EA023045B1 - Новые замещенные производные индола в качестве модуляторов гамма-секретазы - Google Patents

Info

Publication number

EA023045B1

EA023045B1 EA201490287A EA201490287A EA023045B1 EA 023045 B1 EA023045 B1 EA 023045B1 EA 201490287 A EA201490287 A EA 201490287A EA 201490287 A EA201490287 A EA 201490287A EA 023045 B1 EA023045 B1 EA 023045B1

Authority

EA

Eurasian Patent Office

Prior art keywords

group

substituents

alkyloxy

formula

mmol

Prior art date

2011-07-15

Links

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• 229940124648 γ-Secretase Modulator Drugs 0.000 title claims abstract description 10
• VHNYOQKVZQVBLC-RTCGXNAVSA-N (4r,7e,9as)-7-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]-4-(3,4,5-trifluorophenyl)-1,3,4,8,9,9a-hexahydropyrido[2,1-c][1,4]oxazin-6-one Chemical compound C1([C@@H]2COC[C@@H]3CC\C(C(N32)=O)=C/C=2C=C(C(=CC=2)N2C=C(C)N=C2)OC)=CC(F)=C(F)C(F)=C1 VHNYOQKVZQVBLC-RTCGXNAVSA-N 0.000 title abstract description 9
• 150000002475 indoles Chemical class 0.000 title abstract description 4
• 229940054051 antipsychotic indole derivative Drugs 0.000 title abstract description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 274
• 239000003814 drug Substances 0.000 claims abstract description 22
• 239000004480 active ingredient Substances 0.000 claims abstract description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
• 125000000217 alkyl group Chemical group 0.000 claims description 116
• 125000001424 substituent group Chemical group 0.000 claims description 114
• 229910052739 hydrogen Inorganic materials 0.000 claims description 103
• 125000003545 alkoxy group Chemical group 0.000 claims description 100
• 239000001257 hydrogen Substances 0.000 claims description 92
• 229910052736 halogen Inorganic materials 0.000 claims description 78
• 150000002367 halogens Chemical class 0.000 claims description 78
• 125000001153 fluoro group Chemical group F* 0.000 claims description 68
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 68
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 60
• 150000003839 salts Chemical class 0.000 claims description 59
• 230000015572 biosynthetic process Effects 0.000 claims description 58
• 150000002431 hydrogen Chemical class 0.000 claims description 54
• 125000004076 pyridyl group Chemical group 0.000 claims description 41
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 36
• 238000011282 treatment Methods 0.000 claims description 33
• 229910052799 carbon Inorganic materials 0.000 claims description 32
• 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 claims description 29
• 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 claims description 29
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 29
• 206010012289 Dementia Diseases 0.000 claims description 26
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
• 125000002883 imidazolyl group Chemical group 0.000 claims description 17
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
• 201000010099 disease Diseases 0.000 claims description 15
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 14
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 13
• 125000002971 oxazolyl group Chemical group 0.000 claims description 12
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• 238000000034 method Methods 0.000 abstract description 72
• 230000008569 process Effects 0.000 abstract description 2
• 239000000543 intermediate Substances 0.000 description 397
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 276
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 155
• 239000000203 mixture Substances 0.000 description 146
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• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 62
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• 239000003480 eluent Substances 0.000 description 44
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• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 34
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• 210000004556 brain Anatomy 0.000 description 25
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• 239000012267 brine Substances 0.000 description 23
• 239000010410 layer Substances 0.000 description 23
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
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• 229910052740 iodine Inorganic materials 0.000 description 19
• 239000006228 supernatant Substances 0.000 description 19
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 18
• 235000011089 carbon dioxide Nutrition 0.000 description 18
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
• 238000000746 purification Methods 0.000 description 18
• 229920006395 saturated elastomer Polymers 0.000 description 18
• 239000000725 suspension Substances 0.000 description 17
• 229910052794 bromium Inorganic materials 0.000 description 16
• 238000002474 experimental method Methods 0.000 description 16
• 239000002244 precipitate Substances 0.000 description 16
• 125000006239 protecting group Chemical group 0.000 description 16
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• 229910002092 carbon dioxide Inorganic materials 0.000 description 15
• 230000005855 radiation Effects 0.000 description 15
• YHWMFDLNZGIJSD-UHFFFAOYSA-N 2h-1,4-oxazine Chemical compound C1OC=CN=C1 YHWMFDLNZGIJSD-UHFFFAOYSA-N 0.000 description 14
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
• 239000011737 fluorine Substances 0.000 description 14
• 229910052731 fluorine Inorganic materials 0.000 description 14
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 14
• 125000002757 morpholinyl group Chemical group 0.000 description 14
• 230000003287 optical effect Effects 0.000 description 14
• 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 13
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical class CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 13
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 13
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 12
• 238000004458 analytical method Methods 0.000 description 12
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• 239000003826 tablet Substances 0.000 description 12
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 11
• 239000005909 Kieselgur Substances 0.000 description 11
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
• ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 11
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 11
• 238000004519 manufacturing process Methods 0.000 description 11
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• 230000002285 radioactive effect Effects 0.000 description 11
• 210000004027 cell Anatomy 0.000 description 10
• 238000001514 detection method Methods 0.000 description 10
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
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• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
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• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
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• 241000282412 Homo Species 0.000 description 8
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• 125000004432 carbon atom Chemical group C* 0.000 description 7
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 7
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• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical class CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
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