Patent EA-005183-B1 (EA)
Title: Quinolyl propyl piperidine derivatives their preparation and compositions containing them
Inventor: MALLERON JEAN-LUC
IPC: C07D401/14
Filed: 2000-09-14
Abstract: 1. A quinolylpropylpiperidine derivative compound of formula (I) wherein: R1 represents a hydrogen atom, a halogen atom, or a hydroxyl; R'1 represents a hydrogen atom or can represent a halogen atom when R1 is a halogen atom when R1 represents also a halogen atom; and R degree represents a hydrogen atom; or R1 and R degree together form a bond and R2 represents a carboxyl, carboxymethyl, or 2-carboxyethyl radical; hydroxymethyl, alkyloxycarbonyl, alkyloxycarbonylmethyl or alkyloxycarbonyl-2-ethyl, alkyl parts of which contain 1-6 carbon atoms, R3 represents an alkylene radical (having 1 to 6 carbon atoms) substituted by a sulfur atom having phenyl as a substituent, which can contain 1-4 substituents [selected from a halogen atom, hydroxyl, alkyl, alkyloxy trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano or amino], 3 to 7-membered cycloalkyl or aromatic 5-6-membered heterocyclyl comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur and being optionally substituted by [halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, or amino]; or R3 represents a propargyl radical substituted by a phenyl radical which can contain 1 to 4 substituents [chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, and amino]; or substituted by a cycloalkyl radical comprising 3 to 7 members; or substituted by a 5- to 6-membered aromatic heterocyclyl radial comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur and being optionally substituted [halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxy, alkyloxycarbonyl, cyano, or amino]; or R3 represents cinnamyl or 4-phenylbuthene -3-yl; and R4 represents an alkyl radical (comprising 1 to 6 carbon atoms) or an alkenyl-CH2- or an alkynyl-CH2- radical, the alkenyl or alkynyl parts of which comprise 2 to 6 carbon atoms; provided that the alkyl radicals and alkyl portions of radicals are straight- or branched-chain radicals and portions of radicals and comprise, except when specifically mentioned, 1 to 4 carbon atoms; a diastereoisomer thereof, a mixture of diastereoisomers thereof, or a salt thereof. 2. A quinolylpropylpiperidine derivative compound according to claim 1, wherein R1 represents a hydrogen atom, a halogen atom, or a hydroxyl radical; R'1 represents a hydrogen atom, R degree represents a hydrogen atom; or R1 and R degree together form a bond and R'1 represents a hydrogen atom, R2 represents a carboxyl, carboxymethyl, or 2-carboxyethyl radical; hydroxymethyl, alkyloxycarbonyl, alkyloxycarbonylmethyl or alkyloxycarbonyl-2-ethyl, alkyl parts of which contain 1-6 carbon atoms, R3 represents an alkylene radical (having 1 to 6 carbon atoms) substituted by a sulfur atom having phenyl as a substituent, which can be substituted by 1-4 halogen atoms, 3 to 7-membered cycloalkyl or aromatic 5-6-membered heterocyclyl comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur and being optionally substituted by halogen and R4 represents an alkyl radical (comprising 1 to 6 carbon atoms) provided that the alkyl radicals or portions thereof having 1-4 carbon atoms in straight- or branched-chain, a diastereoisomer and a mixture thereof, or a salt thereof. 3. A quinolylpropylpiperidine derivative according to any one of claims 1 or 2, which is (3R,4R)-4-[3-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid, a diastereoisomer thereof, a mixture of diastereoisomers thereof, or a salt thereof. 4. A quinolylpropylpiperidine derivative according to any one claims 1 or 2, which is (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid, or a salt thereof. 5. A quinolylpropylpiperidine derivative according to claim 1, which is (3R,4R)-4-[3-fluoro-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid, a diastereoisomer and a mixture thereof, or a salt thereof. 6. A quinolylpropylpiperidine derivative according to claim 1, which is (3R,4R)-1-[2-(3-fluorophenylthio)ethyl]-4-[3-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetic acid, diastereoisomer and a mixture thereof, or a salt thereof. 7. A quinolylpropylpiperidine derivative according to claim 1, which is (3R,4R)-4-[3-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid, a diastereoisomer and a mixture thereof, or a salt thereof. 8. A process for preparing a quinolylpropylpiperidine derivative of formula (I) according to claim 1, said process comprising condensing an R3 chain as defined in claim 1 onto a in which R4 is defined as in claim 1, R''1, and R'''1 each independently represent a hydrogen atom or together form an oxo radical, and R'2 represents a protected carboxyl, carboxymethyl, or 2-carboxyethyl radical, or an alkyloxycarbonyl, alkyloxycarbonylmethyl, or 2-(alkyloxycarbonyl)ethyl radical, to obtain a quinolylpropylpiperidine derivative of formula (III): in which R"1, R'''1, R'2 and R4 are defined as above and R3 is as defined in claim 1; then, if appropriate, removing the acid-protecting radical, or, if appropriate, reducing the oxo radical represented by R''1 and R'''1 to an alcohol in which R1 represents hydroxyl; then, if appropriate, halogenating the quinolylpropylpiperidine derivative wherein R1 is hydroxyl if it is desired to obtain a quinolylpropylpiperidine derivative in which R1 is a halogen atom, and, if appropriate, dehydrohalogenating the halogenated derivative to obtain a quinolylpropylpiperidine derivative in which R1 and R degree together form a bond, or, if appropriate, dihalogenating the product of formula (III) in which R''1 and R'''1 together form an oxo radical to obtain a quinolylpropylpiperidine derivative in which R1 and R'1 are halogen atoms; and/or, if appropriate, reducing the acid, protected in the form of an R'2 radical, in the 3-position of the piperidine to a hydroxymethyl radical and, optionally, convert a carboxymethyl or 2-carboxyethyl radical by a common technique, then, optionally, removing the acid-protecting radical, and/or, if appropriate, separating diastereoisomers and, if appropriate, converting the obtained product into a salt. 9. The process according to claim 8, wherein the condensation of the R3 radical chain with piperidine is carried out by the action of a derivative of general formula: R3 - X wherein R3 is defined as above; and X represents a halogen atom, a methylsulfonyl radical, a trifluoromethylsulfonyl radical or a p-toluenesulfonyl radical. 10. The process according to any one of claims 8 or 9, wherein when R3 represents propargyl substituted with phenyl, cycloalkyl, or heterocyclyl, the condensation reaction is carried out by condensation of a propargyl halide, followed by substitution of the propargyl chain with a phenyl, cycloalkyl, or heterocyclyl radical. 11. A pharmaceutical composition, comprising at least one derivative compound of formula (I) according to claim 1 alone or in a combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants.