CZ195393A3 - Quinazoline derivative process of its preparation and a pharmaceutical preparation in which it is comprised - Google Patents
Quinazoline derivative process of its preparation and a pharmaceutical preparation in which it is comprised Download PDFInfo
- Publication number
- CZ195393A3 CZ195393A3 CS931953A CS195393A CZ195393A3 CZ 195393 A3 CZ195393 A3 CZ 195393A3 CS 931953 A CS931953 A CS 931953A CS 195393 A CS195393 A CS 195393A CZ 195393 A3 CZ195393 A3 CZ 195393A3
- Authority
- CZ
- Czechia
- Prior art keywords
- amino
- group
- glutamyl
- dihydro
- ylmethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 31
- 238000002360 preparation method Methods 0.000 title claims description 10
- 230000008569 process Effects 0.000 title claims description 9
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- -1 alkyanoylalkyl Chemical group 0.000 claims abstract description 208
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 87
- 239000001257 hydrogen Substances 0.000 claims abstract description 55
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 52
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 43
- 150000003246 quinazolines Chemical class 0.000 claims abstract description 37
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 33
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 30
- 108010016626 Dipeptides Proteins 0.000 claims abstract description 29
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 29
- 150000001408 amides Chemical class 0.000 claims abstract description 24
- 150000002148 esters Chemical class 0.000 claims abstract description 24
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 125000001424 substituent group Chemical group 0.000 claims abstract description 20
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 13
- 125000003396 thiol group Chemical class [H]S* 0.000 claims abstract description 13
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 12
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 9
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 8
- 125000005236 alkanoylamino group Chemical group 0.000 claims abstract description 7
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims abstract description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 6
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 6
- 125000004181 carboxyalkyl group Chemical group 0.000 claims abstract description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 6
- 125000000729 N-terminal amino-acid group Chemical group 0.000 claims abstract description 5
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 5
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims abstract description 5
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 4
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000004966 cyanoalkyl group Chemical group 0.000 claims abstract description 4
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 153
- 150000001875 compounds Chemical class 0.000 claims description 62
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 125000006239 protecting group Chemical group 0.000 claims description 38
- 239000002253 acid Substances 0.000 claims description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 5
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003338 L-glutaminyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C(=O)N([H])[H] 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 claims description 3
- 125000005732 2,6-difluoro-1,4-phenylene group Chemical group [H]C1=C(F)C([*:1])=C(F)C([H])=C1[*:2] 0.000 claims description 3
- 125000005449 2-fluoro-1,4-phenylene group Chemical group [H]C1=C([*:2])C([H])=C(F)C([*:1])=C1[H] 0.000 claims description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- KOSRFJWDECSPRO-NTSWFWBYSA-N (2R)-2-[[(2S)-2-amino-4-carboxybutanoyl]amino]pentanedioic acid Chemical compound N[C@@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(O)=O KOSRFJWDECSPRO-NTSWFWBYSA-N 0.000 claims description 2
- FPZWZCWUIYYYBU-UHFFFAOYSA-N 2-(2-ethoxyethoxy)ethyl acetate Chemical group CCOCCOCCOC(C)=O FPZWZCWUIYYYBU-UHFFFAOYSA-N 0.000 claims description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 125000005999 2-bromoethyl group Chemical group 0.000 claims description 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims description 2
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 2
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 2
- 125000005564 oxazolylene group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 125000005557 thiazolylene group Chemical group 0.000 claims description 2
- 125000005556 thienylene group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 14
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims 2
- OWQDWQKWSLFFFR-NTSWFWBYSA-N (2r)-2-[[(4s)-4-amino-4-carboxybutanoyl]amino]pentanedioic acid Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](C(O)=O)CCC(O)=O OWQDWQKWSLFFFR-NTSWFWBYSA-N 0.000 claims 1
- 150000008575 L-amino acids Chemical class 0.000 claims 1
- JTJZAUVWVBUZAU-UHFFFAOYSA-N N-L-gamma-Glutamyl-L-asparaginsaeure Natural products OC(=O)C(N)CCC(=O)NC(C(O)=O)CC(O)=O JTJZAUVWVBUZAU-UHFFFAOYSA-N 0.000 claims 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 1
- 150000001356 alkyl thiols Chemical class 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- JTJZAUVWVBUZAU-WHFBIAKZSA-N gamma-Glutamylaspartic acid Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(O)=O)CC(O)=O JTJZAUVWVBUZAU-WHFBIAKZSA-N 0.000 claims 1
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 125000005242 carbamoyl alkyl group Chemical group 0.000 abstract description 3
- 150000008574 D-amino acids Chemical group 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 4
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 150000001371 alpha-amino acids Chemical class 0.000 abstract 1
- 235000008206 alpha-amino acids Nutrition 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 67
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 65
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 62
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- 229910052757 nitrogen Inorganic materials 0.000 description 39
- 238000000921 elemental analysis Methods 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000003776 cleavage reaction Methods 0.000 description 16
- 238000001819 mass spectrum Methods 0.000 description 16
- 230000007017 scission Effects 0.000 description 16
- 150000003951 lactams Chemical class 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000007858 starting material Substances 0.000 description 15
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 235000010233 benzoic acid Nutrition 0.000 description 12
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 150000002500 ions Chemical class 0.000 description 11
- 239000005711 Benzoic acid Substances 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 101150111020 GLUL gene Proteins 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 8
- 108010022394 Threonine synthase Proteins 0.000 description 8
- 102000005497 Thymidylate Synthase Human genes 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 238000000132 electrospray ionisation Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 238000010265 fast atom bombardment Methods 0.000 description 8
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- 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 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229960002989 glutamic acid Drugs 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
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- 230000000694 effects Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 6
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
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- 238000005481 NMR spectroscopy Methods 0.000 description 4
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 3
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- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
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- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- NTUGPDFKMVHCCJ-SECBINFHSA-N ditert-butyl (2r)-2-aminopentanedioate Chemical compound CC(C)(C)OC(=O)CC[C@@H](N)C(=O)OC(C)(C)C NTUGPDFKMVHCCJ-SECBINFHSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- OWQDWQKWSLFFFR-WDSKDSINSA-N gamma-Glu-Glu Chemical class OC(=O)[C@@H](N)CCC(=O)N[C@H](C(O)=O)CCC(O)=O OWQDWQKWSLFFFR-WDSKDSINSA-N 0.000 description 1
- 229920000370 gamma-poly(glutamate) polymer Polymers 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 101150021650 gluA gene Proteins 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002700 inhibitory effect on cancer Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000031852 maintenance of location in cell Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 229940127075 other antimetabolite Drugs 0.000 description 1
- KQOATKAFTRNONV-UHFFFAOYSA-N oxolan-2-amine Chemical compound NC1CCCO1 KQOATKAFTRNONV-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 230000001884 polyglutamylation Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- MHZSEPBBOTVGFW-UHFFFAOYSA-N pyrrolidin-1-ylphosphane Chemical compound PN1CCCC1 MHZSEPBBOTVGFW-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 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
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- MRKAVJXPGLUQKP-UHFFFAOYSA-N tetrakis(2-hydroxyethyl)azanium Chemical class OCC[N+](CCO)(CCO)CCO MRKAVJXPGLUQKP-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 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
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 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
-
- 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
- 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
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB919105771A GB9105771D0 (en) | 1991-03-19 | 1991-03-19 | Anti-cancer compounds |
| PCT/GB1992/000476 WO1992016512A1 (en) | 1991-03-19 | 1992-03-18 | Anti-cancer compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CZ195393A3 true CZ195393A3 (en) | 1994-07-13 |
Family
ID=10691801
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS931953A CZ195393A3 (en) | 1991-03-19 | 1992-03-19 | Quinazoline derivative process of its preparation and a pharmaceutical preparation in which it is comprised |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5444061A (https=) |
| EP (1) | EP0509643A1 (https=) |
| JP (1) | JPH06505974A (https=) |
| AU (1) | AU655970B2 (https=) |
| CA (1) | CA2106583A1 (https=) |
| CZ (1) | CZ195393A3 (https=) |
| FI (1) | FI934106A7 (https=) |
| GB (2) | GB9105771D0 (https=) |
| HU (1) | HUT67177A (https=) |
| IE (1) | IE920853A1 (https=) |
| IL (1) | IL101281A0 (https=) |
| MX (1) | MX9201183A (https=) |
| NO (1) | NO933341L (https=) |
| NZ (1) | NZ242023A (https=) |
| SK (1) | SK100993A3 (https=) |
| TW (1) | TW203608B (https=) |
| WO (1) | WO1992016512A1 (https=) |
| ZA (1) | ZA921985B (https=) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9205907D0 (en) * | 1992-03-18 | 1992-04-29 | Cancer Res Inst Royal | Anti-cancer compounds |
| 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 |
| BR9610422A (pt) * | 1995-08-30 | 1999-07-13 | Searle & Co | Derivados de meta-guanidina uréia tiouréia ou ácido aminobenzóico azacíclico como antagonistas de integrina |
| GB9904275D0 (en) | 1999-02-24 | 1999-04-21 | Cancer Res Campaign Tech | Anti-cancer compounds |
| US6545004B1 (en) * | 1999-10-27 | 2003-04-08 | Cytokinetics, Inc. | Methods and compositions utilizing quinazolinones |
| US7671200B2 (en) * | 1999-10-27 | 2010-03-02 | Cytokinetics, Inc. | Quinazolinone KSP inhibitors |
| US7230000B1 (en) | 1999-10-27 | 2007-06-12 | Cytokinetics, Incorporated | Methods and compositions utilizing quinazolinones |
| WO2003070701A2 (en) * | 2002-02-15 | 2003-08-28 | Cytokinetics, Inc. | Syntheses of quinazolinones |
| US7214800B2 (en) * | 2002-05-09 | 2007-05-08 | Cytokinetics, Inc. | Compounds, compositions, and methods |
| CA2485148A1 (en) * | 2002-05-09 | 2003-11-20 | Cytokinetics, Inc. | Pyrimidinone compounds, compositions and methods |
| EP1513820A4 (en) * | 2002-05-23 | 2006-09-13 | Cytokinetics Inc | COMPOUNDS, COMPOSITIONS AND METHODS |
| WO2003106426A1 (en) * | 2002-06-14 | 2003-12-24 | Cytokinetics, Inc. | Compounds, compositions, and methods |
| US20030236430A1 (en) * | 2002-06-21 | 2003-12-25 | Allen David Robert | Preparation of protected amino acids |
| AU2003256805A1 (en) * | 2002-07-23 | 2004-02-09 | Cytokinetics, Inc. | Compounds compositions and methods |
| US20040048853A1 (en) * | 2002-08-21 | 2004-03-11 | Gustave Bergnes | Compounds, compositions, and methods |
| WO2004034972A2 (en) | 2002-09-30 | 2004-04-29 | Cytokinetics, Inc. | Compounds, compositions, and methods |
| JP2007510652A (ja) * | 2003-11-03 | 2007-04-26 | サイトキネティクス・インコーポレーテッド | ピリミジン−４−オン化合物、組成物、および方法 |
| EP1680420A4 (en) * | 2003-11-07 | 2008-09-24 | Cytokinetics Inc | COMPOUNDS, COMPOSITIONS AND METHODS |
| EP1692112A4 (en) * | 2003-12-08 | 2008-09-24 | Cytokinetics Inc | COMPOUNDS, COMPOSITIONS, AND METHODS |
| DK2150514T3 (en) | 2007-04-11 | 2019-02-18 | Merck & Cie | 18F-LABELED FOLATES |
| KR102431436B1 (ko) | 2014-08-29 | 2022-08-10 | 테스 파마 에스.알.엘. | α-아미노-β-카복시뮤콘산 세미알데히드 데카복실라제의 억제제 |
| US12030875B2 (en) | 2018-09-07 | 2024-07-09 | PIC Therapeutics, Inc. | EIF4E inhibitors and uses thereof |
| AU2021230289A1 (en) | 2020-03-03 | 2022-09-29 | PIC Therapeutics, Inc. | eIF4E inhibitors and uses thereof |
| JP2024534127A (ja) | 2021-08-25 | 2024-09-18 | ピク セラピューティクス， インコーポレイテッド | ｅＩＦ４Ｅ阻害剤及びその使用 |
| US12157732B2 (en) | 2021-08-25 | 2024-12-03 | PIC Therapeutics, Inc. | eIF4E inhibitors and uses thereof |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3069468D1 (en) * | 1979-12-19 | 1984-11-22 | Nat Res Dev | Quinazoline derivatives, processes for their preparation, compositions containing them and their use as anti-cancer agents |
| GB8513754D0 (en) * | 1985-05-31 | 1985-07-03 | Jones T R | Anti-cancer quinazoline derivatives |
| US4746659A (en) * | 1985-12-30 | 1988-05-24 | Sri International | Diastereomers of 10-alkyl-10-deazaminopterins and process for preparing the same |
| 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 |
| GB8625019D0 (en) * | 1986-10-18 | 1986-11-19 | Wellcome Found | Compounds |
| GB8707053D0 (en) * | 1987-03-25 | 1987-04-29 | Ici Plc | Anti-tumour agents |
| US4767761A (en) * | 1987-11-04 | 1988-08-30 | Dana-Farber Cancer Institute, Inc. | Ornithine derivatives and their use as methotrexate-resistant cell inhibitors |
| GB8727737D0 (en) * | 1987-11-26 | 1987-12-31 | Ici Plc | Antitumour agents |
| GB8809978D0 (en) * | 1988-04-27 | 1988-06-02 | Ici Plc | Anti-tumour agents |
| 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 |
| US4996207A (en) * | 1990-01-18 | 1991-02-26 | Nair Madhavan G | Three new non-polyglutamatable deazaaminopterins |
| DE69111891T2 (de) * | 1990-05-17 | 1996-04-04 | Smith & Nephew United Inc | Elektrisch leitender und adstringierender Film sowie filmbildende Zusammensetzung zur Verwendung auf der Haut. |
| IL98167A0 (en) * | 1990-05-30 | 1992-06-21 | Ici Plc | Anti-tumour quinazoline derivatives,processes for their preparation and pharmaceutical compositions comprising them |
-
1991
- 1991-03-19 GB GB919105771A patent/GB9105771D0/en active Pending
-
1992
- 1992-03-18 IL IL101281A patent/IL101281A0/xx unknown
- 1992-03-18 HU HU9302636A patent/HUT67177A/hu unknown
- 1992-03-18 AU AU13716/92A patent/AU655970B2/en not_active Expired - Fee Related
- 1992-03-18 GB GB9205906A patent/GB2253849B/en not_active Expired - Fee Related
- 1992-03-18 EP EP92302304A patent/EP0509643A1/en not_active Withdrawn
- 1992-03-18 IE IE085392A patent/IE920853A1/en unknown
- 1992-03-18 WO PCT/GB1992/000476 patent/WO1992016512A1/en not_active Ceased
- 1992-03-18 US US08/122,473 patent/US5444061A/en not_active Expired - Fee Related
- 1992-03-18 ZA ZA921985A patent/ZA921985B/xx unknown
- 1992-03-18 CA CA002106583A patent/CA2106583A1/en not_active Abandoned
- 1992-03-18 MX MX9201183A patent/MX9201183A/es unknown
- 1992-03-18 JP JP4506050A patent/JPH06505974A/ja active Pending
- 1992-03-18 SK SK1009-93A patent/SK100993A3/sk unknown
- 1992-03-19 CZ CS931953A patent/CZ195393A3/cs unknown
- 1992-04-27 TW TW081103276A patent/TW203608B/zh active
- 1992-05-18 NZ NZ242023A patent/NZ242023A/en unknown
-
1993
- 1993-09-20 FI FI934106A patent/FI934106A7/fi not_active Application Discontinuation
- 1993-09-20 NO NO933341A patent/NO933341L/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ242023A (en) | 1993-12-23 |
| TW203608B (https=) | 1993-04-11 |
| HUT67177A (en) | 1995-02-28 |
| JPH06505974A (ja) | 1994-07-07 |
| HU9302636D0 (en) | 1993-12-28 |
| NO933341D0 (no) | 1993-09-20 |
| CA2106583A1 (en) | 1992-09-20 |
| FI934106A7 (fi) | 1993-11-18 |
| GB2253849B (en) | 1995-01-18 |
| GB9205906D0 (en) | 1992-04-29 |
| NO933341L (no) | 1993-11-18 |
| GB9105771D0 (en) | 1991-05-01 |
| US5444061A (en) | 1995-08-22 |
| AU655970B2 (en) | 1995-01-19 |
| FI934106A0 (fi) | 1993-09-20 |
| MX9201183A (es) | 1994-06-30 |
| ZA921985B (en) | 1993-09-20 |
| SK100993A3 (en) | 1994-08-10 |
| WO1992016512A1 (en) | 1992-10-01 |
| IL101281A0 (en) | 1992-11-15 |
| IE920853A1 (en) | 1992-09-23 |
| EP0509643A1 (en) | 1992-10-21 |
| AU1371692A (en) | 1992-10-21 |
| GB2253849A (en) | 1992-09-23 |
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