AU2010270691B8 - BACE inhibitors - Google Patents
BACE inhibitors Download PDFInfo
- Publication number
- AU2010270691B8 AU2010270691B8 AU2010270691A AU2010270691A AU2010270691B8 AU 2010270691 B8 AU2010270691 B8 AU 2010270691B8 AU 2010270691 A AU2010270691 A AU 2010270691A AU 2010270691 A AU2010270691 A AU 2010270691A AU 2010270691 B8 AU2010270691 B8 AU 2010270691B8
- Authority
- AU
- Australia
- Prior art keywords
- thiazin
- mmol
- racemic
- fluorophenyl
- bromo
- 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.)
- Ceased
Links
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 title abstract description 29
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- CZPYPWDKUTWCHV-UHFFFAOYSA-N n-[(4-methoxyphenyl)methyl]hydroxylamine Chemical compound COC1=CC=C(CNO)C=C1 CZPYPWDKUTWCHV-UHFFFAOYSA-N 0.000 description 1
- UQPLOYDUXPVRPX-IHTKTJBKSA-N n-[(4ar,6r,7as)-6-(methoxymethoxy)-7a-[3-(3-methoxyphenyl)phenyl]-4a,5,6,7-tetrahydro-4h-cyclopenta[d][1,3]thiazin-2-yl]benzamide Chemical compound C([C@@H]1C[C@H](C[C@@]1(N=1)C=2C=C(C=CC=2)C=2C=C(OC)C=CC=2)OCOC)SC=1NC(=O)C1=CC=CC=C1 UQPLOYDUXPVRPX-IHTKTJBKSA-N 0.000 description 1
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- BHEUTVZNPWEQEK-SSOJOUAXSA-N n-[3-[(4as,7as)-2-benzamido-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-5-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound N1=CC(F)=CC=C1C(=O)NC1=CC(F)=CC([C@@]23[C@@H](COC2)CSC(NC(=O)C=2C=CC=CC=2)=N3)=C1 BHEUTVZNPWEQEK-SSOJOUAXSA-N 0.000 description 1
- MRZHEMLVOOVESZ-UHFFFAOYSA-N n-[[1-(3-bromo-4-fluorophenyl)-4-hydroxy-2-(hydroxymethyl)cyclopentyl]carbamothioyl]benzamide Chemical compound OCC1CC(O)CC1(C=1C=C(Br)C(F)=CC=1)NC(=S)NC(=O)C1=CC=CC=C1 MRZHEMLVOOVESZ-UHFFFAOYSA-N 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
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- 229920001184 polypeptide Polymers 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- HZFPPBMKGYINDF-UHFFFAOYSA-N pyrimidin-5-ylboronic acid Chemical compound OB(O)C1=CN=CN=C1 HZFPPBMKGYINDF-UHFFFAOYSA-N 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000007617 synaptic impairment Effects 0.000 description 1
- 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 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- FFCAFNFURCALGK-KPZWWZAWSA-N tert-butyl n-[(4ar,7as)-7a-(4-fluoro-3-hydroxyphenyl)-4a,5,6,7-tetrahydro-4h-cyclopenta[d][1,3]thiazin-2-yl]carbamate Chemical compound C1([C@@]23N=C(SC[C@@H]2CCC3)NC(=O)OC(C)(C)C)=CC=C(F)C(O)=C1 FFCAFNFURCALGK-KPZWWZAWSA-N 0.000 description 1
- FFCAFNFURCALGK-VMHBGOFLSA-N tert-butyl n-[(7as)-7a-(4-fluoro-3-hydroxyphenyl)-4a,5,6,7-tetrahydro-4h-cyclopenta[d][1,3]thiazin-2-yl]carbamate Chemical compound C1([C@@]23N=C(SCC2CCC3)NC(=O)OC(C)(C)C)=CC=C(F)C(O)=C1 FFCAFNFURCALGK-VMHBGOFLSA-N 0.000 description 1
- RLHPAPFTMFYTHC-JDMGRSRBSA-N tert-butyl n-[(8as)-8a-(2,4-difluoro-5-pyrimidin-5-ylphenyl)-4a,5,7,8-tetrahydro-4h-pyrano[4,3-d][1,3]thiazin-2-yl]carbamate Chemical compound FC=1C=C(F)C([C@@]23N=C(SCC2COCC3)NC(=O)OC(C)(C)C)=CC=1C1=CN=CN=C1 RLHPAPFTMFYTHC-JDMGRSRBSA-N 0.000 description 1
- PGTWLCZXAUHFFV-UHFFFAOYSA-N tert-butyl n-[7a-(4-fluoro-3-methoxyphenyl)-4a,5,6,7-tetrahydro-4h-cyclopenta[d][1,3]thiazin-2-yl]carbamate Chemical compound C1=C(F)C(OC)=CC(C23C(CCC2)CSC(NC(=O)OC(C)(C)C)=N3)=C1 PGTWLCZXAUHFFV-UHFFFAOYSA-N 0.000 description 1
- GGJDCPLLJXZFFW-UHFFFAOYSA-N tert-butyl n-[7a-[2-fluoro-5-[(5-fluoropyridine-2-carbonyl)amino]phenyl]-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-2-yl]carbamate Chemical compound C1OCC2CSC(NC(=O)OC(C)(C)C)=NC21C(C(=CC=1)F)=CC=1NC(=O)C1=CC=C(F)C=N1 GGJDCPLLJXZFFW-UHFFFAOYSA-N 0.000 description 1
- VMIGUHIVSCWKQH-UHFFFAOYSA-N tert-butyl n-[8a-(5-bromo-2,4-difluorophenyl)-4a,5,7,8-tetrahydro-4h-pyrano[4,3-d][1,3]thiazin-2-yl]carbamate Chemical compound C1COCC2CSC(NC(=O)OC(C)(C)C)=NC21C1=CC(Br)=C(F)C=C1F VMIGUHIVSCWKQH-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- RMNIZOOYFMNEJJ-UHFFFAOYSA-K tripotassium;phosphate;hydrate Chemical compound O.[K+].[K+].[K+].[O-]P([O-])([O-])=O RMNIZOOYFMNEJJ-UHFFFAOYSA-K 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
-
- 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)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22424109P | 2009-07-09 | 2009-07-09 | |
| US61/224,241 | 2009-07-09 | ||
| PCT/US2010/041034 WO2011005738A1 (en) | 2009-07-09 | 2010-07-06 | Bace inhibitors |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| AU2010270691A1 AU2010270691A1 (en) | 2011-12-22 |
| AU2010270691B2 AU2010270691B2 (en) | 2013-08-01 |
| AU2010270691B8 true AU2010270691B8 (en) | 2013-11-28 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2010270691A Ceased AU2010270691B8 (en) | 2009-07-09 | 2010-07-06 | BACE inhibitors |
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| US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
| JP5281794B2 (ja) | 2005-10-25 | 2013-09-04 | 塩野義製薬株式会社 | アミノジヒドロチアジン誘導体 |
| EP2147914B1 (en) | 2007-04-24 | 2014-06-04 | Shionogi&Co., Ltd. | Aminodihydrothiazine derivatives substituted with cyclic groups |
| EP2151435A4 (en) | 2007-04-24 | 2011-09-14 | Shionogi & Co | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
| MY160690A (en) | 2008-01-18 | 2017-03-15 | Eisai R&D Man Co Ltd | Condensed aminodihydrothiazine derivative |
| JP5490692B2 (ja) | 2008-06-13 | 2014-05-14 | 塩野義製薬株式会社 | βセクレターゼ阻害作用を有する含硫黄複素環誘導体 |
| KR20110048491A (ko) * | 2008-07-28 | 2011-05-11 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 스피로아미노디하이드로티아진 유도체들 |
| US8198269B2 (en) * | 2008-09-30 | 2012-06-12 | Eisai R&D Management Co., Ltd. | Fused aminodihydrothiazine derivative |
| WO2010047372A1 (ja) | 2008-10-22 | 2010-04-29 | 塩野義製薬株式会社 | Ｂａｃｅ１阻害活性を有する２－アミノピリミジン－４－オンおよび２－アミノピリジン誘導体 |
| GB0912778D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydro-oxazine derivatives |
| GB0912777D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydropyrimidone derivatives |
| EP2485590B1 (en) | 2009-10-08 | 2015-01-07 | Merck Sharp & Dohme Corp. | Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use |
| UA108363C2 (uk) | 2009-10-08 | 2015-04-27 | Похідні імінотіадіазиндіоксиду як інгібітори bace, композиція на їх основі і їх застосування | |
| WO2011044185A2 (en) | 2009-10-08 | 2011-04-14 | Schering Corporation | Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use |
| WO2011044187A1 (en) | 2009-10-08 | 2011-04-14 | Schering Corporation | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| WO2011071109A1 (ja) * | 2009-12-11 | 2011-06-16 | 塩野義製薬株式会社 | アミノ基を有する縮合ヘテロ環化合物 |
| UA110467C2 (uk) | 2009-12-11 | 2016-01-12 | Шионогі Енд Ко., Лтд. | Похідні оксазину |
| JP5711813B2 (ja) | 2010-06-09 | 2015-05-07 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプＪａｎｓｓｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａ Ｎａａｍｌｏｚｅ Ｖｅｎｎｏｏｔｓｃｈａｐ | βセクレターゼ（ＢＡＣＥ）の阻害剤として有用な５，６−ジヒドロ−２Ｈ−［１，４］オキサジン−３−イル−アミン誘導体 |
| EP2634188A4 (en) | 2010-10-29 | 2014-05-07 | Shionogi & Co | FUSIONED AMINODIHYDROPYRIMIDINE DERIVATIVE |
| EP2634186A4 (en) | 2010-10-29 | 2014-03-26 | Shionogi & Co | naphthyridine |
| WO2012085038A1 (en) | 2010-12-22 | 2012-06-28 | Janssen Pharmaceutica Nv | 5,6-DIHYDRO-IMIDAZO[1,2-a]PYRAZIN-8-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE) |
| GB201100181D0 (en) * | 2011-01-06 | 2011-02-23 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| CN106632401B (zh) | 2011-01-21 | 2020-12-29 | 卫材R&D管理有限公司 | 用于稠合氨基二氢噻嗪衍生物的合成的方法和化合物 |
| GB201101139D0 (en) | 2011-01-21 | 2011-03-09 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| GB201101140D0 (en) * | 2011-01-21 | 2011-03-09 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
| EA023824B1 (ru) | 2011-03-09 | 2016-07-29 | Янссен Фармацевтика Нв | ПРОИЗВОДНЫЕ 3,4-ДИГИДРОПИРРОЛО[1,2-a]ПИРАЗИН-1-ИЛАМИНА, ПРИГОДНЫЕ В КАЧЕСТВЕ ИНГИБИТОРОВ БЕТА-СЕКРЕТАЗЫ (BACE) |
| EP2694489B1 (en) | 2011-04-07 | 2017-09-06 | Merck Sharp & Dohme Corp. | C5-c6 oxacyclic-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| EP2694521B1 (en) | 2011-04-07 | 2015-11-25 | Merck Sharp & Dohme Corp. | Pyrrolidine-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| CN103608345A (zh) | 2011-04-26 | 2014-02-26 | 盐野义制药株式会社 | 噁嗪衍生物和含有该噁嗪衍生物的bace1抑制剂 |
| US8604024B2 (en) | 2011-05-24 | 2013-12-10 | Bristol-Myers Squibb Company | Compounds for the reduction of beta-amyloid production |
| AR086539A1 (es) | 2011-05-24 | 2014-01-08 | Bristol Myers Squibb Co | COMPUESTOS PARA LA REDUCCION DE LA PRODUCCION DE b-AMILOIDE |
| US8927535B2 (en) * | 2011-07-06 | 2015-01-06 | Hoffman-La Roche Inc. | Cyclopropyl-fused-1,3-thiazepines as BACE1 and/or BACE2 inhibitors |
| JP2014524472A (ja) | 2011-08-22 | 2014-09-22 | メルク・シャープ・アンド・ドーム・コーポレーション | Ｂａｃｅ阻害剤としての２−スピロ置換イミノチアジンならびにそのモノオキシドおよびジオキシド、組成物、ならびにそれらの使用 |
| JP6043355B2 (ja) | 2011-08-31 | 2016-12-14 | ファイザー・インク | ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物 |
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