SI21099A - N-(5-(((5-alkil-2-oksazolil)metil)tio)-2-tiazolil) karboksamidni inhibitorji ciklin odvisnih kinaz - Google Patents

N-(5-(((5-alkil-2-oksazolil)metil)tio)-2-tiazolil) karboksamidni inhibitorji ciklin odvisnih kinaz Download PDF

Info

Publication number: SI21099A
Authority: SI; Slovenia
Prior art keywords: citrate; hydrochloride; trifluoroacetate; pharmaceutically acceptable; compound
Prior art date: 2000-07-26

Application number

SI200120051A

Other languages

English (en)

Slovenian (sl)

Inventor

Raj N. Misra

Hai-Yun Xiao

Original Assignee

Bristol-Myers Squibb Company

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.)

2000-07-26

Filing date

2001-05-09

Publication date

2003-06-30

2000-12-01 Priority claimed from US09/727,957 external-priority patent/US6515004B1/en

2000-12-22 Priority claimed from US09/746,060 external-priority patent/US6414156B2/en

2001-05-09 Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company

2003-06-30 Publication of SI21099A publication Critical patent/SI21099A/sl

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125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims description 13
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Classifications

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- 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
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
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- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Immunology (AREA)
Epidemiology (AREA)
Rheumatology (AREA)
Pain & Pain Management (AREA)
Hematology (AREA)
Diabetes (AREA)
Orthopedic Medicine & Surgery (AREA)
Physical Education & Sports Medicine (AREA)
Dermatology (AREA)
Transplantation (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

SI200120051A 2000-07-26 2001-05-09 N-(5-(((5-alkil-2-oksazolil)metil)tio)-2-tiazolil) karboksamidni inhibitorji ciklin odvisnih kinaz SI21099A (sl)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
US61662700A	2000-07-26	2000-07-26
US09/727,957 US6515004B1 (en)	1999-12-15	2000-12-01	N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases
US09/746,060 US6414156B2 (en)	1998-10-21	2000-12-22	Process for preparing azacycloalkanoylaminothiazoles
PCT/US2001/015081 WO2002010162A1 (en)	2000-07-26	2001-05-09	N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases

Publications (1)

Publication Number	Publication Date
SI21099A true SI21099A (sl)	2003-06-30

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ID=27417184

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Application Number	Title	Priority Date	Filing Date
SI200120051A SI21099A (sl)	2000-07-26	2001-05-09	N-(5-(((5-alkil-2-oksazolil)metil)tio)-2-tiazolil) karboksamidni inhibitorji ciklin odvisnih kinaz

Country Status (26)

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EP (1)	EP1303513A1 (et)
JP (1)	JP2004509857A (et)
KR (1)	KR20030016429A (et)
CN (1)	CN100457753C (et)
AR (1)	AR030563A1 (et)
AU (1)	AU2001259704A1 (et)
BG (1)	BG65132B1 (et)
BR (1)	BR0112674A (et)
CA (1)	CA2417254A1 (et)
CZ (1)	CZ2003237A3 (et)
EE (1)	EE200300041A (et)
EG (1)	EG24409A (et)
GE (1)	GEP20043367B (et)
HR (1)	HRP20030116A2 (et)
HU (1)	HUP0303698A2 (et)
IL (2)	IL153591A0 (et)
LV (1)	LV13037B (et)
MX (1)	MXPA03000774A (et)
MY (1)	MY129635A (et)
NO (1)	NO20030394L (et)
PL (1)	PL365170A1 (et)
SI (1)	SI21099A (et)
SK (1)	SK18392002A3 (et)
TW (1)	TWI302533B (et)
WO (1)	WO2002010162A1 (et)
YU (1)	YU4903A (et)

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6414156B2 (en)	1998-10-21	2002-07-02	Bristol-Myers Squibb Company	Process for preparing azacycloalkanoylaminothiazoles
EP2311818B1 (en) *	2002-02-28	2013-01-16	Novartis AG	Combination of a 5-phenylthiazole compound as PI3 kinase inhibitor with an antiinflammatory, bronchodilatory or antihistamine drug
TWI314928B (en)	2002-02-28	2009-09-21	Novartis A	5-phenylthiazole derivatives and use as pi3 kinase inhibitors
US8673924B2 (en)	2002-09-04	2014-03-18	Merck Sharp & Dohme Corp.	Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors
US8580782B2 (en)	2002-09-04	2013-11-12	Merck Sharp & Dohme Corp.	Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors
TW200412966A (en)	2002-09-04	2004-08-01	Schering Corp	Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors
AR041137A1 (es)	2002-09-04	2005-05-04	Pharmacopeia Drug Discovery	Pirazolopirimidinas como inhibidores de quinasa dependientes de ciclinas
EP1543008B1 (en)	2002-09-23	2007-11-07	Schering Corporation	Imidazopyrazines as cyclin dependent kinase inhibitors
NZ538686A (en)	2002-09-23	2008-01-31	Schering Corp	Novel imidazopyrazines as cyclin dependent kinase inhibitors
GB0320197D0 (en) *	2003-08-28	2003-10-01	Novartis Ag	Organic compounds
EP1555264A1 (en) *	2004-01-15	2005-07-20	Sireen AG	Five-membered heterocyclic compounds as inhibitors of SRC family protein kinase.
DE102005008310A1 (de) *	2005-02-17	2006-08-24	Schering Ag	Verwendung von CDKII Inhibitoren zur Fertilitätskontrolle
WO2007022258A1 (en) *	2005-08-17	2007-02-22	Schering Corporation	Novel high affinity thiophene-based and furan-based kinase ligands
DE602006016455D1 (de)	2005-09-09	2010-10-07	Schering Corp	Neue 4-cyano-, 4-amino-, und 4-aminomethylderivative von pyrazoloä1,5-aüpyridinen, pyrazoloä1,5-cüpyrimidinen und 2h-indazolverbindungen und 5-cyano-, 5-amino- und 5-aminomethylderivative von imidazoä1,2-aüpyridinen, und imidazoä1,5-aüpyrazinverbindungen als inhibitoren der cyclinabhänggen kinase
KR20080063806A (ko)	2005-10-06	2008-07-07	쉐링 코포레이션	단백질 키나제 억제제로서의 피라졸로피리미딘
EP2044066A2 (en) *	2006-06-06	2009-04-08	Bristol-Myers Squibb Company	Crystalline forms of n-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl] thio]-2-thiazolyl]-4-piperidinecarboxamide
US20090175852A1 (en)	2006-06-06	2009-07-09	Schering Corporation	Imidazopyrazines as protein kinase inhibitors
CN101578275A (zh)	2006-10-31	2009-11-11	先灵公司	苯胺基哌嗪衍生物及其使用方法
JP4968860B2 (ja)	2006-10-31	2012-07-04	シェーリングコーポレイション	アニリノピペラジン誘導体およびアニリノピペラジン誘導体を使用する方法
MX2009012054A (es)	2007-05-08	2009-11-19	Schering Corp	Metodos de tratamiento que usan formulaciones intravenosas que comprenden temozolomida.
TW200922564A (en)	2007-09-10	2009-06-01	Curis Inc	CDK inhibitors containing a zinc binding moiety
WO2010075542A1 (en)	2008-12-23	2010-07-01	Curis, Inc.	Cdk inhibitors
US8669259B2 (en)	2009-08-26	2014-03-11	Merck Sharp & Dohme Corp.	Heterocyclic amide compounds as protein kinase inhibitors
EP2831282B1 (en)	2012-03-30	2018-07-04	Merck Sharp & Dohme Corp.	Predictive biomarker useful for cancer therapy mediated by a cdk inhibitor
WO2015081867A1 (zh) *	2013-12-04	2015-06-11	杭州民生药物研究院有限公司	吉西他滨衍生物、含该衍生物的组合物及所述衍生物的制药用途

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6262096B1 (en) *	1997-11-12	2001-07-17	Bristol-Myers Squibb Company	Aminothiazole inhibitors of cyclin dependent kinases
US6040321A (en) *	1997-11-12	2000-03-21	Bristol-Myers Squibb Company	Aminothiazole inhibitors of cyclin dependent kinases
ES2237919T4 (es) *	1998-06-18	2007-05-01	Bristol-Myers Squibb Company	Inhibidores aminotiazol sustituidos con carbono de quinasas dependientes de ciclina.
US6414156B2 (en) *	1998-10-21	2002-07-02	Bristol-Myers Squibb Company	Process for preparing azacycloalkanoylaminothiazoles
MY125768A (en) *	1999-12-15	2006-08-30	Bristol Myers Squibb Co	N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases

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- 2001-05-09 PL PL01365170A patent/PL365170A1/xx not_active Application Discontinuation
- 2001-05-09 HU HU0303698A patent/HUP0303698A2/hu unknown
- 2001-05-09 CN CNB018133673A patent/CN100457753C/zh not_active Expired - Fee Related
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Also Published As

Publication number	Publication date
PL365170A1 (en)	2004-12-27
IL153591A0 (en)	2003-07-06
IL153591A (en)	2009-07-20
GEP20043367B (en)	2004-06-10
BR0112674A (pt)	2003-12-30
WO2002010162A1 (en)	2002-02-07
EP1303513A1 (en)	2003-04-23
NO20030394D0 (no)	2003-01-24
AR030563A1 (es)	2003-08-27
HRP20030116A2 (en)	2005-02-28
CN100457753C (zh)	2009-02-04
CN1444584A (zh)	2003-09-24
CZ2003237A3 (cs)	2003-06-18
EE200300041A (et)	2005-04-15
YU4903A (sh)	2006-03-03
EG24409A (en)	2009-05-20
HUP0303698A2 (hu)	2004-04-28
BG107468A (en)	2004-01-30
KR20030016429A (ko)	2003-02-26
TWI302533B (en)	2008-11-01
AU2001259704A1 (en)	2002-02-13
NO20030394L (no)	2003-03-03
CA2417254A1 (en)	2002-02-07
BG65132B1 (bg)	2007-03-30
MXPA03000774A (es)	2003-09-10
LV13037B (en)	2003-11-20
MY129635A (en)	2007-04-30
JP2004509857A (ja)	2004-04-02
SK18392002A3 (sk)	2003-09-11

Publication	Publication Date	Title
SI21099A (sl)	2003-06-30	N-(5-(((5-alkil-2-oksazolil)metil)tio)-2-tiazolil) karboksamidni inhibitorji ciklin odvisnih kinaz
US6515004B1 (en)	2003-02-04	N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases
EP1240165B1 (en)	2005-05-04	N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases
ES2236034T3 (es)	2005-07-16	N- (5-(((5-alquil-2-oxazolil)metil)tio)-2-tiazolil carboxamida inhibidores de las cinasas dependientes de ciclina.
ZA200204349B (en)	2003-09-01	N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases.
LT5106B (lt)	2004-02-25	Nuo ciklinų priklausomų kinazių n-[5-[[[5-alkil-2-oxazolil]metil]tio]-2-tiazolil]karboksamido inhibitoriai
ZA200300452B (en)	2004-06-22	N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases.

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