MXPA06014909A - 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. - Google Patents
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.Info
- Publication number
- MXPA06014909A MXPA06014909A MXPA06014909A MXPA06014909A MXPA06014909A MX PA06014909 A MXPA06014909 A MX PA06014909A MX PA06014909 A MXPA06014909 A MX PA06014909A MX PA06014909 A MXPA06014909 A MX PA06014909A MX PA06014909 A MXPA06014909 A MX PA06014909A
- Authority
- MX
- Mexico
- Prior art keywords
- imidazol
- benzyl
- phenyl
- dimethylpropyl
- amino
- Prior art date
Links
- -1 1-benzyl -4-phenyl-1h-imidazol-2-yl Chemical group 0.000 title claims abstract description 939
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 55
- 201000011510 cancer Diseases 0.000 title claims abstract description 31
- 238000011282 treatment Methods 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 title claims description 210
- 102000010638 Kinesin Human genes 0.000 title claims description 10
- 108010063296 Kinesin Proteins 0.000 title claims description 10
- 239000003112 inhibitor Substances 0.000 title description 10
- 108090000623 proteins and genes Proteins 0.000 title description 9
- 102000004169 proteins and genes Human genes 0.000 title description 8
- 150000003936 benzamides Chemical class 0.000 title 1
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 205
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 170
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 119
- 239000001257 hydrogen Substances 0.000 claims abstract description 105
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 105
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 92
- 125000003118 aryl group Chemical group 0.000 claims abstract description 89
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 81
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 79
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 65
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 55
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 47
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 47
- 125000001424 substituent group Chemical group 0.000 claims abstract description 46
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 42
- 125000005415 substituted alkoxy group Chemical group 0.000 claims abstract description 41
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims abstract description 23
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 23
- 125000004442 acylamino group Chemical group 0.000 claims abstract description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
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- 125000001475 halogen functional group Chemical group 0.000 claims abstract 22
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 257
- 239000000203 mixture Substances 0.000 claims description 145
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- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 91
- 229910052757 nitrogen Inorganic materials 0.000 claims description 71
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 65
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 64
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 59
- 238000000034 method Methods 0.000 claims description 51
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 43
- 125000003545 alkoxy group Chemical group 0.000 claims description 43
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 42
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 40
- 239000002253 acid Substances 0.000 claims description 30
- 125000004104 aryloxy group Chemical group 0.000 claims description 30
- 125000002252 acyl group Chemical group 0.000 claims description 26
- 125000003342 alkenyl group Chemical group 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000000304 alkynyl group Chemical group 0.000 claims description 24
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 24
- UJJLJRQIPMGXEZ-BYPYZUCNSA-N (2s)-oxolane-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCO1 UJJLJRQIPMGXEZ-BYPYZUCNSA-N 0.000 claims description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 19
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
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- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 16
- 229940002612 prodrug Drugs 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
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- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 14
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 14
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 14
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- 208000035475 disorder Diseases 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
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- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 8
- 229960000575 trastuzumab Drugs 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 150000004702 methyl esters Chemical class 0.000 claims description 7
- 230000002062 proliferating effect Effects 0.000 claims description 7
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 6
- 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 claims description 6
- 125000006291 3-hydroxybenzyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 6
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- VKCYHJWLYTUGCC-UHFFFAOYSA-N nonan-2-one Chemical compound CCCCCCCC(C)=O VKCYHJWLYTUGCC-UHFFFAOYSA-N 0.000 claims description 6
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 6
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 6
- SXTODTAIBNOYIO-IBGZPJMESA-N (1r)-1-[4-(3-fluorophenyl)-1-[(3-fluorophenyl)methyl]imidazol-2-yl]-2,2-dimethylpropan-1-amine Chemical compound CC(C)(C)[C@@H](N)C1=NC(C=2C=C(F)C=CC=2)=CN1CC1=CC=CC(F)=C1 SXTODTAIBNOYIO-IBGZPJMESA-N 0.000 claims description 5
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 5
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- 210000004556 brain Anatomy 0.000 claims description 5
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- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 4
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- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
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- 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
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- 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
- C07D405/02—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 two hetero rings
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- 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
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- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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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
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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
- C07D417/06—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 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
- C07D417/02—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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
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| US58092704P | 2004-06-18 | 2004-06-18 | |
| PCT/US2005/022062 WO2006002236A1 (en) | 2004-06-18 | 2005-06-20 | N- (1- (1-benzyl -4-phenyl-1h-imidazol-2-yl) -2,2-dymethylpropyl) benzamide derivatives and related compounds as kinesin spindle protein (ksp) inhibitors for the treatment of cancer |
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|---|---|
| MXPA06014909A true MXPA06014909A (es) | 2007-02-28 |
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| MXPA06014909A MXPA06014909A (es) | 2004-06-18 | 2005-06-20 | 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. |
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| US8748626B2 (en) | 2010-04-15 | 2014-06-10 | Novartis Ag | Oxazole and thiazole compounds as KSP inhibitors |
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| US9498540B2 (en) | 2013-03-15 | 2016-11-22 | Novartis Ag | Cell proliferation inhibitors and conjugates thereof |
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| JP2018525334A (ja) | 2015-06-23 | 2018-09-06 | バイエル ファーマ アクチエンゲゼルシャフト | キネシンスピンドルタンパク質(ksp)阻害剤の抗tweakr抗体との抗体薬物複合体 |
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| CA3027445A1 (en) | 2016-06-15 | 2017-12-21 | Bayer Pharma Aktiengesellschaft | Specific antibody-drug-conjugates (adcs) with ksp inhibitors and anti-cd123-antibodies |
| WO2018114804A1 (de) | 2016-12-21 | 2018-06-28 | Bayer Pharma Aktiengesellschaft | Spezifische antikörper-wirkstoff-konjugate (adcs) mit ksp-inhibitoren |
| MX2019007641A (es) | 2016-12-21 | 2019-09-09 | Bayer Pharma AG | Conjugados de ligando-farmaco (adcs) con grupos escindibles enzimaticamente. |
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| US8735599B2 (en) | 2014-05-27 |
| AU2005258135A1 (en) | 2006-01-05 |
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| JP2008503501A (ja) | 2008-02-07 |
| US20090258016A1 (en) | 2009-10-15 |
| TNSN06419A1 (en) | 2008-02-22 |
| KR101170925B1 (ko) | 2012-08-07 |
| US8318791B2 (en) | 2012-11-27 |
| RU2427572C2 (ru) | 2011-08-27 |
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