CS235172B1 - Aminoalcohol of dibenzo-(b,e)-thiepin series and its hydrochloride - Google Patents
Aminoalcohol of dibenzo-(b,e)-thiepin series and its hydrochloride Download PDFInfo
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- CS235172B1 CS235172B1 CS781383A CS781383A CS235172B1 CS 235172 B1 CS235172 B1 CS 235172B1 CS 781383 A CS781383 A CS 781383A CS 781383 A CS781383 A CS 781383A CS 235172 B1 CS235172 B1 CS 235172B1
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- hydrochloride
- piperidylidene
- chloro
- dihydrodibenzo
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 24
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 title claims abstract description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 title 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims abstract description 5
- 150000003551 thiepines Chemical class 0.000 claims abstract description 3
- 150000001414 amino alcohols Chemical class 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 12
- 150000001875 compounds Chemical class 0.000 abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 9
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 abstract description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 206010011224 Cough Diseases 0.000 abstract description 6
- 241000699670 Mus sp. Species 0.000 abstract description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 abstract description 6
- 241000700159 Rattus Species 0.000 abstract description 6
- 238000009835 boiling Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- -1 1-ethoxycarbonyl-4-piperidylidene Chemical group 0.000 abstract description 4
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 abstract description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 abstract description 4
- 241001465754 Metazoa Species 0.000 abstract description 4
- 230000000954 anitussive effect Effects 0.000 abstract description 4
- 238000001816 cooling Methods 0.000 abstract description 4
- 239000000706 filtrate Substances 0.000 abstract description 4
- 238000002844 melting Methods 0.000 abstract description 4
- 230000008018 melting Effects 0.000 abstract description 4
- 230000007935 neutral effect Effects 0.000 abstract description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract description 4
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 abstract description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 abstract description 3
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 abstract description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 abstract description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 abstract description 3
- 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 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 abstract description 2
- 241000700198 Cavia Species 0.000 abstract description 2
- 206010010904 Convulsion Diseases 0.000 abstract description 2
- 241000699666 Mus <mouse, genus> Species 0.000 abstract description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 abstract description 2
- 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 2
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 abstract description 2
- 206010044565 Tremor Diseases 0.000 abstract description 2
- 230000007059 acute toxicity Effects 0.000 abstract description 2
- 231100000403 acute toxicity Toxicity 0.000 abstract description 2
- 239000000443 aerosol Substances 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract description 2
- 229940025084 amphetamine Drugs 0.000 abstract description 2
- 238000004458 analytical method Methods 0.000 abstract description 2
- 239000000935 antidepressant agent Substances 0.000 abstract description 2
- 229940005513 antidepressants Drugs 0.000 abstract description 2
- 239000003434 antitussive agent Substances 0.000 abstract description 2
- 229940124584 antitussives Drugs 0.000 abstract 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 abstract description 2
- 229960004046 apomorphine Drugs 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 210000004556 brain Anatomy 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 238000004587 chromatography analysis Methods 0.000 abstract description 2
- 238000010520 demethylation reaction Methods 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 abstract description 2
- QRMZSPFSDQBLIX-UHFFFAOYSA-N homovanillic acid Chemical compound COC1=CC(CC(O)=O)=CC=C1O QRMZSPFSDQBLIX-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 230000001665 lethal effect Effects 0.000 abstract description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 abstract description 2
- 235000019341 magnesium sulphate Nutrition 0.000 abstract description 2
- 239000000155 melt Substances 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 210000001577 neostriatum Anatomy 0.000 abstract description 2
- 239000003176 neuroleptic agent Substances 0.000 abstract description 2
- 230000000701 neuroleptic effect Effects 0.000 abstract description 2
- 238000006386 neutralization reaction Methods 0.000 abstract description 2
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 abstract description 2
- 229960003081 probenecid Drugs 0.000 abstract description 2
- 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 2
- 229960003147 reserpine Drugs 0.000 abstract description 2
- 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 2
- 150000003839 salts Chemical class 0.000 abstract description 2
- 150000003335 secondary amines Chemical class 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 229960003279 thiopental Drugs 0.000 abstract description 2
- 231100000816 toxic dose Toxicity 0.000 abstract description 2
- 230000002110 toxicologic effect Effects 0.000 abstract description 2
- 231100000723 toxicological property Toxicity 0.000 abstract description 2
- 239000003204 tranquilizing agent Substances 0.000 abstract description 2
- 230000002936 tranquilizing effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract 3
- 239000002253 acid Substances 0.000 abstract 3
- 239000000047 product Substances 0.000 abstract 2
- 238000010992 reflux Methods 0.000 abstract 2
- 238000002560 therapeutic procedure Methods 0.000 abstract 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 abstract 1
- 229910052782 aluminium Inorganic materials 0.000 abstract 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 abstract 1
- 230000007423 decrease Effects 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 238000010828 elution Methods 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 230000003334 potential effect Effects 0.000 abstract 1
- 239000007787 solid Substances 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Vynález se týká amimoalkoholu dibenzo- (b,e)thiepinové řady vzorce I, (I) tj. 2-chlor-ll-[1- (2-hydroxyethyl)-4-piperidyliden ] -6,11-dihydrodibenzo (b,e)thiepinu, a jeho hydrochloridu. Látka vzorce I a její hydrochlorid mají vlastnosti trankvilizérů a antitusik, což je předpokladem jejich praktického použití v terapii některých nervových a psychických onemocnění a dále v terapii kašle. Farmakodynamické a toxikologické vlastnosti hydrochloridu látky vzorce I lze ověřit v pokusech na zvířatech. Látka byla testována ve formě hydrochloridu při orální aplikaci, přičemž uvedené dávky jsou přepočteny na bá2 zi. Akutní toxicita u myší, LDso = 413 mg/kg; toxické dávky vyvolávají tremor a opakované záchvaty křečí. V dávkách 10 až 25 mg/kg potencuje látka účinek thiopentalu u myší (prodlužuje trvání spánku na 200 % proti kontrole). V dávce 50 mg/kg vykazuje antiamfetaminový účinek u myši (chrání 100 % zvířat před letálním efektem standardní dávky amfetaminu). Testy prokázaly, že látka není neuroleptikem: v dávce 50 mg/kg nepůsobí katalepticky u krys, neovlivňuje apomorfinové stereotypie u krys a neovlivňuje probenecidem indukované zvýšení hladiny kyseliny homovanilové ve striatu krysího mozku. Nemá ani vlastnosti potenciálního antidepresiva, protože v dávce 25 mg/kg neovlivňuje reserpinem vyvolanou ptosu u myší. Naproti tomu v dávce 100 mg/ /kg má antitusický účinek u morčat v testu, který používá k vyvolání kašle aerosolu kyseliny citrónové; uvedená dávka snižuje počet záchvatů kašle o 61 % ve srovnání s kontrolní skupinou. Látku vzorce I podle vynálezu lze připravit třístupňovou syntézou ze známého 2- dihydrodibenzo(b,ejthiepinu vzorce II (F. Gadient a spol., Helv. Chim. Acta 45, 1860, 19B2). Tato látka se v prvním stupniII, R = CH3 III, R = COOC2H5 IV, R = H podrobí reakci s chlormravenčanem ethylnatým ve vroucím, benzenu, čímž se dosáhne N-demethylace a rezultuje karbamát vzorce III, tj. lálkta neutrální povahy. Surový produkt se vyčistí chromatografii na oxidu hlinitém a žádaný karbamát se získá ve vysokém výtěžku. Ve druhém stupni se karbamát vzorce III hydrolyzuje varem s ethanolickým roztokem hydroxidu draselného a získá se krystalický sekundární amin vzorce IV. V posledním stupni se látka IV alkyluje 2-bromethanolem ve vroucím acetonu za přítomnosti uhličitanu draselného. Získaná olejovitá báze vzorce I se převede neutralizací chlorovodíkem nebo kyselinou chlorovodíkovou na krystalický hydrochlorid, který je rovněž předmětem vynálezu. Konečný produkt vzorce I, jakož i meziprodukty vzorců III a IV jsou látky nové, jejichž identita byla zajištěna pomocí analýz i spekter. Podrobnosti právě popsaného způsobu přípravy látky vzorce I jsou uvedeny v následujícím příkladu, jehož účelem je ilustrovat možnosti vynálezu, avšak v žádném případě neopisuje všechny tyto možnosti vyčerpávajícím způsobem, K míchanému roztoku 2,5 kg chlormravenčanu ethylnatého v 6 ml benzenu se při 70 “C přikape teplý roztok 5,6 g 2-chlor-ll4 - (l-methyl-4-piperidyliden j -6,11-dihydrodibenzo(b,e jthiepinu (II) (literatura citována] ve 12 ml benzenu a směs se vaří 2,5 hodiny pod zpětným chladičem. Potom se ochladí, rozloží se vodou a extrahuje se chloroformem. Extrakt se promyje zředěnou kyselinou chlorovodíkovou a vodou, vysuší se síranem hořečnatým a odpaří. Zbytek se chromatografuje na sloupci 200 g neutrálního· oxidu hlinitého (aktivita II). Elucí chloroformem se získá 5,7 g (87 %) 2-chlor-ll- -(l-ethoxykarbonyl-4-piperidyliden)-6,11- krystaluje z cyklohexanu a taje při 125 až 126 °C. Směs 25,0 g karbamátu III, 30 g hydroxidu draselného a 100 ml ethanolu se míchá a zahřívá 1 hodinu pod zpětným chladičem v lázni vyhřáté na 140 °C. Protože směs tuhne, je nutné míchání přerušit po· 30 minut. Po· skončení reakce se směs rozpustí v 1 1 vody a po· ochlazení se vyloučený pevný •produkt odsaje, promyje vodou a vysuší ve vakuu. Ve výtěžku 19,0 g (93 °/o) se získá téměř čistý 2-chlor-ll-(4-piperidylidenj- -6,ll-dihydrodibenzo(b,e)thiepin (IV) tající při 175 až 180 °C. Krystalizací ze směsi benzenu a cyklohexanu se získá zcela čistá látka s t. t. 180 až 182 °C. Směs 12,1 g aminu IV, 6,75 g 2-bromethanolu, 6,75 g uhličitanu draselného a 140 ml acetonu se míchá a vaří 5 hodin pod zpětným chladičem. Po ochlazení se vyloučené soli odfiltrují, promyjí acetonem a filtrát se odpaří. Zbytek se rozpustí v etheru, nerozpuštěné malé množství se opět odfiltruje a k filtrátu se přidá mírný přebytek chlorovodíku ve formě roztoku v etheru. Vyloučený hydrochlorid 2-chlor-ll-[ 1- (2-hydroxyethyl)-4-piperidyliden]-6,ll-dihydrodibenzo(b,e jthiepinu (I) se izoluje filtrací, promyje se etherem a vysuší. Získá se ve výtěžku 11,7 g (76 %). Jedinou krystalizací z vodného methanolu se získá čistá látka tající při 265 až 267 °C.The present invention relates to a dibenzo- (b, e) the thiepine series of Formula I, (AND) i.e., 2-chloro-11- [1- (2-hydroxyethyl) -4-piperidylidene ] -6,11-dihydrodibenzo (b, e) thiepine, a its hydrochloride. The compound of formula I and its hydrochloride have the properties of tranquilizers and antitussives, which is a prerequisite for their practical use in therapy of some nervous and psychological and cough therapy. Pharmacodynamic and the toxicological properties of the hydrochloride the compounds of formula I can be verified in experiments on animals. The substance was tested in hydrochloride form when administered orally; said doses are converted to b2 zi. Acute toxicity in mice, LD 50 = 413 mg / kg; toxic doses induce tremor and repeat seizures. In doses of 10 to 25 mg / kg potentiates thiopental effect in mice (prolongs sleep to 200% against control). It shows at 50 mg / kg antiamphetamine effect in mouse (protects) 100% of the animals before the standard lethal effect amphetamine doses). Tests have shown that the substance is not a neuroleptic: at 50 mg / kg does not cataleptically affect rats, does not affect apomorphine stereotypes in rats and does not affect probenecid-induced increases homovanilic acid levels in the striatum rat brain. It also has no potential properties antidepressants because of the dose 25 mg / kg does not affect reserpine-induced ptos in mice. In contrast, at a dose of 100 mg / / kg has an antitussive effect in guinea pigs in the test, which uses an acid aerosol to induce cough citrónové; said dose decreases the number 61% of cough attacks compared to control group. The compound of formula I according to the invention can be prepared three-step synthesis from the known 2- dihydrodibenzo (b, ejthiepine of formula II (F. Gadient et al., Helv. Chim. Acta 45, 1860, 19B2). This substance was in the first step, R = CH3 III, R = COOC 2 H 5 IV, R = H it is reacted with ethyl chloroformate in boiling, benzene, thereby achieving N-demethylation and carbamate result of formula III, i.e., a neutral nature. Crude the product is purified by chromatography on oxide aluminum and the desired carbamate is obtained in high yield. In the second step, the carbamate is added Formula III is hydrolyzed with ethanolic boiling potassium hydroxide solution a to obtain a crystalline secondary amine of the formula IV. In the last step, IV is alkylated With 2-bromoethanol in boiling acetone in the presence of potassium carbonate. Obtained the oily base of formula I is converted by neutralization with hydrogen chloride or acid hydrochloric acid to crystalline hydrochloride, which is also the subject of the invention. The final product of Formula I as well as the intermediates formulas III and IV are new, whose identity was ensured through analysis i spekter. Details just described the process for the preparation of the compound of formula I are given in the following example is to illustrate the possibilities of the invention, but in in no way does it describe all of these options exhaustively To a stirred solution of 2.5 kg chloroformate of ethyl acetate in 6 ml of benzene at room temperature 70 ° C, a warm solution of 5.6 g of 2-chloro-14 is added dropwise - (1-methyl-4-piperidylidene-6,11-dihydrodibenzo (b, e thiepine (II) (literature cited) in 12 ml of benzene and boil 2.5 hours under reflux. Then take it cooled, quenched with water and extracted chloroform. The extract is washed with dilute hydrochloric acid and water, dried with magnesium sulfate and evaporated. The rest is chromatographed on a 200 g column of neutral · alumina (activity II). Elution with chloroform 5.7 g (87%) of 2-chloro-11- are obtained. - (1-ethoxycarbonyl-4-piperidylidene) -6,11- crystallizes from cyclohexane and melts at 125 ° C 126 ° C. A mixture of 25.0 g of carbamate III, 30 g of hydroxide potassium and 100 ml of ethanol are stirred and stirred under reflux for 1 hour in a bath heated to 140 ° C. Because the mixture solidifies, it is necessary to interrupt the mixing after 30 minutes. After completion of the reaction, the mixture was dissolved in 1 L water and solids are excluded after cooling • suctioning off, washing the product with water and drying it in vacuum. A yield of 19.0 g (93%) is obtained almost pure 2-chloro-11- (4-piperidylidene- -6,11-dihydrodibenzo (b, e) thiepine (IV) melting at 175-180 ° C. Crystallization from benzene and cyclohexane gave a completely pure substance mp 180-182 ° C. A mixture of 12.1 g of amine IV, 6.75 g of 2-bromoethanol, 6.75 g of potassium carbonate and 140 ml The acetone was stirred and refluxed for 5 hours cooler. It was excluded after cooling the salts are filtered off, washed with acetone and the filtrate is filtered evaporates. The residue was dissolved in ether, undissolved a small amount is filtered off again and a slight excess of hydrogen chloride is added to the filtrate as a solution in ether. Excluded 2-chloro-11- [1- (2-hydroxyethyl) -4-piperidylidene] -6,11-dihydrodibenzoic acid hydrochloride (b, e Jthiepine (I) is isolated by filtration, washed with ether and dried. It is obtained in yield 11.7 g (76%). The only crystallization pure methanol is obtained from aqueous methanol melting at 265-267 ° C.
Description
Vynález se týká amimoalkoholu dibenzo(b,e)thiepinové řady vzorce I,The present invention relates to the dibenzo (b, e) thiepine series amimoalcohol,
(I) tj. 2-chlor-ll-[ 1- (2-hydroxyethyl)-4-piperidyliden ] -6,11-dihydrodibenzo (b,e)thiepinu, a jeho hydrochloridu.(I) i.e. 2-chloro-11- [1- (2-hydroxyethyl) -4-piperidylidene] -6,11-dihydrodibenzo (b, e) thiepine, and its hydrochloride.
Látka vzorce I a její hydrochlorid mají vlastnosti trankvilizérů a antitusik, což je předpokladem jejich praktického použití v terapii některých nervových a psychických onemocnění a dále v terapii kašle. Farmakodynamické a toxikologické vlastnosti hydrochloridu látky vzorce I lze ověřit v pokusech na zvířatech. Látka byla testována ve formě hydrochloridu při orální aplikaci, přičemž uvedené dávky jsou přepočteny na bá2 zi. Akutní toxicita u myší, LDso = 413 mg/kg; toxické dávky vyvolávají tremor a opakované záchvaty křečí. V dávkách 10 až 25 mg/kg potencuje látka účinek thiopentalu u myší (prodlužuje trvání spánku na 200 % proti kontrole). V dávce 50 mg/kg vykazuje antiamfetaminový účinek u myši (chrání 100 % zvířat před letálním efektem standardní dávky amfetaminu). Testy prokázaly, že látka není neuroleptikem: v dávce 50 mg/kg nepůsobí katalepticky u krys, neovlivňuje apomorfinové stereotypie u krys a neovlivňuje probenecidem indukované zvýšení hladiny kyseliny homovanilové ve striatu krysího mozku. Nemá ani vlastnosti potenciálního antidepresiva, protože v dávce 25 mg/kg neovlivňuje reserpinem vyvolanou ptosu u myší. Naproti tomu v dávce 100 mg/ /kg má antitusický účinek u morčat v testu, který používá k vyvolání kašle aerosolu kyseliny citrónové; uvedená dávka snižuje počet záchvatů kašle o 61 % ve srovnání s kontrolní skupinou.The compound of formula I and its hydrochloride have the properties of tranquilizers and antitussives, which is a prerequisite for their practical use in the treatment of certain nervous and mental disorders and also in the treatment of cough. The pharmacodynamic and toxicological properties of the hydrochloride of the compound of formula I can be verified in animal experiments. The compound was tested in the form of the hydrochloride when administered orally, the dosages being recalculated to base 2. Acute toxicity in mice, LD 50 = 413 mg / kg; toxic doses induce tremor and repeated seizures. At doses of 10 to 25 mg / kg, the compound potentiates the effect of thiopental in mice (extending sleep duration to 200% over control). At a dose of 50 mg / kg, it shows an antiamphetamine effect in the mouse (protecting 100% of the animals from the lethal effect of the standard amphetamine dose). Tests have shown that the substance is not a neuroleptic: at 50 mg / kg it does not act cataleptically in rats, does not affect apomorphine stereotypes in rats, and does not affect probenecid-induced increase in homovanilic acid levels in rat brain striatum. It also has no potential antidepressant properties as it does not affect reserpine-induced ptosis in mice at 25 mg / kg. In contrast, at a dose of 100 mg / kg, it has an antitussive effect in guinea pigs in a test that uses citric acid aerosol to cause a cough; said dose reduces the number of coughing attacks by 61% compared to the control group.
Látku vzorce I podle vynálezu lze připravit třístupňovou syntézou ze známého 2dihydrodibenzo(b,ejthiepinu vzorce II (F. Gadient a spol., Helv. Chim. Acta 45, 1860, 19B2). Tato látka se v prvním stupniThe compound of formula I according to the invention can be prepared by a three-step synthesis from the known 2-dihydrodibenzo (b, ejthiepine of formula II (F. Gadient et al., Helv. Chim. Acta 45, 1860, 19B2).
II, R = CH3II, R = CH 3
III, R = COOC2H5III, R = COOC 2 H 5
IV, R = H podrobí reakci s chlormravenčanem ethylnatým ve vroucím, benzenu, čímž se dosáhne N-demethylace a rezultuje karbamát vzorce III, tj. lálkta neutrální povahy. Surový produkt se vyčistí chromatografii na oxidu hlinitém a žádaný karbamát se získá ve vysokém výtěžku. Ve druhém stupni se karbamát vzorce III hydrolyzuje varem s ethanolickým roztokem hydroxidu draselného a získá se krystalický sekundární amin vzorce IV. V posledním stupni se látka IV alkyluje 2-bromethanolem ve vroucím acetonu za přítomnosti uhličitanu draselného. Získaná olejovitá báze vzorce I se převede neutralizací chlorovodíkem nebo kyselinou chlorovodíkovou na krystalický hydrochlorid, který je rovněž předmětem vynálezu.IV, R = H is reacted with ethyl chloroformate in boiling benzene to give N-demethylation and the carbamate of formula III, i.e. a neutral substance, is obtained. The crude product is purified by alumina chromatography and the desired carbamate is obtained in high yield. In a second step, the carbamate of formula III is hydrolyzed by boiling with an ethanolic potassium hydroxide solution to give a crystalline secondary amine of formula IV. In the final step, compound IV is alkylated with 2-bromoethanol in boiling acetone in the presence of potassium carbonate. The resulting oily base of formula (I) is converted into a crystalline hydrochloride salt by neutralization with hydrochloric acid or hydrochloric acid.
Konečný produkt vzorce I, jakož i meziprodukty vzorců III a IV jsou látky nové, jejichž identita byla zajištěna pomocí analýz i spekter. Podrobnosti právě popsaného způsobu přípravy látky vzorce I jsou uvedeny v následujícím příkladu, jehož účelem je ilustrovat možnosti vynálezu, avšak v žádném případě neopisuje všechny tyto možnosti vyčerpávajícím způsobem,The end product of formula I as well as the intermediates of formulas III and IV are novel substances whose identity has been assured by both analysis and spectra. The details of the method of preparation of the compound of formula I just described are given in the following example, which is intended to illustrate the possibilities of the invention, but in no way discloses all of these possibilities in an exhaustive manner,
K míchanému roztoku 2,5 kg chlormravenčanu ethylnatého v 6 ml benzenu se při 70 “C přikape teplý roztok 5,6 g 2-chlor-ll- (l-methyl-4-piperidyliden j -6,11-dihydrodibenzo(b,e jthiepinu (II) (literatura citována] ve 12 ml benzenu a směs se vaří 2,5 hodiny pod zpětným chladičem. Potom se ochladí, rozloží se vodou a extrahuje se chloroformem. Extrakt se promyje zředěnou kyselinou chlorovodíkovou a vodou, vysuší se síranem hořečnatým a odpaří. Zbytek se chromatografuje na sloupci 200 g neutrálního· oxidu hlinitého (aktivita II). Elucí chloroformem se získá 5,7 g (87 %) 2-chlor-ll-(l-ethoxykarbonyl-4-piperidyliden )-6,11krystaluje z cyklohexanu a taje při 125 až 126 °C.A warm solution of 5.6 g of 2-chloro-11- (1-methyl-4-piperidylidene) -6,11-dihydrodibenzo (b, e) is added dropwise at 70 ° C to a stirred solution of 2.5 kg of ethyl chloroformate in 6 ml of benzene. The reaction mixture was cooled, quenched with water and extracted with chloroform. The extract was washed with dilute hydrochloric acid and water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is chromatographed on a column of 200 g of neutral alumina (activity II), eluting with chloroform to give 5.7 g (87%) of 2-chloro-11- (1-ethoxycarbonyl-4-piperidylidene) -6,11 crystallized from cyclohexane and melts at 125-126 ° C.
Směs 25,0 g karbamátu III, 30 g hydroxidu draselného a 100 ml ethanolu se míchá a zahřívá 1 hodinu pod zpětným chladičem v lázni vyhřáté na 140 °C. Protože směs tuhne, je nutné míchání přerušit po· 30 minut. Po· skončení reakce se směs rozpustí v 1 1 vody a po· ochlazení se vyloučený pevný •produkt odsaje, promyje vodou a vysuší ve vakuu. Ve výtěžku 19,0 g (93 °/o) se získá téměř čistý 2-chlor-ll-(4-piperidylidenj-6,ll-dihydrodibenzo(b,e)thiepin (IV) tající při 175 až 180 °C. Krystalizací ze směsi benzenu a cyklohexanu se získá zcela čistá látka s t. t. 180 až 182 °C.A mixture of 25.0 g of carbamate III, 30 g of potassium hydroxide and 100 ml of ethanol is stirred and refluxed for 1 hour in a bath heated to 140 ° C. As the mixture solidifies, stirring should be stopped for 30 minutes. After completion of the reaction, the mixture was dissolved in 1 L of water and, after cooling, the precipitated solid product was filtered off with suction, washed with water and dried in vacuo. In a yield of 19.0 g (93%), almost pure 2-chloro-11- (4-piperidylidene) -6,11-dihydrodibenzo (b, e) thiepine (IV) melting at 175-180 ° C was obtained. from a mixture of benzene and cyclohexane a completely pure substance is obtained with mp 180-182 ° C.
Směs 12,1 g aminu IV, 6,75 g 2-bromethanolu, 6,75 g uhličitanu draselného a 140 ml acetonu se míchá a vaří 5 hodin pod zpětným chladičem. Po ochlazení se vyloučené soli odfiltrují, promyjí acetonem a filtrát se odpaří. Zbytek se rozpustí v etheru, nerozpuštěné malé množství se opět odfiltruje a k filtrátu se přidá mírný přebytek chlorovodíku ve formě roztoku v etheru. Vyloučený hydrochlorid 2-chlor-ll- [ 1- (2-hydroxyethyl)-4-piperidyliden]-6,ll-dihydrodibenzo(b,e jthiepinu (I) se izoluje filtrací, promyje se etherem a vysuší. Získá se ve výtěžku 11,7 g (76 %). Jedinou krystalizací z vodného methanolu se získá čistá látka tající při 265 až 267 °C.A mixture of amine IV (12.1 g), 2-bromoethanol (6.75 g), potassium carbonate (6.75 g) and acetone (140 ml) was stirred and refluxed for 5 hours. After cooling, the precipitated salts are filtered off, washed with acetone and the filtrate is evaporated. The residue was dissolved in ether, the insoluble small amount was filtered again and a slight excess of hydrogen chloride was added to the filtrate as a solution in ether. The precipitated 2-chloro-11- [1- (2-hydroxyethyl) -4-piperidylidene] -6,11-dihydrodibenzo (b, e-thiepine (I) hydrochloride) was collected by filtration, washed with ether and dried to give a yield of 11. 7 g (76%) A single crystallization from aqueous methanol gave a pure material, melting at 265-267 ° C.
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