CS240697B1 - Substituted 10-(piperidinoalkyl)-10,11-dihydrodibenzo(a,f)thiepin-10-carbonitriles - Google Patents
Substituted 10-(piperidinoalkyl)-10,11-dihydrodibenzo(a,f)thiepin-10-carbonitriles Download PDFInfo
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- CS240697B1 CS240697B1 CS847795A CS779584A CS240697B1 CS 240697 B1 CS240697 B1 CS 240697B1 CS 847795 A CS847795 A CS 847795A CS 779584 A CS779584 A CS 779584A CS 240697 B1 CS240697 B1 CS 240697B1
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- dihydrodibenzo
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 13
- -1 2-oxo-1-benzimidazolinyl Chemical group 0.000 claims abstract description 7
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 125000005999 2-bromoethyl group Chemical group 0.000 abstract description 3
- 206010012735 Diarrhoea Diseases 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 150000003053 piperidines Chemical class 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 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
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 7
- 229960004192 diphenoxylate Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000001142 anti-diarrhea Effects 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 241001465754 Metazoa 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
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000006260 foam Substances 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
- 239000012453 solvate Substances 0.000 description 2
- ZXQVXEAZKZFEEP-UHFFFAOYSA-N 2,2-diphenylacetamide Chemical class C=1C=CC=CC=1C(C(=O)N)C1=CC=CC=C1 ZXQVXEAZKZFEEP-UHFFFAOYSA-N 0.000 description 1
- BYNBAMHAURJNTR-UHFFFAOYSA-N 3-piperidin-4-yl-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C1CCNCC1 BYNBAMHAURJNTR-UHFFFAOYSA-N 0.000 description 1
- DPJLAXXPKBQTQE-UHFFFAOYSA-N 5-[3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]propyl]-6h-benzo[b][1]benzothiepine-5-carbonitrile Chemical compound C1C2=CC=CC=C2SC2=CC=CC=C2C1(C#N)CCCN(CC1)CCC1N1C2=CC=CC=C2NC1=O DPJLAXXPKBQTQE-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003793 antidiarrheal agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- MKJDUHZPLQYUCB-UHFFFAOYSA-N decan-4-one Chemical compound CCCCCCC(=O)CCC MKJDUHZPLQYUCB-UHFFFAOYSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 1
- UFIVBRCCIRTJTN-UHFFFAOYSA-N difenoxin Chemical compound C1CC(C(=O)O)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 UFIVBRCCIRTJTN-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 1
- 229960001571 loperamide Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QKHMFBKXTNQCTM-UHFFFAOYSA-N norpethidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCNCC1 QKHMFBKXTNQCTM-UHFFFAOYSA-N 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Obor syntetických léčiv, kde jsou substituované 10-(piperidinoalkyl)-10,ll- dihydrodibenzol/b,£/-thiepin-karbonitxily obecného vzorce I, R A CH / W* \____ / pL kde R1 je atom vodíku nebo ethoxykarbonyl, R2 je fenyl nebo 2-oxo-l-benzimidazolinyl, nebo kde celý zbytek CR^-R2 značí spirocyk- licky vázaný l-fenyl-4-oxo-5,5-ÍEidazolidi- nyliden, n je 2 nebo 5, a jejich soli s kyselinou cHlorovodikovou. Látky vzorce I jsou antidiarhoika prakticky použitelná v therapii průjmů různého původu. Lze je připravit substitučními reakcemi 10-(2-břom- ethyl)- a 10-(5-brompropyl)-10,ll-dihydro- dibenzo/b.f/thiepin-10-karbonitrilu s pipe- ridinovými deriváty obecného vzorce II, 1 o IP ve kterém R a R , resp. celý zbytek CR R , znáči totéž jako ve vzorci I.Synthetic drugs wherein the 10- (piperidinoalkyl) -10,11-dihydrodibenzol / b, β-thiepine carbonitxil of formula (I) is substituted, R AND CH / W * \ ____ / pL wherein R 1 is hydrogen or ethoxycarbonyl, R 2 is phenyl or 2-oxo-1-benzimidazolinyl, or wherein the entire CR 1 -R 2 moiety is spirocyclically linked 1-phenyl-4-oxo-5,5-edidazolidinylidene; is 2 or 5, and salts thereof with hydrochloric acid. The compounds of formula (I) are practically useful in the treatment of diarrhea of various origins. They can be prepared by substitution reactions of 10- (2-bromoethyl) - and 10- (5-bromopropyl) -10,11-dihydro-dibenzo [b] thiepine-10-carbonitrile with piperidine derivatives of general formula (II), 1 of IP in which R and R, respectively. the entire CR R, knowing the same as in Formula I.
Description
Vynález se týká substituovaných 10-(piperidinoalkyl)-10,11 dihydrodibenzo/b,f/thiepin-10-karbonitrilů obecného vzorce I,The present invention relates to substituted 10- (piperidinoalkyl) -10,11 dihydrodibenzo [b, f] thiepine-10-carbonitriles of formula I,
2 kde R je atom vodíku nebo ethoxykarbonyl, R je fenyl nebo 2-oxo-1-benzimidazolinyl, nebo kde celý zbytek CR R značí spirocykličky vázaný 1-fenyl-4-oxo-5,5-imidazolidinyliden, n je 2 nebo 3, a jejich soli s kyselinou chlorovodíkovou. Látky vzorce I jsou antidiarhoika, tj· léčiva s protiprůjmovou účinností.Wherein R is hydrogen or ethoxycarbonyl, R is phenyl or 2-oxo-1-benzimidazolinyl, or wherein the rest of CR R is spirocyclic-bound 1-phenyl-4-oxo-5,5-imidazolidinylidene, n is 2 or 3, and their salts with hydrochloric acid. The compounds of formula I are anti-diarrheal drugs, i.e. drugs with anti-diarrheal activity.
Alkaloid morfin vykazuje celý komplex farmakodynamických účinků, mezi kterými figuruje též účinek antidiarhoický, který je výsledkem přímého účinku na muskulaturu střevní stěny· Vzhle dem k svým vlastnostem návykové opiátové drogy je věak morfin v tomto směru therapeuticky nepoužitelný. Systematickým výzkumem byly vyvinuty strukturně vzdálené morfinové analogy, které mají antidiarhoický účinek aniž by měly nežádoucí morfinové efekty; mezi tyto látky patří zejména preparáty difenoxin, difenoxylát a loperamid (Bradshaw M.J., Harvey R.P., Drugs 24. 440, 1982). Všechny tři jmenované preparáty jsou substituované piperidinoal kyldifenylacetonitrily nebo -difenylácetamidy. Nyní bylo zjiště no, že také některé nové substituované piperidinoalkylderiváty 10,11-dihydrodibenzo/b,f/thiepin-10-karbonitrilu vykazují v experimentu na zvířatech (na myších) antidiarhoickou účinnost aAlkaloid morphine exhibits a whole complex of pharmacodynamic effects, including an anti-diarrhea effect resulting from a direct effect on the intestinal wall musculature. Systematic investigations have developed structurally distant morphine analogs which have an anti-diarrhea effect without having undesirable morphine effects; these include, in particular, the diphenoxin, diphenoxylate and loperamide preparations (Bradshaw M.J., Harvey R.P., Drugs 24, 440, 1982). All three of these preparations are substituted piperidinoalkyldiphenylacetonitriles or diphenylacetamides. It has now been found that some of the novel substituted 10,11-dihydrodibenzo [b, f] thiepine-10-carbonitrile piperidinoalkylderivatives also exhibit anti-diarrheal efficacy in animals (mice) and
240 697 mají přitom některé přednosti ve srovnání se známým difenoxylátem (Janssen. P.A.J. et al«, J.Med.Pharm.Chem. 1, 299, 1959).240,697 have some advantages over the known diphenoxylate (Janssen, P. A. J. et al., J. Med. Pharm. Chem., 1, 299, 1959).
Tak např. do rozsahu tohoto vynálezu spadající 10-/2-(4-ethoxy karbony l-4-feiaylpiperidino)ethyl/-10,11-dihydrodibenzo/b,f/ thiepin-10-karbonitril, který byl testován při orálním podání ve formě hydrochloridu, je v dávce 500 mg/kg u myší prakticky netoxický a nevyvolává uhynutí zvířat. Naproti tomu difenoxylát má střední smrtnou dávku LD^0 = 337 mg/kg. Zatím co difenoxylát má v peritoneálním testu u myší asi 3 % analtgetické účinnosti morfinuj jmenovaná látka podle tohoto vynálezu je v tomto testu prak ticky neúčinná. Rovněž diskoordinační působení látky podle vynálezu v testu rotující tyčky u myší (ED^q je vyšší než 50 mg/kg) je nižší než účinek difenoxylátu (Εϋ^θ » 33 mg/kg). V testu experimentálního průjmu, vyvolaného u myší nitrožilním podáním serotoninu v dávce 10 mg/kg (Dšmina et al., Parmacol.Toksikol. 44.For example, the present invention includes 10- [2- (4-ethoxycarbonyl-4-phthalylpiperidino) ethyl] -10,11-dihydrodibenzo [b, f] thiepine-10-carbonitrile, which was tested by oral administration in form hydrochloride, is practically non-toxic at 500 mg / kg in mice and does not induce animal death. In contrast, diphenoxylate has a median lethal dose LD ^ 0 = 337 mg / kg. While the diphenoxylate has about 3% of the analgesic activity in the mouse peritoneal test, the morphine of the present invention is practically ineffective in this test. Also, the discoordination effect of a compound of the invention in a rotating rod test in mice (ED? Q is greater than 50 mg / kg) is less than that of diphenoxylate (ϋϋ? Θ »33 mg / kg). In an experimental test for diarrhea induced in mice by intravenous administration of serotonin at a dose of 10 mg / kg (Dsmina et al., Parmacol.Toksikol. 44.
91» 1981). působí jmenovaná látka podle vynálezu antidiarhoicky statisticky významě v orální dávce 10 mg/kg (difenoxylát působí v orálních dávkách 5-10 mg/kg). Lze tedy uzavřít, že pro jmenovanou látku podle vynálezu lze předpokládat therapeutickou účinnost proti průjmům při nižších vedlejších efektech než jaké jsou spojeny s používáním difenoxylátu.91, 1981). said compound of the invention has an anti-diarrhea effect of statistically significant at an oral dose of 10 mg / kg (diphenoxylate acts at an oral dose of 5-10 mg / kg). Thus, it can be concluded that therapeutic efficacy against diarrhea at lower side effects than that associated with the use of diphenoxylate can be expected for the compound of the invention.
Látky podle vynálezu vzorce I jsou přístupné substitučními reakcemi 10-(2-bromethyl)-10,11-dihydrodibenzo/b,f/thiepin-10karbonitrilu a 10-(3-brompropyl)-10,11-dihydrodibenzo/b,f/thiepin-10-karbonitrilu s piperidinovými deriváty obecného vzorce II,The compounds of the invention of formula I are accessible by substitution reactions of 10- (2-bromoethyl) -10,11-dihydrodibenzo [b, f] thiepine-10-carbonitrile and 10- (3-bromopropyl) -10,11-dihydrodibenzo [b, f] thiepine -10-carbonitrile with piperidine derivatives of the general formula II,
/11// 11 /
12 ve kterém R a R , resp. celý zbytek CR R , značí totéž jako ve vzorci I. Výchozí bromalkylnitrily, jakož i piperidinové deriváty vzorce II jsou látky vesměs známé a na literaturu je odkazováno v jednotlivých příkladech.Substituční reakce se provedou zahříváním komponent s uhličitanem draselným ve vhodném rozpouštědle, s výhodou v acetonu. Produkty se získají budově formě hydrochloridů, které se čistí krystalisací, nebo ve formě basí, které se čistí chromátografií na silikagelu. Látky podle vynálezu jsou nové a k jejich identifikaci bylo použito kromě analys všech běž240 69712 wherein R and R, respectively. the entire CRR radical is the same as in formula I. The starting bromoalkyl nitriles as well as the piperidine derivatives of formula II are generally known and the literature is referred to in the individual examples. The substitution reactions are carried out by heating the components with potassium carbonate in a suitable solvent, preferably acetone. The products are obtained in the form of hydrochlorides which are purified by crystallization or in the form of bases which are purified by chromatography on silica gel. The compounds of the present invention are novel and have been used in addition to the analyzes of all runs240697 to identify them
- 3 ných spektrálních metod. Další podrobnosti o způsobu jejich přípravy jsou patrné z dále uvedených příkladů, které představují pouze ilustraci možností vynálezu, avšak není jejich účelem rozsah vynálezu jakýmkoliv způsobem omezovat.- 3 spectral methods. Further details of the preparation thereof are apparent from the following examples, which are merely illustrative of the possibilities of the invention, but are not intended to limit the scope of the invention in any way.
Příklad 1Example 1
1-/2-(10-Kyan-10,11-dihy dr odib enzo/b,f/1hiep in-10-y1)e thy1/ 4-ethoxykarbony1-4-fenylpiperidin1- / 2- (10-Cyano-10,11-dihydro-dibenzo [b, f] hin-10-yl) -ethyl] -4-ethoxycarbonyl-4-phenylpiperidine
Směs 2,4 g 10-(2-bromethyl)-10,11-dihydrodibenzo/b,f/thiepin-10-karbonitrilu (Šindelář K. et al·, Collect.Czech.Chem. Commun. 48. 1 187, 1983). 5,65 g 4-ethoxykarbonyl-4-fenylpiperidinu (Eisleb 0., Ber.Deut.Chem.Ges. 74. 1 433, 1941). 1,0 g uhličitanu draselného a 50 ml acetonu se míchá a vaří 26 h pod zpětným chladičem. Potom se pevná látka odfiltruje a promyje acetonem, filtrát se odpaří za sníženého tlaku, zbytek se rozpustí ve 100 ml chloroformu, roztok se protřepe s 50 ml zředěné kyseliny chlorovodíkové (1:1)(do vodné fáze přejde pouze hydrochlorid výchozího piperidinového derivátu, zatím co hydrochlorid produktu je v chloroformu rozpustný), potom se chloroformový roztok promyje 50 ml 15% roztoku uhličitanu sodného, vysuší se uhličitanem draselným a odpaří se za sníženého tlaku. Získá seA mixture of 2.4 g of 10- (2-bromoethyl) -10,11-dihydrodibenzo [b, f] thiepin-10-carbonitrile (Shindelar K. et al., Collect.Czech.Chem. Commun. 48, 1 187, 1983) ). 5.65 g of 4-ethoxycarbonyl-4-phenylpiperidine (Eisleb 0, Ber.Deut.Chem.Ges. 74, 1 433, 1941). 1.0 g of potassium carbonate and 50 ml of acetone are stirred and refluxed for 26 h. Then the solid is filtered off and washed with acetone, the filtrate is evaporated under reduced pressure, the residue is dissolved in 100 ml of chloroform, the solution is shaken with 50 ml of dilute hydrochloric acid (1: 1) (only the starting piperidine derivative hydrochloride enters the aqueous phase). the product hydrochloride is soluble in chloroform), then the chloroform solution is washed with 50 ml of 15% sodium carbonate solution, dried over potassium carbonate and evaporated under reduced pressure. It is obtained
3,2 g (93 %) surové olejovité base, která se rozpustí v etheru a zneutralisuje etherickým roztokem chlorovodíku. Vyloučí se 2,62 g hydrochloridu produktu, který se čistí krystalisací ze směsi acetonu a etheru a v čistém stavu taje při 169,5 až3.2 g (93%) of a crude oil base which was dissolved in ether and neutralized with ethereal hydrogen chloride solution. 2.62 g of the hydrochloride of the product are obtained, which product is purified by crystallization from a mixture of acetone and ether and melts in the pure state at 169.5 DEG C.
171,5 °C.171.5 ° C.
Příklad 2Example 2
1-/3-(10-Kyan-10,11-dihydrodibenzo/b,f/thiepin-10-yl)propyl/-4-(2-oxobenzimidazolin-1-yl)piperidin.1- [3- (10-Cyano-10,11-dihydrodibenzo [b, f] thiepin-10-yl) propyl] -4- (2-oxobenzimidazolin-1-yl) piperidine.
K roztoku 2,1 g 4-(2-oxobenzimidazolin-1-yl)piperidinu (Rossi A. et al., Helv.Chim.Acta 43. 1 298, 1960) v 30 ml chloroformu se přidá roztok 3,5 g 10-(3-brompropyl)-10,11-dihydrov dibenzo/b,f/thiep.in-10-karbonitrilu (Šindelář K. et al,, Collect Czech.Chem.Commun. 4θ, 1 Ί87, 1983) ve 100 ml acetonu, přidá se 1,4 g uhličitanu draselného a směs se vaří 14 h pod zpětným chla dičem. Pevná látka se odfiltruje, promyje se acetonem a filtrát se odpaří za sníženého tlaku. Zbytek se rozpustí v 50 ml benzenu a roztok se protřepe se zředěnou kyselinou solnou. Vyloučený oleTo a solution of 2.1 g of 4- (2-oxobenzimidazolin-1-yl) piperidine (Rossi A. et al., Helv.Chim.Acta 43, 1 298, 1960) in 30 ml of chloroform was added a solution of 3.5 g of 10. - (3-bromopropyl) -10,11-dihydric dibenzo [b, f] thiepine-10-carbonitrile (Shindelar K. et al, Collect Czech.Chem.Commun. 4θ, 1 Ί87, 1983) in 100 ml of acetone, 1.4 g of potassium carbonate are added and the mixture is refluxed for 14 h. The solid was filtered off, washed with acetone and the filtrate was evaporated under reduced pressure. The residue is dissolved in 50 ml of benzene and the solution is shaken with dilute hydrochloric acid. Excluded ole
240 097 jovitý hydrochlorid se oddělí dekantací, rozloží se vodným amoniakem a base se isoluje extrakcí chloroformem. Odpařením se získá 5,1 g nehomogenní base ve formě pěny. Rozpustí se v chloroformu a chromátografuje se na sloupci 200 g silikagelu. Po eluci menšího množství méně polární zneěištěniny chloroformem se tímtéž rozpouštědlem eluuje 4,54 g (94 %) olejovité base, která krystaluje z cyklohexanu a vyčistí se rekrystalisací ze směsi acetonu, ethanolu a etheru. Z této směsi krystaluje jako solvát 2:1 s ethanolem a v čistém stavu taje při 118 až 123 °C.240 097 of the hydrochloride are separated by decantation, decomposed with aqueous ammonia and the base isolated by extraction with chloroform. Evaporation gave 5.1 g of inhomogeneous base as a foam. It was dissolved in chloroform and chromatographed on a column of 200 g of silica gel. After eluting a minor amount of the less polar contaminant with chloroform, 4.54 g (94%) of an oily base crystallized from cyclohexane and was purified by recrystallization from a mixture of acetone, ethanol and ether. It crystallizes from this mixture as a 2: 1 solvate with ethanol and melts in the pure state at 118-123 ° C.
Příklad 3 ^8-/3-(10-Kyan-10,11-dihydrodibenzo/b,f/thiepin-10-yl)propyl/r^fenyl-1,3,8-triazaspiro(4,5)dekan-4-onEXAMPLE 3 4- [3- (10-Cyano-10,11-dihydrodibenzo [b, f] thiepin-10-yl) propyl] -4-phenyl-1,3,8-triazaspiro (4,5) decane-4 -he
Směs 2,4 g 1-fenyl-1,3,S-triazaspiro(4,5)děkan-4-onu (Belg.pat. 633 914), 3,5 g 10-(3-brompropyl)-10,11-dihydrodibenzo/b,f/thiepin-10-karbonitrilu (Šindelář K. et al·, citováno),A mixture of 2.4 g of 1-phenyl-1,3, S-triazaspiro (4,5) decan-4-one (Belg. Pat. 633 914), 3.5 g of 10- (3-bromopropyl) -10,11 -dihydrodibenzo [b, f] thiepine-10-carbonitrile (Shindelar K. et al., cited),
1,4 g uhličitanu draselného a 150 ml acetonu se vaří 14 h pod zpětným chladičem, po ochlazení se pevná látka odfiltruje a fil*· trát se ve vakuu odpaří. Nehomogenní zbytek (5,78 g pěny) se rozpustí v chloroformu a chromátografuje Se na sloupci 180 g silikagelu. Po vymytí menšího množství méně polárních složek se směsí chloroformu a ethanolu eluuje homogenní olejovitá base, která krystaluje z ethanolu jako ethanolový solvát 1:1. Získá se ve výtěžku 4,7 g (87 %) a v čistém stavu taje při 100 až 107 °C (ethanol).1.4 g of potassium carbonate and 150 ml of acetone were refluxed for 14 h, after cooling the solid was filtered off and the filtrate was evaporated in vacuo. The inhomogeneous residue (5.78 g of foam) was dissolved in chloroform and chromatographed on a column of 180 g of silica gel. After washing out a smaller amount of the less polar components with a mixture of chloroform and ethanol, a homogeneous oily base elutes which crystallizes from ethanol as a 1: 1 ethanol solvate. It is obtained in a yield of 4.7 g (87%) and melts in the pure state at 100-107 ° C (ethanol).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS847795A CS240697B1 (en) | 1984-10-12 | 1984-10-12 | Substituted 10-(piperidinoalkyl)-10,11-dihydrodibenzo(a,f)thiepin-10-carbonitriles |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS847795A CS240697B1 (en) | 1984-10-12 | 1984-10-12 | Substituted 10-(piperidinoalkyl)-10,11-dihydrodibenzo(a,f)thiepin-10-carbonitriles |
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| Publication Number | Publication Date |
|---|---|
| CS779584A1 CS779584A1 (en) | 1985-06-13 |
| CS240697B1 true CS240697B1 (en) | 1986-02-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS847795A CS240697B1 (en) | 1984-10-12 | 1984-10-12 | Substituted 10-(piperidinoalkyl)-10,11-dihydrodibenzo(a,f)thiepin-10-carbonitriles |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS240697B1 (en) |
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1984
- 1984-10-12 CS CS847795A patent/CS240697B1/en unknown
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| Publication number | Publication date |
|---|---|
| CS779584A1 (en) | 1985-06-13 |
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