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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Compounds of the class of 2-(aminomethyl)-6-phenyl-4H-striazolo(1,5-a)(1,4)benzodiazepines, their 5-oxides and the pharmaceutically acceptable acid addition salts of said compounds and their 5-oxides have valuable pharmacological properties, in particular anticonvulsant effectiveness, and are active ingredients for therapeutic preparations. Specific embodiments are 2-((dimethylamino)-methyl)-6-phenyl-8-chloro-4H-striazolo(1,5 -a)(1,4)benzodiazepine, 2-((methylamino)-methyl)-6phenyl-8-chloro-4H-s-triazolo(1,5 -a)(1,4)benzodiazepine, 2((dimethylamino)-methyl)-6-(o-fluorophenyl)-8-chloro-4H-striazolo(1,5 -a)(1,4)benzodiazepine, 2-((methylamino)-methyl)-6(o-fluorophenyl)-8-chloro-4H-s-triazolo(1,5 -a)(1,4)benzodiazepine and 2-((methylamino)-methyl)-6-(o-chlorophenyl)-8-chloro-4H-striazolo(1,5 -a)(1,4)benzodiazepine.
Description
United States Patent Gagneux et al.
[ Apr. 15, 1975 DIAZEPINE DERIVATIVES Inventors: Andre Gagneux, Basel; Roland Heckendorn, Arlesheim; Rene Meier, Buus, all of Switzerland Assignee: Ciba-Geigy Corporation, Ardsley,
Filed: July 14, 1972 Appl. No.: 272,088
Foreign Application Priority Data July 23, l97l Switzerland 10885/71 US. Cl 260/247.5 EP; 260/141; 260/193; 260/247.1; 260/247.2 R; 260/268 TR; 260/293.59; 260/308 R; 424/248; 424/250; 424/267; 424/269 Int. Cl. C07d 57/02; CO7d 99/02 Field of Search..... 260/308 R, 293.59, 268 TR, 260/247.5 R
References Cited UNITED STATES PATENTS ll/l972 Tawada et al 260/308 R Primary Examiner-Alton D. Rollins Attorney, Agent, or Firm.loseph G. Kolodny; John J. Maitner; Theodore O. Groeger [57] ABSTRACT 4H-s-triazolo[ l ,5-a][ 1,4]benzodiazepine, 2- [(methylamino)-methyl]-6-phenyl-8-chloro-4H-striazolo[1,5-a][1,4]benzodiazepine, 2-
[(dimethylamino)-methyl]-6-(o-fluorophenyl)-8- chloro-4H-s-triazolo[l,5-a][1,4]benzodiazepine, 2- [(methylamino )-methyl ]-6-(o-fluorophenyl )-8-chloro- 4H-s-triazolo[ l,5-a][ 1,4]benzodiazepine and 2- [(methylamino)- methyl]-6-(o-chlor0phenyl)-8-chloro-4H-striazolo[l,5-a][1,4]benzodiazepine.
20 Claims, No Drawings DIAZEPINE DERIVATIVES DETAILED DESCRIPTION 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;,. independently of each other. 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.
In the compounds of the general formula I. R, is. as 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. pcntyloxy. isopentyloxy or hexyloxy group. Preferably. however. substituents of the rings A and B are fluorine. chlorine or bromine atoms. trifluoromethyl groups and/or nitro groups. As alkyl groups having I to 6 carbon atoms. 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. B-hydroxybutyl. Z-hydroxy-l-methylpropyl. Z-hydroxypentyl. Z-hydroxyhexyl and. in particular. Z-hydroxyethyl groups; and as phenylalkyl groups having at most 9 carbon atoms. R- and R are. e.g.. benzyl. phenethyl. a. o-. mor p-methylbenzyl. 3- phenylpropyl or a-methylphenethyl groups.
Alkyl groups R: and R bound together in the B- or 'y-position in the above defined manner form. together with the adjacent nitrogen atom. e.g. the l-pyrrolidinyl. piperidino. hexahydro-lH-azepin-l-yl. morpholino. lpiperazinyl or hexahydro-lH-l.4-diazepin-l-yl group. 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. 2- hydrosyethyl. Z-hydroxypropyl. 3-hydroxypropyl or 3- hydrosybutyl group. whilst all aforementioned rings on carbon atoms can. moreover. be substituted by ethyl. propyl or. in particular. methyl groups.
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 5- oxides and the addition salts of the compounds of the general formula l and of their 5-oxides with inorganic and organic acids possess valuable pharmacological properties. They have. in particular. an anticonvulsive action. such as can be shown. for example. on the mouse in the pentetrazoleconvulsion test after administration of oral doses of from ca. 0.4 mg/kg. as well as in the strychnine convulsion test and in the electroshock test. The following are of special importance: 2- [(dimethylamino )-methyl l-6-phenyl-8-chloro-4H-striazolo[ l.5-a][ 1.4]benzodiazepine. 2-
and [(methylamino )-methyl ]-6-( o-chlorophenyl )-8-chloro- 4H-s-triazolol l.5-al[ l.-l]benzodiazepine. and their pharmaceutically acceptable acid addition salts. Compared with their anticonvulsive action. the sedative action of the new compounds is less pronounced. By virtue of the mentioned properties and others. which can be determined by selected standard tests [cp. W. Theobald and H. A. Kunz. Arzneimittelforsch. 13. I22 (1963 and also W. Theobald et al.. Arzneimittelforsch. l7. Sol 1967)]. the compounds of the general formula l. their S-oxides. and the corresponding pharmaceutically acceptable addition salts with inorganic and organic acids constitute active substances for tranquilisers and anticonvulsants which can be administered. for example. for the treatment of conditions of stress and agitation with no. or with only negligible. effect on vigility; as well as for the treatment of epilepsy.
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.
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. or in place of. the excess compound. 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.
lf. instead of the compound of the general formula III. 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. by addition of at least the equimolar amount of 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. The preparation of the compounds of the general formula II and their reactive esters is described below.
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. It
wherein 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.
In the starting materials of the general formula V. the preparation of which is subsequently described. 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.
such as. e.g. ethylene glycol or diethylene glycol. or in a lower monoalkyl ether of such a glycol. or in a lower alkanol such as methanol or ethanol. Furthermore. 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. and the obtained diazonium salts subsequently coupled with (Z-chloroalkaneamido)-malonic acid diethyl esters of which the alkaneamido group contains 2 to 5 carbon atoms. especially with (Z-chlormtcetamido)- malonic acid diethyl ester ]cp. Ajay Kumar Bose. J. Indian Chem; Soc. 31. l()8l 10 (1954)]. to give the corresponding (Z-chloroalkaneamido Z-benzoylphenylazo )-malonic acid diethyl esters. particularly (2- ChlOI'02lCt3I21l'llldO)-( Z-benzoyl-phenylazo )malonic acid diethyl esters. The coupling products are then converted. by treatment with at least the double-molar amount. preferably the threeto fourfold amount. of sodium hydroxide and subsequent neutralisation. into the compounds of the general formula VII COOH l N N I ll (VII) nia or with hexamethylenetetramine. with the chlorine atom being thus replaced by the amino group. and simultaneously. with elimination of water. ring closure occurring to give carboxylic acids of the general formula lX wherein R, has the meaning given under formula I. and the rings A and B can be substituted as defined there. It is also possible. however. to firstly react the compounds of the general formula Vll with sodium azide. in the presence of potassium iodide. to compounds of the general formula Vlll ioou i l1 CH R (VIII) 0 0 wherein R has the meaning given under formula I. and the rings A and B can be substituted as defined there: and to then cyclise these compounds with triphenylphosphine. with evolution of nitrogen. to compounds of the general formula lX.
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.
LII
in a manner analogous to that for the free acids. with hexamethylenetetramine in absolute ethanol.
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.
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. For example. 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. Such solvents are. e.g. methanol. ether. acetone. methyl ethyl ketone. acetone/ether. acetone/ethanol. methanol/ether or ethanol/ether.
It is possible to use as pharmaceutical active substances. instead of free bases. pharmaceutically acceptable acid addition salts. i.e. salts with such acids of which the anions are not toxic in the case of the dosage amounts in question. Moreover. it is of advantage if the 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.
Other 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. In soft capsules. 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.
The following. for example. aresuitable as 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.
The following specifications further illustrate the production of tablets. dragees. capsules. suppositories and ampoules:
a. An amount of 50 g of 2-[(dimethylamino)- methyl ]-6-phenyl-8-chloro-4H-s-triazolo[ 1.5- all 1.4]benzodiazepine is mixed with 175.80 g of lactose and 169.70 g of potato starch; the mixture is moistened with an alcoholic solution of 10 g of stearic acid. and then granulated through a sieve. After the granulate has dried. the following ingredients are mixed in: 160 g of potato starch. 200 g of talcum. 2.50 g of magnesium stearate and 32 g of colloidal silicon dioxide: the mixture is subsequently pressed to obtain 10.000 tablets each weighing 80 mg and each containing 5 mg of active substance; the tablets may optionally be provided with grooves to render possible a more precise adjustment of the dosage amount. It is also possible to use. as active substance. the same amount of 2- 10 (piperidinomethyl )-6-phenyl-8-ch1oro-4H-striazolol 1.5-all 1.4]benzodiazepine.
b. 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.
c. To produce 1000 capsules each containing 2 mg of active substance. an amount of 2 g of 2- l(methylamino)-methyl]-6-(o-fluorophenyl-8-chloro- 4H-s-triazolol 1.5-a][ 1.4]benzodiazepine hydrochloride is mixed with 256 g of lactose; the mixture is uniformly moistened with an aqueous solution of 2 g of gelatine. and then granulated through a suitable sieve (e.g. sieve 111 according to Ph.Helv. V). The granulate is mixed with 10.0 g of dried maize starch and 15.0 g of talcum. and the mixture evenly filled into 1000 hard gelatine capsules. size I. It is also possible to use. as active substance. the same amount of 2-[(methylamino methyl ]-6-( o-fluorophenyl l-8-chloro-4H-striazolol 1.5-a][ 1.4lbenzodiazepine-fumarate-( 1:2).
d. 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.
e. A solution of 2.0 g of 2-l(methylamino)-methyl]- b-phenyl-8-chloro-4H-s-triazolol 1.5-a H 1.4 ]ben zodiazepinehydrochloride in one litre of water is filled into 1000 ampoules. and these then sterilised. An ampoule contains a 0.2 percent solution of 2 mg of active substance.
The following examples further illustrate the production of the new compounds of the general formula I and of intermediates not hitherto described: these examples. however. do not in any way limit the scope of the invention. Temperatures are expressed in degrees Centigrade.
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 combined benzene extracts are washed five times with ml of water each time; they are dried over sodium sulphate and concentrated in vacuo. The residue is dissolved in chloroform. and the solution chromatographed through a column containing g of basic aluminium oxide. After elution with chloroform. concentration of the eluate by evaporation. and recrystallisation of the residue from cyclohexane. 2-[(dimethylamino)-methyl]-6-phenyl-8- chloro-4H-s-triazolo[ 1 .5-a 1 .-1]benzodiazepine. M.P. 133135. is obtained.
The methanesulphonic acid ester required as starting material is producedas follows:
b. A solution of 58.0 g (0.25 mole) of 2-amino-5- chlorobenzophenone lcp. F. D. Chattaway. J.Chem.-
Soc. 85. 344 (1904)] in 310 ml of glacial acetic acid/- cone. hydrochloric acid (4:1) is diazotised at room temperature. whilst stirring is maintained. with 50 ml (0.25 mole) of aqueous sodium nitrite solution. An amount of 150 g of ice is added to the obtained diazonium salt solution. followed by the rapid addition dropwise of a solution of 52.4 g (0.208 mole) of (2- chloroacetamido)-malonic acid diethyl ester lcp. Ajay Kumar Bose. .l.lndian ChenrSoc. 31. 108-1 1954)] in 600 ml of acetone. An addition is subsequently made dropwise at 5-10. in the course of minutes. of a solution of 276.0 g (2 moles) of potassium carbonate in 500 ml of water; stirring is continued for one hour. and benzene and saturated sodium chloride solution are then added. The benzene solution is separated. washed with saturated sodium chloride solution. dried over sodium sulphate. and concentrated by evaporation to obtain 121 g of crude (2-benzoyl-4-chlorophenylazo)-(2- chloroacetamido)-malonic acid diethyl ester. This crude product is dissolved in 1.5 litres of dioxane; an amount of 36 g (0.9 mole) of sodium hydroxide dissolved in 2 litres of water is then added. the mixture stirred for 30 minutes. and the dioxane evaporated off in vacuo. The residue is diluted with 500 ml of water. and 20 g of active charcoal added; the mixture is well stirred and then filtered through purified diatomaceous earth. An addition is made to the filtrate. with thorough stirring. of 2N hydrochloric acid until an acid reaction to a congo-rcd indicator is obtained: the precipitated carboxylic acid is filtered off under suction. washed with water and then recrystallised from hot methanol. The obtained crystals. containing an equimolar amount of methanol. of 1-(2-benzoyl-4-chlorophenyl )-5- (chloromethyl)-1Hl .2.4-triazole-3-carboxylic acid sinter at 137l38 and melt. with decomposition. at l69l 7 1.
c. An amount of 33.2 g (0.200 mole) of potassium iodide is dissolved in 85 ml of water. and the obtained solution diluted with 850 ml of dioxane; an addition is made at with stirring. of 71.5 g (0. l 75 mole) of the compound produced according to b). and the solution heated for 1 hour at 45-50. An amount of 0.5 litre of concentrated aqueous ammonia solution is thereupon added: the mixture is heated for 2 hours at 4550. and concentrated in vacuo. The residue is dissolved in 2 litres of water. and an addition then made of 2N hydrochloric acid until the solution shows an acid reaction to a congored indicator. The free carboxylic acid precipitates; it is filtered off under suction. washed with water until neutral. subsequently washed with methanol. and dried in vacuo at l20-130. The obtained 6-phenyl-8- chloro-4-H-s-triazolo[1 ,5-a][l ,4]benzodiazepine -2 carboxylic acid decomposes at 170.
This carboxylic acid can also be produced according to d) from the chloromethyl compound obtained by procedure b):
d. An amount of 0.408 g (0.001 mole of the chloromethyl compound obtained according to b). containing an equimolar amount of methanol. and 0.320 g (0.003 mole) of hesamethylenetetramine is dissolved in 20 ml of ethanol. and the solution refluxed for 12 hours. The solution is then concentrated at 40 in vacuo. and the residue dissolved in 20 ml of 0.05N sodium hydroxide solution: 2N hydrochloric acid is then added until the solution shows an acid reaction to a congo-red indicator. and the precipitated crude product processed as under c). The obtained 6-phenyl-8-chloro-4H-striazolo[ l.5a][ l.4]benzodiazepine-2-carboxylic acid melts at 170.
e. An amount of 6.77 g (0.020 mole) of 6-phenyl-8- ch1oro-4H-s-triazolo[ 1.5-a][ 1 .4lbenzodiazepine-2- carboxylic acid [produced according to c) or d)] is suspended in 250 ml of abs. ethanol. Whilst stirring and refluxing are maintained. the solution is saturated with hydrogen chloride gas. The obtained clear solution is refluxed for a further 10 hours. and afterwards concentrated at 40 in vacuo. The residue is dissolved in ml of ice-cold 5% sodium bicarbonate solution and 100 ml of methylene chloride; the organic phase is separataed. washed with water. dried over sodium sulphate. and concentrated at 40 in vacuo. The crude viscous residue is refluxed with 100 ml of ether for one hour. during which process crystallisation occurs. After cooling to 0, the crystals are filtered off under suction and washed with ether to obtain 6-phenyl-8-chloro-4- H-s-triazolo[ 1.5-a][ l.4]benzodiazepine-2-carboxylic acid ethyl ester. M.P. l37138.
f. An amount of l 1.0 g (0.030 mole) of 6-phenyl-8- ch1oro-4H-s-triazolo-[ l .5-a][ 1.4]benzodiazepine-2- carboxylic acid ethyl ester dissolved in 1 10 ml of abs. tetrachlorofuran is added dropwise in the course of 1 hour. with ice cooling. to a suspension of 2.3 g (0.06 mole) of lithium aluminium hydride in ml of abs. tetrahydrofuran. The mixture is stirred for a further 30 minutes at 0-5. and l 1.5 ml of 1N sodium hydroxide solution then added dropwise. The inorganic salts are filtered off; the filtrate is then concentrated in vacuo. the residue dissolved in 200 ml of chloroform. the solution washed with 1N sodium hydroxide solution and then with water. After drying over sodium sulphate. the chloroform solution is concentrated in vacuo. and the residue crystallised from isopropanol. After drying. the obtained 6-phenyl-8-chloro-4H-s-triazolo 1.5- all 1 .4 ]benzodiazepine-2-methanol melts at 186.
g. An amount of 16.25 g (0.05 mole) of the alcohol obtained according to f) and 7.6 g (0.075 mole) of triethylamine is dissolved in 200 ml of abs. methylene chloride. An addition is then made dropwise at 310, with ice cooling and stirring. of 8.6 g (0.075 mole) of metlianesulphochloride dissolved in 50 ml of abs. methylene chloride. After completion of the dropwise addition. the reaction mixture is heated to 20. and stirred for a further 30 minutes. It is then cooled to 5, and 100 m1 of ice-water added. The methylene chloride phase is separated. and washed three times with 100 m1 of ice-water each time; it is then dried with sodium sulphate and concentrated at 30 in vacuo.
The methanesulphonic acid ester of 6-phenyl-8- chloro-4H-s-triazo1o[ 1.5-a][ 1 .4lbenzodiazepine-2- methanol is obtained as a dark-yellow. non-crystallising oil. and is further reacted without purification.
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 residue of 1.7 g is dissolved in ether/ethanol/triethylamine (3:5:2). and the solution chromatographed on a column of 170 g of silica gel. The employed eluting agent is ether/ethanol/triethylamine (315:2 The fractions containing the desired reaction product are combined. and concentrated in vacuo to dryness. Amorphous 2-(aminomethyl)-6-pheny1-8-ch1oro-4H-striazolo[ 1.5-a][ 1.4]benzodiazepine is obtained. which liquifies at 6975.
EXAMPLE 3 A solution of 6.05 g (0.015 mole) of crude methanesulphonic acid ester of 6-phenyl-8-ch1oro-4H-s-triazolo 1.5-a][ 1 .4]benzodiazepine-Z-methanol [produced according to Example 1 g)] in 50 ml of dimethylsulphoxide is slowly added dropwise at -1 7 to a solution of 2.55 g (0.03 mole) ofpiperidine in ml of dimethylsulphoxide: stirring is then carried out for a further 3 hours at room temperature. The reaction mixture is poured on ice-water. and extracted three times with ether. The organic phase is washed twice with water. and once with saturated sodium chloride solution: it is then dried over sodium sulphate and concentrated in vacuo to dryness. The residue is dissolved in benzene/- methylene chloride (1:1). and the solution chromatographed on a column containing 100 g of basic aluminium oxide. elution being performed with the same solvent mixture. The fractions containing the desired reaction product are combined. and concentrated in vacuo. Amorphous Z-(piperidinomethyl)-6-phenyl-8- ch1oro-4H-s-triazolol 1.5-a] 1.4]benzodiazepine is obtained. which liquifies at 5564.
The following are obtained analogously from 6.05 g (0.015 mole) of the same methanesulphonic acid ester:
with 5.4 g (0.077 mole) of pyrrolidinezamorphous 2-[( l-pyrrolidinyl l-methyl ]-6-pheny1-8-ch1oro-4H-striazolo 1.5-al[ 1.4]benzodiazepine. which liquifies at 5363;
with 2.61 g (0.030 mole) of morpholinez- 2- (morpholinomethyl )-6-phenyl-8-ch1oro-4H-striazolo[1.5-a][1.4]benzodiazepine. M.P. 11l-113 after crystallisation from ether:
with 3.05 g (0.030 mole) of 1-methy1piperazine:- 2- [(4-methy1-l-piperaziny1)-methy1]-6-phenyl-8-ch1oro- 4H-s-triazolo[ 1.5-a]l 1.4]benzodiazcpine. M.P. 162163 after crystallisation from ether:
with 2.4 g (0.080 mole) of methylaminezamorphous 2-[ methylamino )-methyl ]-6-pheny1-8-chloro-4H-s- 14 triazolo 1.5-a][ 1.4]benzodiazepine. which liquifies at 56-67.
EXAMPLE 4 Starting with 2.4 g (0.080 mole) of methylamine and 6.32 g (0.015 mole) of crude methanesulphonic acid ester of 6-(o-f1uoropheny1)-8-chloro-4H-s-triazolo[ 1.5- a][1.4]benzodiazepine-2-methano1 there is obtained. analogously to the procedure described in Example 3. 2-[ methylamino )-methyl ]-6-( o-fluorophenyl )-8-. chloro-4H-s-triazo1o[ 1.5-a][ 1.4]benzodiazepine. An addition is made to this compound in 330 ml of ethyl acetate of ethereal hydrogen chloride solution until a sample. to which water has been added. shows a pH- value of ca. 2. After prolonged cooling. the precipitated crystals are filtered off. and recrystallised twice fromethanol. The hydrochloride obtained after drying contains the double-molar amount of crystal water. and melts at 247249.
There is obtained in an analogous manner. starting with 2.4 g (0.08 mole) of methylamine and 6.57 g (0.015 mole) of crude methanesulphonic acid ester of 6-(o-ch1orophenyl )-8-ch1oro-4H-s-triazolo[ 1.5-
a][ 1.4]benzodiazepine -2-methanol. 2- [(methy1amino )-methy1]-6-(ch1orophenyl )-8-ch1oro- 4H-s-triazolol1.5-a]l1.4]benzodiazepine. This is dissolved in ml of ethanol. and a saturated ethanolic fumaric acid solution added until the pH-value of a sample to which water has been added is ca. 6. After cooling. the precipitated crystals are filtered off and recrystallised once from methanol. After drying. the obtained 2-I(methylamino)-methy1l-6-(o-chloropheny1)- 8-ch1oro-4H-s-triazolo[ 1.5-a 1.4 lbenzodiazepinefumarate-(2z1 melts at 199201.
The following 2-[(methylamino)-methy1]- compounds are obtained likewise analogously to Example 3. by the reaction in each case of 2.4 g (0.080 mole) of methylamine with the given amounts (corresponding always to 0.015 mole) of the methanesulphonic acid esters (called in short esters) of the stated alcohols:
from 6.05 g of the ester of 6-(o-ch1oropheny1)-4H-striazolo[ 1.5-a][ 1.4]benzodiazepine-2-methanol:- 2- methylamino )-methyl ]-6-(o-ch1orophenyl )-4H-striazolo[ 1.5-a][ 1.4 lbenzodiazepine;
from 7.07 g of the ester of 6-(01.01.a-trifluoro-o-to1yl)- 8ch1oro-4H-s-triazolo[ l.5-all 1.4]benzodiazepine-2- methanol:- 2-[ methylamino )-methy1]-6-( 01.01.11- trifluoro-o-tolyl )-8-chloro-4H-s-triazolol 1.5- a][ 1.4]benzodiazepine;
from 5.80 g of the ester of 6-phenyl-8-fluoro-4H-striazolo[ 1.5-a][ 1.4]benzodiazepine-2-methano1:- 2- [(methy1amino )-methyl ]-6-pheny1-8-f1uoro-4H-striazolo[ 1.5-a][ 1.4]benzodiazepine'.
from 6.71 g of the ester of 6-phenyl-8-bromo-4H-striazolo[ 1.5-a][ 1.4lbenzodiazepine-Z-methanolz- 2- [(methylamino l-methyl]-6-phenyl-8-bromo-4H-striazolo[ l.5-a][ 1 .4lbenzodiazepine;
from 6.55 g of the ester of 6pheny1-8- (trifluoromethyl )-4H-s-triazolo[ 1 .5- a][ 1.4]benzodiazepine-2-methanol:- 2-
[(methylamino )-methy1]-6-pheny1-8- (trifluoromethyl )-4H-s-triazo1o[ 1 .5- a][ 1.4 ]benzodiazepine:
from 6.20 g of the ester of 6-pheny1-8-nitro-4H-striazolo[ 1.5-a][ 1.4]benzodiazepine-2-methano1:- 2- [(methy1amino)-methyl1-6-phenyl-8-nitr0-4H-striazolo[ 1.5-a][ l .41benzodiazepine.
The methanesulphonic acid esters required as starting materials are produced as follows:
b. The following are obtained analogously to Example l b) with the use of 62.5 g (0.25 mole) of 2-amino-5- chloro-2 '-fluorobenzophenone:- [2-( o-fluorobenzoyl 4-chlorophenylazo 2 chloroacetamido )-malonic acid diethyl ester;
with the use of 66.5 g (0.25 mole) of 2-amino-2'.5- dichlorobenzophenonez- [2-( o-chlorobenzoyl )-4- chlorophenylazo 2-chloroacetamido l-malonic acid diethyl ester;
with the use of 58.0 g (0.25 mole) of 2-amino-2'- chlorobenzophenonez- [o-( o-chlorobenzoyl phenylazo]-(2-chloroacetamidol-malonic acid diethyl ester;
with the use of 75.0 g (0.25 mole) of 2-amino-5- chloro-2'-( trit'luoromethyl )-benzophenone:- [2-( 01.04.01- trifluoro-o-toluoyl )-4-chlorophenylazo H 2 chloroacetamido)-malonic acid diethyl ester:
with the use of 53.8 g (0.25 mole) of 2-amino-5- fluorobenzophenone:- (2-benzoyl-4-fluorophenylazo)- (2-chloroacetamido)-malonic acid diethyl ester:
with the use of 69.9 g (0.25 mole) of 2-amino-5- bromobenzophenone:- (2-benzoyl-4- bromophenylazo 2-chloroacetamido )-malonic acid diethyl ester;
with the use of 66.2 g (0.25 mole) of 2-amino-5- (trifluoromethyl)-benzophenone:- (2-benzoyl-a.a.atrifluoro-p-toylazo 2-chloroacetamido l-malonic acid diethyl ester:
with the use of 60.8 g (0.25 mole) of 2-amino-5- nitrobenzophenonez- (2-benzoyl-4-nitrophenylazo 2- chloroacetamido)-malonic acid diethyl ester.
c. A solution of 8.0 g (0.20 mole) of sodium hydroxide in 400 ml of water is added dropwise. in the course of 2 hours. to a solution of 51.2 g (0. 10 mole) of [2-(ofluorobenzoyl )-4-chlorophenylazo l-( 2- chloroacetamido)-malonic acid diethyl ester in 600 ml of diosane. The temperature of the reaction mixture rises during this time from initially to a maximum of and the pH-value is finally 8.5 to 9.0. The mixture is stirred at room temperature for a further minutes: it is thereupon neutralised by the addition of glacial acetic acid. and concentrated in vacuo. Ice and 5 percent sodium bicarbonate solution are added to the residue: and the mixture then extracted twice with ether. The aqueous phase is retained for further processing. The organic phases are combined. washed with ice-cold 5 percent sodium bicarbonate solution and water. dried over sodium sulphate. and concentrated in vacuo. The residue is recrystallised from isopropanol. After drying. the l-[2-(o-fluorobenzoyl)-4- chlorophenyl ]-5-( chloromethyl l H- l .2.4-triazole-3- carboxylic acid ethyl ester. obtained as the main product. melts at 97-98.
The above aqueous sodium bicarbonate solutions (the original ones and the washing-solutions) are combined; 10 percent hydrochloric acid is added until an acid reaction to a Congo-red indicator is obtained. and the solution extracted three times with methylene chloride. The combined organic extracts are washed with water and with saturated sodium chloride solution. dried over sodium sulphate. and concentrated in vacuo. Crude amorphous 1-[2-(o-fluorobenzoyl)-4- chlorophenyll-5-(chloromethyl)-1H-l.2.4-triazole-3- carboxylic acid is thus obtained as secondary product.
This crude acid can be used direct for cyclisation analogously to Example 1 c) or 1 d).
The following are obtained analogously:
with the use of 52.9 g (0.10 mole) of [2-(0- chlorobenzoyl l-4-chlorophenylazo]-( 2- chloroacetamido)-malonic acid diethyl ester: l-[2-(ochlorobenzoyl )-4-chlorophenyl ]-5-( chloromethyl lH-l .2.4-triazole-3-carboxylic acid ethyl ester and the corresponding acid. M.P. l75;
with the use of 49.4 g (0.10 mole) of {o-(ochlorobenzoyl )-phenylazo]-( 2-chloroacetamido malonic acid diethyl ester:- 1-lo-(o-chlorobenzoyl)- phenyl l-5-(chloromethyl l H- l .2.4-triazole-3- carboxylic acid ethyl ester and the corresponding acid:
with the use of 56.2 g (0.10 mole) of l2-(a.a.atrifluoro-o-toluoyl )-4-chlorophenylazo 2- chl'oroacetamido)-malonic acid diethyl ester:- 1-l2- 01.0:.a-trifluoro-o-toluoyl )-4-chlorophenyl 1-5 (chloromethyl 1 H-] .2.4-triazole-3-carboxylic ethyl ester and the corresponding acid;
with the use of 47.8 g (0.10 mole) of (2-benzoyl-4- fluorophenylazo 2-chloroacetamid0 l-malonic acid diethyl ester:- 1-( 2-benzoy1-4-fluorophenyl )-5- (chloromethy1)-1 H- 1 .2.4-triazole-3-carboxylic acid ethyl ester and the corresponding acid;
with the use of 53.8 g (0.10 mole) of (2-benzoyl-4- bromophenylazo 2-chloroacetamido )-malonic acid diethyl ester:- 1-(2-benzoyl-4-bromophenyl)-5- (chloromethyll-1H-l.2.4-triazole-3-carboxylic acid ethyl ester and the corresponding acid:
with the use of 52.8 g (0.10 mole) of (2-benzoyla.a.a-trifluoro-p-tolylazo 2-ch1oroacetamido malonic acid diethyl ester:- l-(2-benzoyl-a.a.atrifluoro-p-tolyl)-5-(chloromethyl)-lH-1.2.4-triazole- 3-carboxylic acid ethyl ester 'and the corresponding acid:
with the use of 50.4 g (0.10 mole) of (2-benzoyl-4- nitrophenylazo)-(2-chloroacetamido)-malonic acid diethyl ester:- 1-(2-benzoy1-4-nitrophenyl)-5- (chloromethyl)-1H-1.2.4-triazole-3-carboxylic acid ethyl ester and the corresponding acid;
d. A solution of 16.88 g (0.04 mole) of 1-[2-(0- fluorobenzoyl)-4-chlorophenyll-5-(chloromethyl)-1H- 1.2.4-triazole-3-carboxylic acid ethyl ester and 1 1.2 g (0.08 mole) of hexamethylentetramine in 250 ml of abs. ethanol is refluxed for 6 hours. The solution is then concentrated at 40 in vacuo; an amount of 800 ml of ice-water is then added to the residue. and extraction performed twice with methylene chloride. The organic acid phase is washed twice with ice-cold 1N hydrochloricacid and three times with water: it is then dried over sodium sulphate and concentrated in vacuo. The residue is recrystallised from isopropanol. After drying. the obtained 6-(o-fluorophenyl )-8-chloro-4H-s-triazolo[ 1.5- a][ 1.41benzodiazepine-Z-carboxylic acid ethyl ester melts at 177l79.
The following are obtained analogously:
from 17.54 g (0.04 mole) of l-[2-(o-chlorobenzoyl)- 4-chlorophenyl1-5-(chloromethyU-l H-l .2.4-triazole- 3-carboxylic acid ethyl ester:- 6-(o-chlorophenyl)-8- ch1oro-4H-s-triazolo[ 1.5-a][ 1.4]benzodiazepine-2- carboxylic acid ethyl ester:
from 16.16 g (0.04 mole) of l-[o-(o-chlorobenzoyhphenylI-S-(chloromethyU-1H-1.2.4-triazole-3- carboxylic acid ethyl ester:- 6-(o-chlorophenyl)-4H-striazolol l.5-a][ 1.4]benzodiazepine-2-carboxy1ic acid ethyl ester;
from 18.88 g (0.04 mole) of l-l2-(a.a.a-trifluoro-otoluoyl )-4-chlorophenyll-5-(chloromethyl )-1 H-1 .14- triazole-3-carboxy1ic acid ethyl ester:- (w-(cmuxtrifluoro-o-tolyl )-8-chloro-4H-s-triazolol 1.5- all 1.4lbenzodiazepine-Z-carboxylic acid ethyl ester:
from 15.50 g (0.04 mole) of 1-(2-benZoyl-4- fluorophenylt-5-(chloromethyl )-1H-1 .2.4triazole-3- carboxylic acid ethyl ester:- o-phenyl-8-t1uoro-4H-striazolol 1.5-all 1.4]benzodiazepine-Z-carlmxylic acid ethyl ester;
from 17.94 g (0.04 mole) of 1(Z-benzo \'l-4- bromophenyl)-5-(chloromethyl)-1H-1.Z.4-triaZole-3- carboxylic acid ethyl ester:- (1-pheny1-8-bromo-4H'striazolol 1 .5-all 1.4lbenzodiazepine-Z-carboxylic acid ethyl ester.
from 17.50 g (0.04 mole) of l-(l-benzoy'l-mautrifluoro-p-tolyl )-5-(chloromethy1)- 1 H-l .Z.4-triazole- 3-carboxylic acid ethyl ester:- 6-phenyl-8- (trifluoromethyl )-4H-s-triazolo[ 1.5- all 1.4lbenzodiazepine-Z-carboxylic acid ethyl ester;
from 16.58 g (0.04 mole) of 1-( Z-benzoyl- 4nitrophenyl)-5-(chloromethyl)-lH-1.2.4-triazo1e-3- carboxylic acid ethyl ester:- h-phenyl-8-nitro-4H-striazolol 1.5all1.4lbenzodiazepine-Z-carboxylic acid ethyl ester.
e. and f. The following are obtained analogously' to Examples 1 f) and g):
from 11.54 g (0.03 mole) of fi-(o-lluorophenylH4- ch1oro-4H-s-triazolol 1.5-a ll 1.4 lbenzodiazepine-L carboxylic acid ethyl ester:- b-lo-fluorophenyl)-8- chloro-4H-s-triazolol 1.5-a ll 1.4 lbenzodiazepine-Z- methanol. M.P. 138145 (from isopropanol) and its methanesulphonic acid ester (crude product);
from 12.04 g (0.03 mole) of b-(o-chlorophenyl)-8- chloro-4H-s-triazolol 1.5-all 1.4 lbenzodiazepine-Z- carboxylic acid ethyl ester:- 6-(o-chlorophenyl)-8- chloro-4H-s-triazolol 1.5-a ll 1.4 lbenzodiazepine-Z- methanol and its methanesulphonic acid ester:
from 1 1.0 g (0.03 mole) of b-(o-chlorophenyl )-4H-striazolol 1.5-all 1.4lbenzodiazepine-Z-carboxylic acid ethyl ester:- o-(o-chlorophenyl)-4H-s-triazo1ol 1.5- all l.4lbenzodiazepine-Z-methanol and its methanesulphonic acid ester:
from 13.04 g (0.03 mole) of 6-(a.a.a-trifluoro-otolyl )-8-chloro-4H-s-triazolol 1.5- all 1.4lbenzodiazepine-Z-carboxylic acid ethyl ester:- 6-( a.a.a-trifluoro-o-tolyl )-8-chloro-4H-s-triazolol 1.5- ll1.4]benzodiazepine-Z-methanol and its methanesulphonic acid ester;
from 10.50 g (0.03 mole) of 6-phenyl-8-fluoro-4H-striazolol 1.5-all 1.4lbenzodiazepine-Z-carboxylic acid ethyl ester:- 6-phenyl-8-fluoro-4H-s-triazolol 1.5- all 1.4]benzodiazepine-Z-methanol and its methanesulphonic acid ester:
from 12.33 g (0.03 mole) of 6-pheny1-8-bromo-4H-striazolol 1.5-all 1.4lbenzodiazepine-2-carboxylic acid ethyl ester:- o-phenyl-8-bromo-4H-s-triazo1ol1.5- ll 1.4]benzodiazepine-Z-methano1 and its methanesulphonic acid ester:
from 12.0 g (0.03 mole) (trifluoromethyl)-4H-s-triazolo[ 1.5- all1.4lbenzodiazepine-Z-carboxylic acid ethyl ester:- 6-phenyl-8-( tritluoromethyl )-4H-s-triazolo[ 1.5- all l.4lbenzodiazepine- -methanol and its methanesulphonic acid ester:
from 1 1.31 g (0.03 mole) of 6-phenyl-8-nitro-4H-striazolol 1.5-all 1.4lbenzodiazepine-Z-carboxylic acid of 6-phenyl-8- ethyl ester:- o-phenyl-8-nitro-4H-s-triazolol 1.5 all 1.4 lbenzodiazepine-Z-methanol and its methanesulphonic acid ester.
EXAMPLE 5 The following are obtained analogously to Example 1:
with the use of 8.41 g of methanesulphonic acid ester of 6-( o-fluorophenyl )-8-ch1oro-4H-s-triazolo| 1.5- all 1.4 lbenzodiazepine-Z-methanol:- Z- l(dimethylamino)-methyll-6(o-fluorophenyl1-8- ch1oro-4H-s-triazo1ol 1.5-a ll 1.4 lbenzodiazepine. which. after recrystallisation from ether/petroleum ether. melts at 1 141 16; and
with the use of 8.74 g of methanesulphonic acid ester of 6-( o-chlorophenyl )-8-chloro-4H-s-triazolol 1.5- all 1.4lbenzodiazepine-Z-methanolz- 2- [(dimethylamino )-methyl l-6-( o-chlorophenyl )-8- chloro-4H-s-triazolol 1.5-all 1.4lbenzodiazepine.
EXAMPLE 6 The following are obtained. analogously to Example 3. by the reaction of 2.55 g (0.03 mole) of piperidine:
with 6.32 g (0.015 mole) of crude methanesulphonic acid ester of 6-(o-fluoropheny1)-8-chloro-4H-striazolol 1.5-all 1.4 lbenzodiazepine-2-methano1:- 2 (piperidinomethyll-o-to-t'luorophenyl)-8-chloro-4H-striazolol 1.5-all 1.4lbenzodiazepine; and
with 6.57 g (0.015 mole) ofcrude methanesulphonic acid ester of fa-(o-chlorophenyl)-8-chloro-4H-striazolol 1.5-all 1.4 lbenzodiazepine-Z-methanol: 2- (piperidinomethyl )-6-( o-chlorophenyl )-8-chloro-4H-striazolol 1.5-all 1.4 lbenzodiazepine.
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. Ice and 2N sodium hydroxide solution are added to the residue. and extraction performed with a mixture of ether/methylene chloride (5:1 The organic phases are extracted with cold 1N hydrochloric acid. The acid extracts are combined and 5N sodium hydroxide solution added until a pH-value of 10 is obtained: extraction is then carried out with ether. The combined ether extracts are washed with water and with saturated sodium chloride solution. dried over sodium sulphate. and concentrated by evaporation to dryness. Amorphous Z-(aminomethyl)-6-phenyl-8-chloro-4H-striazolol 1.5-al[1.4lbenzodiazepine is obtained. which liquifies at 6975.
a. The following are obtained in an analogous manner:
starting with 1.84 g (0.005 mole) of Z-(azidomethyl 6-(o-fluorophenyl )-8-ch1oro-4H-s-triazo1ol 1 .5-
a] [l ,4lbenzodiazepine 2-(aminornethyl)-6 -(ofluorophenyl )-8-chl0ro-4H-s-triazolol 15 all 1 .4lbenzodiazepine: and
starting with 1.92 g (0.005 mole) of Z-(azidomethyl 6-( o-chlorophenyl )-8-chloro-4H-s-triazolol 1.5-
a l .4]benzodiazepine:- Z-aminomethyl )-o-( ochlorophenyl)-8-chloro-4H's-triazolo[ 1.5- a][ l.4]benzodiazepine.
b. The (azidomethyl)-compounds required as starting materials are produced as follows:
The crude methanesulphonic acid ester produced. according to Example 1 g). from 315g (().(ll mole) of 6-phenyl-S-chloro-4H-s-triazolol l.5-a][ 1.4 lbenzodiazepine-Z-methanol and l.7l g (0.015 mole) of methanesulphonic acid chloride is dissolved in 50 ml of acetone. and a solution of3.25 g (0. l 5 mole) of sodium azide in 25 ml of water added. The reaction mixture is stirred for 1 hour at 30. and thereupon concentrated in vacuo. The obtained crude azidomethyl-compound is dissolved in benzene. and washed once with cold 5 percent sodium bicarbonate solution and twice with water. The organic solution is dried over sodium sulphate. and concentrated in vacuo. The residue is dissolved in benzene. and the solution chromatographed on a column of 30 g of silica gel. elution being performed with benzene. The fractions is which the desired reaction product is dissolved are combined. and concentrated in vacuo. 2-(Azidomethyl)-6-phenyl-8- chloro-4H-s-triazolo[ l.5-a][ 1.4] henzodiazepine is obtained as yellow oil. which can be further reacted direct.
b. 2-(Azidomethyl)-6-(o-fluoro)-8-chloro-4H-striaZoloI l.5-a]l l.4]henzodiazepine and 2- (azidomethyll-o-(o-chlorophenyll-8-chloro-4H-striazolol l.5'a][1.4lbenzodiazepine are obtained analogously with the use of the corresponding crude methanesulphonic acid esters prepared. analogously to Example 1 g). with l.7l of g (0.015 mole) of methanesulphochloride front 3.43 g (().()l mole) of o-(o-fluorophenyl)-8-chloro- 4H-s-triazolo[ l .5-a l.4 lbenzodiazepine-Z-methanol. and
3.59 g ((l.()l mole) of 6-(o-chlorophenyl)-8-chloro- -lH-s-triazolol l.5-a]l 1.4 ]benzodiazepine-2-methanol. respectively.
What we claim is:
l. A diazepine derivative of the formula 1 2. CH2 N 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 ofthe rings A and B. independently ofthe other; is unsubstituted or substituted by one chlorine atom. fluorine atom. bromine atom. trifluoromethyl group. nitro group. alkyl group. or alkoxy group having from 1 to 6 carbon atoms. its S-oxide and the pharmaceutically acceptable acid addition salts of said diazepine derivative or of its S-oxide.
2. A compound according to claim 1 having the formula I. wherein R 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 the pharmaceutically acceptable acid addition salts thereof.
3. A compound according to claim 1 having the formula I. wherein R is hydrogen. 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.
4. 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. A compound having the formula lu given in claim 4. wherein R and R have the meanings given in claim R. represents a fluorine. chlorine or bromine atom or a nitro or trifluoromethyl group. and
R represents a hydrogen. fluorine. chlorine or bromine atom or a trifluoromethyl group.
6. A compound having the formula la given in claim 4, wherein 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. and 5 R represents a hydrogen. fluorine. chlorine or bromine atom or a trifluoromethyl group. and the pharmaceutically acceptable acid addition salts thereof.
7. A compound having the formula lu given in claim 4. wherein 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.
8. A compound having the formula lu given in claim 4. wherein R and R independently of each other. represent a hydrogen atom or the methyl group.
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.
9. 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.
10. A compound according to claim 1 which is l- (aminomethyl l-(i-phenyl-8-chloro-4H-s-triazolo[ 1.5- all 1.4 lbenzodiazepine.
ll. A compound according to claim 1 which is 2- 35 l(methylamino)-methyl]-6-phenyl-8-chloro-4H-striazolol 1.5-aH L4 lbenzodiazepine.
12. A compound according to claim 1 which is Z- (piperidinomethyl)-6-phenyl-8-chloro-4H-striazolol 1.5-a H [.4 lbenzodiazepine. 4o
13. A compound according to claim 1 which is 2-[( lpyrrolidinyl )-methyl l-6-phenyl-8-chloro-4H-striazolol l.5-al[ l .4 lbenzodiazepine.
14. A compound according to claim I which is 2- (morpholinomethyl )-6-phenyl-8-chloro-4H-striazolol l 5-a][ 1.4 Ibenzodiazepine.
15. 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.
16. 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. I
17. 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.
18. A compound according to claim 1 which is 2- (aminomethyl)-6-(o-fluorophenyl)-8-chloro--lH-striazolo[ l.5-a][ L4 lbenzodiazepine.
19. 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
funiarate 20. A compound of the formula IV wherein R represents a lower alkanoyl group. the cyano group. a lower alkoxycarbonyl group. the phenoxycarbonyl. benzyloxycarbonyl. chlorocarbonyl or benzoyl group.
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.
Claims (20)
1. A DIAZEPINE DERIVATIVE OF THE FORMULA I
2. A compound according to claim 1 having the formula I, wherein R1, R2 and R3 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 the pharmaceutically acceptable acid addition salts thereof.
3. A compound according to claim 1 having the formula I, wherein R1 is hydrogen, R2 and R3 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.
4. A compound according to claim 1 having the formula Ia
5. A compound having the formula Ia given in claim 4, wherein R2 and R3 have the meanings given in claim 1, R4 represents a fluorine, chlorine or bromine atom or a nitro or trifluoromethyl group, and R5 represents a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl group.
6. A compound having the formula Ia given in claim 4, wherein R2 and R3, independently of each other, represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, R4 represents a fluorine, chlorine, or bromine atom or a nitro or trifluoromethyl group, and R5 represents a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl group, and the pharmaceutically acceptable acid addition salts thereof.
7. A compound having the formula Ia given in claim 4, wherein R2 and R3, independently of each other, represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, R4 represents a chlorine atom in the 8-position and R5 represents hydrogen or a fluorine or chlorine atom in the ortho-position, and the pharmaceutically acceptable acid addition salts thereof.
8. A compound having the formula Ia given in claim 4, wherein R2 and R3, independently of each other, represent a hydrogen atom or the methyl group, R4 represents a chlorine atom in the 8-position and R5 represents hydrogen or a fluorine or chlorine atom in the ortho-position, and the pharmaceutically acceptable acid addition salts thereof.
9. A compound according to claim 1 which is 2-((dimethylamino)-methyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1, 4)benzodiazepine.
10. A compound according to claim 1 which is 2-(aminomethyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a) (1,4)benzodiazepine.
11. A compound according to claim 1 which is 2-((methylamino)-methyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1, 4)benzodiazepine.
12. A compound according to claim 1 which is 2-(piperidinomethyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1, 4)benzodiazepine.
13. A compound according to claim 1 which is 2-((1-pyrrolidinyl)-methyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1, 4)benzodiazepine.
14. A compound according to claim 1 which is 2-(morpholinomethyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1, 4)benzodiazepine.
15. A compound according to claim 1 which is 2-((4-methyl-1-piperazinyl)-methyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5 -a)(1, 4)benzodiazepine.
16. A compound according to claim 1 which is 2-((methylamino)-methyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo(1,5-a)(1, 4)benzodiazepine and its hydrochloride.
17. A compound according to claim 1 which is 2-((dimethylamino)-methyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo(1,5 -a)(1, 4)benzodiazepine.
18. A compound according to claim 1 which is 2-(aminomethyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo(1,5-a)(1, 4)benzodiazepine.
19. A compound according to claim 1 which is 2-((methylamino)-methyl)-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo(1,5-a)(1, 4)benzodiazepine and its (2:1)-fumarate.
20. A compound of the formula IV
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CH1088571A CH553801A (en) | 1971-07-23 | 1971-07-23 | PROCESS FOR THE PRODUCTION OF NEW DIAZEPIN DERIVATIVES. |
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US272088A Expired - Lifetime US3878205A (en) | 1971-07-23 | 1972-07-14 | Diazepine derivatives |
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JP (1) | JPS561316B1 (en) |
AR (2) | AR194603A1 (en) |
AT (2) | AT318625B (en) |
AU (1) | AU472145B2 (en) |
BE (1) | BE786530A (en) |
CA (1) | CA967956A (en) |
CH (1) | CH553801A (en) |
CS (2) | CS178411B2 (en) |
DD (1) | DD99578A5 (en) |
DE (1) | DE2234652A1 (en) |
FI (1) | FI52729C (en) |
FR (1) | FR2147092B1 (en) |
GB (1) | GB1395416A (en) |
HU (1) | HU165319B (en) |
IE (1) | IE36563B1 (en) |
IL (1) | IL39883A (en) |
NL (1) | NL7209809A (en) |
NO (1) | NO134868C (en) |
PL (1) | PL85681B1 (en) |
SE (1) | SE380804B (en) |
SU (2) | SU472505A3 (en) |
ZA (1) | ZA724839B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USB563070I5 (en) * | 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)
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JPS5747915B2 (en) * | 1974-04-17 | 1982-10-13 | ||
AR127157A1 (en) | 2021-09-29 | 2023-12-27 | Hoffmann La Roche | NEW BENZODIAZEPINE DERIVATIVES AS POSITIVE ALLESTERIC MODULATORS OF GABAA g1 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US3703525A (en) * | 1969-11-15 | 1972-11-21 | Takeda Chemical Industries Ltd | Triazolo(1,5-a)(1,4)benzodiazepine derivatives |
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1971
- 1971-07-23 CH CH1088571A patent/CH553801A/en not_active IP Right Cessation
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- 1972-07-13 ZA ZA724839A patent/ZA724839B/en 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/en 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 CS5172A patent/CS178411B2/cs unknown
- 1972-07-20 CS CS489A patent/CS178450B2/cs unknown
- 1972-07-21 FR FR7226331A patent/FR2147092B1/fr not_active Expired
- 1972-07-21 SU SU1813891A patent/SU472505A3/en active
- 1972-07-21 GB GB3421672A patent/GB1395416A/en not_active Expired
- 1972-07-21 PL PL1972156882A patent/PL85681B1/pl unknown
- 1972-07-21 AT AT631372A patent/AT318625B/en not_active IP Right Cessation
- 1972-07-21 DD DD164605A patent/DD99578A5/xx unknown
- 1972-07-21 HU HUCI1256A patent/HU165319B/hu unknown
- 1972-07-21 AT AT1013073A patent/AT319956B/en not_active IP Right Cessation
- 1972-07-21 AU AU44837/72A patent/AU472145B2/en not_active Expired
- 1972-07-22 JP JP7305972A patent/JPS561316B1/ja active Pending
- 1972-07-24 AR AR243233A patent/AR194603A1/en active
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1973
- 1973-05-29 AR AR248269A patent/AR197989A1/en active
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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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 (en) * | 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 |
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IL39883A0 (en) | 1972-09-28 |
NO134868B (en) | 1976-09-20 |
JPS561316B1 (en) | 1981-01-13 |
BE786530A (en) | 1973-01-22 |
AU472145B2 (en) | 1976-05-20 |
AR194603A1 (en) | 1973-07-31 |
FI52729C (en) | 1977-11-10 |
FR2147092B1 (en) | 1975-08-08 |
SE380804B (en) | 1975-11-17 |
AU4483772A (en) | 1974-01-24 |
HU165319B (en) | 1974-08-28 |
DE2234652A1 (en) | 1973-02-01 |
DD99578A5 (en) | 1973-08-12 |
CA967956A (en) | 1975-05-20 |
NO134868C (en) | 1976-12-29 |
SU497776A3 (en) | 1975-12-30 |
IL39883A (en) | 1976-06-30 |
FR2147092A1 (en) | 1973-03-09 |
AT319956B (en) | 1975-01-27 |
NL7209809A (en) | 1973-01-25 |
AT318625B (en) | 1974-11-11 |
PL85681B1 (en) | 1976-04-30 |
AR197989A1 (en) | 1974-05-24 |
IE36563L (en) | 1973-01-23 |
GB1395416A (en) | 1975-05-29 |
IE36563B1 (en) | 1976-12-08 |
CS178450B2 (en) | 1977-09-15 |
CH553801A (en) | 1974-09-13 |
FI52729B (en) | 1977-08-01 |
SU472505A3 (en) | 1975-05-30 |
ZA724839B (en) | 1973-04-25 |
CS178411B2 (en) | 1977-09-15 |
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