Patent EA-002124-B1 (EA)
Title: Quinoline derivatives
Inventor: GIARDINA GUISEPPE ARNALDO MARI
IPC: A61P11/06
Filed: 1996-11-22
Abstract: 1. A compound of formula (I):   or a salt thereof, or a solvate thereof, wherein, Ar is phenyl; R is C1-C6 alkyl, R1 is hydrogen; R2 represents a moiety -O-(CH2)n-X wherein X is C1-6alkyl optionally substituted with one or two groups selected from hydroxy and amino; carboxy, cyano, C1-C6 alkoxycarbonyl, aminocarbonyl, mono- or di-C1-C6-alkylaminocarbonyl, amino-C1-C6-alkylaminocarbonyl or mono- or di-C1-C6-alkylamino-C1-C6-alkylaminocarbonyl; or X is a group -NX1X2 wherein X1 and X2 each independently represent hydrogen, carboxy-C1-C6-alkylcarbonyl, C1-C6alkoxycarbonyl-C1-C6-alkylcarbonyl, C1-C6alkylcarbonyl, phenylcarbonyl, phenyl-C1-C6alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C1-C6alkylcarbonyl, wherein heteroaryl moiety comprises aromatic heterocyclyc ring comprising 5 or 6 atoms and comprising up to 4 heteroatoms in the ring, selected from S, O, and N; aminocarbonyl, mono- or bis-C1-C6alkylaminocarbonyl, amino-C1-C6 alkylcarbonyl, mono- or bis-C1-C6 alkylamino-C1-C6 alkylcarbonyl, a moiety of formula -CO-T-CO-T1 or a 5 to 9 membered single or fused ring cycloalkyl group optionally comprising 1 or 2 nitrogen atoms and optionally 1 or 2 additional heteroatoms selected from O or N and wherein one or two ring atoms are optionally substituted with C1-C6 alkyl, said ring being optionally fused to a benzene ring; wherein the above mentioned phenyl and heteroaryl groups are optionally substituted with up to two groups selected from hydroxy, C1-C6alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, mono- or bis-C1-C6 alkylamino, mono- or bis-C1-C6 alkylamino-C1-6 alkyl, amino-C1-6 alkoxy, mono- or bis-C1-C6 alkylamino-C1-6-alkoxy, carboxy, C1-C6 alkylcarbonyl, C1-C6alkoxycarbonyl, carboxy-C1-6 alkyl, carboxy-C1-6 alkoxy and C1-C6 alkylcarbonyl-C1-6 alkoxy; and wherein the alkyl moiety of any heteroaryl-C1-6alkyl or phenyl-C1-6 alkyl group is optionally substituted with an amino, a mono-C1-C6 alkylamino or a bis-C1-C6alkyamino group; or X is a C-linked single or fused ring heterocyclic group, any ring being saturated or unsaturated and consisting of 5- to 6- ring atoms, said ring atoms comprising 1 or 2 nitrogen atoms and optionally 1 or 2 additional heteroatoms selected from O or N and wherein one or two ring atoms are optionally substituted with C1-6alkyl, hydroxy, amino, mono- or bis-C1-C6 alkylamino or an oxo substituent; and n is zero or an integer in the range of from 1 to 7 providing that when X is a group -NX1X2, n is only an integer in the range of from 2 to 7 and providing that X1 and X2 are not simultaneously hydrogen; or R2 represents a moiety -NH-CO-NHY wherein Y represents C1-6 alkyl, phenyl, phenyl C1-3 alkyl, a moiety -(CH2)p-X3 wherein p is an integer in the range of from 1 to 4 and X3 is carboxy, C1-6 alkoxycarbonyl, or a moiety -CO-NH-(CH2)q-NX4X5 wherein q is an integer in the range of from 2 to 4 and X4 and X5 each independently represents hydrogen, C1-6 alkyl or C1-6 alkylcarbonyl; R3 is phenyl; T is a C1-C6 alkylene or C2-6alkenylene group; T1 is hydroxy or C1-6 alkoxy. 2 A compound according to Claim 1, wherein R2 is a group -O-(CH2)n-X wherein X represents carboxy or C1-6 alkoxycarbonyl or a C-linked single or fused ring heterocyclic group as defined in relation to formula (I). 3. A compound according to Claim 1, wherein R2 is -O-(CH2)n-X wherein n is an integer 2 or 3 and X is a group -NX1X2 wherein X1 is hydrogen and X2 is a moiety of the above defined formula -CO-T-CO-T1, substituted phenyl-C1-6alkylcarbonyl or heteroarylcarbonyl. 4. A compound according to Claim 1, wherein Ar is phenyl, R is ethyl, R1 is hydrogen and R2 is a moiety -O-(CH2)n-X wherein either: n is 1, 2 or 3 and X is carboxy, C1-6 alkoxycarbonyl, for example ethoxycarbonyl , or the C-linked single or fused ring heterocyclic group defined in relation to formula (I), for example pyridyl; or n is 2 or 3 and X is a group -NX1X2 wherein X1 is hydrogen and X2 is moiety of the above defined formula -CO-T-CO-T1, for example wherein T is ethylene and T1 is OH, or X2 is substituted phenyl-C1-6alkylcarbonyl, for example (2-carboxy)benzylcarbonyl and (2-pyrrolidinomethyl)-benzylcarbonyl or heteroarylcarbonyl, for example 2-pyrazinylcarbonyl. 5. A compound of formula I according to Claim 1, or a salt thereof, or a solvate thereof wherein radicals Ar, R, R1, R2 and R3 have the following meanings:       6. A compound of formula I according to Claim 1, or a salt thereof, or a solvate thereof wherein radicals Ar, R, R1, R2 and R3 have the following meanings:   7. A process for the preparation of a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises reacting a compound of formula (III):   wherein R' and Ar' have the same meanings as R and Ar as defined for formula (I) or a group or atom convertible to R and Ar respectively, with a compound of formula (II) or an active derivative thereof:   wherein R'1, R'2 and R'3 have the same meanings as R1, R2 and R3 respectively as defined in relation to formula (I) or a group convertible to R1, R2 and R3 to form a compound of formula (Ib):   wherein Ar', R', R'1, R'2 and R'3 are as defined above, and optionally thereafter carrying out one or more of the following optional steps: (i) converting any one of Ar', R', R'1, R'2 and R'3 to Ar, R, R1, R2 or R3 respectively as required, to obtain a compound of formula (I); (ii) converting a compound of formula (I) into another compound of formula (I); and (iii) preparing a salt of the compound of formula (I) and/or a solvate thereof. 8. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier. 9. A method for the treatment and/or prophylaxis of conditions which are characterised with excessive stimulation of NK3 and NK2 tachykinin receptors and central nervous system diseases in mammals, which method comprises administering to the mammal in need of such treatment and/or prophylaxis an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. 10. A compound of formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance. 11. A compound of formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, for use in the treatment and/or prohylaxis of conditions which are characterised with excessive stimulation of NK3 and NK2 tachykinin receptors and central nervous system diseases. 12. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for the treatment of conditions which are characterised with excessive stimulation of NK3 and NK2 tachykinin receptors and central nervous system diseases. 13. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof as a combined NK-2/NK-3 antagonist. 14. The use according to Claim 13, wherein the compound of formula (I) having an NK-2/NK-3 binding affinity ratio in the range of from 0.05 to 20. 15. The use according to Claim 13, wherein the compound of formula (I) having an NK-2/NK-3 binding affinity ratio in the range of from 0.1 to 10. 16. The use according to Claim 13, wherein the compound of formula (I) having substantially equal binding affinities for the NK-2 and NK-3 receptors. 17. A method for the treatment and/or prophylaxis of respiratory diseases in mammals which method comprises the administration of an effective, non-toxic, pharmaceutically acceptable amount of a combined NK-2/NK-3 antagonist according to Claim 1.