NO171785B - Analogifremgangsmaate for fremstilling av terapeutisk virksomme kinazolinderivater - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk virksomme kinazolinderivater Download PDFInfo
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- NO171785B NO171785B NO863980A NO863980A NO171785B NO 171785 B NO171785 B NO 171785B NO 863980 A NO863980 A NO 863980A NO 863980 A NO863980 A NO 863980A NO 171785 B NO171785 B NO 171785B
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- NO
- Norway
- Prior art keywords
- spectrum
- nujol
- tetrahydro
- vmax
- ethyl
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- 238000000034 method Methods 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 150000003839 salts Chemical class 0.000 claims abstract description 100
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000001301 oxygen Substances 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 3
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- 238000004519 manufacturing process Methods 0.000 claims description 27
- 239000007858 starting material Substances 0.000 claims description 4
- SXONDGSPUVNZLO-UHFFFAOYSA-N zenarestat Chemical compound O=C1N(CC(=O)O)C2=CC(Cl)=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F SXONDGSPUVNZLO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 239000003937 drug carrier Substances 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 238000002329 infrared spectrum Methods 0.000 description 305
- 238000002844 melting Methods 0.000 description 214
- 230000008018 melting Effects 0.000 description 214
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 141
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
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- 238000006243 chemical reaction Methods 0.000 description 59
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
- -1 inorganic base salt Chemical class 0.000 description 43
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- 238000001816 cooling Methods 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Chemical group 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- 235000011054 acetic acid Nutrition 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000001953 recrystallisation Methods 0.000 description 10
- 230000002411 adverse Effects 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 150000003246 quinazolines Chemical class 0.000 description 9
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 206010012601 diabetes mellitus Diseases 0.000 description 7
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 239000002585 base Substances 0.000 description 6
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- 230000002401 inhibitory effect Effects 0.000 description 6
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- 102000016912 Aldehyde Reductase Human genes 0.000 description 5
- 108010053754 Aldehyde reductase Proteins 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 5
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- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- YKEDZMUEYGWSDX-UHFFFAOYSA-N ethyl 2-[3-[(3,4-dichlorophenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC=C(Cl)C(Cl)=C1 YKEDZMUEYGWSDX-UHFFFAOYSA-N 0.000 description 4
- FQXIRXTVFVCJFQ-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC(Cl)=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F FQXIRXTVFVCJFQ-UHFFFAOYSA-N 0.000 description 4
- FKWQISKKVCKZQK-UHFFFAOYSA-N ethyl 2-[7-bromo-3-[(4-bromo-2-fluorophenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC(Br)=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F FKWQISKKVCKZQK-UHFFFAOYSA-N 0.000 description 4
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- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 3
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- YTXVFFFUJLKZPJ-UHFFFAOYSA-N ethyl 2-(2-carbamoyl-5-chloroanilino)acetate Chemical compound CCOC(=O)CNC1=CC(Cl)=CC=C1C(N)=O YTXVFFFUJLKZPJ-UHFFFAOYSA-N 0.000 description 3
- LLJGEVHBVBZSPW-UHFFFAOYSA-N ethyl 2-[2,4-dioxo-3-(thiophen-2-ylmethyl)quinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC=CS1 LLJGEVHBVBZSPW-UHFFFAOYSA-N 0.000 description 3
- BXYIXOVQBKOXHD-UHFFFAOYSA-N ethyl 2-[3-(naphthalen-2-ylmethyl)-2,4-dioxoquinazolin-1-yl]acetate Chemical compound C1=CC=CC2=CC(CN3C(=O)C4=CC=CC=C4N(C3=O)CC(=O)OCC)=CC=C21 BXYIXOVQBKOXHD-UHFFFAOYSA-N 0.000 description 3
- RXNXRENXWPXPKV-UHFFFAOYSA-N ethyl 2-[3-[(2,3-dichlorophenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC=CC(Cl)=C1Cl RXNXRENXWPXPKV-UHFFFAOYSA-N 0.000 description 3
- AKAUCTUHPKWNCF-UHFFFAOYSA-N ethyl 2-[3-[(2,4-dichlorophenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC=C(Cl)C=C1Cl AKAUCTUHPKWNCF-UHFFFAOYSA-N 0.000 description 3
- SPEYUSKKQUVLAX-UHFFFAOYSA-N ethyl 2-[3-[(2,5-dichlorophenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC(Cl)=CC=C1Cl SPEYUSKKQUVLAX-UHFFFAOYSA-N 0.000 description 3
- WNESAIAAUOCIHA-UHFFFAOYSA-N ethyl 2-[3-[(2,6-dichlorophenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=C(Cl)C=CC=C1Cl WNESAIAAUOCIHA-UHFFFAOYSA-N 0.000 description 3
- KOZXNZUPEYSLOZ-UHFFFAOYSA-N ethyl 2-[3-[(2-fluoro-4-iodophenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC=C(I)C=C1F KOZXNZUPEYSLOZ-UHFFFAOYSA-N 0.000 description 3
- KMEWWLWWXMDNEQ-UHFFFAOYSA-N ethyl 2-[3-[(2-fluoro-4-iodophenyl)methyl]-7-iodo-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC(I)=CC=C2C(=O)N1CC1=CC=C(I)C=C1F KMEWWLWWXMDNEQ-UHFFFAOYSA-N 0.000 description 3
- HSLANDOJIUDCMR-UHFFFAOYSA-N ethyl 2-[3-[(3,5-dichlorophenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC(Cl)=CC(Cl)=C1 HSLANDOJIUDCMR-UHFFFAOYSA-N 0.000 description 3
- NBBVPDRRFINQOP-UHFFFAOYSA-N ethyl 2-[3-[(3-chloro-4-methoxyphenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC=C(OC)C(Cl)=C1 NBBVPDRRFINQOP-UHFFFAOYSA-N 0.000 description 3
- ZZSNTSWAFJHDTG-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F ZZSNTSWAFJHDTG-UHFFFAOYSA-N 0.000 description 3
- JWAJDFKQPUZAOL-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-5,7-dichloro-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC(Cl)=CC(Cl)=C2C(=O)N1CC1=CC=C(Br)C=C1F JWAJDFKQPUZAOL-UHFFFAOYSA-N 0.000 description 3
- UFCVDBHSJQZDTE-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-5-chloro-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC(Cl)=C2C(=O)N1CC1=CC=C(Br)C=C1F UFCVDBHSJQZDTE-UHFFFAOYSA-N 0.000 description 3
- FDZNPQLOQWJZPI-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-5-methoxy-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC(OC)=C2C(=O)N1CC1=CC=C(Br)C=C1F FDZNPQLOQWJZPI-UHFFFAOYSA-N 0.000 description 3
- XAAHMPHKJNTRKN-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-6,7-dichloro-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC(Cl)=C(Cl)C=C2C(=O)N1CC1=CC=C(Br)C=C1F XAAHMPHKJNTRKN-UHFFFAOYSA-N 0.000 description 3
- VDWKKNIEJLDICG-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-6-methoxy-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=C(OC)C=C2C(=O)N1CC1=CC=C(Br)C=C1F VDWKKNIEJLDICG-UHFFFAOYSA-N 0.000 description 3
- MYOSXHFXAHGSIL-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-7-fluoro-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC(F)=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F MYOSXHFXAHGSIL-UHFFFAOYSA-N 0.000 description 3
- CXFCAONYXQXYMX-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-7-methoxy-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC(OC)=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F CXFCAONYXQXYMX-UHFFFAOYSA-N 0.000 description 3
- LAXMBJXWKKMZLH-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-8-chloro-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=C(Cl)C=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F LAXMBJXWKKMZLH-UHFFFAOYSA-N 0.000 description 3
- XFEVGCDDGRFFQZ-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-2-fluorophenyl)methyl]-8-methoxy-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=C(OC)C=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F XFEVGCDDGRFFQZ-UHFFFAOYSA-N 0.000 description 3
- LZHQNYVMTBSXJP-UHFFFAOYSA-N ethyl 2-[3-[(4-bromo-3-chlorophenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC=C(Br)C(Cl)=C1 LZHQNYVMTBSXJP-UHFFFAOYSA-N 0.000 description 3
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- JNDLPDSDAZEUDH-UHFFFAOYSA-N ethyl 2-(benzenesulfonyloxy)propanoate Chemical compound CCOC(=O)C(C)OS(=O)(=O)C1=CC=CC=C1 JNDLPDSDAZEUDH-UHFFFAOYSA-N 0.000 description 1
- APRQNJCJLFIVJQ-UHFFFAOYSA-N ethyl 2-[2-[(3,4-dichlorophenyl)methylcarbamothioyl]anilino]acetate Chemical compound CCOC(=O)CNC1=CC=CC=C1C(=S)NCC1=CC=C(Cl)C(Cl)=C1 APRQNJCJLFIVJQ-UHFFFAOYSA-N 0.000 description 1
- VXXMWQGXGBHNMA-UHFFFAOYSA-N ethyl 2-[2-[(3,4-dichlorophenyl)methylcarbamoyl]anilino]acetate Chemical compound CCOC(=O)CNC1=CC=CC=C1C(=O)NCC1=CC=C(Cl)C(Cl)=C1 VXXMWQGXGBHNMA-UHFFFAOYSA-N 0.000 description 1
- YZTQFOPYJZJWPM-UHFFFAOYSA-N ethyl 2-[3-(3,4-dichlorophenyl)-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1C1=CC=C(Cl)C(Cl)=C1 YZTQFOPYJZJWPM-UHFFFAOYSA-N 0.000 description 1
- NEKXOSWBSUBFJM-UHFFFAOYSA-N ethyl 2-[3-(naphthalen-1-ylmethyl)-2,4-dioxoquinazolin-1-yl]acetate Chemical compound C1=CC=C2C(CN3C(=O)C4=CC=CC=C4N(C3=O)CC(=O)OCC)=CC=CC2=C1 NEKXOSWBSUBFJM-UHFFFAOYSA-N 0.000 description 1
- IDCPHKINXUATAY-UHFFFAOYSA-N ethyl 2-[3-[(4-methylphenyl)methyl]-2,4-dioxoquinazolin-1-yl]acetate Chemical compound O=C1N(CC(=O)OCC)C2=CC=CC=C2C(=O)N1CC1=CC=C(C)C=C1 IDCPHKINXUATAY-UHFFFAOYSA-N 0.000 description 1
- VHUMPXOBXNPIQS-UHFFFAOYSA-N ethyl 2-benzylsulfonyloxyacetate Chemical compound CCOC(=O)COS(=O)(=O)CC1=CC=CC=C1 VHUMPXOBXNPIQS-UHFFFAOYSA-N 0.000 description 1
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 1
- FQTIYMRSUOADDK-UHFFFAOYSA-N ethyl 3-bromopropanoate Chemical compound CCOC(=O)CCBr FQTIYMRSUOADDK-UHFFFAOYSA-N 0.000 description 1
- ZCLGVXACCAZJOX-UHFFFAOYSA-N ethyl 3-chloropropanoate Chemical compound CCOC(=O)CCCl ZCLGVXACCAZJOX-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 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
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal 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
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- FLNDWHKVRHPOFO-UHFFFAOYSA-N n-[(2-fluoro-4-iodophenyl)methyl]-4-iodo-2-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC(I)=CC=C1C(=O)NCC1=CC=C(I)C=C1F FLNDWHKVRHPOFO-UHFFFAOYSA-N 0.000 description 1
- WJMPQZRVEIWYIV-UHFFFAOYSA-N n-[(4-bromo-2-fluorophenyl)methyl]-2-nitro-4-(trifluoromethyl)benzamide Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1C(=O)NCC1=CC=C(Br)C=C1F WJMPQZRVEIWYIV-UHFFFAOYSA-N 0.000 description 1
- VFXWDLRVGAUBMA-UHFFFAOYSA-N n-[(4-bromo-2-fluorophenyl)methyl]-3-chloro-2-nitrobenzamide Chemical compound [O-][N+](=O)C1=C(Cl)C=CC=C1C(=O)NCC1=CC=C(Br)C=C1F VFXWDLRVGAUBMA-UHFFFAOYSA-N 0.000 description 1
- HEMQSPSFPNMJCY-UHFFFAOYSA-N n-[(4-bromo-2-fluorophenyl)methyl]-3-methoxy-2-nitrobenzamide Chemical compound COC1=CC=CC(C(=O)NCC=2C(=CC(Br)=CC=2)F)=C1[N+]([O-])=O HEMQSPSFPNMJCY-UHFFFAOYSA-N 0.000 description 1
- OJYXTHNXUULAIL-UHFFFAOYSA-N n-[(4-bromo-2-fluorophenyl)methyl]-4-chloro-2-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC(Cl)=CC=C1C(=O)NCC1=CC=C(Br)C=C1F OJYXTHNXUULAIL-UHFFFAOYSA-N 0.000 description 1
- SLRQBCUTLSRRQH-UHFFFAOYSA-N n-[(4-bromo-2-fluorophenyl)methyl]-4-iodo-2-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC(I)=CC=C1C(=O)NCC1=CC=C(Br)C=C1F SLRQBCUTLSRRQH-UHFFFAOYSA-N 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 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
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- ISYUCUGTDNJIHV-UHFFFAOYSA-N propyl 2-bromoacetate Chemical compound CCCOC(=O)CBr ISYUCUGTDNJIHV-UHFFFAOYSA-N 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium 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
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 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
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KUYMVWXKHQSIAS-UHFFFAOYSA-N tert-butyl 2-chloroacetate Chemical compound CC(C)(C)OC(=O)CCl KUYMVWXKHQSIAS-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
- 238000010998 test method Methods 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
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- C07D401/02—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 two hetero rings
- C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
-
- 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
- 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
- C07D239/96—Two oxygen atoms
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Diabetes (AREA)
- Ophthalmology & Optometry (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Hematology (AREA)
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- Neurology (AREA)
- Neurosurgery (AREA)
- Reproductive Health (AREA)
- Biomedical Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Den foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av hittil ukjente kinazolinderivater.
Oppfinnelsen angår især fremstilling av hittil ukjente kinazolinderivater og farmasøytisk akseptable salter derav som har aldosereduktase-inhibitorisk virkning.
Ifølge foreliggende oppfinnelse fremtilles således hittil ukjente og nyttige kinazolinderivater og farmasøytisk akseptable salter derav.
Kinazolinderivatene og farmasøytisk akseptable
salter derav kan benyttes til fremstilling av medikamenter for terapeutisk behandling av diabetiske komplikasjoner, så som manglende heling av corneasår, katarakt, neuropati,
retinopati, nefropati.
De hittil ukjente kinazolinderivater fremstillet ifølge
den foreliggende oppfinnelse kan representeres av følgende almene formel I
hvorR<1>og R<2>hver er hydrogen, halogen, lavere alkoksy eller halogen-lavere-alkyl,
R<3>er fenyl(lavere)alkyl som har én eller flere substituent(er) valgt fra halogen, lavere alkoksy, halogen(lavere)alkyl og lavere alkyl;
eller naftyl(lavere)alkyl,
R<4>er karboksy eller beskyttet karboksy,
A er et oksygen- eller svovelatom,
Y er karbonyl, tiokarbonyl eller sulfonyl, og
Z er lavere alkylen.
Egnede salter av forbindelsene I er konvensjonelle farma-søytisk akseptable salter og kan omfatte et salt med en base, så som et uorganisk basesalt, f.eks. et alkalimetallsalt
(f.eks. natriumsalt, kaliumsalt, etc), et jordalkali-metallsalt (f.eks. kalsiumsalt, magnesiumsalt, etc), et ammmoniumsalt, et organisk basesalt, f.eks. et organisk aminsalt (f.eks. trietylaminsalt, pyridinsalt, pikolinsalt, etanolaminsalt, trietanolaminsalt, dicykloheksylaminsalt,N,N'-dibenzyletylendiaminsalt, etc), et salt med en basisk aminosyre (f.eks. arginin, etc); og lignende.
Ifølge den foreliggende oppfinnelse kan kinazolinderivatene I og salter derav fremstilles ved de fremgangsmåter som belyses nedenfor.
Fremgangsmåte 1
Fremgangsmåte 3
eller salter derav hvorR1, R<2>, R3 , R4 , A, Y og Z er som definert ovenfor,
R 4er beskyttet karboksy og
3.
X er en avspaltbar enhet.
Utgangsforbindelsene II, IV og XVI ved de ovenfor anførte fremgangsmåter inneholder hittil ukjente og kjente forbindelser og de hittil ukjente forbindelser kan f.eks. fremstilles ved nedenstående fremgangsmåter.
Fremgangsmåte A-I
eller salter derav eller salter derav Fremgangsmåte A-2 eller salter derav eller salter derav Fremgangsmåte A-3
eller dets reaktive derivat eller salter derav eller salter derav
Fremgangsmåte A-4
eller salter derav eller salter derav Fremgangsmåte A-5 eller salter derav Fremgangsmåte B-l
eller salter derav eller salter derav
Fremgangsmåte B-2
eller salter derav eller salter derav Fremgangsmåte B-3 eller salter derav eller salter derav Fremgangsmåte B-4
eller salter derav eller salter derav
Fremgangsmåte C-l eller salter derav eller salter derav Fremgangsmåte C-2
eller salter derav eller salter derav
hvorR<1>,R2, R<3>, R4, A, X, Y og Z er som definert ovenfor.
I nærværende tekst beskrives detaljert egnede eksempler på de forskjellige definisjoner som ligger innenfor oppfinnelsens område.
Uttrykket "lavere" anvendt i nærværende tekst skal, med mindre annet er anført, betegne 1-6 karbonatomer.
Egnet "halogen" kan omfatte fluor, klor, brom, jod og lignende.
Egnet "lavere alkoksy" kan være rettkjedet eller forgrenet, så som metoksy, etoksy, propoksy, isopropoksy, butoksy, isobutoksy, pentyloksy, isopentyloksy, heksyloksy og lignende, idet et mere foretrukket eksempel kan være C^-alkoksy, og et særlig foretrukket eksempel kan være metoksy. Egnet "halogen-lavere-alkyl" kan omfatte monohalogen- lavere-alkyl (f.eks. klormetyl, brommetyl, klorpropyl, etc), dihalogen-lavere-alkyl (f.eks. 1,2-dikloretyl, 1,2-dibrometyl, 2,2-dikloretyl, etc), trihalogen-lavere-alkyl (f.eks. trifluormetyl, 1,2,2-trikloretyl, etc), idet trihalogen-C^-alkyl er mer foretrukket, og spesielt foretrekkes trifluormetyl.
En egnet "beskyttet karboksy" -kan omfatte forestret karboksy, så som lavere alkoksykarbonyl (f.eks. metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, isopropoksykarbonyl, butoksykarbonyl, tert.-butoksykarbonyl, etc), mono-, di- eller trifenyl-lavere alkoksykarbonyl som kan ha en nitrogruppe (f.eks. benzyloksykarbonyl, 4-nitrobenzyloksykarbonyl, fenetyloksykarbonyl, benzhydryloksykarbonyl, trityloksykarbonyl, etc), og lignende, idet et mer foretrukket eksempel kan være C^,,-alkoksykarbonyl og et særlig foretrukket eksempel kan være etoksykarbonyl.
Egnet "lavere alkylen" kan være rettkjedet eller forgrenet, så som metylen, etylen, trimetylen, tetrametylen, pentametylen, heksametylen, metylmetylen, etyletylen, propylen og lignende, idet et mer foretrukket eksempel kan være C^,,-alkylen, og et særlig foretrukket eksempel kan være metylen og metylmetylen.
En egnet "avspaltbar enhet" kan omfatte hydroksy og en syrerest og et egnet eksempel på en "syrerest" kan være halogen (f.eks. klor, brom, jod, etc), sulfonyloksy (f.eks. metansulfonyloksy, benzensulfonyloksy, toluensulfonyloksy, etc.) og lignende, idet det foretrukne eksempel kan være halogen.
Fremgangsmåtene for fremstilling av kinazolinderivatene I ifølge den foreliggende oppfinnelse beskrives detaljert nedenfor.
1) Fremgangsmåte 1
Forbindelsene I eller salter derav kan fremstilles ved å omsette forbindelsen II eller salter derav med forbindelsen III eller salter derav.
Egnede salter av forbindelsene II og III kan være de samme som for forbindelsene I.
Foretrukne eksempler på forbindelsen III til anvendelse i fremgangsmåten kan være lavere alkylester av halogen-lavere-alkansyre (f.eks. metylkloracetat, metylbromacetat, etylklor-acetat, etylbromacetat, propylbromacetat, tert.-butylkloracetat, etyl-3-klorpropionat, etyl-3-brompropionat, etyl-2-klorpropionat, etyl-2-brompropionat, etc.), lavere alkoksykarbonyl-lavere alkylester av sulfonsyre (f.eks. etoksykarbonylmetylmetansulfonat, 1-etoksykarbonyletylmetansulfonat, etoksykarbonylmetyl-benzensulfonat, 1-etoksykarbonyletylbenzensulfonat, etoksy-karbonylmetyltoluensulfonat, 1-etoksykarbonyl-etyltoluensulfonat, etc.) og lignende.
Denne reaksjon kan utføres i nærvær av en organisk eller uorganisk base, så som alkalimetall (f.eks. litium, natrium, kalium, etc), jordalkalimetall (f.eks. kalsium, etc), alkalimetallhydrid (f.eks. natriumhydrid, etc), jordalkali-metallhydrid (f.eks. kalsiumhydrid, etc), alkalimetallhydroksyd (f.eks. natriumhydroksyd, kaliumhydroksyd, etc), alkalimetallkarbonat (f.eks. natriumkarbonat, kaliumkarbonat, etc), alkalimetallhydrogenkarbonat (f.eks. natriumhydrogenkarbonat, kaliumhydrogenkarbonat, etc), alkalimetallalkoksyd (f.eks. natrium-metoksyd, natriumetoksyd, kalium-tert.-butoksyd, etc), alkalimetallalkansyre (f.eks. natriumacetat, etc), trialkylamin (f.eks. trietylamin, etc), pyridinforbindelse (f.eks. pyridin, lutidin, pikolin, 4-dimetylaminopyridin, etc), kinolin og lignende.
Denne reaksjon utføres vanligvis i et konvensjonelt opp-løsningsmiddel som ikke påvirker reaksjonen på ugunstig måte, så som diklormetan, metanol, etanol, propanol, pyridin, N,N-dimetylformamid, etc., eller en blanding derav.
Reaksjonstemperaturen er ikke kritisk og reaksjonen utføres vanligvis ved en temperatur i området fra avkjøling til oppvarming.
2) Fremgangsmåte 2
Forbindelsene med formel I, eller salter derav, kan fremstilles ved å omsette forbindelsen IV eller salter derav, med forbindelsen V, eller salter derav.
Egnede salter av forbindelsen IV og V kan være de samme som for forbindelsene I.
Denne reaksjon utføres fortrinnsvis i nærvær av en organisk eller uorganisk base, så som dem som er beskrevet i forbindelse med fremgangsmåte 1.
Denne reaksjon kan i det vesentlige utføres på samme måte som reaksjonen ifølge Fremgangsmåte 1 og fremgangsmåten og betingelsene (f.eks. oppløsningsmiddel, reaksjonstemperatur, etc.) er således angitt i beskrivelsen av Fremgangsmåte 1.
3) Fremgangsmåte 3
Forbindelsene med formel I, eller salter derav, kan fremstilles ved å omsette forbindelsene XVI, eller salter derav, med forbindelsen XII.
Egnede salter av forbindelsene XVI kan være de samme som for forbindelsen I.
Denne reaksjon utføres vanligvis i nærvær eller fravær av et konvensjonelt oppløsningsmiddel, som ikke har ugunstig virkning på reaksjonen, så som aceton, benzen, tetrahydrofuran, pyridin, N,N-dimetylformamid, dioksan, etc. eller en blanding derav.
Reaksjonstemperaturen er ikke kritisk og reaksjonen utføres vanligvis under temperaturbetingelser som går fra avkjøling til oppvarming.
4) Fremgangsmåte 4
Forbindelsene I-b, eller salter derav, kan fremstilles ved å hydrolysere forbindelsene I-a.
Egnede salter av forbindelsene I-b kan være de samme som for forbindelse I.
Hydrolysen kan utføres i nærvær av en base eller en syre, og en egnet base kan være de uorganiske baser, som er angitt i forbindelse med Fremgangsmåte 1. En egnet syre kan være en organisk syre (f.eks. maursyre, eddiksyre, propionsyre, tri-fluoreddiksyre, benzensulfonsyre, p-toluensulfonsyre, etc.) og en uorganisk syre (f.eks. saltsyre, hydrogenbromidsyre, svovelsyre, fosforsyre, etc).
Denne reaksjon utføres vanligvis i et konvensjonelt opp-løsningsmiddel som ikke påvirker reaksjonen ugunstig, så som vann, aceton, diklormetan, metanol,- etanol, propanol, pyridin, N,N-dimetylformamid, etc. eller en blanding derav, og dessuten slik at når den base eller syre som skal benyttes i denne reaksjonen er en væske, kan den ytterligere anvendes som opp-løsningsmiddel .
Reaksjonstemperaturen er ikke kritisk og reaksjonen utføres vanligvis under temperaturbetingelser som går fra. avkjøling til oppvarming.
Fremgangsmåtene A, B og C for fremstilling av de hittil ukjente utgangsforbindelser II, IV, XVI og deres mellomproduktforbindelser beskrives detaljert nedenfor.
1) Fremgangsmåte A-I)
Forbindelsen VIII-a, eller salter derav, kan fremstilles ved å omsette forbindelsen VI, eller salter derav, med forbindelser VII, eller salter derav.
Egnede salter av forbindelsen VIII-a kan være salter som er dannet med en base, så som saltene av forbindelsene I, salter dannet med en syre, så som et uorganisk syreaddisjonssalt (f.eks. hydroklorid, hydrobromid, sulfat, fosfat, etc), et organisk syreaddisjonssalt (f.eks. formiat, acetat, trifluoracetat, maleat, tartrat, metansulfonat, benzensulfonat, toluensulfonat, etc).
Egnede salter av forbindelsen VI kan være de samme som for forbindelsen I.
Egnede salter av forbindelsen VII kan være syreaddisjons-salter som eksemplifisert for forbindelsen VIII-a.
Denne reaksjon utføres vanligvis i et konvensjonelt opp-løsningsmiddel som ikke påvirker reaksjonen ugunstig, så som aceton, benzen, tetrahydrofuran, pyridin, N,N-dimetylformamid, etc. eller en blanding derav.
Reaksjonstemperaturen er ikke kritisk og reaksjonen utføres vanligvis under temperaturbetingelser som går fra avkjøling til oppvarming.
2) Fremgangsmåte A-2)
Forbindelsen VIII-b, eller salter derav, kan fremstilles ved å omsette forbindelsen VIII-a,-eller salter derav, med forbindelsen IX.
Egnede salter av forbindelsen VIII-b kan være de samme som saltene for forbindelsen VIII-a.
Denne reaksjon utføres vanligvis i et konvensjonelt opp-løsningsmiddel som ikke påvirker reaksjonen ugunstig, så som diklormetan, metanol, etanol, propanol, pyridin, N,N-dimetyl-formamid, dioksan, etc. eller en blanding derav.
Reaksjonstemperaturen er ikke kritisk og reaksjonen utføres vanligvis under temperaturbetingelser som går fra avkjøling til oppvarming.
3) Fremgangsmåte A-3)
Forbindelsen XI, eller salter derav, kan fremstilles ved å omsette forbindelsen X, eller dens reaktive derivat eller salter derav, med forbindelsen VII, eller salter derav.
Egnede reaktive derivater av forbindelsen X kan omfatte et syrehalogenid, så som syreklorid, syrebromid, etc., syreanhydrid, så som et blandet syreanhydrid med en syre (f.eks. fosforsyre, dialkylfosforsyrling, svovelsyrling, svovelsyre, alkylkarbonat, alifatisk karboksylsyre, aromatisk karboksylsyre, etc), et aktivert syreamid med en heterocyklisk forbindelse (f.eks. imidazol, triazol, etc), en aktivert ester (f.eks. cyanometylester, 2,4-dinitrofenylester, etc), og lignende, idet et foretrukket eksempel kan være syrehalogenid og et aktivert syreamid med én av de ovennevnte heterocykliske forbindelser, og idet et særlig foretrukket eksempel kan være syreklorid og et aktivert syreamid med imidazol.
Egnede salter av forbindelsene XI og X kan være de samme som for forbindelsene I.
Reaksjonen utføres fortrinnsvis i nærvær av en uorganisk eller organisk base, så som et alkalimetallhydroksyd (f.eks. natriumhydroksyd, kaliumhydroksyd, etc), et alkalimetallkarbonat (f.eks. natriumkarbonat, kaliumkarbonat, etc), et alkalimetallhydrogenkarbonat (f.eks. natriumhydrogenkarbonat, kaliumhydrogenkarbonat, tri-lavere alkylamin (f.eks. trimetylamin, trietylamin, etc), pyridin eller dens derivater (f.eks. pikolin, lutidin, 4-dimetylaminopyridin, etc.) og lignende.
Når forbindelsen X anvendes i form av fri syre eller salt derav i denne reaksjon, utføres reaksjonen fortrinnsvis i nærvær av et konvensjonelt kondenseringsmiddel, så som N,N'-dicykloheksylkarbodiimid, N-cykloheksyl-N'-morfolinoetylkarbodiimid, N-etyl-N'-(3-dimetylaminopropyl)karbodiimid, tionylklorid, oksalylklorid, lavere alkoksykarbonylhalogenid (f.eks. etylklorformiat, isobutylklorformiat, etc),1-(p-klorbenzensulfonyloksy)-6-klor-lH-benzotriazol og lignende.
Denne reaksjon utføres dessuten vanligvis i et konvensjonelt oppløsningsmiddel som ikke påvirker reaksjonen ugunstig, så som aceton, diklormetan, kloroform, pyridin, N,N-dimetylformamid, etc. eller en blanding derav. Hvis den base eller det kondenseringsmiddel som skal anvendes er en væske, kan disse dessuten anvendes som oppløsningsmidler.
Reaksjonstemperaturen er ikke kritisk og reaksjonen utføres vanligvis under temperaturbetingelser som går fra avkjøling til oppvarming.
4) Fremgangsmåte A-4
Forbindelsen VIII, eller salter derav, kan fremstilles ved reduksjon av forbindelsen XI eller salter derav.
Egnede salter av forbindelsen VIII kan være de samme som for forbindelsen VIII-a.
Reduksjonen av forbindelsen XI kan utføres ved en konvensjonell fremgangsmåte, f.eks. ved anvendelse av et reduksjonsmiddel så som litiumaluminiumhydrid, tinn(II)klorid, etc; ved kjemisk reduksjon under anvendelse av metall (f.eks. sink, jern, kobber, etc.) og syre (f.eks. saltsyre, svovelsyre, eddiksyre, etc), eller ved katalytisk reduksjon. Katalytisk reduksjon utføres vanligvis i nærvær av en konvensjonell katalysator så som Raney-nikkel, palladium, platina, rhodium, kobber og lignende.
Denne reaksjon utføres vanligvis i et konvensjonelt opp-løsningsmiddel som ikke påvirker reaksjonen ugunstig, så som vann, alkohol (f.eks. metanol, etanol, etc), pyridin, N,N-dimetylformamid, etc. eller en blanding derav, og hvis den syre som skal anvendes i den kjemiske reduksjon dessuten er en væske, kan denne også anvendes som oppløsningsmiddel.
Reaksjonstemperaturen er ikke kritisk og reaksjonen utføres vanligvis under temperaturbetingelser som går fra avkjøling til oppvarming.
5) Fremgangsmåte A-5 og Fremgangsmåte B-2
Forbindelsene II og IV, eller salter derav, kan fremstilles ved å omsette forbindelsene VIII eller XIV, eller salter derav, med forbindelsen XII.
Egnede salter av forbindelsen XIV kan være de samme for som for forbindelsen VIII-a.
Reaksjonen utføres vanligvis i nærvær eller fravær av et konvensjonelt oppløsningsmiddel som ikke påvirker reaksjonen ugunstig, så som aceton, benzen, tetrahydrofuran, pyridin, N,N-dimetylformamid, dioksan, etc, eller en blanding derav.
Reaksjonstemperaturen er ikke kritisk og reaksjonen utføres vanligvis under temperaturbetingelser som går fra avkjøling til oppvarming.
6) Fremgangsmåte B-l
Forbindelsen XIV, eller salter derav, kan fremstilles ved å omsette forbindelsen XIII, eller salter derav, med forbindelsen III, eller salter derav.
Egnede salter av forbindelsene XIII kan være de samme som for forbindelsen VIII-a.
Denne reaksjon utføres fortrinnsvis i nærvær av en organisk eller uorganisk base, så som dem som er nevnt i
forbindelse med Fremgangsmåte 1.
Denne reaksjon kan i det vesentlige utføres på samme måte som for Fremgangsmåte 1, og reaksjonsfremgangsmåten og - betingelsene (f.eks. oppløsningsmiddel, reaksjonstemperatur, etc.) er således angitt i forbindelse med Fremgangsmåte 1.
7) Fremgangsmåte B-3
Forbindelsen XV, eller salter derav, kan fremstilles ved å omsette forbindelsen VI, eller salter derav, med forbindelsen III, eller salter derav.
Egnede salter av forbindelsen XV kan være de samme som for forbindelsene 1.
Denne reaksjon kan i det vesentlige utføres på samme.måte som for Fremgangsmåte 1, og reaksjonsfremgangsmåten og - betingelsene (f.eks. oppløsningsmiddel, reaksjonstemperatur, etc.) er derfor som angitt i forbindelse med Fremgangsmåte 1.
Reaksjonsproduktet av denne fremgangsmåte kan anvendes i den neste fremgangsmåte med eller uten isolering og/eller opp-rensning.
8) Fremgangsmåte B-4
Forbindelsen XIV-a, eller salter derav, kan fremstilles ved å omsette forbindelsen XV, eller salter derav, med NH3.
Egnede salter av forbindelsen XIV-a kan være de samme som for forbindelsen XIV.
Denne reaksjon kan utføres i et konvensjonelt oppløsningsmiddel som ikke påvirker reaksjonen ugunstig, så som vann, metanol, etanol, propanol, pyridin, N,N-dimetylformamid, toluen, dioksan, etc., eller en blanding derav.
Reaksjonstemperaturen er ikke kritisk og reaksjonen utføres vanligvis under temperaturbetingelser som går fra avkjøling til oppvarming.
9) Fremgangsmåte C-l
Forbindelsen XVI, eller salter derav, kan fremstilles ved å omsette forbindelsen VIII, eller salter derav, med
forbindelsen III, eller salter derav.
Denne reaksjon kan i det vesentlige utføres på samme måte som for Fremgangsmåte 1, og reaksjonsfremgangsmåten og - betingelsene (f.eks. oppløsningsmiddel, reaksjonstemperatur, etc.) er som angitt i forbindelse med Fremgangsmåte 1.
10) Fremgangsmåte C-2
Forbindelsen XVI-b, eller salter derav, kan fremstilles ved å omsette forbindelsen XVI-a, eller salter derav, med forbindelsen IX.
Egnede salter av forbindelsene XVI-a og XIV-b kan være de samme som for forbindelsen XVI.
Reaksjonen kan i det vesentlige utføres på samme måte som ved Fremgangsmåte A-2 og reaksjonsfremgangsmåten og - betingelsene (f.eks. oppløsningsmiddel, reaksjonstemperatur, etc.) er derfor som angitt i forbindelse med Fremgangsmåte A-2.
De forbindelser som oppnås i de ovenfor beskrevne fremgangsmåter 1-4 og Fremgangsmåte A, B og C, kan isoleres og opprenses på konvensjonell måte, f.eks. ved ekstraksjon, utfelling, fraksjonert kromatografi, fraksjonert krystallisasjon, omkrystallisasjon og lignende.
De således fremstilte sluttforbindelser I kan, hvis det ønskes, omdannes til farmasøytisk akseptable salter ved konvensjonelle metoder.
De hittil ukjente kinazolinderivater I og farmasøytisk akseptable salter derav, har vist seg å ha aldosereduktase-inhibitorisk virkning og er nyttige, for eksempel som medikamenter til terapeutisk behandling av diabetiske komplikasjoner, så som mangelfull heling av corneasår, katarakt, neuropati, retinopati, nefropati, især katarakt og neuropati.
Verdiene for den aldosereduktase-inhibitoriske virkning hos noen representanter for kinazolinderivatene I er anført nedenfor.
De ovenfor nevnte reaktanter ble blandet og omsatt ved 35°C i 2 minutter og reduksjonen av NADPH-mengde ble målt med "Automatic Reaction Rate Analyzer Model LKB-8600" ( fremstilt av LKB Producter A. B.). Som enhet ble anvendt den enzymaktivitet som bevirket en absorbansendring på 0,001 pr. minutt.
2) Fremgangsmåte for fremstilling av en enzymoppløsning
Kaninøyne ble utskrellet og linsene innsamlet. Linsene ble homogenisert med 3 volumer destillert vann ved 4°C (alle etterfølgende prosedyrer ble også utført ved 4°C) og sentrifugert ved 10.000 x g i 60 minutter. Den overstående væske ble dialysert mot 2 liter 0,05M saltvannsoppløsning og den dialyserte oppløsning ble anvendt som enzymoppløsning.
Hver IC50-verdi (M) betegner den konsentrasjon av prøveforbindelsen som forårsaker inhibering av 50% av aldosereduktase-aktiviteten.
Forsøksresultatene viser at forbindelsene fremstilt ifølge oppfinnelsen har kraftigere aldosereduktase-hemmende aktivitet enn sammenligningsforbindelsen som er generelt beskrevet i DE-A, 2652144 og er den forbindelse som kommer foreliggende oppfinnelse nærmest.
B) In vivo-test
Inhibitorisk virkning av medikamenter på sorbitols akkumulasjon i nervus ischiadicus.
1) Testmetode
Sprague-Dawley-hannrotter (6 uker gamle) ble holdt fastende i 24 timer og deretter gjort diabetiske ved intraperitoneal injeksjon (2 ml/kg) av streptozotocin (75 mg/kg) oppløst i 2 mM citratbuffer (pH 4,5). 7 dager etter streptozotocin-injeksjon ble blodglukose-verdier målt på blod tatt fra halevenen. Rotter med blodglukose- verdier på >300 mg/dl ble anvendt som dyr som var gjort diabetiske ved streptozotocin-induksjon.
Diabetiske dyr ble randomisert oppdelt i 2 grupper (gruppe A og B).
Medikamentet ble suspendert i 0,5% vandig metylcelluloseoppløsning og gitt peroralt til hver rotte i gruppe A én gang daglig i 5 dager (i det følgende betegnet som medikamentbehandlede diabetiske rotter).
Hver rotte i gruppe B og hver normalrotte fikk tilført bæreren (0,5% vandig metylcelluloseoppløsning) (i det følgende betegnet som henholdsvis ubehandlede diabetiske rotter og kontrollrotter).6timer etter den siste tilførsel av medikament eller bærer ble dyrene avlivet og sorbitolinnholdet i nervus ischiadicus ble analysert. Medikamentets inhibitoriske effekt (%) på sorbitol-akkumulasjon i nervus ischiadicus ble beregnet på følgende måte:
I Prosent inhibering.
S Sorbitolinnhold i nervus ischiadicus hos ubehandlede
diabetiske rotter.
SD Sorbitolinnhold i nervus ischiadicus hos medikamentbehandlede diabetiske rotter.
N Sorbitolinnhold i nervus ischiadicus hos kontrollrotter.
(2)Forsøksresultater
Når de farmasøytiske preparater anvendes til mennesker tilføres de fortrinnsvis intravenøst, intramuskulært eller peroralt. Den effektive dose av hver aktiv forbindelse avhenger av den behandlede pasients alder og/eller symptomer. De farmasøytiske preparater inneholder imidlertid vanligvis ca. 50 mg, 100 mg, 250 mg, 500 mg eller 1000 mg av den aktive forbindelse pr. enhetsdoseringsform, og de gis til mennesker eller dyr i en daglig dose på 0,1-100 mg pr. kg legemsvekt.
De følgende eksempler belyser den foreliggende oppfinnelse nærmere.
FREMSTILLING 1
1) En blanding av 2H-3,l-benzoksazin-2,4(1H)-dion (20 g) og 3,4-diklorbenzylamin (16,4 ml) i benzen (200 ml) ble kokt under tilbakeløpskjøling i 3 timer." Etter avkjøling ble oppløsningsmidlet fjernet under redusert trykk, hvilket ga et residuum som ble omkrystallisert fra n-heksan-etylacetat (1:2). hvilket ga 2-amino-N-(3,4-diklorbenzyl)-benzamid (30,5 g).
IR-spektrum (Nujol) : vmaks=3450, 3350, 3300, 1620<c>m"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 3,30 (2H, bred, s) , 4,30 (2H, d, J=7Hz), 6,00-7,70 (7H, m), 8,70 (1H, t, J=7Hz).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som Fremstilling 1-1). 2)2-amino-N-(4-brom-2-fluorbenzyl)benzamid, smeltepunkt 117-117,5°C.
IR-spektrum (Nujol): vmaks= 3470, 3350, 3270, 1765, 1730, 1610, 1585, 1540 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 4,40 (2H, d, J=6Hz) , 6,39 (2H, bred s), 6,4-6,8 (2H, m), 7,0-7,8 (5H, m), 8,70 (1H, t, J=6Hz).
FREMSTILLING 2
En blanding av 2-amino-N-(3,4-diklorbenzyl)benzamid
(3,5g) og fosforpentasulfid (4,74 g) i dioksan (56 ml) ble omrørt ved romtemperatur i 5 timer. Reaksjonsblandingen ble helt i vandig natriumhydrogenkarbonat og ekstrahert med etylacetat. Ekstrakten ble vasket med vann og tørket. Avdamping av oppløsningsmidlet ga et residuum som ble kromatografert på silikagel. Eluering med kloroform etterfulgt av omkrystallisasjon fra isopropyleter ga 2-amino-N-(3,4-diklorbenzyl)benzenkarbotioamid (1,56 g), smeltepunkt 89-91°C. IR-spektrum (Nujol): vmaks = 3370, 1605 cm"<1>.
FREMSTILLING 3
1) Til en oppløsning av 3,4-diklorbenzylamin (3,97 g) og trietylamin (3,5 ml) i kloroform (80 ml) ble det under omrøring satt en oppløsning av 2-nitrobenzensulfonylklorid (5 g) i kloroform (20 ml) ved 0°C og blandingen ble omrørt i 30 minutter ved denne temperatur. Reaksjonsblandingen ble vasket suksessivt med fortynnet saltsyre dg vann og deretter tørket. Avdamping av oppløsningsmidlet ga N-(3,4-diklorbenzyl)-2-nitrobenzensulfonamid (6,87 g).
IR-spektrum (Nujol): vmaks = 3300, 1530, 1160 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,23 (2H, d, J=5Hz) , 7,15-8,03 (7H, m), 8,67 (1H, t, J=5Hz).
Den følgende forbindelse ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 3-1).2) N-(4-brom-2-fluorbenzyl)-3-metoksy-2-nitrobenzamid IR-spektrum (Nujol) : vmaks=3300, 1640, 1610 cm"<1.>NMR-spektrum (DMS0-d6) : S (ppm) = 3,95 (3H, s) , 4,39 (2H, d, J=6Hz), 7,13-7,63 (6H, m), 9,22 (1H, t, J=6Hz).
FREMSTILLING 4
1) En blanding av N-(3,4-diklorbenzyl)-2-nitrobenzensulfonamid (4 g) og jern (2 g) i eddiksyre (30 ml) ble omrørt ved 100°C i 45 minutter. Etter avkjøling ble jernet frafiltrert. Filtratet ble gjort basisk med fortynnet vandig natriumhydroksyd og ekstrahert med etylacetat. Ekstrakten ble vasket med vann, tørket og inndampet. Omkrystallisasjon fra etyleter ga 2-amino-N-(3,4-diklorbenzyl)benzensulfonamid (3,40 g).
IR-spektrum (Nujol): vmaks= 3500, 3380, 3290, 1615 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 3,99 (2H, s) , 5,88 (2H, bred s), 6,44-7,54 (7H, m), 8,12 (1H, bred s) .
Den følgende forbindelse ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 4-1).2) 2-amino-N-(4-brom-2-fluorbenzyl)-3-metoksybenzamid IR-spektrum (Nujol): vmaks= 3500, 3380, 3300, 1630, 1600 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 3,82 (3H, s) , 4,43 (2H, d, J=6Hz), 6,12 (2H, bred s), 6,52-7,57 (6H, m), 8,72 (1H, t,
J=6HZ).
FREMSTILLING 5
1) En blanding av 2-amino-N-3,4-diklorbenzylbenzamid
(0,295 g) og N,N'-karbonyldiimidazol (0,18 g) i benzen (3ml) ble kokt under tilbakeløpskjøling i 15 minutter. Etter avkjøling ble de dannede krystaller oppsamlet og vasket med etanol, hvilket ga 3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin (0,25 g), smeltepunkt 274-275°C. IR-spektrum (Nujol) : vmaks=1710, 1660 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 5,07 (2H, s) , 7,10-8,07 (7H, m), 11,50 (1H, bred s).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 5-1). 2) 3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin, smeltepunkt 251-252°C.
IR-spektrum (Nujol) : vmaks = 1720, 1660 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 5,15 (2H, s) , 8,70-8,0 (7H, m), 11,50 (1H, bred s). 3)3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2-okso-4-tiokso-kinazolin, smeltepunkt 287-288°C.
IR-spektrum (Nujol) : vmaks = 1690, 1590 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 5,73 (2H, s) , 7,13-8,50 (7H, m), 12,03 (1H, bred s).
4)2-(3,4-diklorbenzyl)-3,4-dihydro-3-okso-2H-l,2,4-benzo-tiadiazin-1,1-dioksyd
IR-spektrum (Nujol) : vmais= 1695, 1600 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 5,00 (2H, s) , 7,18-7,95 (7H, m), 11,53 (1H, bred s). 5) 3-(4-brom-2-fluorbenzyl)-8-metoksy-l,2,3,4-tetrahydro-2,4-dioksokinazolin.
IR-spektrum (Nujol) : vmaks = 1720, 1660 cm"<1.>
FREMSTILLING 6
1) En blanding av 2-aminobenzamid (100 g), etylbromacetat
(97,74 ml) og kaliumkarbonat (253,78 g) i N,N-dimetylformamid (400 ml) ble omrørt ved 60°C i 4,5 timer. Etter avkjøling ble
reaksjonsblandingen helt i isvann (2 liter) og de dannede krystaller ble oppsamlet ved filtrering. Det således oppnådde produkt ble opprenset ved omkrystallisasjon fra etanol, hvilket ga etyl N-(2-karbamoylfenyl)aminoacetat (123,93 g) , smeltepunkt 147-148°C.
IR-spektrum (Nujol): vmaks= 3380, 3180, 1740, 1635, 1615 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,22 (3H, t, J=7Hz) , 4,02 (2H, s) , 4,14 (2H, q, J=7Hz), 6,48-6,68 (2H, m) , 7,11-7,68 (4H, m).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 6-1). 2) Etyl N-(2-karbamoyl-5-metoksyfenyl)aminoacetat. IR-spektrum (Nujol): vmaks= 3420, 3390, 3320, 3240, 1725, 1655, 1625cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 3,73 (3H, s), 4,00 (2H, d, J=5Hz), 4,12 (2H, q, J=7Hz), 6,00 (1H, dd, J=2, 8Hz), 6,22 (1H, d, J=2Hz), 7,23 (2H, bred s), 7,57 (1H, d, J=8Hz), 8,73 (1H, t, J=5Hz). 3) Etyl N-(2-karbamoyl-4-metoksyfenyl)aminoacetat, smeltepunkt 108-110°C.
IR-spektrum (Nujol): vraaks = 3375, 3200, 1720, 1645, 1600,
1510 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 3,73 (3H, s), 3,92-4,28 (4H, m), 6,53 (1H, d, J=6Hz), 6,97 (1H, dd, J=2, 6Hz), 7,23 (1H, d, J=2Hz), 7,98 (2H, m).
4) Etyl N-(2-karbamoyl-5-klorfenyl)aminoacetat.
IR-spektrum (Nujol): vmaks= 3420, 1730, 1670, 1645, 1610 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,22 (3H, t, J=7Hz) , 4,14 (2H, q, J=7Hz), 4,08 (1H, d, J=9Hz), 4,82 (1H, d, J=9Hz), 6,50-8,60 (6H, m). 5) Etyl N-(2-karbamoy1-4-klorfenyl)aminoacetat, smeltepunkt 139-140°C.
IR-spektrum (Nujol): vmalcs = 3400, 3225, 1720, 1650, 1615 cm"<1>. NMR-spektrum (CDC13) : S (ppm) = 1,28 (3H, t, J=7Hz) , 3,93 (2H, d, J=6Hz), 4,23 (2H, q, J=7Hz), 6,05 (2H, bred s), 6,47 (1H, d, J=9Hz), 7,24 (1H, dd, J=2, 9Hz), 7,40 (1H, d, J=2Hz), 8,17 (1H, t, J=6Hz). 6) Etyl N- (2-karbairtoyl-3-klorfenyl) aminoacetat, smeltepunkt 151-154°C.
IR-spektrum (Nujol): vmaks= 3370, 3180, 1750, 1645, 1615 cm"<1>. 7) Etyl N-(2-karbamoyl-3-metoksyfenyl)aminoacetat, smeltepunkt 138-140°C.
IR-spektrum (Nujol): vmaks= 3425, 3310, 3180, 1735, 1630, 1605, 1590 cm"<1>.
FREMSTILLING 7
1) En blanding av etyl N-(2-karbamoylfenyl)aminoacetat (54g) og N,N'-karbonyldiimidazol (78,8 g) ble omrørt ved 130°C i 40 minutter. Etter avkjøling ble krystallene oppsamlet ved filtrering og vasket med etanol, hvilket ga etyl 2-(1,2,3,4-tetrahydro-2,4-dioksokihazolin-l-yl)acetat (54,96 g), smeltepunkt 249-250°C.
IR-spektrum (Nujol) : vmaks= 3170, 3050, 1740, 1705, 1685,
1605 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 1,24 (3H, t, J=7Hz) , 4,16 (2H, q, J=7HZ), 4,91 (2H, s), 7,13-8,10 (4H, m).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 7-1).
2) Etyl 2-(l,2,3,4-tetrahydro-7-metoksy-2,4-dioksokinazolin-1-yl)acetat
IR-spektrum (Nujol): vmaks= 3150, 1730, 1710, 1695, 1610 cm"<1>. NMR-spektrum (DMSO-d5) : S (ppm) = 1,22 (3H, t, J=7Hz) , 3,87 (3H, s), 4,18 (2H, q, J=7Hz), 4,92 (2H, s), 6,77 (1H, dd, J=2, 8Hz), 6,93 (1H, d, J=2Hz), 7,97 (1H, d, J=8Hz).3) Etyl 2-(l,2,3,4-tetrahydro-6-metoksy-2,4-dioksokinazolin-1-yl)acetat, smeltepunkt 260-261°C.
IR-spektrum (Nujol) : vmaks= 3175, 3050, 1740, 1705, 1670,
1480 cm"<1>.
NMR-spektrum (DMSO-d6) : 6* (ppm) = 1,22 (3H, t, J=7Hz) , 3,83 (3H, s), 4,20 (2H, q, J=7Hz), 4,88 (2H, s), 7,32 (2H, m), 7,47 (1H, m), 11,73 (1H, bred s).4) Etyl 2-(6-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl)acetat, smeltepunkt 251-252°C.
IR-spektrum (Nujol): vmaks= 1735, 1700 (skulder), 1690,
1610 cm"<1>.
NMR-spektrum (DMSO-d6) : S (ppm) = 1,60 (3H, t, J=7Hz) , 4,15 (2H, q, J=7HZ), 4,90 (2H, s), 7,42 (1H, d, J=9Hz), 7,78 (1H, dd, J=3, 9Hz), 7,95 (1H, d, J=3Hz), 11,90 (1H, bred s). 5) Etyl 2-(5-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-y1)acetat, smeltepunkt 233-23 5°C.
IR-spektrum (Nujol): vmaks= 1735, 1720, 1690, 1590, 1580 cm"<1>. 6) Etyl 2-(l,2,3,4-tetrahydro-5-metoksy-2,4-dioksokinazolin-1-yl)acetat, smeltepunkt 258-260°C.
IR-spektrum (Nujol): vraaks= 3175, 1740, 1700, 1680, 1600, 1590 (skulder) cm"<1>.
FREMSTILLING 8
Etyl N-(2-karbamoyl-5-klorfenyl)aminoacetat (357 g) og N,N'-karbonyldiimidazol (451 g) ble oppløst i 1,4-dioksan (1,5 liter) og 1,4-dioksan ble konsentrert til ca. 0,5 liter ved destillasjon. Den dannede blanding ble omrørt ved 150°C i 30 minutter. Etter avkjøling ble de utfelte krystaller oppsamlet ved filtrering og vasket med etanol, hvilket ga etyl 2-(7-klor-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl)acetat (353 g).
IR-spektrum (Nujol): vmaks= 3200, 3070, 1740, 1710, 1690, 1605, 1580 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 1,23 (3H, t, J=7Hz) , 4,18 (2H, q, J=7HZ), 4,92 (2H, s), 7,32 (1H, dd, J=2, 8Hz), 7,55 (1H, d, J=2Hz), 8,00 (1H, d, J=8Hz).
FREMSTILLING 9
En blanding av 2-benzyloksykarbonylamino-4-klorbenzosyre (564 g) og fosfortribromid (1,5 kg) i dietyleter (9 liter) ble kokt under tilbakeløpskjøling i 40 timer og fikk stå ved romtemperatur i 5 dager. De dannede bunnfall ble oppsamlet ved filtrering og vasket suksessivt med dietyleter (5 liter) og etanol (3 liter), hvilket ga 7-klor-2H-3,1-benzoksazin-2,4(lH)-dion (335 g), smeltepunkt 282-283°C (dekomponering). IR-spektrum (Nujol): vmaks= 3175, 1740 (bred), 1710, 1615 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 7,15 (1H, d, J=l,5Hz), 7,30
(1H, dd, J=l,5, 5Hz), 7,93 (1H, d, J=5Hz), 11,83 (1H, s).
FREMSTILLING 10
Til en suspensjon av 4,6-diklorindolin-2,3-dion (5,95 g)
i eddiksyre (95 ml) ble det under omrøring satt kromtrioksyd (16 g) over en periode på 15 minutter ved 60°C og blandingen ble omrørt ved 70-75°C i 1 time. Etter avkjøling ble reaksjonsblandingen helt i vann (360 ml) og de dannede bunnfall ble oppsamlet ved filtrering. Filtratet ble ekstrahert med etylacetat. Ekstrakten ble vasket med vann og tørket. Fjerning av oppløsningsmidlet ga et residuum som ble slått sammen med bunnfallene. Omkrystallisasjon fra isopropyleter ga 5,7-diklor-2H-3,l-benzoksazin-2,4(1H)-dion (2,85 g), smeltepunkt 267-268°C.
IR-spektrum (Nujol): vmaks= 3225, 3200, 3100»3075, 1790, 1775, 1705, 1610, 1585 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 7,09 (1H, d, J=l,2Hz), 7,48 (1H, d, J=l,2Hz).
FREMSTILLING 11
En blanding av 7-klor-2H-3,l-benzoksazin-2,4(1H)-dion (18,4 g) og 4-brom-2-fluorbenzylamin (26 g) i tetrahydrofuran (200 ml) ble kokt under tilbakeløpskjøling i 15 minutter. Etter avkjøling ble tetrahydrofuran avdampet, hvilket ga et residuum. Omkrystallisasjon fra isopropyleter ga 2-amino-N-(4-brom-2-fluorbenzyl)-4-klorbenzamid (26,6 g), smeltepunkt 119, 5°C.
IR-spektrum (Nujol): vmaks= 3460, 3350, 3260, 1625, 1605 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,4 (2H, d, J=5,6Hz), 6,5-6,8 (4H, m), 7,3-7,6 (4H, m), 8,8 (1H, t, J=5,6Hz).
FREMSTILLING 12
1) Til en oppløsning av 4-brom-2-fluorbenzylamin (2,3 g) og trietylamin (1,55 ml) i kloroform (40 ml) ble det dråpevis under omrøring satt en oppløsning av 4-brom-2-nitrobenzoylklorid (2,69 g) i kloroform (10 ml) ved 0°C og blandingen ble omrørt ved den nevnte temperatur i 1 time.
Reaksjonsblandingen ble vasket suksessivt med fortynnet saltsyre og vann og derpå tørket. Avdamping av oppløsningsmidlet etterfulgt av omkrystalllisasjon fra dietyleter ga 4-brom-2-fluorbenzyl-2-nitrobenzamid (3,60 g), smeltepunkt 192-193°C.
IR-spektrum (Nujol): vmaks= 3275, 1650, 1605, 1555, 1535,
1485cm"1.
NMR-spektrum (DMS0-d6) : S (ppm) = 4,42 (2H, d, J=5,7Hz), 7,39-7,62 (4H, m), 8,02 (1H, dd, J=l,9, 8,2Hz), 8,28 (1H, d, J=l,9Hz), 9,29 (1H, t, J=5,7Hz).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 12
-1) • 2) N-(4-brom-2-fluorbenzyl) -4-jod-2-nitrobenzamid, smeltepunkt 204-205°C.
IR-spektrum (Nujol): \ maks = 3270, 1645, 1580, 1570, 1535,
1485 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 4,42 (2H, d, J=6Hz) , 7,34-7,58 (4H, m), 8,17 (1H, d, J=l,3, 8Hz), 8,36 (1H, d, J=l,3Hz), 9,26 (1H, t, J=5,8Hz). 3) N-(4-brom-2-fluorbenzyl)-4-fluor-2-nitrobenzamid, smeltepunkt 157-159°C.
IR-spektrum (Nujol): vmaks= 3250, 1620, 1540, 1360 cm"<1>. NMR-spektrum (CDC13) : S (ppm) = 4,62 (2H, d, J=5,9Hz), 6,24 (1H, bred s), 7,24-7,78 (6H, m). 4) N-(4-brom-2-fluorbenzyl)-4-klor-2-nitrobenzamid. IR-spektrum (Nujol): vmalcs= 3300, 1645, 1610, 1540, 1360 cm"<1>. 5) N-(4-brom-2-fluorbenzyl) -3-klor-2-nitrobenzamid, smeltepunkt 198-200°C.
IR-spektrum (Nujol):<v>maks= 3260, 1635 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 4,43 (2H, d, J=6Hz) , 7,23-8.07 (6H, m), 9,50 (1H, t, J=6Hz). 6) 4-klor-N-[4-klor-3-(trifluormetyl)benzyl]-2-nitrobenzamid, smeltepunkt 151-152°C.
IR-spektrum (Nujol): vraais= 3260, 1640, 1600, 1550, 1530 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,55 (2H, d, J=6Hz) , 7,52-8.08 (5H, m), 8,17 (1H, d, J=2Hz), 9,33 (1H, t, J=6Hz).
7) N-(4-brom-2-fluorbenzyl)-2-nitro-4-(trifluormetyl)benzamid, smeltepunkt 174-175°C. IR-spektrum (rent): vmaks= 1640, 1530, 1400, 1360, 1320, 1120 cm"1.8) 4-fluor-N-(2-fluor-4-jodbenzyl)-2-nitrobenzamid. IR-spektrum (Nujol): vmaks= 3250, 3050, 1640, 1620, 1605, 1535, 1360 cm"1.
NMR-spektrum (DMSO-d6) : S (ppm) = 4,4 (2H, d, J=5,6Hz), 7,2 (1H, dd, J=8, 8Hz), 7,6-7,8 (5H, m), 8,0 (1H, dd, J=l,8, 8,6Hz), 9,3 (1H, t, J=5,6Hz). 9) N-(2-fluor-4-jodbenzyl)-4-jod-2-nitrobenzamid, smeltepunkt 213-214°C.
IR-spektrum (Nujol) : vmaks= 3270, 3080, 1650, 1540, 1360,
860 cm"<1.>
NMR-spektrum (DMSO-d6) : S (ppm) = 9,29 (1H, t, J=5,8Hz), 8,36-7,18 (6H, m), 4,41 (2H, d, J=5,8Hz).
FREMSTILLING 13
En blanding av 4-brom-2-nitrobenzosyre (3,0 g) og N,N'-karbonyldiimidazol (2,37 g) i tetrahydrofuran (30 ml) ble omrørt ved romtemperatur i 4 timer. Til denne blanding ble det satt en oppløsning av 2-fluor-4-jodbenzylamin (3,37 g) i tetrahydrofuran (10 ml) og den oppnådde blanding ble omrørt ved romtemperatur over natten. Reaksjonsblandingen ble helt i en blanding av etylacetat og 0,5N saltsyre. Den organiske fase ble fraskilt, suksessivt vasket med vann, vandig natriumhydrogenkarbonat, vann og mettet vandig natriumklorid og tørket over magnesiumsulfat. Oppløsningsmidlet ble fjernet under vakuum og det krystallinske residuum ble omkrystallisert fra en blanding av etylacetat og heksan, hvilket ga 4-brom-N-(2-fluor-4-jodbenzyl)-2-nitrobenzamid (4,88 g), smeltepunkt 139-140°C.
IR-spektrum (Nujol) : vmaks = 3260, 1645 cm"<1>.
NMR-spektrum (DMSO-d6) : S (ppm) = 4,43 (2H, d, J=5,6Hz), 7,23 (1H, t, J=8Hz) , 7,58-7,67 (3H, m) , 8,03 (1H, dd, J=2,8Hz), 8,28 (1H, d, J=2HZ), 9,28 (1H, t, J=5,5Hz).
FREMSTILLING 14
1) En blanding av 4-brom-N-(4-brom-2-fluorbenzyl)-2-nitro-benzamid (3,4 g) og jern (1,45 g) i eddiksyre (66 ml) ble omrørt ved 100°c i 30 minutter. Etter avkjøling ble jernet frafiltrert. Filtratet ble inndampet, hvilket ga et residuum som ble gjort basisk med vandig IN natriumhydroksyd og ekstrahert med etylacetat. Ekstrakten ble vasket med vann og tørket. Fjerning av oppløsningsmidlet ga 2-amino-4-brom-N-(4-brom-2-fluorbenzyl)benzamid (3,10 g), smeltepunkt 143-144°C. IR-spektrum (Nujol): vmaks= 3460, 3350, 3260, 1630, 1610, 1580, 1535, 1485 cm"<1>.
NMR-spektrum (DMSO-d6) : S (ppm) = 4,39 (2H, d, J=6Hz) , 6,64 (1H, d, J=l,5Hz), 6,68 (2H, s), 6,92 (1H, d, J=l,5Hz), 7,25-7,54 (4H, m), 8,85 (1H, t, J=5,8Hz).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 14-1). 2) 2-amino-N-(4-brom-2-fluorbenzyl)-4-jodbenzamid, smeltepunkt 180°C.
IR-spektrum (Nujol): vmaks= 3450, 3350, 3275, 1635, 1605, 1570, 1535cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 4,39 (2H, d, J=6Hz) , 6,58 (2H, s), 6,84 (1H, d, J=8Hz), 7,13 (1H, s), 7,25-7,54 (4H, m), 8,84 (1H, t, J=6Hz). 3) 2-amino-N-(4-brom-2-fluorbenzyl)-4-klorbenzamid. IR-spektrum (Nujol): vmaks= 3460, 3350, 3260, 1625, 1605 cm"<1>. 4) 2-amino-N-(4-brom-2-fluorbenzyl)-3-klorbenzamid, smeltepunkt 170-171°C.
IR-spektrum (Nujol): vraaks = 3480, 3375, 3290, 1625, 1605 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,43 (2H, d, J=6Hz) , 6,50 (2H, bred s), 6,57-7,70 (6H, m) , 8,97 (1H, t, J=6Hz). 5) 2-amino-4-klor-N-[4-klor-3-(trifluormetyl)benzyl]benzamid, smeltepunkt 122-125°C. IR-spektrum (Nujol): vmaks= 3450, 3300, 1630, 1580, 1525,
1480cm"1.
NMR-spektrum (DMS0-d6) : S (ppm) = 4,48 (2H, d, J=6Hz) , 6,43-6,93 (4H, m) , 7,47-7,90 (4H, m) , 8,87 (1H, t, J=6Hz) . 6) 2-amino-4-brom-N-(2-fluor-4-jodbenzyl)benzamid,
smeltepunkt 111-112°C.
IR-spektrum (Nujol) : vmalcs = 3400, 3300, 3270, 1630 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,43 (2H, d, J=5,5Hz), 7,24 (1H, t, J=8Hz), 7,57-7,67 (3H, m), 8,16 (1H, dd, J=2, 8Hz), 8,28 (1H, d, J=2HZ), 9,28 (1H, t, J=5,5Hz). 7) 2-amino-4-fluor-N-(2-fluor-4-jodbenzyl)benzamid. IR-spektrum (Nujol): vmaks= 3460, 3350, 3260, 1630, 1600 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,4 (2H, d, J=5,5Hz), 6,3-6,5 (2H, m), 6,8 (2H, s), 7,1 (1H, dd, J=8, 8Hz), 7,5-7,7 (3H, m), 8,8 (1H, t, J=5,5Hz).
FREMSTILLING 15
1) En oppløsning av N-(4-brom-2-fluorbenzyl)-4-fluor-2-nitrobenzamid (4,79 g) og tinn(II)klorid (12,24 g) i etanol (26 ml) ble omrørt ved 70-80°C i 30 minutter under en nitrogenatmosfære. Etter avkjøling ble reaksjonsblandingen helt i iskaldt vann og nøytralisert med vandig mettet natriumhydrogenkarbonat. De dannede bunnfall ble frafiltrert og vasket med etylacetat. Filtratet ble ekstrahert med etylacetat og ekstrakten ble vasket med vann og tørket. Fjerning av oppløsningsmidlet ga 2-amino-N-(4-brom-2-fluorbenzyl)-4-fluorbenzamid (3,58 g), smeltepunkt 120-121°C. IR-spektrum (Nujol): vmaks= 3250, 1610, 1520, 1360 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,41 (2H, d, J=5,6Hz), 6,33 (1H, t, J=8,3HZ), 6,47 (1H, d, J=8,3Hz), 6,78 (2H, s), 7,67-7,27 (4H, m), 8,78 (1H, t, J=5,6Hz).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 15-1). 2) 2-amino-N-(4-brom-2-fluorbenzyl)-4-(trifluormetyl)benzamid", smeltepunkt 174-175°C.
IR-spektrum (Nujol): vmaks= 1640, 1590, 1530, 1370 cm"<1>.
3) 2-amino-N-(2-fluor-4-jodbenzyl)-4-jodbenzamid, smeltepunkt 178-179°C.
IR-spektrum (Nujol): vmaks= 3470, 3150, 3260, 1630, 1600, 1570, 1530, 1300, 860, 720 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 4,44 (2H, d, J=5,5Hz), 6,65-7,70 (6H, m), 8,89 (1H, t, J=5,5Hz).
FREMSTILLING 16
1) 2-amino-4-brom-N-(4-brom-2-fluorbenzyl)benzamid (2,90 g) og N,N'-karbonyldiimidazol (4,68 g) ble oppløst i dioksan (50 ml). Oppløsningen ble inndampet, hvilket ga et residuum som ble omrørt ved 150°C i 30 minutter. Etter avkjøling ble bunnfallene oppsamlet ved filtrering og vasket med etanol, hvilket ga 7-brom-3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin (2,92 g), smeltepunkt >280°C.
IR-spektrum (Nujol): vmaks= 1720, 1660, 1610, 1595, 1580,
1485 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 5,07 (2H, s) , 7,19-7,86 (6H, m) .
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 16-1). 2) 3-(4-brom-2-fluorbenzyl)-7-jod-l,2,3,4-tetrahydro-2,4-dioksokinazolin, smeltepunkt >280°C.
IR-spektrum (Nujol): vmaks= 1715, 1660, 1605, 1590, 1580,
1485cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 5,06 (2H, s) , 7,16 (1H, dd, J=8, 8Hz), 7,32 (1H, d, J=8Hz), 7,51-7,59 (3H, m), 7,66 (1H, d, J=8Hz). 3) 3-(4-brom-2-fluorbenzyl)-7-fluor-l,2,3,4-tetrahydro-2,4-dioksokinazolin, smeltepunkt 250-251°C.
IR-spektrum (Nujol): vmaks= 1720, 1600, 1660, 1360 cm"<1.>NMR-spektrum (DMS0-d6) : S (ppm) = 5,08 (2H, s) , 7,57-6,93 (5H, m) , 8,01 (1H, dd, J=6, 7Hz). 4) 3-(4-brom-2-fluorbenzyl)-7-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin, smeltepunkt >280°C.
IR-spektrum (Nujol): vmaks= 3200, 3060, 1720, 1660, 1615, 1600, 158 0 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 5,1 (2H, s) , 7,2-7,3 (4H, m) , 7,5 (1H, d, J=8Hz), 7,9 (1H, d, J=8Hz). 5) 3-(4-brom-2-fluorbenzyl)-8-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin, smeltepunkt 288-290°C.
IR-spektrum (Nujol): vmaks = 1715, 1660, 1610 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) =5,10(2H, s), 7,10-8,00 (6H, m) .6)7-klor-3-[4-klor-3-(trifluormetyl)benzyl]-1,2,3,4-tetrahydro-2,4-dioksokinazolin, smeltepunkt 239°C.
IR-spektrum (Nujol) : vmaks= 1720, 1700, 1630 cm"<1>. NMR-spektrum (DMSO-d6) : S (ppm) = 5,15 (2H, s) , 7,07-7,40 (2H, m), 7,53-8,13 (4H, m).7) 3-(4-brom-2-fluorbenzyl)-7-trifluormetyl-1,2 ,3,4-tetrahydro-2,4-dioksokinazolin, smeltepunkt 260-261°c. IR-spektrum (Nujol): vmaks= 1720, 1660, 1600, 1380, 1360, 1170, 113 0 cm"<1.>
FREMSTILLING 17
1) En blanding av 2-amino-4-brom-N-(2-fluor-4-jodbenzyl)-benzamid (3,80 g), N,N'-karbonyldiimidazol (5,5 g) og 1,4-dioksan (30 ml) ble tilbakeløpsbehandlet i 2 timer. De dannede krystaller ble oppsamlet ved filtrering, vasket med 1,4-dioksan og tørket over fosforpentoksyd, hvilket ga 7-brom-3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin (2,85 g), smeltepunkt 303-304°C.
IR-spektrum (Nujol) : vmaks = 1715, 1655 cm"<1>.
NMR-spektrum (DMSO-d6) : S (ppm) = 5,05 (2H, s) , 7,00 (1H, t, J=8Hz), 7,37 (2H, s), 7,46 (1H, t, J=8Hz), 7,63 (1H, d, J=9Hz), 7,85 (1H, d, J=9Hz).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 17-1).2)7-fluor-3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin.
IR-spektrum (Nujol): vmaks= 1720, 1660, 1620, 1610, 1600 cm"<1>. NMR-spektrum (DMSO-d6) : S (ppm) = 5,1 (2H, s) , 6,9-7,1 (3H, m) , 7,5 (1H, dd, J=l,4, 8,1Hz), 7,6 (1H, dd, J=l,6, 9,7Hz)#8,0 (1H, dd, J=6,2, 8,8Hz). 3) 3-(2-fluor-4-j odbenzyl)-7-j od-1,2,3,4-tetrahydro-2,4-dioksokinazolin, smeltepunkt 320-322°C.
IR-spektrum (Nujol): vmaks= 3470, 3360, 3270, 1720, 1660, 1600, 1480, 960, 860, 760cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 5,0 (2H, s) , 7,0 (1H, t, J=8Hz), 7,45-7,68 (5H, m).
FREMSTILLING 18
1) Etyl N-(2-karbamoyl-4,5-diklorfenyl)aminoacetat (4,6 g) og N,N'-karbonyldiimidazol (5,12 g) ble oppløst i dioksan (50 ml). Oppløsningen ble inndampet, hvilket ga et residuum som ble omrørt ved 140°C i 30 minutter. Etter avkjøling ble bunnfallene oppsamlet ved filtrering og vasket med etanol, hvilket ga etyl 2-(6,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl)acetat (4,40 g), smeltepunkt >280°C. IR-spektrum (Nujol): vmais= 1735, 1720, 1690, 1605, 1570 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,22 (3H, t, J=7Hz) , 4,17 (2H, q, J=7Hz), 4,90 (2H, s), 7,86 (1H, s), 8,11 (1H, s).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 18-1). 2) Etyl 2-(5,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl)acetat, smeltepunkt 244-247°C. IR-spektrum (Nujol): \ maks = 1750, 1740 (skulder), 1710, 1690, 1590, 1565 cm"<1>.
NMR-spektrum (DMSO-d6) : S (ppm) = 1,22 (3H, t, J=7Hz) , 4,18 (2H, q, J=7HZ), 4,92 (2H, s), 7,49 (1H, s), 7,57 (1H, s), 11,89 (1H, s).
FREMSTILLING 19
1) Til en oppløsning av 7-klor-2H-3,l-benzoksazin-2,4(1H)-dion (330 g) i N,N-dimetylformamid (3,3 liter) ble det satt natriumhydrid (60% i mineralolje, 86,8 g) ved en temperatur under 2 0°C og blandingen ble omrørt ved 5°C i 30 minutter. Til denne oppløsning ble det satt etylbromacetat (222 ml) ved 10°C over en 30 minutters periode, og den dannede blanding ble omrørt ved romtemperatur i 1,5 timer. Til denne reaksjonsblanding ble det satt 28% vandig ammoniakk (696 ml) ved en temperatur under 10°C og den dannede blanding ble omrørt ved 5°C i 20 minutter. Blandingen ble helt i IN saltsyre (16,5 liter). Bunnfallet ble oppsamlet ved filtrering og vasket suksessivt med vann (3 ganger) og dietyleter, hvilket ga etyl N-(2-karbamoyl-5-klorfenyl)aminoacetat (360 g), smeltepunkt 157-155°C.
IR-spektrum (Nujol) : vmaks= 3400, 1725, 1650, 1610 cm"<1>.
NMR-spektrum (DMSO-d6) : S (ppm) = 1,20 (3H, t, J=4,5Hz), 4,05 (2H, d, J=4Hz), 4,15 (2H, q, J=4,5Hz), 6,58 (1H, d, J=l,5Hz), 6,62 (1H, dd, J=l,5, 6Hz), 7,63 (1H, d, J=6Hz), 7,7 (2H, bred), 8,67 (1H, d, J=4Hz).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILLING 19-1). 2) Etyl N-(2-karbamoyl-4,5-diklorfenyl)aminoacetat, smeltepunkt 181°C.
IR-spektrum (Nujol): vmaks= 3400, 3360, 3225, 1720, 1655, 1620, 1570, 1505 cm"<1>.
NMR-spektrum (DMSO-d6) : S (ppm) = 1,21 (3H, t, J=7Hz) , 4,09 (2H, d, J=5,5Hz), 4,15 (2H, q, J=7Hz), 6,80 (1H, s), 7,86 (1H, s), 8,58 (1H, t, J=5,5HZ). 3) Etyl N-(2-karbamoyl-3,5-diklorfenyl)aminoacetat, smeltepunkt 171-173°C.
IR-spektrum (Nujol): vmaks= 3400 (skulder), 3375, 3200, 1750, 1645, 1615, 1585, 1565 cm"<1>.
NMR-spektrum (DMSO-d6) : S (ppm) = 1,21 (3H, t, J=7Hz) , 3,99 (2H, d, J=5,5HZ), 4,14 (2H, q, J=7Hz), 5,87 (1H, t, J=5,5Hz), 6,53 (1H, S) , 6,78 (1H, s) , 7,80 (1H, s) , 7,98 (1H, s).
FREMSTILLING 20
1) En blanding av 2-amino-N-benzylbenzamid (400 mg), etylbromacetat (295 mg) og kaliumkarbonat (244 mg) i N,N-dimetylformamid (10 ml) ble omrørt ved 100°C i 17 timer. Etter avkjøling ble reaksjonsblandingen helt i iskaldt vann og ekstrahert med dietyleter. Ekstrakten ble vasket med vann og tørket. Fjerning av oppløsningsmidlet ga et residuum som ble kromatografert på silikagel. Eluering med kloroform ga etyl 2-[2-(N-benzylkarbamoyl)anilino]acetat (137 mg).
IR-spektrum (Nujol):<v>maks= 1735, 1630 cm"<1>.
NMR-spektrum (CDCl3) : S (ppm) = 3,25 (3H, t, J=7Hz) , 3,95 (2H, d, J=5Hz), 4,20 (2H, q, J=7Hz), 4,60 (2H, d, J=5Hz), 6,60 (2H, d, J=8Hz), 7,10-7,50 (9H, m), 8,00 (1H, bred s).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med FREMSTILING 20-1). 2) Etyl 2-[2-{N-(3,4-diklorbenzyl)karbamoyl}anilino]acetat.
FREMSTILLING 21
En blanding av etyl 2-[2-{N-(3,4-diklorbenzyl)karbamoyl>-anilino]acetat (16,3 g), fosforpentasulfid (19,0 g) og 1,4-dioksan (320 ml) ble tilbakeløpsbehandlet i 1 time. Reaksjonsblandingen ble filtrert og filtratet ble konsentrert under vakuum. Residuet ble kromatografert på silikagel (300 g) under eluering med kloroform, hvilket ga etyl 2-[2-{N-(3,4-diklor-benzyl) tiokarbamoyljanilino]acetat (13,72 g).
IR-spektrum (CHC13) :<v>maks<=>3400, 1740 cm"<1>.
NMR-spektrum (CDC13) : S (ppm) = 1,29 (3H, t, J=7Hz) , 3,83 (2H, s), 4,22 (2H, q, J=7Hz), 4,96 (2H, d, J=5,5Hz), 6,47 (1H, d, J=8Hz), 6,67 (1H, dt, J=l,8Hz), 7,12-7,29 (3H, m), 7,42-7,51 (2H, m), 8,23 (1H, t, J=5,5Hz).
EKSEMPEL 1
1) Til en suspensjon av 3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin (1 g) i N,N-dimetylformamid (15 ml) ble det under omrøring satt natriumhydrid (60% i mineralolje, 0,17 g) ved 0°C og blandingen omrørt i 15 minutter ved denne temperatur. Til denne blanding ble satt etylbromacetat (0,45 ml) og blandingen ble omrørt i 1 time ved romtemperatur. Reaksjonsblandingen ble helt i fortynnet saltsyre og ekstrahert med etylacetat. Ekstrakten ble vasket med saltoppløsning, tørket og inndampet, hvilket ga et residuum. Det således oppnådde produkt ble renset ved omkrystallisasjon fra isopropypleter, hvilket ga etyl 2-[3-(3,4-diklorbenzyl)-1,2, 3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (1,21 g), smeltepunkt 121-122°C.
IR-spektrum (Nujol) : vmaks = 1725, 1700, 1665, 1605 cm"<1>.
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med EKSEMPEL 1-1). 2) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 153-154°C. IR-spektrum (Nujol): vmaks= 1735, 1715, 1665, 1605 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,15 (3H, t, J=7Hz) , 4,15 (2H, q, J=7Hz), 4,97 (2H, s), 5,15 (2H, s), 7,0-8,2 (7H, m). 3) Etyl 2-[3-benzyl-l,2,3,4-tetrahydro-2,4-dioksokinazolin-1-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1700, 1660, 1650 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,30 (3H, t, J=7Hz) , 3,32 (2H, s), 4,25 (2H, q, J=7Hz), 5,10 (2H, d, J=10Hz), 7,30-8,30 (9H, m).
4) Etyl 2-[3-(3,4-diklorfenyl)-l,"2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol) : vmaks= 1740, 1710, 1665, 1605 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,23 (3H, t, J=7Hz) , 4,18 (2H, q, J=7Hz), 4,97 (2H, s), 7,18-8,15 (7H, m). 5) Etyl 2-[3-(3,4-diklorfenyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]propionat, smeltepunkt 130-131°C. IR-spektrum (Nujol): vmaks= 1735, 1700, 1655, 1605 cm"<1>. 6) Etyl 2-[3-(3,4-diklorfenyl)-l,2,3,4-tetrahydro-2-okso-4-tioksokinazolin-l-yl]acetat, smeltepunkt 157-158°C. IR-spektrum (Nujol): vmaks= 1740, 1690, 1605, 1590 cm"<1>. NMR-spektrum (CDCl3) : S (ppm) = 1,27 (3H, t, J=7Hz) , 4,25 (2H, q, J=7Hz), 4,90 (2H, s), 5,85 (2H, s), 6,87-8,85 (7H, m). 7) Etyl 2-[2-(3,4-diklorbenzyl)-3,4-dihydro-3-okso-2H-l,2,4-benzotiadiazin-4-yl]acetat-1,1-dioksyd.
IR-spektrum (CHC13) :<v>maks = 1740, 1690, 1600 cm"<1>.
8) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-8-metoksy-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1755, 1745, 1700, 1660, 1600 cm"<1>. NMR-spektrum (DMSO-d6) : S (ppm) = 1,22 (3H, t, J=7Hz) , 3,83 (3H, s), 4,18 (2H, q, J=7Hz), 5,03 (2H, s), 5,17 (2H, s), 7,00-7,80 (6H, m). 9) Etyl 2-[3-(4-klorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] acetat , smeltepunkt 137°C.
IR-spektrum (Nujol): vmaks= 1730, 1700, 1670, 1605, 1480 cm"<1>. 10) Etyl 2-[3-(2,6-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 182-183°C. IR-spektrum (Nujol): vmaks= 1745, 1720, 1680, 1610, 1480 cm"<1>. 11) Etyl 2-[3-(3,5-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 122-123°C. IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1600, 1570,
1480 cm"<1.>
12) Etyl 2-[3-(2,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1730, 1710, 1660, 1610 cm"<1>.
13) Etyl 2-[3-(2,5-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1705, 1660, 1605 cm"<1>.
14) Etyl 2-[l,2,3,4-tetrahydro-3-(4-metoksybenzyl)-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 135°C.
IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1600, 1480 cm"<1>. 15) Etyl 2-[l,2,3,4-tetrahydro-3-(l-naftylmetyl)-2,4-diokso-kinazolin-l-yl]acetat, smeltepunkt 164-167°C.
IR-spektrum (Nujol): vmaks= 1745, 1700, 1660, 1605 cm"<1>.
16) Etyl 2-[i,2,3,4-tetrahydro-2,4-diokso-3-(2-pyridylmetyl)-kinazolin-l-yl]acetat, smeltepunkt 141-143°C.
IR-spektrum (Nujol): vmaks= 1740, 1700, 1650, 1610 cm"<1>.
17) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-7-metoksy-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol) : vmaks= 1740, 1690, 1650, 1610 cm"<1>.
18) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-6-metoksy-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 160-160,5°C.
IR-spektrum (Nujol): vmaks= 1725, 1700, 1655, 1500, 1480 cm"<1>.19) Etyl 2-[3-(4-brom-2-fluorbenyl)-6-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 146-147°C.
IR-spektrum (Nujol): vmaks= 1730, 1710, 1675, 1610 cm"<1>.
2 0) Etyl 2-[3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 157°C.
IR-spektrum (Nujol): vmaks= 1750, 1705, 1670, 1610, 1480 cm"<1>.21) Etyl 2-[3-(4-klor-2-fluorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 144-145°C. IR-spektrum (Nujol): vmaks= 1730, 1705, 1660, 1610, 1480 cm"<1>.22)Etyl 2-[3-(4-brom-3-klorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 128-129°C. IR-spektrum (Nujol): vmaks= 1735, 1700, 1660, 1600, 1480 cm"<1>. 23) Etyl 2-[3-(2,3-diklorbenzyl)-l,2,3,4-tetrahydro-2,4- dioksokinazolin-l-yl]acetat, smeltepunkt 158-160°C. IR-spektrum (Nujol) : vmaks= 1740, 1705, 1660, 1605, 1480 cm"<1>.24) Etyl 2-[1,2,3,4-tetrahydro-3-(4-metylbenzyl)-2,4-diokso-kinazolin-l-yl] acetat , smeltepunkt 140-141°C.
IR-spektrum (Nujol): vmaks= 1735, 1700, 1660, 1605, 1480 cm"<1>.25) Etyl 2-[3-(4-klor-3-metoksybenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat.
IR-spektrum (Nujol): vmaks= 1740, 1705, 1660, 1610 cm"<1>.
26) Etyl 2-[3-(3-klor-4-metoksybenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat.
IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1605 cm"<1>.
27) Etyl 2-[l,2,3,4-tetrahydro-2,4-diokso-3-(2-tienylmetyl)-kinazolin-l-yl]acetat, smeltepunkt 115-120°C.
IR-spektrum (Nujol) : vmaks= 1730, 1700, 1660, 1605 cm"<1>.
28) Etyl 2-[l,2,3,4-tetrahydro-2,4-diokso-3-(2-naftylmetyl)-kinazolin-l-yl]acetat, smeltepunkt 149-150°C.29) Etyl 2-[3-(4-brom-2-fluorbenzyl)-5-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 186-187°C.
IR-spektrum (Nujol) : vmaks= 1740, 1710, 1670, 1590 cm"<1>.
30) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-5-metoksy-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 166-168°C. IR-spektrum (Nujol): vmaks= 1735, 1710, 1665, 1600, 1580 cm"<1>.31) 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 225-227°C.
IR-spektrum (Nujol) : vmaks= 1695, 1650, 1600 cm"<1>.
32) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 208-210°C. IR-spektrum (Nujol): vmaks=1730, 1700, 1660, 1610 cm"<1>.33) 2-[3-(benzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl ]eddiksyre, smeltepunkt 222-223°C.
IR-spektrum (Nujol) : vmaks= 1725, 1700, 1655, 1605, 1480 cm"<1>.34) 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl ]propionsyre smeltepunkt 93°C.
IR-spektrum (Nujol) : vmaks<=>1700, 1655, 1605 cm"<1>.
35) 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2-okso-4-tioksokinazolin-l-yl]eddiksyre, smeltepunkt 253,5-254,5°C.
IR-spektrum (Nujol): vmaks= 1705, 1680, 1660, 1600, 1585 cm"<1>. 36) 2-[3-(4-klorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl ] eddiksyre, smeltepunkt 229-230°C.
IR-spektrum (Nujol): vmaks= 1725, 1705, 1660, 1600, 1480 cm"<1>. 37) 2-[3-(2,6-diklorbenzy1)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl]eddiksyre, smeltepunkt 273-275°C.
IR-spektrum (Nujol): vmaks= 1720, 1660, 1605, 1475 cm"<1>.
38) 2-[3-(3,5-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 212-213°C
IR-spektrum (Nujol): vmaks= 1740, 1720, 1690, 1635, 1605, 1560, 1480 cm"1.
39) 2-[3-(2,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 223°C
IR-spektrum (Nujol): vmaks= 1720, 1675, 1615 cm"<1>.
40) 2-[3-(2,5-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 207°C
IR-spektrum (Nujol): vmaks=1710, 1665, 1605 cm"<1>.
41) 2-[l,2,3,4-tetrahydro-3-(4-metoksybenzyl)-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 213-215°C.
IR-spektrum (Nujol): vmaks= 1720, 1700, 1660, 1600, 1480 cm"<1>. 42) 2-[l,2,3,4-tetrahydro-3-(1-naftylmetyl)-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 216-218°C.
IR-spektrum (Nujol): vmaks = 1705, 1660, 1605 cm"<1>.
43) 2-[l,2,3,4-tetrahydro-2,4-diokso-3-(2-pyridylmetyl)-kinazolin-l-yl]eddiksyre, smeltepunkt 220-223°C.
IR-spektrum (Nujol): vmaks = 1710, 1660, 1610 cm"<1>.
44) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-7-metoksy-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 222-223°C. IR-spektrum (Nujol): vmaks = 1715, 1660, 1620 cm"<1>. 45) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-6-metoksy-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 224-226°C. IR-spektrum (Nujol): vmaks= 1740, 1690, 1640, 1500, 1480 cm"<1>.46) 2-[3-(4-brom-2-fluorbenzyl)-7-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 223-224°C. IR-spektrum (Nujol): vmaks= 1720, 1700, 1660, 1600 cm"<1>.47) 2-[3-(4-brom-2-fluorbenzyl)-6-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 238-239°C.
IR-spektrum (Nujol): vmaks= 1725, 1710 (skulder), 1665,
1605 cm"<1.>48) 2-[2-(3,4-diklorbenzyl)-3,4-dihydro-3-okso-2H-l,2,4-benzotiadiazin-4-yl]eddiksyre-l,i-dioksyd, smeltepunkt 190°C. IR-spektrum (Nujol) : vmaks= 1720, 1690, 1665 cm"<1>. 49) 2-[3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 217°C.
IR-spektrum (Nujol): vmaks= 1765, 1705, 1645, 1605, 1480 cm"<1>. 50) 2-[3-(4-klor-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 215°C. IR-spektrum (Nujol) : vmaks= 1730, 1710, 1665, 1630, 1610, 1480cm"<1>.51)2-[3-(4-brom-3-klorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 233-234°C.
IR-spektrum (Nujol): vmaks= 1695, 1680, 1600, 1470 cm"<1>.
52) 2-[3-(2,3-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 212°C.
IR-spektrum (Nujol) : vmaks= 1720, 1700, 1660, 1600, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,93 (2H, s) , 5,27 (2H, s) , 6,83-8,23 (7H, m). 53) 2-[l,2,3,4-tetrahydro-3-(4-metylbenzyl)-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 223-224°C. IR-spektrum (Nujol): vmaks= 1725, 1700, 1655, 1605, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 2,27 (3H, s) , 4,88 (2H, s) , 5,10 (2H, s), 6,97-8,20 (8H, m).54) 2-[3-(4-klor-2-metoksybenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 184°C. IR-spektrum (Nujol) : vmaks= 1725, 1700, 1650, 1610 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 3,81 (3H, s) , 4,92 (2H, s) , 5,18 (2H, s), 6,78-8,18 (7H, m). 55) 2-[3-(3-klor-4-metoksybenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 198°C. IR-spektrum (Nujol): vmaks= 1740, 1695, 1640, 1605 cm"<1>. 56) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-8-metoksy-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 204-206°C. IR-spektrum (Nujol) : vmaks= 1730, 1700, 1660, 1600 cm"<1>. 57) 2-[1,2,3,4-tetrahydro-2,4-diokso-3-(2-
tienylmetyl)kinazolin-l-yl]eddiksyre, smeltepunkt 248-250°C (dekomponering).
IR-spektrum (Nujol) : vmaks= 1725, 1700, 1655, 1605 cm"<1>.
58) 2-[l,2,3,4-tetrahydro-3-(2-naftylmetyl)-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 183-185°C. 59) 2-[3-(4-brom-2-fluorbenzyl)-5-klor-l,2,3,4-tetrahydro-2 , 4-dioksokinazolin-l-yl] eddiksyre," smeltepunkt 217-218°C. IR-spektrum (Nujol): vmaks = 1725, 1710, 1660, 1590 cm"<1>. 60) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-5-metoksy-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 253-255°C. IR-spektrum (Nujol) : vmaks= 1735, 1700, 1640, 1600 cm"<1>.
EKSEMPEL 2
1) Til en suspensjon av natriumhydrid (60% mineralolje,
367 mg) i N,N-dimetylformamid (15 ml) ble det under omrøring satt en oppløsning av etyl 2-(l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl)acetat (2,0 g) i N,N-dimetylformamid (35 ml) ved romtemperatur under en nitrogenatmosfære og blandingen ble omrørt ved denne temperatur i 15 minutter. Til denne blanding ble det under omrøring satt 4-klorbenzylklorid (1,48 g) ved romtemperatur og blandingen ble omrørt ved den nevnte temperatur i 1 time. Oppløsningsmidlet ble avdampet i vakuum, hvilket ga et residuum som ble oppløst i etylacetat. Etylacetatoppløsningen ble vasket med vann og tørket. Avdampning av oppløsningsmidlet ga et residuum som ble vasket med n-heksan, hvilket ga etyl 2-[3-(4-klorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (2,55 g), smeltepunkt 137°C.
IR-spektrum (Nujol): vmaks = 1730, 1700, 1670/ 1605, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 4,20 (2H, q, J=7Hz), 5,00 (2H, s), 5,13 (2H, s), 7,17-8,23 (8H, m) .
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med EKSEMPEL 2-1). 2) Etyl 2-[3-(2,6-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 182-183°C. IR-spektrum (Nujol): vmaks= 1745, 1720, 1680, 1610, 1480 cm"<1>. NMR-spektrum (DMSO-d6) : S (ppm) = 1,17 (3H, t, J=7Hz) , 4,15 (2H, q, J=7Hz), 4,93 (2H, s), 5,40 (2H, s), 7,17-8,17 (7H, m). 3) Etyl 2-[3-(3,5-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 122-123°C. IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1600, 1570,
1480 cm"<1>.
NMR-spektrum (DMSO-d6) : S (ppm) = 1,22 (3H, t, J=7Hz), 4,18 (2H, q, J=7Hz), 5,00 (2H, s), 5,17 (2H, s), 7,15-8,23 (7H, m). 4) Etyl 2-[3-(2,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat.
IR-spektrum (Nujol): vmaks= 1730, 1710, 1660, 1610 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 4,17 (2H, q, J=7Hz), 5,00 (2H, s), 5,20 (2H, s), 7,02-8,18 (7H, m). 5) Etyl 2-[3-(2,5-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat.
IR-spektrum (Nujol): vmaks= 1740, 1705, 1660, 1605 cm"<1>. NMR-spektrum (DMSO-d6) : S (ppm) = 1,21 (3H, t, J=7Hz) , 4,18 (2H, q, J=7Hz), 5,00 (2H, s.) , 5,20 (2H, s) , 7,06-8,17 (7H, m) . 6) Etyl 2-[l,2,3,4-tetrahydro-3-(4-metoksybenzyl)-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 135°C.
IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1600, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 3,72 (3H, s), 4,23 (2H, q, J=7Hz), 5,00 (2H, s), 5,10 (2H, s), 6,85 (2H, d, J=9Hz), 7,30 (2H, d, J=9Hz), 7,17-8,20 (4H, m). 7) Etyl 2-[l,2,3,4-tetrahydro-3-(l-naftylmetyl)-2,4-diokso-kinazolin-l-yl] acetat, smeltepunkt 164-167°C.
IR-spektrum (Nujol): vmaks= 1745, 1700, 1660, 1605 cm"<1>. NMR-spektrum (CDC13) : S (ppm) = 1,25 (3H, t, J=7Hz) , 4,23 (2H, q, J=7Hz), 4,90 (2H, s), 5,80 (2H, s), 6,90-8,43 (11H, m). 8) Etyl 2-[l,2,3,4-tetrahydro-2,4-diokso-3-(2-pyridylmetyl)-kinazolin-l-yl]acetat, smeltepunkt 141-143°C.
IR-spektrum (Nujol): vmaks= 1740, 1700, 1650, 1610 cm"<1>. NMR-spektrum (CDC13) : S (ppm) = 1,25 (3H, t, J=7Hz) , 4,23 (2H, q, J=7Hz), 4,90 (2H, s), 5,43 (2H, s), 6,93-8,67 (8H, m).
9) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-7-metoksy-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1690, 1650, 1610 cm"<1>.
NMR-spektrum (DMSO-d6) : 6- (ppm) = 1,20 (3H, t, J=7Hz) , 3,88 (3H, s), 4,14 (2H, q, J=7Hz), 4,97 (2H, s), 5,10 (2H, s), 6,83-8,05 (6H, m). 10) Etyl 2-[3-(4-brom-2-fluorbenzyl)-l,2,3,4-tetrahydro-6-metoksy-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 160-160,5°C.
IR-spektrum (Nujol): vmaks= 1725, 1700, 1655, 1500, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 3,88 (3H, s), 4,23 (2H, q, J=7Hz), 5,00 (2H, s), 5,20 (2H, s), 6,95-7,67 (6H, m). 11) Etyl 2-[3-(4-brom-2-fluorbenzyl)-6-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 146-147°C.
IR-spektrum (Nujol): vmaks= 1730, 1710, 1675, 1610 cm"<1>. NMR-spektrum (CDC13) : <S (ppm) = 1,27 (3H, t, J=7Hz) , 4,25 (2H, q, J=7Hz), 4,87 (2H, s), 5,30 (2H, s), 6,87-8,33 (6H, m). 12) Etyl 2-[3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 157°C.
IR-spektrum (Nujol): vmaks= 1750, 1705, 1670, 1610, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,22 (3H, t, J=7Hz) , 4,18 (2H, q, J=7Hz), 4,98 (2H, s), 5,15 (2H, s), 6,77-8,20 (7H, m). 13) Etyl 2-[3-(4-klor-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 144-145°C. IR-spektrum (Nujol): vmaks= 1730, 1705, 1660, 1610, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,18 (3H, t, J=7Hz) , 4,18 (2H, q, J=7Hz), 4,97 (2H, s), 5,17 (2H, s), 7,10-8,23 (7H, m). 14) Etyl 2-[3-(4-brom-3-klorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 128-129°C. IR-spektrum (Nujol): vmaks= 1735, 1700, 1660, 1600, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,22 (3H, t, J=7Hz) , 4,20 (2H, q, J=7Hz), 5,0 (2H, s), 5,13 (2H, s), 7,10-8,23 (7H, m). 15) Etyl 2-[3-(2,3-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 158-160°C. IR-spektrum (Nujol): vmaks= 1740, 1705, 1660, 1605, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : 6 (ppm) = 1,22 (3H, t, J=7Hz) , 4,20 (2H, q, J=7Hz), 5,02 (2H, s), 5,25 (2H, s), 6,88-8,22 (7H, m). 16) Etyl 2-[l,2,3,4-tetrahydro-3-(4-metylbenzyl)-2,4-diokso-
kinazoliii-l-yl]acetat, smeltepunkt 140-141°C.
IR-spektrum (Nujol): vmaks= 1735, 1700, 1660, 1605, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz), 2,30 (3H,S), 4,25 (2H, q, J=7Hz), 5,03 (2H, s), 5,17 (2H, s), 7,01-8,30 (8H, m).
17) Etyl 2-[3-(4-klor-3-metoksybenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1705, 1660, 1610 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 3,81 (3H, s), 4,16 (2H, q, J=7Hz), 4,98 (2H, s), 5,13 (2H, s), 6,77-8,13 (7H, m).
18)Etyl 2-[3-(3-klor-4-metoksybenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1605 cm"<1>. NMR-spektrum (DMS0-d6) : <S (ppm) = 1,21 (3H, t, J=7Hz) , 3,83 (3H, s), 4,21 (2H, q, J=7Hz), 5,00 (2H, s), 5,08 (2H, s), 6,98-8,18 (7H, m). 19) Etyl 2-[l,2,3,4-tetrahydro-2,4-diokso-3-(2-tienylmetyl)-kinazolin-l-yl]acetat, smeltepunkt 115-120°C.
IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1605 cm"<1>. NMR-spektrum (CDC13) : S (ppm) = 1,25 (3H, t, J=7Hz) , 4,23 (2H, q, J=7Hz), 4,88 (2H, s), 5,42 (2H, s), 6,82-8,40 (7H, m). 20) Etyl 2-[1,2,3,4-tetrahydro-2,4-diokso-3-(2-naftylmetyl)-kinazolin-l-yl]acetat, smeltepunkt 149-150°C.
NMR-spektrum (CDC13) : 6 (ppm) = 1,23 (3H, t, J=7Hz) , 4,22 (2H, q, J=7Hz), 4,87 (2H, s) , 5,43 (2H, s) , 6,87-8,40 (UH, m) .21)Etyl 2-[3-(4-brom-2-fluorbenzyl)-5-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 186-187°C.
IR-spektrum (Nujol): vmaks= 1740, 1710, 1670, 1590 cm"<1>.
22) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-5-metoksy-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 166-168°C. IR-spektrum (Nujol) : vmaks= 1735, 1710, 1665, 1600, 1580 cm"<1>. 23) Etyl 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 121-122°C. IR-spektrum (Nujol) : vmaks= 1725, 1700, 1665, 1605 cm"<1>.24) Etyl 2-[3-(4-brom-2-fluorbenzyl)-l,2,3,4-tetrahydro-2,4- dioksokinazolin-l-yl]acetat, smeltepunkt 153-154°C. IR-spektrum (Nujol): vmaks= 1735, 1715, 1665, 1605 cm"<1>.
25) Etyl 2-[3-benzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl] acetat
IR-spektrum (Nujol): vmaks= 1740, 1700, 1660, 1650 cm"<1>.
26) Etyl 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]propionat, smeltepunkt 130-131°C. IR-spektrum (Nujol): vmaks= 1735, 1700, 1655, 1605 cm"<1>. 27) Etyl 2-[3-(3,4-diklorbenzyl)-l,2,3,4-tetrahydro-2-okso-4-tioksokinazolin-l-yl]acetat, smeltepunkt 157-158°C. IR-spektrum (Nujol) : vmaks= 1740, 1690, 1605, 1590 cm"<1>. 28) Etyl 2-[3-(3,4-diklorbenzyl)-3,4-dihydro-3-okso-2H-l,2,4-benzotiadiazin-4-yl]acetat-1,1-dioksyd
IR-spektrum (CHC13) : vmalcs=1740, 1690, 1600 cm"<1>.
29) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-8-metoksy-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1755, 1745, 1700, 1660, 1600 cm"<1>.
EKSEMPEL 3
1) En blanding av etyl 2-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl)acetat (1,2 g) og vandig IN natriumhydroksyd (3 ml) i metanol (25 ml) ble tilbakeløpsbehandlet i 1 time. Etter avkjøling ble oppløsningsmidlet fjernet under redusert trykk, hvilket ga et residuum som ble surgjort med vandig IN saltsyre og ekstrahert med etylacetat. Ekstrakten ble vasket med saltoppløsning, tørket og inndampet. Det således oppnådde produkt ble renset ved omkrystallisasjon fra isopropyleter, hvilket ga 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre (1,075 g), smeltepunkt 225-227°C.
IR-spektrum (Nujol) : vmaks = 1695, 1650, 1600 cm"<1>. NMR-spektrum (DMS0-d6) : <S (ppm) = 4,88 (2H, s) , 5,13 (2H, s) , 7,17-8,20 (7H, m).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med EKSEMPEL 3-1). 2) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 2 08-210°C. IR-spektrum (Nujol) : vmaks= 1730, 1700, 1660, 1610 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,90 (2H, s) , 5,17 (2H, s),6,9-8,1 (7H, m). 3) 2-[3-benzyl-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]-eddiksyre, smeltepunkt 222-223°C. IR-spektrum (Nujol): vmaks= 1725, 1700, 1655, 1605, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,87 (2H, s) , 5,15 (2H, s) , 7,17-8,23 (9H, m), 4) 2-[3-(3,4-diklorfenyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 268°C.
IR-spektrum (Nujol): vmaks= 1730, 1720, 1670, 1640, 1610 cm"<1>. NMR-spektrum (DMS0-d6) : 5 (ppm) = 4,88 (2H, s) , 7,18-8,17 (7H, m) . 5) 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl ]propionsyre, smeltepunkt 93°C.
IR-spektrum (Nujol) : vmaks = 1700, 1655, 1605 cm"<1>. NMR-spektrum (CDC13) : S (ppm) = 1,70 (3H, d, J=7Hz) , 5,15 (2H, s), 5,38 (1H, q, J=7Hz), 7,00-8,37 (7H, m). 6) 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2-okso-4-tioksokinazolin-l-yl]eddiksyre, smeltepunkt 253,5-254,5°C. IR-spektrum (Nujol): vmaks= 1705, 1680, 1660, 1600, 1585 cm"<1>. NMR-spektrum (DMS0-d6) : 5 (ppm) = 4,95 (2H, s) , 5,80 (2H, s) , 7,20-8,70 (7H, m).7) 2-[3-(4-klorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 229-230°C. IR-spektrum (Nujol): vmaks= 1725, 1705, 1660, 1600, 1480 cm"<1.>NMR-spektrum (DMS0-d6) : S (ppm) = 4,90 (2H, s) , 5,13 (2H, s) , 7,23-8,23 (8H, m). 8) 2-[3-(2,6-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 273-275°C.
IR-spektrum (Nujol): vmaks= 1720, 1660, 1605, 1475 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,85 (2H, s) , 5,40 (2H, s) , 7,07-8,13 (7H, m).9) 2-[3-(3,5-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl ] eddiksyre, smeltepunkt 212-213°C.
IR-spektrum (Nujol): vmal;s= 1740, 1720, 1690, 1635, 1605, 1560, 1480 cm"<1>.
NMR-spektrum (DMSO-d6) : S (ppm) = 4,88 (2H, s), 5,13 (2H, s), 7,13-8,20 (7H, m). 10) 2-[3-(2,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 223°C.
IR-spektrum (Nujol) : vmaks= 1720, 1675, 1615 cm<-1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,90 (2H, s) , 5,18 (2H, s) , 7,00-8,15 (7H, m). 11) 2-[3-(2,5-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 207°C.
IR-spektrum (Nujol) : vmaks= 1710, 1665, 1605 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,90 (2H, s), 5,20 (2H, s), 7,09-8,17 (7H, s). 12) 2-[1,2,3,4-tetrahydro-3-(4-metoksybenzyl)-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 213-215°C.
IR-spektrum (Nujol): vmaks= 1720, 1700, 1660, 1600, 1480 cm"<1>. NMR-spektrum (DMSO-d6) : S (ppm) = 3,70 (3H, s) , 4,88 (2H, s) , 5,08 (2H,S), 6,90 (2H, d, J=6Hz), 7,30 (2H, d, J=6Hz), 7,22-8,22 (4H, m). 13) 2-[1,2,3,4-tetrahydro-3-(1-naftylmetyl)-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 216-218°C. IR-spektrum (Nujol): vmaks=1705, 1660, 1605 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,93 (2H, s) , 5,67 (2H, s) , 7,03-8,40 (UH, m) , 13,20 (1H, bred s) . 14) 2-[l,2,3,4-tetrahydro-2,4-diokso-3-(2-pyridylmetyl)kina-zolin-l-yl]eddiksyre, smeltepunkt 220-223°C.
IR-spektrum (Nujol) : vmaks= 1710, 1660, 1610 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,90 (2H, s) , 5,27 (2H, s) , 7.03- 8,55 (8H, m). 15) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-7-metoksy-2.4- dioksokinazolin-l-yl]eddiksyre, smeltepunkt 222-223°C. IR-spektrum (Nujol) : vmaks= 1715, 1660, 1620 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 3,88 (3H, s) , 4,88 (2H, s) , 5,12 (2H,S), 6,83-8,07 (6H, m). 16) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-6-metoksy-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 224-226°C. IR-spektrum (Nujol): vmaks= 1740, 1690, 1640, 1500, 1480 cm"<1>. NMR-spektrum (DMSO-d6) : S (ppm) = 3,83 (3H, s), 4,87 (2H, s), 5,17 (2H, s), 6,87-7,73 (6H, m) . 17)2-[3-(4-brom-2-fluorbenzyl)-6-klor-l,2,3,4-tetrahydro-2.4- dioksokinazolin-l-yl]eddiksyre, smeltepunkt 238-239°C. IR-spektrum (Nujol): vmaks= 1725, 1710 (skulder), 1665,
1605 cm"<1>
NMR-spektrum (DMS0-d6) : S (ppm) = 4,88 (2H, s) , 5,15 (2H, s) , 7.05- 8,12 (6H, m).18) 2-[2-(3,4-diklorbenzyl)-3,4-dihydro-3-okso-2H-l, 2,4-benzotiadiazin-4-yl]eddiksyre-l,1-dioksyd, smeltepunkt 190°C. IR-spektrum (Nujol) : vmaks= 1720, 1690, 1660 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 3,98 (2H, s), 4,90 (2H, s), 7,20-8,07 (7H, m). 19) 2-[3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl ] eddiksyre, smeltepunkt 217°C.
IR-spektrum (Nujol): vmaks= 1765, 1705, 1645, 1605, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,87 (2H, s), 5,13 (2H, s), 6,77-8,23 (7H, m).20)2-[3-(4-klor-2-fluorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 215°C. IR-spektrum (Nujol): vmaks= 1730, 1710, 1665, 1630, 1610,
1480 cm"<1.>
NMR-spektrum (DMS0-d6) : S (ppm) = 4,88 (2H, s), 5,18 (2H, s), 7,12-8,22 (7H, m). 21)2-[3-(4-brom-3-klorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 233-234°C.
IR-spektrum (Nujol): vmaks= 1695, 1680, 1600, 1470 cm"<1>. NMR-spektrum (DMS0-d6) : 6* (ppm) = 4,93 (2H, s), 5,17 (2H, s) , 7,05-8,25 (7H, m). 22) 2-[3-(2,3-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] eddiksyre, smeltepunkt 212°C.
IR-spektrum (Nujol): vmaks= 1720, 1700, 1660, 1600, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,93 (2H, s), 5,27 (2H, s), 6,83-8,23 (7H, m). 23)2-[l,2,3,4-tetrahydro-3-(4-metylbenzyl)-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 223-224°C. IR-spektrum (Nujol): vmaks= 1725, 1700, 1655, 1605, 1480 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 2,27 (3H, s), 4,88 (2H, s), 5,10 (2H, s), 6,97-8,20 (8H, m) . 24) 2-[3-(4-klor-3-metoksybenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 184°C. IR-spektrum (Nujol) : vmaks= 1725, 1700, 1650, 1610 cm"<1>. NMR-spektrum (DMS0-d6) : 6 (ppm) = 3,81 (3H, s), 4,92 (2H, s), 5,18 (2H, s) , 6,78-8,18 (7H, m) . 25) 2-[3-(3-klor-4-metoksybenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 198°C. IR-spektrum (Nujol): vmaks= 1740, 1695, 1640, 1605 cm"<1.>NMR-spektrum (DMSO-d6) : S (ppm) = 3,83 (3H, s) , 4,90 (2H, s) , 5,08 (2H, s), 6,99-8,15 (7H, m). 26) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-8-metoksy-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 204-206°C. IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1600 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 3,83 (3H, s) , 5,00 (2H, s) , 5,15 (2H, s), 7,13-7,80 (6H, m). 27) 2-[1,2,3,4-tetrahydro-2,4-diokso-3-(2-tienylmetyl)kinazolin-l-yl]eddiksyre, smeltepunkt 248-250°C (dekomponering).
IR-spektrum (Nujol): vmaks= 1725, 1700, 1655, 1605 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,88 (2H, s) , 5,28 (2H, s) , 6,87-8,23 (7H, m) , 12,67 (1H, bred s). 28) 2-[l,2,3,4-tetrahydro-3-(2-na ftylmety1)-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 183-185°C. NMR-spektrum (DMS0-d6) : S (ppm) = 4,92 (2H, s) , 5,33 (2H, s) , 7,23-8,23 (11H, m). 29) 2-[3-(4-brom-2-fluorbenzyl)-5-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 217-218°C. IR-spektrum (Nujol): vmaks= 1725, 1710, 1660, 1590 cm"<1>. 30) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-5-metoksy-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 253-255°C. IR-spektrum (Nujol): vmaks= 1735, 1700, 1640, 1600 cm"<1.>NMR-spektrum (DMSO-d6) : <S (ppm) = 3,83 (3H, s) , 4,83 (2H, s) , 5,08 (2H, s), 6,80-7,80 (6H, m).
EKSEMPEL 4
Til en oppløsning av etyl 2-(7-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl)acetat (176 g) i N,N-dimetylformamid (3,5 liter) ble det satt natriumhydrid (60% i mineralolje,32,3 g) ved 0°C og blandingen ble omrørt ved romtemperatur i 4 timer. Til reaksjonsblandingen ble det satt en oppløsning av 4-brom-2-fluorbenzylbromid (200 g) i N,N-dimetylformamid (100 ml) ved en temperatur under 20°C over en 20 minutters periode, og den dannede blanding ble omrørt ved romtemperatur i 1 time. 3N vandig saltsyre (62,2 ml) ble satt til blandingen ved en temperatur under 15°C, og oppløsningsmidlet ble avdampet i vakuum. Residuet ble helt i en blanding av etylacetat (3 liter) og vann (3 liter) og den dannede blanding ble omrørt i15minutter. Bunnfallet ble frafiltrert og den organiske fase fraskilt. Oppløsningen ble vasket med saltoppløsning, tørket over magnesiumsulfat og inndampet i vakuum. Residuet ble krystallisert ved tilsetning av isopropyleter og krystallene ble oppsamlet ved filtrering og vasket med isopropyleter. De rå krystallene og bunnfallet ble blandet og omkrystallisert fra en blanding av etylacetat (0,9 liter) og n-heksan (0,9 liter), hvilket ga etyl 2-[3-(4-brom-2-fluorbenzyl)-7-klor-1, 2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (251 g). IR-spektrum (Nujol): vmaks= 1740, 1720, 1680, 1610, 1580 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 4,17 (2H, q, J=7HZ), 4,98 (2H, s), 5,13 (2H, s), 7,07-8,15 (6H, m).
EKSEMPEL 5
En blanding av etyl 2-[3-(4-brom-2-fluorbenzyl)-7-klor-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (249 g) og IN vandig natriumhydroksyd (795 ml) i metanol (1,6 liter) ble tilbakeløpsbehandlet i 3 0 minutter under omrøring. Oppløsningsmidlet ble avdampet og residuet ble oppløst i varmt vann (5 liter). Den vandige oppløsning ble helt i iskald 0,5N saltsyre (3 liter). Bunnfallet ble oppsamlet ved filtrering og omkrystallisert fra en blanding av etanol (6 liter) og vann (3 liter), hvilket ga 2-[3-(4-brom-2-fluorbenzyl)-7-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre (198 g),
smeltepunkt 223-224°C.
IR-spektrum (Nujol): vmaks= 1720, 1700, 1660, 1600 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,88 (2H, s) , 5,12 (2H, s) , 7,05-8,12 (6H, m).
EKSEMPEL 6
1) En oppløsning av 3-(4-brom-2-fluorbenzyl)-7-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin (500 mg), etylbromacetat (218 mg) og kaliumkarbonat (360 mg) i N,N-dimetylformamid (5 ml) ble omrørt ved 30°C i 30 minutter. Oppløsningen ble inndampet og residuet ble oppløst i etylacetat. Oppløsningen ble vasket suksessivt med 0,5N vandig saltsyre og vann og deretter tørket over magnesiumsulfat. Oppløsningsmidlet b'le fjernet under vakuum, hvilket ga et krystallinsk residuum som ble krystalllisert fra en blanding av etylacetat og n-heksan, hvilket ga etyl 2-[3-(4-brom-2-fluorbenzyl)-7-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (550 mg). IR-spektrum (Nujol): vmaks= 1740, 1720, 1680, 1610, 1580 cm"<1>.
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med EKSEMPEL 6-1).
2) Etyl 2-[7-fluor-3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1730, 1710, 1680, 1625, 1600,
1570cm"1.
NMR-spektrum (DMS0-d6) : 6* (ppm) = 1,2 (3H, t, J=7,0Hz), 4,2 (2H, q, J=7,0Hz), 5,0 (2H, s), 5,1 (2H, s), 7,0 (1H, dd, J=8, 8Hz), 7,2 (1H, dd, J=8, 8Hz), 7,5-7,7 (3H, m), 8,1 (1H, dd, J=6, 8Hz).
EKSEMPEL 7
1) Til en oppløsning av 7-brom-3-(4-brom-2-fluorbenzyl)-2,4-dioksokinazolin (2,80 g) i N,N-dimetylformamid (56 ml) ble det under omrøring satt natriumhydrid (60% i mineralolje, 334 mg) ved 0°C under en nitrogenatmosfære, bg blandingen ble omrørt ved romtemperatur i 1 time. Til denne blanding ble det dråpevis satt etylbromacetat (0,85 ml) og blandingen ble omrørt ved romtemperatur i 2 timer. Oppløsningsmidlet ble fjernet under redusert trykk, hvilket ga et residuum som ble helt i vann og ekstrahert med etylacetat. Ekstrakten ble vasket med vann og tørket. Fjerning av oppløsningsmidlet etterfulgt av omkrystallisasjon fra isopropyleter ga etyl 2-[7-brom-3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (3,11 g), smeltepunkt 163-164°C. IR-spektrum (Nujol): vmaks= 1740, 1710, 1675, 1600, 1580, 1490 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 4,16 (2H, q, J=7Hz), 4,98 (2H, s), 5,13 (2H, s), 7,14 (1H, dd, J=8, 8HZ), 7,35 (1H, d, J=8Hz), 7,52-7,57 (2H, m), 7,83 (1H, s), 7,99 (1H, d, J=8HZ).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med EKSEMPEL 7-1). 2) Etyl 2-[3-(4-brom-2-fluorbenzyl)-8-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 83-85°C.
IR-spektrum (Nujol): vmaks= 1735, 1710, 1660, 1595 cm"<1>. NMR-spektrum (CDC13) : S (ppm) = 1,25 (3H, t, J=7Hz) , 4,25 (2H, q, J=7Hz), 5,25 (2H, s), 5,27 (2H, s) , 7,10-8,33 (6H, m) .3) Etyl 2-[7-klor-3-(4-klor-3-(trifluormetyl)benzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 13 3-134°C.
IR-spektrum (Nujol): vmaks= 1730, 1700, 1650, 1600 cm"<1>. NMR-spektrum (DMS0-d6) : <S (ppm) = 1,20 (3H, t, J=7Hz), 4,20 (2H, q, J=7HZ), 4,98 (2H, s), 5,18 (2H, s), 7,23-8,20 (6H, m).4) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-7-jod-dioksokinazolin-l-yl]acetat, smeltepunkt 169-169,5°C. IR-spektrum (Nujol): vmaks= 1740, 1710, 1675, 1595, 1575, 1490 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 4,17 (2H, q, J=7Hz), 4,97 (2H, s), 5,12 (2H, s), 7,13 (1H, dd, J=8, 8Hz), 7,34 (1H, d, J=8Hz), 7,55 (1H, d, J=8Hz), 7,75 (2H, m), 7,92 (1H, s). 5)Etyl 2-[3-(4-brom-2-fluorbenzyl)-7-fluor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 144-145°C.
IR-spektrum (Nujol): vmaks=1700, 1660, 1600, 1370 cm"<1>. NMR-spektrum (DMS0-d6) : 6 (ppm) = 1,20 (3H, t, J=7Hz) , 4,16 (2H, q, J=7Hz), 4,96 (2H, s), 5,14 (2H, s), 7,10-7,58 (5H, m), 8,16 (1H, dd, J=7, 7Hz). 6) Etyl 2-[3-(4-brom-2-fluorbenzyl)-7-trifluormetyl-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 150-152°C.
IR-spektrum (Nujol): vmaks = 1700, 1660, 1600, 1370, 1260 cm"<1>. 7) Etyl 2-[7-brom-3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 183-184°C.
IR-spektrum (Nujol): vmaks = 1735, 1710, 1670 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 4,17 (2H, q, J=7Hz), 4,98 (2H, s), 5,11 (2H, s), 6,96 (1H, t, J=8Hz), 7,51 (2H, t, J=8HZ), 7,64 (1H, d, J=10Hz), 7,82 (1H, s), 7,99 (1H, d, J=8Hz). 8) Etyl 2-[3-(2-fluor-4-jodbenzyl)-7-jod-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 184-185°C. IR-spektrum (Nujol): vmaks= 1740, 1715, 1670, 1600, 720 cm"<1.>NMR-spektrum (DMS0-d6) : S (ppm) = 1,2 (3H, t, J=7Hz) , 4,2 (2H, q, J=7Hz), 5,0 (2H, s), 5,1 (2H, s), 7,0 (1H, t, J=8Hz), 7,5-8,3 (5H, m). 9) Etyl 2-[3-(4-brom-2-fluorbenzyl)-6,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat.
IR-spektrum (Nujol): vmais= 1730, 1710, 1675, 1575, 1490 cm"<1>.
10) Etyl 2-[3-(4-brom-2-fluorbenzyl)-5,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1730, 1720, 1680, 1595, 1570 cm"<1.>11) Etyl 2-[7-klor-3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat.
IR-spektrum (Nujol): vmaks= 1740, 1715, 1675, 1610 cm"<1.>
12) Etyl 2-[3-(7-klor-3-(2-fluor-3-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol):<v>raaks=1750, 1720, 1660, 1610 cm"<1>.
13) Etyl 2-[7-klor-3-(3-klor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat.
IR-spektrum (Nujol): vmaks= 1735, 1710, 1670, 1605, 1580 cm"<1.>14) Etyl 2-[7-klor-3-{3,5-bis(trifluormetyl)benzyl}-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat.
IR-spektrum (Nujol) : vmaks= 1735, 1710, 1665, 1610, 1580 cm"<1>. 15) Etyl 2-[6,7-diklor-3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 225-226°C. IR-spektrum (Nujol): vmaks= 1725, 1710, 1675, 1605, 1575 cm"<1>. 16) Natrium 2-[3-(4-brom-2-fluorbenzyl)-7-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt >3 00°C. IR-spektrum (Nujol): vmaks= 3500, 1705, 1670, 1610 cm"<1>. 17) 2-[7-brom-3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre.
IR-spektrum (Nujol) : vmaks= 1725, 1710, 1660, 1600, 1580,
1490cm"<1>.
18) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-7-jod-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol): vmaks= 1710, 1670, 1600, 1580, 1490 cm"<1>.
19) 2-[3-(4-brom-2-fluorbenzyl)-7-fluor-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol) : vmaks= 1710, 1660, 1580, 1360 cm"<1>.
20) 2-[7-klor-3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol): vmaks= 1730, 1710, 1670, 1610 cm"<1>.
21) 2-[7-klor-3-(2-fluor-3-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol): vmaks= 1720, 1700, 1660, 1600 cm"<1>.
22) 2-[7-klor-3-(3-klor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol): vmaks= 1725, 1710, 1665, 1605, 1580 cm"<1>.
23) 2-[7-klor-3-{4-klor-3-(trifluormetyl)benzyl}-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol): vmaks= 1720, 1705, 1660, 1600, 1575 cm"<1>.
24) 2-[7-klor-{3,5-bis(trifluormetyl)benzyl}-1,2 , 3 , 4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol): vmaks= 1740, 1700, 1650, 1605, 1590 cm"<1>.
25) 2-[3-(4-brom-2-fluorbenzyl)-8-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol): vmaks= 1730, 1710, 1670, 1605 (skulder), 1595 cm"<1>.
26) 2-[3-(4-brom-2-fluorbenzyl)-6,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol): vmaks= 1720, 1675, 1600, 1570, 1485 cm"<1>.
27) 2-[3-(4-brom-2-fluorbenzyl)-5,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol): vmaks= 3250, 1730, 1710, 1670, 1665 (skulder), 1605, 1590, 1570cm"<1>.
28) 2-[3-(4-brom-2-fluorbenzyl)-7-trifluormetyl-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre
IR-spektrum (Nujol): vmaks= 1700, 1660, 1580, 1360 cm"<1>.
29) 2-[6,7-diklor-3-(2-fluor-4-j odbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 255-257°C. IR-spektrum (Nujol): vmaks= 1725 (skulder), 1710, 1675, 1600, 1570cm"<1>.30) 2-[7-brom-3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 252-253°C. IR-spektrum (Nujol): vmaks= 1715, 1675, 1600 cm"<1>. 31) 2-[7-fluor-3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 214-215°C. IR-spektrum (Nujol): vmaks= 3480, 1710, 1660, 1620, 1600 cm"<1>. 32) 2-[3-(2-fluor-4-jodbenzyl)-7-jod-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 279-281°C. IR-spektrum (Nujol): vmaks= 1715, 1680, 1600, 1340, 1260, 84 0 cm"<1>. 33) 2-[3-benzyl-l,2,3,4-tetrahydro-4-okso-2-tioksokinazolin-1-yl]eddiksyre, smeltepunkt 194-197°C.
IR-spektrum (Nujol) : vmaks = 1720, 1700 cm"<1>.
34) 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-4-okso-2-tioksokinazolin-l-yl]eddiksyre, smeltepunkt 105-110°C. IR-spektrum (CHC13) : vmaks = 1700 cm"<1>. 35) Etyl 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diti-oksokinazolin-l-yl]acetat, smeltepunkt 155-156°C.
IR-spektrum (Nujol) : vmaks = 1725 cm"<1>.
36) 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-ditiokso-kinazolin-l-yl]acetat, smeltepunkt 222-223°C (dekomponering). IR-spektrum (Nujol) : vmaks = 1710, 1685 cm"<1>
EKSEMPEL 8
1) Til en suspensjon av etyl 2-(6,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (2,0 g) i N,N-dimetylformamid (50 ml) ble det under omrøring satt natriumhydrid (60% i mineralolje, 288 mg) ved romtemperatur og blandingen ble omrørt ved denne temperatur i 1 time. Til denne blanding ble det under omrøring satt 4-brom-2-fluorbenzylbromid (1,93 g) ved romtemperatur, og blandingen ble omrørt ved denne temperatur i 2 timer. Oppløsningsmidlet ble fjernet, hvilket ga et residuum som ble helt i vann. De dannede bunnfall ble oppsamlet ved filtrering og vasket med n-heksan, hvilket ga etyl 2-[3-(4-brom-2-fluorbenzyl)-6,7-diklor-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (2,94 g), smeltepunkt 220-221°C.
IR-spektrum (Nujol): vmaks= 1730, 1710, 1675, 1575, 1490 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 1,20 (3H, t, J=7Hz) , 4,16 (2H, q, J=7Hz), 4,97 (2H, s), 5,12 (2H, s), 7,16 (1H, dd, J=8, 8Hz) , 7,34 (1H, d, J=8Hz), 7,55 (1H, d, J=8Hz), 7,97 (1H, s) , 8,19 (1H, s).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med EKSEMPEL 8-1).2) Etyl 2-[3-(4-brom-2-fluorbenzyl)-5,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 172-173°C.
IR-spektrum (Nujol): vmaks= 1730, 1720, 1680, 1595, 1570 cm"<1>. NMR-spektrum (CDC13) : S (ppm) = 1,30 (3H, t, J=7Hz) , 4,28 (2H, q, J=7HZ), 4,86 (2H, s), 5,26 (2H, s), 6,87-7,33 (5H, m) .3) Etyl 2-[7-klor-3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 178-179°C.
IR-spektrum (Nujol): vmaks= 1740, 1715, 1675, 1610 cm"<1>. NMR-spektrum (CDC13) : <S (ppm) = 1,29 (3H, t, J=7Hz) , 4,27 (2H, q, J=7HZ), 4,85 (2H, s) , 5,28 (2H, s) , 6,97-8,20 (6H, m) . 4) Etyl 2-[7-klor-3-(2-fluor-3-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 140-141°C.
IR-spektrum (Nujol) : vmaks= 1750, 1720, 1660, 1610 cm"<1>.
5) Etyl 2-[7-klor-3-(3-klor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 144-145°c. IR-spektrum (Nujol): vmaks= 1735, 1710, 1670, 1605, 1580 cm"<1>. 6) Etyl 2-[7-klor-3-{3,5-bis(trifluormetyl)benzyl}-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 111-112°C.
IR-spektrum (Nujol): vmaks= 1735, 1710, 1665, 1610, 1580 cm"<1>. 7)Etyl 2-[6,7-diklor-3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 225-226°C. IR-spektrum (Nujol): vmaks= 1725, 1710, 1675, 1605, 1575 cm"<1.>NMR-spektrum (DMS0-d6) : S (ppm) = 1,19 (3H, t, J=7Hz) , 4,16 (2H, q, J=7Hz), 4,97 (2H, s), 5,11 (2H, s), 6,90-7,75 (3H, m) , 7,96 (1H, s), 8,19 (1H, s). 8)Etyl 2-[7-brom-3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1710, 1675, 1600, 1580,
1490 cm"<1.>
9) Etyl 2-[3-(4-brom-2-fluorbenzyl)-8-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol) : vmaks= 1735, 1710, 1660, 1595 cm"<1>.
10)Etyl 2-[7-klor-3-{4-klor-3-(trifluormetyl)benzyl}-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat IR-spektrum (Nujol): vmaks= 1730, 1700, 1650, 1600 cm"<1>. 11)Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-7-j od-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1710, 1675, 1595, 1575,
149 0 cm"<1.>
12) Etyl 2-[3-(4-brom-2-fluorbenzyl)-7-fluor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol) : vmaks= 1700, 1660, 1600, 1370 cm"<1>.
13)Etyl 2-[3-(4-brom-2-fluorbenzyl)-7-trifluormetyl-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1700, 1660, 1600, 1370, 1260 cm"<1>.
14) Etyl 2-[7-fluor-3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1730, 1710, 1680, 1625,1600,
1570 cm"<1.>15) Etyl 2-[7-brom-3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 183-184°C.
IR-spektrum (Nujol): vmaks = 1735, 1710, 1670 cm"<1>.
16) Etyl 2-[3-(2-fluor-4-jodbenzyl)-7-jod-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 184-185°C. IR-spektrum (Nujol): vmaks= 1740, 1715, 1670, 1600, 720 cm"<1>. 17) Etyl 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-diti-oksokinazolin-l-yl]acetat, smeltepunkt 155-156°C.
IR-spektrum (Nujol) : vmaks = 1725 cm"1.
EKSEMPEL 9
En oppløsning av etyl 2-[3-(4-brom-2-fluorbenzyl)-7-klor-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (69 g) og IN vandig natriumhydroksyd (191 ml) i etanol (350 ml) ble omrørt ved 60°C i 3 timer. Etter avkjøling til 0°C ble bunnfallet oppsamlet ved filtrering, vasket med vann og tørket over fosforpentoksyd. Omkrystallisasjon fra vann (3 60 ml) ga natrium 2-[3-(4-brom-2-fluorbenzyl)-7-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (39,2 g), smeltepunkt >300°C. IR-spektrum (Nujol): vmais= 3500, 1705, 1670, 1610 cm"<1>. NMR-spektrum (D20) : S (ppm) =4,66 (2H, s) , 5,21 (2H, s) , 7,1-7,4 (6H, m), 8,04 (1H, d, J=9Hz).
EKSEMPEL 10
1) En oppløsning av etyl 2-[7-brom-3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (3,0 g) og IN vandig natriumhydroksyd (5,83 ml) i metanol (69,6 ml) ble tilbakeløpsbehandlet i 1 time under omrøring. Etter avkjøling ble oppløsningsmidlet avdampet, hvilket ga et residuum som ble surgjort med IN vandig saltsyre og ekstrahert med etylacetat. Ekstrakten ble vasket med saltoppløsning og tørket. Fjerning av oppløsningsmidlet ga et residuum som ble omkrystallisert fra en blanding av etylacetat og n-heksan, hvilket ga 2-[7-brom-3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre (2,36 g), smeltepunkt 217°C. IR-spektrum (Nujol) : vmaks= 1725, 1710, 1660, 1600, 1580,
1490 cm"1.
NMR-spektrum (DMSO-d6) : S (ppm) = 4,90 (2H, s) , 5,13 (2H, s) , 7,14 (1H, dd, J=8, 8HZ), 7,34 (1H, d, J=8Hz), 7,50-7,58 (2H, m) , 7,78 (1H, s) , 7,99 (1H, d, J=8Hz) .
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med EKSEMPEL 10-1). 2) 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-7-jod-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 251-252,5°C. IR-spektrum (Nujol): vraaks = 1710, 1670, 1600, 1580, 1490 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,89 (2H, s), 5,13 (2H, s), 7,13 (1H, dd, J=8, 8Hz), 7,34 (1H, d, J=8Hz), 7,55 (1H, d, J=8Hz), 7,75 (2H, m), 7,89 (1H, s). 3) 2-[3-(4-brom-2-fluorbenzyl)-7-fluor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 210-211°C. IR-spektrum (Nujol): vmaks= 1710, 1660, 1580, 1360 cm"<1.>NMR-spektrum (DMSO-d6) : S (ppm) = 3,50 (1H, bred s) , 4,87 (2H, s), 5,14 (2H, s), 7,10-7,56 (5H, m), 8,15 (1H, dd, J=6,6Hz, 7,5Hz). 4) 2-[7-klor-3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 232-233°C. IR-spektrum (Nujol): vmaks= 1730, 1710, 1670, 1610 cm"<1.>NMR-spektrum (DMSO-d6) : S (ppm) = 4,90 (2H, s), 5,12 (2H, s), 6,93-8,10 (6H, m). 5) 2-[7-klor-3-(2-fluor-3-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 165-167°C. IR-spektrum (Nujol) : vnaks = 1720, 1700, 1660, 1600 cm"<1>. 6) 2-[7-klor-3-(3-klor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 240°C. IR-spektrum (Nujol): vmaks= 1725, 1710, 1665, 1605, 1580 cm"<1.>7) 2-[7-klor-3-{4-klor-3-(trifluormetyl)benzyl}-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 212-213°C.
IR-spektrum (Nujol): vraaks=1720, 1705, 1660, 1600, 1575 cm"<1>. 8) 2-[7-klor-3-{3,5-bis(trifluormetyl)benzyl}-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 202-203°C.
IR-spektrum (Nujol): vmaks= 1740, 1700, 1650, 1605, 1590 cm"<1.>9) 2-[3-(4-brom-2-fluorbenzyl)-8-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 212-215°C. IR-spektrum (Nujol): vmaks= 1730, 1710, 1670, 1605 (skulder), 1595 cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 5,03 (2H, s) , 5,12 (2H, s) , 7,10-8,23 (6H, m). 10) 2- [ 3- (4-brom-2-f luorbenzyl) -6 ,~7-diklor-l ,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 255°C.
IR-spektrum (Nujol): vmaks= 1720, 1675, 1600, 1570, 1485 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,90 (2H, s) , 5,13 (2H, s) , 7,17 (1H, dd, J=8, 8Hz), 7,34 (1H, d, J=8Hz), 7,55 (1H, d, J=8Hz), 7,93 (1H, s), 8,19 (1H, s). 11) 2-[3-(4-brom-2-fluorbenzyl)-5,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 238-239°C.
IR-spektrum (Nujol): vmaks= 3250, 1730, 1710, 1670, 1665 (skulder), 1605, 1590, 1570 cm"<1>.
NMR-spektrum (DMS0-d6) : 5 (ppm) = 4,92 (2H, s) , 5,10 (2H, s) , 7,13-7,63 (5H, m). 12) 2-[3-(4-brom-2-fluorbenzyl)-7-trifluormetyl-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 230-231°C.
IR-spektrum (Nujol): vmaks= 1700, 1660, 1580, 1360 °m"<1>.
13) 2-[6,7-diklor-3(2-fluor-4-jodbenzyl)-1,2,3,4tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 255-257°C. IR-spektrum (Nujol): vmaks= 1725 (skulder), 1710, 1675, 1600, 1570cm"<1>.
NMR-spektrum (DMS0-d6) : S (ppm) = 4,90 (2H, s) , 5,12 (2H, s,), 6,90-7,70 (3H, m), 7,93 (1H, s), 8,18 (1H, s), 13,30 (1H, bred s) . 14) 2-[7-brom-3-(2-fluor-4-j odbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt 252-253°C. IR-spektrum (Nujol): vmaks= 1715, 1675, 1600 cm"<1>. NMR-spektrum (DMS0-d6) : S (ppm) = 4,90 (2H, s) , 5,12 (2H, s) , 6,96 (1H, t, J=8HZ), 7,50 (2H, t, J=8Hz), 7,64 (1H, d, J=10HZ), 7,78 (1H,S), 7,98 (1H, d, J=8Hz). 15) 2-[7-fluor-3-(2-fluor-4-j odbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre, smeltepunkt214-215°C. IR-spektrum (Nujol): vmaks= 3480, 1710, 1660, 1620, 1600 cm"<1>. NMR-spektrum (DMS0-d6) : 6* (ppm) = 4,9 (2H, s) , 5,1 (2H, s) , 7,0 (1H, dd, J=8, 8Hz), 7,2 (1H, dd, J=8, 8Hz), 7,4-7,7 (3H, m), 8,1 (1H, dd, J=7, 8Hz). 16) 2-[3-(2-fluor-4-jodbenzyl)-7-jbd-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yll]eddiksyre, smeltepunkt 279-281°C. IR-spektrum (Nujol): vmaks= 1715, 1680, 1600, 1340, 1260,
840 cm"<1>.
NMR-spektrum (DMS0-d6) : 8 (ppm) = 4,90 (2H, s) , 5,12 (2H, s) , 6,96 (1H, t, J=8Hz), 7,46-7,89 (5H, m).
EKSEMPEL 11
1) En blanding av etyl 2-[2-(N-benzylkarbamoyl)anilino]acetat (1,5 g) og N,N'-tiokarbonyldiimidazol (2,85 g) ble omrørt ved 120°C i 30 minutter. Etter avkjøling ble reaksjonsblandingen fortynnet med kloroform og kromatografert på silikagel. Eluering med kloroform ga etyl 2-(3-benzyl-l,2,3,4-tetrahydro-4-okso-2-tioksokinazolin-l-yl)acetat. En blanding av etyl 2-(3-benzyl-1,2, 3,4-tetrahydro-4-okso-2-tioksokinazolin-l-yl)acetat og IN natriumhydroksyd (2 ml) i metanol (10 ml) ble omrørt i 4 timer ved romtemperatur. Reaksjonsblandingen ble helt i fortynnet saltsyre og ekstrahert med kloroform. Ekstrakten ble vasket med saltoppløsning og tørket. Fjerning av oppløsningsmidlet ga 2-(3-benzyl-l,2,3,4-tetrahydro-4-okso-tioksokinazolin-l-yl)eddiksyre, (280 mg), smeltepunkt 194-197°C.
IR-spektrum (Nujol) : vmaks = 1720, 1700 cm"<1>.
NMR-spektrum (CD30D ): 6 (ppm) = 4,90 (2H, s) , 5,20 (2H, s) , 7,00-7,50 (9H, m).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med EKSEMPEL 11-1). 2) 2-[3-(3,4-diklorbenzy1)-1,2,3,4-tetrahydro-4-okso-2-tioksokinazolin-l-yl]eddiksyre, smeltepunkt 105-110°C. IR-spektrum (CHC13) :<v>maks = 1700 cm"<1>.
EKSEMPEL 12
1) En blanding av etyl 2-[2-{N-(3,4-diklorbenzyl)tiokarbamoyl)anilino]acetat (4,0 g) og N,N'-tiokarbonyldiimidazol (8,97 g) ble oppvarmet ved 120°C i 15 minutter og reaksjonsblandingen ble kromatografert på silikagel (100 g) under eluering med klorform. De fraksjoner som inneholdt den ønskede forbindelse ble samlet og konsentrert under vakuum. Residuet ble omkrystallisert fra en blanding av etylacetat og heksan, hvilket ga etyl 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-ditioksokinazolin-l-yl]-acetat (560 mg), smeltepunkt 155-156°C.
IR-spektrum (Nujol) : vmaks = 1725 cm"<1>.
NMR-spektrum (CDC13) : S (ppm) = 1,31 (3H, t, J=7Hz), 4,30 (2H, q, J=7Hz), 5,55 (2H, bred s), 6,53 (2H, s), 7,06-7,39 (5H, m), 7,71 (1H, dt, J=l,5, 8Hz), 8,71 (1H, dd, J=l,5, 8Hz).
De følgende forbindelser ble i det vesentlige oppnådd på samme måte som beskrevet i forbindelse med EKSEMPEL 12-1). 2) Etyl 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 121-122°C. IR-spektrum (Nujol):\>maks=1725, 1700, 1665, 1605 cm"<1>. 3) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 153-154°C. IR-spektrum (Nujol): vmaks= 1735, 1715, 1665, 1605 cm"<1>. 4) Etyl 2-[3-benzyl-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl] acetat
IR-spektrum (Nujol): vmaks= 1740, 1700, 1660, 1650 cm"<1.>
5) Etyl 2-[3-(3,4-diklorfenyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1710, 1665, 1605 cm"<1.>
6) Etyl 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]propionat, smeltepunkt 130-131°C. IR-spektrum (Nujol): vmaks= 1735, 1700, 1665, 1605 cm"<1>. 7) Etyl 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2-okso-4-tioksokinazolin-l-yl]acetat, smeltepunkt 157-158°C. IR-spektrum (Nujol): vmaks= 1740, 1690, 1605, 1590 cm"<1>. 8) Etyl 2-[2-(3,4-diklorbenzyl)-3,4-dihydro-3-okso-2H-l, 2,4-benzotiadiazin-4-yl]acetat-1,1-dioksyd.
IR-spektrum (CHC13) : vmaks = 1740, 1690, 1600 cm"<1>.
9) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-8-metoksy-2,4-dioksokinaz olin-1-yl]acetat.
IR-spektrum (Nujol): vmaks= 1755, 1745, 1700, 1660, 1600 cm"<1>. 10) Etyl 2-[3-(4-klorbenzyl)-1,2,3,4-tetrahydro-2,4-diokso-kinazolin-l-yl] acetat, smeltepunkt 137°C.
IR-spektrum (Nujol): vmaks= 1730, 1700, 1670, 1605, 1480 cm"<1>. 11) Etyl 2-[3-(2,6-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 182-183°C. IR-spektrum (Nujol): vmaks= 1745, 1720, 1680, 1610, 1480 cm"<1>. 12) Etyl 2-[3-(3,5-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 122-123°C. IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1600, 1570,
1480cm"<1>.
13) Etyl 2-[3-(2,4-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1730, 1710, 1660, 1610 cm"<1>.
14) Etyl 2-[3-(2,5-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1705, 1660, 1605 cm"<1>.
15) Etyl 2-[l,2,3,4-tetrahydro-3-(4-metoksybenzyl)-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 135°C.
IR-spektrum (Nujol) : vmalcs=1730, 1700, 1660, 1600, 1480 cm"<1>. 16) Etyl 2-[1,2,3,4-tetrahydro-3-(1-naftylmetyl)-2,4-diokso-kinazolin-l-yl] acetat, smeltepunkt 164-167°C.
IR-spektrum (Nujol) : vmaks= 1745, 1700, 1660, 1605 cm"<1>.
17) Etyl 2-[l,2,3,4-tetrahydro-2,4-diokso-3-(2-pyridylmetyl)-kinazolin-l-yl]acetat, smeltepunkt 141-143°C.
IR-spektrum (Nujol): vmaks= 1740, 1700, 1650, 1610 cm"<1>.
18) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-7-metoksy-2,4-dioksokinazolin-l-yl]acetat.
IR-spektrum (Nujol): vmaks= 1740, 1690, 1650, 1610 cm"<1>.
19) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-6-metoksy-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 160-160,5°C.
IR-spektrum (Nujol) : vmaks= 1725, 1700, 1655, 1500, 1480 cm"<1>.
20) Etyl 2-[3-(4-brom-2-fluorbenzyl)-6-klor-l,2,3,4- tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 146-147°C.
IR-spektrum (Nujol): vmaks= 1730, 1710, 1675, 1610 cm"<1>.
21) Etyl 2-[3-(2-fluor-4-jodbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 157°C.
IR-spektrum (Nujol): vmal:s = 1750, 1705, 1670, 1610, 1480 cm"<1>. 22) Etyl 2-[3-(4-klor-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 144-145°C. IR-spektrum (Nujol): vmaks= 1730, 1705, 1660, 1610, 1480 cm"<1>. 23) Etyl 2-[3-(4-brom-3-klorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 128-129°C. IR-spektrum (Nujol): vmaks= 1735, 1700, 1660, 1600, 1480 cm"<1>. 24) Etyl 2-[3-(2,3-diklorbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 158-160°C. IR-spektrum (Nujol): vmaks= 1740, 1705, 1660, 1605, 1480 cm"<1>. 25) Etyl 2-[1,2,3,4-tetrahydro-3-(4-metylbenzyl)-2,4-diokso-kinazolin-l-yl] acetat, smeltepunkt 140-141°C.
IR-spektrum (Nujol): vmaks= 1735, 1700, 1660, 1605, 1480 cm"<1>.
26) Etyl 2-[3-(4-klor-3-metoksybenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1705, 1660, 1610 cm"<1>.
27) Etyl 2-[3-(3-klor-4-metoksybenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1605 cm"<1>.
28) Etyl 2-[l,2,3,4-tetrahydro-2,4-diokso-3-(2-tienylmetyl)-kinazolin-l-yl]acetat, smeltepunkt 115-120°C.
IR-spektrum (Nujol): vmaks= 1730, 1700, 1660, 1605 cm"<1>.
29) Etyl 2-[l,2,3,4-tetrahydro-2,4-diokso-3-(2-naftylmetyl)-kinazolin-l-yl]acetat, smeltepunkt 149-150°C. 30) Etyl 2-[3-(4-brom-2-fluorbenzyl)-5-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 186-187°C.
IR-spektrum (Nujol): vmaks= 1740, 1710, 1670, 1590 cm"<1>.
31) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-5-metoksy-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 166-168°C. IR-spektrum (Nujol): vmaks= 1735, 1710, 1665, 1600, 1580 cm"<1>. 32) Etyl 2-[3-(4-brom-2-fluorbenzyl)-7-klor-l,2,3,4-
tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1720, 1680, 1610, 1580 cm"<1>.
33) Etyl 2-[7-fluor-3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1730, 1710, 1680, 1625, 1600,
1570 cm"<1>.34) Etyl 2-[7-brom-3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 163-164°C.
IR-spektrum (Nujol): vmaks= 1740, 1710, 1675, 1600, 1580,
1490 cm"<1>. 35) Etyl 2-[3-(4-brom-2-fluorbenzyl)-8-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 8<*>3-85°C.
IR-spektrum (Nujol): vmaks= 1735, 1710, 1660, 1595 cm"<1>.
36) Etyl 2-[7-klor-3-{4-klor-3-(trifluormetyl)benzyl}-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 133-134°C.
IR-spektrum (Nujol): vmaks= 1730, 1700, 1650, 1600 cm"<1>.
37) Etyl 2-[3-(4-brom-2-fluorbenzyl)-1,2,3,4-tetrahydro-7-jod-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 169-169,5°C. IR-spektrum (Nujol): vmaks= 1740, 1710, 1675, 1595, 1575, 1490 cm"<1>.38) Etyl 2-[3-(4-brom-2-fluorbenzyl)-7-fluor-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 144-145°C.
IR-spektrum (Nujol) : vmaks= 1700, 1660, 1600, 1370 cm"<1>.
39) Etyl 2-[3-(4-brom-2-fluorbenzyl)-7-trifluormetyl-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 150-152°C.
IR-spektrum (Nujol): vmaks= 1700, 1660, 1600, 1370, 1260 cm"<1>. 40) Etyl 2-[7-brom-3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 183-184°C.
IR-spektrum (Nujol) : vmaks = 1735, 1710, 1670 cm"<1>.
41) Etyl 2-[3-(2-fluor-4-jodbenzyl)-7-jod-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 184-185°C.
IR-spektrum (Nujol): vmaks= 1740, 1715, 1670, 1600, 720 cm"<1>.
42) Etyl 2-[3-(4-brom-2-fluorbenzyl)-6,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1730, 1710, 1675, 1575, 1490 cm"<1>.
43) Etyl 2-[3-(4-brom-2-fluorbenzyl)-5,7-diklor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1730, 1720, 1680, 1595, 1570 cm"<1>.
44) Etyl 2-[7-klor-3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1740, 1715, 1675, 1610 cm"<1>.
45) Etyl 2-[7-klor-3-(2-fluor-3-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1750, 1720, 1660, 1610 cm"<1>.
46) Etyl 2-[7-klor-3-(3-klor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1735, 1710, 1670, 1605, 1580 cm"<1>.
47) Etyl 2-[7-klor-3-{3,5-bis(trifluormetyl)benzyl}-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat
IR-spektrum (Nujol): vmaks= 1735, 1710, 1665, 1610, 1580 cm"<1>.48) Etyl 2-[6,7-diklor-3-(2-fluor-4-jodbenzyl)-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat, smeltepunkt 225-226°C. IR-spektrum (Nujol): vmaks= 1725, 1710, 1675, 1605, 1575 cm"<1>.
EKSEMPEL 13
En blanding av etyl 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]acetat (85 mg), IN vandig natriumhydroksyd (0,5 ml) og tetrahydrofuran (1 ml) ble omrørt ved romtemperatur i 20 timer. Reaksjonsblandingen ble helt i en blanding av etylacetat og 0,5N saltsyre. Den organiske fase ble fraskilt, vasket med vann og saltoppløsning samt tørket over magnesiumsulfat. Oppløsningsmidlet ble fjernet og residuet ble krystallisert fra kloroform, hvilket ga 2-[3-(3,4-diklorbenzyl)-1,2,3,4-tetrahydro-2,4-ditioksokinazolin-l-yl]eddiksyre (36 mg), smeltepunkt 222-223°C (dekomponering). IR-spektrum (Nujol) : vmaks= 1710, 1685 cm"<1>. NMR-spektrum (DMSO-d6) : S (ppm) = 5,54 (2H bred s) , 5,75 (2H, s) , 7,17-7,60 (5H, m), 7,88 (1H, t, J=7Hz), 8,16 (1H, d,J=8Hz).
Claims (3)
1. Analogifremgangsmåte for fremstilling av en terapeutisk virksom forbindelse med den generelle formel I
hvorR<1>og R2 hver betegner hydrogen, halogen, lavere alkoksy
eller halogen-lavere-alkyl,
R<3>er fenyl(lavere)alkyl som har én eller flere
substituent(er) valgt fra halogen, lavere alkoksy, halogen(lavere)alkyl og lavere alkyl; eller naftyl(lavere)alkyl,
R<4>er karboksy eller beskyttet karboksy,
A er et oksygen- eller svovelatom,
Y er karbonyl, tiokarbonyl eller sulfonyl, og
Z er lavere alkylen,
eller salter derav,
karakterisert vedat a) en forbindelse med den generelle formel II
hvorR<1>,R<2>,R<3>, A og Y hver er som definert ovenfor, eller salter derav,
omsettes med en forbindelse med den generelle formel III
hvorR<4>og Z hver er som definert ovenfor, og
X er en avspaltbar enhet,
eller salter derav, hvilket gir en forbindelse med den generelle formel I
hvor R<1>, R<2>, R<3>, R<4>, A, Y og Z hver er som definert ovenfor, eller salter derav, eller b) en forbindelse med den generelle formel IV
hvor R<1>, R<2>, R<4>, A, Y og Z hver er som definert ovenfor, eller salter derav,
omsettes med en forbindelse med den generelle formel V
hvorR<3>og X hver er som definert ovenfor,
eller salter derav,
hvilket gir en forbindelse med den generelle formel I hvorR<1>,R<2>,R<3>,R<*>, A, Y og Z hver er som definert ovenfor, eller salter derav, eller c) en forbindelse med den generelle formel XVI
hvorR1,R2,R<3>,R<4>, Y og Z hver er som definert ovenfor, eller salter derav,
omsettes med en forbindelse med den generelle formel XII
hvor A er som definert ovenfor,
hvilket gir en forbindelse med den generelle formel I
hvorR<1>,R2, R<3>,R<4>, A, Y og Z hver er som definert ovenfor, eller salter derav, eller d) en forbindelse med den generelle formel Ia hvor R<1>, R<2>, R<3>, A, Y og Z hver er som definert ovenfor, ogRa<4>er beskyttet karboksy,
hydrolyseres, hvilket gir en forbindelse med den generelle formel Ib
hvor R<1>, R<2>, R<3>, A, Y og Z hver er som definert ovenfor, eller salter derav.
2. Fremgangsmåte ifølge krav 1, for fremstilling av2-[3-(4-brom-2-fluorbenzyl)-7-klor-l,2,3,4-tetrahydro-2,4-dioksokinazolin-l-yl]eddiksyre,karakterisertved at tilsvarende utgangsmaterialer anvendes.
3.Fremgangsmåte ifølge krav 1, for fremstilling av 2- [3 - (4-brom-2-f luorbenzyl) -7-f luor-1, 2, 3, 4-tetrahydro-2 ,<£,-dioksokinazolin-l-yl]eddiksyre,karakterisertved at tilsvarende utgansmaterialer anvendes.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB858524663A GB8524663D0 (en) | 1985-10-07 | 1985-10-07 | Quinazoline derivatives |
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NO863980D0 NO863980D0 (no) | 1986-10-06 |
NO863980L NO863980L (no) | 1987-04-08 |
NO171785B true NO171785B (no) | 1993-01-25 |
NO171785C NO171785C (no) | 1993-05-05 |
Family
ID=10586291
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NO863980A NO171785C (no) | 1985-10-07 | 1986-10-06 | Analogifremgangsmaate for fremstilling av terapeutisk virksomme kinazolinderivater |
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US (2) | US4734419A (no) |
EP (1) | EP0218999B1 (no) |
JP (3) | JPS6296476A (no) |
KR (1) | KR940007270B1 (no) |
CN (1) | CN1017242B (no) |
AT (1) | ATE60761T1 (no) |
AU (1) | AU596611B2 (no) |
CA (1) | CA1289139C (no) |
DE (1) | DE3677452D1 (no) |
DK (1) | DK158838C (no) |
ES (1) | ES2021266B3 (no) |
FI (1) | FI90234C (no) |
GB (1) | GB8524663D0 (no) |
GR (1) | GR3001502T3 (no) |
HK (1) | HK6993A (no) |
HU (1) | HU196972B (no) |
IE (1) | IE59309B1 (no) |
IL (1) | IL80213A (no) |
NO (1) | NO171785C (no) |
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GB8524663D0 (en) * | 1985-10-07 | 1985-11-13 | Fujisawa Pharmaceutical Co | Quinazoline derivatives |
MX7829A (es) * | 1986-08-21 | 1993-08-01 | Pfizer | Quinazolindionas y piridopirimindionas y procedimiento para su preparacion |
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-
1985
- 1985-10-07 GB GB858524663A patent/GB8524663D0/en active Pending
-
1986
- 1986-09-16 ZA ZA867043A patent/ZA867043B/xx unknown
- 1986-09-16 US US06/908,005 patent/US4734419A/en not_active Expired - Lifetime
- 1986-09-23 IE IE252086A patent/IE59309B1/en not_active IP Right Cessation
- 1986-09-25 DK DK459086A patent/DK158838C/da not_active IP Right Cessation
- 1986-09-29 FI FI863917A patent/FI90234C/fi not_active IP Right Cessation
- 1986-10-02 IL IL80213A patent/IL80213A/xx not_active IP Right Cessation
- 1986-10-02 ES ES86113559T patent/ES2021266B3/es not_active Expired - Lifetime
- 1986-10-02 EP EP86113559A patent/EP0218999B1/en not_active Expired - Lifetime
- 1986-10-02 DE DE8686113559T patent/DE3677452D1/de not_active Expired - Fee Related
- 1986-10-02 AT AT86113559T patent/ATE60761T1/de not_active IP Right Cessation
- 1986-10-03 UA UA4028362A patent/UA5562A1/uk unknown
- 1986-10-03 CA CA000519759A patent/CA1289139C/en not_active Expired - Fee Related
- 1986-10-03 SU SU864028362A patent/SU1588283A3/ru active
- 1986-10-06 NO NO863980A patent/NO171785C/no not_active IP Right Cessation
- 1986-10-06 JP JP61237605A patent/JPS6296476A/ja active Granted
- 1986-10-06 AU AU63589/86A patent/AU596611B2/en not_active Ceased
- 1986-10-06 HU HU864192A patent/HU196972B/hu not_active IP Right Cessation
- 1986-10-07 CN CN86106984A patent/CN1017242B/zh not_active Expired
- 1986-10-07 KR KR86008374A patent/KR940007270B1/ko not_active IP Right Cessation
-
1987
- 1987-12-08 US US07/130,297 patent/US4883800A/en not_active Expired - Lifetime
-
1988
- 1988-08-22 JP JP63207570A patent/JPH0794447B2/ja not_active Expired - Lifetime
- 1988-08-22 JP JP63207571A patent/JPH01125322A/ja active Granted
-
1991
- 1991-02-25 GR GR90401160T patent/GR3001502T3/el unknown
-
1992
- 1992-10-27 SG SG1120/92A patent/SG112092G/en unknown
-
1993
- 1993-01-28 HK HK69/93A patent/HK6993A/xx not_active IP Right Cessation
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