CS211322B1 - 2-Substituted 3- (aryloxy) propylamines and their salts - Google Patents

Abstract

The invention relates to 2-substituted 3-(aryloxy)propylamines and their salts with pharmaceutically acceptable inorganic or organic acids, in whose molecules the 2-substituent is methyl or phenyl, aryl is 2-methoxyphenyl, 2-ethoxyphenyl or 2-benzyloxyphenyl and the amino group is substituted by one or two methyls. These substances and their salts have pharmacological effects in animal tests, which create the prerequisites for their use as neurotropic and cardiovascular drugs. The main types of effects are a mild centrally stimulating activity associated with an antireserpine effect (typical of antidepressants), as well as hypotensive and antiarrhythmic activity (usable in the treatment of cardiac arrhythmias). The invention is focused on the substance protection of the described substances, but the examples of implementation also describe methods of preparing the subject substances. These consist in the reactions of potassium salts of guaiacol, 2-ethoxyphenol and 2-benzyloxyphenol with 2-methyl-3-dimethylaminopropyl chloride or 2-phenyl-3-dimethylaminopropyl chloride, respectively, in boiling 2-butanone in the presence of potassium iodide. In this way, N,N-dimethyl-3-(aryloxy)-2-methyl (or phenyl) propyl·· amines are obtained. Their partial demethylation by the action of ethyl chloroformate and subsequent alkaline hydrolysis of the resulting crude carbamates then gives N-methyl-3-(aryloxy)-2-methyl (or phenyl) propylamines. All the bases prepared are oily, but neutralization with acids yields crystalline salts (preferably hydrochlorides or hydrogen maleates).

Description

This invention relates to 2-substituted-3- (aryloxy) propylamines of formula I,

3 ³ (I)

OCH ₂ CHCH ₂ NCH ₃ R ¹ R ²

Wherein R is methyl or phenyl, R is methyl or hydrogen and R is methyl, ethyl or benzyl, and salts thereof with pharmaceutically acceptable anbrgenic or organic acids.

The compounds of formula (I) and their salts are characterized by pharmacological effects which make them useful as neurotrophic and cardiovascular drugs. The main types of effects are mild central stimulatory activity associated with an antireserpine effect (typical of antidepressants), as well as hypotensive and antiarrhythmic (useful in the treatment of cardiac arrhythmias).

Examples of effects of individual substances according to the invention in animal tests:

N, N-Dimethyl-3- (2-methoxyphenoxy) -2-methylpropylamine (hydrogen maleate): Acute toxicity in mice, LD ^ _Q = 30.2 mg / kg iv V iv dose 3 mg / kg prolongs duration of hypnotic effect of standard girl thiopental in mice, 7 times. At an intraperitoneal dose of 40 mg / kg it has a significant antireserpine effect in the reserpine ptosis assay in mice.

N, N-Dimethyl-3- (2-ethoxyphenoxy) -2-methylpropylamine (hydrogen maleate): LDjq ⁼ 25 mg / kg iv In iv dose of 5 mg / kg it increases the activity and reactivity of the mice and thus acts slightly excitatory.

N, N-Dimethyl-3- (2-benzyloxy-phenoxy) -2-methyl-propylamine (hydrogen maleate) LD ^ ₀ = 5.17 mg / kg iv The iv dose of 3 mg / kg reduces blood pressure slightly normotensive rats.

N, N-Dimethyl-3- (2-ethoxyphenoxy-2-phenylpropylamine (hydrochloride)): LD = g = 12.5 mg / kg i.v.

At a dose greater than 2 mg / kg i.v., it increases the activity and activity of mice and induces ataxia.

At i. V. A dose of 1 mg / kg slightly increased the blood pressure of normotensive rats. Overall, it exhibits mild excitatory and sympathomimetic activity.

N, N-Dimethyl-3- (2-benzyloxyphenoxy) -2-phenylpropylamine (hydrogen maleate): LD50 = 20 mg / kg i.v. In an i.v. dose of 2 mg / kg, it has a hypotensive effect; reduces blood pressure of normotensive rats by 20% for at least 10 min. My pronounced antiarrhythmic effect; at i., v. doses of 0.5-1.0 mg / / kg statistically significantly prolonged the latency of ventricular extrasystoles in aconitin-induced rats; in this test, it is more effective than quinidine. j

N-Methyl-3- (2-methoxyphenoxy) -2-methylpropylamine (dibasic maleate): U> ₅₀ = 24.5 mg / kg iv IV iv dose of 2.5 mg / kg prolongs duration of hypnotic effect of standard thiopental dose in mice 4, 8 times. At an ip dose of 40 mg / kg, it has a significant antireserpine effect in the mouse ptosis test. At doses greater than 6 mg / kg i. V., It induces an increase in activity and marked ataxia in mice. The substance has the characteristics of a potential antidepressant.

N-Methyl-3- (2-ethoxyphenoxy) -2-methylpropylamine (hydrogen maleate) .: LD = g = 30 mg / kg i.v.

At doses greater than 6 mg / kg i.v., they act excitably in mice.

N-Methyl-3- (2-benzyloxyphenoxy) -2-methylpropylamine (hydrogen maleate): LD ^ g = 25 mg / kg

At doses of 2.5-5.0 mg / kg i.v., it induces ataxia in the mice in the rotating rod test. At doses greater than 5 mg / kg i.v., it acts excitably in mice. At doses of 1-2.5 mg / kg i.v., it acts hypotensively in normotensive rats, and at twice the dose it has an antiarrhythmic effect (against aconitine arrhythmias) in rats (approximately equal to the effect of quinidine).

In the examples, methods of synthesizing the compounds of the invention are described. The basic method is the reaction of 2-substituted 3-dimethylaminopropyl chlorides of formula II, cich ₂ chch ₂ n (ch ₃ ) ₂ (II) wherein it denotes the same as in formula I, ce III, with potassium salts of 2-substituted phenols of formula OR

^CrOH (III) wherein R R is also equally valid as in Formula I. The reaction is preferably carried out in torture 2-butanone in the presence of potassium iodide. The products are compounds of formula I wherein

2 *

R = methyl. From these compounds, compounds of formula I, where R = H, can be obtained by a two-step process in which the dimethylamino compounds are first treated with ethyl chloroformate in boiling benzene. Partial demethylation is in progress and carbamates of formula IV result,

STEED

Qoch ₂ chch ₂ nch ₂ (IV)

COOC ₂ Hg in which r 'and R' are the same as in formula I. These carbamates are not isolated in the pure state, but as crude products are subjected to hydrolysis with a concentrated solution of potassium hydroxide 2 in ethanol while hot. In this way, compounds of the formula I are obtained in which R = H.

The compounds of the formula I according to the invention are basic in nature and give salts by neutralization with acids. Some of these salts crystallize well and are soluble in water and are therefore preferable to the free bases for preparing dosage forms and for performing pharmacological tests. If such salts are pharmaceutically acceptable, i.e. practically devoid of pharmacodynamic effects, they are part of the present invention.

Examples

N, N-Dimethyl-3- (2-ethoxyphenoxy) -2-methylpropylamine

Neutralization of 2-ethoxyphenol (at 116 ° C / 4.8 kPa, E. Klarmann et al., J. Amer. Chem. Soc. 54, 1204, 1932) with potassium hydroxide in ethanol and evaporation of the solution under reduced pressure affords a solid. potassium salt of 2-ethoxyphenol.

A mixture of 9.5 g of this salt, 7.5 g of 2-methyl-3-dimethylaminopropyl chloride, 80 ml of 2-butanone and 2.0 g of potassium iodide is stirred and refluxed for 16 h. After cooling, the mixture is filtered, the filtrate is evaporated under reduced pressure, 50 ml of 5% sodium hydroxide solution are added to the residue and extracted with benzene. The extract was dried over anhydrous potassium carbonate and distilled. 10.4 g (81%) of the desired base are obtained, boiling at 111-113 ° C / 60 Pa. Neutralization of the base (3.0 g) with maleic acid (1.5 g) in ethanol and addition of ether gave crystalline hydrogen maleate (4.2 g), which crystallized from a mixture of ethanol and ether and melted at 83-84 ° C.

The preparation of the starting 2-methyl-3-dimethylaminopropyl chloride has been described in the literature (J. W, Jones, US Pat. 3,317,474 '; JP Bourguin et al., Helv. Chim. Acta., 1072 (1958); Brajtburg, Pol. Pat. 56,435), but the substance can be conveniently prepared by the novel process described below;

A solution of 47.3 g of 2-methyl-3-dimethylaminopropanol (V, J. Traynelis, J. G. Dadura, J.

Org. Chem., 26, 686 (1961) in 200 ml of benzene is saturated with anhydrous hydrogen chloride while stirring. Then 72 g of thionyl chloride are added dropwise. The mixture was refluxed for 3 hours and the precipitated 2-methyl-3-dimethylaminopropyl chloride hydrochloride was filtered off with suction after cooling, washed with a little benzene and dried in vacuo. 66.4 g (96%) of a substance melting at 172 DEG C. are obtained. Decomposition of the hydrochloride with 50% sodium hydroxide solution liberates the base, which is extracted with ether, dried over potassium carbonate and evaporated. The remaining oily base of 2-methyl-3-dimethylamino-propyl chloride is used for further work in this crude state.

2. H, N-Dimethyl-3- (2-methoxyphenoxy) -2-methylpropylamine

As in the previous case, the potassium salt of 2-methoxyphenol was prepared by neutralizing guaiacol with potassium hydroxide in ethanol and evaporating the solution.

Also the reaction of 11.1 g of this salt, 9.5 g of 2-methyl-3-dimethylaminopropyl-chloride, 2.5 g of potassium iodide in 100 ml of boiling 2-butanone was carried out similarly to the previous case (boiling time 13 h). 11.7 g (77%) of the desired base are obtained, boiling at 90 DEG-95 DEG C./33 mbar. Neutralization with maleic acid gives the hydrogen maleate, which crystallizes from a mixture of ethanol and ether and melts at 121-122 ° C.

3. N, N-Dimethyl-3- (2-benzyloxyphenoxy) -2-methylpropylamine

As in the previous cases, the potassium salt of 2-benzyloxyphenol is prepared by neutralizing the compound (J.H. Jones, G.T.Your. J. Chem. Soc. / C / 1968. 436) with potassium hydroxide in ethanol and evaporating the solution.

Also the reaction of this salt (from 14.0 g of 2-benzyloxyphenol), 10.0 g of 2-methyl-3-dimethylaminopropyl chloride and 2 g of potassium iodide in 80 ml of 2-butanone is carried out analogously to the previous cases (boiling time 16 h) . 17.5 g (84%) of the desired base are obtained, m.p. 163-166 DEG C./73 mbar. Neutralization with maleic acid provides hydrogen maleate which crystallizes. from a mixture of ethanol and ether and melts at 95-97 ° C.

4. N, N-Dimethyl-3- (2-ethoxyphenoxy) -2-phenylpropylamine

A solution of 7.0 g of 2-ethoxyphenol and 3.4 g of potassium hydroxide in ethanol was evaporated to dryness under reduced pressure. To the remaining potassium salt was added 80 mL of 2-butanone, 10.2 g of 2-phenyl-3Λ

The mixture is stirred and refluxed for 16 h. After cooling, it is filtered, the filtrate is evaporated under reduced pressure, the residue is diluted with 5% sodium hydroxide solution and the product is extracted with benzene. The extract was dried over potassium carbonate and distilled. After removal of 5.1 g of the lower boiling fraction (60-95 ° C / 1 mm Hg), 7.0 g (46%) of the desired base were boiled at 148 ° C / 1 mm Hg. Neutralization with hydrogen chloride in ether gives the hydrochloride, which crystallizes from acetone and melts at 57-159 ° C.

The necessary starting 2-phenyl-3-dimethylamino-propyl chloride is mentioned in the literature (G. Benoit, R. Herzog, Bull, Sci. Pharmacol. 42, 34, 102, 1935: Chem. Abstr. Ϋ, 6259,

1939); it can be prepared as follows:

A solution of 75.7 g of 2-phenyl-3-dimethylaminopropionic acid ethyl ester (G. Satzinger, Justus Liebigs Ann. Chem. 728. 64. 1969) in 200 ml of ether is added dropwise over 4 hours to a stirred suspension of 8.2 g of lithium aluminum hydride. in 150 ml of ether and refluxed for 2 h. After cooling, the reaction is quenched by the slow dropwise addition of a solution of 12 g of sodium hydroxide in 33 ml of water, the mixture is stirred for 30 minutes, the solid is filtered off with suction and washed with ether. The filtrate was dried over potassium carbonate and distilled. 50.1 g (82%) of 2-phenyl-3-dimethylaminopropanol are obtained, boiling at 136-146 ° C / 50 mm Hg.

A solution of 2-phenyl-3-dimethylaminopropanol (50.2 g) in benzene (250 ml) was saturated with hydrogen chloride with stirring and then 50 g of thionyl chloride was added dropwise. The mixture is refluxed for 2.5 hours, allowed to stand overnight at room temperature, the precipitated 2-phenyl-3-dimethylaminopropyl chloride hydrochloride is filtered off with suction, washed with petroleum ether and dried in vacuo; 56.4 g (86%), mp 179-181 ° C. The base is liberated with 50% sodium hydroxide solution, isolated by extraction with ether, the extract is evaporated and the oily residue is used in the crude state for further work. '

5. N, N-Dimethyl-3- (2-benzyloxyphenoxy) -2-phenylpropylamine

As in the previous example, a solid potassium salt was prepared from 14.2 g of 2-benzyloxyphenol, to which were added 80 ml of 2-butanone, 14.2 g of 2-phenyl-3-dimethylaminopropyl ether, and 1.5 g of Jooid. The mixture was stirred at reflux for 18 h. Working up as above gave 12.1 g (47%) of the desired base boiling at 197-200 ° C / 93 Pa. Neutralization with maleic acid in ethanol and addition of ethers yields hydrogen maleate, which crystallizes from a mixture of ethanol and ether and melts at 64-68 ° C.

6. N-Methyl-3- (2-methoxyphenoxy) -2-methylpropylamine

A solution of 11.6 g of N, N-dimethyl-3- (2-methoxyphenoxy) -2-methylpropylamine in 40 ml of benzene is brought to reflux and a solution of 8.4 g of chloroformate is added dropwise over 10 minutes while stirring. ethyl acetate in 20 ml of benzene. The mixture was refluxed for 90 min, cooled with washed with hydrochloric acid and water, dried over potassium carbonate and evaporated under reduced pressure. The residue (14.2 g of oily carbamate) was dissolved in 16 ml of ethanol, 14 g of potassium hydroxide was added and the mixture was refluxed for 3 h in a bath at 130-140 ° C. It is then diluted with water and extracted with benzene.

The extract is washed with water and the base is transferred to the aqueous phase by shaking with excess 10% hydrochloric acid. The separated hydrochloride solution is basified with dilute sodium hydroxide solution, the liberated base is extracted with benzene and the extract is worked up by distillation; 8.9 g (82%), mp 102 ° C / 93 Pa. The base thus obtained is converted by neutralization with maleic acid in ethanol into the hydrogen maleate, which is precipitated by the addition of ether and crystallized from a mixture of ethanol and ether, m.p. 84-86 ° C.

7. N-Methyl-3- (2-ethoxyphenoxy) -2-methylpropylamine

As in the previous case, 7.2 g of N, N-dimethyl-3- (2-ethoxyphenoxy) -2-methylpropylamine are reacted with 5.0 g of ethyl chloroformate in 50 ml of boiling benzene. The crude carbamate obtained is hydrolyzed analogously to the previous case with a solution of 10 g of potassium hydroxide in 12 ml of ethanol. 4.7 g (70%) of a base boiling at 103 DEG C./80 mbar are obtained. Neutralization with maleic acid affords hydrogen maleate which crystallizes from a mixture of ethanol and ether and melts at 90-92 ° C.

8. N-Methyl-3- (2-benzyloxyphenoxy) -2-methylpropylamine

As in the previous cases, 13.35 g of N, N-dimethyl-3- (2-benzyloxyphenoxy) -2-methylpropylamine are reacted with 7.3 g of ethyl chloroformate in 60 ml of benzene and then hydrolysis of the crude carbamate with 14 g of potassium hydroxide in 16 ml of ethanol. 6.0 g (47%) of a base with m.p. (153-156 ° C / 67 Pa) are obtained. Neutralization with maleic acid gives hydrogen maleate, which crystallizes from a mixture of ethanol and ether and melts at 75-77 ° C. hydrochloride, mp 87-90 ° C (acetone-ether).

9. N-Methyl-3- (2-benzyloxyphenoxy) -2-phenylpropylamine;

To a boiling solution of N, N-dimethyl-3- (2-benzyloxyphenoxy) -2-phenylpropylamine (7.9 g) in ml of boiling benzene was added dropwise a solution of 3.55 g of ethyl chloroformate in 20 ml of benzene and treated similarly as in previous cases. The crude carbamate obtained (9.2 g) was similarly hydrolyzed with 9 g of potassium hydroxide in 10 ml of ethanol. The base thus obtained (2.6 g oil) provides a means of hydrogen chloride in ether, 2.55 g hydrochloride salt and crystallized from acetone and melted at a constant 24 to J26 ^In C. With analys and spectra were characterized according to a molecular complex such as N-methyl-3 - (2-benzyloxyphenoxy) -2-phenylpropyl-amine and N-methyl-2-phenylallylamine.

Claims (1)

2-substituted 3- (aryloxy) propylamines of formula I OR ^J ( _2- chch ₂ nch ₃₎ R ¹ R ² Wherein R is methyl or phenyl, R is methyl or hydrogen and R is methyl, ethyl or benzyl, and salts thereof with pharmaceutically acceptable inorganic or organic acids.