 2 wherein R 3 and/or R′ 3 are a hydrogen atom, a hydroxyl, —(C 1 –C 6 )alkoxy or —Y—CR 8 R 9 —COOCH 2 —CH 3 group.
13. A compound according to claim 3 wherein R 3 and/or R′ 3 are a hydrogen atom, a hydroxyl, —(C 1 –C 6 )alkoxy or —Y—CR 8 R 9 —COOCH 2 —CH 3 group.
14. A compound according to claim 4 wherein R 3 and/or R′ 3 are a hydrogen atom, a hydroxyl, —(C 1 –C 6 )alkoxy or —Y—CR 8 R 9 —COOCH 2 —CH 3 group.
15. A compound according to claim 5 wherein R 3 and/or R′ 3 are a hydrogen atom, a hydroxyl, —(C 1 –C 6 )alkoxy or —Y—CR 8 R 9 —COOCH 2 —CH 3 group.
16. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable excipient.
17. A pharmaceutical composition comprising a compound according to claim 7 together with a pharmaceutically acceptable excipient.
18. A pharmaceutical composition comprising a compound according to claim 11 together with a pharmaceutically acceptable excipient.
19. A pharmaceutical composition comprising a compound according to claim 15 together with a pharmaceutically acceptable excipient.
20. A method for the treatment of obesity which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 .
21. A method for the treatment of obesity which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 7 .
22. A method for the treatment of obesity which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 11 .
23. A method for the treatment of obesity which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 15 .