NO152048B - Analogifremgangsmaate ved fremstilling av nye, terapeutisk aktive 5h-2,3-benzodiazepinderivater - Google Patents
Analogifremgangsmaate ved fremstilling av nye, terapeutisk aktive 5h-2,3-benzodiazepinderivater Download PDFInfo
- Publication number
- NO152048B NO152048B NO793349A NO793349A NO152048B NO 152048 B NO152048 B NO 152048B NO 793349 A NO793349 A NO 793349A NO 793349 A NO793349 A NO 793349A NO 152048 B NO152048 B NO 152048B
- Authority
- NO
- Norway
- Prior art keywords
- general formula
- denotes
- benzodiazepine
- methyl
- ethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 25
- YVOHCRLDUPTKOH-UHFFFAOYSA-N 5h-2,3-benzodiazepine Chemical class C1C=NN=CC2=CC=CC=C12 YVOHCRLDUPTKOH-UHFFFAOYSA-N 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 60
- -1 hydroxy, acetoxy Chemical group 0.000 claims description 22
- 239000007858 starting material Substances 0.000 claims description 20
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 239000011541 reaction mixture Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 5
- DQZLFOAQOCSCBJ-UHFFFAOYSA-N isochromenylium Chemical class C1=[O+]C=CC2=CC=CC=C21 DQZLFOAQOCSCBJ-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 3
- UUDYWELSMJWOIM-UHFFFAOYSA-N isochromen-6-one Chemical compound O1C=CC2=CC(=O)C=CC2=C1 UUDYWELSMJWOIM-UHFFFAOYSA-N 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 72
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000001953 recrystallisation Methods 0.000 description 27
- 239000000203 mixture Substances 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000000155 melt Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- RUJBDQSFYCKFAA-UHFFFAOYSA-N Tofisopam Chemical compound N=1N=C(C)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 RUJBDQSFYCKFAA-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical class [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960002501 tofisopam Drugs 0.000 description 4
- KCWLEYXMVGFASS-OOJLDXBWSA-N 6-methyl-n-[(1s)-1-phenylethyl]-2,3,4,9-tetrahydro-1h-carbazol-1-amine Chemical compound C1([C@@H](NC2C3=C(C4=CC(C)=CC=C4N3)CCC2)C)=CC=CC=C1 KCWLEYXMVGFASS-OOJLDXBWSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 125000003310 benzodiazepinyl group Chemical group N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- QIMSZSRNPDUPBF-UHFFFAOYSA-N 1-(2-fluorophenyl)-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine Chemical compound FC1=C(C=CC=C1)C1=NN=C(CC2=C1C=C(C(=C2)OC)OC)C QIMSZSRNPDUPBF-UHFFFAOYSA-N 0.000 description 2
- OBLULRQNQYXFMR-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-5-ethyl-4,7,8-trimethyl-5h-2,3-benzodiazepine Chemical compound N=1N=C(C)C(CC)C2=CC(C)=C(C)C=C2C=1C1=CC=C(OC)C(OC)=C1 OBLULRQNQYXFMR-UHFFFAOYSA-N 0.000 description 2
- GBOHYJOUGVPNSU-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-5h-2,3-benzodiazepine-4-carbaldehyde Chemical compound N=1N=C(C=O)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 GBOHYJOUGVPNSU-UHFFFAOYSA-N 0.000 description 2
- DFPIIEOUMLCAGE-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-5-ethyl-8-methoxy-4-methyl-5H-2,3-benzodiazepin-7-ol Chemical compound N=1N=C(C)C(CC)C2=CC(O)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 DFPIIEOUMLCAGE-UHFFFAOYSA-N 0.000 description 2
- MWBAHRRFJNAKHK-UHFFFAOYSA-N 5-ethyl-1-(3-hydroxy-4-methoxyphenyl)-8-methoxy-4-methyl-5H-2,3-benzodiazepin-7-ol Chemical compound N=1N=C(C)C(CC)C2=CC(O)=C(OC)C=C2C=1C1=CC=C(OC)C(O)=C1 MWBAHRRFJNAKHK-UHFFFAOYSA-N 0.000 description 2
- HXKGMQQAXQUEDH-UHFFFAOYSA-N 5-ethyl-7,8-dimethoxy-4-methyl-1-phenyl-5h-2,3-benzodiazepine Chemical compound N=1N=C(C)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=CC=C1 HXKGMQQAXQUEDH-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- BJYYAMSOIWQPBN-UHFFFAOYSA-N ethyl 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-5h-2,3-benzodiazepine-4-carboxylate Chemical compound C12=CC(OC)=C(OC)C=C2C(CC)C(C(=O)OCC)=NN=C1C1=CC=C(OC)C(OC)=C1 BJYYAMSOIWQPBN-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- SQMCFUSVGSBKFK-UHFFFAOYSA-M sodium;5-(cyclohexen-1-yl)-1,5-dimethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].O=C1N(C)C(=O)[N-]C(=O)C1(C)C1=CCCCC1 SQMCFUSVGSBKFK-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DWFDQVMFSLLMPE-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanone Chemical compound FC1=CC=CC=C1C(=O)C1=CC=CC=C1 DWFDQVMFSLLMPE-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- KZOARBQGIQVJDQ-UHFFFAOYSA-N 1-(2-benzoyl-4,5-dimethoxyphenyl)propan-2-one Chemical compound C1=C(OC)C(OC)=CC(CC(C)=O)=C1C(=O)C1=CC=CC=C1 KZOARBQGIQVJDQ-UHFFFAOYSA-N 0.000 description 1
- NUYJXPGEZFOLHN-UHFFFAOYSA-N 1-(2-chlorophenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5h-2,3-benzodiazepine Chemical compound N=1N=C(C)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=CC=C1Cl NUYJXPGEZFOLHN-UHFFFAOYSA-N 0.000 description 1
- HLWPRKYYGMQUDR-UHFFFAOYSA-N 1-(2-chlorophenyl)-7,8-diethoxy-4-methyl-5h-2,3-benzodiazepine Chemical compound C1=2C=C(OCC)C(OCC)=CC=2CC(C)=NN=C1C1=CC=CC=C1Cl HLWPRKYYGMQUDR-UHFFFAOYSA-N 0.000 description 1
- BSDRAQVJZCAZRN-UHFFFAOYSA-N 1-(2-chlorophenyl)-7,8-dimethoxy-4-methyl-5h-2,3-benzodiazepine Chemical compound C1=2C=C(OC)C(OC)=CC=2CC(C)=NN=C1C1=CC=CC=C1Cl BSDRAQVJZCAZRN-UHFFFAOYSA-N 0.000 description 1
- GHQPUNHBHNDUPF-UHFFFAOYSA-N 1-(2-chlorophenyl)-7,8-dimethoxy-4-methyl-5h-2,3-benzodiazepine;hydrochloride Chemical compound Cl.C1=2C=C(OC)C(OC)=CC=2CC(C)=NN=C1C1=CC=CC=C1Cl GHQPUNHBHNDUPF-UHFFFAOYSA-N 0.000 description 1
- PMZRRWSCBGXFCI-UHFFFAOYSA-N 1-(3,4-dihydroxyphenyl)-5-ethyl-4-methyl-5H-2,3-benzodiazepine-7,8-diol Chemical compound OC=1C=C(C=CC1O)C1=NN=C(C(C2=C1C=C(C(=C2)O)O)CC)C PMZRRWSCBGXFCI-UHFFFAOYSA-N 0.000 description 1
- MIUNVEYMOCLRAV-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-4,5-diethyl-7,8-dimethoxy-5h-2,3-benzodiazepine Chemical compound N=1N=C(CC)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 MIUNVEYMOCLRAV-UHFFFAOYSA-N 0.000 description 1
- PXCRHBKDVLDPNR-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-4-ethyl-7,8-dimethoxy-5-methyl-5h-2,3-benzodiazepine Chemical compound C12=CC(OC)=C(OC)C=C2C(C)C(CC)=NN=C1C1=CC=C(OC)C(OC)=C1 PXCRHBKDVLDPNR-UHFFFAOYSA-N 0.000 description 1
- SNLLFFAPVUTMFJ-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-4-ethyl-7-methoxy-3-methylisochromen-6-one Chemical compound C=12C=C(OC)C(=O)C=C2C(CC)=C(C)OC=1C1=CC=C(OC)C(OC)=C1 SNLLFFAPVUTMFJ-UHFFFAOYSA-N 0.000 description 1
- XFYJTSJKEJXPAH-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-propyl-5h-2,3-benzodiazepine Chemical compound C12=CC(OC)=C(OC)C=C2C(CC)C(CCC)=NN=C1C1=CC=C(OC)C(OC)=C1 XFYJTSJKEJXPAH-UHFFFAOYSA-N 0.000 description 1
- VUULZNYCOILCIO-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-5h-2,3-benzodiazepine Chemical compound C12=CC(OC)=C(OC)C=C2C(CC)C=NN=C1C1=CC=C(OC)C(OC)=C1 VUULZNYCOILCIO-UHFFFAOYSA-N 0.000 description 1
- AFNXIFIFZDQRMT-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-5h-2,3-benzodiazepine-4-carboxylic acid Chemical compound N=1N=C(C(O)=O)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 AFNXIFIFZDQRMT-UHFFFAOYSA-N 0.000 description 1
- VCQFUVLZFBNFJG-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-5-ethyl-8-methoxy-4-methyl-7-propan-2-yloxy-5h-2,3-benzodiazepine Chemical compound N=1N=C(C)C(CC)C2=CC(OC(C)C)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 VCQFUVLZFBNFJG-UHFFFAOYSA-N 0.000 description 1
- WPRPCLBGSNSPRO-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-5-ethyl-8-methoxy-4-methyl-7-propoxy-5h-2,3-benzodiazepine Chemical compound C1=2C=C(OC)C(OCCC)=CC=2C(CC)C(C)=NN=C1C1=CC=C(OC)C(OC)=C1 WPRPCLBGSNSPRO-UHFFFAOYSA-N 0.000 description 1
- WYDFDZHLWJDEQZ-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-7,8-dimethoxy-4,5-dimethyl-5h-2,3-benzodiazepine Chemical compound C1=C(OC)C(OC)=CC=C1C1=NN=C(C)C(C)C2=CC(OC)=C(OC)C=C12 WYDFDZHLWJDEQZ-UHFFFAOYSA-N 0.000 description 1
- YNFUOHOMZKWXLU-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-7,8-dimethoxy-4-methyl-5h-2,3-benzodiazepine Chemical compound C1=C(OC)C(OC)=CC=C1C1=NN=C(C)CC2=CC(OC)=C(OC)C=C12 YNFUOHOMZKWXLU-UHFFFAOYSA-N 0.000 description 1
- JCMFGVRRVKRCCA-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-7-ethoxy-5-ethyl-8-methoxy-4-methyl-5h-2,3-benzodiazepine Chemical compound C1=2C=C(OC)C(OCC)=CC=2C(CC)C(C)=NN=C1C1=CC=C(OC)C(OC)=C1 JCMFGVRRVKRCCA-UHFFFAOYSA-N 0.000 description 1
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- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
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- AAVAGGUKVWHXPC-UHFFFAOYSA-N ethyl 2-[[1-(3,4-dimethoxyphenyl)-5-ethyl-8-methoxy-4-methyl-5H-2,3-benzodiazepin-7-yl]oxy]acetate Chemical compound COC=1C=C(C=CC1OC)C1=NN=C(C(C2=C1C=C(C(=C2)OCC(=O)OCC)OC)CC)C AAVAGGUKVWHXPC-UHFFFAOYSA-N 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/02—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 2
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse angår en analogifremgangsmåte for fremstilling av terapeutisk aktive 5H-2,3-benzodiazepinderi-vater av generell formel I:
hvori
R betegner en fenylgruppe som eventuelt er substituert med 1
til 3 halogen-, hydroxy-, acetoxy-, C^_^-alkoxy-, trifluor-methyl-, nitro- og/eller p-klorbenzyloxy- eller benzyloxy-substituenter, eller betegner en benzyl-, 2-tolyl-, 2-furyl-eller 2-thienylgruppe,
R betegner et hydrogenatom, en C-^_^-alkyl- eller
fo2rmylgruppe eller en carboxylsyre-C, .-alkylester,
R betegner et hydrogenatom, C1_4~alkyl, fenyl som er substituert med to C, .-alkoxygrupper,
R <3>betegner hydrogen, C1_3~alkyl, C1_5~alkoxy, hydroxy, acetoxy, carbethoxymethoxy, C1_5-dialkylaminoalkoxy eller 2-klorbenzyloxy, R4 betegner hydrogen eller halogen, C^^-alkyl, C1_5-alkoxy, hydroxy, acetoxy, benzyloxy eller p-klorbenzyloxy,
forutsatt at hvis R betegner 3,4-dimethoxyfenyl, R<1> er methyl
2 3 4
og R er ethyl, er R og R forskjellig fra methoxy,
eller et farmasøytisk akseptabelt syreaddisjonssalt derav-
De nye forbindelser med den generelle formel I har mere betydningsfulle sentralnervevirkninger enn 1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin (tofizopam eller Grandaxin), den eneste hittil syntetiserte 5H-2,3-diazepin-forbindelse. Syntesen og de biologiske egenskaper av Grandaxin er beskrevet i ungarsk patent 155 572, US patent 3 736 315 og sveitsisk patent 519 507.
Analogifremgangsmåten ifølge oppfinnelsen er kjenne-tegnet ved at et 1,5-diketon av generell formel (II):
12 3 4 hvori R, R , R , R og R er som ovenfor definert, et 2-benzopyriliumsalt av generell formel (III): 12 3 4 hvori R, R , R , R og R er som ovenfor definert, og X betegne klorid-, jodid-, tetrafluorborat-, tetraklorferrat-, hexaklor-stannat-, hydrosulfat-, dihydrofosfat- eller perklorat-anion', et 6H-2-benzopyran-6-on av generell formel (IV): 12 4 hvori R, R , R og R er som ovenfor definert, eller en iso-kromenforbindelse av generell formel (V):
hvori R, R1, r2, r3 og R<4> er som ovenfor definert, og R<5> betegner hydrogen og R<6> betegner en fenylgruppe,
omsettes med 1 til 5 mol hydrazin, hydrazinhydrat eller et hydrazin-C1_3~carboxylat, og når en forbindelse av generell formel (II) anvendes som utgangsmateriale, at en uorganisk syre tilsettes til reaksjonsblandingen etter omsetning av utgangs-forbindelsen med hydrazinforbindelsen, og, om ønsket, at forbindelser av generell formel (I) inneholdende fenoliske hydroxygrupper, alkyleres eller aralkyleres etter kjente metoder, eller acyleres i nærvær av et syrbindende middel eller at en acyl-gruppe hydrolyseres til en hydroxygruppe på kjent måte, og at forbindelser av generell formel (I) hvori R''" betegner en methyl-gruppe, fortrinnsvis oxyderes med selendioxyd, mens forbindelser av generell formel (I) hvori R"<*>" betegner en carboxygruppe, decarboxyleres, og/eller, om ønsket, at en fri base av generell formel (I) omdannes til dets farmasøytisk akseptable syreaddisjonssalt, eller at et salt av et 5H-2,3-benzodiazepinderivat av generell formel (I) omdannes til den frie base eller i et annet syreaddisjonssalt.
De farmasøytisk godtagbare syreaddisjonssalter av forbindelsene med den generelle formel (I) kan fremstilles ved å omsette de frie baser, f.eks. med saltsyre, hydrogenbromid, fosforsyre, svovelsyre eller perklorsyre. Når noen av substitu-entene bundet til benzodiazepinringen inneholder et mere basisk nitrogenatom, kan også organiske syrer, som eddiksyre, vinsyre, melkesyre, maleinsyre eller fumarsyre, anvendes som saltdannende midler.
5H-2, 3—benzodiazepinderivatene med den generelle formel (I) renses i alminnelighet, før saltdanningstrinnet, men de urene baser kan imidlertid også underkastes saltdannelse. Hvis en fri base med den generelle formel (I) er vanskelig å krystallisere, foretrekkes det å overføre den til et godt krystalliserbart salt, som rhodanat eller hydroklorid, fra hvilket basen kan frigjøres i ren tilstand, om ønskes.
Hvis et 2-benzopyriliumsalt med den generelle formel (III) anvendes som utgangsmateriale, utføres reaksjonen i nærvær av et syrebindingsmiddel. Et overskudd av hydrazin eller hydrazin-hydrat anvendes bekvemt som syrebindingsmiddel, men alkalimetallhydroxyder, -carbonater, -hydrocarbonater eller organiske baser, f .eks. pyridin eller triethylamin, kan også anvendes. Om nødvendig kan utgangsforbindelsene med de generelle formler (II) , (III) , (IV) og (V) overføres til hverandre før man omsetter dem med hydrazinreaktanten. I henhold til en foretruk-ken fremgangsmåte tilsettes hydrazinreaktanten direkte til den dannede reaksjonsblanding.
Forbindelsene med de generelle formler (II) , (III) og (IV) , som anvendes som utgangsmaterialer ved fremstillingen av benzodiazepinderivatene med den generelle formel (I), er beskrevet i eller kan fremstilles i henhold til de følgende referanser: Ber. Deut. Chem. Ges. 75, 891 (1942), 76, 855 (1943), 77, 6, 343
(1944); J. Am. Chem. SoC 72, 1118 (1950); Acta Chim. Acad. Sei. Hung. 40, 295 (1964), 41, 451 (1964), 57, 181 (1968); Mh. Chem. 96, 369 (1965); ungarsk patent 158 091;
J. Chem. Soc. 1933, 555; J. Org. Chem. L4, 204 (1949);
Ch. Org. Khim. 2, 1492 (1966); Chem. Abstr. 66, 46286p (1967); Dokl. Akad. Nauk. 166, 359 (1966); Khim. eterotsikl. Soedin. 1970, 1003, 1308, 1971, 730; Chem. Abstr. 74 , 12946d, 76293w
(1971), 76, 25035x (1972); Chem. Ber. 104, 2984 (1971); Synthesis 1971, 423.
6H-2-benzopyran-6-on-forbindelsene med den generelle formel (IV) kan også foreligge i den tautomere 2-benzopyrilium-6-oxydform svarende til den generelle formel:
12 4
hvor R, R , R og R er som ovenfor angitt. Uttrykket "en forbindelse med den generelle formel (IV)" omfatter begge disse tautomerer så vel som eventuelle blandinger derav.
Basert på resultatene av de farmakologiske studier har de nye 5H-2,3-benzodiazepinderivater som fremstilles ifølge oppfinnelsen, betraktelige sentralnervesystemvirkninger. Disse forbindelser nedsetter den spontane motor-aktivitet og potensierer virkningene av narkotika.
Forsøkene ble utført på mus. Ved undersøkelsen av den gnerelle oppførsel ble dyrene behandlet intraperitonealt med 100 mg/kg eller oralt med 200 mg/kg av forsøksforbindelsen. Kampoppførselsprøven ble utført ved fremgangsmåten ifølge Tedeschi et al. (J. Pharm. Exp. Ther. 2_5, 28 (1959)). Iakttatel-sene hva angår den generelle oppførsel av dyrene og ED^Q-verdiene erholdt i kampoppførselsforsøket er angitt i tabell 1. I disse forsøk ble 1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin (Grandaxin) anvendt som referanseforbindelse.
Ved undersøkelse av den narkosepotenslerende effekt ble benzodiazepinforbindelsene administrert til mus i orale doser på 12,5, 25, 50 og 100 mg/kg, og 30 minutter senere ble 50 mg/kg natrium-hexobarbital injisert intravenøst i dyrene. Den prosent-vise forlengelse av narkoseperioden, sammenlignet med verdien iakttatt i kontrollgruppen behandlet med bare natriumhexobarbital, ble beregnet. I disse forsøk ble igjen Grandaxin anvendt som referanseforbindelse. Resultatene er angitt i tabell 2.
Data i tabell 1 og 2 viser klart de fordelaktige egenskaper av de nye fremgangsmåteforbindelser.
De nye fremgangsmåteforbindelser kan overføres til farmasøytiske preparater (som tabletter, belagte tabletter, kapsler, oppløsninger, suspensjoner, injeksjonspreparater, etc.) ved metoder vel kjent i faget, ved å blande dem med konvensjonelle farmasøytiske bærere, fortynningsmidler og/eller andre tilsetnin-ger .
Oppfinnelsen belyses detaljert ved de følgende ikke-begrensende eksempler.
Eksempel 1
Fremstilling av 1-( 4- klorfenyl)- 4- methyl- 7, 8- dimethoxy- 5H- 2, 3-benzodiazepin
1,13 g (2,73 mmol) 1-(4-klorfenyl)-3-methyl-6,7-dimethoxy-2-benzopyrilium-perklorat suspenderes i 10 ml methanol. Suspensjonen oppvarmes til kokning og 1,0 ml 98 %-ig hydrazin-hydrat tilsettes. Blandingen inndampes, residuet blandes med
vann, frafiltreres så og tørres. 0,87 g (2,65 mmol) av titelforbindelsen fåes, sm.p. 188 - 198° C. Råproduktet omkrystalliseres fra 30 ml ethanol hvorved man får 0,6312 g (1,92 mmol, 72,5 %) av et hvitt krystallinsk stoff som smelter ved 209 - 211° C.
C18<H>17<C>1N2°2 = 328'8-
Eksempel 2- 18
Fremgangsmåten beskrevet i eksempel 1 ble gjentatt med den forskjell at andre 2-benzopyriliumsalter ble anvendt som utgangsmaterialer, og reaksjonen ble utført i methanol, ethanol eller isopropanol. De følgende forbindelser ble erholdt (den empiriske formel, molekylvekt, smeltepunkt og omkrystallisasjons-medium er angitt for hvert av produktene): Eksempel 2
1-fenyl-4-methyl-5-ethyl-7-methoxy-5H-2,3-benzodiazepin; <C>19H20<N>2° <=><2>92'4' sm-P-: 162 _ 163° c (isopropanol).
Eksempel 3
1-fenyl-4-methyl-5-ethyl-8-methoxy-5H-2,3-benzodiazepin; <C>19H20<N>2° <=><2>92'4' sm-P-: 134 " 135° c (isopropanol).
Eksempel 4
1-(4-methoxyfenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzo-diazepin; C21H24N2°3 <=><3>^2'4' sm'P- 157 - 159° C (isopropanol).
Eksempel 5
1-fenyl-4-methy1-5-(3,4-dimethoxyfenyl)-7,8-dimethoxy-5H-2,3-
benzodiazepin; C26H26<N>2°4 <=> 430'5' sm-P- 90 ~ 93° c (ethanol og vann).
Eksempel 6
1-(3,4-dimethoxyfenyl)-4,5-dimethyl-7,8-dimethoxy-5H-2,3-benzo-diazepin; C2iH24N2°4 <=> 368'4' sm-P- 201 ~ 203° C (1:3 blanding av kloroform og isopropanol).
Eksempel 7
1-(4-methoxyfenyl)-4-methyl-5-(3,4-dimethoxyfenyl)-7,8-dimethoxy-5H-2,3-benzodiazepi<n>} <C>27<H>2<gN>204 = 460,5, sm.p. 99 - 102° C (ethanol).
Eksempel 8
1-(3,4-dimethoxyfenyl)-4,8-dimethyl-5-ethyl-5H-2,3-dibenzodia-ze<pin;><C>2i<H>24<N>2°2 = 33^'4' sm-P- 156 - 158° C (isopropanol).
Eksempel 9
1-(2-tolyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin; C21H24N2°2 = <3>3^'4' sm-P- 17° ~ 171° C (isopropanol).
Eksempel 10
1-(3,4-dimethoxyfenyl)-4-methyl-5-n-buty1-7,8-dimethoxy-5H-2,3-benzodiazepin-hydrat; C2<4H>3Q<N>2<0>4.H20= 428,5, sm.p. 93 - 96° C (ethanol).
Eksempel 11
1-(3-methoxy-4-[p-klorbenzyloxy]-fenyl)-4-methyl-5-ethyl-7-methoxy-8-(p-klorbenzyloxy)-5H-2,3-benzodiazepin; C34<H>3<2C1>2N204= 603,6, sm.p. 103 - 105° C (isopropanol).
Eksempel 12
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-8-klor-5H-2,3-benzodia-zepin; C20H21ClN2O2 = 356,9, sm.p. 185 - 187° C (isopropanol).
Eksempel 13
1-(3,4-dimethoxyfenyl)-4-methyl-5-n-propyl-7,8-dimethoxy-5H-2,3-benzodiazepin-hydra<t;><C>23H28<N>2°4<*>H2° = 414'5' sm-P- 92 - 96° C (ethanol). Forbindelsen som ikke inneholder krystallvann smelter ved 143 - 145° C.
Eksempel 14
1-(3,4-dimethoxyfenyl)-4,5-diethyl-7,8-dimethoxy-5H-2,3-benzo-diazepin; C23H28N2°4<=> 396'5' sm-P- 142 ~ 144° C (isopropanol).
Eksempel 15
1-(3,4-dimethoxyfenyl)-4-n-propyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin; <C>24H30<N>2°4 <=><4>10'5' sm.p. 132 - 134° C (40 % isopropanol ) .
Eksempel 16
1-(3,4-dimethoxyfenyl)-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin-4-carboxylsyre-ethyleste<r;><C>24<H>28<N>2°6 = 440'5' sm-P- 178 180° C (abs. ethanol).
Eksempel 17
1-(2-fluorfenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodia-ze<pin;><C>2qH2^FN202 = 340,4, sm.p. 86 - 88° C (ethanol og vann).
Eksempel 18
1- (3 ,4-dimethoxyf enyl) -4-e.thyl-5-methyl-7 ,8-dimethoxy-5H-2 , 3-benzodiazepin; <C>22H2gN2<0>4<=> 382,5, sm.p. 157 - 158° C (isopropanol ) .
Eksempel 19
Fremstilling av 1-( 3- methoxy- 4- benzyloxyfenyl)- 4- methyl- 5- ethyl-7- methoxy- 8- benzyloxy- 5H- 2, 3- benzodiazepin
8,4 ml rent (100 %) hydrazinhydrat ble tilsatt dråpevis til en omrørt suspensjon av 17,77 g (28,5 mmol) 1-(3-methoxy-4-benzyloxyfenyl)-3-methyl-4-ethyl-6-methoxy-7-benzyloxy-2-benzo-pyrilium-perklorat i 30 ml iseddik ved 80 - 88° C. Reaksjonsblandingen ble omrørt ved 95 - 100° C i 1 time, deretter ble 180 ml 2 %-ig vandig natriumhydroxydoppløsning tilsatt til blandingen. Det utskilte rå 5H-2,3-benzodiazepin-derivat ble ekstrahert i.80 ml kloroform, kloroformfasen ble vasket med 50 ml 1 %-ig vandig natriumhydrogencarbonatoppløsning og 50 ml vann, tørket over ■ natriumsulfat og derpå inndampet. Residuet ble omkrystallisert fra 30 ml methanol. Man fikk 12,57 g (82 %) av titelforbindelsen som et svakt beige, nesten hvitt krystallinsk stoff.
C34H34N204 = 534,7, sm.p. 135 - 137° C.
Hydrokloridet fra produktet (C34H35N204C1 = 571,1) spaltes ved 212 - 213° C etter omkrystallisasjon fra ethanol og vann.
Eksempel 20 - 22
Fremgangsmåten beskrevet i eksempel 19 ble gjentatt med den forskjell at andre 2-benzopyriliumsalter ble anvendt som
utgangsmateriale. De følgende forbindelser ble erholdt:
Eksempel 20
1-(3-methoxy-4-n-butoxyfenyl)-4-methyl-5-ethyl-7-methoxy-8-n-butoxy-5H-2,3-benzodiazepin; <C>28<H>38<N>2°4 = 466'6' sm.p. 108 -
110° C (isopropanol).
Eksempel 21
1-(3-methoxy-4-ethoxyfenyl)-4-methyl-5-ethyl-7-methoxy-8-ethoxy-5H-2,3-benzodiazepin; <C>24<H>30<N>2°4 <=><4>10'5' sm-P- 146 " 148° c (omkrystallisert fra methanol og så kokt i vann). Hydrokloridet av denne forbindelse (C24<H>31N2<0>4C1 = 447,9) spaltes ved 188 - 190° C etter omkrystallisasjon fra methanol.
Eksempel 22
1-(3-methoxy-4-n-propoxyfenyl)-4-methyl-5-ethyl-7-methoxy-8-n-propoxy-5H-2,3-benzodiazepin; <C>26H34N2°4<=> 438'6/ sm-P- 92 ~ 94°C (isopropanol). Hydrokloridet av denne forbindelse (<C>2<gH>3^<N>204Cl= 475,1) spaltes ved 191 - 192° C etter omkrystallisasjon fra methanol og aceton.
Eksempel 23
Fremstilling av 1-( 3, 4, 5- trimethoxyfenyl)- 4- methyl- 5- ethyl- 7, 8-dimethoxy- 5H- 2, 3- benzodiazepin
1,40 g (3,36 mmol) 2-(1-ethylacetonyl)-3 4 ,4 ' , 5, 5 '-pentamethoxybenzofenon oppløses i 5,4 ml isopropanol, og 0,17 5 ml konsentrert svovelsyre tilsettes dråpevis til oppløsningen. Reaksjonsblandingen oppvarmes til kokning, omrøres ved denne temperatur i 1 time, deretter avkjøles blandingen til 60° C og 0,41 ml
(8 mmol) 98 %-ig hydrazinhydrat tilsettes. Den dannede blanding omrøres i ytterligere 1 time. 0,154 g natriumhydrogencarbonat tilsettes i porsjoner til blandingen, blandingen oppvarmes til kokning, avfarves med trekull, filtreres, filtratet inndampes og residuet føres over på et filter med tilsammen 25 ml vann.
Man får 0,835 g (60,5 %) av titelforbindelsen med smeltepunkt
152 - 155° C. Etter omkrystallisasjon fra en liten mengde isopropanol smelter produktet ved 160 - 162° C. <C>23<H>28N2°5 = 412,5.
Eksempel 24
Fremstilling av 1-( 3, 4- dimethoxyfenyl)- 4- methyl- 7, 8- dimethoxy- 5H-2, 3- benzodiazepin
Man går frem som beskrevet i eksempel 23 med den forskjell at 2-acetonyl-3',4,4<1>,5-tetramethoxybenzofenon anvendes som utgangsmateriale. Titelforbindelsen smelter ved 158 - 159°C etter omkrystallisasjon fra absolutt ethano<l.><C>20<H>22N2°4 = 3 54,4.
Eksempel 25
Fremstilling av 1-( 4- klorfenyl)- 4- methyl- 5- ethyl- 7, 8- dimethoxy-5H- 2, 3- benzodiazepin
Man går frem som beskrevet i eksempel 23 med den forskjell at 2-(1-ethylacetonyl)-4,5-dimethoxy-4'-klorbenzofenon anvendes som utgangsmateriale. Titelforbindelsen smelter ved 160 - 162° C etter omkrystallisasjon fra isopropanol.
C20<H>21<C>1N2°2 = 356'9-
Eksempel 2 6
Fremstilling av 1-( 2- klorfenyl)- 4- methyl- 5- ethyl- 7, 8- dimethoxy-5H- 2, 3- benzodiazepin
En blanding av 10,37 g (28,9 mmol) 2-(1-ethylacetonyl)-4 , 5-dimeT!thoxy-2 '-klorbenzof enon, 10,5 ml iseddik og 2,65 ml konsentrert saltsyre oppvarmes til 9 5° C under omrøring. Blandingen avkjøles til 60° C, og 2,14 ml 98 %-ig hydrazinhydrat tilsettes til blandingen i porsjoner, hvorpå temperaturen av blandingen heves til 85° C. Etter 30 minutter tilsettes en oppløsning av 1,4 4 g natriumhydroxyd i 4,5 ml vann til blandingen, fulgt av 10 ml methanol. Den erholdte oppløsning helles i 130 ml vann,
og det utskilte 5H-2,3-benzodiazepinderivat isoleres. Man får 9,04 g (88 %) av titelforbindelsen med smeltepunkt 129 - 131° C. C20H21C1N2°2 = 356'9* Råproduktet kan omkrystalliseres f.eks. fra ethanol. Produktet med den høyeste renhetsgrad smelter ved 147 - 149° C. Rhodanidsaltet av titelforbindelsen (<C>20<H>22<C>1N2C>2-SCN = 425,95) smelter ved 169 - 171° C etter omkrystallisasjon fra isopropanol.
Eksempel 2 7
Fremstilling av 1- fenyl- 4- methyl- 7, 8- dimethoxy- 5H- 2, 3- benzo-diazepin
Man går frem som beskrevet i eksempel 26 med den forskjell at 2-acetonyl-4,5-dimethoxybenzofenon anvendes som utgangsmateriale. Titelforbindelsen smelter ved 169 - 170° C etter om-krystallisas jon fra methanol, dimethylformamid og vann.
<C>18<H>18<N>2°2 <=><2>94'4-
Eksempel 28
Fremstilling av l- benzyl- 4- methyl- 7, 8- dimethoxy- 5H- 2, 3-benzodiazepin
0,13 ml 98 %-ig hydrazinhydrat tilsettes til en varm oppløsning av 0,75 g (2,4 mmol) benzyl-(2-acetonyl-4,5-dimethoxyfenyl)-keton i 20 ml isopropanol. Blandingen kokes i 1 time og inndampes så til en femtedel av sitt opprinnelige volum, hvorpå titelforbindelsen fraskilles som et krystallinsk stoff som smelter ved 116 - 118° C. <C>19<H>20<N>2°2 <=><3>08'4-
Eksempel 29
Fremstilling av 1-( 2- jodfenyl)- 4- methyl- 7, 8- dimethoxy- 5- 2, 3-benzodiazepin
En blanding av 2,26 g (5,32 mmol) 2-acetony.l-4,5-dimethoxy-21 -jodbenzofenon, 20 ml methanol og 0,75 ml rent (100 %) hydrazinhydrat kokes i 20 minutter. Blandingen inndampes, residuet blandes med vann og filtreres. De erholdte 2,2 g av 1-(2-hydrazonopropyl)-4,5-dimethoxy-2'-jodbenzofenon oppløses i 20 ml methanol mettet med gassformig hydrogenklorid, og oppløsningen inndampes. Residuet gjøres alkalisk med 5 %-ig vandig natrium-hydroxydoppløsning. Det utskilte 5H-2,3-benzodiazepinderivat frafiltreres og vaskes med 5 x 3 ml vann. Man får 1,57 g (71 %) av titelforbindelsen med smeltepunkt 115 - 117° C (forbindelsen krymper fra 78° C) . C^gH^II^G^ .H20 = 438,3. Hydrokloridet av titelforbindelse<n> (<C>l8HlgIN202Cl = 456,7) spaltes ved 166 - 168°C etter omkrystallisasjon fra ethanol og ether.
Eksempel 3 0
Fremstilling av 1-( 2- klorfenyl)- 4- methyl- 7, 8- diethoxy- 5H- 2, 3-benzodiazepin
Man går frem som beskrevet i eksempel 29 med den forskjell at 2-acetonyl-4,5-diethoxy-2'-klorbenzofenon anvendes som utgangsmateriale. Titelforbindelsen smelter ved 150 - 152° C etter omkrystallisasjon fra isopropan<ol.><C>2<q>H2^C1N202 = 356,9.
Eksempel 31
Fremstilling av 1-( 2- klorfenyl)- 4- methyl- 7, 8- dimethoxy- 5H- 2, 3-benzodiazepin- hydroklorid
Man går frem som beskrevet i eksempel 26 med den forskjell at 2-acetonyl-4,5-dimethoxy-2'-klorbenzofenon anvendes som utgangsmateriale. Det dannede rå 1-(2-klorfenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepin behandles med absolutt ethanol inneholdende saltsyre for å få det rene hydroklorid. C18H18C1N2°2C1 = 365'3- Titelforbindelsen spaltes ved 186 - 188° C etter omkrystallisasjon fra absolutt ethanol og ether.
Eksempel 32
Fremstilling av 1-( 2- jodfenyl)- 4- methyl- 5- ethyl- 7, 8- dimethoxy-5H- 2, 3- benzodiazepin- hydroklorid
Man går frem som beskrevet i eksempel 26 med den forskjell at 2-(1-ethylacetonyl)-4,5-dimethoxy-2'-jodbenzofenon anvendes som utgangsmateriale. Det dannede rå 1-(2-jodfenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin behandles med absolutt ethanol inneholdende hydrogenklorid for å få det rene hydroklorid. C20H22IN2O2Cl = 484,8. Titelforbindelsen spaltes ved 168 - 170° C etter omkrystallisasjon fra absolutt ethanol og ether.
Eksempel 33
Fremstilling av 1-( 2- fluorfenyl)- 4- methyl- 7, 8- dimethoxy- 5H- 2, 3-benzodiazepin
Man går frem som beskrevet i eksempel 26 med den forskjell at 2-acetonyl-4,5-dimethoxy-2<1->fluorbenzofenon anvendes som utgangsmateriale. Det rå 1-(2-fluorfenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepin behandles med isopropanol inneholdende hydrogenklorid for å få rent hydroklorid. C^gH^gFN202Cl = 348,8. Titelforbindelsen smelter ved 175 - 178 C etter omkry-stallsasjon fra isopropanol og ether.
Eksempel 34
Fremstilling av 1-( 3, 4- dimethoxyfenyl)- 4, 7, 8- trimethyl- 5- ethyl-5H- 2, 3- benzodiazepin
5 ml absolutt ethanol inneholdende hydrogenklorid tilsettes til 1,33 g rått 1-(3,4-dimethoxyfenyl)-4,7,8-trimethyl-5-ethyl-5H-2,3-benzodiazepin, en forbindelse fremstilt ved fremgangsmåten beskrevet i eksempel 1, og den dannede oransjerød oppløsning inndampes. Residuet oppløses i 5 ml vann, og 0,5 g ammoniumrhodanin tilsettes til oppløsningen. Det utskilte mate-riale f raf Utreres, vaskes med 6 x 2 ml vann og tørres. Man fikk 1,48 g rått 1-(3,4-dimethoxyfenyl)-4,7,8-trimethyl-5-ethyl-5H-2,3-benzodiazepinrhodanid med smeltepunkt 132 - 134° C. Etter omkrystallisasjon fra isopropanol smelter saltet ved 142 - 144°C. ken titelforbindelse kan frigjøres fra det omkrystalliserte rhodanid ved å behandle det med et alkali- eller ammoniumhydroxyd. <C>22<H>26<N>2°2'<H>2° <=> 368,5. Produktet omkrystallisert fra isopropanol og vann krymper fra 79° C.
Eksempel 3 5
Rensning av 1- fenyl- 4- methyl- 5- ethyl- 7, 8- dimethoxy- 5H- 2, 3-benzodiazepin over rhodanidet
Man går frem som beskrevet i eksempel 34 med den forskjell at urent 1-fenyl-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin anvertdes som utgangsmateriale. Det rene rhodanid av denne forbindelse smelter ved 175 - 177° C etter omkrystallisasjon fra absolutt ethanol. Basen frigjort fra rhodanidet inneholder krystallvann (C^H^^C^. H20 = 340,4) og krymper fra 77°C (etter omkrystallisasjon fra ethanol og vann).
Eksempel 3 6
Fremstilling av l- benzyl- 4, 5- dimethyl- 7, 8- dimethoxy- 5H- 2, 3-benzodiazepin
En blanding av 1,11 g (4,1 mmol) l-benzal-3,4-dimethyl-6,7-dimethoxyisokromen, 5,5 ml isopropanol og 0,25 ml (5,2 mmol) 98 %-ig hydrazinhydrat kokes i 3 timer og avkjøles så. Titelforbindelsen utskilles fra blandingen i ren tilstand. (-:20H22N2<^2 = 322,4, sm.p. 136 - 138° C (etter omkrystallisasjon fra isopropanol).
Isokromenforbindelsen som anvendes som utgangsmateriale, fremstilles som følger: En blanding av 2,08 g (10 mmol) a-methyl-3,4-dimethoxy-fenylaceton, 1,36 g (10 mmol) fenyleddiksyre og 20 g polyfosfor-syre holdes ved 100° C i 10 minutter. Den tykke, honninglignende reaksjonsblanding oppløses i 100 ml vann, og den guligbrune opp-løsnings pH innstilles på 6 med fast natriumcarbonat. Man får 2,16 g (73 %) rått l-benzal-3,4-dimethyl-6,7-dimethoxy-isokromen. Etter omkrystallisasjon fra ethanol smelter forbindelsen ved
158 - 160° C.
Eksempel 3 7
Fremstilling av l- benzyl- 4- methyl- 5- ethyl- 7, 8- dimethoxy- 5H-2, 3- benzodiazepin
Man går frem som beskrevet i eksempel 36 med den forskjell- at l-benzal-3-methyl-4-ethyl-6,7-dimethoxyisokromen anvendes som utgangsmateriale. Titelforbindelsen smelter ved 133 - 135° C etter omkrystallisasjon fra isopropanol.
C21H24N2°2 = 336'4-
Eksempel 3 8
Fremstilling av 1-( 3, 4- dimethoxyfenyl)- 4- methyl- 5- ethyl- 7-hydroxy- 8- methoxy- 5H- 2, 3- benzodiazepin
a) 34,5 ml 98 %-ig hydrazinhydrat tilsettes dråpevis i løpet av 5 minutter til en omrørt oppløsning av 115 g (0,325 mol)
1-(3,4-dimethoxyfenyl)-3-methyl-4-ethyl-7-methoxy-6H-2-benzo-pyran-6-on i 115 ml iseddik. Under denne operasjon holdes opp-løsningen ved 80 - 110° C. Oppløsningen neddykkes i et vannbad
(95 - 100° C) i 1 time, fortynnes så med 140 ml 2 %-ig vandig natriumhydroxydoppløsning og avkjøles. 5H-2,3-benzodiazepin-derivatet utskilles som et beige, krystallinsk stoff. De faste stoffer frafiltreres, vaskes med 4 x 50 ml vann og tørres. Man får 111,7 g råprodukt med smeltepunkt 210 - 212° C. For å rense råproduktet oppløses det i 225 ml dimethylformamid ved 100 -
130° C, og oppløsningen avfarves med 2 g aktivert kull. Kullet frafiltreres og vaskes med 3 x 50 ml dimethylformamid. Oppløs-ningen fortynnes med 13 00 ml destillert vann, hvorpå det rene produkt utskilles i krystallinsk form. Man får 110,35 g (94 %)
av titelforbindelsen med smeltepunkt 210 - 212° C. Ifølge gass-kromatografisk undersøkelse er renhetsgraden av produktet over 9<9><%.><C>21<H>24<N>2<0>4 = 369,4.
Hydrokloridet av produktet (C^H^IS^O^jCl) spaltes ved
218 - 220° C etter omkrystallisasjon fra isopropanol.
b) 1,2 ml 98 %-ig hydrazinhydrat tilsettes dråpevis til en omrørt suspensjon av 4,35 g (0,01 mol) 1-(3,4-dimethoxyfenyl)-3-methyl-4-ethyl-6-hydroxy-7-methoxy-2-benzopyroliumbromid i 15 ml 50 %-ig vandig eddiksyre ved 80 - 100° C. Blandingen oppvarmes til 90 - 100° C og fortynnes med 200 ml 10 %-ig vandig natrium-kloridoppløsning, hvorpå råproduktet utskilles. Råproduktet kan renses ved å felle det med vann fra en dimethylformamid- eller ethanoloppløsning. Utbyttet varierer mellom 92 % og 95 %. Produktet smelter ved 210 - 212° C, og ingen smeltepunktsnedsettelse kan iakttas når det blandes med forbindelsen fremstilt ved fremgangsmåte a) . c) Man går frem som beskrevet under punkt a) med den forskjell at iseddiken erstattes med et tidobbelt volum methanol.
Etter 1 times kokning inndampes oppløsningen og residuet, eventuelt behandlet med vann, omkrystalliseres fra dimethylformamid og vann som beskrevet under punkt a). Titelforbindelsen, som smelter ved 210 - 212° C, fåes i et utbytte på 95 %.
Eksempel 39 - 44
De følgende hydroxyfenyl-5H-2,3-benzodiazepinderivater fremstilles som beskrevet i metodene a) - c) i eksempel 38: Eksempel 39
1-(3-methoxy-4-hydroxyfenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin; C2l<H>2<4N>2°4 = 368,4, sm.p. 130 - 132° C
(ethanol og vann).
Eksempel 4 0
1-(4-methoxy-3-hydroxyfenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepin; C20H22N2°4 = 3^4,4, sm.p. 143 - 14 <5> C (ethanol og vann). Perkloratet av forbindelsen
(C20H23N2°4 C104) spaltes ved 196 - 198° C etter omkrystallisasjon fra isopropanol.
Eksempel 41
1-(3-methoxy-4-hydroxyfenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepin; G20H22N2°4 = 3->4'4' sm-P- 210 212° C under spaltning (dimethylformamid og vann).
Eksempel 4 2
1-(3,4-dihydroxyfenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepin; C]_9H20N2°4 = 340,4' sm.p. 254 - 255° C under spaltning (dimethylformamid og vann). Hydrobromidet av forbindelsen (CigH21N204Br) spaltes ved 206 - 208° C etter omkrystallisasjon fra ethylacetat.
Eksempel 43
1-(3-methoxy-4-hydroxyfenyl)-4-methyl-5-ethyl-7,8-dihydroxy-5H-2,3-benzodiazepin;
C19H20<N>2°4 = 340'4' sm-P- 252 - 253° C under spaltning (dimethylformamid og vann). Hydrosulfatet av forbindelsen (ci9H21<N>2°4 HS04) spaltes ved 195 - 198° C etter omkrystallisasjon fra ethylacetat.
Eksempel 44
1-(3,4-dihydroxyfenyl)-4-methyl-5-ethyl-7,8-dihydroxy-5H-2,3-benzodiazepin; ci8Hi8N2°4<=> 326,3, sm.p. 250 - 251° under spaltning (dimethylformamid og vann). Hydrokloridet av forbindelsen (C18HigN204Cl) spaltes ved 268 - 270° C etter omkrystallisasjon fra isopropanol.
Eksempel 45- 50
Acetylering av l- aryl- 5H- 2, 3- benzodiazepiner med den generelle formel ( I) sominneholder én eller flere fenoliske hydroxygrupper 5 mmol utgangsmateriale med den generelle formel (I) inneholdende én eller flere fenoliske hydroxygrupper suspenderes i 5 ml tørr pyridin ved 20 - 25° C, og et 50 % overskudd av eddiksyreanhydrid, beregnet på antallet av fenoliske hydroxygrupper, tilsettes. Blandingen varmes bare meget svakt og det faste stoff oppløses hurtig. Reaksjonsblandingen holdes ved 20 - 25° C i 5 - 20 timer, og derpå felles det acerylerte produkt med 5 0 ml vann. Råproduktet omkrystalliseres fortrinnsvis fra isopropanol eller vandig isopropanol.
I ovenstående reaksjon kan også acetylklorid anverides i stedet for eddiksyreanhydrid, og pyridinmediet kan erstattes av for eksempel triethylamin eller en benzen-, aceton- eller dimethyl-formamidoppløsning av et alkalimetallcarbonat.
De følgende forbindelser ble fremstilt i henhold til ovenstående fremgangsmåte: Eksempel 4 5
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-acetoxy-8-methoxy-5H-2,3-benzodiazepin; sm.p. 175 - 176° C.
Eksempel 4 6
1-(3-methoxy-4-acetoxyfenyl)-4-methyl-5-ethyl-7-methoxy-8-acetoxy-5H-2,3-benzodiazepin, sm.p. 178 - 180° C.
Eksempel 47
1-(4-methoxy-3-acetoxyfenyl)-4-methyl-5-ethyl-7-acetoxy-8-
methoxy-5H-2,3-benzodiazepin, sm.p. 168 - 170° C.
Eksempel 4 8
1-(3,4-diacetoxyfenyl)-4-methyl-5-ethyl-7-acetoxy-8-methoxy-5H-2,3-benzodiazepin, sm.p. 153 - 155° C.
Eksempel 4 9
1-(3-methoxy-4-acetoxyfenyl)-4-methyl-5-ethyl-7,8-diacetoxy-5H-2,3-benzodiazopin, sm.p. 162 - 164° C.
Eksempel 50
1-(3,4-diacetoxyfenyl)-4-methyl-5-ethyl-7,8-diacetoxy-5H-2,3-benzodiazepin, sm.p. 120 - 122° C.
Eksempel 51
Fremstilling av 1-( 4- methoxy- 3- hydroxyfenyl)- 4- methyl- 5- ethyl- 7-hydroxy- 8- methoxy- 5H- 2, 3- benzodiazepin
En blanding av 0,44 g 1-(4-methoxy-3-acetoxyfenyl)-4-methyl-5-ethyl-7-acetoxy-8-methoxy-5H-2,3-benzodiazepin (fremstilt som beskrevet i eksempel 47), 8 ml ethanol, 8 ml vann og 0,4 g kaliumhydroxyd omrøres i en nitrogenatmosfære i 15 minutter.
50 ml 20 %-ig vandig natriumkloridoppløsning og 0,6 g ammonium-klorid tilsettes til oppløsningen. Bunnfallet fraskilles og omkrystalliseres fra 7,5 ml 20 %-ig vandig dimethylformamid. Man får 0,23 g rent 1-(4-methoxy-3-hydroxyfenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepin som spaltes ved 210 -
212° C. Denne forbindelse er identisk med produktet erholdt i eksempel 41, og ingen smeltepunktsdepresjon kan sees når de to produkter blandes,med hverandre.
Eksempel 52
Fremstilling av 1-( 3, 4- dimethoxyfenyl)- 5- ethyl- 7, 8- dimethoxy- 5H-2, 3- benzodiazepin
Ethyl-1-(3,4-dimethoxyfenyl)-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin-4-carboxylat (forbindelsen fremstilt i henhold til eksempel 16) hydrolyseres til 1-(3,4-dimethoxyfenyl)-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin-4-carboxylsyre som spaltes ved 133 - 135° C. Denne forbindelse kan decarboxyleres hurtig i varm dimethylformamid for å få titelforbindelsen som smelter ved 149 - 161° C etter omkrystallisasjon fra isopropanol.
<C>21<H>24N2°4 = 368'4-
Eksempel 53
Fremstilling av 1-( 3, 4- dimethoxyfenyl)- 4- formyl- 5- ethyl- 7, 8-dimethoxy- 5H- 2, 3- benzodiazepin
6,05 g selendioxyd tilsettes i løpet av 1,5 timer til
en omrørt suspensjon av 19,1 g (0,05 mol) 1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepin i 150 ml 80 %-ig vandig dioxan ved en innvendig temperatur på 84 - 87° C. Det metalliske selen fjernes fra blandingen ved klaring, og den gule oppløsning inndampes i vakuum. Det tykke, honninglignende residuum omrøres med 100 ml vann, hvorpå titelforbindelsen utskilles som et gult pulver. Produktet frafiltreres, vaskes med 5 x 10 ml vann og tørres i vakuum. Man får 19,3 g (96 %) rått l-(3,4-dimethoxyfenyl)-4-formyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiaze-pin med smeltepunkt 103 - 105° C. Etter omkrystallisasjon fra acetom og cyclohexan smelter produktet ved 108 - 110° C, <C>22<H>24N2°5 = 396'45'
Eksempel 54 - 62
Den fenoliske hydroxy-gruppe i 1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepin, forbindelsen erholdt i eksempel 38, alkyleres eller aralkyleres på i og for seg kjent vis hvorved man får de følgende produkter: Eksempel 54
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-n-butoxy-8-methoxy-5H-2,3-benzodiazepin; <C>^<H>^^O^ = 424,5, sm.p. 147 - 150° C (isopropanol) .
Eksempel 55
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-isopropoxy-8-methoxy-5H-2,3-benzodiazepin; <C>24H3Q<N>2<0>4 = 410,5, sm.p. 109 - 111° C (isopropanol).
Eksempel 56
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-(3-dimethylaminopropoxy)-8-methoxy-5H-2,3-benzodiazepin; <C>26<H>35<N>3°4 = 4^3'6' sm-P- 126 ~ 128° C (isopropanol).
Eksempel 57
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-sek-butoxy-8-methoxy-5H-2,3-benzodiazepin; <C>25<H>32N2°4 = 425'5' sm-P- 130 132° C
(50 % vandig ethanol).
I O Z U H O
Eksempel 58
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-ethoxy-8-methoxy-5H-2,3-benzodiazepin; <C>23<H>28<N>2°4 <=> 396, 4 ' sm-P- 125 ~ 127° c -(5° % vandig ethanol).
Eksempel 5 9
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-n-propoxy-8-methoxy-5H-2,3-benzodiazepin; <C>24<H>3Q<N>2<0>4 <=><4>10,5, sm.p. 110 - 112° C (50 % vandig ethanol).
Eksempel 60
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-(2-diethylaminoethoxy)-8-methoxy-5H-2,3-benzodiazepin-dihydroklorid; C27<H>3<gN>3<0>4Cl2<= >540,5, sm.p. 159 - 162° C under spaltning (isopropanol).
Eksempel 61
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-(2-klorbenzyloxy)-8-methoxy-5H-2,3-benzodiazepin, C28H2gClN204 = 493,0, sm.p. 150 - 151° C (80 % vandig ethanol).
Eksempel 62
1-(3,4-dimethoxyfenyl)-4-methyl-5-ethyl-7-carbethoxymethoxy-8-methoxy-5H-2,3-benzodiazepin; <C>25<H>3Q<N>206 = 454,5, sm.p. 141 - 142° C (50 % vandig ethanol).
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktive 5H-2,3-benzodiazepinderivater av generell formel I:hvori R betegner en fenylgruppe som eventuelt er substituert med 1 til 3 halogen-, hydroxy-, acetoxy-, C^_4~alkoxy-, trifluor- methyl-, nitro- og/eller p-klorbenzyloxy- eller benzyloxy-substituenter, eller betegner en benzyl-, 2-tolyl-, 2-furyl-eller 2-thienylgruppe,R"<*>" betegner et hydrogenatom, en C^_4~alkyl- eller fo2rmylgruppe eller en carboxylsyre-C, .-alkylester, R betegner et hydrogenatom, C-^^-alkyl, fenyl som er substituert med to C^_4-alkoxygrupper, i R3 betegner hydrogen, C^_3-alkyl, C?1_^-alkoxy, hydroxy, acetoxy, carbethoxymethoxy, C, _c.-dialkylaminoalkoxy eller 2-klorbenzyloxy, R <4>betegner hydrogen eller halogen, C-^^-alkyl, C-L_^-alkoxy, hydroxy, acetoxy, benzyloxy eller p-klorbenzyloxy, forutsatt at hvis R betegner 3,4-dimethoxyf enyl, R"*" er methyl 2 3 4 og R er ethyl, er R og R forskjellig fra methoxy, eller et farmasøytisk akseptabelt syreaddisjonssalt derav, karakterisert ved at et 1,5-diketon av generell formel (II): 12 3 4 hvori R, R , R , R og R er som ovenfor definert, et 2-benzopyriliumsalt av generell formel (III): 12 3 4 hvori R, R , R , R og R er som ovenfor definert, og X betegner klorid-, jodid-, tetrafluorborat-, tetraklorferrat-, hexaklor-stannat-, hydrosulfat-, dihydrofosfat- eller perklorat-anion, et 6H-2-benzopyran-6-on av generell formel (IV): 12 4 hvori R, R , R og R er som ovenfor definert, eller en iso-kromenforbindelse av generell formel (V): 1 2 3 4 5 hvori R, R , R , R og R er som ovenfor definert, og R betegner hydrogen og R^ betegner en fenylgruppe, omsettes med 1 til 5 mol hydrazin, hydrazinhydrat eller et hydrazin-C-L_3-carboxylat, og når en forbindelse av generell formel (II) anvendes som utgangsmateriale, at en uorganisk syre tilsettes til reaksjonsblandingen etter omsetning av utgangs-forbindelsen med hydrazinforbindelsen, og, om ønsket, at forbindelser av generell formel (I) inneholdende fenoliske hydroxygrupper,. alkyleres eller aralkyleres etter kjente metoder, eller acyleres i nærvær av et syrbindende middel eller at en acyl-gruppe hydrolyseres til en hydroxygruppe på kjent måte, og at forbindelser av generell formel (I) hvori R<1> betegner en methyl-gruppe, fortrinnsvis oxyderes med selendioxyd, mens forbindelser av generell formel (I) hvori R<1> betegner en carboxygruppe, decarboxyleres, og/eller, om ønsket, at en fri base av generell formel (I) omdannes til dets farmasøytisk akseptable syreaddisjonssalt, eller at et salt av et 5H-2,3-benzodiazepinderivat av generell formel (I) omdannes til den frie base eller i et annet syreaddisjonssalt.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU78GO1426A HU179018B (en) | 1978-10-19 | 1978-10-19 | Process for producing new 5h-2,3-benzodiazepine derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO793349L NO793349L (no) | 1980-04-22 |
| NO152048B true NO152048B (no) | 1985-04-15 |
| NO152048C NO152048C (no) | 1985-07-24 |
Family
ID=10996876
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO793349A NO152048C (no) | 1978-10-19 | 1979-10-18 | Analogifremgangsmaate ved fremstilling av nye, terapeutisk aktive 5h-2,3-benzodiazepinderivater |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US4322346A (no) |
| JP (1) | JPS5592377A (no) |
| AT (1) | AT373589B (no) |
| AU (1) | AU532079B2 (no) |
| BE (1) | BE879404A (no) |
| BG (1) | BG60270B2 (no) |
| CA (1) | CA1125749A (no) |
| CH (1) | CH643835A5 (no) |
| CS (1) | CS236456B2 (no) |
| DD (1) | DD146596A5 (no) |
| DE (1) | DE2940483A1 (no) |
| DK (1) | DK155327C (no) |
| ES (1) | ES485163A1 (no) |
| FI (1) | FI66604C (no) |
| FR (1) | FR2439189A1 (no) |
| GB (1) | GB2034706B (no) |
| GR (1) | GR74034B (no) |
| HU (1) | HU179018B (no) |
| IT (1) | IT1220947B (no) |
| NL (1) | NL190552C (no) |
| NO (1) | NO152048C (no) |
| PL (1) | PL124063B1 (no) |
| SE (1) | SE439919B (no) |
| SU (1) | SU1402258A3 (no) |
| YU (1) | YU41887B (no) |
Families Citing this family (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU186760B (en) * | 1981-03-12 | 1985-09-30 | Gyogyszerkutato Intezet | Process for preparing 3,4-dihydro-5h-2,3-aenzodiazepine derivatives |
| HU191702B (en) * | 1984-06-27 | 1987-03-30 | Gyogyszerkutato Intezet | New process for preparing 1-aryl-5 h-2,3-benzodiazepines |
| HU191698B (en) * | 1984-07-27 | 1987-03-30 | Gyogyszerkutato Intezet | Process for producing new 1-aryl-5h-2beta-benzodiazepines |
| HU195788B (en) * | 1986-05-21 | 1988-07-28 | Gyogyszerkutato Intezet | Process for producing 1-/hydroxy-stiryl/-5h-2,3-benzobiazepines and pharmaceutical compositions containing them |
| JPH01311400A (ja) * | 1988-06-09 | 1989-12-15 | Kyocera Corp | 発光標識体の点灯方法 |
| JPH0251568U (no) * | 1988-10-07 | 1990-04-11 | ||
| JPH0324693U (no) * | 1989-07-18 | 1991-03-14 | ||
| HU207055B (en) * | 1990-10-17 | 1993-03-01 | Gyogyszerkutato Intezet | Process for producing new 5h-2,3-benzodiazepine derivative and pharmaceutical compositions comprising same |
| HU208429B (en) * | 1991-05-03 | 1993-10-28 | Gyogyszerkutato Intezet | Process for producing 1-/3-chloro-phenyl/-4-methyl-7,8-dimethoxy-5h-2,3-benzodiazepine of high purity |
| ATE228115T1 (de) * | 1991-06-28 | 2002-12-15 | Smithkline Beecham Corp | Bizyklische fibrinogenantagonisten |
| US5939412A (en) * | 1992-06-26 | 1999-08-17 | Smithkline Beecham Corporation | Bicyclic fibrinogen antagonists |
| US6458784B1 (en) | 1994-06-29 | 2002-10-01 | Smithkline Beecham Corporation | Vitronectin receptor antagonists |
| SK283859B6 (sk) * | 1995-02-09 | 2004-03-02 | EGIS Gyógyszergyár Rt. | 1-[2'-(Substituovaný)vinyl]-5H-2,3-benzodiazepínové deriváty, spôsob ich prípravy a medziprodukty na ich prípravu, liečivá ich obsahujúce a ich použitie |
| DE69612413T2 (de) * | 1995-02-09 | 2001-09-27 | Egyt Gyogyszervegyeszeti Gyar | 1-(Hetero)Arylvinyl-5H-2,3-benzodiazepinderivative verwendbar zur Behandlung von Erkrankungen des Zentralnervensystems, sowie Benzopyrylium Intermediate zu ihrer Herstellung |
| HU224435B1 (hu) * | 1995-02-09 | 2005-10-28 | EGIS Gyógyszergyár Rt. | Benzodiazepin-származékok, eljárás előállításukra, alkalmazásukra és ezeket tartalmazó gyógyászati készítmények |
| US5977101A (en) * | 1995-06-29 | 1999-11-02 | Smithkline Beecham Corporation | Benzimidazoles/Imidazoles Linked to a Fibrinogen Receptor Antagonist Template Having Vitronectin Receptor Antagonist Activity |
| DE19604920A1 (de) * | 1996-02-01 | 1997-08-07 | Schering Ag | Neue 2,3-Benzodiazepinderivate, deren Herstellung und Verwendung als Arzneimittel |
| ES2111493B1 (es) * | 1996-02-08 | 1999-08-01 | Egyt Gyogyszervegyeszeti Gyar | Derivados de 1-(2- (vinilo substituido ) ) -5h-2,3-benzo-diazepina, procedimiento para su preparacion, composiciones farmaceuticas que los contienen y utilizaciones correspondientes. |
| ZA972746B (en) * | 1996-04-04 | 1998-10-09 | Egyt Gyogyszervegyeszeti Gyar | Novel 2,3-benzodiazepine derivatives |
| HU9600871D0 (en) * | 1996-04-04 | 1996-05-28 | Gyogyszerkutato Intezet | New 2,3-benzodiazepine derivatives |
| HUP9701284A3 (en) * | 1997-07-24 | 2005-11-28 | Egyt Gyogyszervegyeszeti Gyar | Use of 2,3-benzodiazepine derivatives for producing pharmaceutical compositions for treating and prophylacting illnesses and conditions connected with the endogene opioide system |
| HU227128B1 (en) * | 1999-07-07 | 2010-07-28 | Egyt Gyogyszervegyeszeti Gyar | New 2,3-benzodiazepine derivatives |
| FR2824065A1 (fr) * | 2001-04-26 | 2002-10-31 | Neuro3D | Composes inhibiteurs des phosphodiesterases des nucleotides cycliques, preparation et utilisations |
| US6649607B2 (en) * | 2001-05-18 | 2003-11-18 | Vela Pharmaceuticals, Inc. | Compositions and methods for treating or preventing convulsions or seizures |
| WO2004024163A1 (en) * | 2002-09-13 | 2004-03-25 | Motac Neuroscience Limited | Treatment of basal ganglia-related movement disorders with 2,3-benzodiazepines |
| WO2004026299A1 (en) * | 2002-09-17 | 2004-04-01 | Motac Neuroscience Limited | Treatment of dyskinesia |
| JP2006514084A (ja) * | 2002-12-03 | 2006-04-27 | ヴェラ ファーマスーティカルズ インコーポレイテッド | １−（３−ヒドロキシ−４−メトキシフェニル）−４−メチル−５−エチル−７，８−ジメトキシ−５ｈ−２，３−ベンゾジアゼピンの製薬組成物及びその用途 |
| CA2508542A1 (en) * | 2002-12-03 | 2004-06-17 | Vela Pharmaceuticals, Inc. | Pharmaceutical composition of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5h-2,3-benzodiazepine and uses thereof |
| US7022700B2 (en) * | 2002-12-03 | 2006-04-04 | Vela Pharmaceuticals, Inc. | Method of increasing neutrophil production using optically-pure (R)-2,3-benzodiazepines |
| US6864251B2 (en) * | 2002-12-03 | 2005-03-08 | Vela Pharmaceuticals, Inc. | Treatment of LTB4-mediated inflammatory disorders with optically-pure (R)-2,3-benzodiazepines |
| US6638928B1 (en) * | 2002-12-03 | 2003-10-28 | Vela Pharmaceuticals, Inc. | Treatment of irritable bowel syndrome and nonulcer dyspepsia with substituted 2,3-benzodiazepines |
| US20040162284A1 (en) * | 2003-02-19 | 2004-08-19 | Harris Herbert W. | Method of lowering body temperature with (S) tofisopam |
| US20040224943A1 (en) * | 2003-02-19 | 2004-11-11 | Leventer Steven M. | Method of lowering body temperature with (R) - 2,3-benzodiazepines |
| US20070021412A1 (en) * | 2003-05-16 | 2007-01-25 | Vela Pharmaceuticals, Inc. | Treatment of gastrointestinal dysfunction and related stress with an enantiomerically-pure (S) 2,3-benzodiazepine |
| JP4611308B2 (ja) * | 2003-05-16 | 2011-01-12 | ヴェラ アクイジション コーポレイション | 鏡像的に純粋な（ｒ）２，３−ベンゾジアゼピンを使用する胃腸の機能不全及び関連するストレスの治療 |
| US20040254173A1 (en) * | 2003-06-13 | 2004-12-16 | Leventer Steven M. | Modulation of dopamine responses with substituted (S)-2,3-benzodiazepines |
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| US7541355B2 (en) * | 2005-05-23 | 2009-06-02 | Vela Acquisition Corporation | Conversion process for 2,3-benzodiazepine enantiomers |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE30014E (en) | 1966-12-09 | 1979-05-29 | Egyesult Gyogyazer-es Tapozergyar | 1-(3,4-Dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine |
| DK118660B (da) * | 1966-12-09 | 1970-09-21 | Egyt Gyogyszervegyeszeti Gyar | Analogifremgangsmåde til fremstilling af 1-(3',4'-dimethoxyphenyl)-3-methyl-4-ethyl-6,7-dimethoxy-isoquinolin-N-imid. |
| GB1202579A (en) * | 1966-12-09 | 1970-08-19 | Egyt Gyogyszervegyeszeti Gyar | Pharmacologically active new isoquinoline derivative and process for preparing same |
| ZA712798B (en) * | 1970-11-06 | 1972-02-23 | Egyt Gyogyszervegyeszeti Gyar | New,pharmaceutically active 2,3-diazabicyclo(5.4.0)undecapentaene derivative and process for preparing same |
-
1978
- 1978-10-19 HU HU78GO1426A patent/HU179018B/hu not_active IP Right Cessation
-
1979
- 1979-10-03 YU YU2410/79A patent/YU41887B/xx unknown
- 1979-10-04 AT AT0647279A patent/AT373589B/de not_active IP Right Cessation
- 1979-10-05 DE DE19792940483 patent/DE2940483A1/de active Granted
- 1979-10-12 SE SE7908481A patent/SE439919B/sv not_active IP Right Cessation
- 1979-10-15 BE BE1/9569A patent/BE879404A/fr not_active IP Right Cessation
- 1979-10-16 FI FI793209A patent/FI66604C/fi not_active IP Right Cessation
- 1979-10-16 AU AU51817/79A patent/AU532079B2/en not_active Ceased
- 1979-10-16 FR FR7925698A patent/FR2439189A1/fr active Granted
- 1979-10-16 CH CH929279A patent/CH643835A5/de not_active IP Right Cessation
- 1979-10-16 CS CS797020A patent/CS236456B2/cs unknown
- 1979-10-17 GR GR60290A patent/GR74034B/el unknown
- 1979-10-17 DD DD79216290A patent/DD146596A5/de not_active IP Right Cessation
- 1979-10-18 BG BG45206A patent/BG60270B2/bg unknown
- 1979-10-18 JP JP13471879A patent/JPS5592377A/ja active Granted
- 1979-10-18 SU SU792832177A patent/SU1402258A3/ru active
- 1979-10-18 DK DK440179A patent/DK155327C/da not_active IP Right Cessation
- 1979-10-18 IT IT7926579A patent/IT1220947B/it active
- 1979-10-18 CA CA337,955A patent/CA1125749A/en not_active Expired
- 1979-10-18 GB GB7936185A patent/GB2034706B/en not_active Expired
- 1979-10-18 PL PL1979219034A patent/PL124063B1/pl unknown
- 1979-10-18 NO NO793349A patent/NO152048C/no unknown
- 1979-10-18 NL NLAANVRAGE7907692,A patent/NL190552C/xx not_active IP Right Cessation
- 1979-10-18 ES ES485163A patent/ES485163A1/es not_active Expired
-
1980
- 1980-09-26 US US06/191,811 patent/US4322346A/en not_active Expired - Lifetime
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