Patent EA-003613-B1 (EA)
Title: Ureidopiperidine derivatives as selective human nk3 receptor antagonists
Inventor: AULOMBARD ALAIN
IPC: C07D401/14
Filed: 1999-10-04
Abstract: 1. A compound of the formula: in which: R1 and R2 each represent, independently of one another, hydrogen or a (C1-C3)alkyl; R3 represents hydrogen as well as its salts with mineral or organic acids and its solvates. 2. A compound according to claim 1 in the form of an (R) configuration (+) isomer. 3. 1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(N',N'-dimethylureido)-4-phenylpiperidin-1-]propyl]piperidine and its salts and solvates. 4. 1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(N',N'-dimethylureido)-4-phenylpiperidin-1-]propyl]piperidine in the form of the (+) isomer, and its solvates. 5. A process for the preparation of a formula (I) compound in accordance with Claim 1, of its salts and its solvates, characterized in that: a1) a compound with the formula: in which G represents a methyl, phenyl, tolyl or trifluoromethyl group is treated with a piperidine derivative with the formula: in which R4 represents an NR3CONR1R2 group or a COOH group, R1, R2 and R3 being as defined in Claim 1; b1) when R4 = COOH, the compound thus obtained with the formula: is converted to a formula (I) compound; c1) the compound thus obtained at stage a1) or stage b1) is optionally converted to one of its salts or solvates. 6. A process for the preparation of a formula (I) compound in accordance with Claim 1, of its salts and solvates, characterized in that a2) a compound with the formula: treated in which G is as defined in Claim 5, and Pr represents a protective group selected from the trityl, tert-butoxycarbonyl or benzyloxycarbonyl group is with a piperidine derivative with the formula: in which R4 represents an NR3CONR1R2 group or a COOH group; b2) the protective group Pr of the compound thus obtained with the formula: is selectively eliminated; c2) the compound thus obtained with the formula: is treated with a benzoyl halide; d2) when the group R4 = COOH, the compound thus obtained with the formula: is converted to a formula (I) compound; e2) the compound thus obtained at stage c2) or at stage d2) is optionally converted to one of its salts or solvates. 7. A process for the preparation of a formula (I) compound in accordance with Claim 1, of its salts and its solvates, characterized in that: a3) an alcohol with the formula: is oxidized; b3) the aldehyde thus obtained with the formula: is treated with a piperidine derivative with the formula: in which R4 is as defined in claim 9; c3) when R4 = COOH, the compound thus obtained with the formula: is converted to a formula (I) compound; d3) the compound thus obtained at stage b3) or stage c3) is optionally converted to one of its salts or solvates. 8. A process for the preparation of a formula (I) compound in accordance with Claim 1, of its salts and its solvates, characterized in that: a4) a compound with the formula: is treated, in the presence of a base, with the tert-butyl ester of (4-phenylpiperidin-4-ylcarbamic acid with the formula: in which R' - (C1-C6) alkyl; b4) the compound thus obtained with the formula: is deprotected by the action of an acid; c4) the compound thus obtained with the formula: is first treated by a reactive derivative carbonic acid in the presence or absence of a base, then with an amine with the formula NR1R2 in order to obtain the desired formula (I) compound. 9. A process in accordance with Claim 5 or 8 for the preparation of a formula (I) compound having the (R) configuration, of its salts and its solvates, characterized in that a compound with the formula: in which G is as defined in Claim 5, is used, in the form of the (+) isomer, as the starting material. 10. A process in accordance with Claim 7 for the preparation of a formula (I) compound having the (R) configuration, of its salts and its solvates, characterized in that an alcohol with the formula: in the form of the (+) isomer is used as the starting material. 11. A compound with the formula: in racemic form or in an optically pine form, as well as its salts. 12. Pharmaceutical composition containing, as an active principle, a compound in accordance with any of Claims 1 to 4 or one of its pharmaceutically acceptable salts and solvates. 13. Use of a formula (I) compound or one of its pharmaceutically acceptable salts and solvates for the preparation of medicaments intended for the treatment of any pathology in which neurokinin B and human NK3 receptors are involved. 14. Use in accordance with Claim 13 for the preparation of medicaments intended for the treatment of respiratory disorders. 15. Use in accordance with Claim 13 for the preparation of medicaments intended for the treatment of central nervous system diseases. 16. Use in accordance with Claim 13 for the preparation of medicaments intended for the treatment of pain. 17. Use in accordance with Claim 13 for the preparation of medicaments intended for the treatment of gastrointestinal disorders.