CA2516418A1 - 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury - Google Patents
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury Download PDFInfo
- Publication number
- CA2516418A1 CA2516418A1 CA002516418A CA2516418A CA2516418A1 CA 2516418 A1 CA2516418 A1 CA 2516418A1 CA 002516418 A CA002516418 A CA 002516418A CA 2516418 A CA2516418 A CA 2516418A CA 2516418 A1 CA2516418 A1 CA 2516418A1
- Authority
- CA
- Canada
- Prior art keywords
- dichloro
- methoxyphenyl
- amino
- methoxy
- ethoxy
- 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.)
- Abandoned
Links
- -1 2,4-dichloro-5-methoxyphenyl Chemical group 0.000 title claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims description 8
- 238000011282 treatment Methods 0.000 title description 20
- 208000037906 ischaemic injury Diseases 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 230000008728 vascular permeability Effects 0.000 claims abstract description 19
- 208000014674 injury Diseases 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 230000008733 trauma Effects 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 230000000302 ischemic effect Effects 0.000 claims description 20
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 12
- 206010061216 Infarction Diseases 0.000 claims description 11
- 230000007574 infarction Effects 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 230000007971 neurological deficit Effects 0.000 claims description 9
- 230000007213 cerebrovascular event Effects 0.000 claims description 7
- 230000005764 inhibitory process Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 230000004112 neuroprotection Effects 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 230000001052 transient effect Effects 0.000 claims description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- 206010021143 Hypoxia Diseases 0.000 claims description 6
- 230000002490 cerebral effect Effects 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- NPTUGALLOCBPCM-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-ethoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(OCC3CCN(C)CC3)C(OCC)=CC2=C1NC1=CC(OC)=C(Cl)C=C1Cl NPTUGALLOCBPCM-UHFFFAOYSA-N 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- JQGPWNQWNMMMAS-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-ethoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(OCCC3CCN(C)CC3)C(OCC)=CC2=C1NC1=CC(OC)=C(Cl)C=C1Cl JQGPWNQWNMMMAS-UHFFFAOYSA-N 0.000 claims description 3
- PCSXTJQETYJEOI-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-ethoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(OCCN3CCN(C)CC3)C(OCC)=CC2=C1NC1=CC(OC)=C(Cl)C=C1Cl PCSXTJQETYJEOI-UHFFFAOYSA-N 0.000 claims description 3
- OSJKQGUEJYZHQM-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-ethoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(OCCCC3CCN(C)CC3)C(OCC)=CC2=C1NC1=CC(OC)=C(Cl)C=C1Cl OSJKQGUEJYZHQM-UHFFFAOYSA-N 0.000 claims description 3
- FEPWXPAVJHFWGS-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-ethoxy-7-[3-(4-ethylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(OCCCN3CCN(CC)CC3)C(OCC)=CC2=C1NC1=CC(OC)=C(Cl)C=C1Cl FEPWXPAVJHFWGS-UHFFFAOYSA-N 0.000 claims description 3
- SNJXHAGNHXWXDO-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-ethoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OCC)=CC2=C1NC1=CC(OC)=C(Cl)C=C1Cl SNJXHAGNHXWXDO-UHFFFAOYSA-N 0.000 claims description 3
- FCIILWHQWNLPJU-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinoline-3-carbonitrile Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCC4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl FCIILWHQWNLPJU-UHFFFAOYSA-N 0.000 claims description 3
- QXWCRBMAGJJKTO-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCC4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl QXWCRBMAGJJKTO-UHFFFAOYSA-N 0.000 claims description 3
- HOHWAQXKWAAULM-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-7-[(1-ethylpiperidin-4-yl)methoxy]-6-methoxyquinoline-3-carbonitrile Chemical compound C1CN(CC)CCC1COC1=CC2=NC=C(C#N)C(NC=3C(=CC(Cl)=C(OC)C=3)Cl)=C2C=C1OC HOHWAQXKWAAULM-UHFFFAOYSA-N 0.000 claims description 3
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 claims description 3
- 230000007954 hypoxia Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- TXAYKQMEBQBGLR-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCC4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl TXAYKQMEBQBGLR-UHFFFAOYSA-N 0.000 claims description 2
- UNVLTPQRCHRNDB-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-3-carbonitrile Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UNVLTPQRCHRNDB-UHFFFAOYSA-N 0.000 claims description 2
- SUGCHLACYQMXHH-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-propylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile Chemical compound C1CN(CCC)CCN1CCCOC1=CC2=NC=C(C#N)C(NC=3C(=CC(Cl)=C(OC)C=3)Cl)=C2C=C1OC SUGCHLACYQMXHH-UHFFFAOYSA-N 0.000 claims description 2
- 206010002660 Anoxia Diseases 0.000 claims description 2
- 241000976983 Anoxia Species 0.000 claims description 2
- 206010019196 Head injury Diseases 0.000 claims description 2
- 208000010496 Heart Arrest Diseases 0.000 claims description 2
- 206010028923 Neonatal asphyxia Diseases 0.000 claims description 2
- 208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 claims description 2
- 230000007953 anoxia Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 208000033300 perinatal asphyxia Diseases 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 208000005809 status epilepticus Diseases 0.000 claims description 2
- 210000004204 blood vessel Anatomy 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 239000006207 intravenous dosage form Substances 0.000 claims 1
- 208000027418 Wounds and injury Diseases 0.000 abstract description 7
- 230000006378 damage Effects 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 108010058765 Oncogene Protein pp60(v-src) Proteins 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 20
- 208000006011 Stroke Diseases 0.000 description 19
- 238000004458 analytical method Methods 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000001914 filtration Methods 0.000 description 15
- 108060006706 SRC Proteins 0.000 description 14
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000012312 sodium hydride Substances 0.000 description 14
- 229910000104 sodium hydride Inorganic materials 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 102000001332 SRC Human genes 0.000 description 13
- 208000028867 ischemia Diseases 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012634 fragment Substances 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 9
- 230000004927 fusion Effects 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- 210000003657 middle cerebral artery Anatomy 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 8
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 8
- 230000006735 deficit Effects 0.000 description 7
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 238000001665 trituration Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 230000010410 reperfusion Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- HKMBTDKVFJXFTJ-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-6-ethoxy-7-fluoroquinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(F)C(OCC)=CC2=C1NC1=CC(OC)=C(Cl)C=C1Cl HKMBTDKVFJXFTJ-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 241000700157 Rattus norvegicus Species 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000012746 preparative thin layer chromatography Methods 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 4
- BOQICIDBVOCNQA-UHFFFAOYSA-N 7-fluoro-6-methoxy-4-oxo-1h-quinoline-3-carbonitrile Chemical compound N1C=C(C#N)C(=O)C2=C1C=C(F)C(OC)=C2 BOQICIDBVOCNQA-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 235000010290 biphenyl Nutrition 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- AJROJTARXSATEB-UHFFFAOYSA-N 2,4-dichloro-5-methoxyaniline Chemical compound COC1=CC(N)=C(Cl)C=C1Cl AJROJTARXSATEB-UHFFFAOYSA-N 0.000 description 3
- AXSYHFQBQMKSGH-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-7-fluoro-6-methoxyquinoline-3-carbonitrile Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(F)C=C3N=CC=2C#N)=C1Cl AXSYHFQBQMKSGH-UHFFFAOYSA-N 0.000 description 3
- CTPFVVJNDXWGGI-UHFFFAOYSA-N 7-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-6-methoxyquinoline-3-carbonitrile Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCl)C=C3N=CC=2C#N)=C1Cl CTPFVVJNDXWGGI-UHFFFAOYSA-N 0.000 description 3
- GASHKCRNJZBFBE-UHFFFAOYSA-N 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyanilino)-6-methoxyquinoline-3-carbonitrile Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCCl)C=C3N=CC=2C#N)=C1Cl GASHKCRNJZBFBE-UHFFFAOYSA-N 0.000 description 3
- NJBZOGXZFBSRIS-UHFFFAOYSA-N 7-fluoro-6-methoxy-4-oxo-1h-quinoline-3-carboxamide Chemical compound N1C=C(C(N)=O)C(=O)C2=C1C=C(F)C(OC)=C2 NJBZOGXZFBSRIS-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000032382 Ischaemic stroke Diseases 0.000 description 3
- 108050006955 Tissue-type plasminogen activator Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- KTMGNAIGXYODKQ-VOTSOKGWSA-N ethyl (e)-2-cyano-3-ethoxyprop-2-enoate Chemical compound CCO\C=C(/C#N)C(=O)OCC KTMGNAIGXYODKQ-VOTSOKGWSA-N 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 108010087686 src-Family Kinases Proteins 0.000 description 3
- 102000009076 src-Family Kinases Human genes 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- KJZLJGZZDNGGCA-UHFFFAOYSA-N (1-methylpiperidin-4-yl)methanol Chemical compound CN1CCC(CO)CC1 KJZLJGZZDNGGCA-UHFFFAOYSA-N 0.000 description 2
- QLEIDMAURCRVCX-UHFFFAOYSA-N 1-propylpiperazine Chemical compound CCCN1CCNCC1 QLEIDMAURCRVCX-UHFFFAOYSA-N 0.000 description 2
- PGPXRIFFCBCWEO-UHFFFAOYSA-N 2-(1-methylpiperidin-4-yl)ethanol Chemical compound CN1CCC(CCO)CC1 PGPXRIFFCBCWEO-UHFFFAOYSA-N 0.000 description 2
- LJWAPDSCYTZUJU-UHFFFAOYSA-N 3-fluoro-4-methoxyaniline Chemical compound COC1=CC=C(N)C=C1F LJWAPDSCYTZUJU-UHFFFAOYSA-N 0.000 description 2
- XLEYXHRMSUPJST-UHFFFAOYSA-N 3-fluoro-4-phenylmethoxyaniline Chemical compound FC1=CC(N)=CC=C1OCC1=CC=CC=C1 XLEYXHRMSUPJST-UHFFFAOYSA-N 0.000 description 2
- HQWUPLKDABZELG-UHFFFAOYSA-N 4-chloro-7-fluoro-6-hydroxyquinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(F)C(O)=CC2=C1Cl HQWUPLKDABZELG-UHFFFAOYSA-N 0.000 description 2
- BGYLADSNTDSOMR-UHFFFAOYSA-N 7-fluoro-4-oxo-6-phenylmethoxy-1h-quinoline-3-carbonitrile Chemical compound C1=C2C(O)=C(C#N)C=NC2=CC(F)=C1OCC1=CC=CC=C1 BGYLADSNTDSOMR-UHFFFAOYSA-N 0.000 description 2
- CKIFZMDHCWPBKW-UHFFFAOYSA-N 7-fluoro-6-methoxy-4-oxo-1h-quinoline-3-carboxylic acid Chemical compound OC(=O)C1=CN=C2C=C(F)C(OC)=CC2=C1O CKIFZMDHCWPBKW-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229910052693 Europium Inorganic materials 0.000 description 2
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- ZCILODAAHLISPY-UHFFFAOYSA-N biphenyl ether Natural products C1=C(CC=C)C(O)=CC(OC=2C(=CC(CC=C)=CC=2)O)=C1 ZCILODAAHLISPY-UHFFFAOYSA-N 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- FUJNUQDCBRIKRF-UHFFFAOYSA-N ethyl 7-fluoro-6-methoxy-4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=C(F)C(OC)=CC2=C(O)C(C(=O)OCC)=CN=C21 FUJNUQDCBRIKRF-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000000021 kinase assay Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 210000001577 neostriatum Anatomy 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 230000007658 neurological function Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- SPFMQWBKVUQXJV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;hydrate Chemical compound O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O SPFMQWBKVUQXJV-BTVCFUMJSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 1
- QHTUMQYGZQYEOZ-UHFFFAOYSA-N 2-(4-methylpiperazin-1-yl)ethanol Chemical compound CN1CCN(CCO)CC1 QHTUMQYGZQYEOZ-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- QYRYQOHCDCTGHJ-UHFFFAOYSA-N 3-(1-methylpiperidin-4-yl)propan-1-ol Chemical compound CN1CCC(CCCO)CC1 QYRYQOHCDCTGHJ-UHFFFAOYSA-N 0.000 description 1
- AMUHRVSHYZFFKQ-UHFFFAOYSA-N 3-(4-ethylpiperazin-1-yl)propan-1-ol Chemical compound CCN1CCN(CCCO)CC1 AMUHRVSHYZFFKQ-UHFFFAOYSA-N 0.000 description 1
- JKRSQNBRNIYETC-UHFFFAOYSA-N 3-(4-methylpiperazin-1-yl)propan-1-ol Chemical compound CN1CCN(CCCO)CC1 JKRSQNBRNIYETC-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- BIEFBSIFAKMKOT-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyanilino)-7-[3-(4-ethylpiperazin-1-yl)propoxy]-6-methoxyquinoline-3-carbonitrile Chemical compound C1CN(CC)CCN1CCCOC1=CC2=NC=C(C#N)C(NC=3C(=CC(Cl)=C(OC)C=3)Cl)=C2C=C1OC BIEFBSIFAKMKOT-UHFFFAOYSA-N 0.000 description 1
- APRZHQXAAWPYHS-UHFFFAOYSA-N 4-[5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-1,3-thiazol-2-yl)tetrazol-3-ium-2-yl]benzenesulfonate Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=C(OCC(O)=O)C=CC=2)=NN1C1=CC=C(S([O-])(=O)=O)C=C1 APRZHQXAAWPYHS-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- HOQINUIIFHZUMM-UHFFFAOYSA-N 4-chloro-6-ethoxy-7-fluoroquinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(F)C(OCC)=CC2=C1Cl HOQINUIIFHZUMM-UHFFFAOYSA-N 0.000 description 1
- PNVRUIFACIJUKH-UHFFFAOYSA-N 4-chloro-7-fluoro-6-methoxyquinoline-3-carbonitrile Chemical compound N#CC1=CN=C2C=C(F)C(OC)=CC2=C1Cl PNVRUIFACIJUKH-UHFFFAOYSA-N 0.000 description 1
- QNWHOCFQMBGSLT-UHFFFAOYSA-N 4-chloro-7-fluoro-6-phenylmethoxyquinoline-3-carbonitrile Chemical compound FC1=CC2=NC=C(C#N)C(Cl)=C2C=C1OCC1=CC=CC=C1 QNWHOCFQMBGSLT-UHFFFAOYSA-N 0.000 description 1
- CRDISMZBOJPSJG-UHFFFAOYSA-N 7-fluoroquinoline-3-carbonitrile Chemical compound C1=C(C#N)C=NC2=CC(F)=CC=C21 CRDISMZBOJPSJG-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 101150012716 CDK1 gene Proteins 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 102100035861 Cytosolic 5'-nucleotidase 1A Human genes 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 101100059559 Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139) nimX gene Proteins 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 208000006893 Fetal Hypoxia Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101000802744 Homo sapiens Cytosolic 5'-nucleotidase 1A Proteins 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010060840 Ischaemic cerebral infarction Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000862969 Stella Species 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 108091036066 Three prime untranslated region Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 101100273808 Xenopus laevis cdk1-b gene Proteins 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Chemical group 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 210000004004 carotid artery internal Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 208000023569 ischemic bowel disease Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 238000011859 neuroprotective therapy Methods 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 230000001144 postural effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001749 primary amide group Chemical group 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 210000005227 renal system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Vascular Medicine (AREA)
- Neurosurgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US44931603P | 2003-02-21 | 2003-02-21 | |
| US60/449,316 | 2003-02-21 | ||
| PCT/US2004/004904 WO2004075898A1 (en) | 2003-02-21 | 2004-02-19 | 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2516418A1 true CA2516418A1 (en) | 2004-09-10 |
Family
ID=32927510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002516418A Abandoned CA2516418A1 (en) | 2003-02-21 | 2004-02-19 | 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US20040229880A1 (enExample) |
| EP (1) | EP1594502A1 (enExample) |
| JP (1) | JP2006522023A (enExample) |
| KR (1) | KR20050102133A (enExample) |
| CN (1) | CN1750824A (enExample) |
| AR (1) | AR043253A1 (enExample) |
| AU (1) | AU2004216235A1 (enExample) |
| BR (1) | BRPI0407441A (enExample) |
| CA (1) | CA2516418A1 (enExample) |
| CO (1) | CO5640114A2 (enExample) |
| CR (1) | CR7931A (enExample) |
| EC (1) | ECSP055972A (enExample) |
| MX (1) | MXPA05008706A (enExample) |
| NO (1) | NO20054070L (enExample) |
| RU (1) | RU2005129333A (enExample) |
| TW (1) | TW200423938A (enExample) |
| UA (1) | UA80472C2 (enExample) |
| WO (1) | WO2004075898A1 (enExample) |
| ZA (1) | ZA200506621B (enExample) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG146681A1 (en) * | 2003-11-06 | 2008-10-30 | Wyeth Corp | 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (cml) |
| RU2007111704A (ru) * | 2004-10-22 | 2008-11-27 | Вайет (Us) | 4[(2,4-дихлоро-5-метоксифенил)амино]-6-алкокси-7-этинил-3-хинолинкарбонитрилы для лечения ишемического поражения |
| MX2008000384A (es) * | 2005-07-01 | 2008-03-07 | Wyeth Corp | Formas cristalinas de 4-[(2,4-dicloro-5-metoxifenil)amino]-6-metox i-7-[3-(4-metil-1-piperazinil)propoxi]-3-quinolinocarbonitrilo y metodos para su preparacion. |
| MX342879B (es) | 2010-07-30 | 2016-10-14 | Oncotherapy Science Inc * | Derivados de quinolina e inhibidores de cinasa de cremallera de leucina embrionica materna que los contienen. |
| CN103772392A (zh) * | 2012-10-23 | 2014-05-07 | 杨子娇 | 一类治疗房角狭窄的化合物及其用途 |
| IN2014CH00840A (enExample) | 2014-02-20 | 2015-09-18 | Apotex Inc | |
| TWI672141B (zh) | 2014-02-20 | 2019-09-21 | 美商醫科泰生技 | 投予ｒｏｓ１突變癌細胞之分子 |
| US20160256457A1 (en) * | 2014-06-10 | 2016-09-08 | Beth Israel Deaconess Medical Center, Inc. | Methods for treating or preventing acute vascular leak |
| AU2015355220B2 (en) | 2014-12-02 | 2020-02-27 | Ignyta, Inc. | Combinations for the treatment of neuroblastoma |
| WO2017029584A1 (en) * | 2015-08-19 | 2017-02-23 | Sun Pharmaceutical Industries Limited | Amorphous form of bosutinib |
| KR20180096621A (ko) | 2015-12-18 | 2018-08-29 | 이그니타, 인코포레이티드 | 암의 치료용 조합물 |
| CN107814769B (zh) * | 2016-09-14 | 2021-05-07 | 正大天晴药业集团股份有限公司 | 一种博舒替尼的纯化方法 |
| WO2019018570A1 (en) | 2017-07-19 | 2019-01-24 | Ignyta, Inc. | PHARMACEUTICAL COMPOSITIONS CONTAINING ENTRECTINIB |
| JP7311498B2 (ja) | 2017-10-17 | 2023-07-19 | イグナイタ インコーポレイテッド | 薬学的組成物および剤形 |
| CN111646940B (zh) * | 2019-03-04 | 2024-01-30 | 鲁南制药集团股份有限公司 | 一种博舒替尼中间体的制备方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6002008A (en) * | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
| US6297258B1 (en) * | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| US6521618B2 (en) * | 2000-03-28 | 2003-02-18 | Wyeth | 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors |
| TWI275390B (en) * | 2002-04-30 | 2007-03-11 | Wyeth Corp | Process for the preparation of 7-substituted-3- quinolinecarbonitriles |
| US20060167021A1 (en) * | 2002-10-04 | 2006-07-27 | Caritas St. Elizabeth's Medical Center Of Boston, Inc. | Inhibition of src for treatment of reperfusion injury related to revascularization |
-
2004
- 2004-02-18 US US10/780,973 patent/US20040229880A1/en not_active Abandoned
- 2004-02-18 TW TW093103901A patent/TW200423938A/zh unknown
- 2004-02-19 AU AU2004216235A patent/AU2004216235A1/en not_active Withdrawn
- 2004-02-19 BR BR0407441-6A patent/BRPI0407441A/pt not_active IP Right Cessation
- 2004-02-19 CN CNA2004800046743A patent/CN1750824A/zh active Pending
- 2004-02-19 JP JP2006503706A patent/JP2006522023A/ja not_active Withdrawn
- 2004-02-19 EP EP04712889A patent/EP1594502A1/en not_active Withdrawn
- 2004-02-19 RU RU2005129333/04A patent/RU2005129333A/ru not_active Application Discontinuation
- 2004-02-19 MX MXPA05008706A patent/MXPA05008706A/es unknown
- 2004-02-19 UA UAA200508924A patent/UA80472C2/uk unknown
- 2004-02-19 KR KR1020057015377A patent/KR20050102133A/ko not_active Withdrawn
- 2004-02-19 CA CA002516418A patent/CA2516418A1/en not_active Abandoned
- 2004-02-19 WO PCT/US2004/004904 patent/WO2004075898A1/en not_active Ceased
- 2004-02-20 AR ARP040100546A patent/AR043253A1/es not_active Application Discontinuation
-
2005
- 2005-08-03 CR CR7931A patent/CR7931A/es not_active Application Discontinuation
- 2005-08-17 CO CO05081472A patent/CO5640114A2/es not_active Application Discontinuation
- 2005-08-18 ZA ZA200506621A patent/ZA200506621B/en unknown
- 2005-08-19 EC EC2005005972A patent/ECSP055972A/es unknown
- 2005-09-01 NO NO20054070A patent/NO20054070L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004075898A1 (en) | 2004-09-10 |
| TW200423938A (en) | 2004-11-16 |
| US20040229880A1 (en) | 2004-11-18 |
| NO20054070D0 (no) | 2005-09-01 |
| MXPA05008706A (es) | 2005-10-05 |
| KR20050102133A (ko) | 2005-10-25 |
| RU2005129333A (ru) | 2006-01-27 |
| CO5640114A2 (es) | 2006-05-31 |
| AR043253A1 (es) | 2005-07-20 |
| JP2006522023A (ja) | 2006-09-28 |
| ZA200506621B (en) | 2008-02-27 |
| NO20054070L (no) | 2005-11-14 |
| ECSP055972A (es) | 2006-01-16 |
| BRPI0407441A (pt) | 2006-01-31 |
| AU2004216235A1 (en) | 2004-09-10 |
| UA80472C2 (en) | 2007-09-25 |
| CR7931A (es) | 2006-02-07 |
| CN1750824A (zh) | 2006-03-22 |
| EP1594502A1 (en) | 2005-11-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2764027C (en) | Quinoline or isoquinoline compounds useful for treating premature aging and in particular progeria | |
| KR100621272B1 (ko) | 퀴놀린 및 퀴나졸린 유도체 | |
| EP2799437B1 (en) | Quinoline and cinnoline derivatives and use thereof | |
| CA2516418A1 (en) | 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury | |
| JP4217480B2 (ja) | 新規化合物 | |
| JP2003514860A (ja) | 新規化合物 | |
| CA2574685A1 (en) | Quinazolin-4-yl- piperidine and cinnolin-4-yl- piperidine derivatives as pde10 inhibitors for the treatment of cns disorders | |
| AU2002210474A1 (en) | Quinoline and quinazoline derivatives as ligands for the neuropetide Y receptor | |
| WO2013013614A1 (zh) | 4-(3-杂芳基芳基氨基)喹唑啉和1-(3-杂芳基芳基氨基)异喹啉作为Hedgehog通路抑制剂及其应用 | |
| CN101679272B (zh) | 作为腺苷a3受体配体的三唑并[1,5-a]喹啉类 | |
| JP6916562B2 (ja) | 化合物、その薬学的に許容される塩、溶媒和物、立体異性体及び互変異性体、並びに薬物組成物、過剰増殖性障害治療剤、過剰増殖性障害予防剤、薬物、癌治療剤、癌予防剤、及びキナーゼシグナル伝達調節剤 | |
| WO2001064680A1 (en) | Myt1 kinase inhibitors | |
| EP1802581B1 (en) | 4 [(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-7-ethynyl-3-quinolinecarbonitriles for the treatment of ischemic injury | |
| WO2005047259A1 (en) | 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (cml) | |
| JPH107571A (ja) | 肺癌治療におけるナフタレン誘導体の使用 | |
| CN115594671B (zh) | 苯并噻唑类衍生物及其制备方法和用途 | |
| HK1104555B (en) | 4 [(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-7-ethynyl-3-quinolinecarbonitriles for the treatment of ischemic injury |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |