FI108793B - Menetelmä terapeuttisesti käyttökelpoisten kinatsoliinijohdannaisten valmistamiseksi - Google Patents
Menetelmä terapeuttisesti käyttökelpoisten kinatsoliinijohdannaisten valmistamiseksi Download PDFInfo
- Publication number
- FI108793B FI108793B FI931067A FI931067A FI108793B FI 108793 B FI108793 B FI 108793B FI 931067 A FI931067 A FI 931067A FI 931067 A FI931067 A FI 931067A FI 108793 B FI108793 B FI 108793B
- Authority
- FI
- Finland
- Prior art keywords
- formula
- acid
- compound
- prop
- amino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 39
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims abstract description 16
- 230000008569 process Effects 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 150000002148 esters Chemical class 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000001424 substituent group Chemical group 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 4
- -1 pyridine-2,5-diyl Chemical group 0.000 claims description 126
- 150000001875 compounds Chemical class 0.000 claims description 66
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 44
- 239000007858 starting material Substances 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- IQLCQQXYCNNYFN-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)butanoic acid Chemical compound CCC(C(O)=O)C=1N=NNN=1 IQLCQQXYCNNYFN-UHFFFAOYSA-N 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 150000003246 quinazolines Chemical class 0.000 abstract description 38
- 150000003839 salts Chemical class 0.000 abstract description 28
- 230000000259 anti-tumor effect Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 239000000203 mixture Substances 0.000 description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 239000000047 product Substances 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000000921 elemental analysis Methods 0.000 description 16
- 238000012360 testing method Methods 0.000 description 15
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 239000005711 Benzoic acid Substances 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 108010022394 Threonine synthase Proteins 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 235000010233 benzoic acid Nutrition 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- OXQBUBWERGUDCQ-BYPYZUCNSA-N methyl (2s)-2-amino-4-(2h-tetrazol-5-yl)butanoate Chemical compound COC(=O)[C@@H](N)CCC1=NN=NN1 OXQBUBWERGUDCQ-BYPYZUCNSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LTKHPMDRMUCUEB-IBGZPJMESA-N CB3717 Chemical compound C=1C=C2NC(N)=NC(=O)C2=CC=1CN(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 LTKHPMDRMUCUEB-IBGZPJMESA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 102000005497 Thymidylate Synthase Human genes 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 6
- 230000000340 anti-metabolite Effects 0.000 description 6
- 229940100197 antimetabolite Drugs 0.000 description 6
- 239000002256 antimetabolite Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 5
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000010265 fast atom bombardment Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- WZPWTXZSQHIABL-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) benzoate Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1OC(=O)C1=CC=CC=C1 WZPWTXZSQHIABL-UHFFFAOYSA-N 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 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 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 4
- 230000001884 polyglutamylation Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 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 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 230000009471 action Effects 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 102000004419 dihydrofolate reductase Human genes 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- ZCMMQKVHAWGLGE-UHFFFAOYSA-N tert-butyl 4-(methylamino)benzoate Chemical compound CNC1=CC=C(C(=O)OC(C)(C)C)C=C1 ZCMMQKVHAWGLGE-UHFFFAOYSA-N 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- IEJSCSAMMLUINT-NRFANRHFSA-N (2s)-2-[[4-[(2,7-dimethyl-4-oxo-1h-quinazolin-6-yl)methyl-prop-2-ynylamino]-2-fluorobenzoyl]amino]-4-(2h-tetrazol-5-yl)butanoic acid Chemical compound C([C@H](NC(=O)C1=CC=C(C=C1F)N(CC#C)CC=1C=C2C(=O)N=C(NC2=CC=1C)C)C(O)=O)CC=1N=NNN=1 IEJSCSAMMLUINT-NRFANRHFSA-N 0.000 description 2
- NDDVIOZMIVZKPN-UHFFFAOYSA-N (4-oxo-1h-quinazolin-2-yl)methyl 2,2-dimethylpropanoate Chemical compound C1=CC=C2C(=O)NC(COC(=O)C(C)(C)C)=NC2=C1 NDDVIOZMIVZKPN-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 2
- 206010027654 Allergic conditions Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- NMMIHXMBOZYNET-UHFFFAOYSA-N Methyl picolinate Chemical compound COC(=O)C1=CC=CC=N1 NMMIHXMBOZYNET-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- WVNPVKQVEDUCRU-UHFFFAOYSA-N [6-(bromomethyl)-2,7-dimethyl-4-oxoquinazolin-3-yl]methyl 2,2-dimethylpropanoate Chemical compound N1=C(C)N(COC(=O)C(C)(C)C)C(=O)C2=C1C=C(C)C(CBr)=C2 WVNPVKQVEDUCRU-UHFFFAOYSA-N 0.000 description 2
- MCRATMMZSNXDCZ-UHFFFAOYSA-N [6-(bromomethyl)-7-chloro-2-methyl-4-oxoquinazolin-3-yl]methyl 2,2-dimethylpropanoate Chemical compound ClC1=C(CBr)C=C2C(=O)N(COC(=O)C(C)(C)C)C(C)=NC2=C1 MCRATMMZSNXDCZ-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 229960003896 aminopterin Drugs 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 description 2
- VLNZUSMTOFYNPS-UHFFFAOYSA-N diethylphosphorylformonitrile Chemical compound CCP(=O)(CC)C#N VLNZUSMTOFYNPS-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 150000002224 folic acids Chemical class 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- ZXNAKIXWULRNEZ-LBPRGKRZSA-N methyl (2s)-4-cyano-2-(phenylmethoxycarbonylamino)butanoate Chemical compound N#CCC[C@@H](C(=O)OC)NC(=O)OCC1=CC=CC=C1 ZXNAKIXWULRNEZ-LBPRGKRZSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NYYHRRYBRKXCPC-UHFFFAOYSA-N tert-butyl 2-fluoro-4-(methylamino)benzoate Chemical compound CNC1=CC=C(C(=O)OC(C)(C)C)C(F)=C1 NYYHRRYBRKXCPC-UHFFFAOYSA-N 0.000 description 2
- RUTOCMQSWSYTLX-UHFFFAOYSA-N tert-butyl 3-amino-2-fluoro-4-prop-2-ynylbenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(CC#C)C(N)=C1F RUTOCMQSWSYTLX-UHFFFAOYSA-N 0.000 description 2
- LYDRKKWPKKEMNZ-UHFFFAOYSA-N tert-butyl benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1 LYDRKKWPKKEMNZ-UHFFFAOYSA-N 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 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 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- IJEDRMBVQWYIPF-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 4-[[7-chloro-3-(2,2-dimethylpropanoyloxymethyl)-2-methyl-4-oxoquinazolin-6-yl]methyl-methylamino]benzoate Chemical compound C=1C(C(N(COC(=O)C(C)(C)C)C(C)=N2)=O)=C2C=C(Cl)C=1CN(C)C(C=C1)=CC=C1C(=O)OC1=C(F)C(F)=C(F)C(F)=C1F IJEDRMBVQWYIPF-UHFFFAOYSA-N 0.000 description 1
- FUIIJTFNOZZVQR-UHFFFAOYSA-N (2-methyl-4-oxoquinazolin-3-yl)methyl 2,2-dimethylpropanoate Chemical compound CC1=NC2=CC=CC=C2C(N1COC(C(C)(C)C)=O)=O FUIIJTFNOZZVQR-UHFFFAOYSA-N 0.000 description 1
- DXFDIQNGJWQJGA-VKHMYHEASA-N (2s)-2-amino-4-(2h-tetrazol-5-yl)butanoic acid Chemical compound OC(=O)[C@@H](N)CCC1=NN=NN1 DXFDIQNGJWQJGA-VKHMYHEASA-N 0.000 description 1
- JIMLDJNLXLMGLX-JTQLQIEISA-N (2s)-5-amino-5-oxo-2-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 JIMLDJNLXLMGLX-JTQLQIEISA-N 0.000 description 1
- PUWCKGSRHZMFOX-UHFFFAOYSA-N (6-ethyl-2,7-dimethyl-4-oxoquinazolin-3-yl)methyl 2,2-dimethylpropanoate Chemical compound N1=C(C)N(COC(=O)C(C)(C)C)C(=O)C2=C1C=C(C)C(CC)=C2 PUWCKGSRHZMFOX-UHFFFAOYSA-N 0.000 description 1
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 125000006083 1-bromoethyl group Chemical group 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- MKBPYKMWOHCHEH-UHFFFAOYSA-N 2-[[4-[(2,7-dimethyl-4-oxo-1h-quinazolin-6-yl)methyl-methylamino]-2-fluorobenzoyl]amino]-4-(2h-tetrazol-5-yl)butanoic acid Chemical compound C=1C(C(NC(C)=N2)=O)=C2C=C(C)C=1CN(C)C(C=C1F)=CC=C1C(=O)NC(C(O)=O)CCC1=NN=NN1 MKBPYKMWOHCHEH-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000005449 2-fluoro-1,4-phenylene group Chemical group [H]C1=C([*:2])C([H])=C(F)C([*:1])=C1[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 1
- FFZXPIXYZUUCME-UHFFFAOYSA-N 4-[1-[3-(2,2-dimethylpropanoyloxymethyl)-2,7-dimethyl-4-oxoquinazolin-6-yl]ethyl-prop-2-ynylamino]benzoic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C=1C(C(N(COC(=O)C(C)(C)C)C(C)=N2)=O)=C2C=C(C)C=1C(C)N(CC#C)C1=CC=C(C(O)=O)C=C1 FFZXPIXYZUUCME-UHFFFAOYSA-N 0.000 description 1
- QEQSGABFNGPRTF-UHFFFAOYSA-N 4-[[3-(2,2-dimethylpropanoyloxymethyl)-2,7-dimethyl-4-oxoquinazolin-6-yl]methyl-prop-2-ynylamino]-2-fluorobenzoic acid Chemical compound CC1=CC=2N=C(C)N(COC(=O)C(C)(C)C)C(=O)C=2C=C1CN(CC#C)C1=CC=C(C(O)=O)C(F)=C1 QEQSGABFNGPRTF-UHFFFAOYSA-N 0.000 description 1
- PDFPKTOGRVOJON-UHFFFAOYSA-N 4-[[3-(2,2-dimethylpropanoyloxymethyl)-2-methyl-4-oxoquinazolin-6-yl]methyl-methylamino]-2-fluorobenzoic acid Chemical compound C=1C=C2N=C(C)N(COC(=O)C(C)(C)C)C(=O)C2=CC=1CN(C)C1=CC=C(C(O)=O)C(F)=C1 PDFPKTOGRVOJON-UHFFFAOYSA-N 0.000 description 1
- WJRDIWVHQMKECE-UHFFFAOYSA-N 4-[[3-(2,2-dimethylpropanoyloxymethyl)-2-methyl-4-oxoquinazolin-6-yl]methyl-prop-2-ynylamino]benzoic acid Chemical compound C1=C2C(=O)N(COC(=O)C(C)(C)C)C(C)=NC2=CC=C1CN(CC#C)C1=CC=C(C(O)=O)C=C1 WJRDIWVHQMKECE-UHFFFAOYSA-N 0.000 description 1
- QHERSCUZBKDVOC-UHFFFAOYSA-N 4-amino-2-fluorobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C(F)=C1 QHERSCUZBKDVOC-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- YZRXOGYAOOJFLQ-UHFFFAOYSA-N 5-[(2,7-dimethyl-4-oxo-1h-quinazolin-6-yl)methyl-prop-2-ynylamino]pyridine-2-carboxylic acid Chemical compound C1=C2C(=O)NC(C)=NC2=CC(C)=C1CN(CC#C)C1=CC=C(C(O)=O)N=C1 YZRXOGYAOOJFLQ-UHFFFAOYSA-N 0.000 description 1
- HEMIZZJFQIXEQL-UHFFFAOYSA-N 6-ethyl-2,7-dimethyl-1h-quinazolin-4-one Chemical compound N1=C(C)NC(=O)C2=C1C=C(C)C(CC)=C2 HEMIZZJFQIXEQL-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- DOOSZDQHWGIAPA-NRFANRHFSA-N C([C@@H](C(=O)OC)NC(=O)C=1N=CC(=CC=1)N(CC#C)CC=1C(=CC2=C(C(NC(C)=N2)=O)C=1)C)CC1=NN=NN1 Chemical compound C([C@@H](C(=O)OC)NC(=O)C=1N=CC(=CC=1)N(CC#C)CC=1C(=CC2=C(C(NC(C)=N2)=O)C=1)C)CC1=NN=NN1 DOOSZDQHWGIAPA-NRFANRHFSA-N 0.000 description 1
- RLXNUYXIAIWFAH-IBGZPJMESA-N C([C@H](NC(=O)C1=CC=C(C=C1)N(CC=1C(=CC2=C(C(NC(C)=N2)=O)C=1)C)C)C(O)=O)CC1=NN=NN1 Chemical compound C([C@H](NC(=O)C1=CC=C(C=C1)N(CC=1C(=CC2=C(C(NC(C)=N2)=O)C=1)C)C)C(O)=O)CC1=NN=NN1 RLXNUYXIAIWFAH-IBGZPJMESA-N 0.000 description 1
- UMJKPHDKGHQBAT-UHFFFAOYSA-N CC(C)(C)OC(=O)C1=C(C=C(C=C1)CC#C)N Chemical compound CC(C)(C)OC(=O)C1=C(C=C(C=C1)CC#C)N UMJKPHDKGHQBAT-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 241000611421 Elia Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 206010064147 Gastrointestinal inflammation Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000002397 Kinins Human genes 0.000 description 1
- 108010093008 Kinins Proteins 0.000 description 1
- 125000003338 L-glutaminyl group Chemical class O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 1
- 241000283986 Lepus Species 0.000 description 1
- 241000343203 Lidia Species 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- ZKGNPQKYVKXMGJ-UHFFFAOYSA-N N,N-dimethylacetamide Chemical compound CN(C)C(C)=O.CN(C)C(C)=O ZKGNPQKYVKXMGJ-UHFFFAOYSA-N 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 229940122149 Thymidylate synthase inhibitor Drugs 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- JSRLJPSBLDHEIO-SHYZEUOFSA-N dUMP Chemical compound O1[C@H](COP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C=C1 JSRLJPSBLDHEIO-SHYZEUOFSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000008263 liquid aerosol Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- NLFPDMRYQJELPQ-NSHDSACASA-N methyl (2s)-2-(phenylmethoxycarbonylamino)-4-(2h-tetrazol-5-yl)butanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)OCC=1C=CC=CC=1)CC1=NN=NN1 NLFPDMRYQJELPQ-NSHDSACASA-N 0.000 description 1
- VXGRMCZTYDXKQW-YFKPBYRVSA-N methyl (2s)-2-aminopentanoate Chemical compound CCC[C@H](N)C(=O)OC VXGRMCZTYDXKQW-YFKPBYRVSA-N 0.000 description 1
- UGLQIOYVRJQLOG-NSHDSACASA-N methyl (2s)-5-amino-5-oxo-2-(phenylmethoxycarbonylamino)pentanoate Chemical compound NC(=O)CC[C@@H](C(=O)OC)NC(=O)OCC1=CC=CC=C1 UGLQIOYVRJQLOG-NSHDSACASA-N 0.000 description 1
- PNGLVIJLTRZPBE-UHFFFAOYSA-N methyl 5-(prop-2-ynylamino)pyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(NCC#C)C=N1 PNGLVIJLTRZPBE-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- PZOAOCJXYBNSJQ-UHFFFAOYSA-N n-(2-cyano-4-ethyl-5-methylphenyl)acetamide Chemical compound CCC1=CC(C#N)=C(NC(C)=O)C=C1C PZOAOCJXYBNSJQ-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229940127075 other antimetabolite Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- FCCRKNYAZJHMME-UHFFFAOYSA-N tert-butyl 4-amino-2-fluorobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(N)C=C1F FCCRKNYAZJHMME-UHFFFAOYSA-N 0.000 description 1
- KYORUZMJUKHKFS-UHFFFAOYSA-N tert-butyl 4-aminobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(N)C=C1 KYORUZMJUKHKFS-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 239000003734 thymidylate synthase inhibitor Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- JKVRTUCVPZTEQZ-UHFFFAOYSA-N tributyltin azide Chemical compound CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-] JKVRTUCVPZTEQZ-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 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
- C07D401/14—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 three or more hetero 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Adhesives Or Adhesive Processes (AREA)
- Dental Preparations (AREA)
- Golf Clubs (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9205320 | 1992-03-11 | ||
| GB929205320A GB9205320D0 (en) | 1992-03-11 | 1992-03-11 | Anti-tumour compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI931067A0 FI931067A0 (fi) | 1993-03-10 |
| FI931067L FI931067L (fi) | 1993-09-12 |
| FI108793B true FI108793B (fi) | 2002-03-28 |
Family
ID=10711936
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI931067A FI108793B (fi) | 1992-03-11 | 1993-03-10 | Menetelmä terapeuttisesti käyttökelpoisten kinatsoliinijohdannaisten valmistamiseksi |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5955463A (cs) |
| EP (1) | EP0562734B1 (cs) |
| JP (1) | JP3160111B2 (cs) |
| KR (1) | KR100221011B1 (cs) |
| AT (1) | ATE131823T1 (cs) |
| AU (1) | AU659277B2 (cs) |
| CA (1) | CA2090942C (cs) |
| CZ (1) | CZ281811B6 (cs) |
| DE (1) | DE69301048T2 (cs) |
| DK (1) | DK0562734T3 (cs) |
| ES (1) | ES2081178T3 (cs) |
| FI (1) | FI108793B (cs) |
| GB (2) | GB9205320D0 (cs) |
| GR (1) | GR3018501T3 (cs) |
| HK (1) | HK21297A (cs) |
| HU (1) | HU211127A9 (cs) |
| IL (1) | IL104984A (cs) |
| NO (1) | NO301543B1 (cs) |
| NZ (1) | NZ247122A (cs) |
| RU (1) | RU2111209C1 (cs) |
| TW (1) | TW223635B (cs) |
| ZA (1) | ZA931447B (cs) |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9223352D0 (en) * | 1992-11-06 | 1992-12-23 | Ici Plc | Tricyclic compounds |
| GB9408936D0 (en) * | 1994-05-05 | 1994-06-22 | Cancer Res Inst | Anti-cancer compounds |
| US5804396A (en) * | 1994-10-12 | 1998-09-08 | Sugen, Inc. | Assay for agents active in proliferative disorders |
| US5837815A (en) * | 1994-12-15 | 1998-11-17 | Sugen, Inc. | PYK2 related polypeptide products |
| US5837524A (en) * | 1994-12-15 | 1998-11-17 | Sugen, Inc. | PYK2 related polynucleotide products |
| AU5984296A (en) * | 1995-06-07 | 1996-12-30 | Sugen, Inc. | Quinazolines and pharmaceutical compositions |
| US7119174B2 (en) | 1995-12-18 | 2006-10-10 | Sugen, Inc. | Diagnosis and treatment of AUR1 and/or AUR2 related disorders |
| US6716575B2 (en) | 1995-12-18 | 2004-04-06 | Sugen, Inc. | Diagnosis and treatment of AUR1 and/or AUR2 related disorders |
| US6818440B2 (en) | 1997-04-28 | 2004-11-16 | Sugen, Inc. | Diagnosis and treatment of alk-7 related disorders |
| US6228641B1 (en) | 1997-05-20 | 2001-05-08 | Sugen, Inc. | Diagnosis and treatment of PTP04 related disorders |
| US6342593B1 (en) | 1997-06-11 | 2002-01-29 | Sugen, Inc. | Diagnosis and treatment of ALP related disorders |
| US7115710B2 (en) | 1997-06-11 | 2006-10-03 | Sugen, Inc. | Diagnosis and treatment of PTP related disorders |
| US6388063B1 (en) | 1997-06-18 | 2002-05-14 | Sugen, Inc. | Diagnosis and treatment of SAD related disorders |
| CA2318403A1 (en) | 1998-01-21 | 1999-07-29 | Sugen, Inc. | Human orthologues of wart |
| AU3642499A (en) | 1998-04-14 | 1999-11-01 | Sugen, Inc. | Ste20-related protein kinases |
| US6235213B1 (en) * | 1998-05-18 | 2001-05-22 | Micron Technology, Inc. | Etching methods, methods of removing portions of material, and methods of forming silicon nitride spacers |
| US6861442B1 (en) | 1998-12-30 | 2005-03-01 | Sugen, Inc. | PYK2 and inflammation |
| RU2256654C2 (ru) * | 1999-01-22 | 2005-07-20 | Кирин Бир Кабусики Кайся | Хинолиновые и хиназолиновые производные |
| US7074800B1 (en) * | 1999-02-10 | 2006-07-11 | Astrazeneca Ab | Quinazoline derivatives as angiogenesis inhibitors |
| GB9904275D0 (en) | 1999-02-24 | 1999-04-21 | Cancer Res Campaign Tech | Anti-cancer compounds |
| AU783082B2 (en) | 1999-10-22 | 2005-09-22 | Pharmacia & Upjohn Company | Drosophila G protein coupled receptors, nucleic acids, and methods related to the same |
| US6143776A (en) * | 2000-02-02 | 2000-11-07 | Sunesis Pharmaceuticals, Inc. | Tosylproline analogs as thymidylate synthase inhibitors |
| DE60134224D1 (de) | 2001-08-10 | 2008-07-10 | Ford Global Tech Inc | Ansaugkrümmer |
| EP2311850A1 (en) | 2001-08-31 | 2011-04-20 | BTG International Limited | Anti-cancer cyclopenta[g]quinazoline compounds |
| DK1420809T3 (da) | 2001-08-31 | 2011-12-19 | Btg Int Ltd | Anvendelse af cyclopenta[G]quinazolinderivater til behandling af cancer |
| SI1562955T1 (sl) * | 2002-11-04 | 2008-06-30 | Astrazeneca Ab | Derivati kinazolina kot inhibitorji Src-triozin kinaze |
| GB0317631D0 (en) * | 2003-07-28 | 2003-08-27 | Btg Int Ltd | Synthetic method |
| TW200526638A (en) * | 2003-10-22 | 2005-08-16 | Smithkline Beecham Corp | 2-(3,4-dimethylphenyl)-4-{[2-hydroxy-3'-(1H-tetrazol-5-yl)biphenyl-3-yl]-hydrazono}-5-methyl-2,4-dihydropyrazol-3-one choline |
| TW200533664A (en) * | 2004-02-18 | 2005-10-16 | Astrazeneca Ab | Tetrazole compounds and their use as metabotropic glutamate receptor antagonists |
| AU2006324477A1 (en) | 2005-12-15 | 2007-06-21 | Medimmune Limited | Combination of angiopoietin-2 antagonist and of VEGF-A, KDR and/or Flt1 antagonist for treating cancer |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2065653B (en) * | 1979-12-19 | 1983-03-09 | Nat Res Dev | Anti-cancer quinazoline derivatives |
| JPS5692876A (en) * | 1979-12-19 | 1981-07-27 | Nat Res Dev | Anticancerous quinazoline derivative |
| GB8513754D0 (en) * | 1985-05-31 | 1985-07-03 | Jones T R | Anti-cancer quinazoline derivatives |
| GB8607683D0 (en) * | 1986-03-27 | 1986-04-30 | Ici Plc | Anti-tumor agents |
| US5187167A (en) * | 1986-03-27 | 1993-02-16 | Imperial Chemical Industries Plc | Pharmaceutical compositions comprising quinazolin-4-one derivatives |
| US4725687A (en) * | 1986-04-28 | 1988-02-16 | Southern Research Institute | 5-methyl-5-deaza analogues of methotrexate and N10 -ethylaminopterin |
| GB8707053D0 (en) * | 1987-03-25 | 1987-04-29 | Ici Plc | Anti-tumour agents |
| US4857530A (en) * | 1987-11-03 | 1989-08-15 | Warner-Lambert Company | Substituted quinazolinones as anticancer agents |
| US4999424A (en) * | 1988-11-10 | 1991-03-12 | The Pennsylvania State University | GAR transformylase inhibitor |
| US5252573A (en) * | 1988-12-15 | 1993-10-12 | Imperial Chemical Industries Plc | Anti-tumor agents |
| GB8829296D0 (en) * | 1988-12-15 | 1989-01-25 | Ici Plc | Anti-tumour compounds |
| ZA913730B (en) * | 1990-05-30 | 1992-02-26 | Ici Plc | Anti-tumor compounds |
| US5145854A (en) * | 1991-11-27 | 1992-09-08 | Nair Madhavan G | 1-formyl-5,8,10-trideazafolates |
-
1992
- 1992-03-11 GB GB929205320A patent/GB9205320D0/en active Pending
-
1993
- 1993-02-25 AU AU33782/93A patent/AU659277B2/en not_active Ceased
- 1993-03-01 ZA ZA931447A patent/ZA931447B/xx unknown
- 1993-03-03 CA CA002090942A patent/CA2090942C/en not_active Expired - Fee Related
- 1993-03-08 CZ CZ93362A patent/CZ281811B6/cs not_active IP Right Cessation
- 1993-03-08 IL IL104984A patent/IL104984A/en not_active IP Right Cessation
- 1993-03-09 GB GB9304807A patent/GB2264946B/en not_active Expired - Fee Related
- 1993-03-09 ES ES93301780T patent/ES2081178T3/es not_active Expired - Lifetime
- 1993-03-09 EP EP93301780A patent/EP0562734B1/en not_active Expired - Lifetime
- 1993-03-09 AT AT93301780T patent/ATE131823T1/de not_active IP Right Cessation
- 1993-03-09 DK DK93301780.8T patent/DK0562734T3/da active
- 1993-03-09 US US08/028,158 patent/US5955463A/en not_active Expired - Fee Related
- 1993-03-09 DE DE69301048T patent/DE69301048T2/de not_active Expired - Fee Related
- 1993-03-10 FI FI931067A patent/FI108793B/fi active
- 1993-03-10 KR KR1019930003536A patent/KR100221011B1/ko not_active Expired - Fee Related
- 1993-03-10 RU RU93004793A patent/RU2111209C1/ru not_active IP Right Cessation
- 1993-03-10 NO NO930881A patent/NO301543B1/no unknown
- 1993-03-11 NZ NZ247122A patent/NZ247122A/xx not_active IP Right Cessation
- 1993-03-11 JP JP05052593A patent/JP3160111B2/ja not_active Expired - Fee Related
- 1993-03-16 TW TW082101928A patent/TW223635B/zh active
-
1995
- 1995-06-14 HU HU95P/P00202P patent/HU211127A9/hu unknown
- 1995-12-21 GR GR950403484T patent/GR3018501T3/el unknown
-
1997
- 1997-02-27 HK HK21297A patent/HK21297A/xx not_active IP Right Cessation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI108793B (fi) | Menetelmä terapeuttisesti käyttökelpoisten kinatsoliinijohdannaisten valmistamiseksi | |
| US5081124A (en) | Method of producing antitumor effect using quinazolin-4-one derivatives | |
| US5187167A (en) | Pharmaceutical compositions comprising quinazolin-4-one derivatives | |
| AU640016B2 (en) | Hydroquinazoline derivatives | |
| EP0318225B1 (en) | 6-Aryl aminomethyl quinoline derivatives and their use as anti-tumour agents | |
| GB2227016A (en) | Quinazoline derivatives | |
| SK286959B6 (sk) | Bicyklické heterocyklické zlúčeniny, spôsob ich prípravy, farmaceutický prostriedok s ich obsahom a ich použitie | |
| CA2121816A1 (en) | Substituted heterocycles as angiotensin ii antagonists | |
| WO1994007869A1 (en) | Quinazoline derivatives | |
| US5789417A (en) | Tricyclic compounds with pharmaceutical activity | |
| EP0339976B1 (en) | Anti-tumour agents | |
| US5747499A (en) | Anti-cancer compounds | |
| EP0365763A1 (en) | Antiproliferative cyclic compounds | |
| JPH0789957A (ja) | ビフェニルメチルアミン誘導体 | |
| US5252573A (en) | Anti-tumor agents | |
| WO1995009158A1 (en) | Tricyclic derivatives | |
| GB2272217A (en) | Anti-cancer cyclopentaquinazolines | |
| MXPA01003424A (es) | Compuestos quimicos |