• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The invention relates to substituted fused heterocyclic compounds, in particular 5,11-dihydro-11- {C (1-methyl-4-piperidinyl) -amino-carbonyl-bH-dibenz t, e azepin-6--one (PA) or its salts with antimuscarinic action, and can be used in medicine. To detect activity among compounds of this class, new PAs and its salts were obtained. PAs are synthesized from 1-methyl-4-amino-piperidine and the reaction derivative of 5,11-dihydro-6H-dibenz b, e azepin-6-one-11-carboxylic acid in a mixture of CHC1, and tionyl chloride. The distribution is carried out either as a base of PA or as a salt. PA tests show that it exhibits an anti-oncogenic effect and inhibition of salivation better than the known 5,10-dihydro-5- (4-methyl-1-piperazinyl) acetyl-11H-dibenzo-4, 4 diazepin-11-one with minimal toxicity (1000 mg / kg of live weight). 1 tab. O) 00 about cx 05
    公开号:SU1308196A3
    申请号:SU853834159
    申请日:1985-01-09
    公开日:1987-04-30
    发明作者:Эберлейн Вольганг；Труммлитц Гюнтер；Энгель Вольфгард；Шмидт Гюнтер；ХАММЕР Рудольф；Джиашетти Антонио
    申请人:Др.Карл Томэ Гмбх (Фирма)；
    IPC主号:
    专利说明:

    11308196
    This invention relates to the field of the production of a new azepine derivative, namely, 5,11-dihydro-11- (1 ethyl-4-piperidinyl) -amino carbo-n1 | -bH-dibenz 1, e az8-pin-6-one formulas
    az slak l sla v te te ka slak chi su ki t su y o pr t about
    10 I II
    ch0 C-l H- N-CH j
    or its salts with antlmusk-J5 rinovym action,
    1 (the purpose of the invention is to obtain new compounds with valuable pharmacological action.
    Example 11. 5,11-DIGIDRO-11- - (1-methyl-4-piperidine 1) -amino-carbonyl-bH-dibenz 1), e azepin-6-one.
    2.5 g (0.01 mol) of 5,11-dihydro-bH-dibenz b, e azepin-6-one-11-carboxylic acid in a mixture of 50 ml of chloroform and 15 ml of thionyl chloride are heated under reflux to complete dissolving. The solvent is subsequently removed in vacuo and the resulting residue is taken up in 50 ml of dioxane. To this solution is added dropwise a mixture of 2.2 g (0.02 mol) of 4-amino-1-methylpiperidine in 50 ml of dioxane and further stirred
    In suspension of 2.5 g (0.01 mol) of 5.11 -dihydro-6-oxo-6H-dibenz 1, e - azepine-11-carboxylic acid and 2.0 g (0.02 mol) of triethylamine in 150 ml Under ice-cooling, ethyl acetate was added dropwise with 1.8 g (0.01 mol) of ethyl chloroformate. Stir additionally for 1 hour at room temperature and then a solution of 1.25 g (0.01 mol) of 4-α-amino-1-methyl-piperidine in 20 ml of ethyl acetate is added dropwise. After standing overnight, the reaction mixture was shaken several times with dilution with hydrochloric acid, the aqueous acidic extracts were removed and neutralized by the addition of solid sodium bicarbonate. The aqueous solution is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness in vacuo. After mixing the residue with a small amount of ether, crystals with m.p. 230-231 ° C. Output 1.8 g (51% of theoretical).
    Example 3. 5,11-Dihydro-11- - (1-methyl-4-piperidinyl-amino carbonyl-bH-dibenz GH, e azepin-6-one.
    To a suspension of 5 g (0.02 mol) of 5,11-dihydro-6-oxo-bH-dibenz t, eJ azepine-11-carboxylic acid in 100 ml of tetrahydrofuran was added 3.5 g
    20
    25
    for 60 minutes at 50 ° C. Then cry-35 (mol) N, N -carbonyldiimidazole and heat this mixture for 30 minutes to 40 ° C. Then 2.5 g (0.022 mol) of 4-amino-1-methyl -piperidine and heat another 2 hours to.
    40 After cooling, the solvent is removed in vacuo and the resulting residue is purified by chromatography on a column of silica gel (the solvent is ethylene chloride and methanol in a 9: 1 ratio). From eta45 nola get 4.8 (68%) of the above compound st. square 230-231 0. Example 4. 5,11-Dihydro-11-. - {(1-methyl-4-piperidinyl) -amino-carbonyl-bH-dibenz 1, e azepin-6-one.
    50 Suspension 5 g (0.02 mol) of 5,11-dihydro-6-oxo-6H-dibenz b, e-azepine-11-carboxylic acid and 4.5 g (0.022 mol) of N, N-dicyclohexylcarbodiimide in 180 tetrahydrofuran
    55 heated for 60 min. Sequentially, 2.5 g (0.022 mol) of 4-amino-1-methyl-piperidine are added dropwise to the reaction solution and heated for another 2 hours to 40-50 C. After cooling in vacuo, a little water is added to the residue, the solution is potassium carbonate and extracted with ethyl acetate. The combined extracts are filtered on active carbon and subsequently evaporated to dryness in vacuo. Purification of the crude product is carried out by chromatography on silica gel using methanol as eluent. Colorless crystals are obtained with mp. 230g-231 C. Yield 1.3 g (36% of theoretical). The base is converted to hydrochloride by dissolving it in ethyl acetate, mixing with saturated hydrogen chloride with a methanol solution in the cold and removing excess hydrogen chloride and solvent in vacuo. M.p. hydrochloride 315-316 ° C.
    Example 2. 5,11-Dihydro-11- - (1-methyl-4-piperidinyl) -amino carbon w-bH-dibenz b, e azepin-6-one.
    In suspension of 2.5 g (0.01 mol) of 5.11 -dihydro-6-oxo-6H-dibenz 1, e - azepine-11-carboxylic acid and 2.0 g (0.02 mol) of triethylamine in 150 ml Under ice-cooling, ethyl acetate was added dropwise with 1.8 g (0.01 mol) of ethyl chloroformate. Stir additionally for 1 hour at room temperature and then a solution of 1.25 g (0.01 mol) of 4-α-amino-1-methyl-piperidine in 20 ml of ethyl acetate is added dropwise. After standing overnight, the reaction mixture was shaken several times with dilution with hydrochloric acid, the aqueous acidic extracts were removed and neutralized by the addition of solid sodium bicarbonate. The aqueous solution is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness in vacuo. After mixing the residue with a small amount of ether, crystals with m.p. 230-231 ° C. Output 1.8 g (51% of theoretical).
    Example 3. 5,11-Dihydro-11- - (1-methyl-4-piperidinyl-amino carbonyl-bH-dibenz GH, e azepin-6-one.
    To a suspension of 5 g (0.02 mol) of 5,11-dihydro-6-oxo-bH-dibenz t, eJ azepine-11-carboxylic acid in 100 ml of tetrahydrofuran was added 3.5 g
    (mol) N, N -carbonyldiimidazo3
    Neither the solution is concentrated in vacuo and the residue to be purified is purified by chromatography on silica gel (eluant is methylene chloride and methanol in a ratio of 9: 1). Crystals are obtained from the eluate. 230-231 ° C. The yield of 3.7 g (53% of theoretical).
    Example 5: 5g 5,11-dihydro -1 1-f (1-methyl-4-piperidinyl (α-amino carbonyl-bH-dibene t, e azepin-6-one is dissolved in ethanol and added as calculated for salt form) the amount of L-tartaric acid. After concentration of the solution, 5,11-DIHYDRO-11- (1-methyl-4-piperidine) -amino carbonyl 1-6H-dibenz ts, e azepin-6-one in the form of 1 / 2-tartrate with mp 200 C (with decomposition). Yield 85%.
    Pharmacological studies. Oxotremorine, a specific muscarinic receptor agonist, excites in rats a disorder of the function of the ventricular mucosa and increases salivary secretion. The selective action of the antimuscarinic substance on the stomach is determined.
    As experimental animals, 10 female albino rats with a body weight of 120-150 g for each group are left without food for 24 hours before the start of the experiment, but with free access to drinking water.
    To determine the muscarinic effect of oxotremorine, for each of the symptoms studied, a dose and effect curve is made using at least 3 doses for each symptom. When using an antimuscarinic substance, a dose of approx. Tremorin is taken which causes the corresponding symptom in 90-100% of animals, mg / kg:, Disorder
    functions el-
    gastric zygoma 0.62 Saliva secretion 0.083 Each antimuscarinic substance is given to the experimental animal in uniformly increasing doses 15 minutes before the administration of oxotremorine intravenously. The control groups, instead of the test agent, are given only the solvent or suspending agent in the appropriate amount. Immediately after administration of oxotremorine, the animals are placed in a glass cage for 15 minutes to observe them.







    1964
    The examination of the drug by oxotremorine-induced saliva delivery is carried out in a blind way, i.e. The examiner does not know what the animals were administered and at what dose.
    The results of the experiment are determined as the percentage inhibition of the ox-tremorous effect (i.e., the percentage of animals without the corresponding symptom is determined. The ED, p values are determined by the method of Lichfield and Wilcoxon (see J. Pharmacol. Exp. Jher. 96 1949).
    Evaluation of the effects of disorders of the gastric mucosa is performed as follows.
    Disruption of the function of the gastric mucosa is caused by intravenous injection of 0.62 mg / kg of oxotremorine 30 minutes after oral administration of 1 mg / kg of neostigmine (a cholinesterase inhibitor). 60 minutes after the administration of neostigmine, the animals are sacrificed, the stomachs are removed, opened and examined for mucosal function disorders. The protective effect of the test substance is determined in percent of inhibition, i.e. The percentage of animals without damage to the mucosa is determined. ED values are determined by the method of Lichfield and Wilcoxon.
    In the experiments, a new compound A, its hydrochloride B and tartrate B, as well as the known compound X, where A is 5,11-DIHYDRO-11- (1-methyl-4-piperidine 1) -amino carbonyl) -6H-dibenz B, e} azepin-6-one, B - hydrochloride of compound A, B - tartrate of compound A, X - 5,10-dihydro-5- - (4-methyl-1-piper azinyl) acetyl-11H-dibenzo 1 ), e 1,4} diazepin-11-OH,
    The results of the experiments are tabulated.
    22 20
    190
    185
    Table continuation
    or its salts, characterized in that the reactive carboxylic acid derivative of the formula
    The data in the table indicate that Compounds A, B, and C have better properties compared to known Compound X, Compounds A, B, and C are non-toxic at doses up to 1000 µg / kg (orally) i
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 5,11-dihydro-11- - 1-methyl-4-piperidinsh1) -amino / - carboNilZ -bH-dibenz (b, {) azepin-6-one of the formula
     V
    N-C ..
    -CH-J
    about with tn - /) - sn
    - /
    subjected to interaction with 1-methyl-f5 -4-amino-PIPERIDINE formula
    N SN
    with the subsequent selection of the target product in free form or in the form of a salt.
    Editor M.Rybchenko
    Compiled by I. Bocharova
    Tehred M. Khodanich Proofreader M. Sharoshi
    1645/58
    Circulation 372Subscribe
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, N {-35, Raushsk nab. 4/5
    Production-printing enterprise, Uzhgorod, st. Project, 4
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    优先权:
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