CS215495B1 - Heterocyclic 1- (1-phenyl-3-dimethylaminopropyl) amines and their salts - Google Patents

Abstract

The invention relates to new heterocyclic 1-(1-phenyl-3-dimethylaminopropyl)amines, i.e. in particular 1-(1-phenyl-3-dimethylaminopropyl)piperidine and 1-(1-phenyl-3-dimethylaminopropyl)-4-substituted piperazines, where the 4-substituent is a hydrogen atom, alkyl, hydroxyalkyl, cyclopropylmethyl, phenyl, benzyl or ethoxycarbonyl, and their salts with pharmaceutically acceptable acids (mostly maleates are mentioned). The substances according to the invention are characterized by therapeutically useful pharmacological activity, in particular hypotensive, antiarrhythmic, locally. anesthetic and positively inotropic; in particular the antiarrhythmic activity is significant and makes the substances potential drugs against cardiac arrhythmias. The substances according to the invention are prepared by (1) the reaction of N,N-dimethyl-3-chloro-3-phenylpropylamine hydrochloride with piperidine or the corresponding N-substituted piperazines in the presence of potassium carbonate in boiling acetone, (2) the hydrolysis of 1-(1-phenyl-3-dimethylaminopropyl)-4-ethoxycarbonylpiperazine with boiling potassium hydroxide in a small volume of ethanol, (3) the alkylation of 1-(1-phenyl3-dimethylaminopropyl)piperazine with the corresponding halides, especially cyclopropylmethyl bromide, in 1-butanol in the presence of potassium carbonate at 120 ° C. The bases obtained are converted into salts by neutralization with acids, preferably with ί methylene acid.

Description

The compounds of the invention are prepared by (1) reaction of N, N-dimethyl-3-chloro-3-phenylpropylamine hydrochloride with piperidine or the corresponding N-substituted piperazines in the presence of potassium carbonate in boiling acetone, (2) hydrolysis of 1- (1-phenyl- (3) alkylation of 1- (1-phenyl-3-dimethylaminopropyl) piperazine with appropriate halides, in particular cyclopropylmethyl bromide, in 1-butanol in the presence of potassium carbonate at 120 ° C. The bases obtained are converted into salts by neutralization with acids, preferably phosphinic acid.

The invention relates to heterocyclic 1- (1-phenyl-3-dimethylaminopropyl) amines of the general formula I CH ₂ CH ₂ N (CH ₃ ) ₂

CH wherein X is CH ₂ or NR ¹ , wherein R ¹ is hydrogen, alkyl or hydroxyalkyl of 1 to 3 carbon atoms, cyclopropylmethyl, phenyl, benzyl or ethoxycarbonyl, and their pharmaceutically acceptable salts with inorganic or organic acids.

The compounds of the formula I according to the invention and their salts are characterized by their pharmacological activity which makes them useful in therapy. Their antiarrhythmic efficacy, hypotensive, positively inotropic and local anesthetic efficacy are most significant. Thus, the compounds of the invention are particularly useful as therapeutic agents against cardiac arrhythmias.

The efficacy of the compounds of the invention has been demonstrated in pharmacological tests using routine methods in experimental animals (in vivo) or isolated organs (in vitro). The following properties can be mentioned for the individual substances according to the invention:

1- (1-Phenyl-3-dimethylaminopropyl) -4- (3-hydroxypropyl) piperazine was tested as tris (hydrogen maleate). Acute toxicity in mice, LD ₅₀ = 87.5 mg / kg iv At 18 mg / kg iv, mild and short-term decreases in blood pressure are induced in normotensive rats. The substance has a slight positive inotropic effect on the isolated rabbit atrium.

1- (1-Phenyl-3-dimethylaminopropyl) -4-phenylpiperazine was tested as bis (hydrogen maleate). Acute toxicity (mice), LD ₅₀ = 5 mg / kg iv At a dose of 1 mg / kg iv, it causes significant short-term blood pressure decreases in normotensive rats. At the same dose, the compound has a significant antiarrhythmic effect against ventricular extrasystoles in aconitin-induced rats (this effect is higher than that of quinidine and procainamide used as standards). At 1%, it induces complete and long-lasting anesthesia in the guinea pig infiltration anesthesia test (is equipotent with procaine).

- (1-Phenyl-3-dimethylaminopropyl) -4-benzylpiperazine was tested as tris (hydrogen maleate). LD _S0 = 25 mg / kg iv At 5 mg / kg iv, it causes moderate and short-term decreases in blood pressure in normotensive rats.

- (1-Phenyl-3-dimethylaminopropyl) -4- (ethoxycarbonyl) piperazine was tested as bis (hydrogen maleate). LD ₅₀ = 125 mg / kg iv At doses of 25 mg / kg iv, it causes short-term decreases in blood pressure in rats and has a mild antiarrhythmic effect on ventricular fibrillation induced by chloroform inhalation in mice.

1- (1-Phenyl-3-dimethylaminopropyl) piperazine was tested as dimaleinate. LD ₅₀ = 100 mg / kg iv At doses of 20 mg / kg iv, it causes short blood pressure drops in rats, has a mild antiarrhythmic effect against chloroform arrhythmia in mice, and has a mild positive inotropic effect in the rabbit heart test in vitro.

1- (Phenyl-3-dimethylaminopropyl) -4- (cycloprophylmethyl) piperazine was tested as tris (hydrogen maleate). LD ₅₀ = 87.5.mg / kg iv At doses of 17 mg / kg iv, it causes short-term decreases in blood pressure in rats and has antiarrhythmic effects against chloroform arrhythmia in mice.

1- (1-Phenyl-3-dimethylaminopropyl) piperidine was tested as bis (hydrogen maleate). LD ₅₀ = 75 mg / kg iv At doses of 15 mg / kg iv, it causes short-term decreases in blood pressure in rats and has an antiarrhythmic effect on chloroform arrhythmia in mice.

Methods for preparing the compounds of the invention are described in the Examples. The basic preparation is the reaction of N, N-dimethyl-3-chloro-3-phenylpropylamine hydrochloride (T. Tsuji et al., Chem. Pharm. Bull. 8, 763, 1960; H. Nishimura and H. Takamatsu, Yakugaku Zasshi 84 B. Molloy and K. Schmiegel, U.S. Pat. No. 4,018,895, U.S. Pat. No. 2,500,110; Chem. Abstr. 55, 26,995, 1961; 62, 1587, 1965; 87,134,520 (1977); piperidine or 1-substituted piperazines: 1-methylpiperazine, 1- (3-hydroxypropyl) piperazine (T. Zawisza et al., Acta Pol. Pharm, 22,477, 1965), 1-phenylpiperazine (ZJ Vejdelek et al., Collect. Czech. Chem. Commun., 40, 1204 (1975), 1-benzylpiperazine, 1- (ethoxycarbonyl) piperazine, etc. The reaction is preferably carried out in boiling acetone in the presence of anhydrous potassium carbonate.

The (1-phenyl-3-dimethylaminopropyl) piperazine is preferably obtained by hydrolyzing 1- (1-phenyl-3-dimethylaminopropyl) -4- (ethoxycarbonyl) piperazine with boiling potassium hydroxide in a small volume of ethanol. Its N ⁴ -substituted derivatives can also be prepared by alkylation with the appropriate halides, e.g. cyclopropylmethyl bromide, in 1-butanol in the presence of potassium carbonate at 120 ° C.

The bases of the formula I prepared by the above methods can be converted into salts which are more soluble in water than the free bases by neutralization with inorganic or organic acids and are suitable for the production of pharmaceutical forms and for pharmacological tests.

Example 1

- (1-Phenyl-3-dimethylaminopropyl) -4-methylpiperazine

A mixture of 7.0 g of N, N-dimethyl-3-chloro-3-phenylpropylamine hydrochloride, 7.0 g of 1-methylpiperazine, 5.0 g of anhydrous potassium carbonate and 70 ml of acetone is stirred and refluxed for 10 hours. After cooling, the precipitated inorganic salts are filtered off with suction and the filtrate is evaporated under reduced pressure. The residue is dissolved in 80 ml of benzene, washed thoroughly with water, dried over potassium carbonate and worked up by distillation. 4.70 g (60%) of an oily base having a melting point of 125 DEG C./50 mbar are obtained. The product is neutralized with 6.3 g of maleic acid in 10 ml of boiling ethanol; Cooling and addition of 10 ml of ether gave 9.0 g of tris (hydrogen maleate), which crystallized from ethanol and melted in the pure state at 164-165 ° C.

Example 2

- (1-Phenyl-3-dimethylaminopropyl) -4- (3-hydroxypropyl) piperazine

A mixture of 9.36 g of N, N-dimethyl-3-chloro-3-phenylpropylamine hydrochloride, 14.42 g of 1- (3-hydroxypropyl) piperazine, 6.7 g of anhydrous potassium carbonate and 100 ml of acetone is stirred and boiled for 8 h. under reflux. After standing overnight, the product is filtered off with suction, the filtrate is evaporated under reduced pressure and the residue is dissolved in 100 ml of benzene. The solution is washed with 50 ml of water, the aqueous phase is extracted with chloroform and the benzene and chloroform solutions are combined. After drying over magnesium sulfate, distillation is carried out. 8.4 g (69%) of an oily base are obtained, boiling at 170 DEG C./40 mbar. Neutralization with maleic acid in ethanol and addition of ether gives crystalline tris (hydrogen maleate) which crystallizes from ethanol and melts in the pure state at 142-143 ° C.

Example 3

- (1-Phenyl-3-dimethylaminopropyl) -4-phenylpiperazine

A mixture of 10.0 g of N, N-dimethyl-3- i -chloro-3-phenylpropylamine hydrochloride, 7.5 g of 1-phenylpiperazine, 12.4 g of anhydrous potassium carbonate and 70 ml of acetone is stirred and refluxed for 7 h. . After standing overnight an additional 3.0 g of 1-phenylpiperazine is added and the mixture is boiled for an additional 8 h. After cooling, the inorganic salts are filtered off, the filtrate is evaporated under reduced pressure, the residue is dissolved in 150 ml of benzene and washed with water . The benzene was evaporated and the residue (15.5 g) was chromatographed on a column of 300 g of neutral alumina (activity II). Elution with benzene gave 11.5 g (83%) of a homogeneous oily base which, by neutralization with maleic acid in ethanol, gave a crystalline dimaleinate. It crystallizes from aqueous ethanol and melts in the pure state at 173-174 ° C.

Example 4 1- (1-Phenyl-3-dimethylaminopropyl) -4-benzylpiperazine

A mixture of 8.0 g of N, N-dimethyl-3-chloro-3-phenylpropylamine hydrochloride, 9.0 g of 1-benzylpiperazine, 10.0 g of potassium carbonate and 70 ml of acetone is stirred and refluxed for 14 h. After cooling, it is filtered and the filtrate is evaporated in vacuo. The residue is chromatographed on a column of 300 g of neutral alumina (activity II). Elution with benzene gave 9.30 g (81%) of a homogeneous oily base which was neutralized with maleic acid in ethanol. 17.4 g of tris (hydrogen maleate) are obtained, which crystallizes from aqueous ethanol and melts at 166-168 ° C.

Example 5 215495 1- (1-Phenyl-3-dimethylaminopropyl) -4- (ethoxycarbonyl) piperazine

A mixture of 23.4 g of N, N-dimethyl-3-chloro-3-phenylpropylamine (hydrochloride), 39.5 g of 1- (ethoxycarbonyl) piperazine, 16.7 g of potassium carbonate and 200 ml of acetone is stirred and boiled 8. h under reflux. After standing overnight, it is filtered, the filtrate is evaporated under reduced pressure, the residue is dissolved in 200 ml of benzene, the solution is washed with water, dried over sodium sulphate and distilled. 27.7 g (87%) of an oily base having a melting point of 175 DEG C./80 mbar are obtained. Neutralization with maleic acid in ethanol and addition of ether gives a crystalline bis (hydrogen maleate) which crystallizes from ethanol and melts at 105-107 ° C.

Example 6

- (1-Phenyl-3-dimethylaminopropyl) piperazine

A mixture of 20.5 g of 1- (1-phenyl-3-dimethylaminopropyl) -4- (ethoxycarbonyl) piperazine (Example 5), 10.3 g of potassium hydroxide and 20 ml of ethanol is stirred and refluxed for 2.5 hours in bath at a temperature of 120 to 125 ° C. After cooling, the mixture was diluted with 150 ml of water and extracted with benzene. The aqueous phase was saturated with potassium carbonate and extracted with chloroform. The benzene and chloroform extracts were combined, dried over potassium carbonate and worked up by distillation; 11.5 g (73%) of an oily base, m.p. 123 DEG C./0.5 mbar. Neutralization with maleic acid gives the dimaleinate, which crystallizes from ethanol and melts at 156-159 ° C.

Example 7 1- (1-Phenyl-3-dimethylaminopropyl) -4- (cyclopropylmethyl) piperazine

A mixture of 7.1 g of 1- (1-phenyl-3-dimethylaminopropyl) piperazine (Example 6), 4.5 g of potassium carbonate, 4.45 g of cyclopropylmethyl bromide and 80 ml of 1-butanol is stirred and heated for 120 to 125 hours. Deň: 32 ° C. After cooling, it is filtered, the filtrate is evaporated under reduced pressure and the residue is chromatographed on a column of 230 g of neutral alumina (activity II). Elution with benzene gave 3.0 g (35%) of a homogeneous oily base which was neutralized with 3.35 g of maleic acid in 6 ml of boiling ethanol. After addition of 20 ml of ether and standing overnight, 5.3 g of tris (hydrogen maleate) crystallized with m.p. 141-143 ° C (acetone).

Example 8

- (1-Phenyl-3-dimethylaminopropyl) piperidine

A mixture of N, N-dimethyl-3-chloro-3-phenylpropylamine hydrochloride (7.60 g), piperidine (8.20 g), potassium carbonate (9.0 g) and acetone (70 ml) was stirred and refluxed for 15 h. After standing overnight, it is filtered and washed with acetone, and the filtrate is evaporated under reduced pressure while heating on a boiling water bath to remove excess piperidine present. The residue (7.8 g, 98%) is an almost homogeneous base which is neutralized with maleic acid in ethanol. 13.1 g of bis (hydrogen maleate) are obtained, which product is purified by crystallization from ethanol and melts in the pure state at 162 ° C. Decomposition of this salt with aqueous ammonia β and extraction with benzene yields the pure base boiling at 109 ° C / 50 Pa.

Claims (1)

SUBJECT OF THE INVENTION Heterocyclic 1- (1-phenyl-3-dimethylaminopropyl) amines of formula I wherein X is CH ₂ or NR ¹ wherein IR ¹ is hydrogen, alkyl or hydroxy of 1 to 3 carbon atoms, cyclopropylmethyl, phenyl, benzyl or ethoxycarbonyl, and their pharmaceutically acceptable salts with inorganic or organic acids.