FR2558159A1 - 3-Alkoxy-2-(N-pyrrolidino)-N-pyridyl-N-arylmethylpropylamines, their preparation and their therapeutic use - Google Patents

Abstract

Compounds of formula: in which Ar represents a substituted phenyl radical or a pyridyl radical; Ar' represents a pyridyl radical; R represents a linear or branched alkyl radical having 1 to 7 carbon atoms and their pharmaceutically acceptable salts. Use in the treatment of cardiovascular disorders such as angina pectoris, hypertension and rhythm disorders.

Description

 The present invention relates to novel 3-alkoxy2- (N-pyrrolidino) -N-pyridyl N-arylmethyl propylamines, their preparation and their therapeutic application.

dans laquelle Ar représente un radical phényle substitué ou le radical pyridyle; Ar' représente un radical pyridyle;
R représente un radical alkyle linéaire ou ramifié ayant 1 à 7 atomes de carbone.These new compounds more precisely meet the following general formula:

wherein Ar represents a substituted phenyl radical or the pyridyl radical; Ar 'represents a pyridyl radical;
R represents a linear or branched alkyl radical having 1 to 7 carbon atoms.

 According to a preferred embodiment, R represents the isobutyl radical and Ar 'the 2-pyridyl radical.

 In the definition of Ar, a "substituted phenyl" radical denotes in particular the 4-methoxyphenyl and 3,4-methylenedioxyphenyl radicals.

 The compounds of formula I having an asymmetric carbon atom, the invention also relates to the separate optical isomers of said compounds.

 The present invention also relates to the addition salts of the compounds of formula I with pharmaceutically acceptable inorganic or organic acids.

The pharmacological studies have shown that the compounds of the invention have interesting cardiovascular properties making it possible to envisage their application in human therapeutics as antiangorous, antihypertensive or antidysrhythmic drugs.
The compounds of the invention may be prepared according to the method corresponding to the cibares reaction scheme:

(Hal represents a halogen)
In a first step, after carrying out a metallization with an alkaline metallizing agent, a pyridylamine was condensed with a 2-halo-1-alkoxy-3-pyrrolidino propane.

 In a second step, the compound obtained was treated with an ArCH2-HaL halide.

 As the metathalising agent in the first step, for example, sodium hydride or sodium amide is used. As a halide, for example, ArCH2Cl chloride is used.

According to a variant of the process, the compounds of the invention may also be prepared by performing in. a first step the condensation of a pyridylamine and an aldehyde ArCHO to give an imine, which is reduced in situ and converted into metallation purified N-pyridyl-N-arylmethylamine ArCH2-NH-Ar formula: which condenses with a 2-halo 1-alkoxy 3-pyrrolidino propane of formula:

As a reducing agent, for example, sodium borohydride is used and sodium hydride or amide is used as the metalating agent. These synthetic methods are illustrated in more detail with reference to. examples below.

EXAMPLE 1: 3-Isobutoxy-2- (N-pyrrolidino) -N- (2-pyridyl) -N- (4-methoxybenzyl) propylamine.

 In a first step, 2-amino pyridine (0.21M) was introduced into a 2-liter tri-neck with magnetic stirring 209 in 400 mb of toluene, and then 7.5. g (0.25M) 80 X sodium hydride. The mixture was refluxed for 1/2 hour, allowed to warm to room temperature, 46.14 g (0.21 M) of 2-chloro-1-isobutoxy-3-pyrrolidino propane were added in one portion and refluxed for one hour. 3 hours. After allowing the reaction mixture to return to ambient temperature, it was washed with water, dried over magnesium sulphate, filtered, and evaporated. solvent to. The residue was then dried under reduced pressure and 38.8 g of 3- (2-pyridyl) amino-2-pyrrolidino-1-i-sobutoxypropane were obtained, boiling point E0.05 = 1540 ° C.

 In a second step, 14 g of the preceding amine in 250 ml of toluene and then 29 (0.067 M) of 80% sodium hydride, which had been heated for half an hour, were introduced into a 500 ml tri-neck. reflux, allowed to return to room temperature and then added 10.2 g (0.065 M) of freshly prepared 4-chloro methyl anisole, then brought the mixture reflux for 3 hours. After allowing the mixture to warm to room temperature, it was washed with water, dried over magnesium sulfate, filtered, evaporated and the solvent distilled off under reduced pressure.

There was thus obtained 4.29 of title product having boiling point E0.05 = 200 ° C., and for elemental analysis: C% HZ
Theory 72.51 8.87 10.57
Found 73.16 8.89 10.50
EXAMPLE 2: 3-Isobutoxy-2- (N-pyrrolidino) -N- (2-pyridyl)
N- (4-pyridyl) methyl propylamine
In a first stage, 300 ml of toluene, 22.49 (0.2 M) of 4-pyridine carboxaldehyde and 18.8 g (0.2 M) of 2-amino pyridine were introduced into a flask. The theoretical amount of water was removed (3.6 ml), the toluene was evaporated, taken up in 300 ml of methanol, and then added in small quantities, 9 g (0.24 M). ) of Na BH4 while keeping the reactor in an ice-water bath, and left stirring for 2 hours at room temperature. The methanol is then evaporated, taken up in water, extracted with dichloromethane, washed. dried over Na 2 SO 4, filtered, then evaporated. taken up in 100 ml of isopropyl ether. 2- (4-pyridyl) methylamino pyridine builds up; after filtration, rinsing with isopropyl ether and drying under vacuum, 20 g of product having a melting point F = 110.30 ° C. were obtained.

 In a second stage, 10 g - (0.054 M) of the above diamine was dissolved in 200 ml of toluene, 2.9 g (Q, 081 M) of 80% NaH was added and refluxed for 1 hour. hour. After allowing to warm to room temperature, 13 g (0.059M) of 2-chloro-1-isobutoxy-3-pyrrolidino propane was added and refluxed for 9 hours. The medium was then hydrolysed, washed with water, the toluene phase dried over MgSO 4, filtered, the solvent evaporated and then the residue was distilled off under reduced pressure.

 There was thus obtained 6 g of the title compound having boiling point Ex 05 = 170-1740c.

EXAMPLE 3: 3-Isobutoxy-2- (N-pyrrolidino) -N- (2-pyridyl)
N- (3,4-methylenedioxy) benzylpropylamine.

 Proceeding as indicated in Example 2, but replacing 4-pyridine carboxaldehyde with 3,4- (methylenedioxy) benzaldehyde, 2- (3,4-methylenedioxy) phenylmethylamino pyridine was prepared in a first step.

 In a second step, 15 g (0.066 M) of the above amine was dissolved in 200 ml of toluene, then 2.7 g (0.089 M) of NaH was added and heated for 1/2 hour at reflux. To return to room temperature, 16 g (0.073 M) of 2-chloro-1-isobutoxy-3-pyrrolidino propane was added and refluxed for 8 hours. After allowing the excess of NaH to warm to room temperature and hydrolysed, the product was extracted according to the usual methods and 5.3 g of the product of the titer were obtained, boiling point E0.05 = 210. C.

 The compounds of the invention have been found to possess interesting anti-calcium properties demonstrated in vitro by the usual methods of molecular pharmacology [VAN ROSSUM Arch. Int. Pharmacodyn. Ther. 143, 299-330 (1963)].

In vivo, the anti-anginal activity was investigated by measuring the usual haemodynamic parameters in the anesthetized dog (percent change and duration of action):
- Heart rate using ECG electrodes
subcutaneous.

Coronary arterial flow using an electronic flow meter
tromagnétique.

Antitachycardial action (inhibition of effects
positive chronotropes of isoprenaline).

 The compounds of the invention are administered by I.V. at the dose of 5 mg.kg-1 and the results reported in Table I below.

TABLE I
EXAMPLE 1 EXAMPLE 3
Frequency Variation% - 27% -7% heart rate Duration (mn) 45 mn 5 mn
Flow Variation% + 84% + 160% coronary Duration (mn) 25 mn 3 mn
Anti-Variation action% - 73% - 21% tachycardisante Time (mn)> 45 mn> 60 mn
These results show for the compounds of the invention, and in particular for Example 1, significant and long-lasting bradycardic and antitachycardic effects, as well as a marked coronarodilator effect.

The compounds of the invention have furthermore been shown to have reduced toxicity: their acute oral toxicity in mice is generally greater than 500 mg.kg 1
This set of pharmacological properties makes it possible to envisage the application of the compounds of the invention in human therapy as a medicament for the treatment of cardiovascular disorders such as
Angina pectoris, hypertension or rhythm disorders.

 Combined with the usual pharmaceutical excipients, they may be administered o-ral or intravenously at daily doses of between 1 and 15 mg per kg of body weight.

Claims (9)

1.Compounding compounds:

 wherein Ar represents a substituted phenyl radical or the pyridyl radical; Ar 'represents a pyridyl radical; R represents a linear or branched alkyl radical having 1 to 7 carbon atoms and pharmaceutically acceptable salts thereof.  2.Compounds according to claim 1, characterized in that Ar 'represents the 2-pyridyl radical and R represents the isobutyl radical.  3.Compounds according to one of claims 1 or 2 characterized in that Ar denotes the radical 4-methoxy phenyl or rad-ical 3,4-dioxymethylene phenyl  4.Compounds according to one of claims 1 or 3, characterized in that Ar 'denotes the 4-pyridyl radical.  5.Procédé for obtaining compounds according to any one of claims ~ 1 to 4 characterized in that one condenses an N-pyridyl-2-pyrrolidino-3-alkoxy propylamine of formula

 with an arylmethyl halide of formula Ar-CH2-Hal, the radicals Ar, Ar 'and R having the meaning indicated in claims 1 to 4.  6.Procédé for obtaining the compounds according to any one of claims 1 to 4 characterized in that an N-pyridyl-N-arylmethylamine of formula Ar CH2-NH-Ar 'with a 2-halo-1-alkoxy-3-pyrrolidino propane of formula

 the radicals Ar, Ar 'and R having the meaning indicated in claims t to 4.  7.Application as drugs, compounds according to any one of claims 1 to 4.  8. A pharmaceutical composition useful as a medicament for cardiovascular disorders, especially angina pectoris, hypertension, and arrhythmias, characterized in that it comprises as active ingredient at least one of the compounds according to one of claims 1 to 4 in combination with de-s appropriate excipients.  9. Pharmaceutical composition according to claim 8, characterized in that it contains an amount of active ingredient such that it is possible to administer daily doses of between 1 and 15 mg per kg of body weight.