RU2363468C1 - Use of naloxone and naltrexone derivatives in making pain-killing drugs - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutics and medicine, and use of naloxone and naltrexone derivatives in making pain-killing drugs with a central mechanism of action.

EFFECT: developing highly effective drugs which are not addictive.

6 cl, 5 tbl, 3 ex

Description

The invention relates to medicine and relates to the use of derivatives of naloxone and naltrexone for the preparation of pain medication.

Pain medications, also known as analgesics, are used to relieve pain, acute or chronic, caused by various reasons, such as an attack of migraine, cephalgia; various musculoskeletal pains; birth pain; renal colic; pain with burns; as well as preoperative or postoperative analgesia.

The most effective central-acting analgesics are opioid analgesics (e.g., morphine), which, acting on the central opiate receptors of the brain, stop the pain syndrome. However, opioid analgesics with prolonged use cause drug dependence. Therefore, there is a need to create new analgesics that are comparable in effectiveness to opioid analgesics, but do not cause dangerous side effects, such as drug addiction.

Naloxone and naltrexone are non-specific opiate receptor antagonists that are widely used in medicine to alleviate the effects of opiate receptor agonists. These antagonists easily penetrate the blood-brain barrier and inhibit the action of antagonists, such as morphine. Naloxone and naltrexone do not cause drug dependence.

Known methylated derivatives of naltrexone and naloxone - N-methylnaloxone and N-methylnaltrexone, which retain the properties of opiate receptor antagonists, but lose their ability to penetrate the blood-brain barrier. These compounds exhibit biological activity only in peripheral tissues; therefore, they were classified as peripheral opiate receptor antagonists. Unlike regular naloxone, methylnaloxone does not cause “precipitation” of withdrawal syndrome in morphine-dependent subjects [Yuan C.S., Israel R.J. Expert Opin. Investig. Drugs 2006, Vol. 15 (6), P.541-552]. It was shown that in large doses, methylnaloxone can be antagonistic to the analgesic and depressive effects of opiates [T. Lewanowitsch, Miller J.H., Irvine R.J. Life Sci., 2006, Vol. 78 (7), P.682-688]. N-methylnaloxone and N-methylnaltrexone suppress withdrawal syndrome in morphine-dependent rats [Sudakov SK, Rusakova IV, Trigub MM, Pomytkin IA BEBiM, 2007, T.143, No. 5, p. 545-547].

We found that the introduction of methylated derivatives of naltrexone and naloxone into the bloodstream causes a central analgesic effect, despite the fact that these compounds do not penetrate the brain. This effect is unknown and cannot be predicted in the obvious way based on the known mechanism of action of these compounds.

The objective of the invention is the creation of a safe and effective analgesic drug of a central mechanism of action that does not cause drug dependence.

The invention consists in the use of a compound of general formula (I)

where R is allyl or cyclopropylmethyl, X is a pharmaceutically acceptable anion; for the preparation of pain medication.

Preferably, the compound of formula (I) is N-methylnaloxone, N-methylnaltrexone, or a pharmaceutically acceptable salt thereof. More preferably, compound (I) is N-methylnaloxone iodide or N-methylnaltrexone iodide.

The compounds of formula (I) of the present invention can be used to prepare painkillers in various dosage forms. Such forms include, but are not limited to injections, tablets, capsules, powders, solutions for parenteral or enteral administration.

Using the present invention, it becomes possible to stop pain syndromes of various etiologies without the side effects caused by opiate receptor agonists.

The following examples demonstrate the invention. The examples are illustrative only and are not intended to limit in any way the present invention.

Example 1. The introduction of the compounds of formula (I) relieves pain.

The experiments were carried out on 50 Wistar rats, males, weighing 200-220 g at the beginning of the experiments. The rats were kept under artificial lighting (12 hours a day), constant access to standard combined feed and water in 10 animals cages. In all rats, the latent period of tail withdrawal from hot (56 ° C) water was determined. After that, rats were injected intraperitoneally with 1 ml / kg of isotonic sodium chloride solution (control, n = 10) or 5 mg / kg of methylnaloxone iodide (experiment, n = 10). After that, the latent period of tail tail withdrawal from hot water was again recorded in rats 10, 30, 60, 120, and 180 min after intraperitoneal administration. The differences were considered significant at p <0.05, calculating the t-test for unpaired cases. The results are shown in Table 1.

Table 1 Ratio of latency of tail tail withdrawal in rats after drug administration to latent period before drug administration Time min Latency Ratio Control (saline solution) N-methylnaloxone 0 1,0 1,0 10 1,1 1.8 * thirty 1,2 2.3 * 60 1,2 1.9 * 120 1,2 1.7 * 180 1,1 1.5 *

Significantly different from control, P <0.05 (n = 10).

Table 1 shows that N-methylnaloxone has a significant central analgesic effect with peripheral administration.

Example 2. Injectable forms of anesthetic drug containing compound (I).

An exemplary composition of a unit dosage form of anesthetic is presented in Tables 2 and 3.

table 2 Ingredient % by weight N-methylnaloxone iodide 1-20 Phosphate buffer, pH 5.0-7.5 Water for injections up to 100

Injection preparation. The ingredients of table 2 are mixed in a manner known from the technical level in the indicated proportions and placed in ampoules under an inert gas (nitrogen).

Table 3 Ingredient % by weight N-methylnaltrexone iodide 1-20 Phosphate buffer, pH 5.0-7.5 Water for injections up to 100

Injection preparation. The ingredients of table 3 are mixed in a manner known from the technical level in the indicated proportions and placed in ampoules under an inert gas (nitrogen).

Example 3. Tableted forms of anesthetic drug containing a compound of formula (I).

An exemplary composition of a unit dosage form of anesthetic is presented in Tables 4 and 5.

Table 4 Ingredient % by weight N-methylnaloxone iodide 1-20 Magnesium stearate 0.1 Potato starch up to 100

Preparation of tablets. The ingredients of table 4 are mixed in the indicated proportions and are formed into tablets in a manner known from the technical level.

Table 5 Ingredient % by weight N-methylnaltrexone iodide 1-20 Magnesium stearate 0.1 Potato starch up to 100

Preparation of tablets. The ingredients of table 5 are mixed in the indicated proportions and are formed into tablets in a manner known from the technical level.

Claims (6)

1. The use of the compounds of General formula (I)

where R is allyl or cyclopropylmethyl, X is a pharmaceutically acceptable anion; for the preparation of pain medication. 2. The use according to claim 1, characterized in that the compound (I) is N-methylnaloxone or its pharmaceutically acceptable salt. 3. The use according to claim 2, characterized in that the compound (I) is N-methylnaloxone iodide, 4. The use according to claim 1, characterized in that the compound (I) is N-methylnaltrexone or a pharmaceutically acceptable salt thereof. 5. The use according to claim 4, characterized in that the compound (I) is N-methylnaltrexone iodide. 6. The use according to claim 1, characterized in that the analgesic drug is prepared in a unit dosage form selected from the group consisting of injections, tablet form, capsule form, powder, solution, syrup, gel and cream.