Patent EA-002436-B1 (EA)
Title: Substituted triazolo-pyridazine derivatives as ligands for gaba receptors
Inventor: BROUGHTON Howard
IPC: C07D487/08
Filed: 1997-07-17
Abstract: 1. A compound of formula I, or a salt or a prodrug thereof:   wherein Y represents hydrogen or C1-6 alkyl; and Z represents C1-6 alkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, aryl, C3-7 heterocycloalkyl, hetetroaryl, or di(C1-6)alkylamino, any of which groups may be optionally substituted; or Y and Z are taken together with the two intervening carbon atoms to form a ring selected from C5-9 cycloalkenyl, C6-10 bicycloalkenyl, tetrahydropyridinyl, pyridinyl and phenyl, any of which rings may be optionally benzo-fused and/or substituted; R<1> represents C3-7 cycloalkyl, phenyl, furyl, thienyl or pyridinyl, any of which groups may be optionally substituted; and R<2> represents cyano(C1-6) alkyl, hydroxy(C1-6)alkyl, C3-7 cycloalkyl(C1-6)alkyl, propargyl, C3-7 heterocycloalkylcarbonyl(C1-6)alkyl, aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted; provided that, when optional substituents for Y, Z, R<1> and R<2> are selected from the group, comprising (C1-6) alkyl, aryl(C1-6) alkyl, pyridyl(C1-6) alkyl, halo, halo(C1-6) alkyl, cyano, cyano(C1-6) alkyl, hydroxy, hydroxymethyl, (C1-6) alkoxy, C3-7 cycloalkyl-(C1-6) alkoxy, C3-7 -cycloalkoxy, amino(C1-6) alkyl, di(C1-6) alkyl-amino(C1-6) alkyl, di(C1-6) alkylaminocarbonyl(C1-6) alkyl, N-(C1-6) alkylpiperidinyl, pyrrolidinyl(C1-6) alkyl, piperazinyl(C1-6) alkyl, morpholinyl(C1-6) alkyl, di(C1-6) alkylmorpholinyl(C1-6) alkyl, and imidazolyl(C1-6) alkyl; wherein the term "aryl" represents the groups phenyl and naphthyl, preferably phenyl; the term "heterocycloalkyl" represents the groups azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl; the term "heteroaryl" represents the groups pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pirazinyl, quinoxalinyl, furyl, benzofuryl,dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, izothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl; with proviso that if Y and Z taken together with the two intervening carbon atoms form an optionally substituted phenyl ring, then R<2> is not hydroxy(C1-6) alkyl. 2. A compound as claimed in Claim 1 wherein Y represents hydrogen. 3. A compound as claimed in Claim 1 or Claim 2 wherein Z represents methyl, ethyl, isopropyl, tert-butyl, 1,1-dimethylpropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, cyclobutenyl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl, chloro-thienyl or diethylamino. 4. A compound as claimed in any one of Claims 1, 2 or 3 wherein R<1> represents cyclopropyl, phenyl, methylphenyl, fluorophenyl, difluorophenyl, methoxyphenyl, furyl, thienyl, methyl-thienyl or pyridinyl. 5. A compound as claimed in Claim 1 represented by formula IIA, and salts and prodrugs thereof:   wherein R<1> is as defined in Claim 1; R<12> represents hydroxy; or C3-7 cycloalkyl, C3-7 heterocycloalkylcarbonyl, aryl or heteroaryl, any of which groups may be optionally substituted. 6. A compound as claimed in Claim 1 represented by formula IIB, and salts and prodrugs thereof:   wherein Y<1> represents hydrogen or methyl; Z<1> represents C1-6 alkyl, C3-7 -cycloalkyl, C4-7 -cycloalkenyl, aryl, C3-7 -heterocycloalkyl, heteroaryl or di(C1-6)alkylamino, any of which groups may be optionally substituted; R<1> is as defined in Claim 1; m is 1 or 2; and R<22> represents aryl or heteroaryl, either of which groups may be optionally substituted. 7. A compound of Claim 6, wherein m is 1. 8. A compound of Claim 6, wherein R<22> represents phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, or tetrazolyl, any of which groups may be optionally substituted with one or more substituents chosen from the group, comprising methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmetoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl and morpholinylmethyl. 9. A compound as claimed in Claim 6 represented by formula IIC, and pharmaceutically acceptable salts thereof:   wherein R<1> is as defined in Claim 1; Q represents the residue of a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring; R<5> represents hydrogen or methyl; and R<6> represents hydrogen or methyl. 9. A compound selected from: 3-phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3,7-diphenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4,3-b]pyridazine; 3-phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phflialazine; 7,8-dimethyl-3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4,3-b]pyridazine; 7-methyl-3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4,3-b]pyridazine; 7-ethyl-3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4,3-b]pyridazine; 7,8-benzo-3-phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-1,2,4-triazolo [3,4-a]phthalazine; 8-methyl-3,7-diphenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4,3-b]pyridazine; 3-phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-methano)-1,2,4-triazolo [3,4-a]phthalazine; 3-phenyl-5-(pyridin-2-ylmethoxy)-l,2,3a,4,7-pentaazacyclopenta-[α]naphthalene; 3-phenyl-5-(pyridin-2-ylmethoxy)-l,2,3a,4,8-pentaazacyclopenta-[α]naphthalene; 8-methyl-3-phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-1,2,4-triazolo [3,4-a]phthalazine; 3-phenyl-6-(2-pyridyl)methyloxy-(7,8-pentano)-1,2,4-triazolo[4,3-b]pyridazine; 8,8-dimethyl-3-phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine; 3-phenyl-7-(piperidin-1-yl)-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 3-phenyl-7-(pyridin-4-yl)-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 3-phenyl-5-(pyridin-2-ylmethoxy)-6,7,8,9-tetrahydro-l,2,3a,4,8-pentaazacyclopenta [α] naphthalene; 3-phenyl-5-(pyridin-2-ylmethoxy)-6,7,8,9-tetrahydro-l,2,3a,4,7-pentaazacyclopenta[α]naphthalene; 7-methyl-3-phenyl-5-(pyridin-2-ylmethoxy)-6,7,8,9-tetrahydro-l,2,3a,4,7-pentaazacyclopenta[α]naphthalene; 3-phenyl-6-(pyridin-2-ylmethoxy)-7-(thiophen-2-yl)-1,2,4-triazolo[4.3-b]pyridazine; 3-phenyl-6-(pyridin-2-ylmethoxy)-7-(thiophen-3-yl)-1,2,4-triazolo[4,3-b]pyridazine; 3-phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-propano)-1,2,4-triazolo[3,4-a]phthalazine; 3-(4-methyl)phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo [3,4-a]phthalazine; 3-(3-methoxy)phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo [3,4-a]phthalaztne; 3-(2-fluoro)phenyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazme; 3-(3-pyridyl)-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3-cyclopropyl-6-(2-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-[(6-methyl)-2-pyridyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo [3,4-a]phthalazine; 6-[(3-methyl)-2-pyridyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo [3,4-a]phthalazine; 6-[(4-methyl)-2-pyridyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,l0-ethano)-1,2,4-triazolo [3,4-a]phthalazine; 6-[(5-methyl)-2-pyridyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3-phenyl-6-(3-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3-phenyl-6-(4-pyridyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3-phenyl-6-[2-(1-methyl)imidazolyl]methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-(3-cyanophenyl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-[1-(3,5-dimethyl)pyrazolyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-[4-(2-methyl)thiazolyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3-phenyl-6-(2-quinoxalinyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3-phenyl-6-(3-pyridazinyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazme; 6-(1-benzylimidazol-2-yl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3-phenyl-6-(isoquinolin-1-yl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-(1-ethylimidazol-2-yl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3-phenyl-6-(1-pyrazolyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3-phenyl-6-(N-pyrrolidinylcarbonyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-[4-(3-methyl)pyridyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 3-phenyl-6-(2-quinolinyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-(2-imidazolyl)methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo [3,4-a]phthalazine; 3-phenyl-6-(2-thiazolyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-[2-(5-methyl)thiazolyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-[2-(4-methyl)thiazolyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-[2-(3,5-dimethyl)pyridyl]methyloxy-3-phenyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo(3,4-a]phthalazine; 3-phenyl-6-(2-pyrazinyl)methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine; 6-[2-(4,6-dimethyl)pyridyl]methyloxy-3-phenyl