CS260096B1 - 11-(1-methyl-4-piperidylidene)-6,11-dihydrodibenzo/b,e/thiepine-2-carbonitrile and its oxalate - Google Patents
11-(1-methyl-4-piperidylidene)-6,11-dihydrodibenzo/b,e/thiepine-2-carbonitrile and its oxalate Download PDFInfo
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- CS260096B1 CS260096B1 CS873859A CS385987A CS260096B1 CS 260096 B1 CS260096 B1 CS 260096B1 CS 873859 A CS873859 A CS 873859A CS 385987 A CS385987 A CS 385987A CS 260096 B1 CS260096 B1 CS 260096B1
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- methyl
- thiepine
- dihydrodibenzo
- piperidylidene
- oxalate
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 title claims abstract description 10
- CNMLDHHGACPLTP-UHFFFAOYSA-N thiepine-2-carbonitrile Chemical compound N#CC1=CC=CC=CS1 CNMLDHHGACPLTP-UHFFFAOYSA-N 0.000 title abstract description 3
- -1 1-methyl-4-piperidylidene Chemical group 0.000 claims abstract description 7
- CUPOOAWTRIURFT-UHFFFAOYSA-N thiophene-2-carbonitrile Chemical compound N#CC1=CC=CS1 CUPOOAWTRIURFT-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 230000001078 anti-cholinergic effect Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 150000002576 ketones Chemical class 0.000 abstract description 2
- ZCQVEMXIVISDLV-UHFFFAOYSA-M magnesium;1-methylpiperidin-4-ide;chloride Chemical compound [Mg+2].[Cl-].CN1CC[CH-]CC1 ZCQVEMXIVISDLV-UHFFFAOYSA-M 0.000 abstract description 2
- 238000006386 neutralization reaction Methods 0.000 abstract description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 2
- LEKPFOXEZRZPGW-UHFFFAOYSA-N copper;dicyanide Chemical compound [Cu+2].N#[C-].N#[C-] LEKPFOXEZRZPGW-UHFFFAOYSA-N 0.000 abstract 1
- 239000002552 dosage form Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 230000003340 mental effect Effects 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 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 description 3
- 241000700159 Rattus Species 0.000 description 3
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 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 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 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 description 3
- 229960003147 reserpine Drugs 0.000 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 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 2
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- MYGXGCCFTPKWIH-UHFFFAOYSA-N 4-chloro-1-methylpiperidine Chemical compound CN1CCC(Cl)CC1 MYGXGCCFTPKWIH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000891 anti-reserpine Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000003102 mental depression Diseases 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Řešení spadá do oboru synthetických léčiv. Jeho předmětem je antiřeserpinoVě, centrálně tlumivě a anticholinergicky účinný 11-(l-metyl-4-piperidyliden)-6,11- -dihydrodibenzo/b,e/thiepin-2-karbonitril a jeho oxalát. Svými farmakologickými vlastnostmi tato látka naznačuje praktickou použitelnost v therapii duševních depresí. Je přístupná syntézou, která vychází z 2-bromdibenzo/b,e/thiepin-ll(6Hj- -onu. Reakcí tohoto ketonu s l-metyl-4- piperidylmagnesiumchloridem se získá 2-brom-ll-(l-metyl-4-piperidyl)-6,11- -dihydrodibenzo/b,e/thiepin-ll-ol, který se dehydratuje kysele katalýzovanou reakcí na 2-brom-ll-(l-metyl-4-piperidyliden)- -6,ll-dihydrodibenzo/b,e/thiepin. Závěrečným stupněm je reakce této látky s kyanidem mědnatým v hexametylfosfortriamidu při 150 °C. Neutralizací získané base kyselinou oxalovou se získá krystalický hydrogenoxalát, který je vhodný k farmakologickým testům i k výrobě lékových forem.The solution is within the synthetic field drugs. Its subject is anti-superficial, centrally buffered and anticholinergic effective 11- (1-methyl-4-piperidylidene) -6,11- -dihydrodibenzo / b, e-thiepine-2-carbonitrile and its oxalate. By their pharmacological properties usability in mental therapy depression. It is accessible by synthesis that based on 2-bromo-dibenzo / b, e / thiepine-11 (6Hj- -on. Reaction of this ketone with 1-methyl-4- piperidylmagnesium chloride is obtained 2-bromo-11- (1-methyl-4-piperidyl) -6,11- -dihydrodibenzo / b, e / thiepin-11-ol, which dehydrates acid catalysed by reaction to 2-bromo-11- (1-methyl-4-piperidylidene) - -6, 11-dihydrodibenzo / b, e / thiepine. Final the degree of reaction is cyanide copper in hexamethylphosphoric triamide at 150 ° C. Neutralization of the base obtained with acid oxalic, crystalline hydrogen oxalate is obtained, which is suitable for pharmacological tests for the manufacture of dosage forms.
Description
260096 2
Vynález se týká ll-(l-metyl-4-piperidyliden '-6,ll-dihydrodibenzo/b,e/thiepin-2-karbo-nitrilu vzorce I
a jeho oxalátu. 3 Látka vzorce I a její oxalát jsou podle testů na myších a krysách intensivně antireserpinově účinné, Ciipž naznačují vlastnosti potenciálních antidepresiv. V biochemickofarmakologic-kých testech vykázala látka vzorce 1 silnou afinitu k muskarinovým receptorům, což jerovněž typické pro tricyklické antidepresiva. Látka vzorce I, její oxalát a případně idalší soli představují tedy možná léčiva proti stavům duševní deprese.
Vlastnosti látky vzorce I a jejího oxalátu (v této formě byla látka I testována)lze doložit těmito konkrétními údaji (byla podávána orálně). V dávce 10 mg/kg látka vzorce Iintensivně antagonisuje hypothermický efekt reserpinu u myší. V dávce 50 mg/kg signifikantněantagonisuje tvorbu žaludečních vředů u krys, které jsou vyvolány působením reserpinu. V dávce 25 mg/kg signifikantně blokuje reserpinovou ptosu u myší. Látka je též výrazněcentrálně tlumivě účinná! v dávce 10 mg/kg snižuje v testu podle Dewse spontánní lokomotoric-kou aktivitu myší v intervalu 1 h na 31 %, v intervalu 3 h na 52 % kontrolních hodnot. Při intraperitoneálním podáni 30 mg/kg vykazuje výrazné anticholinergní působeníu myší v testu oxotremorinového třesu; střední účinná dávka ED^q je 2,12 mg/kg. Konečně prokazuje v testu in vitro silnou afinitu k muskarinovým reďeptorům vytěsňováním /^H/chinuklidyl-benzilátu z vazby na receptorech v krysím mozku; střední inhibiční koncentrace IC^q je109,6 nM (podobná hodnota jako u desípraminu). Látka vzorce I je přístupná syntézou, která vychází ze známého 2-bromdibenzo/b,e/thiepin-ll(6H)-onu (Protiva M. et al., Experientia 18., 326, 1962; Rajšner M. et el., Cesk. Farm.
11, 451, 1962). Tento keton se v prvním stupni podrobí reakci s l-metyl-4-piperidylmagnesium-chloridem (Adlerová E. et al., Česk. Farm. 12, 122, 1963) , probíhající nejlépe v tetra-hydrofuranu, kterou se získá terciární alkohol vzorce II
(II).
Tento alkohol se v dalším stupni dehydratuje kysele katalyzovanou reakcí na olefinický «
amin vzorce III
(III) . 3 260096 S výhodou se k tomu použije zahřívání se zředěnou kyselinou sírovou, nejlépe 10 až30%. V posledním stupni se olefinický hromovaný amin vzorce III transformuje na žádanoulátku vzorce I reakcí s kyanidejn mědnatým v hexametylfosfortriamidu 150 °C. Base vzorce Ije krystalická látka tající při 171 až 172 °C.
Neutralizací kyselinou oxalovou poskytuje krystalický hydrogenoxalát, který krysta-lizuje ze směsi vodného acetonu a etheru jako hemihydrát tající pří 169 až 171 °C. Všechnylátky ve vynálezu popsané jsou nové. Jejich identita byla.zajištěna jednak analýzami,jednak spektrálními metodami. Další podrobnosti o provedení uvedeného způsobu přípravylátky vzorce I jsou uvedeny v příkladu.
Reakcí 1,85 g hořčíku s 10,0 g 4-chlor-l-metylpiperidinu ve 40 ml tetrahydrofuranuse připraví Grignardovo činidlo. K nastartování reakce se kromě krystalku jodu použijeasi 10 kapek 1,2-dibrometanu. Po skončení exothermní reakce se směs zahřívá k varu podzpětným chladičem po dobu 2 h, přičemž prakticky všechen hořčík zreaguje. Po ochlazenína teplotu místnosti se za míchání během 5 min přidá roztok 12,25 g 2-bromdibenzo/b,e/thiepin--ll(6H)-onu (literatura citována) v dalších 40 ml tetrahydrofuranu, směs se vaří 2 h podzpětným chladičem, po stání přes noc při teplotě místnosti se rozloží pomalým přidáním 100 ml20% roztoku chloridu amonného a směs se zfiltruje. Organická fáze filtrátu se oddělí,basický produkt se z ní vyextrahuje protřepáním do 50 ml 10% ledově chladné kyseliny chloro-vodíkové a promyje se vodou.
Vodné fáze se spojí a ihned se zalkalizují vodným amoniakem; base se extrahuje chloro-formem, extrakt se vysuší bezvodým uhličitanem draselným a odpaří se za sníženého tlaku.
Odparek (15 g) se přiměje ke krystalizaci směsí benzenu a petroletheru. Získá se 6,0 g(37 %) 2-brom-ll-(l-metyl-4-piperidyl)-6-ll-dihydrodibenzo/b,e/thiepin-ll-olu (II), kterýpo rekrystalizaci z uvedené směsi rozpouštědel taje při 196,5 až 199,5 °C a analytickybyl identifikován jako 6:1 solvát s benzenem.
Roztok 5,8 g předešlé látky ve 100 ml 20% kyseliny sírové se zahřívá za míchání 2 hna teplotu 100 až 120 °C. Po ochlazení se zalkalizuje 20% roztokem hydroxidu sodného,base se isoluje extrakcí benzenem a extrakt se odpaří. Zbytek se přivede ke krystalizacipůsobením malého množství etheru. Získá se 3,75 g (70 %) 2-brom-ll-(l-metyl-4-piperidyliden)-6,ll-dihydrodibenzo/b,e/thiepinu (III), který po rekrystalizaci ze směsi benzenu a petroletheruje zcela homogenní a taje při 167,5 až 169 °C.
Směs 3,55 g předešlé látky, 1,8 g kyanidu mědného a 10 ml hexametylfosfortriamiduse zahřívá 14 h za míchání na 150 °C. Po ochlazení se roztřepe mezi benzen a zředěný vodnýamoniak, po filtraci se benzenová fáze filtrátu oddělí, promyje se vodou, vysuší uhličitanemdraselným a odpaří. Ze zbytku se krystalizaci ze směsi benzenu a petroletheru separuje0,3 g krystalického vedlejšího produktu a matečný louh se chromatografuje na sloupci 200 gneutrálního kysličníku hlinitého (aktivita II).
Benzenem se eluuje malé množství méně polární příměsi a směsí benzenu a chloroformuse eluuje 0,96 g (31 %) žádaného 11-(l-metyl-4-piperidyliden)-6,ll-dihydi'odibenzo/b,e/-thiepin-2-karbonitrilu (I), který krystalizuje ze směsi benzenu a petroletheru a v čistémstavu taje při 171 až 172 °C. Neztralizací dihydrátem kyseliny oxalové ve směsi acetonua etheru poskytuje hemihydrát hydrogenoxalátu, který taje při 169 až 171 °C.
260096 2
The invention relates to 11- (1-methyl-4-piperidylidene-6,11-dihydrodibenzo [b] thiepine-2-carbonitrile of formula I)
and its oxalate. 3 The compounds of formula I and its oxalate are, according to tests in mice and rats, intensively antireserpine-effective, suggesting the properties of potential antidepressants. In biochemical pharmacological tests, the compound of formula 1 showed strong affinity for muscarinic receptors, which is also typical of tricyclic antidepressants. Thus, the compound of formula (I), its oxalate and optionally other salts, are possibly drugs against mental depression.
The properties of the compound of formula (I) and its oxalate (in which form I was tested) can be illustrated by these specific data (orally). At 10 mg / kg, the compound of formula Iintensively antagonizes the hypothermic effect of reserpine in mice. At a dose of 50 mg / kg, it significantly antagonizes the formation of gastric ulcers in reserpine-induced rats. At 25 mg / kg, it significantly blocks reserpine ptosis in mice. The fabric is also dramatically dampening effective! At 10 mg / kg, the Dewse test reduces the spontaneous locomotor activity of mice at 1 h to 31%, at 3 h to 52% of control values. At intraperitoneal administration of 30 mg / kg, the mice show significant anticholinergic activity in the oxotremorine tremor assay; the mean effective dose of ED 50 is 2.12 mg / kg. Finally, it demonstrates, in an in vitro assay, strong affinity for muscarinic receptors by displacing βH / quinuclidylbenzilate from binding to receptors in rat brain; the mean IC50 inhibitory concentration is 109.6 nM (similar to desopropamine). The compound of formula I is accessible by synthesis starting from the known 2-bromodibenzo [b, e] thiepine-11 (6H) -one (Protiva M. et al., Experientia 18, 326, 1962; Rajshner M. et al. Cesk. Farm.
11, 451 (1962). This ketone is reacted with 1-methyl-4-piperidylmagnesium chloride (Adler E. et al., Czech. Farm. 12, 122, 1963) in the first step, preferably in tetrahydrofuran to give the tertiary alcohol of formula II
(II).
This alcohol is dehydrated in the next step by acid-catalyzed olefinic reaction.
amine of formula III
(III). Preferably, heating is carried out with dilute sulfuric acid, preferably 10-30%. In the last step, the olefin accumulated amine of formula III is transformed into the desired compound of formula I by reaction with copper cyanide in hexamethylphosphoric triamide 150 ° C. The base of formula I is a crystalline substance melting at 171-172 ° C.
Neutralization with oxalic acid gives crystalline hydrogen oxalate which crystallizes from a mixture of aqueous acetone and ether as the hemihydrate melting at 169-171 ° C. All of the compounds of the invention described are novel. Their identity was secured by both analyzes and spectral methods. Further details on carrying out the above process of preparation of Formula I are given in the Example.
Reaction of 1.85 g of magnesium with 10.0 g of 4-chloro-1-methylpiperidine in 40 ml of tetrahydrofuran gives the Grignard reagent. In addition to the iodine crystal, 10 drops of 1,2-dibromoethane were used to start the reaction. Upon completion of the exotherm, the mixture was heated to reflux with reflux for 2 h, with virtually all of the magnesium reacted. After cooling to room temperature, a solution of 12.25 g of 2-bromo-dibenzo / b, e / thiepine-11 (6H) -one (literature cited) in an additional 40 ml of tetrahydrofuran was added with stirring for 5 min, the mixture was refluxed for 2 h After standing overnight at room temperature, it was quenched by the slow addition of 100 mL of 20% ammonium chloride solution and filtered. The organic phase of the filtrate is separated, the basic product is extracted by shaking into 50 ml of 10% ice-cold hydrochloric acid and washed with water.
The aqueous phases are combined and immediately basified with aqueous ammonia; the base is extracted with chloroform, the extract is dried over anhydrous potassium carbonate and evaporated under reduced pressure.
The residue (15 g) was induced to crystallize with a mixture of benzene and petroleum ether. 6.0 g (37%) of 2-bromo-11- (1-methyl-4-piperidyl) -6-11-dihydrodibenzo [b, e] thiepin-11-ol (II) are obtained which, after recrystallization from the mixture, The solvents melted at 196.5-199.5 ° C and were analytically identified as a 6: 1 benzene solvate.
A solution of 5.8 g of the above compound in 100 ml of 20% sulfuric acid was heated to 100-120 ° C with stirring for 2 hours. After cooling, it is basified with 20% sodium hydroxide solution, the base is isolated by extraction with benzene and the extract is evaporated. The residue is crystallized by treatment with a small amount of ether. 3.75 g (70%) of 2-bromo-11- (1-methyl-4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine (III) are obtained which, after recrystallization from benzene / petroleum ether, is completely homogeneous and melts at 167.5 to 169 ° C.
A mixture of 3.55 g of the preceding material, 1.8 g of cuprous cyanide and 10 ml of hexamethylphosphoric triamide was heated to 150 ° C with stirring for 14 h. After cooling, it was partitioned between benzene and dilute aqueous ammonia, after filtration the benzene phase of the filtrate was separated, washed with water, dried with potassium carbonate and evaporated. From the residue, 0.3 g of crystalline by-product is separated from the benzene / petroleum ether mixture and the mother liquor is chromatographed on a column of 200 gneutral alumina (activity II).
A small amount of less polar admixture is eluted with benzene and 0.96 g (31%) of the desired 11- (1-methyl-4-piperidylidene) -6,11-dihydro-dibenzo [b, e] thiopine is eluted with benzene / chloroform. Of 2-carbonitrile (I), which crystallizes from a mixture of benzene and petroleum ether and melts at 171-172 ° C in the pure state. Hydroxylate hemihydrate melting at 169-171 ° C provides unextraction with oxalic acid dihydrate in acetone / ether.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS873859A CS260096B1 (en) | 1987-05-27 | 1987-05-27 | 11-(1-methyl-4-piperidylidene)-6,11-dihydrodibenzo/b,e/thiepine-2-carbonitrile and its oxalate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS873859A CS260096B1 (en) | 1987-05-27 | 1987-05-27 | 11-(1-methyl-4-piperidylidene)-6,11-dihydrodibenzo/b,e/thiepine-2-carbonitrile and its oxalate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS385987A1 CS385987A1 (en) | 1988-03-15 |
| CS260096B1 true CS260096B1 (en) | 1988-11-15 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS873859A CS260096B1 (en) | 1987-05-27 | 1987-05-27 | 11-(1-methyl-4-piperidylidene)-6,11-dihydrodibenzo/b,e/thiepine-2-carbonitrile and its oxalate |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS260096B1 (en) |
-
1987
- 1987-05-27 CS CS873859A patent/CS260096B1/en unknown
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| Publication number | Publication date |
|---|---|
| CS385987A1 (en) | 1988-03-15 |
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