17-acetate-21-pivalate 17, 21-dihydroxypregna-4-ene-3,20 - dione with alcohol and anxiolytic activity

 

(57) Abstract:

17-Acetate-21-pivalate 17,21-dihydroxypregna-4-ene-3,20-dione of formula 1 has alcohol and anxiolytic activity and is a product of waterproofing inactive steroid hormone cortexone by acylation of 17 and 21 of the hydroxyl groups with acetic acid and pivaloyloxy acids. New steroid pregnanolone structure has properties to reduce craving for alcohol and prevent recurrence of alcoholism, and can also be used for the treatment of anxiety disorders in different nosological groups of mental patients. table 4.

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 anticonvulsant activity of these compounds. The disadvantages of these compounds is to limit their actions only protivosudorojna the ASS="ptx2">

In pharmacology is not known steroid compounds without hormonal properties with a wide range of alcohol activity.

The technical result of the invention is to provide synthetic compounds 17-acetate-21-pivalate 17, 21-dihydroxypregna-4-ene-3,20-dione, which is not a steroid hormone that has anxiolytic properties and reduces craving for alcohol in chronically alcoholic animals after long-term removal of ethanol. This result is achieved by using a synthetic compound which is a product of hydrophobization side chain of natural inactive steroid hormone cortexone by acylation of 17 and 21 of the hydroxyl groups in the form of esters with molecules of acetic acid and Pivovarova acids with the following chemical formula: 17-acetate-21 pivaloate 17, 21-dihydroxypregna-4-ene-3,20-dione.

< / BR>
The method of obtaining 17-acetate-21-pivalate 17, 21-dihydroxypregna-4-ene-3,20-dione. To a solution of 5 g 17, 21-dihydroxypregna-4-ene-3,20-dione in 5 ml of pyridine, add 5 ml of pivaloate, and is heated to 50oWith and precipitation occurs. The mixture is left for 3 hours, then diluted with water, otfit 98,6%), so pl. 258-260 (from ethanol), IR spectrum , cm-1); 1140, 1165, 1612, 1650, 1720, 3450, PMR-spectrum (M. D. ): 0,73 (18-CH3) 1,27 (21-C(CH3)3), 2,73 (17-OH), a 4.86 duplicates. and 5,07 duplicates. (AB system, Jab= 18.3 Hz, 21-CH2). 5,73 (C4H). A solution of 6 g of pivaloate in 12 ml of dry pyridine and 70 ml of CH3COCl boiled for 7 hours, the excess of CH3COCl evaporated in vacuo, the residue diluted with methanol and poured into water. The precipitation is filtered off and dried in air. Obtain 5.7 g of the acetate of pivaloate, which without purification forth in further transformations. A solution of 5.7 g of the acetate of pivaloate and 0.6 g of sulfosalicylic acid in 125 ml of ethyl acetate and 27 ml of acetic acid is boiled for 3 hours, then evaporated in vacuum ethyl acetate, the residue is diluted with acetone and poured into water. The precipitation is filtered off and purified by passing through a column of SiO2(40-100 mesh) under a stream of nitrogen in the system ether-hexane (3:1). Obtain 2.8 g of 17-acetate-21-pivalate 17, 21-dihydroxypregna-4-ene-3,20-dione (yield 54%), so pl. 159-162oIR spectrum ( cm-1): 1145, 1155, 1610, 1670, 1735, PMR-spectrum (M. D. ): 0,73 (18-CH3), 1,18 (19-CH3), 1,25 (21-C(CH3)3), 2,1 (17-OAc), 4,59 duplicates. and 4,89 duplicates. (AB-system, Jab=16.5 Hz, 21-CH2-), 5,73 (C4-H).

Example 1. The effect of 17-acetate-21-pivalate 17, 21-Eski alcoholic for 4 months rats.

Rats (male) breed Wistar initial weight 100-120 g is subjected to chronic alcoholism by providing animals a 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 of the Pharmacological Committee of the Ministry of health on experimental (pharmacological) the study of drugs proposed for clinical testing as a means for the treatment and prevention of alcoholism (In kN. "Guiding instructional materials for experimental and clinical study of new drugs", Part 3, Moscow, 1981, c. 95).

The effect of steroid on craving for alcohol during two months of taking ethanol was studied in chronically alcoholic for 4 months rats, pre-selected conditions dvuhsotletnego test the level of alcohol consumption by the method described above. 2 months after removal of alcohol animals were again tested on the level of the consumed connection is able to reduce the dose of alcohol consumed after two months of taking ethanol in rats. As follows from the results of the experiments are presented in table. 1, the control alcoholic animals, the dose of alcohol consumed after two months of taking practically did not change and remained relatively high. On the contrary, the introduction of steroid compounds in a dose of 5 mg/kg orally daily for two months of the removal of alcohol is accompanied by a significant reduction in the dose of alcohol consumed (P < 0,05). This effect lasts for 9 days of observation after the introduction of the substance

Example 2. The effect of 17-acetate-21-pivalate 17, 21-dihydroxypregna-4-ene-3,20 dione on craving for alcohol after two months of taking in chronically alcoholic for 10 months in rats.

The experiments were carried out as described in example 1 method, however, the rats were subjected to longer within 10 months of alcoholism. As shown by the results of the experiments are presented in table. 2, after the introduction of the proposed steroid in the period of removal of alcohol and the provision of animals for a possibility to consume ethanol in the conditions of free choice, in the experimental group of rats ethanol consumption was reduced by half compared to the original Isakov, after taking the difference between the experimental and control groups of rats significantly increased by reducing the consumption of ethanol under the influence of the claimed compounds (P < 0,05).

In the control group of rats was observed only a slight decrease in the consumption of ethanol, quickly returned within one week to the original level.

In contrast, in the experimental group the restoration of the level of consumption was significantly delayed, and an additional 7-day course introducing the claimed compounds for this reduced the background even in double dose (10 mg/kg) had no appreciable effect.

Example 3. The study of anxiolytic activity 17-acetate-21-pivalate 17, 21-dihydroxypregna-4-ene-3,20-dione. For the experimental investigation of the availability of anxiolytic activity of the claimed compounds used two behavioral test: test "bright-dark" camera (In Ukr.: "Pharmacol. Biochem. Behav", 1980, V. 13, p. 167) and the test of the conflict situation, or Vogel (Ukr.: "Psychopharmacol", 1971, V. 21, P. 1).

Animal testing in the test of Vogel was performed using a camera "Lick suspension test. For 72 hours prior to the experiment, animals deprived of water with an excess of standard brittoniana is injected into the animals stomach claimed steroid in doses of 2 mg/kg and 10 mg/kg and after 60 minutes in the conditions of connection of electric current 0.5 mA power electrode to the cell floor and the drinking water register number of approaches to the drinker and the number of shocks, get the animal while the drinkers, as well as their relationship to the number of approaches to the drinker. The total time spent by the animal waterers determine with less latent period of the first approach for the five-minute observation interval on the second day of testing.

As follows from the results of experiments, in control experiments, the average time spent by the animal waterers is 24715 seconds while applying DC power of 5 μa and practically did not change with increasing current to 10 µa, making 2599 seconds. The number of shocks was reduced in 4 times from 368 to 94 strike, and their number per unit of time in 3.8 times from 0.14 to 0.03 to 0.37 of 0.014. Relations between the number of shocks to the number of approaches to the drinker when the current of 10 μa was 2,27 0,32.

Anxiolytic properties of the claimed compounds measured according to this method, manifested most clearly in the dose of 2 mg/kg when applying more current to 10 µa. The number of shocks transmitted to animals at each approach to the drinking has increased almost in 2 times and amounted to 4.41 of 0.65 (P < 0,05). This confirms the ability of the proposed steroid to ease the fear in rats.

Anxiolytic effect of the claimed compounds confirmation is meshaut in the center of the maze and watch for 5 minutes, recording the time spent in the light compartment. The results of the experiments are presented in table. 3, show that with the introduction of the proposed steroid anxiolytic effect manifests itself in a relatively low dose of 2 mg/kg, as indicated by a significant increase in the time spent by rats in the lit compartment of the maze. At five increasing doses of the substances to 10 mg/kg the effect is not increased, but rather diminished.

Example 4. The effect of 17-acetate-21-pivalate 17, 21-dihydroxypregna-4-ene-3,20-dione aggressive-defensive behavior.

Aggressive-defensive behavior were analyzed in pairwise grouped rats placed on the electric Playground, which was supplied current, the voltage is increased to 2 volts every 15 seconds irritation; it was recorded voltage that causes a painful reaction (peep) and aggression (fight). Anxiolytic effect of the claimed compounds is detected and its impact on active defensive reaction from grouped in pairs of rats when they electrobios stimulation. Thus in rats under the influence of steroid does not change the threshold passive defensive reaction (peep), whereas the threshold of the active-defensive reaction (d is scivetti (P < 0,05).

Declare steroid compound 17-acetate-21-pivalate 17, 21-dihydroxypregna-4-ene-3,20-dione, which is not a steroid hormone, has alcohol and anxiolytic activity and increases the resistance of animals to adapt to long-term deprivation of ethanol after chronic alcohol intoxication, reduces craving for alcohol.

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

Specified allows you to use this connection as the basis for the development of tools used in remission for the prevention of recurrences of alcoholism, which is one of the primary goals in the treatment of this disease and for the treatment of anxiety disorders in the framework of different nosological groups of mental patients.

Steroid pregnanolone structure - 17-acetate-21-pivalate 17,21-dihydroxypregna-4-ene-3,20-dione following structural formula

< / BR>
with alcohol and anxiolytic activity.

 

Same patents:

The invention relates to 14,17-C2-bridged steroids of formula I, where R3- O, R6- Hor-(C1-C4)-alkyl, where R6and R7together form an additional bond; R7-or-(C1-C4)-alkyl, where R6and R6both H, or R9and R10each H or together form a bond, R11and R12each H or together form a bond, R13- CH3or2H5; R15- H or C1-C3-alkyl; R16and R16independently H, (C1-C3)-alkyl or C1-C4alkenyl or together form a (C1-C3-alkyliden; R15and R16together form a cyclewhere n = 1, and h - O and R16- N- H, (C1-C3)-alkyl,- H, (C1-C3)-alkyl,- H, (C1-C3)-alkyl or HE; except 14,17-ethano-19-norpregna-4-ene-3,20-dione

The invention relates to substituted derivatives of 19-norpregnane, methods of producing these compounds and pharmaceutical compositions containing them

The invention relates to substituted derivatives of 19-norpregnane, methods of producing these compounds and pharmaceutical compositions containing them

Steroid compound // 2160279
The invention relates to extrenely steroids that are associated with neuroepithelial cells in the vomeronasal organ of the human body

The invention relates to the field of organic synthesis

The invention relates to the field of organic synthesis

The invention relates to a derivative 11,21-bisphenyl-19-norpregnane formula I, in which R1selected from H, halogen, NR5R6and R5and R6independently are hydrogen or C1-6-alkyl; R2represents hydrogen; R1and R2together are C1-3-alkylenedioxy, optionally substituted by one or more halogen atoms; R3represents methyl; R4choosing among C(O)-NR5R6, SOnC1-6-alkyl, optionally substituted by one or more halogen atoms, SOnC3-6-cycloalkyl, SO2-NR5R6, 2-oxopyrrolidin or NR5R6where R5and R6independently are hydrogen, C1-6-alkyl, or R5and R6together form a C3-6-alkylen, n = 1 or 2, R7represents N or C1-7-alkyl; R8represents H; X is chosen among the (H, HE, O and MO; or their pharmaceutically acceptable salts

The invention relates to medicine and relates to a means for relief of alcohol withdrawal syndrome
The invention relates to medicine, namely to create tools for the treatment of alcohol intoxication

The invention relates to medicine, pharmacology, and relates to means for reducing the consumption of ethyl alcohol and the severity of the pathological craving for ethanol

The invention relates to medicine, namely to addiction
The invention relates to pharmacy and medicine, namely to medicines for the treatment of patients with chronic alcoholism and methods of treatment
The invention relates to medicine, namely to addiction
The invention relates to medicine and, in particular, to addiction

Set alcohol funds // 2146529
The invention relates to medicine, namely to biologically active additives used in addiction, for control and treatment status hangover after acute alcohol intoxication, as well as for prevention and treatment of alcoholism

The invention relates to new derivatives of benzimidazole and their salts formed by the addition of acids, the way they are received and microbicide tool based on them
Up!