NOVEL PIPERIDINECARBOXAMIDE DERIVATIVES, METHOD FOR PREPARING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
The invention relates to compounds of formula (I): as well as their salts with inorganic or organic acids, their solvates and/or their hydrates, which exhibit a very high affinity both for the human NK 2 receptors for neurokinin A and for the human NK 3 receptors for neurokinin B and are antagonists of the said receptors. The invention also relates to their method of preparation, the pharmaceutical compositions containing them and their use for the preparation of medicaments.
1 . A compound of formula (I):
wherein:
R 1 , represents a hydrogen atom or a methyl radical;
B represents a direct bond or a —CH 2 — group;
Z represents a phenyl, a 2,3-dichlorophenyl or a 2,6-dichlorophenyl; or
a salt thereof.
2 . The compound of formula (I) according to claim 1 , in the form of an optically pure isomer.
3 . The compound according to claim 1 , which is selected from the group consisting of:
N,N-dimethyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer;
N-methyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl)-morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer;
N,N-dimethyl-1-[2-[4-2,3-dichlorobenzoyl)-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, laevorotatory isomer;
N,N-dimethyl-1-[2-[4-(2,6-dichlorophenyl)acetyl]-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer;
N,N-dimethyl-1-[2-[4-[2-(2,3-dichlorophenyl)acetyl]-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer; and
N-methyl-1-[2-[4-[2-(2,3-dichlorophenyl)acetyl]-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer;
or a salt thereof.
4 . The compound according to claim 1 , which is:
N,N-dimethyl-1-[2-[4-benzoyl-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]-4-(piperidin-1-yl)piperidine-4-carboxamide, dextrorotatory isomer;
or a salt thereof.
5 . A method for preparing a compound of formula (I) according to claim 1 , or a salt thereof,
comprising:
reacting a compound of formula (II):
in which B and Z are as defined for a compound of formula (I) according to claim 1 , with a compound of formula (III):
in which R 1 is as defined for a compound of formula (I) according to claim 1 , in the presence of an acid, in a solvent; and
reducing the intermediate iminium salt formed by means of a reducing agent.
6 . A method for preparing a compound of formula (I) according to claim 1 , or a salt thereof comprising:
reacting a compound of formula (IV):
in which B and Z are as defined for a compound of formula (I) in claim 1 and Y represents a methyl, phenyl, tolyl or trifluoromethyl group, with a compound of formula (III):
in which R 1 is as defined for a compound of formula (I) in claim 1 .
7 . A method for preparing a compound of formula (I) according to claim 1 , or a salt thereof comprising:
reacting a compound of formula (V):
in which R 1 is as defined for a compound of formula (I) according to claim 1 , with a functional derivative of an acid of formula (VI):
HOOC—B-Z (VI)
in which B and Z are as defined for a compound of formula (I) according to claim 1 .
8 . A pharmaceutical composition comprising, as active ingredient, a compound according to claim 1 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
9 . A pharmaceutical composition according to claim 8 , containing from 0.1 to 1000 mg of active ingredient in dosage unit form in which the active ingredient is mixed with at least one pharmaceutical excipient.
10 . A pharmaceutical composition comprising, as active ingredient, a compound according to claim 2 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
11 . A pharmaceutical composition comprising, as active ingredient, a compound according to claim 3 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
12 . A pharmaceutical composition comprising, as active ingredient, a compound according to claim 4 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.
13 . A method for treating any pathology where either neurokinin A and/or NK 2 receptors, or neurokinin B and/or NK 3 receptors, or both neurokinin A and neurokinin B and/or NK 2 and NK 3 receptors are involved which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
14 . A method for treating any pathology where either neurokinin A and/or NK 2 receptors, or neurokinin B and/or NK 3 receptors, or both neurokinin A and neurokinin B and/or NK 2 and NK 3 receptors are involved which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
15 . A method for treating any pathology where either neurokinin A and/or NK 2 receptors, or neurokinin B and/or NK 3 receptors, or both neurokinin A and neurokinin B and/or NK 2 and NK 3 receptors are involved which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
16 . A method for treating any pathology where either neurokinin A and/or NK 2 receptors, or neurokinin B and/or NK 3 receptors, or both neurokinin A and neurokinin B and/or NK 2 and NK 3 receptors are involved which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.
17 . A method for treating chronic obstructive bronchitis, asthma, urinary incontinence, irritable bowel syndrome, Crohn's disease, ulcerative colitis, depression, anxiety, epilepsy and schizophrenia, which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
18 . A method for treating chronic obstructive bronchitis, asthma, urinary incontinence, irritable bowel syndrome, Crohn's disease, ulcerative colitis, depression, anxiety, epilepsy and schizophrenia, which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
19 . A method for treating chronic obstructive bronchitis, asthma, urinary incontinence, irritable bowel syndrome, Crohn's disease, ulcerative colitis, depression, anxiety, epilepsy and schizophrenia, which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
20 . A method for treating chronic obstructive bronchitis, asthma, urinary incontinence, irritable bowel syndrome, Crohn's disease, ulcerative colitis, depression, anxiety, epilepsy and schizophrenia, which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.