EA019892B1 - Ингибиторы bace - Google Patents
Ингибиторы bace Download PDFInfo
- Publication number
- EA019892B1 EA019892B1 EA201270149A EA201270149A EA019892B1 EA 019892 B1 EA019892 B1 EA 019892B1 EA 201270149 A EA201270149 A EA 201270149A EA 201270149 A EA201270149 A EA 201270149A EA 019892 B1 EA019892 B1 EA 019892B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- mmol
- thiazin
- racemic
- fluorophenyl
- mixture
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 13
- 101150058765 BACE1 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 269
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 230000008520 organization Effects 0.000 claims 1
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 abstract description 34
- 102100021257 Beta-secretase 1 Human genes 0.000 abstract description 29
- 238000011282 treatment Methods 0.000 abstract description 20
- -1 hydroxyethyl moiety Chemical group 0.000 description 307
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 177
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 151
- 239000000203 mixture Substances 0.000 description 135
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 122
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 120
- 238000002360 preparation method Methods 0.000 description 118
- 238000000034 method Methods 0.000 description 84
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 73
- 239000011541 reaction mixture Substances 0.000 description 71
- 239000000243 solution Substances 0.000 description 67
- CFEYOSPJMWYBRK-UHFFFAOYSA-N 2H-1,3-thiazin-2-ylcarbamic acid Chemical compound OC(=O)NC1SC=CC=N1 CFEYOSPJMWYBRK-UHFFFAOYSA-N 0.000 description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- 239000000126 substance Substances 0.000 description 50
- 239000002904 solvent Substances 0.000 description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 239000012044 organic layer Substances 0.000 description 39
- 238000010898 silica gel chromatography Methods 0.000 description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 36
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- 238000005481 NMR spectroscopy Methods 0.000 description 33
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- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 32
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- 229910052736 halogen Inorganic materials 0.000 description 27
- 125000004076 pyridyl group Chemical group 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
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- 238000006243 chemical reaction Methods 0.000 description 25
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 14
- 239000012458 free base Substances 0.000 description 14
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- 230000002401 inhibitory effect Effects 0.000 description 13
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- 125000005336 allyloxy group Chemical group 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
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- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000007790 solid phase Substances 0.000 description 11
- MCPRYBIHGJROPH-UHFFFAOYSA-N 2H-1,3-thiazin-2-amine dihydrochloride Chemical compound Cl.Cl.S1C(N=CC=C1)N MCPRYBIHGJROPH-UHFFFAOYSA-N 0.000 description 10
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 10
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- 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 8
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22424109P | 2009-07-09 | 2009-07-09 | |
| PCT/US2010/041034 WO2011005738A1 (en) | 2009-07-09 | 2010-07-06 | Bace inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201270149A1 EA201270149A1 (ru) | 2012-06-29 |
| EA019892B1 true EA019892B1 (ru) | 2014-07-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201270149A EA019892B1 (ru) | 2009-07-09 | 2010-07-06 | Ингибиторы bace |
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| EP (1) | EP2451793B1 (OSRAM) |
| JP (1) | JP5666578B2 (OSRAM) |
| KR (1) | KR101362557B1 (OSRAM) |
| CN (1) | CN102471296B (OSRAM) |
| AR (1) | AR077277A1 (OSRAM) |
| AU (1) | AU2010270691B8 (OSRAM) |
| BR (1) | BR112012000525A2 (OSRAM) |
| CA (1) | CA2764429C (OSRAM) |
| CL (1) | CL2012000033A1 (OSRAM) |
| CO (1) | CO6480979A2 (OSRAM) |
| CR (1) | CR20120011A (OSRAM) |
| DO (1) | DOP2012000004A (OSRAM) |
| EA (1) | EA019892B1 (OSRAM) |
| EC (1) | ECSP12011581A (OSRAM) |
| HN (1) | HN2012000012A (OSRAM) |
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| PE (1) | PE20120632A1 (OSRAM) |
| SG (1) | SG177594A1 (OSRAM) |
| TN (1) | TN2011000673A1 (OSRAM) |
| TW (1) | TWI405765B (OSRAM) |
| WO (1) | WO2011005738A1 (OSRAM) |
| ZA (1) | ZA201109385B (OSRAM) |
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- 2012-08-16 US US13/587,161 patent/US20120323001A1/en not_active Abandoned
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008133273A1 (ja) * | 2007-04-24 | 2008-11-06 | Shionogi & Co., Ltd. | アルツハイマー症治療用医薬組成物 |
| US20090209755A1 (en) * | 2008-01-18 | 2009-08-20 | Yuichi Suzuki | Fused aminodihydrothiazine derivatives |
| US20100093999A1 (en) * | 2008-09-30 | 2010-04-15 | Eisai R&D Management Co., Ltd. | Novel fused aminodihydrothiazine derivative |
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| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): AM AZ BY KZ KG MD TJ TM RU |