DE2022790C3 - 10-methyl-5- [(4-methylpiperazino) -acetyl J-5,10dihydro-IIH-dibenzo [b, e] [1,4] diazepin-11-one, a process for its preparation and pharmaceuticals containing it - Google Patents
10-methyl-5- [(4-methylpiperazino) -acetyl J-5,10dihydro-IIH-dibenzo [b, e] [1,4] diazepin-11-one, a process for its preparation and pharmaceuticals containing itInfo
- Publication number
- DE2022790C3 DE2022790C3 DE19702022790 DE2022790A DE2022790C3 DE 2022790 C3 DE2022790 C3 DE 2022790C3 DE 19702022790 DE19702022790 DE 19702022790 DE 2022790 A DE2022790 A DE 2022790A DE 2022790 C3 DE2022790 C3 DE 2022790C3
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- dibenzo
- diazepin
- acetyl
- methylpiperazino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- -1 4-methylpiperazino Chemical group 0.000 title claims description 11
- 238000000034 method Methods 0.000 title description 4
- 238000002360 preparation method Methods 0.000 title description 4
- 239000003814 drug Substances 0.000 title description 2
- 239000000126 substance Substances 0.000 description 15
- 239000002253 acid Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 210000004051 Gastric Juice Anatomy 0.000 description 4
- 210000002784 Stomach Anatomy 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229960004373 Acetylcholine Drugs 0.000 description 2
- 229960002028 Atropine Sulfate Drugs 0.000 description 2
- JPKKQJKQTPNWTR-CHYDPLAESA-N CHEMBL3182372 Chemical compound O.OS(O)(=O)=O.O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1.O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 JPKKQJKQTPNWTR-CHYDPLAESA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 210000001072 Colon Anatomy 0.000 description 2
- 208000007101 Muscle Cramp Diseases 0.000 description 2
- 206010028334 Muscle spasms Diseases 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010068760 Ulcers Diseases 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002048 spasmolytic Effects 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- ONNKTUJUWIMYOX-UHFFFAOYSA-N CN1C2=C(N(C3=C(C1=O)C=CC=C3)C(CN1CCN(CC1)C)=O)C=CC=C2 Chemical compound CN1C2=C(N(C3=C(C1=O)C=CC=C3)C(CN1CCN(CC1)C)=O)C=CC=C2 ONNKTUJUWIMYOX-UHFFFAOYSA-N 0.000 description 1
- 240000007524 Camellia sinensis var. sinensis Species 0.000 description 1
- 208000000718 Duodenal Ulcer Diseases 0.000 description 1
- UYXAWHWODHRRMR-UHFFFAOYSA-N Hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N Methyl radical Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 210000004400 Mucous Membrane Anatomy 0.000 description 1
- 210000001187 Pylorus Anatomy 0.000 description 1
- 210000001562 Sternum Anatomy 0.000 description 1
- 206010042220 Stress ulcer Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003444 anaesthetic Effects 0.000 description 1
- 230000002921 anti-spasmodic Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007799 cork Substances 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 230000001186 cumulative Effects 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000020828 fasting Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 229960002456 hexobarbital Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002656 inhibitory effect on ulcer Effects 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000005528 methosulfate group Chemical group 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000001148 spastic Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Description
= C-CH7-N N-CH,= C-CH 7 -N N-CH,
und seine Säureadditionssalze nach Patent 1795175, dadurch gekennzeichnet, daß R1 den Methylrest bedeutet.and its acid addition salts according to patent 1795175, characterized in that R 1 denotes the methyl radical.
2. Verfahren zur Herstellung von 10-Methyl-5 - [(4 - methylpiperazino) - acetyl] - 5,10 - dihydro-11 H-dibenzo[b,e][l,4]diazepin-ll-on, gemäß Anspruch 1 und von seinen Säureadditionssalzen mit anorganischen oder organischen Säuren, dadurch gekennzeichnet, daß ein 5-Halogenacetyl -10 - methyl - 5,10 - dihydro -11H - dibenzo-[b,e][l,4]diazepin-ll-on der allgemeinen For-2. Process for the preparation of 10-methyl-5 - [(4 - methylpiperazino) - acetyl] - 5,10 - dihydro-11 H -dibenzo [b, e] [1,4] diazepin-II-one, according to Claim 1 and its acid addition salts with inorganic or organic acids, characterized in that a 5-haloacetyl -10 - methyl - 5,10 - dihydro -11H - dibenzo- [b, e] [1,4] diazepin-II-one the general form
N-CN-C
O = C-CH2-HaIO = C-CH 2 -HaI
in der Hai ein Halogenatom bedeutet, in an sich bekannter Weise mit N-Methylpiperazin umgesetzt wird und gegebenenfalls die so erhaltene Verbindung mit einer anorganischen oder organischen Säure in ihr Säureadditionssalz überführt wird.in which Hai means a halogen atom, reacted in a manner known per se with N-methylpiperazine and optionally the compound thus obtained with an inorganic or organic one Acid is converted into its acid addition salt.
3. Arzneimittel, bestehend aus 10-Methyl-5 - [(4 - methylpiperazino) - acetyl] - 5,10 - dihydro-11 H-dibenzo[b,e][l,4]diazepin-ll-on oder seinen Säureadditionsalzen neben üblichen Trägerund Hilfsstoffen.3. Medicinal product consisting of 10-methyl-5 - [(4 - methylpiperazino) - acetyl] - 5,10 - dihydro-11 H-dibenzo [b, e] [1,4] diazepin-II-one or its acid addition salts in addition to the usual carriers and Auxiliary materials.
5050
Gegenstand des Patents 1795 176 sind N'-substituierte 5-Aminoacetyl-5,10-dihydro-l 1 H-dibenzo-[b,e][l,4]diazepin-l 1-one der allgemeinen Formel laPatent 1795 176 relates to N'-substituted 5-aminoacetyl-5,10-dihydro-l 1 H-dibenzo- [b, e] [l, 4] diazepine-l 1-one of the general formula la
(la)(la)
= C-CH2-R4 in der R, ein Wasserstoffiitom oder die Methyl= C-CH 2 -R 4 in the R, a hydrogen atom or the methyl
gruppe, R2 und R3 Wasserstoff- oder Halogenatome, für R2 in 2- oder 3-Stellung, und R4 einen über das Stickstoffatom an das Kohlenstoffatom der Acetylgruppe gebundenen Pyrrolidino-, Piperidino-, Morpholino- oder Piperazinorest, wobei der Piperazinorest an seiner Iminogruppe durch die Methyl- oder Hydroxyäthylgruppe oder einen gegebenenfalls durch eine Methylgruppe substituierten Benzylresi substituiert sein kann, bedeutet, sowie ίο deren physiologisch verträgliche Säureadditionssalze mit anorganischen oder organischen Säuren, ein dem Verfahren gemäß obigem Anspruch 2 entsprechendes Verfahren zu deren Herstellung sowie diese enthaltende Arzneimittel.group, R 2 and R 3 are hydrogen or halogen atoms, for R 2 in the 2- or 3-position, and R 4 is a pyrrolidino, piperidino, morpholino or piperazino radical bonded to the carbon atom of the acetyl group via the nitrogen atom, the piperazino radical can be substituted on its imino group by the methyl or hydroxyethyl group or a benzylresi optionally substituted by a methyl group, means, as well as ίο their physiologically acceptable acid addition salts with inorganic or organic acids, a process corresponding to the process according to claim 2 above for their preparation and containing them Drug.
Gegenstand dieser Erfindung ist nun 10-Methyl-5 - [(4 - methylpiperazino) - acetyl] - 5,10 - dihydro-11 H-dibenzo[b, e][ 1,4]diazepin-l 1 -on.This invention now relates to 10-methyl-5 - [(4 - methylpiperazino) - acetyl] - 5,10 - dihydro-11 H-dibenzo [b, e] [1,4] diazepin-l 1 -one.
Diese Substanz fällt zwar unter den Schutzumfang des Patents 17 95 176, ist aber dort nicht beschrieben. Es wurde nun gefunden, daß diese Substanz eine ausgezeichnete ulcus- und sekretionshemmende Wirkung auf die Magenschleimhäute ausübt.Although this substance falls under the scope of protection of patent 17 95 176, it is not described there. It has now been found that this substance has an excellent ulcer and secretion-inhibiting effect on the gastric mucous membranes.
Die erfindungsgemäße Verbindung wird dadurch erhalten, daß man ein 5-Halogen-acetyl-lO-methyl-5,10-dihydro-11 H-dibenzo[b,e][l,4]diazepin-11 -on (Formel II) mit N-Methylpipera/in nach bekannten Methoden umsetzt.The compound according to the invention is obtained by adding a 5-halo-acetyl-10-methyl-5,10-dihydro-11 H-dibenzo [b, e] [l, 4] diazepin-11-one (formula II) with N-methylpipera / in according to known ones Implements methods.
Die Umsetzung erfolgt vorteilhaft in einem indifferenten Lösungsmittel, gegebenenfalls unter Zusatz eines säurebindenden Mittels, bei erhöhten Temperaturen, vorzugsweise bei der Siedetemperatur des verwendeten Lösungsmittels. Als Lösungsmittel werden (") vorzugsweise Äthanol, Aceton oder Dioxan verwendet,The reaction is advantageously carried out in an inert solvent, optionally with an additive an acid-binding agent, at elevated temperatures, preferably at the boiling point of the one used Solvent. The solvents used (") are preferably ethanol, acetone or dioxane,
es können aber auch aromatische Kohlenwasserstoffe wie Benzol oder Toluol eingesetzt werden. Setzt man das N-Methylpiperazin in einem genügenden Überschuß ein, so kann dieses den frei werdenden Halogenwasserstoff binden, man kann aber auch andere halogenwasserstoffbindende Mittel wie Alkalicarbonate oder Alkalihydrogencarbonate zusetzen.however, aromatic hydrocarbons such as benzene or toluene can also be used. If you set the N-methylpiperazine in a sufficient excess, so this can free the hydrogen halide bind, but you can also use other hydrogen halide binding agents such as alkali metal carbonates or add alkali hydrogen carbonates.
Das 10-Methyl - 5 - [(4- methylpiperazino)- acetyl]-5,10-dihydro-11 H-dibenzo[b,e][l,4]diazepin-11 -on kann gewünschtenfalls durch Umsetzung mit anorganischen oder organischen Säuren nach bekannten Methoden in seine physiologisch verträglichen Säureadditionssal/c überführt werden. Als Säuren haben sich beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Weinsäure, Fumarsäure, Zitronensäure, Maleinsäure, Bernsteinsäure, Oxalsäure als geeignet erwiesen.The 10-methyl - 5 - [(4-methylpiperazino) acetyl] -5,10-dihydro-11 H-dibenzo [b, e] [l, 4] diazepin-11-one can, if desired, by reaction with inorganic or organic acids according to known methods into its physiologically acceptable acid addition salt / c be convicted. As acids, for example, hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, tartaric acid, fumaric acid, citric acid, maleic acid, succinic acid, Oxalic acid proved suitable.
Die Ausgangsverbindungen der Formel Il sind liieraturbekannt oder lassen sich in Anlehnung an literaturbekannte Methoden herstellen (A. M.M ο η r ο et al.. J. Med. Chem. 6, 255 [1963]).The starting compounds of the formula II are known in nature or can be based on Establish methods known from the literature (A. M.M ο η r ο et al. J. Med. Chem. 6, 255 [1963]).
Die dabei entstehenden Verbindungen der Formel II brauchen nicht isoliert und gereinigt werden, sie können in rohem Zustand für die Herstellung der Endverbindung eingesei/i werden.The resulting compounds of formula II do not need to be isolated and purified, they can be used in the raw state for the production of the end connection.
Das 10- Methyl - 5 - [(4 - methylpiperazino)- acctyl]-5,10-dihydro-11 H-diben7.o[b.c][l,4]diazcpin-l 1 -ondifumarat = Substanz A wurde mit dem bekannten N-(//-Cyclohexyl-//-hydroxy-//-phenylethyl)-N'-methylpipcrazinmcthosulfat = Substanz B, bezüglich der Ulkiishemmwirkung und der akuten Toxizitäl vergleichend untersucht.The 10-methyl-5 - [(4-methylpiperazino) -acctyl] -5,10-dihydro-11 H-diben7.o [b.c] [l, 4] diazcpin-l 1 -one difumarate = substance A was with the known N - (// - Cyclohexyl - // - hydroxy - // - phenylethyl) -N'-methylpipcrazine methosulfate = Substance B, comparing ulcer-inhibiting effect and acute toxicity examined.
Die hemmende Wirkung auf die Bildung von Stress-Ulcera wurde in Anlehnung an die Methode von Takagi.Jap. J. Pha.mac. IS, 9—18 (1968) bestimmt.The inhibitory effect on the formation of stress ulcers was based on the method of Takagi.Jap. J. Pha.mac. IS, 9-18 (1968).
Gefütterte Ratten beiderlei Geschlechts von einem Körpergewicht zwischen 240 und 260 g wurden einzeln in kleine Drahtkäfige gesetzt und anschließend senkrecht in ein Wasserbad, welches bei einer Temperatur von 23° C konstant gehalten wurde, 16 Stunden lang so eingestellt, daß nur noch der Kopf und das Brustbein über der Wasseroberfläche verblieben. Die Wirksubstanzen wurden etwa 5 bis 1Oi Minuten vorher den Tieren peroral verabreicht. Pro Substanz wurden 5 Tiere verwendet. Die Kontrolltiere erhielten in gleicher Weise an Stelle des Wirkstoffe 1 ml 0,9%iger physiologischer Kochsalzlösung. Nach 16 Stunden wurden die Rauen mittels einer Uberdosis von Chloräthyl getötet, und anschließend wurde ihnen der Magen entnommen. Der Magen wurde entlang der großen Kurvatur aufgeschnitten und auf eine Korkscheibe ausgespannt. Die Auswertung erfolgte wiederum nach dem in Med. Exp. 4, 284 bis 292 (1961) beschriebenen Schema. Es wurden für die beiden Substanzen A und B folgende Werte gefunden:Fed rats of both sexes weighing between 240 and 260 g were given individually placed in small wire cages and then vertically in a water bath, which is at a temperature of 23 ° C was kept constant, set for 16 hours so that only the head and the Sternum remained above the surface of the water. The active ingredients were about 5 to 10 minutes beforehand administered orally to the animals. 5 animals were used per substance. The control animals received in in the same way, instead of the active ingredients, 1 ml 0.9% physiological saline solution. After 16 hours the roughs were killed by an overdose of chloroethyl, and then they were taken from the stomach. The stomach was cut open along the great curvature and on one Cork disc stretched out. The evaluation was again carried out according to the method described in Med. Exp. 4, 284 to 292 (1961) described scheme. The following values were found for the two substances A and B:
Subsian/ % Hemmwirkung auf Ulcusbildung nach oraler
Verabreichung vonSubsian /% inhibitory effect on ulcer formation after oral
Administration of
5 6,25 10 12,5 255 6.25 10 12.5 25
mg kg mg/kg mg/kg mg kg mg kgmg kg mg / kg mg / kg mg kg mg kg
Die Beeinflussung der Magensaftsekretion wurde nach der Methode von S h a y et al., Gastroenterology 5, 43—61 (1945) ermittelt. Nüchternen, männlichen Ratten des Stammes FW 49 im Gewicht von 140 bis 150 g wurde in Hexobarbital-Narkose (100 mg/kg i. p.) der Pylorus unterbunden. Die Substanzen wurden unmittelbar nach der Pylorusligatur intraduodenal oder 30 Minuten bis 1 Stunde nach der Pylorusligator intraperitoneal in der Dosis von 12 mg/kg verabreicht. Pro Substanz wurden jeweils 10 Tiere eingesetzt. Die Kontrolltiere erhielten in der gleichen Weise 0,25 mg 0,9%ige physiologische Kochsalzlösung verabreicht. Nach 5 Stunden wurden die Ratten in Chloräthyl-Narkose getötet, der Magen entnommen, dieser entlang der Kurvatur eröffnet und der Magensaft aufgefangen. Die freie und die gesamte Salzsäure des Magensaftes wurde durch Titration mit n/50-Natronlauge bestimmt.The gastric juice secretion was influenced by the method of S h a y et al., Gastroenterology 5, 43-61 (1945). Fasted male rats of strain FW 49 weighing The pylorus was tied off 140 to 150 g under hexobarbital anesthesia (100 mg / kg i.p.). the Substances were administered intraduodenally or 30 minutes to 1 hour immediately after pyloric ligation after the pyloric ligator administered intraperitoneally at the dose of 12 mg / kg. Per substance were 10 animals each used. The control animals received 0.25 mg 0.9% physiological in the same way Saline solution administered. After 5 hours, the rats were sacrificed under a chloroethyl anesthetic, the stomach removed, this opened along the curvature and the gastric juice collected. The free and the total hydrochloric acid in the gastric juice was determined by titration with n / 50 sodium hydroxide solution.
Die Substanz A zeigt bei der Dosis von 12 mg/kg eine nahezu 80%ige Reduktion des abgeschiedenen Magensaftes. Die Substanz A schränkt die Menge der in den Magen abgeschiedenen freien und der gesamten Salzsäure bei einer Dosierung von 20 mg/kg um 50 bis 70% ein.Substance A shows at the dose of 12 mg / kg an almost 80% reduction in gastric juice secreted. The substance A restricts the amount of free and total hydrochloric acid deposited in the stomach at a dosage of 20 mg / kg 50 to 70% a.
Die spasmolytische Wirkung wurde in vitro am Meerschweinchen-Colon in der Versuchsanordnung nach R. Magnus, Pflügers Archiv 102, 123 (1904) bestimmt. Zur Krampferzeugung diente Acetylcholin, als Vergleichssubstanz Atropinsulfat. Das Spastikum wurde eine Minute vor der Zugabe des Spasmolyti-The spasmolytic effect was demonstrated in vitro on the guinea pig colon in the experimental set-up determined from R. Magnus, Pflügers Archiv 102, 123 (1904). Acetylcholine was used to generate cramps, as a comparison substance, atropine sulfate. The spastic was one minute before the addition of the spasmolytic
kums zugesetzt, die Einwirkungszeit des Spasmolytikums betrug eine Minute. Dabei wurde gefunden, daß die Substanz A nur V24 der Wirkung des Atropinsulfats bei einer Krampferzeugung durch Acetylcholin am Meerschweinchen-Colon erreicht.Cumulative added, the exposure time of the antispasmodic was a minute. It was found that substance A only V24 the effect of atropine sulfate when acetylcholine induces cramps in the guinea pig colon.
Die Toxizität wurde nach peroraler Applikation der Wirksubstanzen an nüchternen, weißen Mäusen
von 18 bis 20 g Körpergewicht bestimmt und die DL50 nach L i t c h f i ε 1 d und W i 1 c ο χ ο η errechnet.
Die Beobachtungszeit betrug 14 Tage. Es kam je Dosis eine Gruppe von 5 bis 10 Mäusen zur Anwendung,
Die LD50 für Substanz A wurde hierbei zu 3400 mg/kg, die der Substanz B zu 810 mg/kg
gefunden.
Das nachstehende Beispiel dient zur näheren Erläuterung der Erfindung:The toxicity was determined after oral application of the active substances to fasting, white mice of 18 to 20 g body weight and the DL 50 was calculated according to L itchfi ε 1 d and W i 1 c ο χ ο η. The observation time was 14 days. A group of 5 to 10 mice was used per dose. The LD 50 for substance A was found to be 3400 mg / kg, that for substance B to be 810 mg / kg.
The following example serves to explain the invention in more detail:
300,7 g S-Chloracetyl-S.lO-dihydro-lO-methyl-UH-dibenzo[b,e][l,4]diazepin-ll-on (F. = 160°C)300.7 g of S-chloroacetyl-S.10-dihydro-10-methyl-UH-dibenzo [b, e] [1,4] diazepin-II-one (F. = 160 ° C)
und 250 g N-Methylpiperazin wurden in 3 Liter Isopropanol 5 Stunden unter Rückfluß erhitzt. Nach
dem Eindampfen im Vakuum wurde der Rückstand in 3 Liter 20%iger Salzsäure gelöst, mit Aktivkohle
behandelt und filtriert. Das Filtrat wurde mit NaOH alkaiisch
gemacht und mit Methylenchlorid ausgeschüttelt. Die Methylenchlorid-Extrakte wurden mit
Natriumsulfat getrocknet, filtriert und eingedampft. Den Rückstand (338 g braunes öl) versetzte man mit
216 g Fumarsäure, gab zur Lösung Aktivkohle, erhitzte 15 Minuten unter Rückfluß und saugte ab.
Das noch heiße Filtrat wurde mit 900 ml Essigester verset7t und über Nacht stehengelassen. Die ausgeschiedenen
weißen Kristalle sind das Dihydrogenfumarat des 10-Methyl-5-[(4-methylpiperazino)-acetyl]
- 5,10 - dihydro -11 H - dibenzo[b, e][ 1,4]diazepin-11-on
vom F. = 166 bis 168° C.
Ausbeute: 75% der Theorie.and 250 g of N-methylpiperazine were refluxed in 3 liters of isopropanol for 5 hours. After evaporation in vacuo, the residue was dissolved in 3 liters of 20% strength hydrochloric acid, treated with activated charcoal and filtered. The filtrate was made alkaline with NaOH and extracted with methylene chloride. The methylene chloride extracts were dried with sodium sulfate, filtered and evaporated. 216 g of fumaric acid were added to the residue (338 g of brown oil), activated charcoal was added to the solution, the mixture was heated under reflux for 15 minutes and filtered off with suction. The still hot filtrate was mixed with 900 ml of ethyl acetate and left to stand overnight. The separated white crystals are the dihydrogen fumarate of 10-methyl-5 - [(4-methylpiperazino) acetyl] - 5,10 - dihydro -11 H - dibenzo [b, e] [1,4] diazepin-11-one from F. = 166 to 168 ° C.
Yield: 75% of theory.
Dihydrogenfumaraf. C21H24N4O2+ 2C4H4O4 (5%.6).Dihydrogen fumaraf. C 21 H 24 N 4 O 2 + 2C 4 H 4 O 4 (5% .6).
Berechnet .... C 58,38, H 5,41, N 9,39;
gefunden .... C 58,10, H 5,65, N 9,47.Calculated .... C 58.38, H 5.41, N 9.39;
found .... C 58.10, H 5.65, N 9.47.
Die Verbindung 10-Methyl-5-5-[(4-methylpiperazinol-acetyl]-5,10-dihydro-llH-dibenzo[b,e][1.4]- diazepin-11-on läßt sich in an sich bekannter Weise in die üblichen pharmazeutischen Zubereitungsformen, z. B. in Lösungen, Tabletten, Dragees oder in Teezubereitungen, einarbeiten. Die Einzeldosis beträgt Tür Erwachsene bei peroraler Applikation 2 bis 20 mg, bevorzugt 5 bis 10 mg, die Tagesdosis 10 bis 80 mg, bevorzugt 10 bis 40 mg.The compound 10-methyl-5-5 - [(4-methylpiperazinol-acetyl] -5,10-dihydro-IIH-dibenzo [b, e] [1.4] - diazepin-11-one can be in a known manner in the usual pharmaceutical preparation forms, e.g. B. in solutions, tablets, coated tablets or in tea preparations, incorporate. The single dose for adults is 2 to 20 mg for oral administration, preferably 5 to 10 mg, the daily dose 10 to 80 mg, preferably 10 to 40 mg.
Claims (1)
R1 Oί 1. 5 - [(4 - Methylpiperazino) - acetyl] - 5,10 - dihydro-11 H-dibenzo [be] [1,4] diazepin-II-one of the general formula I
R 1 O
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI216269 | 1969-07-22 | ||
| FI692162A FI49509C (en) | 1968-08-20 | 1969-07-22 | Process for the preparation of pharmacologically active 5,10-substituted 5,10-dihydro-11H-dibenzo [b, e] -1,4] deazepin-11-ones and their salts. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2022790A1 DE2022790A1 (en) | 1971-02-11 |
| DE2022790B2 DE2022790B2 (en) | 1976-07-08 |
| DE2022790C3 true DE2022790C3 (en) | 1977-07-07 |
Family
ID=
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