CS225571B1 - 10-/dimetyaminealkyl/-10-11-dihydrodibenzo/b,f/thiepine-10-carbonitriles and their salts - Google Patents
10-/dimetyaminealkyl/-10-11-dihydrodibenzo/b,f/thiepine-10-carbonitriles and their salts Download PDFInfo
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- 150000003839 salts Chemical class 0.000 title claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 230000002048 spasmolytic effect Effects 0.000 description 3
- WQMAANNAZKNUDL-UHFFFAOYSA-N 2-dimethylaminoethyl chloride Chemical compound CN(C)CCCl WQMAANNAZKNUDL-UHFFFAOYSA-N 0.000 description 2
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004266 acetylcholine chloride Drugs 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 2
- 229910001626 barium chloride Inorganic materials 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 description 2
- XFSBVAOIAHNAPC-XTHSEXKGSA-N 16-Ethyl-1alpha,6alpha,19beta-trimethoxy-4-(methoxymethyl)-aconitane-3alpha,8,10alpha,11,18alpha-pentol, 8-acetate 10-benzoate Chemical compound O([C@H]1[C@]2(O)C[C@H]3[C@@]45C6[C@@H]([C@@]([C@H]31)(OC(C)=O)[C@@H](O)[C@@H]2OC)[C@H](OC)[C@@H]4[C@]([C@@H](C[C@@H]5OC)O)(COC)CN6CC)C(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-XTHSEXKGSA-N 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 description 1
- -1 3-Dimethylaminopropyl Chemical group 0.000 description 1
- XFSBVAOIAHNAPC-UHFFFAOYSA-N Aconitin Natural products CCN1CC(C(CC2OC)O)(COC)C3C(OC)C(C(C45)(OC(C)=O)C(O)C6OC)C1C32C4CC6(O)C5OC(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229940039750 aconitine Drugs 0.000 description 1
- STDXGNLCJACLFY-UHFFFAOYSA-N aconitine Natural products CCN1CC2(COC)C(O)CC(O)C34C5CC6(O)C(OC)C(O)C(OC(=O)C)(C5C6OC(=O)c7ccccc7)C(C(OC)C23)C14 STDXGNLCJACLFY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000000891 anti-reserpine Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 230000000881 depressing effect Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Vynález se týká 10-(dimethylaminoalkyl)-10,11-dihydrodibenzo (b,f) thiepin-10-karbonitrilů obecného vzorce I,The present invention relates to 10- (dimethylaminoalkyl) -10,11-dihydrodibenzo (b, f) thiepine-10-carbonitriles of formula I,
Cbi kde n značí 2 nebo 3, a jejich solí s farmaceuticky nezávadnými anorganickými nebo organickými kyselinami.Wherein n denotes 2 or 3, and salts thereof with pharmaceutically acceptable inorganic or organic acids.
Látky vzorce I vykazují therapeutlcky použitelné farmokodynamické vlastnosti (mírný centrálně tlumivý, analgetický, spasmolytický, antihistaminový a ántiarytmický efekt), které z nich. činí léčiva použitelná zejména při bolestivých spasmech hladkých svalů zažívacího a urogenitálního systému. Dále jsou uvedena konkrétní farmakologická data o látkách podle vynálezu, která byla získána v pokusech na zvířatech a na isolovaných orgánech.The compounds of formula I exhibit therapeutically useful pharmacokodynamic properties (mild centrally depressing, analgesic, spasmolytic, antihistamine, and orthiarythmic effect), among them. makes medicaments especially useful in painful spasms of the smooth muscles of the digestive and urogenital systems. The following provides specific pharmacological data on the compounds of the invention obtained in animal and isolated organ experiments.
10- (2-Dimethylaminoethyl J -10,11-dlhydrodibenzo(b,f )thiepin-10-karbonitril (I, n = 2) byl testován ve formě hydrogenoxalátu. Jeho akutní toxicita u myší (LD50J při intravenosním podání je 45 mg/kg, při orálním podání 240 mg/kg. V testu rotující tyčky na myších vyvolávají orální dávky 10 až 50 mg/ /kg ataxii u 10 až 50 % zvířat, přičemž není jasná závislost efektu na dávce. Orální dávka 10 mg/kg signifikantně inhibuje spontánní aktivitu myší v paprskovém testu podle Dewse. Analgetická účinnost je prokazatelná u myší za použití jednak chemické stimulace (intraperitoneální aplikace kyseliny octové), EDS0 = 9,3 mg/kg p. o., jednak při použití mechanické stimulace (tlak), ED50 — = 11,4 mg/kg ρ. o. V koncentracích 1 až 10 (Ug/ml vykazuje látka spasmolytický efekt na isolovaném krysím duodenu jak proti acetylcholinovým, tak i baryumchloridovým kontrakcím. V dávkách 2,5 až 5,0 mg/kg s. c. vykazuje látka antihistaminový účinek v testu detoxikace histaminu u morčat. V i. p. dávce 9 mg/kg má látka signifikantní antireserpinový efekt v testu ptosy u myší a v téže dávce, podané intravenosně, vyvolává krátkodobé a hluboké poklesy krevního tlaku u normotensních krys.10- (2-Dimethylaminoethyl) -10,11-dlhydrodibenzo (b, f) thiepine-10-carbonitrile (I, n = 2) was tested in the form of hydrogen oxalate and has an acute toxicity in mice (LD 50 J by intravenous administration of 45 mg / kg, when administered orally 240 mg / kg In the rotating mouse test, oral doses of 10 to 50 mg / kg induce ataxia in 10 to 50% of the animals, with no clear dose-response effect. significantly inhibits the spontaneous activity of mice in the Dews ray test Analgesic efficacy is demonstrated in mice using both chemical stimulation (intraperitoneal acetic acid), ED 50 = 9.3 mg / kg po and mechanical stimulation (pressure), ED 50 - = 11.4 mg / kg o.O. At concentrations 1 to 10 (Ug / ml) the substance shows a spasmolytic effect on isolated rat duodenum against both acetylcholine and barium chloride contractions. kg sc shows antihistamine At an ip dose of 9 mg / kg, the compound has a significant antireserpine effect in the ptosis test in mice and at the same dose, administered intravenously, causes short and deep reductions in blood pressure in normotensive rats.
10- (3-Dimethylaminopropyl) -10,11-dihydrodibenzo(b,f Jthiepin-10-karbonitril (I, n = = 3) byl testován ve formě hydrogenmaleinátu. Akutní toxicita u myší (LD50) je při10- (3-Dimethylaminopropyl) -10,11-dihydrodibenzo (b, f) Thiepine-10-carbonitrile (I, n = 3) was tested in the form of hydrogen maleate Acute toxicity in mice (LD 50 ) is at
i. v. podání 35 mg/kg a při orálním podání 325 mg/kg. Podobně jako u předešlé látky vyvolávají dávky 10 až 50 mg/kg p. o. ataxii u 10 až 50 % myší v testu rotující tyčky; ani v tomto případě není jednoznačná závislost účinku na dávce. Analgetická účinnost u myší při chemické stimulací, ED50 = 1,3 mg/kg p. o.; při mechanické stimulaci, ED50 = = 3,0 mg/kg p. o. V koncentracích 1 až 10 ,ug/ml vykazuje látka spasmolytický účinek vůči acetylcholinu a baryumchloridu na isolovaném krysím duodenu (snížení kontrakcí na 50% ve srovnání s kontrolou). V intravenosních dávkách 2,5 až 7 mg/kg prokazuje látka antiarytmický účinek u krys vůči akonitinu. Intravenosní dávka 7 mg/kg vyvolává krátkodobé hluboké poklesy krevního tlaku u normotensních krys.iv administration at 35 mg / kg and oral administration at 325 mg / kg. As with the former, doses of 10 to 50 mg / kg after ataxia elicit 10 to 50% of the mice in the rotating rod test; again, the dose-response effect is not clear. Analgesic efficacy in mice by chemical stimulation, ED 50 = 1.3 mg / kg po; on mechanical stimulation, ED 50 = 3.0 mg / kg po at concentrations of 1 to 10 µg / ml, the substance exhibits a spasmolytic effect against acetylcholine and barium chloride on isolated rat duodenum (contraction reduction to 50% compared to control). At intravenous doses of 2.5 to 7 mg / kg, the compound shows an antiarrhythmic effect in rats against aconitine. An intravenous dose of 7 mg / kg induces short-term deep reductions in blood pressure in normotensive rats.
Látky podle vynálezu jsou přístupné alkylací 10,11-dihydrodibenzo (b,f) thiepin-10-karbonitrilu 2-dimethylaminoethylchloridem nebo 3-dimethylaminopropylchloridem. Při této reakci se s výhodou použije hydridu sodného jako činidla vytvářejícího potřebný karbanion a reakce se provede v dimethylformamidu při teplotách 50 až 120 °C. Podrobnosti přípravy látek vzorce I jsou popsány v příkladech provedení.The compounds of the invention are accessible by alkylation of 10,11-dihydrodibenzo (b, f) thiepine-10-carbonitrile with 2-dimethylaminoethyl chloride or 3-dimethylaminopropyl chloride. In this reaction, sodium hydride is preferably used as the necessary carbanion forming agent and the reaction is carried out in dimethylformamide at temperatures of 50 to 120 ° C. Details of the preparation of the compounds of formula I are described in the Examples.
Látky vzorce I podle vynálezu jsou nové. Base je v případě látky I (n = 2) krystalická, v případě látky I (n = 3) je olejovitá. Obě poskytují neutralisací farmaceuticky nezávadnými anorganickými nebo organickými kyselinami krystalické soli, které jsou vhodnější než base k farmakologickým testům a pro přípravu lékových forem. Novou látkou je též výchozí 10,ll-dihydrodibenzo(b,f )thiepin-10-karbonitril, jehož příprava je popsána v prvním příkladu provedení. Identita nových látek byla zajištěna analysami a spektry.The compounds of the formula I according to the invention are novel. The base is crystalline for compound I (n = 2) and oily for compound I (n = 3). Both provide, by neutralization with pharmaceutically acceptable inorganic or organic acids, crystalline salts that are more suitable than bases for pharmacological testing and for the preparation of dosage forms. The novel substance is also the starting 10,11-dihydrodibenzo (b, f) thiepine-10-carbonitrile, the preparation of which is described in the first embodiment. The identity of the new compounds was ensured by analyzes and spectra.
Příklad 1Example 1
Směs 11,35 g 10,11-dihydrodibenzo (b,f)thiepin-10-karbonitrilu, 50 ml dimethylformamidu a 2,35 g 80% hydridu sodného (suspense v oleji] se míchá 10 min. při 50 °C, potom se přidá 7,7 g 2-dimethylaminoethylchloridu a směs se míchá 20 min. při 90 °C. Po ochlazení se nalije do 400 ml vody, extrahuje se benzenem, benzenová fáze se protřepe se 400 ml 3M—HC1, kyselá vodná vrstva se zalkalisuje 20% roztokem hydroxidu sodného a base se isoluje extrakcí benzenem. Extrakt se vysuší uhličitanem draselným a jeho odpařením se získá 13,1 g (89%) krystalické base tající při 75 až 85 °C.A mixture of 11.35 g of 10,11-dihydrodibenzo (b, f) thiepine-10-carbonitrile, 50 ml of dimethylformamide and 2.35 g of 80% sodium hydride (suspension in oil) was stirred for 10 min at 50 ° C, then 7.7 g of 2-dimethylaminoethyl chloride are added and the mixture is stirred for 20 min at 90 DEG C. After cooling, it is poured into 400 ml of water, extracted with benzene, the benzene phase is shaken with 400 ml of 3M HCl, the acidic aqueous layer is made alkaline. The extract was dried with potassium carbonate and evaporated to give 13.1 g (89%) of a crystalline base melting at 75-85 ° C.
Krystalisací ze směsi benzenu a petroletheru se získá čistá látka tající při 88 až 89 °C. Neutralisací kyselinou oxalovou v ethanolu se získá hydrogenoxalát, který krystaluje z 95% ethanolu a taje při 192 až 194 °C.Crystallization from a mixture of benzene and petroleum ether gave a pure material, m.p. 88-89 ° C. Neutralization with oxalic acid in ethanol gives the hydrogen oxalate, which crystallizes from 95% ethanol and melts at 192-194 ° C.
Použitý výchozí 10,11-dihydrodibenzo (b,f )thiepin-10-karbonitril (II, R =H) je látkou novou, kterou lze připravit ze známého 10-bromdibezo(b,f )thiepinu (J. O.! Jílek a spol., Collect. Czech. Chem. Commun. 32, 3186, 1967) tímto postupem:The starting 10,11-dihydrodibenzo (b, f) thiepine-10-carbonitrile (II, R = H) used is a novel compound which can be prepared from the known 10-bromdibezo (b, f) thiepine (JO ! Jílek et al., Collect. Czech. Chem. Commun. 32, 3186, 1967) by the following procedure:
Směs 14,8 g 10-bromdibenzo(b,f Jthiepinu, 9,0 g kyanidu měďného a 75 ml dimethylformamidu se míchá a vaří 5 h pod zpětným chladičem. Potom se vlije do 300 ml vychlazeného konc. vodného amoniaku. Produkt se extrahuje dichlormethanem, extrakt se promyje 2M—HC1 a vodou, vysuší še síranem hořečnatým a odpaří. Krystalický zbytek se překrystaluje z 25 ml hexanu. Filtrací a zpracováním matečného louhu se získá 10,0 g (83 %) dibenzo(b,f)thiepin-10-karbonitrilu tajícího při 133 až 137 °C, který je dostatečně čistý pro další zpracování. Zcela čistá látka se získá krystalisací z benzenu a taje při 136 až 137 °C.A mixture of 14.8 g of 10-bromodibenzo (b, f) thiepine, 9.0 g of copper (I) cyanide and 75 ml of dimethylformamide is stirred and refluxed for 5 hours, then poured into 300 ml of cold concentrated aqueous ammonia. The extract was washed with 2M HCl and water, dried (MgSO4) and evaporated, the crystalline residue was recrystallized from 25 ml of hexane to give 10.0 g (83%) of dibenzo (b, f) thiepin-10. -carbonitrile melting at 133-137 ° C, which is sufficiently pure for further processing, is obtained by crystallization from benzene and melts at 136-137 ° C.
K míchanému roztoku 102 g dibenzo(b,f )thiepin-10-karbonitrilu ve 2,8 1 ethanolu se přikape roztok 49,1 g borohydridu sodného ve 200 ml vody obsahující 1,2 ml 20% roztoku hydroxidu sodného. Směs se vaří 1 h pod zpětným chladičem a ethanol se odpaří za sníženého tlaku. Zbytek se zředí vodou a extrahuje se benzenem. Extrakt se promyje 4% roztokem hydroxidu sodného a vodou, vysuší se uhličitanem draselným, odpaří za sníženého tlaku a zbytek se krystaluje z ethanolu. Získá se 86,2 g (84%) 10,11-dihydrodibenzo (b,f)thiepin-10-karbonitrilu tajícího při 91,5 až 93 °C. Rekrystalisací z ethanolu se získá zcela čistá látka s t. t. 95 až 96 °C.To a stirred solution of 102 g of dibenzo (b, f) thiepine-10-carbonitrile in 2.8 L of ethanol was added dropwise a solution of 49.1 g of sodium borohydride in 200 ml of water containing 1.2 ml of 20% sodium hydroxide solution. The mixture was refluxed for 1 h and the ethanol was evaporated under reduced pressure. The residue was diluted with water and extracted with benzene. The extract was washed with 4% sodium hydroxide solution and water, dried over potassium carbonate, evaporated under reduced pressure and the residue crystallized from ethanol. 86.2 g (84%) of 10,11-dihydrodibenzo (b, f) thiepine-10-carbonitrile melting at 91.5 to 93 ° C is obtained. Recrystallization from ethanol gave a pure product, m.p. 95-96 ° C.
Příklad 2Example 2
Podobným způsobem jako v předešlém případě se provede alkylace 11,35 g 10,11dihydrodibenzo (b,f) thiepin-10-karbonitrilu 8,9 g 3-dimethylaminopropylchloridu v 50 ml dimethylformamidu za přítomnosti 2,35 g 80% hydridu sodného. Podobným zpracováním se získá 14,8 g (96%) surové olejovité base, která se převede neutralisací kyselinou oxalovou v acetonu a přídavkem etheru na 16,3 g (78%) hydrogenoxalátu tajícího při 127 až 129 °C (ethanol-ether).In a similar manner as above, alkylation of 11.35 g of 10.11-dihydrodibenzo (b, f) thiepine-10-carbonitrile was carried out with 8.9 g of 3-dimethylaminopropyl chloride in 50 ml of dimethylformamide in the presence of 2.35 g of 80% sodium hydride. Similar work-up gave 14.8 g (96%) of crude oily base which was converted by neutralization with oxalic acid in acetone and addition of ether to 16.3 g (78%) of hydrogen oxalate melting at 127-129 ° C (ethanol-ether).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS701182A CS225571B1 (en) | 1982-10-01 | 1982-10-01 | 10-/dimetyaminealkyl/-10-11-dihydrodibenzo/b,f/thiepine-10-carbonitriles and their salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS701182A CS225571B1 (en) | 1982-10-01 | 1982-10-01 | 10-/dimetyaminealkyl/-10-11-dihydrodibenzo/b,f/thiepine-10-carbonitriles and their salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS225571B1 true CS225571B1 (en) | 1984-02-13 |
Family
ID=5418439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS701182A CS225571B1 (en) | 1982-10-01 | 1982-10-01 | 10-/dimetyaminealkyl/-10-11-dihydrodibenzo/b,f/thiepine-10-carbonitriles and their salts |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS225571B1 (en) |
-
1982
- 1982-10-01 CS CS701182A patent/CS225571B1/en unknown
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