CA2651072A1 - Substituted 2-amino-fused heterocyclic compounds - Google Patents

Info

Publication number

CA2651072A1

CA2651072A1 CA002651072A CA2651072A CA2651072A1 CA 2651072 A1 CA2651072 A1 CA 2651072A1 CA 002651072 A CA002651072 A CA 002651072A CA 2651072 A CA2651072 A CA 2651072A CA 2651072 A1 CA2651072 A1 CA 2651072A1

Authority

CA

Canada

Prior art keywords

cr8r9

trans

amino

cr5r6

carboxamide

Prior art date

2006-05-01

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 299
• 238000000034 method Methods 0.000 claims abstract description 52
• 150000003839 salts Chemical class 0.000 claims abstract description 39
• 239000012453 solvate Substances 0.000 claims abstract description 18
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• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 8
• 230000001404 mediated effect Effects 0.000 claims abstract description 6
• 229910052739 hydrogen Inorganic materials 0.000 claims description 908
• -1 azido, hydroxy Chemical group 0.000 claims description 275
• 125000000623 heterocyclic group Chemical group 0.000 claims description 84
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 61
• 229910052757 nitrogen Inorganic materials 0.000 claims description 41
• 125000000217 alkyl group Chemical group 0.000 claims description 30
• 125000003118 aryl group Chemical group 0.000 claims description 30
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 23
• 125000005843 halogen group Chemical group 0.000 claims description 17
• 125000004432 carbon atom Chemical group C* 0.000 claims description 13
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
• 208000008589 Obesity Diseases 0.000 claims description 9
• 235000020824 obesity Nutrition 0.000 claims description 9
• 125000001424 substituent group Chemical group 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
• 201000010099 disease Diseases 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• 230000001684 chronic effect Effects 0.000 claims description 5
• 208000027866 inflammatory disease Diseases 0.000 claims description 5
• 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 4
• 230000001154 acute effect Effects 0.000 claims description 4
• 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 4
• 201000008980 hyperinsulinism Diseases 0.000 claims description 4
• 210000005240 left ventricle Anatomy 0.000 claims description 4
• 210000004185 liver Anatomy 0.000 claims description 4
• 210000000056 organ Anatomy 0.000 claims description 4
• 229910052760 oxygen Inorganic materials 0.000 claims description 4
• 229910052717 sulfur Inorganic materials 0.000 claims description 4
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• 208000010412 Glaucoma Diseases 0.000 claims description 3
• 208000031226 Hyperlipidaemia Diseases 0.000 claims description 3
• 206010020772 Hypertension Diseases 0.000 claims description 3
• 208000031773 Insulin resistance syndrome Diseases 0.000 claims description 3
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 3
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 3
• 125000005842 heteroatom Chemical group 0.000 claims description 3
• 201000001421 hyperglycemia Diseases 0.000 claims description 3
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• 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 2
• 208000006029 Cardiomegaly Diseases 0.000 claims description 2
• 206010056370 Congestive cardiomyopathy Diseases 0.000 claims description 2
• 206010012289 Dementia Diseases 0.000 claims description 2
• 206010052337 Diastolic dysfunction Diseases 0.000 claims description 2
• 201000010046 Dilated cardiomyopathy Diseases 0.000 claims description 2
• 206010048554 Endothelial dysfunction Diseases 0.000 claims description 2
• 206010019280 Heart failures Diseases 0.000 claims description 2
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• 241000700605 Viruses Species 0.000 claims description 2
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• 125000004043 oxo group Chemical group O=* 0.000 claims description 2
• 208000037803 restenosis Diseases 0.000 claims description 2
• 201000008827 tuberculosis Diseases 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 243
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 232
• 238000005481 NMR spectroscopy Methods 0.000 description 189
• 150000003857 carboxamides Chemical class 0.000 description 162
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 154
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 117
• 238000002360 preparation method Methods 0.000 description 115
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
• 239000000203 mixture Substances 0.000 description 98
• 239000000243 solution Substances 0.000 description 97
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 81
• 239000007787 solid Substances 0.000 description 80
• 239000002904 solvent Substances 0.000 description 75
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
• 239000000543 intermediate Substances 0.000 description 65
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 61
• 241001024304 Mino Species 0.000 description 59
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
• 238000006243 chemical reaction Methods 0.000 description 59
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 49
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 48
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
• 238000001819 mass spectrum Methods 0.000 description 48
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 46
• 235000019439 ethyl acetate Nutrition 0.000 description 44
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 41
• HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 39
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
• 238000005160 1H NMR spectroscopy Methods 0.000 description 37
• 239000000047 product Substances 0.000 description 37
• GYBHRTQLUQOYID-UHFFFAOYSA-N quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1 GYBHRTQLUQOYID-UHFFFAOYSA-N 0.000 description 37
• 239000000725 suspension Substances 0.000 description 35
• 239000002585 base Substances 0.000 description 34
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 30
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
• TYHCBIKGTCZFTK-UHFFFAOYSA-N quinazoline-7-carboxamide Chemical compound C1=NC=NC2=CC(C(=O)N)=CC=C21 TYHCBIKGTCZFTK-UHFFFAOYSA-N 0.000 description 28
• 239000011541 reaction mixture Substances 0.000 description 28
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 27
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 26
• 239000012044 organic layer Substances 0.000 description 26
• 238000004809 thin layer chromatography Methods 0.000 description 26
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 23
• 239000012043 crude product Substances 0.000 description 23
• KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 23
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 21
• VYCKDIRCVDCQAE-UHFFFAOYSA-N isoquinolin-3-amine Chemical compound C1=CC=C2C=NC(N)=CC2=C1 VYCKDIRCVDCQAE-UHFFFAOYSA-N 0.000 description 21
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 20
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• 239000012267 brine Substances 0.000 description 18
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
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• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 16
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• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 16
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• 238000003756 stirring Methods 0.000 description 16
• BXDZOYLPNAIDOC-UHFFFAOYSA-N N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethyl]piperidine-4-carboxamide Chemical compound CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(CC(=O)NCCOCCOCCOCCNc4cccc5C(=O)N(C6CCC(=O)NC6=O)C(=O)c45)CC3)s2)o1 BXDZOYLPNAIDOC-UHFFFAOYSA-N 0.000 description 15
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• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 12
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• 125000003342 alkenyl group Chemical group 0.000 description 5
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