Patent EA-003603-B1 (EA)
Title: N-[(substituted five-membered di- or triaza diunsaturated ring)carbonyl] guanidine derivatives for the treatment of ischemia
Inventor: HAMANAKA ERNEST S
IPC: A61K31/41
Filed: 1999-02-05
Abstract: i-N,N-(C1-C4)alkylcarbamoyl, cyano, (C1-C4)alkylth1. A compound having the Formula I Formula I a promono-N or di-N,N-(C1-C4)alkylaminosulfonyl, wherein said (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)alkanoyl, (C1-C4)alkylthio, mono-N- or di-N,N-(C1-C4)alkynyl, or phenyl(C1-C4)alkyl, said (C3-C7)cycloalkyly, (C1-C4)alkoxycarbonyl, (C1-C4)alkanoyl, (C1-C4)alkanoylamino, (C1-C4)alkanoyloxy, (C1-C4)alkoxycadi- substituted independently with (C1-C4)alkoxy,  amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, (C1alkyl, M or M(C1-C4)alkyl, any of said previous (Culfonyl or mono-N or di-N,N-(C1-C4)alkylaminosulfonyl or optionally substituted with one to nine flulkyl optionally mono- or di-substituted independently with hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio,in R<2> is a quinazolinyl, phthalazinyl, quinoliny4)alkyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl or mono-N- or di-N,N-(C1-C4)alkylaminosulfonyl; andlyl, benzimidazolyl, indazolyl, indolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyrated, fully saturated or fully unsaturated five to eight membered ring optionally having one to thrptionally mono- or di-substituted independently on sulfur and nitrogen, or, a bicyclic ring consistioxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl, (C1-C4)aed or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; said M is optionally substituted, on one ring if the moiety is monocyclic, orn said (C1-C4)alkoxy, (C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkylamino substituents are optionally dependently selected from R<6>, R<7> and R<8>, wherein one of R<6>, R<7> and R<8> is optionally a pa,N-(C1-C4)alkylamino, mono-N or di-N,N-(C1-C4)alkyurated three to seven membered ring optionally havN,N-(C1-C4)alkylaminosulfonyl or optionally substiy from oxygen, sulfur and nitrogen optionally substituted with (C1-C4)alkyl and additionally R<6>, R<7> and R<8> are optionally hydroxy, nitro, halo, zol-7-yl)-3-methyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2,1,3-benzothiadiazol-4-yl)-3-methyl-1H-pyr-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- aceutically acceptable salt thereof. 107. A compound as recited in claim 1 wherein the compound is [4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, mono-N or di-N,N-(C1-C4)alkylaminosulfonyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C5-C7)cycloalk wherein R<1> is methyl and R<2> is indazol-7-yl or a pharmaceutically acceptable salt thereof. 109.-(C1-C4)alkylamino or (C3-C7)cycloalkyl R<6>, R<7>s methyl and R<2> is 2,1,3-benzothiadiazol-4-yl oruted independently with hydroxy, (C1-C4)alkoxycarbonyl, (C3-C7)cycloalkyl, (C1-C4)alkanoyl, (C1-C4)a methyl and R<2> is quinolin-5-yl or a pharmaceutibonylamino, sulfonamido, (C1-C4)alkylsulfonamido, recited in claim 1 wherein Z is R<4> is (C1-C4)alkyl, (C3-C7)cycloalkyl, phenyl or phenyl(C1-C4)alkyl, said (C1-C4)alkyl optionally substituted with from one to nine fluorines; said R<4> substituent optionally mono- or di-substituted independently with (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsu-C4)alkyl, (C3-C7)cycloalkyl, phenyl or phenyl(C1-C4)alkyl, said (C1-C4)alkyl optionally substituteding one or two heteroatoms selected independently tuent optionally mono- or di-substituted independently with (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl or (C1-C4)alkylsulfonyl; and R<2> isc ring consisting of two fused five and/or six membered partially saturated, fully saturated or fully unsaturated rings taken independently having one unsubstituted (C1-C4)alkyl or unsubstituted (C3-C7)cycloalkyl; or R<2> is phenyl(C1-C4)alkyl, or a  optionally substituted on carbon or nitrogen with up to three substituents independently selected for fully unsaturated rings taken independently having one to four heteroatoms selected independentlyly saturated, or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen optionally substituted with (C1-C4)al>, R<7> and R<8> is optionally a partially saturatnally hydroxy, nitro, halo, (C1-C4)alkoxy, (C1-C4) seven membered ring optionally having one to threoyl, (C1-C4)alkanoyloxy, (C1-C4)alkanoylamino, (C1sulfur and nitrogen optionally substituted with (C1-C4)alkyl and additionally R<6>, R<7> and R<8> are optionally hydroxy, nitro, halo, (C1-C4)alkoxy, rbamoyl, cyano, thiol, (C1-C4)alkylthio, (C1-C4)al4)alkanoyl, (C1-C4)alkanoyloxy, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkynyl or (C5-C7)cycloalkenyl, wherein said (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)alkanoyl, (C1-C4)alkylthio, mono-N- or di-N,N-(C1-C4)alkylamino or 1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, mono-N or di-N,N-(C1-C4)alkylaminosulfonyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C5-C7)cycloalkenyl, wherein said (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C7)alkanoyl, (C1-C4)alkylthio, mono-N- or di-N,N-(C1-C4)alkylamo, (C1-C4)alkylsulfonamido, amino, mono-N- or di-Nituents are optionally mono-substituted independently with hydroxy, (C1-C4)alkoxycarbonyl, (C3-C7)cycloalkyl, (C1-C4)alkanoyl, (C1-C4)alkanoylamino, (C1-C4)alkanoyloxy, (C1-C4)alkoxycarbonylamino, sull or optionally substituted with one to nine fluoror di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, nitro, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-N- or di-N,N-(C1-C4)alkylaminosulfonyl or optionally substituted with one to nine fluorines; or wherein R<4> is (C1-C4)alkyl, (C3-ree heteroatoms selected independently from nitrog(C1-C4)alkyl optionally substituted with from one to nine fluorines, said R<4> substituent optionall saturated or fully unsaturated five to six member4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl oelected independently from oxygen, sulfur and nitrogen, said ring optionally mono-substituted with (or two heteroatoms selected independently from nitrogen, sulfur and oxygen or R<5> is unsubstituted bon or nitrogen with hydroxy, halo, (C1-C4)alkoxy,r R<5> is phenyl(C1-C4)alkyl, or a bicyclic ring consisting of two fused five and/or six membered partially saturated, fully saturated or fully unsaturated rings taken independently having one to fouramino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylca sulfur and oxygen, said R<5> substituents optionainyl, (C1-C4)alkylsulfonyl or mono-N or di-N,N-(C1hree substituents independently selected from R<6>, (C1-C4)alkyl, (C1-C4)alkanoyl, (C1-C4)alkylthio, mono-N- or di-N,N-(C1-C4)alkylamino are optionally mono-substituted with hydroxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkanoyl, (C1-C4)alkanoylamino, (C1-C4)alkanoyloxy, (C1-C4)alkoxycarbonylamino, sulfonaogen optionally substituted with (C1-C4)alkyl and additionally R<6>, R<7> and R<8> are optionally hydroxy, nitro, halo, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl, formyl, (C1-C4)alkanoyl, (C1 di-N,N-(C1-C4)alkylaminosulfonyl or optionally suxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C4)alkylthio, (C1-C4)alkylsulfi cinnolinyl, benzodioxanyl, quinoxalinyl, benzopyr)alkylaminosulfonyl, (C2-C4)alkenyl, (C2-C4)alkynyyl, indazolyl, indolyl, benzotriazolyl, benzoxazolxy, (C1-C4)alkyl, (C1-C4)alkanoyl, (C1-C4)alkylthio, mono-N- or di-N,N-(C1-C4)alkylamino or (C3-C7)cycloalkyl R<6>, R<7> and R<8> substituents are optr di-substituted independently with hydroxy, halo,y, (C1-C4)alkoxycarbonyl, (C3-C7)cycloalkyl, (C1-Cl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylaminxy, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-Cno-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono4)alkylamino, carbamoyl, mono-N or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, nitro, (C1-C4)alkylthnyl, wherein said (C1-C4)alkoxy, (C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkylamino substituents are optionally mono-substituted with hydroxy, (C1-C4)alkanoylamino, (C1-C4)alkylsulfonamido, amino, monoM or M(C1-C4)alkyl, any of said previous (C1-C4)alkyl moieties optionally having from one to nine flo-N- or di-N,N-(C1-C4)alkylaminosulfonyl or optiontionally mono- or di-substituted independently with hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl or (C1-C4)alkylsulfonyl, (C1-C4)alkprising the chronic oral administration to a human in need of such treatment of a therapeutically effective amount of a compound, a prodrug of said compound as recited in claim1 or a pharmaceutically acceptable salt of said compound or of said prodrug. 115. A compound as recited in claim 1 wherein Z is R<2> is (C1-C4)alkyl, (C3-C7)cycloalkyl, M or M(C1-C4)alkyl, any of said previous (C1-C4)alkyl m two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, slsulfinyl or (C1-C4)alkylsulfonyl, (C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl or mono-N- or both rings if the moiety is bicyclic, on carbon or nitrogen with up to three substituents indepenfluorines; wherein M is a partially saturated, fulone of R<6>, R<7> and R<8> is optionally a partialmbered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four hetero4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl, for and oxygen; said M is optionally substituted, on lkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, ammo, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,y selected from R<6>, R<7> and R<8>, wherein one olthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl,turated, fully saturated, or fully unsaturated thr