Blocker withdrawal syndrome resulting from addiction to excessive consumption of drugs or substances, addictive, pharmacological composition based on it and the way to relieve or avoid withdrawal symptoms

 

(57) Abstract:

Usage: in medicine to relieve or avoid withdrawal syndrome resulting from addiction to excessive consumption of drugs or substances that are addictive. The invention is: to relieve or avoid withdrawal syndrome resulting from addiction to excessive consumption of drugs or substances, addictive, using aneroid or its pharmaceutically priemlemo salt orally or parenterally in a daily dose of from 0.1 to 40 mg, which is administered within the time determined depending on the severity of the syndrome. 3 S. p. f-crystals.

The invention relates to a new use some diphenylmethyl-piperazinecarboxamide, in particular amperozide, 4 [4,4-bis(forfinal)butyl] N-ethyl-1-piperazinecarboxamide and their salts in the treatment of substance abuse. More specifically this invention relates to the attenuation of withdrawal symptoms and behavior change is a desire among patients with substance abuse.

In the complex mechanisms in the brain that underlie addiction to alcohol, involved different classes of nerve receptors and neurotransmitters. Experimental data support opioide the nature of pre - or postsynaptic and enabled the synthesis and/or release of neurotransmitters to the same extent in the manifestations of alcoholism, at the present time is not known.

Drug dependence is extremely difficult to remove. It is true, there is a dependence on ethanol, amphetamine, barbiturates, benzodiazepines, cocaine, nicotine, opioids, phencyclidine, and the like. Despite active research, so far there is no medication that can specific to counteract, for example, the desire to drink for persons dependent on alcohol. Preliminary studies have shown that, for example, blockers of serotonin uptake (for example, zimelidine, sertraline) reduces voluntary alcohol consumption in rats and humans. However, the mechanisms of action of these substances is not well understood. There is considerable experimental evidence that exposure to alcohol can be a manifestation of a more General role of inhibitor that serotonin plays in food intake. Of course blockers capture of serotonin and serotonin agonists have been shown to reduce the number of reactions oral consumption, such as eating, as well as a number of flavoring liquids, such as alcohol.

Found that the blocker of serotonin uptake sertraline reduces alcohol consumption by rats. Simultaneously with the action is (Gill R. et al, Alconol 5: 355-358, 1988; Myers R. D. and Quarfordt, S. D. Pharmacol Biochem. Behav. 40: 923-28, 1991). Certainly it seems that the effect of sertraline on the consumption of alcohol is associated with the action of the blocker of serotonin uptake in povedenie reactions oral consumption. Therefore, reduction in alcohol consumption should not be unexpected. Moreover, within a certain period after treatment with sertraline alcohol consumption returns to the level before treatment. There is therefore a need for more specific and effective agent for use in the treatment of substance abuse.

Currently, it was found that diphenylbutylpiperidine having the formula:

< / BR>
where R1and R2are groups independently selected from the group: H, alkyl chain, straight or branched, with 1 to 10 carbon atoms, cycloalkyl with 3-8 carbon atoms, aralkyl with 7-9 carbon atoms, alkenyl with 2-10 carbon atoms, fanilow, unsubstituted and substituted with from 1 to 3 substituting groups selected from halogen, in particular F, Cl and Br, lower Akilov with 1-5 carbon atoms, lower alkoxy group with 1-5 carbon atoms; unsubstituted amines or with substituents in the form of one or two lower alkyl groups of 1-5 as: H, lower Akilov having 1-3 carbon atoms, and phenyl;

R7selected from hydrogen, halogen, in particular F, Cl and Br, lower alkoxy group of 1-3 carbon atoms, and-CF and H O or S and pharmaceutically acceptable salts

are extremely efficient and specific suppression of alcohol dependence.

This discovery describes a completely new way of treatment of addiction to drugs, alcohol, nicotine, and the like. These substances were found, both chemically and pharmacologically distinct from those drugs, which are still offered for the treatment of drug dependence.

Specifically, the invention relates to the field of relief or prevention of a withdrawal syndrome resulting from addiction to the medication, drug or substance that caused the addiction, and/or for the suppression of dependence on drugs or substances causing addiction.

Substances such as these are known from the prior art [2] which is included as a reference, as well as their use in other areas of medicine (see U.S. patent[3] [4] 5013735).

The invention relates to a method of treatment of diseases of addiction to various verbatim-piperazine-carboxamide according to formula I, as explained above. Preferred at the present time are such compounds where R1methyl, ethyl or n-, ISO - or cyclopropyl; R2-H; R3, R4, R5and R6is hydrogen, or R3and R6hydrogen, and R4and5methyl, or R4and R5hydrogen, and R3and R6methyl; R7hydrogen or halogen, preferably one Deputy in each benzene ring is F, and X is 0; or a physiologically acceptable salt.

The most preferred substance is currently aneroid or its physiologically acceptable salt. Amperozide, chemical name 4-[4,4-bis(4-forfinal)butyl] -N-ethyl-1-piperazinecarboxamide, is a psychotropic compound obtained Bjork A. K. K. et al (U.S. patent 4308387) impact mainly on emotional behavior mediated by action on the limbic region of the brain (Christensson, E. and A. Pharmacol. Toxicol. 66: Suppl. I, 5-7, 1990). While the mechanism of action of amperozide on emotional behavior remains unknown, studies show that amperozide serotoninergicheskie antagonist (Svartengren J. and Simonsson, P. Pharmacol Toxicol. 66; Suppl. 1, 8-11, 1990) and also acts as a blocker of serotonin uptake [1] Recent discoveries allow p to learning and memory.

In [1] stated: "inhibitors of serotonin uptake could be useful in the treatment of addiction, for example, citalopram and zimelidine, which, apparently, suppress cravings for alcohol". However, in the article mentioned no mention of the fact that blockers of serotonin uptake reduces the number of reactions in eating behavior. Obviously, the blockade of serotonin uptake in itself does not create the basis for pharmacological specificity of action in the treatment of substance abuse. Therefore, the basic statement of the above article Eriksson E. does not give the average expert guide to selecting products that meet the need for more specific and effective agents for use in the treatment of disorders related to the abuse of various substances.

The invention also relates to the use of therapeutically effective amount of a substance corresponding to the formula I for the preparation of compositions for treatment of disorders related to the abuse of various substances, as well as to the composition as such.

Re-introduction of the subject of certain medications, such as opiates (e.g. morphine), cocaine, benzodiazepines (eg, diazepam), or substances that cause protestersto or substances. When a drug or substance that causes addiction, differs from the dependent entity, he develops certain symptoms, including disorders and mood and longing this medication or substance. These symptoms together can be described as a withdrawal or abstinence syndrome in connection with the present invention. Recipes, including pharmacologically active compounds that are the subject of this invention are disclosed in U.S. patents [2] [3] N 5013735 included it for reference. Examples of such formulations, which are expected to be suitable for use in the treatment of disorders related to the abuse of various substances can be:

Capsules containing (per capsule),mg:

Active ingredient 10

Lactose 250

Starch 120

The stearate 5

Tablets containing (on a tablet),mg:

Active ingredient 10

Avicel 108

Colloidal silicon dioxide 10

Talc 20

Magnesium stearate 2

Injectable solution (100 ml), mg:

The active ingredient 1000

Metagen 100

NaCI 700

NCI 0,1 N to pH 3.5

Water sterile 100 ml

A therapeutically effective amount, expressed as 1 mg per day misslowpoweramie various substances, should be about 0.1 to 40 mg, preferably 0.1 to 20 mg, and mainly 1 to 20 mg, depending on the individual status of the person should be treated, age, weight and response to treatment of each individual patient. Accurate individual dose, as well as the daily dose will therefore be determined in accordance with conventional medical rules as instructed by the doctor. The animal experiments described below, showed that the introduction of twice a day gives a therapeutic effect, and it is expected that the same will be observed when the matter will be assigned to the people.

Accordingly, we can expect that the active ingredient will be administered to the patient in need of such treatment, the usual routes of administration and in the usual pharmaceutical forms. These forms include solutions, suspensions, emulsions, tablets, capsules and powders prepared with pharmaceutically acceptable carriers for pills administration, or sterile solution for parenteral administration.

When one of the methods of the invention, the daily dose of active substance is entered long at a constant level of receipt of the drug throughout the period of introduction, for example, by using special the stability or ease of administration. The pharmaceutical composition may also contain additional therapeutically useful agents other than the pharmacologically active compounds of this invention for the combined treatment.

Twenty years of research has consistently demonstrated that drugs that abuses people, usually willingly consumed laboratory animals. Ethanol, amphetamine, barbiturates, benzodiazepines, cocaine, nicotine, opioids, and phencyclidine and the like only a few examples of substances that cause addiction in humans, and readily absorbed animal models of human disease). The value of modeling disease in animals, studies of pharmacological and behavioral mechanisms underlying drug dependence, shown repeatedly. Indeed, animal models are our only opportunity to explore connections to facilitate or modify behavioral attraction to drugs. In this regard, there is considerable experimental evidence that the common mechanism of the process pernicious addiction exists in the brain stem, where are patterns that determine addiction to slow the total of the invention, without limiting, however, the breadth of its application.

Example 1.Preparation of tablets amperozide.

Tablet amperozide the following composition, mg:

Aneroid hydrochloride 5,0

Lactose 105,5

Microcrystalline cellulose 13,0

Starch glycolate, sodium 5,2

Dioxide silicone 0,65

Magnesium stearate 0,65

To get a tablet for paroling application, preformed mass (core) covered conventional sucrose shell.

Example 2. The effect of amperozide on alcohol consumption, caused by censida in rats.

The effect of amperozide, administered systemically, was determined on rats Sprague

Dawley,whose chronic alcoholism caused by a series of intraperitoneal injections of cyanamide, in accordance with the methodology of the experiment described earlier (Criteher E. C. and Myers, R. D. Alconol. 4: 347-353, 1987). Recorded consumption of food and water and was determined by the weight of the body.

Amperozide, injected subcutaneously at a dose of 2.5 mg/kg twice daily after 3 days, significantly changed the desire for alcohol. The immediate effect was observed after the introduction of amperozide both in terms of absolute quantity in g/kg, and the ratio of alcohol and water. Average consumption in g/kg was reduced (P&l is the liquid was decreased similarly in relation to topicname level, especially important is the fact that no significant impacts caused by amperozide, in relation to changes in body weight or quantity consumed by the rats food and water during treatment in comparison with doopity level that shows the pharmacological specificity of action of this medication.

It is especially remarkable discovery that amperozide entered in the mode of stable dosing with osmotic minipump Alzet implanted in subscapularis region, at a dose of 5 mg/kg/day for 7 days significantly reduced alcohol consumption in rats who received a course of cyanamide, both in absolute terms g/kg, and the ratio of alcohol and water. In terms of absolute alcohol consumption average absorbed amount g/kg decreased (P <0,01) from 7.0 to 3.4 g/kg of alcohol at the time of receipt of amperozide (in the blood). After 4 days systemic injections of amperozide, i.e. after minipump will be exempt from drugs, absolute consumption in g/kg of alcohol rats remained oppressed. Moreover, when the prevailing consumption patterns were examined after 30, 70, 110 and 140-day intervals after the cessation of receipt of amperozide, the decline continued. At that time, acting on the consumption of alkaloid, for the first time demonstrate the lasting impact of drugs on abnormal alcohol consumption and clearly shows that these compounds are suitable for preventing and reducing dependence on agents that cause it.

1. Application amperozide-[4,4-bis(4-forfinal)butyl]-N-ethyl-1-piperazinecarboxamide} or its pharmaceutically acceptable salts for relief or prevention of a withdrawal syndrome resulting from addiction to excessive consumption of drugs or substances that are addictive.

2. Pharmaceutical composition for the relief or prevention of a withdrawal syndrome resulting from addiction to excessive consumption of drugs or substances, addictive, which contains aneroid or its pharmaceutically acceptable salt in the following ratio of components, mg standard dose:

Aneroid or its pharmaceutically acceptable salt is 0.1 to 40.0

Filler Rest

3. The way of mitigation or prevention of a withdrawal syndrome resulting from addiction to excessive consumption of drugs or substances, addictive, by the introduction of a drug given orally or parenterally, characterized in that amperozide in the

 

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