Patent EA-004932-B1 (EA)
Title: Imidazoimidazoles and triazoles as anti-inflammatory agents
Inventor: WU JIANG-PING
IPC: A61P17/06
Filed: 2000-07-12
Abstract: 1. A compound of the formula I wherein: A<1> is =N- or =C(H)-; A<2> is =N-, =C(H)-, or =C(R')- wherein R' is halogen, -CN, -Oalkyl, -CO2alkyl or -SO2alkyl, wherein the foregoing alkyl moieties are of 1 to 3 carbon atoms; D is =N-, =C(R<1>)-, =C(H)-, =C(SO2R<1>), =C(S(O)R<1>)-, =C(C(O)R<1>)-, =C(C(O)H)-, or =C(NHR<1A>)-, =C(SR<1A>)-, =C(OR<1A>)-, wherein R<1> is selected from the class consisting of: (A) -R<100> which is: branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or more hydrogen atoms are optionally and independently replaced with: (i) halogen, (ii) oxo, (iii) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl or heteroaryl group are optionally and independently replaced with: (a) alkyl of 1 to 3 carbon atoms, (b) -COOH, (c) -SO2OH, (d) -PO(OH)2, (e) a group of the formula -COOR<8>, wherein R<8> is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula -NR<9>R<10>, wherein R<9> and R<10> are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R<9> andR<10> constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (g) a group of the formula -CONR<11>R<12>, wherein R<11> and R<12> are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R<11> and R<12> constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by -O-, -S-, S(O)-, SO2-, -NH-, or -NMe-, (h) a group of the formula -OR<13>, wherein R<13> is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (i) a group of the formula -SR<14>, wherein R<14> is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (j) -CN, or (k) an amidino group of the formula wherein R<15>, R<16> and R<17> are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R<15>, R<16> andR<17> may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom (s) between them form a heterocyclic ring, (l) halogen, (m) a group of the formula -NHCONHalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms, (n) a group of the formula -NHCOOalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms, (iv) a group of the formula -COOR<18>, wherein R<18> is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (v) -CN, (vi) a group of the formula -CONR<19>R<20>, wherein R<19> and R<20> are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R<19> and R<20> constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by -O-, -S-, S(O)-, SO2-, -NH-, or -NMe-, (vii) a group of the formula -OR<21>, wherein R<21> is a hydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of -OH, -Oalkyl (wherein the alkyl moiety contains 1 to 6 carbon atoms), -NH2, -NHMe and -NMe2, (viii) a group of the formula -SR<22>, wherein R<22> is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of -OH, -Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), -NH2, -NHMe and -NMe2, (ix) a group of the formula -NR<23>R<24>, wherein R<23> and R<24> are each, independently, (a) a hydrogen atom, (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of -OH, -Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), -NH2, -NHMe and -NMe2, (c) a group of the formula -(CH2)mCOOH, wherein m is 0,1 or 2, (d) a group of the formula -(CH2)nCOOR<25>, wherein n is 0, 1 or 2, and wherein R<25> is straight or branched alkyl of 1 to 6 carbon atoms, or (e) a group of the formula -(CH2)nCONHR<25>, wherein n is 0,1 or 2, and wherein R<25> is straight or branched alkyl of 1 to 6 carbon atoms, (x) a quaternary group of the formula wherein R<26>, R<27> andR<28> are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Q- is a pharmaceutically acceptable counter ion, (xi) a saturated, or partially unsaturated heterocyclic group consisting of 3 to 7 ring atoms selected from N, O, C and S, including but not limited to imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally mono- or polysubstituted with oxo, and (xii) a cycloalkyl group of 3 to 7 carbon atoms, (B) branched or unbranched carboxylic acid groups of 3 to 6 carbon atoms, (C) branched or unbranched phosphonic acid groups of 2 to 6 carbon atoms, (D) branched or unbranched sulfonic acid groups of 2 to 6 carbon atoms, (E) amidino groups of the formula wherein r is 2,3,4,5 or 6, and R<29>, R<30> and R<31> are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R<29>, R<30> and R<31> may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom (s) between them form a heterocyclic ring, (F) guanidino groups of the formula wherein s is 2,3,4,5 or 6, and R<32>, R<33>, R<34> and R<35> are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R<32>, R<33>, R<34> and R<35> may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom (s) between them form a heterocyclic ring, (G) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl or heteroaryl group are optionally and independently replaced with: (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO2OH, (iv) -PO(OH)2, (v) a group of the formula -COOR<36>, wherein R<36> is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of the formula -NR<37>R<38>, wherein R<3> and R<38> are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R<37> and R<38> constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, (vii) a group of the formula -CONR<39>R<40>, wherein R<39> and R<40> are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R<39> and R<40> constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by -O-, -S-, S(O)-, SO2-, -NH-, or -NMe-, (viii) a group of the formula -OR<41>, wherein R<41> is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of the formula -SR<42>, wherein R<42> is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (x) -CN, or (xi) an amidino group of the formula wherein R<43>, R<44> and R<45> are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R<43>, R<44> and R<45> may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom (s) between them form a heterocyclic ring, (H) groups of the formula -NR<46>R<47>, wherein R<46> and R<47> are each independently a hydrogen atom, phenyl which is optionally mono-or polysubstituted with halogen, or R<100> wherein R<100> is as hereinbefore defined, (I) saturated or unsaturated heterocyclic groups consisting of 3 to 7 ring atoms selected from N, O, C and S, or bicyclic heterocyclic groups consisting of 8 to 11 atoms selected from N, O, C and S, including but not limited to imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl