ZA200601989B - Malonamide derivatives blocking the activity of gamasecretase - Google Patents

Malonamide derivatives blocking the activity of gamasecretase Download PDF

Info

Publication number: ZA200601989B
Authority: ZA; South Africa
Prior art keywords: methyl; malonamide; dibenzo; azepin; pentafluoro
Prior art date: 2003-09-09

Application number

ZA200601989A

Other languages

English (en)

Inventor

Flohr Alexander

Jakob-Roetne Roland

Peters Jens-Uwe

Galley Guido

Kitas Eric Argirios

Wostl Wolfgang

Original Assignee

Hoffmann La Roche

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.)

2003-09-09

Filing date

2006-03-08

Publication date

2007-05-30

2006-03-08 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

2007-05-30 Publication of ZA200601989B publication Critical patent/ZA200601989B/en

Links

230000000694 effects Effects 0.000 title description 9
230000000903 blocking effect Effects 0.000 title description 3
WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical class NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims description 137
125000000217 alkyl group Chemical group 0.000 claims description 63
239000000203 mixture Substances 0.000 claims description 50
238000000034 method Methods 0.000 claims description 46
229910052736 halogen Inorganic materials 0.000 claims description 31
150000002367 halogens Chemical class 0.000 claims description 27
229910052739 hydrogen Inorganic materials 0.000 claims description 27
239000001257 hydrogen Substances 0.000 claims description 27
-1 azepin-7-yl Chemical group 0.000 claims description 22
150000003839 salts Chemical class 0.000 claims description 21
150000002431 hydrogen Chemical class 0.000 claims description 17
239000002253 acid Substances 0.000 claims description 13
238000004519 manufacturing process Methods 0.000 claims description 13
208000024827 Alzheimer disease Diseases 0.000 claims description 12
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
125000006193 alkinyl group Chemical group 0.000 claims description 9
239000003814 drug Substances 0.000 claims description 9
125000001424 substituent group Chemical group 0.000 claims description 8
125000003545 alkoxy group Chemical group 0.000 claims description 7
239000000126 substance Substances 0.000 claims description 7
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
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 claims description 5
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
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125000000753 cycloalkyl group Chemical group 0.000 claims description 3
150000002148 esters Chemical class 0.000 claims description 2
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125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
WHZDHYBSANDATP-UHFFFAOYSA-N 2-(4,4,4-trifluorobutyl)propanediamide Chemical compound NC(=O)C(C(N)=O)CCCC(F)(F)F WHZDHYBSANDATP-UHFFFAOYSA-N 0.000 claims 1
GJRLJCUANNYTKT-UHFFFAOYSA-N 2-fluoro-2-methyl-n-(3-methylbutyl)-n'-(5-methyl-6-oxo-7h-benzo[d][1]benzazepin-7-yl)propanediamide Chemical compound CN1C(=O)C(NC(=O)C(C)(F)C(=O)NCCC(C)C)C2=CC=CC=C2C2=CC=CC=C21 GJRLJCUANNYTKT-UHFFFAOYSA-N 0.000 claims 1
VEENFWCXHBRKDQ-DTIOYNMSSA-N 2-methyl-n-[(3s)-1-methylsulfonyl-4-oxo-5-(2,2,2-trifluoroethyl)-2,3-dihydro-1,5-benzodiazepin-3-yl]-n'-(2,2,3,3,3-pentafluoropropyl)propanediamide Chemical compound FC(F)(F)CN1C(=O)[C@@H](NC(=O)C(C(=O)NCC(F)(F)C(F)(F)F)C)CN(S(C)(=O)=O)C2=CC=CC=C21 VEENFWCXHBRKDQ-DTIOYNMSSA-N 0.000 claims 1
DUTWIQOZSNGNLR-UHFFFAOYSA-N cyclopropylmethyl 1,4-diazepine-1-carboxylate Chemical compound C1=CC=NC=CN1C(=O)OCC1CC1 DUTWIQOZSNGNLR-UHFFFAOYSA-N 0.000 claims 1
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125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
239000002002 slurry Substances 0.000 description 1
WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
239000011343 solid material Substances 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000007858 starting material Substances 0.000 description 1
239000000725 suspension Substances 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000007916 tablet composition Substances 0.000 description 1
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
125000005500 uronium group Chemical group 0.000 description 1
238000005550 wet granulation Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1

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
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
- 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
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/14—[b,f]-condensed

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)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Epidemiology (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Neurosurgery (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Biomedical Technology (AREA)
Chemical Kinetics & Catalysis (AREA)
Neurology (AREA)
General Chemical & Material Sciences (AREA)
Psychiatry (AREA)
Hospice & Palliative Care (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Other In-Based Heterocyclic Compounds (AREA)
Pyrane Compounds (AREA)
Hydrogenated Pyridines (AREA)

ZA200601989A 2003-09-09 2006-03-08 Malonamide derivatives blocking the activity of gamasecretase ZA200601989B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
EP03019683		2003-09-09

Publications (1)

Publication Number	Publication Date
ZA200601989B true ZA200601989B (en)	2007-05-30

Family

ID=34224068

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
ZA200601989A ZA200601989B (en)	2003-09-09	2006-03-08	Malonamide derivatives blocking the activity of gamasecretase

Country Status (34)

Country	Link
US (1)	US7160875B2 (fr)
EP (1)	EP1711470B1 (fr)
JP (2)	JP4571639B2 (fr)
KR (3)	KR100834177B1 (fr)
CN (1)	CN100593539C (fr)
AR (1)	AR045609A1 (fr)
AT (1)	ATE428698T1 (fr)
AU (1)	AU2004270361B2 (fr)
BR (1)	BRPI0413533A (fr)
CA (1)	CA2537440C (fr)
CO (1)	CO5660268A2 (fr)
CR (1)	CR8264A (fr)
CY (1)	CY1109225T1 (fr)
DE (1)	DE602004020680D1 (fr)
DK (1)	DK1711470T3 (fr)
EA (1)	EA009940B1 (fr)
EC (1)	ECSP066414A (fr)
ES (1)	ES2322652T3 (fr)
HR (1)	HRP20090266T1 (fr)
IL (1)	IL173905A (fr)
MA (1)	MA28034A1 (fr)
MX (1)	MXPA06002562A (fr)
MY (1)	MY141308A (fr)
NO (1)	NO20061047L (fr)
NZ (1)	NZ545538A (fr)
PL (1)	PL1711470T3 (fr)
PT (1)	PT1711470E (fr)
RS (1)	RS20060146A (fr)
SI (1)	SI1711470T1 (fr)
TN (1)	TNSN06077A1 (fr)
TW (1)	TW200519092A (fr)
UA (1)	UA83501C2 (fr)
WO (1)	WO2005023772A1 (fr)
ZA (1)	ZA200601989B (fr)

Families Citing this family (42)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP1592684B1 (fr) *	2003-02-04	2008-07-30	F. Hoffmann-La Roche Ag	Derives de malonamide utilises comme inhibiteurs de la gamma-secretase
KR100834177B1 (ko) *	2003-09-09	2008-05-30	에프. 호프만-라 로슈 아게	감마-세크리테이즈의 활성을 차단하는 말론아미드 유도체
EP1673347B1 (fr) *	2003-10-06	2015-08-19	F. Hoffmann-La Roche AG	Derives de dibenzo-azepine et de benzo-diazepine utilises en tant qu'inhibiteurs de la gamma-secretase
US7211573B2 (en)	2004-12-08	2007-05-01	Hoffmann-La Roche Inc.	Malonamide derivatives
CN101410378B (zh) *	2006-03-27	2012-12-05	霍夫曼-拉罗奇有限公司	作为γ分泌酶抑制剂的丙二酰胺衍生物
WO2008034735A2 (fr) *	2006-09-20	2008-03-27	F. Hoffmann-La Roche Ag	Dérivés 4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazépine
CN101622232A (zh) *	2007-02-02	2010-01-06	弗·哈夫曼-拉罗切有限公司	6-氧代-6,7-二氢-5h-二苯并[b,d]氮杂䓬-7-基衍生物
WO2008110488A1 (fr) *	2007-03-15	2008-09-18	F. Hoffmann-La Roche Ag	Malonamides comme antagonistes des récepteurs de l'orexine
US7579464B2 (en)	2007-05-25	2009-08-25	Hoffmann-La Roche Inc.	Process for preparation of enantiomerically pure compounds
AU2009203776A1 (en) *	2008-01-11	2009-07-16	F. Hoffmann-La Roche Ag	Use of a gamma-secretase inhibitor for treating cancer
US8741889B2 (en)	2008-01-11	2014-06-03	Hoffmann-La Roche Inc	Method of treating non-small cell lung cancer and colon cancer with gamma-secretase inhibitor
US8309299B2 (en) *	2010-05-19	2012-11-13	Hoffmann-La Roche Inc.	Combination therapy and method for assessing resistance to treatment
WO2012040444A2 (fr) *	2010-09-24	2012-03-29	Bristol-Myers Squibb Company	Traitement de patients présentant un début de maladie d'alzheimer
KR101330184B1 (ko)	2010-10-15	2013-11-15	성균관대학교산학협력단	감마-세크레타제 저해제를 유효성분으로 함유하는 류마티스성 관절염의 예방 또는 치료용 조성물
WO2012050370A2 (fr) *	2010-10-15	2012-04-19	성균관대학교산학협력단	Composition pour prévenir ou traiter la polyarthrite rhumatoïde contenant un inhibiteur de sécrétase gamma en tant que composant actif
US20120114638A1 (en)	2010-11-08	2012-05-10	John Boylan	Combination therapy
US20120184529A1 (en)	2011-01-14	2012-07-19	Demario Mark D	Combination therapy
US20120225860A1 (en)	2011-03-02	2012-09-06	John Frederick Boylan	Method for administration of a gamma secretase inhibitor
TWI530489B (zh)	2011-03-22	2016-04-21	必治妥美雅史谷比公司	雙（氟烷基）－１，４－苯二氮呯酮化合物
AR087107A1 (es)	2011-07-27	2014-02-12	Lilly Co Eli	Compuesto inhibidor de la señalizacion de la trayectoria notch
WO2014047397A1 (fr)	2012-09-21	2014-03-27	Bristol-Myers Squibb Company	Composés de fluoralkyl- et de fluorocycloalkyl-1,4-benzodiazépinone utilisables en tant qu'inhibiteurs du récepteur notch
WO2014047369A1 (fr)	2012-09-21	2014-03-27	Bristol-Myers Squibb Company	Composés de 1,5-benzodiazépinone substituée
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
EP2897947B1 (fr)	2012-09-21	2016-10-26	Bristol-Myers Squibb Company	Composés d'alkyl, fluoroalkyl-1, 4-benzodiazepinone
EP2897954B1 (fr)	2012-09-21	2016-10-26	Bristol-Myers Squibb Company	Composés fluoroalkyl-1,4-benzodiazépinones
WO2014047370A1 (fr)	2012-09-21	2014-03-27	Bristol-Myers Squibb Company	Composés fluoroalkyl benzodiazépinones
US9242940B2 (en)	2012-09-21	2016-01-26	Bristol-Myers Squibb Company	N-substituted bis(fluoroalkyl)-1,4-benzodiazepinone compounds
EP2897960B1 (fr)	2012-09-21	2016-08-03	Bristol-Myers Squibb Company	Composés hétérocycliques tricycliques utilisables en tant qu'inhibiteurs du récepteur notch
WO2014047391A1 (fr)	2012-09-21	2014-03-27	Bristol-Myers Squibb Company	Promédicaments de composés 1,4-benzodiazépinones
WO2014165718A1 (fr)	2013-04-04	2014-10-09	Bristol-Myers Squibb Company	Traitement combiné pour le traitement de maladies prolifératives
EP2932966A1 (fr)	2014-04-16	2015-10-21	Novartis AG	Inhibiteurs de la gamma sécrétase pour traiter des maladies respiratoires
CN109071450B (zh) *	2015-10-30	2021-06-22	帕珀莱恩医疗公司	二苯并氮杂卓化合物及其治疗耳部疾病和病症的用途
MX390370B (es)	2016-12-16	2025-03-20	Pipeline Therapeutics Inc	Metodos para tratar la sinaptopatia coclear
EP3615068A1 (fr)	2017-04-28	2020-03-04	Novartis AG	Agent ciblant le bcma et polythérapie incluant un inhibiteur de gamma-sécrétase
WO2018201056A1 (fr)	2017-04-28	2018-11-01	Novartis Ag	Cellules exprimant un récepteur antigénique chimérique ciblant le bcma, et polythérapie comprenant un inhibiteur de gamma sécrétase
EP3668844A1 (fr) *	2017-08-15	2020-06-24	Bayer Aktiengesellschaft	4-oxo-2,3,4,5-tétrahydro-1h-1,5-benzodiazépine-7-carboxamides
UY38251A (es)	2018-06-01	2019-12-31	Novartis Ag	Moléculas de unión contra bcma y usos de las mismas
KR20220024729A (ko)	2019-06-24	2022-03-03	노파르티스 아게	B-세포 성숙 항원을 표적으로 하는 다중특이성 항체에 대한 투여 요법 및 병용 요법
CN116234898A (zh) *	2020-07-23	2023-06-06	普渡研究基金会	用于治疗肥胖症和代谢紊乱的Notch信号传导抑制剂
CA3229806A1 (fr) *	2021-08-31	2023-03-09	Basf Se	Malonamides herbicides contenant un systeme cyclique condense
CN119095890A (zh)	2022-11-04	2024-12-06	株式会社Lg化学	全息图记录介质和包括其的光学元件
CN116621721B (zh) *	2023-04-12	2025-03-18	珠海市柏瑞医药科技有限公司	一种壬二酰胺的制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
ATE194340T1 (de) *	1992-12-10	2000-07-15	Pfizer	Aminomethylen substituierte heterocyclische verbindungen und ihre verwendung alssubstanz p antagonisten
US5672598A (en) *	1995-03-21	1997-09-30	The Procter & Gamble Company	Lactam-containing hydroxamic acids
CA2404273A1 (fr) *	2000-04-11	2001-10-18	Bristol-Myers Squibb Pharma Company	Lactames substitues utilises en tant qu'inhibiteurs de production de proteine a.beta.
GB0012671D0 (en) *	2000-05-24	2000-07-19	Merck Sharp & Dohme	Therapeutic agents
EP1592684B1 (fr) *	2003-02-04	2008-07-30	F. Hoffmann-La Roche Ag	Derives de malonamide utilises comme inhibiteurs de la gamma-secretase
KR100834177B1 (ko) *	2003-09-09	2008-05-30	에프. 호프만-라 로슈 아게	감마-세크리테이즈의 활성을 차단하는 말론아미드 유도체

2004
- 2004-08-31 KR KR1020067004763A patent/KR100834177B1/ko not_active Expired - Fee Related
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- 2004-08-31 SI SI200431116T patent/SI1711470T1/sl unknown
- 2004-08-31 EA EA200600503A patent/EA009940B1/ru not_active IP Right Cessation
- 2004-08-31 UA UAA200602854A patent/UA83501C2/uk unknown
- 2004-08-31 EP EP04764665A patent/EP1711470B1/fr not_active Expired - Lifetime
- 2004-08-31 ES ES04764665T patent/ES2322652T3/es not_active Expired - Lifetime
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- 2004-08-31 CA CA2537440A patent/CA2537440C/fr not_active Expired - Fee Related
- 2004-08-31 MX MXPA06002562A patent/MXPA06002562A/es active IP Right Grant
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- 2004-08-31 BR BRPI0413533-4A patent/BRPI0413533A/pt not_active Application Discontinuation
- 2004-08-31 KR KR1020077017457A patent/KR100838852B1/ko not_active Expired - Fee Related
- 2004-08-31 WO PCT/EP2004/009700 patent/WO2005023772A1/fr not_active Ceased
- 2004-09-02 US US10/933,177 patent/US7160875B2/en not_active Expired - Lifetime
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2006
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- 2006-03-07 TN TNP2006000077A patent/TNSN06077A1/fr unknown
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2009
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Also Published As

Publication number	Publication date
EP1711470A1 (fr)	2006-10-18
JP2010229153A (ja)	2010-10-14
EA009940B1 (ru)	2008-04-28
ATE428698T1 (de)	2009-05-15
AU2004270361B2 (en)	2009-06-25
ES2322652T3 (es)	2009-06-24
BRPI0413533A (pt)	2006-10-10
HRP20090266T1 (en)	2009-06-30
KR100834177B1 (ko)	2008-05-30
AR045609A1 (es)	2005-11-02
KR20070087233A (ko)	2007-08-27
MA28034A1 (fr)	2006-07-03
KR20060054455A (ko)	2006-05-22
TNSN06077A1 (fr)	2007-10-03
CA2537440A1 (fr)	2005-03-17
CN100593539C (zh)	2010-03-10
US7160875B2 (en)	2007-01-09
NO20061047L (no)	2006-04-04
EA200600503A1 (ru)	2006-08-25
KR100838852B1 (ko)	2008-06-16
US20050054633A1 (en)	2005-03-10
SI1711470T1 (sl)	2009-08-31
KR20070087690A (ko)	2007-08-28
IL173905A (en)	2011-05-31
CR8264A (es)	2008-09-22
CN1875005A (zh)	2006-12-06
NZ545538A (en)	2008-12-24
UA83501C2 (uk)	2008-07-25
PL1711470T3 (pl)	2009-09-30
JP2007505063A (ja)	2007-03-08
CY1109225T1 (el)	2014-07-02
AU2004270361A1 (en)	2005-03-17
JP4571639B2 (ja)	2010-10-27
RS20060146A (sr)	2008-06-05
CO5660268A2 (es)	2006-07-31
HK1099014A1 (zh)	2007-08-03
WO2005023772A1 (fr)	2005-03-17
MXPA06002562A (es)	2006-06-20
TW200519092A (en)	2005-06-16
CA2537440C (fr)	2012-07-10
DK1711470T3 (da)	2009-06-08
IL173905A0 (en)	2006-07-05
ECSP066414A (es)	2006-09-18
PT1711470E (pt)	2009-05-21
EP1711470B1 (fr)	2009-04-15
DE602004020680D1 (de)	2009-05-28
MY141308A (en)	2010-04-16

Publication	Publication Date	Title
ZA200601989B (en)	2007-05-30	Malonamide derivatives blocking the activity of gamasecretase
EP2018368B1 (fr)	2012-12-05	Dérivés de malonamide en tant qu'inhibiteurs de la gamma secrétase
ZA200506212B (en)	2006-05-31	Malonamide derivatives as gamma-secretase inhibitors
US7544679B2 (en)	2009-06-09	6-oxo-6,7-dihydro-5h-dibenzo[b,d]azepin-7-yl derivatives
EP1673347B1 (fr)	2015-08-19	Derives de dibenzo-azepine et de benzo-diazepine utilises en tant qu'inhibiteurs de la gamma-secretase
US20040235819A1 (en)	2004-11-25	Benzoxazepinone derivatives
US7414049B2 (en)	2008-08-19	4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine derivatives
HK1099014B (en)	2010-11-19	Malonamide derivatives blocking the activity of gama-secretase