DK141908B - METHOD OF ANALOGUE FOR THE PREPARATION OF 1,8-DIBROMO-6- (O-CHLORPHENYL) -4H-S-TRIAZOLO- (3,4-C) -THIENO- (2,3-E) -1,4-DIAZEPINE OR ACID ADDITION SALTS. - Google Patents
METHOD OF ANALOGUE FOR THE PREPARATION OF 1,8-DIBROMO-6- (O-CHLORPHENYL) -4H-S-TRIAZOLO- (3,4-C) -THIENO- (2,3-E) -1,4-DIAZEPINE OR ACID ADDITION SALTS. Download PDFInfo
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- DK141908B DK141908B DK288778A DK288778A DK141908B DK 141908 B DK141908 B DK 141908B DK 288778 A DK288778 A DK 288778A DK 288778 A DK288778 A DK 288778A DK 141908 B DK141908 B DK 141908B
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- DK
- Denmark
- Prior art keywords
- diazepine
- thieno
- triazolo
- dibromo
- addition salts
- Prior art date
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- 239000002253 acid Substances 0.000 title description 8
- 150000003839 salts Chemical class 0.000 title description 6
- 238000000034 method Methods 0.000 title description 5
- 238000002360 preparation method Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 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
- 238000002474 experimental method Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 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 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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- CKFGINPQOCXMAZ-UHFFFAOYSA-N methanediol Chemical compound OCO CKFGINPQOCXMAZ-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000011302 passive avoidance test Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 150000004911 1,4-diazepines Chemical class 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CSDWGIAYTPKLRV-UHFFFAOYSA-N ClC1=CC=CC=C1C(C(N1C2)=NN2Br)=NCC(C=C2)=C1[S+]2Br Chemical compound ClC1=CC=CC=C1C(C(N1C2)=NN2Br)=NCC(C=C2)=C1[S+]2Br CSDWGIAYTPKLRV-UHFFFAOYSA-N 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
- 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
- RSPISYXLHRIGJD-UHFFFAOYSA-N OOOO Chemical compound OOOO RSPISYXLHRIGJD-UHFFFAOYSA-N 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
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 206010047924 Wheezing Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 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
- 230000002082 anti-convulsion Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 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
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 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
- 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
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229960005152 pentetrazol Drugs 0.000 description 1
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- 210000002784 stomach Anatomy 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
141908141908
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af den hidtil ukendte forbindelse, l,8-dibrom-6- (o-chlorphenyl)-4H-s—triazolb-r[3,4- c]-thieno-[2,3-e]-l,4-diazepin med den i patentkravet an-5 givne formel I, eller dens fysiologisk acceptable syreadditionssalte .The present invention relates to an analogous process for the preparation of the novel compound, 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolb-r [3,4-c] -thieno- [2,3- e] -1,4-diazepine of the formula I as claimed, or its physiologically acceptable acid addition salts.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man bromerer en forbindelse med den i patentkravet angivne formel II, og at man eventuelt overfører forlo bindeisen med formlen I i et fysiologisk acceptabelt syreadditionssalt deraf.The process according to the invention is characterized by bromiding a compound of the formula II as claimed and optionally transferring the precursor of the formula I into a physiologically acceptable acid addition salt thereof.
Brameringen kan udføres i et opløsningsmiddel, såsom 'carbantetrachlorid, chloroform, methylenchlorid, dioxan, tetrahydrofuran, dimethylformaafd eller et egnet 15 carbonhydrid, eventuelt under tilsætning af en tertiær organisk base, såsom pyridin, eller også ved hjælp af et halogensuccinimid. Der anvendes afhængigt af det anvendte udgangsmateriale og den anvendte fremgangsmåde en reaktionstemperatur mellem stuetemperatur og tilbagesvalings-2o temperaturen af reaktionsblandingen.The bromination may be carried out in a solvent such as carbon tetrachloride, chloroform, methylene chloride, dioxane, tetrahydrofuran, dimethylformafide or a suitable hydrocarbon, optionally with the addition of a tertiary organic base such as pyridine, or also by a halogen succinimide. Depending on the starting material used and the method used, a reaction temperature between room temperature and the reflux temperature of the reaction mixture is used.
Forbindelsen med formlen I kan om ønsket på sædvanlig måde overføres i dens fysiologisk acceptable syreadditionssalte. Til saltdannelse egnede syrer er f. eks. hydrogenhalogenidsyrer, svovlsyre, phosphorsyre, 25 salpetersyre, cychlohexylsulfaminsyre, citronsyre, vinsyre, ascorbinsyre, maleinsyre, myresyre, salicylsyre eller methan- eller toluensulfonsyre og lignende.The compound of formula I may, if desired, be transferred in its usual manner into its physiologically acceptable acid addition salts. Suitable salts are, for example, hydrogen halide acids, sulfuric acid, phosphoric acid, nitric acid, cychlohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid or methane or toluene sulfonic acid and the like.
Fremstilling af udgangsforbindelsen med formlen II kan ske ved omsætning af 7-brom-5-(o-chlorphenyl)-3H-3o [2,3-e]-thieno-l,4-diazepin-2-thion med myresyrehydrazid eller ved omsætning af 7-brom-5-(o-chlorphenyl)-2-hydra-zino-3H-[2,3-e]-thieno-l,4-diazepin med myresyre.The starting compound of formula II may be prepared by reacting 7-bromo-5- (o-chlorophenyl) -3H-3 [2,3-e] -thieno-1,4-diazepine-2-thione with formic acid hydrazide of 7-bromo-5- (o-chlorophenyl) -2-hydrazino-3H- [2,3-e] -thieno-1,4-diazepine with formic acid.
Forbindelsen med formlen I og dens syreadditionssalte udviser værdifulde terapeutiske egenskaber. Den 35 har ved anvendelse ved forskellige farmaceutiske afprøvningsmetoder vist anxiolytisk, spændingsopløsende og muskelrelaxerende aktivitet og har først og fremmest 2 141908 en kraftig antikonvulsiv virkning. Dens yderst ringe giftighed er også bemærkelsesværdig. Den er kendte thie-no-l,4-diazepiner uden yderligere triazolring, således som de f.eks. kendes fra DE-offentliggørelsesskrift nr.The compound of formula I and its acid addition salts exhibit valuable therapeutic properties. It 35, when used in various pharmaceutical testing methods, has shown anxiolytic, stress-relieving and muscle relaxant activity and, first and foremost, has a strong anticonvulsant effect. Its extremely low toxicity is also remarkable. It is known thie-no-1,4-diazepines without additional triazole ring, such as those e.g. is known from DE publication no.
5 2 155 403 og nr. 2 221 623, overlegen, især med hensyn til den ved den såkaldte pentetrazolprøve påviselige antikonvulsive aktivitet, medens den i virkemåde ganske vist ligner de fra DE-offentliggørelsesskrift nr.No. 5,215,403 and No. 2,221,623, particularly with respect to the anti-convulsive activity detectable by the so-called pentetrazole test, while in effect similar to those of DE Publication No.
2.229.845 og fra beskrivelsen til dansk patentansøgning 10 nr. 668/74 kendte 6-arylthieno[2,3-e]-4H-s-triazolo-[3,4-c]-l,4-diazepiner, men med hensyn til aktivitet overgår disse. Dette vil fremgå af følgende farmakologiske forsøg, hvor forbindelsen fremstillet ifølge den foreliggende opfindelse sammenlignedes med kemisk nærbe-15 slægtede forbindelser, kendt fra DE-offentliggørelses-skrift nr. 2.229.845 og fra beskrivelsen til dansk patentansøgning nr. 668/74.2,229,845 and from the specification to Danish patent application 10 No. 668/74 known 6-arylthieno [2,3-e] -4H-s-triazolo- [3,4-c] 1,4-diazepines, but with respect to to activity these outperform. This will be apparent from the following pharmacological experiments in which the compound prepared according to the present invention was compared with chemically closely related compounds, known from DE Publication No. 2,229,845 and from the specification to Danish Patent Application No. 668/74.
Ved disse forsøg anvendtes albino-mus (NMRI) med legemsvægt på 20-25 g eller albino-rotter (FW49) med 20 legemsvægt på 140-200 g. Med undtagelse af "Passive Avoi-dance-Test" anvendtes for hver dosis 10 dyr. "Passive Avoidance-Test" gennemførtes med 4 dyr for hvef dosis.In these experiments, albino mice (NMRI) with body weight of 20-25 g or albino rats (FW49) with 20 body weight of 140-200 g were used. With the exception of the "Passive Avoi-Dance Test", 10 doses were used for each dose. . "Passive Avoidance Test" was conducted with 4 animals for wheeze dose.
Testforbindelserne suspenderedes i olivenolie og indførtes i alle tilfælde i maven ved hjælp af svælg-25 sonde.The test compounds were suspended in olive oil and in all cases introduced into the stomach by a pharyngeal probe.
1. Pentetrazolantagonisme:1. Pentetrazole antagonism:
Den dosis, ved hvilken den letale virkning af 125 mg/kg pentylentetrazol, som indgives intraperitone-alt en time efter indgivelse af testforbindelsen, ophæves 30 hos 50% af dyrene. (M.I.Gluckmann, Curr. Ther. Res.,2, 721 (1965)).The dose at which the lethal effect of 125 mg / kg pentylenetetrazole administered intraperitoneally one hour after administration of the test compound is abolished in 50% of the animals. (M.I.Gluckmann, Curr. Ther. Res., 2, 721 (1965)).
2. Konfliktsituation (hæmning af "Passive Avoidance"):2. Conflict situation (inhibition of "Passive Avoidance"):
Den dosis, ved hvilken dyrene, der befinder sig i en konfliktsituation, 10 gange trykker på en knap for at 35 få foderpille, selv om et samtidig indskudt signal angiver, at der samtidig med foderpillen sker en afstraffelse i form af et elektrisk stød. (J.Geller, Arch. Int.The dose at which the animals are in a conflict situation presses a button 10 times to receive a feed pill, although a simultaneously inserted signal indicates that a punishment in the form of an electric shock occurs simultaneously with the feed pill. (J. Geller, Arch. Int.
141908 3141908 3
Pharmacodyn., 149, 243 (1964)).Pharmacodyn., 149, 243 (1964)).
3. Kamp-musetest ("Isolation induced fight"):3. Combat mouse test ("Isolation induced fight"):
Den dosis, ved hvilken aggressiviteten af udvokser-de, i 3-4 uger isolerede og i mørke holdte hanmus for 5 50% af dyrenes vedkommende er hæmmet over for unge hanmus. (Wirth, Gosswald, Horlein, Risse und Kreiskott,The dose at which the aggressiveness of adults, for 3-4 weeks, isolated and kept in dark male mice for 5 50% of the animals is inhibited against young male mice. (Wirth, Gosswald, Horlein, Risse und Kreiskott,
Arch. int. Pharmacodyn. 115: 1-31 (1956)).Arch. int. Pharmacodyn. 115: 1-31 (1956)).
4. LD50:4. LD50:
Den dosis, som 50% af dyrene overlever. (Licht-10 field u. Wilcoxon, J.Pharmacol. Exptl. Therap. 96 99 (1949))The dose that 50% of animals survive. (Licht-10 field u. Wilcoxon, J. Pharmacol. Exptl. Therap. 96 99 (1949))
De angivne værdier blev i alle forsøgene udmålt grafisk. Resultaterne fremgår af efterfølgende tabel.The values indicated were graphically measured in all experiments. The results are shown in the following table.
Alle de afprøvede forbindelser kan sammenfattes i formlen / ΝχAll the compounds tested can be summarized in the formula / Νχ
15 r3 /2X15 r3 / 2X
K -\1 3 NK - \ 1 3 N
E--C..7E - C..7
>-N> N
20 i iF"2 12 3 25 Betydningen af symbolerne R , R og R for forbindelsen fremstillet ifølge opfindelsen og for de fra dansk patentansøgning nr. 668/74 kendte forbindelser og den fra DE-offentliggørelsesskrift nr. 2.229.845 kendte forbindelse fremgår af tabellen: 141908 4 S Μ20 in IF "2 12 3 25 The meaning of the symbols R, R and R for the compound made according to the invention and for the compounds known from Danish Patent Application No. 668/74 and the compound known from DE Publication No. 2,229,845 are shown in the table. : 141908 4 S Μ
Ή ° IΉ ° I
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5 1419085 141908
Enkeltdosis af de omhandlede forbindelser er 0,05-50 og fortrinsvis 0,1-25 mg (oral), og den daglige dosis er 5-150 mg.The single dose of the subject compounds is 0.05-50 and preferably 0.1-25 mg (oral) and the daily dose is 5-150 mg.
De omhandlede forbindelser kan anvendes alene 5 eller i kombination med andre farmakologisk aktive stoffer, såsom f.eks. spasmolytika eller β-receptorblokeren-de midler. Egnede anvendelsesformer er f.eks. tabletter, kapsler, stikpiller, opløsninger, safter, emulsioner eller dispergerbare pulvere.The present compounds can be used alone or in combination with other pharmacologically active substances such as e.g. spasmolytics or β-receptor blocking agents. Suitable uses are e.g. tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders.
10 Fremgangsmåden ifølge opfindelsen forklares nær mere i det efterfølgende eksempel.The process of the invention is explained in more detail in the following example.
Eksempel 1,8-Dibrom-6-(o-chlorphenyl)-4H-s-triazolo-[3,4-c]-15 thieno-[2,3-e]-l,4-diazepin.Example 1,8-Dibromo-6- (o-chlorophenyl) -4H-s-triazolo- [3,4-c] -thieno- [2,3-e] 1,4-diazepine.
a) 10 g 8-brom-6-(o-chlorphenyl)-4H-s-triazolo-(3,4-c]-thieno-[2,3-e]-l,4-diazepin opløses i en blanding af 20 ml pyridin og 100 ml methylenglycol og opvarmes i 7 timer. Derpå tilsættes over et tidsrum af 5 minutter 20 en opløsning af 6,3 g brom i 25 ml methylenchlorid, der opvarmes i yderligere 3 timer under tilbagesvaling. Derpå afkøles reaktionsblandingen, fortyndes med methylenchlorid, og opløsningen udrystes 2 gange med 1 N saltsyre og én gang med vand. Efter tørring inddampes methylen-25 chloridopløsningen, og remanensen omkrystalliseres af ethanol.a) 10 g of 8-bromo-6- (o-chlorophenyl) -4H-s-triazolo- (3,4-c] -thieno- [2,3-e] -1,4-diazepine are dissolved in a mixture of 20 ml of pyridine and 100 ml of methylene glycol are heated for 7 hours, then over a period of 5 minutes 20 is added a solution of 6.3 g of bromine in 25 ml of methylene chloride, which is heated for a further 3 hours under reflux. methylene chloride and the solution is shaken twice with 1N hydrochloric acid and once with water, and after drying, the methylene chloride solution is evaporated and the residue is recrystallized from ethanol.
Der opnås 7,0 g (60%) af titelforbindelsen med smp. 210-211°C.7.0 g (60%) of the title compound is obtained, m.p. 210-211 ° C.
b) Udgangsmaterialet opnås på følgende måde: 30 27 g 7-brom-5-(o-chlorphenyl)-2-hydrazino-3H- (2,3-e]-thieno-l,4-diazepin med smp. 300°C (dekomp.) koges under tilbagesvaling i 30 minutter i en blanding af 23 ml orthomyresyreethylester og 300 ml ethanol. Opløsningsmidlet afdampes, og remanensen udrives med ether.b) The starting material is obtained as follows: 27 g of 7-bromo-5- (o-chlorophenyl) -2-hydrazino-3H- (2,3-e] -thieno-1,4-diazepine, mp 300 ° C (decomp.) is refluxed for 30 minutes in a mixture of 23 ml of orthoic acid ethyl ester and 300 ml of ethanol, the solvent is evaporated and the residue is triturated with ether.
35 Udbytte: 26 g med smp.: 214-216°C.Yield: 26 g, mp 214-216 ° C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK288778A DK141908C (en) | 1974-03-02 | 1978-06-27 | METHOD OF ANALOGUE FOR THE PREPARATION OF 1,8-DIBROMO-6- (0-CHLORPHENYL) -4H-S-TRIAZOLO- (3,4-C) -THIENO- (2,3-E) -1,4-DIAZEPINE OR ACID ADDITION SALTS. |
Applications Claiming Priority (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2410030A DE2410030C3 (en) | 1974-03-02 | 1974-03-02 | 8-Bromo-6-phenyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepines, processes for their preparation and pharmaceutical compositions containing them |
| DE2410030 | 1974-03-02 | ||
| 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 |
| DE2435041 | 1974-07-20 | ||
| DE19742445430 DE2445430B2 (en) | 1974-07-20 | 1974-09-24 | 1 - SUBSTITUTED 6-ARYL-4H-STRIAZOLO SQUARE CLIP ON 3.4C SQUARE BRACKET TO THIENO SQUARE BRACKET ON 2.3 SQUARE BRACKET TO 1,4-DIAZEPINE, METHOD OF MANUFACTURING THEM AND MEDICINAL PRODUCTS CONTAINING THESE |
| DE2445430 | 1974-09-24 | ||
| DE2460776A DE2460776C2 (en) | 1974-07-20 | 1974-12-21 | 1-substituted 6-aryl-4H-s-triazolo- (3,4c) -thieno- (2,3e) -1,4-diazepines, processes for their production, pharmaceutical preparations containing them and intermediates and processes for the production of these intermediates |
| DE2460776 | 1974-12-21 | ||
| DK80775 | 1975-02-28 | ||
| DK80775A DK141876C (en) | 1974-03-02 | 1975-02-28 | METHOD OF ANALOGUE FOR PREPARING SUBSTITUTED 6-ARYL-4H-S-TRIAZOLO- (3,4-C) -THIENO (2,3-E) -1,4-DIAZEPINES OR ACID ADDITION SALTS. |
| DK288778 | 1978-06-27 | ||
| DK288778A DK141908C (en) | 1974-03-02 | 1978-06-27 | METHOD OF ANALOGUE FOR THE PREPARATION OF 1,8-DIBROMO-6- (0-CHLORPHENYL) -4H-S-TRIAZOLO- (3,4-C) -THIENO- (2,3-E) -1,4-DIAZEPINE OR ACID ADDITION SALTS. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK288778A DK288778A (en) | 1978-06-27 |
| DK141908B true DK141908B (en) | 1980-07-14 |
| DK141908C DK141908C (en) | 1980-12-01 |
Family
ID=27544222
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK288778A DK141908C (en) | 1974-03-02 | 1978-06-27 | METHOD OF ANALOGUE FOR THE PREPARATION OF 1,8-DIBROMO-6- (0-CHLORPHENYL) -4H-S-TRIAZOLO- (3,4-C) -THIENO- (2,3-E) -1,4-DIAZEPINE OR ACID ADDITION SALTS. |
Country Status (1)
| Country | Link |
|---|---|
| DK (1) | DK141908C (en) |
-
1978
- 1978-06-27 DK DK288778A patent/DK141908C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK141908C (en) | 1980-12-01 |
| DK288778A (en) | 1978-06-27 |
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| PUP | Patent expired |