RU2003125937A - 1,3-Dioxo -2,3-dihydro-1H-pyrrolo [3,4-C] Quinolines (OPTIONS), PHARMACEUTICAL COMPOSITIONS (OPTIONS), METHOD FOR PRODUCING THEREO (OPTIONS) AND METHODS OF TREATMENT (OPTIONS) - Google Patents

Claims (8)

1. Substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] quinolines of the general formula 1

or their pharmaceutically acceptable salts, N-oxides or hydrates in which R ¹ , R ² and R ³ mean independently selected from a hydrogen atom, a halogen atom, CF ₃ , CN, NO ₂ , an inert substituent selected from the group consisting of a low or non-reactive radical C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl, substituted aralkyl, C ₇ -C ₁₂ heterocyclylalkyl, substituted heterocyclylalkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl , C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C ₂ -C ₁₂ alkoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, (CH ₂ ) _m -O- (C ₁ -C ₇ alkyl), - (CH ₂ ) _m -N (C ₁ -C ₇ alkyl) _n , aryl, substituted substituted aryl, substituted alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl, where m and n are from 1 to 7, an optionally substituted hydroxyl group, an optionally substituted carboxy-C ₂ -C ₆ alkyl group, an optionally substituted carbamoyl group, with the proviso that two of R ¹ , R ² and R ^{3 are} hydrogen; R ⁴ represents a hydrogen atom, a halogen atom, an inert substituent, substituted C ₁ -C ₇ alkyl, substituted C ₂ -C ₇ alkenyl, an optionally substituted amino group or an optionally substituted hydroxyl group; R ⁵ represents a hydrogen atom, an inert substituent selected from the group consisting of a low or non-reactive radical C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ - C ₁₂ aralkyl, substituted aralkyl. C ₇ -C ₁₂ heterocyclylalkyl, substituted heterocyclylalkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C ₇ -C ₁₂ alkoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, - (CH ₂ ) _m -O- (C ₁ -C ₇ alkyl), - (CH ₂ ) _m -N (C ₁ -C ₇ alkyl) _n aryl, substituted aryl, substituted alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl, where m and n are from 1 to 7, optionally substituted hydroxyC _1-5 alkyl, optionally substituted amino group, optionally substituted hydroxyl group y, substituted C ₁ -C ₇ alkyl, substituted C ₂ -C ₇ alkenyl, substituted C ₂ -C ₇ alkynyl, substituted in the alkyl or aryl moiety of C ₇ -C ₁₂ aralkyl, substituted in alkyl or heterocyclic C ₇ -C ₁₂ heterocyclylalkyl substituted in the alkyl or aryl moiety of C ₇ -C ₁₂ alkaryl; substituted C ₃ -C ₁₀ cycloalkyl; substituted C ₃ -C ₁₀ cycloalkenyl; substituted phenyl; substituted aryl; substituted heterocyclyl; R ⁸ represents a group

or R ⁸ represents a hydrogen atom, a halogen atom, CF ₃ , CN, NO ₂ , an inert substituent selected from the group consisting of a low or non-reactive radical C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl , C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl, substituted aralkyl, C ₇ -C ₁₂ heterocyclylalkyl, substituted heterocyclylalkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, phenyl substituted phenyl, toluyl, xylenyl, biphenyl, C ₂ -C ₁₂ alkoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, (CH ₂ ) _m -O- (C ₁ -C ₇ alkyl), - ( CH ₂ ) _m —N (C ₁ -C ₇ alkyl) _n , aryl, substituted aryl, substituted alkoxy, ft oralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl, where m and n are from 1 to 7; an optionally substituted hydroxyl group, an optionally substituted carboxyC _1-6 alkyl group, an optionally substituted carbamoyl group; R ⁶ and R ⁷ independently represent a hydrogen atom, an inert substituent, an optionally substituted amino C _1-7 alkyl, an optionally substituted amino group, an optionally substituted hydroxyl group; or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached represent a 3-10 membered ring, optionally further comprising a heteroatom selected from the group of oxygen, nitrogen or sulfur, optionally fused and optionally substituted; excluding N-oxide 2-methyl (or 2-phenyl) -3,4-quinolindicarboximide; 2- (2-dimethyl (or diethyl) aminoethyl) - or 2- (3-dimethylaminopropyl) -4-methyl-1H-pyrrolo [3,4-c] quinoline-1,3 (2H) -dione and 8-bromo -2- (2-dimethyl (or diethyl) aminostyl) - or 8-bromo-2- (3-dimethylaminopropyl) -4-methyl-1H-pyrrolo [3,4-c] quinoline-1,3 (2H) - dyons and compounds 1 in which at the same time R ¹ = R ² = R ³ = R ⁸ = R ⁵ = H, and R ⁴ = H or CH ₃ ; compounds 1, in which at the same time R ¹ = R ² = R ³ = R ⁸ = H, and R ⁴ = CH ₃ , 2- (3,4-dichlorophenyl) vinyl, NH ₂ , NHC (O) CH ₃ and R ⁵ = 2- (dibutylamino) ethyl, 2-pyrrolidin-1-yl-ethyl, 2-piperidn-1-yl-ethyl; compounds 1, in which at the same time one of R ^{1 is} R = H, Cl, Br, and the other two are H, R ⁸ = Cl, Br, NO ₂ , R ⁴ = CH ₃ , CHBr ₂ , phenyl, R ⁵ = H CH ₃ ; compounds 1, in which at the same time two of R ¹ -R ³ mean hydrogen, and one of R ¹ -R ³ and R ⁸ represent the same or different hydrogen atom, halogen atom, CF ₃ , CN, OH, alkyl, cycloalkyl, alkoxy alkylthio, R ⁴ = H, alkyl, phenyl; R ⁵ = H, alkyl, cycloalkyl, alkoxy, cycloalkyloxy, benzyl, phenyl, 2- (1-methylpyrrol-2-yl) ethyl, 2-morpholin-4-yl-ethyl, 2- (4-fluorobenzoylamino) ethyl; compounds 1, in which at the same time R ¹ = H, R ⁸ = substituted sulfamoyl group, R ⁴ = CH ₃ , R ⁵ = inert substituent; R ¹ -R ^{3 is} hydrogen, R ^{4 is} styryl, R ^{5 is} p-tolyl, p-methoxyphenyl, phenyl, R ^{8 is} hydrogen, chlorine, bromine, methyl, nitro; R ¹ = R ² = R ³ = R ⁵ = H, and R ^{4 is an} aminocarbamoyl group. 2. A pharmaceutical composition in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, with protease (caspase) activity, intended for the treatment and prevention of various diseases of animals and people associated with increased activation of apoptosis, containing pharmaceutically effective as an active substance the amount of the compound of general formula 1 according to claim 1. 3. A method of obtaining a pharmaceutical composition according to claim 2, by mixing an inert diluent and / or excipient with an active substance, characterized in that the compounds of general formula 1 according to claim 1 are used as the active substance. 4. A pharmaceutical composition in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, with protease (caspase) activity, intended for the treatment and prevention of various diseases of animals and people associated with increased activation of apoptosis, containing a pharmaceutically effective substance as an active substance the amount of 1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] quinolines of the general formula 1

or their pharmaceutically acceptable salts, N-oxides or hydrates in which R ¹ , R ² and R ³ mean independently selected from a hydrogen atom, a halogen atom, CF ₃ , CN, NO ₂ , an inert substituent selected from the group consisting of a low or non-reactive radical C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl, substituted aralkyl, C ₇ -C ₁₂ heterocyclylalkyl, substituted heterocyclylalkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl , C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C ₂ -C ₁₂ alkoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, (CH ₂ ) mO- (C ₁ - C ₇ alkyl), - (CH ₂ ) mN (C ₁ -C ₇ alkyl) _n , aryl, substituted th aryl, substituted alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl, where m and n are from 1 to 7, an optionally substituted hydroxyl group, an optionally substituted carboxy-C ₂ -C ₆ alkyl group, an optionally substituted carbamoyl group, with the proviso that two of R ¹ , R ² and R ^{3 are} hydrogen; R ⁴ represents a hydrogen atom, a halogen atom, an inert substituent, substituted C ₁ -C ₇ alkyl, substituted C ₁ -C ₇ alkenyl, an optionally substituted amino group or an optionally substituted hydroxyl group; R ⁵ represents a hydrogen atom, an inert substituent selected from the group consisting of a low or non-reactive radical C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ - C ₁₂ aralkyl, substituted aralkyl, C ₇ -C ₁₂ heterocyclylalkyl, substituted heterocyclylalkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C ₂ -C ₁₂ alkoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, - (CH ₂ ) mO- (C ₁ -C ₇ alkyl), - (CH ₂ ) mN (C ₁ -C ₇ alkyl) _n aryl, substituted aryl, substituted alkoxy, fluoroalkyl, aryloxyalkyl, heter cyclic, substituted heterocyclyl and nitroalkyl, where m and n are from 1 to 7, optionally substituted hydroxyC _1-5 alkyl, optionally substituted amino group, optionally substituted hydroxyl group, substituted C ₁ -C ₇ alkyl, substituted C ₂ -C ₇ alkenyl substituted C ₂ -C ₇ alkynyl, substituted in the alkyl or aryl C ₇ -C ₁₂ aralkyl fragment, substituted in the alkyl or heterocyclic C ₇ -C ₁₂ heterocyclylalkyl, substituted in the alkyl or aryl C ₇ -C ₁₂ alkaryl, substituted C ₃ -C ₁₀ cycloalkyl substituted with C ₃ -C ₁₀ cycloalkene sludge, substituted phenyl, substituted aryl, substituted heterocyclyl; R ⁸ represents a group

or R ⁸ represents a hydrogen atom, a halogen atom, CF ₃ , CN, NO ₂ , an inert substituent selected from the group consisting of a low or non-reactive radical C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl, substituted aralkyl, C ₇ -C ₁₂ heterocyclylalkyl, substituted heterocyclylalkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylene, biphenyl, C ₂ -C ₁₂ alkoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, (CH ₂ ) mO- (C ₁ -C ₇ alkyl), - (CH ₂₎ mN (C ₁ -C ₇ alkyl) _n, aryl, substituted aryl, substituted alkoxy, fluoro lkil, aryloxyalkyl, heterocyclyl, substituted heterocyclyl, and nitroalkyl, where m and n has a value from 1 to 7, optionally substituted hydroxyl group, an optionally substituted karboksiS _1-6 alkyl group optionally substituted carbamoyl group; R ⁶ and R ⁷ independently represent: a hydrogen atom, an inert substituent, an optionally substituted amino C _1-7 alkyl, an optionally substituted amino group, an optionally substituted hydroxyl group, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached, represent a 3-10 membered ring, optionally further comprising a heteroatom selected from the group: oxygen, nitrogen or sulfur, optionally fused and optionally substituted. 5. A method of obtaining a pharmaceutical composition according to claim 4 by mixing an inert diluent and / or excipient with an active substance, characterized in that the compounds of general formula 1 according to claim 4 are used as the active substance. 6. A method for the treatment or prevention of diseases or conditions in animals and humans associated with increased activation of apoptosis, which is to prescribe to patients in need of treatment an effective amount of the pharmaceutical composition according to claim 4. 7. A method for the treatment or prevention of diseases or conditions in animals and humans, in the pathogenesis of which caspases are involved, which consists in prescribing to patients in need of treatment an effective amount of the pharmaceutical composition according to claim 4. 8. The use of 1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] quinoline of the general formula 1:

or its pharmaceutically acceptable salt, N-oxide or hydrate as “pharmacological tools” of caspase inhibitors intended for experimental (in vivo, in vitro) studies of apoptosis processes in which R ¹ , R ² and R ³ mean independently selected from a hydrogen atom, a halogen atom, CF ₃ , CN, NO ₂ , an inert substituent selected from the group consisting of a low or non-reactive radical C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl, substituted aralkyl, C ₇ -C ₁₂ heterocyclylalkyl, substituted heterocyclylalkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl , C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C ₂ -C ₁₂ alkoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, (CH ₂ ) mO- (C ₁ - C ₇ alkyl), - (CH ₂ ) mN (C ₁ -C ₇ alkyl) _n , aryl, substituted th aryl, substituted alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl; where m and n are from 1 to 7, an optionally substituted hydroxyl group, an optionally substituted carboxy-C ₂ -C ₆ alkyl group, an optionally substituted carbamoyl group, provided that two of R ¹ , R ² and R ^{3 are} hydrogen; R ⁴ represents a hydrogen atom, a halogen atom, an inert substituent, substituted C ₁ -C ₇ alkyl, substituted C ₂ -C ₇ alkenyl, an optionally substituted amino group or an optionally substituted hydroxyl group; R ⁵ represents a hydrogen atom, an inert substituent selected from the group consisting of a low or non-reactive radical C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ - C ₁₂ aralkyl, substituted aralkyl, C ₇ -C ₁₂ heterocyclylalkyl, substituted heterocyclylalkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C ₂ -C ₁₂ alkoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, - (CH ₂ ) mO- (C ₁ -C ₇ alkyl), - (CH ₂ ) mN (C ₁ -C ₇ alkyl) _n aryl, substituted aryl, substituted alkoxy, fluoroalkyl, aryloxyalkyl, goethe rocyclyl, substituted heterocyclyl and nitroalkyl; where m and n are from 1 to 7, optionally substituted hydroxyC _1-5 alkyl, optionally substituted amino group, optionally substituted hydroxyl group, substituted C ₁ -C ₇ alkyl, substituted C ₂ -C ₇ alkenyl, substituted C ₂ -C ₇ alkynyl substituted in the alkyl or aryl moiety C ₇ -C ₁₂ aralkyl substituted in the alkyl moiety or heterocyclic C ₇ -C ₁₂ heterocyclylalkyl, substituted in the alkyl or aryl moiety C ₇ -C ₁₂ alkaryl, substituted C ₃ -C ₁₀ cycloalkyl substituted by C ₃ -C ₁₀ cycloalkenyl, substituted phenyl, substituted aryl, substituted th heterocyclyl; R ⁸ represents a group

or R ⁸ represents a hydrogen atom, a halogen atom, CF ₃ , CN, NO ₂ , an inert substituent selected from the group consisting of a low or non-reactive radical C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl, substituted aralkyl, C ₇ -C ₁₂ heterocyclylalkyl, substituted heterocyclylalkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylene, biphenyl, C ₂ -C ₁₂ alkoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, (CH ₂ ) mO- (C ₁ -C ₇ alkyl), - (CH ₂₎ mN (C ₁ -C ₇ alkyl) _n, aryl, substituted aryl, substituted alkoxy, fluoro lkil, aryloxyalkyl, heterocyclyl, substituted heterocyclyl, and nitroalkyl, where m and n has a value from 1 to 7, optionally substituted hydroxyl group, an optionally substituted karboksiS _1-6 alkyl group optionally substituted carbamoyl group; R ⁶ and R ⁷ independently represent a hydrogen atom, an inert substituent, an optionally substituted amino C _1-7 alkyl, an optionally substituted amino group, an optionally substituted hydroxyl group, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached represent 3-10 membered cycle, optionally further comprising a heteroatom selected from the group: oxygen, nitrogen or sulfur, optionally condensed and optionally substituted; or R ⁸ represents a hydrogen atom, a halogen atom, CF ₃ , CN, NO ₂ , an inert substituent, an optionally substituted hydroxyl group, an optionally substituted carboxyC _1-6 alkyl group, an optionally substituted carbamoyl group.