TWI272271B - Process for preparing certain pyrrolotriazine compounds - Google Patents
Process for preparing certain pyrrolotriazine compounds Download PDFInfo
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- TWI272271B TWI272271B TW092119890A TW92119890A TWI272271B TW I272271 B TWI272271 B TW I272271B TW 092119890 A TW092119890 A TW 092119890A TW 92119890 A TW92119890 A TW 92119890A TW I272271 B TWI272271 B TW I272271B
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- compound
- group
- formula
- alkyl
- substituted
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- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 150000003921 pyrrolotriazines Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- -1 alkyl magnesium salt Chemical class 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 239000002841 Lewis acid Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 150000007517 lewis acids Chemical class 0.000 claims description 8
- 150000002978 peroxides Chemical class 0.000 claims description 8
- 229940126214 compound 3 Drugs 0.000 claims description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 239000012038 nucleophile Substances 0.000 claims description 6
- 229940100198 alkylating agent Drugs 0.000 claims description 5
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 229940125782 compound 2 Drugs 0.000 claims description 5
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 150000004791 alkyl magnesium halides Chemical class 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 229960001922 sodium perborate Drugs 0.000 claims description 2
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 238000006722 reduction reaction Methods 0.000 claims 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 claims 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 229910001623 magnesium bromide Inorganic materials 0.000 claims 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims 1
- 229910001629 magnesium chloride Inorganic materials 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 claims 1
- 229940031826 phenolate Drugs 0.000 claims 1
- BJDYCCHRZIFCGN-UHFFFAOYSA-N pyridin-1-ium;iodide Chemical compound I.C1=CC=NC=C1 BJDYCCHRZIFCGN-UHFFFAOYSA-N 0.000 claims 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 9
- 102000009465 Growth Factor Receptors Human genes 0.000 abstract description 8
- 108010009202 Growth Factor Receptors Proteins 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 8
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 abstract description 7
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 abstract description 6
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract description 6
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract description 6
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 abstract description 5
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 230000019491 signal transduction Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 70
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 229910052698 phosphorus Inorganic materials 0.000 description 31
- 239000000243 solution Substances 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 206010028980 Neoplasm Diseases 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 239000002585 base Substances 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 9
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 9
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 210000002889 endothelial cell Anatomy 0.000 description 8
- 239000003102 growth factor Substances 0.000 description 8
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 201000004681 Psoriasis Diseases 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 230000001772 anti-angiogenic effect Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 5
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
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- 239000000706 filtrate Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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| US6867300B2 (en) * | 2000-11-17 | 2005-03-15 | Bristol-Myers Squibb Company | Methods for the preparation of pyrrolotriazine compounds useful as kinase inhibitors |
| BR0309669A (pt) * | 2002-04-23 | 2005-03-01 | Bristol Myers Squibb Co | Compostos de anilina de pirrolo-triazina úteis como inibidores de cinase |
| DE60325469D1 (de) | 2002-04-23 | 2009-02-05 | Bristol Myers Squibb Co | Als kinase inhibitoren geeignete arylketonpyrrolotriazin-verbindungen |
| TWI329112B (en) * | 2002-07-19 | 2010-08-21 | Bristol Myers Squibb Co | Novel inhibitors of kinases |
| KR20050099525A (ko) | 2003-02-05 | 2005-10-13 | 브리스톨-마이어스 스큅 컴퍼니 | 피롤로트리아진 키나제 억제제의 제조 방법 |
| US7102001B2 (en) * | 2003-12-12 | 2006-09-05 | Bristol-Myers Squibb Company | Process for preparing pyrrolotriazine |
| US20060014741A1 (en) * | 2003-12-12 | 2006-01-19 | Dimarco John D | Synthetic process, and crystalline forms of a pyrrolotriazine compound |
| US7064203B2 (en) | 2003-12-29 | 2006-06-20 | Bristol Myers Squibb Company | Di-substituted pyrrolotriazine compounds |
| MY145634A (en) * | 2003-12-29 | 2012-03-15 | Bristol Myers Squibb Co | Pyrrolotriazine compounds as kinase inhibitors |
| US7102002B2 (en) * | 2004-06-16 | 2006-09-05 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
| US20050288290A1 (en) | 2004-06-28 | 2005-12-29 | Borzilleri Robert M | Fused heterocyclic kinase inhibitors |
| US7432373B2 (en) * | 2004-06-28 | 2008-10-07 | Bristol-Meyers Squibb Company | Processes and intermediates useful for preparing fused heterocyclic kinase inhibitors |
| TW200600513A (en) * | 2004-06-30 | 2006-01-01 | Bristol Myers Squibb Co | A method for preparing pyrrolotriazine compounds |
| US7253167B2 (en) * | 2004-06-30 | 2007-08-07 | Bristol-Myers Squibb Company | Tricyclic-heteroaryl compounds useful as kinase inhibitors |
| US7102003B2 (en) * | 2004-07-01 | 2006-09-05 | Bristol-Myers Squibb Company | Pyrrolotriazine compounds |
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| US7504521B2 (en) * | 2004-08-05 | 2009-03-17 | Bristol-Myers Squibb Co. | Methods for the preparation of pyrrolotriazine compounds |
| TW200618803A (en) | 2004-08-12 | 2006-06-16 | Bristol Myers Squibb Co | Process for preparing pyrrolotriazine aniline compounds useful as kinase inhibitors |
| US7151176B2 (en) * | 2004-10-21 | 2006-12-19 | Bristol-Myers Squibb Company | Pyrrolotriazine compounds |
| US7514435B2 (en) * | 2005-11-18 | 2009-04-07 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
| BRPI0619146A2 (pt) | 2005-12-02 | 2011-09-13 | Bayer Pharmaceuticals Corp | derivados de 4-amino-pirroltriazina substituìda úteis no tratamento de disordens e doenças hiperproliferativas associadas com angiogênesis |
| PE20070855A1 (es) | 2005-12-02 | 2007-10-14 | Bayer Pharmaceuticals Corp | Derivados de 4-amino-pirrolotriazina sustituida como inhibidores de quinasas |
| US8063208B2 (en) | 2006-02-16 | 2011-11-22 | Bristol-Myers Squibb Company | Crystalline forms of (3R,4R)-4-amino-1-[[4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol |
| CA2650059A1 (en) * | 2006-04-21 | 2007-11-01 | Bristol-Myers Squibb Company | Process for the preparation of [(1r), 2s]-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester |
| EP2405270B1 (en) | 2006-06-30 | 2013-07-17 | Merck Sharp & Dohme Corp. | IGFBP2-Biomarker |
| US7851623B2 (en) * | 2006-11-02 | 2010-12-14 | Astrazeneca Ab | Chemical process |
| ATE518946T1 (de) * | 2007-02-08 | 2011-08-15 | Codexis Inc | Ketoreduktasen und anwendungen davon |
| EP2212432A4 (en) | 2007-10-22 | 2011-10-19 | Schering Corp | COMPLETELY HUMAN ANTI-VEGF ANTIBODIES AND USE PROCEDURES |
| TW201035100A (en) | 2008-12-19 | 2010-10-01 | Cephalon Inc | Pyrrolotriazines as ALK and JAK2 inhibitors |
| US8691981B2 (en) * | 2010-02-03 | 2014-04-08 | Bristol-Myers Squibb Company | Crystalline forms of (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide |
| CN102603718B (zh) * | 2012-02-08 | 2014-01-29 | 武汉凯斯瑞科技有限公司 | 西地尼布的合成方法 |
| CN103420892A (zh) * | 2012-05-18 | 2013-12-04 | 苏州爱斯鹏药物研发有限责任公司 | 一种4-氟吲哚的制备方法 |
| BR112015010109A2 (pt) | 2012-11-05 | 2017-07-11 | Nant Holdings Ip Llc | derivados de indol-5-ol substituídos e suas aplicações terapêuticas |
| WO2014145403A1 (en) | 2013-03-15 | 2014-09-18 | Nantbio, Inc. | Substituted indol-5-ol derivatives and their therapeutic applications |
| WO2015081783A1 (zh) * | 2013-12-06 | 2015-06-11 | 江苏奥赛康药业股份有限公司 | 吡咯并[2,1-f][1,2,4]三嗪类衍生物及其制备方法和用途 |
| US9388239B2 (en) | 2014-05-01 | 2016-07-12 | Consejo Nacional De Investigation Cientifica | Anti-human VEGF antibodies with unusually strong binding affinity to human VEGF-A and cross reactivity to human VEGF-B |
| EP3356345B1 (en) | 2015-09-30 | 2023-11-08 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Heteroaryl derivatives as sepiapterin reductase inhibitors |
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| WO2000071129A1 (en) | 1999-05-21 | 2000-11-30 | Bristol-Myers Squibb Company | Pyrrolotriazine inhibitors of kinases |
| JP2004505965A (ja) * | 2000-08-09 | 2004-02-26 | アストラゼネカ アクチボラグ | 化合物 |
| US6670357B2 (en) | 2000-11-17 | 2003-12-30 | Bristol-Myers Squibb Company | Methods of treating p38 kinase-associated conditions and pyrrolotriazine compounds useful as kinase inhibitors |
| EE200300227A (et) | 2000-11-17 | 2003-10-15 | Bristol-Myers Squibb Company | P38 kinaasiga seotud haigusseisundite ravimeetodid ja kinaasi inhibiitoritena kasulikud pürrolotriasiiniühendid |
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| WO2004009542A3 (en) | 2004-05-13 |
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| AU2003256645A1 (en) | 2004-02-09 |
| PL375316A1 (en) | 2005-11-28 |
| IL165985A0 (en) | 2006-01-15 |
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| MXPA05000344A (es) | 2005-03-31 |
| WO2004009542A2 (en) | 2004-01-29 |
| CA2492861A1 (en) | 2004-01-29 |
| CN1665817A (zh) | 2005-09-07 |
| JP2006502120A (ja) | 2006-01-19 |
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