FI76791C - Foerfarande foer framstaellning av 2-amino-4-hydroxikinazolinderivat med anticanceraktivitet. - Google Patents
Foerfarande foer framstaellning av 2-amino-4-hydroxikinazolinderivat med anticanceraktivitet. Download PDFInfo
- Publication number
- FI76791C FI76791C FI803957A FI803957A FI76791C FI 76791 C FI76791 C FI 76791C FI 803957 A FI803957 A FI 803957A FI 803957 A FI803957 A FI 803957A FI 76791 C FI76791 C FI 76791C
- Authority
- FI
- Finland
- Prior art keywords
- group
- formula
- cooh
- compound
- amino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 230000001093 anti-cancer Effects 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 62
- 150000002148 esters Chemical class 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 7
- 125000004185 ester group Chemical group 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- SDTFBAXSPXZDKC-UHFFFAOYSA-N 2-imino-1,2,3,4-tetrahydroquinazolin-4-one Chemical class C1=CC=C2C(=O)NC(N)=NC2=C1 SDTFBAXSPXZDKC-UHFFFAOYSA-N 0.000 claims description 5
- 229920002643 polyglutamic acid Polymers 0.000 claims description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 4
- LTKHPMDRMUCUEB-UHFFFAOYSA-N 2-[[4-[(2-amino-4-oxo-1h-quinazolin-6-yl)methyl-prop-2-ynylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1C=C2NC(N)=NC(=O)C2=CC=1CN(CC#C)C1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 LTKHPMDRMUCUEB-UHFFFAOYSA-N 0.000 claims description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- 229930195714 L-glutamate Natural products 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 101100506443 Danio rerio helt gene Proteins 0.000 claims 2
- 101100506445 Mus musculus Helt gene Proteins 0.000 claims 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- -1 alkadienyl Chemical group 0.000 description 30
- 239000000243 solution Substances 0.000 description 26
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 25
- 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 23
- 229960000485 methotrexate Drugs 0.000 description 23
- 239000000047 product Substances 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000000921 elemental analysis Methods 0.000 description 12
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 9
- 108020001096 dihydrofolate reductase Proteins 0.000 description 9
- 229910000019 calcium carbonate Inorganic materials 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 150000005690 diesters Chemical class 0.000 description 7
- 230000005012 migration Effects 0.000 description 7
- 238000013508 migration Methods 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229960000304 folic acid Drugs 0.000 description 6
- 235000019152 folic acid Nutrition 0.000 description 6
- 239000011724 folic acid Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 4
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 4
- 235000008191 folinic acid Nutrition 0.000 description 4
- 239000011672 folinic acid Substances 0.000 description 4
- 229960002989 glutamic acid Drugs 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229960001691 leucovorin Drugs 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting 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
- 230000003389 potentiating effect Effects 0.000 description 4
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 description 3
- 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 3
- ZCFWWXMAJYLZJU-UHFFFAOYSA-N 2-amino-6-(bromomethyl)-1h-quinazolin-4-one;hydrobromide Chemical compound Br.C1=C(CBr)C=C2C(=O)NC(N)=NC2=C1 ZCFWWXMAJYLZJU-UHFFFAOYSA-N 0.000 description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 230000006820 DNA synthesis Effects 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000000340 anti-metabolite Effects 0.000 description 3
- 229940100197 antimetabolite Drugs 0.000 description 3
- 239000002256 antimetabolite Substances 0.000 description 3
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000010908 decantation Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229940104230 thymidine Drugs 0.000 description 3
- QUHSPLVBAACUQP-SFHVURJKSA-N (2s)-2-[[4-[(2-amino-4-oxo-1h-quinazolin-6-yl)methyl-(2-fluoroethyl)amino]benzoyl]amino]pentanedioic acid Chemical compound C=1C=C2NC(N)=NC(=O)C2=CC=1CN(CCF)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QUHSPLVBAACUQP-SFHVURJKSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010034133 Pathogen resistance Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229960005261 aspartic acid Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- RJXFBLRRPYBPTM-ZDUSSCGKSA-N diethyl (2s)-2-[(4-aminobenzoyl)amino]pentanedioate Chemical compound CCOC(=O)CC[C@@H](C(=O)OCC)NC(=O)C1=CC=C(N)C=C1 RJXFBLRRPYBPTM-ZDUSSCGKSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000004052 folic acid antagonist Substances 0.000 description 2
- 150000002224 folic acids Chemical class 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003966 growth inhibitor Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 229910001410 inorganic ion Inorganic materials 0.000 description 2
- 238000004452 microanalysis Methods 0.000 description 2
- 239000011368 organic material Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000005460 tetrahydrofolate Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- BPBDWXCEFRHHDC-UHFFFAOYSA-N 2,2-dimethyl-n-(6-methylquinazolin-2-yl)propanamide Chemical compound N1=C(NC(=O)C(C)(C)C)N=CC2=CC(C)=CC=C21 BPBDWXCEFRHHDC-UHFFFAOYSA-N 0.000 description 1
- KSLWZHWJFFDMMK-UHFFFAOYSA-N 2-(chloromethyl)-1h-quinazolin-4-one Chemical compound C1=CC=C2NC(CCl)=NC(=O)C2=C1 KSLWZHWJFFDMMK-UHFFFAOYSA-N 0.000 description 1
- JTOFFLNJTLRRLO-UHFFFAOYSA-N 2-(chloromethyl)quinazoline;hydrochloride Chemical compound Cl.C1=CC=CC2=NC(CCl)=NC=C21 JTOFFLNJTLRRLO-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
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- XNRDLSNSMTUXBV-UHFFFAOYSA-N 2-fluoroethyl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCCF)C=C1 XNRDLSNSMTUXBV-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- LMDIDOFTXQERLH-UHFFFAOYSA-N 2-methyl-4-nitrobenzoyl chloride Chemical compound CC1=CC([N+]([O-])=O)=CC=C1C(Cl)=O LMDIDOFTXQERLH-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 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 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 208000018501 Lymphatic disease Diseases 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 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 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- YSKGCHRMWGVTTL-ZDUSSCGKSA-N diethyl (2s)-2-[(4-amino-2-chlorobenzoyl)amino]pentanedioate Chemical compound CCOC(=O)CC[C@@H](C(=O)OCC)NC(=O)C1=CC=C(N)C=C1Cl YSKGCHRMWGVTTL-ZDUSSCGKSA-N 0.000 description 1
- WSEQLMQNPBNMSL-FJXQXJEOSA-N diethyl (2s)-2-aminopentanedioate;hydron;chloride Chemical compound Cl.CCOC(=O)CC[C@H](N)C(=O)OCC WSEQLMQNPBNMSL-FJXQXJEOSA-N 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- PCTLYGKHPBZRCZ-UKLTVQOFSA-N maitotoxin-3 Chemical compound C[C@H]1CC[C@H]2O[C@@]3(C)C[C@H]4O[C@H]5C[C@H]6O[C@](O)(C[C@@H](O)CO)[C@@H](O)[C@@H](OS(O)(=O)=O)[C@@H]6O[C@@H]5C=C[C@@H]4O[C@@H]3CC[C@@H]2O[C@@H]2C[C@@H]3O[C@]4(C)CC(=C)C[C@](C)(O[C@H]4C[C@H]3O[C@@H]12)[C@@H](O)CC(=O)CC\C=C(/C)C=C PCTLYGKHPBZRCZ-UKLTVQOFSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002213 purine nucleotide Substances 0.000 description 1
- 230000006825 purine synthesis Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical class C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7943715 | 1979-12-19 | ||
| GB7943715 | 1979-12-19 | ||
| GB8006813 | 1980-02-28 | ||
| GB8006813 | 1980-02-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI803957L FI803957L (fi) | 1981-06-20 |
| FI76791B FI76791B (fi) | 1988-08-31 |
| FI76791C true FI76791C (fi) | 1988-12-12 |
Family
ID=26273917
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI803957A FI76791C (fi) | 1979-12-19 | 1980-12-18 | Foerfarande foer framstaellning av 2-amino-4-hydroxikinazolinderivat med anticanceraktivitet. |
Country Status (17)
| Country | Link |
|---|---|
| US (2) | US4447608A (cg-RX-API-DMAC7.html) |
| EP (1) | EP0031237B1 (cg-RX-API-DMAC7.html) |
| AU (1) | AU543237B2 (cg-RX-API-DMAC7.html) |
| CA (1) | CA1184900A (cg-RX-API-DMAC7.html) |
| DE (1) | DE3069468D1 (cg-RX-API-DMAC7.html) |
| DK (1) | DK157019C (cg-RX-API-DMAC7.html) |
| ES (3) | ES497884A0 (cg-RX-API-DMAC7.html) |
| FI (1) | FI76791C (cg-RX-API-DMAC7.html) |
| GB (1) | GB2065653B (cg-RX-API-DMAC7.html) |
| GR (1) | GR72847B (cg-RX-API-DMAC7.html) |
| HU (1) | HU193505B (cg-RX-API-DMAC7.html) |
| IE (1) | IE51188B1 (cg-RX-API-DMAC7.html) |
| IL (1) | IL61756A (cg-RX-API-DMAC7.html) |
| NO (1) | NO154919C (cg-RX-API-DMAC7.html) |
| NZ (1) | NZ195876A (cg-RX-API-DMAC7.html) |
| PT (1) | PT72232B (cg-RX-API-DMAC7.html) |
| YU (1) | YU321180A (cg-RX-API-DMAC7.html) |
Families Citing this family (73)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4684653A (en) * | 1985-03-08 | 1987-08-04 | The Trustees Of Princeton University | Pyrido(2,3-d)pyrimidine derivatives |
| US4927828A (en) * | 1985-03-08 | 1990-05-22 | The Trustees Of Princeton University | Diastereoisomeric tetrahydropyrido-(2,3,d) pyrimidine derivatives |
| US5026851A (en) * | 1985-03-08 | 1991-06-25 | The Trustees Of Princeton University | Pyrido[2,3-]pyrimidine derivatives |
| GB8513754D0 (en) * | 1985-05-31 | 1985-07-03 | Jones T R | Anti-cancer quinazoline derivatives |
| US5187167A (en) * | 1986-03-27 | 1993-02-16 | Imperial Chemical Industries Plc | Pharmaceutical compositions comprising quinazolin-4-one derivatives |
| GB8607683D0 (en) * | 1986-03-27 | 1986-04-30 | Ici Plc | Anti-tumor agents |
| US4833145A (en) * | 1986-06-30 | 1989-05-23 | The Trustees Of Princeton University | 4(3H)-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine derivatives |
| US4902796A (en) * | 1986-10-20 | 1990-02-20 | The Trustees Of Princeton University | 6-alkenyl and ethynyl derivatives of 2-amino-4-hydroxypyrido[2,3-d]pyrimidines |
| US4818819A (en) * | 1986-10-20 | 1989-04-04 | The Trustees Of Princeton University | Process for the preparation of fused pyridine compounds |
| 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 |
| GB8727737D0 (en) * | 1987-11-26 | 1987-12-31 | Ici Plc | Antitumour agents |
| JP2830008B2 (ja) * | 1988-04-01 | 1998-12-02 | 武田薬品工業株式会社 | 縮合ピリミジン誘導体 |
| US5223620A (en) * | 1988-04-01 | 1993-06-29 | Takeda Chemical Industries, Ltd. | Pyrido[2,3-d]pyrimidine compounds useful as intermediates |
| GB8809978D0 (en) * | 1988-04-27 | 1988-06-02 | Ici Plc | Anti-tumour agents |
| EP0365763A1 (en) * | 1988-09-30 | 1990-05-02 | Agouron Pharmaceuticals, Inc. | Antiproliferative cyclic compounds |
| 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 |
| US4996206A (en) * | 1989-12-11 | 1991-02-26 | The Trustees Of Princeton University | N-(pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivatives |
| US5160727A (en) * | 1990-02-13 | 1992-11-03 | Warner-Lambert Company | Tumor cell sensitization method using quinazolinedione derivatives |
| US5286726A (en) * | 1990-04-12 | 1994-02-15 | The Regents Of The University Of Michigan | Difluoroglutamic acid conjugates with folates and anti-folates for the treatment of neoplastic diseases |
| IL98167A0 (en) * | 1990-05-30 | 1992-06-21 | Ici Plc | Anti-tumour quinazoline derivatives,processes for their preparation and pharmaceutical compositions comprising them |
| US6762188B1 (en) | 1990-06-19 | 2004-07-13 | Smithkline Beecham Corporation | Pharmaceutically active benzoquinazoline compounds |
| GB9013615D0 (en) * | 1990-06-19 | 1990-08-08 | Wellcome Found | Pharmaceutical compounds |
| GB9105771D0 (en) * | 1991-03-19 | 1991-05-01 | Cancer Res Inst Royal | Anti-cancer compounds |
| US5145854A (en) * | 1991-11-27 | 1992-09-08 | Nair Madhavan G | 1-formyl-5,8,10-trideazafolates |
| GB9205320D0 (en) * | 1992-03-11 | 1992-04-22 | Ici Plc | Anti-tumour compounds |
| GB9205907D0 (en) * | 1992-03-18 | 1992-04-29 | Cancer Res Inst Royal | Anti-cancer compounds |
| US5430148A (en) * | 1992-03-31 | 1995-07-04 | Agouron Pharmaceuticals, Inc. | Antiproliferative quinazolines |
| CH684644A5 (de) * | 1992-07-13 | 1994-11-15 | Eprova Ag | 5,10-Methylentetrahydrofolsäure-Cyclodextrin-Einschlussverbindungen. |
| GB9223352D0 (en) * | 1992-11-06 | 1992-12-23 | Ici Plc | Tricyclic compounds |
| US5821231A (en) * | 1993-12-06 | 1998-10-13 | Cytel Corporation | CS-1 peptidomimetics, compositions and methods of using same |
| US5770573A (en) * | 1993-12-06 | 1998-06-23 | Cytel Corporation | CS-1 peptidomimetics, compositions and methods of using the same |
| CN1142832A (zh) * | 1993-12-06 | 1997-02-12 | 赛特尔公司 | Cs-1模拟肽，利用该肽的组合物和方法 |
| WO1995015973A1 (en) * | 1993-12-06 | 1995-06-15 | Cytel Corporation | Cs-1 peptidomimetics, compositions and methods of using the same |
| 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 |
| WO1996040648A1 (en) * | 1995-06-07 | 1996-12-19 | Sugen, Inc. | Quinazolines and pharmaceutical compositions |
| US5593999A (en) * | 1995-06-07 | 1997-01-14 | Nair; Madhavan G. | Non-classical folate analogue inhibitors of glycinamide ribonucleotide formyltransferase (GARFT) |
| 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 |
| ATE271603T1 (de) * | 1996-12-11 | 2004-08-15 | Sugen Inc | Identifizierungsverfahren für substanzen die an das pyk2 polypeptid binden |
| 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 |
| AU2237899A (en) * | 1998-01-21 | 1999-08-09 | Sugen, Inc. | Human orthologues of wart |
| WO1999053036A2 (en) * | 1998-04-14 | 1999-10-21 | Sugen, Inc. | Ste20-related protein kinases |
| US6861442B1 (en) * | 1998-12-30 | 2005-03-01 | Sugen, Inc. | PYK2 and inflammation |
| GB9904275D0 (en) | 1999-02-24 | 1999-04-21 | Cancer Res Campaign Tech | Anti-cancer compounds |
| US6479552B2 (en) | 1999-09-23 | 2002-11-12 | G.D. Searle & Co. | Use of substituted N, N-disubstituted diamino compounds for inhibiting cholesteryl ester transfer protein activity |
| US6677382B1 (en) | 1999-09-23 | 2004-01-13 | Pharmacia Corporation | Substituted N,N-bis-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity |
| US6803388B2 (en) | 1999-09-23 | 2004-10-12 | Pfizer, Inc. | (R)-Chiral halogenated substituted n,n-bis-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity |
| WO2001031005A2 (en) * | 1999-10-22 | 2001-05-03 | Pharmacia & Upjohn Company | Drosophila g protein coupled receptors, nucleic acids, and methods related to the same |
| US20030162223A1 (en) * | 1999-10-22 | 2003-08-28 | Lowery David E. | Drosophila G protein coupled receptors, nucleic acids, and methods related to the same |
| US7364866B2 (en) * | 1999-10-22 | 2008-04-29 | Pharmacia & Upjohn Company | Drosophila G protein coupled receptors, nucleic acids, and methods related to the same |
| EP1237909A2 (en) * | 1999-11-16 | 2002-09-11 | PHARMACIA & UPJOHN COMPANY | Human g protein-coupled receptors |
| US20030082534A1 (en) * | 1999-11-16 | 2003-05-01 | Peter Lind | Novel G protein-coupled receptors |
| US6143776A (en) * | 2000-02-02 | 2000-11-07 | Sunesis Pharmaceuticals, Inc. | Tosylproline analogs as thymidylate synthase inhibitors |
| US20030003451A1 (en) * | 2000-02-23 | 2003-01-02 | Gabriel Vogeli | Novel G protein-coupled receptors |
| US20030027308A1 (en) * | 2000-05-30 | 2003-02-06 | Sugen Incorporated | Novel human protein phosphatases identified from genomic sequencing |
| CA2321345A1 (fr) * | 2000-10-02 | 2002-04-02 | Abdelbast Guerfi | Utilisation du graphite dans un composite pour reduire l'accumulation de glace |
| US20040157306A1 (en) * | 2000-11-13 | 2004-08-12 | Sugen Incorporated | Mammalian protein phosphatases |
| US20050069976A1 (en) * | 2001-02-14 | 2005-03-31 | Peter Lind | Protein-coupled receptor |
| KR100983962B1 (ko) | 2001-08-31 | 2010-09-27 | 비티지 인터내셔널 리미티드 | 항암제로서 사용되는 시클로펜타[ｇ]퀴나졸린 화합물 |
| ES2373644T3 (es) | 2001-08-31 | 2012-02-07 | Btg International Limited | Uso de derivados de ciclopenta[g]quinazolina para el tratamiento del c�?ncer. |
| WO2003042390A1 (en) * | 2001-11-13 | 2003-05-22 | Sugen, Inc. | Mammalian protein phosphatases |
| US7537774B2 (en) * | 2005-12-23 | 2009-05-26 | Orion Therapeautics, Llc | Therapeutic formulation |
| JP2010511382A (ja) * | 2006-12-01 | 2010-04-15 | エージェンシー フォー サイエンス，テクノロジー アンド リサーチ | 癌関連タンパク質キナーゼ |
| CA2670379C (en) | 2007-04-11 | 2015-06-23 | Merck Eprova Ag | 18f-labelled folates |
| US8273617B2 (en) | 2009-09-30 | 2012-09-25 | Suvolta, Inc. | Electronic devices and systems, and methods for making and using the same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1021196A (en) * | 1964-02-20 | 1966-03-02 | Parke Davis & Co | Novel amino acids and means for producing the same |
| US3471498A (en) * | 1967-08-11 | 1969-10-07 | Parke Davis & Co | Certain n-p-((2,4-diamino-6-quinazolinyl)-methyl)benzoylamino acids |
-
1980
- 1980-12-16 GB GB8040202A patent/GB2065653B/en not_active Expired
- 1980-12-16 DE DE8080304539T patent/DE3069468D1/de not_active Expired
- 1980-12-16 EP EP80304539A patent/EP0031237B1/en not_active Expired
- 1980-12-17 HU HU803031A patent/HU193505B/hu unknown
- 1980-12-18 YU YU03211/80A patent/YU321180A/xx unknown
- 1980-12-18 ES ES497884A patent/ES497884A0/es active Granted
- 1980-12-18 IE IE2672/80A patent/IE51188B1/en unknown
- 1980-12-18 PT PT72232A patent/PT72232B/pt unknown
- 1980-12-18 NZ NZ195876A patent/NZ195876A/xx unknown
- 1980-12-18 NO NO803868A patent/NO154919C/no unknown
- 1980-12-18 CA CA000367126A patent/CA1184900A/en not_active Expired
- 1980-12-18 FI FI803957A patent/FI76791C/fi not_active IP Right Cessation
- 1980-12-18 AU AU65495/80A patent/AU543237B2/en not_active Ceased
- 1980-12-18 DK DK540080A patent/DK157019C/da not_active IP Right Cessation
- 1980-12-18 GR GR63713A patent/GR72847B/el unknown
- 1980-12-18 IL IL61756A patent/IL61756A/xx unknown
-
1981
- 1981-12-30 ES ES508454A patent/ES8307762A1/es not_active Expired
- 1981-12-30 ES ES508453A patent/ES8308314A1/es not_active Expired
-
1982
- 1982-10-19 US US06/435,215 patent/US4447608A/en not_active Expired - Lifetime
-
1984
- 1984-03-20 US US06/591,566 patent/US4564616A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ES8300716A1 (es) | 1982-11-01 |
| ES508454A0 (es) | 1983-08-01 |
| FI803957L (fi) | 1981-06-20 |
| ES508453A0 (es) | 1983-09-01 |
| US4564616A (en) | 1986-01-14 |
| DK540080A (da) | 1981-06-20 |
| ES8308314A1 (es) | 1983-09-01 |
| DK157019B (da) | 1989-10-30 |
| GB2065653A (en) | 1981-07-01 |
| DE3069468D1 (en) | 1984-11-22 |
| GB2065653B (en) | 1983-03-09 |
| ES8307762A1 (es) | 1983-08-01 |
| NO154919B (no) | 1986-10-06 |
| AU6549580A (en) | 1981-06-25 |
| YU321180A (en) | 1983-06-30 |
| PT72232A (en) | 1981-01-01 |
| NO154919C (no) | 1987-01-14 |
| EP0031237A1 (en) | 1981-07-01 |
| NO803868L (no) | 1981-06-22 |
| IL61756A0 (en) | 1981-01-30 |
| ES497884A0 (es) | 1982-11-01 |
| EP0031237B1 (en) | 1984-10-17 |
| FI76791B (fi) | 1988-08-31 |
| PT72232B (en) | 1981-11-02 |
| IE802672L (en) | 1981-06-19 |
| CA1184900A (en) | 1985-04-02 |
| IE51188B1 (en) | 1986-10-29 |
| GR72847B (cg-RX-API-DMAC7.html) | 1983-12-07 |
| AU543237B2 (en) | 1985-04-04 |
| HU193505B (en) | 1987-10-28 |
| IL61756A (en) | 1987-02-27 |
| DK157019C (da) | 1990-03-26 |
| NZ195876A (en) | 1983-11-18 |
| US4447608A (en) | 1984-05-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI76791C (fi) | Foerfarande foer framstaellning av 2-amino-4-hydroxikinazolinderivat med anticanceraktivitet. | |
| Rewcastle et al. | Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids | |
| ES2424642T3 (es) | Compuestos y composiciones como inhibidores de la proteína quinasa | |
| AU753716B2 (en) | Cyclin dependent kinase inhibitors | |
| NZ251804A (en) | Aromatic quinazoline derivatives and medicaments | |
| EP0923287A1 (en) | Nonclassical pyrrolo 2,3-d]pyrimidine antifolates | |
| EP0572437A1 (en) | 2,4-diaminoquinazoline derivatives to increase the anti-tumor effect. | |
| AU667568B2 (en) | Process for preparing 5-substituted pyrrolo{2,3-d}pyrimidines | |
| RU2266280C2 (ru) | Замещенные производные n-бензилиндол-3-ил-глиоксиловой кислоты, обладающие противоопухолевым действием (варианты), их кислотно-аддитивные соли (варианты), фармацевтический препарат, фармацевтическая форма | |
| US5128345A (en) | Carcinostatic composition comprising indolquinolines | |
| US7875716B2 (en) | Inhibitors of folic acid-dependent enzymes | |
| CN104910118B (zh) | 一类双香豆素类化合物及其制备方法和用途 | |
| WO2020077944A1 (zh) | 嘌呤系列衍生物及其制备方法和用途 | |
| Shcherbakov et al. | Modification of polyfluoro-containing 3-(ethoxycarbonyl) flavones by biogenic amines and amino acids | |
| CN116102575B (zh) | 环状2-氨基嘧啶类化合物及其用途 | |
| Mareedu et al. | Synthesis of 2-(morpholin-4-yl)-5-(piperazin-1-yl) pyrido [4, 3-d] pyrimidine derivatives, crsystal structure, molecular docking studies, and anti-oxidant activities | |
| Rosowsky et al. | Methotrexate analogs. 16. Importance of the side-chain amide carbonyl group as a structural determinant of biological activity | |
| CN102229563A (zh) | 4-氨基喹啉衍生物及其制备方法和用途 | |
| Makowski et al. | Quinazoline antifolate thymidylate synthase inhibitors: Replacement of glutamic acid by aminophosphonic acids | |
| JPH0512347B2 (cg-RX-API-DMAC7.html) | ||
| KR19990066390A (ko) | 신규한 이소퀴놀린계 항암 활성 화합물 | |
| JPH0780886B2 (ja) | 三環結合ヒドロキシグアニジン、その製造法及びそれを含む抗癌組成物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM | Patent lapsed |
Owner name: NATIONAL RESEARCH DEVELOPMENT |