17,21-diacetate 17,21-dihydroxypregna-4-ene-3,20-dione with alcohol and adaptogenic activity

 

(57) Abstract:

The invention relates to medicine, namely to pharmacology, and relates to the use of compounds of formula I

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as alcohol and adaptogenic means increased efficiency. 1 Il., 3 table.

The invention relates to medicine, namely to pharmacology, in particular experimental search for the basis for the synthesis of drugs.

Known experimental study on the model of alcohol withdrawal syndrome anticonvulsant activity neurosteroids compounds 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 alpha, 21-hydroxy-5-alpha-pregnan-20-one. In Ukr.: Alcohol Clin Exp Res. 1995 Apr; 19 (2) C. 350-55. The presence of these compounds for anticonvulsant activity.

The disadvantages of these compounds is to limit their actions only anticonvulsant activity, as well as their impact on the processes of reproduction, which narrows the possibilities of their use.

Known substance 17, 21-diacetate 17, 21-dihydroxypregna-4-ene 3,20-dione with litotrepsii action. In the journal of General biology, 46, 1985, No. 5.

In pharmacology is not known steroid compounds without hormonal properties, having a wide range is irenie Arsenal substances, non-steroid hormones, which prevent the formation of alcoholic motivation in rats, reduces craving for alcohol in chronically alcoholic animals, and has adaptogenic properties.

This result is achieved by using 17, 21-diacetate 17, 21-dihydroxypregna-4-ene-3,20-dione as alcohol and adaptogenic funds with the chemical formula:

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Example 1. The influence of 17, 21-diacetate 17, 21-dihydroxypregna-4-ene-3,20-dione to the formation of alcoholic motivation in rats.

Rats (male) breed Wistar initial weight 100-120 g is subjected to chronic alcoholism by providing animals for 8 months 10% solution of ethanol as the sole source of liquid in the absence of restrictions on the consumption of standard briquetted feed. During this period rats were periodically tested (within 10 days) consumption of 10% solution of ethanol while giving the animals water, as described in the Methodological recommendations pharmakologische Committee of the Ministry of health on experimental (pharmacological) the study of drugs proposed for clinical testing as a means for the definition study of new drugs", Part 3, M , 1981, S. 95). In the process of alcoholism animals received course the introduction of the claimed compounds in doses of 10 mg/kg to 50 mg/kg

The compound was administered daily orally in the form of a suspension in tween-80. A control group of rats received tween-80. During the introduction of substances of animal testing on the preferred alcohol consumption, as described above. The results of the determinations conducted using blind control, shown in the drawing. As follows from the results presented in the drawing, the inventive steroid compound in the exchange application prevents the formation of alcoholic motivation, and this effect depends on the dose. A slight decrease in the consumption of alcohol is manifested in the introduction of steroid at a dose of 10 mg/kg, while increasing the dose to 50 mg/kg dose of consumed alcohol is reduced to 60% in comparison with the baseline period. In the control group of animals marked the formation of alcoholic motivation that manifests itself in the dose increasing consumption of alcohol and reducing the amount of water consumed. As follows from the results presented in the drawing, during the whole period of alcoholism in the control group of rats retained the neck, alcohol consumption is significantly reduced, this increases the amount of water consumed. This suggests that protivooskolochnye effect connections, resulting prophylactic course of application, is maintained throughout the period of alcoholism and is manifested in the reduction of alcohol motivation.

Example 2. The influence of 17, 21-diacetate 17, 21-dihydroxypregna-4-ene-3.20-dione on craving for alcohol after two months of taking in chronically alcoholic rats.

The effect of compounds on craving for alcohol at 2 months of taking ethanol was studied in chronically alcoholic for 4 months rats, pre-selected conditions dvuhsotletnego test the level of alcohol consumption. 2 months after removal of alcohol animals were again tested by the level of its consumption Claimed the substance was administered at a dose of 25 mg/kg within two months of taking alcohol. Registered quantity consumed by rats alcohol and behavior of animals in the open field test and in the maze with light and dark compartment before and after the removal of ethanol. In the open-field test took into account the following indicators of behavior: activity, respectively, in the peripheral and Central sectors of the field, the vertical component of the activity (S), taking into account the number of rises on his hind legs, shifted activity-grooming (G), consider the number of episodes of washing, and also the vegetative component behavior accounted for by the number of defecations (D). These figures were recorded for 3 min observation interval.

Declare steroid compound is able to reduce the dose of alcohol consumed after two months of taking ethanol in rats with already established alcohol dependence. As follows from the experimental results, the control alcoholic animals, the dose of alcohol consumed increased after two months of taking alcohol from 117 to 230%, averaging 161,324,8% in 50% of animals (group of 8 rats), the rest has not changed. On the contrary, the introduction of steroid compounds at a dose of 25 mg/kg orally daily for two months of the removal of alcohol is accompanied by a significant reduction in the dose of alcohol consumed up to 51.3 16.8 percent in 50% of animals (group of 8 rats), the remaining alcohol consumption did not change (P < 0,05).

As follows from the results, the development of pathological attraction to ethanol in rats as a result of chronic alcoholism leads to naruse their ethanol. Animals treated during the removal of alcohol declare steroid compound, restored violations indicative of the behavior caused by the action of alcohol. When this animal is increased orientation in the maze, reduced time spent in the light compartment. The claimed connection also eliminates the animals behavioral depression, activates the emotional sphere and the behavior of animals in the open field becomes more adaptive.

Example 3. In the experiment investigating adaptogenic activity 17, 21-diacetate 17, 21-dihydroxypregna-4-ene-3,20-dione by its ability to increase physical endurance of animals in terms of the inevitable stress of the voyage with cargo.

Activity in the conditions of the inevitable stress was assessed by the number of animal movements in the pool of water at a temperature of 25oa 5-minute time interval after swimming with maximum physical load with attached tail cargo. The claimed compound was administered daily at a dose of 25 mg/kg orally for 10 days before sailing with cargo and once in the same dose for the day before sailing without cargo.

Under stress, under the influence of the load test the inevitable swimming rat at contactual the emergence of behavioral depression, stress voyage with cargo (P<0,05).

The stress caused repeated reusable daily immobilization of Wistar rats during a 3 week period. The immobilization was carried out for three weeks by putting rats in close houses of alternate planting for rent in shared cells with access to feed and water. The claimed compound was administered at a dose of 25 mg/kg daily for 10 days prior to the first immobilization and then every other day for the entire period of immobilization.

As follows from the conducted experiments, the three-week immobilization four rats of the six control animals with passive responses to stress were killed, and in the experimental group who received steroid compound, all animals survived and were characterized by a higher behavioral activity (P<0,05). The results obtained indicate that the claimed compound has adaptogenic properties, enhancing the exchange application the resistance of animals to STL to hypoxia.

Rats (5 animals in the experimental and control groups) were placed on one animal in individual airtight containers and recorded lifespan in minutes. Declare the steroid was administered according to the scheme described in the previous examples.

As follows from the obtained results, in animals treated with the inventive steroid compound, the life expectancy in hypoxia was more. The increase in life expectancy have amounted to 12.3 3,6 min (P< 0,05), indicating increased reserve capacity for adaptation in rats treated with the inventive steroid compound.

Declare steroid compound 17, 21-diacetate 17, 21-dihydroxypregna-4-ene-3,20-dione, which is not a steroid hormone, prevents the formation of alcoholic motivation in rats and increases the resistance of animals to adapt to long-term deprivation of ethanol after chronic alcohol intoxication, reduces craving for alcohol, expands the Arsenal protivoallergennyh funds.

The claimed connection allatoxin. LD50in mice with intraperitoneal injection is more than 1 g/kg

Specified allows the use of this compound as osnovyvaetsja one of the primary goals in the treatment of alcoholism. The presence of the adaptogenic properties of the compounds can be used in various stressful situations that given the limited range of such tools increases its importance as the basis for the synthesis of drugs with adaptogenic properties.

Application 17, 21 - diacetate 17, 21-dihydroxypregna-4-ene-3,20-dione of the formula

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as alcohol and adaptogenic funds.

 

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