CS237484B1 - 11-piperazino-6,11dihydrodibenzo /b,e/ thiepines and salts of the same - Google Patents
11-piperazino-6,11dihydrodibenzo /b,e/ thiepines and salts of the same Download PDFInfo
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- 150000003839 salts Chemical class 0.000 title claims abstract description 12
- 150000003551 thiepines Chemical class 0.000 title claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 150000007524 organic acids Chemical class 0.000 claims abstract description 6
- 235000005985 organic acids Nutrition 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- 238000012937 correction Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 13
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 7
- 241000699670 Mus sp. Species 0.000 abstract description 5
- 241000700159 Rattus Species 0.000 abstract description 4
- 239000000935 antidepressant agent Substances 0.000 abstract description 4
- 229940005513 antidepressants Drugs 0.000 abstract description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 abstract description 4
- 238000006386 neutralization reaction Methods 0.000 abstract description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 abstract description 4
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 abstract description 3
- TXQLUKMSYDOGDH-UHFFFAOYSA-N 1-(2-ethoxyethyl)piperazine Chemical compound CCOCCN1CCNCC1 TXQLUKMSYDOGDH-UHFFFAOYSA-N 0.000 abstract description 3
- BMEMBBFDTYHTLH-UHFFFAOYSA-N 1-(2-methoxyethyl)piperazine Chemical compound COCCN1CCNCC1 BMEMBBFDTYHTLH-UHFFFAOYSA-N 0.000 abstract description 3
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 abstract description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 abstract description 3
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 abstract description 3
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 abstract description 3
- 239000011976 maleic acid Substances 0.000 abstract description 3
- 235000006408 oxalic acid Nutrition 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 abstract description 3
- 229960003147 reserpine Drugs 0.000 abstract description 3
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- 238000003556 assay Methods 0.000 abstract description 2
- 239000002552 dosage form Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 125000004429 atom Chemical group 0.000 abstract 1
- 230000003340 mental effect Effects 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- -1 4-methylpiperazino Chemical group 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- DUUGKQCEGZLZNO-UHFFFAOYSA-N 5-hydroxyindoleacetic acid Chemical compound C1=C(O)C=C2C(CC(=O)O)=CNC2=C1 DUUGKQCEGZLZNO-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000000891 anti-reserpine Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 201000003102 mental depression Diseases 0.000 description 2
- 230000000701 neuroleptic effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RVWZUOPFHTYIEO-UHFFFAOYSA-N 5-hydroxyindoleacetic acid Natural products C1=C(O)C=C2C(C(=O)O)=CNC2=C1 RVWZUOPFHTYIEO-UHFFFAOYSA-N 0.000 description 1
- 239000003310 5-hydroxyindoleacetic acid Substances 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003354 anti-apomorphinic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- QRMZSPFSDQBLIX-UHFFFAOYSA-N homovanillic acid Chemical compound COC1=CC(CC(O)=O)=CC=C1O QRMZSPFSDQBLIX-UHFFFAOYSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 230000001562 ulcerogenic effect Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Vynález spadá do oboru syntetických léčiv. Jeho předmětem jsou 1l-piperazino-6,11-dihydrodibenzo(b,e)thiepiny obecného vzorce I, ve kterém R značí atom vodíku nebo atom chloru a R1 je atom vodíku, methyl nebo ethyl, a jejich soli s organickými kyselinami. Látky vzorce I a jejich soli vykazují signifikantní účinnost v testech antagonizace efektů reserpinu u myší a krys, což je typické pro potenciální antidepresiva. Látky podle vynálezu lze tedy použít v terapii duševních depresí. Látky vzorce I jsou přístupné substitučními reakcemi příslušných ll-chlor-6,11-dihydrodibenzo(b,e)thiepinů s 1-(2-hydroxyethyl)piperazinem, l-(2-methoxyethyl)piperazinem a 1-(2-ethoxyethyl)- piperazinem za různých podmínek, které jsou zčásti popsány v příkladech. Neutralizací získaných bází vzorce I organickými kyselinami, s výhodou kyselinou oxalovou nebo kyselinou maleinovou, se získají příslušné krystalické soli, které jsou vhodné k provádění farmakologických testů a k přípravě lékových forem.The invention is within the scope of synthetic drugs. Its subject matter is 11-piperazino-6,11-dihydrodibenzo (b, e) thiepines formula I, wherein R represents a hydrogen atom or an atom chlorine and R 1 is hydrogen, methyl or ethyl, and their salts with organic acids. The compounds of formula I and their salts exhibit significant efficacy in antagonization assays effects of reserpine in mice and rats, which is typical of potential antidepressants. Substances thus, the invention can be used in mental therapy depression. The compounds of formula I are accessible substitution reactions of the respective 11-chloro-6,11-dihydrodibenzo (b, e) thiepines with 1- (2-hydroxyethyl) piperazine, 1- (2-methoxyethyl) piperazine and 1- (2-ethoxyethyl) - piperazine under various conditions that are partially described in the examples. Neutralization of the base of formula I obtained with organic acids, preferably oxalic acid or maleic acid are obtained crystalline salts which are suitable for implementation pharmacological tests and preparation dosage forms.
Description
Vynález spadá do oboru syntetických léčiv. Jeho předmětem jsou 1l-piperazino-6,11-dihydrodibenzo(b,e)thiepiny obecného vzorce I,The invention falls within the field of synthetic drugs. It relates to 1-piperazino-6,11-dihydrodibenzo (b, e) thiepines of formula I,
ve kterém R značí atom vodíku nebo atom chloru a R1 je atom vodíku, methyl nebo ethyl, a jejich soli s organickými kyselinami. Látky vzorce I a jejich soli vykazují signifikantní účinnost v testech antagonizace efektů reserpinu u myší a krys, což je typické pro potenciální antidepresiva. Látky podle vynálezu lze tedy použít v terapii duševních depresí. Látky vzorce I jsou přístupné substitučními reakcemi příslušných ll-chlor-6,11-dihydrodibenzo(b,e)thiepinů s 1-(2-hydroxyethyl)piperazinem, l-(2-methoxyethyl)piperazinem a 1-(2-ethoxyethyl)piperazinem za různých podmínek, které jsou zčásti popsány v příkladech. Neutralizací získaných bází vzorce I organickými kyselinami, s výhodou kyselinou oxalovou nebo kyselinou maleinovou, se získají příslušné krystalické soli, které jsou vhodné k provádění farmakologických testů a k přípravě lékových forem.wherein R is hydrogen or chlorine and R 1 is hydrogen, methyl or ethyl, and salts thereof with organic acids. The compounds of formula I and their salts show significant efficacy in reserpine antagonist assays in mice and rats, typical of potential antidepressants. Thus, the compounds of the invention may be used in the treatment of mental depression. Compounds of formula I are accessible by substitution reactions of the respective 11-chloro-6,11-dihydrodibenzo (b, e) thiepines with 1- (2-hydroxyethyl) piperazine, 1- (2-methoxyethyl) piperazine and 1- (2-ethoxyethyl) piperazine under various conditions, which are partially described in the examples. By neutralizing the bases of the formula I obtained with organic acids, preferably oxalic acid or maleic acid, the corresponding crystalline salts are obtained which are suitable for carrying out pharmacological tests and for preparing dosage forms.
Vynález se týká 1l-piperazino-6,11-dihydrodibenzo(b,e)thiepinu obecného vzorce 1,The invention relates to 1-piperazino-6,11-dihydrodibenzo (b, e) thiepine of the general formula 1,
ve kterém R značí atom vodíku nebo atom chloru a R^ je atom vodíku, methyl nebo ethyl, a jejich soli s organickými kyselinami.wherein R represents a hydrogen atom or a chlorine atom and R 6 is a hydrogen atom, methyl or ethyl, and salts thereof with organic acids.
Literatura (Seidlová V. et al., Monatsch. Chem. 96, 650, 1965; Protiva M., Farmace, Ed. Sc. 21, 76, 1966) popisuje 11-(4-methylpiperazino)-6,11-díhydrodibenzo(b,e)thiepin, pro který je udáván náznak antidepresivních a centrálně tlumivých účinků. Nyní bylo zjištěno, že tyto účinky lze vystupňovat jednak zavedením vhodného substituentu do jednoho z benzenových jader a dále zavedením hydrofilního substituentu na dusíkový atom N4 piperazinového zbytku (2-hydroxyethyl nebo nižší 2-alkoxyethyl).The literature (Seidl V. et al., Monatsch. Chem. 96, 650, 1965; Protiva M., Pharmace, Ed. Sc. 21, 76, 1966) describes 11- (4-methylpiperazino) -6,11-dihydrodibenzo ( b, e) thiepine for which there is an indication of antidepressant and centrally depressant effects. It has now been found that these effects can be exacerbated by introducing a suitable substituent into one of the benzene rings and by introducing a hydrophilic substituent on the nitrogen atom of the N 4 piperazine moiety (2-hydroxyethyl or lower 2-alkoxyethyl).
Látky obecného vzorce I a jejich soli vykazují vlastnosti potenciálních antidepresiv, což se projevuje jejich antireserpinovou aktivitou v testech na zvířatech. Na základě tohoto zjištění lze látky podle vynálezu považovat za užitečné při léčbě duševních depresí. Typickou látkou podle vynálezu je 11-/4-(2-methoxyethyl)piperazino/-6,11-dihydrodibenzo(b,e)thiepin, který byl farmakologicky testován ve formě oxalátu při orálním podání. Akutní toxicita u myší, LD5g = 531 mg/kg. Látky vykazují antireserpinový účinek v testu ptosy u myši v dávce 25 mg/kg (intenzita účinku srovnatelná s účinky prakticky používaných preparátů, jako jsou např. imipramin a prothíaden).The compounds of formula (I) and their salts exhibit the properties of potential antidepressants, as demonstrated by their antireserpine activity in animal tests. Based on this finding, the compounds of the invention may be considered useful in the treatment of mental depression. A typical compound of the invention is 11- [4- (2-methoxyethyl) piperazino] -6,11-dihydrodibenzo (b, e) thiepine which has been pharmacologically tested in the form of oxalate by oral administration. Acute toxicity in mice, LD 5 g = 531 mg / kg. The substances show an antireserpine effect in the ptosis test in mice at a dose of 25 mg / kg (intensity of action comparable to that of practically used preparations such as imipramine and prothadenin).
V testu antagonizace ulcerogenního účinku reserpinu u krys je látka účinná od dávky 50 mg/kg. Naproti tomu látka nejeví ani náznaky neuroleptických účinků, takže není třeba se obávat vedlejších účinků, jaké bývají na neuroleptickou aktivitu vázány. Tak v dávce 50 mg/kg látka nemá antiapomorfinovou aktivitu, a to ani vůči stereotypiím ani vůči agitaci. V dávce 20 mg/kg ovlivňuje spontánní motilitu myší ve smyslu útlumu jen nesignifikantně. Konečně v dávce 80 mg/kg neovlivňuje hladiny dopaminu, kyseliny homovanilové a kyseliny 5-hydroxyindoloctové ve striatu krysího mozku, z čehož vyplývá, že neovlivňuje obrat a metabolismus dopaminu a serotoninu. V testech in vitro inhibuje růst mikroorganismů Staphylococcus pyogenes aureus a Trichophyton mentagrophytes v koncentraci 50 ^um/ml, což naznačuje určité specifické chemoterapeutické působení.In the test for antagonizing the ulcerogenic effect of reserpine in rats, the compound is effective from a dose of 50 mg / kg. On the other hand, the substance does not show any signs of neuroleptic effects, so there is no need to worry about side effects associated with neuroleptic activity. Thus, at a dose of 50 mg / kg, the agent has no antiapomorphine activity, either against stereotypes or against agitation. At a dose of 20 mg / kg, the spontaneous motility of mice in the sense of inhibition affects only insignificantly. Finally, at a dose of 80 mg / kg, it does not affect the levels of dopamine, homovanilic acid and 5-hydroxyindole acetic acid in the rat brain striatum, indicating that it does not affect the dopamine and serotonin turnover and metabolism. In in vitro assays, it inhibits the growth of Staphylococcus pyogenes aureus and Trichophyton mentagrophytes at a concentration of 50 µm / ml, suggesting some specific chemotherapeutic action.
Látky podle vynálezu obecného vzorce 1 lze připravit substitučními reakcemi 11-chlor-6,11-dihydrodibenzo(b,e)thiepinú obecného vzorce II,The compounds of the formula I according to the invention can be prepared by substitution reactions of 11-chloro-6,11-dihydrodibenzo (b, e) thiepines of the formula II,
H Cl ností uhličitanu draselného ve vhodném vroucím rozpouštědle, např. v benzenu . Získané báze I jsou vesměs olejovité a neutralizací kyselinami poskytují krystalické soli. Jako stálé a dobře krystalující se ukázaly být soli s alifatickými dikarboxylovými kyselinami (oxalovou, maleinovou), které jsou rovněž předmětem tohoto vynálezu.H% by weight of potassium carbonate in a suitable boiling solvent, e.g. benzene. The bases I obtained are generally oily and give crystalline salts by acid neutralization. Salts with aliphatic dicarboxylic acids (oxalic, maleic), which are also subject of the present invention, have proved to be stable and well crystallized.
Všechny výchozí látky při přípravě látek obecného vzorce I použité jsou známé a pokud nejsou komerčně dostupné, je v příkladech uvedena literatura, podle které je lze připravit. Všechny nové látky v tomto vynálezu popsané, byly zajištěny z hlediska jejich identity analýzami a spektry. Dále uvedené příklady představují pouze ilustraci metod a podmínek, jimiž a za nichž lze látky vzorce I připravit; není jejich účelem popisovat všechny možné syntetické metody.All of the starting materials used in the preparation of the compounds of formula (I) are known and, if not commercially available, the examples refer to the literature by which they can be prepared. All of the novel compounds described in this invention were assured in terms of their identity by analysis and spectra. The following examples are merely illustrative of the methods and conditions under which the compounds of Formula I may be prepared; it is not intended to describe all possible synthetic methods.
Příklad 1Example 1
2-chlor-ll-/4-(2-hydroxyethyl)piperazino/-10,11-dihydrodibenzo(b,e)thiepin2-chloro-11- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzo (b, e) thiepine
K míchanému roztoku 5,6 g 2,ll-dichlor-6,11-dihydrodibenzo(b,e)thiepinu (Malen Ch. et « al., NSR zveřejňovaoí spis 2 065 636) v 15 ml chloroformu.se přikape 5,2 g 1-(2-hydroxyethyl)piperazinu. Proběhne exothermní reakce, směs se míchá 40 min bez zahřívání a potom 1 h pod zpětným chladičem v lázni o teplotě 70 až 75 °C. Po ochlazení se směs rozdělí mezi vodu a chloroform, organická vrstva se vysuší uhličitanem draselným a odpaří za sníženého tlaku. Zbytek se rozpustí v ethanolu a za míchání se po kapkách přidá mírný přebytek roztoku chlorovodíku v éteru. Vzniklý olejovitý hydrochlorid se oddělí dekantací, promyje se éterem, rozloží vodným amoniakem a přečištěná báze se izoluje extrakci éterem. Extrakt se vysuší uhličitanem draselným, zfiltruje s aktivním uhlím a odpaří. Získá se 5,6 g (75 %) surové olejovité báze. Neutralizací kyselinou maleinovou v ethanolu se získá maleinát, který je zprvu hygroskopický, avšak po rekrystalizací ze směsi ethanolu a éteru tuto vlastnost ztrácí a taje při 168 až 170 °C.To a stirred solution of 5.6 g of 2,11-dichloro-6,11-dihydrodibenzo (b, e) thiepine (Malen Ch. Et al., U.S. Pat. No. 2,065,636) in 15 ml of chloroform was added dropwise 5.2. g of 1- (2-hydroxyethyl) piperazine. An exothermic reaction is carried out, the mixture is stirred for 40 min without heating and then under reflux in a 70-75 ° C bath for 1 h. After cooling, the mixture was partitioned between water and chloroform, the organic layer was dried over potassium carbonate and evaporated under reduced pressure. The residue was dissolved in ethanol and a slight excess of a solution of hydrogen chloride in ether was added dropwise with stirring. The resulting oily hydrochloride was separated by decantation, washed with ether, quenched with aqueous ammonia, and the purified base was isolated by ether extraction. The extract was dried over potassium carbonate, filtered with charcoal and evaporated. 5.6 g (75%) of a crude oil base are obtained. Neutralization with maleic acid in ethanol gives the maleate, which is initially hygroscopic, but loses this property after recrystallization from a mixture of ethanol and ether and melts at 168-170 ° C.
Příklad 2Example 2
11-/4-(2-methoxyethyl)piperazino/-6,11-dihydrodibenzo(b,e)thiepin11- [4- (2-methoxyethyl) piperazino] -6,11-dihydrodibenzo (b, e) thiepine
Směs 4,9 g 1l-chlor-6,11-dihydrodibenzo(b,e)thiepinu (Seidlová V. et al., citováno), ml benzenu, 4,1 g 1-(2-methoxyethyl)piperazinu (Polívka Z. et al., Collect. Czech. Chem. Commun. 48, 2 395, 1983) a 4,3 g uhličitanu draselného se míchá 1 h při teplotě místnosti a potom vaří 1,5 h pod zpětným chladičem. Po ochlazení se pevné složky směsi odfiltrují, filtrát se promyje vodou a báze se extrahuje do 100 ml ledově chladné 2,5M-HC1. Získaný vodný roztok se ihned zalkalizuje vodným amoniakem a báze se izoluje extrakcí benzenem. Zpracováním extraktu se získá 6,1 g (86 %) žádané olejovité báze. Neutralizací kyselinou oxalovou v ethanolu se získá krystalický oxalát, který po rekrystalizací z ethanolu taje při 170 až 171 °C.A mixture of 4.9 g of 1-chloro-6,11-dihydrodibenzo (b, e) thiepine (Seidlová V. et al., Cited), ml of benzene, 4.1 g of 1- (2-methoxyethyl) piperazine (Polek Z. et al., Collect. Czech. Chem. Commun. 48, 2,395,1983) and 4.3 g of potassium carbonate are stirred at room temperature for 1 h and then refluxed for 1.5 h. After cooling, the solids of the mixture were filtered off, the filtrate was washed with water and the base was extracted into 100 ml of ice-cold 2.5M-HCl. The resulting aqueous solution was immediately basified with aqueous ammonia and the base isolated by extraction with benzene. Working up the extract yielded 6.1 g (86%) of the desired oil base. Neutralization with oxalic acid in ethanol gives a crystalline oxalate which melts at 170-171 ° C after recrystallization from ethanol.
Příklad 3Example 3
11-/4-(2-ethoxyethyl)piperazino/-6,11-dihydrodibenzo(b,e)thiepin11- [4- (2-ethoxyethyl) piperazino] -6,11-dihydrodibenzo (b, e) thiepine
Podobnou reakcí 4,9 g ll-chlor-6,11-dihydrodibenzo(b,e)thiepinu se 4,2 g l-(2-ethoxyethyl)piperazinu (Polívka Z. et al., citováno) ve 20 ml benzenu za přítomnosti 4,3 g uhličitanu draselného podobně jako v předchozím příkladu se získá 5,8 g (79 %) olejovité báze, která se převede na krystalický oxalát, t.t. 152 až 154 °C (ethanol).Similar reaction of 4.9 g of 11-chloro-6,11-dihydrodibenzo (b, e) thiepine with 4.2 g of 1- (2-ethoxyethyl) piperazine (Polívka Z. et al., Cited) in 20 ml of benzene in the presence of 4.3 g of potassium carbonate, similar to the previous example, yielded 5.8 g (79%) of an oily base which was converted to crystalline oxalate, m.p. 152 DEG-154 DEG C. (ethanol).
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Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS149384A CS237484B1 (en) | 1984-03-01 | 1984-03-01 | 11-piperazino-6,11dihydrodibenzo /b,e/ thiepines and salts of the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS149384A CS237484B1 (en) | 1984-03-01 | 1984-03-01 | 11-piperazino-6,11dihydrodibenzo /b,e/ thiepines and salts of the same |
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| Publication Number | Publication Date |
|---|---|
| CS237484B1 true CS237484B1 (en) | 1985-08-15 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS149384A CS237484B1 (en) | 1984-03-01 | 1984-03-01 | 11-piperazino-6,11dihydrodibenzo /b,e/ thiepines and salts of the same |
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| Country | Link |
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| CS (1) | CS237484B1 (en) |
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1984
- 1984-03-01 CS CS149384A patent/CS237484B1/en unknown
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