NO130400B - - Google Patents

Description

Analogy method for the production of

therapeutically active isoxazolidine derivatives.

The present invention relates to an analogous process for the production of new isoxazolidine derivatives with d-a general formula:

where n is 0 or 1, and F^, F^2 and R independently represent a hydroxy, alkoxy or alkanoyloxy group with 1-4 carbon atoms, and where one of these groups may be hydrogen.

The new isoxazolidine compounds act on the central nervous system, as indicated by their efficacy in rat pole-climbing avoidance tests. The new compounds are quite unique in that they show a very high degree of activity in said samples, while they have practically no activity in they are tested for psycho-sedative and neuro-depressive effects on mice. This property, together with very low toxicity, means that the compounds can be classified as selectively psychoactive. In other words, the compounds affect anxiety behavior without impairing consciousness and without muscle effects. Compounds similar to those with the formula I stated above are known from US patent 3-268,407, and as an example can be mentioned 3,4,5-trimethoxycinnamic acid amides which act on the central nervous system as generic depressants.

The new compounds of formula I are prepared according to the invention by reacting isoxazolidine, either in the form of a free base or in the form of acid addition salts with acids, with an acyl chloride

with formula

where n has the same meaning as stated above, and R^, R^ and Rg independently represent alkoxy or alkanoyloxy groups with 1-4 carbon atoms and where one of these groups may be hydrogen,' in the presence of an organic nitrogen base. The reaction is carried out in an organic, anhydrous solvent. The reaction takes place at temperatures from approx. 0°C to the boiling point of the mixture. Room temperature should preferably be used as the lower limit.

The amount of reagents is not critical, but the best results are obtained when essentially equimolar amounts of the isoxazolidine and the acyl chloride are used, while the nitrogen-containing organic base is added in more or less excess, preferably in a ratio of 1, 1 - 1.5 mol for each equivalent of total acid present at the end of the reaction. When one or more of the substituents in the benzene ring in the starting acyl chloride are alkanoyloxy groups, the compound produced can optionally be subjected to alkaline hydrolysis, whereby the acyl groups are split off and the corresponding phenol is obtained. This step is carried out according to usual methods, e.g. by using an excess of a base selected from the group consisting of ammonium hydroxide and alkali metal hydroxides in an aqueous medium. However, it has also been found to be able to use organic bases.

The following examples illustrate the invention.

Example 1

2-(5,4,5-trimethoxybenzoyl)-isoxazolidine

219.1 grams of isoxazolidine hydrochloride dissolved in 3.5 liters of methylene chloride was slowly added to 620 ml of triethylamine. After stirring for 15 minutes, 461 grams of 3,4,5-trimethoxybenzoyl chloride in 2.2 liters of methylene chloride were added over the course of 40 minutes while keeping the temperature below 30°C. The reaction was first carried out at room temperature for 1 hour with stirring, and then under reflux for a further 2 hours. The mixture was cooled, washed with water, 5% hydrochloric acid, 5% sodium bicarbonate and finally with water to neutrality. The organic phase was separated, dried over sodium sulphate after which the solvent was distilled off in vacuo. The residue consisting of 2-(3,4,5-trimethoxybenzoyD-isoxazolidine) was crystallized from diisopropyl ether. Yield 470 grams (88.0%), mp 75-76°C.

Analysis:

Example 2 2-(3,4-dimethoxybenzoyl)-isoxazolidine Using the same method as in example 1, 2-(3,4-dimethoxybenzoyl)-isoxazolidine was prepared by adding 6.1 grams of 3,4-dimethoxybenzoyl chloride dissolved in 107 ml of methylene chloride to a suspension of 3.92 grams of isoxazolidine hydrochloride and 10.2 ml of triethylamine in 72 ml of methylene chloride. Yield 4.4 grams (60.7%), melting point 87.5-88.5°€. Analysis:

Example 3

2 - ( 4- acetoxy-- 3, 5- dimethoxybenzoyl )- isoxazolidine

This compound was prepared by the same method as in example r, using 4.65 grams of isoxazolidine hydrochloride, 14.3 ml of triethylamine and 11 grams of 4-acetoxy-3,-5-dimethoxybenzoyl chloride. Yield 10 grams (81.7%), melting point 120-121°C.

Analysis:

Example 4

2-( 4- acetoxy- 3, 5~ dimethoxyc innamoyl)- isoxazolidine

This substance was prepared as described in example 1, using 2.96 grams of isoxazolidine hydrochloride, 9.1 ml of triethylamine and 7.7 grams of 4-acetoxy-3,5-dimethoxycinnamoyl chloride. Yield 5.9 grams (68.0%), melting point 155-156°C.

Analysis:

Example 5

2-(3,5~dimethoxy-4-hydroxybenzoyl)-isoxazolidine

4 grams of 2-(4-acetoxy-3,5-dimethoxybenzoyl)-isoxazolidine were suspended in 40 ml of water and 20 ml of concentrated ammonia solution. The suspension was heated to approx. 80°C whereby a complete dissolution of the solid was obtained. The hot liquid was filtered and brought to pH 7 with dilute hydrochloric acid, then cooled on ice for 2 hours. The formed crystals consisting of 2-(3,5-dimethoxy-4-hydroxybenzoyl)-isoxazolidine were collected by filtration and dried over phosphorus pentoxide. Yield 2.68 grams (78.1%), mp 75~76°C. Analysis:

Example 6

2-( 3, 5~ dimethoxy- 4- hydroxycinnamoyl)- isoxazolidine

2.56 grams of 2-(4-acetoxy-3,5-dimethoxycinnamoyl)-isoxazolidine was suspended in a mixture of 3.6 ml of water, 4 ml of concentrated ammonia solution and 20 ml of ethanol. The suspension was held at 60°C for 2 hours, adjusted while hot to pH 7 and then cooled on ice for 3 hours. The precipitate formed consisting of 2-(3,5-dimethoxy-4-hydroxycinnamoyl)-isoxazolidine was collected and dried as described above. Yield 2.1 grams (94.4%), melting point 166-167°C.

Analysis:

As mentioned above, the nervous response to the new compounds was indicated by the pole-climbing avoidance test in rats. This test was carried out as described by Cook and V/eidley in Annals N.

Y. Acad. Pollock. 66 7^0 (1957 )., with some modifications like this

is described by Maffii in J. Pharm. Pharmacol. 11 129 (1959)-

The device consists of a heat- and sound-insulated box equipped with a

grid of steel rods as a floor, and these are connected to an electrical stimulator. The box also contains a sound source, as well as a wooden stand in the middle which forms the safe area. The rats avoid the electric shocks by climbing the pole. After the rats are released into the box, they are subjected to the following test: 15 seconds of silence, 15 seconds of acoustic stimulation, 30 seconds of both electrical and acoustic stimulation. When the animal reacts, the test is terminated. Climbing the wooden pole during the silent period is called CR^Cseconds conditioned response), climbing the pole during the acoustic stimulation is called CR^ (primary conditioned response) and climbing during the electrical stimulation is called UR (unconditioned response). interpreted as a nervous reaction.

The lack of psychosedative, neurosedative and neurovegetative effects in the new compounds was established through an observation of mice according to the test schedule set forth by Irwin, Gordon Res. Conf. With. Chem., New London, N.M. 3-7/8, 133 (1959).

This procedure includes systematically observing groups

of 3 mice per dose, and where these are treated with increasing doses of the substance. The observed changes are then noted.

Lack of effect on arterial pressure ..was measured in carotid pulse-

vein in cats during, anesthesia with sodium hexobarbital,

'40 mg per kg intraper itonally. The products were injected into the femoral artery. A minimum reduction of 20% in pressure over at least 20 minutes was considered significant.

The results in mg/kg for some representative compounds

is indicated in table I.-

Claims (1)

Analogous process for the preparation of therapeutically active isoxazolidine derivatives with the general formula: where n is 0 or 1, and R^, R^ and R^ independently represent a hydroxy, alkoxy or alkanoyioxy group with 1-4 carbon atoms, and where one of these groups can be hydrogen, characterized by reacting isoxazolidine with a approximately equimolar amount of an acyl chloride with the formula: where n has the same meaning as stated above, and R^, R,- and Rg are alkoxy or alkanoyloxy groups with 1-4 carbon atoms, and where one of these groups may be hydrogen, in a solvent in the presence of an organic nitrogen base, and when one or more of the substituents in the benzene ring are alkanoyloxy groups, these groups convert into the corresponding hydroxy groups by alkaline hydrolysis.