JP2009516697A - 癌および炎症性疾患の治療のためのｉｋｋ−ベータ阻害剤としての［４−（ベンゾ［ｂ］チオフェン−２−イル）ピリミジン−２イル］アミン誘導体 - Google Patents
癌および炎症性疾患の治療のためのｉｋｋ−ベータ阻害剤としての［４−（ベンゾ［ｂ］チオフェン−２−イル）ピリミジン−２イル］アミン誘導体 Download PDFInfo
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- JP2009516697A JP2009516697A JP2008541463A JP2008541463A JP2009516697A JP 2009516697 A JP2009516697 A JP 2009516697A JP 2008541463 A JP2008541463 A JP 2008541463A JP 2008541463 A JP2008541463 A JP 2008541463A JP 2009516697 A JP2009516697 A JP 2009516697A
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- benzo
- carboxylic acid
- mmol
- thiophene
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- 238000011282 treatment Methods 0.000 title claims abstract description 32
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 15
- 201000011510 cancer Diseases 0.000 title claims abstract description 15
- 208000027866 inflammatory disease Diseases 0.000 title claims abstract description 10
- -1 Benzo [B] thiophen-2-yl Chemical group 0.000 title claims description 243
- 150000001412 amines Chemical class 0.000 title description 12
- 102000001284 I-kappa-B kinase Human genes 0.000 title description 2
- 108060006678 I-kappa-B kinase Proteins 0.000 title description 2
- 239000003112 inhibitor Substances 0.000 title 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 336
- 238000000034 method Methods 0.000 claims description 140
- 150000003839 salts Chemical class 0.000 claims description 45
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 7
- 208000005017 glioblastoma Diseases 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- BNFAYJPQCPZQND-UHFFFAOYSA-N 2-[5-chloro-2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-n-cyclopropyl-1-benzothiophene-4-carboxamide Chemical compound C1CN(C)CCN1CCCNC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 BNFAYJPQCPZQND-UHFFFAOYSA-N 0.000 claims description 6
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 5
- 206010023774 Large cell lung cancer Diseases 0.000 claims description 5
- 201000009546 lung large cell carcinoma Diseases 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 claims description 3
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000006301 indolyl methyl group Chemical group 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- ZPPCVOFLGDUHFM-UHFFFAOYSA-N n-cyclopropyl-2-[5-methyl-2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-1-benzothiophene-4-carboxamide Chemical compound C1CN(C)CCN1CCCNC1=NC=C(C)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 ZPPCVOFLGDUHFM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 703
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 398
- 239000007787 solid Substances 0.000 description 308
- 239000000203 mixture Substances 0.000 description 278
- 239000000243 solution Substances 0.000 description 227
- 238000002360 preparation method Methods 0.000 description 136
- 239000012458 free base Substances 0.000 description 119
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 112
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 239000000725 suspension Substances 0.000 description 90
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 88
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- 239000003921 oil Substances 0.000 description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 63
- 238000010898 silica gel chromatography Methods 0.000 description 61
- 238000006243 chemical reaction Methods 0.000 description 60
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 58
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 239000012299 nitrogen atmosphere Substances 0.000 description 48
- 239000000741 silica gel Substances 0.000 description 46
- 229910002027 silica gel Inorganic materials 0.000 description 46
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 40
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 40
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 38
- 239000000047 product Substances 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 34
- 238000003756 stirring Methods 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- 239000012044 organic layer Substances 0.000 description 32
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 29
- 238000001914 filtration Methods 0.000 description 29
- 238000000746 purification Methods 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 239000002253 acid Substances 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 24
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 21
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 21
- 239000000543 intermediate Substances 0.000 description 21
- 238000001816 cooling Methods 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- 239000011734 sodium Substances 0.000 description 19
- HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 description 18
- RGUABPVONIGVAT-UHFFFAOYSA-N 3-(4-methylpiperazin-1-yl)propan-1-amine Chemical compound CN1CCN(CCCN)CC1 RGUABPVONIGVAT-UHFFFAOYSA-N 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
- 238000010828 elution Methods 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 238000001035 drying Methods 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
- 239000007789 gas Substances 0.000 description 13
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 12
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
- 239000013058 crude material Substances 0.000 description 12
- QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical compound Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 12
- 101100508533 Drosophila melanogaster IKKbeta gene Proteins 0.000 description 11
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- GSQDFHSGLFZEMW-UHFFFAOYSA-N n-cyclopropyl-2-(2,5-dichloropyrimidin-4-yl)-1-benzothiophene-4-carboxamide Chemical compound ClC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 GSQDFHSGLFZEMW-UHFFFAOYSA-N 0.000 description 11
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- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 10
- IEXCRLAGBWKVPW-UHFFFAOYSA-N 2-[5-chloro-2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-n-cyclopropyl-1-benzothiophene-4-carboxamide;trihydrochloride Chemical compound Cl.Cl.Cl.C1CN(C)CCN1CCCNC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 IEXCRLAGBWKVPW-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
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- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 9
- XSGXZJPLDGFVCT-UHFFFAOYSA-N 2-(2-chloro-5-methylpyrimidin-4-yl)-n-cyclopropyl-1-benzothiophene-4-carboxamide Chemical compound CC1=CN=C(Cl)N=C1C1=CC2=C(C(=O)NC3CC3)C=CC=C2S1 XSGXZJPLDGFVCT-UHFFFAOYSA-N 0.000 description 8
- OPQRMLFPDZPBKA-UHFFFAOYSA-N 2-(5-bromo-2-chloropyrimidin-4-yl)-n-cyclopropyl-1-benzothiophene-4-carboxamide Chemical compound ClC1=NC=C(Br)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 OPQRMLFPDZPBKA-UHFFFAOYSA-N 0.000 description 8
- QMGXBFGQSMSXST-UHFFFAOYSA-N 2-[5-chloro-2-[2-(1-methylpiperidin-4-yl)ethylamino]pyrimidin-4-yl]-1-benzothiophene-4-carboxamide Chemical compound C1CN(C)CCC1CCNC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(N)=O)=N1 QMGXBFGQSMSXST-UHFFFAOYSA-N 0.000 description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
- OQIMJOXSDVGEBU-UHFFFAOYSA-N 6-bromo-1-benzothiophene Chemical compound BrC1=CC=C2C=CSC2=C1 OQIMJOXSDVGEBU-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 8
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- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- 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 8
- QZYIDMYWRACBRQ-UHFFFAOYSA-N tert-butyl 4-(3-aminopropyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CCCN)CC1 QZYIDMYWRACBRQ-UHFFFAOYSA-N 0.000 description 8
- SHKGXHKLGJPRFV-UHFFFAOYSA-N 2-[5-methyl-2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-1-benzothiophene-6-carboxylic acid Chemical compound C1CN(C)CCN1CCCNC1=NC=C(C)C(C=2SC3=CC(=CC=C3C=2)C(O)=O)=N1 SHKGXHKLGJPRFV-UHFFFAOYSA-N 0.000 description 7
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 7
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 7
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- 125000006239 protecting group Chemical group 0.000 description 7
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- 125000001424 substituent group Chemical group 0.000 description 7
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- IZXMGGLFJGYNBW-UHFFFAOYSA-N 3-(4-propan-2-ylpiperazin-1-yl)propan-1-amine Chemical compound CC(C)N1CCN(CCCN)CC1 IZXMGGLFJGYNBW-UHFFFAOYSA-N 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 6
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
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- ANCBHJKEYPZCTE-UHFFFAOYSA-N ethyl 5-carbamoyl-4-methyl-2-[(2,3,4,5,6-pentafluorobenzoyl)amino]thiophene-3-carboxylate Chemical compound CC1=C(C(N)=O)SC(NC(=O)C=2C(=C(F)C(F)=C(F)C=2F)F)=C1C(=O)OCC ANCBHJKEYPZCTE-UHFFFAOYSA-N 0.000 description 6
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- HFCUTESXGRGMSQ-UHFFFAOYSA-N n-cyclopropyl-1-benzothiophene-4-carboxamide Chemical compound C=1C=CC=2SC=CC=2C=1C(=O)NC1CC1 HFCUTESXGRGMSQ-UHFFFAOYSA-N 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 description 5
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- DAUYIKBTMNZABP-UHFFFAOYSA-N thiophene-3-carboxamide Chemical compound NC(=O)C=1C=CSC=1 DAUYIKBTMNZABP-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 108091008023 transcriptional regulators Proteins 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229910000166 zirconium phosphate Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US73809705P | 2005-11-18 | 2005-11-18 | |
| PCT/US2006/060911 WO2007092095A2 (en) | 2005-11-18 | 2006-11-15 | [4-(benzo [b] thi0phen-2-yl) pyrimidin-2yl] -amine derivatives as ikk-beta inhibitors for the treatment of cancer and inflammatory diseases. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2009516697A true JP2009516697A (ja) | 2009-04-23 |
| JP2009516697A5 JP2009516697A5 (enExample) | 2009-12-17 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008541463A Ceased JP2009516697A (ja) | 2005-11-18 | 2006-11-15 | 癌および炎症性疾患の治療のためのｉｋｋ−ベータ阻害剤としての［４−（ベンゾ［ｂ］チオフェン−２−イル）ピリミジン−２イル］アミン誘導体 |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US7547691B2 (enExample) |
| EP (1) | EP1989200B1 (enExample) |
| JP (1) | JP2009516697A (enExample) |
| KR (1) | KR100990771B1 (enExample) |
| CN (1) | CN101309918B (enExample) |
| AR (1) | AR057911A1 (enExample) |
| AT (1) | ATE437873T1 (enExample) |
| AU (1) | AU2006337626B2 (enExample) |
| BR (1) | BRPI0618245A2 (enExample) |
| CA (1) | CA2629336A1 (enExample) |
| CR (1) | CR9947A (enExample) |
| DE (1) | DE602006008187D1 (enExample) |
| DK (1) | DK1989200T3 (enExample) |
| EA (1) | EA014426B1 (enExample) |
| EC (1) | ECSP088456A (enExample) |
| ES (1) | ES2329085T3 (enExample) |
| IL (1) | IL190489A0 (enExample) |
| MA (1) | MA30053B1 (enExample) |
| NO (1) | NO20082594L (enExample) |
| PE (1) | PE20070833A1 (enExample) |
| PL (1) | PL1989200T3 (enExample) |
| PT (1) | PT1989200E (enExample) |
| SI (1) | SI1989200T1 (enExample) |
| TN (1) | TNSN08227A1 (enExample) |
| TW (1) | TW200800201A (enExample) |
| WO (1) | WO2007092095A2 (enExample) |
| ZA (1) | ZA200803940B (enExample) |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RS51423B (sr) | 2006-03-31 | 2011-02-28 | Janssen Pharmaceutica N.V. | Benzoimidazol-2-il pirimidini i pirazini kao modulatori histaminskog h4 receptora |
| WO2008011557A2 (en) * | 2006-07-20 | 2008-01-24 | Borchardt Allen J | Heteroaryl inhibitors of rho kinase |
| MX2009006635A (es) | 2006-12-21 | 2009-06-30 | Lilly Co Eli | Compuestos de imidazolidinonil aminopirimidina para el tratamiento de cancer. |
| AU2007334039B2 (en) | 2006-12-21 | 2012-02-16 | Eli Lilly And Company | Imidazolidinonyl aminopyrimidine compounds for the treatment' of cancer |
| BRPI0811433A2 (pt) | 2007-05-16 | 2016-03-22 | Lilly Co Eli | compostos do tipo triazolil aminopirimidina |
| US8114872B2 (en) | 2007-05-16 | 2012-02-14 | Eli Lilly And Company | Triazolyl aminopyrimidine compounds |
| PT2310012E (pt) | 2008-06-30 | 2015-04-02 | Janssen Pharmaceutica Nv | Processo para a preparação de derivados de pirimidina substituída |
| US9371311B2 (en) | 2008-06-30 | 2016-06-21 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine derivatives |
| KR101123178B1 (ko) * | 2009-04-09 | 2012-06-13 | (주)에스메디 | 2-아릴벤조싸이오펜 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 퇴행성 뇌질환의 진단 또는 치료용 약학적 조성물 |
| WO2011022473A1 (en) | 2009-08-19 | 2011-02-24 | Ambit Biosciences Corporation | Biaryl compounds and methods of use thereof |
| MX2012012502A (es) | 2010-04-27 | 2013-01-18 | Hutchison Medipharma Ltd | Compuestos pirimidinil indol. |
| US20140194383A1 (en) | 2011-04-07 | 2014-07-10 | Cornell University | Monomers capable of dimerizing in an aqueous solution, and methods of using same |
| US9245773B2 (en) | 2011-09-02 | 2016-01-26 | Taiwan Semiconductor Manufacturing Company, Ltd. | Semiconductor device packaging methods and structures thereof |
| CN103159742B (zh) * | 2011-12-16 | 2015-08-12 | 北京韩美药品有限公司 | 5-氯嘧啶类化合物及其作为egfr酪氨酸激酶抑制剂的应用 |
| JP6250561B2 (ja) | 2012-02-08 | 2017-12-20 | サノビオン ファーマシューティカルズ インクＳｕｎｏｖｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． | ヘテロアリール化合物およびそれらの使用方法 |
| US9227978B2 (en) | 2013-03-15 | 2016-01-05 | Araxes Pharma Llc | Covalent inhibitors of Kras G12C |
| JO3805B1 (ar) | 2013-10-10 | 2021-01-31 | Araxes Pharma Llc | مثبطات كراس جي12سي |
| CN105085434B (zh) * | 2014-05-09 | 2018-02-09 | 上海特化医药科技有限公司 | 硫乙拉嗪或其中间体的制备方法 |
| WO2017076888A1 (en) * | 2015-11-03 | 2017-05-11 | Janssen Pharmaceutica Nv | 2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carboxylic acids and amides and methods of making the same |
| CN110087687A (zh) | 2016-07-29 | 2019-08-02 | 赛诺维信制药公司 | 化合物、组合物及其用途 |
| CA3032302A1 (en) | 2016-07-29 | 2018-02-01 | Taleen G. Hanania | Compounds and compositions and uses thereof |
| US11279689B2 (en) | 2017-01-26 | 2022-03-22 | Araxes Pharma Llc | 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer |
| EP3573964A1 (en) * | 2017-01-26 | 2019-12-04 | Araxes Pharma LLC | Benzothiophene and benzothiazole compounds and methods of use thereof |
| US11274093B2 (en) | 2017-01-26 | 2022-03-15 | Araxes Pharma Llc | Fused bicyclic benzoheteroaromatic compounds and methods of use thereof |
| WO2018140514A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | 1-(6-(3-hydroxynaphthalen-1-yl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one derivatives and similar compounds as kras g12c inhibitors for the treatment of cancer |
| EP3630745A2 (en) | 2017-05-25 | 2020-04-08 | Araxes Pharma LLC | Covalent inhibitors of kras |
| CN110831933A (zh) | 2017-05-25 | 2020-02-21 | 亚瑞克西斯制药公司 | 喹唑啉衍生物作为突变kras、hras或nras的调节剂 |
| CN111183138A (zh) | 2017-08-02 | 2020-05-19 | 赛诺维信制药公司 | 异色满化合物以及用途 |
| BR112021001709A2 (pt) | 2018-08-01 | 2021-05-04 | Araxes Pharma Llc | compostos espiro heterocíclicos e métodos de uso dos mesmos para o tratamento de câncer |
| MX2021010880A (es) | 2019-03-14 | 2022-01-18 | Sunovion Pharmaceuticals Inc | Sales de un compuesto de isocromanilo y formas cristalinas, procesos de preparacion, usos terapeuticos y composiciones farmaceuticas de las mismas. |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989011279A1 (en) * | 1988-05-16 | 1989-11-30 | Georgia State University Foundation, Inc. | Nucleic acid interacting unfused heteropolycyclic compounds |
| WO2004089913A1 (en) * | 2003-04-11 | 2004-10-21 | Novartis Ag | Aminopyrimidine derivatives and their medical use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4932735B2 (ja) * | 2004-12-17 | 2012-05-16 | アムジエン・インコーポレーテツド | アミノピリミジン化合物および使用方法 |
-
2006
- 2006-10-23 TW TW095139053A patent/TW200800201A/zh unknown
- 2006-11-15 PT PT06850430T patent/PT1989200E/pt unknown
- 2006-11-15 US US12/093,024 patent/US7547691B2/en not_active Expired - Fee Related
- 2006-11-15 PE PE2006001456A patent/PE20070833A1/es not_active Application Discontinuation
- 2006-11-15 AT AT06850430T patent/ATE437873T1/de active
- 2006-11-15 AU AU2006337626A patent/AU2006337626B2/en not_active Ceased
- 2006-11-15 WO PCT/US2006/060911 patent/WO2007092095A2/en not_active Ceased
- 2006-11-15 KR KR1020087011830A patent/KR100990771B1/ko not_active Expired - Fee Related
- 2006-11-15 EP EP06850430A patent/EP1989200B1/en active Active
- 2006-11-15 ES ES06850430T patent/ES2329085T3/es active Active
- 2006-11-15 SI SI200630446T patent/SI1989200T1/sl unknown
- 2006-11-15 EA EA200801362A patent/EA014426B1/ru not_active IP Right Cessation
- 2006-11-15 CA CA002629336A patent/CA2629336A1/en not_active Abandoned
- 2006-11-15 DK DK06850430T patent/DK1989200T3/da active
- 2006-11-15 BR BRPI0618245-3A patent/BRPI0618245A2/pt not_active IP Right Cessation
- 2006-11-15 CN CN2006800428126A patent/CN101309918B/zh not_active Expired - Fee Related
- 2006-11-15 JP JP2008541463A patent/JP2009516697A/ja not_active Ceased
- 2006-11-15 PL PL06850430T patent/PL1989200T3/pl unknown
- 2006-11-15 DE DE602006008187T patent/DE602006008187D1/de active Active
- 2006-11-17 AR ARP060105065A patent/AR057911A1/es unknown
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2008
- 2008-03-27 IL IL190489A patent/IL190489A0/en unknown
- 2008-04-29 CR CR9947A patent/CR9947A/es not_active Application Discontinuation
- 2008-05-08 ZA ZA200803940A patent/ZA200803940B/xx unknown
- 2008-05-16 EC EC2008008456A patent/ECSP088456A/es unknown
- 2008-05-16 TN TNP2008000227A patent/TNSN08227A1/en unknown
- 2008-06-10 NO NO20082594A patent/NO20082594L/no not_active Application Discontinuation
- 2008-06-13 MA MA31035A patent/MA30053B1/fr unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989011279A1 (en) * | 1988-05-16 | 1989-11-30 | Georgia State University Foundation, Inc. | Nucleic acid interacting unfused heteropolycyclic compounds |
| WO2004089913A1 (en) * | 2003-04-11 | 2004-10-21 | Novartis Ag | Aminopyrimidine derivatives and their medical use |
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