SK285757B6 - Ftalazíny s aktivitou inhibujúcou angiogenézu, spôsob ich prípravy, ich použitie a prostriedky, ktoré ich obsahujú - Google Patents

Info

Publication number

SK285757B6

SK285757B6 SK1096-99A SK109699A SK285757B6 SK 285757 B6 SK285757 B6 SK 285757B6 SK 109699 A SK109699 A SK 109699A SK 285757 B6 SK285757 B6 SK 285757B6

Authority

SK

Slovakia

Prior art keywords

group

phenyl

formula

alkyl

compound

Prior art date

1997-02-13

Links

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• 238000000034 method Methods 0.000 title claims abstract description 105
• 238000002360 preparation method Methods 0.000 title claims abstract description 42
• 230000033115 angiogenesis Effects 0.000 title claims abstract description 18
• 230000008569 process Effects 0.000 title claims abstract description 15
• 239000000203 mixture Substances 0.000 title claims description 119
• LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 title description 15
• 230000002401 inhibitory effect Effects 0.000 title description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 431
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 46
• 201000010099 disease Diseases 0.000 claims abstract description 45
• 238000011282 treatment Methods 0.000 claims abstract description 36
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
• 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 claims abstract description 22
• -1 cyano, carboxy Chemical group 0.000 claims description 199
• 125000000217 alkyl group Chemical group 0.000 claims description 181
• 229910052757 nitrogen Inorganic materials 0.000 claims description 117
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 91
• 150000003839 salts Chemical class 0.000 claims description 89
• 125000003545 alkoxy group Chemical group 0.000 claims description 84
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 83
• 125000001424 substituent group Chemical group 0.000 claims description 81
• 238000006243 chemical reaction Methods 0.000 claims description 71
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 70
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 66
• 125000003282 alkyl amino group Chemical group 0.000 claims description 65
• 150000001204 N-oxides Chemical class 0.000 claims description 56
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
• 229910052736 halogen Inorganic materials 0.000 claims description 50
• 150000002367 halogens Chemical class 0.000 claims description 47
• 125000004432 carbon atom Chemical group C* 0.000 claims description 46
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 45
• 206010028980 Neoplasm Diseases 0.000 claims description 42
• 229910052739 hydrogen Inorganic materials 0.000 claims description 41
• 239000007858 starting material Substances 0.000 claims description 35
• 125000001589 carboacyl group Chemical group 0.000 claims description 33
• 125000004414 alkyl thio group Chemical group 0.000 claims description 31
• 125000002947 alkylene group Chemical group 0.000 claims description 31
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 31
• 125000006239 protecting group Chemical group 0.000 claims description 30
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 27
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 27
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
• 125000004043 oxo group Chemical group O=* 0.000 claims description 26
• 125000004149 thio group Chemical group *S* 0.000 claims description 26
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 25
• 125000004423 acyloxy group Chemical group 0.000 claims description 24
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 23
• 125000000623 heterocyclic group Chemical group 0.000 claims description 23
• 241001465754 Metazoa Species 0.000 claims description 22
• 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 21
• 125000003277 amino group Chemical group 0.000 claims description 20
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
• 125000003118 aryl group Chemical group 0.000 claims description 19
• 229920006395 saturated elastomer Polymers 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
• 125000005843 halogen group Chemical group 0.000 claims description 17
• 125000000524 functional group Chemical group 0.000 claims description 16
• 125000002252 acyl group Chemical group 0.000 claims description 15
• 125000004076 pyridyl group Chemical group 0.000 claims description 15
• 150000003254 radicals Chemical class 0.000 claims description 15
• 241000282414 Homo sapiens Species 0.000 claims description 14
• 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 14
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 14
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 13
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 13
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 12
• 239000001257 hydrogen Substances 0.000 claims description 12
• 201000011510 cancer Diseases 0.000 claims description 11
• 125000003342 alkenyl group Chemical group 0.000 claims description 10
• 230000005764 inhibitory process Effects 0.000 claims description 10
• 150000003512 tertiary amines Chemical class 0.000 claims description 10
• YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
• 239000001301 oxygen Chemical group 0.000 claims description 8
• 229910052717 sulfur Chemical group 0.000 claims description 8
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 7
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
• 239000011593 sulfur Chemical group 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 6
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 6
• 229910052751 metal Inorganic materials 0.000 claims description 6
• 239000002184 metal Substances 0.000 claims description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
• 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
• 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 5
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 5
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
• UIOAQJNADLELPQ-UHFFFAOYSA-N C[C]1OCCO1 Chemical group C[C]1OCCO1 UIOAQJNADLELPQ-UHFFFAOYSA-N 0.000 claims description 4
• 230000014399 negative regulation of angiogenesis Effects 0.000 claims description 4
• ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 3
• 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 3
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
• LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 3
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 3
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
• 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 3
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
• 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
• 241000534944 Thia Species 0.000 claims description 3
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 3
• 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 3
• 125000001626 borono group Chemical group [H]OB([*])O[H] 0.000 claims description 3
• UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 3
• 239000012024 dehydrating agents‎ Substances 0.000 claims description 3
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
• XPCHMPWXUOYJGJ-UHFFFAOYSA-N n-(4-methylphenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C1=CC(C)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 XPCHMPWXUOYJGJ-UHFFFAOYSA-N 0.000 claims description 2
• FOZIFOSSSDWNSN-UHFFFAOYSA-N n-benzyl-4-(pyridin-4-ylmethyl)phthalazin-1-amine Chemical compound C=1C=CC=CC=1CNC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 FOZIFOSSSDWNSN-UHFFFAOYSA-N 0.000 claims description 2
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims 10
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims 10
• 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 10
• 125000000542 sulfonic acid group Chemical group 0.000 claims 6
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 4
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims 2
• 239000000825 pharmaceutical preparation Substances 0.000 claims 2
• 229940127557 pharmaceutical product Drugs 0.000 claims 2
• 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
• 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
• 239000012453 solvate Substances 0.000 claims 1
• 230000000694 effects Effects 0.000 abstract description 14
• 239000003814 drug Substances 0.000 abstract description 7
• 125000006701 (C1-C7) alkyl group Chemical group 0.000 abstract 1
• 230000002074 deregulated effect Effects 0.000 abstract 1
• 238000004519 manufacturing process Methods 0.000 abstract 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 333
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 210
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 195
• WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 116
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 109
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 88
• 239000000243 solution Substances 0.000 description 81
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 70
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
• 235000002639 sodium chloride Nutrition 0.000 description 63
• 239000002253 acid Substances 0.000 description 52
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 42
• 239000011541 reaction mixture Substances 0.000 description 42
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
• 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 40
• 239000000741 silica gel Substances 0.000 description 38
• 229910002027 silica gel Inorganic materials 0.000 description 38
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
• 238000001816 cooling Methods 0.000 description 36
• 238000001035 drying Methods 0.000 description 35
• LVSFOJFCLFTXTO-UHFFFAOYSA-N 1-chloro-4-(pyridin-4-ylmethyl)phthalazine Chemical compound C12=CC=CC=C2C(Cl)=NN=C1CC1=CC=NC=C1 LVSFOJFCLFTXTO-UHFFFAOYSA-N 0.000 description 33
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 33
• 239000000047 product Substances 0.000 description 32
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
• 238000003818 flash chromatography Methods 0.000 description 30
• 239000012044 organic layer Substances 0.000 description 30
• DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 30
• 239000004480 active ingredient Substances 0.000 description 27
• 239000000725 suspension Substances 0.000 description 27
• 238000004128 high performance liquid chromatography Methods 0.000 description 25
• 239000002904 solvent Substances 0.000 description 25
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
• 238000005160 1H NMR spectroscopy Methods 0.000 description 23
• 238000009835 boiling Methods 0.000 description 23
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 20
• QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 19
• DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 description 19
• 239000013078 crystal Substances 0.000 description 19
• 238000002425 crystallisation Methods 0.000 description 19
• 230000008025 crystallization Effects 0.000 description 19
• 239000000706 filtrate Substances 0.000 description 19
• 238000001953 recrystallisation Methods 0.000 description 19
• 150000008064 anhydrides Chemical class 0.000 description 18
• 239000000460 chlorine Substances 0.000 description 18
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
• 229910052938 sodium sulfate Inorganic materials 0.000 description 17
• 235000011152 sodium sulphate Nutrition 0.000 description 17
• 238000003756 stirring Methods 0.000 description 16
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 229910052801 chlorine Inorganic materials 0.000 description 15
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
• 210000004027 cell Anatomy 0.000 description 14
• 238000000921 elemental analysis Methods 0.000 description 14
• 150000002148 esters Chemical class 0.000 description 14
• 238000001914 filtration Methods 0.000 description 14
• 239000002245 particle Substances 0.000 description 14
• ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 14
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
• 239000012267 brine Substances 0.000 description 13
• 239000003795 chemical substances by application Substances 0.000 description 13
• 239000000155 melt Substances 0.000 description 13
• 239000012299 nitrogen atmosphere Substances 0.000 description 13
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 13
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
• 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 12
• 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 12
• 238000004587 chromatography analysis Methods 0.000 description 12
• 238000001704 evaporation Methods 0.000 description 12
• 230000008020 evaporation Effects 0.000 description 12
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
• 239000012298 atmosphere Substances 0.000 description 11
• 239000002585 base Substances 0.000 description 11
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 10
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
• 238000005406 washing Methods 0.000 description 10
• NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 9
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
• 150000001408 amides Chemical class 0.000 description 9
• 229910021529 ammonia Inorganic materials 0.000 description 9
• 230000015572 biosynthetic process Effects 0.000 description 9
• 230000012010 growth Effects 0.000 description 9
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 9
• 239000010410 layer Substances 0.000 description 9
• 230000001613 neoplastic effect Effects 0.000 description 9
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
• 235000017557 sodium bicarbonate Nutrition 0.000 description 9
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
• FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 8
• 238000010992 reflux Methods 0.000 description 8
• 230000001225 therapeutic effect Effects 0.000 description 8
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