DK2945632T3 - HETEROBICYCLO SUBSTITUTED - [1,2,4] TRIAZOL [1,5-C] QUINAZOLIN-5-AMINE COMPOUNDS SUITABLE FOR TREATMENT OR PREVENTION OF DISORDERS IN CENTRAL NERVOUS SYSTEM - Google Patents

Info

Publication number

DK2945632T3

DK2945632T3 DK13866588.0T DK13866588T DK2945632T3 DK 2945632 T3 DK2945632 T3 DK 2945632T3 DK 13866588 T DK13866588 T DK 13866588T DK 2945632 T3 DK2945632 T3 DK 2945632T3

Authority

DK

Denmark

Prior art keywords

amine

methoxy

quinazolin

triazole

ethyl

Prior art date

2012-12-28

Links

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• 230000002265 prevention Effects 0.000 title claims abstract 4
• KWHDQPVGKVPPPS-UHFFFAOYSA-N quinazolin-5-amine Chemical class C1=NC=C2C(N)=CC=CC2=N1 KWHDQPVGKVPPPS-UHFFFAOYSA-N 0.000 title claims description 200
• -1 SUBSTITUTED - [1,2,4] TRIAZOL Chemical class 0.000 title claims description 180
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 13
• 210000003169 central nervous system Anatomy 0.000 title claims description 6
• 150000001875 compounds Chemical class 0.000 claims abstract description 300
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
• 208000012902 Nervous system disease Diseases 0.000 claims abstract description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 89
• 150000003839 salts Chemical class 0.000 claims description 80
• 125000000217 alkyl group Chemical group 0.000 claims description 72
• XYVBVIVKSJMEIW-UHFFFAOYSA-N C1=CC=C2C3=CN=NN3C(N)=NC2=C1 Chemical compound C1=CC=C2C3=CN=NN3C(N)=NC2=C1 XYVBVIVKSJMEIW-UHFFFAOYSA-N 0.000 claims description 67
• 125000001424 substituent group Chemical group 0.000 claims description 51
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 49
• 229910052736 halogen Inorganic materials 0.000 claims description 43
• 125000004432 carbon atom Chemical group C* 0.000 claims description 41
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
• 150000002367 halogens Chemical class 0.000 claims description 34
• 125000005843 halogen group Chemical group 0.000 claims description 29
• 125000003118 aryl group Chemical group 0.000 claims description 28
• 229910052799 carbon Chemical group 0.000 claims description 27
• 229910052757 nitrogen Inorganic materials 0.000 claims description 27
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 27
• 125000001072 heteroaryl group Chemical group 0.000 claims description 24
• 229910052739 hydrogen Inorganic materials 0.000 claims description 21
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 13
• 125000006413 ring segment Chemical group 0.000 claims description 13
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
• 239000001257 hydrogen Substances 0.000 claims description 11
• 150000001412 amines Chemical class 0.000 claims description 10
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 150000001721 carbon Chemical group 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 9
• 125000001153 fluoro group Chemical group F* 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
• 208000015114 central nervous system disease Diseases 0.000 claims description 8
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 125000005842 heteroatom Chemical group 0.000 claims description 5
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 125000002950 monocyclic group Chemical group 0.000 claims description 2
• JZIBVTUXIVIFGC-UHFFFAOYSA-N 2H-pyrrole Chemical compound C1C=CC=N1 JZIBVTUXIVIFGC-UHFFFAOYSA-N 0.000 claims 10
• 125000004260 quinazolin-2-yl group Chemical group [H]C1=NC(*)=NC2=C1C([H])=C([H])C([H])=C2[H] 0.000 claims 10
• 150000003852 triazoles Chemical class 0.000 claims 7
• RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 claims 6
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 5
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
• PXNJNSJHOIQDOY-UHFFFAOYSA-N 5-methyl-3h-pyrrole Chemical compound CC1=CCC=N1 PXNJNSJHOIQDOY-UHFFFAOYSA-N 0.000 claims 3
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims 3
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
• JGSIAOZAXBWRFO-UHFFFAOYSA-N 3-methylsulfanyl-1-phenyl-4,5-dihydrobenzo[g]indazole Chemical compound C1CC2=CC=CC=C2C2=C1C(SC)=NN2C1=CC=CC=C1 JGSIAOZAXBWRFO-UHFFFAOYSA-N 0.000 claims 2
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
• IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims 2
• HNVIQLPOGUDBSU-OLQVQODUSA-N (2s,6r)-2,6-dimethylmorpholine Chemical compound C[C@H]1CNC[C@@H](C)O1 HNVIQLPOGUDBSU-OLQVQODUSA-N 0.000 claims 1
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
• QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims 1
• LWTIGYSPAXKMDG-UHFFFAOYSA-N 2,3-dihydro-1h-imidazole Chemical compound C1NC=CN1 LWTIGYSPAXKMDG-UHFFFAOYSA-N 0.000 claims 1
• IRTLROCMFSDSNF-UHFFFAOYSA-N 2-phenyl-1h-pyrrole Chemical compound C1=CNC(C=2C=CC=CC=2)=C1 IRTLROCMFSDSNF-UHFFFAOYSA-N 0.000 claims 1
• SUWOQIFACNCUKF-UHFFFAOYSA-N 3-(trifluoromethyl)-4,5-dihydro-1h-pyrazole Chemical compound FC(F)(F)C1=NNCC1 SUWOQIFACNCUKF-UHFFFAOYSA-N 0.000 claims 1
• YWDCYRQSJPWRFK-UHFFFAOYSA-N 3-cyclopropyl-4,5-dihydro-1h-pyrazole Chemical compound C1CC1C1=NNCC1 YWDCYRQSJPWRFK-UHFFFAOYSA-N 0.000 claims 1
• XDLSMBDBMXQDFE-UHFFFAOYSA-N 5-propan-2-yl-3h-pyrrole Chemical compound CC(C)C1=CCC=N1 XDLSMBDBMXQDFE-UHFFFAOYSA-N 0.000 claims 1
• QTIBUWFVGRJDRR-UHFFFAOYSA-N CN1N=CC(C2(C=C(CN(CN3N=CN=C3)CC3)C3=CC2)OC)=C1 Chemical compound CN1N=CC(C2(C=C(CN(CN3N=CN=C3)CC3)C3=CC2)OC)=C1 QTIBUWFVGRJDRR-UHFFFAOYSA-N 0.000 claims 1
• YCLQFTINUCVGFV-UHFFFAOYSA-N ClC1=NCC=C1 Chemical compound ClC1=NCC=C1 YCLQFTINUCVGFV-UHFFFAOYSA-N 0.000 claims 1
• JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 claims 1
• 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims 1
• 150000002431 hydrogen Chemical class 0.000 claims 1
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims 1
• IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 1
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims 1
• NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 claims 1
• 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 claims 1
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 1
• NOYGBDOUZKESFV-UHFFFAOYSA-N quinazoline-7-carbonitrile Chemical compound C1=NC=NC2=CC(C#N)=CC=C21 NOYGBDOUZKESFV-UHFFFAOYSA-N 0.000 claims 1
• 101150051188 Adora2a gene Proteins 0.000 abstract description 15
• 239000005557 antagonist Substances 0.000 abstract description 10
• 208000025966 Neurological disease Diseases 0.000 abstract 2
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 213
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 122
• 239000011541 reaction mixture Substances 0.000 description 86
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
• 239000000203 mixture Substances 0.000 description 80
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 61
• 239000007787 solid Substances 0.000 description 60
• 229910001868 water Inorganic materials 0.000 description 60
• 239000000243 solution Substances 0.000 description 57
• 238000002360 preparation method Methods 0.000 description 48
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 39
• 239000000047 product Substances 0.000 description 38
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 37
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
• 235000019439 ethyl acetate Nutrition 0.000 description 36
• 239000000758 substrate Substances 0.000 description 36
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
• 238000000034 method Methods 0.000 description 31
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
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• 239000012043 crude product Substances 0.000 description 25
• OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 22
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• 239000002552 dosage form Substances 0.000 description 18
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
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• 239000002244 precipitate Substances 0.000 description 11
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• XEJNGBAJXWQGBH-UHFFFAOYSA-N 2-(5-amino-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)ethyl methanesulfonate Chemical class C12=NC(CCOS(C)(=O)=O)=NN2C(N)=NC2=C1C=CC=C2OC XEJNGBAJXWQGBH-UHFFFAOYSA-N 0.000 description 6
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