TW201410676A - 芳基內醯胺激酶抑制劑 - Google Patents
芳基內醯胺激酶抑制劑 Download PDFInfo
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- TW201410676A TW201410676A TW102127296A TW102127296A TW201410676A TW 201410676 A TW201410676 A TW 201410676A TW 102127296 A TW102127296 A TW 102127296A TW 102127296 A TW102127296 A TW 102127296A TW 201410676 A TW201410676 A TW 201410676A
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- Prior art keywords
- amino
- naphthyridin
- group
- oxy
- alkyl
- Prior art date
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- -1 Aryl lactam Chemical class 0.000 title claims description 199
- 229940043355 kinase inhibitor Drugs 0.000 title description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 421
- 239000000203 mixture Substances 0.000 claims abstract description 154
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 102100038079 AP2-associated protein kinase 1 Human genes 0.000 claims abstract description 9
- 101710148635 AP2-associated protein kinase 1 Proteins 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 claims description 124
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 44
- 125000005843 halogen group Chemical group 0.000 claims description 43
- 125000003118 aryl group Chemical group 0.000 claims description 39
- 238000011282 treatment Methods 0.000 claims description 38
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 34
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 29
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 150000001412 amines Chemical class 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 23
- HPFOEWJXDNWCTH-UHFFFAOYSA-N 6h-benzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC=C2C(=O)NC3=CC=CC=C3C2=C1 HPFOEWJXDNWCTH-UHFFFAOYSA-N 0.000 claims description 21
- 125000003277 amino group Chemical group 0.000 claims description 21
- 125000005605 benzo group Chemical group 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 208000002193 Pain Diseases 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 230000036407 pain Effects 0.000 claims description 10
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 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
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 201000000980 schizophrenia Diseases 0.000 claims description 8
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
- 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 208000004296 neuralgia Diseases 0.000 claims description 6
- 208000021722 neuropathic pain Diseases 0.000 claims description 6
- 229910052727 yttrium Inorganic materials 0.000 claims description 6
- XCKUSTFLSTVTCR-AWEZNQCLSA-N 8-[(2s)-2-amino-4-methylpentoxy]-2,6-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound N1=C(C)C=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3N(C)C(=O)C2=C1 XCKUSTFLSTVTCR-AWEZNQCLSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000001769 aryl amino group Chemical group 0.000 claims description 5
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 4
- XWZXCIPLOWRHAC-UHFFFAOYSA-N 8-(2-amino-5,5,5-trifluoropentoxy)-6-methylbenzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC=C2C(=O)N(C)C3=CC(OCC(N)CCC(F)(F)F)=CC=C3C2=C1 XWZXCIPLOWRHAC-UHFFFAOYSA-N 0.000 claims description 4
- JOCMZPAMMJDEEF-IBGZPJMESA-N 8-[(2s)-2-amino-4-methylpentoxy]-6-benzylbenzo[c][2,7]naphthyridin-5-one Chemical compound C=1C(OC[C@@H](N)CC(C)C)=CC=C(C2=CC=NC=C2C2=O)C=1N2CC1=CC=CC=C1 JOCMZPAMMJDEEF-IBGZPJMESA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- ATCROYCGFZTPSQ-LBPRGKRZSA-N 8-[(2s)-2-amino-4-methylpentoxy]-6h-benzo[c][2,7]naphthyridin-5-one Chemical compound N1=CC=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3NC(=O)C2=C1 ATCROYCGFZTPSQ-LBPRGKRZSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 3
- 125000004992 haloalkylamino group Chemical group 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- LOZLKDVGPQCIRZ-INIZCTEOSA-N 4,6-dimethyl-8-[(2s)-4-methyl-2-(methylamino)pentoxy]-5-oxobenzo[c][2,7]naphthyridine-9-carbonitrile Chemical compound CN1C(=O)C2=C(C)N=CC=C2C2=C1C=C(OC[C@@H](NC)CC(C)C)C(C#N)=C2 LOZLKDVGPQCIRZ-INIZCTEOSA-N 0.000 claims description 2
- GIJACGNPPUYZEJ-LBPRGKRZSA-N 4-amino-8-[(2s)-2-amino-4-methylpentoxy]-6-methylbenzo[c][2,7]naphthyridin-5-one Chemical compound N1=CC=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3N(C)C(=O)C2=C1N GIJACGNPPUYZEJ-LBPRGKRZSA-N 0.000 claims description 2
- OOOPDKTUMJEDEK-INIZCTEOSA-N 8-[(2s)-2-amino-3-cyclobutylpropoxy]-4,6,9-trimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound C([C@H](N)COC1=CC2=C(C3=CC=NC(C)=C3C(=O)N2C)C=C1C)C1CCC1 OOOPDKTUMJEDEK-INIZCTEOSA-N 0.000 claims description 2
- HRMGBYSRWUAWIG-AWEZNQCLSA-N 8-[(2s)-2-amino-4-methylpentoxy]-4,6-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound N1=CC=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3N(C)C(=O)C2=C1C HRMGBYSRWUAWIG-AWEZNQCLSA-N 0.000 claims description 2
- DNJVIWQGOSPTGR-LBPRGKRZSA-N 8-[(2s)-2-amino-4-methylpentoxy]-9-bromo-6-methylbenzo[c][2,7]naphthyridin-5-one Chemical compound CN1C(=O)C2=CN=CC=C2C2=C1C=C(OC[C@@H](N)CC(C)C)C(Br)=C2 DNJVIWQGOSPTGR-LBPRGKRZSA-N 0.000 claims description 2
- 208000001640 Fibromyalgia Diseases 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- WMPDMMUFIRDMPA-AWEZNQCLSA-N n-[8-[(2s)-2-amino-4-methylpentoxy]-6-methyl-5-oxobenzo[c][2,7]naphthyridin-2-yl]acetamide Chemical compound N1=C(NC(C)=O)C=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3N(C)C(=O)C2=C1 WMPDMMUFIRDMPA-AWEZNQCLSA-N 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- CGUAZCQWONVSAJ-UHFFFAOYSA-N 1-[(1-fluoro-6-methyl-5H-benzo[c][2,7]naphthyridin-8-yl)oxy]-2,4-dimethylpentan-2-amine Chemical compound NC(COC=1C=CC2=C(N(CC3=CN=CC(=C23)F)C)C1)(CC(C)C)C CGUAZCQWONVSAJ-UHFFFAOYSA-N 0.000 claims 1
- PRTTZMKZMXANFG-UHFFFAOYSA-N 2-amino-2,4-dimethylpentanenitrile Chemical compound CC(C)CC(C)(N)C#N PRTTZMKZMXANFG-UHFFFAOYSA-N 0.000 claims 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 claims 1
- NBHCBBXZBQCGBZ-UHFFFAOYSA-N 8-(2-amino-2,4-dimethylpentoxy)-7-fluoro-4,6-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC(C)=C2C(=O)N(C)C3=C(F)C(OCC(C)(N)CC(C)C)=CC=C3C2=C1 NBHCBBXZBQCGBZ-UHFFFAOYSA-N 0.000 claims 1
- QWYVFLDYWGJEQU-HNNXBMFYSA-N 8-[(2s)-2-amino-3-cyclopropylpropoxy]-4,6,9-trimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound C([C@H](N)COC1=CC2=C(C3=CC=NC(C)=C3C(=O)N2C)C=C1C)C1CC1 QWYVFLDYWGJEQU-HNNXBMFYSA-N 0.000 claims 1
- NQXBZPJVVGIFBJ-HNNXBMFYSA-N 8-[(2s)-2-amino-4-methylpentoxy]-4,6-dimethyl-5-oxobenzo[c][2,7]naphthyridine-9-carbonitrile Chemical compound CN1C(=O)C2=C(C)N=CC=C2C2=C1C=C(OC[C@@H](N)CC(C)C)C(C#N)=C2 NQXBZPJVVGIFBJ-HNNXBMFYSA-N 0.000 claims 1
- WVWZWEDZULHZHM-HNNXBMFYSA-N 8-[(2s)-2-amino-4-methylpentoxy]-4,6-dimethyl-9-(1,3-thiazol-5-yl)benzo[c][2,7]naphthyridin-5-one Chemical compound CC(C)C[C@H](N)COC1=CC=2N(C)C(=O)C3=C(C)N=CC=C3C=2C=C1C1=CN=CS1 WVWZWEDZULHZHM-HNNXBMFYSA-N 0.000 claims 1
- KVRKKRBPFCLMMG-ZDUSSCGKSA-N 8-[(2s)-2-amino-4-methylpentoxy]-4-methyl-6h-benzo[c][2,7]naphthyridin-5-one Chemical compound N1=CC=C2C3=CC=C(OC[C@@H](N)CC(C)C)C=C3NC(=O)C2=C1C KVRKKRBPFCLMMG-ZDUSSCGKSA-N 0.000 claims 1
- YPEZYWFTKZJJJZ-AWEZNQCLSA-N 8-[(2s)-2-amino-4-methylpentoxy]-6,9-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound CN1C(=O)C2=CN=CC=C2C2=C1C=C(OC[C@@H](N)CC(C)C)C(C)=C2 YPEZYWFTKZJJJZ-AWEZNQCLSA-N 0.000 claims 1
- ODUGXJAXPWAZJC-HNNXBMFYSA-N 8-[(2s)-2-amino-4-methylpentoxy]-6-(2-methoxyethyl)benzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC=C2C(=O)N(CCOC)C3=CC(OC[C@@H](N)CC(C)C)=CC=C3C2=C1 ODUGXJAXPWAZJC-HNNXBMFYSA-N 0.000 claims 1
- APIXEYSCHSPEJC-INIZCTEOSA-N 8-[(2s)-2-amino-4-methylpentoxy]-6-(cyclopropylmethyl)benzo[c][2,7]naphthyridin-5-one Chemical compound C=1C(OC[C@@H](N)CC(C)C)=CC=C(C2=CC=NC=C2C2=O)C=1N2CC1CC1 APIXEYSCHSPEJC-INIZCTEOSA-N 0.000 claims 1
- OYOIIDJCDNWRLV-ZDUSSCGKSA-N 8-[(2s)-2-amino-4-methylpentoxy]-7-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC(C)=C2C(=O)N(C)C3=C(Cl)C(OC[C@@H](N)CC(C)C)=CC=C3C2=C1 OYOIIDJCDNWRLV-ZDUSSCGKSA-N 0.000 claims 1
- IBOVYPMCAGZYGE-LBPRGKRZSA-N 8-[(2s)-2-amino-4-methylpentoxy]-7-fluoro-4-methyl-6h-benzo[c][2,7]naphthyridin-5-one Chemical compound C1=NC(C)=C2C(=O)NC3=C(F)C(OC[C@@H](N)CC(C)C)=CC=C3C2=C1 IBOVYPMCAGZYGE-LBPRGKRZSA-N 0.000 claims 1
- UDYNBTZVRFJLDX-LOACHALJSA-N 8-[(2s)-2-amino-4-methylpentoxy]-9-(1-hydroxyethyl)-4,6-dimethylbenzo[c][2,7]naphthyridin-5-one Chemical compound CN1C(=O)C2=C(C)N=CC=C2C2=C1C=C(OC[C@@H](N)CC(C)C)C(C(C)O)=C2 UDYNBTZVRFJLDX-LOACHALJSA-N 0.000 claims 1
- UDIIMGJDZJDIMZ-ZDUSSCGKSA-N 8-[(2s)-2-amino-5,5-difluoropent-4-enoxy]-4,6-dimethyl-5-oxobenzo[c][2,7]naphthyridine-9-carbonitrile Chemical compound C12=CC(C#N)=C(OC[C@@H](N)CC=C(F)F)C=C2N(C)C(=O)C2=C1C=CN=C2C UDIIMGJDZJDIMZ-ZDUSSCGKSA-N 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 619
- 230000014759 maintenance of location Effects 0.000 description 360
- 235000019439 ethyl acetate Nutrition 0.000 description 270
- 239000011541 reaction mixture Substances 0.000 description 210
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 180
- 239000000243 solution Substances 0.000 description 178
- 230000002829 reductive effect Effects 0.000 description 168
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 162
- 238000004128 high performance liquid chromatography Methods 0.000 description 155
- 239000007787 solid Substances 0.000 description 137
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 122
- 238000005481 NMR spectroscopy Methods 0.000 description 108
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 95
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 89
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 79
- 238000006243 chemical reaction Methods 0.000 description 75
- 239000012044 organic layer Substances 0.000 description 75
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 65
- 239000011734 sodium Substances 0.000 description 65
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 64
- 239000012267 brine Substances 0.000 description 56
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 50
- 238000000746 purification Methods 0.000 description 49
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 43
- 239000000543 intermediate Substances 0.000 description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 40
- 239000012043 crude product Substances 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- 239000010410 layer Substances 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
- 229910052938 sodium sulfate Inorganic materials 0.000 description 35
- 235000011152 sodium sulphate Nutrition 0.000 description 35
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 32
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 31
- 239000005909 Kieselgur Substances 0.000 description 31
- 239000000463 material Substances 0.000 description 31
- 125000006239 protecting group Chemical group 0.000 description 29
- 238000003786 synthesis reaction Methods 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 28
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 28
- 239000002585 base Substances 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 26
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 25
- 239000002253 acid Substances 0.000 description 24
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 22
- 229910000024 caesium carbonate Inorganic materials 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 20
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 20
- 239000012071 phase Substances 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 19
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- 229920006395 saturated elastomer Polymers 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 18
- 238000001816 cooling Methods 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 17
- 229910000104 sodium hydride Inorganic materials 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 16
- 238000002953 preparative HPLC Methods 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 15
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- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000012855 volatile organic compound Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- 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]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- 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)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Psychology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261677856P | 2012-07-31 | 2012-07-31 | |
| US13/946,344 US8901305B2 (en) | 2012-07-31 | 2013-07-19 | Aryl lactam kinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW201410676A true TW201410676A (zh) | 2014-03-16 |
Family
ID=50026068
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW102127296A TW201410676A (zh) | 2012-07-31 | 2013-07-30 | 芳基內醯胺激酶抑制劑 |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US8901305B2 (cg-RX-API-DMAC7.html) |
| EP (1) | EP2880032B1 (cg-RX-API-DMAC7.html) |
| JP (1) | JP2015528018A (cg-RX-API-DMAC7.html) |
| CN (1) | CN104507941A (cg-RX-API-DMAC7.html) |
| AR (1) | AR093758A1 (cg-RX-API-DMAC7.html) |
| BR (1) | BR112015001890A2 (cg-RX-API-DMAC7.html) |
| CA (1) | CA2880523A1 (cg-RX-API-DMAC7.html) |
| EA (1) | EA201590268A1 (cg-RX-API-DMAC7.html) |
| ES (1) | ES2602965T3 (cg-RX-API-DMAC7.html) |
| MX (1) | MX2015000980A (cg-RX-API-DMAC7.html) |
| TW (1) | TW201410676A (cg-RX-API-DMAC7.html) |
| WO (1) | WO2014022167A1 (cg-RX-API-DMAC7.html) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2016509066A (ja) | 2013-02-22 | 2016-03-24 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | アダプター関連キナーゼ１（ａａｋ１）の阻害剤としての５ｈ−クロメノ［３，４−ｃ］ピリジン |
| US10253027B2 (en) | 2013-07-08 | 2019-04-09 | Bristol-Myers Squibb Company | Aryl lactam kinase inhibitors |
| US9737542B2 (en) | 2013-10-11 | 2017-08-22 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
| US20160333006A1 (en) * | 2014-01-29 | 2016-11-17 | Bristol-Myers Squibb Company | Aryl lacta kinase inhibitors |
| HRP20181899T1 (hr) | 2014-04-02 | 2019-01-11 | Bristol-Myers Squibb Company | Biaril inhibitori kinaze |
| ES2740224T3 (es) * | 2015-04-10 | 2020-02-05 | Bristol Myers Squibb Co | 6H-isocromeno[3,4-c]piridinas y benzo[c][1,7]naftiridin-6-(5H)-onas como inhibidores de la cinasa asociada a adaptador 1 (AAK1) |
| US10246469B2 (en) | 2015-10-01 | 2019-04-02 | Bristol-Myers Squibb Company | Biaryl kinase inhibitors |
| US10544120B2 (en) | 2015-10-01 | 2020-01-28 | Bristol-Myers Squibb Company | Biaryl kinase inhibitors |
| EP4010081A4 (en) * | 2019-08-08 | 2023-07-26 | Institute For Cancer Research d/b/a The Research Institute of Fox Chase Cancer Center | POLYTHERAPY FOR THE TREATMENT OF CANCER |
| CN114853664B (zh) * | 2022-06-02 | 2023-09-29 | 河南大学 | 一种钯催化条件下合成α,β-不饱和杂环己基酮类化合物的方法 |
| CN116102542A (zh) * | 2023-02-15 | 2023-05-12 | 如东众意化工有限公司 | 环丙唑醇精制母液中环丙唑醇的回收方法 |
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| US5464764A (en) | 1989-08-22 | 1995-11-07 | University Of Utah Research Foundation | Positive-negative selection methods and vectors |
| WO1993004169A1 (en) | 1991-08-20 | 1993-03-04 | Genpharm International, Inc. | Gene targeting in animal cells using isogenic dna constructs |
| RU95113454A (ru) | 1992-12-02 | 1997-06-10 | Пфайзер Инк. (US) | Катехольные диэфиры как селективные ингибиторы фдэiv, фармацевтическая композиция, способы лечения |
| US5709861A (en) | 1993-04-22 | 1998-01-20 | Emisphere Technologies, Inc. | Compositions for the delivery of antigens |
| AUPS137402A0 (en) * | 2002-03-26 | 2002-05-09 | Fujisawa Pharmaceutical Co., Ltd. | Novel tricyclic compounds |
| WO2003086325A2 (en) | 2002-04-05 | 2003-10-23 | Boehringer Ingelheim Pharmaceuticals, Inc. | Cyanamides useful as reversible inhibitors of cysteine proteases |
| WO2004056744A1 (en) | 2002-12-23 | 2004-07-08 | Janssen Pharmaceutica N.V. | Adamantyl acetamides as hydroxysteroid dehydrogenase inhibitors |
| EP1593667A4 (en) | 2003-02-12 | 2009-03-04 | Takeda Pharmaceutical | Amine derivative |
| WO2005000309A2 (en) | 2003-06-27 | 2005-01-06 | Ionix Pharmaceuticals Limited | Chemical compounds |
| CA2555287A1 (en) * | 2004-02-18 | 2005-08-25 | David Garrett Loughhead | Heterocyclic gaba-a subtype selective receptor modulators |
| JP2008504276A (ja) | 2004-06-24 | 2008-02-14 | インサイト・コーポレイション | アミド化合物およびその医薬としての使用 |
| CN100494167C (zh) | 2005-08-02 | 2009-06-03 | 天津大学 | 抗乙肝病毒的叔胺氧化物及制备方法和制备药物的应用 |
| AU2006326247A1 (en) * | 2005-12-15 | 2007-06-21 | F. Hoffmann-La Roche Ag | Tricyclic lactam derivatives, their manufacture and use as pharmaceutical agents |
| JP2007217408A (ja) | 2006-01-19 | 2007-08-30 | Tanabe Seiyaku Co Ltd | 医薬組成物 |
| CA2645031A1 (en) * | 2006-03-07 | 2007-09-13 | Bristol-Myers Squibb Company | Pyrrolotriazine aniline prodrug compounds useful as kinase inhibitors |
| IN2014KN02423A (cg-RX-API-DMAC7.html) | 2006-04-07 | 2015-05-01 | Vertex Pharma | |
| WO2008022154A2 (en) | 2006-08-14 | 2008-02-21 | Wyeth | Methods of identifying agents for treating neurological disorders |
| EA200900799A1 (ru) * | 2006-12-22 | 2009-12-30 | Новартис Аг | Гетероарилгетероарильные соединения как ингибиторы cdk, предназначенные для лечения рака, воспаления и борьбы с вирусными инфекциями |
| JP2012526844A (ja) * | 2009-05-15 | 2012-11-01 | ザ ユニバーシティ オブ ケンタッキー リサーチ ファウンデーション | Ｍｃｉおよびアルツハイマー病の処置 |
| FR2955109B1 (fr) * | 2010-01-08 | 2012-09-07 | Sanofi Aventis | Derives de 5-oxo-5,8-dihydro-pyrido[2, 3-d]pyrimidine, leur preparation et leur application en therapeutique |
| US8791257B2 (en) * | 2010-03-31 | 2014-07-29 | Bristol-Myers Squibb Company | Substituted pyrrolotriazines as protein kinase inhibitors |
| EP3235499A3 (en) | 2012-03-09 | 2018-01-17 | Lexicon Pharmaceuticals, Inc. | Inhibition of adaptor associated kinase 1 for the treatment of pain |
| MX347917B (es) | 2012-03-09 | 2017-05-17 | Lexicon Pharmaceuticals Inc | Compuestos a base de imidazo[1,2-b]piridazina, composiciones que los comprenden, y metodos para su uso. |
| US8703953B2 (en) | 2012-03-09 | 2014-04-22 | Bristol-Myers Squibb Company | Aryl ether-base kinase inhibitors |
| PT2834243T (pt) | 2012-03-09 | 2018-08-01 | Lexicon Pharmaceuticals Inc | Compostos à base de pirazolo[1,5-a]pirimidina, composições que os compreendem e métodos para a sua utilização |
-
2013
- 2013-07-19 US US13/946,344 patent/US8901305B2/en active Active
- 2013-07-24 CA CA2880523A patent/CA2880523A1/en not_active Abandoned
- 2013-07-24 BR BR112015001890A patent/BR112015001890A2/pt not_active Application Discontinuation
- 2013-07-24 JP JP2015525460A patent/JP2015528018A/ja not_active Withdrawn
- 2013-07-24 WO PCT/US2013/051831 patent/WO2014022167A1/en not_active Ceased
- 2013-07-24 EP EP13744927.8A patent/EP2880032B1/en active Active
- 2013-07-24 MX MX2015000980A patent/MX2015000980A/es unknown
- 2013-07-24 EA EA201590268A patent/EA201590268A1/ru unknown
- 2013-07-24 CN CN201380041073.9A patent/CN104507941A/zh active Pending
- 2013-07-24 ES ES13744927.8T patent/ES2602965T3/es active Active
- 2013-07-30 TW TW102127296A patent/TW201410676A/zh unknown
- 2013-07-31 AR ARP130102716A patent/AR093758A1/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX2015000980A (es) | 2015-04-10 |
| US8901305B2 (en) | 2014-12-02 |
| EP2880032B1 (en) | 2016-10-05 |
| BR112015001890A2 (pt) | 2017-07-04 |
| CA2880523A1 (en) | 2014-02-06 |
| EA201590268A1 (ru) | 2015-05-29 |
| US20140038999A1 (en) | 2014-02-06 |
| JP2015528018A (ja) | 2015-09-24 |
| CN104507941A (zh) | 2015-04-08 |
| WO2014022167A1 (en) | 2014-02-06 |
| EP2880032A1 (en) | 2015-06-10 |
| AR093758A1 (es) | 2015-06-24 |
| ES2602965T3 (es) | 2017-02-23 |
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