US3878205A - Diazepine derivatives - Google Patents
Diazepine derivatives Download PDFInfo
- Publication number
- US3878205A US3878205A US272088A US27208872A US3878205A US 3878205 A US3878205 A US 3878205A US 272088 A US272088 A US 272088A US 27208872 A US27208872 A US 27208872A US 3878205 A US3878205 A US 3878205A
- Authority
- US
- United States
- Prior art keywords
- chloro
- benzodiazepine
- methyl
- triazolo
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 125000002576 diazepinyl group Chemical class N1N=C(C=CC=C1)* 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 239000002253 acid Substances 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- CSTQKEUDWLINGO-UHFFFAOYSA-N 1-(8-chloro-6-phenyl-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl)-N-methylmethanamine Chemical compound CNCC1=NN2C(CN=C(C3=C2C=CC(=C3)Cl)C3=CC=CC=C3)=N1 CSTQKEUDWLINGO-UHFFFAOYSA-N 0.000 claims abstract 2
- ORBQPAGGYGBJRT-UHFFFAOYSA-N 1-[8-chloro-6-(2-fluorophenyl)-4h-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-n-methylmethanamine Chemical compound C12=CC(Cl)=CC=C2N2N=C(CNC)N=C2CN=C1C1=CC=CC=C1F ORBQPAGGYGBJRT-UHFFFAOYSA-N 0.000 claims abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 239000011737 fluorine Substances 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 239000000460 chlorine Chemical group 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 150000004908 diazepines Chemical class 0.000 claims description 3
- OHPATFMBIKOOLG-UHFFFAOYSA-N (8-chloro-6-phenyl-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl)methanamine Chemical compound NCC1=NN2C(CN=C(C3=C2C=CC(=C3)Cl)C3=CC=CC=C3)=N1 OHPATFMBIKOOLG-UHFFFAOYSA-N 0.000 claims 1
- MONQCJSEJXZAQS-UHFFFAOYSA-N 1-(8-chloro-6-phenyl-4h-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl)-n,n-dimethylmethanamine Chemical compound C12=CC(Cl)=CC=C2N2N=C(CN(C)C)N=C2CN=C1C1=CC=CC=C1 MONQCJSEJXZAQS-UHFFFAOYSA-N 0.000 claims 1
- OIJHDURVGZHRNA-UHFFFAOYSA-N 1-[8-chloro-6-(2-chlorophenyl)-4h-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-n-methylmethanamine Chemical compound C12=CC(Cl)=CC=C2N2N=C(CNC)N=C2CN=C1C1=CC=CC=C1Cl OIJHDURVGZHRNA-UHFFFAOYSA-N 0.000 claims 1
- FMWDMODXOSHGPE-UHFFFAOYSA-N 1-[8-chloro-6-(2-fluorophenyl)-4h-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-n,n-dimethylmethanamine Chemical compound C12=CC(Cl)=CC=C2N2N=C(CN(C)C)N=C2CN=C1C1=CC=CC=C1F FMWDMODXOSHGPE-UHFFFAOYSA-N 0.000 claims 1
- VJQBZTZBMSIEQX-UHFFFAOYSA-N 4-[(8-chloro-6-phenyl-4h-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl)methyl]morpholine Chemical compound C=1C(Cl)=CC=C(N2N=3)C=1C(C=1C=CC=CC=1)=NCC2=NC=3CN1CCOCC1 VJQBZTZBMSIEQX-UHFFFAOYSA-N 0.000 claims 1
- OQLFONMCOAFHPE-UHFFFAOYSA-N 8-chloro-2-[(4-methylpiperazin-1-yl)methyl]-6-phenyl-4h-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine Chemical compound C1CN(C)CCN1CC1=NN2C3=CC=C(Cl)C=C3C(C=3C=CC=CC=3)=NCC2=N1 OQLFONMCOAFHPE-UHFFFAOYSA-N 0.000 claims 1
- BYQNLQMTWCLDQE-UHFFFAOYSA-N 8-chloro-6-phenyl-2-(piperidin-1-ylmethyl)-4h-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine Chemical compound C=1C(Cl)=CC=C(N2N=3)C=1C(C=1C=CC=CC=1)=NCC2=NC=3CN1CCCCC1 BYQNLQMTWCLDQE-UHFFFAOYSA-N 0.000 claims 1
- BXVKVAKPVUTCHJ-UHFFFAOYSA-N 8-chloro-6-phenyl-2-(pyrrolidin-1-ylmethyl)-4h-[1,2,4]triazolo[1,5-a][1,4]benzodiazepine Chemical compound C=1C(Cl)=CC=C(N2N=3)C=1C(C=1C=CC=CC=1)=NCC2=NC=3CN1CCCC1 BXVKVAKPVUTCHJ-UHFFFAOYSA-N 0.000 claims 1
- GIUWFNSXGRJZHB-UHFFFAOYSA-N [8-chloro-6-(2-fluorophenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]methanamine Chemical compound NCC1=NN2C(CN=C(C3=C2C=CC(=C3)Cl)C3=C(C=CC=C3)F)=N1 GIUWFNSXGRJZHB-UHFFFAOYSA-N 0.000 claims 1
- 229940049706 benzodiazepine Drugs 0.000 abstract description 25
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 230000001773 anti-convulsant effect Effects 0.000 abstract 1
- 229960003965 antiepileptics Drugs 0.000 abstract 1
- 150000001557 benzodiazepines Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 65
- 239000000243 solution Substances 0.000 description 63
- -1 2- hydroxybutyl Chemical group 0.000 description 39
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 239000013543 active substance Substances 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 235000011167 hydrochloric acid Nutrition 0.000 description 10
- 229960000443 hydrochloric acid Drugs 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000007524 organic acids Chemical class 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 239000008298 dragée Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 7
- 239000000155 melt Substances 0.000 description 7
- 150000007522 mineralic acids Chemical class 0.000 description 7
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000001828 Gelatine Substances 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 6
- 125000004494 ethyl ester group Chemical group 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 6
- 239000000829 suppository Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
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- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
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- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 5
- 125000001841 imino group Chemical group [H]N=* 0.000 description 5
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
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- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-N tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- DIAZEPINE DERIVATIVES Inventors: Andre Gagneux, Basel; Roland Heckendorn, Arlesheim; Rene Meier, Buus, all of Switzerland Assignee: Ciba-Geigy Corporation, Ardsley,
- the present invention relates to new diazepine derivatives. to processes for their production. to therapeutic preparations containing the new compounds. and to the use thereof.
- the compounds according to the invention correspond to the general formula l wherein R, represents hydrogen. or an alkyl group having from 1 to 3 carbon atoms.
- R- and R represent a hydrogen atom. an alkyl or hydroxyalkyl group having from l to 6 carbon atoms. or an aralkyl group having from 7 to 9 carbon atoms. whereby. when R;- and R simultaneously represent alkyl groups as aforesaid. these alkyl groups may optionally be bound together in the B- or y-position either directly or via an oxygen atom or imino group. or alkylimino or hydroxyalkylimino group having at most 4 carbon atoms. and wherein each of the rings A and B. independently of the other. is unsubstituted or substituted by one or more chlorine atoms. fluorine atoms. bromine atoms. trifluoromethyl groups. nitro groups and/or alkyl and/or alkoxy groups having from I to 6 carbon atoms.
- the invention also relates to the S-osides of the compounds of the general formula I. and to the addition salts of the compounds of the general formula I and of their S-oxides with inorganic and organic acids.
- alkyl group e.g. the methyl. ethyl or propyl group.
- Suitable alkyl groups as substituents of the rings A and B each having I to 6 carbon atoms are. e.g. the methyl. ethyl. propyl. isopropyl. butyl. isobutyl. tert.butyl. pentyl. isopentyl. neopentyl. tert.pentyl or hexyl group: and suitable alkosy groups having 1 to 6 carbon atoms are. e.g. the methoxy. ethoxy. propoxy. isopropoxy. butoxy. isobutoxy.
- substituents of the rings A and B are fluorine. chlorine or bromine atoms. trifluoromethyl groups and/or nitro groups.
- R, and R are. e.g. ethyl. propyl. isopropyl. butyl. isobutyl. pentyl. isopentyl or hexyl groups. and preferably methyl groups: as hydroxyalkyl groups having at most 6 carbon atoms.
- R: and R;, are. e.g. Z-hydroxypropy'l. 3-hydroxypropyl. 2- hydroxybutyl.
- R- and R are. e.g.. benzyl. phenethyl. a. o-. mor p-methylbenzyl. 3- phenylpropyl or a-methylphenethyl groups.
- the two last-mentioned groups can be substituted in the -l-position. i.e. in the imino group. e.g. by a methyl. ethyl. propyl. isopropyl. butyl. isobutyl.
- a preferred class of diazepine derivatives are those. wherein R, is hydrogen and wherein the rings A and B are unsubstituted or substituted by a single substituent defined under formula l.
- These diazepine derivatives correspond to the general formula la and R, and R independently of each other. represent a hydrogen. fluorine. chlorine or bromine atom. a trifluoromethyl or nitro group or an alkyl or alkoxy group having from 1 to 6 carbon atoms.
- the radical R is preferably in the 8-position and is. in particular. one of the mentioned halogen atoms. especially chlorine. also the nitro group or the trifluoromethyl group.
- the radical R is preferably hydrogen or a fluorine. chlorine or bromine atom or the trifluoromethyl group in any desired position. particularly. however. it is hydrogen or is a fluorine or chlorine atom in the o-position.
- the compounds of the general formula I. their oxides and the corresponding acid addition salts are produced according to the invention by the reaction of a reactive ester of a compound of the general formula ll (1H CH C wherein R. has the meaning given under formula I. and the rings A and B can be substituted as defined there. or of the S-oxide of such a compound. with a compound of the general formula III (IIT) wherein R and R have the meaning given under formula l. or with an alkali metal derivative of such a compound: and. optionally. the conversion of the obtained reaction product into an addition salt with an inorganic or organic acid.
- a reactive ester of a compound of the general formula ll (1H CH C wherein R. has the meaning given under formula I. and the rings A and B can be substituted as defined there. or of the S-oxide of such a compound. with a compound of the general formula III (IIT) wherein R and R have the meaning given under formula l. or with an alkali metal derivative of such a compound:
- Suitable reactive esters of hydroxy compounds of the general formula ll are. e.g. sulphonic acid esters such as the methanesulphonic acid esters. the oand ptoluenesulphonic acid esters. the 0- or p-nitrobenzenesulphonic acid esters. or the 0- or p-chlorobenzenesulphonic acid esters.
- Further suitable reactive esters of compounds of the general formula ll are their hydrohalic acid esters. especially chlorides or bromides. as well as the iodides produced in situ from them.
- An excess of the basic compound to be reacted of the general formula II] can serve as reaction medium. and simultaneously as acid-binding agent. It is also possible to use as the reaction medium. in addition to.
- an inert organic solvent e.g. a lower alkanol such as methanol. ethanol. propanol. isopropanol or butanol. a ketone such as acetone or methyl ethyl ketone. also. e.g. dioxane. tetrahydrofuran. dimethylformamide or dimethylsulphoxide. whereby. optionally. the compound of the general formula lll may be also used in excess as an aqueous solution: or. alternatively. it is'possible to use. instead of this excess. or in addition to it. another acid-binding agent. e.g. a tertiary organic base such as ethyldiisopropylamine or collidine. or an inorganic basic substance such as. e.g. potassium carbonate.
- an inert organic solvent e.g. a lower alkanol such as methanol. ethanol. propanol. isopropanol or
- an alkali metal derivative of such a compound is used as reaction component. e.g. a sodium. lithium or potassium derivative. then it is preferable to use hydrocarbons such as benzene. toluene or xylene. ethereal liquids such as 1.2-dimethoxyethane. tetrahydrofuran or dioxane. or acid amides such as dimethylformamide or hexamethylphosphoric acid triamide. or sulphoxides such as dimethylsulphoxide. as solvents.
- the formation of the alkali metal derivatives of the compounds of formula III. with the exception of ammonia. is preferably effected in situ. e.g.
- alkali metal hydride such as sodium hydride.
- alkali metal amide such as sodium or lithium amide. or of an alkali-metaI-organic compound such as phenylor butyllithium.
- the reaction temperatures are preferably between 0 and C. or the boiling temperature of the employed reaction medium.
- a second process for the production of compounds of the general formula I wherein R and R are hydrogen atoms. whilst R has the meaning given under formula I. and the rings A and B can be substituted as defined there. and of their S-oxides and the corresponding acid addition salts. comprises the reduction of a compound of the general formula IV CH N M.
- R has the meaning given under formula I. and the rings A and B can be substituted as defined there. or of the 5-oxide of such a compound; and. optionally. the conversion of the obtained reaction product into an addition salt with an inorganic or organic acid.
- the reduction of the azides of the general formula IV. the preparation of which is described below. can be carried out both by chemical methods and by catalytic hydrogenation. e.g. in the presence of palladium charcoal catalysts. platinum oxide or Raney nickel. in an organic solvent such as dioxane. ethanol. methanol or tetrahydrofurat'i. at room temperature and under normal pressure.
- a suitable chemical method is. in particular. the reduction with tin(ll)-chloride in lower alkanolicaqueous. especially ethanolic-aqueous. alkali solution. particularly sodium hydroxide solution. at temperatures of between ca. and the boiling temperature of the reaction mixture. preferably between ca. 0 and room temperature.
- a third process for the production of compounds of the general formula I of which the radical R is hydrogen. or in which the lower alkyl groups R; and R are bound in the B- or y-position by an imino group. whilst R, has the meaning given under formula I. and the rings A and B can be substituted as defined there. as well as of oxides of such compounds and the corresponding acid addition salts. comprises the hydrolysis of a compound of the general formula V CH N A l ⁇ N N l (v) CH R wherein R represents an acyl radical. or a lower alkyl group bound to a lower alkyl group R in the B- or 'y-position by an acylimino group.
- R and R- have the meanings given under formula I. and the rings A and B can be substituted as defined there. or of the S-oxide of such a compound: and. optionally. the conversion of the obtained reaction product into an addition salt with an inorganic or organic acid.
- R or the acyl radical of the imino group is. in particular. a lower alkanoyl group such as the acetyl or formyl group. the cyano group. a lower alkoxycarbonyl group such as the methoxycarbonyl. ethoxycarbonyl or tert- .butoxycarbonyl group. a phenoxycarbonyl or benzyloxycarbonyl group. also a corresponding thiocarbonyl group. or the acyl radical of another monofunctional derivative ofcarbonic acid such as. e.g. the chlorocarbonyl group. or an arenecarbonyl group such as the benzoyl group.
- Hydrolysis can be performed with the aid of an alkali metal hydroxide. e.g. potassium or sodium hydroxide. at a temperature of ca. 50 to'l2()C. e.g. in a higher boiling organic solvent containing hydroxyl groups.
- an alkali metal hydroxide e.g. potassium or sodium hydroxide.
- a temperature of ca. 50 to'l2()C e.g. in a higher boiling organic solvent containing hydroxyl groups.
- hydrolysis can also be carried out in an acid medium. e.g. with hydrogen bromide or hydrogen chloride in acetic acid. or with alkanolic hydrochloric acid. at a temperature of ca. 50 to lC or at the boiling temperature of the reaction mixture.
- the compounds of the general formula ll. on which the reactive esters required as starting materials for the first process are based. are obtained. for example. starting with compounds of the general formula VI CO (VI) wherein the rings A and B can be substituted as defined under formula I.
- Such compounds are described in the literature. e.g. Z-amino-S-chlorobenzophenone lcp. F. D. Chattaway. .l.Chem.Soc. 85. 344 (1904)]. or 2- amino-Z'.5-dichlorobenzophenone ]cp. L. H. Sternbach et al.. J. Org. Chem. 26. 4488 (196] )1.
- the cornpounds of the general formula Vl are diazotised.
- the carboxylic acids of the general formula [X are converted in a manner known per se. e.g. with ethanol or methanol containing hydrogen chloride. into their ethyl or methyl esters; and these reduced with lithium aluminium hydride. in an ethereal solvent such as tetrahydrofuran and at temperatures of around 0C. to compounds of the general formula ll.
- the ethyl esters of the carboxylic acids of the general formula IX required for the reducation can also be obtained by the treatment of the aforementioned coupling products with at most the double-molar amount of sodium hydroxide under mild reaction conditions. i.e. at room temperature and with neutralisation before processing: and the subsequent reaction of the ethyl esters of carboxylic acids of the general formula VI! obtained as the main product.
- the compounds of the general formula ll obtained by reduction are converted in a manner known per se. e.g. by reaction with a sulphonic acid chloride such as methanesulphonic acid chloride or p-toluenesulphonic acid chloride. in an inert organic solvent such as methylene chloride. in the presence of an organic base such as triethylamine or ethyl-diisopropylamine. or by reaction with thionyl chloride or phosphorus tribromide and. optionally. subsequently with potassium iodide. into suitable reactive esters.
- a sulphonic acid chloride such as methanesulphonic acid chloride or p-toluenesulphonic acid chloride.
- an inert organic solvent such as methylene chloride.
- an organic base such as triethylamine or ethyl-diisopropylamine.
- thionyl chloride or phosphorus tribromide and.
- the compounds of the general formula IV serving as starting materials for the second process are produced by the reaction of reactive esters of compounds of the general formula ll. e.g. methanesulphonic acid esters. with alkali metal azides such as sodium azide. in inert organic or organic-aqueous solvents. such as. e.g. aqueous acetone.
- the starting materials of the general formula V used in the third process. in which R is an acyl group. are obtained. for example. analogously to the firstmentioned process by employing. instead of an alkali metal compound of a starting material of the general formula 11]. e.g. an alkali metal compound of a formamide. acetamide or cyanamide substituted in the amide group by R. or of a carbamic acid-lower alkyl ester. -phenyl ester or -benzyl ester substituted on the nitrogen atom by R.
- the compounds of the general formula I obtained by the processes according to the invention. and also the S-oxides of these compounds. are optionally converted. in the usual manner. into their addition salts with inorganic and organic acids.
- the acid desired as salt component is added to a solution of a compound of the general formula I in an organic solvent.
- Organic solvents in which the formed salt is difficultly soluble are preferably chosen for the reaction. so that the salt can be separated by filtration.
- solvents are. e.g. methanol. ether. acetone. methyl ethyl ketone. acetone/ether. acetone/ethanol. methanol/ether or ethanol/ether.
- salts to be used as pharmaceutical active substances crystallise well and are not. or only slightly. hygroscopic.
- the following may be used. for example. for salt formation with compounds of the general formula 1: hydrochloric acid. hydrobromic acid. sulphuric acid. phosphoric acid. methanesulphonic acid. ethanesulphonic acid. Z-hydroxyethanesulphonic acid. acetic acid. lactic acid. succinic acid. fumaric acid. maleic acid. malic acid. tartaric acid. citric acid. benzoic acid. salicylic acid. phenylacetic acid. mandelic acid and embonic acid.
- the new active substances are administered orally. rectally or parenterally.
- the dosage amount depends on the mode of administration. on the species. on the age and on the individual condition.
- the daily doses of the free bases. of their 5-oxides. or of pharmaceutically acceptable salts of the free bases vary between 0.02 mg/kg and 2 mg/kg for warm-blooded animal's.
- Suitable dosage units. such as dragees. tablets. suppositories or ampoules. preferably contain 0.5-25 mg of an active substance according to the invention.
- Dosage units for oral administration contain as active substance preferably between 1-50 percent of a compound of the general formula 1. or of a pharmaceutically acceptable salt thereof.
- the dosage units are prepared by the combination of the active substance with. e.g. solid pulverulent carriers such as lactose. saccharose. sorbitol. mannitol: starches such as potato starch. maize starch or atnylopectin. also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine. optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols. to form tablets or dragee cores.
- the dragee cores are coated. for example. with concentrated sugar solutions which may also contain. e.g. gum arabic. talcum and/or titanium dioxide; or with a lacquer dissolved in readily volatile organic solvents or solvent mixtures.
- Dyestuffs can be added to these coatings in order to facilitate. for example. identification of the various doses of active substance.
- suitable oral dosage units are hard gelatine capsules. as well as soft closed capsules made from gelatine and a softener. such as glycerin.
- the hard capsules contain the active substance preferably as a granulate. in admixture. for example. with fillers such as maize starch. and/or lubricants such as talcum or magnesium stearate. and optionally stabilisers such as so-- dium metabisulphite (Na- 5 or ascorbic acid.
- the active substance is preferably dissolved or suspended in suitable liquids such as polyethylene glycols. to which likewise stabilisers may be added.
- Suitable dosage units for rectal administration are. e.g. suppositories consisting of a combination of an active substance and a suppository foundation substance.
- base substances natural or synthetic triglycerides. paraffin hydrocarbons. polyethylene glycols or higher alkanols. Hard gelatine capsules consisting of a combination of the active substance and a foundation substance are likewise suitable. Suitable foundation substances are. e.g. liquid triglycerides. polyethylene glycols or paraffin hydrocarbons.
- Ampoules for parenteral administration particularly for intramuscular administration. preferably contain a water-soluble salt of an active substance in a concentration of preferably 0.1 2 percent. optionally together with suitable stabilisers and buffer substances. in aqueous solution.
- a granulate is produced from 50 g of 2- I (dimethylamino )-methyl ]-6-(o-fluorophenyl )-8- chloro-4H-s-triazolo 1.5-a][ 1.4]benzodiazepine. 175.90 g of lactose and the alcoholic solution of 10 g of stearic acid: after drying.
- the granulate is mixed with 56.60 g of colloidal silicon dioxide. 165 g oftalcum. 20 g of potato starch and 2.50 g of magnesium stearate: and the mixture finally pressed to obtain 10.000 dragee cores.
- These are then coated with a concentrated syrup made from 502.28 g of crystallised saccharose. 6 g of shellac. 10 g of gum arabic. 0.22 g of dyestuff and 1.5 g of titanium dioxide; the coated dragees are finally dried.
- the obtained dragees each weigh 100 mg and each contain 5 mg of active substance.
- a suppository mixture is prepared from 1.0 g of 2- [(dimethylamino)-methyl]-6-pheny1-8-chloro-4H-striazolol 1.5-a1l 1.4]benzodiazepine and 169.0 g of adeps-solidus; from the prepared mixture are then poured 100 suppositories each containing 10 mg of active substance.
- EXAMPLE 1 a An amount of 8.05 (0.02 mole) of methanesulphonic acid ester of 6-phenyl-8-chloro-4H striazolol 1.5-all1.4]benzodiazepine-Z-methanol is dissolved in ml of dimethylsulphoxide; the solution is then added dropwise at 510. with stirring. to a mixture of 10 g (0.09 mole) of 40.5 percent aqueous dimethylamine solution and 20 ml of dimethylsulphoxide. The reaction mixture is then allowed to warm up to room temperature. and is stirred for a further hour at 2025. It is thereupon poured on 0.5 litre of icecold water. and extraction carried out twice with 250 ml of benzene each time.
- the methanesulphonic acid ester required as starting material is producedas follows:
- This carboxylic acid can also be produced according to d) from the chloromethyl compound obtained by procedure b):
- EXAMPLE 2 The methanesulphonic acid ester prepared according to Example 1 g) from 4.9 g (0.015 mole) of 6-phenyl-8- ch1oro-4H-s-triazo1ol 1 .5-a1l 1.4 lbenzodiazepine-Z- methanol and 2.58 g (0.023 mole) of methanesulphonic acid chloride is dissolved in 50 m1 of methanol: the solution is then added dropwise to 100 ml of boiling methanol. which is continuously saturated by the introduction of ammonia gas. Refluxing is carried out for 4 hours with the further introduction of ammonia gas. and the reaction mixture then concentrated in vacuo to dryness.
- Sodium hydroxide solution (0.1N) is added to the residue and extraction performed with benzene.
- the benzene extract is washed once with water. and at terwards repeatedly extracted with 0.1N acetic acid.
- the acid extracts are combined. rendered alkaline with conc. ammonia. and extracted with benzene.
- the combined benzene extracts are washed with water and with saturated sodium chloride solution. dried over sodium sulphate. and concentrated to dryness.
- the methanesulphonic acid esters required as starting materials are produced as follows:
- This crude acid can be used direct for cyclisation analogously to Example 1 c) or 1 d).
- EXAMPLE 7 a A solution of 1.69 g (0.0075 mole) of tin(ll)- chloridedihydrate in 24 m1 of 2N sodium hydroxide solution is slowly added dropwise at 05 to a solution of 1.75 g (0.005 mole) of Z-(azidomethyl)6phenyl-8- chloro-4H s-triazolol 1.5-all 1.4lbenzodiazepine in 175 ml of percent aqueous ethanol. The reaction mixture immediately becomes cloudy. After completion of the dropwise addition. the reaction mixture is stirred fora further 30 minutes at 5-1(); it is then neutralised with 2N hydrochloric acid. and concentrated in vacuo to dryness.
- R and R have the meanings given in claim 1. and wherein each of the rings A and B. independently of the other. is unsubstituted or substituted by one fluorine atom. chlorine atom. bromine atom. trifluoromethyl group or nitro group. and the pharmaceutically acceptable acid addition salts thereof.
- a compound according to claim 1 having the for- R and R have the meanings given in claim 1 and R and R,-.. independently of each other. represent a hydrogen. fluorine. chlorine or bromine atom. a trifluoromethyl or nitro group or an alkyl or alkoxy group having from I to 6 carbon atoms. its S-oxide and the pharmaceutically acceptable acid addition salts of said compound of the formula la or of its 5-oxide 5.
- R represents a hydrogen. fluorine. chlorine or bromine atom or a trifluoromethyl group.
- R and R independently of each other. represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.
- R represents a fluorine. chlorine. or bromine atom or a nitro or trifluoromethyl group.
- 5 R represents a hydrogen. fluorine. chlorine or bromine atom or a trifluoromethyl group. and the pharmaceutically acceptable acid addition salts thereof.
- R and R independently of each other. represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.
- R represents a chlorine atom in the 8-position and R represents hydrogen or a fluorine or chlorine atom in the ortho-position. and the pharmaceutically acceptable acid addition salts thereof.
- R represents a chlorine atom in the 8-position and R represents hydrogen or a fluorine or chlorine atom in the ortho-position. and the pharmaceutically acceptable acid addition salts thereof.
- a compound according to claim 1 which is 2- l(dimethylamino )-methyl ]-6-phenyl-8-chloro-4H-s- 3o triazolol l.5-a][ l .4 lbenzodiazepine.
- a compound according to claim 1 which is l- (aminomethyl l-(i-phenyl-8-chloro-4H-s-triazolo[ 1.5- all 1.4 lbenzodiazepine.
- a compound according to claim 1 which is 2- 35 l(methylamino)-methyl]-6-phenyl-8-chloro-4H-striazolol 1.5-aH L4 lbenzodiazepine.
- a compound according to claim 1 which is Z- (piperidinomethyl)-6-phenyl-8-chloro-4H-striazolol 1.5-a H [.4 lbenzodiazepine. 4o
- a compound according to claim 1 which is 2-[( lpyrrolidinyl )-methyl l-6-phenyl-8-chloro-4H-striazolol l.5-al[ l .4 lbenzodiazepine.
- a compound according to claim I which is 2- (morpholinomethyl )-6-phenyl-8-chloro-4H-striazolol l 5-a][ 1.4 Ibenzodiazepine.
- a compound according to claim 1 which is 2-[ (4- methyl 1 -piperazinyl )-methyl ]-6-phenyl-8-chloro-4H- s-triazolol l.5-a][ 1.4]benzodiazepine.
- a compound according to claim 1 which is 2- 1(methylamino )-methyl ]-6-( o-fluorophenyl )-8-chloro- 4H-s-tria7.olo[l.5-a][1.4]benzodiazepine and its hy drochloride.
- a compound according to claim 1 which is 2- ltdimethylamino )-meth vl ]-6-( o-fluorophenyl )-8- chloro-4H-s-triazolo[ l .5a][ l.4 lbenzodiazepine.
- a compound according to claim 1 which is 2- (aminomethyl)-6-(o-fluorophenyl)-8-chloro--lH-striazolo[ l.5-a][ L4 lbenzodiazepine.
- a compound according to claim 1 which is 2- ⁇ (rneth vlamino )-methyll-o-(o-chlorophenyl )-8-chloro- 4H-s-triazolo[ l.5-a][ 1.4]benzodiazepine and its (2:1
- R and R have the meanings given in claim 1 and wherein each of the rings A and B. independently of the other. is unsubstituted or substituted as indicated in claim 1, and its S-oxide.
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- Chemical & Material Sciences (AREA)
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CH1088571A CH553801A (de) | 1971-07-23 | 1971-07-23 | Verfahren zur herstellung von neuen diazepinderivaten. |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USB563070I5 (es) * | 1975-03-28 | 1976-03-09 | ||
US4209516A (en) * | 1974-01-14 | 1980-06-24 | Ciba-Geigy Corporation | Triazole derivatives |
US4209515A (en) * | 1974-06-14 | 1980-06-24 | Ciba-Geigy Corporation | Triazole derivatives |
US4510141A (en) * | 1982-09-13 | 1985-04-09 | Ciba-Geigy Corporation | Tricyclic polyazaheterocycles for treating depression or anxiety |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5747915B2 (es) * | 1974-04-17 | 1982-10-13 | ||
CN118019742A (zh) | 2021-09-29 | 2024-05-10 | 豪夫迈·罗氏有限公司 | 作为GABA A γ1 PAM的新颖苯并二氮杂䓬衍生物 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3703525A (en) * | 1969-11-15 | 1972-11-21 | Takeda Chemical Industries Ltd | Triazolo(1,5-a)(1,4)benzodiazepine derivatives |
-
0
- BE BE786530D patent/BE786530A/xx unknown
-
1971
- 1971-07-23 CH CH1088571A patent/CH553801A/xx not_active IP Right Cessation
-
1972
- 1972-06-28 FI FI721828A patent/FI52729C/fi active
- 1972-07-11 IL IL39883A patent/IL39883A/en unknown
- 1972-07-12 IE IE982/72A patent/IE36563B1/xx unknown
- 1972-07-13 ZA ZA724839A patent/ZA724839B/xx unknown
- 1972-07-13 SE SE7209242A patent/SE380804B/xx unknown
- 1972-07-14 US US272088A patent/US3878205A/en not_active Expired - Lifetime
- 1972-07-14 NL NL7209809A patent/NL7209809A/xx not_active Application Discontinuation
- 1972-07-14 DE DE2234652A patent/DE2234652A1/de active Pending
- 1972-07-17 CA CA147,245A patent/CA967956A/en not_active Expired
- 1972-07-19 NO NO2588/72A patent/NO134868C/no unknown
- 1972-07-20 CS CS489A patent/CS178450B2/cs unknown
- 1972-07-20 CS CS5172A patent/CS178411B2/cs unknown
- 1972-07-21 SU SU1813891A patent/SU472505A3/ru active
- 1972-07-21 DD DD164605A patent/DD99578A5/xx unknown
- 1972-07-21 HU HUCI1256A patent/HU165319B/hu unknown
- 1972-07-21 GB GB3421672A patent/GB1395416A/en not_active Expired
- 1972-07-21 FR FR7226331A patent/FR2147092B1/fr not_active Expired
- 1972-07-21 AU AU44837/72A patent/AU472145B2/en not_active Expired
- 1972-07-21 AT AT1013073A patent/AT319956B/de not_active IP Right Cessation
- 1972-07-21 AT AT631372A patent/AT318625B/de not_active IP Right Cessation
- 1972-07-21 PL PL1972156882A patent/PL85681B1/pl unknown
- 1972-07-22 JP JP7305972A patent/JPS561316B1/ja active Pending
- 1972-07-24 AR AR243233A patent/AR194603A1/es active
-
1973
- 1973-05-29 AR AR248269A patent/AR197989A1/es active
-
1974
- 1974-01-30 SU SU1993157A patent/SU497776A3/ru active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3703525A (en) * | 1969-11-15 | 1972-11-21 | Takeda Chemical Industries Ltd | Triazolo(1,5-a)(1,4)benzodiazepine derivatives |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4209516A (en) * | 1974-01-14 | 1980-06-24 | Ciba-Geigy Corporation | Triazole derivatives |
US4209515A (en) * | 1974-06-14 | 1980-06-24 | Ciba-Geigy Corporation | Triazole derivatives |
USB563070I5 (es) * | 1975-03-28 | 1976-03-09 | ||
US3996230A (en) * | 1975-03-28 | 1976-12-07 | The Upjohn Company | 1-Piperazino-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines |
US4510141A (en) * | 1982-09-13 | 1985-04-09 | Ciba-Geigy Corporation | Tricyclic polyazaheterocycles for treating depression or anxiety |
Also Published As
Publication number | Publication date |
---|---|
ZA724839B (en) | 1973-04-25 |
IE36563L (en) | 1973-01-23 |
AT319956B (de) | 1975-01-27 |
IE36563B1 (en) | 1976-12-08 |
HU165319B (es) | 1974-08-28 |
SU497776A3 (ru) | 1975-12-30 |
DD99578A5 (es) | 1973-08-12 |
FR2147092B1 (es) | 1975-08-08 |
IL39883A (en) | 1976-06-30 |
CA967956A (en) | 1975-05-20 |
NO134868B (es) | 1976-09-20 |
SE380804B (sv) | 1975-11-17 |
GB1395416A (en) | 1975-05-29 |
FR2147092A1 (es) | 1973-03-09 |
IL39883A0 (en) | 1972-09-28 |
CS178411B2 (es) | 1977-09-15 |
BE786530A (fr) | 1973-01-22 |
AU472145B2 (en) | 1976-05-20 |
CS178450B2 (es) | 1977-09-15 |
DE2234652A1 (de) | 1973-02-01 |
PL85681B1 (es) | 1976-04-30 |
JPS561316B1 (es) | 1981-01-13 |
NL7209809A (es) | 1973-01-25 |
AU4483772A (en) | 1974-01-24 |
CH553801A (de) | 1974-09-13 |
FI52729C (fi) | 1977-11-10 |
AR194603A1 (es) | 1973-07-31 |
SU472505A3 (ru) | 1975-05-30 |
AT318625B (de) | 1974-11-11 |
AR197989A1 (es) | 1974-05-24 |
NO134868C (es) | 1976-12-29 |
FI52729B (es) | 1977-08-01 |
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