CN109180669A - Imino group thiadiazine dioxide derivative and application thereof - Google Patents
Imino group thiadiazine dioxide derivative and application thereof Download PDFInfo
- Publication number
- CN109180669A CN109180669A CN201811035271.5A CN201811035271A CN109180669A CN 109180669 A CN109180669 A CN 109180669A CN 201811035271 A CN201811035271 A CN 201811035271A CN 109180669 A CN109180669 A CN 109180669A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- base
- alkoxy
- compound
- cooh
- Prior art date
- 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.)
- Granted
Links
- JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 title abstract description 12
- 125000001841 imino group Chemical group [H]N=* 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 291
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 62
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 47
- 201000010099 disease Diseases 0.000 claims abstract description 46
- 238000002360 preparation method Methods 0.000 claims abstract description 43
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 40
- 239000003814 drug Substances 0.000 claims abstract description 39
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims abstract description 22
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 18
- -1 hydrate Substances 0.000 claims description 206
- 229910052731 fluorine Inorganic materials 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 229910052801 chlorine Inorganic materials 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 229910052794 bromium Inorganic materials 0.000 claims description 44
- 229910052740 iodine Inorganic materials 0.000 claims description 44
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 42
- 229910052805 deuterium Inorganic materials 0.000 claims description 42
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 38
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 35
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 30
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 30
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 28
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000000651 prodrug Substances 0.000 claims description 18
- 229940002612 prodrug Drugs 0.000 claims description 18
- 208000024891 symptom Diseases 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 201000010374 Down Syndrome Diseases 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 208000018737 Parkinson disease Diseases 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 239000003112 inhibitor Substances 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 12
- MUKYLHIZBOASDM-UHFFFAOYSA-N 2-[carbamimidoyl(methyl)amino]acetic acid 2,3,4,5,6-pentahydroxyhexanoic acid Chemical compound NC(=N)N(C)CC(O)=O.OCC(O)C(O)C(O)C(O)C(O)=O MUKYLHIZBOASDM-UHFFFAOYSA-N 0.000 claims description 10
- 208000000044 Amnesia Diseases 0.000 claims description 10
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 10
- 241000819233 Tribulus <sea snail> Species 0.000 claims description 10
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 10
- 231100000863 loss of memory Toxicity 0.000 claims description 10
- 206010025482 malaise Diseases 0.000 claims description 10
- 239000002207 metabolite Substances 0.000 claims description 10
- 229940124597 therapeutic agent Drugs 0.000 claims description 10
- 229940047183 tribulus Drugs 0.000 claims description 10
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 claims description 9
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 230000006735 deficit Effects 0.000 claims description 8
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 8
- 150000004820 halides Chemical class 0.000 claims description 8
- 229960004136 rivastigmine Drugs 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 7
- 206010012289 Dementia Diseases 0.000 claims description 7
- 239000005864 Sulphur Substances 0.000 claims description 7
- 208000010877 cognitive disease Diseases 0.000 claims description 7
- 230000004770 neurodegeneration Effects 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 6
- 230000006933 amyloid-beta aggregation Effects 0.000 claims description 6
- 239000005557 antagonist Substances 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 5
- 206010039966 Senile dementia Diseases 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 206010002022 amyloidosis Diseases 0.000 claims description 5
- 229960003530 donepezil Drugs 0.000 claims description 5
- 238000001631 haemodialysis Methods 0.000 claims description 5
- 230000000322 hemodialysis Effects 0.000 claims description 5
- 230000000116 mitigating effect Effects 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 claims description 4
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 4
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 229940099433 NMDA receptor antagonist Drugs 0.000 claims description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims description 4
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 229960003980 galantamine Drugs 0.000 claims description 4
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 claims description 4
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 4
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 claims description 4
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 claims description 4
- 229960004640 memantine Drugs 0.000 claims description 4
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 4
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 claims description 4
- 235000001968 nicotinic acid Nutrition 0.000 claims description 4
- 239000011664 nicotinic acid Substances 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 229960001685 tacrine Drugs 0.000 claims description 4
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 4
- 230000009529 traumatic brain injury Effects 0.000 claims description 4
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 claims description 3
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 3
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 claims description 3
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical group N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 claims description 3
- YSEXMKHXIOCEJA-FVFQAYNVSA-N Nicergoline Chemical compound C([C@@H]1C[C@]2([C@H](N(C)C1)CC=1C3=C2C=CC=C3N(C)C=1)OC)OC(=O)C1=CN=CC(Br)=C1 YSEXMKHXIOCEJA-FVFQAYNVSA-N 0.000 claims description 3
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 3
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 claims description 3
- 208000018756 Variant Creutzfeldt-Jakob disease Diseases 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 239000000556 agonist Substances 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 208000005881 bovine spongiform encephalopathy Diseases 0.000 claims description 3
- 230000002490 cerebral effect Effects 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 229960003914 desipramine Drugs 0.000 claims description 3
- 229940125753 fibrate Drugs 0.000 claims description 3
- 239000003540 gamma secretase inhibitor Substances 0.000 claims description 3
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 3
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims description 3
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 229940127592 mGluR2/3 antagonist Drugs 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 229960005297 nalmefene Drugs 0.000 claims description 3
- 229960003642 nicergoline Drugs 0.000 claims description 3
- 229960003512 nicotinic acid Drugs 0.000 claims description 3
- 229960001476 pentoxifylline Drugs 0.000 claims description 3
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- 229960004526 piracetam Drugs 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 claims description 3
- 229960001534 risperidone Drugs 0.000 claims description 3
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 claims description 3
- 229960003946 selegiline Drugs 0.000 claims description 3
- 239000000387 serotonin 5-HT4 receptor agonist Substances 0.000 claims description 3
- 239000003751 serotonin 6 antagonist Substances 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960004688 venlafaxine Drugs 0.000 claims description 3
- 239000011782 vitamin Substances 0.000 claims description 3
- 229940088594 vitamin Drugs 0.000 claims description 3
- 235000013343 vitamin Nutrition 0.000 claims description 3
- 229930003231 vitamin Natural products 0.000 claims description 3
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 3
- 229960000820 zopiclone Drugs 0.000 claims description 3
- 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 claims description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 229940122601 Esterase inhibitor Drugs 0.000 claims description 2
- 108091007911 GSKs Proteins 0.000 claims description 2
- 102000004103 Glycogen Synthase Kinases Human genes 0.000 claims description 2
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 claims description 2
- 102100036834 Metabotropic glutamate receptor 1 Human genes 0.000 claims description 2
- 102100038357 Metabotropic glutamate receptor 5 Human genes 0.000 claims description 2
- 229940123925 Nicotinic receptor agonist Drugs 0.000 claims description 2
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002329 esterase inhibitor Substances 0.000 claims description 2
- 239000003395 histamine H3 receptor antagonist Substances 0.000 claims description 2
- 108010014719 metabotropic glutamate receptor type 1 Proteins 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000000181 nicotinic agonist Substances 0.000 claims description 2
- 229960001158 nortriptyline Drugs 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 229940124648 γ-Secretase Modulator Drugs 0.000 claims description 2
- 150000003851 azoles Chemical class 0.000 claims 1
- 210000004204 blood vessel Anatomy 0.000 claims 1
- 229960001231 choline Drugs 0.000 claims 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims 1
- 125000002541 furyl group Chemical group 0.000 claims 1
- 108091006073 receptor regulators Proteins 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 60
- 238000011282 treatment Methods 0.000 abstract description 22
- 229940125759 BACE1 protease inhibitor Drugs 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 133
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
- 239000002585 base Substances 0.000 description 110
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 67
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- 238000003786 synthesis reaction Methods 0.000 description 62
- 230000015572 biosynthetic process Effects 0.000 description 61
- 238000006243 chemical reaction Methods 0.000 description 56
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 52
- 239000007787 solid Substances 0.000 description 50
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 49
- 238000000132 electrospray ionisation Methods 0.000 description 46
- 150000002500 ions Chemical class 0.000 description 45
- 238000004949 mass spectrometry Methods 0.000 description 45
- 235000019439 ethyl acetate Nutrition 0.000 description 44
- 238000005160 1H NMR spectroscopy Methods 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 229910052799 carbon Inorganic materials 0.000 description 33
- 239000000203 mixture Substances 0.000 description 32
- 238000000746 purification Methods 0.000 description 31
- 238000010898 silica gel chromatography Methods 0.000 description 31
- 239000000243 solution Substances 0.000 description 31
- 239000003795 chemical substances by application Substances 0.000 description 29
- 239000012043 crude product Substances 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 27
- 150000001721 carbon Chemical group 0.000 description 26
- 125000001424 substituent group Chemical group 0.000 description 23
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 18
- 125000004429 atom Chemical group 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 18
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 18
- 239000002552 dosage form Substances 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 15
- 239000003826 tablet Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 230000006837 decompression Effects 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- WVVGJJXQPIOHNV-UHFFFAOYSA-N (2-fluoro-5-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=C(F)C(C(=O)C=2C=CC=CC=2)=C1 WVVGJJXQPIOHNV-UHFFFAOYSA-N 0.000 description 12
- 238000007445 Chromatographic isolation Methods 0.000 description 12
- 238000011097 chromatography purification Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- WJRKNLONLOMALV-UHFFFAOYSA-N 5-chloropyridine Chemical compound ClC1=C=NC=C[CH]1 WJRKNLONLOMALV-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- FGFKWZWDTXCIDN-UHFFFAOYSA-N 3,5-dimethyl-2H-1,2,4-thiadiazine Chemical compound CC=1N=C(NSC=1)C FGFKWZWDTXCIDN-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 125000002619 bicyclic group Chemical group 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 230000002335 preservative effect Effects 0.000 description 7
- 229930192474 thiophene Natural products 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 238000007911 parenteral administration Methods 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 229940126077 BACE inhibitor Drugs 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 239000012131 assay buffer Substances 0.000 description 5
- 239000007891 compressed tablet Substances 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 239000003349 gelling agent Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000000375 suspending agent Substances 0.000 description 5
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- WYTSRYSZKIUCSI-UHFFFAOYSA-N CC=1NS(C=CN1)(=O)=O Chemical compound CC=1NS(C=CN1)(=O)=O WYTSRYSZKIUCSI-UHFFFAOYSA-N 0.000 description 4
- 102000008946 Fibrinogen Human genes 0.000 description 4
- 108010049003 Fibrinogen Proteins 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 4
- 229940012952 fibrinogen Drugs 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- DQMWMUMCNOJLSI-UHFFFAOYSA-N n-carbamothioylbenzamide Chemical compound NC(=S)NC(=O)C1=CC=CC=C1 DQMWMUMCNOJLSI-UHFFFAOYSA-N 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- DROIHSMGGKKIJT-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound CCCS(N)(=O)=O DROIHSMGGKKIJT-UHFFFAOYSA-N 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 4
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 3
- 238000011818 5xFAD mouse Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000000544 cholinesterase inhibitor Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 239000008297 liquid dosage form Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000016273 neuron death Effects 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- 235000010603 pastilles Nutrition 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000011698 potassium fluoride Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- OUVLUQAZXRHABI-UHFFFAOYSA-N s-propan-2-ylthiohydroxylamine Chemical compound CC(C)SN OUVLUQAZXRHABI-UHFFFAOYSA-N 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- JYKZHOIVKRPRSI-UHFFFAOYSA-N NC=1C=C(C=CC1)C1(N=CN(S(C1)(=O)=O)C)C Chemical compound NC=1C=C(C=CC1)C1(N=CN(S(C1)(=O)=O)C)C JYKZHOIVKRPRSI-UHFFFAOYSA-N 0.000 description 2
- 239000007990 PIPES buffer Substances 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 206010036049 Polycystic ovaries Diseases 0.000 description 2
- 102000015499 Presenilins Human genes 0.000 description 2
- 108010050254 Presenilins Proteins 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 208000025698 brain inflammatory disease Diseases 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 210000000274 microglia Anatomy 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 2
- 229960001227 oxiracetam Drugs 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000008299 semisolid dosage form Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000007940 sugar coated tablet Substances 0.000 description 2
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 235000019640 taste Nutrition 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 2
- 229960001475 zolpidem Drugs 0.000 description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- GDSOZVZXVXTJMI-SNAWJCMRSA-N (e)-1-methylbut-1-ene-1,2,4-tricarboxylic acid Chemical class OC(=O)C(/C)=C(C(O)=O)\CCC(O)=O GDSOZVZXVXTJMI-SNAWJCMRSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- 150000005070 1,2,3-oxadiazoles Chemical class 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 150000005071 1,2,4-oxadiazoles Chemical class 0.000 description 1
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ARKIFHPFTHVKDT-UHFFFAOYSA-N 1-(3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=CC([N+]([O-])=O)=C1 ARKIFHPFTHVKDT-UHFFFAOYSA-N 0.000 description 1
- 102100027831 14-3-3 protein theta Human genes 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- XCHCHGNNHHKGLR-UHFFFAOYSA-N 4h-1,2,4-thiadiazine 1,1-dioxide Chemical compound O=S1(=O)NC=NC=C1 XCHCHGNNHHKGLR-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000006888 Agnosia Diseases 0.000 description 1
- 241001047040 Agnosia Species 0.000 description 1
- 102000001049 Amyloid Human genes 0.000 description 1
- 108010094108 Amyloid Proteins 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 1
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 1
- 108010017640 Aspartic Acid Proteases Proteins 0.000 description 1
- 102000004580 Aspartic Acid Proteases Human genes 0.000 description 1
- 241000163925 Bembidion minimum Species 0.000 description 1
- 102100021257 Beta-secretase 1 Human genes 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 125000006519 CCH3 Chemical group 0.000 description 1
- PCEIHMZWJWOMJF-UHFFFAOYSA-N COC1=CC=C(CC(CC)S(=O)(=O)NC)C=C1 Chemical compound COC1=CC=C(CC(CC)S(=O)(=O)NC)C=C1 PCEIHMZWJWOMJF-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010001483 Glycogen Synthase Proteins 0.000 description 1
- 206010018473 Glycosuria Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 208000027382 Mental deterioration Diseases 0.000 description 1
- 206010027374 Mental impairment Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 description 1
- ULWYIVYFPIPRRK-UHFFFAOYSA-N N1C=CC=CC=C1.[S] Chemical compound N1C=CC=CC=C1.[S] ULWYIVYFPIPRRK-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229920002730 Poly(butyl cyanoacrylate) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 101800001111 Soluble APP-alpha Proteins 0.000 description 1
- 102400000571 Soluble APP-alpha Human genes 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- COGNCXJCCDGTDV-UHFFFAOYSA-N [O].N1C=CC=CC=C1 Chemical compound [O].N1C=CC=CC=C1 COGNCXJCCDGTDV-UHFFFAOYSA-N 0.000 description 1
- KILYNHHCRKVDRU-UHFFFAOYSA-N [S].C1CC2(C)C(=O)CC1C2(C)C Chemical compound [S].C1CC2(C)C(=O)CC1C2(C)C KILYNHHCRKVDRU-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-M alpha-D-galacturonate Chemical compound O[C@H]1O[C@H](C([O-])=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-M 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 230000007792 alzheimer disease pathology Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003942 amyloidogenic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000008344 brain blood flow Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 235000010410 calcium alginate Nutrition 0.000 description 1
- 239000000648 calcium alginate Substances 0.000 description 1
- 229960002681 calcium alginate Drugs 0.000 description 1
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- SIXOAUAWLZKQKX-UHFFFAOYSA-N carbonic acid;prop-1-ene Chemical compound CC=C.OC(O)=O SIXOAUAWLZKQKX-UHFFFAOYSA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- MRKZAZMYXYSBDG-UHFFFAOYSA-N cyclopentyl propanoate Chemical compound CCC(=O)OC1CCCC1 MRKZAZMYXYSBDG-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000005238 degreasing Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 150000002012 dioxanes Chemical class 0.000 description 1
- LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000001408 fungistatic effect Effects 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 150000002244 furazanes Chemical class 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000009395 genetic defect Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 150000002386 heptoses Chemical class 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-M lactobionate Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-M 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N methyl monoether Natural products COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- NJTGANWAUPEOAX-UHFFFAOYSA-N molport-023-220-454 Chemical compound OCC(O)CO.OCC(O)CO NJTGANWAUPEOAX-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- WGQLJNNCVCEPNS-UHFFFAOYSA-N n-[(4-methoxyphenyl)methyl]-n-methylmethanesulfonamide Chemical compound COC1=CC=C(CN(C)S(C)(=O)=O)C=C1 WGQLJNNCVCEPNS-UHFFFAOYSA-N 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012875 nonionic emulsifier Substances 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- CKQVRZJOMJRTOY-UHFFFAOYSA-N octadecanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCCCC(O)=O CKQVRZJOMJRTOY-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- OYSMISPYDVWGPI-UHFFFAOYSA-N oxane thiophene Chemical compound O1CCCCC1.S1C=CC=C1 OYSMISPYDVWGPI-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940056211 paraffin Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960000969 phenyl salicylate Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- KIBFBTVPDRASNT-UHFFFAOYSA-N piperidine-3,5-dione Chemical compound O=C1CNCC(=O)C1 KIBFBTVPDRASNT-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 230000036301 sexual development Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000029305 taxis Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Ophthalmology & Optometry (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses imino group thiadiazine dioxide derivatives and application thereof, in particular it relates to a kind of novel imino group thiadiazine dioxide derivative and the pharmaceutical composition comprising such compound, they can be used as BACE-1 inhibitor.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and they preparation treatment with beta-amyloid protein (" A β ") related disease, the especially purposes in the drug of Alzheimer disease.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to novel imino group thiadiazine dioxide derivative and comprising
The pharmaceutical composition and its application method and purposes of these compounds.Particularly, novel imino group thiophene two of the present invention
Piperazine dioxide derivative can be used as BACE-1 inhibitor, have for preventing, treating or mitigating with beta-amyloid protein (" A β ")
The disease of pass, especially Alzheimer disease.
Background technique
Beta-amyloid protein (" A β ") is the chief component of beta amyloid fibrinogen and patch, disease related with A β
Including but not limited to: dull-witted, senile dementia, alzheimer's disease, Ahl tribulus sea silent sickness, Parkinson's disease and/or Down syndrome
Relevant dementia, Down syndrome, attention deficit symptom, Ahl tribulus sea silent sickness, Parkinson's disease and/or Down syndrome phase
The attention deficit symptom of pass, the loss of memory, the loss of memory relevant to Parkinson's disease, the relevant memory of Ahl tribulus sea silent sickness
It loses, apoplexy, neurodegeneration, amyloidosis, beta amyloid angiosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, blood
Liquid Complication of dialysis (is derived from β2Microglobulin, and complication is thus generated in hemodialysis patients), glaucoma, II type glycosuria
Disease, the relevant amyloid of diabetes generate, traumatic brain injury (" TBI "), bovine spongiform encephalopathy, and Corticobasal becomes
Property, stein-leventhal syndrome, microglia hyperplasia and brain inflammation, smell damage, Ahl tribulus sea silent sickness, Parkinson's disease
And/or Down syndrome relevant smell damage, itch, Creutzfeld-Jakob disease, mild cognitive impairment (" MCI ") or
Alzheimer disease.
Alzheimer disease (Alzheimer ' s disease, AD) is the main Types of senile dementia, is that the elderly recognizes
Know the Etiological with mental deterioration, is the Neuro-degenerative disease for seriously affecting the progress sexual development of life of elderly person quality
Disease.Clinically with memory disorders, aphasia, appraxia, agnosia, the damage of visual space technical ability, execution dysfunction and personality and behavior
The performance of the generalized dementias such as change is characterized.Alzheimer disease not only deteriorates personal and quality of social life, can also make patient
It agonizes with other people of surrounding.Alzheimer disease is that the 4th height after cancer, heart disease and cerebral hemorrhage is dead
Die reason.
It is estimated that in worldwide, suffer from AD more than 2 million peoples, and think AD be cause it is dull-witted most common
The reason of.AD is the disease by neuronal degeneration and characterized by losing, and also will form neurofibrillary tangles and senile plaques.
According to the multiple epidemiological surveys in China as a result, the illness rate of AD is about 5% in over-65s crowd, disease incidence
Generally increase with the increase at age.The Research statistics of developed country are shown with the number of the patient with Alzheimer disease
Amount ratio is also the increase with the age and increases.Wherein, in more than 60 years old crowds, more than 70 years old crowds and more than 80 years old crowds
Illness rate is respectively 15-20%, 30-40% and 60%.It can be seen that the case where suffering from AD in more than 80 years old crowds, is very serious, often
Alzheimer disease is just suffered to a people in spouse.
There are many causes of disease for leading to Alzheimer disease.Firstly, according to existing research, the disease with Alzheimer disease
People has the acetylcholine of low concentration, and when acetylcholinesterase is suppressed, the concentration by increasing acetylcholine improves Ah
The symptom of Alzheimer's disease;Second, by using estrogen, antioxidant, radical scavenger or anti-inflammatory agent can between take over control
The only further deterioration of Alzheimer disease;Third, by preventing gradually controlling with irreversible degeneration for cynapse and neuron
Treat Alzheimer disease;4th, postpone the progress of Alzheimer disease, institute by studying the inherent cause of Alzheimer disease
State inherent cause be related to the synthesis of beta-amyloid protein, progress, the accumulation of neuron and in cortex beta-amyloid protein it is heavy
Product.Similarly, the governing factor of the extracellular concentration of beta-amyloid protein is reduced by discovery, and is selectively removed in intracerebral
Beta-amyloid protein deposit, can treat Alzheimer disease.
Currently, the treatment of Alzheimer disease is only limitted to treat its symptom, rather than treat its underlying etiology.In order to
The medicament for improving symptom and ratifying includes, for example, N-methyl-D-aspartate receptor antagonist (for example, Memantine), acetyl gallbladder
Alkali esterase inhibitor (for example, donepezil, rivastigmine, galanthamine, Tacrine).Clinically there are no can effectively reverse
Cognitive impairment improves the drug for the treatment of Alzheimer disease.Acetylcholinesterase inhibitor (donepezil, Rivastigmine, Shi Shan
Alkali first, galanthamine) treatment is light-and moderate AD patients have certain curative effect, but are also temporary relief of symptoms, it can not further hinder
The only decaying of nerve cell, and it is accompanied by serious adverse reaction.Use in conjunction brain blood flow and cerebral metabolism such as Oxiracetam
(oxiracetam) have certain curative effect in terms of improving memory, but more when be as intelligence development agent exist.Therefore, anxious
The new drug that can improve or treat Alzheimer disease need to be developed.And the drug development of the target spot around A β, recognized always
To be the new approach got a good chance of.
A β peptide is the small peptide generated by the proteolysis cracking for being referred to as the transmembrane protein of amyloid precusor protein (" APP ").APP
Fracture generates A β peptide: being broken in the N-terminal neighbouring position of A β by beta-secretase activity, passes through γ-points in the C-terminal neighbouring position of A β
Secreting enzymatic activity fracture, (APP can be also broken by alpha-secretase activity, generate secretion, non-starch sample section, referred to as soluble
APPα).It is by beta-secretase enzyme activity that the site β APP, which is broken enzyme (Beta site APP Cleaving Enzyme, " BACE-1 "),
Property and be responsible for generate A β main aspartyl protease.Research inhibits BACE-1 it has been shown that passing through so as to inhibit A β
Generation.
In AD, ternary structural can be formed by the A β peptide that beta-secretase and gamma-secretase activity are formed, assemble shape
Amyloidogenic fibrinogen.In addition, A β peptide can form A β oligomer (also known as " A beta-aggregation object " or " Abeta oligomer ").Aβ
The small multimeric structure that oligomer is made of 2-12 A β peptide (being different from A β fibrinogen in its structure).Amyloid fibrils
Can be deposited on outside neuron to memory and the important brain area domain of cognitive ability with densified form, referred to as neuritis spot, decline
Old spot or diffusion spot.When injecting in cell culture or in the brain of rat, A β oligomer is cytotoxin.This A β bites
Spot is formed and deposited and/or A β oligomer is formed, and the neuronal death and cognitive impairment that occur as a result, is AD pathology
Some marks of physiology.Other marks of AD Pathological Physiology further include: the cell being made of the Protein tau of abnormal Phosphorylation
Interior neurofibrillary tangles and neuroinflamation.
Evidence suggests A β, A β plaque block, A β fibrinogen, A β aggregate and/or A β oligomer rise in AD Pathological Physiology
To origin cause of formation effect (Ohno, et al.Neurobiology of Disease, 2007, No.26,134-145).It is known that APP and
Gene mutation in presenilin (presenilins) 1/2 (PS1/2) can lead to familial AD, and think familial AD's
The cause of disease is that the generation of the 42- amino acid form of A β increases.It has been proved that A β can neurotoxic in culture and in vivo.For example, working as
When being injected into the brain of old primate, fibrous A β leads to the neuronal death around injection site.And it also reported A
Other direct and indirect evidences of effect of the β in the cause of disease of AD.
BACE-1 has become the treatment targeting for the treatment of Alzheimer disease.For example, McConlogue group it is stated that
The AD class lesion that the part of BACE-1 enzymatic activity reduces and the adjoint reduction of A β level inhibits A β to motivate in which can dramatically, so that β-points
Secrete enzyme become in AD for therapy intervention targeting (McConlogue, et al.J.Bio.Chem., Sep.2007,
Vol.282,No.36).Luo group is reported that the mouse for lacking BACE-1 still has normal phenotype, and eliminates β-starch
Sample albumen forms (Luo, et al.Nature Neuroscience, March 2001, Vol.4, No.3).Roberds group is
Through determination, beta-secretase is active to inhibit or loses the phenotypic defects that not will cause extreme, and the adjoint property for also resulting in A β reduces
(Roberds,et al.HumanMol.Genetics,2001,Vol.10,No.12,1317-1324).Ohno group has reported
Road, in 5XFAD mouse, the genetic defect of BACE-1 can eliminate A β and be formed, hinder amyloid beta deposition, prevent in brain skin
Layer and (the brain area domain for showing most serious amyloidosis in 5XFAD mouse) middle neuron loss found of getting a foothold, and
Memory impairment can be saved in 5XFAD mouse.The group also reports that A β is finally responsible to the neuronal death in AD, and
Infer BACE-1 inhibit to can be used as treatment AD effective ways (Ohno, et al.Neurobiology of Disease, 2007,
No.26,134-145)。
Currently, the treatment potentiality of A β deposition is inhibited to promote many groups to remove characterization BACE-1 and identified that BACE-1 inhibits
Agent.People also have carried out some research BACE-1 inhibitor:
2011044181 A1 of WO discloses the imino group thiophene as BACE inhibitor (BACE-1 or BACE-2 inhibitor)
Diazine dioxide compound, composition and their purposes are generated for preventing or treating with beta-amyloid protein (" A β ")
Relevant various lesions, including Alzheimer disease.
2016118404 A1 of WO discloses the amino connection as BACE inhibitor (BACE-1 or BACE-2 inhibitor)
Imino group thiadiazine dioxide compound, composition and their purposes that group replaces, for preventing or treating A Erci
The silent disease in sea.
2014093190 A1 of WO discloses the imino group thiophene as BACE inhibitor (BACE-1 or BACE-2 inhibitor)
Diazine dioxide compound, composition and their purposes, for preventing or treating Alzheimer disease.
2016040226 A1 of WO discloses the S- imino group-as BACE inhibitor (BACE-1 or BACE-2 inhibitor)
S- oxyimino group thiadiazine compound, composition and their purposes, for preventing or treating Alzheimer disease.
2015187437 A1 of WO discloses sub- as the C2- carbocyclic ring of BACE inhibitor (BACE-1 or BACE-2 inhibitor)
Amino thiazine dioxide compound, composition and their purposes, for preventing or treating Alzheimer disease.
Summary of the invention
Novel imino group thiadiazine dioxide derivative the present invention provides one kind as BACE-1 inhibitor,
It can be used for treating by beta-amyloid protein (" A β ") mediation by inhibiting BACE-1 to inhibit the generation of A β, therefore
Disease, especially for treating Alzheimer disease.And it is shown experimentally that, imino group thiadiazine titanium dioxide of the invention
The property of object derivative is stablized, good security, has good pharmacodynamics and a pharmacokinetic property, such as good brain/
Blood plasma ratio (brain plasma ratio), good bioavilability or good metabolic stability etc..Therefore, have good
Good potential applicability in clinical practice.
The present invention also provides prepare the method for this kind of compound, the pharmaceutical composition containing this kind of compound and this kind of
The purposes of the pharmaceutical composition of compound and this kind of compound in medicine preparation.
On the one hand, the present invention relates to a kind of compound, be formula (I) or formula (I ') compound represented or formula (I) or
Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, the medicine of compound shown in formula (I ')
Acceptable salt or its prodrug on,
Wherein: each R1a、R1b、R1c、R1d、R1e、R2、R3、R4、R5、R6、R7、R8, X, Y and Z have contain as described in the present invention
Justice.
In one embodiment, X CRxOr N.
In one embodiment, Y S, O or NH.
In one embodiment, Z is CH or N.
In one embodiment, R1a、R1b、R1c、R1dAnd RxIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-
NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C
(=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6
Halogenated alkoxy, C1-C6Alkylthio group, C1-C6The C that alkylamino, hydroxyl replace1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base,
C6-C10Aryl or 5-10 unit's heteroaryl.
In one embodiment, R1eFor H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、
C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl
In one embodiment, R2And R3It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-
COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6What halogenated alkoxy or hydroxyl replaced
C1-C6Alkyl.
In one embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-
C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
In one embodiment, R5For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-
C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
In one embodiment, R6And R7It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-
COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6What halogenated alkoxy or hydroxyl replaced
C1-C6Alkyl.
In one embodiment, R8For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-
C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
In one embodiment, R1a、R1b、R1c、R1dAnd RxIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-
NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C4Alkyl) ,-C
(=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4
Halogenated alkoxy, C1-C4Alkylthio group, C1-C4The C that alkylamino, hydroxyl replace1-C4Alkyl, C3-C6Naphthenic base, 3-6 circle heterocyclic ring base,
C6-C10Aryl or 5-10 unit's heteroaryl.
In another embodiment, R1a、R1b、R1c、R1dAnd RxIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-
NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-CH3,-C (=O)-
OCH3, methyl, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propinyl ,-CHF2、-CF3、-CHFCH2F、-
CF2CHF2、-CH2CF3、-CH2CF2CHF2, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF2、-OCF3、-
OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, hydroxyl
Methyl, 2- hydroxyethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperazine
Piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, tetrazole base, furans
Base, thienyl, thiazolyl, oxazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, indyl or quinoline
Base.
In one embodiment, R1eFor H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、
C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl.
In another embodiment, R1eFor H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、
Methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R2And R3It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-
COOH ,-C (=O) NH2、C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4What halogenated alkoxy or hydroxyl replaced
C1-C4Alkane.
In another embodiment, R2And R3It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-
COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup
Or isopropyl oxygroup.
In one embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-
C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl.
In another embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、
Methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R5For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-
C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl.
In another embodiment, R5For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、
Methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R6And R7It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-
COOH ,-C (=O) NH2、C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4What halogenated alkoxy or hydroxyl replaced
C1-C4Alkyl.
In another embodiment, R6And R7It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-
COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup
Or isopropyl oxygroup.
In one embodiment, R8For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-
C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl.
In another embodiment, R8For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、
Methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
On the one hand, the present invention relates to a kind of compounds, are formula (II) or formula (II ') compound represented or formula
(II) or the stereoisomer of compound shown in formula (II '), tautomer, nitrogen oxides, hydrate, solvate, metabolism
Product, pharmaceutically acceptable salt or its prodrug,
Wherein: each R1a、R1b、R1c、R1d、R1e、R2、R3、R4、R5、R6、R7、R8, X, Y and Z have contain as described in the present invention
Justice.
In one embodiment, compound of the present invention for the compound with one of following structure or has
The stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, hydrate, solvate, metabolism produce
Object, pharmaceutically acceptable salt or its prodrug:
Another aspect, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes chemical combination disclosed by the invention
Object.
In one embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable excipient,
Carrier, adjuvant or their any combination.
In another embodiment, pharmaceutical composition of the present invention further includes additional therapeutic agent, wherein institute
Additional therapeutic agent is stated to be nalmefene, Risperidone, Rivastigmine, Memantine, mitzapine, Venlafaxine, desipramine, first is gone to replace
Woods, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, pentoxifylline, Tacrine, donepezil, Garland
He is quick, rivastigmine, vitamin e, fibrates, niacin, nicotinic receptor agonist, nicotinic acetylcholine receptor excitement
Agent, anticholinesterase, N-methyl-D-aspartate receptor antagonist, the promotor of α secretase activity, glycogen synthetase
Kinases beta inhibitor, the inhibitor of amyloid aggregation, gamma-secretase inhibitors, gamma secretase modulators, 3 antagonism of histamine H
Agent, histone deacetylase inhibitors, PDE-4 inhibitor, PDE-10 inhibitor, mGluR1 receptor modulators or antagonist,
MGluR5 receptor modulators or antagonist, mGluR2/3 antagonist, 5-HT4Agonist, 5-HT6Receptor antagonist or GABAAReversely
Agonist.
Another aspect, the present invention relates to the purposes of compound disclosed by the invention or pharmaceutical composition in medicine preparation,
The generation that the drug is used to inhibit BACE-1 to inhibit A β.
In another aspect, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine preparation,
The drug is for preventing, treating or mitigating disease related with beta-amyloid protein.
In one embodiment, the disease related with beta-amyloid protein is dementia, senile dementia, with alzheimer '
Silent disease, Parkinson's disease and/or the relevant dementia of Down syndrome, Down syndrome, attention deficit symptom, with Alzheimer
Disease, Parkinson's disease and/or the relevant attention deficit symptom of Down syndrome, the loss of memory, memory relevant to Parkinson's disease
It loses, the relevant loss of memory of Ahl tribulus sea silent sickness, apoplexy, neurodegeneration, amyloidosis, beta amyloid angiosis, greatly
Cerebral amyloid angiopathy, hereditary cerebral hemorrhage, complication of hemodialysis, glaucoma, type-2 diabetes mellitus, the relevant starch of diabetes
Shape albumen generates, traumatic brain injury, bovine spongiform encephalopathy, mild cognitive impairment or Alzheimer disease.
In another embodiment, the disease related with beta-amyloid protein is Alzheimer disease.
On the other hand, the present invention relates to formula (I), (I '), preparation, separation and the purifying of compound shown in (II) or (II ')
Method.
Biological results show that the compounds of this invention passes through and inhibit BACE-1 to inhibit the generation of A β, and can be used as
Preferable BACE-1 inhibitor.
Any embodiment in either present invention face can be combined with other embodiments, as long as they are not
It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention
The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its
Content in terms of him will make more specific complete description below.All bibliography in this specification pass through whole reference
In this.When the disclosure of the specification and citation are variant, it is subject to the disclosure of the specification.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This
Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim
In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention
The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined
One or more or contradict in the case where (including but not limited to defined in term, term application, institutes different from the application
Technology of description, etc.), it is subject to the application.
It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments
Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity,
It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element
With the periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can
With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:
1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry
Description in March, John Wiley&Sons, New York:2007, entire contents are incorporated by reference into the present invention.
There is apparent conflict unless otherwise indicated or in context, the article " one " used in the present invention, " one
(kind) " and " described " are intended to include "at least one" or " one or more ".Therefore, these articles used in the present invention refer to
The article of one or more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more
It uses or uses in the embodiment that one component is taken into account in the embodiment.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group
Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different
Structure body (cis/trans isomers), atropisomer, etc..
Term " chiral molecules " be with its mirror image cannot be overlapped property molecule;And " achiral molecule " refers to and it
The molecule that mirror image can be overlapped.
Term " enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
Term " racemate " or " racemic mixture " refer to the equimolar mixture of two enantiomters, the mixing
Object lacks optical activity.
Term " diastereoisomer " refer to there are two or multiple chiral centers and its molecule not solid of mirror image each other
Isomers.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereo-isomerism
Body mixture can be operated such as electrophoresis and chromatography, such as HPLC by high resolution analysis and be separated.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill
Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and
Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons,
Inc,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light
The ability that face rotates.When describing optically active compound, indicate molecule about one using prefix D and L or R and S
A or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are revolved for linearly polarized light caused by appointed compound
The symbol turned, wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.It is a kind of specific
Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:
50 mixtures are known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or three-dimensional spy
When anisotropic, such case may occur in which.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer
Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists
(R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake
Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer
It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they
Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits
?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques
Point.If compound contains a double bond, substituent group may be E or Z configuration;If containing disubstituted cycloalkanes in compound
The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties
Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization
Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method
Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production
Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping
Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates
and Resolutions(Wiley Interscience,New York,1981);Principles of Asymmetric
Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012);Eliel,
E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables
of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre
Dame Press,Notre Dame,IN 1972);Chiral Separation Techniques:A Practical
Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,
2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low
Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve
The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer)
Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and
Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to compounds some in this way, raw material, composition and/or dosage form, they are cured rationally
Learn judgement in the range of, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with reasonable benefit
The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced .. "
The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention
It includes, but is not limited to D, F, Cl, Br, I, N3、-CN、-NO2、-NH2、-OH、-SH、-COOH、-CONH2,-C (=O) NHCH3,-C (=
O)N(CH3)2,-C (=O)-alkyl ,-C (=O)-alkoxy, alkyl, alkenyl, alkynyl, halogenated alkyl, alkoxy, haloalkoxy
Base, alkylthio group, alkylamino, the alkyl of hydroxyl substitution, naphthenic base, heterocycle, aryl, heteroaryl etc..
In general, term it is " substituted " indicate specifically replaced to one or more hydrogen atoms in structure or group
Replaced base.Unless otherwise indicated, a substituent group can be replaced in each substitutive reasonable position of group.
Replaced the specific substituent group of one or more that more than one position can be selected from given structural formula, then substituent group
It can each reasonable position be replaced in structural formula identical or differently.
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode
" each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used
To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol
In same group, do not influenced mutually between expressed specific option between the same symbol.
Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right
As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small
Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by
Trying object is people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations
In scheme, " patient " refers to people.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise
Content.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special
It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term
“C1-C6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Term " D " indicates single D-atom.
Term " halogen " and " halogenated " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine
(I)。
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1-20 carbon atom, the straight chain of saturation or
Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention
Replace.In one embodiment, alkyl group contains 1-6 carbon atom;In another embodiment, alkyl group contains 1-4
A carbon atom;Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited
In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH
(CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH
(CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), etc..
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger
And site, that is, there is a carbon-to-carbon sp2Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention
Replaced the substituent group stated comprising the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".In an embodiment
In, alkenyl group includes 2-8 carbon atom;In another embodiment, alkenyl group includes 2-6 carbon atom;In another reality
It applies in scheme, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH=
CH2), allyl (- CH2CH=CH2), 1- acrylic is (that is, acrylic ,-CH=CH-CH3), etc..
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger
And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention
Replaced the substituent group stated.In one embodiment, alkynyl group includes 2-8 carbon atom;In another embodiment, alkynyl
Group includes 2-6 carbon atom;In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example packet of alkynyl group
It includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyl is (that is, propinyl ,-C ≡ C-CH3),
Etc..
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has
Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party
In case, alkoxy base contains 1-6 carbon atom;In another embodiment, alkoxy base contains 1-4 carbon atom;?
In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more
Replaced the substituent group that the present invention describes.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,-
OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH
(CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen
Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t-
BuO, t- butoxy ,-OC (CH3)3), etc..
Term " alkylthio group " indicates that alkyl group is connected by sulphur atom with molecule rest part, and wherein alkyl group has
Meaning as described in the present invention.Unless otherwise detailed instructions, the alkylthio radicals contain 1-12 carbon atom.In an embodiment party
In case, alkylthio radicals contain 1-6 carbon atom;In another embodiment, alkylthio radicals contain 1-4 carbon atom;?
In another embodiment, alkylthio radicals contain 1-3 carbon atom.The alkylthio radicals can be optionally one or more
Replaced the substituent group that the present invention describes.
The example of alkylthio radicals includes, but is not limited to, methyl mercapto (MeS ,-SCH3), ethylmercapto group (EtS ,-
SCH2CH3), 1- rosickyite base (n-PrS, n- rosickyite base ,-SCH2CH2CH3), 2- rosickyite base (i-PrS, i- rosickyite base ,-SCH
(CH3)2), 1- butylthio (n-BuS, n- butylthio ,-SCH2CH2CH2CH3), 2- methyl-l- rosickyite base (i-BuS, i- fourth sulphur
Base ,-SCH2CH(CH3)2), 2- butylthio (s-BuS, s- butylthio ,-SCH (CH3)CH2CH3), 2- methyl -2- rosickyite base (t-
BuS, t- butylthio ,-SC (CH3)3), etc..
Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base
Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.It closes
Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- first ammonia
Base, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..The alkylamino radicals are optionally by one or more sheets
It invents replaced described substituent group.
Term " alkyl that hydroxyl replaces " indicates alkyl group replaced one or more hydroxyls, and wherein alkyl group has
There is meaning as described in the present invention;Such example includes, but is not limited to, methylol, 2- hydroxyethyl, 2- hydroxyl -1- third
Base, 3- hydroxyl -1- propyl, 2,3- dihydroxypropyl etc..
Term " halogenated alkyl " indicates alkyl group replaced one or more halogen atoms, and wherein alkyl group has
Meaning as described in the present invention, such example includes, but is not limited to ,-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-
CH2CF3、-CHFCH3、-CH2CH2F、-CF2CH3、-CH2CF2CHF2Deng.In one embodiment, C1-C6Halogenated alkyl includes fluorine
Substituted C1-C6Alkyl;In another embodiment, C1-C4Halogenated alkyl includes fluorine-substituted C1-C4Alkyl;In another implementation
In scheme, C1-C2Halogenated alkyl includes fluorine-substituted C1-C2Alkyl.
Term " halogenated alkoxy " indicate alkoxy base replaced one or more halogen atoms, wherein alkoxy base
Group has meaning as described in the present invention, and such example includes, but is not limited to ,-OCHF2、-OCF3、-OCHFCH2F、-
OCF2CHF2、-OCH2CF3、-OCHFCH3、-OCH2CH2F、-OCF2CH3、-OCH2CF2CHF2Deng.In one embodiment, C1-C6
Halogenated alkoxy includes fluorine-substituted C1-C6Alkoxy;In another embodiment, C1-C4Halogenated alkoxy includes fluorine-substituted
C1-C4Alkoxy;In yet another embodiment, C1-C2Halogenated alkoxy includes fluorine-substituted C1-C2Alkoxy.
Term " n former molecular " or " n member ", wherein n is integer, typically describes the number of ring member nitrogen atoms in molecule
Mesh, the number of ring member nitrogen atoms is n in the molecule.For example, piperidyl is the molecular heterocycle of 6 originals or 6 circle heterocyclic ring bases,
And cyclohexyl is the molecular naphthenic base of 6 originals or 6 yuan of naphthenic base.
Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies
System.Bicyclic or three-ring system may include condensed ring, bridged ring and loop coil.In one embodiment, naphthenic base includes that 3-10 carbon is former
Son;In another embodiment, naphthenic base includes 3-8 carbon atom;In yet another embodiment, naphthenic base includes 3-6 carbon
Atom.The group of naphthene base is optionally replaced one or more substituent groups described in the invention.Group of naphthene base
Example includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, etc..
Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to comprising 3-12 annular atom, non-aromatic
The unsaturated monocyclic, bicyclic or tricyclic system of saturation or part of property, wherein described bicyclic or three-ring system may include thick
Ring, bridged ring and loop coil.One or more atoms are independently replaced by hetero atom in its middle ring, and the hetero atom has such as this hair
The bright meaning.In one embodiment, heterocycle is monocyclic heterocycles base (the 2-6 carbon atom of 3-8 annular atom composition
With selected from N, O, P, the 1-3 hetero atom of S is optionally obtained replaced one or more oxygen atoms in this S or P as SO,
SO2, PO, PO2Group);In another embodiment, heterocycle is bicyclic heterocyclic radical (4-9 of 7-12 annular atom composition
Carbon atom and it is selected from N, O, P, the 1-3 hetero atom of S optionally obtain picture replaced one or more oxygen atoms in this S or P
SO, SO2, PO, PO2Group).The heterocyclyl groups are optionally taken by one or more substituent groups described in the invention
Generation.
The annular atom of heterocycle can be carbon-based or heteroatom group.Wherein ,-the CH of ring2Group is optionally by-C (=O)-
Substitution, the sulphur atom of ring are optionally oxidized to S- oxide, and the nitrogen-atoms of ring is optionally oxidized to N- oxygen compound.Heterocycle
The example of base includes, but are not limited to Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-
Pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran
Base, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H-
Pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithiane
Base, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diaza
Base, sulphur azepineBase, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, etc..- CH in heterocycle2Group quilt-C (=
O)-substitution example includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- bis-
Oxo-piperidine base, hybar X base, etc..The example that sulphur atom is oxidized in heterocycle include, but are not limited to sulfolane base,
Thio-morpholinyl 1,1- dioxide, etc..The heterocyclyl groups are optionally by one or more described in the invention
Replaced substituent group.
Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double
The carbocyclic ring system of ring and tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 original
Molecular ring.Aryl group by the armaticity ring of aryl group with parent molecule in general, but unnecessarily connect.Term
" aryl " can be used interchangeably with term " aromatic rings " or " aromatic ring ".The example of aryl group may include phenyl, indenyl, naphthalene
And anthryl.The aryl group is optionally replaced one or more substituent groups described in the invention.
Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom,
Bicyclic and three-ring system, wherein at least one ring system are aromatic, and at least one ring system includes one or more miscellaneous
Atom, wherein each ring system includes 5-7 former molecular ring.Heteroaryl groups are in general, but unnecessarily pass through heteroaryl
The armaticity ring of base group is connect with parent molecule.Term " heteroaryl " can be with term " hetero-aromatic ring ", " heteroaromatic " or " heteroaryl
Compounds of group " is used interchangeably.The heteroaryl groups are optionally replaced one or more substituent groups described in the invention.
In one embodiment, 5-10 former molecular heteroaryl includes 1,2,3 or 4 hetero atom for being independently selected from O, S and N.
The example of heteroaryl groups includes, but is not limited to, 2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals,
4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazole
Base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, 5-
Pyrimidine radicals, pyridazinyl (such as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazole
Base (such as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3-
Oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,3- triazolyl, 1,2,3- thio biphosphole base, 1,3,4- sulphur
For di azoly, 1,2,5- thio biphosphole base, pyrazinyl, cyanuro 1,3,5;Also include below bicyclic, but be not limited to these
It is bicyclic: benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- quinoline
Quinoline base, 3- quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), imidazo
[1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,
2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine
Base, etc..
When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance
It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group
Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl
(BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl
Substituent group be used to block or protect the functionality of hydroxyl, suitable blocking group includes trialkylsilkl, acetyl group, benzene
Formoxyl and benzyl." carboxy protective group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general
Carboxyl-protecting group includes-CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy
Ylmethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro second
Base, etc..Description general for blocking group can refer to document: Greene et al., Protective Groups in
Organic Synthesis,John Wiley&Sons,New York,1991and Kocienskiet al.,Protecting
Groups,Thieme,Stuttgart,2005。
Term " prodrug " used in the present invention represents a compound and is converted into vivo formula (I), (I '), (II) or
(II ') compound represented.Such conversion is hydrolyzed in blood by pro-drug or is through enzymatic conversion in blood or tissue
The influence of precursor structure.Pro-drug compounds of the present invention can be ester, and ester can be used as precursor medicine in existing invention
Object has phenyl ester class, aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.
Such as a compound in the present invention includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other
Prodrug form include phosphate, if these phosphate compounds are obtaining through the di on parent.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change
The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art
It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound
Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound
Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine
Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe
pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,
1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base
The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid
Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature
Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist
Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur
Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal
Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid
Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur
Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste
Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through
The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any
The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium
With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting
When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid
Compound, phosphoric acid compound, nitric acid compound, C1-C8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association
Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second
Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention
Molecule can be combined with a hydrone, such as monohydrate;In another embodiment, a compounds of this invention molecule
It can be combined with more than one hydrone, such as dihydrate;In yet another embodiment, a compounds of this invention point
Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non-
The biological effectiveness of the compound of hydrated form.
Any disease of term " treatment " or illness refer to that improving disease or illness (slows down in some of these embodiments
Or prevent or mitigate disease or the development of its at least one clinical symptoms).In other embodiments, " treatment " refer to mitigation or
Improve at least one body parameter, including the body parameter that may not be discovered by patient.In other embodiments, it " controls
Treat " refer in terms of (such as stablizing perceptible symptom) on body or physiologically (such as parameter of stable body) or above-mentioned two
Adjust disease or illness.In other embodiments, " treatment " refers to the breaking-out, generation or evil for preventing or delaying disease or illness
Change.
Term " preventing " or " prevention " refer to that the reduction for obtaining the risk of disease or obstacle (that is: makes at least one clinical condition of disease
Shape stops development in main body, which may face or be inclined in advance in face of this disease, but without undergoing or show
The symptom of disease).
Term " additional therapeutic agent " refers to the therapeutic agent as adjuvant treatment or drug combination.
Imino group thiadiazine dioxide derivative of the present invention, pharmaceutically acceptable salt, pharmaceutical preparation and
Its composition, can by inhibiting BACE-1 to inhibit the generation of A β, to disease related with beta-amyloid protein (" A β "),
The treatment of especially Alzheimer disease has potential purposes.
Unless otherwise mentioned, all suitable isotope variations of the compound of the present invention, stereoisomer, tautomerism
Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure
All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When
Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure
Body is with regard to this clear and definition.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal
Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide)
It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or
It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
Formula (I), (I '), compound shown in (II) or (II ') can exist in a salt form.In one embodiment, institute
It states salt and refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refer to substance or composition must with comprising preparation
Other ingredients and/or compatible chemically and/or in toxicology with the mammal of its treatment.In another embodiment, described
Salt is not necessarily pharmaceutically acceptable salt, can be and is used to prepare and/or purifies formula (I), (I '), shown in (II) or (II ')
Compound and/or for separating this formula (I), (I '), the intermediate of the enantiomer of compound shown in (II) or (II ').
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety.
In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca,
Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds
The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both.
Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.?
Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company,
Easton,Pa.,(1985);" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical
Salts:Properties, Selection, and Use) ", Stahland Wermuth (Wiley-VCH, Weinheim,
Germany, 2002) list that other is suitable for salt can be found in.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same
The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more
A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention
Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, the present invention relates to preparation formula (I), (I '), the intermediates of compound shown in (II) or (II ').
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One
In embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, excipient, adjuvant, molten
Matchmaker or their combination.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray
Type.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, including formula (I), (I '), compound shown in (II) or (II ') or its individually
Stereoisomer, the racemic or non-racemic mixture of isomers or its pharmaceutically acceptable salt or solvate.?
In an embodiment of the invention, described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, auxiliary
Agent or excipient, and optionally, others treatment and/or prevention ingredient.
It is that suitable carrier, adjuvant and excipient are well known to those skilled in the art and be described in detail in for example
Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery
Systems(2004)Lippincott,Williams&Wilkins,Philadelphia;Gennaro A.R.et al.,
Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams&
Wilkins,Philadelphia;With Rowe R.C., Handbook of Pharmaceutical Excipients (2005)
In Pharmaceutical Press, Chicago.
It further comprise that additional control is carried out to patient comprising the treatment method that the compounds of this invention or pharmaceutical composition are administered
Treat agent (combination therapy) administration, wherein additional therapeutic agent be nalmefene, Risperidone, Rivastigmine, Memantine, mitzapine,
Venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, pentoxifylline
Alkali, Tacrine, donepezil, galanthamine, rivastigmine, vitamin e, fibrates, niacin, nicotinic receptor excitement
Agent, nicotinic acetylcholine receptors alpha7, anticholinesterase, N-methyl-D-aspartate receptor antagonist, α secretase
Active promotor, glycogen synthase kinase beta inhibitor, the inhibitor of amyloid aggregation, gamma-secretase inhibitors, γ points
Secrete enzyme adjustment agent, histamine H 3 antagonists, histone deacetylase inhibitors, PDE-4 inhibitor, PDE-10 inhibitor,
MGluR1 receptor modulators or antagonist, mGluR5 receptor modulators or antagonist, mGluR2/3 antagonist, 5-HT4Agonist,
5-HT6Receptor antagonist and GABAAInverse agonist or their any combination.
" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency
Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other at
Split-phase is held, and interaction the effect of to avoid will be greatly reduced disclosed compound of present invention when administering to a patient and will lead to not
It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example
Such as, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group
The specific function in object is closed to select pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature
Certain pharmaceutically acceptable excipient.The certain pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected
Agent.Facilitate to carry or transport the compounds of this invention when may be selected to administer to a patient from an organ of body or partially to body
Another organ or partial certain pharmaceutically acceptable excipient.May be selected enhancing patient compliance it is certain pharmaceutically
Acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, adhesive,
Disintegrating agent, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant
Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization
Agent, surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable excipient can provide more than one
Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are which other
Excipient.
Technical staff grasps the knowledge and skills of this field, so that they can select for the suitable of appropriate amount of the invention
Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable
Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's
Pharmaceutical Sciences(Mack Publishing Company),The Handbook of
Pharmaceutical Additives(Gower Publishing Limited),and The Handbook
ofPharmaceutical Excipients(the American Pharmaceutical Association and the
Pharmaceutical Press)。
In order to prepare pharmaceutical composition with compound described in the invention, pharmaceutically acceptable carrier can be solid
Body or liquid-carrier.Solid form preparations include pulvis, tablet, dispersible granule, capsule, cachet and suppository.Powder
Agent and tablet may include the active component of about 5 to about 95%.Suitable solid carrier is known in the art, example
Such as, magnesium carbonate, magnesium stearate, talcum powder, sugar or lactose.Tablet, pulvis, cachet and capsule may be used as be suitble to it is oral
Solid dosage forms.The example of pharmaceutical acceptable carrier and method for preparing various compositions can obtain in following: A.Gennaro
(ed.),Remington's Pharmaceutical Sciences,18th ed.,1990,Mack Publishing
Company Co.,Easton,Pennsylvania。
In Remington:The Science and Practice of Pharmacy, 21st edition, 2005,
ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of
Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel
The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation
Well-known technique, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life
Object effect, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention
Outside the incompatible any commonly employed carrier of compound, pays close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field
The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing
Company)。
Therefore, on the other hand, the present invention relates to the technique of preparation pharmaceutical composition, described pharmaceutical composition includes the present invention
Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination, the technique include that mixing is each
Kind ingredient.Pharmaceutical composition comprising disclosed compound of present invention can mix under such as environment temperature and atmospheric pressure to make
It is standby.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example
Such as, dosage form includes those dosage forms for being suitable for following administration route: (1) being administered orally, such as tablet, capsule, caplet agent, ball
Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet;(2) parenteral, example
Such as sterile solution agent, suspension and redissolution powder;(3) cutaneous penetration, such as transdermal patch tablet;(4) rectally, such as bolt
Agent;(5) it sucks, such as aerosol, solution and dry powder doses;(6) local administration, for example, it is cream, ointment, lotion, molten
Liquor, paste, spray, foaming agent and gelling agent.
It will also be appreciated that certain compounds of the invention can exist for treating in a free form, or if appropriate
Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative
Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or
Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment,
Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with
It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration.
Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or
Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to gastric acid effect but dissolving or being disintegrated in intestines
The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to fatty acid, rouge
Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds
Piece can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble
The compressed tablets of thin layer or the film covering of substance.Film coating includes, but are not limited to hydroxyethyl cellulose, carboxymethyl cellulose
Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.It is multiple
Tabletting is the compressed tablets by preparing more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active constituent are individual or describe with the present invention
Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrating agent, controlled release polymer, profit
Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl
Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, and one section
It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell,
It is by being added glycerol, sorbierite or the plasticizing of similar polyalcohol.It is raw that soft gelatin shell may include the pre- preventing microorganism of preservative
It is long.Suitable preservative be as described in the present invention those, including methylparaben and propylben and sorbic acid.This
Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in
Solution and suspension in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S.
Patent U.S.Pat.Nos.4,328,245;It is prepared described in 4,409,239 and 4,410,545.The capsule can also be adopted
With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension
Agent, elixir and syrup.Emulsion is two-phase system, and one of liquid is thoroughly dispersed in pellet form in another liquid,
It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and
Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used
The acetal of receiving, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal;And have one or more
The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense
The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol
It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Pharmaceutical composition provided by the invention can be configured to be suitable for any dosage form to patient's inhalation, such as dry powder
Agent, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention can be prepared
At be suitable for dry powder doses to the dosage form of patient's inhalation.In yet another embodiment, pharmaceutical composition disclosed in this invention
It can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Dry powder composite by inhalation delivery to lung is usual
Include fine powdered compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable taxes
Shape agent.Pharmaceutically acceptable excipient dawn known to those skilled in the art be especially suitable for dry powder doses comprising cream
Sugar, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding is prepared.It is general next
It says, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value with laser diffractometry (for example, surveyed
Amount) it defines.
The pharmaceutical composition for being suitable for cutaneous penetration can be prepared into discontinuous patch agent, it is intended that keep with the epidermis of patient
It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as
Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis,
Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil
Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example
Such as atoleine and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.It is used according to medium property
Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and
Cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
The compounds of this invention can also be in conjunction with the soluble polymer as target medicine carrier.Such polymer packet
Include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or
The oxide polylysine that palmitoyl residues replace.In addition, compound disclosed in this invention can with realizing drug
Control release used in one kind Biodegradable polymeric combination, for example, polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyrate,
Polyorthoester, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel crosslinking or amphiphilic block copolymer.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely
Body administration.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest
In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed
Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection
Body form.Such dosage form can be prepared according to conventional method known to the technical staff in pharmaceutical science field (referring to
Remington:The Science and Practice of Pharmacy, ibid).
Be intended for parenteral administration pharmaceutical composition may include one or more pharmaceutically acceptable carriers and
Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life
Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth
Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent
And inert gas.
Pharmaceutical composition provided by the invention can be administered by rectal suppository, by by drug with it is suitable nonirritant
Excipient (such as cupu oil, the glyceride of polyethylene glycol synthesis) mixing, be solid under room temperature, then in rectum intraluminal fluid
Change or dissolution discharges drug.Due to individual difference, bigger variation can be presented in the severity of symptom, and every kind of medicine has
Its unique treatment characteristic, therefore, for the accurate administration mode of each individual, dosage form and therapeutic scheme all should be by operation
Doctor determines.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins
Punching-, control-, targeting-and sequencing releasing pattern.
Term as used herein " therapeutically effective amount " refers to each active component for being enough to show beneficial therapeutic effect
Total amount.For example, being administered or making the amount for the symptom for being enough to treat, curing or mitigating disease for reaching balance in vivo.Special controls
Effective quantity needed for treatment scheme depends on many factors, the disease including treatment, the severity of disease, the certain drug used
Activity, administration mode, the clearance rate of certain drug, duration for the treatment of, drug combination, the age, weight, gender, diet and
The health etc. of patient.This field description as described in " therapeutically effective amount " other factors in need of consideration can be found in Gilman et
al.,eds.,Goodman And Gilman’s:The Pharmacological Bases of Therapeutics,8th
ed.,Pergamon Press,1990;Remington's Pharmaceutical Sciences,17th ed.,Mack
Publishing Company,Easton,Pa.,1990。
Those skilled in the art (for example, attending physician, pharmacists or others skilled in the art) can readily determine that and give
The suitable dose of the compounds of this invention of patient, and can according to patient health situation, the age, weight, administration frequency, other
Active component using and/or the indication of given compound change.The dosage of the compounds of this invention can be about
The range of 0.001-500mg/kg body weight/day.In one embodiment, the compounds of this invention or the compound is pharmaceutically acceptable
The dosage of salt or solvate about 0.01-25mg/kg body weight/day.It in another embodiment, can according to concrete application
Quantity with the reactive compound being varied or adjusted in the unit dose of preparation, from about 1mg to about 100mg, preferably approximately
1mg to about 50mg, more preferably from about 1mg are to about 25mg.In another embodiment, for oral administration, it is proposed that
Typical day dosage regimen preferably 1mg/ days to 200mg/ days, can be given in about 1mg/ days to about 500mg/ days ranges
Two to four separate doses.
Term " administration " shows individual and provides the drug of therapeutically effective amount, and administration mode includes oral, sublingual, vein, skin
Under, it is percutaneously, intramuscular, it is intradermal, it is intrathecal, on dura mater, intraocularly, and encephalic, sucking, rectum, vagina etc..Form of administration includes paste, is washed
Agent, tablet, capsule, pill, dustability powder agent, granule, suppository, sublimed preparation, pastille, injection, sterile solution or non-aqueous
Solution, suspending agent, emulsion, patch agent etc..Active component and nontoxic pharmaceutically acceptable carrier (such as glucose, lactose,
Gum arabic, gelatin, mannitol, gelatinized corn starch, magnesium trisilicate, talcum powder, cornstarch, keratin, silica gel, potato starch,
Urea, dextran etc.) it is compound.
Preferred administration route can change with Clinical symptoms, and the variation of dosage is necessarily dependent upon patient being treated
The case where, doctor can determine suitable dosage according to individual patient.The therapeutically effective amount of per unit dose depends on weight, raw
Manage the vaccination regimen of function and selection.The weight of compound when the compound of per unit dose refers to each administration does not include carrying
The weight (containing carrier in drug) of body.
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped
In ampulla, bottle or syringe.The multi-dose parenteral administration must comprising it is antibacterial or fungistatic concentrations resist it is micro-
Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.
Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect
It prepares, or the substance co-formulation with the expected effect of supplement.
In one embodiment, treatment method of the invention includes that this hair of safe and effective amount is given to patient in need
Bright compound or pharmaceutical composition comprising the compounds of this invention.Each embodiment of the present invention includes by patient in need
It gives the compounds of this invention of safe and effective amount or the pharmaceutical composition comprising the compounds of this invention, is referred to treat the present invention
Disease.
In one embodiment, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be by any
Suitable administration route is administered, including Formulations for systemic administration and local administration.Formulations for systemic administration include oral administration, parenteral,
Cutaneous penetration and rectally.Typical parenteral refers to through injection or administered by infusion, including intravenous, intramuscular and skin
Lower injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasal administration.One
In a embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be oral administration.Another
In embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalation.It is also real one
It applies in scheme, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be intranasal administration.
In one embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can disposably give
Medicine, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, daily administration one
It is secondary, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, it is taken twice daily.
It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.The compounds of this invention or comprising
The appropriate dosage regimen of the pharmaceutical composition of the compounds of this invention depends on the pharmacokinetic property of the compound, such as inhales
Receipts, distribution and half-life period, these can be by determination of technical staff.In addition, the compounds of this invention or including the compounds of this invention
The appropriate dosage regimen of pharmaceutical composition, the duration including implementing the program are treated disease depending on treated disease
The severity of disease, the age of patient under consideration and physical condition, the medical history of patient under consideration while the property of therapy are thought
The factor within the scope of technical staff's knowledge and experience such as therapeutic effect wanted.Such technical staff should also be understood that for
Reaction of the individual patient to dosage regimen, or when individual patient needs to change as time goes by it may require that adjust it is suitable to
Prescription case.
The compounds of this invention can be administered simultaneously, or before it or later with one or more other therapeutic agents.This hair
Bright compound can be administered with other therapeutic agents by identical or different administration route respectively, or therewith with same pharmaceutical composition
Form administration.This is selected by those skilled in the art according to the actual conditions of the bodies such as the health of patient, age, weight.If
It is formulated as fixed dosage, this combination product uses the compound of the present invention (within dosage range described herein) and its
His forms of pharmacologically active agents (within its dosage range).
Correspondingly, in one aspect, the present invention includes drug combination comprising a certain number of at least one of the invention
Compound or pharmaceutically acceptable salt thereof, solvate, ester or pro-drug and a effective amount of one or more above-mentioned additional therapeutic agents.
In addition, the compounds of this invention can be administered with prodrug forms.In the present invention, " prodrug " of the compounds of this invention is
When administering to a patient, the functional derivatives of the compounds of this invention can be finally released in vivo.This hair is given with prodrug forms
When bright compound, one of implementable following manner of those skilled in the art or more: the internal action of compound (a) is changed
Time;(b) the internal acting duration of compound is changed;(c) the internal conveying or distribution of compound are changed;(d) modification
Close the internal solubility of object;And the side effect or other difficult points for (e) overcoming compound to be faced.It is used to prepare the typical of prodrug
Functional derivatives, comprising in vivo chemically or the variant of compound that cracks of the mode of enzyme.Comprising prepare phosphate,
Amide, ester, monothioester, carbonate and carbaminate these variants be well-known to those skilled in the art.
The purposes of the compounds of this invention and pharmaceutical composition
Compound provided by the invention and pharmaceutical composition can be used for preparing by inhibiting BACE-1 to inhibit the production of A β
Raw drug can be used for preparation for treating and beta-amyloid protein (" A β ") related disease, especially alzheimer '
The drug for disease of writing from memory.
Specifically, the amount of compound effectively can be selected detectably in the compound of the present invention or pharmaceutical composition
Property by inhibiting BACE-1 to inhibit the generation of A β.
The compound of the present invention can be applied to, but be not limited to, and use the compound of the present invention or pharmaceutical composition
Effective quantity administers to a patient to prevent, treat or mitigate and beta-amyloid protein (" A β ") related disease.Described and β-starch
The related disease of sample albumen (" A β "), further comprises but is not limited to, dull-witted, senile dementia, Ahl tribulus sea silent sickness, pa gold
Gloomy disease and/or the relevant dementia of Down syndrome, Down syndrome, attention deficit symptom, Ahl tribulus sea silent sickness, Parkinson
Disease and/or the relevant attention deficit symptom of Down syndrome, the loss of memory, the loss of memory relevant to Parkinson's disease, with Ah
The relevant loss of memory of Alzheimer's disease, apoplexy, neurodegeneration, amyloidosis, beta amyloid angiosis, Cerebral Amyloid blood
Pipe disease, hereditary cerebral hemorrhage, complication of hemodialysis (are derived from β2Microglobulin, and thus generated simultaneously in hemodialysis patients
Send out disease), glaucoma, type-2 diabetes mellitus, the relevant amyloid generation of diabetes, traumatic brain injury (" TBI "), Niu Haimian
Shape encephalopathy, corticobasal degeneration, stein-leventhal syndrome, microglia hyperplasia and brain inflammation, alzheimer's disease, smell
Damage, Ahl tribulus sea silent sickness, Parkinson's disease and/or the relevant smell damage of Down syndrome, itch, Creutzfeld-
Jakob disease, mild cognitive impairment (" MCI ") or Alzheimer disease.
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on
Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.?
This, the compound of the present invention includes its pharmaceutically acceptable derivates.
General synthesis step
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only
Method of the invention is practiced in offer.
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further
Explanation, the wherein definition of substituent group such as formula (I), (I '), shown in (II) or (II ').Following reaction scheme and embodiment are used
In the contents of the present invention are further illustrated.
The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps
Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention
Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention
It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention
, or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient
Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical
Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou
Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry
Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase
It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride
It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N-
Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below
Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopy is with CDC13、
DMSO-d6、CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as referring to mark
It is quasi-.When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used
(triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), brs
(broadened singlet, wide is unimodal), dd (doublet of doublets, double doublet), ddd (doublet of
Doublet of doublets, in pairs doublet), dt (doublet of triplets, double triplets), td (triplet
Of doublets, three doublets), tt (triplet of triplets, three triplets).Coupling constant J, with hertz (Hz) table
Show.
The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-M of Agilent (column model:
Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%-95% (contains 0.1%
The CH of formic acid3CN) in (H containing 0.1% formic acid2O the ratio in), using electrospray ionisation (ESI), at 210nm/254nm,
It is detected with UV.
Pure compound uses 1260 pre-HPLC or Calesep pump of Agilent, 250 pre-HPLC (pillar type
Number: NOVASEP 50/80mm DAC), detected in 210nm/254nm with UV.
The use of logogram word below is through the present invention:
CH2Cl2, DCM methylene chloride KF potassium fluoride
CDC13Deuterated chloroform μ g microgram
Mg milligrams of DMSO dimethyl sulfoxide
DMSO-d6G grams of deuterated dimethyl sulfoxide
ML, ml milliliters of EtOAc, EA ethyl acetate
CH3OH, MeOH methanol μ L, μ l microlitres
CD3OD deuterated methanol nL, nl nanoliter
PE petroleum ether (60-90 DEG C) min minutes
RT, rt, r.t. room temperature h hours
Boc2O, every liter of nanomole of Boc acid anhydrides di-tert-butyl dicarbonate nM, nmol/L
Two ethanesulfonic acid μM of PIPES piperazine -1,4-, μm every liter of ol/L micromole
Tris-HCl tri- (methylol) aminomethane-M, mol/L moles every liter of hydrochloric acid
Glycerol glycerol mmol, mM mM
Following synthetic schemes describes the step of preparation disclosed compound of present invention, unless otherwise stated, wherein each R1a、
R1b、R1c、R1d、R4There is definition of the present invention with X.
Synthetic schemes 1
Wherein, PMB refers to 4- methoxy-benzylPh refers to phenyl
Formula (16) compound represented can be prepared by following process: formula (1) compound represented and formula (2) institute
Show compound react, obtain formula (3) compound represented;Then formula (3) compound represented with (4) shown in compound reaction,
Obtain formula (5) compound represented.Formula (5) compound represented deprotection base obtain formula (6) compound represented;Then formula
(6) compound represented and benzoyl isothiocyanate obtain formula (7) compound represented.Formula (7) compound represented removing
Benzoyl obtain formula (8) compound represented.Formula (8) compound represented ring closure reaction obtain formula (9) compound represented;
Formula (9) in compound represented protecting group obtain formula (10) compound represented.Formula (10) nitro quilt in compound represented
Reduction obtain formula (11) shown in product.Formula (11) compound represented react to obtain with benzoyl isothiocyanate formula (12) institute
The product shown;Formula (12) compound represented removing benzoyl obtain formula (13) compound represented;Formula (13) shown in change
Close object and formula (14) compound represented react to obtain formula (15) compound represented;Formula (15) compound represented deprotection
Base obtain formula (16) shown in target product.
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
Embodiment 1 (R) -5- (the fluoro- 5- of 2- ((4- (4- fluorophenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5-
The synthesis of dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
The synthesis of step 1) (R, E)-N- (1- (the fluoro- 5- nitrobenzophenone of 2-) ethylidene) -2- methylpropane -2- sulfenamide
By 1- (the fluoro- 5- nitro-phenyl of 2-) ethyl ketone (5g, 27.3mmol), (R)-(+)-t-butyl sulfonamide (3.8g,
31mmol) it is added in 100mL single necked round bottom flask with anhydrous tetrahydro furan (25mL), addition tetraethyl titanate (13.7g,
60.1mmol), it reacts 12 hours for lower 70 DEG C of nitrogen protection.It is cooled to room temperature after reaction, reaction solution is poured into water (50mL)
In, filtering, filter cake is washed (40mL × 2) with methylene chloride, merges organic phase, and decompression is spin-dried for, column chromatographic isolation and purification (petroleum
Ether/ethyl acetate (v/v)=20/1~5/1) title compound is obtained as yellow solid (7.1g, 91.0%).
MS(ESI,pos.ion)m/z:287.2[M+H]+;
1H NMR(600MHz,CDCl3) δ (ppm) 8.59-8.51 (m, 1H), 8.31 (dd, J=14.9,12.1Hz, 1H),
7.30 (dd, J=16.0,6.5Hz, 1H), 2.81 (s, 3H), 1.33 (s, 9H)
Step 2) (R) -2- ((R) -1,1- dimethyl ethyl sulfenamide) -2- (the fluoro- 5- nitrobenzophenone of 2-)-N- (4- first
Oxy-benzyl)-N- methylpropane -1- sulfonamide synthesis
N- (4- methoxybenzyl)-N- methylmethanesulfonamide (1.60g, 6.98mmol) is placed in 100mL two mouth flask, nitrogen
Anhydrous tetrahydro furan (20mL) is added under gas shielded, low temperature bathes cooling 10 minutes at -30 DEG C, is then slowly added into n-BuLi
(4.5mL, 1.6M) is stirred 0.5 hour;It is then slowly added into (R, E)-N- (1- (the fluoro- 5- nitrobenzophenone of 2-) ethylidene) -2- first
Base propane -2- sulfenamide (1.00g, 3.49mmol are dissolved in 5mL tetrahydrofuran), the reaction was continued 0.5 hour.Saturation chlorine is added
Change aqueous ammonium (5mL) to be quenched, add water (50mL), ethyl acetate extracts (100mL × 2), collects organic phase, decompression rotation
It is dry, column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound be yellow oil (0.85g,
47%).
MS(ESI,pos.ion)m/z:516.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.59 (dd, J=6.8,2.7Hz, 1H), 8.26 (dt, J=8.4,
3.3Hz, 1H), 7.28 (d, J=6.1Hz, 1H), 7.23 (d, J=8.3Hz, 2H), 6.88 (d, J=8.5Hz, 2H), 6.04 (s,
1H), 4.32-4.18 (m, 2H), 3.99-3.84 (m, 2H), 3.82 (d, J=6.7Hz, 3H), 2.81-2.70 (m, 3H), 1.95
(s,3H),1.38(s,9H).
The synthesis of step 3) (R) -2- amino -2- (the fluoro- 5- nitro-phenyl of 2-)-N- methyl-propan -1- sulfonamide
By (R) -2- ((R) -1,1- dimethyl ethyl sulfenamide) -2- (the fluoro- 5- nitrobenzophenone of 2-)-N- at 25 DEG C
(4- methoxy-benzyl)-N- methylpropane -1- sulfonamide (5.85g, 11.3mmol), methylene chloride (90mL) and methanol (30mL)
It is added in 500mL single necked round bottom flask, is added concentrated hydrochloric acid (10mL), continues to be stirred to react 1.5 hours;Stop reaction, decompression
It is spin-dried for;Then trifluoroacetic acid (15mL) and 1 is added, 3- dimethoxy benzene (10mL) continues to be stirred to react 16 hours;Stop anti-
It answers, water (100mL) and ethyl acetate (100mL) is added, water phase is collected in liquid separation, and sodium carbonate solid is added and is adjusted to pH=10, adds
Enter methylene chloride (100mL) extraction, organic phase is collected in liquid separation, and decompression is spin-dried for, column chromatographic isolation and purification (methylene chloride/methanol
(v/v)=40/1) obtaining title compound is yellow solid (2.28g, 69%).
MS(ESI,pos.ion)m/z:292.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.66 (dd, J=6.9,2.7Hz, 1H), 8.27-8.18 (m, 1H),
7.22 (dd, J=10.7,9.2Hz, 1H), 4.18 (t, J=10.9Hz, 1H), 3.89 (d, J=14.4Hz, 1H), 3.46 (d, J
=14.4Hz, 1H), 2.72 (d, J=5.2Hz, 3H), 1.67 (s, 3H)
Step 4) (R)-N- ((2- (the fluoro- 5- nitrobenzophenone of 2-) -1- (N- Methylsulfamoyl) propane -2- base) thio ammonia
Formyl) benzamide synthesis
At 25 DEG C by (R) -2- amino -2- (the fluoro- 5- nitro-phenyl of 2-)-N- methyl-propan -1- sulfonamide (0.34g,
It 1.17mmol) is added in 100mL single necked round bottom flask with methylene chloride (5mL), benzoyl isothiocyanate is added dropwise
(0.300g, 1.84mmol) continues to be stirred to react 10 hours;Organic phase decompression is spin-dried for, column chromatographic isolation and purification (petroleum ether/second
Acetoacetic ester (v/v)=2/1) title compound is obtained as yellow solid (0.5g, 94.3%).
MS(ESI,pos.ion)m/z:455.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 11.67 (d, J=37.2Hz, 1H), 9.01 (s, 1H), 8.30 (dd, J=
6.8,2.5Hz, 1H), 8.25-8.16 (m, 1H), 7.88 (d, J=7.7Hz, 2H), 7.64 (t, J=7.4Hz, 1H), 7.52 (t,
J=7.6Hz, 2H), 7.21 (dd, J=11.1,9.1Hz, 1H), 4.84 (dd, J=26.0,9.6Hz, 2H), 3.76 (t, J=
17.6Hz, 1H), 2.87 (d, J=5.1Hz, 3H), 2.27 (s, 3H)
The synthesis of step 5) (R) -2- (the fluoro- 5- nitrobenzophenone of 2-)-N- methyl -2- thiocarbamide propane -1- sulfonamide
By (R)-N- ((2- (the fluoro- 5- nitrobenzophenone of 2-) -1- (N- Methylsulfamoyl) propane -2- base) sulphur at 25 DEG C
For carbamyl) benzamide (7.8g, 17.2mmol) and methanol (100mL) is added in 500mL single necked round bottom flask, carbon is added
Sour sodium (1.80g, 17.0mmol) continues to be stirred to react 0.5 hour.It is added ammonium chloride (1.00g, 18.7mmol), it is organic to subtract each other
Pressure is spin-dried for, and it is yellow solid that column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=1/1), which obtains title compound,
(4.3g, 71.5%).
MS(ESI,pos.ion)m/z:351.2[M+H]+;
1H NMR(400MHz,DMSO-d6)δ(ppm)8.25-8.16(m,2H),8.07(s,1H),7.46-7.39(m,
1H), 7.18 (s, 1H), 7.06 (d, J=4.8Hz, 1H), 4.03 (q, J=7.1Hz, 1H), 3.82 (d, J=14.1Hz, 1H),
2.61 (d, J=4.8Hz, 3H), 1.96 (s, 3H)
Step 6) (R) -5- (the fluoro- 5- nitrobenzophenone of 2-) -3- imino group -2,5- dimethyl -1,2,4- thiadiazine 1,1- bis-
The synthesis of oxo compound
At 25 DEG C by (R) -2- (the fluoro- 5- nitrobenzophenone of 2-)-N- methyl -2- thiocarbamide propane -1- sulfonamide (0.5g,
It 1.43mmol) is added in 100mL single necked round bottom flask, is added iodomethane (0.608g, 4.28mmol) with ethyl alcohol (20mL), after
Continuous reaction 12 hours.It then heats to 70 DEG C to react 3 hours, stops reaction, decompression is spin-dried for, and is added water (20mL), ethyl acetate
It extracts (50mL), liquid separation, organic phase decompression is spin-dried for, and column chromatographic isolation and purification (methylene chloride/methanol (v/v)=40/1) is marked
Topic compound is yellow solid (0.298g, 66%).
MS(ESI,pos.ion)m/z:317.1[M+H]+;
1H NMR(400MHz,CD3OD) δ (ppm) 8.45 (dt, J=13.3,6.7Hz, 1H), 8.30-8.19 (m, 1H),
7.35 (dd, J=11.2,9.0Hz, 1H), 3.34-3.31 (m, 2H), 3.17 (s, 3H), 1.74 (s, 3H)
Step 7) (R)-tert-butyl (5- (the fluoro- 5- nitrobenzophenone of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two
Piperazine -3- methylene) carbamate synthesis
By (R) -5- (the fluoro- 5- nitrobenzophenone of 2-) -3- imino group -2,5- dimethyl -1,2,4- thiadiazine 1 at 25 DEG C,
1- dioxo compound (0.47g, 1.49mmol), triethylamine (0.3g, 2.96mmol) and methylene chloride (10mL) are added to 100mL
In single necked round bottom flask, Boc acid anhydrides (0.500g, 2.29mmol) then is added, continues to be stirred to react 12 hours;Stop reaction,
Decompression is spin-dried for, and it is white solid that column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=6/1), which obtains title compound,
(0.5g, 81%).
MS(ESI,pos.ion)m/z:361.0[M+H-56]+;
1H NMR(400MHz,CDCl3) δ (ppm) 7.28 (s, 1H), 6.91 (dd, J=11.9,8.5Hz, 1H), 6.61
(dt, J=9.4,2.7Hz, 2H), 4.29 (dd, J=14.1,2.1Hz, 1H), 3.68 (d, J=14.1Hz, 1H), 3.27 (s,
3H),1.88(s,3H),1.57(s,9H).
Step 8) (R)-tert-butyl (5- (5- amino -2- fluorophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two
Piperazine -3- methylene) carbamate synthesis
By (R)-tert-butyl (5- (the fluoro- 5- nitrobenzophenone of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- at 25 DEG C
Thiadiazine -3- methylene) to be added to 100mL mono- for carbamate (0.5g, 1.2mmol), palladium carbon (150mg) and methanol (15mL)
In mouth round-bottomed flask, it is stirred to react under hydrogen balloon 24 hours.Stop reaction, filtering, filtrate decompression is spin-dried for, column chromatographic isolation and purification
It is white solid (0.424g, 91.4%) that (petrol ether/ethyl acetate (v/v)=3/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:387.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 7.28 (s, 1H), 6.91 (dd, J=11.9,8.5Hz, 1H), 6.61
(dt, J=9.4,2.7Hz, 2H), 4.29 (dd, J=14.1,2.1Hz, 1H), 3.68 (d, J=14.1Hz, 1H), 3.27 (s,
3H),1.88(s,3H),1.57(s,9H).
Step 9) (R)-tert-butyl (5- (5- (3- benzoyl thiourea base) -2- fluorophenyl) -2,5- dimethyl -1,1- dioxy
Generation -1,2,4- thiadiazine -3- methylene) carbamate synthesis
By (R)-tert-butyl (5- (5- amino -2- fluorophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- at 25 DEG C
Thiadiazine -3- methylene) carbamate (0.27g, 0.70mmol) and methylene chloride (5mL) be added to 100mL single neck round bottom
In flask, it is added dropwise benzoyl isothiocyanate (0.228g, 1.4mmol), continues to be stirred to react 10 hours;Organic phase decompression rotation
It is dry, column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=4/1) obtain title compound be faint yellow solid (0.19g,
49%).
MS(ESI,pos.ion)m/z:550.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.11 (s, 1H), 8.00 (dd, J=7.3,2.6Hz, 1H), 7.94-
7.86 (m, 2H), 7.69 (t, J=7.4Hz, 1H), 7.63 (ddd, J=8.5,3.9,2.8Hz, 1H), 7.58 (t, J=7.7Hz,
2H), 7.18 (dd, J=11.4,8.8Hz, 1H), 4.34 (d, J=14.1,1H), 3.72 (d, J=14.1Hz, 1H), 3.27 (s,
3H),1.95(s,3H),1.58(s,9H).
Step 10) (R)-tert-butyl (5- (the fluoro- 5- thiocarbamide phenyl of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene
Diazine -3- methylene) carbamate synthesis
By (R)-tert-butyl (5- (5- (3- benzoyl thiourea base) -2- fluorophenyl) -2,5- dimethyl -1,1- at 25 DEG C
Dioxo -1,2,4- thiadiazine -3- methylene) carbamate (1.07g, 1.95mmol) and methanol (20mL) is added to
In 100mL single necked round bottom flask, it is added sodium carbonate (0.2g, 1.89mmol), continues to be stirred to react 0.5 hour.Ammonium chloride is added
(0.1g, 1.9mmol), organic phase decompression are spin-dried for, and column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) is marked
Topic compound is white solid (823mg, 94.9%).
MS(ESI,pos.ion)m/z:446.1[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)10.68(s,1H),7.92(s,1H),7.28-7.18(m,3H),4.22
(d, J=13.7Hz, 1H), 3.63 (d, J=14.2Hz, 1H), 3.27 (s, 3H), 1.96 (s, 3H), 1.57 (s, 9H).
Step 11) (R)-tert-butyl (5- (the fluoro- 5- of 2- ((4- (4- fluorophenyl) thiazol-2-yl) amino) phenyl) -2,5- two
Methyl-1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
By (R)-tert-butyl (5- (the fluoro- 5- thiocarbamide phenyl of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- at 25 DEG C
Thiadiazine -3- methylene) carbamate (200mg, 0.45mmol), the bromo- 1- of 2- (4- fluorophenyl) ethyl ketone (98mg,
It 0.45mmol) is added in 100mL single necked round bottom flask with ethyl alcohol (20mL), continues to be stirred to react 2 hours.Unsaturated carbonate is added
Hydrogen sodium solution (15mL) and methylene chloride (30mL), liquid separation, organic phase decompression are spin-dried for, column chromatographic isolation and purification (petroleum ether/acetic acid
Ethyl ester (v/v)=6/1) title compound is obtained as white solid (215mg, 84.9%).
MS(ESI,pos.ion)m/z:564.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 10.65 (s, 1H), 7.82 (dd, J=8.8,5.4Hz, 2H), 7.65-
7.57 (m, 1H), 7.36 (d, J=15.8Hz, 1H), 7.20-7.04 (m, 3H), 6.76 (s, 1H), 4.37 (d, J=12.7Hz,
1H), 3.70 (d, J=14.1Hz, 1H), 3.28 (s, 3H), 1.94 (s, 3H), 1.59 (s, 9H)
Step 12) (R) -5- (the fluoro- 5- of 2- ((4- (4- fluorophenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5-
The synthesis of dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
At 25 DEG C by (R)-tert-butyl (5- (the fluoro- 5- of 2- ((4- (4- fluorophenyl) thiazol-2-yl) amino) phenyl) -2,
5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate (210mg, 0.37mmol) and dichloromethane
Alkane (5mL) is added in 50mL single-necked flask, is added Hydrochloride/ethyl acetate (2mL, 4M), is stirred to react 2 hours;Stop
Reaction, decompression are spin-dried for, and are added saturated sodium bicarbonate solution (20mL), and methylene chloride extraction (20mL × 2) is then added, is associated with
Machine phase, anhydrous sodium sulfate (2g) dry, filter, and filtrate decompression is spin-dried for, column chromatographic isolation and purification (methylene chloride/methanol (v/v)=
20/1) obtaining title compound is white solid (0.166g, 96.1%).
MS(ESI,pos.ion)m/z:464.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 7.85-7.76 (m, 2H), 7.58 (dd, J=6.8,2.5Hz, 1H),
7.52-7.44 (m, 1H), 7.14-7.01 (m, 3H), 6.69 (s, 1H), 5.32 (s, 1H), 3.92 (t, J=11.5Hz, 1H),
3.73 (t, J=12.4Hz, 1H), 3.24 (s, 3H), 1.80 (d, J=5.4Hz, 3H)
Embodiment 2 (R) -5- (the fluoro- 5- of 2- ((4- (4- chlorphenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5-
The synthesis of dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
Step 1) (R)-tert-butyl (5- (the fluoro- 5- of 2- ((4- (4- chlorphenyl) thiazol-2-yl) amino) phenyl) -2,5- two
Methyl-1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (the fluoro- 5- thiocarbamide phenyl of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate
(200mg, 0.45mmol) and the bromo- 1- of 2- (4- chlorphenyl) ethyl ketone (105mg, 0.45mmol) the reaction system in ethyl alcohol (10mL)
Standby, crude product obtains title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1) as white
Solid (0.24g, 92.2%).
MS(ESI,pos.ion)m/z:580.0[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 10.65 (s, 1H), 7.78 (d, J=8.6Hz, 2H), 7.61-7.57 (m,
1H), 7.38 (t, J=13.0Hz, 2H), 7.15 (dd, J=11.5,8.8Hz, 1H), 6.82 (s, 1H), 4.38 (d, J=
14.1Hz, 1H), 3.69 (d, J=14.1Hz, 1H), 3.27 (s, 3H), 1.81 (s, 3H), 1.60 (s, 9H)
Step 2) (R) -5- (the fluoro- 5- of 2- ((4- (4- chlorphenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5-
The synthesis of dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (the fluoro- 5- of 2- ((4- (4- chlorphenyl) thiazol-2-yl) amino) phenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene
Diazine -3- methylene) carbamate (230mg, 0.39mmol), Hydrochloride/ethyl acetate (2mL, 4M) is in methylene chloride
Reaction preparation, crude product are marked through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in (10mL)
Topic compound is white solid (0.187g, 98.2%).
MS(ESI,pos.ion)m/z:480.0[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 7.77 (t, J=8.8Hz, 2H), 7.62-7.55 (m, 1H), 7.48 (dd,
J=8.3,3.4Hz, 1H), 7.37 (d, J=8.5Hz, 2H), 7.12-6.98 (m, 1H), 6.75 (s, 1H), 3.92 (t, J=
11.4Hz, 1H), 3.71 (d, J=14.0Hz, 1H), 3.24 (s, 3H), 1.80 (d, J=4.8Hz, 3H)
Embodiment 3 (R) -5- (the fluoro- 5- of 2- ((4- (4- methoxyphenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -
The synthesis of 2,5- dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
Step 1) (R)-tert-butyl (5- (the fluoro- 5- of 2- ((4- (4- methoxyphenyl) thiazol-2-yl) amino) phenyl) -2,
5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (the fluoro- 5- thiocarbamide phenyl of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate
The reaction in ethyl alcohol (10mL) of (200mg, 0.45mmol) and the bromo- 1- of 2- (4- methoxyphenyl) ethyl ketone (103mg, 0.45mmol)
Preparation, for crude product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1), it is white for obtaining title compound
Color solid (0.208g, 80.5%).
MS(ESI,pos.ion)m/z:576.3[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 10.64 (s, 1H), 7.78 (d, J=8.8Hz, 2H), 7.66-7.57 (m,
1H), 7.24 (dt, J=11.4,5.7Hz, 1H), 7.14 (dd, J=11.6,8.9Hz, 1H), 6.96 (d, J=8.8Hz, 2H),
6.70 (s, 1H), 4.37 (d, J=12.7Hz, 1H), 4.15 (dd, J=14.3,7.2Hz, 1H), 3.87 (s, 3H), 3.27 (s,
3H),1.94(s,3H),1.61(s,9H).
Step 2) (R) -5- (the fluoro- 5- of 2- ((4- (4- methoxyphenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -
The synthesis of 2,5- dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (the fluoro- 5- of 2- ((4- (4- methoxyphenyl) thiazol-2-yl) amino) phenyl) dioxo-1,2-2,5- dimethyl-1,1-,
4- thiadiazine -3- methylene) carbamate (200mg, 0.35mmol), Hydrochloride/ethyl acetate (2mL, 4M) is in dichloro
Reaction preparation, crude product are obtained through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in methane (10mL)
It is white solid (0.15g, 90.8%) to title compound.
MS(ESI,pos.ion)m/z:476.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 7.78 (t, J=7.8Hz, 2H), 7.59 (dd, J=6.9,2.7Hz,
1H), 7.47 (dd, J=8.6,3.6Hz, 1H), 7.05 (dd, J=11.6,8.7Hz, 1H), 6.94 (d, J=8.8Hz, 2H),
6.66 (d, J=11.3Hz, 1H), 5.32 (s, 1H), 3.91 (d, J=13.8Hz, 1H), 3.86 (s, 3H), 3.75-3.67 (m,
1H), 3.22 (s, 3H), 1.79 (d, J=6.3Hz, 3H)
Embodiment 4 (R)-5- (the fluoro- 5- of 2- ((4- (4- cyano-phenyl) thiazol-2-yl) amino) phenyl) imido grpup-2-3-,
The synthesis of 5- dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
Step 1) (R)-tert-butyl (5- (the fluoro- 5- of 2- ((4- (4- cyano-phenyl) thiazol-2-yl) amino) phenyl) -2,5-
Dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (the fluoro- 5- thiocarbamide phenyl of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate
(200mg, 0.45mmol) and the bromo- 1- of 2- (4- cyano-phenyl) ethyl ketone (100mg, 0.45mmol) the reaction system in ethyl alcohol (10mL)
Standby, crude product obtains title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1) as white
Solid (0.201g, 78.4%).
MS(ESI,pos.ion)m/z:571.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 10.66 (s, 1H), 7.94 (d, J=8.4Hz, 2H), 7.71 (t, J=
11.3Hz, 2H), 7.66 (dd, J=8.5,3.6Hz, 1H), 7.50 (s, 1H), 7.17 (dd, J=11.6,8.8Hz, 1H), 6.99
(s, 1H), 4.42-4.33 (m, 1H), 4.15 (q, J=7.1Hz, 1H), 3.28 (s, 3H), 1.95 (s, 3H), 1.60 (s, 9H)
Step 2) (R)-5- (the fluoro- 5- of 2- ((4- (4- cyano-phenyl) thiazol-2-yl) amino) phenyl) imido grpup-2-3-,
The synthesis of 5- dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (the fluoro- 5- of 2- ((4- (4- cyano-phenyl) thiazol-2-yl) amino) phenyl) -2,5- dimethyl -1,1- dioxo -1,2,4-
Thiadiazine -3- methylene) carbamate (190mg, 0.33mmol), Hydrochloride/ethyl acetate (2mL, 4M) is in dichloromethane
Reaction preparation, crude product are obtained through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in alkane (10mL)
Title compound is white solid (0.145g, 92.5%).
MS(ESI,pos.ion)m/z:471.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 7.94 (t, J=8.4Hz, 2H), 7.69 (d, J=8.5Hz, 2H), 7.60
(dd, J=6.9,2.8Hz, 1H), 7.53-7.46 (m, 1H), 7.13-7.04 (m, 1H), 6.93 (s, 1H), 5.32 (s, 1H),
3.91 (t, J=12.7Hz, 1H), 3.71 (d, J=14.0Hz, 1H), 3.25 (s, 3H), 1.79 (d, J=4.6Hz, 3H)
Embodiment 5 (R) -5- (the fluoro- 5- of 2- ((4- (5- fluorine pyridine -2- base) thiazol-2-yl) amino) phenyl) -3- imines
The synthesis of base -2,5- dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
Step 1) (R)-tert-butyl (5- (the fluoro- 5- of 2- ((4- (5- fluorine pyridine -2- base) thiazol-2-yl) amino) phenyl) -2,
5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (the fluoro- 5- thiocarbamide phenyl of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate
(260mg, 0.58mmol) and the bromo- 1- of 2- (5- fluorine pyridine -2- base) ethyl ketone (200mg, 0.92mmol) is anti-in ethyl alcohol (10mL)
It should prepare, through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1), obtain title compound is crude product
White solid (0.3g, 91.0%).
MS(ESI,pos.ion)m/z:565.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.46 (d, J=2.8Hz, 1H), 8.00 (dd, J=8.7,4.6Hz,
1H), 7.77-7.68 (m, 1H), 7.51 (td, J=8.5,2.9Hz, 1H), 7.35 (s, 1H), 7.32 (dd, J=6.9,2.7Hz,
1H), 7.28 (s, 1H), 7.15 (dd, J=11.6,8.8Hz, 1H), 4.39-4.35 (m, 1H), 3.69 (d, J=14.1Hz,
1H), 3.22 (s, 3H), 1.94 (d, J=9.4Hz, 3H), 1.52 (s, 9H)
Step 2) (R) -5- (the fluoro- 5- of 2- ((4- (5- fluorine pyridine -2- base) thiazol-2-yl) amino) phenyl) -3- imido grpup -
The synthesis of 2,5- dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (the fluoro- 5- of 2- ((4- (5- fluorine pyridine-2- base) thiazol-2-yl) amino) phenyl) dioxo-1,2-2,5- dimethyl-1,1-,
4- thiadiazine -3- methylene) carbamate (300mg, 0.53mmol), Hydrochloride/ethyl acetate (2mL, 4M) is in dichloro
Reaction preparation, crude product are obtained through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in methane (10mL)
It is white solid (0.21g, 85.1%) to title compound.
MS(ESI,pos.ion)m/z:465.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.42 (d, J=2.5Hz, 1H), 7.91 (dd, J=8.7,4.5Hz,
1H), 7.54 (t, J=8.1Hz, 2H), 7.42 (td, J=8.4,2.8Hz, 1H), 7.22 (s, 1H), 7.02 (dd, J=11.5,
8.7Hz, 1H), 3.96 (d, J=13.8Hz, 1H), 3.67 (d, J=14.0Hz, 1H), 3.20 (s, 3H), 1.74 (s, 3H)
Embodiment 6 (R) -5- (the fluoro- 5- of 2- ((4- (5- chloropyridine -2- base) thiazol-2-yl) amino) phenyl) -3- imines
The synthesis of base -2,5- dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
Step 1) (R)-tert-butyl (5- (the fluoro- 5- of 2- ((4- (5- chloropyridine -2- base) thiazol-2-yl) amino) phenyl) -2,
5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (the fluoro- 5- thiocarbamide phenyl of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate
(260mg, 0.58mmol) and the bromo- 1- of 2- (5- chloropyridine -2- base) ethyl ketone (200mg, 0.85mmol) is anti-in ethyl alcohol (10mL)
It should prepare, through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1), obtain title compound is crude product
White solid (0.31g, 91.4%).
MS(ESI,pos.ion)m/z:581.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.53 (d, J=2.1Hz, 1H), 7.93 (t, J=9.9Hz, 1H),
7.85-7.73 (m, 2H), 7.40 (s, 1H), 7.36 (dd, J=6.9,2.7Hz, 1H), 7.13 (dd, J=11.7,8.9Hz,
1H), 4.40 (dd, J=14.1,1.9Hz, 1H), 3.67 (d, J=14.1Hz, 1H), 3.18 (s, 3H), 1.94 (d, J=
7.4Hz,3H),1.48(s,9H).
Step 2) (R) -5- (the fluoro- 5- of 2- ((4- (5- chloropyridine -2- base) thiazol-2-yl) amino) phenyl) -3- imido grpup -
The synthesis of 2,5- dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (the fluoro- 5- of 2- ((4- (5- chloropyridine-2- base) thiazol-2-yl) amino) phenyl) dioxo-1,2-2,5- dimethyl-1,1-,
4- thiadiazine -3- methylene) carbamate (310mg, 0.53mmol), Hydrochloride/ethyl acetate (2mL, 4M) is in dichloro
Reaction preparation, crude product are obtained through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in methane (10mL)
It is white solid (0.21g, 81.8%) to title compound.
MS(ESI,pos.ion)m/z:481.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.50 (d, J=2.0Hz, 1H), 7.86 (t, J=11.8Hz, 1H),
7.66 (dd, J=8.4,2.2Hz, 1H), 7.53 (d, J=6.6Hz, 2H), 7.28 (s, 1H), 7.06-6.96 (m, 1H), 3.96
(d, J=13.8Hz, 1H), 3.66 (d, J=14.0Hz, 1H), 3.20 (s, 3H), 1.75 (s, 3H)
Embodiment 7 (R) -5- (3- ((4- (4- fluorophenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5- diformazan
The synthesis of base -1,2,4- thiadiazine 1,1- dioxo compound
The synthesis of step 1) (R, E) -2- methyl-N- (1- (3- nitrobenzophenone) ethylidene) propane -2- sulfenamide
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by m-nitroacetophenone
(8.0g, 48.4mmol), (R)-(+)-t-butyl sulfonamide (6.5g, 54mmol) and tetraethyl titanate (21mL,
99.16mmol) the reaction preparation in tetrahydrofuran (65mL), crude product is through silica gel column chromatography separating purification (petroleum ether/acetic acid second
Ester (v/v)=10/1), obtaining title compound is yellow solid (11g, 85%).
MS(ESI,pos.ion)m/z:269.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.68 (s, 1H), 8.33 (dd, J=8.2,1.1Hz, 1H), 8.20 (d, J
=7.7Hz, 1H), 7.63 (t, J=8.0Hz, 1H), 2.83 (s, 3H), 1.34 (s, 9H)
Step 2) (R) -2- ((R) -1,1- dimethyl ethyl sulfenamide)-N- (4- methoxy-benzyl)-N- methyl -2-
The synthesis of (3- nitrobenzophenone) propane -1- sulfonamide
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by N- (4- methoxyl group
Benzyl)-N- methylmethanesulfonamide (687mg, 2.99mmol), n-BuLi (1.2mL, 3.0mmol, 2.5M) and (R, E) -2- first
Base-N- (1- (3- nitrobenzophenone) ethylidene) propane -2- sulfenamide (402mg, 1.49mmol) is in tetrahydrofuran (10mL)
Reaction preparation, crude product obtain title compound through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=2/1)
For yellow solid (364mg, 48.8%).
MS(ESI,pos.ion)m/z:498.3[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.40 (s, 1H), 8.18 (dd, J=8.2,1.3Hz, 1H), 7.83 (d, J
=7.8Hz, 1H), 7.57 (t, J=8.0Hz, 1H), 7.22 (d, J=8.6Hz, 2H), 6.87 (d, J=8.6Hz, 2H), 5.90
(s, 1H), 4.24 (dd, J=31.9,14.3Hz, 2H), 3.80 (s, 3H), 3.77 (d, J=14.2Hz, 1H), 3.56 (d, J=
14.1Hz,1H),2.75(s,3H),1.93(s,3H),1.36(s,9H).
The synthesis of step 3) (R) -2- Amino-N-methyl -2- (3- nitrobenzophenone) propane -1- sulfonamide
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by (R) -2- ((R) -
1,1- dimethyl ethyl sulfenamide)-N- (4- methoxy-benzyl)-N- methyl -2- (3- nitrobenzophenone) propane -1- sulfonamide
(2.50g, 5.02mmol), concentrated hydrochloric acid (6.0mL), trifluoroacetic acid (15mL) and phenylene dimethyl ether (4.70mL, 35.2mmol) exist
Reaction preparation in methylene chloride (30mL) and methanol (10mL), crude product is through silica gel column chromatography separating purification (methylene chloride/methanol
(v/v)=40/1), obtaining title compound is yellow oil (1g, 73%).
MS(ESI,pos.ion)m/z:274.0[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.42 (s, 1H), 8.14 (dd, J=8.1,1.2Hz, 1H), 7.91 (d, J
=7.9Hz, 1H), 7.56 (t, J=8.0Hz, 1H), 3.52 (d, J=14.4Hz, 1H), 3.40 (d, J=14.3Hz, 1H),
2.68 (d, J=5.1Hz, 3H), 1.73 (s, 3H)
Step 4) (R)-N- ((1- (N- Methylsulfamoyl) -2- (3- nitrobenzophenone) propane -2- base) thiocarbamoyl)
The synthesis of benzamide
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by (R) -2- amino -
N- methyl -2- (3- nitrobenzophenone) propane -1- sulfonamide (1g, 3.66mmol) and benzoyl isothiocyanate (657mg,
4.02mmol) the reaction preparation in methylene chloride (10mL), crude product is through silica gel column chromatography separating purification (petroleum ether/acetic acid second
Ester (v/v)=2/1), obtaining title compound is yellow solid (1.56g, 97.7%).
MS(ESI,pos.ion)m/z:437.0[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)11.67(s,1H),8.93(s,1H),8.25-8.08(m,2H),7.94-
7.79 (m, 2H), 7.74-7.59 (m, 2H), 7.55 (dd, J=13.3,7.6Hz, 3H), 4.89 (d, J=14.2Hz, 1H),
3.71 (d, J=14.2Hz, 1H), 2.85 (t, J=5.4Hz, 3H), 2.14 (s, 3H)
The synthesis of step 5) (R)-N- methyl -2- (3- nitrobenzophenone) -2- thiocarbamide propane -1- sulfonamide
This step title compound method referring to described in 1 step 5 of embodiment is prepared, i.e., by (R)-N- ((1-
(N- Methylsulfamoyl) -2- (3- nitrobenzophenone) propane -2- base) thiocarbamoyl) benzamide (1.56g, 3.57mmol)
The reaction preparation in methanol (35mL) with sodium carbonate (379mg, 3.57mmol), crude product is through silica gel column chromatography separating purification (stone
Oily ether/ethyl acetate (v/v)=1/1), obtaining title compound is yellow solid (1.12g, 94%).
MS(ESI,pos.ion)m/z:333.2[M+H]+;
1H NMR(400MHz,DMSO-d6) δ (ppm) 8.13 (s, 1H), 8.11-8.00 (m, 2H), 7.79 (d, J=
7.8Hz, 1H), 7.60 (t, J=8.0Hz, 1H), 7.15 (s, 1H), 6.99-6.93 (m, 1H), 4.03 (d, J=7.1Hz, 1H),
3.86 (d, J=14.1Hz, 1H), 3.33 (s, 4H), 1.81 (s, 3H)
Step 6) (R) -3- imino group -2,5- dimethyl -5- (3- nitrobenzophenone) -1,2,4- thiadiazine 1,1- dioxo
The synthesis of object
This step title compound method referring to described in 1 step 6 of embodiment is prepared, i.e., by (R)-N- methyl-
2- (3- nitrobenzophenone) -2- thiocarbamide propane -1- sulfonamide (1.12g, 3.37mmol) and iodomethane (0.64mL, 10mmol) are in second
Reaction preparation, crude product are obtained through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=40/1) in alcohol (30mL)
Title compound is yellow solid (718mg, 71.4%).
MS(ESI,pos.ion)m/z:299.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.37 (d, J=1.8Hz, 1H), 8.23-8.06 (m, 1H), 7.76 (d, J
=7.8Hz, 1H), 7.53 (t, J=8.0Hz, 1H), 3.58 (q, J=13.8Hz, 2H), 3.24 (s, 3H), 1.75 (s, 3H)
Step 7) (R)-tert-butyl (2,5- dimethyl -5- (3- nitrobenzophenone) -1,1- dioxo -1,2,4- thiadiazine -3-
Methylene) carbamate synthesis
This step title compound method referring to described in 1 step 7 of embodiment is prepared, i.e., by (R) -3- imido
Base -2,5- dimethyl -5- (3- nitrobenzophenone) -1,2,4- thiadiazine 1,1- dioxo compound (718mg, 2.41mmol), three second
Amine (0.67mL, 4.8mmol) and Boc acid anhydrides (0.84mL, 3.6mmol) reaction preparation, crude product in methylene chloride (20mL)
Through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1), obtaining title compound is white solid
(880mg, 91.8%).
MS(ESI,pos.ion)m/z:343.0[M+H-56]+;
1H NMR(400MHz,CDCl3)δ(ppm)10.74(s,1H),8.27-8.17(m,2H),7.77-7.69(m,1H),
7.62 (t, J=7.9Hz, 1H), 3.96 (d, J=14.1Hz, 1H), 3.75 (d, J=14.1Hz, 1H), 3.26 (s, 3H), 1.93
(s,3H),1.55(s,9H).
Step 8) (R)-tert-butyl (5- (3- aminophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3-
Methylene) carbamate synthesis
This step title compound method referring to described in 1 step 8 of embodiment is prepared, i.e., by (R)-tert-butyl
(2,5- dimethyl -5- (3- nitrobenzophenone) -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate (867mg,
It 2.176mmol) is prepared with palladium carbon (180mg) reaction in methanol (15mL), crude product is through silica gel column chromatography separating purification (petroleum
Ether/ethyl acetate (v/v)=3/1), obtaining title compound is white solid (680mg, 84.8%).
MS(ESI,pos.ion)m/z:369.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 10.49 (s, 1H), 7.18 (t, J=7.8Hz, 1H), 6.71 (d, J=
8.0Hz, 1H), 6.68-6.56 (m, 2H), 3.81 (d, J=14.0Hz, 1H), 3.66 (d, J=14.0Hz, 1H), 3.27 (s,
3H),1.87(s,3H),1.53(s,9H).
Step 9) (R)-tert-butyl (5- (3- (3- benzoyl thiourea) phenyl) dioxo-1,2-2,5- dimethyl-1,1-,
4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 9 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (3- aminophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate (1.93g,
5.24mmol) passed through with benzoyl isothiocyanate (0.94g, 5.8mmol) reaction preparation in methylene chloride (20mL), crude product
Silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=4/1), obtain title compound be yellow solid (2.7g,
96.8%).
MS(ESI,pos.ion)m/z:532.1[M+H]+;
Step 10) (R)-tert-butyl (2,5- dimethyl -1,1- dioxo -5- (3- thiocarbamide phenyl) -1,2,4- thiadiazine -
3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 10 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (3- (3- benzoyl thiourea) phenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- methylene) amino first
The reaction preparation in methanol (30mL) of acid esters (2.7g, 5.08mmol) and sodium carbonate (0.717g, 6.76mmol), crude product is through silicon
Plastic column chromatography isolates and purifies (petrol ether/ethyl acetate (v/v)=2/1), obtain title compound be white solid (2.0g,
92.1%).
MS(ESI,pos.ion)m/z:428.2[M+H]+;
1H NMR(400MHz,DMSO-d6)δ(ppm)10.23(s,1H),9.77(s,1H),7.46(s,1H),7.36(d,J
=4.8Hz, 2H), 7.23-7.18 (m, 1H), 4.56 (d, J=14.3Hz, 1H), 4.35 (d, J=14.3Hz, 1H), 3.03 (s,
3H),1.76(s,3H),1.59(s,9H).
Step 11) (R)-tert-butyl (5- (3- ((4- (4- fluorophenyl) thiazol-2-yl) amino) phenyl) -2,5- dimethyl -
1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(2,5- dimethyl -1,1- dioxo -5- (3- thiocarbamide phenyl) -1,2,4- thiadiazine -3- methylene) carbamate (476mg,
It 1.11mmol) is prepared with the bromo- 1- of 2- (4- fluorophenyl) ethyl ketone (242mg, 1.11mmol) reaction in ethyl alcohol (10mL), crude product
Through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1), obtaining title compound is yellow solid
(0.504g, 82.9%).
MS(ESI,pos.ion)m/z:546.2[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)10.61(s,1H),7.86-7.78(m,2H),7.59(s,1H),7.39
(dd, J=3.8,1.3Hz, 2H), 7.12 (t, J=8.7Hz, 2H), 7.08-7.02 (m, 1H), 6.79 (s, 1H), 3.90 (d, J
=14.0Hz, 1H), 3.70 (d, J=14.0Hz, 1H), 3.29 (s, 3H), 1.93 (s, 3H), 1.60 (s, 3H)
Step 12) (R) -5- (3- ((4- (4- fluorophenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5- diformazan
The synthesis of base -1,2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (3- ((4- (4- fluorophenyl) thiazol-2-yl) amino) phenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -
3- methylene) carbamate (504mg, 0.923mmol), Hydrochloride/ethyl acetate (2mL, 4M) is in methylene chloride
Reaction preparation, crude product are marked through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in (10mL)
Topic compound is brown solid (0.275g, 66.8%).
MS(ESI,pos.ion)m/z:446.1[M+H]+;
1H NMR(400MHz,DMSO-d6) δ (ppm) 10.26 (s, 1H), 7.98 (dd, J=8.8,5.6Hz, 2H), 7.78
(s, 1H), 7.61 (dd, J=8.0,1.4Hz, 1H), 7.34-7.22 (m, 4H), 7.09 (d, J=7.9Hz, 1H), 3.90 (d, J
=13.9Hz, 1H), 3.63 (brs, 1H), 3.08 (s, 3H), 1.58 (s, 3H)
Embodiment 8 (R) -5- (3- ((4- (4- chlorphenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5- diformazan
The synthesis of base -1,2,4- thiadiazine 1,1- dioxo compound
Step 1) (R)-tert-butyl (5- (3- ((4- (4- chlorphenyl) thiazol-2-yl) amino) phenyl) -2,5- dimethyl -
1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(2,5- dimethyl -1,1- dioxo -5- (3- thiocarbamide phenyl) -1,2,4- thiadiazine -3- methylene) carbamate (200mg,
It 0.47mmol) is prepared with the bromo- 1- of 2- (4- chlorphenyl) ethyl ketone (109mg, 0.47mmol) reaction in ethyl alcohol (5mL), crude product
Through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1), obtaining title compound is white solid
(0.25g, 95.1%).
MS(ESI,pos.ion)m/z:563.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 10.62 (s, 1H), 7.85 (s, 1H), 7.78 (d, J=8.6Hz, 2H),
7.59 (s, 1H), 7.43-7.40 (m, 1H), 7.38 (d, J=3.8Hz, 2H), 7.05 (dt, J=11.8,4.9Hz, 1H), 6.84
(s, 1H), 3.90 (d, J=14.0Hz, 1H), 3.69 (d, J=14.0Hz, 1H), 3.30 (s, 3H), 1.93 (s, 3H), 1.52
(s,9H).
Step 2) (R) -5- (3- ((4- (4- chlorphenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5- diformazan
The synthesis of base -1,2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (3- ((4- (4- chlorphenyl) thiazol-2-yl) amino) phenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -
3- methylene) carbamate (250mg, 0.44mmol), Hydrochloride/ethyl acetate (2mL, 4M) is at methylene chloride (5mL)
Middle reaction preparation, crude product obtain title compound through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1)
Object is white solid (0.127g, 61.8%).
MS(ESI,pos.ion)m/z:463.0[M+H]+;
1H NMR(400MHz,DMSO-d6) δ (ppm) 10.26 (s, 1H), 7.98 (dd, J=8.8,5.6Hz, 2H), 7.78
(s, 1H), 7.61 (dd, J=8.0,1.4Hz, 1H), 7.34-7.22 (m, 4H), 7.09 (d, J=7.9Hz, 1H), 3.90 (d, J
=13.9Hz, 1H), 3.63 (brs, 1H), 3.08 (s, 3H), 1.58 (s, 3H)
Embodiment 9 (R) -5- (3- ((4- (4- methoxyphenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5-
The synthesis of dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
Step 1) (R)-tert-butyl (5- (3- ((4- (4- methoxyphenyl) thiazol-2-yl) amino) phenyl) -2,5- diformazan
Base -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(2,5- dimethyl -1,1- dioxo -5- (3- thiocarbamide phenyl) -1,2,4- thiadiazine -3- methylene) carbamate (300mg,
It 0.70mmol) is prepared with the bromo- 1- of 2- (4- methoxyphenyl) ethyl ketone (160mg, 0.70mmol) reaction in ethyl alcohol (5mL), slightly
For product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1), obtaining title compound is yellow solid
(0.361g, 92.2%).
MS(ESI,pos.ion)m/z:558.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.24 (s, 1H), 7.81 (d, J=8.8Hz, 2H), 7.47 (s, 1H),
7.41-7.33 (m, 2H), 7.07-7.01 (m, 1H), 6.97 (d, J=8.8Hz, 2H), 6.75 (s, 1H), 3.87 (s, 3H),
3.78 (d, J=14.0Hz, 1H), 3.60 (d, J=14.0Hz, 1H), 3.29 (s, 3H), 1.88 (s, 3H), 1.52 (s, 9H)
Step 2) (R) -5- (3- ((4- (4- methoxyphenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5- two
Methyl-1, the synthesis of 2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (3- ((4- (4- methoxyphenyl) thiazol-2-yl) amino) phenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two
Piperazine -3- methylene) carbamate (361mg, 0.65mmol), Hydrochloride/ethyl acetate (2mL, 4M) is in methylene chloride
Reaction preparation, crude product obtain title through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in (5mL)
Compound is yellow solid (0.243g, 82.0%).
MS(ESI,pos.ion)m/z:458.1[M+H]+;
1H NMR(400MHz,DMSO-d6) δ (ppm) 10.26 (s, 1H), 7.98 (dd, J=8.8,5.6Hz, 2H), 7.78
(s, 1H), 7.61 (dd, J=8.0,1.4Hz, 1H), 7.34-7.22 (m, 4H), 7.09 (d, J=7.9Hz, 1H), 3.90 (d, J
=13.9Hz, 1H), 3.81 (s, 3H), 3.63 (brs, 1H), 3.08 (s, 3H), 1.58 (s, 3H)
Embodiment 10 (R) -5- (3- ((4- (4- cyano-phenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5- two
Methyl-1, the synthesis of 2,4- thiadiazine 1,1- dioxo compound
Step 1) (R)-tert-butyl (5- (3- ((4- (4- cyano-phenyl) thiazol-2-yl) amino) phenyl) -2,5- diformazan
Base -1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(2,5- dimethyl -1,1- dioxo -5- (3- thiocarbamide phenyl) -1,2,4- thiadiazine -3- methylene) carbamate (200mg,
0.47mmol) prepared with the bromo- 1- of 2- (4- cyano-phenyl) ethyl ketone (104mg, 0.46mmol) reaction in ethyl alcohol (5mL), it is thick to produce
For object through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1), obtaining title compound is yellow solid
(0.193g, 74.6%).
MS(ESI,pos.ion)m/z:553.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 10.63 (s, 1H), 7.95 (d, J=8.5Hz, 2H), 7.73 (d, J=
8.5Hz, 2H), 7.62 (d, J=12.3Hz, 2H), 7.47-7.39 (m, 2H), 7.01 (s, 1H), 3.94 (d, J=14.0Hz,
1H), 3.75 (t, J=11.9Hz, 1H), 3.30 (s, 3H), 1.96 (s, 3H), 1.62 (s, 9H)
Step 2) (R) -5- (3- ((4- (4- cyano-phenyl) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5- diformazan
The synthesis of base -1,2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (3- ((4- (4- cyano-phenyl) thiazol-2-yl) amino) phenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two
Piperazine -3- methylene) carbamate (193mg, 0.35mmol), Hydrochloride/ethyl acetate (2mL, 4M) is in methylene chloride
Reaction preparation, crude product obtain title through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in (5mL)
Compound is white solid (0.118g, 74.7%).
MS(ESI,pos.ion)m/z:453.2[M+H]+;
1H NMR(400MHz,DMSO-d6) δ (ppm) 10.26 (s, 1H), 7.98 (dd, J=8.8,5.6Hz, 2H), 7.78
(s, 1H), 7.61 (dd, J=8.0,1.4Hz, 1H), 7.34-7.22 (m, 4H), 7.09 (d, J=7.9Hz, 1H), 3.90 (d, J
=13.9Hz, 1H), 3.63 (brs, 1H), 3.08 (s, 3H), 1.58 (s, 3H)
Embodiment 11 (R)-5- (3- ((4- (5- fluorine pyridine-2- base) thiazol-2-yl) amino) phenyl) imido grpup-2-3-,
The synthesis of 5- dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
Step 1) (R)-tert-butyl (5- (3- ((4- (5- fluorine pyridine -2- base) thiazol-2-yl) amino) phenyl) -2,5- two
Methyl-1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(2,5- dimethyl -1,1- dioxo -5- (3- thiocarbamide phenyl) -1,2,4- thiadiazine -3- methylene) carbamate (200mg,
It 0.47mmol) is prepared with the reaction in ethyl alcohol (5mL) of the bromo- 1- of 2- (5- fluorine pyridine -2- base) ethyl ketone (132mg, 0.61mmol), slightly
For product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1), obtaining title compound is yellow solid
(0.245g, 95.8%).
MS(ESI,pos.ion)m/z:547.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 10.64 (s, 1H), 8.46 (d, J=2.8Hz, 1H), 7.99 (dd, J=
8.7,4.5Hz, 1H), 7.66 (s, 1H), 7.51 (td, J=8.5,2.9Hz, 1H), 7.43-7.35 (m, 3H), 7.09-7.02
(m, 1H), 3.92 (d, J=12.4Hz, 1H), 3.72 (d, J=14.0Hz, 1H), 3.30 (s, 3H), 1.96 (s, 3H), 1.60
(s,9H).
Step 2) (R) -5- (3- ((4- (5- fluorine pyridine -2- base) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5-
The synthesis of dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (3- ((4- (5- fluorine pyridine -2- base) thiazol-2-yl) amino) phenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene
Diazine -3- methylene) carbamate (245mg, 0.45mmol), Hydrochloride/ethyl acetate (2mL, 4M) is in methylene chloride
Reaction preparation, crude product obtain title through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in (5mL)
Compound is white solid (0.115g, 57.5%).
MS(ESI,pos.ion)m/z:446.1[M+H]+;
1H NMR(400MHz,DMSO-d6) δ (ppm) 10.26 (s, 1H), 7.98 (dd, J=8.8,5.6Hz, 2H), 7.78
(s, 1H), 7.61 (dd, J=8.0,1.4Hz, 1H), 7.34-7.22 (m, 4H), 7.09 (d, J=7.9Hz, 1H), 3.90 (d, J
=13.9Hz, 1H), 3.63 (brs, 1H), 3.08 (s, 3H), 1.58 (s, 3H)
Embodiment 12 (R)-5- (3- ((4- (5- chloropyridine-2- base) thiazol-2-yl) amino) phenyl) imido grpup-2-3-,
The synthesis of 5- dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
Step 1) (R)-tert-butyl (5- (3- ((4- (5- chloropyridine -2- base) thiazol-2-yl) amino) phenyl) -2,5- two
Methyl-1,1- dioxo -1,2,4- thiadiazine -3- methylene) carbamate synthesis
This step title compound method referring to described in 1 step 11 of embodiment is prepared, i.e., by (R)-tert-butyl
(2,5- dimethyl -1,1- dioxo -5- (3- thiocarbamide phenyl) -1,2,4- thiadiazine -3- methylene) carbamate (200mg,
It 0.47mmol) is prepared with the reaction in ethyl alcohol (5mL) of the bromo- 1- of 2- (5- chloropyridine -2- base) ethyl ketone (142mg, 0.61mmol), slightly
For product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=6/1), obtaining title compound is pale yellow colored solid
Body (0.171g, 64.9%).
MS(ESI,pos.ion)m/z:563.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 10.64 (s, 1H), 8.55 (d, J=2.2Hz, 1H), 7.92 (d, J=
8.4Hz, 1H), 7.77 (dd, J=8.5,2.4Hz, 1H), 7.67 (s, 1H), 7.43 (d, J=6.7Hz, 1H), 7.39 (dd, J=
7.7,4.9Hz, 2H), 7.09-7.02 (m, 1H), 3.94 (d, J=14.0Hz, 1H), 3.75-3.73 (m, 1H), 3.30 (s,
3H),1.96(s,3H),1.59(s,9H).
Step 2) (R) -5- (3- ((4- (5- chloropyridine -2- base) thiazol-2-yl) amino) phenyl) -3- imido grpup -2,5-
The synthesis of dimethyl -1,2,4- thiadiazine 1,1- dioxo compound
This step title compound method referring to described in 1 step 12 of embodiment is prepared, i.e., by (R)-tert-butyl
(5- (3- ((4- (5- chloropyridine -2- base) thiazol-2-yl) amino) phenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene
Diazine -3- methylene) carbamate (293mg, 0.52mmol), Hydrochloride/ethyl acetate (2mL, 4M) is in methylene chloride
Reaction preparation, crude product are marked through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) in (10mL)
Topic compound is yellow solid (0.142g, 58.9%).
MS(ESI,pos.ion)m/z:463.1[M+H]+;
1H NMR(400MHz,DMSO-d6) δ (ppm) 10.26 (s, 1H), 7.98 (dd, J=8.8,5.6Hz, 2H), 7.78
(s, 1H), 7.61 (dd, J=8.0,1.4Hz, 1H), 7.34-7.22 (m, 4H), 7.09 (d, J=7.9Hz, 1H), 3.90 (d, J
=13.9Hz, 1H), 3.63 (brs, 1H), 3.08 (s, 3H), 1.58 (s, 3H)
Biologic test
Embodiment A:BACE-1 inhibitor enzyme level external activity evaluation method
Experimental method
1.1X assay buffer and test-compound are prepared
(1)1X assay buffer(20nM PIPES,pH5.0;0.1%Brij-35;10%Glycerol)
(2) test-compound is prepared
Test-compound is diluted to respectively by 1mM using 100%DMSO, control compound MK-8931 is diluted to 100 μM.
45 μ L, 1mM test-compound solution and 100 μM of MK- are separately added into 384 orifice plate of Echo (Labcyte, P-05525)
8931 solution.Test-compound is diluted 9 times with 3 times of dilution gradient precisions.Pass through (550 sound wave of Labcyte echo of Echo 550
Liquor-transferring system equipment) by 100nL test-compound solution from starting sheet be transferred to test board (PerkinElmer,
Cat.No.6008289).Into control wells, 100nL DMSO is added.DMSO final concentration of 1% in all holes.
2.BACE-1 enzyme solutions are prepared
(1) BACE-1 enzyme solutions are prepared using 1X assay buffer, concentration is twice of final concentration of test, and test is dense eventually
Degree is 3nM.
(2) using electronic multichannel pipettor, 5 μ L BACE-1 enzyme solutions, solution rapid centrifugation is added in every hole in test board.
(3) it is incubated at room temperature 15min.
3.2X APP substrate solution is prepared
(1) APP substrate solution is prepared using 1X assay buffer, solution concentration is twice of final concentration of test.
Final concentration: Biotin-APP substrate-K 25nM;5 μM of non-biotinylation and unmarked APP substrate.
(2) using electronic multichannel pipettor, 5 μ L APP substrate solutions are added in every hole in test board, start to react.
(3) solution rapid centrifugation.
4. reaction
After sealing test plate, in 28 DEG C of incubation 4h.
5.Homogeneous Time-Resolved Fluorescence (HTRF) detection
(1) prepare 2X detection buffer (25mM Tris-HCl, pH 8.0;0.0005%Brij-35;250mM
KF)
(2) Streptavidin-XLent solution is prepared using 2X detection buffer, concentration is test final concentration
2 times of (10 μ g/mL).
(3) use electronic multichannel pipettor that 10 μ L Streptavidin-XLent solution are added with end in the every hole of test board
Only react.
(4) after centrifuge quickly mixes, in 25 DEG C of balance 60min.
6. collecting data
Data are collected in EnVison software.
7. data are analyzed
(1) HTRF fluorescence ratio (665nm/615nm*10000) is copied out from EnVison software.
(2) HTRF fluorescence ratio is converted into percentage inhibiting value.Maximum value and minimum value are handled: numerical value is more than
Avg ± 3SD is considered as deviation value.The ratio that deviation value is deleted controls within 20%.
A. inhibiting rate=(sample ratio-minimum value)/(maximum value-minimum value) * 100
B. minimum value is the HTRF fluorescence ratio of BACE-1 enzyme and APP substrate, and maximum value is the bottom assay buffer and APP
The HTRF ratio of object.
(3) data are fitted with the presentation of Excel form, curve using GraphPad Prism 5.
(4) each compound IC50Value, which calculates, uses 5 four parameter fitting model of GraphPad Prism:
Y=Bottom+ (Top-Bottom)/(1+ (IC50/ X) ^HillSlope), Y is % inhibiting rate, and X is that compound is dense
Degree.
It the results are shown in Table A.
Table A the compounds of this invention is to BACE-1 enzyme level In-vitro Inhibitory Effect test result
Example No. | IC50(μM) | Example No. | IC50(μM) |
Embodiment 1 | 3.55 | Embodiment 7 | 8.79 |
Embodiment 2 | 8.01 | Embodiment 9 | 9.31 |
Embodiment 3 | 3.14 | Embodiment 10 | 4.58 |
Embodiment 4 | 2.29 | Embodiment 11 | 2.46 |
Embodiment 5 | 0.91 | Embodiment 12 | 3.81 |
Embodiment 6 | 1.38 | -- | -- |
Experimental result shows that the compounds of this invention has preferable BACE-1 inhibiting effect.
In the description of this specification, reference term " one embodiment ", " embodiment ", " some embodiments ", " show
The description of example ", specific examples or " some examples " etc. means to combine the specific spy of the embodiment, embodiment or example description
Sign, structure, material or feature are contained at least one embodiment of the present invention, embodiment or example.In this specification
In, schematic expression of the above terms are necessarily directed to identical embodiment, embodiment or example.Moreover, description
Particular features, structures, materials, or characteristics can be in any one or more embodiments, embodiment or example with suitable
Mode combines.In addition, without conflicting with each other, those skilled in the art can be by difference described in this specification
Embodiment, embodiment or example and different embodiments, embodiment or exemplary feature are combined.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, modifies, replacement and variant.
Claims (10)
1. a kind of compound is compound shown in formula (I) or formula (I ') compound represented or formula (I) or formula (I ')
Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or it
Prodrug,
Wherein:
X is CRxOr N;
Y is S, O or NH;
Z is CH or N;
R1a、R1b、R1c、R1dAnd RxIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、-COOH、-C
(=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy),
C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkane sulphur
Base, C1-C6The C that alkylamino, hydroxyl replace1-C6Alkyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C6-C10Aryl or 5-10 member are miscellaneous
Aryl;
R1eFor H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Alkyl halide
Base, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl;
R2And R3It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkane
Base, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl;
R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Alkyl halide
Base, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl;
R5For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Alkyl halide
Base, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl;
R6And R7It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkane
Base, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl;With
R8For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Alkyl halide
Base, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
2. compound according to claim 1, wherein R1a、R1b、R1c、R1dAnd RxBe each independently H, D, F, Cl, Br,
I、-CN、-NO2、-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-
(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-
C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4The C that alkylamino, hydroxyl replace1-C4Alkyl, C3-C6Naphthenic base,
3-6 circle heterocyclic ring base, C6-C10Aryl or 5-10 unit's heteroaryl.
3. compound according to claim 1 or 2, wherein R1a、R1b、R1c、R1dAnd RxBe each independently H, D, F, Cl,
Br、I、-CN、-NO2、-NH2,-OH ,-SH ,-COOH ,-C (=O) NH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=
O)-CH3,-C (=O)-OCH3, methyl, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propinyl ,-
CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl
Oxygroup ,-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2, methyl mercapto, ethylmercapto group, first ammonia
Base, dimethylamino, ethylamino, methylol, 2- hydroxyethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, azelidinyl,
Pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals,
Triazol radical, tetrazole base, furyl, thienyl, thiazolyl, oxazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzene
And imidazole radicals, indyl or quinolyl.
4. compound according to claim 1, wherein R1eFor H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-
COOH ,-C (=O) NH2、C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4What halogenated alkoxy or hydroxyl replaced
C1-C4Alkyl;
R2And R3It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C4Alkane
Base, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl;
R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C4Alkyl, C1-C4Alkyl halide
Base, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl;
R5For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C4Alkyl, C1-C4Alkyl halide
Base, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl;
R6And R7It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C4Alkane
Base, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl;
R8For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C4Alkyl, C1-C4Alkyl halide
Base, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl.
5. compound according to claim 1 or 4, wherein R1eFor H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-
COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup
Or isopropyl oxygroup;
R2And R3It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, methyl, second
Base, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup;
R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl
Base ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup;
R5For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl
Base ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup;
R6And R7It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, methyl, second
Base, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup;
R8For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl
Base ,-CF3、-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
6. compound according to claim 1, be formula (II) or formula (II ') compound represented or formula (II) or
Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, the medicine of compound shown in formula (II ')
Acceptable salt or its prodrug on,
7. compound according to claim 1 or 6 for the compound with one of following structure or has one of following
The stereoisomer of the compound of structure, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically
Acceptable salt or its prodrug:
8. a kind of pharmaceutical composition includes compound described in claim 1-7 any one;With
The pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or their times
Meaning combination.
9. pharmaceutical composition according to claim 8, optionally further includes additional therapeutic agent, wherein described is attached
Adding therapeutic agent is nalmefene, Risperidone, Rivastigmine, Memantine, mitzapine, Venlafaxine, desipramine, nortriptyline, azoles
Pyrrole is smooth, zopiclone, Nicergoline, Piracetam, selegiline, pentoxifylline, Tacrine, donepezil, galanthamine,
Rivastigmine, vitamin e, fibrates, niacin, nicotinic receptor agonist, nicotinic acetylcholine receptors alpha7, choline
Esterase inhibitor, N-methyl-D-aspartate receptor antagonist, the promotor of α secretase activity, glycogen synthase kinase β suppression
Preparation, the inhibitor of amyloid aggregation, gamma-secretase inhibitors, gamma secretase modulators, histamine H 3 antagonists, histone
Deacetylase inhibitors, PDE-4 inhibitor, PDE-10 inhibitor, mGluR1 receptor modulators or antagonist, mGluR5 receptor
Regulator or antagonist, mGluR2/3 antagonist, 5-HT4Agonist, 5-HT6Receptor antagonist or GABAAInverse agonist.
10. pharmaceutical composition described in compound described in claim 1-7 any one or claim 8-9 any one exists
The purposes in drug is prepared, the drug is for preventing, treating or mitigating disease related with beta-amyloid protein;
Wherein, the disease related with beta-amyloid protein is dementia, senile dementia, Ahl tribulus sea silent sickness, Parkinson's disease
And/or the relevant dementia of Down syndrome, Down syndrome, attention deficit symptom, Ahl tribulus sea silent sickness, Parkinson's disease
And/or the relevant attention deficit symptom of Down syndrome, the loss of memory, the loss of memory relevant to Parkinson's disease, with A Er
The relevant loss of memory of Ci Haimo disease, apoplexy, neurodegeneration, amyloidosis, beta amyloid angiosis, Cerebral Amyloid blood vessel
Disease, hereditary cerebral hemorrhage, complication of hemodialysis, glaucoma, type-2 diabetes mellitus, the relevant amyloid of diabetes generate,
Traumatic brain injury, bovine spongiform encephalopathy, mild cognitive impairment or Alzheimer disease.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811035271.5A CN109180669B (en) | 2018-09-06 | 2018-09-06 | Iminothiadiazine dioxide derivatives and their use |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811035271.5A CN109180669B (en) | 2018-09-06 | 2018-09-06 | Iminothiadiazine dioxide derivatives and their use |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109180669A true CN109180669A (en) | 2019-01-11 |
CN109180669B CN109180669B (en) | 2022-05-27 |
Family
ID=64914823
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811035271.5A Active CN109180669B (en) | 2018-09-06 | 2018-09-06 | Iminothiadiazine dioxide derivatives and their use |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109180669B (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102639135A (en) * | 2009-10-08 | 2012-08-15 | 先灵公司 | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
WO2017095759A1 (en) * | 2015-12-04 | 2017-06-08 | Merck Sharp & Dohme Corp. | C5-c6-carbocyclic fused iminothiadiazine dioxides as bace inhibitors, compositions, and their use |
-
2018
- 2018-09-06 CN CN201811035271.5A patent/CN109180669B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102639135A (en) * | 2009-10-08 | 2012-08-15 | 先灵公司 | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
WO2017095759A1 (en) * | 2015-12-04 | 2017-06-08 | Merck Sharp & Dohme Corp. | C5-c6-carbocyclic fused iminothiadiazine dioxides as bace inhibitors, compositions, and their use |
Also Published As
Publication number | Publication date |
---|---|
CN109180669B (en) | 2022-05-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2006212761B2 (en) | Combination therapy | |
KR101419157B1 (en) | Pyrazine derivatives and their use in the treatment of neurological disorders | |
CN110437205A (en) | Pyridine alkenyl piperidine derivative and application thereof | |
CA2913223A1 (en) | Pyrazolopyrrolidine derivatives and their use in the treatment of disease | |
CN102264743A (en) | Mlk inhibitors and methods of use | |
CN106243088B (en) | Substituted diethylenediamine compound and its application method and purposes | |
JP2015534993A (en) | MGlu2 / 3 antagonists for the treatment of autistic disorders | |
US10428054B2 (en) | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof | |
CN111004214B (en) | Pyridylpiperidine derivatives and use thereof | |
CN106008488A (en) | Cyan indoles derivative and preparation method and use thereof | |
CN101925596A (en) | Beta-amino acid derivatives for treatment of diabetes | |
CN110240557A (en) | Pyrrolidine derivative and application thereof | |
CN110272425A (en) | Pyridine acyl octahydro pyrrolo- [3,4-c] azole derivatives and application thereof | |
CN109180670A (en) | Imino group thiadiazine dioxide derivative and application thereof | |
CN109251155A (en) | Alpha-aminoamide derivatives and application thereof | |
CN106349228B (en) | Substituted quianzolinones and its preparation method and application | |
CN109988170A (en) | Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof | |
CN108997328A (en) | Imino group thiadiazine dioxide derivative and application thereof | |
CN108863983A (en) | Imino group thiadiazine dioxide derivative and application thereof | |
CN109796447A (en) | Imino group thiadiazine dioxide derivative and application thereof | |
CN109180669A (en) | Imino group thiadiazine dioxide derivative and application thereof | |
CN109734712A (en) | The pyrrolidine derivative and application thereof that aryl or heteroaryl replace | |
CN109180671A (en) | Imino group thiadiazine dioxide derivative and application thereof | |
CN112010818B (en) | Morpholinamide derivatives and uses thereof | |
CN110467611A (en) | Imino group thiadiazine dioxide derivative and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CP03 | Change of name, title or address |
Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |
|
CP03 | Change of name, title or address |