RU2015960C1 - Process for preparing phenylkylamines or salts of these compounds - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: the product: phenylalkylamines of the general formula: C₆H₅CH₂CH(R₁)NH(R₂) (1) wherein R₁ is straight or branched C₂-C₈-alkyl, C₇-C₁₀-phenylalkyl, C₃-C₈-cycloalkyl, phenyl; R₂ is C₁-C₈-alkyl, C₁-C₈- alkyl substituted with a halogen atom, hydroxy or alkoxy containing from 1 to 4 carbon atoms; alkyl containing 3 carbon atoms and substituted with phenyl; C₃-C₈ cycloalkyl provided that R₁ and R₂ together contain at least 5 carbon atoms, and in the case when is ethyl; R₁ cannot be isobutyl, or salts of these compounds. Reagent 1: an amine of the general formula: R₂ (2) wherein C₆H₅CH₂CH(R₁)NH₂ is as defined above. Reagent 2: R₁ (3) wherein X is halogen, a sulfonic acid ester residue; XCH(R₃)R₄ is hydrogen, R₃-alkyl, C₁-C₇-alkyl substituted with a halogen atom, hydroxy or alkyl containing from 1 to 4 carbon atoms, alkyl containing 2 carbon atoms substituted with phenyl; C₁-C₇ is hydrogen or R₄ and R₃ and R₄ are alkyl provided that they together contain not more than 5 carbon atoms or R₃-R₄ together with CH can form a cycloalkyl ring containing from 3 to 8 carbon atoms. Reaction conditions: in the presence of an acid binding agent such as an excess amount of an amine, an organic or inorganic base or an alkaline ion exchanger followed, if necessary, by conversion of the compound of the formula (1) into a salt. EFFECT: improved properties of the resulting compounds. 7 tbl

Description

 The invention relates to organic synthesis and relates to the production of new phenylalkylamines or their salts having biological activity and used as an active principle in pharmaceutical preparations stimulating the central nervous system.

 The novel phenylalkylamines of the invention exert their effect on the body primarily by inhibiting the neuronal uptake of biogenic amines.

 It is known that the most important dose-dependent effect of the so-called indirectly acting sympathomimetic amines, chemically belonging to the class of phenylalkylamines (for example, endogenous phenylethylamine (PEA and tyramine), consists in the isolation of catecholamines (primarily norepinephrine) from plasma stocks of neurons. other non-endogenous phenylalkylamines (for example, amphetamine and methamphetamine) possess. Moreover, the effect of the release of norepinephrine and (depending on the dose) the effect of other transmissions for metabolic reasons, it is strong and long acting.Metamphetamine also significantly inhibits the neuronal uptake of endogenous sympathomimetic amines of indirect action, but this effect in vivo is completely suppressed by the release of norepinephrine.

 The invention is based on the fact that in the class of phenylalkylamines a modification of the chemical structure is proposed that can completely eliminate the known characteristics and the dominant effect of this group of compounds, namely the effect of inducing the outflow of transfer amines, and on the other hand, it can enhance the effect so far subordinate groups of compounds (namely, inhibition of neuronal uptake of sympathomimetic amines) in a selective way. In this way, stimulants characterized by a new spectrum of action can be obtained.

где R₁ обозначает алкил с прямой или разветвленной цепью, содержащий от 2 до 8 углеродных атомов; фенилалкил, содержащий от 7 до 10 углеродных атомов; фенил или циклоалкил, содержащий от 3 до 8 углеродных атомов;
R₂ обозначает алкил с прямой или разветвленной цепью, содержащий от 1 до 8 углеродных атомов; алкил, содержащий от 1 до 8 углеродных атомов, замещенный атомом галогена, гидроксилом, алкоксигруппой, содержащей от 1 до 4 углеродных атомов; алкил, содержащий 3 атома углерода и замещенный фенилом, или циклоалкил, содержащий от 3 до 8 углеродных атомов, при условии, что R₁ и R₂ вместе содержат по меньшей мере пять углеродных атомов, и причем, в том случае, когда R₁ - этил, R₂ не может обозначать изобутил, или солей этих соединений.In accordance with the invention it is proposed to obtain biologically active phenylalkylamines of the general formula I

where R ₁ denotes a straight or branched chain alkyl containing from 2 to 8 carbon atoms; phenylalkyl containing from 7 to 10 carbon atoms; phenyl or cycloalkyl containing from 3 to 8 carbon atoms;
R ₂ represents a straight or branched chain alkyl containing from 1 to 8 carbon atoms; alkyl containing from 1 to 8 carbon atoms, substituted by a halogen atom, hydroxyl, alkoxygroup containing from 1 to 4 carbon atoms; alkyl containing 3 carbon atoms and substituted by phenyl, or cycloalkyl containing from 3 to 8 carbon atoms, provided that R ₁ and R ₂ together contain at least five carbon atoms, and moreover, in the case when R ₁ - ethyl, R ₂ cannot denote isobutyl, or salts of these compounds.

где R₁ имеет указанные значения, с соединением общей формулы III X-

где X - атом галогена или сложноэфирная группа сульфоновой кислоты,
R₃ - атом водорода или алкил С₁-С₇, который может быть замещен галогеном, гидроксилом, алкокси-группой с 1-4 атомами углерода, алкил, содержащий два атома углерода, замещенный фенилом,
R₄ - атом водорода, или
R₃ и R₄ обозначают алкил, при условии, что они совместно содержат не более пяти атомов углерода или R₃ и R₄ могут вместе с СН образовывать циклоалкильное кольцо с 3-8 атомами углерода, после чего, если желательно, соединения общей формулы I подвергают превращению в соли, образуемые с органической или минеральной кислотой, и/или выделяют соединения общей формулы I из солей в свободном состоянии.According to the invention, phenylalkylamines of the general formula I are obtained by reacting an amine of the general formula II

where R ₁ has the indicated meanings, with a compound of the general formula III X-

where X is a halogen atom or an ester group of a sulfonic acid,
R ₃ is a hydrogen atom or C ₁ -C ₇ alkyl, which may be substituted by halogen, hydroxyl, alkoxy group with 1-4 carbon atoms, alkyl containing two carbon atoms substituted by phenyl,
R ₄ is a hydrogen atom, or
R ₃ and R ₄ are alkyl, provided that they together contain no more than five carbon atoms or R ₃ and R ₄ can form a cycloalkyl ring with 3-8 carbon atoms together with CH, after which, if desired, the compounds of general formula I are converted to salts formed with an organic or mineral acid, and / or the compounds of general formula I are isolated from salts in the free state.

 The specified alkylation reaction is carried out in the presence of an acid binding agent. For this purpose, an excess of the starting amine compound or an organic or inorganic base (for example triethylamine or potassium carbonate) can be used; a basic ion exchange resin may also be used.

 The compounds of the general formula I obtained according to the invention are free base oil-soluble, oil-like substances which, if desired, can be converted to crystalline, water-soluble salts. The salt production process can be carried out using pharmaceutically acceptable inorganic or organic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, maleic acid and the like). The compounds of general formula I and their biologically acceptable acid adducts can be used as active substances in the preparation of pharmaceutical compositions for humans.

 These pharmaceutical compositions based on the new compounds can be prepared according to methods known in the pharmaceutical industry. The active substance can be used in conventional dosage forms (for example, in the form of tablets, pills, dragees, capsules, injectable preparations and the like). Said pharmaceutical compositions may include conventional carriers, additives, lubricants, excipients, auxiliary agents and the like.

 Compounds of general formula I markedly inhibit tyramine-initiated release of norepinephrine from the plasma pores of neurons by inhibiting the absorption of tyramine. In contrast to the known phenylalkylamines, the compounds of general formula I do not exhibit the effect of isolating norepinephrine. At the same time, the compounds of formula I strongly inhibit the neural absorption of norepinephrine and dopamine, significantly enhancing the catecholaminergic effect, but unlike amphetamine and methamphetamine, they do not affect the serotonergic effect even when introduced into the body in large doses.

 The compounds of general formula I are stimulants of the central nervous system, which exhibits a stimulating effect in pharmacological tests for training and antidepressant drugs, only to a moderate degree increase mobility and metabolism, do not show a noticeable anorectal effect and are only slightly toxic.

 In contrast to the main group of known psychoenergetic agents, the compounds of general formula I do not possess a monoamine oxidase (MAO) inhibitory effect. If we consider the mechanism of their action and chemical structure, they significantly differ from the known tricyclic antidepressants.

 Based on the foregoing, it can be argued that phenylalkylamines of the general formula I constitute a psychopharmacone group with a new mechanism of action acceptable for increasing mental activity (learning, preserving memory) and for the medical treatment of clinical models of depression, as well as diseases accompanied by noticeable defects in learning ability and memorization, like Alzheimer's disease, presumably without the side effects characteristic of known stimulants that cause catecholamine secretion.

 In accordance with the activity of the compounds of the invention, the treatment method comprises treating healthy or sick people with a pharmaceutical composition comprising an effective amount of a compound of general formula I or a pharmaceutically acceptable acid adduct thereof.

 Preferred daily doses are about 10-150 mg, in particular about 30 mg. Such pharmaceutical compositions are preferably administered orally, parenterally or sublingually.

 Due to its low toxicity, the compounds of general formula I can also be used to treat children in an appropriately calculated dosage.

 An acceptable veterinary dose is 2-8 mg / kg.

 Compounds of general formula IV form a subgroup of compounds of general formula I, which is particularly favorable.

Ниже приведены примеры, которыми не ограничиваются рамки и объем притязаний.

The following are examples that do not limit the scope and scope of the claims.

PRI me R 1. a) 16.3 g (0.1 mol) of 1-phenyl-2-pentylamine are dissolved in 180 ml of ethyl acetate and 80 g of K ₂ CO ₃ are added, after which 12.3 g are added dropwise to the mixture. (0.1 M) isopropyl bromide. The mixture was refluxed for 8 hours. The inorganic salt was filtered off and the filtrate was purified with activated carbon. Then the filtrate was evaporated and the residue was dissolved in hydrochloric acid ethanol, and the resulting solution was evaporated again. After crystallization from a mixture of ethanol and ethyl ether, 17.5 (72%) N-isopropyl-1-phenyl-2-pentylamine hydrochloride is obtained with a melting point of 136-139 ^about S.

 b) 16.3 (0.1 mol) of 1-phenyl-2-pentylamine is dissolved in 180 ml of toluene and 30 ml of a 20% aqueous NaOH solution are added, after which 12.3 g (0.1 mol) are added dropwise. isopropyl bromide. The mixture was stirred for 3 hours at room temperature and heated under reflux for the next 3 hours. The toluene phase was separated, the aqueous phase was extracted with benzene. The combined organic phases were purified and evaporated. The salt formation was carried out similarly to the above. Thus, 14.6 g (60%) of N-isopropyl-1-phenyl-2-pentylamine hydrochloride are obtained.

 c) The procedure described in a) is repeated using 30.3 g (0.3 mol) of triethylamine as an acid-binding agent instead of potassium carbonate.

g) A process is carried out similarly to that described in paragraph a) using 1200 ml of the macroporous anion exchanger Amberlist A-26 (OH-form) suspended in 1000 ml of ethyl acetate instead of potassium carbonate. The reaction mixture is carried out at 60 ^{° C} for 12 hours. The ion exchanger was filtered off and washed with ethyl acetate, then the process is carried out as described in a.). Thus, 11.3 g (50%) of N-isopropyl-1-phenyl-2-pentylamine hydrochloride are obtained.

 PRI me R s 2-15. The compounds listed in table 1 were obtained analogously to example 1 a).

PRI me R 16. 16.3 g (0.14 mol) of 1-phenyl-2-butylamine is dissolved in 70 ml of benzene and 2.96 g (0.01 mol) of ethyl para-toluenesulfonate are added dropwise, dissolved in 20 ml of benzene (m.p. 34 ° ^C). The reaction mixture is boiled for 3 hours and concentrated. The residue was dissolved in benzene and extracted with sodium hydroxide and then with water (each time twice). The benzene extracts are dried and concentrated. Excess starting materials are removed by distillation under vacuum at 122-124 ^{° C} (fP _10). The residue was dissolved in ethanol and hydrochloric acid in ethanol was added to form hydrochloric acid salt. Upon precipitation with diethyl ether, 15.4 g of N-ethyl-1-phenyl-1-butylamine hydrochloride are obtained, so pl. 145-147 ^about S.

EXAMPLE 17 To a solution of 67.5 g (0.5 mol) of 1-phenyl-2-propylamine in 340 ml of benzene, 17.0 g (0.074 mol) of 2-methoxyethyl tosylate are added. The reaction mixture was heated to boiling for 3 hours and then evaporated. The residue is treated with benzene, extracted with 100 ml of a 10% sodium hydroxide solution and washed with 700 ml of water. The benzene phase is dried and evaporated. The resulting crude N- (2-methoxy-ethyl) -1-phenyl-2-propylamine was purified by vacuum distillation. The resulting pure product has a boiling point of 94-102 ^about With 8 mmHg, n _D ²⁰ = 1,5012. The specified base is converted into salt by addition of acid by treatment with a mixture of ethanol-hydrochloric acid. The precipitate of crystalline hydrochloride is filtered off and dried. The product has so pl. 115-118 ^about C (acetone).

 II. Biological examples.

 II / 1. Determining the effect of in vivo release of norepinephrine on cats (in vivo).

 The condition of the blinking membrane of the anesthetized cat is constantly recorded using an auxotonic self-recording kimograph. The release of norepinephrine initiates a blinking distillation contraction depending on the dose of the substance. Intraperitoneal administration of 1 mg-kg PEA initiates a reduction in the blinking membrane. A dose of 1 mg / kg amphetamine and methamphetamine causes such a reduction over an extended period of time. During the test, the compounds of general formula I do not cause any reduction in the membrane.

 II / 2. Determination of psychostimulating effect in rats.

 a) Modified hopping test.

 During this test, small doses of amphetamine (up to 1-2 mg / kg) improve, while increased doses of amphetamine (more than 3 mg / kg) impair the ability to learn and remember, depending on the specific dose. The compounds of general formula 1 improve performance in a dosage of 0.5-15 mg / kg, depending on the specific dose. Thus, the new compounds are free from the worsening effect that is characteristic in large doses for amphetamine due to activation of the serotonergic system. Doses in excess of 10 mg / kg are considered very large.

 c) Test with a shuttle camera.

 In accordance with this test procedure, daily administration of a dose of 1 mg / kg subcutaneous amphetamine into the body causes a significant increase in desire to develop a conditioned reflex and maintain it for five days of observation. However, an increase in ability is accompanied by an unnaturally strong reaction to intermediate signals. The effect of higher doses of amphetamine (5-10 mg / kg) cannot even be estimated in the shuttle chamber due to the occurrence of an extremely high general mobility phenomenon.

 The daily administration of 0.5 mg / kg of the compound in accordance with Example 4 significantly improves the ability compared with the control experiment without signs of increased overall mobility.

 The compound in accordance with example 2 increased the ability to learn and maintain skills from the very first day and throughout the test, even with the introduction of an extremely high daily dose of 15 mg / kg. While the ability of experimental animals is unusually high, the amplification of the reflex to intermediate signals can be considered moderate, given the extremely high learning ability. Animals to which the compound in accordance with example 2 was introduced into the body 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 completion of the course of drug administration. In accordance with the results of the said tests, the compounds of the invention achieve an exceptionally sharp effect of enhancing learning ability, said effect being very strong and broad, but achieved by a different mechanism in comparison with the mechanism of action of amphetamine.

 II / 3. Determination of antagonism to depression caused by the action of tetrabenazine in rat training trials.

 a) Jump test.

 The fixed conditioned reflex achieved during the hopping tests cannot be inhibited by the compounds of the general formula I even in large doses (for example, at a dose of 15 mg / kg of the compound according to Example 7). Such a reflex can be completely suppressed only by large doses of tetrabenazine (5 mg / kg), while the depressive effect of tetrabenazine can be effectively counteracted by the compound in accordance with Example 7 at a dose of 15 mg / kg.

 c) Test with a shuttle camera.

 In accordance with the results of this test, depression caused by tetrabenazine can be resisted using compounds of general formula I. In table. 2 shows the numerical values obtained in a number of tests carried out using the compound in accordance with example 7.

 Similar results are obtained when using the compounds in accordance with examples 2 and 12.

In the table. 2 is indicated:
C - control experiment (physical solution of sodium chloride daily subcutaneously, N = 12);
T - 0.5 mg / kg tetrabenazine subcutaneously daily, N = 12;
Y - 0.5 mg / kg tetrabenazine + 10 mg / kg of the compound according to example 7 subcutaneously daily, N = 12.

F + =% of animals exhibiting a conditioned reflex
f + =% of animals responding to a non-standard stimulus
f - =% of animals that do not even respond to a non-standard stimulus.

 lR = number of responses to intermediate signals.

 II / 4. Determination of the effect on the mobility of rats.

 The tests are carried out in a shuttle chamber without supplying current and light. The number of spontaneous movements from one chamber wall to another within 30 minutes is recorded and summed to help the device. This test is carried out with a group of animals, which includes 112 rats of the race CFY of both sexes weighing 180-200 each. Before starting the test, the test compound of general formula I is 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 2 and 7 do not increase mobility at a dose of 10 mg / kg, while the compounds of examples 2, 6 and 12 increase mobility to a certain extent. The effect of increasing 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 completely opposed by the compound of example 2 already at a dose of 1 mg / kg. In the course of these trials, DMI has an effect that is more likely to be in itself inhibitory than an antagonistic effect in relation to mobility depression caused by tetrabenazine.

 II / 5. Determination of the effect exerted on metabolism in rats.

 During this test, compounds of general formula I accelerate metabolism to a much lesser extent over a shorter period of time than either amphetamine or 1-deprenyl.

 II / 6. Determination of the effect on food intake in rats.

 Administration orally or subcutaneously to a well-fed animal with good feeding of the compound in accordance with 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 affect the amount of food consumed by rats that 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 in accordance with examples 2 and 12 causes an effect of suppressing hunger, which is approximately identical to the effect caused by amphetamine at a dose of 0.5 mg / kg during the first hour.

II / 7. Determination of the in vivo uptake of ³ N-noradrenaline by an insufficient layer of rat cortex (in vivo).

The cortex is homogenized in 0.32 M sucrose solution by a Teflon pot, the cell nuclei are sedimented by centrifugation at ⁰ ° C for 20 min in an amount of 1000 D. For testing using a dedicated layer thus insufficient. The absorption process is carried out in a Krebs-Heinseleit solution, saturated with carbogen, in a final volume of 1 ml at a concentration of ³ N-noradrenaline 5.10 ^-8 mol. The operation of pre-incubation and incubation is carried out at 37 ^about C for 5 minutes each. The reaction was stopped by adding 4 ml of ice-cold Krebs solution and the tissue was separated by CF / B filtration. The relative absorbance is determined using a 10 ^-4 M solution nizaksetina at 37 ^C. The radioactivity CF / B - filter paper is determined by measuring scintillation fluid in a toluene-PPO-POPOP product "tritone".

 The results obtained are summarized in table 3.

 Determination of the effect of enhancing dopaminerin action on isolated rat striatum preparations.

 In the course of conducting preliminary tests on animals, they are injected subcutaneously into the body for 3 weeks, and 2 hours after the final injection, the organ is removed.

 The results obtained are summarized in tables 4 and 5.

 II / 8. Acute toxicity of E. (in rats).

 The results obtained are summarized in table 6.

 II / 9. Inhibition of the effect of secretions of norepinephrine under the action of tyramine in rabbits, pulmonary arterial preparation (in laboratory conditions).

 The test procedure includes the following steps.

 1) Construction of a control schedule for tyramine under the conditions of cumulative dosing (doses of tyramine: 1, 3, 8, 18 mg / kg).

 2) After washing for 20 minutes, re-plotting for tyramine.

 3) Balancing using a single dose of the test compound of General formula I for 30 minutes

 4) Plotting for thiamine in the presence of test compounds as described in section 1).

 5) After washing for 20 minutes, re-plotting the graph for teramin.

 The results obtained are summarized in table 7.

Claims (1)

The method of producing phenylalkylamines of the General formula

where R ₁ is C ₂ is straight or branched chain C ₈ alkyl, C ₇ is C ₁₀ phenylalkyl, cycloalkyl C ₃ is C ₈ phenyl;
R ₂ - C ₁ - C ₈ straight or branched chain alkyl, C ₁ - C ₈ alkyl substituted with a halogen atom, hydroxyl, alkoxy group containing from 1 to 4 carbon atoms, alkyl containing three carbon atoms and substituted with phenyl, C ₃ - C ₈ -cycloalkyl, provided that the groups R ₁ and R ₂ together contain at least five carbon atoms and when R ₁ is ethyl, R _{2 is} not isobutyl,
or salts of these compounds, characterized in that the amine of the general formula

where R ₁ has the indicated meanings,
reacted with a compound of the general formula
X-

where X is halogen, a sulfonic acid ester residue;
R ₃ is hydrogen, C ₁ -C ₇ straight or branched chain alkyl, C ₁ -C ₇ alkyl substituted with a halogen atom, hydroxyl, alkoxy, containing from 1 to 4 carbon atoms, alkyl containing two carbon atoms, substituted phenyl;
R ₄ is hydrogen, or R ₃ and R ₄ is alkyl, provided that they together contain no more than 7 carbon atoms, or R ₃ and R ₄ together with CH can form a cycloalkyl ring with 3 to 8 carbon atoms,
using an acid-binding agent — an excess of an amine, an organic or inorganic base, or an alkaline ion exchanger, with isolation of the product in its free form or in the form of a salt.

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