FR2637287A1 - 2-Hydroxy-5-[2-(1-pyrrolidinyl)ethoxy]-p-cymene esters, the process for the preparation of the said products and the medicaments containing the said compounds as active principle - Google Patents

Abstract

The present invention relates to the esters of hydroxy-2 [(pyrrolidinyl-1) -2 ethoxy] -5 p-cymene of formula: (CF DRAWING IN BOPI) in which R is chosen from phenyl, benzyl, furyl, diethylamino and tert.-butyl, and salts of said esters with a pharmaceutically acceptable acid, a process for the preparation of these esters and medicaments containing said esters.

Description

Esters of 2-hydroxy-2-pyropyrrolidinyl-2-ethoxy-3-p-cymene, the method of preparation of said products, and the drugs containing said compounds as active ingredient.

 The present invention relates, as novel products, to certain esters of 2-hydroxy-2-pyrrolidinyl-2-ethoxy-3-p-cymene, a process for the preparation of these derivatives; it also relates to the medicaments containing, as active ingredient, at least one of said compounds.

dans laquelle
R est choisi parmi les radicaux phényl, benzyl, furyl, diéthylamino et tert.-butyl.The chemicals according to the invention have the general formula

in which
R is selected from phenyl, benzyl, furyl, diethylamino and tert.-butyl radicals.

 The products according to the invention may also be in the form of salts of the products of formula (I) with a pharmaceutically acceptable acid, for example hydrochloric acid.

 Examples of products having structures similar to those of the products of formula (I) have already been described, for example in the French patent application 87 05770 and in the European patent application 87 401002.8, but said products of formula (I) have, until now, never been described and are therefore new.

 The present invention also relates to a process for preparing the products of formula (I) and their salts.

 The process for the preparation of the compounds of formula (I) consists in esterifying 2-hydroxy-2- (1-pyrrolidinyl) ethoxy] -5-p-cymene by reacting this compound with a suitably chosen acid chloride.

 The salts, for example the hydrochlorides, are obtained in known manner by contacting a solution of formula (I) with the acid in question (for example by bubbling hydrochloric acid into a solution of the product of formula (I) .

The following example illustrates in a nonlimiting manner the process for preparing the products according to the invention (product of formula (I) and its hydrochloride, in which R is the benzyl radical.)
Example
Synthesis of (phenylacetoxy) -2- (1-pyrrolidinyl) -2-ethoxy-3-p-cymene monohydrochloride. Code name: B 1224. Formula product (I) with R = phenylacetyl as ionochlorhydrate.

(1) Preparation of (phenylacetoxy) -2-E (pyrrolidinyl-1) -2 ethoxy3-5 p-cymene
In a 500 ml neck, equipped with a condenser, a magnetic stirrer, an introduction funnel and a thermometer, are introduced
26.34 g (0.1 mole) of 2-hydroxy-2- [(pyrrolidinyl) -2-ethoxy] -5-p-cymene
250 ml of toluene
10.62 g (0.105 mol) of triethylamine.

 To this solution was added dropwise 16.23 g (0.105 mol) of phenylacetic acid chloride (exothermic reaction).

 The reaction medium is heated at 700C for 60 h.

 The evolution of the reaction is studied by vapor phase chromatography.

 After cooling to room temperature, pour over 500 ml of water loaded with sodium chloride.

 Decant the toluene phase and counter-extract the aqueous phase with 3 x 200 ml of methylene chloride.

 The organic phases are combined, washed with water charged with sodium chloride until neutral, and dried over sodium sulfate.

 After filtration, the solvent is evaporated under vacuum.

 45.7 g of a brown oil are obtained.

 Gross yield:> 100 X.

 The crude product is taken up in ethyl ether.

 The organic phase is washed with 3 × 200 ml H 2 O, dried over sodium sulphate. After filtration, the solvent is evaporated under vacuum.

 38 g of a yellowish oil are obtained.

Yield after purification: 99.6 X.

Purity C.P.V. = 98%.

(2) Preparation of the monohydrochloride
19.07 g (0.05 mol) of this product are dissolved in 660 ml of anhydrous ethyl ether. The solution is saturated with a stream of dry gaseous hydrochloric acid on an ice bath. The crystals formed are filtered on a sintered glass, washed with anhydrous ethyl ether and then dried under vacuum over phosphorus pentoxide at 600 ° C.

 16.58 g of cream crystals are obtained (crude yield 79.3%).

 FBK = 150-1520C.

 After recrystallization from ethyl acetate, 11.75 g of white crystals are isolated (yield after recrystallization = 56.2%).

 Said crystals have an FBK melting point of 154-1550 ° C, IR and NMR spectra consistent with the proposed structure, a T.B.A.H. 98.4 X, a title AgNO3 of 100.6 X, purity in gas chromatography greater than 99%.

 Using the same method as that described in the example above, various hydrochlorides of the products of formula (I) were obtained.

 The summary table below illustrates the results obtained in the synthesis of the various products of formula (I).

Note: AcOEt = ethyl acetate
IPA = isopropanol
EtOH = ethanol.

<tb><SEP> Raw <SEP> Formula <SEP> F <SEP> C
<tb> N <SEP> code <SEP> R <SEP> Formula <SEP> gross <SEP> F <SEP> c
<tb><SEP><PN)<SEP> ldt <SEP>
<tb><SEP> (soLvant <SEP> recrtst.)
#####
<tb> B <SEP> 1224 <SEP> t <SEP>> - <SEP> CH <SEP> - <SEP> 56.2
<tb><SEP><417.97)<SEP> (AcOEt)
<tb><SEP> 61) <SEP> C23W30CL <SEP> P03 <SEP> ZDO <SEP> - <SEP> 202
<tb><SEP> 60.2
<tb> B <SEP> lt26
<tb><SEP> (403.94) <SEP> (cost / ilon)
<tb><SEP> C2II <SEP> 5 <SEP> (398.98) <SEP> (AcOEtXI.PA)
<tb> B <SEP> 1246 <SE> O <SEP> C21H28cl <SE> NO <SEP> 4 <SEP> 65.6 <SE> 167 <SEP> - <SEP> 168
<tb><SEP> 0 <SEP> (393.9)
<tb><SEP> CII3
<tb><SEP> I <SEP> 21 <SEP> 34 <SEP> MO3 <SEP> 214 <SEP> - <SEP> 215
<tb> B <SEP> 1289 <SEP> CH3- <SEP> C <SEP> - <SEP> 62.2
<tb><SEP> 1 <SEP> (383.95) <SEP> (AcOEt / EtOH)
<tb><SEP> CH
<tb><SEP> 3
<Tb>

 The toxicopharmacological properties of the products which are the subject of the present invention are described below.

1. Acute toxicity in mice
a) Principle
The molecules were administered orally, using a single-dose oesophageal tube in the male mouse (18-22 g).

Mortality was recorded during a 14-day observation period. The results are expressed in the form of dose Lethal 50 (LD 50) in mg.kg b) Results
They are presented in Table I.

TABLE I

<tb><SEP> Product <SEP> B <SEP> 1224 <SEP> B <SEP> 1226 <SEP> B <SEP> 1242 <SEP> B <SEP> 1246 <SEP> B <SEP> 1289
<tb><SEP> DL <SEP> 50
<tb><SEP> mg. <SEP> kg <SEP>><SEP> 1000 <SEP> 200 <SEP> 100 <SEP> 717 <SEP> 320
<tb>(<SEP> golden)
<tb> 2. Pharmacology studies
2.1 Determination of alpha-blocking activity on the channel
isolated rat deferens
a) Principle
Stimulation of postsynaptic alpha-adrenergic receptors by norepinephrine causes contraction of the isolated vas deferens.

This contraction is inhibited in a dose-dependent manner by the substances having an alpha-blocking potential. We are looking for
The concentration of product in the presence of which the concentration of norepinephrine must be doubled to obtain the same effect as in the absence of said product.

 The changed logarithm of this concentration is the pA2 of the product.

b) Results
They are reported in Table II. The pA2 of most molecules are between 6 and 7. These products therefore have an alpha-blocking activity of interest, at concentrations of between 10 6M and 107M. This adrenolytic effect has been sought in vivo.

TABLE II

<tb> Product <SEP> B <SEP> 1224 <SEP> B <SEP> 1226 <SEP> B <SEP> 1242 <SEP> B <SEP> 1246 <SEP> B <SEP> 1289
<tb><SEP> pA2 <SEP> 7.09 <SEP> 7.07 <SEP><<SEP> 6 <SEP> 6.96 <SE> 6.00
<Tb>
2.2 Determination of adrenolytic action in rats
a) Principle
Intravenous injection of norepinephrine (0.4 mg.kg-1) in the rat caused death of 10% of the animals. The prior administration of a substance with sympatholytic property allows this to reduce this activity.

 The claimed substances were orally injected 30 minutes before intravenous injection of noradrenaline.

b) Results
15 are expressed as ED 50: effective dose
1.5C corresponding to the dose, in mg / kg, protecting 50% of the animals.

 D.E. 50 of the claimed products are shown in Table III.

 The molecules tested are active at doses below 100 mg.ks-1, with respect to the lethal effect of norepinephrine, thus confirming the activity demonstrated on isolated organs.

TABLE 111

<tb> Product <SEP> n <SEP> 1224 <SEP> B <SEP> 1226 <SEP> B <SEP> 1242 <SEP> B <SEP> 1246 <SEP> 5 <SEP> 1289
<tb><SEP> DE <SEP> 50 <SEP> 60 <SEP> 23 <SEP> 14 <SEP> 27 <SEP> 24
<tb> mg. <SEP> kg-1
<Tb>
The products according to the present invention have, with respect to the known products and with respect to the products of formula (I), in which R would have different meanings, a greater activity, in particular alpha-blocking on vas deferens and a better tolerance.

 This increase in alpha-blocking activity, associated with a decrease in toxicity, is particularly evident for B 1224.

 The D.L. 50 of this product is, in fact, greater than 1 g.kg kg orally. As a result, the therapeutic coefficient of B 1224, defined as the ratio of active dose to toxic dose, is greater than 17.

 These data make it possible to predict a good activity of the products according to the invention, in particular B 1224, with a good margin between the therapeutic effect and the possible side effects. The products according to the invention may be used, for example, in neurological dysuria and urinary disorders related to prostatic adenoma.

 The products may be administered by the venous route (in the form of an intravenous infusion solution) orally (for example in the form of capsules, capsules, tablets or drinkable drops) rectally (in the form of suppositories).

The doses and treatment regimens will depend on the subject and the condition to be treated: for example 10 to 50 mg intravenously and 200 to 800 mg per oral and rectal in several daily doses.

Claims (3)

1. Esters of 2-hydroxy-E (pyrrolidin-1-yl) -2-ethoxy] -5-p-cymene of formula

 in which R is selected from phenyl, benzyl, furyl, diethylamino and tert.-butyl, and salts of said esters with a pharmaceutically acceptable acid. 2. Process for the preparation of the products of formula (I), characterized in that 2-hydroxy-2- (2-pyrrolidinyl) ethoxy] -5-p-cymene is esterified with an acid chloride of formula

 3. New drugs having alphablocking activity on the vas deferens, characterized in that they contain at least one product of formula (I).