EA027968B1 - Гетероциклические карбоксамиды в качестве модуляторов активности киназ - Google Patents

Info

Publication number

EA027968B1

EA027968B1 EA201400736A EA201400736A EA027968B1 EA 027968 B1 EA027968 B1 EA 027968B1 EA 201400736 A EA201400736 A EA 201400736A EA 201400736 A EA201400736 A EA 201400736A EA 027968 B1 EA027968 B1 EA 027968B1

Authority

EA

Eurasian Patent Office

Prior art keywords

amino

carboxamide

group

quinazoline

title compound

Prior art date

2011-12-22

Links

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• Global Dossier
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• -1 Heterocyclic carboxamides Chemical class 0.000 title claims abstract description 155
• 230000000694 effects Effects 0.000 title description 10
• 108091000080 Phosphotransferase Proteins 0.000 title description 8
• 102000020233 phosphotransferase Human genes 0.000 title description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 29
• 201000010099 disease Diseases 0.000 claims abstract description 26
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 20
• 201000011510 cancer Diseases 0.000 claims abstract description 17
• 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 10
• 150000001875 compounds Chemical class 0.000 claims description 231
• 238000000034 method Methods 0.000 claims description 129
• 239000000203 mixture Substances 0.000 claims description 52
• 150000003839 salts Chemical class 0.000 claims description 43
• IXLVUUFUDRJUSL-RPBOFIJWSA-N 5-[[4-(3-acetamidophenyl)phenyl]methyl]-n-[(1s,2r)-2-phenylcyclopropyl]-1,3-oxazole-4-carboxamide Chemical compound CC(=O)NC1=CC=CC(C=2C=CC(CC3=C(N=CO3)C(=O)N[C@@H]3[C@H](C3)C=3C=CC=CC=3)=CC=2)=C1 IXLVUUFUDRJUSL-RPBOFIJWSA-N 0.000 claims description 27
• GYBHRTQLUQOYID-UHFFFAOYSA-N quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1 GYBHRTQLUQOYID-UHFFFAOYSA-N 0.000 claims description 24
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
• 125000006413 ring segment Chemical group 0.000 claims description 18
• 238000002360 preparation method Methods 0.000 claims description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 239000004480 active ingredient Substances 0.000 claims description 9
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
• 125000000217 alkyl group Chemical group 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 125000004432 carbon atom Chemical group C* 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 206010061218 Inflammation Diseases 0.000 claims description 5
• 125000004429 atom Chemical group 0.000 claims description 5
• 230000004054 inflammatory process Effects 0.000 claims description 5
• 230000033115 angiogenesis Effects 0.000 claims description 4
• 229910052799 carbon Inorganic materials 0.000 claims description 4
• 206010012601 diabetes mellitus Diseases 0.000 claims description 4
• RFPUAYMRJMGCAD-UHFFFAOYSA-N 5-[[4-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-yl]amino]quinoline-8-carboxamide Chemical compound C12=CC=CN=C2C(C(=O)N)=CC=C1NC1CNCC1C1=CC=CC(OC(F)(F)F)=C1 RFPUAYMRJMGCAD-UHFFFAOYSA-N 0.000 claims description 3
• ZIRLUWNUUJIIGT-UHFFFAOYSA-N 5-[[4-[4-(trifluoromethoxy)phenyl]pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C12=CN=CN=C2C(C(=O)N)=CC=C1NC1CNCC1C1=CC=C(OC(F)(F)F)C=C1 ZIRLUWNUUJIIGT-UHFFFAOYSA-N 0.000 claims description 3
• 201000004624 Dermatitis Diseases 0.000 claims description 3
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 3
• 208000032612 Glial tumor Diseases 0.000 claims description 3
• 206010018338 Glioma Diseases 0.000 claims description 3
• 208000007766 Kaposi sarcoma Diseases 0.000 claims description 3
• 201000004681 Psoriasis Diseases 0.000 claims description 3
• 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 3
• 208000016780 Scleredema Diseases 0.000 claims description 3
• 206010055953 Scleroedema Diseases 0.000 claims description 3
• 206010064930 age-related macular degeneration Diseases 0.000 claims description 3
• 208000010668 atopic eczema Diseases 0.000 claims description 3
• 125000000623 heterocyclic group Chemical group 0.000 claims description 3
• 229910052739 hydrogen Inorganic materials 0.000 claims description 3
• 208000002780 macular degeneration Diseases 0.000 claims description 3
• 201000001441 melanoma Diseases 0.000 claims description 3
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 3
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
• 208000007754 scleredema adultorum Diseases 0.000 claims description 3
• 208000017520 skin disease Diseases 0.000 claims description 3
• 230000005747 tumor angiogenesis Effects 0.000 claims description 3
• 230000004862 vasculogenesis Effects 0.000 claims description 3
• QFZWBDDVPDKVEO-UHFFFAOYSA-N 5-[[4-[3-fluoro-4-(trifluoromethyl)phenyl]piperidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C12=CN=CN=C2C(C(=O)N)=CC=C1NC1CNCCC1C1=CC=C(C(F)(F)F)C(F)=C1 QFZWBDDVPDKVEO-UHFFFAOYSA-N 0.000 claims description 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
• 229910052740 iodine Inorganic materials 0.000 claims description 2
• 125000002950 monocyclic group Chemical group 0.000 claims description 2
• 125000005936 piperidyl group Chemical group 0.000 claims description 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
• 208000002193 Pain Diseases 0.000 claims 2
• 206010033645 Pancreatitis Diseases 0.000 claims 2
• 201000011066 hemangioma Diseases 0.000 claims 2
• 206010020718 hyperplasia Diseases 0.000 claims 2
• 208000017169 kidney disease Diseases 0.000 claims 2
• 208000017497 prostate disease Diseases 0.000 claims 2
• 208000037803 restenosis Diseases 0.000 claims 2
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
• 229910052717 sulfur Inorganic materials 0.000 claims 1
• 238000004519 manufacturing process Methods 0.000 abstract description 4
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 131
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 102
• 239000000543 intermediate Substances 0.000 description 92
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 77
• 230000007062 hydrolysis Effects 0.000 description 75
• 238000006460 hydrolysis reaction Methods 0.000 description 75
• 150000002825 nitriles Chemical class 0.000 description 70
• 239000011541 reaction mixture Substances 0.000 description 62
• 239000000243 solution Substances 0.000 description 52
• 238000005859 coupling reaction Methods 0.000 description 50
• JSWVSPDINVTLGF-UHFFFAOYSA-N 5-bromoquinazoline-8-carbonitrile Chemical compound C1=NC=C2C(Br)=CC=C(C#N)C2=N1 JSWVSPDINVTLGF-UHFFFAOYSA-N 0.000 description 47
• 238000006243 chemical reaction Methods 0.000 description 44
• 230000008878 coupling Effects 0.000 description 43
• 238000010168 coupling process Methods 0.000 description 43
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
• 238000005481 NMR spectroscopy Methods 0.000 description 40
• 150000001408 amides Chemical class 0.000 description 35
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
• 239000007787 solid Substances 0.000 description 20
• 239000012267 brine Substances 0.000 description 19
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
• 239000012453 solvate Substances 0.000 description 18
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
• 239000000651 prodrug Substances 0.000 description 17
• 229940002612 prodrug Drugs 0.000 description 17
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 150000001412 amines Chemical class 0.000 description 15
• 238000002953 preparative HPLC Methods 0.000 description 15
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
• 241000124008 Mammalia Species 0.000 description 13
• 230000015572 biosynthetic process Effects 0.000 description 13
• 239000012043 crude product Substances 0.000 description 13
• 238000003786 synthesis reaction Methods 0.000 description 13
• 239000002253 acid Substances 0.000 description 12
• 238000010511 deprotection reaction Methods 0.000 description 12
• 239000000047 product Substances 0.000 description 12
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
• 102000001253 Protein Kinase Human genes 0.000 description 11
• 239000003112 inhibitor Substances 0.000 description 11
• 239000007788 liquid Substances 0.000 description 11
• 108060006633 protein kinase Proteins 0.000 description 11
• 108090000623 proteins and genes Proteins 0.000 description 11
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 10
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
• 239000012044 organic layer Substances 0.000 description 10
• 238000000746 purification Methods 0.000 description 10
• 239000002904 solvent Substances 0.000 description 10
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• 239000013058 crude material Substances 0.000 description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 8
• 102000004190 Enzymes Human genes 0.000 description 8
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• 210000004027 cell Anatomy 0.000 description 8
• 238000004296 chiral HPLC Methods 0.000 description 8
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• HPQRQAOVNXWEEQ-UHFFFAOYSA-N quinoline-8-carboxamide Chemical compound C1=CN=C2C(C(=O)N)=CC=CC2=C1 HPQRQAOVNXWEEQ-UHFFFAOYSA-N 0.000 description 8
• 238000003756 stirring Methods 0.000 description 8
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
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• RPMSTHVPCJNFMM-UHFFFAOYSA-N 5-aminoquinoline-8-carboxamide Chemical compound C1=CN=C2C(C(=O)N)=CC=C(N)C2=C1 RPMSTHVPCJNFMM-UHFFFAOYSA-N 0.000 description 6
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
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• 150000007513 acids Chemical class 0.000 description 6
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• WBGTURPOYNRUKM-UHFFFAOYSA-N methyl 5-bromoquinazoline-8-carboxylate Chemical compound N1=CN=C2C(C(=O)OC)=CC=C(Br)C2=C1 WBGTURPOYNRUKM-UHFFFAOYSA-N 0.000 description 6
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