FR2547582A1 - Substituted 3-aminomethyl-5-methyl-1,4-dioxanes, their preparation and their application in therapeutics - Google Patents

Abstract

Compounds corresponding to the formula: in which R1 represents hydrogen and R2 represents an alkyl or aralkyl radical, or else R1 and R2 represent, together with the nitrogen atom to which they are bonded, a substituted heterocyclic radical; R3 and R4 separately represent a lower alkyl radical or the phenyl radical, or together a cycloalkyl radical. Application to the treatment of hypertension (high blood pressure).

Description

dans laquelle R1 représente l'hydrogène et R2 représente un radical alkyle ou aralkyle, ou bien R1 et R2 représentent ensemble avec l'atome d'azote auquel ils sont liés un radical hétérocyclique substitué tel que le radical $-(benzimidazoli- din-20ne-l-yl)pipéridyle,ou un radical 4-phényl pipérazinyle dans lequel le reste phényle peut être substitué par un halogène,un radical alkyle, un radical alcoxy ou le radical trifluorométhyle; R3 et R4 représentent séparément un radical alkyle inférieur ou le radical phényle,ou ensemble un radical cycloalkyle tel que le radical cyclohexyle,ainsi que les sels pharmaceutiquement acceptables de ces composés.The present invention relates to novel substituted aminomethyl-5-methyl-1,4-dioxanes having the following general formula:

wherein R 1 represents hydrogen and R 2 represents an alkyl or aralkyl radical, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a substituted heterocyclic radical such as the radical $ - (benzimidazolidin-20) 1-yl) piperidyl, or a 4-phenylpiperazinyl radical in which the phenyl residue may be substituted by a halogen, an alkyl radical, an alkoxy radical or the trifluoromethyl radical; R 3 and R 4 represent separately a lower alkyl radical or the phenyl radical, or together a cycloalkyl radical such as the cyclohexyl radical, as well as the pharmaceutically acceptable salts of these compounds.

 The invention also relates to the application of these compounds in human therapy because of their interesting antihypertensive properties.

5 o 15 20 25 30
Le 3-hydroxyméthyl 5-méthyl 1,4dioxanne substitué en 6 par R3 et Rq peut lui-même être préparé à partir de matières premières usuelles en effectuant successivement les réactions suivantes.The invention also relates to a process for obtaining said compounds by condensation in an organic solvent in the presence of triethylamine, an amine
NHR1R2 and a 3-hydroxymethyl-5-methyl-1,4-dioxane substituted at 6 by R3 and R4, and which can be previously converted into mesylate by the action of mesyl chloride, which corresponds to the following reaction scheme:

5 o 15 20 25 30
The 6-hydroxymethyl-5-methyl-1,4-dioxane substituted at 6 with R 3 and R 2 can itself be prepared from standard raw materials by successively carrying out the following reactions.

 In a first step, a tertiary acetylenic alcohol is condensed with 1-benzyloxy-2,3-epoxypropane in the presence of a solution of boron trifluoride in ether.

 In a second step, the cyclization of the acetylenic compound previously obtained is carried out by causing the potash to act in an anhydrous aromatic solvent medium.

 In the last step, the desired alcohol is obtained by reduction under hydrogen pressure in the presence of a catalyst (Pd / C).

This succession of reactions corresponds to the following diagram

[R3 et R4 ont les significations précédemment indiquées et X représente l'hydrogène, un halogène, un radical alkyle, un radical alcoxy, ou le radical trifluorométhyle].

According to a variant of the process, when -NR 1 R 2 represents the substituted 4-phenylpiperazinyl radical, the compounds of the invention may also be prepared by cyclization of a 1-phenyl-4- [3- (propyne 2-yloxy) -2 hydroxy J propyl piperazine by action of a strong base9puis catalytic reduction of the compound obtained. This variant corresponds to the following scheme:

[R 3 and R 4 have the previously indicated meanings and X represents hydrogen, a halogen, an alkyl radical, an alkoxy radical, or the trifluoromethyl radical].

The invention is further illustrated by the following examples:
EXAMPLE 1
3- [4- (2-methoxyphenyl) piperazinyl] methyl-5-methyl
"-cyclohexyl 1,4-dioxane
Preparation of 3-hydroxy methyl 5-methyl-6-cyclohyexyl-1,4-dioxane
In a first step, was introduced into a tricolor containing 3 moles (342 g) of ethynyl cyclohexanol and 6 ml of a 10% solution of BF3 etherate, 1 mole (l64g) 1-benzyloxy-2,3-epoxypropane in now the temperature between 45 and 50 C; the reaction mixture was then brought to 600 ° C. for one hour, allowed to return to ambient temperature, then the excess BF.sub.3 etherate was hydrolysed and the product obtained was extracted by extraction with ether.

 There was thus obtained 100 g of an oil having a boiling point of E0.5 = 160-165 ° C.

 In a second step, 24 g of powdered potassium hydroxide and 100 g of the previously obtained acetylenic derivative were introduced into a reactor containing 1 liter of anhydrous xylene and then refluxed with an azeotropic tube for 3 hours. The xylene solution was then washed with water, dried over Na2SO4, filtered, evaporated and distilled.

 There was thus obtained 64 g of product having boiling point E 0.5 = 157 C.

In the last step, a hydrogen-containing flask containing 64 g of the above compound in 150 ml of 960 g and 14 g of 10% palladium on carbon was introduced into a "Parr-type" hydrogenator under pressure. proceed for 2 hours, then the catalyst was filtered and rinsed, evaporated to dryness and 20 g of the alcohol of the title condensation with 4- (2-methoxyphenyl) piperazine were obtained:
In a first stage, the mesylate of the preceding alcohol is prepared: in a tricolor containing 20 g of alcohol and 60 ml of pyridine, 10 ml of mesyl chloride are added dropwise, keeping the temperature between
At the end of the addition, the reaction medium was allowed to warm to room temperature, evaporated to dryness, taken up in ether, washed with water, dried over Na 2 SO 4, filtered and evaporated at room temperature. dry.

 23.5 g of mesylate used in the following stage were thus obtained.

In a reactor containing 100 ml of toluene and 10 ml of triethylamine, 11.13 g of mesylate and 6.4 g of 4- (2-methoxyphenyl) piperazine were introduced, and the mixture was then refluxed for 6 hours with control. the end of reaction by thin layer chromatography. Then it was evaporated to dryness, taken up with ether, washed with water, dried over
Na 2 SO 4 and evaporated to dryness. The hydrochloric acid was then reacted to give 4 g of the title compound as dihydrochloride having mp = 2190 ° C. The fumarate of said compound having a melting point F = 199 ° C. has also been produced.

The fumaric acid dosage of this last salt corresponds to:
% theoretical: 23.66
Found%: 23,63
EXAMPLE 2: 3! 2-methylphenethylamino] methyl 5-methyl
6-oxohexyl 1,4 dioxane.

 In a reactor containing 100 ml of toluene, 11.1 g of the alcohol mesylate prepared as in Example 1, 4.5 g of amphetamine and 10 ml of triethylamine were introduced and the mixture was refluxed for 8 minutes. hours, controlling the end of the reaction by thin layer chromatography. It was then evaporated to dryness, taken up in ether, washed with water, dried over Na 2 804, filtered and evaporated to dryness, and then the hydrochloride of the title compound.

There was thus obtained 3 g of product having melting point
F = 1580C and for elemental analysis:
C% H%
Calculated 67.87 9.11 3.95
Found 66.79 9.10 3.92 EXAMPLE 3: 3- [4- (2-Methoxyphenyl) piperazinyl) methyl
5-methyl 6-methyl 6'-phenyl 1,4 dioxane
In a flask equipped with an azeotropic tube containing 300 ml of xylene, 39.4 g of 1- (2-methoxyphenyl) -4- [2-hydroxy-3- (1-methyl-1-phenyl) propyl) The reaction was complete, filtered, washed with very little water, dried over Na 2 SO 4, and the solvent evaporated to give the base a solution of 2-yloxypropyl piperazine and 5 g of potassium hydroxide powder. crystallized having melting point F = 1200 C. The reduction was then carried out by introducing into a hydrogenator "Parr type" under pressure of 28 kg / cm a flask to be hydrogenated containing 12.5 g of the previous base in 100 ml. alcohol at 950 and 3.25 g of 5% palladium on carbon
At the end of the chromatographically controlled reaction, thin layer, the solvent was filtered and evaporated.

 There was thus obtained 8.59 of the title compound, in the form of a base having a melting point of F = 106 ° C.

According to the same process, the compounds whose characteristics are summarized in Table I below were also prepared.
TABLE I

<tb><SEP> COMPOUND <SEP> POINT <SEP> FROM <SEP> FUSION
<tb><SEP> N <SEP>#<SEP>#<SEP> (BASE <SEP> or <SEP> SEL)
<tb><SEP> 1 <SEP>#<SEP>#<SEP> 202 C
<tb><SEP> (Fumarate)
<tb><SEP> 2 <SEP>#<SEP>#<SEP> 187 C
<tb> (Fumarate)
<tb><SEP> 3 <SEP>#<SEP>#<SEP> 189 C
<tb> (Example <SEP> 1) <SEP> (Fumarate)
<tb><SEP> 4 <SEP>#<SEP>#<SEP> 189 C
<tb> (Hydrochloride)
<tb><SEP> 5 <SEP>#<SEP>#<SEP> 158 C
<tb> (Example <SEP> 2) <SEP> (Hydrochloride)
<tb><SEP> 6 <SEP>#<SEP><SEP>#<SEP> 217 C
<tb><SEP> (Hydrochloride)
<tb><SEP> 7 <SEP>#<SEP>#<SEP> 190 C
<tb><SEP> (Fumarate)
<tb> 8 <SEP>#<SEP>#<SEP> 206 C
<tb><SEP> (Fumarate)
<tb><SEP> 9 <SEP>#<SEP>#<SEP><SEP> 106 C
<tb> (Example <SEP> 3) <SEP> (Base)
<tb> 10 <SEP>#<SEP>#<SEP> 184 C
<tb> (Hydrochloride)
<Tb>
The antihypertensive activity of the compounds of the invention has been demonstrated according to various pharmacological tests and in particular according to the tests, the protocol of which is summarized below:
Action on blood pressure in the rat spontaneously
hypertensive vigil
Systolic blood pressure was collected in the SH rat by an indirect method using the NARCO type PE 300 electrophygmomanometer.

 In Table II below, the percent decrease in arterial pressure after administration of the compounds of the invention orally was indicated.

Action on blood pressure in the vigilant hypertensive dog
Hypertension was created in the dog, by bilateral renal arterioconstriction. The pressure was sensed by transcutaneous insertion into a femoral artery of a catheter connected to a pressure cell
Statham Db.

 In Table II below, the percentage decrease in blood pressure and the duration of action after administration of the compounds of the invention orally.

TABLE II
COMPOUND RAT DOG Duration
Dose PO% decrease Dose PO% dim
mg / kg -1 mg / kg-1 ml 3 5 21% 25 -30.3%> 275 5 / / 25 22%> 300 6 / / 25 -29% # 300 8 30 -26.2% 50 - 20.5% / 9 30 -19.6% 25 -29X) 255
In addition, the LD 50, evaluated in the mouse orally, is greater than 100 mg / kg, the side effects being manifested by excitation phases for higher doses.

 These pharmacological properties make it possible to recommend the application of the compounds according to the invention in human therapy, as a medicament for the treatment of hypertension.

 Combined with the usual pharmacological excipients, the products can be administered at doses of between 10 and 500 mg.

Claims (6)

 in which R1 represents hydrogen and R2 represents an alkyl or aralkyl radical, or else R1 and R2 together with the nitrogen atom to which they are bonded represent a substituted heterocyclic radical such as the 4- (benzimidazolidin-2-one) radical; 1-yl) piperidyl or a 4-phenylpiperazinyl radical in which the phenyl residue may be substituted with a halogen, an alkyl radical, an alkoxy radical or the trifluoromethyl radical; R 3 and R 4 represent separately a lower alkyl radical or the phenyl radical, or together a cycloalkyl radical such as the cyclohexyl radical, and their pharmaceutically acceptable salts.

 1,3-aminomethyl-5-methyl-1,4-dioxanes characterized in that they correspond to the formula:  2.Compounds according to claim 1, characterized in that R1 and R2 represent, with the nitrogen atom to which they are bonded, the optionally substituted 4-phenylpiperazinyl radical.  3. Process for the preparation of the compounds according to claim 1, characterized in that an amine NHR1R2 is reacted with a 6-substituted-3-hydroxymethyl-5-methyl-1,4-dioxane by R3 and R4, said alcohol being previously transformed into mesylate by the action of mesyl chloride.  4. Process for the preparation of the compounds according to claim 2, characterized in that the cyclization of a 1-phenyl-4 - [2-hydroxy-3-propyn-2-yloxy] propyl piperazine is carried out and then the reduction is carried out. of the compound thus obtained.  5. Pharmaceutical composition useful especially in the treatment of hypertension characterized in that it comprises, as active ingredient, one of the compounds according to any one of claims 1 or 2 associated with the usual pharmaceutical excipients.  6. Pharmaceutical composition according to claim 5, characterized in that it is presented in a form allowing a daily dosage of between and 500 mg.