DE1695043C2 - Pharmaceutical compositions having sedative and tranquilizing properties - Google Patents

Description

C CO

R ² CO-NR ³

in which R ¹ and R ² , which can be identical or different. Allyl or phenyl groups or alkyl groups with 1 to 6 carbon atoms, such as ethyl or isopentyl groups, mean and R ^{1 means} l-carbamoyloxyO-butoxypropyl or 2-carbamoyloxy-3-ethoxypropyl groups, together with a compound the general formula

R ¹ CO-N-R ³

C CO Π

R ² CO-NH

and a blending of the general formula

IO

15th

20th

R ¹ CO-NH

C CO

R ² CO-NH

ra

30th

35

wherein R ¹ , R ^J and R ^{J have} the meanings given above, in an amount of 30 to 45% by weight of a compound of the formula I, 40 to 60% by weight of a compound of the formula II and 10 to 20% by weight. -% of a compound of the formula HI contain.

2. Medicines with sedative and Iran swelling properties according to claim 1, characterized by the content of the following three active ingredients fen:

a) 35% N, N '* Dl- (2-carbamoyloxy-3-butoxy-propyl) -phenobarbital

b) 50% N- (2-carbamoyloxy-3-butoxy-propyl) -phenobarbital and so on

c) 15% phenobarbital valley.

55

The present invention relates to sedative medicaments which are used in disorders psychological and / or organic Act of origin, and which have a specific effect against Hyperernotlvltät.

The invention relates to new pharmaceutical compositions which are of considerable therapeutic interest because of their activity against tfeitiof and their remarkable combination of tranquilizer and sedative properties, which make them suitable for the treatment of hyperemotivity, for example nervous tension. Fear and fright states, inhibitions, phobles, overwork, lability due to psychomotor disorders, infantile disorders, fear of the dark, stuttering, nervous twitching, emotlonejie vasomotor disorders and tremors, for example of emotional, alcoholic, medical or psychological origin,

Compounds of the formula I given below are already known in which, however, a group R ¹ denotes a hydrogen atom. Their synthesis and some of their properties are described in Helvetica Chimica Acta, XLIV, pages 105 to 113 (November 2, 1960). Such compounds are good sedatives with no hypnotic properties.

It has now surprisingly been found that the compounds of the formula I in which both groups R ^{3 are} an aliphatic group have a very pronounced anti-tremor and even spasmolytic action which is significantly above that of the compounds of the formula I with a group R ³ = Hydrogen lies.

For example, the compound of the formula I in which R ^{1 is} the group

-CH ₂ -CH-CH ₂ -OHC ₄ H ₉ C-CO-NH ₂

means 'very successful'. In numerous cases of tremors or tremors of very different origins declining alcoholism and mental or senility disorders tested.

In addition, it has surprisingly been found that the combination of a compound of the formula I with at least one compound of a similar formula, but in which the second radical R ^{J is} a hydrogen atom, and with at least one customary malonylurea (ie of the formula I and both radicals R ^J = H ) also has exceptional tranquilizer properties.

The invention therefore relates to pharmaceutical compositions with sedative and tranquilizer ends Properties and is characterized in that it is a compound of the general formula

R ¹ CO-N -R ³

C CO I

R ² CO-NR ³

in which R ¹ and R ³ , which can be the same or different, denote allyl or phenyl groups or alkyl groups having 1 to 6 carbon atoms, such as ethyl or isopentyl groups, and R ^J denotes 2-carbamoyloxy-3- (butoxy ) -propyl- or 2-carbamoyloxy-3-ethoxy-propyl groups, together with a compound of the general formula

R ¹ CO -NR ³

C CO Π

R ² CO -NH

and a compound of the general formula R 'CO-NH

CO

CO-NH

wherein R ^1, R * and R ¹ are as defined above, in an amount of 30 to 45 wt, -% of a compound of formula I, 40 to GO wt _T -% of a compound deF formula IJ and 10 to 20 wt. -% of a compound of the formula III included.

The compounds of general formula I can be prepared by any suitable method. A method for preparing a compound of formula I according to the invention consists in introducing a group R ³ on the unsubstituted nitrogen atom of a compound of formula II. This is expediently brought about by reacting an alkali metal derivative of the compound of the formula II with a compound of the formula Hal-R ¹ in which Hal is a halogen atom, preferably chlorine or bromine, and R ^{J has} the meaning given above. The alkali metal is preferably sodium. In a further process for the preparation of a compound of the formula I, a di-alkali metal derivative, for example the Dt-nauium derivative of a compound of the formula III with a compound of the formula Hal-R ³ , in which Hal is a halogen atom and R ³ is defined as above is implemented. It is often expedient to react a mixture of the mono- and di-alkali metal derivatives, for example the sodium derivatives, of a compound of the formula III with a compound of the formula Hal-R ³ . The resulting mixture of compounds of formulas I, II and III can then be used directly in the preparation of the pharmaceutical compositions without separation. This is advantageous because such a separation is difficult, but if necessary it can be achieved by customary methods, for example bromomatographically and / or by repeated precipitation.

The compounds of the formula III, the barbiturates, have been known for a long time; a wlciitiye connection of this Class is phenyl-ethyl-malonyl-urea or phenobarbital.

It has already been mentioned that the union of the compounds of formulas I, II and III properties possesses that is distinct not only from those of the generally known compounds of the formula III and of those of the far less active against tremor Compounds of formula II, but also of those of the compounds of formula I, which, although they are very have valuable properties against tremor, have no sleeping pill properties, differentiate.

For a better understanding of the above invention, reference will now be made to a particular one using an example Composition referred to, which has been studied in detail and which clearly shows the nature and that Explained interest of the invention.

A particularly preferred composition according to the invention, the properties of which are described below, is defined by the following quantitative data:

Composition A: Compound of formula I. Compound of formula II Compound of formula III (Phenobarbltal)

In the compounds I ₁ II and III are: R '= phenyl, R ¹ = s ethyl and R ³ = R ⁴ = Z-carbamoyloxy-3-butoxypropyl.

The properties and therapeutic index of Phenobarbltal - one hypnotic and one sedative - are generally known, so that they do not have to be listed here in detail. In contrast, the Properties of the compounds of the formulas I and H and those of the association of the compounds of

35% 50 » 15 «

Formulas I, II and Ui completely unexpected and different from one another, so that it is of interest to describe them in comparison with those of one of the best %, Z, known Tranqui-Hser, nSmllch Meprobamat. This comparison is given in the following table, in which the dose is always given in mg / kg body weight of the test method used in the usual way. In the first line of the table the LD _{10 is} given, while in the other numbers the ED is listed as follows:

test

Meprobamate I

Il

WWII

LDso 1800

Hypnotism. Effect 800 Cardlazol

Sch-ck test 75

Strychnyn shock test> 1000

Rota Rod Test 350

> 3000> 3000 1500 > 2000> 3000 750

> 500> 500 40

>75> 300 300 (for 25%) (for 0%)

irregular. irregular. 350

50

It follows that

a) the union of the compounds of the formulas I, II and III causes effects that are qualitatively similar in the specified tests to those of meprobamate, but in the doses that are used much lower cherishing,

b) the influence of the small amounts of phenobarbital on the properties of the association of the compounds of formulas I, II and III in particular as far as toxicity is concerned, is very limited. In view of this, it should be noted that the connection of formula I has practically no acute toxicity.

The table also shows that the compositions according to the invention show effects that are comparable with the comparison substance meprobamate with regard to the hypnotic effect and in the Rota-Rod test. the However, compositions according to the invention have a significantly superior anticonvulsant effect, which is evident from the cardiazole shock and strychnine shock tests.

In addition, composition A according to the invention has a pronounced potentiating effect on pentobarbital anesthesia, which makes it possible to reduce the hypnotic dose (ED _S0 ) of pentobarbital more than is possible with meprobamate.

Tabel

substance

dose used

EDso mg / kg

Pentobarbital -

⁵⁵ Add. A Meprobamat EDso of pentobarbital + 250 mg / kg add. A EDjo of pentobarbital + 250 mg / kg meprobamate

Antitremor cloud

41 12.4

21

Tremorin was intraperetoneally with a Dose of 20 mg / kg administered to mice, creating tremor syndrome and parasympathomimetic signs.

The substances to be examined for their antagonistic action were taken orally for 45 minutes administered after administration of the tremor.

The tremoi-j-'vsmm effect is from the following Table:

Tabel

substance

ED »mg / kg

Add. Λ
Meprobamate

85
100

Side effects on the autonomic nervous system
100 mg / kg of Composition A was administered to dogs by the oral route. There were no significant changes in the arterial blood pressure and no effects of the injection of acetylcholine, histamine and adrenaline (Frommel et al, HeIv. Physiol. Actal9, 241, 1961).

This pharmacological examination was confirmed and completed by clinical examinations carried out in some tens of patients suffering from mental disorders or suffered from organic origin and in particular tremor.

These experiments have actually shown that with the same dosage

a) the compounds of formula II aH were effective sedatives, but less active in terms of experienced tremor, regardless of whether it was of emotional or organic origin,

b) the compounds of the formula I alone have an antitremor effect and even have a spasmolytic effect, but less active in treatment are emotlonal disorders, they have no hypnotic activity,

c) in contrast, the union of the compounds of formulas I and II, even in small amounts Phenobarbltal (III) striking and surprising Provided results because the individual activities of the compounds were greatly increased.

In addition, Composition A has undergone extensive psychiatric clinical examinations. In summary, the following could be stated:

1. Excellent tolerance by adults and children;

2. An anxiety-reducing, sedative, tranquilizing one and sleep inducing effect;

3. a very reliable anti-tremor effect in the case of tremors and in particular permanent tremors such as senile, presenile, hereditary tremor and especially tremor from poisoning.

Composition A therefore has significant clinical interest in the treatment of a wide variety neurotic conditions in patients of all ages.

Compositions containing the appropriate amounts of compounds of formulas I, II and HI possessed all of the effects of tranquilizers (e.g., those of the benzodlazepine type or meprobamate). The compositions are particularly useful in the treatment of all those resulting from hyperemutivity Disorders, e.g. nervous tension, anxiety and fright, inhibitions, phobias, overwork, lability due to psychomotor disorders, infantile disorders, fear of the dark, stuttering, nervous twitching, emotional vasomotor Disorders and tremors, for example of emotional, alcoholic, medical or psychological origin. Secondary effects, such as constant sleepiness, intestinal disorders and changes in the Percon-Hchkelt properties various other sedatives

ίο are practically absent.

The following examples are intended to explain the invention in more detail without restricting it. In each example is a monosodium salt of a barbiturate of the formula NI initially present. This is disproportionate and results in the disodium salt in equilibrium with the monosodium barbilurate and the free barbituric acid Formula HI, and it can be seen that the molar percentage of the disodium salt is always equal to that of barbituric acid. When reacting with the I-chloropropane reagent the resulting compounds of formein I, II and III are essentially the same Proportions such as the sodium salts must be present. Where just the percentage of the compound of the formula I is given, the proportions of the other compounds can easily be calculated.

Example I.

25.4 g of sodium phenobarbital is dissolved in 100 ml of methanol suspended and 21 g of l-chloro ^ -carbamoyloxy-J-buioxypropane admitted. The mixture is heated on the water bath and the solvent is progressively driven off until a dry residue is obtained which is about 35% N, N-di-2-carbamoyloxy-3-butoxypropyl) phenobarbital contains.

Example 2

As in the previous example, the sodium ethylate is made from 23 g of sodium in one liter of absolute methanol and 184 g of diethylbarbituric acid are then added. The reaction product must be on Reflux to be boiled to dissolve it. After 30 minutes, add a further 300 ml of methanol and then 209 g of l-chloro ^ -carbamyloxy-S-butoxy-propane, which had previously been melted, was added with stirring. The methanol is then completely removed, finally in a vacuum up to 92 ° C puf a water bath. When the implementation is complete, the from contains The crude product freed impurities 36.4% of the compound I, 45.4% of the compound II and 18.2% of the compound III (not converted).

Example 3

In the same way as in the previous examples, 5.75 g of sodium are dissolved in 150 ml of methanol dissolved and added 56.7 g of amobarbital in 250 ml of methanol. After vigorous stirring, 50 g of 1-chloro-2-carbamyloxy-j-ethoxy-propane are added added and the solution is made up to 400 ml with methanol. The methanol is evaporated as in the previous examples, and a mixture results containing 30iS N, N'-DI- (2-carbamyloxy-3-ethoxypropyl) -amobarbltal.

Claims (1)

Claims; 1. Pharmaceutical compositions with sedative and tranquilizer properties thereby characterized in that it is a compound of the general formula R ¹ CO-N-R ³