• 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 present invention provides 5.6;8,9-tetrahydro-7H-di- benz(d,f)azonine derivatives of the formula: wherein R1 and R2, which are the same or different, are hydrogen or halogen atoms or lower alkyl or lower alkoxy radicals, R3 is a hydrogen atom or a lower alkyl radical, R4 is a hydrogen atom or a lower alkyl or lower alkanoyl radical and n is 1 or 2; and the pharmaceutically acceptable salts thereof formed with inorganic and organic acids; but excluding 6-benzyl-2,12-dimethoxy-1-hydroxy-7-methyl-5,6;8,9-tetrahy- dro-7H-dibenz(d,f)azonine in which case R1, R2 and R4 are hydrogen, n is 1 and R3 is methyl. The lower alkyl, lower alkanoyl and lower alkoxy radicals are straight chain or branched radicals containing 1 to 5 carbon atoms. The present invention also provides a process for the production of these compounds, as well as pharmaceutical compositions containing them. The compounds are useful as antiarrhythmic agents and as local anaesthetics; they do not cause some of the unsatisfactory side effects associated with known agents.
    公开号:SU1036249A3
    申请号:SU813252271
    申请日:1981-02-25
    公开日:1983-08-15
    发明作者:Затцингер Герхард；Херрманн Манфред；Фричи Эдгар；Барманн Хайнрих；Ганзер Фолькер；Вагнер Бернд；Штайнбрехер Вольфганг
    申请人:Гедеке Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention of CrS to the method of obtaining new derivatives 5,6,8, -tetrahydro-7H-dibenz. () Azonine of the general formula HjCO, where R and R are the same or different hydrogen atoms, x ra, fluorine, methyl, m tox group R is hydrogen or methyl., R is hydrogen, methyl, acetone of 1 or 2 or their salts, provided that R, R and R are not at the same time hydrogen atoms, and R is methyl with valuable pharmacological properties. A known method of producing diben zazonin by the interaction of thebaine or nortebain with the Grigne re t.l reagent. The purpose of the invention is the preparation of buty derivatives of dibenzazonin, a region that provides pharmacological activity. This goal is achieved in that, according to the method based on the known reaction (I), a formula is combined. where R has the indicated meanings, is reacted with the Grignard reagent of the general formula (cNg) h9X; R and R have the indicated values; X is a chlorine, bromine or iodine atom, after which the resulting prod uct, if desired, alkylirut, or an acylir, has a hydroxy group with hydrochloride, giving them the desired product in free form or in the form of salts by known methods. The process for the preparation of the target compounds is carried out in conventional solvents using Grignard reagents, for example diethyl ether or an aromatic hydrocarbon, for example benzene or toluene, or in a mixture of these solvents, at a temperature ranging from -15 to methylene chloride can also be used. The decomposition of the Grignard complex can be carried out under especially mild conditions by means of a concentrated aqueous solution of ammonium chloride. The oxygen alkylation of compounds of the general formula I, in which R represents a hydrogen atom, can be carried out using alkylation agents that are commonly used in the case of phenolic groups, for example dialkyl sulfates or diazoalkanes. In the event that R, which is a methyl radical, is desired, higher yields can be achieved by performing methylation using phenyltrimette lammonium hydroxide. P D and m e D 1. (-) - 6-benzyl-2,12-, -dimethoxy-1-hydroxy-7-methyl-5, 6,8,9-tetrahydro-7H-dibenz (d,) azonine . A solution of Grignard reagent is obtained from 5.4 g of magnesium shavings and 25 ml of benzyl chloride (0.23 mol of each of the reagents) and 125 ml of anhydrous diethyl ether. To the resulting solution, a solution of 31.1 g (0.1 mol of thebaine) is added dropwise over 25 minutes and the resulting yellow solution is heated at reflux for 2 h, then cooled, decomposed with a concentrated aqueous solution of chloride ammonium and filtered through silica gel. The organic phase is separated and extracted first with water and then with 1 N hydrochloric acid. The layer containing hydrochloric acid is neutralized with 2N aqueous sodium carbonate solution and the precipitated ethyl acetate is recovered. When carefully adding a saturated solution of hydrogen chloride in ethyl acetate, an oily by-product is first precipitated. Then the hydrochloride of the desired product is precipitated from the decanted solution as a result of adding an additional portion of hydrochloric acid in ethyl acetate. In this way, 9.9 g (23%; 23%; from the theory of (-) benzyl-2D2-dimethoxy-l-hydroxy-7-methyl-5, 6,8,9-tetrahydro-7H-dibenz (d, f) azonine in the form of a salt of acid salt. After recrystallization from propan-2-ol, colorless crystals are obtained, having the melting point of 245-24 ° C M4 -28.70 ° (C,; 1 water). Example 2. (-) B- (3-methoxybenzyl) -2,12-dilyutoxy-1-hydroxy-7-methyl-5, b, 8 j 9-tetrahydro-H-dibenz (d,) azonine. A solution of the Grignard reagent is supplied with 5.4 g (0.225 mol) of magnesium shavings activated with iodine and 34.5 g (O, -225 mol) of freshly prepared m-methoxybenzyl chloride in 200 ml of dry diethyl ether. The resulting Grignard reagent was introduced into the reaction. With 31.1 g (0.1 mol) of thebaine, the same operations were carried out in the same sequence as in Example 1. In this way, 14.3 g (30.5% from the theory of K -) - b (3-methoxybenzyl) -2,12-dimethoxy-1-hydroxy-7-methyl-5, 6,8,9-tetrahyd po-7H-dibenz (d,) aeonin in the form of hydrochloric acid salt. After recrystallization from ethanol, the products are obtained in the form of colorless crystals, melting point 248, fcij -45-, 9 (C, 1 water). Example 3. (-) - 6- (4-fluorobenzyl) -2,12-dimethoxy-1-hydroxy-7-methyl-5, 6,8,9-tetrahydro-7H-dibenz (a,) azonine. A solution of Grignard reagent is obtained from 8.2 g (0.34 mol) of magnesium shavings (activated by iodine) and 63.2 g of LO, 34 mol) of p-fluorobenzylbromide in 350 ml of anhydrous diethyl ether. The resulting Grignard reagent was reacted with 36.5 g (0.15 mol of tebanna, dissolved in 600 ml of benzene), and the reaction mixture was treated according to the method described in Example 1. This method yields 17.6 g (25% of theory ) (-) 6- (4-fluorobenzyl) -2,12-dimethoxy-1-hydroxy-7-methyl-5, 6,8,9-tetrahydro-7H-dibenz (d, f) azonine as a hydrochloric acid salt, containing 0.5 mol of water of crystallization. After recrystallization from propan-2-one, the product is obtained in the form of colorless crystals; melting point, ToiJ If -31, (C, 1 water). Example 4. (-) - 6- (2 -chlorobenzyl) -2, 12-dimethoxy-1-hydr hydroxy-7-methyl-5, 6,8,9-tetrahydro-7H-di6eHa (d,) azonine. A solution of Grignard reagent is obtained from 4.4 g of 1o, 18 mol of magnesium chips, activated by iodine, and 28.4 g (o, 18 mol) o-chlorobenzyl chloride in 100 MP of anhydrous diethyl ether. The resulting Grignard reagent is reacted with 12.5 g of 10.04 mol) of tebaine in 225 ml of anhydrous HOJq benzene and the reaction is treated according to the method described in Example 1. 14.5 g (76.5% of O (-) - € - (2-chlorobenzyl) -2,12-dimethoxy -1-hydroxy-7-methyl-5,6,8, 9-tetrahydro-7H-dibenz (e,) aeronine in the form of a hydrochloric acid salt, having the form b colorless crystals having a after; recrystallization from a mixture of ethyl acetate and propan-2-ol (1: 1 to about 240 ° C. melting point -133.4 "(C, 1 water). Example 5. (4;) - 6-benzyl-7-methyl- 5, 6,8,9-tetrahydro-1,2,12-trimetoxy-7H-dibenz (d,) azonine From 13.2 g (0.08 mol) (-) - 6-benzyl-2, 12- dimethoxy-1-hydroxy-7-methyl-5,6,8,9-tetrahydro-7H-dibenz (d,) azonine hydrochloride, prepared according to the method described in p) Imer 1, receive the free base by exposure to 2n. an aqueous solution of sodium carbonate, and the free base thus obtained is recovered with a mixture of 50 ml of toluene and 5 ml of dimethylformamide. The solution is heated to 100-105 ° C and mixed with 0.09 mol of a 20% aqueous solution of phenyltrimethylammonium oxide hydrate in methanol. The reaction mixture is heated for 1.5 hours so that methanol is simultaneously distilled off, and at the end of heating the boiling point of the reaction mixture is about. The reaction mixture is then heated at the same temperature for 1 hour, after which the solvent is removed in vacuo and the residue is separated from dimethylaniline by steam distillation. The residue is chromatographed on 125 g of silica gel (0.003-0.2 VIM J in toluene. Elution is carried out with 0.6 l of toluene containing 1% ethanol and the fractions obtained are analyzed by IR / NMR. Pure product (purity 98.5% ) is obtained in the form of a non-crystalline, practically colorless resin. Thin-layer chromatography: rylica gel 25 254, methanol / HCf {i: .9 by volume), 0.55. In this way, 7.8 g (65% of the theory of (+) -6-benzyl-7-methyl-5,6,8,9-tetrahydro-1, 2,12-trimethoxy-7H-dibene (d,) azounin) are obtained. Example 6. (-) - 6- (3-methoxybenzyl) -7-methyl-5,6,8,9-tetrahydro-1, 2,12-trimethoxy-7H-dibenz (d, f) azonine. 8, 5 g (O, 02 mol) (-) - 6- (3-methoxybenzyl) -2,12-dimethoxy-1-hydroxy-7-methyl-5,6,8,9-. tetrahydro-7H-dkbenz (d,) azone (prepared according to the method described in Example 2) is dissolved in 50 ml of toluene and 5 ml of dimethylformamide and mixed with 0.08 mol of a 20% aqueous solution of phenyltrimethylammonium oxide hydrate in methanol, after which the reaction is carried out in the same manner as described in The product obtained is purified on a chromatherapy column filled with 80 g of silica gel (0.063-0.2 mm). Thus, 6.2 g of (-) - b- (3-methoxybenzyl) are obtained. ) -7-methyl 5,6,8,9-tetrahydro-1, 2,12-trimethoxy-7H-di6eH3 (d, f) ahernine in the form of a practically colorless resin, yield 69.4%.
    The sample is subjected to thin layer chromatography (silica gel 254, methanol / chloroform 1: 9 by volume Rg p, 55) 5 Degree of purity: 99.3% (chromatography), oi I-Z // CC, 1 methanol) ..
    PRI and eper 7. {-) - 1-acetoxy-6- (3-methoxybenzyl) -7-methyl-5,6,8, 9-tetrahydro-2,12-dimethoxy-7H-di- ;; ; 10 6eH3 (d, f) azonine.
    15.2 g (0.032 mol) (-) - b- (3-methoxybenzyl) -2,12-dimethoxy-1-hydroxy-7-netide-5, 6, 8,9-tetraido-7H-dibenz (d) Azonin, obtained according to the method described in Example 2, is heated for 6 hours at a temperature from 120 to 130s with 50 ml of acetic acid. it anhydride. The main part of acetic anhydride after the reaction is distilled -. -. in vacuum. The residue is partitioned between water and diethyl ether and the ether phase is extracted with an aqueous solution of sodium carbonate. The residue after distillation of the organic phase in the vacuum is extracted with toluene and chromatographed on 250 g of silica gel (0.060, 2 mm), using toluene + 1% methanol for elution. In this way, 10.0 g (67.5% of theory) of (-) - 1-acetoxy-b- (3-methoxy-30 benzyl) -7-methyl-5,6,8,9-tetrahydro2, 12- dimethoxy-7H-dibenz (d,) Az6nyna in the form of a practically colorless resin. Thin layer chromatography: silica gel f 254, methanol / chloroform 35 1: 9 by volume, R 0.55, purity: 99.7% (chromatography), 20 (0, 1 methanol).
    Pr im 6 p 8. (-) - 1-acetoxy-b-6enzyl-2, 12-dime.oksi-7-methyl-: -5,6,8,9-tetrahydro-7H-dibenz (d, f a) azonine. .
    9.0 g (0.02 mol) of (-) - b-benzyl-2 p12-dimethoxy-1-hydroxy-7-methyL-5, 6,8,9-tetrahydro-7H-dibenz (d, f) 45 Azonine (prepared according to the method described in Example 1) is introduced into the reaction and processed according to a method similar to that described in Example 3. This cnoco6oNf gives 50 8.7 g (97% of the theory of G (-) - 1-acetic x-6-benzyl -2, 12-dimethyl-7-methyl-5, b, 8,9-tetrahydro-H-dibenz (d, f) azonine in the form of a practically colorless resin. Thin layer chromatography; silica gel-254, methanol / chloroform 1: 9 by volume, Rf 0.5, purity 95.3% (chromatography), CctJlr -2,. (C, 1 methanol).
    Example 9. b-benzyl-2,12-. -dimethoxy-1-hydroxy-5,6,8,9-tetra-O hydro-7I-dibenz (d, f) azonine.
    A solution of Grignard reagent is obtained from 8.5 g (0.35 mol) of magnesium shavings and 40 ml (0.35 mol) of benzyl chloride in anhydrous diethyl 65
    on air. The obtained reagent is reacted with 30 g (0.1 mol) of nortebain while in tetrahydrofuran. After 2 h after heating at 55 ° C, the reaction mixture is mixed with a saturated aqueous solution of ammonium chloride and a subsequent treatment is carried out. In this way, 1b g of crude base is obtained, which is purified on a chromatographic column (silica gel / toluene + 2% methanol). 6-benzyl-2,12-dimethoxy-1-hydroxy-5, 6, 8,9-tetrahydro-7H-dibenz (d, f) azonine is obtained in the form of colorless crystals / which can be subjected to recrystallization from a mixture of 3-ethyl acetate / chlorine methylene} temperature melt NIN b2-65 ° C
    Example 10. (+) - 2,12-dimethoxy-1-hydroxy-7-methyl-b. Fvnethyl-5,6,8,9-tetrahydro-7H-dibenz (d,) azonine.
    A solution of Grignard reagent is obtained from 5.5 g (0.23 mol) of activated magnesium shavings and 41.5 g (0.24 mol) of phenethyl bromide in 200 ml of anhydrous diethyl ether. To the resulting reagent is added dropwise at 35- 40c solution of 31.5 g (0.1 mol) of tebaine in 0.4 l of dry benzene. After heating under reflux for 2 hours, the reaction mixture is decomposed with a solution of 48 g of ammonium chloride in 200 ml of water. As a result of the subsequent treatment, after transferring the base to the hydrochloride, by reaction with hydrogen chloride in ethyl acetate, 7.3 g (21% of) (+) - 2,12-dimethoxy-1-hydroxy-7-methyl-6-phenethyl-5 are obtained. , b, 8,9-tetragon id .po-7H-dibenz (d, f) azonine as a hydrochloric acid salt, melting point 227, after recrystallization from propan-2-ol.
    Example 11. (-) - 6- (2,6-dichlorobenzyl) -2,12-dimethoxy-7-methyl-1-hydroxy-7H-dibenz (d, f) azonine.
    A solution of Grignard reagent is obtained from 6.6 g (0.265 mol |) of activated magnesium chips and 54.3 g of 10.265 mol; 7 2,6-dichlorobenzyl chloride in dry diethyl ether. According to the described method, the obtained reagent is reacted with 39 g (0.125 Molvol of tebaine in dry benzene. The 4 reaction mixture is entrained for 2 hours and decomposed with a concentrated aqueous solution of ammonium chloride. After separation of the organic layer and its processing, a crude base is obtained which translates t in hydrochloride as a result of exposure to hydrogen chloride in ethyl acetate. Thus, 34.5 g (52% of the theory of I) -6- (2, 6-dichlorobenzyl) -2,12-dimethoxy-7-methyl-1- hydroxy-7H-dibenz (d, f) azonine in the form of hydrochloric acid salt-temperature melting point 255c after recrystallization from propan-2-ol. P RIM er 12, (-) - b- (3-methylbenzyl) -2,12-dimethoxy-7-methyl-1-hydroxy-5, b , 8,9-tetrahydro-I-dibe (d, f) a30HHH. A solution of Grignard reagent is obtained from 7.7 g (0.31 mol) of magnesium shavings and 57 g (0.31 mol of 3-methylbenzyl bromide in dry diethyl ether re according to a method similar to that described in Example 1. The resulting reagent is mixed with a solution of 45.5 g (0.145 mol) of thebaine in 525 ml of benzene. The reaction is complete after heating for 2 hours at 50 ° C. After treatment in the usual manner, 40 g of an unpurified base are obtained, from which, by exposure to chlorine-hydrogen in ethyladetate (propan-2-ol (2: 1 by volume)), (-) - b- (a-methylbenzyl) -2 are precipitated 12-dimethoxy-7-methyl-1-hydroxy-5, b, 8,9-tetrahydro-7H-dibenz (d,) aeronine as a hydrochloric acid salt. The yield is 15.1 g (31% of theory) temperature melting after recrystallization from propan-2-ol. In order to prepare pharmaceutical compositions, the active products can be mixed with conventional additives and liquid or solid carriers. General formulas (I can be administered by the oral or parenteral route in the form of liquid or solid formulations in a wide range of dosages. Commonly used additives for liquid formulations include, for example, tartrate and citrate buffers, ethanol complexing agents (for example, ethylenediaminetetraacetate necks and its non-toxic salts) as well as high molecular weight polymers (eg, liquid polymer ethylene oxide), introduced to control the viscosity of the formulation. As examples of solid carriers, starch, lactose, mannitol, methylcellulose, talc, fine silicic acids, high molecular weight fatty acids (e.g., stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal, and vegetable and solid high molecular weight polymers (for example, polyethylene glycol L. Compositions intended for oral administration may, if desired, contain substances that impart a certain taste to them and / or make them sweet. According to the invention, they range from 0.1-100 mg depending on the indications for their use.The activity of the described compounds is illustrated by the following experimental data: 1. Methodology, 1.1.Arrhythmias caused by the disturbance of extracellular electrolytic equilibrium in rats.In rats exposed to narcotic means, caused by arrhythmias due to the intravenous administration of calcium chloride solution. After the termination of the administration, the arrhythmias continued for a certain period of time (modification of the method yes, according to Malinow. The duration of the arrhythmia phase was reduced due to prophylactic therapy of agents for the treatment of arrhythmia. The activity of the compounds according to the invention was compared with the activity of procainamide and fenitroin. : 1.2. Electrophysiological study of the heart ventricle in guinea pigs. The guinea pigs were stimulated by the electrical impulse of the left ventricle of the heart, and the amplitude of heart contractions was recorded. As a result of the second stimulation, a period of time was determined during which the heart muscle could no longer respond to it in the form of separately resolving contractions. The indicated time was defined as the absence of excitement, 1.3. Pressing the cardiac artery in dogs, In dogs under anesthesia, the rib cage and pinned the heart artery (lateral branch R, interventr, post, .- or R, circumflexus) according to method A, C, Harris . Changes in the rhythm of cardiac contractions due to this operation were recorded on the following day after treatment in animals after relieving the effects of anesthesia by treatment with compounds according to the invention with their intragastric and intravenous route. As a standard; positive effects were used with procainamide. From the data of electrocardiography, the time after administration of the tested compounds was determined, during which the sinusoidal rhythm was clearly visible. 1.4. Local anesthetic effect on the rabbit eye. In rabbits, irritation of the cornea was caused by horsehair, which had a deflection under the influence of a pressure of about 250 mg (modification of the method described, von-Frey X) After driving the anesthetic drug into the space adjacent to the mucous membrane of the eye, the number of irritation by horsehair decreased, the drive During the time interval equal to 4 min S, more than 1000 consecutive acts of irritation were performed in each case, and in this case the resultant was taken to be 100%. No study was no more than 60 minutes. The effect of the compounds according to the invention was compared with the effects of tetracaine and procai iamide. 1.5 Acute toxicity to mice ... The compounds according to the invention were administered intragastrically to male mice (NMRI) and 2025 body weight The experimental group for each dose consisted of four animals. The value of the BP value was determined after 7 days.s 2 Results .. 2.1 Arrhythmias in rats. The results obtained for arrhythmias caused by chloride, calcium are given in Table. 1. The average period of existence of arrhythms was calculated for experiments with a number of animals of at least 10. All compounds according to the invention reduce the period of existence of arrhythmias compared to control animals that have not undergone treatment with any anti-arrhythmic agent. . The compounds according to the invention have a better effect compared with Sprockin Amide, or, in the case of using a compound according to Example 11, the same effect with respect to reducing the period of arrhythmia. With such an experiment, phenytoin does not have anti-arrhythmic effect at all. 2.2. No excitation time in studies on the left ventricle of guinea pigs. No excitation time during left ventricular examinations. Keer ser / guinea pigs were determined as described and ranged from 161 to 200 ms. In tab. 2 contains information on the maximum concentrations of the tested compounds, as well as on the average length of time for the absence of excitation, measured at the indicated concentrations, in comparison with the initial value. In each case, data were obtained from at least six trials. The compounds according to the invention have an activity exceeding the activity of the compounds used for comparison, such as aimalin, phenytoin, procainamide, and virepamil, 2.3. Clamping the heartart in a dog. The compounds according to examples 1 (Table 3)., 4 (Table 4) and 10 (Table 5) were tested on dogs subjected to pinching of the cardiac artery. The results obtained when using procainamide, are listed in Table. 6. Each of the compounds was tested on at least five animals in each case. The test compounds according to the invention, when administered internally, even in small doses have a stronger effect than procainamide; Their activity in the intestine after intragastric administration cannot be illustrated. The experiments performed illustrate a very wide range of therapeutic effects of the compounds according to the invention. In tab. 7 contains the results of experiments on eye irritation in rabbits. In this table, in addition to the concentration of solutions of the test compounds excreted into the eye, adjacent to the cornea, the effectiveness of the effect of the compound (see the description of the research method used) and the duration of exposure are given. In each of the cases, the test lasted no more than 60 minutes. When tested by this method, procainamide is inactive, and tetracaine has a maximum effect (100%) for 44 minutes. The compounds according to the invention exhibit a longer period of activity.
    VO g
    h th
    ABOUT


    H)
    VO
    s
    rH
    at
    O t
    about
    about
    ъ
    "
    1L
    Ol CM

    "
    t ts
    PM tS
    oe
    - (
    oh oh
    about
    "
    "about
    about
    W1
    VO MS
    s
    t-h
    ABOUT
    00

    about
    (P
    s
    P
    s
    and
    f o
    VO
    g
    VO
    and
    tn
    G4
    rH
    um
    SU1
    about)
    VO
    I
    P
    V
    0
    I
    AO
    "-I
    II
    F “. I 0) S and about S to
    & §Llg§
    Dosage mg / kg Average duration of arrhythmia, min. Dosage mg / kg. Average duration of arrhythmia, NMH J pg. from. “and dosage, mg / kg C1rodn duration of arrhythmia, min T
    2.4. Local anesthetic effect. The effect of the compound according to APA "Ep 1 on c with a squeezed heart artery / 4 intra- (10 intra- (15 intra- (20 intra- | (25 intra-intragastrino-gastro-gastro-gastro-gastro-gastro) but)). . about : . 62 49 99 105 198, Effect of the corjriacHC compound of Example 4 on dogs With a constricted heart artery 4 intra- (40 intra- (60 intra- (80 intraperitoneally) gastro) gastrointestinal) 6891 103 139 The effect of the compound according to 10 on dogs with constricted heart artery (2 intra- (5 intra u- (10 intragastar- (40, intrajudicated) percutaneous) percutaneous), 40105169185 T а 1 l and C a Procainamide effect on dogs with constricted heart artery Dosage,, (10 intramg / kg Venous) Average duration of arrhythmia, min; 19 Table 3 Table 4. “Ft IT a b l and c a 5. h .
    Local anesthetic effect on the rabbit eye
    OD
    3 5
    8 10
    eleven
    12
    Procainamine
    Tetracaine
    Table V
    89
    About 49
    Acute toxicity to mice
    The compound according to example 1
    12
    3h
    4 5 6 7
    eight . 10 11 12
    Procainamide phenytoin
    Table 8
    (The value of LD-50. Intragastric) mg / kg
    680
    1000
    6.00
    loop
    About 1000 300
    900 1200
    600
    More than 1600 1200 1200. 150
    权利要求:
    Claims (1)
    [1]
    1. A method of obtaining derivatives of 5,6,8,9-tetrahydro-7H-dibenz (d, f) azonine of the formula I 0 wherein R and R z are the same or different hydrogen atoms ( chlorine, fluorine, methyl, methoxy group;
    R - hydrogen or methyl;
    R 4 is hydrogen, methyl, acetyl η = 1 or 2 or their salts, provided that R 1 , R 2 and R 4 are not simultaneously hydrogen atoms, and R is methyl, characterized in that the compound of formula II is reacted with a reagent Grignard general formula And! ·
    K * · where n, R and R z have the indicated meanings; X is an atom of chlorine, bromine or iodine, after which the resulting product j is optionally alkylated or the existing hydroxy group is acylated, followed by isolation of the desired products in free form or in the form of salts.
    类似技术:
    公开号 | 公开日 | 专利标题
    EP0348341B1|1994-11-23|Aminoalkyl indoles, process for their preparation and pharmaceutical compositions thereof
    CS199690B2|1980-07-31|Process for preparing derivatives of spiro-hydantoine
    DE2718669C2|1987-06-11|
    EP0104489A1|1984-04-04|Aminoalkyl steroids
    EP0286278A1|1988-10-12|Indanamine derivatives useful as antiarrhythmic agents
    BG60835B2|1996-04-30|Epininester, method for its preparation and medicamentous compounds
    SU1036249A3|1983-08-15|Process for preparing derivatives of 5,6,8,9-tetrahydro-7h-dibenz-|-azonine or their salts
    EP0816338B1|2003-02-12|3-|oxindole derivatives
    SU1468424A3|1989-03-23|Method of producing derivatives of hydantoin
    DE2724478C2|1986-05-22|5,11-Dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one derivatives, processes for their preparation and pharmaceuticals containing these compounds
    US4001271A|1977-01-04|3-|-2-phenyl-isoindolin-1-ones
    EP0262404A1|1988-04-06|Glucosylmoranoline derivatives
    RU2272027C2|2006-03-20|Derivatives of 3-hydroxypiperidine and pharmaceutical composition based on thereof
    EP0150235A1|1985-08-07|Derivatives of 3-pyrrolidinopropiophenone and a process for preparation thereof
    US4695589A|1987-09-22|Alpha-|benzenemethanols
    EP0228314A2|1987-07-08|Use of ethanol/amine derivatives in treating or preventing hyperlipemia
    EP0187012B1|1989-06-21|Novel compositions
    US4235803A|1980-11-25|1,6-Dimesyl-3,4-dimethyl-D-mannitol and a process for the preparation thereof
    US4327095A|1982-04-27|Methoxy derivatives of 1,4-dithiepino-[2,3-c]-pyrrole
    CH620204A5|1980-11-14|
    EP0013017A1|1980-07-09|4-Homoisotwistane-aminoacid amides and pharmaceutical compositions containing same
    US4026899A|1977-05-31|Benzo and benzothiopyranoindazole N-oxides
    US3884925A|1975-05-20|Diisoquinolyl-dipyridyl-butanes, their salts and their manufacturing process
    US4720501A|1988-01-19|2-|-imidazo|pyridine derivatives and salts thereof useful in the treatment of myocardial insufficiency
    US4000306A|1976-12-28|Anti-arrhythmic compositions containing isoindoline derivatives
    同族专利:
    公开号 | 公开日
    DE3160909D1|1983-10-27|
    AT4708T|1983-10-15|
    DE3007710C2|1982-04-15|
    FI810632L|1981-08-30|
    JPS56158766A|1981-12-07|
    AU6767081A|1981-09-03|
    AU539348B2|1984-09-20|
    EP0035360A2|1981-09-09|
    HU182298B|1983-12-28|
    EP0035360B1|1983-09-21|
    EP0035360A3|1981-09-23|
    FI75340C|1988-06-09|
    DE3007710A1|1981-09-10|
    FI75340B|1988-02-29|
    US4415495A|1983-11-15|
    ZA81863B|1982-03-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE181510C|
    US3751487A|1969-12-11|1973-08-07|Hoffmann La Roche|Alkoxy substituted-2,2'-biphenyldimethanols|
    US3932384A|1972-08-17|1976-01-13|Shionogi & Co., Ltd.|Dibenzazecines|DE3419099A1|1984-05-23|1985-11-28|Gödecke AG, 1000 Berlin|RACEMIC ASOCAINOL, METHOD FOR THE PRODUCTION THEREOF, AND THE USE THEREOF IN THE FIGHT AGAINST REITING LINE MALFUNCTIONS|
    DE3541994A1|1985-11-28|1987-06-04|Goedecke Ag|METHOD FOR ISOMERIZING ASOCAINOL|
    US5302716A|1986-01-16|1994-04-12|Schering Corporation|Fused benzazepines|
    US4973586A|1986-01-16|1990-11-27|Schering Corporation|Fused benzazepines, compositions of, and medical use thereof|
    IL86131D0|1987-04-24|1988-11-15|Boehringer Ingelheim Kg|Benzo-and thieno-3,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them|
    WO1993004408A1|1991-08-16|1993-03-04|Eastman Kodak Company|Ferrite green beads and method of producing carrier particles|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE3007710A|DE3007710C2|1980-02-29|1980-02-29|5,6; 8,9-Tetrahydro-7H-dibenzazonine derivatives, processes for their preparation and pharmaceuticals|
    [返回顶部]