CS264934B1 - Derivatives of 1-/10,11-dihydrodibenzo/b,f/thiepin-10-yl/piperazine,their hydrochloride and process for preparing them - Google Patents
Derivatives of 1-/10,11-dihydrodibenzo/b,f/thiepin-10-yl/piperazine,their hydrochloride and process for preparing them Download PDFInfo
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- CS264934B1 CS264934B1 CS881524A CS152488A CS264934B1 CS 264934 B1 CS264934 B1 CS 264934B1 CS 881524 A CS881524 A CS 881524A CS 152488 A CS152488 A CS 152488A CS 264934 B1 CS264934 B1 CS 264934B1
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- dihydrodibenzo
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title description 10
- 238000004519 manufacturing process Methods 0.000 title 1
- 150000003840 hydrochlorides Chemical class 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 150000004885 piperazines Chemical class 0.000 claims abstract description 6
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 abstract description 9
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 abstract description 7
- 230000001387 anti-histamine Effects 0.000 abstract description 7
- 239000000739 antihistaminic agent Substances 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 6
- 230000002804 anti-anaphylactic effect Effects 0.000 abstract description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 abstract description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 abstract description 5
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 abstract description 5
- GUMPYDGUYXOYML-UHFFFAOYSA-N 3-(3-chloropropyl)-1h-benzimidazol-2-one Chemical compound C1=CC=C2NC(=O)N(CCCCl)C2=C1 GUMPYDGUYXOYML-UHFFFAOYSA-N 0.000 abstract description 4
- 208000026935 allergic disease Diseases 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 229960001340 histamine Drugs 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241000700199 Cavia porcellus Species 0.000 description 6
- -1 3- (4- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl Chemical group 0.000 description 5
- 206010002198 Anaphylactic reaction Diseases 0.000 description 5
- 208000003455 anaphylaxis Diseases 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 230000036783 anaphylactic response Effects 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 3
- CRIUKHLDPKZTLO-BTJKTKAUSA-N (z)-but-2-enedioic acid;1-(3-chloro-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)piperazine Chemical compound OC(=O)\C=C/C(O)=O.C12=CC(Cl)=CC=C2SC2=CC=CC=C2CC1N1CCNCC1 CRIUKHLDPKZTLO-BTJKTKAUSA-N 0.000 description 2
- ZYUDAIAKGACNCP-UHFFFAOYSA-N 1-(3-chloro-5,6-dihydrobenzo[b][1]benzothiepin-6-yl)piperazine Chemical compound C1C2=CC(Cl)=CC=C2SC2=CC=CC=C2C1N1CCNCC1 ZYUDAIAKGACNCP-UHFFFAOYSA-N 0.000 description 2
- 208000009079 Bronchial Spasm Diseases 0.000 description 2
- 208000014181 Bronchial disease Diseases 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001784 detoxification Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 231100000925 very toxic Toxicity 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MZDUAERLLATSFT-UHFFFAOYSA-N 3-[3-[4-(3-chloro-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)piperazin-1-yl]propyl]-1h-benzimidazol-2-one Chemical compound C12=CC(Cl)=CC=C2SC2=CC=CC=C2CC1N1CCN(CCCN2C(NC3=CC=CC=C32)=O)CC1 MZDUAERLLATSFT-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- BAINIUMDFURPJM-UHFFFAOYSA-N oxatomide Chemical compound O=C1NC2=CC=CC=C2N1CCCN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 BAINIUMDFURPJM-UHFFFAOYSA-N 0.000 description 1
- 229960002698 oxatomide Drugs 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000028527 righting reflex Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- VGKODZCNDHJSOX-UHFFFAOYSA-N trihydrate;tetrahydrochloride Chemical compound O.O.O.Cl.Cl.Cl.Cl VGKODZCNDHJSOX-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Řešení spadá do oboru syntetických léčiv. Jeho předmětem jsou 1-(3-(4-(10,11- -dihydrodibenzo/b,f/thiepin-10-yl)-1- -piperazinyl)propyl)-1,3-dihydro-2H-benzimidazol-2-on, jeho 2- a 8-chlor- a methylthio-deriváty, jejich hydrochloridy a způsob jejich přípravy. Látky podle řešení vykazují v testech na zvířatech antihistaminové a antianafylaktické působení a přicházejí v úvahu k praktickému použití v terapii alergických onemocnění. Jejich způsob přípravy spočívá v substituční reakci 1-(10,11-dihydrodibenzo/b,f/thiepin-10- -yl)piperazinů s l-(3-chlorpropyl)-l,3-dihydro-2H-benzimidazo1-2-oněm. Hydrochloridy se získají neutralizační reakcí připravených bází chlorovodíkem nebo kyselinou chlorovodíkovou.The solution is in the synthetic field drugs. Its subject matter is 1- (3- (4- (10,11- -dihydrodibenzo / b, f / thiepin-10-yl) -1- -piperazinyl) propyl) -1,3-dihydro-2H-benzimidazol-2-one, its 2- and 8-chloro- and methylthio derivatives, their hydrochlorides and process their preparation. Substances according to solution antihistamine in animal tests and antianaphylactic action and come for practical use in the treatment of allergic diseases. Their the method of preparation consists in a substitution reaction 1- (10,11-dihydrodibenzo / b, f / thiepine-10- -yl) piperazines with 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazole-2-one. Hydrochlorides are obtained by the neutralization reaction prepared base with hydrogen chloride or acid hydrochloric acid.
Description
Vynález se týká derivátů 1-(10,11-dihydrodibenzo/b,f/thiepin-10-yl)piperazinu obecného vzorce IThe present invention relates to 1- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine derivatives of the general formula I
2 ve kterém R , R značí kombinace H,H, H,C1, Cl,H a H/SCH^, jejich hydrochloridů a způsobu jejich přípravy.2 wherein R, R is a combination of H, H, H, Cl, Cl, H and H / SCH 2, their hydrochlorides and a process for their preparation.
Látky obecného vzorce 1 a jejich hydrochloridy vykazují v testech na zvířatech antihistaminové a antianafylaktické působení. Přicházejí tedy v úvahu k praktickému použití v terapii alergických onemocnění včetně astmatu.The compounds of the formula I and their hydrochlorides show antihistamine and antianaphylactic activity in animal tests. They are therefore suitable for practical use in the treatment of allergic diseases including asthma.
Pro hydrochloridy jednotlivých látek obecného vzorce I lze uvést tato farmakologická a toxikologická data získaná v testech na zvířatech při orálním podání:For hydrochlorides of the individual compounds of the formula I, the following pharmacological and toxicological data obtained in animal tests when administered orally:
1-(3-(4-(10,11-dihydrodibenzo/b,f/thiepin-10-yl)-1-piperazinyl)propyl)-1,3-dihydro-2H1 21- (3- (4- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H1 2
-benzimidazol-2-on (I, R =R =H). V testu akutní toxicity na myších je střední smrtná dávka LD^q rovna 180 mg/kg. V dávce 3,0 mg/kg vykazuje látka výrazný protektivní účinek v testu histaminového aerosolu u morčat; “ 4,6 mg/kg. Látka signifikantně prodlužuje trvání prekonvulsního intervalu. Dále vykazuje mírný antihistaminový účinek v testu detoxikace histaminu u morčat; dávka 10 mg/kg chrání 25 % zvířat. V téže dávce má velice výrazný ochranný účinek v testu pasivní kožní anafylaxe u krys (chrání 80 % zvířat) (Martin U., Romer D., Arzneim.-Forsch, 29, 770, 1978); ED^^ je 1/9 mg/kg. V tomto testu je látka přibližně třikrát účinnější než antialergický preparát oxatomid (Richards D. M. et al., Drugs 27, 210,-benzimidazol-2-one (I, R = R = H). In the acute toxicity test in mice, the mean lethal dose LD 150 is equal to 180 mg / kg. At a dose of 3.0 mg / kg, the compound exhibits a significant protective effect in the guinea pig histamine aerosol test; '4.6 mg / kg. The substance significantly prolongs the duration of the preconvulsive interval. It also shows a mild antihistamine effect in the guinea pig histamine detoxification test; a dose of 10 mg / kg protects 25% of the animals. At the same dose, it has a very pronounced protective effect in the passive skin anaphylaxis test in rats (protects 80% of animals) (Martin U., Romer D., Arzneim.-Forsch, 29, 770, 1978); The ED50 was 1/9 mg / kg. In this test, the substance is approximately three times more potent than the antiallergic preparation oxatomide (Richards D. M. et al., Drugs 27, 210,
1984), který se osvědčil zvláště v léčbě chronické kopřivky a alergické rhinitidy.1984), which has proven itself particularly in the treatment of chronic urticaria and allergic rhinitis.
1- (3-(4 - (2-chlor-10,11-dihydrodibenzo/b,f/thiepin-10-yl)-l-piperazinyl)propyl)-1,3-di1 21- (3- (4- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl) -1,3-di12
-hydro-2H-benzimidazol-2-on (I, R =C1, R ~ H). Akutní toxicita na myších, LD5Q = 800 mg/kg.-hydro-2H-benzimidazol-2-one (I, R = Cl, R-H). Acute toxicity in mice, LD 5Q = 800 mg / kg.
V dávce 3,0 mg/kg má látka výrazný antihistaminový účinek v testu histaminového aerosolu u morčat; =3,3 mg/kg. Látka signifikantně prodlužuje trvání prekonvulsního intervalu.At a dose of 3.0 mg / kg, the compound has a pronounced antihistamine effect in the guinea pig histamine aerosol test; = 3.3 mg / kg. The substance significantly prolongs the duration of the preconvulsive interval.
Dále vykazuje mírný antihistaminový účinek v testu detoxikace histaminu u morčat; dávka 10 mg/kg chrání 25 % zvířat před letálním účinkem histaminu. V téže dávce vykazuje statisticky významnou antianafylaktickou účinnost v testu pasivní kožní anafylaxe u krys (blokáda anafylaktické reakce z 42 %).It also shows a mild antihistamine effect in the guinea pig histamine detoxification test; a dose of 10 mg / kg protects 25% of the animals from the lethal effect of histamine. At the same dose, it shows statistically significant anti-anaphylactic efficacy in a passive cutaneous anaphylaxis test in rats (anaphylactic reaction blockade 42%).
1-(3-(4-(8-chlor-10,11-dihydrodibenzo/b,f/thiepin-10-yl)-1-piperazinyl)propyl)-1,3-di1 9 hydro-2H-benzimidazol-2-on- (I, R = H, R“ = Cl). V testu akutní toxicity u myší je látka velmi málo jedovatá; v dávce 500 mg/kg nevyvolává hynutí a toxickým příznakem je pouze centrální útlum. V testu histaminového aerosolu u morčat je její antihistaminové působení velmi mírné; v dávce 3,0 mg/kg chrání pouze 1/8 zvířat před histaminovým bronchospasmem.1- (3- (4- (8-chloro-10,11-dihydro-dibenzo / b, f / thiepin-10-yl) -1-piperazinyl) propyl) -1,3-9 DI1 dihydro-2H-benzimidazol-2 -on- (I, R = H, R '= Cl). In the acute toxicity test in mice, the substance is very toxic; at a dose of 500 mg / kg, it does not induce dying and only central depression is a toxic sign. In the guinea pig histamine aerosol test, its antihistamine action is very mild; at a dose of 3.0 mg / kg, only 1/8 of the animals protect against histamine bronchospasm.
V dávce 10 mg/kg má statisticky významný antianafylaktický účinek v testu pasivní kožní anafylaxe u krys (blokáda reakce z 15 až 42 %).At a dose of 10 mg / kg, it has a statistically significant anti-anaphylactic effect in the passive cutaneous anaphylaxis test in rats (15-42% blockade of response).
1-(3-(4-)8-(methylthio)-10,11-dihydrodibenzo/b,f/thiepin-10-yl)-1-piperazinyl)propyl)1 21- (3- (4-) 8- (methylthio) -10,11-dihydrodibenzo [b, f (thiepin-10-yl) -1-piperazinyl) propyl) 1 2
-1,3-dihydro-2H-benzimidazol-2-on {I, R = H, R = SCH^). Z hlediska akutní toxicity u myší je velmi málo jedovatá ; dávka 500 mg/kg je letální pro 10 % a dávka 1 000 mg/kg pro 20 % zvířat. Toxickými příznaky nejvyšší uvedené dávky jsou intensivní centrální útlum a ztráta vzpřimovaciho reflexu. V dávce 3,0 mg/kg látka vykazuje antihistaminové působení v testu histaminového aerosolu u morčat; v této dávce chrání prakticky 50 % zvířat před histaminovým bronchospasmem. V dávce 10 mg/kg má statisticky významný antianafylaktický účinek v testu pasivní kožní anafylaxe u krys (blokáda reakce z 15 až 42 S ve srovnání s kontrolou).-1,3-dihydro-2H-benzimidazol-2-one (I, R = H, R = SCH 2). It is very toxic in acute toxicity in mice; the 500 mg / kg dose is lethal for 10% and the 1000 mg / kg dose for 20% of the animals. Toxic symptoms of the highest dose mentioned are intense central depression and loss of righting reflex. At a dose of 3.0 mg / kg, the compound exhibits antihistamine activity in a guinea pig histamine aerosol test; at this dose, virtually 50% of the animals protect against histamine bronchospasm. At a dose of 10 mg / kg, it has a statistically significant anti-anaphylactic effect in the passive cutaneous anaphylaxis test in rats (reaction blocking from 15 to 42 S compared to control).
CS 264 934 BlCS 264 934 Bl
Způsob přípravy látek obecného vzorce I, který je rovněž součástí tohoto vynálezu, spočívá v substituční reakci piperazinových derivátů obecného vzorce IIThe process for the preparation of the compounds of the formula I, which is also part of this invention, consists in the substitution reaction of piperazine derivatives of the formula II
2 ve kterem R a R značí totéž jako ve vzorci I, s 1-(3-chlorpropyl)-1,3-dihydro-2H-benzimidazol-2-onem (US. pat. 4 200 641; Belg. pat. 852 405; NSR zveřejňovací spis 2 714 437). Piperazi nové deriváty vzorce II, tj. 1-(10,11-dihydrodibenzo/b,f/thiepin-10-yl)piperazin (Jílek J. O. et al., Collect. Czech. Chem. Commun. 32, 3 186, 1967), l-(2-chlor-10,ll-dihydrodibenzo/b,f/thiepin-10-yl)piperazin (Valenta V. et. al., Collect. Czech. Chem. Commun. 44, 3 008, 1979), 1-(8-chlor-l0,11-dihydrodibenzo/b,f/thiepin-10-yl)piperazin (Jílek J. O. et al., Collect. Czech. Chem. Commun. 36, 2 226, 1971) a 1-(8-(methylthio)-10,11-dihydrodibenzo/b, f,/thiepin-10-yl)piperazin (předešlá citace) jsou látky vesměs známé. Uvedenou substituční reakci lze provést za různých podmínek, avšak výhodné je provést ji ve vroucím toluenu za přítomnosti triethylaminu a malého množství jodidu draselného. Surové produkty obecného vzorce I lze bud přímo čistit krystalizací a získat homogenní báze obecného vzorce I, nebo je nutné surové produkty čistit chromatografií, k čemuž se dobře hodí neutrální kysličník hlinitý (aktivita II). Působením chlorovodíku nebo kyseliny chlorovodíkové se provede neutralizace bází na hydrochloridy, které jsou rovněž součástí vynálezu. Tyto většinou krystalizují jako solváty s vodou.2 wherein R and R are the same as in Formula I, with 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 4,200,641; Belg. Pat. 852,405) NSR Publication No. 2,714,437). Piperazine derivatives of formula II, i.e. 1- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine (Jílek JO et al., Collect. Czech. Chem. Commun. 32, 3 186, 1967) 1- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine (Valenta V. et al., Collect. Czech. Chem. Commun. 44, 3 008, 1979), 1- (8-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine (Jílek JO et al., Collect. Czech. Chem. Commun. 36, 2226, 1971) and 1- ( 8- (methylthio) -10,11-dihydrodibenzo [b, f, thiepin-10-yl] piperazine (previous reference) are generally known. The substitution reaction can be carried out under various conditions, but it is preferred to carry out the reaction in boiling toluene in the presence of triethylamine and a small amount of potassium iodide. The crude products of formula I can either be directly purified by crystallization to obtain a homogeneous base of formula I, or the crude products need to be purified by chromatography, which is well suited for neutral alumina (activity II). By treatment with hydrochloric or hydrochloric acid, bases are neutralized to the hydrochlorides, which are also part of the invention. These usually crystallize as solvates with water.
Dále uvedené příklady mají za účel ilustrovat možnosti přípravy látek obecného vzorce I podle tohoto vynálezu, avšak není jejich účelem všechny možnosti vyčerpávajícím způsobem popisovat. Všechny látky, v příkladech popsané, jsou nové a jejich identita byla zajištěna obvyklými analytickými a spektrálními metodami.The following examples are intended to illustrate the preparation possibilities of the compounds of formula (I) of the present invention, but are not intended to be exhaustive. All substances described in the examples are new and their identity has been assured by conventional analytical and spectral methods.
Příklad 1Example 1
1- (3 - (4 - (10,11-dihydrodibenzo/b,f/thiepin-10-yl)-1-piperazinyl)propyl)-1,.3-dihydro-2H1 21- (3- (4- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H1 2
-benzimidazol-2-on (I, R = R = H)-benzimidazol-2-one (I, R = R = H)
K 50 ml toluenu se postupně přidá 4,5 g 1-(10,11-dihydrodibenzo/b,f/thiepin-10-yl)piperazinu, 4,8 g 1-(3-chlorpropyl)-1, 3-dihydro-2H-benzimidazol-2-onu, 2,3 g triethylaminu a 0,15 g jodidu draselného a směs se za míchání vaří 20 h pod zpětným chladičem (lázeň 125 až 135 °C). Po zředění 30 ml toluenu se ještě za tepla promyje 60 ml vody, což se ještě jednou opakuje. Toluenový roztok se vysuší bezvodým uhličitanem draselným a odpaří se za sníženého tlaku. Nehomogenní zbytek (8,6 g) se chromatografuje na sloupci 230 g kysličníku hlinitého. Elucí benzenem se odstraní malé množství málo polárních znečištěnin a potom se benzenem se 3 % ethanolu eluuje 4,6 g (65 %) žádané báze, která krystalizuje ze směsi ethanolu a di (2-propyl)etheru a taje při 146 až 147 °C. Neutralizací chlorovodíkem ve směsi ethanolu a etheru a krystalizací surového produktu z 95 % ethanolu se získá monohydrát dihydrochloridu, t.t. 181 až 382 °C.4.5 g of 1- (10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine, 4.8 g of 1- (3-chloropropyl) -1,3-dihydro- 2H-benzimidazol-2-one, 2.3 g of triethylamine and 0.15 g of potassium iodide, and the mixture is heated under reflux (bath 125-135 ° C) for 20 h. After dilution with 30 ml of toluene, it is washed while still warm with 60 ml of water, which is repeated once more. The toluene solution was dried over anhydrous potassium carbonate and evaporated under reduced pressure. The inhomogeneous residue (8.6 g) is chromatographed on a column of 230 g of alumina. Elution with benzene removes a small amount of low polar contaminants and then elutes with benzene from 3% ethanol 4.6 g (65%) of the desired base, which crystallizes from a mixture of ethanol and di (2-propyl) ether and melts at 146-147 ° C. . Neutralization with hydrogen chloride in ethanol / ether and crystallization of the crude product from 95% ethanol gave the dihydrochloride monohydrate, m.p. Mp 181-382 ° C.
Příklad 2Example 2
1- (3 - (4 - (2-chlor-1 0 ,11-dihydrodibenzo/b, f /thiepin-10-yl) -1-piperazinyl) propyl-1,3-di3 2 hydro-2H-benzimidazol-2-on (I, R = Cl, R = H)1- (3- (4- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl-1,3-di3 2 hydro-2H-benzimidazole-2 -on (I, R = Cl, R = H)
Podobně jako v předešlém příkladu se provede reakce 6,2 g 1-(2-chlor-10,11-dihydrodibenzo/b, f/thiepin-10-yl) piperazinu s 5,95 g 1-(3-chlorpropyl)-1,3-dihydro-2H-benzimidazol-2-onu za přítomnosti 2,84 g triethylaminu a 0,15 g jodidu draselného v 70 ml toluenu. Analogickým zpracováním se získá surový produkt, který se chromatografuje na 220 g kysličCS 264 934 Bl niku hlinitého. Žádaná homogenní báze se získá ve výtěžku 73 %, t.t. 113 až 114 °C (aceton). Neutralizací báze chlorovodíkem ve směsi ethanolu, benzenu a etheru a krystalizací surového produktu z 85% vodného ethanolu se získá seskvihydrát dihydrochloridu, t.t. 167 až 168 °C.As in the previous example, 6.2 g of 1- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine are reacted with 5.95 g of 1- (3-chloropropyl) -1 3-dihydro-2H-benzimidazol-2-one in the presence of 2.84 g of triethylamine and 0.15 g of potassium iodide in 70 ml of toluene. Analogous work-up gives a crude product which is chromatographed on 220 g of aluminum oxide. The desired homogeneous base is obtained in a yield of 73%, m.p. 113 DEG-114 DEG C. (acetone). Neutralization of the base with hydrogen chloride in a mixture of ethanol, benzene and ether and crystallization of the crude product from 85% aqueous ethanol gives the dihydrochloride sesquihydrate, m.p. Mp 167-168 ° C.
Příklad 3Example 3
1-(3-(4 - (8-chlor-10,11-dihydrodibenzo/b,f/thiepin-10-yl)-1-piperazinyl)propyl)-1,3-dihydro-2H-benzimidazol-2-on (I, r3 - H, = Cl)1- (3- (4- (8-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl) -1,3-dihydro-2H-benzimidazol-2-one (I, r3-H, = Cl)
Podobně jako v předešlých příkladech se provede reakce 6,6 g 1-(8-chlor-10,11-dihydrodibenzo/b, f/thiepin-10-yl)piperazinu s 6,3 g 1-(3-chlorpropyl)-1,3-dihydro-2H-benzimidazol-2-onu za přítomnosti 3,1 g triethylaminu a 0,15 g jodidu draselného ve 100 ml vroucího toluenu (18 h). Získaný nehomogenní produkt (11,0 g) se vyčistí krystalizací z 20 ml ethanolu? získá se 7,65 g (76 %) žádané báze tající při 177 až 178 °C. Neutralizací báze chlorovodíkem ve směsi ethanolu, benzenu a etheru a krystalizací surového produktu z 95% ethanolu se připraví monohydrát dihydrochloridu, t.t. 178 až 179 °C.As in the previous examples, 6.6 g of 1- (8-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine are reacted with 6.3 g of 1- (3-chloropropyl) -1 3-dihydro-2H-benzimidazol-2-one in the presence of 3.1 g of triethylamine and 0.15 g of potassium iodide in 100 ml of boiling toluene (18 h). The inhomogeneous product obtained (11.0 g) is purified by crystallization from 20 ml of ethanol? 7.65 g (76%) of the desired base melting at 177-178 ° C is obtained. By neutralizing the base with hydrogen chloride in a mixture of ethanol, benzene and ether and crystallizing the crude product from 95% ethanol, dihydrochloride monohydrate is obtained, m.p. 178-179 ° C.
Příklad 4Example 4
1-(3-(4-(8-(methylthio)-10,11-dihydrodibenzo/b, f/thiepin-10-yl)-1-pipera.myl)propyl-1,31 21- (3- (4- (8- (methylthio) -10,11-dihydrodibenzo [b, f] thiepin-10-yl) -1-piperazinyl) propyl-1,31 2
-dihydro-2h-benzimidazol-2-on (I, R = H, R = SCHg)-dihydro-2h-benzimidazol-2-one (I, R = H, R = SCH)
Jako v předešlých příkladech se provede reakce 6,8 g 1-(8-(methylthio)-10,11-dihydrodibenzo/b,f/thiepin-10-yl)piperazinu s 6,3 g 1-(3-chlorpropyl)-1,3-dihydro-2H-benzimidazol-2-onu za přítomnosti 3,1 g triethylaminu a 0,15 g jodidu draselného ve 100 ml vroucího toluenu (20 h). Získaný surový produkt (10,5 g) se chromatografuje na 300 g kysličníku hlinitého. Elucí benzenem s 3 % ethanolu se získá 6,9 g (67 %) homogenní báze, která krystalizuje ze směsi di(2-propyl)etheru a acetonu a taje při 109 až 111 °C. Neutralizací chlorovodíkem ve směsi acetonu a etheru a krystalizací produktu z 85% ethanolu se získá monohydrát dihydrochloridu, t.t. 198 °C.As in the previous examples, 6.8 g of 1- (8- (methylthio) -10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazine are reacted with 6.3 g of 1- (3-chloropropyl) - 1,3-dihydro-2H-benzimidazol-2-one in the presence of 3.1 g of triethylamine and 0.15 g of potassium iodide in 100 ml of boiling toluene (20 h). The crude product obtained (10.5 g) is chromatographed on 300 g of alumina. Elution with benzene with 3% ethanol gave 6.9 g (67%) of a homogeneous base, which crystallized from a mixture of di (2-propyl) ether and acetone and melted at 109-111 ° C. Neutralization with hydrogen chloride in acetone / ether and crystallization of the product from 85% ethanol gave the dihydrochloride monohydrate, m.p. Mp 198 ° C.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS881524A CS264934B1 (en) | 1988-03-09 | 1988-03-09 | Derivatives of 1-/10,11-dihydrodibenzo/b,f/thiepin-10-yl/piperazine,their hydrochloride and process for preparing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS881524A CS264934B1 (en) | 1988-03-09 | 1988-03-09 | Derivatives of 1-/10,11-dihydrodibenzo/b,f/thiepin-10-yl/piperazine,their hydrochloride and process for preparing them |
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| Publication Number | Publication Date |
|---|---|
| CS152488A1 CS152488A1 (en) | 1988-12-15 |
| CS264934B1 true CS264934B1 (en) | 1989-09-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| CS881524A CS264934B1 (en) | 1988-03-09 | 1988-03-09 | Derivatives of 1-/10,11-dihydrodibenzo/b,f/thiepin-10-yl/piperazine,their hydrochloride and process for preparing them |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004031384A1 (en) * | 2002-10-01 | 2004-04-15 | Riken | Mouse-origin proteins forming domain or use thereof |
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1988
- 1988-03-09 CS CS881524A patent/CS264934B1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004031384A1 (en) * | 2002-10-01 | 2004-04-15 | Riken | Mouse-origin proteins forming domain or use thereof |
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| Publication number | Publication date |
|---|---|
| CS152488A1 (en) | 1988-12-15 |
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