CS200271B1 - Derivative of 4,5-dihydrothieno/2,3-b/-1-benzothiepine and salts of the same - Google Patents
Derivative of 4,5-dihydrothieno/2,3-b/-1-benzothiepine and salts of the same Download PDFInfo
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- CS200271B1 CS200271B1 CS89079A CS89079A CS200271B1 CS 200271 B1 CS200271 B1 CS 200271B1 CS 89079 A CS89079 A CS 89079A CS 89079 A CS89079 A CS 89079A CS 200271 B1 CS200271 B1 CS 200271B1
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- 150000003839 salts Chemical class 0.000 title claims description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- BDIDFKZHGHHCJR-UHFFFAOYSA-N 1-(8-fluoro-4,5-dihydrothieno[2,3-b][1]benzothiepin-4-yl)-4-methylpiperazine Chemical compound C1CN(C)CCN1C1C(C=CS2)=C2SC2=CC(F)=CC=C2C1 BDIDFKZHGHHCJR-UHFFFAOYSA-N 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 230000003389 potentiating effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- -1 4-methylpiperazino Chemical group 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 3
- 229960001076 chlorpromazine Drugs 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- MJSGXOXCPKTZTK-UHFFFAOYSA-N 2-(2-bromo-4-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C=C1Br MJSGXOXCPKTZTK-UHFFFAOYSA-N 0.000 description 2
- MPZUACZSFQRCST-UHFFFAOYSA-N 8-fluoro-5H-thieno[2,3-b][1]benzothiepin-4-one Chemical compound FC1=CC2=C(CC(C3=C(S2)SC=C3)=O)C=C1 MPZUACZSFQRCST-UHFFFAOYSA-N 0.000 description 2
- 208000009132 Catalepsy Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- SWEDAZLCYJDAGW-UHFFFAOYSA-N Thiophene-2-thiol Chemical compound SC1=CC=CS1 SWEDAZLCYJDAGW-UHFFFAOYSA-N 0.000 description 2
- 206010047853 Waxy flexibility Diseases 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 2
- 229960004046 apomorphine Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000001914 calming effect Effects 0.000 description 2
- 239000003874 central nervous system depressant Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000000701 neuroleptic effect Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-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
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003354 anti-apomorphinic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000002903 catalepsic effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Tento vynález se týká derivátu 4,5-dihydrothieno (2,3-b)-l-benzothipienu vzorce I,This invention relates to a 4,5-dihydrothieno (2,3-b) -1-benzothipiene derivative of the formula I,
tj. 8-fluor-4-(4-methylpiperazino)-4,5-dihydrothieno (2,3-b)-l-benzothipienu, a jeho farmaceuticky nezávadných solí s anorganickými a organickými kyselinami.i.e. 8-fluoro-4- (4-methylpiperazino) -4,5-dihydrothieno (2,3-b) -1-benzothipiene, and pharmaceutically acceptable salts thereof with inorganic and organic acids.
Látka vzorce I a její soli se vyznačují intensivní centrálně tlumivou a kataleptickou aktivitou, takže je lze označit jako neuroleptika použitelná při léčbě schizofrenních psychos. Pro testy na zvířatech byla látka vzorce I použita ve formě maleinátu; dále uváděné dávky jsou věak přepočty na basi. V testu akutní toxicity na myáích vykazuje látka střední smrtnou dávku 80 mg/kg při orálním podáni. Z hlediska toxicity je tedy prakticky shodná s chlorothepinem, který je zaveden do therapeutická praxe (K.Náhunek a spol. Farmakoterap. Zp'rávy 17/4/, 311 /1971/). V testi inkoordinačni aktivity na rotující tyčce u myší vykazuje látka vzorce I střední účinnou dávku ΕΟ,-θ = 0,36 mg/kg orálně. V tomto testu, který koresponduje s centrálně tlumivou účinností, je tedy látka vzorce 1 přibližně 40krát účinrějěí než chlorpromazin a 10x účinnější než chlorothepiu.The compound of formula I and its salts are characterized by intense central depressant and cataleptic activity, so that they can be termed neuroleptics useful in the treatment of schizophrenic psychoses. For animal testing, the compound of formula I was used in the form of a maleate; the dosages given below are, however, recalculated based on. In the acute toxicity test in mice, the substance exhibits a mean lethal dose of 80 mg / kg when administered orally. Thus, in terms of toxicity, it is virtually identical to chlorothepine, which is introduced into therapeutic practice (K. Nahunek et al. Pharmacotherapy. Reports 17 (4), 311 (1971)). In the incoordinating activity test on a rotating rod in mice, the compound of formula I exhibits a mean effective dose of εΟ, -θ = 0.36 mg / kg orally. Thus, in this assay, which corresponds to centrally depressant activity, the compound of Formula 1 is approximately 40 times more potent than chlorpromazine and 10 times more potent than chlorothepia.
200 271200 271
200 271200 271
V testu inhibicbe-lokomotorické aktivity u myti podle Dewse, kdy se hodnoceni pohyblivosti provádí pomocí fotobuňky, vykazuje látka vzorce 1 střední účinnou dávku ΕΟ^θ3 0,24 mg/kg orálně. Také výsledky tohoto testu odpovídají centrální tlumivé aktivitě. Látka vzorce 1 je v tomto testu 20x účinnější než chlorpromazin a 5x účinnější než chlorothepin. Látka tedy vykazuje zklidňovací účinek vysoké intensity, ěehož lze využít zvláště u agitovaných psychotikň, kde rychlé zklidnění je prvořadým úkolem. V testu katalepsie na krysách, kterého se používá jako měřítka neuroleptického působení, je střední účinná dávka látky vzorce 1 ED5q=,1,4 mg/kg orálně. V tomto testu je látka vzorce 1 vlče než lOx účinnější než chlorpromazin a asi 3x účinnější než chlorothepin. V testu antiapomorflnového působení u krys inhibuje látka vzorce 1 pouze agitaci, indukovanou apomorfinem, což opět koresponduje s centrálně tlumivým působením. V tomto tesntu snižuje dávka S mg/kg orálně látky vzorce I agitaci u krys, vyvolanou standardní dávkou apomorfinu na 68 % kontrolní hodnoty (tj. 100%). Podle těchto výsledků lze látku vzorce I charakterizovat jako mocně účinný trankvilizér s neuroleptickou komponentou, dokumentovanou vysokou účinností v testu katalepsie.In the Dews Inhibition-Locomotor Activity Inhibition Assay, where the mobility evaluation is performed using a photocell, the compound of Formula 1 exhibits a median effective dose of ΟΟ 3 of 0.24 mg / kg orally. Also the results of this test correspond to the central buffer activity. In this test, the compound of Formula 1 is 20 times more potent than chlorpromazine and 5 times more potent than chlorothepine. Thus, the substance exhibits a calming effect of high intensity, which can be used especially in agitated psychotics, where rapid calming is a primary concern. The catalepsy assay in rats, which is used as a measure neuroleptic action, the medium effective dose of compound of formula 1 ED q = 5, 1.4 mg / kg orally. In this test, the compound of Formula 1 is more than 10 times more potent than chlorpromazine and about 3 times more potent than chlorothepine. In the anti-apomorphine test in rats, the compound of Formula 1 inhibits only apomorphine-induced agitation, which again corresponds to a central depressant action. In this assay, a dose of S mg / kg orally of the compound of Formula I reduces agitation in rats induced by a standard dose of apomorphine to 68% of the control value (i.e., 100%). According to these results, the compound of formula I can be characterized as a potent tranquilizer with a neuroleptic component, documented by its high efficiency in the catalepsy assay.
Látku vzorce 1 lze připravit celou řadou metod, z nichž zvláště výhodná spočívá v substituční reakci 4-chlor-8-fluor-4,5-dihydrothieno(2,3-b)-l-benzothipienu vzorce IIThe compound of formula 1 can be prepared by a variety of methods, of which the substitution reaction of 4-chloro-8-fluoro-4,5-dihydrothieno (2,3-b) -1-benzothipiene of formula II is particularly preferred.
Cl ( IX )Cl (IX)
1-methylpierazinem. Rovněž tuto substituční reakci lze provést za různých podmínek, avšak zvláště výhodná varianta spočívá v zahříváni látky vzorce 11 s více než 100% přebytkem 1-methylpžperazinu ve vroucím chloroformu. Látka vzorce I se potom isoluje z reakční směsi na základě svá basicity. Podrobnosti postupu přípravy jsou popsány v přikladu provedeni vynálezu. Tam je popsána též příprava látky vzorce 11, která je nová a dosud nebyla v literatuře popsána.1-methylpierazine. Also this substitution reaction can be carried out under various conditions, but a particularly preferred variant consists in heating the compound of formula 11 with more than 100% excess of 1-methylperazine in boiling chloroform. The compound of formula I is then isolated from the reaction mixture by virtue of its basicity. Details of the preparation process are described in the Examples. There is also described the preparation of the compound of formula 11 which is novel and has not been described in the literature.
Jak je z vzorce patrné, je látka vzorce I dvojsytnou zásadou, ktorá poskytuje neutralisací kyselinami příslušné soli, z nichž některé výborně krystalují a jsou více nebo méně rozpustné vezvodě. Tyto soli jsou potom výhodnější než volná base vzorce I pro testování * účinnosti na zvířatech i pro přípravu lékových forem pro praktická použití v therapii. Velmi výhodnou Soli je neutrální maleinát, který krystaluje ze směsi ethanolu a etheru a taje v čistém stavu při 151 až 153 °C. Konečná látka, její maleinát, jakož i meziprodukty její přípravy, byly charakterizovány analysami a spektry (UF, IČ, lH-NMR a leF-NllR), které vesměs potvrdily identitu látek.As can be seen from the formula, the compound of formula I is a dibasic base which provides acid neutralization with the appropriate salts, some of which crystallize excellently and are more or less soluble in water. These salts are then more advantageous than the free base of Formula I for both animal testing and preparation of dosage forms for practical use in therapy. A very preferred salt is a neutral maleate which crystallizes from a mixture of ethanol and ether and melts in the pure state at 151-153 ° C. The final product, the maleate, as well as intermediates for its preparation, were characterized and Analysis of the spectrum (UV, IR, lH-NMR and F-NllR le), all of which confirmed the identity of the substances.
Přiklad provedení :Example:
Směs 5,0 g 4-chlor-8-fluor-4,5-dihydrothieno (2,3-b)-l-běnzothipienu (II), 4','7 gA mixture of 5.0 g of 4-chloro-8-fluoro-4,5-dihydrothieno (2,3-b) -1-benzothipiene (II), 4 ', 7 g
1-methylpiperazinu a 25 ml chloroformu se vaří 4 hodiny pod zpětným chladičem. Po ochlazeni se zředí 100 ml chloroformu, promyje se důkladně vodou a basický produkt se třepáním extrahuje do přebytečné 10% kyseliny sirově. Kyselý vodný roztok se oddělí, zalkalizuje se hydroxidem amonným a uvolněná base se Isoluje extrakci chloroformem. Extrakt se suší bez31-methylpiperazine and 25 ml of chloroform were refluxed for 4 hours. After cooling, it is diluted with 100 ml of chloroform, washed thoroughly with water, and the basic product is extracted by shaking into excess 10% sulfuric acid. The acidic aqueous solution was separated, basified with ammonium hydroxide, and the liberated base was isolated by extraction with chloroform. The extract was dried without 3
200 271 vodým uhličitanem draselným a odpaří se za sníženého tlaku. Ve výtěžku 3,5 g se získá krystalická base s t.t. 122 až 125 °C. Rerystalisací z 80% vodného ethanolu se získá zcela čistá látka s t.t. 124 až 126 °C. Neutralisací kyselinou maleinovou ve směsi ethanolu a etheru se připraví krystalický neutrální maleinát s t.t. 151 až 153 °C. Látku lze rekrystalovat ze směsi ethanolu a etheru.200 271 aqueous potassium carbonate and evaporated under reduced pressure. Yield: 3.5 g. Mp 122-125 ° C. Rerystallization from 80% aqueous ethanol gave a pure product with m.p. Mp 124-126 ° C. By neutralization with maleic acid in a mixture of ethanol and ether, crystalline neutral maleate of m.p. Mp 151-153 ° C. The material can be recrystallized from a mixture of ethanol and ether.
Výchozí nový 4-chlor-8-fluor-4,5-dihydrothiéno (2,3-b)-l-benzothiepin (II) se získá např. dále popsaným postupem, který vychází ze známého 2-thiofenthiolu (W.H.Houff a R.D, Schuetz, J.Amer.Chem.Soc. 75, 5316/1953/) a dále známé kyseliny (2-brom-4-fluorfenyl) octové (M.Sajšner a spol., Collect.Czech.Chem.Commun.42, 3079 /1977/).The starting novel 4-chloro-8-fluoro-4,5-dihydrothiene (2,3-b) -1-benzothiepine (II) is obtained, for example, by the following procedure, starting from the known 2-thiophenethiol (WHHouff and RD, Schuetz, J.Amer.Chem.Soc., 75, 5316 (1953), and further known (2-bromo-4-fluorophenyl) acetic acid (M.Sajner et al., Collect.Czech.Chem.Commun. 42, 3079). (1977)).
Směs 23,3 g (2-brom-4-fluorfenyl) octové kyseliny, 12,8 g 2-thiofenthiolu, 18 ml dimethylformamidu, 2 g molekulárnímědi a 42 g bezvodého uhličitanu draselného se míchá a ♦A mixture of 23.3 g of (2-bromo-4-fluorophenyl) acetic acid, 12.8 g of 2-thiophenethiol, 18 ml of dimethylformamide, 2 g of molecular copper and 42 g of anhydrous potassium carbonate is stirred and
zahřívá 5 hodin pod zpětným chladičem v lázni o teplotě 160 °C. Po ochlazeni se tavenina rozpustí ve vodě, roztok se zfiltruje a uhlím a filtrát se okyselí kyselinou solnou. Produkt se isoluje extrakcí chloroformem. Zpracováním extraktu se získá 26 g surové olejovité kyseliny /4-fluor-2-(2-thienylthio)fenyl/octové, která krystaluje z benzenu a v čistém stavu taje při 129 až 131,5 °C.was heated under reflux in a 160 ° C bath for 5 hours. After cooling, the melt is dissolved in water, the solution is filtered with charcoal and the filtrate is acidified with hydrochloric acid. The product was isolated by extraction with chloroform. The extract was worked up to give 26 g of crude oleic acid (4-fluoro-2- (2-thienylthio) phenyl) acetic acid which crystallized from benzene and melted at 129-131.5 ° C in pure form.
Směs 40 ml toluenu, 5,5 g kyseliny /4-fluor-2-(2-thienylthio)-fenyl/octové a 7,2 g kysličníku fosforečného se vaří 5,5 hodiny pod zpětným chladičem. Potom se toluenový roztok dekantací oddělí od nerozpustného polopevného podílu, který se promyje dalším toluenem. Spojené toluenové roztoky se promyjí 10% roztokem hydroxidu sodného, vysuší se uhličitanem sodným a odpaří za sníženého tlaku. Ve výtěžku 4,0 g se získá surový 8-fluorthieno(2,3-b)-l-benzothiepin-4(5H)-on s t.t. 158 až 164 °C. Č istá látka se získá krystalisací z ethanolu; taje potom při 165 až 167 °C.A mixture of 40 ml of toluene, 5.5 g of (4-fluoro-2- (2-thienylthio) phenyl) acetic acid and 7.2 g of phosphorus pentoxide was refluxed for 5.5 hours. Thereafter, the toluene solution is separated by decantation from an insoluble semi-solid which is washed with additional toluene. The combined toluene solutions were washed with 10% sodium hydroxide solution, dried over sodium carbonate and evaporated under reduced pressure. Yield 4.0 g of crude 8-fluorothieno (2,3-b) -1-benzothiepin-4 (5H) -one, m.p. Mp 158-164 ° C. The pure material is obtained by crystallization from ethanol; it melts at 165-167 ° C.
K míchané suspensí 4,0 g 8-fluorthieno (2,3-b)-l-benzothiepin-4(5H)-onu ve 40 ml rthanolu se zvolna přidá 0,8 g borohydridu sodného a vzniklý roztok se ponechá v klidu při teplotě místnosti po dobu 2 hodin. Potom se odpaří za sníženého tlaku, zbytek se rozloží vodou a extrahuje chloroformem. Extrakt se suši uhličitanem draselným a odpaří. Získá se 3,8 g téměř čistého 8-fluor-4,5-dihydrothieno(2,3-b)-l-benzothiepin-4-olu, který krystaluje ze směsi benzenu a petroletheru a v čistém stavu taje při 110 až 111 °C.To a stirred suspension of 4.0 g of 8-fluorothieno (2,3-b) -1-benzothiepin-4 (5H) -one in 40 ml of rthanol was slowly added 0.8 g of sodium borohydride and the resulting solution was allowed to stand at room temperature. room for 2 hours. It is then evaporated under reduced pressure, the residue is quenched with water and extracted with chloroform. The extract was dried with potassium carbonate and evaporated. 3.8 g of almost pure 8-fluoro-4,5-dihydrothieno (2,3-b) -1-benzothiepin-4-ol are obtained, which crystallizes from a mixture of benzene and petroleum ether and melts in the pure state at 110 to 111 °. C.
Roztok 5,2 g 8-fluor-4,5-dihydrothieno (2,3-b)-l-benzot.hiepin-4-olu v 50 ml benzenu se za přítomnosti 3,0 g práškovitého bezvodého chloridu vápenatého sytí po dobu 1 hodiny bezvodým chlorovodíkem při teplotě místnosti, onechá se další 1 hodinu v klidu, směs se zfiltruje a filtrát se odpaří za sníženého tlaku. Získá se 5,5 g čistého 4-chlor-8-fluor-4,5dihydrothieno (2,3-b)-l-benzothipienu s t.t. 135 až 140 °C. Látka krystaluje z cyklohexanu, avšak teplota tání se krystalisací již nezvyšuje. Získaná látka představuje bezprostřední meziprodukt přípravy látky vzorce I.A solution of 5.2 g of 8-fluoro-4,5-dihydrothieno (2,3-b) -1-benzothiidin-4-ol in 50 ml of benzene is saturated in the presence of 3.0 g of powdered anhydrous calcium chloride for 1 hour. hours at room temperature with anhydrous hydrogen chloride, allowed to stand for a further 1 hour, the mixture was filtered and the filtrate was evaporated under reduced pressure. 5.5 g of pure 4-chloro-8-fluoro-4,5-dihydrothieno (2,3-b) -1-benzothipiene of m.p. Mp 135-140 ° C. The material crystallizes from cyclohexane, but the melting point no longer increases. The compound obtained is an intermediate intermediate for the preparation of the compound of formula I.
200 271200 271
PŘEDMĚT VYNÁLEZUSUBJECT OF THE INVENTION
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS89079A CS200271B1 (en) | 1979-02-08 | 1979-02-08 | Derivative of 4,5-dihydrothieno/2,3-b/-1-benzothiepine and salts of the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS89079A CS200271B1 (en) | 1979-02-08 | 1979-02-08 | Derivative of 4,5-dihydrothieno/2,3-b/-1-benzothiepine and salts of the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS200271B1 true CS200271B1 (en) | 1980-09-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS89079A CS200271B1 (en) | 1979-02-08 | 1979-02-08 | Derivative of 4,5-dihydrothieno/2,3-b/-1-benzothiepine and salts of the same |
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| Country | Link |
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| CS (1) | CS200271B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7915249B2 (en) | 2005-01-27 | 2011-03-29 | Janssen Pharmaceutical Nv | Heterocyclic tetracyclic tetrahydrofuran derivatives as 5HT2 inhibitors in the treatment of CNS disorders |
-
1979
- 1979-02-08 CS CS89079A patent/CS200271B1/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7915249B2 (en) | 2005-01-27 | 2011-03-29 | Janssen Pharmaceutical Nv | Heterocyclic tetracyclic tetrahydrofuran derivatives as 5HT2 inhibitors in the treatment of CNS disorders |
| US8404729B2 (en) | 2005-01-27 | 2013-03-26 | Janssen Pharmaceutica, Nv | Heterocyclic tetracyclic tetrahydrofuran derivatives |
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