RU2001121084A - New derivatives of N-triazolylmethylpiperazine as antagonists of neurokinin receptors - Google Patents

Claims (9)

1. Compounds of General Formula I

in which R ¹ represents hydrogen or lower alkyl; R ² is (ness.) Alkyl, di (ness.) Alkylamino (ness.) Alkyl, (ness.) Alkoxycarbonyl (ness.) Alkyl, optionally one or two disubstituted (ness.) Alkyl cyclo (hetero) alkyl with 5- 6 atoms of the ring, optionally containing 1-2 double bonds, optionally one or two disubstituted in the (hetero) phenyl ring with halogen, (lower) alkyl and / or (lower) alkoxy group (hetero) phenyl (lower) alkyl, (lower .), the alkyl chain of which is optionally mono- or disubstituted by (lower alkyl.) alkyl or spiro-C ₄ -C ₅ alkylene, or represents optionally mono- or disubstituted in the phenyl ohm ring by halogen, (lower alkyl.) alkyl and / or (lower alkyl.) alkoxy phenyl (lower). alkoxy and R ³ is (ness.) Alkyl, (ness.) Alkoxycarbonyl (ness.) Alkyl or optionally one or two disubstituted (ness.) Alkyl cyclo (hetero) alkyl with 5-6 ring atoms, or R ² and R ³ both together with the nitrogen atom to which they are attached form a cyclic group of the formula a

in which a denotes nitrogen, oxygen, methylene or methylidene, the double bond of which is formed together with an adjacent carbon atom in position 3 of group a, n denotes an integer from 1 to 3, R ⁴ is hydrogen, (ness.) Alkyl, (ness.) Alkoxy (ness.) Alkyl, (ness.) Alkoxycarbonyl, (ness.) Alkoxycarbonyl (ness.) Alkyl, di (ness.) Alkylamino (ness.) Alkyl optionally one or two disubstituted with halogen, (ness.) alkyl and / or (ness.) alkoxy group (hetero) vinyl, optionally one or two disubstituted in the (hetero) phenyl ring with halogen, (ness.) alkyl and / or (ness. ) alkoxygroup (hetero) phenyl (ness.) alkyl, (ness.) alkyl chain of which is optionally one or two disubstituted (ness.) alkyl, cyclo (hetero) alkyl with 5-6 ring atoms or cyclo (hetero) alkyl ( izsh.) alkyl, cyclo (hetero) alkyl group of which contains 5-6 ring atoms, and R ⁵ denotes hydrogen, (ness.) Alkyl or (ness.) Alkoxy (ness.) Alkyl, or R ⁴ and R ⁵ both together represent a spiroethylenedioxy group bonded to the carbon atom of the group a, bonded to two adjacent atoms of the a ₃ -C ₄ group of alkylene or annelated with two adjacent carbon atoms of the a group of phenyl, or R ² and R ^3, together with the nitrogen atom to which they are bonded, form a pyrrolidine ring disubstituted with C ₄ alkylene bonded respectively through two adjacent carbon atoms, as well as physiologically acceptable acid addition salts of the compounds of formula I. 2. The compounds of General formula I according to claim 1, in which R ¹ denotes hydrogen, R ² denotes (ness.) Alkyl, di (ness.) Alkylamino (ness.) Alkyl, (ness.) alkoxycarbonyl (ness.) alkyl, optionally monosubstituted (ness.) alkyl cyclo (hetero) alkyl with 5-6 ring atoms, optionally one or two disubstituted in the (hetero) phenyl ring (ness.) alkyl or (ness. ) alkoxy group (hetero) phenyl (ness.) alkyl or mono or disubstituted in the phenyl ring (ness.) alkyl or (ness.) alkoxygroup phenyl-C ₂ -C ₄ alkyl and R ³ means (ness.) alkyl or (ness. .), alkoxycarbonyl (lower alkyl.) alkyl, with the proviso that R ² and R ³ do not simultaneously represent isobutyl, or R ² and R ³ both together with the nitrogen atom to which they are connected They form a cyclic group of formula a, wherein n is an integer from 1 to 3, provided that n is 2 or 3 if R ⁴ and R ⁵ are both hydrogen and at the same time A is methylene, R ⁴ denotes hydrogen, ( ness.) alkyl, (ness.) alkoxy (ness.) alkyl, (ness.) alkoxycarbonyl (ness.) alkyl, di (ness.) alkylamino (ness.) alkyl, optionally monosubstituted (ness.) alkyl or (ness. ) an alkoxy group (hetero) phenyl, optionally monosubstituted in a (hetero) phenyl ring with halogen, lower alkyl or a lower alkoxy alkylene (hetero) phenyl lower alkyl, iklo (hetero) alkyl with 5-6 ring atoms, or cyclo (hetero) alkyl (lower alkyl.) alkyl, cyclo (hetero) alkyl group of which contains 5-6 ring atoms, and R ⁵ is hydrogen, (lower alkyl.) alkyl or ( ness.) alkoxy (ness.) alkyl, provided that R ⁴ and R ^{5 are} not bonded to the same ring atom of group a, or R ⁴ and R ⁵ both together represent a spiroethylenedioxy group attached to the carbon atom of a or two adjacent ring atoms of the group a ₃ -C ₄ alkylene. 3. The compounds of general formula I according to claim 1 or 2, wherein the 1H-indol-3-ylmethyl group-bearing carbon atom of the C-2 piperazine ring has an R configuration. 4. The compounds of general formula I according to any one of the preceding paragraphs, wherein the optionally present group a is substituted with substituents R ⁴ and R ^5, pyrrolidine, while R ⁴ and R ^{5 are} both not hydrogen at the same time, or are respectively substituted with R ⁴ and R ⁵ 2,5-dihydropyrrole, piperidine, piperazine, morpholine or diazepan. 5. (2R) -1 [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) -4 - {[5 (morpholinomethyl) -2H-1,2,3-triazole- 4-yl] methyl} piperazine according to claim 4. 6. Dihydrochloride (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) -4 {[5- (morpholinomethyl) -2H-1,2,3- triazol-4-yl] methyl} piperazine according to claim 5. 7. Medicines containing a pharmacologically effective amount of a compound according to claim 1 and conventional pharmaceutical excipients and / or carriers. 8. A method of obtaining compounds of General formula I

in which R ¹ denotes hydrogen or (ness.) alkyl, R ² is (ness.) Alkyl, di (ness.) Alkylamino (ness.) Alkyl, (ness.) Alkoxycarbonyl (ness.) Alkyl, optionally one or two disubstituted (ness.) Alkyl cyclo (hetero) alkyl with 5- 6 atoms of the ring, optionally containing 1-2 double bonds, optionally one or two disubstituted in the (hetero) phenyl ring with halogen, (lower) alkyl and / or (lower) alkoxy group (hetero) phenyl (lower) alkyl, (lower .) the alkyl chain of which is optionally one or two disubstituted (lower) with alkyl or spiro-C ₄ -C ₅ alkylene, or is optionally one or two disubstituted in phenyl the ring with halogen, lower alkyl and / or lower alkoxy phenyl lower alkoxy and R ³ is (ness.) Alkyl, (ness.) Alkoxycarbonyl (ness.) Alkyl or optionally one or two disubstituted (ness.) Alkyl cyclo (hetero) alkyl with 5-6 ring atoms, or R ² and R ³ both together with the nitrogen atom to which they are attached form a cyclic group of the formula a

in which A represents nitrogen, oxygen, methylene or methylidene, the double bond of which is formed together with an adjacent carbon atom in position 3 of group a; n is an integer from 1 to 3; R ⁴ is hydrogen, (ness.) Alkyl, (ness.) Alkoxy (ness.) Alkyl, (ness.) Alkoxycarbonyl, (ness.) Alkoxycarbonyl (ness.) Alkyl, di (ness.) Alkylamino (ness.) Alkyl optionally one or two disubstituted with halogen, (ness.) alkyl and / or (ness.) alkoxy group (hetero) phenyl, optionally one or two disubstituted in the (hetero) phenyl ring with halogen, (ness.) alkyl and / or (ness. ) alkoxygroup (hetero) phenyl (ness.) alkyl, (ness.) alkyl chain of which is optionally one or two disubstituted (ness.) alkyl, cyclo (hetero) alkyl with 5-6 ring atoms or cyclo (hetero) al keel (ness.) alkyl, cyclo (hetero) alkyl group of which contains 5-6 atoms of the cycle, and R ⁵ denotes hydrogen, (ness.) Alkyl or (ness.) Alkoxy (ness.) Alkyl, or R ⁴ and R ⁵ both together represent a spiroethylenedioxy group bonded to the carbon atom of the group a, bonded to two adjacent atoms of the a ₃ -C ₄ group of alkylene or annelated with two adjacent carbon atoms of the a group of phenyl, or R ² and R ^3, together with the nitrogen atom to which they are bonded, form a pyrrolidine ring disubstituted with C ₄ alkylene bonded respectively through two adjacent carbon atoms, as well as their physiologically acceptable acid addition salts, characterized in that a) a compound of General formula II

where R ¹ has the above meanings, is subjected to interaction with the compound of General formula III

where R ² and R ³ have the above meanings and where the reactive groups present are blocked by the corresponding protecting groups, or b) the compound of General formula IV

where R ¹ has the above meanings, is subjected to interaction with the compound of General formula V

where R ² and R ³ have the above meanings and where the reactive groups present are blocked by the corresponding protecting groups and then the optionally used protecting groups are again cleaved off, after which the resulting compound of formula I is converted, if necessary, into its acid addition salt or the acid addition salt is converted to free compound of formula I. 9. Compounds of General Formula IV

where R ¹ denotes hydrogen or (ness.) alkyl.