CA2610509A1 - 1-methyl-1h-pyrazole-4-carboxamides useful as cancer chemotherapeutic agents - Google Patents

1-methyl-1h-pyrazole-4-carboxamides useful as cancer chemotherapeutic agents Download PDF

Info

Publication number: CA2610509A1
Authority: CA; Canada
Prior art keywords: alkyl; alkoxy; substituted; groups; independently
Prior art date: 2005-06-03
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.): Abandoned

Application number

CA002610509A

Other languages

English (en)

French (fr)

Inventor

Philip Wickens

Harold C. E. Kluender

Zhenqiu Hong

Ellalahewage Sathyajith Kumarasinghe

Charles Kreiman

Mingbao Zhang

Istvan Enyedy

Chih-Yuan Chuang

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.)

Bayer Pharma AG

Original Assignee

Individual

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.)

2005-06-03

Filing date

2006-06-02

Publication date

2006-12-14

2006-06-02 Application filed by Individual filed Critical Individual

2006-12-14 Publication of CA2610509A1 publication Critical patent/CA2610509A1/en

Status Abandoned legal-status Critical Current

Links

239000002246 antineoplastic agent Substances 0.000 title abstract description 5
JHAHAUYJIIKYIC-UHFFFAOYSA-N 1-methylpyrazole-4-carboxamide Chemical class CN1C=C(C(N)=O)C=N1 JHAHAUYJIIKYIC-UHFFFAOYSA-N 0.000 title abstract description 4
150000001875 compounds Chemical class 0.000 claims abstract description 172
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
-1 perfluoro Chemical group 0.000 claims description 99
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 81
125000005843 halogen group Chemical group 0.000 claims description 80
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 71
125000003545 alkoxy group Chemical group 0.000 claims description 60
125000004093 cyano group Chemical group *C#N 0.000 claims description 58
238000000034 method Methods 0.000 claims description 57
125000000217 alkyl group Chemical group 0.000 claims description 56
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 51
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 38
229910052757 nitrogen Inorganic materials 0.000 claims description 38
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
206010028980 Neoplasm Diseases 0.000 claims description 26
125000003282 alkyl amino group Chemical group 0.000 claims description 24
150000003839 salts Chemical class 0.000 claims description 24
229910052731 fluorine Inorganic materials 0.000 claims description 21
125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 19
125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
239000011737 fluorine Substances 0.000 claims description 16
125000001153 fluoro group Chemical group F* 0.000 claims description 16
125000004423 acyloxy group Chemical group 0.000 claims description 15
201000011510 cancer Diseases 0.000 claims description 15
125000000623 heterocyclic group Chemical group 0.000 claims description 15
238000011282 treatment Methods 0.000 claims description 14
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
201000010099 disease Diseases 0.000 claims description 11
125000001475 halogen functional group Chemical group 0.000 claims description 7
125000002757 morpholinyl group Chemical group 0.000 claims description 7
125000004568 thiomorpholinyl group Chemical group 0.000 claims description 7
229910052739 hydrogen Inorganic materials 0.000 claims description 6
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
125000004185 ester group Chemical group 0.000 claims description 4
230000003301 hydrolyzing effect Effects 0.000 claims description 4
125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 3
241000124008 Mammalia Species 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
229910052736 halogen Inorganic materials 0.000 claims description 3
150000002367 halogens Chemical class 0.000 claims description 3
239000000546 pharmaceutical excipient Substances 0.000 claims description 3
230000008569 process Effects 0.000 claims description 3
230000002265 prevention Effects 0.000 claims 3
238000004519 manufacturing process Methods 0.000 claims 2
239000000203 mixture Substances 0.000 abstract description 36
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 149
238000002360 preparation method Methods 0.000 description 117
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 103
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 92
239000000543 intermediate Substances 0.000 description 89
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 85
238000006243 chemical reaction Methods 0.000 description 64
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 64
239000000243 solution Substances 0.000 description 60
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 55
235000019439 ethyl acetate Nutrition 0.000 description 53
239000000047 product Substances 0.000 description 45
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
229940093499 ethyl acetate Drugs 0.000 description 43
238000005160 1H NMR spectroscopy Methods 0.000 description 41
238000004128 high performance liquid chromatography Methods 0.000 description 40
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 39
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 38
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 37
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 32
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
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235000011152 sodium sulphate Nutrition 0.000 description 29
239000011541 reaction mixture Substances 0.000 description 28
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 25
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
239000000284 extract Substances 0.000 description 21
150000001412 amines Chemical class 0.000 description 20
239000007787 solid Substances 0.000 description 20
238000003756 stirring Methods 0.000 description 20
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238000005481 NMR spectroscopy Methods 0.000 description 17
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
125000004432 carbon atom Chemical group C* 0.000 description 16
235000017557 sodium bicarbonate Nutrition 0.000 description 16
229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 15
239000000741 silica gel Substances 0.000 description 15
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239000007858 starting material Substances 0.000 description 15
239000003656 tris buffered saline Substances 0.000 description 15
WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 14
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
RRWQVXDAUNCCGU-UHFFFAOYSA-N 4-(chloromethyl)pyridin-2-amine Chemical compound NC1=CC(CCl)=CC=N1 RRWQVXDAUNCCGU-UHFFFAOYSA-N 0.000 description 13
239000012267 brine Substances 0.000 description 13
239000002904 solvent Substances 0.000 description 13
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 13
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
239000000463 material Substances 0.000 description 12
238000000746 purification Methods 0.000 description 12
229920006395 saturated elastomer Polymers 0.000 description 12
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
ZVXKYWHJBYIYNI-UHFFFAOYSA-N 1h-pyrazole-4-carboxamide Chemical compound NC(=O)C=1C=NNC=1 ZVXKYWHJBYIYNI-UHFFFAOYSA-N 0.000 description 11
238000003556 assay Methods 0.000 description 11
239000003153 chemical reaction reagent Substances 0.000 description 11
238000001816 cooling Methods 0.000 description 11
239000000725 suspension Substances 0.000 description 11
239000002585 base Substances 0.000 description 10
238000004587 chromatography analysis Methods 0.000 description 10
239000012044 organic layer Substances 0.000 description 10
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
229940086542 triethylamine Drugs 0.000 description 10
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 10
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 9
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
239000002253 acid Substances 0.000 description 9
239000007822 coupling agent Substances 0.000 description 9
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
230000033115 angiogenesis Effects 0.000 description 8
239000012043 crude product Substances 0.000 description 8
WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 7
CVYQRDKVWVBOFP-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxol-5-amine Chemical compound NC1=CC=C2OC(F)(F)OC2=C1 CVYQRDKVWVBOFP-UHFFFAOYSA-N 0.000 description 7
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 7
108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 7
150000002148 esters Chemical class 0.000 description 7
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125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
PZBJVXQYZPOKGP-UHFFFAOYSA-N 5-amino-n-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methylpyrazole-4-carboxamide Chemical compound CN1N=CC(C(=O)NC=2C=C3OC(F)(F)OC3=CC=2)=C1N PZBJVXQYZPOKGP-UHFFFAOYSA-N 0.000 description 6
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 6
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125000001424 substituent group Chemical group 0.000 description 6
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 6
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BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
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WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
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DJXJARQPGKYVNA-UHFFFAOYSA-N trifluoromethanolate Chemical class [O-]C(F)(F)F DJXJARQPGKYVNA-UHFFFAOYSA-N 0.000 description 1
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DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

CA002610509A 2005-06-03 2006-06-02 1-methyl-1h-pyrazole-4-carboxamides useful as cancer chemotherapeutic agents Abandoned CA2610509A1 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US68745405P	2005-06-03	2005-06-03
US60/687,454		2005-06-03
PCT/US2006/021550 WO2006133006A2 (en)	2005-06-03	2006-06-02	1-methyl-1h-pyrazole-4-carboxamides useful as cancer chemotherapeutic agents

Publications (1)

Publication Number	Publication Date
CA2610509A1 true CA2610509A1 (en)	2006-12-14

Family

ID=37498955

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002610509A Abandoned CA2610509A1 (en)	2005-06-03	2006-06-02	1-methyl-1h-pyrazole-4-carboxamides useful as cancer chemotherapeutic agents

Country Status (4)

Country	Link
EP (1)	EP1891047A4 (de)
JP (1)	JP2008545756A (de)
CA (1)	CA2610509A1 (de)
WO (1)	WO2006133006A2 (de)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US8614234B2 (en)	2009-09-03	2013-12-24	Allergan, Inc.	Compounds as tyrosine kinase modulators
US9340555B2 (en)	2009-09-03	2016-05-17	Allergan, Inc.	Compounds as tyrosine kinase modulators
AU2010303567B2 (en) *	2009-10-06	2016-06-09	Millennium Pharmaceuticals, Inc	Heterocyclic compounds useful as PDK1 inhibitors
KR20140105459A (ko)	2011-12-09	2014-09-01	키에시 파르마슈티시 엣스. 피. 에이.	키나아제 억제제
ES2612259T3 (es)	2011-12-09	2017-05-16	Chiesi Farmaceutici S.P.A.	Inhibidores de cinasa
HK1220459A1 (zh)	2013-06-06	2017-05-05	奇斯药制品公司	激酶抑制剂
AR105955A1 (es) *	2015-09-08	2017-11-29	Santen Pharmaceutical Co Ltd	Método para producir una piridinacarboxamida
WO2019068572A1 (de)	2017-10-04	2019-04-11	Bayer Aktiengesellschaft	Heterocyclen-derivate als schädlingsbekämpfungsmittel
EP3765466B1 (de)	2018-03-12	2022-05-25	Bayer Aktiengesellschaft	Kondensierte bicyclische heterocyclen-derivate als schädlingsbekämpfungsmittel
CN111989328B (zh)	2018-04-20	2023-04-18	拜耳公司	作为害虫防治剂的杂环衍生物

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Publication number	Priority date	Publication date	Assignee	Title
US6878714B2 (en) *	2001-01-12	2005-04-12	Amgen Inc.	Substituted alkylamine derivatives and methods of use
WO2003037336A1 (en) *	2001-11-02	2003-05-08	Pfizer Products Inc.	1-(5-sulfonyl-pyridin-2-yl)-5-(methylidene-cycloalkylmethoxy)-1h-pyrazole-4-carbonitrile derivatives and other compounds as cyclooxygenase inhibitors for the treatment of arthritis, neurodegeneration and colon cancer

2006
- 2006-06-02 JP JP2008514922A patent/JP2008545756A/ja active Pending
- 2006-06-02 EP EP06772019A patent/EP1891047A4/de not_active Withdrawn
- 2006-06-02 WO PCT/US2006/021550 patent/WO2006133006A2/en not_active Ceased
- 2006-06-02 CA CA002610509A patent/CA2610509A1/en not_active Abandoned

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Publication number	Publication date
WO2006133006A2 (en)	2006-12-14
EP1891047A2 (de)	2008-02-27
JP2008545756A (ja)	2008-12-18
WO2006133006A3 (en)	2007-02-22
EP1891047A4 (de)	2008-07-09

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Date	Code	Title	Description
2011-06-02	FZDE	Dead

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