• 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:
    Pharmaceutical composition comprising as active ingredient a compound of general Formula (I), wherein R<1> stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms; phenyl alkyl having 7 to 10 carbon atoms; phenyl; or cycloalkyl comprising 3 to 8 carbon atoms; R<2> stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms, alkyl comprising 1 to 8 carbon atoms substituted by halogen, hydroxy, alkoxy having 1 to 4 carbon atoms or by one or two phenyl groups; phenyl; or cycloalkyl having 3 to 8 carbon atoms, with the proviso that groups R<1> and R<2> together contain at least three carbon atoms. The invention also relates to a process for the preparation of compounds of the general Formula (I) by methods known per se. The compounds of the general Formula (I) are psychostimulants having a new spectrum of effect which can be used in therapy for increasing psychical activity (learning and retention) and for treating clinical patterns of depression and deficites of learning and retention like in Alzheimer's disease, and are void of side effects (e.g. due to catecholamine release) of known stimulants.
    公开号:SU1746882A3
    申请号:SU884355858
    申请日:1988-05-24
    公开日:1992-07-07
    发明作者:Кнолл Йожеф；Шимаи Антал；Синньеи Ева；Шофмаи Ева；Терек Золитан；Можолитш Карой；Бергманн Янош
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of phenylalkylamines or their pharmacologically acceptable salts, new biologically active compounds that can be used in medicine.
    It is known that the most important dose-dependent effect of having an indirect effect on sympathomimetic amines belonging to the class of phenylalkylamines (for example, endogenous phenylethylamine and tyramine) is to isolate osatecholamines (primarily noradrenaline) from the plasma neuron stocks. Other non-endogenous phenylalkylamines have similar properties (for example, amphetamine and methamphetamine). The effect of release of norepinephrine and (c. Dose-dependent) the effect of other transfer amines (e.g. serotonin) for metabolic reasons is strong and long lasting. Methamphetamine also appreciably inhibits the neuronal uptake of endogenous sympathomimetic indirect amines, however, this effect in In vivo conditions is completely inhibited by the release of norepinephrine.
    2
    O 00 00
    Yu

    w
    Phenylalkylamine derivatives are known to have the ability to inhibit the absorption of tyramine.
    The disadvantage of these compounds is the lack of selectivity and the ability to inhibit monoamine oxidase (MAO).
    The purpose of the invention is to obtain new derivatives of phenylalkylamines - low-toxic compounds that exhibit a high antidepressant effect, but at the same time selective, not showing the ability to inhibit MAO.
    The goal is achieved by the fact that with the method of producing phenylalkylamines of the general formula

    cH-Nf-m2 (l)
    where RI is straight or branched alkyl, phenylalkyl. Cycloalkyl Sz-Sv. phenyl;
    R2 is a straight or branched lower alkyl, lower alkyl substituted by a halogen atom, hydroxyl, C1-C4 alkoxy group, alkyl containing 3 carbon atoms and substituted by phenyl, C3-C1 cycloalkyl, and R2 together contain from 5 to 13 carbon atoms, and in the case when RI denotes ethyl, R2 cannot denote isobutyl, or the pharmacologically acceptable salts of these compounds are amine of the general formula
    H2N - R2 (I)
    subjected to interaction with the ketone of the General formula
    Rl
    sn2-about 3
    where RI and R2 are as indicated, followed by reduction of the resulting product by catalytic hydrogenation in the presence of palladium or Rene nickel or using a complex metal hydride, sodium dithionite or aluminum amalgam and isolating the desired product as a base or pharmacologically acceptable salt.
    EXAMPLE 1 To a solution of 16.2 g (0.1 mol) of benzyl propyl ketone in 200 ml of methanol was added 23.6 g (0.4 mol) of isopropylamine and 6 g of 5% palladium on charcoal as a catalyst. and the reaction mixture is subjected to hydrogenation under a pressure of 7 to 10 atm with simultaneous shaking. After absorbing the calculated amount of hydrogen, the reaction mixture
    filtered, the filtrate is evaporated, and the residue is dissolved in ethanol containing hydrochloric acid. The mixture is evaporated. The residual M-isopropyl-1-phenyl2-pentylamine hydrochloride can be purified by recrystallization. M.p. 136-139 ° C.
    Example 2. To a solution of 16.2 g (0.1 mol) of benzylpropyl ketone in 30 ml of methanol was added a solution of 7.5 g (0.1 mol) of 3-propanol0 lamin in 20 ml of methanol. The mixture is left to stand, after which 1.9 g of sodium borohydride is added to it, the reaction mixture is allowed to stand again, and after that it is evaporated. The residual crude M- (3-hydroxy-5-ropyl) -1-phenyl-2-pentylamine is purified by distillation in vacuo. Bp with a residual pressure of 0.5 mm Hg 100-110 ° C, 20 to 1.5173.
    The solution of the said base in diethyl ether is acidified to a pH of 2 by adding an ethereal solution of oxalic acid. The precipitated oxylate is filtered and dried. M.p. 144- 146 ° C (ethyl acetate).
    5 Example. To a solution of 19.62 g (0.1 mol) of deoxybenzoin in 130 ml of methanol, 7.8 g (0.13 mol) of n-propylamine are added and after keeping in a calm state for a few hours, 3.78 g ( 0.1 mol
    0 sodium borohydride). The reaction mixture is allowed to stand and then evaporated. The residue is dissolved in water and extracted with benzene. The benzene solution is acidified with 10% hydrochloric acid with simultaneous stirring. The precipitated crystalline N-Npopil-1,2-diphenylethylamine hydrochloride is filtered off and dried. M.p. 229-231 ° С (with a mixture of ethanol and diethyl ether).
    0
    EXAMPLE 4 11.0 g (0.068 mol) of benzyl propyl ketone was dissolved in 110 ml of benzene, after which 8.0 g (0.135 mol) of n-propylamine and 22.6 g (0.2 g) were added to the solution. mol) without aqueous calcium chloride, the reaction mixture is stirred at 40-50 ° C for 6 hours, then it is filtered and evaporated. The crude ketimine thus obtained is dissolved in 120 ml of methanol, and then in
    0, the solution was added 6.4 g (0.17 mol) of sodium borohydride. The reaction mixture is allowed to stand, after which it is poured from 500 ml of water and extracted five times with each time.
    5 times 100 ml of benzene. The benzene solution is dried and evaporated. The crude N-nponwH-phenyl-2-pentylamine thus obtained is purified by distillation in vacuo. Bp with a residual pressure of 7 mm Hg. 112-120 ° C, 20-1.5030 each.
    The ethyl acetate solution of this base is acidified by adding ethanol containing hydrochloric acid to it. The precipitated hydrochloride is purified and dried. M.p. 122-124 ° C (mixture of ethanol and diethyl ether).
    EXAMPLE 5 14.82 g (0.1 mol) of benzyl ethyl ketone is dissolved in 100 ml of 96% ethanol. 12.12 g (0.1 mol) of 2-phenylethylamine was added to the solution, the mixture was stirred for half an hour, after which 3.5 g of amalgamated aluminum foil was added with stirring. The reaction mixture was stirred at 55 ° C for 20 hours, filtered and evaporated. The crude M- (2-phenylethyl) -1-phenyl-2-butylamine thus obtained is purified by distillation in vacuo. Bp 171-173 ° С / 1 mm Нд, po 20- 1,5471.
    14.5 g of this base is dissolved in 14.5 ml of anhydrous ethanol and the solution is acidified to pH 2 by the addition of ethanol containing hydrochloric acid. 800 ml of diethyl ether are added in portions to the purified solution. The solution is cooled and the precipitated hydrochloride is filtered off and dried. M.p. 127-131 ° C (mixture of ethanol and diethyl ether).
    Example 6. To a solution of 21.03 g (0.1 mol) of 1,3-diphenylacetone in 140 ml of 96% ethanol, 11.8 g (0.2 mol) of n-propylamine are added, the mixture is stirred for 1 h, after which 3.5 g of amalgamated aluminum foil is added to it. Next, the reaction mixture was stirred at 55 ° C for 20 h, filtered and evaporated. The residue is dissolved in benzene and acidified with stirring with 10% hydrochloric acid. The precipitated crystalline M-propyl-1,3-diphenyl-2-propylamine hydrochloride is filtered off and evaporated. M.p. 174-176 ° C (mixture of ethanol and diethyl ether).
    EXAMPLE 7 To a solution of 29.6 g (0.2 mol) of benzyl ethyl ketone in 200 ml of 96% ethanol was added 34 ml (0.5 mol) of propylamine, and the mixture was stirred for 1 h. after which 6.75 g of amalgamated aluminum foil is added to it. The reaction mixture was further stirred at 55 ° C for 5 hours, after which 60 ml of 40% sodium hydroxide solution was added to it with stirring. The mixture is filtered and the filtrate is evaporated. The residue is dissolved in benzene, washed with water and extracted with 150 ml of 10% hydrochloric acid. The acidic solution is alkalinized by adding a 40% sodium hydroxide solution, subjected to extraction treatment with benzene, benzene.
    ten
    15
    0
    five
    0
    5 5
    five
    0
    0
    the solution is dried and evaporated. The residual M-propyl-1-phenyl-2-butylamine is purified by distillation in vacuo. Bp 84-88 ° C at a residual pressure of 0.5 mm Hg, according to "1.4956.
    This base is dissolved in diethyl solution and the solution is acidified by the addition of ethanol containing hydrochloric acid. The precipitated crystalline hydrochloride is filtered and dried. M.p. 98-100 ° C (ethyl acetate).
    EXAMPLE 8: 2.45 g (0.077 mol) of 1-phenyl-2-pentanoltolyl ester is dissolved in 4.551 g (0.077 mol) of n-propylamine. The reaction in a mixture at 160-170 ° C proceeds for 7 hours. After cooling, the reaction mixture is dissolved in benzene and washed with water. The benzene phase is shaken with a 10% acetic acid solution. The acetic acid solution is made alkaline with sodium hydroxide solution and the separated oil is shaken with benzene. After drying, filtration and evaporation, 0.68 g of 1M-propyl-1-phenyl-2-pentylamine is obtained.
    PRI me R 9. A mixture of 5 g of alkaline hydroxy-propyl) -1-phenyl-2-propylamine (prepared according to example 2) and 20 ml of concentrated hydrobromic acid is heated to boiling for 5 hours. The reaction mixture is evaporated and the residue each time 25 ml of benzene is dehydrated each time. The crude N- (3-bromopropyl) -1-phenyl-2-propylamine hydrobromide thus obtained is purified by recrystallization from ethyl acetate. M.p. 94-96 C.
    I'll try it on. Reduction of benzyl propyl ketone with sodium dithionate.
    16.2 g (0.1 mol) of benzyl propyl ketone are dissolved in 200 ml of dimethylformamide a and 11.8 g (0.2 mol) of n-propylamine are added. The reaction mixture was allowed to react for 1 hour at 25 ° C, then 21.17 g (0.252 mol) of sodium bicarbonate was added. The mixture is stirred for 2 hours at 110 ° C. At the end of the reaction, the mixture is poured onto 1 l of water and alkalinized with 40% alkali. The finely separated is extracted with benzene, dried and concentrated. The residue is distilled and 12.9 g (63%) of the main distillate are obtained, with a boiling point. 112-120 ° C at 7 mm Hg. Po20 1.5030.
    Examples 11-16. The following compounds listed in Table 1 produce analogs - but examples 1-10.
    Preparation of pharmaceutical compositions comprising a compound of general formula (I) as an active substance. The product is used as active substance.
    Example 4, but any other compound of general formula (I) may be used.
    Example 17. The preparation of hard gelatin capsules containing the composition, the composition of which is given in table 2.
    Capsules are prepared as follows (a total of 1000 capsules). 30.0 g of the active substance are homogenized together with 67.0 g of corn starch, 50 g of Avicel product and 50 g of lactose. The homogeneous powder mixture is granulated using an alcohol solution of polyvinylpyrrolidone on No. 18 sieve, dried and re-granulated on No. 24 sieve. After the second granulation, talc is added and the Suap fit No. 1 capsules prepared in this way are filled manually or by machine . Cooked granules free from dust, polished and packaged.
    EXAMPLE 18: Suppositories of the formulation shown in Table 3 are prepared.
    Suppositories are prepared as follows (a total of 1000 suppositories). 2975 g of Massa Estarinum RC are weighed into a diplikator whose temperature is maintained at 39-40 ° C and melted. 25 g of the active agent are added to the molten mass for suppositories and mixed until complete dissolution (approximately 5-10 min) Suppositories weighing 3.0 g each are cast from this melt. After cooling, the excess suppository mass is removed. Suppository-ready suppositories are removed and packaged. Adeps solidus hastfett DAB (Dynamite Nobel company).
    Example 9. Preparation of dragees (coated pills) of the composition shown in Table 4.
    The dragee core is prepared as follows. The active ingredient, corn starch and lactose are homogenized. The product Luvlscol and stearin are dissolved in isopropanol. The homogeneous powder mixture is granulated using an isopropanol solution. The granules are dried and re-granulated on a sieve No. 16. Add Avicel product and talc and homogenize the mixture. Dragee cores are prepared using a convex head with a diameter of 10 mm. The core thus prepared can be coated with a layer of syrup or film by known methods.
    Example 20: Preparing tablets of the composition shown in Table 5.
    Tablets are prepared as follows. The active ingredient, corn starch and lactose are sieved and homogenized, after which the mixture is granulated using approximately 5% aqueous gelatin solution. The granules are dried to a residual moisture content of 2% and re-granulated on sieve No. 18. To these granules, as the outer phase, the remaining corn starch, talc and magnesium stearate are added and the final mixture is pressed into tablets using
    0 forms with a diameter of 8 mm.
    PRI me R 21. Formulation for injections: L-propyl-1-phenyl-2-pentalamine hydrochloride 30 mg; sodium chloride 8.9 mg; ammonia hydroxide solution concentration 1.7% to
    5 pH 3.0-8.0; distilled water up to 1.00 ml per dose. Biological examples. In vivo determination of the release of noradrenaline in cats.
    0 The state of the flashing membrane of the anesthetized cat is continuously recorded using an auxotonic self-recording kymograph. Isolation of noradrenaline initiates compression of the migratory membrane depending on the dose of the substance. Intraperitoneal administration of phenylethiamine initiates a contraction of the blink membrane, which, by its nature, is temporary. However, amphetamine and methamphetamine cause such a reduction over a long period of time. During this test, the compounds of general formula (I) do not cause a reduction in
    5 membranes.
    Determination of psychostimulating effect in rats.
    Modified jump test.
    0 During this test, small doses of amphetamine (up to 1-2 mg / kg) improve, while higher doses of amphetamine (more than 3 mg / kg) impair the ability to learn and remember, depending on the specific dose.
    Compounds of general formula (I) improve performance at a dosage of 0.5-15 mg / kg, depending on the specific dose. Thus, the proposed compounds are free from the degrading effect that is characteristic in large doses for amphetamine due to the activation of the serotonergic system (doses higher than 10 mg / kg are considered to be very large).
    Test with a shuttle camera. In accordance with this test procedure, daily administration of a dose of 1 mg / kg subcutaneously with amphetamine causes a significant increase in the desire to develop a conditioned reflex and maintain it within five days of observation. However, an enhanced ability is accompanied by an unnaturally strong response to intermediate signals. The effect of higher doses of amphetamine (5-10 mg / kg) cannot be evaluated in the shuttle chamber due to the appearance of an exceptionally high total mobility.
    Daily administration of 0.5 mg / kg of the compound according to Example 4 allows a significantly increased ability compared with the control experiment without signs of increased overall mobility. The compound of Example 4 enhanced the ability to learn and retain the skills from the first day and throughout the entire test period even when an extremely high daily dose of 15 mg / kg was administered to the body. While the ability of experimental animals is unusually high, the enhancement of the reflex to intermediate signals can be considered moderate if one takes into account the exceptionally high ability to learn. The animals to which the compound of Example 4 was administered at a dose of 15 mg / kg fully retain the ability achieved at the end of the one-week training period, even 6 weeks after the completion of the course of drug administration. In accordance with the results of the tests, the proposed compounds achieve an extremely sharp affect on the enhancement of learning ability, the effect being very strong and wide, but is achieved by a different mechanism compared to the mechanism of amphetamine action.
    Determination of antagonism to tetrabenazine-induced depression in rat learning trials.
    Jump test.
    A fixed conditioned reflex, achieved during jump tests, cannot be inhibited by compounds of general formula (I) even in large doses (for example, at a dose of 15 mg / kg of the compound of example 7). Such a reflex can be completely suppressed only with large doses of tetrabenazine (5 mg / kg). while the depressive effect of tetrabenazine can effectively counteract the compound of Example 7 at a dose of 15 mg / kg.
    Test with a shuttle camera.
    In accordance with the results of this test, tetrabenazine-induced depression can be countered with compounds of the general formula (I).
    The results of tests carried out using the compound according to Example 7 are shown in Table 6.
    Similarly, the results are obtained when using the compounds in examples 4 and 13.
    Thus, the proposed compounds have an antidepressant effect.
    Determination of the effect on the motility of rats.
    The test is carried out in a shuttle chamber without the supply of current and light. The number of spontaneous movements from one wall of the chamber to the other within 30 minutes is recorded and summed with the help of the device. This test is carried out with a group of animals that includes 112 rats of the CFY race of both sexes weighing 180-200 g each. Before starting the test, the test compound of general formula (I) was administered subcutaneously to the animals together with tetrabenazine and desmethylimipramine (DMI), respectively, used as a comparative compound.
    In accordance with the results of this test, the compounds of examples 3 and 7 do not increase mobility at a dose of 10 mg / kg. while the compounds of examples 4, 6 and 13, to a certain extent, increase mobility. The effect of increased mobility caused by 1 mg / kg of tetrabenazine is markedly opposed by the compound of example 7 at a dose of 2.5 mg / kg and is completely counteracted by the compound of example 4 at a dose of 1 mg / kg. In the course of these trials, DMI has an inhibitory effect rather than an antagonistic effect on tetrabenazine-induced mobility depression.
    Determination of the effect exerted on rat metabolism.
    During this test, compounds of general formula (I) accelerate the metabolism to a much lesser extent for a shorter period of time than amphetamine or 1-deprenyl,
    Determination of the effect on food intake in rats.
    Oral or subcutaneous administration of well-fed animals with good feeding of the compound of Example 7 at a dose of 15 mg / kg does not change the amount of food they consume (amphetamine exhibits an anorectic effect already at a dose of 1 mg / kg}. At a similar dose, it does not affecting the amount of food consumed by rats who were not allowed to eat for 96 hours in which hunger was completely suppressed by amphetamine for 3–4 hours at a dose of 2–5 mg / kg.
    A dose of 5 mg / kg of the compounds of examples 4 and 13 causes an effect of suppressing the feeling of hunger, which is approximately identical to the effect caused by amphetamine at a dose of 0.5 mg / kg during the first hour.
    Determination of the in vivo uptake of H-noradrenaline by an inadequate layer of the rat cortex.
    The cortex is homogenized in a 0.32 M sucrose solution using a teflon pot, the cell nuclei are sedimented by centrifugation at 0 ° C for 20 minutes in an amount of 1000 g. The supernatant layer thus isolated is used for the tests. The absorption process is carried out in Krebs-Heinzleit's solution, saturated with carbogen, in a final volume of 1 ml at a concentration of H-norepinephrine - 5 mol. Pre-incubation and incubation operations were carried out at 37 ° C for 5 minutes each. The reaction is stopped by adding 4 ml of ice-cold Krebs solution and the fabric is separated by GF / B filtration. Relative absorption is determined using a 10 M solution of nizoketin at 37 ° C. The radioactivity of the GF / B filter paper is determined by measuring the scintillation of a liquid in a toluene – PPO – POPOP mixture — the Triton product.
    Data on the absorption of 2H-norepinephrine by the inadequate layer of rat cortex (tested in vivo) are given in Table 7.
    Determination of the effect of enhancing the dopaminerine effect on isolated cristacetate preparations.
    During ex vivo animal testing, they were injected subcutaneously with the compound for 3 weeks, and 2 hours after the final injection, the organ was removed.
    These changes in the concentration of dopamin (DA) and DO PAC in the bath with the organ under laboratory conditions (mol – min) are given in Table 8.
    These changes in the concentration of DA and DOPAC in the bath with the organ in in vivo tests (mol., Min-1) are given in Table 9.
    Determination of acute toxicity (in rats). The results are shown in Table. ten.
    Inhibition of the release effect of noradrenaline under the action of tyramine in rabbits, pulmonary arterial drug (in laboratory conditions).
    The test procedure includes the following stages: construction of a control schedule for tyramine under cumulative dosage conditions (dose of tyramine 1.3.8 and 18 µg / ml); after washing for 20 minutes, re-scheduling for
    tyramine; equilibration using a single dose of a test compound of general formula (I) for 30 minutes; plotting for tyramine in the presence of test compounds; After 20 minutes of washing, re-plotting for tyramine.
    The results are shown in Table 11.
    Testing has shown that
    权利要求:
    Claims (1)
    [1]
    The proposed compounds have low toxicity, have high antidepressant activity, but do not exhibit the ability to inhibit monoamine oxide. Invention Formula
    The method of obtaining phenylal kil amines of General formula
    25
    Bi
    -CHfCH-NHU2
    0
    five
    0
    five
    0
    five
    where Ri is straight- or branched-chain alkyl Ca-Sw, phenylalkyl St-Syu, cycloalkyl C3-Ce, phenyl;
    R2 is straight or branched lower alkyl, lower alkyl. substituted by a halogen atom, hydroxyl, alkoxy group. alkyl containing 3 carbon atoms and substituted with phenyl, cycloalkyl, provided that the groups RI and Ra together contain from 5 to 13 carbon atoms, and in the case when RI denotes ethyl, Ra cannot denote isobutyl, or their pharmacologically acceptable salts, characterized in that the amine of the general formula
    H2N - R2
    subjected to interaction with the ketone of the General formula
    I1
    CH2-C 0
    where Ri and R are as indicated, followed by reduction of the resulting product by catalytic hydrogenation in the presence of palladium or Rene nickel or using a complex metal hydride, sodium dithionite or aluminum amalgam and isolating the desired product as a base or pharmacologically acceptable salt.
    Table 1
    table 2
    Table 3
    Table A
    15
    Note C - control experiment (physiological chloride solution
    sodium sc daily, N - 12); T - 0.5 mg / kg tetrabenazic subcutaneously daily, N - 12; V — 0.5 mg / kg tetrabenaine + 10 mg / kg of the compound of Example 7, subcutaneously daily, N 12; F + - animals exhibiting a conditioned reflex,%; f - animals reacting to a non-standard stimulus,%:
    f animals that do not react even to a non-standard stimulus,%. IR is the number of reactions to intermediate signals.
    1746882
    16 Table 5
    Table 6
    17
    € tatistic results.
    A more concentrated solution can not be prepared.
    1746882
    18 Table 7
    Table 8
    Table 9
    Table 10
    nineteen
    1746882
    20 Table 11
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    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU864101A|HU207280B|1986-09-25|1986-09-25|Process for producing new phenyl-alkyl-amines and pharmaceutical compositions containing them|LV930485A| LV5226A3|1986-09-25|1993-06-08|Saturation of phenylalkylamine or its pharmacologically acceptable form|
    LTRP653A| LT2581B|1986-09-25|1993-06-12|FEEDBACK OF PHENYLALKYLAMINE OR PHARMACEUTICAL-BASED SALT|
    MD940140A| MD114B1|1986-09-25|1994-04-21|Process for obtaining phenylalkylamines or their salts which can be used in pharmaceuticals|
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