Patent EA-001771-B1 (EA)
Title: Quinoline-4-carboxamide derivatives, their preparation and their use as neurokinin-3 (-k-3) and neurokinin-2 (-k-2) receptor antagonists
Inventor: GIARDINA GIUSEPPE AMALDO MARIA
IPC: C07D401/12
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, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, R1 represents hydrogen, C1-C6 alkyl; R2 represents hydrogen, C1-C6 alkyl, hydroxy, halogen, cyano, amino, mono- or di- C1-C6 alkylamino, C1-C6 alkylsulphonylamino, mono- or di- C1-C6 alkanoylamino wherein any alkyl group is optionally substituted with an amino group or with a mono- or di- C1-C6 alkylamino group, or R2 is a moiety -X-(CH2)n-Y wherein X is a bond or -O- and n is an integer in the range of from 1 to 5 providing that when X is -O- n is only an integer from 2 to 5 and Y represents a group NY1Y2 wherein Y1 and Y2 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkenyl, phenyl or phenyl-C1-C6alkyl or Y is hydroxy, halogen or an N-linked single or fused heterocyclic group, wherein any single or fused ring is saturated or unsaturated and comprises 5 or 6 ring atoms, said ring atoms optionally comprise 1 or 2 additional heteroatoms, selected from O and N and wherein one or two ring atoms are optionally substituted by one or two oxogroups or by one or two groups selected from hydroxy, C1-C6alkoxycarbonyl, C1-C6alkyl, phenyl or naphthyl or aromatic heterocyclic group, comprising 5 or 6 ring atoms, said ring atoms comprise 1 or 2 nitrogen atoms, or substituents on adjacent ring atoms form aromatic carbocyclic ring, wherein said phenyl, naphthyl or aromatic heterocyclic group optionally substituted by one or two groups selected from C1-C6alkyl, C1-C6alkoxy, hydroxy, halo or halo C1-C6alkyl; R3 represents phenyl; and R4 represents hydrogen or C1-C6 alkyl. 2. A compound according to Claim 1, wherein R represents ethyl. 3. A compound according to any one of Claims 1 or 2 wherein R2 represents a moiety -X-(CH2)n-Y. 4. A compound according to any one of Claims 1 to 3, wherein the moiety -X-(CH2)n-Y is a moiety of formula (a):   wherein T represents C1-C6alkyl, C1-C6alkoxycarbonyl, optionally substituted phenyl or phenyl C1-C6 alkyl or an aromatic heterocyclic group, comprising 5 or 6 ring atoms, said ring atoms comprise 1 or 2 nitrogen atoms, and/or X is O and n is 2 or 3 or X is a bond and n is 1, 2 or 3. 5. A compound according to Claim 4, wherein T represents a methyl group. 6. A compound according to Claim 4, wherein T represents a phenyl group, substituted with one or more C1-C6alkoxy groups. 7. A compound according to Claim 4, wherein T represents a pyrimidine group. 8. A compound according to Claim 1, wherein -X-(CH2)n-Y is a moiety of formula (b):   wherein X is -O- or a bond, n is 1, 2 or 3, T1 and T2 each independently represents hydroxy, C1-C6alkoxycarbonyl, C1-C6alkyl, phenyl or phenyl-C1-C6alkyl or aromatic heterocyclic group, having single or fused rings, comprising 5 or 6 ring atoms, comprising 1 or 2 nitrogen atoms, or T1 and T2 selected together with the carbon atoms to which they are attached form aromatic carbocyclic ring; said phenyl or phenyl C1-C6 alkyl or aromatic heterocyclic groups are optionally substituted with one or two groups, selected from C1-C6alkyl, C1-C6alkoxy, hydroxy, halo or halo-C1-C6alkyl; or C1-C6alkyl, or one of T1 and T2 is oxygroup and the other is selected from the above mentioned groups as appropriate. 9. A compound according to Claim 8, wherein T1 and T2 together with the carbon atoms to which they are attached form aromatic carbocyclic ring. 10. A compound according to Claim 8, wherein n is an integer 1 or 2. 11. A compound according to Claim 1, wherein Ar is phenyl, R is ethyl, R1 is hydrogen, R2 is a moiety -X-(CH2)n-Y wherein X is -O-, n is 1, 2 or 3 and Y is a moiety formula (a) as defined in Claim 4 or a moiety of formula (b) as defined above in Claim 8. 12. A compound according to Claim 1, selected from the compounds with the following meanings of radicals Ar, R, R1, R2 and R4:       13. A compound according to Claim 1, selected from the compounds with the following meanings of radicals Ar, R, R1, R2 and R4:   14. A method for obtaining the compound of formula (I) or salt thereof and/or solvate thereof, comprising the reacting of compound of formula (III):   wherein R', R4' and Ar' are R, R4 and Ar as defined for formula (I) or a group or atom convertible to R, R4 and Ar respectively, with a compound of formula (II) or an active derivative thereof:   wherein R'1, R'2 and R'3 are 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, R'3 and R'4 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, R'3 and R'4 to Ar, R, R1, R2, R3 or R4 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. 15. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier. 16. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof as an active therapeutic substance.