• 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:
    Beschrieben werden 3-Amino-1 -benzoxepin-5(2H) -on-Derivate der Formel worin R1 - R4 die in den Ansprüchen angegebene Bedeutung haben, sowie deren Säureadditionssalze und Verfahren zu ihrer Herstellung. Die Verbindungen eignen sich zur Behandlung von Spasmen des Magen-Darm-Traktes
    公开号:SU955860A3
    申请号:SU802950853
    申请日:1980-07-25
    公开日:1982-08-30
    发明作者:Олендорф Хайнрих-Вильхельм；Вольф Клаус-Улльрих；Каупманн Вильхельм；Хайнеманн Хеннинг
    申请人:Кали-Хеми Фарма Гмбх (Фирма)；
    IPC主号:
    专利说明:

    where R has the indicated meanings or a compound of the formula 3 where R and R4 have the indicated meanings X - chlorine or bromine, is reacted with an amine of the formula. B =, where R and R2 have the indicated values, in an organic inert solvent medium at a temperature of -20 ° C. to the boiling point of the reaction medium and isolate the desired product in free form or in the form of a salt, or, if necessary, salt is converted to base. The interaction of 2,3, 4,5, tetrahydro-1-benzoxepine-3, 5-dione derivatives of formula (I) with an amine may be favored by the addition of atalytic amounts of inorganic or organic acids, for example, hydrochloric, sulfuric, p-toluenesulfonic acids or formic. Use as an inert organic solvent, such as chloroform, dichloromethane, benzene or toluene. The reaction is prod d t in the temperature range of 0-150 s. The reaction is improved by removing the water formed during the reaction. When the compound of the formula (IG}) interacts with the amine as an inert solvent, it is, for example, chloroform, chloromethane, dimethyl formamide, dcoxane or tetrahydrofurus. The process is carried out at temperatures ranging from - to - 50 ° C, and the reaction preferably carried out in the presence of an organic base, for example triethylamine, or an excess amount of the amine used. The compounds of the formula (M t) can be obtained by the interaction of a 2,3,4,5-tetrahydro-1-benzoxepine-3,5-dione derivative of the formula II) with the corresponding acid halide. As the acid halides, phosphorus halides, phosphorus trigens are used. , thioiyl chloride or | rxalyl chloride. Example 1. A solution of 88 g, (0.5 mol) 2,3,4,5-tetrahydro-1-benzoxepin-3.5 ddion and at the tip of a p-toluenesulfonic acid spatula in 750 ml of toluene, mixed, mixed with 44 g ( O, 5, mol) N, f-dimethylethylenediamine and then stir at room temperature. Continue to mix until the reaction ends. The resulting concentration of the solution was filtered off with suction and recrystallized from benzene with ligroin. Obtain 108 g (88% of theoretical.) 3 - /}% - dimethylaminoethylamino / -1-benzoxepin-5 / 2H / -o and with a pour point of 100-101 C. Example 2. A solution of 17.6 g (0.1 mol) 2,3,4,5-tetrahydro-1-benzoxepin-3, 5, dione and at the tip of the p-toluenesulfonic acid spatula in 200 ml of dichloromethane, stirring, mixed with 6 g (0.1 mol) of isopropyl amine and then at stir at room temperature until the reaction is complete. The residue obtained after concentration is concentrated by suction and recrystallized from butyl acetate. This gives 13.5 g (62% of theoretical.) 3-isopropylamino-1-benzoxepin-5 / 3N / -one with a pour point of 150-152 ° C. Example 3. In a boiling solution of 52.6 g (0.3 mol), 4,5-tetrahydro-1-benzoxepin-3, 5-dione and at the tip of a p-toluenesulfok spatula slots in 225 ml of toluene with stirring dimethylamine is administered. The resulting water is separated at a water separator. After completion of the reaction, the solution is concentrated, the resulting residue is filtered off with suction and recrystallized from chloroform with ether. 42 g (69% of the theoretical.) Of 3-dimethylamino-1-benzoxepine-5 / 2H / -one are obtained with a pour point temperature of 136138 0 .. First. Measured 4. In a boiling solution of 160 g (0.9 mol) 2,3,4,5-tetrahydro-1-benoxipin-3, 5, dione and 1 ml of formic acid in 500 ml of dichloromethane with methylamine are added with stirring. The formed water is separated at a water separator. After completion of the reaction, the solution is cooled with ice, the 3-methylamino-1-benzoxepin-5 / 2H / -one is sucked off and recrystallized from methanol. 140 g (81% of theory) of compound with temperature, yield point a76j: 178c, are obtained. - Example 5. ammonia is added to a boiling solution / 70.4 g (0.4 mol) of 2,3,4,5-tetrahydro-1-benzoxepin-3, 5-dione in 400 ml of chloroform. The resulting iodine is separated at a water separator. After completion of the reaction, the solution is cooled, 3-amino-1-benzoxepin-5 / 2H / -one is sucked off and recrystallized from chloroform. The yield is 60.5 g (86% of theoretical.), The pour point is 196-200 ° C. EXAMPLE 6. A solution of 35.2 g (0.2 mol) is 2.3.4, 5-tetrahydro-1-ben-1 zoxepine-3,5-dione in 200 ml of dichloromethane was added 38.1 g (OZ mol) oxalyl chloride. After 14 hours at room temperature, the solvent is filtered off with suction and the remaining oil is distilled. The fraction passing at 150-170 ° C (3 mbar), consisting mainly of H-chloro-1-benzoxepine-5/2 / -one, is placed in 100 ml of chloroform. The resulting solution is cooled with ice and, dropwise, cooled, it is washed with an excess of piperidine dissolved in dichloromethane. This mixture is stirred until the end of the reaction at, then the reaction solution is poured onto ice and the organic phase is separated, the latter is washed, dried, and evaporated. 3-piperidi no-1-benzoxepin-5/2 / -one is perecrystallized from ether. 19.3 are obtained (40% of the theoretical. Assigned to 2,3,4 5-tetrahydro-1-benzoxepine-3,5-dione compounds with a pour point of 101-103 s. I Example 7. By the method described in examples 1 -6, with similar yields from 2., 3, 4, 5-tetrahydro-1-benzoxepin-3, 5-dione ir, r-dimethyl-dimethylaminopropylamine, dl-butylamine, benzylamine, morpholine, -di di methylaminopropylamine, phenethylamine diethylamine, pyrrolidine, / -methoxymethylamine, N-benzylpiperazine or tert, butylamine, the compounds shown in Table 1 are obtained. Infrared spectrum () D605 cm-- Example 8. In the manner described in Examples 1-6, with similar yields of 2,3,4, 5-tetrahydro-7-fluoro-1-benzoxepin-3, 5thione, 2,3,4,5-tetrahydro-7-nitro-1-benzoxepin-3 , 5-dione, 2,3,4,5-tetrahydro-7, 8-lichloro-1-benzoxepin-3,5 dione, 2,3,4,5-tetrahydro-7, 8-dimethyl-1-benzoxepine- H, 5-dione, 2,3,4, 5-tetrahydro-7-bromo-1-benzoxepin-3, 5-dione, 2,3,4,5-tetrahydro-7-methoxy-1-benz sepIn-3 , 5-dione, 2,3,4,5-tetragt-8-methoxy-1-benzoxepin-3, 5-di.,., 2, 3, 4, 5-tetraHYDRO-7-CHLOR-1- Zoxepin-3,5dione, 2, 3 .. ST trahydro-8-chloro-1-ben5ox kch-3, .- dione, 2,3,4,5-tetrahydg 1-methyl 1-benzoxepin-3, 5-dione, . . , 4,5-tetrahydro-7- -ethyl-1-benz. - sepin-3,5-dione, 2,3, 4,5-tetragi,: -8-methyl-1-benzoxepin-3, 5-dio:. 2,3,4,5-tetrahydro-7-chloro-8-methyl-1-benzoxepin-3, 5-dione, 2, 3, -4, 5-tetrahydro-8-tert. butyl-1-benzoxepine-3, 5-dione and methylamine, dimethylamine or -dimethylaminopropi: amine, the compounds shown in Table 1 are obtained. 2. Example 9. To a solution of 242 g (1 mol) of methyl 2-acetate-4-chloro-phenoacetic acid methyl ester cooled to -20 ° C in 300 ml of dimethylformamide, 30.1 g are added in small portions with stirring ( 1 moL) of sodium hydride (80% in oil so that the temperature does not rise above -10 ° C. After that, stirring at -15 s for 45 min. Then the solution is carefully poured into ice water and extracted once with toluene. After acidifying the aqueous phase, the precipitated product is filtered off with suction and recrystallized from cyclohexane with toluene. 126 g of 2,3,4,5-tetrahydro-7-chloro-1-benzoxepin-3, 5-dione with a pour point 131134 ° C (60% of theoretical.) are obtained. Example 10. To a solution of 28.7 g (0, 1 mol of 2-acetyl-4-bromo-phenoxy-acetic acid methyl ester in 150 ml of dry tetrahydrofuran is added dropwise with stirring, 8.8 g (0.11 mol) of lithium tert-butylate in 50 ml of dry tetrahydrofuran so that the temperature is maintained at interval C. Then the suspension is poured into 400 ml of petroleum ether and the precipitated 2,3,4,5-tetrahydro-7-bromo-1-benzoxepin-3, 5-dione lithium salt is sucked off. This salt was added to a mixture of 150 ml and 11 ml of hydrochloric acid (32%). The precipitated product is filtered off with suction, dissolved in dichloromethane, the solution is washed with a saturated sodium chloride solution, dried with sodium sulfate, evaporated and the residue is recrystallized from cyclohexane. Obtain 11.7 g (46% otteoret.) 2,3, 4,5-tetrahydro-7-bromo-1-benzoxepin-3, 5-dione with a pour point 110-112s. Example 11. The method described in examples 9 and 10, when applied, is a scientific research institute of sodium hydride or lithium tert-butyl ligate with similar yields of 2-acetyl-4-methyl / phenoxyacetic acid methyl ester, 2-acetyl methyl ester 5-methyl - / - phenoxyacetic acid, methyl ester / 2-acetyl-5-chloro / -phenoxyacetic acid, methyl ester / 2-acetyl-4-fluoro / -phenoxyacetic acid, methyl ester / 2-acetyl-4-methoxy / -phenoxyacetic acid, methyl ester / 2 -acetyl-5-methoxy / -phenoxyacetic acid methyl ester / 2 -acetyl-4, 5dichloro-pheno {ssiuksu acid methyl ester / 2-acetyl-4-chloro-5-methyl / phenoxyacetic acid, methyl ester / 2-acetyl-4,5 -dimethyl / phenoxyacetic acid, methyl ester / 2-acetyl-5-tert. butyl / -phenoxoacetic acid, methyl / 2-acetyl-4-ethyl / phenoxyacetic acid methyl ester, methyl ester, 2-acetylphenoxyacetic acid, and the others are prepared as shown in Table 3. Infrared Spectrum CH .C1: 1676.i 1738 cm.
    Example 12. The solution obtained from 35,2-g 2, 3, 4, 5-tetrahydro-1-benzoxepin-3, 5-dione and oxaIaIllhlorid described in example 6. method, Himself 3-chloro-1 benzoxepine-572N / -she is. in 100 LLL chloroform is cooled to -20 ° C and added dropwise while cooling to an excess of piperidine dissolved in dichloromethane. The mixture was stirred at -20 ° C until the end of the reaction, then poured onto ice and the organic phase was separated, which was washed with water, dried and evaporated. The residue, which is a 3-piperidino-1-benzoxepin-5 / 2H / -one, is recrystallized from ether. As a result, 22.1 g {46% of theoretical. output per 2,3,4,5-tetrahydro-1-benz. oxepin-3-, 5-dione J of the target product. Melting point 101-103 ° C.
    The compounds of formula (I) have been found to inhibit and regulate spasms of smooth muscles in the gastrointestinal tract while there are no chemical or pharmacological references to the side effects of known parasympatholytics.
    Description of formacological research methods.
    1. Acute toxicity. Acute T-day-toxicity was established after a single use. NMR was prepared for intraperitoneal in a white mouse. The calculation of Cfljgj was performed by electronic data processing by probit analysis.
    2. Checking peristalsis of the stomach To determine stomach peristalsis in rats weighing approximately
    200 g anesthetized ketamine; hydrochloride with xylazine, a vascular catheter was inserted into the jugular S vein, and a tracheal catheter was inserted into the trachea. A stomach probe was wrapped in the stomach through a soy three-way valve (they are connected to the S ta.tham pressure transducer (P 2 call). The stomach on the pylorus and the quad was covered with a ligature. Then the stomach was filled with 3 ml of 0.9% solution solution Salts. Stomach pressures were continuously recorded by a Watanabe multicorder (MC 641).
    For the experiments, the peristaltic movements of the Research Institute were performed with a prolonged intravenous effect of 50 mg / kg / h of barium chloride and the appearance of the amplitudes and frequencies of the pressure waves exerted by the stomach were measured (reference data). For-: the test substances were dissolved in a physiological saline solution. salts were either suspended in tylose MH50, intrabrc dinno used at a dose of 20 mg / kg, and changes in the amplitude and frequency of pressure waves were determined. /
    Analysis of the data shows that shortly after the application of the substances of the formula (I), there is a decrease in the pressure of the taltic movements of the stomach, which is found in a distinct decrease in amplitudes. The frequency varies only slightly, as can be seen in the table below. Unfamiliar: The toxicity of the substances is high and they are well tolerated The next advantage is the observed rapid onset of action.
    The following substances were investigated using the described methods:
    And Z-methylamino-1-benzoxepin-5 / 2H / -OH
    B 3-metnlamino-8-chloro-1-benzoxepin-5 / 2H / -one
    In 3-isopropylamino-1-benzoxPIN-5 / 2H / -OH
    G 3-amino-1g-benzoxepin-5 / 2H / -one
    D 3- / -butylamino / -1-benzoxepin-5 / 2H / -OH
    E Z-phenethylamino-1-benzoxepine. -5 / 2H / -OH
    E 3- / K-benzylpiperazino / -1-benzoxepin-5 / 2H / -one.
    F 3-morpholino-1-benzoxepine--. -5 / 2Н / -ОН
    3 3- / methoxyethylamino / -1-benzoxepin-5 / 2H / -one
    And 3-methylamino-8-methyl-1-benzo-. ksepin-5 / 2H / -one
    K 3-methylamino-7-methyl-1-benzoxepin-5 / 2H / -one
    L 3-methyls1Mino-8-tert.butyl-1-benzoxepin-5 / 2H / -one
    M 3-methylamino-7-chloro-1-benzoxepin-5 / 2H / -one
    H 3-methylamino-7-fluoro-1-benzoxepin-5 / 2H / -6n
    The research results are summarized in table. four.
    The pharmacologically observable actions allow to expect favorable results in various spastic conditions both in the gastrointestinal tract and in the human biliary tract system.
    Prepared drugs as an active substance contain formul (t) or their pharmacologically tolerable salts in combination with common pharmacologically tolerable carrier substances and / or solvents. Drugs can be applied orally or parenterally, they are made in the form of tablets, capsules, syrup, dried powder, injectable and infusible solutions or suspensions. However, they can also be made in the form of candles. Oral preparations are usually preferred.
    The dosage of the jrpB drugs depends on various factors, such as the type and severity of the disease or the compound used. Usually, when taken orally, a single dose of from 1 to 50, in particular from 2 to 20 mg, is sufficient to obtain satisfactory results. P r and m er. Capsules with 10 mg of 3-Methylamino-1-benzoxepine-5 / 2H / -one as an active substance. Composition, h .: Active substance 10. Lactose65 Cornstarch (dry) 40. Compound
    3- / P,% - Dimethyl-dimethylaminopropylamino / -1-bechzoxepin-5 / 2H / -one
    3- / n-Butylamino / -1-benzoxepin-5 / 2H / -one
    3-Benzylamino-1-benzoxepin-5 / 2H / -ph
    3-Morpholino-1-benzoxepin-5 / 2H / -one
    3- / 13-Dimethylaminopropylamino / -1-benzoxPIN-5 / 2H / -OH
    3-Phenethylamino-1-benzoxepin-5 / 2H / -one
    3-Dimetipamino-1-benzoxepin-5 / 2H /.- he
    3-Pyrrolidino-1-benzoxepin-5 / 2H / -one
    3 /} b-Methoxyethylamino / -1-benzoxepin-5 / 2H / -one
    3- / M-Benzylpiperazino / -1-benzoxepin-2/2 / -one
    3- / T-butylamino / -1-benzoxepin-5 / 2H / -one
     TABLE I Soluble starch Magnesium stearate Method of manufacture. The active substance is mixed, with lactose It is corn starch. The resulting mixture is moistened with a 15% aqueous solution of soluble starch and granulated. The wet mass is rubbed through a 1.6 mm sieve, dried on a lattice with and then rubbed through a 1.0 mm sieve. After stirring the granulate with magnesium stearate, 120 mg capsules are obtained from the resulting mixture so that each capsule contains 10 mg of the active substance. Table 1 Pour Point, С
    3-Methylamino-7-fluoro-1-benzoxepin-5 / 2H / -one (0.25% 0)
    Z-Methylamino-7,8-ichlor-1-benzoxepin-5 / 2B / -one
    216-219
    238-241
    eleven
    3-Methylamino-7-nitro-1-benzoxepin-5 / 2H / -one
    at
    Z-Methylamino-7,8-dimethyl-1-benzoxepin-5 / 2H / -one
    3-Methylamino-7-bromo-1-benzoxepin-5 / 2H / -one
    3-Methylamino-7-methoxy-1-benzoxepin-5 / 2H / -one
    3-Methylamino-8-methoxy-1-benzoxepin-5 / 2H / -o
    3-Methylamino-7-chloro-1-beneoxepin-5 / 2H / -one
    3-Methylamino-8-chloro-1-6-benzoxepin-5 / 2H / -one
    3-Methylamino-7-methyl-1-benzoxepin-5 / 2H / -one
    3-Methylamino-7-ethyl-1-6-benzoxepin-5 / 2H / -one
    3-Methylamino-8-chloro-1-6-benzoxepin-5 / 2H / -one
    3- / -Dimethylaminopropylamino / -7-chloro-1-benzoxepin-5 / 2H / -one hydrochloride
    3-Methylamino-7-chloro-8-methyl-1-benzoxepin-5 / 2H / -OH
    3-Methylamino 8-methyl-1-benzoxepin-5 / 2H / -one
    Z-Methylamino-8-tert.butyl-1-benzoxepin-5 / 2H / -OH
    2, j 3,4,5-Tetrahydro-7-methyl-1-benzoxepin-3, 5-dione
    2,3,4,5-Tetrahydro-8-methyl-1-benzoxepin-3, 5-dione
    2,3,4,5-Tetrahydro-8-chloro-1-benzoxepine-3, 5-dione
    2,3,4,5-Tetrahydro-7-fluoro-1-benzoxepin-3, 5-dione
    955860
    12 Continued table. 2
    Table 3
    124-127
    97-98
    152-154
    138-140
    2,3,4,5-Tetrahydro-7-methoxy-1-benzoxepin-3, 5-dione
    2,3,4,5-Tetrahydro-8-methoxy-1-benzoxepin-3, 5-dione.
    2,3,4,5-Tetrahydro-7,8-dichloro-1-benzoxepi-3, 5-dione
    2,3,4,5-Tetrahydro-7-chloro-8-methyl-1-benzoxepin-3, 5-dione
    2,3 4,5-Tetrahydro-7,8-dimethyl-1-benzoxepine-3, 5-dione
    2,3,4,5-Tetrahydro-8-tert.butyl-1-benzoxepin-3, 5-dione
    2,3,4,5-Tetrahydro-7-ethyl-1-benzoxepin-3, 5-dione
    2,3,4,5-Tetrahydro-1-benzoxepin-3,5-dione
    2,3,4,5-Tetrahydro-7-nitro-1-benzoxepin-3, 5-dione
    AT
    R
    d
    E E F 3 And
    Continued table. 3
    Table
    75
    权利要求:
    Claims (1)
    [1]
    72 46 37 Claim 1. The method for producing 3-amino-1-benzoxepin-5- (2H) -one derivatives of the formula,,, and R ,, independently of each other in each case of hydrogen, C-C-alkyl, which at the end of the chain may have an unsubstituted phenyl residue or C, 2 -C5-alkyl, which at the end of the chain may be substituted by a methoxy group, or one of the two radicals R and hydrogen or g-alkyl, and the other - C -C alkyl, substituted at the end of the chain by the group NRg-R, where R 5 independently of each other in each individual case is hydrogen or C -C-alkyl, or alkyl groups RJ and R together with the N-atom, to which they are bound, form a piperidine, morpholine, pyrrolidine or N-benzylpiperazine ring, R-J and R; - independently from each other in each case, hydrogen or halogen, Cf-Gi-alkyl or O-C-alkoxy group, or one of the two radicals R is a nitro group, and the other is hydrogen.
    Continued table. four
    i :::::::; ii ::: i ::::;
     - g -,
    + 15-
    + 10 - -1 + 1 - or their salts, characterized in that, the compound of the formula </ BR> where R- and Rii have the indicated meanings, or a compound of the formula, O BC. Where Rg and RJ}. have the indicated meanings; X is chlorine or bromine, is reacted with a.min by the formula where R and Rj. have the indicated values in the environment of an organic inert solvent and a temperature of -2 (f O to the boiling point of the reaction medium and the desired product is isolated in free form or in the form of a salt, or, if necessary, the salt is converted into the base. Priorities in the examination 1. R. Elderfield. Heterocyclic compounds. M., publishing house of foreign literature, v.2, p.18.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE1593760A1|1967-02-01|1972-06-08|Boehringer Sohn Ingelheim|Process for the production of new benz-epine derivatives|
    US3991082A|1975-03-03|1976-11-09|Warner-Lambert Company|4-Substituted-2,3-dihydro-1-benzoxepin-3,5-diones and tautomers|
    US4153612A|1977-10-31|1979-05-08|The Upjohn Company|2-Benzoxepins|DE3440295A1|1984-11-05|1986-05-15|Kali-Chemie Pharma Gmbh, 3000 Hannover|METHOD FOR DIASTEREOSELECTIVE REDUCTION OF 3-AMINO-1-BENZOXEPIN-5-ONES|
    DE3440296A1|1984-11-05|1986-05-15|Kali-Chemie Pharma Gmbh, 3000 Hannover|3-AMINO-2,3-DIHYDRO-1-BENZOXEPINE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    GB0412139D0|2004-06-01|2004-06-30|Exxonmobil Chem Patents Inc|Olefin oligomerization process|
    JP4916481B2|2008-05-27|2012-04-11|ティーオーエー株式会社|Equipment housing|
    US8722896B2|2008-12-17|2014-05-13|The Regents Of The University Of California|Prokineticin receptor antagonists and uses thereof|
    WO2011025027A1|2009-08-31|2011-03-03|ソニー株式会社|Signal transmission device, electronic device, and signal transmission method|
    US11261141B2|2017-12-14|2022-03-01|Exxonmobil Chemical Patents Inc.|Processes for isomerizing alpha olefins|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19792931398|DE2931398A1|1979-08-02|1979-08-02|NEW 1-BENZOXEPIN-5-ON DERIVATIVES AND THEIR SALTS, METHODS AND INTERMEDIATE PRODUCTS FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
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