DE2251036A1 - Medicaments contg. dipropylacetic acid derivs - for use as CNS depres-sants, diuretics, having low toxicity and relative freedom from side effects - Google Patents

Abstract

Novel therapeutic compsns. contain a cpd. of formula (I):- (n-Pr)2CHCOY (where Y is OM, OR or NHZ; M is H, alkali(ne earth) metal, Mg or Zn; R is 1-9C alkyl; Z is H or CONH2) in combination with a diluent or carrier. The compsns. are pref. administered orally as capsules, tablets, syrups or suspensions, or rectally as suppositories, (esp. contng. cocoa butter as carrier). The unit dose is pref. 50-200 mg. (I).

Description

Therapeutic composition.

The present invention relates to therapeutic compositions, which have proven to be generally effective as a central nervous system depressant have proven and accordingly as anticonvulsants, tranquilizers, muscle relaxants and depressants are useful for the thermoregulatory centers. You are too as a diuretic and as a potentiator for medicines with the same direction therapeutic effectiveness. The compositions have a low Toxicity and are relatively free from side effects.

According to the invention it was found that dipropyl acetic acid and certain Derivatives have the same therapeutic properties. Dipropylacetic acid and many derivatives thereof have been known for a long time and are various Methods of manufacture and purification have been described in the literature. The earliest of these processes relates to the manufacture of dipropyl acetic acid himself and is in Ber. 29 (1896) on pages 1998 to 2001. Neither in this still in later publications showing the preparation of the acid and their derivatives, however, an indication is included that they are any have therapeutic efficacy.

The object of the present invention is to provide a therapeutic composition. This includes, as an effective ingredient, a compound represented by the following formula in which Y is an -Ol group, in which M is a hydrogen atom, an alkali atom, an alkaline earth atom, a magnesium or zinc atom, or an -OR group in which R is a linear or branched-chain lower alkyl radical with about 1 to 9 denotes carbon atoms, or denotes a -NHZ group in which Z denotes a hydrogen atom or the amide radical -CO-NR2, in conjunction with a pharmaceutically acceptable diluent or carrier.

Pharmaceutically acceptable diluents or carriers to be used with mixed with the active ingredient to form the compositions of the invention are known, and the carrier used depends, among other things, on the method the administration of the compositions. The compositions according to the invention can be adapted for oral, rectal or parenteral administration, however Oral and rectal preparations are the most important. The oral compositions can for example in orm of capsules, tablets or liquid preparations, such as e.g., syrups or suspensions; the rectal preparations are preferably lying in h'orm of suppositories. In this case, a preferred carrier is cocoa butter, and the preferred ratio of cocoa butter to active ingredient is about 10: 1 <parts by weight).

The liquid preparations are preferably in the form of aqueous media Solutions before, including solutions in Welsser, which small amounts with water Miscible solvents, such as iithy alcohol or glycerine or tetrahydrofurfuryl ethylene glycol ether r, contain, should be understood.

Preferred compounds which are among the active ingredients of the invention Counting compositions are dipropylacetic acid itself and the alkali salts thereof, especially sodium dipropyl acetate.

The preferred one used in the compositions of the present invention Ester derivative is that in which the radical R = ethyl. This ester is an oily liquid made with olive oil and melted cocoa butter is miscible, making it particularly suitable for administration in the form of suppositories suitable is. In the same way, dipropylacetamide and dipropylacetylurea are special suitable for rectal administration, as this is based on the basic substances that are normally used to be used to make suppositories that are miscible.

Dipropylacetamide, which is soluble in tetrahydrofurfurylethylene glycol, is also suitable for oral administration in aqueous solution.

It has been found that the anti-epileptic effectiveness of dipropylacetamide and Dipropylacety] urea is generally greater than that of the ore acid or the other derivatives of Formula I. It is believed; that this difference in the effectiveness is related to the presence of nitrogen in the molecule.

The effective daily dose of the compounds as the active ingredient the composition is about 200 to 1000 mg with single doses ranging from about 50 to 200 mg, depending on the condition, age, weight and sex of the patient depends.

The present invention is further illustrated by the following examples explained: Example 1 suppositories with di-n-propyl acetic acid component pure Di-n-propylacetic acid 200 mg glycoll 200 mg cocoa butter q.s. on 2 g of the butter is melted and the di-n-propyl acetic acid mixed with it. Before that was the glycocolla has been finely ground, and it is then added to the mixture, which subsequently is cooled with stirring. The cooled oil is poured into suitable molds and cooled down quickly.

Example 2 Suppositories with di-n-propylacetamide and di-n-propylacetyl urine substance constituent amount di-n-propylacetamide 200 m -.

Cocoa butter q.s. to 2 g The butter is melted and the di-n-propylacetamide dissolved in it while the butter is heated. The mixture becomes slow with stirring chilled. There is a crystallization of the amide in the mixture, which then poured into a suitable mold and quickly cooled.

The same procedure is used for making suppositories with di-n-propylacetylurea applied.

Example 3 Sodium di-n-propyl acetate tablets.

1000 tablets are used to represent a tablet administration form with 100 mg each of the active ingredient prepared by adding 100 g of sodium di-n-propyl acetate, B g of corn starch are granulated with 15 ml of water. The granules are then through sent a sieve and dried. The dried granules are 6 g of talc and 2 g magnesium stearate as a lubricant and 12 g additional corn starch as a disintegrant admitted. The material obtained in this way then becomes 1000 tablets that each contain 100 mg of the active ingredient, pressed. The tablets are then notched to make it easier to split in half if desired will.

Example 4 Di-n-propylacetamide syrup.

Ingredient Amount of di-n-propylacetamide 500 mg Te trahydrofurfurylethylene glycol 20 ml syrup q.s. on 100 ml The compositions according to the invention are in particular of great value as an anticonvulsant as they can be used in various ways without loss the effectiveness can be administered.

The effectiveness of the active ingredient and certain compositions according to the present invention by the following laboratory tests and chemical Tests demonstrated.

Pharmacological tests. Antiepileptic efficacy.

(a) Experiments with rabbits.

The minimum dose of metrazole (pentylenetetrazole) was in the marginal vein of the ear to induce 100% seizure in the animals. It was found this dose to be 30 mg / kg. The preventive will either administered rectally, intraperitoneally or intravenously within 15 to 6 hours, before the animal is injected with metrazol. The protection is considered perfect, if there is no seizure or if it is very severe in its duration and intensity is decreased, in one or the other of the two phases (tone or Clone phase). A partial protective effect is given in Pehlen in one of the two phases obtain.

(b) Experiments with mice.

The experiments are carried out in two different ways: 1) The The first type of experiment corresponds to the one carried out with the rabbits However, the dose of metrazol causes death in 95-10000 of the cases got to. It was found that this dose was 64 mg / kg when administered intravenously in the caudal vein was cheating.

2) The second type is an experimental group to test the effectiveness against Seizures due to maximum standard electric shocks and low-frequency electric shocks as well as the usual metrazoline injection. Since these attempts from the literature are well known, only a brief description of them will be given.

The ability of the Drug measured, the tone component of the hind leg extensor muscle during seizures by maximum Elektroschoch ("Iv S" attempt) to prevent that by overmaximal Current using 50 mA alternating current, 0.2 sec. Stimulus duration and corneal electrodes were caused. Through the low-frequency electric shock attacks ("i.f. EST" attempt) the effectiveness of the drug is tested, the stimulus threshold of the electric shock attack, at the house by direct current in an intensity that is twice the stimulus threshold corresponds, using current surges of 0.2 millisecond duration and one Stimulus duration of 3 seconds at 6 bumps per second is twice as long to increase. A grass stimulator (Model S4B) was used for the "i.f." Test. Other details of the various modes of operation used on the mouse Endpoints and the characteristics of the electroshock apparatus are detailed in "J. Pharmacology and Experimental Therapy ", 106, 319, 1952. The Metrazol Test was by usual subcutaneous injection of metrazol at 85 mg / kg, as in the publications mentioned above.

(c) Experiments with rats.

The same standard tests were carried out on these animals, as described under (b) 2).

(1) Di-n-propylacetic acid.

Di-n-propyl acetic acid (DPA) is a colorless liquid that is present in Water is very sparingly soluble. Twelve mice were given 200 mg / kg of di-n-propylacetic acid administered in the form of suppositories, being the indicated dose was mixed with liquefied cocoa butter. After an X, it was 45 minutes each mouse administered 64 mg / kg metrazol as described in Experiment 1 for mice became. Complete protection against death was achieved at 40 C / a of the nose.

Di-n-propyl acetic acid was also rectally found in the cocoa butter mixture described 12 inches at doses between 200 mg / kg and 400 mg / kg. The time intervals is between the administration of this composition and the metrazoline injection given in Table I together with the results of the experiment.

Table I Dose of Di-n-Propyl Number Time Results Acetic Acid the distance mg / kg animals 200 6 1 hour and 2 seizures 45 min. 2 partial seizures 2 complete. Protection 200 2 1 hour 2 seizures 300 2 1 hour and full 45 min protection 400 2 1 hour and complete 45 minutes protection (2) sodium di-n-propyl acetate.

Sodium di-n-propyl acetate is a white powder and is strong in water soluble. The sodium salt is preferably obtained from D-n-propyl acetic acid by reaction formed with sodium hydroxide in an aqueous solution.

The sodium salt was given in doses from 168 mg / kg to 420 mg / kg in 21 rabbits administered intraperitoneally. The time after Injection for administration of metrazol varied from 15 minutes to 6 hours. Practically complete protection was at a dose of 200 mg / kg with a scit interval of 40 minutes before the Injection of metrazol achieved. Similar attempts have been made by the intravenous route carried out and the protection threshold and a comparable level of protection was found in the following number of rabbits and the doses mentioned: 3 rabbits at 25 mg / kg, 3 rabbits at 50 mg / kg and 2 rabbits at 100 mg / kg.

Thirty mice were injected with sodium di-n-propyl acetate intraperitoneally Routes injected in the following manner: 10 animals received 50 mg / kg; 6 animals were 100 mg / kg and 14 animals were given 200 mg / kg. , ie were after the Method 1 for mice with a 30 minute interval between administration of the sodium salt of di-n-propyl acetic acid and of metrazol. The results Ures as follows: 40% survived at the dose of 50 mg / kg; 50% survived at 100 mg / kg and 57% survived at the dose of 200 mg / kg.

The effectiveness of the sodium salt is also due to the protection it provides Rats received when subjected to the maximum standard electric shock test, to see. Thirty minutes before the shock treatment, 400 mg / kg of sodium di-n-propyl acetate are added Orally administered to seven rats and another seven injected orally at 800 mg / kg. Complete protection was given in all seven animals injected with the larger dose were found, while three of the seven animals that received the smaller dose were protected.

Toxicity tests.

It was found, following the method of Karber and Berhens, that the DL-50 value of dipropylacetic acid, which the mouse subcutaneously in the form of an aqueous Solution of sodium dipropyl acetate administered wait, was 862 mg / kg kg (progression factor the dose 1.25).

Further tests carried out according to conventional methods led to the conclusion that the compounds according to formula (1) not only in the the above-mentioned uses (as an anti-seizure drug, tranquilizer and muscle relaxant) are effective, but that also have a more or less pronounced potentiating effect between the derivatives of formula (1) and other drugs with an unidirectional Effectiveness is related to the inherent effects of dipropyl acetic acid and those of the derivatives of the type as already described and in some cases by way of example have been explained in more detail, is tolerable.

For this reason, the present invention also relates to pharmaceuticals Pra) arate, which is a combination of a drug of formula (I) as defined above is, with other drugs with the same effectiveness, especially -substituted Derivatives of barbituric acid with a sedative and / or sleeping aid effect, such as phenobarbitone and nembutal, cited by way of example only.

Potentiation test.

a) Injectable Anesthetics: While Pentothal, which is intravenously in given at an amount of 7 mg / kg rabbit will not cause sleep by intraperitoneal injection of dipropyl acetic acid in the form of sodium dipropyl acetate before injecting the same amount of Pentothal deeper ehlaf brought about, whereby the duration varies depending on the dose administered.

b) Gaseous anesthetics: While 5 cc of diethyl ether, which in a 3 l vial was atomized, mice not longer than 2 to 3 minutes and guinea pigs cannot euthanize for longer than 4 to 5 minutes, the animals could by previous Injection of a dose of 170 mg / kg dipropyl acetic acid as an aqueous solution of sodium dipropyl acetate be euthanized for 11 to 15 minutes.

c) Sleep Aid: In mice that have received a previous subcutaneous injection of dipropyl acetic acid as an aqueous solution of sodium dipropyl acetate in one dose of 73 mg / kg, the duration of sleep was increased 2.6 times than normal is achieved by subcutaneous injection of 30 to 40 mg / kg Nembutal alone.

d) Antiepilepsy drugs: by intraperitoneal administration of 8 mg / kg Gardenal was 75% protected against the Cardiazol crisis in mice. By Administration of 8 mg / kg Gardenal, the 50 mg / kg dipropylacetic acid in the form of Sodium dipropyl acetate has been admixed, 100% protection is effected.

Diuretic effectiveness.

An intraperitoneal injection of 100 mg / kg dipropylacetic acid in The form of an aqueous solution of sodium dipropyl acetate caused a in rats Increase in diuresis in the same order of magnitude as an intraperitoneal injection of 8 mg / kg acetazolamide, i.e. a compound previously used in therapy as diuretic has been used extensively.

Clinical Varsearch.

Therapeutic effect on epilepsia minor.

Three patients with epilepsia minor with disturbance of the elel.-tro-encephalogram suffered, were daily with 0.8 to 1 g of sodium dipropyl acetate in 20% aqueous Solution treated, with administration in the form of drops in 4 or 5 doses of 0.2 g took place.

After 10 days of treatment it was observed that the lines of the encephalograph returned to normal without any toxic symptoms or tolerance symptoms occurred.

Other therapeutic effects.

Other tests carried out according to conventional methods showed that the compounds of forms (1) also have a inhibitory soothing Effect (measured on the Actograph) on the thermoregulatory centers and muscle relaxation exercise.

Because of the clear rotating effect, as shown above between Derivatives of formula (I) and other drugs affecting the central nervous system act in a way that with the Y; strengthening of dipropylacetic acid and / or its Derivatives of the type as defined above and described by way of example. been are compatible, the present invention also relates to pharmaceuticals Compositions comprising a combination of an if-drug of formula (I), such as whether it is defined with other drugs with the same effectiveness on the central nervous system, especially substituted derivatives of barbituric acid with a sedative, anesthetic and sleeping aid effectiveness, such as the only Examples include phenobarbitone, nembutal and pentothal.

Claims (7)

Claims Therapeutic composition, characterized in that it is a compound of the formula comprises, in which Y an -Old group, in which X is an AX; hydrogen atom, an alkali atom, an alkaline earth atom, a magnesium or zinc atom or an -OR group, in which R is a linear or branched-chain lower alkyl radical with about to 9 carbon atoms, or represents a -NHZ group in which Z represents a hydrogen atom or the amide radical -CO-NH2, in conjunction with a pharmaceutically acceptable diluent or carrier. 2. Solid composition according to claim 1, characterized in that that this is in the form of capsules or tablets for oral administration. 3. Solid composition according to claim 1, characterized in that that this is in the form of suppositories for rectal administration. 4. Composition according to claim 3, characterized in that the Carrier consists of cocoa butter and the ratio of cocoa butter to the effective Compound is approximately "10: 1 (parts by weight). 5. Composition according to claim 2-4, characterized in that between about 50 and 200 mg of the active compound are obtained. 6. Liquid composition according to claim 1, characterized in that that this is in the form of syrup or suspensions. 7. Composition according to claim 1 to 6, characterized in that that the active compound di-n-propyl acetic acid, sodium di-n-propyl acetate, di-n-propylacetamide, Di-n-propyl acetic acid ethyl ester, di-n-propylacetylurea or zinc-di-n-propyl acetate is.