Patent EA-003272-B1 (EA)
Title: Derivatives of dihydro- and tetrahydroquinoline, process for preparing them and pharmaceutical compositions containing them
Inventor: CASARA PATRICK
IPC: C07D221/20
Filed: 1999-10-22
Abstract: 1. A compound selected from those of formula (I): wherein: R1 represents hydrogen atom or group. wherein A represents hydrogen atom or group-BNZ1Z2 in which B represents linear or branched (C1 -C6)alkylene group and Z1 and Z2 independently represent hydrogen atom or alkyl, (C3 -C8) cycloalkyl, or optionally substituted aryl group or, together with the nitrogen atom carrying them, form an optionally substituted heterocycloalkyl or heteroaryl group, R2 and R3 each independently represents alkyl group, (C3 -C8)cycloalkyl group, heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, cycloalkylalkyl group, heterocycloalkylalkyl group, optionally substituted arylalkyl group, optionally substituted heteroarylalkyl group, or aminoalkyl group optionally substituted on the nitrogen atom by one or two groups selected from alkyl, cycloalkyl, aryl, and arylalkyl, or R2 and R3 together with the carbon atom carrying them, form a (C3 -C8)cycloalkyl group or a monocyclic heterocycloalkyl group unsubstituted or substituted by alkyl, cycloalkyl, cycloalkylalkyl, aryl, or arylalkyl group, R40 represents hydrogen atom or a group selected from optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl, or a group Q or -V-Q wherein V represents group of alkylene, alkenylene, or alkynylene, and Q represents optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocycloalkyl group, or optionally substituted heteroaryl group, R41 and R5 together form a bond or each represents hydrogen atom, R6, R7, R8 and R9 each independently represents hydrogen atom, halogen atom, alkyl group, (C3 -C8)cycloalkyl group, or -OW wherein W represents hydrogen atom, alkyl group, acyl group, (C3 -C8)cycloalkyl group, heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl (provided that R6, R7, R8 and R9 cannot all simultaneously represent hydrogen and that at least one of them represents -OW as defined hereinbefore), with the proviso that: - R2 and R3 represent alkyl group: - if each of R6 to R9 independently represents hydrogen atom, alkyl group or -OW wherein W represents alkyl group, and R41 and R5 together form a bond, then R40 is other than hydrogen atom or alkyl group, - if a single group -OW is present in the molecule and represents hydroxy group, then R40 is other than hydrogen group, - if a single group -OW is present in the molecule and represents methoxy group, then R40 is other than hydroxyalkyl group, - the compound of formula (I) being other than 7-methoxy-2,2-diphenyl-1,2-dihydroquinoline, - the term "alkyl" means linear and branched chain with 1-6 carbon atoms, - the term "acyl" means alkylcarbonyl group, wherein alkyl is as defined over, - the term "alkenyl"means linear and branched chain with 2-6 carbon atoms, containing 1-3 triple bonds, - the term "alkynyl" means linear and branched chain with 2-6 carbon atoms, containing 1-3 triple bonds, - the term "alkylene" means linear and branched chain bivalent group with 2-6 carbon atoms, - the term "alkenylene" means line and series circuit bivalent group with 2-6 carbon atoms, containing 1-3 triple bonds, - the term "alkynylene" means linear and branched chain bivalent group with 2-6 carbon atoms, containing 1-3 triple bonds, - the "aryl" means phenyl, naphthyl or biphenyl group, - the term "heterocycloalkyl" means mono- or bi-cyclic group with 4-11 members, containing from 1 to 6 heteroatoms, selected from nitrogen, oxygen and sulfur, - the term "substituted", used regarding aryl or arylakyl, shows, that concerning groups are substituted with one or more atoms of halo or alkyl, linear and branched (C1-C6)alkoxy, linear and branched (C1-C6)perhalogenalkyl, amino (optionally substituted by 1 or 2 alkyl groups), cyano, carboxy, linear and branched (C1-C6)alkoxycarbonyl, aminocarbonyl(optionally substituted on nitrogen atom by 1 or 2 alkyl groups), nytro, or hydroxy groups, - the term " substituted" used regarding the expressions of alkyl, alkynyl, and cycloalkyl, shows that such groups are sustituted by one or more groups, selected from hydroxy, linear or branched (C1-C6) alkoxy, linear or branched (C1-C6) alkylthio, amino (optionally substituted by 1 or 2 alkyl groups), carboxy, nitro, cyano, linear or branched (C1-C6) alkoxycarbonyl and aminocarbonyl (optionally substituted on nitrogen atom by 1 or 2 alkyl groups), - the term " substituted" used regarding heterocycloalkyl, heteroaryl and heteroarylalkyl, shows that concerning groups are substituted by one or more atoms of halo or alkyl, linear and branched (C1-C6)alkoxy, linear and branched (C1-C6)perhalogenalkyl, amino (optionally substituted by 1 or 2 alkyl groups), cyano, carboxy, linear and branched (C1-C6)alkoxycarbonyl, aminocarbonyl(optionally substituted on nitrogen atom by 1 or 2 alkyl groups), nytro, or hydroxy, or oxogroups, their enantiomer and diastereoisomer, and an addition salt thereof with a pharmaceutically-acceptable acid and base. 2. A compound of formula (I) by claim 1, wherein R1 represents hydrogen atom, their enantiomer and diastereoisomer, and an addition salt thereof with a pharmaceutically-acceptable acid and base. 3. A compound of formula (I) by claim 1, wherein R6, R7, R8 and R9 each independently represents hydrogen atom, alkyl group, or group -OW wherein W represents alkyl, acyl, or phenyl, their enantiomer and diastereoisomer, and an addition salt thereof with a pharmaceutically-acceptable acid and base. 4. A compound of formula (I) by claim 1, wherein R2 and R3 each represents alkyl group, their enantiomer and diastereoisomer, and an addition salt thereof with a pharmaceutically-acceptable acid and base. 5. A compound of formula (I) by claim 1, wherein R2 and R3 together form an optionally substituted cycloalkyl or heterocycloalkyl group, their enantiomer and diastereoisomer, and an addition salt thereof with a pharmaceutically-acceptable acid and base. 6. A compound of formula (I) by claim 1, wherein R40 represents hydrogen atom or V-Q, V being alkylene and Q being heterocycloalkyl group, their enantiomer and diastereoisomer, and an addition salt thereof with a pharmaceutically-acceptable acid and base. 7. A compound of formula (I) by claim 1, wherein R1 represents hydrogen atom, R2 and R3 represent alkyl group or together form a cycloalkyl group, R40 represents hydrogen atom or -V-Q wherein V represents alkylene and Q represents heterocycloalkyl, and R6, R7, R8 and R9 each independently represents hydrogen atom, alkyl group or -OW wherein W represents alkyl, acyl, or phenyl group, it's being understood that R6, R7, R8 and R9 cannot all represent hydrogen atom and that, at least, one of them represents -OW as defined hereinbefore, their enantiomer and diastereoisomer, and an addition salt thereof with a pharmaceutically-acceptable acid and base. 8. A compound of formula (I) by claim 7, wherein R2 and R3 together form cycloalkyl group, their enantiomer and diastereoisomer, and an addition salt thereof with a pharmaceutically-acceptable acid and base. 9. A compound of formula (I) by claim 7, wherein R2 and R3 represent alkyl group, their enantiomer and diastereoisomer, and an addition salt thereof with a pharmaceutically-acceptable acid and base. 10. A compound of formula (I) by claim 1 which is selected from 6-ethoxy-2,2,5,7,8-pentamethyl-1,2,3,4-tetrahydroquinoline, and an addition salt thereof with a pharmaceutically acceptable acid. 11. A compound of formula (I) by claim 1which is selected from 6-ethoxy-1,2-dihydroquinoline-2-spirocyclohexane, and an addition salt thereof with a pharmaceutically acceptable acid. 12. Process for preparing of compounds of formula (I), wherein substituted aniline of formula (II): wherein R6, R7, R8, and R9 are such as defined for formula (I), is to be exposed to: - either effect of halogenated acetylyde of formula (III): wherein R2, and R3 are such as defined for formula (I), G represents hydrogen atom or trialkylsilyl group and Hal represents halogen atom, with obtaining of compound of formula (IV): where R2, R3, R6, R7, R8, R9 and G are such as defined over, -or effect of carbonyl compound of formula (V): where R2 and R3 are such as defined for formula (I), with obtaining of compound of formula (VI): where R2, R3, R6, R7, R8, R9 and G are such as defined over, compound of formula (VI) is to be exposed to effect of acetylyde of formula (III) in alkaline medium, as defined over, with obtaining of compound of formula (VI), as defined over, which (compound of formula (VI)), wherein it's applicable after disintegration of trialkysilyl group, is exposed to reaction of cycle closure by heating in presence of correspondent catalyst, with obtaining of compound of formula (I/a): particular case of compounds of formula(I), where R2, R3, R6, R7, R8, R9 are such as defined over, which is after maintenance nitrogen atom ring, can be successively exposed to hydroxyhalogenation reaction and oxidation reaction benzyl position, with obtaining of compound of formula (VIII): where R2, R3, R6, R7, R8, R9 are such as defined over, Hal represents halogen atom and P is maintaining group for nitrogen atom ring (for e.g. acetyl, trifluoacetyl, tert-butoxycarbonyl or benzyloxycarbonyl group), that are exposed to nucleophylic substitution reaction with obtaining of compound of formula (IX): where R2, R3, R6, R7, R8, R9 and P are such as defined over, Y represents either group R40, that is such as defined for formula (I), but different from hydrogen atom, or forerunner of group, which, after removal of maintaining from nitrogen atom ring, is exposed to carbonyl functional recovery reaction with the following elimination with obtaining of the compound of formula (X): where R2, R3, R6, R7, R8, R9 and Y are such as defined over, that (compound of formula (VI)