CA2694209C - Azepine derivatives as gamma-secretase inhibitors - Google Patents

Azepine derivatives as gamma-secretase inhibitors Download PDF

Info

Publication number: CA2694209C
Authority: CA; Canada
Prior art keywords: methyl; compound; phenyl; compounds; azepin
Prior art date: 2007-08-14
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.): Expired - Fee Related

Application number

CA2694209A

Other languages

English (en)

French (fr)

Other versions

CA2694209A1 (en

Inventor

Melinda Joy Hope Miller

Warren Jaye Porter

Jon Kevin Reel

Almudena Rubio-Esteban

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Eli Lilly and Co

Original Assignee

Eli Lilly and Co

Priority date (The priority date 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 date listed.)

2007-08-14

Filing date

2008-08-04

Publication date

2013-09-17

2008-08-04 Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co

2009-02-19 Publication of CA2694209A1 publication Critical patent/CA2694209A1/en

2013-09-17 Application granted granted Critical

2013-09-17 Publication of CA2694209C publication Critical patent/CA2694209C/en

Status Expired - Fee Related legal-status Critical Current

2028-08-04 Anticipated expiration legal-status Critical

Links

150000001538 azepines Chemical class 0.000 title description 2
239000003540 gamma secretase inhibitor Substances 0.000 title description 2
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239000003085 diluting agent Substances 0.000 claims description 7
230000002401 inhibitory effect Effects 0.000 claims description 7
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238000000034 method Methods 0.000 abstract description 21
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
239000000243 solution Substances 0.000 description 36
238000006243 chemical reaction Methods 0.000 description 26
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
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239000002245 particle Substances 0.000 description 1
238000005897 peptide coupling reaction Methods 0.000 description 1
229910052698 phosphorus Inorganic materials 0.000 description 1
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230000000704 physical effect Effects 0.000 description 1
229920001223 polyethylene glycol Polymers 0.000 description 1
229920000193 polymethacrylate Polymers 0.000 description 1
239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
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235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229940069328 povidone Drugs 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000002265 prevention Effects 0.000 description 1
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
239000000047 product Substances 0.000 description 1
201000002212 progressive supranuclear palsy Diseases 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 1
238000001243 protein synthesis Methods 0.000 description 1
230000006337 proteolytic cleavage Effects 0.000 description 1
230000005855 radiation Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
230000004044 response Effects 0.000 description 1
CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
235000019204 saccharin Nutrition 0.000 description 1
229940081974 saccharin Drugs 0.000 description 1
239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
239000000523 sample Substances 0.000 description 1
230000007017 scission Effects 0.000 description 1
238000007423 screening assay Methods 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
239000012056 semi-solid material Substances 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
229940083542 sodium Drugs 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
239000011734 sodium Substances 0.000 description 1
235000019333 sodium laurylsulphate Nutrition 0.000 description 1
235000010288 sodium nitrite Nutrition 0.000 description 1
229940079832 sodium starch glycolate Drugs 0.000 description 1
239000008109 sodium starch glycolate Substances 0.000 description 1
229920003109 sodium starch glycolate Polymers 0.000 description 1
239000011343 solid material Substances 0.000 description 1
239000002904 solvent Substances 0.000 description 1
239000008107 starch Substances 0.000 description 1
229940032147 starch Drugs 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
231100000212 subchronic toxicity study Toxicity 0.000 description 1
239000000758 substrate Substances 0.000 description 1
235000011149 sulphuric acid Nutrition 0.000 description 1
239000000829 suppository Substances 0.000 description 1
239000000454 talc Substances 0.000 description 1
235000012222 talc Nutrition 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
CRJXCNMGTGXBEP-MBIQTGHCSA-N tert-butyl n-[(2s)-1-[(1-methyl-2-oxo-5-phenyl-3h-azepin-3-yl)amino]-1-oxopropan-2-yl]carbamate Chemical compound C1=CN(C)C(=O)C(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C)C=C1C1=CC=CC=C1 CRJXCNMGTGXBEP-MBIQTGHCSA-N 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
230000001225 therapeutic effect Effects 0.000 description 1
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RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
229940033663 thimerosal Drugs 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
230000014616 translation Effects 0.000 description 1
TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/12—Nitrogen atoms not forming part of a nitro radical
- 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
- A61P25/28—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

Landscapes

Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Animal Behavior & Ethology (AREA)
Medicinal Chemistry (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Biomedical Technology (AREA)
Neurosurgery (AREA)
Neurology (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA2694209A 2007-08-14 2008-08-04 Azepine derivatives as gamma-secretase inhibitors Expired - Fee Related CA2694209C (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US95572007P	2007-08-14	2007-08-14
US60/955,720		2007-08-14
PCT/US2008/072049 WO2009023453A1 (en)	2007-08-14	2008-08-04	Azepine derivatives as gamma-secretase inhibitors

Publications (2)

Publication Number	Publication Date
CA2694209A1 CA2694209A1 (en)	2009-02-19
CA2694209C true CA2694209C (en)	2013-09-17

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ID=39811736

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA2694209A Expired - Fee Related CA2694209C (en)	2007-08-14	2008-08-04	Azepine derivatives as gamma-secretase inhibitors

Country Status (11)

Country	Link
US (1)	US8188069B2 (2)
EP (1)	EP2178844A1 (2)
JP (1)	JP5385904B2 (2)
KR (1)	KR101136260B1 (2)
CN (1)	CN101778826B (2)
AU (1)	AU2008287124B2 (2)
BR (1)	BRPI0815135A2 (2)
CA (1)	CA2694209C (2)
EA (1)	EA017286B1 (2)
MX (1)	MX2010001754A (2)
WO (1)	WO2009023453A1 (2)

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US20130060023A1 (en) *	2011-09-07	2013-03-07	Satori Pharmaceuticals, Inc.	Compounds useful for treating neurodegenerative disorders
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CN104797569A (zh)	2012-09-21	2015-07-22	百时美施贵宝公司	取代的1,5-苯并二氮杂*酮化合物
CN104797584A (zh)	2012-09-21	2015-07-22	百时美施贵宝公司	作为notch抑制剂的三环杂环化合物
CN105308030A (zh)	2012-09-21	2016-02-03	百时美施贵宝公司	烷基、氟烷基-1,4-苯并二氮杂*酮化合物
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WO2014047392A1 (en)	2012-09-21	2014-03-27	Bristol-Myers Squibb Company	Fluoroalkyl-1,4-benzodiazepinone compounds
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US9242940B2 (en)	2012-09-21	2016-01-26	Bristol-Myers Squibb Company	N-substituted bis(fluoroalkyl)-1,4-benzodiazepinone compounds
TWI614238B (zh)	2012-09-21	2018-02-11	必治妥美雅史谷比公司	雙（氟烷基）－１，４－苯并二氮呯酮化合物及其前藥
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US11370823B2 (en)	2014-10-29	2022-06-28	Massachusetts Eye And Ear Infirmary	Efficient delivery of therapeutic molecules to cells of the inner ear
US11185536B2 (en)	2015-12-04	2021-11-30	Massachusetts Eye And Ear Infirmary	Treatment of hearing loss by inhibition of casein kinase 1
EP3407901B1 (en)	2016-01-29	2021-07-21	Massachusetts Eye & Ear Infirmary	Expansion and differentiation of inner ear supporting cells and methods of use thereof
EP3442528B1 (en)	2016-04-12	2021-05-26	Eli Lilly and Company	Combination therapy with notch and pi3k/mtor inhibitors for use in treating ovarian cancer
JP6911047B2 (ja)	2016-04-12	2021-07-28	イーライリリーアンドカンパニー	がんの処置のための、Ｎｏｔｃｈ阻害剤およびＣＤＫ４／６阻害剤の併用療法
JP6840774B2 (ja)	2016-05-16	2021-03-10	ザジェネラルホスピタルコーポレイション	肺上皮エンジニアリングにおけるヒト気道幹細胞
JP7194022B2 (ja)	2016-05-20	2022-12-21	イーライリリーアンドカンパニー	Ｎｏｔｃｈ阻害剤とＰＤ－１またはＰＤ－Ｌ１阻害剤との併用療法
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MX2019009552A (es)	2017-02-17	2019-10-02	Hutchinson Fred Cancer Res	Terapias de combinacion para el tratamiento de canceres relacionados con el antigeno de maduracion de celulas b (bcma) y trastornos autoinmunitarios.
US20200179511A1 (en)	2017-04-28	2020-06-11	Novartis Ag	Bcma-targeting agent, and combination therapy with a gamma secretase inhibitor
EP3615055A1 (en)	2017-04-28	2020-03-04	Novartis AG	Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor
MX2020004568A (es)	2017-11-06	2020-10-05	Juno Therapeutics Inc	Combinación de una terapia celular y un inhibidor de gamma secretasa.
WO2019148067A1 (en)	2018-01-26	2019-08-01	Massachusetts Eye And Ear Infirmary	Treatment of hearing loss
KR102870868B1 (ko)	2018-06-01	2025-10-15	노파르티스 아게	Bcma에 대한 결합 분자 및 이의 용도
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2008
- 2008-08-04 JP JP2010521080A patent/JP5385904B2/ja not_active Expired - Fee Related
- 2008-08-04 EA EA201070278A patent/EA017286B1/ru not_active IP Right Cessation
- 2008-08-04 US US12/669,048 patent/US8188069B2/en not_active Expired - Fee Related
- 2008-08-04 AU AU2008287124A patent/AU2008287124B2/en not_active Ceased
- 2008-08-04 WO PCT/US2008/072049 patent/WO2009023453A1/en not_active Ceased
- 2008-08-04 MX MX2010001754A patent/MX2010001754A/es active IP Right Grant
- 2008-08-04 CN CN2008801030083A patent/CN101778826B/zh not_active Expired - Fee Related
- 2008-08-04 CA CA2694209A patent/CA2694209C/en not_active Expired - Fee Related
- 2008-08-04 EP EP08827545A patent/EP2178844A1/en not_active Withdrawn
- 2008-08-04 KR KR1020107002906A patent/KR101136260B1/ko not_active Expired - Fee Related
- 2008-08-04 BR BRPI0815135-0A2A patent/BRPI0815135A2/pt not_active IP Right Cessation

Also Published As

Publication number	Publication date
JP2010536766A (ja)	2010-12-02
BRPI0815135A2 (pt)	2015-02-03
CN101778826A (zh)	2010-07-14
KR101136260B1 (ko)	2012-04-19
EA201070278A1 (ru)	2010-06-30
JP5385904B2 (ja)	2014-01-08
KR20100032924A (ko)	2010-03-26
EA017286B1 (ru)	2012-11-30
WO2009023453A1 (en)	2009-02-19
US20100197660A1 (en)	2010-08-05
EP2178844A1 (en)	2010-04-28
US8188069B2 (en)	2012-05-29
MX2010001754A (es)	2010-05-14
CA2694209A1 (en)	2009-02-19
AU2008287124B2 (en)	2013-06-06
AU2008287124A1 (en)	2009-02-19
CN101778826B (zh)	2012-10-31

Legal Events

Date	Code	Title	Description
2010-11-08	EEER	Examination request
2015-09-15	MKLA	Lapsed	Effective date: 20150804

Publication	Publication Date	Title
CA2694209C (en)	2013-09-17	Azepine derivatives as gamma-secretase inhibitors
CA2427227C (en)	2010-08-17	Lactam compound
AU2002243192A1 (en)	2002-08-29	Lactam compound to inhibit beta-amyloid peptide release or synthesis
US7468365B2 (en)	2008-12-23	Lactam compound
EP1353910B1 (en)	2007-05-23	Lactam compound
AU2002224321A1 (en)	2002-08-01	Lactam compound
WO1999032453A1 (en)	1999-07-01	POLYCYCLIC α-AMINO-⊂-CAPROLACTAMS AND RELATED COMPOUNDS
EP3172206B1 (en)	2019-01-30	Pyridyl-triazabicycles
CA2390376A1 (en)	2001-05-17	.beta.-aminoacid compounds useful for inhibiting .beta.-amyloid peptide release and/or its synthesis
CA2425558C (en)	2012-01-03	Lactam compound
US6958330B1 (en)	2005-10-25	Polycyclic α-amino-ε-caprolactams and related compounds
US20040077627A1 (en)	2004-04-22	Lactam compound
HK1059731B (en)	2007-08-24	Lactam compound to inhibit beta-amyloid peptide release or synthesis