CS263975B1 - Derivat 5h-dibenzo/b,f/azepine and salts thereof - Google Patents
Derivat 5h-dibenzo/b,f/azepine and salts thereof Download PDFInfo
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- CS263975B1 CS263975B1 CS88563A CS56388A CS263975B1 CS 263975 B1 CS263975 B1 CS 263975B1 CS 88563 A CS88563 A CS 88563A CS 56388 A CS56388 A CS 56388A CS 263975 B1 CS263975 B1 CS 263975B1
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- salts
- azepine
- dibenz
- formula
- methylpiperazine
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- 150000003839 salts Chemical class 0.000 title claims abstract description 9
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 title 1
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- LCGTWRLJTMHIQZ-UHFFFAOYSA-N 5H-dibenzo[b,f]azepine Chemical class C1=CC2=CC=CC=C2NC2=CC=CC=C21 LCGTWRLJTMHIQZ-UHFFFAOYSA-N 0.000 claims description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 abstract description 6
- 230000001078 anti-cholinergic effect Effects 0.000 abstract description 4
- 230000000767 anti-ulcer Effects 0.000 abstract description 4
- 238000006386 neutralization reaction Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- KRNSRCBAMKWWLM-UHFFFAOYSA-N 1-benzo[b][1]benzazepin-11-yl-2-chloroethanone Chemical compound C1=CC2=CC=CC=C2N(C(=O)CCl)C2=CC=CC=C21 KRNSRCBAMKWWLM-UHFFFAOYSA-N 0.000 abstract description 3
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 abstract description 2
- -1 4-methyl-1-piperazinyl Chemical group 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract 2
- 208000025865 Ulcer Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 4
- 229960004633 pirenzepine Drugs 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- HGMITUYOCPPQLE-UHFFFAOYSA-N 3-quinuclidinyl benzilate Chemical compound C1N(CC2)CCC2C1OC(=O)C(O)(C=1C=CC=CC=1)C1=CC=CC=C1 HGMITUYOCPPQLE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 231100000460 acute oral toxicity Toxicity 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002496 gastric effect Effects 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
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Řešení spadá do oboru syntetických léčiv. Jeho předmětem je derivát 5H-idibenz- (b,f Jazepinu, konkrétně 5-[2-(4-methyl-l-pi- perazinyl Jacetyl] -5H-dibenz(b,f) azepin, a dále jeho soli s farmaceuticky nezávadnými anorganickými nebo organickými kyselinami. Látka a její soli jsou málo toxické a vyznačují se vysokým stupněm protivředo- vé a anticholinergické účinnosti. Přicházejí tedy v úvahu jako léčiva proti vředové chorobě. Jmenovaná látka je přístupná substituční reakcí 5-(chloracetyl)-5H-dibenz(b,f )- azepinu s 1-methylpiperazinem. Získaná báze je krystalická a neutralizačními reakcemi poskytuje soli, z nichž jsou uvedeny bis- (hydrogenmaleinát) a idihydrochloridThe solution lies in the field of synthetic drugs. The subject of the invention is a 5H-idibenz- (b, f Jazepine derivative, namely 5- [2- (4-methyl-1-piperazinyl Jacetyl) -5H-dibenz (b, f) azepine], and salts thereof with pharmaceutically acceptable salts. The substance and its salts are of low toxicity and are characterized by a high degree of anti-ulcer and anticholinergic activity and are therefore suitable as medicaments for ulcerative disease, which is amenable to the substitution reaction of 5- (chloroacetyl) -5H-dibenz ( b, f) -azepine with 1-methylpiperazine The base obtained is crystalline and the neutralization reactions provide the salts from which bis- (hydrogen maleate) and idihydrochloride are mentioned
Description
Vynález se týká derivátu 5H-dibenzo(b,f )azepinu vzorce IThe invention relates to a 5H-dibenzo (b, f) azepine derivative of the formula I
CÓCHZ r~\CÓCH Z r ~ \
NNCH^ (I) a jeho solí s farmaceuticky nezávadnými anorganickými nebo organickými kyselinami. Látku vzorce I podle vynálezu lze označit jako 5-[2-(4-methyl-l-píperazinyl)acetyl ] -5H-diibenz (b,f Jazepin.NNCH3 (I) and its salts with pharmaceutically acceptable inorganic or organic acids. The compound of formula I according to the invention may be designated as 5- [2- (4-methyl-1-piperazinyl) acetyl] -5H-diibenz (b, f Jazepin).
Látka vzorce I a její soli, s výhodou dihydrochlorid, se vyznačují protivředovou a anticholinergickou účinností, takže přicházejí v úvahu jako léčiva proti vředové chorobě. Akutní toxicita dihydrochloridu při orálním podání, stanovená na myších, je velmi nízká; LDso = 928 mg/kg. Protivředová účinnost v testu indomethacinem vyvolávaných žaludečních lézl u krys je značná; střední inhibiční dávka EDso při orálním podání je 42,3 mg/kg. Látka je svou účinností velmi blízká protivředovému preparátu ,,pirenzeplnu“ (Kitagawa H. et al., Arzneim.— Forsch. 28, 2 122, 1978), jehož EDň0 je 32,7 mg/kg. Anticholinergická aktivita, která je typická pro právě jmenovaný „pirenzepin“, byla pro látku podle vynálezu prověřována dvěma metodami. V první řadě to byl test mydriasy u myší. Mydriatický účinek byl stanovován po podání orálních dávek 10 a 100 mg/kg a byl hodnocen počtem positivně reagujících zvířat v procentech z celkového počtu zvířat v pokusu. V tomto testu je látka vzorce I podle vynálezu rovnocenná pirenzepinu, protože obě látky jsou v obou dávkách 100i% účinné. Jako druhé kritérium anticholinergní aktivity byla zvolena afinita látky k muskarinovým receptům v krysím mozku. Jako ligand byl použit (3H)chinuklidlnylbenzilát v koncentraci 0,5 nM a afinita látky vzorce I byla vyjádřena jako střední inhibiční koncentrace (ICso v nM), která inhibuje z 50% vazbu ligandu na receptory: ICso = 439,8 nM (afinita pirenzepinu je jen o málo vyšší (ICso = 275,3 nM).The compound of the formula I and its salts, preferably the dihydrochloride, have anti-ulcer and anticholinergic activity and are therefore suitable as anti-ulcer drugs. The acute oral toxicity of dihydrochloride, as determined in mice, is very low; LD 50 = 928 mg / kg. The anti-ulcer efficacy in the indomethacin-induced gastric lesion test in rats is considerable; the mean inhibitory dose of ED50 for oral administration is 42.3 mg / kg. The substance is very similar in activity to the anti-ulcer preparation "pirenzepin" (Kitagawa H. et al., Arzneim. Forsch. 28, 2 122, 1978), whose ED 50 is 32.7 mg / kg. The anticholinergic activity, which is typical of the just named "pirenzepine", has been tested by two methods for the substance of the invention. First of all it was a test of mydriasis in mice. The mydriatic effect was determined after oral doses of 10 and 100 mg / kg and was evaluated by the number of positively responding animals as a percentage of the total number of animals in the experiment. In this test, the compound of formula I of the invention is equivalent to pirenzepine because both compounds are 100% active at both doses. As a second criterion of anticholinergic activity, the affinity of the substance to muscarinic recipes in rat brain was chosen. ( 3 H) quinuclidinyl benzilate at a concentration of 0.5 nM was used as the ligand and the affinity of the compound of formula I was expressed as the mean inhibitory concentration (IC 50 in nM) which inhibits 50% of the ligand binding to the receptors: IC 50 = 439.8 nM pirenzepine is only slightly higher (IC 50 = 275.3 nM).
Látka vzorce I podle vynálezu je přístupná substituční reakcí známého 5-(chloracetyl)-5H-dibenz(b,f)azepinu (Arya V. P. et al., Indián J. Chem. 15 B, 148, 1977) s 1-methylpiperazinem. Tuto reakci lze provést za různých podmínek: při teplotách 40 ,až 100 stupňů Celsia, v různých netečných rozpouštědlech nebo bez prostředí, za použití přebytku 1-methylpiperazinu nebo za přítomnosti alkalických kondenzačních činidel, s výhodou alkalických uhličitanů a potom za použití ekvivalentu 1-methylpiperazinu atd. Jednoduché provedení této reakce, které je popsáno v příkladu, používá 1-methylpiperazinu jako reakčního prostředí, tj. za použití jeho přebytku, kdy reakce probíhá dostatečně rychle již při teplotách 50 až 75 °C.The compound of the formula I according to the invention is accessible by a substitution reaction of the known 5- (chloroacetyl) -5H-dibenz (b, f) azepine (Arya, V.P. et al., Indian J. Chem. 15 B, 148, 1977) with 1-methylpiperazine. This reaction can be carried out under various conditions: at temperatures of 40 to 100 degrees Celsius, in various inert solvents or without environment, using excess 1-methylpiperazine or in the presence of alkaline condensing agents, preferably alkali carbonates, and then using 1-methylpiperazine equivalent etc. A simple embodiment of this reaction, as described in the example, uses 1-methylpiperazine as the reaction medium, i.e. using an excess thereof, the reaction proceeding at a sufficiently rapid rate already at temperatures of 50-75 ° C.
Látka vzorce I je nová; její identita byla zajištěna analyticky i pomocí spekter. Báze vzorce I je krystalická a k jejímu čištění je vhodná krystalizace ze směsi ethanolu a etheru. Neutralizací farmaceuticky nezávadnými anorganickými nebo organickými kyselinami poskytuje krystalické soli, které jsou zahrnuty do předmětu vynálezu a pro farmakologické testy i pro přípravu lékových forem jsou výhodnější než báze.The compound of formula I is new; its identity was assured analytically and using spectra. The base of formula (I) is crystalline and is purified by crystallization from a mixture of ethanol and ether. Neutralization with pharmaceutically acceptable inorganic or organic acids provides crystalline salts which are included in the subject invention and are more preferred than bases for pharmacological tests and for preparation of dosage forms.
Podrobnosti jedné z možností přípravy látky I jsou uvedeny v příkladu, který představuje pouhou ilustraci těchto možností.The details of one of the preparation options for compound I are given in the example, which is merely an illustration of these options.
PříkladExample
Směs 5,0 g 5-(chloracetyl)-5H-dibenz(b,f)azepinu a 7,4 g 1-methylpiperazinu se míchá 6 h při teplotě 55 °C. Za tepla se zředí 100 ml chloroformu, roztok se po· ochlazení promyje několikrát vodou, vysuší se síranem hořečnatým a odpaří se za sníženého tlaku. Zbytek stáním krystalizuje a představuje 4,9 g (79%) surového· produktu vzorce I, který taje při 121 až 126,5 °C. Vzorek pro analýzu se překrystalizuje ze směsi ethanolu a etheru, t. t. 128,5 až 131 °C. Neutralizací kyselinou maleinovou ve směsi ethanolu a etheru se získá krystalický bis(hydrogenmaleinát) tající při 107 až 110 °'C. Neutralizací báze chlorovodíkem ve směsi ethanolu a etheru se získá krystalický dihydrochlorid, t. t. 203,5 až 207 °G (95 % ethanol-ether).A mixture of 5- (chloroacetyl) -5H-dibenz (b, f) azepine (5.0 g) and 1-methylpiperazine (7.4 g) was stirred at 55 ° C for 6 h. Dilute hot with 100 ml of chloroform, wash the solution several times with water after cooling, dry over magnesium sulphate and evaporate under reduced pressure. The residue crystallizes on standing and represents 4.9 g (79%) of the crude product of formula I, melting at 121-126.5 ° C. The sample for analysis was recrystallized from ethanol-ether, mp 128.5-131 ° C. Neutralization with maleic acid in ethanol / ether yields crystalline bis (hydrogen maleate) melting at 107-110 ° C. Neutralization of the base with hydrogen chloride in a mixture of ethanol and ether gave a crystalline dihydrochloride, m.p. 203.5-207 ° C (95% ethanol-ether).
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Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS88563A CS263975B1 (en) | 1988-01-29 | 1988-01-29 | Derivat 5h-dibenzo/b,f/azepine and salts thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS88563A CS263975B1 (en) | 1988-01-29 | 1988-01-29 | Derivat 5h-dibenzo/b,f/azepine and salts thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS56388A1 CS56388A1 (en) | 1988-09-16 |
| CS263975B1 true CS263975B1 (en) | 1989-05-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS88563A CS263975B1 (en) | 1988-01-29 | 1988-01-29 | Derivat 5h-dibenzo/b,f/azepine and salts thereof |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS263975B1 (en) |
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1988
- 1988-01-29 CS CS88563A patent/CS263975B1/en unknown
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| Publication number | Publication date |
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| CS56388A1 (en) | 1988-09-16 |
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