DK154432B - Analogifremgangsmaade til fremstilling af (1,2)-anellerede 7-phenyl-1,4-benzodiazepiner eller farmaceutisk acceptable syreadditionssalte deraf - Google Patents
Analogifremgangsmaade til fremstilling af (1,2)-anellerede 7-phenyl-1,4-benzodiazepiner eller farmaceutisk acceptable syreadditionssalte deraf Download PDFInfo
- Publication number
- DK154432B DK154432B DK341479AA DK341479A DK154432B DK 154432 B DK154432 B DK 154432B DK 341479A A DK341479A A DK 341479AA DK 341479 A DK341479 A DK 341479A DK 154432 B DK154432 B DK 154432B
- Authority
- DK
- Denmark
- Prior art keywords
- phenyl
- benzodiazepine
- alkyl
- chloro
- acid addition
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 11
- 150000003839 salts Chemical class 0.000 title claims abstract description 11
- 239000002253 acid Substances 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229940049706 benzodiazepine Drugs 0.000 title abstract description 5
- -1 3,4-methylene Chemical group 0.000 claims abstract description 52
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical group 0.000 claims abstract description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 3
- 241000790917 Dioxys <bee> Species 0.000 claims abstract 2
- 230000000694 effects Effects 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- DRRPDESGPTUCIQ-UHFFFAOYSA-N 7-phenyl-1h-1,4-benzodiazepine Chemical class C=1C=C2NC=CN=CC2=CC=1C1=CC=CC=C1 DRRPDESGPTUCIQ-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 230000002496 gastric effect Effects 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims 4
- 229910052783 alkali metal Inorganic materials 0.000 claims 3
- 229910052739 hydrogen Inorganic materials 0.000 claims 3
- 239000001257 hydrogen Substances 0.000 claims 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- 229910000272 alkali metal oxide Inorganic materials 0.000 claims 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- 208000007107 Stomach Ulcer Diseases 0.000 claims 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 208000000718 duodenal ulcer Diseases 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- 201000005917 gastric ulcer Diseases 0.000 claims 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 claims 1
- 208000025865 Ulcer Diseases 0.000 abstract description 14
- 231100000397 ulcer Toxicity 0.000 abstract description 13
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 239000011593 sulfur Chemical group 0.000 abstract 1
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical group N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 35
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- IKPCZIDHBPJYAA-UHFFFAOYSA-N 1h-1,2-benzodiazepine;dihydrochloride Chemical compound Cl.Cl.N1N=CC=CC2=CC=CC=C12 IKPCZIDHBPJYAA-UHFFFAOYSA-N 0.000 description 4
- GUWHTWOKAZNQIF-UHFFFAOYSA-N 7-chloro-1-(2-chloroethyl)-2-(chloromethyl)-5-phenyl-2,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N(CCCl)C(CCl)CN=C1C1=CC=CC=C1 GUWHTWOKAZNQIF-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229960002456 hexobarbital Drugs 0.000 description 4
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 4
- 229960000905 indomethacin Drugs 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- KUEHLWULHYJMNT-UHFFFAOYSA-N 1-(2-chloroethyl)-2-(chloromethyl)-5-phenyl-2,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC=CC=C2N(CCCl)C(CCl)CN=C1C1=CC=CC=C1 KUEHLWULHYJMNT-UHFFFAOYSA-N 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 206010022998 Irritability Diseases 0.000 description 3
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical group C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- ZFYIQPIHXRFFCZ-QMMMGPOBSA-N (2s)-2-(cyclohexylamino)butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC1CCCCC1 ZFYIQPIHXRFFCZ-QMMMGPOBSA-N 0.000 description 2
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 2
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- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate trihydrate Substances [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 2
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- 239000012074 organic phase Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- NKTROCRBBTZUPL-UHFFFAOYSA-N pyrazino[1,2-a][1,4]benzodiazepine Chemical class N1=CC2=CC=CC=C2N2C=CN=CC2=C1 NKTROCRBBTZUPL-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 230000004622 sleep time Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- TZIMUPXHFQECHP-BTJKTKAUSA-N (z)-but-2-enedioic acid;9-chloro-7-phenyl-2,4,4a,5-tetrahydro-1h-[1,4]oxazino[4,3-a][1,4]benzodiazepine Chemical compound OC(=O)\C=C/C(O)=O.C12=CC(Cl)=CC=C2N2CCOCC2CN=C1C1=CC=CC=C1 TZIMUPXHFQECHP-BTJKTKAUSA-N 0.000 description 1
- KYRVDFBYINNTBR-UHFFFAOYSA-N 1,3,5,2,4-trioxadithiepane 2,2,4,4-tetraoxide Chemical compound O=S1(=O)OCCOS(=O)(=O)O1 KYRVDFBYINNTBR-UHFFFAOYSA-N 0.000 description 1
- RGGLEJFUEMKQSH-UHFFFAOYSA-N 1,4-benzodiazepin-2-one Chemical class O=C1C=NC=C2C=CC=CC2=N1 RGGLEJFUEMKQSH-UHFFFAOYSA-N 0.000 description 1
- JTYRIICDQHNSNN-UHFFFAOYSA-N 1,5-benzodiazocine Chemical class N1=CC=CN=CC2=CC=CC=C21 JTYRIICDQHNSNN-UHFFFAOYSA-N 0.000 description 1
- UDEDWHHJCQONDX-UHFFFAOYSA-N 1-(2-chloroethyl)-2-(chloromethyl)-5-(2-chlorophenyl)-8-methyl-2,3-dihydro-1,4-benzodiazepine Chemical compound C=1C(C)=CC=C2C=1N(CCCl)C(CCl)CN=C2C1=CC=CC=C1Cl UDEDWHHJCQONDX-UHFFFAOYSA-N 0.000 description 1
- DKJMWSBFAYVACF-UHFFFAOYSA-N 1-(2-chloroethyl)-2-(chloromethyl)-7,8-dimethyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine Chemical compound C1=2C=C(C)C(C)=CC=2N(CCCl)C(CCl)CN=C1C1=CC=CC=C1 DKJMWSBFAYVACF-UHFFFAOYSA-N 0.000 description 1
- HOTMICSDQXUGFL-UHFFFAOYSA-N 1-(2-chloroethyl)-2-(chloromethyl)-7-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC(C)=CC=C2N(CCCl)C(CCl)CN=C1C1=CC=CC=C1 HOTMICSDQXUGFL-UHFFFAOYSA-N 0.000 description 1
- CNJVWIUTZAJDAI-UHFFFAOYSA-N 10-methoxy-3-methyl-7-phenyl-2,4,4a,5-tetrahydro-1H-pyrazino[1,2-a][1,4]benzodiazepine Chemical compound COC1=CC2=C(C(=NCC3N2CCN(C3)C)C2=CC=CC=C2)C=C1 CNJVWIUTZAJDAI-UHFFFAOYSA-N 0.000 description 1
- QRLWEUQRQCXMNI-UHFFFAOYSA-N 10-methoxy-7-phenyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine Chemical compound C=1C(OC)=CC=C2C=1N1CCNCC1CN=C2C1=CC=CC=C1 QRLWEUQRQCXMNI-UHFFFAOYSA-N 0.000 description 1
- AKHKUSYWHIRPGY-UHFFFAOYSA-N 10-methoxy-7-phenyl-2,4,4a,5-tetrahydro-1h-[1,4]thiazino[4,3-a][1,4]benzodiazepine Chemical compound C=1C(OC)=CC=C2C=1N1CCSCC1CN=C2C1=CC=CC=C1 AKHKUSYWHIRPGY-UHFFFAOYSA-N 0.000 description 1
- SHOQEHIZBWYOQK-UHFFFAOYSA-N 10-phenyl-5,14,16-trioxa-2,9-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(18),9,11,13(17)-tetraene Chemical compound C1=2C=C3OCOC3=CC=2N2CCOCC2CN=C1C1=CC=CC=C1 SHOQEHIZBWYOQK-UHFFFAOYSA-N 0.000 description 1
- XFEAECPMCAQPTK-UHFFFAOYSA-N 11-nitro-7-phenyl-2,4,4a,5-tetrahydro-1h-[1,4]oxazino[4,3-a][1,4]benzodiazepine Chemical compound [O-][N+](=O)C1=CC=CC2=C1N1CCOCC1CN=C2C1=CC=CC=C1 XFEAECPMCAQPTK-UHFFFAOYSA-N 0.000 description 1
- JIVBGAGPUWYUEV-UHFFFAOYSA-N 1h-1,4-benzodiazepine;dihydrochloride Chemical compound Cl.Cl.N1C=CN=CC2=CC=CC=C12 JIVBGAGPUWYUEV-UHFFFAOYSA-N 0.000 description 1
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- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- KZGIKBDGFRQLNN-UHFFFAOYSA-N 3,10-dimethyl-7-phenyl-2,4,4a,5-tetrahydro-1H-pyrazino[1,2-a][1,4]benzodiazepine Chemical compound CN1CC2N(C3=C(C(=NC2)C2=CC=CC=C2)C=CC(=C3)C)CC1 KZGIKBDGFRQLNN-UHFFFAOYSA-N 0.000 description 1
- WGTASENVNYJZBK-UHFFFAOYSA-N 3,4,5-trimethoxyamphetamine Chemical compound COC1=CC(CC(C)N)=CC(OC)=C1OC WGTASENVNYJZBK-UHFFFAOYSA-N 0.000 description 1
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 1
- HTWPBCGBKVFWDO-UHFFFAOYSA-N 3,9,10-trimethyl-7-phenyl-2,4,4a,5-tetrahydro-1H-pyrazino[1,2-a][1,4]benzodiazepine Chemical compound CN1CC2N(C3=C(C(=NC2)C2=CC=CC=C2)C=C(C(=C3)C)C)CC1 HTWPBCGBKVFWDO-UHFFFAOYSA-N 0.000 description 1
- PSKUQQDBFSAJRE-UHFFFAOYSA-N 3,9-dimethyl-7-phenyl-2,4,4a,5-tetrahydro-1h-pyrazino[1,2-a][1,4]benzodiazepine;dihydrochloride Chemical compound Cl.Cl.C1N(C)CCN(C2=CC=C(C)C=C22)C1CN=C2C1=CC=CC=C1 PSKUQQDBFSAJRE-UHFFFAOYSA-N 0.000 description 1
- OWOORDQPGDXMFT-UHFFFAOYSA-N 3-butyl-9-chloro-7-phenyl-2,4,4a,5-tetrahydro-1H-pyrazino[1,2-a][1,4]benzodiazepine Chemical compound C1N(CCCC)CCN(C2=CC=C(Cl)C=C22)C1CN=C2C1=CC=CC=C1 OWOORDQPGDXMFT-UHFFFAOYSA-N 0.000 description 1
- OOFBETMWPZNHIF-UHFFFAOYSA-N 3-methyl-7-phenyl-2,4,4a,5-tetrahydro-1h-pyrazino[1,2-a][1,4]benzodiazepine Chemical compound C1N(C)CCN(C2=CC=CC=C22)C1CN=C2C1=CC=CC=C1 OOFBETMWPZNHIF-UHFFFAOYSA-N 0.000 description 1
- FYTPYKNNZBHZSO-UHFFFAOYSA-N 3-methyl-9-nitro-7-phenyl-2,4,4a,5-tetrahydro-1H-pyrazino[1,2-a][1,4]benzodiazepine Chemical compound [N+](=O)([O-])C=1C=CC2=C(C(=NCC3N2CCN(C3)C)C2=CC=CC=C2)C=1 FYTPYKNNZBHZSO-UHFFFAOYSA-N 0.000 description 1
- YNHGHPCGMBEGEU-UHFFFAOYSA-N 5-phenyl-1h-1,4-benzodiazepine Chemical class C12=CC=CC=C2NC=CN=C1C1=CC=CC=C1 YNHGHPCGMBEGEU-UHFFFAOYSA-N 0.000 description 1
- GPZUXQBMOKYCQP-UHFFFAOYSA-N 7-(2-fluorophenyl)-2,4,4a,5-tetrahydro-1h-[1,4]oxazino[4,3-a][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C(C1=CC=CC=C11)=NCC2N1CCOC2 GPZUXQBMOKYCQP-UHFFFAOYSA-N 0.000 description 1
- JTXKOFKWABSCKJ-UHFFFAOYSA-N 7-(2-fluorophenyl)-2,4,4a,5-tetrahydro-1h-[1,4]thiazino[4,3-a][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C(C1=CC=CC=C11)=NCC2N1CCSC2 JTXKOFKWABSCKJ-UHFFFAOYSA-N 0.000 description 1
- IKXKTKMVPNAYHM-UHFFFAOYSA-N 7-phenyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine Chemical class C1NCCN(C2=CC=CC=C22)C1CN=C2C1=CC=CC=C1 IKXKTKMVPNAYHM-UHFFFAOYSA-N 0.000 description 1
- VWPWKXZYSJONRH-UHFFFAOYSA-N 7-phenyl-2,4,4a,5-tetrahydro-1h-[1,4]oxazino[4,3-a][1,4]benzodiazepine Chemical compound C1OCCN(C2=CC=CC=C22)C1CN=C2C1=CC=CC=C1 VWPWKXZYSJONRH-UHFFFAOYSA-N 0.000 description 1
- KGNJOLWSFQTQOL-UHFFFAOYSA-N 7-phenyl-9-(trifluoromethyl)-2,4,4a,5-tetrahydro-1h-[1,4]oxazino[4,3-a][1,4]benzodiazepine Chemical compound C12=CC(C(F)(F)F)=CC=C2N2CCOCC2CN=C1C1=CC=CC=C1 KGNJOLWSFQTQOL-UHFFFAOYSA-N 0.000 description 1
- UZOUKRMMSQJZIW-UHFFFAOYSA-N 9,10-dichloro-3-methyl-7-phenyl-2,4,4a,5-tetrahydro-1H-pyrazino[1,2-a][1,4]benzodiazepine Chemical compound ClC=1C(=CC2=C(C(=NCC3N2CCN(C3)C)C2=CC=CC=C2)C=1)Cl UZOUKRMMSQJZIW-UHFFFAOYSA-N 0.000 description 1
- QKCZQTQGYHTWFM-UHFFFAOYSA-N 9,10-dichloro-7-phenyl-2,4,4a,5-tetrahydro-1h-[1,4]oxazino[4,3-a][1,4]benzodiazepine Chemical compound C1=2C=C(Cl)C(Cl)=CC=2N2CCOCC2CN=C1C1=CC=CC=C1 QKCZQTQGYHTWFM-UHFFFAOYSA-N 0.000 description 1
- JGUINPIATPLAKE-UHFFFAOYSA-N 9-bromo-7-(2-chlorophenyl)-3,10-dimethyl-2,4,4a,5-tetrahydro-1H-pyrazino[1,2-a][1,4]benzodiazepine Chemical compound BrC=1C(=CC2=C(C(=NCC3N2CCN(C3)C)C2=C(C=CC=C2)Cl)C=1)C JGUINPIATPLAKE-UHFFFAOYSA-N 0.000 description 1
- HSETWNWNKVJFTR-UHFFFAOYSA-N 9-bromo-7-phenyl-2,4,4a,5-tetrahydro-1h-[1,4]oxazino[4,3-a][1,4]benzodiazepine Chemical compound C12=CC(Br)=CC=C2N2CCOCC2CN=C1C1=CC=CC=C1 HSETWNWNKVJFTR-UHFFFAOYSA-N 0.000 description 1
- ARPDSRZVJCTVKG-UHFFFAOYSA-N 9-chloro-7-(2-chlorophenyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N2CCNCC2CN=C1C1=CC=CC=C1Cl ARPDSRZVJCTVKG-UHFFFAOYSA-N 0.000 description 1
- CQNVLOANBVMUOX-UHFFFAOYSA-N 9-chloro-7-[3-(trifluoromethyl)phenyl]-2,4,4a,5-tetrahydro-1H-[1,4]thiazino[4,3-a][1,4]benzodiazepine Chemical compound ClC=1C=CC2=C(C(=NCC3N2CCSC3)C3=CC(=CC=C3)C(F)(F)F)C1 CQNVLOANBVMUOX-UHFFFAOYSA-N 0.000 description 1
- MAOFJHWQHUHBSY-UHFFFAOYSA-N 9-chloro-7-phenyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N2CCNCC2CN=C1C1=CC=CC=C1 MAOFJHWQHUHBSY-UHFFFAOYSA-N 0.000 description 1
- GPVWFCMYTICFMU-UHFFFAOYSA-N 9-chloro-7-phenyl-3-propan-2-yl-2,4,4a,5-tetrahydro-1h-pyrazino[1,2-a][1,4]benzodiazepine;dihydrochloride Chemical compound Cl.Cl.C1N(C(C)C)CCN(C2=CC=C(Cl)C=C22)C1CN=C2C1=CC=CC=C1 GPVWFCMYTICFMU-UHFFFAOYSA-N 0.000 description 1
- LRJKMXDJHALVSU-UHFFFAOYSA-N 9-fluoro-3-methyl-7-phenyl-2,4,4a,5-tetrahydro-1H-pyrazino[1,2-a][1,4]benzodiazepine dihydrochloride Chemical compound Cl.Cl.C1N(C)CCN(C2=CC=C(F)C=C22)C1CN=C2C1=CC=CC=C1 LRJKMXDJHALVSU-UHFFFAOYSA-N 0.000 description 1
- LRWUYBHARRZTOP-UHFFFAOYSA-N 9-fluoro-7-phenyl-2,4,4a,5-tetrahydro-1h-[1,4]thiazino[4,3-a][1,4]benzodiazepine Chemical compound C12=CC(F)=CC=C2N2CCSCC2CN=C1C1=CC=CC=C1 LRWUYBHARRZTOP-UHFFFAOYSA-N 0.000 description 1
- FVZRZJCBVMLTRL-UHFFFAOYSA-N 9-methyl-7-phenyl-2,4,4a,5-tetrahydro-1h-[1,4]oxazino[4,3-a][1,4]benzodiazepine Chemical compound C12=CC(C)=CC=C2N2CCOCC2CN=C1C1=CC=CC=C1 FVZRZJCBVMLTRL-UHFFFAOYSA-N 0.000 description 1
- DDTSYRBXKLDUCV-UHFFFAOYSA-N 9-nitro-7-phenyl-2,4,4a,5-tetrahydro-1h-[1,4]oxazino[4,3-a][1,4]benzodiazepine Chemical compound C12=CC([N+](=O)[O-])=CC=C2N2CCOCC2CN=C1C1=CC=CC=C1 DDTSYRBXKLDUCV-UHFFFAOYSA-N 0.000 description 1
- FRFMIZBABBRIKH-UHFFFAOYSA-N 9-nitro-7-phenyl-2,4,4a,5-tetrahydro-1h-[1,4]thiazino[4,3-a][1,4]benzodiazepine Chemical compound C12=CC([N+](=O)[O-])=CC=C2N2CCSCC2CN=C1C1=CC=CC=C1 FRFMIZBABBRIKH-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 238000011785 NMRI mouse Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- RYWKEARBEMOIEI-UHFFFAOYSA-N S(=O)(=O)(O)C1=CC=C(C)C=C1.S(=O)(=O)(O)C1=CC=C(C)C=C1.N1C=CN=CC2=C1C=CC=C2 Chemical compound S(=O)(=O)(O)C1=CC=C(C)C=C1.S(=O)(=O)(O)C1=CC=C(C)C=C1.N1C=CN=CC2=C1C=CC=C2 RYWKEARBEMOIEI-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000002857 effect on ulcer Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 210000004744 fore-foot Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical class ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000001003 psychopharmacologic effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 description 1
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012345 traction test Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
i
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Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte [1,2]-annelerede 7-phenyl-l,4-benzodiaze-piner med den i krav l's indledning angivne almene formel I eller farmaceutisk acceptable syreadditionssalte deraf.
5 Som bekendt udviser 5-phenyl-l,4-benzodiazepinderivater, såsom 5-phenyl-1,4-benz odiaz ep in- 2- oner, på grund af deres CNS-virksomhed også en vis stressulcushæmmende virkning.
Men virkningen er ikke tilstrækkelig til, at disse stoffer kan anvendes til virksom behandling af patienter.
10 Det har nu overraskende vist sig, at de hidtil ukendte [l,2]-annelerede 7-phenyl-l,4-benzodiazepinderivater med formlen I kun har har en forholdsvis ringe CNS-virksom-hed, men til gengæld udviser en god ulcushæmmende virkning ved ulcuslidelser af forskellig oprindelse, således at 15 de egner sig til ulcusterapi af maven og duodenum.
Som alkyl- eller alkenylgrupper på iminonitrogenatomet kommer ligekædede eller forgrenede grupper med 1-5 car-bonatomer på tale, såsom methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopen-20 tyl, allyl, 2- eller 3- eller 4-pentenyl. Foretrukne er methyl og ethyl, som er substitueret med en endestillet phenylgruppe, samt ethyl eller propyl, som i endestilling er substitueret med chlor, hydroxy eller methoxy. For sub-stituenterne R - R på phenylringene kommer som halogen-25 atomer fluor,chlor, brom eller iod, især fluor, chlor eller brom på tale. Alkylgrupperne med 1-4 carbonatomer i alkyl-, alkoxy- eller alkylthiogrupper kan være ligekædede eller forgrenede, hvorved der især ved flersubstitution på den enkelte phenylgruppe foretrækkes methyl, såsom me-30 thyl, methoxy, methylthio eller methylendioxy.
Ved mono- eller disubstitution på phenylringen i 1,4-ben- 4 5 zodiazepinskelettet, befinder R og R sig fortrinsvis i 9- og/eller 10-stilling. Ved substitution med fluor, nitro
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2 eller trifluormethyl foretrækkes mono substitution i 9-stil-ling, for methoxy og methylthio monosubstitution i 10-stilling.
Ved monosubstitution foretrækkes på 7-phenylgruppen halogen, 5 methyl, methoxy eller trifluormethyl i 2'- eller 3*-stilling. Ved polysubstitution med ens eller forskellige sub-stituenter foretrækkes 3’ »4’- eller 3^41,5’- stillingeme. På tale kommer halogen, især chlor, samt methyl, methoxy og/eller methylendioxy eller ethylendi- 10 oxy·
De hidtil ukendte forbindelser og deres salte udviser værdifulde terapeutiske egenskaber, især viser de en udpræget ulcushæmmende virkning. Det er kendt at ulcuslidelsens ætiologi er af meget komplex natur. Da der med de hidtil 15 sædvanlige farmaceutiske præparater altid kun har kunnet øves indflydelse på delaspekter af dette mangesidede forløb, kunne der også kun opnås begrænsede resultater (se Blum, Schweiz. Med. Wochenschrift, 106 (1976) side 1457).
Ifølge Demling (L. Demling, Klin. Gastroenterologie I, 20 (1973), side 202) er i tilfælde af mave- eller tarmulce- ration ligevægten af de på slimhinden indvirkende aggressive og defensive faktorer forstyrret. En terapi må derfor gå ud på at genoprette denne ligevægt.
Det er kendt, at psykofarmaka, især 5-pb.enyl-l,4-benzo-25 diazepin-2-on-derivater, har en stressafskærmende virkning og således udviser en vis stressulcushæmmende virkning.
Disse p'sysokofarmaka har imidlertid på grund af for ringe virkning ved tålelig dosering ikke kunnet vinde frem inden for ulcusterapien. Deres CNS-virkninger, såsom sedering 30 og indvirkning på muskeltonus, er tillige uønskede ved den ambulante terapi.
De ifølge opfindelsen fremstillede [l,2]-annelerede 1,4-
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3 benzodiazepinderivater udviser i modsætning hertil foruden indvirkningen på den af stress "betingede ulcus en overraskende god virkning på ulcus af anden patogenese, således blandt andet på den af lægemidler inducerede 5 ulcus, som f. eks. den af indomethacin forårsagede ul cus. Bemærkelsesværdig ved de her omhandlede stoffer er manglen på de kommercielle l,4-benzodiazepin-2-on-deri-vaters udprægede CNS-virkning, således at der ved ind-givning af terapeutiske mængder af de ifølge opfindelsen 10 fremstillede forbindelser eller syreadditionssalte deraf ikke må regnes med forstyrrende bivirkninger, såsom f. eks. sedation eller indvirkning på muskeltonus. Som følge af deres ringe toxicitet udviser stofferne tillige en god terapeutisk bredde. De egner sig derfor især til anven-15 delse ved den ambulante ulcusbehandling.
Beskrivelse af de farmakologiske undersøgelsesmetoder 1. Akut toxicitet
Den akutte 7-dages toxicitet bestemmes ved engangs ind-givning pr. os til den hvide fastende NMRI-mus. Beregnin-20 gen af LD^Q-værdierne foregår via EDB ved hjælp af en probitanalyse (L. Cavalli-Sforza, Gustav-Fischer-Verlag, Stuttgart (1964), Grundbegriffe der Biometrie, Kapitel 10, side 153 - 190).
2. Prøvning på indomethacinulcus hos rotten 25 (Modificeret forsøgsanordning ifølge U. Jahn og R.W. Ad- drian,Arzneim.Forsch. (Drug Res.) 19, (1969)» side 36)
Prøvestoffet indgives mindst 6 hanrotter med en legems-vægt på 155 - 190 g i 0,5 ml suspensionsmedium/100 g dyre-vægt pr. os. Dyrene i kontrolgruppen får det tilsvarende 30 volumen af suspensionsmediet. 1 time efter indgivningen indgives rotterne p.o. 40 mg/kg indomethacin i 0,5 ml
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4 suspensionsmedium/100 g dyrevægt til frembringelse af ulcera. Dyrene dræbes 24 timer efter indomethacin-ind-givningen.
Bedømmelsen foregår modificeret efter 0. Miinchow, (Arz-5 neim.Forsch. (Drug Res.) 4, (1954) side 341 - 344).
Der beregnes middelværdi og standardafvigelse af ulcus-tallene og derefter prøve- og standardstoffets hæmmende virkning i % i forhold til kontrollen.
3. Prøvning af de muskulutrope egenskaber 10 Ved tractionsprøvningen indgives musene forsøgsstoffet pr. os. Efter 120 minutter hænges musene med forpoterne på en tynd vandret udspændt tråd. Som ED^q gælder den dosis, hvorved nøjagtig halvdelen af dyrene ikke inden for 5 sekunder også berører tråden med bagpoteme. (W.
15 Theobald et al., Arzneim.Forsch. 17, 561 (1967)). Ved denne prøvning måles prøvestoffernes indflydelse på mus-keltonus.
4. Prøvning for centraldæmpende egenskaber (Forlængelse af hexobarbitalsovetiden) 20 Prøvestoffet indgives musene pr. os. Efter 30 minutter får dyrene yderligere en i.v. injektion af 64 mg/kg hexo-barbital. Tidspunktet for indtagelsen af sideleje fastslås, og varigheden af sidelejet sammenlignes med en kun med hexobarbital behandlet kontrolgruppe. Som ED,.g 25 defineres en dosis, hvorved halvdelen af dyrene bibehol der et med faktoren 4 forlænget sideleje i forhold til kontrolgruppen (J.W. Kemp, M. Tannhauser og E. A. Swin-yard, Arch.int. Pharmacodyn. 193 (1971), 37 - 47).
Følgende forbindelser blev undersøgt ved de ovenfor be-30 skrevne metoder:
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5 A) 1,2,4,4a-tetrahyd.ro-9-clilor-7-phenyl-5H[l, 4] oxazino-[4,3-a][l,4]benzodiazepin-maleinat B) l,2,4,4a-tetrahydro-9-fluor-7-phenyl-5H[l,4]oxazino-[4,3-a][1,4]benzodiazepin 5 c) 1» 2,4,4a-tetrahydro-9-methyl-7-phenyl-5H[l,4]oxazi- no[4,3-a][l,4]benzodiazepin D) 1,2,4,4a-tetrahydro-10-methyl-7-phenyl-5H[l,4]oxazi-no[4,3-a][l,4]benzodiazepin E) 1,2,4,4a-tetrahydro-9-chlor-5-(2’-chlorphenyl)-5H[l, 10 4][l,4]oxazino[4,3-a][l,4]benzodiazepin F) X,2,4,4a-tetrahydro-10-methoxy-7-phenyl-5H[l,4]-oxa-zino[4,3-a][l,4]benzodiazepin G) 1,2,4,4a-tetrahydro-10-chlor-9-methyl-7-phenyl-5H- [l,4]oxazino[4,3-a][l,4]benzodiazepin 15 H) 1,2,4,4a-1 etrahydr 0-9- chlor-7-phenyl-5H [l, 4 ] -thiazino-[4,3-a][l,4}benzodiazepin I) 1,2,3,4,4a,5-hexahydro-9-chlor-3-allyl-7-phenyl-pyra-zino[l,2-a][l,4]benzozepin-dihydrochlorid.l,5 mol H2O.0,3 mol isopropanol 20 K) 1,2,3,4,4a, 5-hexahydro-9-chlor-3-phenethyl-7-phenyl-pyrazina[l,2-a][l,4]benzodiazepin L) 1,2,3»4,4a,5-hexahydro-3>9-dimethyl-7-phenyl-pyrazino-[l,2-a][l,4]benzodiazepin-dihydrochlorid S) Standard: 7-chlor-l-methyl-5-phenyl-l,3-dihydro-2H-l,4-25 benzodiazepin-2-on (diazepam)
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6
TABEL
For- LD^q p.o. Ulcus induceret af Fraktions - 4 ganges fortin- (mg/kg) indomethacin p.o. prøvning længelse af del- (mg/kg) % hæmning ED^Q hexobarbital- se (mg/kg) sovetid __ (mg/kg) A 2250 150 61 285,0 31,6 B >1370 100 77 >296 80,3 C >1430 200 68 >316 139 0 >1470 100 70 >316 138 E >1470 100 86 >316 11,8 F >1430 100 42 >308 202 G >1520 200 77 >327 119 H >1470 100 74 316 153 1 1090 200 81 >316 100 K >1310 200 85 >284 110 L 1010 250 70 >215 164 S 887 12») 28 4,2 1,5 x) Standarden diazepam viser allerede ved lav dosering en stærk psykofarmakologisk virkning, således at en højere dosering til opnåelse af en bedre ulcushæmning ikke er tolererbar.
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7
Af de fundne værdier fremgår entydigt, at de ifølge opfindelsen fremstillede forbindelser ved ringe CNS-virkning har en god ulcusvirkning.
Forbindelsen med den almene formel I og deres salte kan 5 på kendt måde indarbejdes i de sædvanlige farmaceutiske tilberedningsformer, f. eks. i opløsninger, komposito-rier, tabletter, kapsler eller drageer. Enkeltdosis udgør for voksne ved oral indgivning 50/150 mg, og dagsdosis 150 - 450 mg.
10 Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav l's kendetegnende del anførte.
Fortrinsvis anvendes som udgangsmaterialer forbindelser med formlen II, hvori Y og Z har den samme betydning.
Særlig gunstig er anvendelsen af forbindelser med form-15 len II, hvori Y og Z betyder chloratomer. Hvis der anvendes forbindelser med formlen II, hvori Y og Z betyder sul-fonyloxygrupper, så har især toluensulfonyloxygruppen vist sig anvendelig. Forbindelserne kan på i sig selv kendt måde fremstilles ud fra forbindelserne med formlen III
\ _ '-^h2oh brf FT j rIA.1 R2
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8 1 5 hvori R - Rv har den i krav 1 angivne betydning ved omsætning med de tilsvarende sulfonylchlorider, f. eks. p-toluensulfonylchlorid, i nærvær af et inert opløsningsmiddel. Derved er det ikke nødvendigt, at man isolerer den 5 dannede sulfonsyreester før den videre omsætning.
>
Til fremstilling af de annelerede oxazino- og thiazino-[4,3-a][l,4]benzodiazepinderivater omsættes forbindelserne med den almene formel II fortrinsvis med hydroxider, carbonater eller sulfider af natrium, kalium, calcium el-10 ler barium. I almindelighed foretrækkes det at gennemføre ringslutningen i nærvær af et organisk opløsningsmiddel, f. eks. lavere alkoholer, acetone, diethylether, dioxan, tetrahydrofuran, pyridin, dimethylsulfoxid eller dimethyl-formamid, hvorved tilsætningen af vand kan være fordel-15 agtig. Reaktionen begunstiges, når reaktionsdeltagerae foreligger i opløsning.
Ved fremstillingen af de annelerede pyrazino[l, 2-a] [l,4]-benzodiazepiner kan de samme opløsningsmidler anvendes, men det er også muligt at anvende den primære organiske 20 amin som opløsningsmiddel.
Omsætningen kan gennemføres ved normaltryk eller forhøjet tryk . Især ved ringslutning i nærvær af ammoniak eller lavt kogende aminer arbejder man i en lukket beholder.
Den efterfølgende substitution med halogen eller nitro 25 i 1,4-benzodiazepinsystemets phenylring er mulig på i sig selv kendt måde. Som halogeneringsmidler kan f. eks. anvendes N-chlorsuccinimid eller N-bromsuccinimid. Til indføring af nitrogruppen kan anvendes de sædvanlige nitre-ringsreagenser, f. eks. kobber (il)- nitrat-trihydrat i 50 eddikesyreanhydrid.
Endvidere er det muligt i l,2,3,4,4a,5-hexahydro-7-phe-nyl-pyrazino [l, 2-a] [l, 4]benzodiazepinderivaterae med form-
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9 len I at alkylere NH-gruppen bagefter på i sig selv kendt måde. Sædvanlige metoder er omsætning af disse forbindelser med halogenalkyler (se Houben-Weyl, Bd. XI/1, (1957) ' side 24 ff.), med dialkylsulfat, f. eks. dimethyl- eller 5 diethylsulfat eller ethylendisulfat (samme, side 207), • med sulfonsyreestere med formlen R'-SO^R, hvori R’ f. eks.
er methyl, phenyl eller 4-methylphenyl, og R er en alkyl-gruppe (samme, side 217) eller med ethylen- og propylen-oxid (samme, side 311).
10 Endvidere er det muligt i l,2,3,4,4a,5-hexahydro-3-(hydro-xyalkyl)-7-phenyl-pyrazino [l, 2-a ] [l, 4]benzodiazepineme med formlen I bagefter at overføre hydroxyalkylgruppen i en methoxyalkylgruppe (se Houben-Weyl, Bd. VI/3 (1965) side 24) eller i en halogenalkylgruppe (samme, Bd. V/3, 15 (1962) side 862).
Fremstillingen af 1,4-benzodiazepinderivateme med formlen II, 1 5
hvori R - Rv har den i krav 1 angivne betydning, og Y
og Z er halogenatomer, samt af 1,4-benzodiazepinderivater- 1 5 ne med formlen III, hvori R - R har den i krav 1 angivne 20 betydning, er beskrevet i DE offentliggørelsesskrift nr. 22 21 558 og i DE patentskrift nr. 25 20 937. Som grundreaktion må anses ringslutningen af acyldiaminer med phosphor oxychlorider ved temperaturer mellem ca. 90 og ca.
130° C; derved opnås enten direkte 1,4-benzodiazepineme 25 med formlen II eller blandinger af 1,5-benzodiazociner og 1,4-benzodiazepiner, som derefter kan omlejres til 1,4-benzodiazepinderivater ved behandling med nucleophile reagenser.
De efterfølgende eksempler tjener til nærmere belysning 30 af fremgangsmåden ifølge opfindelsen.
EKSEMPEL 1
En opløsning af 20 g 7-chlor-l-(β-chlorethyl)-2-chlorme-
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10 thyl-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin i 100 ml dioxan og 250 ml 6% natriumhydroxidopløsning opvarmes under tilbagesvaling i 5,5 timer. Efter afdampning af opløsningsmidlet i vakuum isoleres stoffet fra chloroform 5 og chromatograferes derefter på aluminiumoxid af aktivitet strin II med methylenchlorid. Der opnås.'12,8 g 1,2,4, * 4a-tetrahydro-9-chlor-7-phenyl-5H[l,4]oxazino[4,3-a][l,4]-benzodiazepin som olie. Maleinatet krystalliserer fra isopropanol/ether med smp. 143 - 145° C. Den fra hexan 10 krystalliserede base smelter ved 156 - 158° C.
På samme måde får man ud fra 1- (β-chlorethyl) -2-chlormethyl-5-phenyl-2,3-dihydro-lH- 1,4-benzodiazepin samt de tilsvarende 7-fluor-, 7-brom-, 7-nitro-, 7-methyl-, 8-methyl-, 7-trifluormethyl-, 7,8-15 dimethyl-, 8-methoxy-, 7,-8-dichlor-, 8-chlor-7-methyl-, 7-brom-8-methyl- og 7,8-methylendioxy-derivater eller ud fra 7-chlor-l-(β-chlorethyl)-2-chlormethyl-5-[(31-tri-fluormethylphenyl)- eller (3,4'-dichlorphenyl)]-2,3-di-hydro-lH-l,4-benzodiazepin eller 7-fluor-l-(β-chlorethyl)-20 2-chlormethyl-5-(3* ,4’ ,5'-trimethoxyphenyl)-2,3-dihydro- 1H-1,4-benzodiazepin
de følgende forbindelser Smp. 0 C
1,2,4,4a-tetrahydro-7-phenyl-5H[l,4]oxazino-[4,3-a][l,4]benzodiazepin 102 - 105 25 1,2,4,4a-tetrahydr o-9-f luor-7-phenyl-5H- j [l,4]oxazino[4,3-a][l,4]benzodiazepin 154 - 156 1,2,4,4a-tetrahydro-9-brom-7-phenyl-5H- [l, 4]oxazino [4,3-a] [l, 4]benzodiazepin 176 - 179 1,2,4,4a-tetrahydro-9-nitro-7-phenyl-5H-30 [l,4]oxazino[4,3-a][l,4]benzodiazepin 142 - 145
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11
Smp. 0 C
1,2,4,4a-tetrahydro-9-methyl-7-phenyl-5H- [1.4] oxazino[4,3-a][l,4]benzodiazepin 174 - 176 l,2,4,4a-tetrahydro-10-methyl-7-ph.enyl-5H- [1.4] oxazino[4,3-a][l,4]benzodiazepin 123 - 124 5 1,2,4, 4a-tetrahydro-9-trifluormethyl-7-phenyl-5H- [1.4] oxazino[4,3-a][l,4]benzodiazepin olie x) 1,2,4,4a-tetrahydro-9 jlO-dimethyl-7-phenyl-5H[l,4]oxazino[4,3-a][l,4]benzodiazepin 132 - 134 1,2,4,4a-tetrahydro-10-methoxy-7-phenyl-5H-10 [l,4]oxazino[4,3-a][l,4]benzodiazepin 107 - 110 1,2,4,4a-tetrahydro-9,10-dichlor-7-phenyl-5H[l,4]oxazino[4,3-a][l,4]benzodiazepin 163 - 165 1,2,4,4a-tetrahydro-10-chlor-9-niethyl-7“Pbe-nyl-5H[l,4]oxazino[4,3-a][l,4]benzodiazepin 115 - 118 15 1,2,4,4a-tetrahydro-9-bΓom-10-methyl-7-ph.enyl- 5H[l,4]oxazino[4,3-a][l,4]benzodiazepin 117 - 119 1,2,4,4a-tetrahydro-9,10-meth.ylendioxy-7-ph.e-nyl-5H[l,4]oxazino[4,3-a][l,4]benzodiazepin 156 - 158 1,2,4,4a-tetrahydro-9-chlor-7-(31-trifluorme-20 thylphenyl-5H [l, 4 ] oxazino [ 4,3-a ] [ 1,4 ]benzo- diazepin 104 - 107 1,2,4,4a-tetrahydro-9-chlor-7-(3 *,4f-dichlor-phenyl-5H[l,4]oxazino[4,3-a][l,4]benzodiazepinl45 - 148 1,2,4,4a-tetrahydro-9-fluor-7-(3*,^*»4·'>5'-tri-25 methoxyphenyl) - 5H [l, 4 ] oxaz ino [4,3-a][1,4] -ben- zodiazepin 165 - 166 12
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EKSEMPEL 2
Til en omrørt suspension af 8,0 g 7-chlor-l-(β-hydroxyethyl)- 2-hydroxymethyl-5- (2 ’-chlorphenyl) -2,3-dihydr o-lH-1,4- ; benzodiazepin og 5,2 g p-toluensulfochlorid i 80 ml dio-5 xan sættes 2 g kaliumhydroxid i 17,2 ml vand, og derpå i opvarmes under tilbagesvaling i 1 time. Den organiske fase skilles fra den vandige fase og inddampes i vakuum. Reaktionsproduktet isosleres fra chloroform. Efter chro-matografi på aluminiumoxid af aktivitetstrin II med chlo-10 roform opnås 4,8 g 1,2,4,4a-tetrahydro-9-chlor-7-(21-chlorphenyl )-5H[l,4]oxazino[4,3-a][l,4]benzodiazepin med smp.
140 - 141° C.
Tilsvarende får man ud fra 1-(β-hydroxyethyl)-2-hydroxymethyl-5-[(21-chlorphenyl)-15 eller (2,-fluorphenyl)]-2,3-dihydro-lH-l,4-benzodiazepin: 1,2,4,4a-tetrahydr0-7-(21-chlorphenyl)-5H[l,4]oxazino-[4,3-a][l,4]benzodiazepin som olie. IR: 1615 cm-^ (C=N) og 1,2,4,4a-tetrahydro-7-(2'-fluorphenyl)-5H[l,4]oxazino-[4,3-a][l,4]benzodiazepin som olie. IR: 1610 cm"·1· (C=N).
20 EKSEMPEL 3 10,0 g 7-chlor-1-(β-chlorethyl)-2-chlormethy1-5-pheny1- 2,3-dihydro-lH-l,4-benzodiazepin opvarmes i 100 ml ethanol med 7,2 g natriumsulfid-nonahydrat under tilbagesva- i ling i 4 timer. Opløsningsmidlet afdampes i vakuum, og 25 reaktionsproduktet isoleres fra chloroform. Efter chroma- tografisk rensning på aluminiumoxid af aktivitetstrin II med methylenchlorid opnås ved krystallisation fra hexan 5,4 g l,2,4,4a-tetrahydro-9-chlor-7-phenyl-5H[l,4]thia-zino[4,3-a][l,4]benzodiazepin med smp. 136 - 138° C.
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13 På samme måde får man ud fra 1-(β-chlorethyl)-2-chlorme-thyl-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin, dets 7-fluor-, 7-nitro-, 7-methyl- og 8 -methoxy-derivater og dets 2'-fluorphenyl-derivat samt 7-chlor-l-(β-chlorethyl)-5 2-chlormethyl-5-(31-trifluormethylphenyl) -2,3-dihydro- 1H-1,4-benzodiazepin, de følgende forbindelser:
Smp. ° C
1,2,4,4a-tetrahydro-7-phenyl-5H[l, 4]thiazino-[4,3-a.][l,4]benzodiazepin 125 - 128 10 1,2,4,4a-tetrahydro-9-fluor-7—phenyl-5H- [1.4] thiazino[4,3-a] [l,4]benzodiazepin 168 — 170 1,2,4,4a-tetrahydro-9-nitro-7-phenyl-5H- [1.4] thiazino[4,3-a][l,4]benzodiazepin 166 - 172 1,2,4,4q-tetrahydro-9-methyl-7-phenyl-5H-15 [l,4]thiazino[4,3-a][l,4]benzo:diazepin 143 - 146 1,2,4,4a-tetrahydro-10-methoxy-7-phenyl-5H- [1.4] thiazino[4,3-a][l,4]benzodiazepin 125 — 131 1,2,4,4a-tetrahydr0-7-(2'-fluorpheny1)-5 H- [1.4] thiazino[4,3-a][l,4]benzodiazepin olie 20 IR: 1610 cm"1 (C=N) 1,2,4,4a-tetrahydro-9-chlor-7-(3’-trifluor-methylphenyl)-5H[l,4]thiazino[4,3-a][l,4]-benzodiazepin 102 — 104 EKSEMPEL 4 25 10 g 7-chlor-l-(β-chlorethyl)-2-chlormethyl-5-phenyl- 2,3-dihydro-lH-l,4-benzodiazepin i 200 ml methanol om-
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14 sættes med ammoniakgas i en gasautoklav ved 90 - 95° C i 16 timer. Efter afdampning af opløsningsmidlet i vakuum optages reaktionsblandingen i chloroform og vaskes med fortyndet vandig natriumhydroxidopløsning. Efter tørring og 5 afdampning af opløsningsmidlet i vakuum optages det opnåede olieagtige reaktionsprodukt i ether. Fra den koncentrerede opløsning krystalliserer g 1,2,3,4,4a,5-hexahydro-9-chlor-7-phenyl-pyrazino [l, 2-a] [l, 4]benzodiazepin med smp. 132 - 135° C.
10 På samme måde får man ud fra 1- (β-chlorethyl) -2-chlorme-thyl-5-phenyl- 2,3-dihydro-lH-l, 4-benz odiazepin, det s 7-brom-, 7-methyl-, 8-methoxy-, 7,8-dimethyl- og 7-brom- 8-methyl-derivater, samt 7-chlor-l-(p-chlorethyl)-2-chlor- methyl)-5-(21-chlorphenyl)-2,3-dihydro-lH-l,4-benzodiaze-15 pin og henholdsvis 7-chlor- og 7-brom-l-(f5-chlorethyl )-2- chlormethyl-5-(31,4'-dichlorphenyl)-2,3-dihydro-lH-l,4-ben-zodiazepin de følgende forbindelser
Smp. 0 C
1,2,3,4,4a-hexahydr o-7-phenyl-pyrazino-20 [l,2-a][l,4]benzodiazepin. IR:3500 cm-1 (NH) olie 1610 cm-1 (C=N) 1,2,3,4,4a,5-hexahydro-9-brom-7-phenyl-pyrazino[l,2-a][l,4]benzodiazepin 133 - 138 1,2,3,4,4a, 5-hexahydr o-9-methyl-7-phenyl-25 pyrazino[l,2-a][l,4]benzodiazepin-ditosylat 192 - 198 1,2,3,4,4a, 5-hexahydro-10-methoxy-7-phenyl-pyrazino[l,2-a][l,4]benzodiazepin olie IR: 3500 cm-1 (NH) 1610 cm"1 (C=N) 30 1,2,3,4,4a, 5-hexahydr o-9,10-dimethyl-7-phenyl-
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15
Smp. 0 C
pyrazino[l,2-a][l,4]benzodiazepin-ditosylat 232 - 234 1,2,3,4,4a, 5-hexahydr o- 9-brom- 10-me thyl- 7 -phe-nyl-pyrazlno[l,2-a][l,4]benzodiazepin-ditosylat 260 - 263 5 1,2,3,4,4a,5-hexahydro-9-chlor-7-(2'-chlor- phenyl)-pyrazino [l, 2-a] [l,4.]benzodiazepin 131 - 137 1,2,3,4,4a,5-hexahydro-9-chlor-7-(31,4*-di-chlorphenyl^pyrazinoE 1,2-a][ 1,4]benzodiazepin olie IR: 3500 cm _1 (NH) 10 1610 cm -1 (C=N) 1,2,3,4,4a,5-hexahydro-9-brom-7-(31,4'-di-, chlorphenyl) -pyrazino [l, 2-a]'Il, 4]benzodiaze-pin-dihydrochlorid . 1 mol isopropanol. 0,3 mol H20 210 - 212 15 EKSEMPEL 5 18,4 g 7-chlor-l-(β-chlorethyl)-2-chlormethyl-5-phenyl- 2,3-dihydro-lH-l,4-benzodiazepin i 200 ml methanol omsættes med 10 g methylamin i en glasautoklav ved .110° C i 16 timer. Efter oparbejdning af reaktionsproduktet op-20 når man 12 g 1,2,3,4,4a,5-hexahydro-9-chlor-3-methyl-7-phenyl-pyrazino [l, 2-a] [l, 4]benzodiazepindihydrochlorid.
1 mol H20 med smp. 262° C (under nedbrydning). På tilsvarende måde får man ud fra 7-chlor-l-(β-chlorethyl)- 2-chlormethyl-5-phenyl-2,3-dihydro-lH-l,4-benzodlazepin 25 i methanol med henholdsvis :a) isopropylamin, b)n-butylamin, c)tert.-butylamin, d)allylamin, e) ethanolamin og f) β-(3,4-dimethoxyphenyl) -ethylamin følgende forbindelser
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16
Smp. 0 C
a) 1,2,3,4,4a, 5-hexahydro-9-chlor-3-isopropyl- 7-phenyl-pyrazino [l, 2-a ] [l, 4]benzodiazepin-dihydrochlorid . 2,5 mol H20 236 - 245 * 5 b) l,2,3,4,4a,5-hexahydro-9-chlor-3-butyl- 7-phenyl-pyrazino[l,2-a][l,4]benzodiazepin 104 - 106 c) 1,2,3,4,4a,5-hexahydro-9-chlor-3-tert.-butyl- 7-phenyl-pyrazino[l,2-a][l,4]benzodiazepin 143 - 146 d) 1,2,3,4,4a,5-hexahydro-9-chlor-3-allyl-7-phe- 10 nyl-pyrazino[l, 2-a] [l,4]benzodiazepin-dihydro- chlorid . 1,5 mol ELjO . 0,3 mol isopropanol 230 - 233 x e) 1,2,3,4,4a, 5-hexahydro-9-chlor-3- ( β-hydroxy- ethyl)-7-pbenyl-pyrazino[l, 2-a] [l,4]benzo- 129 - 131 diazepin 15 som dihydrochlorid . 2,5 mol H20 216 x f) 1,2,3,4,4a,5-hexahydro-9-chlor-3-(3,4-dimetho-xyethyl) - 7-pb.eny 1-pyr az ino [l, 2-a] [l, 4] benzodiazepin-dihydrochlorid-dihydrat 180 x x under nedbrydning 20 EKSEMPEL 6
Hvis methylamin i metiianolisk opløsning ved temperaturer mellem 90 og 95° C i en glasautoklav omsættes med a) 7-chlor-l-(β-chlorethyl)-2-chlormethyl-5-(21-chlor-phenyl)-2,3-dihydro-lH-l,4-benzodiazepin 25 b) 7-chlor-l-(β-chlorethyl)-2-chlormethyl-5-(2*-metho- xyphenyl)-2,3-dihydro-lH-l,4-benzodiazepin.
c) 7-methyl-l-^-chlorethyl)-2-chlormethyl-5-phenyl-2,3-dihydro-lH-1,4-benzodiazepin DK 154432 Β 17 d) 8-methyl-l-(β-chlorethyl)-2-chlormethyl-5-phenyl- 2.3- dihydro-lH-l,4-benzodiazepin e) 8-methyl-l- ( β-chlorethyl) -2-chlormethyl-5- (2' -chlor-phenyl)-2,3-dihydro-lH-l,4-benzodiazepin 5 f) 7-brom-8-methyl-l-(p-chlorethyl)-2-chlormethyl-5-(2*- chlorphenyl) - 2,3-dihydr o-lH-1,4-benz odiazepin g) 7,8-dimethyl-l- ( β-chlorethyl)-2-chlormethyl-5-phe-nyl-2,3-dihydro-lH-l,4-benzodiazepin h) -m) 1- (β-chlorethyl )-2-chlormethyl-5-phenyl-2,3-di- 10 hydro-lH-l,4-benzodiazepin samt dets 7-fluor-, 7-nitro-, 7,8-dichlor- og 8-methoxy-derivater, og n) 1-(β-chlorethyl)-2-chlormethyl-5-(21-chlorphenyl)- 2.3- dihydro-l,4-benzodiazepin så får man
15 Smp. ° C
a) 1,2,3,4,4a,5-hexahydro-9-chlor-3-methyl- 7- (2 * -chlorphenyl) -pyrazino [l,.2-a] [l,4]— benzodiazepin 1^7 - 138 b) 1,2,3,4,4a, 5-hexahydro-9-chlor-3-methyl- 20 7- (21 -methoxyphenyl) -pyrazino [ 1,2-a ] [ 1,4 ] - benzodiazepin; IR: 1615 cm-1 (C=N) olie c) 1,2,3,4,4a, 5-hexahydr o-3,9-dimethyl-7-phe- nyl-pyrazino[l,2-a][l,4]benzodiazepin-dihydrochlorid . 1,5 mol H20 250 - 233 25 d) 1,2,3,4,4a,5-hexahydro-3,10-dimethyl- 7-phenyl-pyrazino[l,2-a][l,4]benzodiazepin 164 - 165
DK 154432 B
18
Smp. 0 C
e) 1,2,3,4,Aa, 5-hexahydro-3,10-dimethyl- 7- (2 * -chlorphenyl) -pyrazino [l, 2-a] [l, 4]-benzodiazepin 145 - 147 f) 1,2,3,4,4a,5-hexahydro-9-brom-3,10-di-5 methyl-7-(2’-clilorphenyl)-pyTazlno[l, 2-a]- [l,4]benzodiazepin 106 - 108 g) 1,2,3,4,4a, 5-hexahydro-3,9,10-trimethyl- 7-phenyl-pyrazino[l, 2-a] [l, 4]benzodiazepin 139 - 140 h) 1,2,3,4,4a, 5-hexahydro-3-methyl-7-phenyl- 10 pyrazino[l, 2-a] [l, 4]benzodiazepin 111 - 114 i) 1,2,3,4,4a,5-hexahydro-9-fluor-3-methyl- 7-phenyl-pyrazino[l,2-a][l,4]benzodiazepin-dihydrochlorid . 0,3 mol ethanol 200 x x) nedbrydning 15 k) 1,2,3,4,4a,5-hexahydro-9-nitro-3-methyl- 7-phenyl-pyrazino[l,2-a][l,4]benzodiazepin 191 - 194 l) 1,2,3,4,4a,5-hexahydro-9,10-dichlor-3-me-thyl-7-phenyl-pyrazino[l,2-a] [l,4]benzodiazepin 158 - 160 m) 1,2,3,4,4a, 5-hexahydro-10-methoxy-3-methyl- 20 7-phenyl-pyrazino[l,2-a][l,4]benzodiazepin 121 - 123 n) 1,2,3,4,4a,5-hexahydro-3-methyl-7-(21-chlorphenyl) -pyrazino [l, 2-a] [l,4]benzodiazepin 136 - 138 EKSEMPEL 7 3,7 g 7-ehlor—1-(p-chlorethyl)-2-chlormethyl-5-phenyl-25 2,3-dihydro-lH-l,4-benzodiazepin opvarmes i 50 ml benzyl- amin til 120° C i 5,5 timer. Derefter afdampes det over-
DK 154432 B
19 skydende benzylamin i vakuum, reaktionsproduktet tilsættes fortyndet natriumhydroxidopløsning og isoleres fra chloroform. Det fra ethanol omkrystalliserede 1,2,3»4,4a, 5-hexahydro-9-chlor-3-benzyl-7-phenyl-pyrazino[l,2-a]-5 [l,4]benzodiazepin-dihydrochlorid . 1 mol ethanol har et smp. på 236 - 239° C (nedbrydning). Udbytte 3 g.
Tilsvarende får man ud fra 7-chlor-1-(β -chlorethyl)-2-chlormethyl-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin med henholdsvis β-methoxyethylamin, 1,3-aminopropanol, 10 phenethylamin, isopentylamin og neopentylamin de følgende forbindelser:
Smp. ° C
1,2,3,4,4a,5-hexahydro-9-chlor-3-(β-methoxy-ethyl)-7-phenylpyrazino[l,2-a][l,4]benzo-15 diazepindihydrochlorid . 0,7 mol H2O 237 - 240 1,2,3,4,4a,5-hexahydro-9-chlor-3-( If -hydroxy-propyl)-7-phenylpyrazino[l,2-a][l,4]benzodia-zepindihydrochlorid . 1 mol ^O 250 x 1,2,3,4,4a, 5-hexahydro-9-chlor-3- (phenethyl) -20 7-phenylpyrazino[l,2-a][l,4]benzodiazepin 119 - 121 1,2,3,4,4a,5-hexahydro-9-chlor-3-isopentyl-7-phenylpyrazino[l,2-a][l,4]benzodiazepin-dihydrochlorid . 0,5 mol l^O . 1 mol ethanol 240 - 245 1,2,3,4,4a,5-hexahydro-9-chlor-3-neopentyl-25 7-phenylpyrazino[l,2-a][l,benzodiazepin- dihydrochlorid . 0,3 mol H^O . 1 mol ethanol 215 x x) nedbrydning
DK 154432 B
20 EKSEMPEL 8 4,0 g 1,2,3,4,4a,5-hexahydro-9--chlor-3-(β-hydr oethyl)-7-phenyl-pyrazino[l, 2-a] [l, 4]benzodiazepin-dihydro-chlorid . 2,5 mol I^O opvarmes med 15 ml thionylchlorid 5 under tilbagesvaling i 20 minutter. Derpå afdampes opløsningsmidlet, basen frigøres med fortyndet vandig natriumhydroxidopløsning under isafkøling og isoleres fra chloroform. Ved omkrystallisation fra isopropanol opnås 3,2 g 1,2,3,4,4a, 5-hexahydro-9-chlor-3- ( β-chlorethyl) -7-phenyl-10 pyrazino[l,2-a][l,4]benzodiazepin-dihydrochlorid . 1,0 mol I^O . 0,6 mol isopropanol med smp. 220° C (nedbrydning).
EKSEMPEL 9 5,5 g l,2,4,4a-tetrahydro-7-(2,-chlorphenyl)-5H-15 [l,4]oxazino[4,3-a][l,4]benzodiazepin opløses i 45 ml eddike syr eanhydr id og tilsættes ved 35° C portionsvis 5,-14 g kobber (Il)-nitrat-trihydrat. Temperaturen holdes i 1,5 timer, hvorefter reaktionsopløsningen hældes ud på is.
Efter tilsætning af vandig fortyndet natriumhydroxidopløs-20 ning og ammoniakopløsning isoleres reaktionsproduktet fra . chloroform. Efter søolechromatografi på aluminiumoxid af aktivitetstrin II med methylenchlorid/chloroform opnås fra ether 2,0 g krystallinsk 1,2,4,4a-tetrahydro-9-nitro-7-(2'-chlorphenyl)-5H[l,4]oxazino[4,3-a][l,4]benzodiaze-25 pin med smp. 164 - 166° C og 1,2 g isomert l,2,4,4a-tetra-hydro-ll-nitro-7-(21-chlorphenyl)-5H[l,4]oxazino[4,3-a]- [l,4]benzodiazepin som olie IR: 1595, 1615 cm (C=C, C=N).
På tilsvarende måde får man ud fra det 5-phenylsubstitue-30 rede derivat. l,2,4,4a-tetrahydro-9-nitro-7-phenyl-5H[l,4]-oxazino[4,3-a][l,4]benzodiazepin med smp. 142 - 145° C og 1,2,4,4a-tetrahydro-ll-nitro-7-phenyl-5H[l, 4] oxazino-[4,3-a][l,4]benzodiazepin med smp. 184 - 186° C.
DK 154432B
21 EKSEMPEL 10 4,9 g 1,2,3,4,4,a,5-hexahydro-9-chlor-3-(p-chlorethyl)-7-phenyl-pyrazino [l, 2-a ] [l ,4 ]benzodiazepin-dihydro-chlorid. 1,0 mol H^O .0,6 mol isopropanol sættes til en 5 opløsning af 0,75 g natrium i 70 ml methanol og opvarmes i 5 timer under' tilbagesvaling. Den efter afdampning af opløsningsmidlet tilbageværende remanens opløses i chloroform, og den organiske fase vaskes med vand. Efter afdampning af opløsningsmidlet opnås 3,3 g l,2,3,4,4a,5-hexa-10 hydr o-9-chlor-3- ( β-methoxyethyl)-7-phenyl-pyrazino [l, 2-a]- [l,4]benzodiazepin. Stoffet krystalliserer fra ethanol som dihydrochlorid med 0,7 mol vand med smp. 237 - 240° C.
EKSEMPEL 11 4.0 g 1,2,3,4,4a,5-hexahydro-9-chlor-3-(β-hydroxyethyl)- 15 7-phenyl-pyrazino [l, 2-a] [l, 4]benzodiazepin-dihydroDhlorid.
2,5 mol H^O sættes til 0,8 g natriumhydrid i 100 ml dime-thylformamid. Efter tilsætning af 1,5 g methyliodid får reaktionsopløsningen lov at stå i 4 timer ved stuetemperatur. Det efter afdampning af opløsningsmidlet opnåede rå-20 produkt renses ved chromatografi på aluminiumoxid af aktivitetstrin II med chloroform. Der opnås 1,7 g 1,2,3,4, 4a, 5-hexahydr o-9-chlor-3- ( β-methoxyethyl) -7-phenyl-pyrazino [l, 2-a] [l,4]benzodiazepin. Stoffet krystalliserer fra ethanol som dihydrochlorid med 0,7 mol vand med smp. 237 -25 240° C.
EKSEMPEL 12 10.0 g l,2,4,4a-tetrahydro-5-(2,fluorphenyl)-5H[l,4]-oxazino[4,3-a][l,4]benzodiazepin i 150 ml methylenchlorid opvarmes med 6,0 g N-bromsuecinimid under tilbagesvaling 30 i 3,5 timer. Efter sædvanlig oparbejdning opnås 4,D g o-lieagtigt 1,2,4,4a-tetrahydro-9-brom-7-(2 * fluorphenyl)-SHI!,4]oxazino[4,3-a][l,4]-benzodiazepin; IR: 1610 cm-1.
Claims (2)
1. Analogifremgangsmåde til fremstilling af [1,2]-anellerede 7-phenyl-l,4-benzodiazepiner med den almene formel I r4>Cn (I) r V^~r1 R2 hvori X betyder 0, S eller NR, hvor r betyder hydrogen, 5 alkyl med 1-5 carbonatomer, som eventuelt er substitueret i endestilling med phenyl, som kan være substitueret med 1 eller 2 methoxygrupper eller med 3,4-methylendioxy eller 3,4-ethylendioxy·, eller R betyder alkyl med 2-5 carbonatomer, som er substitueret i endestilling med ha-10 logen, hydroxy eller methoxy, eller R betyder alkenyl med 3-5 carbonatomer, og r1 - r5 er ens eller forskellige og hver for sig betyder hydrogen, halogen, trifluormethyl,. -nitro, alkyl, alkoxy eller alkylthio, hvor alkylgruppen kan indeholde 1-4 carbonatomer, eller to nabostillede 15 grupper tilsammen betyder methylendioxy eller ethylen- . dioxy, eller farmaceutisk acceptable syreadditionssalte deraf, kendetegnet ved, at en forbindelse med formlen i DK 154432 B rue — ch9y r5 I ) (II) R3-Rl hvori R1 - R3 har den ovenstående betydning, og Y og Z er ens eller forskellige og hver for sig betyder en reaktiv gruppe, såsom halogen, især chlor eller brom, toluen-sulfonyloxy. , benzensulfonyloxy eller methansulfonyloxy, 5 ringsluttes i nærvær af et alkalimetal- eller jordalka- limetalhydroxid, alkalimetal- eller jordalkalimetalcar-bonat, alkalimetal- eller j ordalkalimetalsulfid eller en aminoforbindelse RNl^» hvor R har den ovenstående betydning, eller det tilsvarende alkalimetalamid ved tempe-10 raturer mellem 60 og 120° C, eventuelt i nærvær af et inert opløsningsmiddel, hvorpå den dannede base om ønsket overføres i et farmaceutisk acceptabelt syreadditionssalt deraf, eller, om ønsket, den frie base isoleres fra syreadditionssaltet.
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at de reaktive grupper Y og Z er ens og betyder chlor eller toluensulfonyloxy. DK 154432 B Fremgangsmåde til fremstilling af (1,2)- anellerede 7 phe-nyl-1,4-benzodiazepiner eller syreadditionssalte SAMMENDRAG: [l5 2 ]^-ane lierede 7-phenyl-l, 4-benzodiazepiner med formlen r3——r1 R2 hvori X er >0, >S eller ^NR, hvor R er C-^_^-alkyl, som eventuelt bærer en endestillet phenylgruppe, der kan være substitueret med 1 eller 2 methoxygrupper eller med en 3,4-methylendioxy- eller 3,4-ethylendioxygruppe, eller R er C? ς-alkylsubstitueret med halogen, hydroxy eller me-^ -2 15 thoxy, eller R er C^_^-alkenyl, og R - Rv er hydrogen, halogen, trifluormethyl, nitro, C^^-alkyl, C^^-alkoxy eller C^_^-alkylthio, eller to nabostillede grupper tilsammen er methylendioxy eller ethylendioxy, eller syreadditionssalte deraf fremstilles ved ringslutning af for- bindeiser med formeln II DK 154432 HpC------ R5 I r3 —— r1 hvor Y og Z erens eller forskellige reaktive grupper, i nærvær af et alkalimetal- eller jordalkalimetalhyd.ro-xid, -carbonat eller -sulfid eller en aminoforbindelse RNH^ eller det tilsvarende alkalimetalamid ved temperaturer mellem 60 og 120° C, eventuelt i nærvær af et inert opløsningsmiddel. De reaktive grupper Y og Z er fortrinsvis begge chlor eller toluensulfonyloxy. Forbindelserne I udviser ved ringe CNS-virkning en god virkning på ulcus i maven og duodenum.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2835708 | 1978-08-16 | ||
| DE19782835708 DE2835708A1 (de) | 1978-08-16 | 1978-08-16 | Neue eckige klammer auf 1,2 eckige klammer zu-anellierte 7-phenyl-1,4-benzodiazepinderivate, verfahren zu deren herstellung und arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK341479A DK341479A (da) | 1980-02-17 |
| DK154432B true DK154432B (da) | 1988-11-14 |
| DK154432C DK154432C (da) | 1989-04-10 |
Family
ID=6047065
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK341479A DK154432C (da) | 1978-08-16 | 1979-08-15 | Analogifremgangsmaade til fremstilling af (1,2)-anellerede 7-phenyl-1,4-benzodiazepiner eller farmaceutisk acceptable syreadditionssalte deraf |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US4338314A (da) |
| EP (1) | EP0008045B1 (da) |
| JP (1) | JPS5559189A (da) |
| AT (1) | ATE260T1 (da) |
| AU (1) | AU530949B2 (da) |
| CA (1) | CA1126729A (da) |
| DE (2) | DE2835708A1 (da) |
| DK (1) | DK154432C (da) |
| ES (1) | ES483387A1 (da) |
| FI (1) | FI65431C (da) |
| GR (1) | GR82414B (da) |
| HU (1) | HU178256B (da) |
| IE (1) | IE48800B1 (da) |
| IL (1) | IL57922A (da) |
| NO (1) | NO151121C (da) |
| NZ (1) | NZ191311A (da) |
| PH (1) | PH16155A (da) |
| PT (1) | PT70006A (da) |
| SU (1) | SU904526A3 (da) |
| ZA (1) | ZA794234B (da) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3151597A1 (de) * | 1981-12-28 | 1983-07-07 | Kali-Chemie Pharma Gmbh, 3000 Hannover | (1,2)-anellierte 1,4-benzodiazepin-verbindungen sowie verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| FR2521563A1 (fr) * | 1982-02-17 | 1983-08-19 | Lipha | Benzodiazepines-1,3 condensees, procedes de preparation et medicaments les contenant |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1695211U (de) | 1954-08-04 | 1955-03-24 | Bertram Fa Ludwig | Kaiserschnitt-tuch fuer schweine. |
| US3523947A (en) * | 1966-11-23 | 1970-08-11 | Hoffmann La Roche | 1-cyclic amidine-5-aryl-1,4-benzodiazepine and process |
| US3734912A (en) * | 1971-05-04 | 1973-05-22 | Upjohn Co | Certain pyrimido(1,2-a)(1,4)benzodiazepin-1(5h)-ones |
| NL7107667A (da) | 1971-06-04 | 1972-12-06 | ||
| BE790356A (fr) * | 1971-10-21 | 1973-04-20 | Takeda Chemical Industries Ltd | Derives de benzodiazepine |
| BE790508A (fr) | 1971-10-26 | 1973-04-25 | Hoffmann La Roche | Derives de benzodiazepine |
| US3822259A (en) * | 1971-11-02 | 1974-07-02 | Upjohn Co | 7-phenyl-1h(1,3)-oxazino(3,2-a)(1,4)benzodiazepine-1,3(2h)-diones |
| US3875181A (en) * | 1971-12-20 | 1975-04-01 | Hoffmann La Roche | 3-Acetyl-(1,2 -a)imidazo-1,4-benzodiazepines |
| DE2520937C3 (de) * | 1975-05-10 | 1978-10-12 | Kali-Chemie Ag, 3000 Hannover | 7-Brom-1 -methyl^-alkoxymethyl-S-(2-halogenphenyl)-lH-23-dihydro-l,4benzodiazepinderivate, deren Säureadditionssalze und pharmazeutische Präparate |
| DE2221558C2 (de) * | 1972-05-03 | 1982-12-02 | Kali-Chemie Ag, 3000 Hannover | 5-Phenyl-2,3-dihydro-1H-1,4-benzodiazepine und ihre Säureadditionssalze, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
| CH567031A5 (da) * | 1972-05-18 | 1975-09-30 | Ciba Geigy Ag | |
| NL7315281A (da) * | 1972-11-13 | 1974-05-15 | ||
| US4006135A (en) * | 1974-06-19 | 1977-02-01 | Ddsa Pharmaceuticals | Hydroxymethyl benzodiazepine derivatives |
-
1978
- 1978-08-16 DE DE19782835708 patent/DE2835708A1/de not_active Withdrawn
-
1979
- 1979-07-27 AT AT79102678T patent/ATE260T1/de not_active IP Right Cessation
- 1979-07-27 DE DE7979102678T patent/DE2961136D1/de not_active Expired
- 1979-07-27 EP EP79102678A patent/EP0008045B1/de not_active Expired
- 1979-07-30 IL IL57922A patent/IL57922A/xx unknown
- 1979-07-31 PT PT70006A patent/PT70006A/pt unknown
- 1979-08-07 PH PH22874A patent/PH16155A/en unknown
- 1979-08-07 SU SU792798349A patent/SU904526A3/ru active
- 1979-08-10 HU HU79KA1534A patent/HU178256B/hu unknown
- 1979-08-10 IE IE1538/79A patent/IE48800B1/en unknown
- 1979-08-13 ZA ZA00794234A patent/ZA794234B/xx unknown
- 1979-08-13 GR GR59829A patent/GR82414B/el unknown
- 1979-08-14 ES ES483387A patent/ES483387A1/es not_active Expired
- 1979-08-14 FI FI792524A patent/FI65431C/fi not_active IP Right Cessation
- 1979-08-14 NZ NZ191311A patent/NZ191311A/xx unknown
- 1979-08-15 AU AU49941/79A patent/AU530949B2/en not_active Ceased
- 1979-08-15 NO NO792671A patent/NO151121C/no unknown
- 1979-08-15 DK DK341479A patent/DK154432C/da not_active IP Right Cessation
- 1979-08-16 US US06/067,146 patent/US4338314A/en not_active Expired - Lifetime
- 1979-08-16 CA CA333,936A patent/CA1126729A/en not_active Expired
- 1979-08-16 JP JP10362679A patent/JPS5559189A/ja active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| NO792671L (no) | 1980-02-19 |
| IE48800B1 (en) | 1985-05-15 |
| FI65431B (fi) | 1984-01-31 |
| JPS5559189A (en) | 1980-05-02 |
| NZ191311A (en) | 1982-03-16 |
| AU530949B2 (en) | 1983-08-04 |
| DE2961136D1 (en) | 1981-12-10 |
| ES483387A1 (es) | 1980-04-16 |
| DE2835708A1 (de) | 1980-03-06 |
| CA1126729A (en) | 1982-06-29 |
| PH16155A (en) | 1983-07-12 |
| IE791538L (en) | 1980-02-16 |
| AU4994179A (en) | 1980-02-21 |
| EP0008045A1 (de) | 1980-02-20 |
| DK154432C (da) | 1989-04-10 |
| NO151121C (no) | 1985-02-13 |
| NO151121B (no) | 1984-11-05 |
| DK341479A (da) | 1980-02-17 |
| JPS634545B2 (da) | 1988-01-29 |
| IL57922A0 (en) | 1979-11-30 |
| GR82414B (da) | 1984-12-13 |
| HU178256B (en) | 1982-04-28 |
| EP0008045B1 (de) | 1981-09-30 |
| SU904526A3 (ru) | 1982-02-07 |
| PT70006A (en) | 1979-08-01 |
| ZA794234B (en) | 1980-08-27 |
| FI65431C (fi) | 1984-05-10 |
| ATE260T1 (de) | 1981-10-15 |
| FI792524A7 (fi) | 1980-02-17 |
| US4338314A (en) | 1982-07-06 |
| IL57922A (en) | 1982-12-31 |
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