JP2006508102A - Ｇａｂａａ受容体のリガンドとしての４−イミダゾール−１−イルメチル−ピリミジン誘導体 - Google Patents
Ｇａｂａａ受容体のリガンドとしての４−イミダゾール−１−イルメチル−ピリミジン誘導体 Download PDFInfo
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- JP2006508102A JP2006508102A JP2004549490A JP2004549490A JP2006508102A JP 2006508102 A JP2006508102 A JP 2006508102A JP 2004549490 A JP2004549490 A JP 2004549490A JP 2004549490 A JP2004549490 A JP 2004549490A JP 2006508102 A JP2006508102 A JP 2006508102A
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- Prior art keywords
- alkyl
- compound
- imidazol
- ylmethyl
- propyl
- 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.)
- Pending
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- 239000003446 ligand Substances 0.000 title abstract description 12
- MIQCQUJDYOHTOK-UHFFFAOYSA-N 4-(imidazol-1-ylmethyl)pyrimidine Chemical class C1=CN=CN1CC1=CC=NC=N1 MIQCQUJDYOHTOK-UHFFFAOYSA-N 0.000 title abstract description 8
- 102000027484 GABAA receptors Human genes 0.000 title 1
- 108091008681 GABAA receptors Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 288
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims abstract description 169
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims abstract description 167
- 230000000694 effects Effects 0.000 claims abstract description 69
- 238000000034 method Methods 0.000 claims abstract description 50
- 230000027455 binding Effects 0.000 claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 31
- 229940079593 drug Drugs 0.000 claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 102000005962 receptors Human genes 0.000 claims description 170
- 108020003175 receptors Proteins 0.000 claims description 170
- -1 nitro, cyano, amino Chemical group 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 66
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 229910052736 halogen Inorganic materials 0.000 claims description 51
- 150000002367 halogens Chemical class 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 238000003556 assay Methods 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 150000002431 hydrogen Chemical class 0.000 claims description 25
- 208000019901 Anxiety disease Diseases 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000004076 pyridyl group Chemical group 0.000 claims description 20
- 230000036506 anxiety Effects 0.000 claims description 19
- 125000000335 thiazolyl group Chemical group 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 17
- 208000019116 sleep disease Diseases 0.000 claims description 17
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 13
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 12
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001544 thienyl group Chemical group 0.000 claims description 11
- 208000024827 Alzheimer disease Diseases 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 9
- XWXPSQYSSKCHSM-UHFFFAOYSA-N 4-chloro-6-[[2-(3-fluoropyridin-2-yl)imidazol-1-yl]methyl]-5-propylpyrimidine Chemical compound CCCC1=C(Cl)N=CN=C1CN1C(C=2C(=CC=CN=2)F)=NC=C1 XWXPSQYSSKCHSM-UHFFFAOYSA-N 0.000 claims description 8
- 150000005215 alkyl ethers Chemical class 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 230000006403 short-term memory Effects 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 7
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 7
- 230000008859 change Effects 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 7
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 6
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 6
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 230000007831 electrophysiology Effects 0.000 claims description 6
- 238000002001 electrophysiology Methods 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
- 238000000376 autoradiography Methods 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- 230000007781 signaling event Effects 0.000 claims description 5
- 208000000044 Amnesia Diseases 0.000 claims description 4
- 230000002708 enhancing effect Effects 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- DOOMJOTXYRUNHE-UHFFFAOYSA-N 4-chloro-6-[[2-(3-fluoropyridin-2-yl)imidazol-1-yl]methyl]-2-methyl-5-propylpyrimidine Chemical compound CCCC1=C(Cl)N=C(C)N=C1CN1C(C=2C(=CC=CN=2)F)=NC=C1 DOOMJOTXYRUNHE-UHFFFAOYSA-N 0.000 claims description 3
- FIPOFHABVOQICE-UHFFFAOYSA-N 4-chloro-6-[[2-(6-fluoropyridin-2-yl)imidazol-1-yl]methyl]-2-methyl-5-propylpyrimidine Chemical compound CCCC1=C(Cl)N=C(C)N=C1CN1C(C=2N=C(F)C=CC=2)=NC=C1 FIPOFHABVOQICE-UHFFFAOYSA-N 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- VWZWVOKGBLPJEQ-UHFFFAOYSA-N n-ethyl-6-[[2-(6-fluoropyridin-2-yl)imidazol-1-yl]methyl]-5-propylpyrimidin-4-amine Chemical compound N1=CN=C(NCC)C(CCC)=C1CN1C(C=2N=C(F)C=CC=2)=NC=C1 VWZWVOKGBLPJEQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 208000020685 sleep-wake disease Diseases 0.000 claims description 3
- 239000006188 syrup Substances 0.000 claims description 3
- 235000020357 syrup Nutrition 0.000 claims description 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 2
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 2
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 2
- LVPNLQRMQLZNRJ-UHFFFAOYSA-N 2-[1-[(6-methyl-5-propylpyrimidin-4-yl)methyl]imidazol-2-yl]-1,3-thiazole-4-carbonitrile Chemical compound CCCC1=C(C)N=CN=C1CN1C(C=2SC=C(N=2)C#N)=NC=C1 LVPNLQRMQLZNRJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- CQWSUQFUXOGROX-UHFFFAOYSA-N 3-[1-[(5-ethyl-6-methylpyrimidin-4-yl)methyl]imidazol-2-yl]benzonitrile Chemical compound CCC1=C(C)N=CN=C1CN1C(C=2C=C(C=CC=2)C#N)=NC=C1 CQWSUQFUXOGROX-UHFFFAOYSA-N 0.000 claims description 2
- PMMQEAQIWITGAS-UHFFFAOYSA-N 4-[[2-(3-fluoropyridin-2-yl)imidazol-1-yl]methyl]-2-methyl-5-propylpyrimidine Chemical compound CCCC1=CN=C(C)N=C1CN1C(C=2C(=CC=CN=2)F)=NC=C1 PMMQEAQIWITGAS-UHFFFAOYSA-N 0.000 claims description 2
- GYRJTUNYEMZWFP-UHFFFAOYSA-N 4-[[2-(3-fluoropyridin-2-yl)imidazol-1-yl]methyl]-5-propyl-6-pyrazol-1-ylpyrimidine Chemical compound N1=CN=C(N2N=CC=C2)C(CCC)=C1CN1C=CN=C1C1=NC=CC=C1F GYRJTUNYEMZWFP-UHFFFAOYSA-N 0.000 claims description 2
- SEHOOVWAIBDEGP-UHFFFAOYSA-N 4-[[2-(3-fluoropyridin-2-yl)imidazol-1-yl]methyl]-5-propyl-6-pyridin-3-ylpyrimidine Chemical compound N1=CN=C(C=2C=NC=CC=2)C(CCC)=C1CN1C=CN=C1C1=NC=CC=C1F SEHOOVWAIBDEGP-UHFFFAOYSA-N 0.000 claims description 2
- HGFXMIVRKIKTSF-UHFFFAOYSA-N 4-[[2-(3-fluoropyridin-2-yl)imidazol-1-yl]methyl]-5-propyl-6-pyridin-4-ylpyrimidine Chemical compound N1=CN=C(C=2C=CN=CC=2)C(CCC)=C1CN1C=CN=C1C1=NC=CC=C1F HGFXMIVRKIKTSF-UHFFFAOYSA-N 0.000 claims description 2
- GTUBRXFVNOIVLZ-UHFFFAOYSA-N 4-[[2-(6-fluoropyridin-2-yl)imidazol-1-yl]methyl]-6-methoxy-5-propylpyrimidine Chemical compound N1=CN=C(OC)C(CCC)=C1CN1C(C=2N=C(F)C=CC=2)=NC=C1 GTUBRXFVNOIVLZ-UHFFFAOYSA-N 0.000 claims description 2
- ASYVLNSLBMHJQD-UHFFFAOYSA-N 5-(3-fluoropropyl)-4-[[2-(3-fluoropyridin-2-yl)imidazol-1-yl]methyl]-6-methylpyrimidine Chemical compound CC1=NC=NC(CN2C(=NC=C2)C=2C(=CC=CN=2)F)=C1CCCF ASYVLNSLBMHJQD-UHFFFAOYSA-N 0.000 claims description 2
- XFXGHXOOVFSOMW-UHFFFAOYSA-N 6-[[2-(6-fluoropyridin-2-yl)imidazol-1-yl]methyl]-5-propylpyrimidin-4-amine Chemical compound CCCC1=C(N)N=CN=C1CN1C(C=2N=C(F)C=CC=2)=NC=C1 XFXGHXOOVFSOMW-UHFFFAOYSA-N 0.000 claims description 2
- WJXTVWLBDVTBPV-UHFFFAOYSA-N 6-[[2-(6-fluoropyridin-2-yl)imidazol-1-yl]methyl]-n,n-dimethyl-5-propylpyrimidin-4-amine Chemical compound N1=CN=C(N(C)C)C(CCC)=C1CN1C(C=2N=C(F)C=CC=2)=NC=C1 WJXTVWLBDVTBPV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000004650 C1-C8 alkynyl group Chemical group 0.000 claims description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
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- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000003834 intracellular effect Effects 0.000 claims description 2
- VTWJSXSCJVTOMB-UHFFFAOYSA-N n-methyl-6-[[2-[3-(methylamino)pyridin-2-yl]imidazol-1-yl]methyl]-5-propylpyrimidin-4-amine Chemical compound N1=CN=C(NC)C(CCC)=C1CN1C(C=2C(=CC=CN=2)NC)=NC=C1 VTWJSXSCJVTOMB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 230000019491 signal transduction Effects 0.000 claims description 2
- IGGHPDQDHZHESP-UHFFFAOYSA-N 2-[1-[(6-methyl-5-propylpyrimidin-4-yl)methyl]imidazol-2-yl]pyridine-3-carbonitrile Chemical compound CCCC1=C(C)N=CN=C1CN1C(C=2C(=CC=CN=2)C#N)=NC=C1 IGGHPDQDHZHESP-UHFFFAOYSA-N 0.000 claims 1
- DPUHYMKVRVPMFF-UHFFFAOYSA-N 2-[6-[[2-(3-fluoropyridin-2-yl)imidazol-1-yl]methyl]-5-propylpyrimidin-4-yl]-1,3-thiazole Chemical compound N1=CN=C(C=2SC=CN=2)C(CCC)=C1CN1C=CN=C1C1=NC=CC=C1F DPUHYMKVRVPMFF-UHFFFAOYSA-N 0.000 claims 1
- RXDRQWJPNILHRD-UHFFFAOYSA-N 4-[[2-(2,5-difluorophenyl)imidazol-1-yl]methyl]-5-ethyl-6-methylpyrimidine Chemical compound CCC1=C(C)N=CN=C1CN1C(C=2C(=CC=C(F)C=2)F)=NC=C1 RXDRQWJPNILHRD-UHFFFAOYSA-N 0.000 claims 1
- RLBFRGZDFITHTJ-UHFFFAOYSA-N 4-[[2-(3-fluoropyridin-2-yl)imidazol-1-yl]methyl]-5-propyl-6-pyrazin-2-ylpyrimidine Chemical compound N1=CN=C(C=2N=CC=NC=2)C(CCC)=C1CN1C=CN=C1C1=NC=CC=C1F RLBFRGZDFITHTJ-UHFFFAOYSA-N 0.000 claims 1
- QXTHTFNMHARPIB-UHFFFAOYSA-N 4-[[2-(3-fluoropyridin-2-yl)imidazol-1-yl]methyl]-5-propyl-6-pyridin-2-ylpyrimidine Chemical compound N1=CN=C(C=2N=CC=CC=2)C(CCC)=C1CN1C=CN=C1C1=NC=CC=C1F QXTHTFNMHARPIB-UHFFFAOYSA-N 0.000 claims 1
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- AZNBUWWLYBFJIK-UHFFFAOYSA-N 4-methyl-5-propyl-6-[[2-[6-(trifluoromethyl)pyridin-2-yl]imidazol-1-yl]methyl]pyrimidine Chemical compound CCCC1=C(C)N=CN=C1CN1C(C=2N=C(C=CC=2)C(F)(F)F)=NC=C1 AZNBUWWLYBFJIK-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C07D401/14—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 three or more hetero rings
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
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|---|---|---|---|
| US42494502P | 2002-11-08 | 2002-11-08 | |
| PCT/IB2003/004978 WO2004041808A1 (en) | 2002-11-08 | 2003-11-04 | 4-imidazol-1-ylmethyl-pyrimidine derivatives_as ligands for gabaa receptors |
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| JP2006508102A true JP2006508102A (ja) | 2006-03-09 |
| JP2006508102A5 JP2006508102A5 (enExample) | 2006-12-21 |
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| US (1) | US6951864B2 (enExample) |
| EP (1) | EP1560822B1 (enExample) |
| JP (1) | JP2006508102A (enExample) |
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| AU (1) | AU2003276514A1 (enExample) |
| CA (1) | CA2495708A1 (enExample) |
| DE (1) | DE60307499T2 (enExample) |
| ES (1) | ES2268488T3 (enExample) |
| WO (1) | WO2004041808A1 (enExample) |
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| CN100579579C (zh) | 2002-10-01 | 2010-01-13 | 诺华疫苗和诊断公司 | 抗癌及抗感染性疾病组合物及其使用方法 |
| EP1594848A1 (en) | 2003-02-19 | 2005-11-16 | Neurogen Corporation | Aryl acid pyrimidinyl methyl amides, pyridazinyl methyl amides and related compounds |
| EP1619948A4 (en) * | 2003-05-05 | 2007-02-14 | Neurogen Corp | SUBSTITUTED IMIDAZOLOPYRAZINE AND TRIAZOLOPYRAZINE DERIVATIVES: GABAA RECEPTOR LIGANDS |
| ATE350382T1 (de) | 2003-07-25 | 2007-01-15 | Neurogen Corp | Imidazopyrimidine und triazolopyrimidine: benzodiazepinrezeptorliganden |
| MXPA06014909A (es) | 2004-06-18 | 2007-02-28 | Chiron Corp | Derivados de n-(1-(1-bencil -4-fenil-1h -imidazol -2-il)-2, 2-dimetilpropil) benzamida y compuestos relacionados como inhibidores de proteina de huso de cinesina (ksp) para el tratamiento del cancer. |
| GEP20125415B (en) | 2007-01-05 | 2012-03-12 | Novartis Ag | Imidazole derivatives as kinesin spindle protein inhibitors (eg-5) |
| US20150374705A1 (en) | 2012-02-14 | 2015-12-31 | Shanghai Institues for Biological Sciences | Substances for treatment or relief of pain |
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| PA8535601A1 (es) * | 2000-12-21 | 2002-11-28 | Pfizer | Derivados benzimidazol y piridilimidazol como ligandos para gabaa |
| US7030128B2 (en) * | 2001-03-23 | 2006-04-18 | Merck Sharp & Dohme Ltd. | Imidazo-pyrimidine derivatives as ligands for GABA receptors |
| CN100579579C (zh) * | 2002-10-01 | 2010-01-13 | 诺华疫苗和诊断公司 | 抗癌及抗感染性疾病组合物及其使用方法 |
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2003
- 2003-11-04 DE DE60307499T patent/DE60307499T2/de not_active Expired - Fee Related
- 2003-11-04 AT AT03810562T patent/ATE335732T1/de not_active IP Right Cessation
- 2003-11-04 EP EP03810562A patent/EP1560822B1/en not_active Expired - Lifetime
- 2003-11-04 WO PCT/IB2003/004978 patent/WO2004041808A1/en not_active Ceased
- 2003-11-04 CA CA002495708A patent/CA2495708A1/en not_active Abandoned
- 2003-11-04 ES ES03810562T patent/ES2268488T3/es not_active Expired - Lifetime
- 2003-11-04 JP JP2004549490A patent/JP2006508102A/ja active Pending
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|---|---|
| US6951864B2 (en) | 2005-10-04 |
| EP1560822A1 (en) | 2005-08-10 |
| CA2495708A1 (en) | 2004-05-21 |
| EP1560822B1 (en) | 2006-08-09 |
| DE60307499T2 (de) | 2007-02-01 |
| WO2004041808A1 (en) | 2004-05-21 |
| DE60307499D1 (de) | 2006-09-21 |
| AU2003276514A1 (en) | 2004-06-07 |
| ES2268488T3 (es) | 2007-03-16 |
| ATE335732T1 (de) | 2006-09-15 |
| US20040102457A1 (en) | 2004-05-27 |
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