AU2012277912B2 - 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives - Google Patents

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Publication number

AU2012277912B2

AU2012277912B2 AU2012277912A AU2012277912A AU2012277912B2 AU 2012277912 B2 AU2012277912 B2 AU 2012277912B2 AU 2012277912 A AU2012277912 A AU 2012277912A AU 2012277912 A AU2012277912 A AU 2012277912A AU 2012277912 B2 AU2012277912 B2 AU 2012277912B2

Authority

AU

Australia

Prior art keywords

methyl

triazolo

quinoxaline

chlorophenyl

quinoxalin

Prior art date

2011-06-27

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

Links

• Espacenet
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• 150000001875 compounds Chemical class 0.000 claims abstract description 418
• PDOPFYRTIVSUKL-UHFFFAOYSA-N 4-(azepan-1-yl)-[1,2,4]triazolo[4,3-a]quinoxaline Chemical class C1CCCCCN1C1=NC2=CC=CC=C2N2C1=NN=C2 PDOPFYRTIVSUKL-UHFFFAOYSA-N 0.000 claims abstract description 174
• 238000000034 method Methods 0.000 claims abstract description 136
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 70
• 208000035475 disorder Diseases 0.000 claims abstract description 47
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 39
• 208000012902 Nervous system disease Diseases 0.000 claims abstract description 33
• 238000003384 imaging method Methods 0.000 claims abstract description 32
• 208000030159 metabolic disease Diseases 0.000 claims abstract description 27
• 230000002265 prevention Effects 0.000 claims abstract description 21
• 238000001727 in vivo Methods 0.000 claims abstract description 12
• 238000000338 in vitro Methods 0.000 claims abstract description 10
• 238000002600 positron emission tomography Methods 0.000 claims abstract description 9
• 230000008569 process Effects 0.000 claims abstract description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 155
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 129
• -1 Ci_6alkyl Chemical group 0.000 claims description 114
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 114
• 125000004076 pyridyl group Chemical group 0.000 claims description 85
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 82
• 150000003839 salts Chemical class 0.000 claims description 74
• 229910052739 hydrogen Inorganic materials 0.000 claims description 54
• 239000001257 hydrogen Substances 0.000 claims description 54
• 239000012453 solvate Substances 0.000 claims description 54
• 125000001424 substituent group Chemical group 0.000 claims description 41
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 41
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
• 125000002757 morpholinyl group Chemical group 0.000 claims description 40
• 125000003386 piperidinyl group Chemical group 0.000 claims description 32
• 208000019901 Anxiety disease Diseases 0.000 claims description 31
• 238000010438 heat treatment Methods 0.000 claims description 29
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 27
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 27
• 208000028017 Psychotic disease Diseases 0.000 claims description 27
• 239000003814 drug Substances 0.000 claims description 27
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 26
• QNSRYVDGWDXBHV-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]quinoxaline Chemical compound C1=CC=C2N3C=NN=C3C=NC2=C1 QNSRYVDGWDXBHV-UHFFFAOYSA-N 0.000 claims description 25
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 25
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
• 208000002193 Pain Diseases 0.000 claims description 23
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
• 239000012442 inert solvent Substances 0.000 claims description 23
• 230000036407 pain Effects 0.000 claims description 22
• 208000024891 symptom Diseases 0.000 claims description 22
• 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 21
• 208000019022 Mood disease Diseases 0.000 claims description 21
• 208000016285 Movement disease Diseases 0.000 claims description 21
• 208000015114 central nervous system disease Diseases 0.000 claims description 21
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 21
• 208000020706 Autistic disease Diseases 0.000 claims description 20
• 230000007812 deficiency Effects 0.000 claims description 20
• 208000011117 substance-related disease Diseases 0.000 claims description 20
• 206010013654 Drug abuse Diseases 0.000 claims description 19
• 230000019771 cognition Effects 0.000 claims description 19
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 16
• 150000003254 radicals Chemical group 0.000 claims description 16
• 238000004519 manufacturing process Methods 0.000 claims description 14
• 239000003937 drug carrier Substances 0.000 claims description 13
• APSYYKGWNWKKOC-UHFFFAOYSA-N quinoxaline-5-carboxamide Chemical compound C1=CN=C2C(C(=O)N)=CC=CC2=N1 APSYYKGWNWKKOC-UHFFFAOYSA-N 0.000 claims description 13
• 238000002360 preparation method Methods 0.000 claims description 12
• 239000003054 catalyst Substances 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
• 239000008177 pharmaceutical agent Substances 0.000 claims description 10
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 10
• 150000001412 amines Chemical class 0.000 claims description 9
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 7
• YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 claims description 7
• 229910052722 tritium Inorganic materials 0.000 claims description 7
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 6
• 229910052757 nitrogen Inorganic materials 0.000 claims description 6
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 6
• 239000008174 sterile solution Substances 0.000 claims description 6
• 150000003891 oxalate salts Chemical class 0.000 claims description 5
• PPPQPLAZICCCNM-UHFFFAOYSA-N quinoxaline-6-carboxamide Chemical compound N1=CC=NC2=CC(C(=O)N)=CC=C21 PPPQPLAZICCCNM-UHFFFAOYSA-N 0.000 claims description 5
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
• HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 4
• SAAYZFAHJFPOHZ-UHFFFAOYSA-N quinoxalin-5-amine Chemical compound C1=CN=C2C(N)=CC=CC2=N1 SAAYZFAHJFPOHZ-UHFFFAOYSA-N 0.000 claims description 4
• 238000006268 reductive amination reaction Methods 0.000 claims description 4
• URLXPSUXGAGTAF-UHFFFAOYSA-N 1-(2,6-dichlorophenyl)-n-ethyl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide Chemical compound N12C3=CC(C(=O)NCC)=CC=C3N=C(C)C2=NN=C1C1=C(Cl)C=CC=C1Cl URLXPSUXGAGTAF-UHFFFAOYSA-N 0.000 claims description 3
• LFPMUKYZLLOJCK-UHFFFAOYSA-N 1-[1-(5-butoxy-2-chlorophenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]-n,n-dimethylmethanamine Chemical compound CCCCOC1=CC=C(Cl)C(C=2N3C4=CC(CN(C)C)=CC=C4N=C(C)C3=NN=2)=C1 LFPMUKYZLLOJCK-UHFFFAOYSA-N 0.000 claims description 3
• MWOGXMHCBKOPQQ-UHFFFAOYSA-N 4-methyl-1-phenyl-n-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide Chemical compound N=1N=C2C(C)=NC3=CC=C(C(=O)NCC=4N=CC=CC=4)C=C3N2C=1C1=CC=CC=C1 MWOGXMHCBKOPQQ-UHFFFAOYSA-N 0.000 claims description 3
• KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 claims description 3
• HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 3
• 125000001207 fluorophenyl group Chemical group 0.000 claims description 3
• NDAIEAHJBPRDFW-UHFFFAOYSA-N 1-[1-(2-chloro-5-ethoxyphenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]-n,n-dimethylmethanamine Chemical compound CCOC1=CC=C(Cl)C(C=2N3C4=CC(CN(C)C)=CC=C4N=C(C)C3=NN=2)=C1 NDAIEAHJBPRDFW-UHFFFAOYSA-N 0.000 claims description 2
• SRNXYBWTUXBFQS-UHFFFAOYSA-N 1-[1-(5-butoxy-2-chlorophenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]-n-methylmethanamine Chemical compound CCCCOC1=CC=C(Cl)C(C=2N3C4=CC(CNC)=CC=C4N=C(C)C3=NN=2)=C1 SRNXYBWTUXBFQS-UHFFFAOYSA-N 0.000 claims description 2
• KDLJETKCCNQONU-UHFFFAOYSA-N 1-[1-[5-(cyclopropylmethoxy)pyridin-3-yl]-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]-n,n-dimethylmethanamine Chemical compound N12C3=CC(CN(C)C)=CC=C3N=C(C)C2=NN=C1C(C=1)=CN=CC=1OCC1CC1 KDLJETKCCNQONU-UHFFFAOYSA-N 0.000 claims description 2
• UNICJUYOQQVHAZ-UHFFFAOYSA-N 1-[[1-(2-chloro-5-propan-2-yloxyphenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]methyl]piperidin-4-ol Chemical compound CC(C)OC1=CC=C(Cl)C(C=2N3C4=CC(CN5CCC(O)CC5)=CC=C4N=C(C)C3=NN=2)=C1 UNICJUYOQQVHAZ-UHFFFAOYSA-N 0.000 claims description 2
• FBLAQBPJSVGFII-UHFFFAOYSA-N 4-methyl-1-phenyl-n-(3-phenylpropyl)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide Chemical compound N=1N=C2C(C)=NC3=CC=C(C(=O)NCCCC=4C=CC=CC=4)C=C3N2C=1C1=CC=CC=C1 FBLAQBPJSVGFII-UHFFFAOYSA-N 0.000 claims description 2
• QYYMHMXTKXJDBS-UHFFFAOYSA-N 4-methyl-1-phenyl-n-(pyridin-3-ylmethyl)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide Chemical compound N=1N=C2C(C)=NC3=CC=C(C(=O)NCC=4C=NC=CC=4)C=C3N2C=1C1=CC=CC=C1 QYYMHMXTKXJDBS-UHFFFAOYSA-N 0.000 claims description 2
• BLGZTKFEGIQNDY-UHFFFAOYSA-N 4-methyl-1-phenyl-n-(pyridin-4-ylmethyl)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide Chemical compound N=1N=C2C(C)=NC3=CC=C(C(=O)NCC=4C=CN=CC=4)C=C3N2C=1C1=CC=CC=C1 BLGZTKFEGIQNDY-UHFFFAOYSA-N 0.000 claims description 2
• HWOZZQIWEJEHTR-UHFFFAOYSA-N n-[[1-(2-chloro-5-propan-2-yloxyphenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]methyl]pyridin-3-amine Chemical compound CC(C)OC1=CC=C(Cl)C(C=2N3C4=CC(CNC=5C=NC=CC=5)=CC=C4N=C(C)C3=NN=2)=C1 HWOZZQIWEJEHTR-UHFFFAOYSA-N 0.000 claims description 2
• HXWSGMZHUJKHOE-UHFFFAOYSA-N n-ethyl-1-(2-methoxyphenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide Chemical compound N12C3=CC(C(=O)NCC)=CC=C3N=C(C)C2=NN=C1C1=CC=CC=C1OC HXWSGMZHUJKHOE-UHFFFAOYSA-N 0.000 claims description 2
• PNBCGXHQDAXONB-UHFFFAOYSA-N n-ethyl-4-methyl-1-(6-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide Chemical compound N12C3=CC(C(=O)NCC)=CC=C3N=C(C)C2=NN=C1C1=CC=C(C)N=C1 PNBCGXHQDAXONB-UHFFFAOYSA-N 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 18
• HKESOTAQVZHJQQ-UHFFFAOYSA-N C1=NN=C2N1C1=CC(=CC=C1N=C2)C(=O)N Chemical compound C1=NN=C2N1C1=CC(=CC=C1N=C2)C(=O)N HKESOTAQVZHJQQ-UHFFFAOYSA-N 0.000 claims 2
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• BLJXRMKAAJLGJY-UHFFFAOYSA-N 1-[1-(2-chloro-5-propoxyphenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]-n,n-dimethylmethanamine Chemical compound CCCOC1=CC=C(Cl)C(C=2N3C4=CC(CN(C)C)=CC=C4N=C(C)C3=NN=2)=C1 BLJXRMKAAJLGJY-UHFFFAOYSA-N 0.000 claims 1
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
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• TVELNZSUPLTMOH-UHFFFAOYSA-N 4-[[4-methyl-1-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]methyl]morpholine Chemical compound CC1=NC=CC=C1C1=NN=C2N1C1=CC(CN3CCOCC3)=CC=C1N=C2C TVELNZSUPLTMOH-UHFFFAOYSA-N 0.000 claims 1
• OSRCHTRPIOGYBD-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]quinoxaline-7-carboxamide Chemical compound C1=NN=C2N1C1=CC=C(C=C1N=C2)C(=O)N OSRCHTRPIOGYBD-UHFFFAOYSA-N 0.000 claims 1
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims 1
• OMJDTJPGMCDEOB-UHFFFAOYSA-N n-[[4-methyl-1-(5-propoxypyridin-3-yl)-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]methyl]cyclobutanamine Chemical compound CCCOC1=CN=CC(C=2N3C4=CC(CNC5CCC5)=CC=C4N=C(C)C3=NN=2)=C1 OMJDTJPGMCDEOB-UHFFFAOYSA-N 0.000 claims 1
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• DBZJUMHACWPWRD-UHFFFAOYSA-N n-ethyl-4-methyl-1-pyridin-3-yl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide Chemical compound N12C3=CC(C(=O)NCC)=CC=C3N=C(C)C2=NN=C1C1=CC=CN=C1 DBZJUMHACWPWRD-UHFFFAOYSA-N 0.000 claims 1
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