NO791222L - PROCEDURE FOR THE PREPARATION OF TETRAHYDROALSTONE INDIVATIVES - Google Patents

Description

The present invention relates to a method for the production of tetrahydroalstonine derivatives, and their addition salts with pharmaceutically acceptable acids.

Tetrahydroalstonin, which is a natural product that can be produced e.g. from Catharanthus lanceus and from Rauwolfia vomitoria, is known and its biological activity is described in French Patent Document No. 1,397,537 and Belgian Patent Document No. 834,585.

The invention thus relates to a method for producing compounds of formula (I)

in which

is hydroxyalkyl, alkyl or alkoxycarbonyl, or et

hydrogen atom,

R 2 is hydroxyl, straight or branched 1 to 6 alkoxy

carbon atoms which may carry halogen substituents, or

cycloalkylalkyloxy, cycloalkyloxy, alkyloxy which may bear a piperidino, morpholino, piperazino or pyrrolidino group/ or a dialkylaminoalkyloxy group, amino, alkylamino, dialkylamino, cycloalkylamino, or a radical

OMe (Me = alkali metal or alkaline earth metal).

with the exception of the compound in which R1= H and R2= CH^O,

the aforementioned alkyl radicals and alkoxy radicals having 1 to 6 carbon atoms, the cycloalkyl radicals and the cycloalkoxy radicals having 3 to 6 carbon atoms, as well as their addition salts with pharmaceutically acceptable acids.

The peculiarity of the method according to the invention is that an acid of formula (I), in which R^ = hydrogen and R 2 = OH is prepared by saponification of tetrahydroalstonine, after which the desired esters of formula (I) are prepared in known ways by esterification of the acid and/or one of its functional derivatives or by transesterification of tetrahydroalstonine, the desired amides (I) being prepared by amidation of the acid or one of its functional derivatives, and the derivatives (I) bearing a substituent in the 1-position are obtained by starting from corresponding compounds (I) in which R^= H by formulation or by reaction with an alkyl halide or with an alkoxycarbonyl halide.

The compounds (I) are therapeutically active with effects on the central nervous system, as anti-anoxic compounds and as psychotropic compounds, especially as antidepressants.

The following examples illustrate the invention. Analyzes and spectra IR, RMN, UV and mass confirm the structure of the compounds.

THA = tetrahydroalstonine.

EXAMPLE 1 16,17-didehydro-19α-methyl-oxayohimbane-16-carboxylic acid and its hydrochloride

30 g of THA are introduced into an aqueous solution of ethanolic potassium hydroxide (21 g of KOH, 600 ml of water and 600 ml of ethanol). The mixture is boiled under reflux for 2.5 hours.

Ethanol is removed by distillation under reduced pressure until a residue is obtained which occupies approximately 1/5 of the original volume. The residue is dissolved in water, the solution is neutralized with 6N hydrochloric acid until pH = 7 and extracted 6 times with 500 ml of chloroform. The chloroform fractions obtained by decantation are combined, washed with water and dried over anhydrous sodium sulfate.

After filtration, chloroform is removed in a water bath at 40°C under reduced pressure.

25 g of the acid (I) is obtained.

The hydrochloride of the acid is produced by dissolving the acid

in chloroform and passing a current of hydrogen chloride gas through the solution.

Temp. = 225°C with cleavage, [a]^<5>= -26.6° (C = 0.6; EtOH)

EXAMPLE 2 Isobutyl ester of 16,17-didehydro-19a-methyl-oxayohimbane-16-carboxylic acid and its hydrochloride

9 g of the acid from example 1 are dissolved in 300 ml of anhydrous chloroform and free of alcohol.

2.35 ml of pyridine freshly distilled over potassium hydroxide are added at once.

2.5 ml of oxalyl chloride in solution in 10 ml of anhydrous chloroform is added.

The reaction mixture is then set aside for 3 hours below

stirring at ambient temperature.

The acid chloride thus formed is added to the solution

30 ml freshly distilled isobutyl alcohol. Stirring at ambient temperature is continued for 1 hour.

300 ml of distilled water is added and evaporated to dryness. 1000 ml of water is added to the oily residue, the mixture is made alkaline using a 10% ammonia solution and extracted 4 times with 400 ml of chloroform. The chloroform fractions obtained by decantation are combined, washed with water and then dried over anhydrous sodium sulfate. After filtration, chloroform is removed in a water bath at 40°C under reduced pressure.

The obtained residue is made soluble in 300 ml of chloroform by stirring at 50°C in the presence of 2 g of activated vegetable charcoal. After filtration, the mixture is evaporated to dryness and the residue is taken up in a small amount of isobutanol and an anhydrous solution of hydrochloric acid ether is added to pH 1. The formed crystals are filtered off with suction.

6 g of the hydrochloride of the isobutyl ester are obtained.

Temp. = 250°C with cleavage, ["cj^<5>= -3.8° (c=1; CHC13).

EXAMPLE 3 Morloline ethyl ester of 16,17-didehydro-1α-methyl-oxayohimbane-carboxylic acid and its hydrochloride.

10.56 g of THA are dissolved in 400 ml of anhydrous benzene distilled over calcium chloride.

690 mg of metallic sodium previously washed with anhydrous benzene are added while stirring and under an argon atmosphere.

The reaction mixture is allowed to react for approximately 10 min. and added over the course of 15 min. 4.3 g of morpholino ethanol previously dissolved in 20 ml of anhydrous benzene. The mixture is boiled under reflux for 5 hours and 30 minutes. under argon in the presence of molecular sieves.

After removing excess sodium by filtration is added

1 1 water and the mixture is extracted with benzene. It is washed with 100 ml of water, dried over sodium sulphate and evaporated to dryness.

The product obtained is dissolved in methanol, after which the hydrochloric acid ether is added.

The hydrochloride crystallizes.

Temp. = 305°C, [a]^<5>= -12.6° (c=0.54; H2O)

EXAMPLE 4 The cyclopropylamide of 16,17-didehydro-19α-methyl-oxayohimbane-16-carboxylic acid and its hydrochloride.

10.5 g of the acid from example 1 is dissolved in 350 ml of anhydrous chloroform which is free of alcohol.

2.8 ml of pyridine just distilled over potassium hydroxide are added at once, after which 3 ml of the oxalyl chloride previously dissolved in 12 ml of anhydrous chloroform are added.

The reaction mixture is set aside for 3 hours at ambient temperature with stirring.

To the solution of the acid chloride formed in this way, 20 ml of cyclopropylamine are added over the course of 15 minutes. and the mixture is kept under stirring for a further 30 min. after the addition has been completed.

1 1 water is added. The organic layer and the aqueous residual phase are extracted 3 times with 500 ml of chloroform. The four organic phases are combined, washed with water and dried over anhydrous sodium sulfate.

After filtration, chloroform is removed in a water bath at 40°C under reduced pressure.

The residue is dissolved in a minimum amount of methanol (approximately 20 ml) and anhydrous hydrochloric acid ether is added to pH = 1.

The formed precipitate is isolated and dried.

The hydrochloride of the amide is obtained.

Temp. = 225 - 228°C, [af]^<5>= -59.7° (c=1; DMF)

EXAMPLE 5 The methyl ester of 1-hydroxymethyl-16,17-didehydro-19a-methyloxayohimbane-16-carboxylic acid

To 5 g of THA dissolved in 50 ml of chloroform, 200 ml of an aqueous solution of formaldehyde 30% in the presence of 1 ml of acetic acid is added.

The mixture is kept at 50°C with stirring for 2 hours, after which the reaction mixture is left at ambient temperature for approximately 15 hours.

300 ml of distilled water is poured over the reaction mixture which is extracted 4 times with methylene chloride, after which it is washed with water, dried over sodium sulphate and evaporated to dryness.

The mixture is chromatographed through a column of silica gel using pure chloroform, then using a mixture of chloroform/methanol (99/1) which elutes 3 g of the desired product.

The product is crystallized in a mixture of methylene chloride/ether after treatment with vegetable charcoal

Temp. = 171°C, [a]^<5>= -186° (c=1; CHC13)

EXAMPLE 6 Methyl spheres of 1-methoxycarbonyl-16,17-didehydro-19α-methyl-oxayohimbane-16-carboxylic acid 14 g of tetrahydroalstonine dissolved in 120 ml of dimethylsulphoxide are added to 3.84 g of sodium hydride while stirring and under argon.

7.52 g of methyl chloroformate are then added using a dropping funnel while stirring and cooling at a temperature of approximately +5°C. The reaction mixture is left under stirring for 1 hour and water is slowly added (approximately 1 1). The ether is extracted 4 times, washed with water, dried over sodium sulphate and then evaporated to dryness.

The product crystallizes from a mixture of methyphene chloride/methanol (1/1).

Temp. = 183°C, [α]^<5>= -276.8° (c=1.17; CHCl 3 )

The compounds produced by the method according to the invention and which constitute examples thereof are reproduced in the following table (I).

HC1 = the hydrochloride.

EXAMPLE 7 The ethyl amide of 1-ethoxycarbonyl-16,17-didehydro-19a-methyl-oxayohimbane-16-carboxylic acid

By means of a dropping funnel, 7.4 g of the ethyl amide of 16,17-didehydro-19a-methyl-oxayohimbane-16-carboxylic acid in solution in 70 ml of DMF are added to a flask containing 2 g of sodium hydride. The operation is carried out under argon with stirring.

The mixture is allowed to react for 30 min. after which 4 ml of ethyl chloroformate is added dropwise.

The mixture is cooled in an ice bath and water is added. It is extracted 5 times with ether, washed with water, dried over sodium sulphate and evaporated to dryness. The ether extract is dissolved in a mixture of chloroform and ethanol which is evaporated and put away in the cold. The crystallized product is obtained.

Temp. = 240°C

The compounds that can be prepared by the method according to the invention were subjected to various pharmacological tests.

The compounds were subjected to the mouse hypobaric anoxia test and tested for effects on the duration of sleep induced by sodium=-4-hydroxybutyrate in the curarized rat.

HYPOBARIC ANOXIA

Mice of strain CD1 are kept in an atmosphere with reduced oxygen content by establishing a partial negative pressure (190 mm Hg corresponding to 5.25% oxygen).

The survival time of the animals is noted. This time is extended using agents that are able to favor oxygenation in tissues and especially in the brain. The investigated compounds are administered in several doses intraperitoneally for 10 min. too attempted. The percentage increase in survival time compared to values obtained in control animals is calculated. The mean active dose (MAD) that increases the survival time by 100% is determined graphically.

DAM for the compounds prepared according to the invention varies from 10 to 60 mg/kg administered i.p.

INFLUENCE ON THE DURATION OF "SLEEP"

This effect is determined by the effect of the compounds on the duration of the "sleep" induced by sodium 4-hydroxybutyrate (GHB) in rats curarized under artificial respiration in which electrocorticographic activity is recorded by means of cortical electrodes.

The compounds that can be produced by the method according to the invention reduce the total duration of sleep by 20 to 40% compared to the control experiment.

The toxicity of the compounds was determined by intraperitoneal administration in mice.

LD 50 varies from 300 to 1,000 mg/kg.

The pharmacological examination of the compounds shows that they are active in tests with hypobaric anoxia in mice while at the same time having little toxicity and that they exceed a considerable effect demonstrated in experiments with "sleep" induced by means of sodium-4-hydroxy-butyrate.

The compounds simultaneously have an antianoxia effect and a

psychotropic effect, and can be used in the therapy for the treatment of reduced activity, especially in the fight against behavioral disorders accompanied by vascular brain damage and cerebral sclerosis in geriatrics, as well as for the treatment of unconsciousness due to skull injuries, and in the treatment of depressive states.

The compounds can be used either alone or together with usual additives for administration, especially oral or parenteral administration, and the total dose is from 10 to 200 mg.

Claims (1)

Process for the preparation of tetrahydroalstonine derivatives of the general formula (I) in which is a hydroxyalkyl, alkyl or alkoxycarbonyl radical or a hydrogen atom, R2 is a hydroxyl radical, or a straight or branched alkoxy radical with 1 to 6 carbon atoms and which may be halogen-substituted, a cycloalkyl alkoxy radical, a cycloalkoxy radical, an alkoxy radical bearing a piperidino, morpholino, piperazino or pyrrolidino group, a dialkylaminoalkoxy radical, an amino radical, an alkylamino radical, a dialkylamino radical, a cycloalkylamino radical, or a radical OMe (Me=alkali metal or alkaline earth metal), with the exception of the compound in which R^ =H and R^ CH^ O, the alkyl or alkoxy radicals having 1 to 6 carbon atoms, The cycloalkyl and cycloalkoxy radicals have 3 to 6 carbon atoms, as well as addition salts thereof with pharmaceutically acceptable acids, characterized by preparing the acid (I) in which R^ =H and R2 =OH by saponification of tetrahydroalstonine, then prepare the esters (I) using known methods, in particular by esterification of the acid or one of its functional derivatives or by transesterification of tetrahydroalstonine, after which the amides (I) are either prepared by amidation of the acid or one of its functional derivatives, and the compounds (I) which carry a substituent in the 1-position are prepared by starting from corresponding compounds (I) in which R^ is H by formylation or by reaction with an alkyl halide or alkoxycarbonyl halide.