EA029312B1 - Производные имидазопирролидинона и их применение при лечении заболеваний - Google Patents

Info

Publication number

EA029312B1

EA029312B1 EA201592256A EA201592256A EA029312B1 EA 029312 B1 EA029312 B1 EA 029312B1 EA 201592256 A EA201592256 A EA 201592256A EA 201592256 A EA201592256 A EA 201592256A EA 029312 B1 EA029312 B1 EA 029312B1

Authority

EA

Eurasian Patent Office

Prior art keywords

chlorophenyl

dihydropyrrolo

imidazol

dimethyl

isopropyl

Prior art date

2013-05-27

Links

• Espacenet
• Global Dossier
• Discuss

• 238000011282 treatment Methods 0.000 title claims description 61
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 48
• 201000010099 disease Diseases 0.000 title description 38
• LOROIKRUMJLRJU-UHFFFAOYSA-N 4,6-dihydro-1h-pyrrolo[2,3-d]imidazol-5-one Chemical class N1C=NC2=C1CC(=O)N2 LOROIKRUMJLRJU-UHFFFAOYSA-N 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 413
• 238000000034 method Methods 0.000 claims abstract description 223
• 150000003839 salts Chemical class 0.000 claims abstract description 69
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
• 238000004519 manufacturing process Methods 0.000 claims abstract description 8
• -1 cyano, methyl Chemical group 0.000 claims description 764
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 577
• CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 claims description 436
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 62
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 34
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 27
• 239000003814 drug Substances 0.000 claims description 26
• 206010028980 Neoplasm Diseases 0.000 claims description 21
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
• 229910052736 halogen Inorganic materials 0.000 claims description 19
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
• 150000002367 halogens Chemical class 0.000 claims description 16
• 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 16
• 108090000623 proteins and genes Proteins 0.000 claims description 16
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
• 201000011510 cancer Diseases 0.000 claims description 15
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 15
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
• 229910052739 hydrogen Inorganic materials 0.000 claims description 13
• 102000004169 proteins and genes Human genes 0.000 claims description 10
• 230000000694 effects Effects 0.000 claims description 9
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 9
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 9
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 3
• 125000004463 2,4-dimethyl-thiazol-5-yl group Chemical group CC=1SC(=C(N1)C)* 0.000 claims description 2
• GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims description 2
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 2
• 230000001225 therapeutic effect Effects 0.000 abstract description 10
• 239000013543 active substance Substances 0.000 abstract description 3
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 556
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 449
• 239000000203 mixture Substances 0.000 description 177
• 239000011541 reaction mixture Substances 0.000 description 159
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 147
• 230000002829 reductive effect Effects 0.000 description 139
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• 239000000284 extract Substances 0.000 description 87
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• 229910052796 boron Inorganic materials 0.000 description 66
• 239000012267 brine Substances 0.000 description 66
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 66
• 238000010898 silica gel chromatography Methods 0.000 description 60
• 239000012071 phase Substances 0.000 description 57
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 54
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
• 239000002585 base Substances 0.000 description 48
• 238000002953 preparative HPLC Methods 0.000 description 48
• 238000005481 NMR spectroscopy Methods 0.000 description 47
• 239000002904 solvent Substances 0.000 description 44
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 41
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
• 239000000706 filtrate Substances 0.000 description 37
• 238000004809 thin layer chromatography Methods 0.000 description 37
• 239000007858 starting material Substances 0.000 description 36
• 239000000725 suspension Substances 0.000 description 32
• 238000004237 preparative chromatography Methods 0.000 description 31
• 239000000741 silica gel Substances 0.000 description 31
• 229910002027 silica gel Inorganic materials 0.000 description 31
• 238000000746 purification Methods 0.000 description 30
• 238000001514 detection method Methods 0.000 description 28
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
• 238000004440 column chromatography Methods 0.000 description 26
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 26
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
• 238000000926 separation method Methods 0.000 description 24
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
• 238000006243 chemical reaction Methods 0.000 description 23
• 239000002253 acid Substances 0.000 description 21
• 238000002425 crystallisation Methods 0.000 description 20
• 230000008025 crystallization Effects 0.000 description 20
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
• 239000000126 substance Substances 0.000 description 20
• 238000000825 ultraviolet detection Methods 0.000 description 20
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
• 239000012043 crude product Substances 0.000 description 18
• 229910052805 deuterium Inorganic materials 0.000 description 17
• 229940124597 therapeutic agent Drugs 0.000 description 17
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
• 239000002994 raw material Substances 0.000 description 16
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 239000012298 atmosphere Substances 0.000 description 15
• 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 15
• 229920006395 saturated elastomer Polymers 0.000 description 15
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
• 239000000543 intermediate Substances 0.000 description 14
• 239000003921 oil Substances 0.000 description 14
• 235000019198 oils Nutrition 0.000 description 14
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 13
• 125000000217 alkyl group Chemical group 0.000 description 13
• 239000012044 organic layer Substances 0.000 description 13
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
• 238000003756 stirring Methods 0.000 description 13
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• DHADXDMPEUWEAS-UHFFFAOYSA-N (6-methoxypyridin-3-yl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=N1 DHADXDMPEUWEAS-UHFFFAOYSA-N 0.000 description 11
• BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 11
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• RWOUCFQSBNTZNR-UHFFFAOYSA-N ethyl 2-bromo-5-[(4-chlorophenyl)-hydroxymethyl]-1-propan-2-ylimidazole-4-carboxylate Chemical compound N1=C(Br)N(C(C)C)C(C(O)C=2C=CC(Cl)=CC=2)=C1C(=O)OCC RWOUCFQSBNTZNR-UHFFFAOYSA-N 0.000 description 11
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• IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 10
• 125000006239 protecting group Chemical group 0.000 description 10
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