CA2492861A1 - Process for preparing certain pyrrolotriazine compounds - Google Patents
Process for preparing certain pyrrolotriazine compounds Download PDFInfo
- Publication number
- CA2492861A1 CA2492861A1 CA002492861A CA2492861A CA2492861A1 CA 2492861 A1 CA2492861 A1 CA 2492861A1 CA 002492861 A CA002492861 A CA 002492861A CA 2492861 A CA2492861 A CA 2492861A CA 2492861 A1 CA2492861 A1 CA 2492861A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- substituted
- hydrogen
- afford
- 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
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- 150000003921 pyrrolotriazines Chemical class 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 114
- 238000011282 treatment Methods 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 102000009465 Growth Factor Receptors Human genes 0.000 claims abstract description 13
- 108010009202 Growth Factor Receptors Proteins 0.000 claims abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims abstract description 9
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 230000019491 signal transduction Effects 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 40
- -1 alkoxy anion Chemical class 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 28
- 230000008569 process Effects 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 150000002978 peroxides Chemical class 0.000 claims description 12
- 239000002168 alkylating agent Substances 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 11
- 230000001603 reducing effect Effects 0.000 claims description 11
- 239000002841 Lewis acid Substances 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 229940125898 compound 5 Drugs 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 150000007517 lewis acids Chemical class 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 229940100198 alkylating agent Drugs 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 239000012038 nucleophile Substances 0.000 claims description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 9
- 230000008728 vascular permeability Effects 0.000 claims description 9
- 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 8
- 229940126214 compound 3 Drugs 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical group [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 8
- 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 description 7
- 230000001772 anti-angiogenic effect Effects 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 7
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 6
- 229910015900 BF3 Inorganic materials 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 229940125797 compound 12 Drugs 0.000 claims description 6
- 230000002152 alkylating effect Effects 0.000 claims description 5
- 230000001093 anti-cancer Effects 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 229940127089 cytotoxic agent Drugs 0.000 claims description 5
- 239000002254 cytotoxic agent Substances 0.000 claims description 5
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 5
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 5
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 5
- 229960001922 sodium perborate Drugs 0.000 claims description 5
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 102000001253 Protein Kinase Human genes 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 150000004703 alkoxides Chemical class 0.000 claims description 4
- 150000004791 alkyl magnesium halides Chemical class 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 claims description 4
- 108060006633 protein kinase Proteins 0.000 claims description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 229940126543 compound 14 Drugs 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 3
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 239000000852 hydrogen donor Substances 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 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
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 abstract description 11
- 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 9
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 abstract description 7
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 abstract description 7
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 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 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 26
- 206010028980 Neoplasm Diseases 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 11
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 11
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- QISSVLCQDNIJCS-UHFFFAOYSA-N 2-fluoro-1h-indole Chemical compound C1=CC=C2NC(F)=CC2=C1 QISSVLCQDNIJCS-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 210000002889 endothelial cell Anatomy 0.000 description 7
- 239000003102 growth factor Substances 0.000 description 7
- IPRZVDNMKMONNN-UHFFFAOYSA-N 1-(2-fluoro-3-hydroxy-6-nitrophenyl)propan-2-one Chemical compound CC(=O)CC1=C(F)C(O)=CC=C1[N+]([O-])=O IPRZVDNMKMONNN-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- PWDPRNDZBPRZKC-UHFFFAOYSA-N 1-(2-fluoro-6-nitro-3-phenylmethoxyphenyl)propan-2-one Chemical compound C1=C([N+]([O-])=O)C(CC(=O)C)=C(F)C(OCC=2C=CC=CC=2)=C1 PWDPRNDZBPRZKC-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 125000005236 alkanoylamino group Chemical group 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
- 230000002062 proliferating effect Effects 0.000 description 5
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- ARCACZWMYGILNI-UHFFFAOYSA-N 1,2,3-trifluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1F ARCACZWMYGILNI-UHFFFAOYSA-N 0.000 description 4
- ICTSDDZTPXZWEM-UHFFFAOYSA-N 1-(2,3-difluoro-6-nitrophenyl)propan-2-one Chemical compound CC(=O)CC1=C(F)C(F)=CC=C1[N+]([O-])=O ICTSDDZTPXZWEM-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
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Landscapes
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| US10/622,280 | 2003-07-18 | ||
| PCT/US2003/022755 WO2004009542A2 (en) | 2002-07-19 | 2003-07-21 | Process for preparing certain pyrrolotriazine compounds |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| US7851623B2 (en) * | 2006-11-02 | 2010-12-14 | Astrazeneca Ab | Chemical process |
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| 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 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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2003
- 2003-07-18 US US10/622,280 patent/US6933386B2/en not_active Expired - Lifetime
- 2003-07-18 TW TW092119890A patent/TWI272271B/zh not_active IP Right Cessation
- 2003-07-21 WO PCT/US2003/022755 patent/WO2004009542A2/en not_active Ceased
- 2003-07-21 BR BR0312648-0A patent/BR0312648A/pt not_active IP Right Cessation
- 2003-07-21 PL PL03375316A patent/PL375316A1/xx not_active Application Discontinuation
- 2003-07-21 JP JP2004523221A patent/JP2006502120A/ja not_active Withdrawn
- 2003-07-21 IL IL16598503A patent/IL165985A0/xx unknown
- 2003-07-21 CN CN038162016A patent/CN1665817A/zh active Pending
- 2003-07-21 AU AU2003256645A patent/AU2003256645A1/en not_active Abandoned
- 2003-07-21 CA CA002492861A patent/CA2492861A1/en not_active Abandoned
- 2003-07-21 MX MXPA05000344A patent/MXPA05000344A/es active IP Right Grant
- 2003-07-21 EP EP03765846A patent/EP1554281A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| US6933386B2 (en) | 2005-08-23 |
| EP1554281A2 (en) | 2005-07-20 |
| WO2004009542A3 (en) | 2004-05-13 |
| TWI272271B (en) | 2007-02-01 |
| BR0312648A (pt) | 2005-08-02 |
| EP1554281A4 (en) | 2009-02-25 |
| TW200409776A (en) | 2004-06-16 |
| AU2003256645A1 (en) | 2004-02-09 |
| PL375316A1 (en) | 2005-11-28 |
| IL165985A0 (en) | 2006-01-15 |
| US20040077858A1 (en) | 2004-04-22 |
| MXPA05000344A (es) | 2005-03-31 |
| WO2004009542A2 (en) | 2004-01-29 |
| CN1665817A (zh) | 2005-09-07 |
| JP2006502120A (ja) | 2006-01-19 |
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