CS203085B2 - Method of producing novel substituted 6-aryl-4h-s-triazolo/3,4-c/thieno/2,3-e/-1,4-diazepines - Google Patents
Method of producing novel substituted 6-aryl-4h-s-triazolo/3,4-c/thieno/2,3-e/-1,4-diazepines Download PDFInfo
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- CS203085B2 CS203085B2 CS785955A CS595578A CS203085B2 CS 203085 B2 CS203085 B2 CS 203085B2 CS 785955 A CS785955 A CS 785955A CS 595578 A CS595578 A CS 595578A CS 203085 B2 CS203085 B2 CS 203085B2
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- triazolo
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- 238000000034 method Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 28
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
- 239000000460 chlorine Chemical group 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 11
- 238000007792 addition Methods 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 8
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 7
- -1 alkali metal alkoxide Chemical class 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OMXRYYPDXHPHQN-UHFFFAOYSA-N 7h-thieno[2,3-e][1,4]diazepine Chemical class C1=CN=CC2=CCSC2=N1 OMXRYYPDXHPHQN-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000906446 Theraps Species 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000007530 organic bases Chemical group 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- SMEGJBVQLJJKKX-HOTMZDKISA-N [(2R,3S,4S,5R,6R)-5-acetyloxy-3,4,6-trihydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@@H]1[C@H]([C@@H]([C@H]([C@@H](O1)O)OC(=O)C)O)O SMEGJBVQLJJKKX-HOTMZDKISA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
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- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
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- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
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- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
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- 239000004208 shellac Substances 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
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Vynález se týká způsobu výroby nových substituovaných i6-aryl-4H-s-triazolo[ 3,4-c ] thíeno[2,3-e]-l,4-'diazepinů obeonéhoi vzorce I i ] -1,4-diazepinů
Nové sloučeniny obecného vzorce I a jejich adiční soli s kyselinami se mohou podle vynálezu získat tím, že sloučenina obecného vzorce VI
kde
Rl značí vodíkový, chlorový nebo bromový atom, neibo alkylovou skupinu o 1 až 4 uhlíkových atomech,
Rž znamená vodíkový, chlorový nebo bromový attím, nitroskupimu nebo trifluormethylOvoiu skupinu a
R3 značí chlorový nebo bromový atom, alkoxy skupinu nebo alkylmerkaptoskupiriu vždy s 1 až 3 uhlíkovými atomy, jakož i jejich fyziologicky neškodných ádiičnfch solí s kyselinami.
kde
Ri a Rž mají uvedený význam, chloruje inebo brómuje, načež se je-li to žádoucí, chlorový nebo bromový atom ve sloučenině vymění za alkoxyskupinu nebo alkylmerkaptoskupinu a popřípadě získaná sloučenina obecného vzorce I převede ve fyziologicky neškodnou adiční sůl s kyselinou.
K výrobě konečných látek obecného vzorce I se sloučenina obecného vzorce VI
203083 brómuje nebo· chloruje. Halogenace se provádí v rozpouštědlech jako v tetrachlormethanu, chloroformu, methylenchloridu, dioxanu, tetrahydrofuranu, dimethylformarnidu nebo ve vhodném uhlovodíku, popřípadě za přídavku terciární organické báze jako pyridinu nebo halogansukcinimidu. Reakční teplota při této reakci se pohybuje podle použité výchozí látky a použitého postupu mezi teplotou místnosti a teplotou varu reakční směsi vařené pod zpětným chladičem.
Takto získanou 8-halogenovanou sloučeninu je možné pddle potřeby převést v odpovídající alkoxy- nebo lalkylmerkaptosloučeminu.
V případě zavedení alkoxyskupiny se halogenovaná sloučenina rozpustí v alkoholátu alkalického kovu a tento roztok se zahřívá pod zpětným chladičem.
Pro přípravu alkylmierkapto-sloučenin se halogenovaná sloučenina rozpustí v aprotiíckém rozpouštědle, jako dioxanu, tetrahydrofuranu, dimethylformamidu nebo hexamethylfosfortriamidu '(HMPT) nebo v alkoholu a ponechá reagovat s merkaptidem alkalického· kovu; merkaptid alkalického kovu se při této reakci může vyrobit in šitu, například uváděním merkaptanu do roztoku alkoholátu alkalického kovu, který obsahuje rozpuštěnou halogenovanou sloučeninu.
Konečné látky obecného vzorce I se mohou převést podle potřeby obvyklým způsobem ve fyziologicky neškodné adiční sloučeniny s kyselinami. Vhodné kyseliny k přípravě solí jsou například kyseliny halogenovodíkové, kyselina sírová, fosforečná, dusičná, cyklohexylsulfaminová, citrónová, vinná, askorbová, maleinová, mravenčí, salicylová nebo methan- nebo toluensulfonová a podobně.
Výroba látek obecného vzorce VI je popsána v německém zveřejňovacím spisu DOS 2 410 030 a provádí se tak, že se sloučenina obecného vzorce II
kde
X znamená skupinu SH, NH2, nižší alkoxyskupinu nebo alkylmerkaptoskupinu a
Ri a R2 mají uvedený význam, nechá reagovat s orthoesterem kyseliny mravenčí,
Sloučeniny obecného vzorce I, popřípadě jejich adiční sloučeniny s kyselinami vykazují cenné terapeutické vlastnosti. Ukázaly se při použití různých farmakologických testovacích metod účinné anxiolyticky, uvolňovaly napětí a měly svalově relaxační účinek, nadto pak intenzívní antikoinvulzívní účinek. Mají rovněž tu vlastnost, že zvyšují u savců podstatně příjem potravy. Povšimnutí hodná je též jejich význačně nízká toxicita. Předčí známé thieno-l,4-diazepiny bez přídavného triazolového kruhu, které jsou známy například ze zveřejňovacích spisů DOS 2155 403 a 2 2(2)1 623, zvláště jejich velmi silně vyznačený v tzv. pentetrazolovém testu prokazatelný antikonvulzívní účinek, přičemž se sice podobají známým 8-aikyl-6-arylthieno[ 2,3-e ] -4H-s-!triazolO[ 3,4-c ] -1,4-diazepinům ze zveřejňovacího spisu DOS 2 229 845·, ale mají vzhledem k jejich účinnosti svoiji účinnost více než desetkrát vyšší. Jako zvláště cenné se ukázaly takové sloučeniny, a popřípadě jejich adiční soli s kyselinami, ve kterých Ri je bromový atoim, R2 značí chlorový nebo bromový atom a R3 značí bromový atom nebo methoxyekupinu, zvláště pak
1.8-dibrom-6-o-chlorfenyl-4H-s-triazolo[ 3,4-c ]thienol[ 2,3-e ]-l,4-diazepin (Rl = Br, R2 = Cl, R3 = Br J a
8-briom-6-oi-chlorfenyl-l-imethoxy-4H-s-triazoloi[ 3,4-c j thienoj 2,3-e ] -1,4-diazepin (Rl = Br, R2 = Cl, R3 = OCH3] a jejich adiční soli s kyselinami.
K testům se použily bílé myši o tělesné hmotnosti 20 až 25 g nebo bílé krysy FW 49 o tělesné hmotnosti 140 až 200 g. S výjimkou Gellerova testu konfliktní situace se ipro každou .dávku -použilo 10 zvířat. Gellerův test konfliktní situace se prováděl se 4 zvířaty pro každou dávku. Testované látky byly suspendovány v olivovém oleji a ve všech případech zavedeny do žaludku pomočí hltanové sondy.
1. Pentetrazolový antagonismus:
Dávka, která zruší u 50 % zvířat letální účinek 125 mg/kg pentylentetrazolu, který byl pódán intraperitoneálně 1 hodinu po dávce testované látky [Μ. I. Gluckmann,
Curr, Ther. Res., 7, 721 (1965) ].
2. Gellerův test:
Dávka, při které zvířata, která jsou v konfliktní situaci, desetkrát stisknou předmět kulatého tvaru, aby získala pilulku potravy, ačkoli současně zapnutý signál oznámí, že společně s pilulkou potravy budou potrestána ve formě elektrické rány (J. Geller, Arch. Int. Pharmacodyn., 149, 243 (1964)].
3. Test boijoivnosti myší:
Dávika, při které u 50 % zvířat ustane agresivita. Stanovuje se u vyrostlých samců, kteří během 3 až 4 týdnů Izolace byli udržováni v temnu, proti mladým samcům myší. [Wirth, GOsswald, Horlein, Risse und Kreiskott, Arch. Int. Pharmacodym. 115: 1 až 31 (19S8) ].
4, LD5o:
Dávka, kterou přežije 50 % zvířat. [Liťchfield a Wilcoxon, J. Pharmacol, Exptl. Therap. 96, 99 (1949)].
Zjištěné hodnoty byly u všech testů zjištěny graficky. Výsledky testů jsou uvedeny v této· tabulce:
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Jednotlivá dávka sloučenin podle vynálezu činí 0,05 až 50', s výhodou 0,1 až 25 m,g (orálně) a 5 až 150 mg jako denní dávka.
Sloučeniny, které lze získat podle vynálezu ss mohou používat samotné nebo ve směsích s jinými sloučeninami podle vynálezu nebo též v kombinaci s dalšími farmakologicky aktivními látkami, jako spasmolytiky nebo' látkami blokujícími jl-receptory. Vhodné lékové formy jsou například tablety, kapsle, čípky, roztoky, šťávy, emulze nebo dispergovatelmé prášky. Příslušné tablety se mohou například připravit mícháním účinné látky nebo účinných látek se známými pomocnými látkami, například inertními! zřeďujícími prostředky, jako uhličitanem vápenatým, fosforečnanem vápenatým nebo mléčným cukrem, látkami usnadňujícími rozpadnutí tablet, jako kukuřičným škrobem nebo kyselinou alginovou, pojidly, jako škrobem nebo želatinou, kluznými látkami, jako stearátem hořečnatým nebo mastkem, a/nebo prostředky k dosažení depotního účinku, jako karboxypolymsthylenem, ikarboxymeťhylcelulózou, ftalátem acetylcelulózy nebo polyvinylacetátem. Tablety se mohou sestávat z více vrstev.
Dražé se mohou odipoivídajícně získat povlékáními jader získaných analogicky jako tablety, obvyklými prostředky k tornu účelu používanými, například kolidonem nebo šelakem, arabískou gumou, mastkem, kysličníkem titaničitými nebo cukrem. K docílení depotního účinku nebo k zabránění vzniku inkompatibilit může se také jádro sestávat z více vrstev. Rovněž tak i povlak dražé může být z více vrstev, přičemž se mohou použít pomooné látky uvedené již u přípravy tablet.
Šťávy ze sloučenin podle vynálezu, popřípadě jejich kombinací mohou též dodatečně obsahovat sladící prostředky, jako sacharin, cyklamát, glycerin nebo cukr, rovněž tak chuťová korigencia, například aromatické látky, jako vanilin nebo pomerančový extrakt. Mimoto mohou obsahovat pomocné látky k udržení suspenzí nebo zahušťovací látky, jako. natriumkarboxymethylcelulózu, smáčedla, například kondenzační produkty vyšších alifatických alkoholů s ethylenoxidem, nebo ochranné látky jako p-hydroxybenzoáty.
Injekční roztoky se připravují obvyklými pojstupy, například za přídavku konzervačních látek, jako p-hydroxybenzoátů, nebo stabilizátorů, jako alkalických solí kyseliny ethyleindiamintetraoctové a pak se plní do fiol nebo ampulí.
Jednu nebo více účinných látek, popřípadě kombinací účinných látek obsahující kapsle se mohou například vyrobit tak, že se účinné látky smísí s netečnými nosiči, jako například s mléčným cukrem nebo sorbřtem a naplní se do želatinových kapslí.
Vhodné čípky se dají například vyrobit smícháním k tomu vhodných nosičů jako neutrálních tuků nebo polyethylenglykolu, popřípadě jeho derivátů.
Příklad 1, l,8-Dibro®-6- (o-chlorfenyl) -4H-s-triazolo[ 3,4-c ] thiendj 2,3-e ] -1,4-diazepin
a) 10 g 8-brom-6-<( o-chlorfenyl )-4H-s-triazolo [3,4-c ] thienof 2,3-e ] -1,4-diazepinu se rozpustí ve směsi sestávající ze 20 ml pyridinu a 1O0 ml methylenchloridu a zahřívá ise po dobu 7 hodin. Poté se během 5 minut přidá 6,3 g bromu rozpuštěného ve
2,5 ml methylenchloridu, a zahřívá se další 3 hodiny pod zpětným 'Chladičem.. Nato se reakční směs ochladí, zředí se imethylenchloiridem, a roztok se vytřepe dvakrát s 1 N kyselinou chlorovodíkovou a jednou s vodou. Po sušení se methylenchlorid odpaří a odparek se ipřekryistaluje z ethanolu.
Získá se 7,0 g titulní sloučeniny (tj. 60 proč.) o teplotě tání 210 až 211 °C.
b) Výchozí sloučenina se získá tímto postupem:
g 7-brom-5-(o-chloirfenylj-2-hydrazino-3H-[ 2,3-e ]thieno-l,4-diazepinu o teplotě tání asi 300°C (rozklad), se vaří pod zpětným chladičem po dobu 30 minut ve směsi sestávající ze 23 ml kyseliny orthomravenčí a 300 ml ethanolu. Rozpouštědlo se odpaří a odparek se rozetře s etherem..
Výtěže činí 20 g látky o teplotě tání 214 až 216 °C.
Příklad 2
8-Brom-6-t (o-chlorfenyl )-l-me'thoxy-3H-s-triazo,loi[ 3,4-c ] thienoj 2,3-e ] -1,4-diazepin.
g l,8-dibrom-6-( o-chlorfenyl )-4H-s-tr.iazolo[ 3,4-c jthienoj 2,3-e J -1,4-díazepiinu se zahřívá po dobu 2 hodin pod zpětným chladičem v roztoku 0,6 g sodíku v 70 ml methanolu. Reakční směs se odpaří, zředí vodou a poté se vytřepe mathylenohloridem. Methylenchloridová fáze se vysuší a methylenchlorid se odpaří. Z Odparku se po překrystalování s ethanolem získá 7 g (tj. 76 % teorie] titulní sloučeniny o teplotě tání 198 až 200 QC.
Příklad 3
8-Br om-6- (o-chlorfenyl) -1-methylimerkapto-4HHS-trlazold[ 3,4-c jthieno[ 2,3-e ] -1,4-diazepin
0,15 g sodíku se rozpustí ve 40 ml absolutního methanolu a do roztoku se zavede
34.0 mg methylmeirkaptanu. Potom se k roztoku přidá 2,5 g l,8-diibrom-6-(o-chlorfe203085 nyl) -4H-s-triazolol[ 3,4-c ] thleno|[ 2,3-e ] -1,4-•diazepinu a zahřívá se na teplotu mezi 40 až 50 °C. Po· uplynutí asi 30 minut nelze již chromatografií na tenké vrstvě prokázat žádnou dibrdmsloučeninu. Roztok se potom odpaří, odparek se rozpustí v methylenchloridu, miethylenchlorid se několikrát vytřepe vodou, organická báze vysuší, rozpouštědlo se odpaří a odparek chromatografuje na sloupci kysličníku křemičitého.
Získá se 920 mg, tj. 40 % titulní sloučeniny o teplotě tání 158 až 160 °C.
Dále byly podle svrchu popsaného postupu získány konečné produkty, uvedené v následujících příkladech zahrnutých do tabulky.
Tabulka
Příklad číslo Rl R2 R3 TeplotaThe present invention relates to a process for the preparation of novel substituted 16-aryl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepines of the formula (I) -1,4-diazepines
The novel compounds of the formula I and their acid addition salts can be obtained according to the invention by the compound of the formula VI
where
R1 represents a hydrogen, chlorine or bromine atom, or a C1-4 alkyl group,
R @ 2 represents a hydrogen, chlorine or bromine atti, a nitro group or a trifluoromethyl group, and
R @ 3 denotes a chlorine or bromine atom, an alkoxy group or an alkyl mercapto group in each case having from 1 to 3 carbon atoms, as well as their physiologically acceptable acid addition salts.
where
R1 and R2 are as defined above, chlorine or bromine, whereupon, if desired, the chlorine or bromine atom in the compound is replaced by an alkoxy or alkylmercapto group and the optionally obtained compound of formula I is converted into a physiologically acceptable acid addition salt.
For the preparation of the final compounds of the formula I, a compound of the formula VI is used
203083 brominates or chlorinates. The halogenation is carried out in solvents such as carbon tetrachloride, chloroform, methylene chloride, dioxane, tetrahydrofuran, dimethylformamide or a suitable hydrocarbon, optionally with the addition of a tertiary organic base such as pyridine or halo succinimide. The reaction temperature in this reaction varies between room temperature and the reflux temperature of the reaction mixture, depending on the starting material used and the procedure used.
The 8-halogenated compound thus obtained can be converted, if desired, into the corresponding alkoxy- or alkyl-mercapto compound.
If an alkoxy group is introduced, the halogenated compound is dissolved in an alkali metal alcoholate and the solution is heated to reflux.
To prepare alkylmercapto compounds, the halogenated compound is dissolved in an aprotic solvent such as dioxane, tetrahydrofuran, dimethylformamide or hexamethylphosphoric triamide (HMPT) or in an alcohol and reacted with an alkali metal mercaptide; The alkali metal mercaptide can be produced in situ in this reaction, for example by introducing mercaptan into an alkali metal alcoholate solution containing the dissolved halogenated compound.
The final compounds of the formula I can be converted into physiologically harmless acid addition compounds, as required, in the customary manner. Suitable acids for preparing salts are, for example, hydrohalic acid, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid or methane- or toluenesulfonic acid and the like.
The preparation of the compounds of the general formula VI is described in German Offenlegungsschrift No. 2,410,030 and is carried out by the compound of the general formula II
where
X is SH, NH2, lower alkoxy or alkylmercapto;
R1 and R2 are as defined above, reacted with formic acid orthoester,
The compounds of the formula I or their acid addition compounds have valuable therapeutic properties. They have been shown to be effective anxiolytically, relieve tension and have a muscular relaxant effect, and an intense anticoinvulsive effect, using various pharmacological test methods. They also have the property of substantially increasing food intake in mammals. Their remarkably low toxicity is also noteworthy. The known thieno-1,4-diazepines without an additional triazole ring, which are known, for example, from DOS 2155 403 and 2 (2) 1623, in particular their very strong anticonvulsant effect in the so-called pentetrazole test, surpasses resemble the known 8-alkyl-6-arylthieno [2,3-e] -4H-s-1 ; The triazolo [3,4-c] -1,4-diazepines of DOS 2,229,845, but have a potency of more than ten times higher due to their efficacy. Particularly valuable have been those compounds and, where appropriate, acid addition salts thereof, in which R1 is a bromine atom, R2 is a chlorine or bromine atom and R3 is a bromine atom or a methoxy group, especially
1,8-dibromo-6-o-chlorophenyl-4H-s-triazolo [3,4-c] thienol [2,3-e] -1,4-diazepine (R 1 = Br, R 2 = Cl, R 3 = Br J and
BRIO-8-ol-6-chlorophenyl-l-dimethoxy-4H-s-triazole [3,4-c thienoj 2,3-e] -1,4-diazepine (R = Br, R 2 = Cl, R 3 = OCH3] and their acid addition salts.
White mice weighing 20-25 g or white FW 49 rats weighing 140-200 g were used for the tests. Except for the Geller conflict test, 10 animals were used for each dose. Geller's conflict test was performed with 4 animals for each dose. The test substances were suspended in olive oil and in all cases introduced into the stomach by a pharynx probe.
1. Pentetrazole antagonism:
Dose that abolishes the lethal effect of 125 mg / kg of pentylentetrazole in 50% of animals administered intraperitoneally 1 hour after the dose of test substance [Μ. I. Gluckmann,
Curr. Ther. Res., 7, 721 (1965)].
2. Geller test:
A dose at which animals in conflict are pressing a round object ten times to obtain a food pill, although a signal on at the same time announces that together with the food pill they will be punished in the form of an electrical wound (J. Geller, Arch. Int. Pharmacodyn) 149, 243 (1964)].
3. Mice Boijoivity Test:
Dose at which aggressiveness ceases in 50% of animals. It is determined in adult males who were kept in the dark during 3-4 weeks of Isolation against young male mice. [Wirth, Gosswald, Horlein, Risse and Kreiskott, Arch. Int. Pharmacodym. 115: 1-31 (19S8)].
4, LD50:
Dose that survives 50% of the animals. [Lichfield and Wilcoxon, J. Pharmacol, Exptl. Therap. 96, 99 (1949)].
The values were determined graphically in all tests. The test results are shown in the following table:
20308S
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A single dose of the compounds of the invention is 0.05 to 50 ', preferably 0.1 to 25 m, g (orally) and 5 to 150 mg as a daily dose.
The compounds obtainable according to the invention can be used alone or in admixture with other compounds of the invention or also in combination with other pharmacologically active substances, such as spasmolytics or β-receptor blocking agents. Suitable dosage forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. The tablets may, for example, be prepared by mixing the active ingredient (s) with known excipients, for example inert excipients. diluents such as calcium carbonate, calcium phosphate or milk sugar, tablet disintegrating agents such as corn starch or alginic acid, binders such as starch or gelatin, glidants such as magnesium stearate or talc, and / or a depot effect, such as carboxypolymethylene, carboxymethylcellulose, acetylcellulose phthalate, or polyvinyl acetate. Tablets may consist of multiple layers.
Dragees can optionally be obtained by coating cores obtained analogously to tablets, by conventional means for the purpose used, for example, collidone or shellac, Arabian gum, talc, titanium dioxide or sugar. To achieve a depot effect or to prevent incompatibilities, the core may also consist of multiple layers. Likewise, the dragee coating may consist of several layers, with the aid of the substances already mentioned in the preparation of tablets.
The juices of the compounds of the invention, or combinations thereof, may also additionally contain sweetening agents such as saccharin, cyclamate, glycerin or sugar, as well as flavorings, for example flavoring agents such as vanillin or orange extract. In addition, they may contain suspending aids or thickening agents, such as. sodium carboxymethylcellulose, wetting agents, for example the condensation products of higher aliphatic alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Injectable solutions are prepared by conventional means, for example, with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as the alkali salts of ethylenediaminetetraacetic acid, and are then filled into vials or ampoules.
For example, one or more active ingredients, or active ingredient combinations comprising capsules, may be prepared by mixing the active ingredients with inert carriers such as milk sugar or sorbent and filling them in gelatin capsules.
Suitable suppositories can be prepared, for example, by mixing suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.
Example 1, 8-Dibro®-6- (o-chlorophenyl) -4H-s-triazolo [3,4-c] thiene-2,3-e] -1,4-diazepine
(a) 10 g of 8-bromo-6 - <(o-chlorophenyl) -4H-s-triazolo [3,4-c] thienof 2,3-e] -1,4-diazepine are dissolved in a mixture consisting of 20 ml pyridine and 10 ml of methylene chloride and heated for 7 hours. Then 6.3 g of bromine dissolved in
The reaction mixture was cooled, diluted with imethylene chloride, and the solution was shaken twice with 1 N hydrochloric acid and once with water. After drying, the methylene chloride was evaporated and the residue was recrystallized from ethanol.
7.0 g of the title compound (i.e. 60 proc.), M.p. 210 DEG-211 DEG C. are obtained.
(b) The starting compound is obtained as follows:
g of 7-bromo-5- (o-chlorophenyl) -2-hydrazino-3H- [2,3-e] thieno-1,4-diazepine, melting at about 300 ° C (decomposition), is heated at reflux for a period of time. 30 minutes in a mixture consisting of 23 ml of orthoformic acid and 300 ml of ethanol, the solvent was evaporated and the residue was triturated with ether.
Yield 20 g, m.p. 214-216 ° C.
Example 2
8-Bromo-6- (o-chlorophenyl) -1-methoxy-3H-s-triazo, loi [3,4-c] thieno [2,3-e] -1,4-diazepine.
gl, 8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diaazepiin was heated at reflux for 2 hours in solution of 0.6 g of sodium in 70 ml of methanol. The reaction mixture was evaporated, diluted with water and then shaken with methylene chloride. The methylene chloride phase was dried and the methylene chloride was evaporated. From the residue after recrystallization with ethanol to give 7 g (i.e. 76%] of the title compound, mp 198-200 ° C Q
Example 3
8-bromo-6- (o-chlorophenyl) -1-methylmercapto-4HHS-trlazo [3,4-cthieno [2,3-e] -1,4-diazepine
Dissolve 0.15 g of sodium in 40 ml of absolute methanol and introduce into the solution
34.0 mg of methylmeercaptan. Then 2.5 gl, 8-diibromo-6- (o-chlorophenyl203085 nyl) -4H-s-triazololo [3,4-c] thleno [2,3-e] -1,4- diazepine and heated to a temperature between 40 to 50 ° C. After about 30 minutes, no dibromo compound can be detected by thin layer chromatography. The solution is then evaporated, the residue is dissolved in methylene chloride, the methylene chloride is shaken several times with water, the organic base is dried, the solvent is evaporated and the residue is chromatographed on a column of silica.
920 mg (40%) of the title compound of melting point 158-160 ° C is obtained.
Further, the end products listed in the following examples included in the table were obtained according to the above procedure.
Table
Example number R1 R2 R3 TemperatureClaims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CS785955A CS203085B2 (en) | 1974-07-20 | 1978-09-14 | Method of producing novel substituted 6-aryl-4h-s-triazolo/3,4-c/thieno/2,3-e/-1,4-diazepines |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2435041A DE2435041C3 (en) | 1974-07-20 | 1974-07-20 | 8-Substituted 6-aryl-4H-s-triazolo [3,4c] thieno [23e] 1,4-diazepines, process for their preparation, their use in medicaments and pharmaceutical preparations containing them |
CS751284A CS203083B2 (en) | 1974-03-02 | 1975-02-26 | Method of producing novel substituted 6-aryl-4h-o-triazolo/3,4-c/thieno/2,3-e/1,4-diazepines |
CS785955A CS203085B2 (en) | 1974-07-20 | 1978-09-14 | Method of producing novel substituted 6-aryl-4h-s-triazolo/3,4-c/thieno/2,3-e/-1,4-diazepines |
Publications (1)
Publication Number | Publication Date |
---|---|
CS203085B2 true CS203085B2 (en) | 1981-02-27 |
Family
ID=25745411
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CS785955A CS203085B2 (en) | 1974-07-20 | 1978-09-14 | Method of producing novel substituted 6-aryl-4h-s-triazolo/3,4-c/thieno/2,3-e/-1,4-diazepines |
Country Status (1)
Country | Link |
---|---|
CS (1) | CS203085B2 (en) |
-
1978
- 1978-09-14 CS CS785955A patent/CS203085B2/en unknown
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