NO144885B - Analogifremgangsmaate ved fremstilling av terapeutisk aktive benzodiazepinderivater - Google Patents
Analogifremgangsmaate ved fremstilling av terapeutisk aktive benzodiazepinderivater Download PDFInfo
- Publication number
- NO144885B NO144885B NO793013A NO793013A NO144885B NO 144885 B NO144885 B NO 144885B NO 793013 A NO793013 A NO 793013A NO 793013 A NO793013 A NO 793013A NO 144885 B NO144885 B NO 144885B
- Authority
- NO
- Norway
- Prior art keywords
- compound
- methyl
- general formula
- dihydro
- indicated above
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000001557 benzodiazepines Chemical class 0.000 title description 2
- 230000001225 therapeutic effect Effects 0.000 title description 2
- -1 cyano, carboxy, amino, carbamoyl Chemical group 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical group CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 5
- 125000003545 alkoxy group Chemical group 0.000 claims 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical class CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- BTJMOXDWIPVCRO-UHFFFAOYSA-N 2,3,4-trimethoxybenzamide Chemical class COC1=CC=C(C(N)=O)C(OC)=C1OC BTJMOXDWIPVCRO-UHFFFAOYSA-N 0.000 claims 1
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical class N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims 1
- DXNQLZJOTVNBOZ-UHFFFAOYSA-N [O]C(=O)Nc1ccccc1 Chemical group [O]C(=O)Nc1ccccc1 DXNQLZJOTVNBOZ-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 150000001447 alkali salts Chemical class 0.000 claims 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims 1
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000006627 ethoxycarbonylamino group Chemical group 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 239000012434 nucleophilic reagent Substances 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 claims 1
- 229940031826 phenolate Drugs 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims 1
- 125000005544 phthalimido group Chemical group 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000010992 reflux Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000002026 chloroform extract Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 206010010904 Convulsion Diseases 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical group N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 2
- BMFGBFFDRUAKBF-UHFFFAOYSA-N 7-chloro-2-(chloromethyl)-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine;hydrochloride Chemical compound Cl.C12=CC(Cl)=CC=C2N(C)C(CCl)CN=C1C1=CC=CC=C1 BMFGBFFDRUAKBF-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- 241001465754 Metazoa Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 2
- 229960002456 hexobarbital Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- OWTMQYXQCWHKLV-UHFFFAOYSA-N (7-chloro-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepin-2-yl)methanamine Chemical compound C12=CC(Cl)=CC=C2N(C)C(CN)CN=C1C1=CC=CC=C1 OWTMQYXQCWHKLV-UHFFFAOYSA-N 0.000 description 1
- XMHXJASVEDTELA-UHFFFAOYSA-N (7-chloro-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepin-2-yl)methanol Chemical compound C12=CC(Cl)=CC=C2N(C)C(CO)CN=C1C1=CC=CC=C1 XMHXJASVEDTELA-UHFFFAOYSA-N 0.000 description 1
- LNSSSNFABNPARN-UHFFFAOYSA-N (7-chloro-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepin-2-yl)methanol hydrochloride Chemical compound Cl.C12=CC(Cl)=CC=C2N(C)C(CO)CN=C1C1=CC=CC=C1 LNSSSNFABNPARN-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- AWFYPPSBLUWMFQ-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=C2 AWFYPPSBLUWMFQ-UHFFFAOYSA-N 0.000 description 1
- JJDYTEYOBWJZFZ-UHFFFAOYSA-N 2-[7-bromo-1-methyl-5-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1,4-benzodiazepin-2-yl]acetonitrile Chemical compound C12=CC(Br)=CC=C2N(C)C(CC#N)CN=C1C1=CC=CC=C1C(F)(F)F JJDYTEYOBWJZFZ-UHFFFAOYSA-N 0.000 description 1
- YDRKECYABNCSTE-UHFFFAOYSA-N 2-[7-chloro-1-methyl-5-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1,4-benzodiazepin-2-yl]acetonitrile Chemical compound C12=CC(Cl)=CC=C2N(C)C(CC#N)CN=C1C1=CC=CC=C1C(F)(F)F YDRKECYABNCSTE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZNCTZFTUAXQUHQ-UHFFFAOYSA-N 7-chloro-1-methyl-5-phenyl-2-(piperidin-1-ylmethyl)-2,3-dihydro-1,4-benzodiazepine Chemical compound C1N=C(C=2C=CC=CC=2)C2=CC(Cl)=CC=C2N(C)C1CN1CCCCC1 ZNCTZFTUAXQUHQ-UHFFFAOYSA-N 0.000 description 1
- JXJWBZYNEKJTGJ-UHFFFAOYSA-N 7-chloro-2-(chloromethyl)-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N(C)C(CCl)CN=C1C1=CC=CC=C1 JXJWBZYNEKJTGJ-UHFFFAOYSA-N 0.000 description 1
- PRBVUEPFUYZZGR-UHFFFAOYSA-N 7-chloro-2-(chloromethyl)-5-(2-chlorophenyl)-1-methyl-2,3-dihydro-1,4-benzodiazepine;hydrochloride Chemical compound Cl.C12=CC(Cl)=CC=C2N(C)C(CCl)CN=C1C1=CC=CC=C1Cl PRBVUEPFUYZZGR-UHFFFAOYSA-N 0.000 description 1
- HTTLCBVCGWYRQH-UHFFFAOYSA-N 7-chloro-2-(methoxymethyl)-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine;hydrochloride Chemical compound Cl.C12=CC(Cl)=CC=C2N(C)C(COC)CN=C1C1=CC=CC=C1 HTTLCBVCGWYRQH-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
- HWONLMWOUMXCCO-UHFFFAOYSA-N CN1C(C=CC(Cl)=C2)=C2C(C2=CC=CC=C2)=NCC1CN(C(C1=CC=CC=C11)=O)C1=O Chemical compound CN1C(C=CC(Cl)=C2)=C2C(C2=CC=CC=C2)=NCC1CN(C(C1=CC=CC=C11)=O)C1=O HWONLMWOUMXCCO-UHFFFAOYSA-N 0.000 description 1
- 206010053398 Clonic convulsion Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 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 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 206010043994 Tonic convulsion Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002539 anti-aggressive effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000002566 clonic effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 101150100175 inuE gene Proteins 0.000 description 1
- VGNXHRVCGURILB-UHFFFAOYSA-N isocyanic acid;phenol Chemical compound N=C=O.OC1=CC=CC=C1 VGNXHRVCGURILB-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000003170 musculotropic effect Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/5545—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having eight-membered rings not containing additional condensed or non-condensed nitrogen-containing 3-7 membered rings
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D245/06—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Foreliggende oppfinnelse angår fremstilling av terapeutisk aktive benzodiazepinderivater som angitt i innledningen til kravet ved en fremgangsmåte som angitt i kravets karakteristikk.
For fremstilling av ikke-giftige syreaddisjonssalter er f.eks. hydrogenklorid, eddiksyre, propionsyre, diethyleddiksyre, malonsyre, ravsyre/ fumarsyre, maleinsyre, melkesyre, vinsyre, eplesyre, citronsyre, svovelsyre, hydrobromsyre eller orthofosfor-syre egnet. Disse syreaddisjonsforbindelser anvendes farmasøyt-isk likesom den frie base og har særlig den fordel at de er opp-løselige i vann.
Fremgangsmåteforbindelsene kan anvendes i form av vanlige farmasøytiske preparater som psykosedative midler med ringe muskulotrope egenskaper til behandling av psykisk syke mennesker. Forbindelsene kan administreres såvel pr. os som parenteralt.
Fra litteraturen er det kjent at forbindelsene med benzo - 1,4-diazepin-strukturen er verdifulle legemidler (se Burger, Medicinal Chemistry, (1970), 3- opplag).
Benzo-1,4-diazepin-forbindelsene méd formel I er ikke tid-ligere kjent. De nye forbindelser oppviser eh verdifull innflyt-else på sentralnervesystemet. Forbindelsene har ant ikonvulsiv., sedativ, muskelavslappende såvel som psykosedativ virkning. Dette kan vises ved farmakologiske standardforsøk på små forsøksdyr.
De nye forbindelser skiller seg overraskende ganske spesielt ut ved god forlikelighet (terapeutisk bredde) sammenlignet med handelspreparater.
Undersøkelsene strekker seg til bestemmelsene av følgende aktiviteter:
1. Prøving av antikonvulsive egenskaper:
a) Elektrosjokkanfall:
Metode:
Undersøkelsesforbindelsene ble prøvet efter perorål administrasjon til grupper på 5 mus hver i logaritmiske doseringsav^ stander på 0,l673 (Hackenberg, u. og H. Bartling, Naun<y>n-Schmiede-berg's Arch.exp.Path. u. Pharmak. 235, 437~463 (1959). 1 time efter administrasjon ble 2 elektroder heftet ved ørene- på dyrene, og den elektriske stimulering ble utløst. Opptredelsen eller uteblivelsen av toniske ekstensoranfall ble registrert, og den prosentuelle be-skyttelsesvirkning mot anfall ble beregnet.
b) Pent et ra zolkrampe :
Metode: Undersøkelsesforbindelsene. ble likeledes administrert pr. os i logaritmiske doseringer (avstand 0,l673) til grupper hver på 10 mus. 6o minutter efter administrasjon av forsøksforbindelsene ble pentetrazol injisert subkutant i en dose på. 100 mg/kg. Opptredelsen av kloniske og toniske konvulsjoner og død ble iakttatt i løpet av 45 minutter. Totalobservasjonstiden ble utstrakt til 3 timer. Beskyttelsesvirkningen mot konvulsjon og død ble bestemt ved sammenligning med samtidig utførte kontrollforsøk. Den effek-tive dose ED^0 mot konvulsjoner ble beregnet fra probit/log. dos-. eringskurveri. 2. Undersøkelse på antiaggressive egenskaper hos de elektrisk opphissede kampmus :
Metode:
Tedeschi, R. E. et al. J. Pharmacol. Exptl. Therap. 125, 28
(1959). 1 time efter administrasjon pr. os av undersøkelsesforbind-elsen ble 8 muspar pr. dose prøvet i kampprøven efter den ovenfor angitte metode. Den logaritmiske doseringsavstand utgjorde likeledes 0,1673. Opphisselsestiden utgjorde 3 minutter. 3. Undersøkelse av narkosepotensierende egenskaper efter administrasjon av hexobarbital:
Metode:
Undersøkelsesforbindelsene ble administrert pr. os logarit-misk i doseavstander på 0,3324- 30 minutter efter administrasjon ble hexobarbital administrert i en dose på 65 mg/kg intravenøst. Tiden av søvnen ble målt. E^^o = ^° n,inu1;'ters ligging på siden.
4• Akutt toksisitet:
Den akutte toksisitet ble bestemt efter en gangs administrasjon pr. os til hvite fastende NMRl-mus. Beregningen skjedde ifølge metoden til Litchfield, J. T. og F. Wilcoxbn (J. Pharmacol. Exptl. Therap. 96, 99 (1949).
Utgangsmaterialene som anvendes ved foreliggende fremgangsmåte, kan fremstilles som angitt i NO-paterit 142 866.
Forbindelsene med formel I som kan fremstilles, er angitt i
tabellen nedenfor.
Eksempel 1
70 g 7-klor-l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid i 1 liter vann og 1 liter dioxan ble oppvarmet under tilbakeløp med 500 ml 20%-ig natronlut i 1 time. Derefter ble dioxanet avdestillert i vakuum, den vandige oppløsning ble ekstrahert med kloroform, og kloroformekstraktet ble inndampet i vakuum. Det oljeaktige residuum ble opptatt i isopropanol og tilsatt etherisk saltsyre. Man fikk 7-klor-l-methyl-2-hydroxymethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 22 7 - 235°C.
Eksempel 2
7-klor-l-ethyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin taes opp i 200 ml dioxan og kokes derpå under til-bakeløp i 1 time med 100 ml 20%-ig natriumhydroxydoppløsning. Efter fjernelse av dioxanet i vakuum ekstraheres den vandige opp-løsning méd kloroform, og dette kloroformekstrakt inndampes i vakuum. Det oljeaktige residuum taes opp i isopropanol og til-settes etherisk saltsyre. Man får 7-klor-l-ethyl-2-hydroxymethyl-5-fenyl-lH-2,3-dihydro-l,4-benzodiazepin-hydroklorid med smp.
196 - 202°C.
Eksempel 3
7,5 g 7-klor-l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid ble oppvarmet med en oppløsning av 2 g natrium i 100 ml methanol i 24 timer under tilbakeløp. Derefter ble en del av methanolen avdestillert, reaksjonsblandingen tilsatt vann og ekstrahert med kloroform. Kloroformekstraktene ble inndampet i vakuum, residuet tatt opp i benzen og filtrert over aluminiumoxyd (aktivitetstrinn II) med benzen. Benzen-eluatet ble oppsamlet og inndampet. Den erholdte olje ble oppløst i isopropanol og tilsatt etherisk saltsyre. Man fikk 3,4 g 7-klor-l-methyl-2-methoxymethyl-2,3-dihydro-5-fenyl-lH-1,4-benzodiazepin-hydroklorid med smp. 198 - 210°C.
På analogt vis ble følgende forbindelser med formel I fremstilt:
Eksempel 4
10 g 7-klor-l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid-isopropanol ble oppvarmet med 100 ml piperidin i 14 timer under tilbakeløp. Derpå ble over-skudd av piperidin avdestillert, residuet tilsatt vann og ekstrahert med kloroform. Kloroformekstraktene ble inndampet i vakuum og residuet krystallisert fra ether. Man fikk 6,8 g
(77% av det teoretiske beregnet på klormethylforbindelsen) 7-klor-l-methyl-2-piperidinomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin i form av svakt gulfarvede krystaller med smp. 143 - 145°C.
Analogt med dette eksempel ble de følgende forbindelser fremstilt:
7-klor-l-methyl-2-morfolinomethyl-5-fenyl-2 ,.3-dihydro-lH-l, 4-
benzodiazepin i et utbytte på 45%. Smp. for dihydrokloridet: 237-245°C. 7-klor-l-methyl-2-(N-methyl)-piperazinomethyl-5-fenyl-2,3-dihydro-
1H-1,4-benzodiazepin i et utbytte på 46%. Smp. av trihydro-kloridet inneholdende 1 mol ethanol: 214-215°C. 7-klor-l-methyl-2-benzylaminomethyl-5-fenyl-2,3-dihydro-lH-l,4-
benzodiazepin. Utbytte: 40%. Smp. av dihydrokloridet: 165-168°C.
7-klor-l-methyl-2-aminomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-dihydroklorid med smp. 206-209°C (inneholdende
0,5 mol isopropanol).
Eksempel 5
5 g l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid inneholdende 0,65 mol isopropanol og 0,5 mol H20 ble oppvarmet med 50 ml N-methylpiperazin i 10 timer under tilbakeløp. Efter avdestillering av overskuddet av N-methylpiperazin ble residuet tilsatt vann og ekstrahert med kloroform. Kloroformekstraktene ble inndampet i vakuum. Derved fikk man l-methyl-2-(N-methyl)-piperazinomethyl-5-fenyl-2,3-dihydro-1H-1,4-benzodiazepin som en olje i et utbytte på 78%. Eksempel 6 10 g 7-klor-l-methyl-2-klormethyl-5-(2 *-klorfenyl)-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid ble oppvarmet med 100 ml morfolin i 15 timer under tilbakeløp. Efter opparbeidelse av reaksjonsblandingen fikk man 7-klor-l-methyl-2-morfolinomethyl-5-(2<1->klorfenyl)-2,3-dihydro-lH-l,4-benzodiazepin med smp. 136-138°C.
Eksempel 7
127 g 7-klor-l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin ble oppløst i 1000 ml methanol, tilsatt 70 g kaliumjodid og 78 g kaliumfthalimid og oppvarmet under tilbakeløp i 24 timer. Derpå ble oppløsningen filtrert varm og inndampet i vakuum: Det erholdte bunnfall ble frafiltrert og omkrystallisert fra methanol. Man fikk 7-klor-l-methyl-2-fthalimidomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin med smp. 151-152°C i 60% utbytte.
På lignende måte fikk man 7-klor-l-methyl-2-(3,4,5-tri-methoxy)-benzoylaminomethyl-5-fenyl-lH-2,3-dihydro-l,4-benzodiazepin-hydroklorid med smp. 180°C, og 7-klor-l-methyl-2-acetamidomethyl-5-fenyl-lH-2,3-dihydro-l,4-benzodiazepin-hydroklorid med smp. 184-186°C.
Ved fremgangsmåtene i eksempel 4-7 ble de følgende forbindelser med formel I fremstilt:
Eksempel 8
10 g 7-klor-l-methyl-2-aminomethyl-5-feriyl-2,3-dihydro-lH-1,4-benzodiazepin ble omsatt i 200 ml methylenklorid med 4,36 g fenolisocyanat. Ethanol ble så tilsatt efter 24 timer, og oppløs-ningen ble inndampet i vakuum. Residuet ble tatt opp med ether og omsatt med en isopropanoloppløsning av hydrogenklorid. Det dannede bunnfall ble fjernet ved filtrering og omkrystallisert fra isopropanol/vann.
Man fikk 7-klor-l-methyi-2-fenyluréidomethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid med smp. 198 - 207°C.
Eksempel 9
En oppløsning av 21 g 7-klor-l-methyl-2-aminomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin ble efter hverandre tilsatt med 7,1 g triethylamin og 7,6 g ethylklorformiat. Efter 24 timer blé reaksjonsblandingen vasket med vann, methylenkloridfasen ble fraskilt, tørret over natriumsulfat og inndampet i vakuum. Råproduktet ble filtrert med toluen over A^O^ (aktivitetstrinn II-III) , eluatet ble oppsamlet og inndampet i vakuum. For felning av hydrokloridet ble deri erholdte olje oppløst i isopropanol og tilsatt etherisk hydrogenklorid. Man fikk 7-klor-l-' methyl-2-ethoxycarbonylaminomethy1-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 196-197°C.
Eksempel 10
88 g 7-klor-l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-1,4-berizodiazepin ble oppløst i 1000 ml methanol og.oppvarmet med 19,8 g kaliumcyanid og 2 g kaliumjodid i 24 timer under til-bakeløp. Derefter ble oppløsningsmidlet avdestillert i vakuum, residuet ble tilsatt vann og ekstrahert med kloroform. De for-enede kloroformekstrakter ble vasket med vann, tørret over natriumsulfat og inndampet i vakuum. Residuet ble oppløst i isopropanol og tilsatt etherisk hydrogenklorid. Man fikk 7-klor-l-methyl-2-cyanomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 210-214°C i et utbytte på 87,5%.
Fra 7-klor-l-methyl-2-klormethyl-5-(2'-klorfenyl)-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid fikk man i lignende ut-, bytte 7-klor-l-methyl-2-cyanomethyl-5-(2'-klorfenyl)-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid med smp. 171-174°C.
Fra 7-klor-l-methyl-2-klormethyl-5-(2'-fluorfenyl)-2,3-dihydro-lH-1,4-benzbdiazepin fikk man i lignende utbytte 7-klor-l-methyl-2-cyanomethyl-5-(2'-fluorfenyl)-2,3-dihydro-lH-l, 4-benzodiazepin-hydroklorid med smp. 221-225°C.
Videre fikk man fra 7-brom-l-methyl-2-klormethyl-5-(2'-klorfenyl)-2,3-dihydro-lH-l,4-benzodiazepin 7-brom-l-methyl-2-cyanomethyl-5-(2'-klorfenyl)-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 147-149°C.
7-brom-l-methyl-2-klormethyl-5-(2'-fluorfenyl)-2,3-dihydro-1H-1,4-benzodiazepin ga 7-brom-l-methyl-2-cyanomethyl-5-(2'-fluorfenyl)-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 218-220°C.
7-klor-l-methyl-2-klormethyl-5-(2'-trifluormethylfenyl)-2,3-dihydro-lH-1,4-benzodiazepin ga 7-klor-l-methyl-2-cyanomethyl-5-(2 ' -trif luormethylfenyl)-2 ,3-dihydro-lH-l, 4-benzodiazepin som en olje.
7-brom-l-methyl-2-klormethyl-5-(2'-trifluormethylfenyl)-2,3-dihydro-lH-1,4-benzodiazepin ga 7-brom-l-methyl-2-cyanomethyl-5-(2'-trifluormethylfenyl)-2,3-dihydro-lH-l,4-benzodiazepin som en olje.
Eksempel 11
72,3 g 7-klor-l-methyl-2-cyanomethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydrokldrid ble oppløst i 360 ml 18%-ig ethanol-oppløsning av hydrogenklorid og hensatt ved 40°C inntil intet av utgangsmaterialet kunne påvises ved tynnskiktskromatografi. Massen ble så behandlet med ether og omkrystallisert• Man fikk således 7-klor-l-methyl-2-ethoxycarbonyImethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 204-206°C.
Eksempel 12
71,1 g 7-klor-:l-methyl-2-ethoxycarbonylmethyl-5-f enyl-2, 3-dihydro-lH-1,4-benzodiazepin-hydroklorid ble oppvarmet i 450 ml methanol med 900 ml ml 10%-ig natriumhydroxyd i 1" time' uridéf til-, bakeløp. Efter avdestillering av oppløsniirgsmidlet ble det erholdte bunnfall tatt opp i kloroform og behandlet med gass-formig hydrogenklorid. Efter frafiltrering av det utfelte natrium-klorid ble kloroformoppløsningen inndampet i vakuum. Residuet ble omkrystallisert fra methanol/ether. Man fikk således 7-klor-l-methyl-2-carboxymethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid som ble spaltet ved 229°C.
11,5 g av det således erholdte syrederivat ble omsatt i
200 ml methylenklorid ved 0°C efter hverandre med 8,5 ml triethylamin og 3,7 g av ethylklorformiat. 25 ml av en 70%-ig vandig isopropylaminoppløsning ble så tilsatt efter 30 minutter. Massen ble til slutt vasket med vann efter 24 timer, og methylenkloridfasen ble fraskilt, tørret over natriumsulfat og inndampet i vakuum. Residuet ble oppløst i ether og omsatt med en isopropanol-oppløsning av hydrogenklorid. Man fikk således 7-klor-l-methyl-2-isopropylcarbamoylmethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 220-223°C.
Eksempel 13
11,5 g 7-klor-l-methyl-2-carboxymethyl-5-fenyl-2,3-dihydro-1H-1,4-benzodiazepin-hydroklorid ble omsatt i 200 ml methylenklorid ved 0°C efter hverandre med 8,5 ml triethylamin og 3,7 g ethylklorformiat. 25 ml av en konsentrert vandig ammoniakkoppløs-ning ble så tilsatt efter 30 minutter. Massen ble så vasket med vann efter 24 timer, og methylenkloridfasen ble fraskilt, tørret over natriumsulfat og inndampet i vakuum. Residuet ble oppløst
i ether og omsatt med en methanoloppløsning av hydrogenklorid. Man fikk således 7-klor-l-methyl-2-carbamoylmethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid med smp. 229-23.1°C. Molekylvekten av hydrokloridet, bestemt ved massespektroskopi, var 364.
Eksempel 14
En oppløsning av 16,5 g 7-klor-l-methyl-2-hydroxymethyl-5-fenyl-2, 3-dihydro-lH-l, 4-benzodiazepin i 5,0 ml methylenklorid ble fremstilt. Oppløsningen ble så omsatt med 6 ml ethyliso-cyanat. Massen ble så efter 24 timer omsatt med en liten mengde methanol, og oppløsningsmidlet ble avdestillert under vakuum. Residuet ble omkrystallisert fra aceton. Man fikk således 7-klor-l-methyl-2-(ethylcarbamoyloxy)-methyl-5-fenyl-2,3-dihydro-1H-1,4-benzodiazepin med smp. 175-177°C.
Claims (1)
- Analogifremgangsmåte ved fremstilling av terapeutisk aktive benzodiazepinderivater med den generelle formel:hvor R1 er hydrogen, lavere alkyl eller benzyl,R2 er hydroxy, rettkjedet eller forgrenet alkoxy med 1-5 carbonatomer, ethoxycarbonyl, cyano, carboxy, amino, carbamoyl, methylcarbonylamino, ethoxycarbonylamino, isopropylcarbamoyl, methyl-carbamoyloxy, ethylcarbamoyloxy, fenoxy, klorfenoxy, benzoyloxy, fenylthio, benzylamino, trimethoxybenzoylamino, fenylcarbamoyloxy, ureido, methylureido, isopropylureido, fenylureido, fthalimido, methylpiperazino, morfolino eller piperidino, og A og B er benzenringer som kan være substituert med halogen, alkyl med 1-4 carbonatomer, alkoxy med 1-4 carbonatomer, trifluormethyl, eller nitro, eller A kan være substituert med methylthio eller ethylendioxy;såvel som syreaddisjonssalter derav,karakterisert ved at a) en forbindelse med den generelle formel I, hvor R2 er klor eller brom, og R^, A og B er som ovenfor angitt, under-kastes alkalisk hydrolyse, hvorved man får en forbindelse med formel I hvor R2 er hydroxy, og R^, A og B er som ovenfor angitt, eller b) en forbindelse med den generelle formel I, hvor R2 er hydroxy, og 'R^, A og Ber som ovenfor angitt,.omsettes med methyl-, ethyl- eller fenyl-isocyanat, hvorved man får en for-, bindelse med formel I hvor R2 er hhv. methyl-, ethyl- eller fenyl-carbamoyloxy, eller c) en forbindelse med den generelle formel I, hvor R2 er klor eller brom, og R^, Å og.B er som ovenfor angitt, omsettes med et nucleofilt reagens bestående av ammoniakk, benzylamin, morfolin, methylpiperazin, piperidin, alkalisalter av fthalimid, tri-methoxybenzamid, acetamid, benzoat, cyanid, alkoholat med 1-5 carbonatomer, fenolat, klorfenolat eller thiofenolat ved forhøyet temperatur i et inert oppløsningsmiddel, hvorved man får en forbindelse hvor R2 er amino, benzylamino, morfolino, methylpiperazino, piperidino, fthalimido, trimethoxybenzoylamino, methylcarbonylamino, benzoyloxy, cyano, alkoxy med 1-5 carbonatomer, fenoxy, klorfenoxy eller fenylthio, eller d) en forbindelse med den generelle formel I hvor R2 er amino, og R^, A og B er som ovenfor angitt, omsettes med kaliumiso-cyanat, methyl-, isopropyl- eller fenylisocyanat for dannelse av den tilsvarende forbindelse hvor R2 er ureido, methyl-, isopropyl- eller fenylureido, eller e) en forbindelse med formel I hvor R2 er amino, og R^, A og B er som ovenfor angitt, behandles efter hverandre med triethylamin og ethylklorformiat, hvorved man får en forbindelse hvor R2 er ethoxycarbonylamino, ellerf) en forbindelse med den generelle formel I, hvor R2 er cyano, og Rj, A og B er som ovenfor angitt, behandles med ethanolisk hydrogenklorid, hvorved man får en forbindelse hvor R2 er ethoxycarbonyl, eller g) eri forbindelse med den generelle formel I, hvor R0 er ethoxycarbonyl, og R^, A og B er som ovenfor angitt, behandles med alkali og derpå med hydrogenklorid-gass, hvorved mån får en forbindelse hvor R2 er carboxy, eller h) en forbindelse med den generelle formel I, hvor R2 er carboxy, og R^, A og B er som ovenfor angitt, behandles efter hverandre med triethylamin, ethylklorformiat og ammoniakk eller isopropylamin, hvorved man får en forbindelse hvor R2 er carbamoyl eller isopropylcarbamoyl,og en dannet, fri base eventuelt overføres til et syreaddisjonssalt derav, eller et dannet syreaddisjonssalt eventuelt overføres til den frie base.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2221558A DE2221558C2 (de) | 1972-05-03 | 1972-05-03 | 5-Phenyl-2,3-dihydro-1H-1,4-benzodiazepine und ihre Säureadditionssalze, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO793013L NO793013L (no) | 1973-11-06 |
| NO144885B true NO144885B (no) | 1981-08-24 |
| NO144885C NO144885C (no) | 1981-12-02 |
Family
ID=5843904
Family Applications (6)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO1797/73A NO142866C (no) | 1972-05-03 | 1973-05-02 | Nye benzodiazepinderivater for anvendelse som ugangsmateriale og fremgangsmaate ved fremstilling derav |
| NO75751349A NO145761C (no) | 1972-05-03 | 1975-04-16 | Benzodiazocinderivater for anvendelse som utgangsmaterialer ved fremstilling av benzodiazepinderivater, og en ny fremgangsmaate for fremstilling av disse benzodiazocinderivater |
| NO76761580A NO143347C (no) | 1972-05-03 | 1976-05-07 | Utgangsmateriale for fremstilling av benzodiazepinderivater |
| NO780402A NO142476C (no) | 1972-05-03 | 1978-02-06 | Fremgangsmaate ved fremstilling av benzodiazepinderivater |
| NO793012A NO144386C (no) | 1972-05-03 | 1979-09-19 | Fremgangsmaate ved fremstilling av benzodiazepinderivater |
| NO793013A NO144885C (no) | 1972-05-03 | 1979-09-19 | Analogifremgangsmaate ved fremstilling av terapeutisk aktive benzodiazepinderivater |
Family Applications Before (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO1797/73A NO142866C (no) | 1972-05-03 | 1973-05-02 | Nye benzodiazepinderivater for anvendelse som ugangsmateriale og fremgangsmaate ved fremstilling derav |
| NO75751349A NO145761C (no) | 1972-05-03 | 1975-04-16 | Benzodiazocinderivater for anvendelse som utgangsmaterialer ved fremstilling av benzodiazepinderivater, og en ny fremgangsmaate for fremstilling av disse benzodiazocinderivater |
| NO76761580A NO143347C (no) | 1972-05-03 | 1976-05-07 | Utgangsmateriale for fremstilling av benzodiazepinderivater |
| NO780402A NO142476C (no) | 1972-05-03 | 1978-02-06 | Fremgangsmaate ved fremstilling av benzodiazepinderivater |
| NO793012A NO144386C (no) | 1972-05-03 | 1979-09-19 | Fremgangsmaate ved fremstilling av benzodiazepinderivater |
Country Status (18)
| Country | Link |
|---|---|
| US (6) | US3998809A (no) |
| JP (3) | JPS5541231B2 (no) |
| AT (3) | AT327927B (no) |
| BE (1) | BE799001A (no) |
| CA (3) | CA1009232A (no) |
| CH (5) | CH605834A5 (no) |
| DD (1) | DD105222A5 (no) |
| DE (3) | DE2265371C3 (no) |
| DK (3) | DK147050C (no) |
| ES (1) | ES414279A1 (no) |
| FR (3) | FR2183735B1 (no) |
| GB (3) | GB1429666A (no) |
| IL (5) | IL42158A (no) |
| NL (1) | NL179111C (no) |
| NO (6) | NO142866C (no) |
| SE (3) | SE409709B (no) |
| SU (2) | SU625607A3 (no) |
| ZA (1) | ZA733013B (no) |
Families Citing this family (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4244869A (en) * | 1972-05-03 | 1981-01-13 | Kali-Chemie A.G. | Benzodiazepine derivatives and process of making them |
| DE2265371C3 (de) * | 1972-05-03 | 1980-12-11 | Kali-Chemie Ag, 3000 Hannover | N-(3-Benzoylaminopropyl)-aniline |
| 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 |
| ES469020A1 (es) * | 1977-05-10 | 1979-09-01 | Kali Chemie Pharma Gmbh | Procedimiento para la preparacion de nuevos 1-acil-2-hidroxi-1,3-diaminopropanos |
| DE2720968C2 (de) * | 1977-05-10 | 1986-05-07 | Kali-Chemie Pharma Gmbh, 3000 Hannover | N↓1↓-Acyl-2-hydroxy-1,3-diaminopropane und Arzneimittel |
| DE2720908A1 (de) * | 1977-05-10 | 1978-11-23 | Kali Chemie Pharma Gmbh | Arzneimittel mit ulkustherapeutischem effekt |
| US4123430A (en) * | 1977-11-10 | 1978-10-31 | G. D. Searle & Co. | 2-Aryl-4-(1-piperazinyl)-3H-1,5-benzodiazepines |
| DE2754112A1 (de) * | 1977-12-05 | 1979-06-13 | Kali Chemie Pharma Gmbh | 1,4-benzodiazepinderivate, ihre salze und diese verbindungen enthaltende arzneipraeparate |
| DE2810349A1 (de) * | 1978-03-10 | 1979-09-20 | Kali Chemie Pharma Gmbh | Verfahren zur herstellung von 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro- 1,5-benzodiazocinen |
| US4368159A (en) * | 1978-05-15 | 1983-01-11 | Hoffmann-La Roche Inc. | Intermediates to produce imidazodiazepines |
| US4368158A (en) * | 1978-05-15 | 1983-01-11 | Hoffmann-La Roche Inc. | Intermediates to produce imidazodiazepines |
| US4371468A (en) * | 1978-05-15 | 1983-02-01 | Hoffmann-La Roche Inc. | Intermediates to produce imidazodiazepines |
| US4368157A (en) * | 1978-05-15 | 1983-01-11 | Hoffmann-La Roche Inc. | Intermediates to produce imidazodiazepines |
| DE2827801A1 (de) * | 1978-06-24 | 1980-01-10 | Kali Chemie Pharma Gmbh | Neue n tief 1 -benzoyl-n tief 2 -phenyl-1,3-diaminopropan-2-ole, verfahren zu deren herstellung und arzneimittel |
| DE2835708A1 (de) * | 1978-08-16 | 1980-03-06 | Kali Chemie Pharma Gmbh | Neue eckige klammer auf 1,2 eckige klammer zu-anellierte 7-phenyl-1,4-benzodiazepinderivate, verfahren zu deren herstellung und arzneimittel |
| JPS5775313A (en) * | 1980-10-30 | 1982-05-11 | Fanuc Ltd | Numerical controller of machine tool |
| DE3048264A1 (de) * | 1980-12-20 | 1982-09-09 | Kali-Chemie Pharma Gmbh, 3000 Hannover | 2-acylaminomethyl-1,4-benzodiazepine und deren salze sowie verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| DE3124013A1 (de) * | 1981-06-19 | 1982-12-30 | Kali-Chemie Pharma Gmbh, 3000 Hannover | 2-acylaminomethyl-1,4-benzodiazepin-verbindungen sowie verfahren und zwischenprodukte zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| DE3138769A1 (de) * | 1981-09-30 | 1983-04-14 | Kali-Chemie Pharma Gmbh, 3000 Hannover | 7-brom-5-(2-halogenphenyl)-1h-2,3-dihydro-1,4- benzodiazepin-verbindungen sowie verfahren und zwischenprodukte zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| 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 |
| DE3221402A1 (de) * | 1982-06-05 | 1983-12-08 | Kali-Chemie Pharma Gmbh, 3000 Hannover | 5-phenyl-1,4-benzodiazepine enthaltende analgetisch wirksame pharmazeutische zubereitungen |
| US4493168A (en) * | 1983-06-16 | 1985-01-15 | Coburn Optical Industries, Inc. | Calibration gauge for computer-controlled lens generator, or the like |
| US4602886A (en) * | 1983-12-28 | 1986-07-29 | Smit Adrianus J | Multi-color marking implement |
| US4786449A (en) * | 1983-12-28 | 1988-11-22 | Clowny Corporation | Method for manufacture of multi-color marking implements |
| US4684646A (en) * | 1984-06-26 | 1987-08-04 | Merck & Co., Inc. | 2-acylaminomethyl-1,4-benzodiazepine derivatives as CCK-antagonists |
| EP0170024A3 (en) * | 1984-06-26 | 1990-01-31 | Merck & Co. Inc. | Use of 2-acylaminomethyl-1,4-benzodiazepine derivatives for the production of pharmaceutical compositions and process for the preparation for pharmaceutical compositions |
| US4724237A (en) * | 1984-06-26 | 1988-02-09 | Merck & Co., Inc. | 2-substituted-aminomethyl-1,4-benzodiazepines |
| JPS61114933A (ja) * | 1984-11-12 | 1986-06-02 | Tokyo Electric Co Ltd | 事務機の給紙装置 |
| JPH0618794Y2 (ja) * | 1987-06-17 | 1994-05-18 | 株式会社スギノマシン | ウォータジェット加工機 |
| JPH0418564Y2 (no) * | 1988-01-08 | 1992-04-24 | ||
| US5856497A (en) * | 1995-12-11 | 1999-01-05 | Boehringer Ingelheim Pharmaceuticals, Inc. | Asymmetric synthesis of α-cycloalkylalkyl substituted methanamines |
| US5670640A (en) * | 1996-02-02 | 1997-09-23 | Hoffmann-La Roche Inc. | Process for the manufacture of imidazodiazepine derivatives |
| AU3207297A (en) * | 1996-07-01 | 1998-01-21 | Pharmacia & Upjohn Company | Process for the production of 8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo{1,5-a}benzod iazepine |
| US6821935B1 (en) | 1999-08-27 | 2004-11-23 | Procter & Gamble Company | Color safe laundry methods employing zwitterionic formulation components |
| US7109156B1 (en) | 1999-08-27 | 2006-09-19 | Procter & Gamble Company | Controlled availability of formulation components, compositions and laundry methods employing same |
| EP1206520A1 (en) * | 1999-08-27 | 2002-05-22 | The Procter & Gamble Company | Fast-acting formulation components, compositions and laundry methods employing same |
| US6818607B1 (en) | 1999-08-27 | 2004-11-16 | Procter & Gamble Company | Bleach boosting components, compositions and laundry methods |
| CN1384867A (zh) | 1999-08-27 | 2002-12-11 | 宝洁公司 | 稳定性提高的配制组分、使用该组分的组合物和洗衣方法 |
| US6903060B1 (en) | 1999-08-27 | 2005-06-07 | Procter & Gamble Company | Stable formulation components, compositions and laundry methods employing same |
| MXPA02002125A (es) * | 1999-08-27 | 2002-09-18 | Procter & Gamble | Componentes aumentadores del blanqueado, composiciones y metodos de lavanderia. |
| US6825160B1 (en) | 1999-08-27 | 2004-11-30 | Procter & Gamble Company | Color safe laundry methods employing cationic formulation components |
| US7557076B2 (en) * | 2002-06-06 | 2009-07-07 | The Procter & Gamble Company | Organic catalyst with enhanced enzyme compatibility |
| US7169744B2 (en) | 2002-06-06 | 2007-01-30 | Procter & Gamble Company | Organic catalyst with enhanced solubility |
| US20050113246A1 (en) * | 2003-11-06 | 2005-05-26 | The Procter & Gamble Company | Process of producing an organic catalyst |
| AR051659A1 (es) * | 2005-06-17 | 2007-01-31 | Procter & Gamble | Una composicion que comprende un catalizador organico con compatibilidada enzimatica mejorada |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2721215A (en) * | 1952-06-12 | 1955-10-18 | Hoffmann La Rache Inc | Diphenylacetyl diamines |
| US2785200A (en) * | 1953-06-08 | 1957-03-12 | Abbott Lab | Dichlorobenzoyl-ethylenediamine |
| US2721214A (en) * | 1953-06-09 | 1955-10-18 | Parke Davis & Co | Process for producing acylamido diols |
| US3501460A (en) * | 1966-06-03 | 1970-03-17 | Hoffmann La Roche | Dehydration process for forming benzodiazepines |
| US3576868A (en) * | 1966-06-03 | 1971-04-27 | Hoffmann La Roche | Benzoyl amino ethyl aniline derivatives |
| US3577557A (en) * | 1966-12-09 | 1971-05-04 | Sandoz Ag | Benzo(1,5)diazocinones |
| US3723414A (en) * | 1970-02-13 | 1973-03-27 | Schering Corp | 1-polyfluoroalkyl benzodiazepines |
| DE2166116A1 (de) * | 1970-04-24 | 1973-02-15 | Teikoku Hormone Mfg Co Ltd | Verfahren zur herstellung von n-(dialkylaminoalkylen)-2-alkoxy(oder -alkenyloxy)4-amino-5-halogenbenzamiden |
| DK137857B (da) * | 1970-09-03 | 1978-05-22 | Takeda Chemical Industries Ltd | Analogifremgangsmåde til fremstilling af 2-amino-1,5-benzodiazocinderivater eller farmaceutisk acceptable salte deraf. |
| JPS4728284Y1 (no) * | 1970-09-14 | 1972-08-26 | ||
| US4021224A (en) * | 1971-12-09 | 1977-05-03 | Stauffer Chemical Company | Herbicide compositions |
| DE2265371C3 (de) * | 1972-05-03 | 1980-12-11 | Kali-Chemie Ag, 3000 Hannover | N-(3-Benzoylaminopropyl)-aniline |
| US3975443A (en) * | 1972-06-06 | 1976-08-17 | Allen & Hanburys Limited | 1-(3,4-dichlorobenzamidomethyl)-cyclohexyldimethylamine |
| GB1374366A (en) * | 1972-07-21 | 1974-11-20 | Science Union & Cie | Propanol derivatives and a process for their preparation |
| US3957870A (en) * | 1973-07-19 | 1976-05-18 | Imperial Chemical Industries Limited | Organic compounds |
-
1972
- 1972-05-03 DE DE2265371A patent/DE2265371C3/de not_active Expired
- 1972-05-03 DE DE2221558A patent/DE2221558C2/de not_active Expired
- 1972-05-03 DE DE2265370A patent/DE2265370C2/de not_active Expired
-
1973
- 1973-04-16 DD DD170247A patent/DD105222A5/xx unknown
- 1973-04-19 NL NLAANVRAGE7305570,A patent/NL179111C/xx not_active IP Right Cessation
- 1973-04-25 GB GB2491075A patent/GB1429666A/en not_active Expired
- 1973-04-25 GB GB1974173A patent/GB1429665A/en not_active Expired
- 1973-04-25 GB GB3581775A patent/GB1429667A/en not_active Expired
- 1973-04-26 CH CH598873A patent/CH605834A5/xx not_active IP Right Cessation
- 1973-04-26 CH CH1605677A patent/CH611608A5/xx not_active IP Right Cessation
- 1973-04-26 CH CH1605577A patent/CH611607A5/xx not_active IP Right Cessation
- 1973-04-26 CH CH1605777A patent/CH611609A5/xx not_active IP Right Cessation
- 1973-04-30 CA CA169,889A patent/CA1009232A/en not_active Expired
- 1973-04-30 CA CA169,890A patent/CA984388A/en not_active Expired
- 1973-05-01 JP JP4900373A patent/JPS5541231B2/ja not_active Expired
- 1973-05-01 US US05/355,986 patent/US3998809A/en not_active Expired - Lifetime
- 1973-05-01 IL IL42158A patent/IL42158A/xx unknown
- 1973-05-01 IL IL48141A patent/IL48141A/xx unknown
- 1973-05-01 IL IL47693A patent/IL47693A/xx unknown
- 1973-05-02 SE SE7306128A patent/SE409709B/sv unknown
- 1973-05-02 BE BE130663A patent/BE799001A/xx not_active IP Right Cessation
- 1973-05-02 DK DK238573A patent/DK147050C/da not_active IP Right Cessation
- 1973-05-02 ES ES414279A patent/ES414279A1/es not_active Expired
- 1973-05-02 FR FR7315752A patent/FR2183735B1/fr not_active Expired
- 1973-05-02 NO NO1797/73A patent/NO142866C/no unknown
- 1973-05-03 SU SU731918571A patent/SU625607A3/ru active
- 1973-05-03 SU SU1920527A patent/SU526290A3/ru active
- 1973-05-03 AT AT143875*1A patent/AT327927B/de not_active IP Right Cessation
- 1973-05-03 AT AT389873A patent/AT327919B/de not_active IP Right Cessation
- 1973-05-03 ZA ZA733013A patent/ZA733013B/xx unknown
- 1973-05-03 AT AT389973A patent/AT327920B/de not_active IP Right Cessation
-
1974
- 1974-12-19 FR FR7442122A patent/FR2248278B1/fr not_active Expired
-
1975
- 1975-04-16 NO NO75751349A patent/NO145761C/no unknown
- 1975-07-11 IL IL47693A patent/IL47693A0/xx unknown
- 1975-09-19 IL IL48141A patent/IL48141A0/xx unknown
-
1976
- 1976-04-02 FR FR7609742A patent/FR2296616A1/fr active Granted
- 1976-05-07 NO NO76761580A patent/NO143347C/no unknown
- 1976-05-12 US US05/685,537 patent/US4096141A/en not_active Expired - Lifetime
- 1976-09-02 CA CA260,433A patent/CA1020570A/en not_active Expired
- 1976-09-23 US US05/725,989 patent/US4098786A/en not_active Expired - Lifetime
- 1976-10-04 US US05/729,142 patent/US4216167A/en not_active Expired - Lifetime
- 1976-12-29 SE SE7614680A patent/SE422460B/xx unknown
- 1976-12-29 SE SE7614681A patent/SE7614681L/xx not_active Application Discontinuation
-
1977
- 1977-05-20 DK DK222977A patent/DK144969C/da not_active IP Right Cessation
- 1977-05-20 DK DK223077A patent/DK223077A/da unknown
- 1977-12-09 JP JP52148666A patent/JPS589101B2/ja not_active Expired
- 1977-12-09 JP JP52148667A patent/JPS5813535B2/ja not_active Expired
-
1978
- 1978-01-01 CH CH1605877A patent/CH620423A5/de not_active IP Right Cessation
- 1978-01-23 US US05/871,741 patent/US4243585A/en not_active Expired - Lifetime
- 1978-02-06 NO NO780402A patent/NO142476C/no unknown
-
1979
- 1979-09-19 NO NO793012A patent/NO144386C/no unknown
- 1979-09-19 NO NO793013A patent/NO144885C/no unknown
-
1984
- 1984-04-24 US US06/602,279 patent/US4595531A/en not_active Expired - Fee Related
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO144885B (no) | Analogifremgangsmaate ved fremstilling av terapeutisk aktive benzodiazepinderivater | |
| US4191765A (en) | 1-Aryloxy-2-hydroxy-3-aminopropanes | |
| RUBAT et al. | Anticonvulsant activity of 3-oxo-5-substituted benzylidene-6-methyl-(4H)-2-pyridazinylacetamides and 2-pyridazinylacetylhydrazides | |
| GB1603228A (en) | Indole derivatives a process for preparing them and pharmaceutical compositions containing them | |
| DE2142317A1 (de) | Hypnotisches mittel | |
| CN103073524B (zh) | 4-[4-(取代苯基)哌嗪基-1]-丁胺甲酸取代芳香酯衍生物及其制备方法 | |
| AU569537B2 (en) | Novel 1-piperazinecarboxamide derivatives | |
| FI79527B (fi) | Foerfarande foer framstaellning av nya antiarytmiska aminoguanidinderivat. | |
| Szmuszkovicz et al. | A new nontricyclic antidepressant agent. Synthesis and activity of N-[trans-2-dimethylaminocyclopentyl]-N-(3, 4-dichlorophenyl) propanamide and related compounds | |
| US3408446A (en) | Suppressing coughs and increasing secretions in warm-blooded animals with n-(amino-3,5-dihalobenzyl)-camphidines | |
| IE46802B1 (en) | 2-methoxy-5-chloro aniline derivatives | |
| US3968214A (en) | 5-Methylthio-pyrimidine vasodilators | |
| US4673682A (en) | Isoquinoline derivatives, pharmaceutical formulations based on these compounds and the use thereof | |
| PL125663B1 (en) | Process for preparing novel derivatives of n-(trimethoxybenzyl)-piperazine | |
| EP0046572B1 (en) | 6-quinazolinesulfonyl derivatives and process for preparation thereof | |
| SU927111A3 (ru) | Способ получени оксимэфиров или их солей | |
| CA1108182A (en) | Bis(nitrosoureido)-polyol derivatives and process for their preparation | |
| DK166022B (da) | Bis-(piperazinyl- eller homopiperazinyl)-alkaner og syreadditionssalte deraf, fremgangsmaade til deres fremstilling, farmaceutiske praeparater indeholdende forbindelserne, fremgangsmaade til fremstilling af saadanne praeparater og anvendelse af forbindelserne til fremstilling af et farmaceutisk praeparat med antiallergisk og antiinflammatorisk virkning | |
| US3663548A (en) | 1,4-disubstituted 2-phenyl piperazines | |
| US3810897A (en) | N-substituted-n-alkanol piperazine carbamates and acid addition salts thereof | |
| JPS6069089A (ja) | ジヒドロピリジン−５−ホスホネ−ト誘導体およびその製造法 | |
| US4714702A (en) | Quinazolinone derivative | |
| US4268511A (en) | 3-Amino(1H,3H)quinazoline-2,4-dione derivatives and their therapeutic applications | |
| DD154487A5 (de) | Verfahren zur herstellung von 1-benzoxepin-5(2h)-on-derivaten | |
| JPS62129271A (ja) | ピリジン化合物およびその製法 |