DE2361488C3 - Use of tri-n-propyl acetic acid derivatives - Google Patents

Description

wherein Y is the group NH ₂ or the group OM, in which M is an alkali metal, in the treatment of pathological mood swings.

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The invention relates to the use of at least one derivative of the general formula

CH ₃ -CH ₂ -CH ₂ O

CH ₃ -CH ₂ -CH ₂ -CCY

CH ₃ CH ₂ CH ₂

35

wherein Y is the group NH ₂ or the group OM, in which M represents an alkali metal, for the treatment of pathological mood swings.

The compounds mentioned can all be prepared by known processes, for example according to the following:

a) When Y is the group NH ₂ , tri-n-propylacetonitrile becomes tri-n-propylacetonitrile under mild conditions hydrolyzed in an acidic medium, preferably sulfuric acid, as described in J. Amer. Chem. Soc. 70 3091 (1948).

b) If Y is the group OM, then it becomes a base of the formula

55

MOH,

wherein M has the abovementioned meaning, reacted with tri-n-propyl acetic acid

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Corresponding pharmaceutical or veterinary compositions contain at least one compound of the as essential active ingredient above general formula, expediently in connection with a suitable pharmaceutical Carrier.

According to special Ausfühnmgsformen the Invention, according to the invention, sodium tri-n-pro

pyl acetate or tri-n-propyl acetamide is used

Have pharmacological experiments on laboratory animals shown that the compounds of the general formula have properties that are useful in the treatment of pathological conditions caused by disorders of the central nervous system, and from Disorders are very valuable in the field of neuropsychiatry. It was unexpectedly found that these compounds have a particularly valuable healing effect on pathological mood swings and are valuable tranquilizers. In particular, these compounds can be extraordinary are useful means of activating or disinhibiting patients suffering from serious apathy or communication difficulties who can be described as apragmatic and for example in certain types of schizophrenia occurrence.

All derivatives of the above general formula are known compounds insofar as they are under the general formula of British Patent No. 760114 which refers to reducing substances the level of chclesterol in the blood is also related to tri-n-propylacetamide in British Patent No. 4 69 921, in which it is described as slightly spasmolytic, and in "Arch, for Experim. Pathology and Pharmacology ", 186 (July / Sept 1937), in which it was published by K. Junkmann is described as chess spasmolytic and as somewhat more potent as a sleep aid, especially Apart from the fact that the information is mentioned regarding tri-n-propylacetamide the dosage and testing criteria in these two publications are not very precise neither of the two texts even remotely suggests that the connections between the general Formula which can be ascribed to particular applicability according to the invention.

Regarding the effectiveness that can be ascribed to the compounds of the general formula as a result of pharmacological tests, should in particular it should be mentioned that the use of the previously known neuroleptic agents and anti-depressants is accompanied by undesirable side effects is, for example, of extrapyramidal disorders in the case of neuroleptics and total mood reversals in the case of both species of funds. In contrast, the compounds referred to do not have these disadvantages. It was found, that their effect already occurs with nozzles which are considerably below the dose that results in a behavioral disorder.

The compounds used according to the invention In addition to a satisfactory tranquilizer effect, they also have a wide spectrum of neurotropic properties, that of the known ones Tranquilizer outperforms. They are also for di: treatment of pathological mood swings and especially the treatment of severe apragmaticism is extremely valuable.

The following is a summary of the given pharmacological tests that were carried out to determine the toxicity of the compounds and to determine the presence of said pharmacologically valuable properties.

The LD50 value was determined in mice by intraperito Adequate administration determined by the Karber and Behrens method. One got preferred for usable compounds give the following results:

link LD 50 value in mg / kg Sodium tri-n-propyl acetate 327 Tri-n-propylacetamide 340

which corresponds to 20 to 80 times the daily therapeutic dose of the compounds

The so-called "Rota Rod Test" (Boissier therapy 1958, XIII, pages 1074-1118) used This test is used to determine the animals' ability to coordinate their movements. He will be with groups of 10 mice each, each weighing about 25 g. The compound under investigation becomes administered to the animals of each group by the intraperitoneal route in doses such that the next group receives a higher dose than the previous group. 30 minutes after Administration, the mice are placed on a wooden roller 4.8 cm in diameter for 2 minutes rotates at a speed of 4 revolutions per minute The roller has a rough surface in order to to prevent the animals from sliding off.

On this basis, the neurotoxic dose 50 (NTD ₃₀ ) can be determined, ie the dose of the compound at which half of the animals can no longer remain on the roller for a specified period of time.

The following results were obtained with the compounds preferably used:

link NTDso value in mg / kg

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Sodium tri-u-propyl acetate 120 Tri-n-propylacetamide 68

The hypnotic properties of the compounds used according to the invention were determined by observing the body posture reflex

Male mice of breed OF 1, weighing about 25 g, were divided into groups of 10 animals each The animals in one group were given a higher dose of the compound to be investigated ai < administered to the previous group

Then the number of animals was determined at different times after the administration Reflex lost.

In this way, the HD »value was determined at various points in time after administration; H. the Dose of the compound to be investigated which leads to the loss of the posture reflex in 50% of the animals at a specific point in time after administration.

The results are shown in the following table:

Table I. link Time after administration

Min. 30 min. 45 min.

60 min.

Natnum-tn-n-propyl acetate, 120 130 HDso value in mg / kg Tri-n-propylacetamide, 90 110 HDso value in mg / kg

150 110

200 120

The tranquilizer properties of the compounds used according to the invention were determined by the “chimney test”, the “evasion test” and the “Hole-board test”, which is described by Boissier in “Med. Exp. "1960, 3, pages 81-84," Therapy "1965, XX. Pages 895-905 or in "Therapy", 1964, XIX, pages 571-589, determined.

a) Chimney test

With the help of this test, one can identify two groups of factors, namely neuromuscular factors (Muscle strength, flexibility, coordination of movements) and psychological factors (curiosity, fear, Flight instinct).

The test was carried out on groups of 10 mice each weighing about 25 g Compound was administered intraperitoneally to the groups in such a way that each group had a higher one Dose received as the previous group. The mice were put in one at a time, head first inserted a 30 cm long test tube, which was matched to the μ size of the mouse that the animal through Moving backwards could escape the glass in less than 30 seconds. It became the number of animals found who failed to do this.

In this way the EDw value could be determined, i.e. H. the dose of the compound at which it is 50% of the animals failed to escape from the test tube within 30 seconds.

The following results were obtained with the compounds preferably used:

link ED ₅₀ -WeH in mg / kg Sodium tri-n-propyl acetate 72 Tri-n-propylacetamide 32

This tranquilizer effect was achieved with only half the dose that is necessary to achieve the to impair neuromuscular functions in the "Rota Rod Test".

b) evasion test

With this test it is possible to examine the urge to explore in mice. A parallel-piped, lidless plywood box is used,

there is also an inclined plane made of plywood, which is covered with a tight net On the inclined plane there is a 2 cm below the point where the plane rests on the box wall horizontal marking line attached The entire device is placed in an artificially lighted room placed from which all shrill noises are kept away. Each time a mouse crosses the marking line in an upward direction, an "exit" designated

The test was carried out on groups of 28 mice weighing approximately 22 g. The animals in each group received a dose of the intraperitoneal route investigating compound, namely a group

10 each a larger dose than the previous group.

Thirty minutes after the compound was administered, the animals were placed in the box in groups and For 10 seconds by a moving board on the Bottom of the box held. The average length of time was determined after which the first »exit« took place, as well as the total number of "exits" per group during each minute, and this Observations continued for 5 minutes. The same data were recorded for a control group that did not administer any compound had been. The following results were obtained with the compounds preferably used:

Table II Total number of . 2 min. Leaks per group . 4 min . 5 min. Average link I min 3 min Z '.' until first »Austre 50 38 42 th in seconds 48 44 43 41 28 14th Comparison animals 54 43 25th Sodium tri-n-propyl acetate 37 34 28 50 mg / kg 44 31 21 Sodium tri-n-propyl acetate 37 26th 35 75 mg / kg 46 27 20th Tri-n-propylacetamide 43 31 25th 10 mg / kg 40 38 49 Tri-n-propylacetamide 50 mg / kg

c) perforated board test

This test enables a quantitative determination of the mice's urge to explore in relation to their curiosity. The material used is a Board of 40 χ 40 cm in size and 1.7 cm thick used in which 16 holes of 3 cm in diameter have been cut. The board is placed on 4 legs that are so high (1.5 m) that the holes are Animals appear bottomless. The experiment is carried out in the greatest possible silence

The test was carried out with groups of 10 male mice each of the breed OFl, which weighed about 23 g, carried out. The animals in each group were administered a dose of the test compound by the intraperitoneal route to one group each a higher dose than the previous group. The test compound was not administered to the control group.

30 minutes after the administration, the animals of each group were placed in the middle of the board and there the total number of holes explored per minute by each group was recorded for 5 minutes.

The results obtained with the compounds preferably used according to the invention are shown in FIG listed in the following table:

Table III link Total number of holes explored

Min. 2 min. 3 min. 4 min.

Comparison animals 32 Sodium tri-n-propyl acetate 50 mg / kg 15 Sodium tri-n-propyl acetate 75 mg / kg 2 Tri-n-pfopylaeetamide 10 mg / kg 30 Tri-n-propylacetamide 50 mg / kg 8

5 min.

35 32 43 33 13th 14th 19th 17th 6th 3 1 7th 28 28 35 27 10 4th 6th 1"

The above results show that both sodium tri-n-propyl acetate and tri-n-propyl acetamide are the Decrease the curiosity of the animals.

The antidepressants cancel out the sedative effect of

Reserpine on ούζτ delay them, as was determined by experiments with ptosis in rats. By the intraperitoneal route, groups of 5 male rats of the breed CF 1, weighing about 300 g, were one

Dose of 50 mg / kg of the compound to be tested administered. 30 minutes later it was on the same Route 5 mg / kg Reerpin administered. It was observed how much time from the administration of the reserpine until the ptosis occurred, the ptosis j being rated in each eye according to the following scale became:

0 = eyelids open

1 = eyelids ¹ A closed

2 = eyelids Ui closed

3 = eyelids ⁱ l * closed

4 = eyelids completely closed

For example, if an animal had a ptosis of I in one eye and Ί in the other eye, it was rated 1.5.

The results obtained with tri-n-propylacetamide are listed in the following table, with each «result being the average of 10 measurements (i Animals in which both eyes were evaluated 'are shown:

link Ptosis 2 hours. 3 hours. 4SId. 6 hours 1 H. 2.0 3.3 4.0 4.0 Vprolpirhstiprp 0.6 2.6 3.6 3.8 4.0 Tri-n-propy! Acetamide
10 mg / kg 0.2 2.4 3.4 3.5 3.8 Tri-n-propylacetamide
20 mg / kg 0 0.8 2.3 3.2 4.0 Tri-n-propylacetamide
30 mg / kg 0 0.8 2.3 3.0 4.0 Tri-n-propylacetamide
40 mg / kg 0

The active ingredients used according to the invention can be used in any form suitable for human and animal medicine. The administration units can, for example, or v, hard gelatin capsules, ampoules or present syrup for oral administration, a sterile solution for parenteral administration, and suppositories for rectal administration in the form of optionally coated tablets, soft.

Depending on the chosen route of administration, include -in the therapeutic compositions according to the invention

■ e— ■■ es - · ■ - · - "e - ~ * * ~ * ··· * - *

a suitable carrier, the latter being, for example, one or more of the following Components may be composed: talc. j-> Magnesium stearate, milk sugar. Sucrose. Carboxymethyl cellulose. Starches, kaolin. Levilit, cocoa butter.

The following examples serve to explain in more detail the preparation of the active ingredients or their Preparation for use according to the invention. -> n

An advantageous process for the preparation of tri-n-propylacetamide is described below:

into a 4 liter flask fitted with a dropping funnel and a mechanical stirrer, a solution of 123 g (3MoI) of acetonitrile and 1410 g (11.4MoI) n-propyl bromide in 520 g toluene given. The solution was heated to 50 ° C. with stirring, after which it was 90% strength over 5 hours Suspension of 431 g of sodium amide in 775 g of toluene was slowly added through the dropping funnel, care was taken to keep the temperature above 50 ° C. During this process, observed that the reflux temperature rose from 50 to 75 ° C. The flask containing the sodium amide suspension contained, was then rinsed with 180 g of toluene The reaction mixture was allowed to cool to room temperature and stirred for an additional 14 hours The reaction mixture and the rinsing liquid were then gradually carefully poured into Poured ice water containing 2000 g of purified water and 500 g of ice. The mixture was for 30 minutes stirred and the organic layer decanted and washed three times with 1 l of water, after which then the Toluene was evaporated. The oily residue was distilled under reduced pressure (2 mm Hg), and the distillation fraction was collected, which had a boiling point between 68 and 70 ° C. One received 400 g of tri-n-propylacetonitrile, which is a yield of 80% corresponded.

iu 4;

Given a solution of 550 g of sulfuric acid. While stirring, 110 g (0.66 mol) of tri-n-propylacetonitrile were added over the course of 20 minutes and at room temperature. The temperature of the reaction mixture rose to 8O ⁰ C and was increased to 6 hours at 105-C HO ^0. Then the solution was cooled to 10 ° C. and slowly poured into ice water (1000 g of purified water and 200 g of ice). As the solution was poured into the ice water, a dough-like precipitate formed naturally and afterwards. As soon as the process was finished , the mixture was stirred for 15 minutes and the precipitate was separated off by centrifugation and taken up twice with 350 g of ethyl ether . The ethereal solution was washed first twice with 200 g of water containing 10% sodium bicarbonate and then washed twice with 250 g of water. The mixture was dried over 125 g of anhydrous sodium sulfate for 24 hours, after which the sodium sulfate was removed by centrifugation. Thereafter, the ether was removed on a rotary evaporator and an oil was obtained which crystallized into fine needles which were kept under vacuum until they had reached a constant weight. In this way, 113 g of crude tri-n-propylacetamide were obtained, which corresponds to a yield of 92.6%. The crude product was then converted into 150 g by heating

Dissolved petroleum ether. After dissolution, 1.15 g of "CECA WSL-Black" were added and the mixture was refluxed for 30 minutes. The additive was filtered off while the mixture was still hot. The filtrate was cooled for 3 hours at -15 ⁰ C, after which the formed * from lung / was separated by centrifugation and dried for 24 hours in a drying oven at 40 ° C under a vacuum of 20 mm Hg. 98.5 g of pure tri-propylacetaride were obtained, which corresponds to a yield of pure product of 87.1%. Melting point: 69 ° C.

Sodium tri-n-propyl acetate can, for example, such as can be produced as follows:

A flask equipped with a dropping funnel was charged with 480 g of distilled dioxane and then 80 g (0.432 mol) of tri-n-propylacetamide, which was stirred up by stirring. became, "S". A stream of dry hydrochloric acid gas was bubbled through the dioxane solution at room temperature for 20 minutes (ie a total of 100g hydrochloric acid gas). Upon completion of this process, 88g (0.86 mol) of freshly distilled butyl nitrite was slowly passed through the dioxane solution over a period of 2 hours The temperature of the reaction medium rose from 31 to 43 ° C., necessitating cooling in a water bath, after which the solution was kept for 2 hours at a temperature of 85-90 ° C. The dioxane was then reduced under reduced pressure of 201 m Hg evaporated to give a dough-like residue at room temperature. This residue was dissolved in 290 g of a 10% aqueous solution of potassium hydroxide. The aqueous layer was decanted and extracted twice with 75 g of ethyl ether. The potassium solution was mixed with 118 g of a 36% solution of hydrochloric acid (10-20 ⁰ C) acidified, after which the oily phase was decanted. the aqueous P Hase was extracted twice with 75 g of ethyl ether, after which the oily phase and the essential extracts were combined. The ethereal solution was washed twice with 100 g of water and dried over 100 g of anhydrous sodium sulfate for 24 hours. The sodium sulfate was then removed by centrifugation. The ethyl ether was evaporated under atmospheric pressure and the residue recovered under 7 mm Hg. The fraction obtained had a boiling point of 126-128 ° C and rapidly crystallized. In this way 61 g of crude tri-n-propyl acetic acid were obtained, which corresponds to a yield of 76%. The crude product was then dissolved in 75 g of ethyl ether by heating. The ethereal solution was filtered off while it was hot and the filtrate was kept at a temperature of -30 ° C for 4 hours. The precipitate which formed was separated by centrifugation and dried in a desiccator for 6 hours under reduced pressure of 20 mm Hg. 46 g of pure tri-n-propyl acetic acid were obtained, which corresponds to a yield of 75.4% of pure product and an overall yield of 57.3%.

in melting point: 67 ° C.

Into a flask equipped with a dropping funnel and mechanical stirrer were 30 g (0.161 mol) of pure tri n-propyl acetic acid, the preparation of which has been described above is, and given 75 g of toluene. The mixture was stirred until completely dissolved, after which it was a hot solution of 6.45 g of sodium hydroxide in 30 g

ethsno! by the Tro ⁿ itrich * ^p r ^

7.u

1 g of CECA WSL-Black was added and the whole mixture was refluxed with stirring for 1 hour. The additive was then filtered off and the remaining mixture was distilled by gradually adding 88 g of toluene through the dropping funnel in order to prevent the mixture from turning into a solid. The distillation was stopped as soon as the temperature at the top of the column had reached 105 ° C., after which the mixture was then cooled to room temperature. The resulting precipitate was separated off by centrifugation and rinsed twice with 20 g of acetone. Then, it was dried for two hours in a rotary evaporator at 80 ⁰ C, and then again at 105 ° C under atmospheric pressure for 4 hours in a ventilated oven. In this way, 30 g of sodium ^: tri-n-propyl acetate were obtained, which corresponds to a yield of 89.5%.

example

According to known pharmaceutical methods, soft gelatin capsules were made with the following ingredients manufactured:

component

mg per capsule

Tri-n-propylacetamide

talc

Magnesium stearate

150

15th

167

Claims (1)

Claim: Use of at least one derivative of the general formula CH ₃ -CH ₂ -CH ₂ O CH ₃ -CH ₂ -CH ₂ -CCY CH ₃ CH ₂ CH ₂