RU2322977C1 - Synthetic analgesic agent and method for treatment based on this agent - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to drugs and concerns non-narcotic synthetic analgesic agent. Agent comprises derivative of gamma-pyrone as an active component chosen from group consisting of meconic acid, methyl-comenic acid, comenic acid taken in the amount from 0.05 mg to 300 mg for a single dose, and a pharmacologically compatible liquid filling agent in the following ratio of components, wt.-%: active substance, 0.5-95, and liquid filling agent, the balance. Agent represents a formulation designated for systemic dosing. Also, invention discloses a method for treatment of pain syndrome of different etiology based on administration of non-narcotic synthetic analgesic agent. Invention provides the novel synthetic non-narcotic analgesic agent without negative adverse effects.

EFFECT: valuable medicinal properties of agent.

9 cl, 2 tbl, 7 ex

Description

The group of inventions relates to pharmaceuticals and medicine, in particular to a non-narcotic synthetic analgesic agent based on derivatives of gamma-pyrone, and a method of treatment using them.

The invention, in terms of the composition of the analgesic, can be used to produce new generation analgesics.

It should be especially noted that, according to the specificity of the effect on animals and humans, the proposed analgesic agent is not an opiate or an opiate-like compound, and according to the analgesic properties, the proposed agent is comparable to the analgesic effects of drugs belonging to the group of large analgesics,

The invention can be applied in medicine and veterinary medicine for its intended purpose for the relief of pain syndrome of various etiologies and during the treatment of drug dependence.

Analgesics, or analgesics (from the Greek. Algos - pain and an - without), are medicines that have a specific ability to weaken or eliminate the feeling of pain [Mashkovsky M. D. Medicines 14th edition. M .: New wave, 2003.V.1. P.145].

An analgesic (analgesic) effect can be exerted not only by the analgesics themselves, but also by other substances belonging to different pharmacological groups. So, the drugs used for anesthesia (general anesthesia) may have an analgesic effect, and some of them in appropriate concentrations and doses (for example, trichlorethylene, nitrous oxide) are used specifically for analgesia. Local anesthetics in essence of their action are also analgesic for pain associated with spasms of smooth muscles, antispasmodic and anticholinergic drugs can have an analgesic effect.

In the proper sense of the word, analgesic means drugs whose dominant effect is analgesia, which occurs as a result of resorptive action and is not accompanied in therapeutic doses by turning off consciousness and a pronounced violation of motor functions.

According to the chemical nature, nature and mechanisms of pharmacological activity, modern analgesics are divided into two groups.

The main representatives of the first group of analgesics are salicylic acid derivatives (sodium salicylate, acetylsalicylic acid, salicylamide, etc.), pyrazolone derivatives - antipyrine, amidopyrine, analgin, para-aminophenol (or aniline) derivatives - phenacetin, paracetamol [Mashkovsky M. D. Medicines 14th edition. M .: New wave, 2003.V.1. P.146]. These analgesics are synthetic drugs.

The analgesic activity of drugs belonging to the first group is manifested in certain types of pain, mainly in neuralgic, muscle, joint pain, with headache and toothache. With severe pain associated with injuries, abdominal surgery, etc., they are practically ineffective.

These funds exhibit antipyretic effect in febrile conditions and anti-inflammatory effect, expressed to varying degrees in different analgesics of this group.

The use of these drugs does not affect the respiratory and cough centers. In therapeutic doses, drugs belonging to this group do not cause phenomena of euphoria, mental and physical dependence. However, prolonged use, for example, analgin, is accompanied by an increase in the dose of the drug to achieve the desired analgesic effect. In addition, the most commonly used drugs from this group - analgin and acetylsalicylic acid (aspirin) - have a number of negative side effects. Currently, analgin as a drug is banned for use in 18 countries.

In the mechanism of action of the analgesics of the first group, a certain role is played by the effect on the thalamic centers, which leads to inhibition of the conduct of pain impulses to the cerebral cortex. An important role in the mechanism of action of salicylates is played by the inhibition of prostaglandin biosynthesis, as well as the stimulating effect on the pituitary gland, the adrenal glands, which promotes the release of corticosteroids. Of significant importance in the action of the analgesics of the first group is their effect on the kinin system (antagonism with the allergic effect of bradykinin, etc.).

Analgesics of the second group include natural compounds - morphine and related alkaloids (opiates) and synthetic compounds with opiate-like properties (opioids). They are characterized by strong analgesic activity, providing the possibility of their use in injuries (surgical interventions, wounds, etc.) and in diseases accompanied by severe pain (malignant neoplasms, myocardial infarction, withdrawal symptoms in patients with drug and drug dependence, etc.) . Therefore, they are also called large analgesics.

According to the sources of production and chemical structure, the analgesics of the second group include natural alkaloids - morphine and codeine, contained in sleeping pills; semisynthetic compounds obtained by chemical modification of a morphine molecule (ethyl morphine); synthetic compounds (promedol, fentanyl, pentazocine, nalbuphine, butorphanol, tramadol, etc.). Most synthetic drugs are obtained by reproducing the simplified structure of morphine. By chemical modification of the morphine molecule, compounds are also obtained that are its pharmacological antagonists (naloxone). Morphine as an analgesic is prescribed for adults by mouth in a single dose of up to 0.02 g (daily dose of 0.05 g). A single dose lasts 3-5 hours. For acute and chronic pain, morphine is prescribed epidurally. 0.2-0.5 ml of a 1% solution of morphine in isotonic sodium chloride solution is introduced. The action manifests itself after 10-15 minutes, after 1-2 hours a very pronounced analgesic effect is observed, lasting for 8-12 hours. To reduce side effects, atropine, metacin or other anticholinergics are often prescribed with morphine. Method of release: tablets of 0.01 g, 1% solution in ampoules and syringe tubes of 1 ml [ibid. P.145]. Morphine and its analogues in the order of the Ministry of Health of the Russian Federation No. 326 (1997) are not listed in lists A and B; they are included in the "List of narcotic drugs whose circulation in the Russian Federation is limited and in respect of which control measures are established in accordance with the legislation of the Russian Federation" (list No. 2).

Morphine and its analogues have a specific effect on the central nervous system of a person, which manifests itself in the development of euphoric states. With the repeated use of these drugs, syndromes of mental and physical dependence (drug dependence) arise, which limits the possibility of their long-term use. Long-term use of drugs of the group of large analgesics is accompanied by the need to increase the dose of the drug to achieve an analgesic effect. This is due to the addiction to the action of lower (therapeutic) concentrations of substances with their long-term use. The action of these analgesics is not limited to the analgesic effect. To one degree or another, they have a negative effect on the cardiovascular and respiratory systems. Exceeding the required dose of drugs can provoke respiratory arrest due to inhibition of the respiratory center, blocking the cough reflex. Toxic properties in relation to the central nervous system are manifested in sleeping pills, depressive states that replace euphoria, the occurrence of hallucinations. All representatives of the group of large analgesics have an effect on intestinal motility and tone of the bladder. Prolonged use of drugs of this group can provoke nausea, vomiting, diarrhea and is accompanied by a number of other negative side effects.

In patients with advanced physical dependence syndrome, depriving them of an analgesic drug may develop a painful condition - withdrawal syndrome, which, as a rule, is accompanied by a powerful algic component.

In connection with the expressed narcogenic potential, the analgesics of the second group are subject to storage, prescription and release from pharmacies in accordance with special rules. In recent years, a number of large analgesics used that have a pronounced narcogenic potential (tecodine, hydrocodone phosphate, phenadone, some finished dosage forms containing opium and codeine) are excluded from the list of medicines in the Russian Federation [Mashkovsky M. D. Medicines 14th edition. M .: New wave, 2003. V.1 .. S.145].

The mechanism of action of large analgesics is not well understood. Neurophysiological studies indicate inhibition of the thalamic centers of pain sensitivity by the indicated analgesics and blocking the transmission of pain impulses to the cerebral cortex. However, in their effect, these analgesics differ from representatives of the first group, since they affect the ability of the central nervous system to summarize subthreshold impulses.

Recently, data have been obtained on the presence of specific “opiate” receptors in the brain and other organs [Mashkovsky M. D. Medicines 14th edition. M .: New wave, 2003.V.1. P.146]. Endogenous ligands, that is, specific physiologically active compounds forming in the body that bind to these receptors, are neuropeptides - primarily enkephalins and endorphins and recently discovered in the USA prof. D. Zadina endomorphins [Zadina J.E., Hackler L., Ge L, Kastin A. A potent and selective endogenous agonist for the μ-opiate receptor // Nature 1997, V.386. P.499-502]. Endogenous ligands are released in large quantities into the systemic circulation when stressful reactions occur, both positively and negatively emotionally colored. The greatest number of endogenous morphines is released at the stage of a shock during the development of a general adaptation syndrome. They have an analgesic effect, which can often be accompanied by euphoric conditions [Selye G. Stress without distress: trans. from English / Total. ed. E.M. Kreps; Foreword Yu.M. Saarma. - M .: Progress, 1979. - 124 p.].

An important role in the processing of information of this kind is assigned, as shown below, to the so-called pleasure center of the lateral hypothalamus. On the model of self-stimulation with irritation of this center, most of the known analgesic and psychotropic drugs are currently tested [Zvartau E.E. The effect of chronic administration of morphine on the reward system in rats. Pharmacology and Toxicology, 1978, 3, p. 529-535; Zvartau E.E. The effect of naloxone on the emotionally positive and antinociceptive effects of stimulation of the hypothalamus in rats. Bull. expert. biol. and honey., 1979, 88, N 11, p. 43-45; Zvartau E.E., Patkina N.A. Motivational components and self-stimulation during behavioral reactions caused by electrical stimulation of the hypothalamus. Zhurn. higher nervous activ., 1974, N 3, S. 529-535; Bespalov A., Lebedev A., Panchenko G., Zvartau E. Effects of abused drugs on thresholds and breaking points of intracranial self-stimulation in rats. Eur. Neuropsychopharmacol., 1999, 9, N 5, p. 377-383].

The binding of morphine with receptors to endogenous opiates is ensured by the fact that a certain part of its molecule has structural, including conformational similarity with the tyrosine residue of enkephalins and endorphins. Thus, exogenous analgesic morphine (like other opiates and opioids close in structure to it), when introduced into the body, interacts with the same receptors that are designed to bind endogenous ligands. Chronic administration of exogenous substances of opioid nature by the feedback mechanism blocks the synthesis of their own endogenous. When you stop taking exogenous drugs, the pain syndrome also develops due to the lack of intrinsic endogenous compounds.

Opiate receptors are isolated in a separate population that is heterogeneous. It was shown that opiate receptors exist in the form of different subpopulations (subgroups): μ (mu) (or OP ₃ according to the IUPHAR system), æ (kappa) (OP ₂ ), σ (sigma), δ (delta) (OP ₁ ), having different physiological significance. It is believed that mu receptors mediate supraspinal analgesia, euphoria, respiratory depression and physical dependence, kappa receptors mediate spinal analgesia, miosis, sedation. Different endogenous ligands and large analgesics can bind predominantly to one or another subgroup of receptors, which can determine the characteristics of their pharmacological action.

A variety of large analgesics differ in the nature of binding to opiate receptors. Some of them (morphine, promedol, fentanyl, etc.) are “pure” complete agonists; binding to receptors, they exert a physiological (pharmacological) effect characteristic of endogenous ligands. Others are “pure” antagonists (naloxone, naltrexone). Contacting the receptors, they seem to close them, thus blocking the action of exogenous opiates. The third group includes drugs of a mixed type of action (antagonist agonists) that bind differently to different subgroups of opiate receptors and therefore have an agonistic effect on one type of action and an antagonistic effect on the other (tramadol, nalorphine, pentazocine, nalbuphine, etc. .).

The latest generation synthetic analgesic belonging to the group of opiate receptor antagonist agonists, tramadol, is ± trans-2 - [(dimethylamino) methyl] -1- (m-methoxyphenyl) cyclohexanol hydrochloride [Mashkovsky MD Medicines 14th edition. M .: New wave, 2003.V.1. P.157]. The drug tramadol, selected as a prototype of the proposed analgesic agent, has a high analgesic activity, gives a quick and lasting effect. Tramadol is inferior in activity to morphine, therefore it is used, respectively, in large doses.

Tramadol is effective when administered orally and parenterally. When administered intravenously, it has an analgesic effect after 5-10 minutes when administered orally, after 30-40 minutes. Valid for 3-5 hours.

The treatment method using tramadol is selected as a prototype for the treatment method of the proposed analgesic agent.

A well-known drug is used for severe acute and chronic pain: in the postoperative period, with injuries, in cancer patients, as well as before surgery.

It is possible to use the drug to relieve acute and tonic pain, as well as to stop the algic component of the withdrawal syndrome that develops after refusing to take drugs.

Adults and children over 14 years of age are administered intravenously (slowly dropwise), intramuscularly or subcutaneously, 0.05-0.1 g (1-2 ampoules), up to 0.4 g (400 mg) per day. Inside appoint (with a small amount of liquid) in capsules of 0.05 g - up to 8 capsules (0.4 g) per day or in the form of drops - 20 drops (contains 0.05 g of tramadol) to receive in a small amount of water up to 8 times a day. You can use the drug in the form of rectal suppositories, 1 suppository (0.1 g) up to 4 times a day.

For children under 14 years of age, the drug is not prescribed due to lack of knowledge (the drug is relatively recently introduced into medical practice). The drug should not be used for a long time (to avoid addiction).

Method of release: capsules of 0.05 g in a package of 10-20 pieces; drops (with a content of 1 ml of 0.1 g of the drug) in vials in a package of 10 pieces; 5% solution in ampoules of 1 and 2 ml in a package of 5 and 50 ampoules; rectal suppositories of 0.1 g in a package of 5 pieces.

Unlike other opioids in equianalgetic doses, tramadol does not cause constipation, does not inhibit blood circulation and respiration. Of the possible side effects, the development of nausea, dizziness, and in rare cases, vomiting should be noted. These reactions, usually transient, in most cases do not require discontinuation of the drug and can be stopped by the appointment of metoclopramide. In general, tramadol has proven itself in clinical practice. According to various sources, the effectiveness of tramadol in traumatology, orthopedics, surgery and oncology varies from 66 to 94%. In addition to the use of tramadol as an analgesic, it has been used since 1989 (although the mechanism of this action is still unclear) for the relief of muscle tremor in the immediate post-narcotic and postoperative periods.

Storage: tramadol is included in List No. 1 of potent substances of the Standing Committee on Drug Control of the Ministry of Health of the Russian Federation (1998).

Tramadol is not a “pure” agonist, therefore, it is objectively inferior in effectiveness to morphine. Like morphine, with repeated doses it causes addiction and intoxication in most patients. To achieve an analgesic effect with prolonged use, it is necessary to increase the dose of the drug.

It should be noted that the comparison of the invention is carried out with drugs approved in the Russian Federation: tramadol, morphine hydrochloride and analgin. The last two drugs are described in sufficient detail above, so the description of tramadol is given below.

The effect of large analgesics on peripheral organs (intestines, etc.) is due to interaction with the opiate receptors localized in them. Activation of opiate intestinal receptors is associated with a “positive" nonspecific effect of food.

A pronounced local anesthetic effect is not observed in most opiates. However, in recent years it has been found that they have a strong analgesic effect with epidural and subarachnoid administration. This effect is associated with a direct effect on the neural systems of the spinal cord, which are involved in the formation of pain flow of impulses. This method of administering opiates is used to relieve severe acute and chronic pain.

Painful stimulation of the modulating systems of the spinal cord in the postoperative period leads to an expansion of receptor fields and an increase in the sensitivity of neuronal structures that perceive pain. The result is the formation of chronic postoperative neuropathic pain syndromes. In particular, from one to two-thirds of patients who have undergone surgery on the chest for a long period of time suffer from post-rototomy pain. Pain in the postoperative period is accompanied by hyperactivity of the sympathetic nervous system, which is manifested by such clinical symptoms as tachycardia, arterial hypertension, increased vascular resistance. In people without concomitant pathology, cardiac output usually increases, but with dysfunction of the left ventricle, it can decrease. Sympathetic activation provoked by pain syndrome is one of the factors causing postoperative hypercoagulation due to increased platelet adhesion and inhibition of fibrinolysis. The risk of thrombosis is increased. Against this background, patients with a high risk of cardiac complications are more likely to develop acute myocardial infarction.

A separate area of application of analgesics of the second group is the use in the treatment of cancer and in the treatment of withdrawal symptoms.

Symptoms of drug and drug dependence are manifested primarily in the form of depression, neurosis, frequent changes in mood and, as a result, in increased excitability, insomnia. Patients experience pain.

It is well known that there are many patients who become drug or drug dependent for both medical and non-medical (social) reasons. Drug dependence is a state of periodic or chronic intoxication that is harmful to the patient and is obtained due to the prescribed repeated administration of the appropriate medication. A drug-dependent patient and drug addict show a constant desire to use a medicine (drug) and fall into a painful condition - withdrawal syndrome - with drug withdrawal or drug inaccessibility [BES, M .: BDT, 1997. P.8].

For the treatment of drug and drug addiction, various pharmacological approaches are used. Such approaches typically involve attempting to cure the drug for "asking" or alleviating the concomitant symptoms. So, in US patent No. 4786653 describes the use of drugs with phenylzine or its equivalent phenylalkylhydrazine as an active principle, which are physiologically incompatible with addictive drugs such as amphitamine and cocaine. US patent No. 4696818 relates to a method of prescribing herbal infusions for the treatment of drug and drug-dependent patients. US Pat. No. 3,308,631 describes a method for treating addiction to different types of drugs using 2-imino-5-phenyl-4-oxazolidinone. US Pat. Nos. 4,117,161 and 4,124,715 disclose methods and compositions for treating drug and amphetamine cravings associated with the administration of alpha-methyl-para-tyrosine. A common drawback of these drugs is, as a rule, their selective effectiveness in relation to a particular drug and side effects in the form of relapses and negative effects on the liver.

The main method of treating the most complex and stable opioid dependence is also to stop taking the drug and withdraw the next withdrawal syndrome. The only officially approved treatment method in Europe and the USA is to prescribe one of three types of drugs in the form of replacement therapy: group 1 drugs - naltrexone, naloxone, nalmefin and antaxone (naltrexone, naloxone, nalmephine, and antaxone); 2. Group - pentazocine (pentazocine), butorphanol (butorphanol), nalbuphine (nalbuphine), buprenorphine (buprenorphine), tramadol (tramadole); 3. The group includes methadone and other drugs that bind more weakly to the opioid receptor and have a more controlled effect on the receptor. Each of the above medicines has its own disadvantages. A common drawback of these drugs is that they do not fully stop the algic component of opiate withdrawal syndrome. Drugs have a number of side effects, there is a high risk of death. In the case of methadone, according to reviews of drug-dependent patients published in the open press of the United States, drug dependence is stronger than drug dependence, in particular on heroin, there is no open data regarding the algic component of the drug.

The appropriate drug is prescribed depending on the history of the patient’s pathology - whether he was a drug addict, who took the drug, or received a drug (drug) dependence as a result of taking a particular drug. Therefore, the method of replacement therapy is selected individually. The daily dose does not exceed 0.5 g, otherwise it will quickly become addictive already to the replacement drug.

A common drawback of the known methods is that the duration of this kind of replacement therapy is quite long, it is 3-6 months, and during this time, because of their physiological instability and general weakening of the body, patients often refuse to be treated.

It is known that all of the above funds by themselves are addictive, have a lot of side effects in relation to the cardiovascular, respiratory, reproductive systems and adversely affect the patient’s liver. Despite the obvious drawbacks, the replacement therapy method is widely used in world practice, since there is currently no effective alternative to it.

In the Russian Federation, due to the reasons mentioned above, currently the method of substitution therapy, as well as the means used (for example, methadone), are prohibited (Law of the Russian Federation “On Narcotic Drugs and Psychotropic Substances”).

For the treatment of drug and drug dependence, drugs are used that remove the patient from intoxication and depression - antidepressants (e.g., imitriptyline) and antipsychotics (aminosine, azaleptin) in large doses, then a long-term rehabilitation is carried out with the help of psychotherapy. The known technique is objectively ineffective, as it is the precursor of replacement therapy. High doses of drugs are toxic, cause new intoxication of the body. However, with persistent, dosed use of appropriate drugs in combination with individual psychotherapy and rehabilitation under the supervision of a psychologist in special groups and, most importantly, with a strong desire to recover from the patient himself and the attention of relatives, in some cases, especially if treatment is started at the beginning of the manifestation of dependence, it is possible to avoid relapses.

The use of drugs of the group of large analgesics in the complex treatment of patients with cancer is necessary primarily to improve the quality of life of patients. Despite the presence of all the side effects and disadvantages listed above, morphine and morphine-like compounds in this case have the main advantage - they provide relief of pain. Thus, the use of drugs of this series in patients with cancer is ethically and socially justified. However, publications appeared (see below), in which it was proved that morphine and its analogues, with prolonged use, even in small doses, can inhibit the work of Na / K-ATPase membrane of nerve cells. When the pump function is turned off, sodium and potassium ions begin to move due to diffusion, the potential difference on both sides of the cell membrane decreases, the osmotic pressure changes, and ultimately the cell dies. Thus, it can be assumed that with prolonged use of morphine and its analogues, the cause of death of the body is not the main disease, for example, oncological pathology, but cell death provoked by negative side effects of opiates.

The use of derivatives of gamma-pyrone for medical purposes as food additives is known (WO No. 92/13850), for the treatment of iron deficiency anemia (US patent No. 4575502), diabetes (US patent No. 5888993); allergies (US patent No. 4198426). Representatives of gamma-pyrone derivatives have never been proposed for use as analgesics and drugs used in the postoperative period, in complex therapy in the treatment of cancer patients and the algic component of the withdrawal syndrome in drug-dependent patients.

Previously it was shown (Krylov B.V., Schegolev B.F. RF patent for the invention N 2209062 "A substance with a sedative effect, priority 19.03.2002) that kamenovo acid can be used as a mild sedative, not addictive .

The use of comenic acid described in patent N 2209062 does not discredit the novelty of the invention, since it is believed that mild sedatives do not stop pain of various etiologies, including postoperative pain, oncological pain, the algae component of withdrawal symptoms. Mild sedatives may not be strong analgesics. The comparison was carried out with the simplest mild agents, such as valerian. Special studies on the subtle mechanisms of the effects of narcotic and non-narcotic analgesic drugs on animals and humans are a separate area of work.

An attempt to use derivatives of gamma-pyrone as analgesic agents was made in a number of different classes of compounds, while comenic acid was not the first among the derivatives tested.

These and other data have contributed to the emergence in recent years of a large number of studies devoted to the study of the mechanisms of postoperative pain and sensitization, the development of new methods of analgesia, the optimization of organizational approaches to the management of cancer patients, the search for new effective analgesics, and the study of the effect of the adequacy of analgesia on the outcome of treatment.

The development of new effective synthetic non-opioid analgesics and therapeutic methods for the rehabilitation and treatment of drug and drug dependence with their help also remains an urgent problem. Such drugs ideally should not have negative side effects in relation to the cardiovascular system, liver, and kidneys.

Thus, the analysis of the prior art did not allow to find a solution that completely coincides in the totality of essential features with the claimed, which confirms the novelty of a non-narcotic synthetic analgesic agent based on derivatives of gamma-pyrone.

The objective of the present invention is to provide a new highly effective synthetic non-narcotic analgesic agent that does not have the negative side pharmacological effects inherent in known analogues and a method for the treatment of pain syndrome of various etiologies, including the algic component of opiate withdrawal syndrome.

This problem is solved by a group of inventions united by a single inventive concept, a non-narcotic synthetic analgesic agent and a method of treating pain of various etiologies with this agent.

The technical result of the invention is to create a highly effective synthetic non-narcotic analgesic drug of non-opioid nature, intended for the relief of pain syndrome of various origins, including in the postoperative period, in cancer patients and patients with opiate withdrawal syndrome, accompanied by an algic component. Negative side effects of the proposed remedy are absent. An analgesic in therapeutic doses does not affect the cardiovascular system, blood count, respiratory system. Neurotoxic effects are absent. The proposed tool is not addictive and addictive.

This effect was achieved as a result of the study by the inventors of the elements of the subtle mechanism of the effects of narcotic and non-narcotic substances on the central nervous system and the group of gamma-pyrone derivatives unexpectedly exhibiting the ability to selectively activate the membrane signaling pathway discovered by the authors, including the membrane receptor, Na, K-ATPase of a nociceptive neuron and slow tetrodotoxin-resistant sodium channel [Krylov B.V., Derbenev A.V., Podzorova S.A., Lyudino M.I., Kuzmin A.V., Izvarina N.L. Morphine reduces the potential sensitivity of slow sodium channels // Russian Fiziol. journal 1999.V. 85, No. 2. S.225-236].

In addition to the effects indicated above, the following should be noted as a technical result.

1. The proposed tool can be performed in dosage form. The form for parenteral or intranasal administration is a solution or suspension, which ensures the manifestation of analgesic properties by means of delivery to the target (nociceptor) through the bloodstream.

2. The proposed tool is able to act once (simultaneously) and to stabilize the process, depending on the severity of the underlying disease, a course of the drug may be prescribed in the form of an injection of a solution or intranasal administration of a suspension.

3. The proposed tool is non-toxic, since its active principle is non-toxic. So, it is known that one of the representatives of gamma-pyrone derivatives - comenic acid - is part of the widely used antibacterial drug baliz-2. This fact indicates its non-toxicity [Zubareva RP, Shurygin A.Ya., Zlishcheva L.I. Clinical evaluation of the drug baliz-2. Surgery, No. 1, pp. 12-15 (1987); Konstantinova A.D., Zlishcheva L.I., Ratgauz G.L., Shurygin A.Ya. The effect of the antibacterial drug baliz-2. J. microbiol. epidemic. Immunol., No. 12, p.20-24 (1984)]. The inventors of special studies have established the toxicity of not only comenic, but also meconic and methylcomenic acids, which can act as active principles of the claimed funds.

4. Active substances for the claimed funds are technologically available. The methodology for their synthesis is given below.

The present invention differs from the known analogues, primarily morphine and tramadol, with essential features associated with the nature of the active principle (derivatives of gamma-pyrone and their amount in the composition of the product).

5. The proposed tool in a therapeutic dose does not affect the blood formula, cardiovascular and respiratory systems.

6. The authors experimentally established that the proposed tool is pyrogen-free, that is, does not increase body temperature.

The specified technical result is achieved by the fact that the proposed non-narcotic synthetic analgesic agent contains an active principle - a gamma pyrone derivative selected from the group consisting of meconic acid, methyl comenic acid, comenic acid - in an amount of from 0.05 mg to 300 mg for a single dose and a pharmacologically compatible liquid excipient, in the following ratio of components, wt.%:

active principle 0.5-95,

liquid filler - the rest,

and representing a form intended for systematic use.

According to the invention, the liquid filler is selected from the range: water, ethanol, glycerol, saline.

According to the invention, the agent further comprises an emulsifying agent and / or a buffering agent.

According to the invention, the agent is provided in a dosage form for parenteral or intranasal administration.

According to the invention, the form for parenteral or intranasal administration is a solution or suspension.

The specified technical result in relation to these objects is also achieved by the fact that a method for the treatment of pain syndrome of various etiologies is proposed, which consists in parenteral or intranasal administration of a non-narcotic synthetic analgesic agent in a dose of 0.05 to 300 mg of active principle from 1 to 2 times per day, daily for 7-14 days, depending on the diagnosis and severity of the patient's condition until a therapeutic effect is achieved.

The introduction of funds in a dose greater than 300 mg per day is impractical, since the analgesic effect does not increase, but at the same time, a mild sedative effect of the claimed drug begins to appear.

According to the invention, the agent is administered parenterally as a course of injection or intranasally.

According to the invention, in order to achieve a therapeutic effect in cancer patients to improve the quality of life, the course of treatment can be extended up to 30 days or more depending on the severity of the disease.

Only the combination of essential features of the claimed synthetic analgesic funds allows to achieve the specified technical result.

The ability of derivatives of gamma-pyrone to analgesic activity was discovered by the inventors in the process of research. The mechanism of their action discovered by the authors, which, in fact, denies addiction to the drug, is disclosed by the inventors in the present description.

It should be emphasized that analgesics that do not have negative side effects and are comparable in degree of analgesia with drugs belonging to the group of large analgesics have not yet been created.

The set of essential features of the proposed method of treatment allows to achieve a technical result, consisting in the long-term relief of pain syndrome of various etiologies, which allows high-quality therapy to treat the underlying disease, which is especially important for cancer patients.

The proposed method for the treatment of pain of various etiologies is gentle, as the tool used in it has no negative side effects, and its mechanism of action is highly selective. Treatment proceeds much faster (from 5 days to 1 month, depending on the severity and cause of the underlying disease) than in known analogues (from 14 days to 6 months). Treatment is not addictive, addictive and, therefore, the need for a constant increase in the dose of the drug.

The proposed method of treatment differs from the known ones using analgin, tramadol, morphine hydrochloride by a number of essential features: the use of a new analgesic agent in specific doses and duration of exposure, the effect of this agent on the specific mechanism of membrane signaling, universal drug use possibilities - with parenteral and intranasal administration, the drug implements analgesic properties 10 minutes after getting into the bloodstream. The analgesic effect lasts up to 24 hours.

Only the set of essential features of the proposed method of treatment allows to achieve the specified technical result - relief of pain of various etiologies, including in patients with drug and drug dependence.

Indeed, there is still no known method for treating the algae component of drug and drug dependence, the implementation of which results in a similar subtle selective effect on the corresponding membrane signaling system and activation of the signaling pathway, in which the sodium pump plays the role of signal transducer, rather than G-proteins, which to relieve withdrawal symptoms without intoxication, addiction and relapse due to relief of its algic component.

Thus, the proposed composition of the analgesic by qualitative and quantitative characteristics, as well as the method of treatment based on it with the achievement of the specified technical result, were completely unobvious and were identified during a long-term scientific research.

The invention is illustrated in tables.

Table 1 shows the formalin test data.

Table 2 shows the effect of comenic acid, analgin and morphine on the pain sensitivity of mice using the “hot plate” method.

To confirm the compliance of the proposed solution to the requirement of "industrial applicability", as well as to better understand the essence of the invention, we give examples of its specific implementation.

Example 1. Preparation of an analgesic

Reagents used for the preparation of non-narcotic synthetic analgesic:

Mekonova, Kamenovo and methyl-Kamenovo acid synthesized according to the method [Garkusha Zh.A. J. general chemistry, t.31, s.2573 (1961)]. Comenic acid (5-hydroxy-4-oxopyrone-2-carboxylic acid) is a hard-to-reach natural compound whose chemical synthesis has so far not been sufficiently developed. Known methods are either accompanied by the receipt of a large number of by-products that are difficult to separate, or lead to unsatisfactory yields of the target product and, finally, require the implementation of multi-stage synthesis, each of these stages being an independent scientific research.

We have developed a modified scheme for the synthesis of comenic acid, the first stage of which is based on the Dieckmann condensation reaction between acetone and diethyl oxalate under the influence of sodium ethylate. Slight traces of water sharply reduce the yield or lead to a complete absence of the resulting 2,4,6-pimelic acid diethyl ester. We were able to carry out the reaction with a yield of 74%.

Physico-chemical characteristics of the obtained substances corresponded to the characteristics indicated in the literature [Garkusha Zh.A. J. general chemistry, t.31, s. 2573 1961].

The next step is bromination of ether and its subsequent hydrolysis. After performing these operations, we obtained meconic acid with a total yield of 46%, counting on the initial diethyl ether.

The meconic acid obtained in this way, whose properties completely coincide with the literary ones, was easily decarboxylated at a temperature above 120 ° C in an acidic medium with the formation of the final product, comenic acid. The yield of comenic acid at this stage was 80%, which corresponds to published data. Physicochemical and spectral data also corresponded to literature.

A liquid form (solution or suspension) is prepared by dissolving or suspending the previously synthesized active principle in water, or physiological saline, or glycerol, or ethanol with the addition of (if necessary) emulsifying agents, pH buffering agents. As a rule, a 1-5% aqueous solution of the active principle is used.

The following synthetic analgesic agents were obtained by the described method:

1. an aqueous solution for injection, including the active principle - comenic acid - in an amount of from 0.05 to 300 mg.

2. physiological saline for injection, including the active principle - comenic acid - in an amount of from 0.05 to 300 mg.

3. a suspension in glycerol for intranasal administration, including the active principle - meconic acid - in an amount of from 0.05 to 300 mg.

4. a suspension in glycerol for intranasal administration, including the active principle - comenic acid - in an amount of from 0.05 to 300 mg.

5. an aqueous solution for injection, including the active principle - meconic acid - in an amount of from 0.05 to 300 mg.

6. physiological saline for injection, including the active principle - meconic acid - in an amount of from 0.05 to 300 mg.

7. an aqueous solution for injection, including the active principle - methyl-comenic acid - in an amount of from 0.05 to 300 mg.

8. physiological saline for injection, including the active principle - methyl-comenic acid - in an amount of from 0.05 to 300 mg.

9. suspension in glycerol for intranasal administration, including the active principle - methyl-comenic acid - in an amount of from 0.05 to 300 mg.

Example 2. The mechanism of action of derivatives of gamma-pyrone.

The proposed treatment tool and method are based on an in-depth understanding of the physiological role of the molecular mechanism for modulating a nociceptive signal discovered by the inventors when it is transmitted from the membrane receptor to the Na / K ATPase of a nociceptive neuron and further to modulation of tetrodotoxin-resistant Na channels [Krylov B.V. et al. Morphine reduces the potential sensitivity of slow sodium channels // Russian Physiological Journal. 1999. T. 85, No. 2. S.225-236]. Derivatives of gamma-pyrone were used by the authors to activate the signaling pathways they discovered. These compounds were tested in vitro, taking into account the new mechanism of transduction of Na, K-ATPase signal of a nociceptive signal on the way from the membrane receptor to the tetrodotoxin-resistant Na channel, discovered by the inventors. It should be noted that drugs belonging to the group of large analgesics do not activate this membrane signaling mechanism. Moreover, opiates, in particular morphine, inhibit the work of Na, K-ATPase neurons [Biser P.S., Thayne K.A., Fleming W.W., Taylor D.A. Na, K-ATPase alphasubunit isoform distribution and abundance in guinea-pig longitudinal muscle / mienteric plexus after exposure to morphine. Brain Res. 2002 Mar. 29; 931 (2): 186-93]. As a result of this, irreversible morphological changes in cells, tissues and organs occur, leading to death.

The subtle mechanism of action of derivatives of gamma-pyrone on the central nervous system and its differences from the action of morphine and its analogues is described below.

As mentioned above, morphine is one of the 20 alkaloids that make up opium. He is the most studied opioid receptor agonist, triggering a sequence of intracellular signaling processes, the first step of which is the emergence of ligand-receptor binding. At the same time, morphine binds to receptors from a well-studied class of cell membrane receptors. Morphine activation of opioid receptors associated with potassium and calcium ion channels leads to analgesic and sedative effects. In this case, G-proteins act as a transducer of a nociceptive signal. Opioids (and opiates) reduce pain sensitivity by reducing calcium-dependent release of neurotransmitters from presynaptic terminals, delaying signal transmission between neurons.

The authors of the present invention have recently shown that there is an unknown interaction (a new signaling pathway in the cell membrane of a sensory neuron) between the membrane receptor, Na, K-ATPase and the activation portal system of the tetrodotoxin-resistant sodium channel. G-proteins are not involved in this mechanism (that is why gamma-pyrone derivatives are not addictive already at the molecular and cellular levels). Moreover, opiates do not directly affect tetrodotoxin-resistant sodium channels, which are responsible for coding the pain signal [Ogata N., Ohishi Y. Molecular diversity of structure and function of the voltage-gated Na channels // Jpn. J. Pharmacol. 2002. V. 88. P. 365; Borovikova LV, Borovikov DV, Ermishkin VV, Revenko SV The resistance of cutaneous feline C-fiber mechano-heat-sensitive unit termination to tetrodotoxin and its possible relation to tetrodotoxin-resistant sodium channels // Primary Sensory Neuron. 1997. V.2. Number 3. P. 65; Cardenas CG, Dei Mar LP, Cooper BY, Scroggs RS 5HT ₄ receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin-sensitive rat sensory neurons // J. Neuroscience. 1997. V.17, No. 19. P.7181-7189].

Due to its significant differences in the mechanism of action of the claimed funds act analgesically and are not addictive. Molecules of narcotic analgesics, when interacting with the opioid receptor, form weak hydrogen bonds. According to the invention, the active principle of a number of derivatives of gamma-pyrone interacts with the membrane receptor we have discovered, forming bonds of a different nature. These are not hydrogen bonds (as previously thought) that are weak in nature, but rather bonds of the type of ion-ion interactions. Further, the signal activates Na, K-ATPase (and not G-proteins, as in the case of opiates), starts its transducer function (the signal is amplified). Analgesically, and the effect at the cellular level is realized by reducing the potential sensitivity (excitability) of tetrodotoxin-resistant sodium channels. It should be noted that morphine, according to recent literature data, inhibits the activity of Na, K-ATPase, blocks its pumping function [Biser P.S., Thayne K.A., Fleming W.W., Taylor D.A. Na, K-ATPase alpha-subunit isoform distribution and abundance in guinea-pig longitudinal muscle / mienteric plexus after exposure to morphine. Brain Res. 2002 Mar. 29; 931 (2): 186-93], thereby causing negative side effects.

Known analogues from the group of large analgesics (tramadol, morphine hydrochloride, butorphanol, omnopon) are objectively unable to exhibit the properties of the claimed agents.

As a result, the basis of the present invention lies in the idea of activating a fundamentally different way from the opiate than the coding of nociceptive information. The existence of this mechanism only confirms the theory of the polymodality of nociceptors and the presence in the human and animal body of several parallel ways of protecting their integrity from superpowerful nociceptive stimuli. Pain reduction occurs when the Na / K-ATPase realizes the transducer function when the nociceptive signal is transferred to tetrodotoxin-resistant sodium channels with a further decrease in the threshold of their excitability.

Addiction to funds is absent.

Example 3. Confirmation of the analgesic effect using a formalin test

The most adequate model in the study of drugs with an analgesic effect is the formalin test. The formalin test was carried out according to the method described in a number of manuals: Dubuisson D., Dennis S.G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats // Pain. 1977. V.4. P.161-174; Tjolsen A., Berge O.-G, Hunskaar S, Rosland J.H., Hole K. The formalin test: an evaluation of the method // Pain. 1992. V. 51. P.5-17, as well as Henry J.L., Yashpal K., Pitcher G.M., Coderre T.J. Physiological evidence that the "interphase" in the formalin test is due to active inhibition // Pain. 1999. V.89. P.57-63; Dallel R., Raboisson P., Clavelou P. Evidence for a peripheral origin of the tonic nociceptive response to subcutaneous formalin // Pain. 1995. V. 61. P.11-16; Abbott F.V., Melzack R, Samuel C. Morphine analgesia in the tail-test and formalin pain tests is mediated by different neural systems // Exp. Neurol. 1982. V.75. P.644-651; Abbott F.V., Ocvirk R., Najafee R. et al. Improving the efficiency of the formalin test // Pain. 1999. V.83. P.561-569.

This test allows you to track the reactions of the rat organism throughout the entire transmission path of the nociceptive signal.

A certain set of animal behavioral acts indicates the presence of an analgesia effect. The first phase of the behavioral response is provoked by the direct effect of formalin on nociceptive neurons, and the second phase reflects the acute pain generated by damaged tissue [Abbott F., Guy E. Effects of morphine, pentobarbital and amphetamine on formalin-induced behaviors in infant rats: sedation verses specific suppression of pain Pain 62 (1995). P.303-312 .; Clavelou P., Dallel R., Orliuguet T., Woda A., Raboisson P. - The orofacial formalin test in rats: effects of different formalin concentrations // Pain 62 (1995). P.295-303; Hong Y., Abbott F.V. Peripheral opioid modulation of pain and inflammation in the formalin test // Eur. J. of Pharmacology 227 (1995) P. 21-28].

As a rule, it is possible to determine the level at which nociceptive information is closed - spinal or supraspinal. Experimental data obtained in humans have shown that formalin causes burning pain, which in its characteristics coincides with acute pain that occurs in various diseases, including cancer or due to surgical intervention [Abbott F., Guy E. Effects of morphine, pentobarbital and amphetamine on formalin-induced behaviors in infant rats: sedation verses specific suppression of pain Pain 62 (1995). P.303-312; Dallel R., Raboisson P., Clavelou P., Saade M., Woda A. Evidence for a peripheral origin of the tonic nociceptive response to subcutaneous formalin. Pain, 61 (1995) ;. 1 (April.), 11-16; Hong Y., Abbott F.V. Peripheral opioid modulation of pain and inflammation in the formalin test // Eur. J. of Pharmacology 227 (1995) P.21-28]. The experiments were carried out on male Wistar rats weighing 200-250 g in accordance with the methods of [Guiding and methodological materials for the experimental and clinical study of new drugs. Part 2. M., 1980, p.126-133].

For the experiments, the claimed agents were used on the basis of different gamma pyrons and their derivatives: meconic acid, methyl comenic acid, comenic acid.

50 μl of a 5% formalin solution was injected subcutaneously into the left hind paw of the animal, the inventive agents were administered intraperitoneally at a dose of 40 mg / kg.

The spinal (peripheral level of pain signal transmission) level is characterized by flexion + shaking patterns, supraspinal (characterizing the involvement of central structures in the nociceptive impulse reception) - by licking patterns.

Formalin test data using Comenic acid at a dose of 40 mg / kg.

Table 1 Experience protocol Control n Average Comenic acid n Average n animals 8 eleven Both phases are present 8 cg + vstr 4 cg + vstr 4 lick 3 on lick. Both phases are absent. four Flex + Shake Patterns Missing phase 1 17.1 ± 0.3 n = 8 7 15.3 ± 0.1 * n = 4 Missing phase 2 294.6 ± 1.4 n = 8 3 93.7 ± 0.4 * n = 4 Lick patterns Missing phase 1 four 21.5 ± 0.4 n = 4 6 30.3 * ± 0.3 n = 1 Missing phase 2 219.5 ± 0.9 n = 4 four 204.7 ± 1.1 * n = 3 * - significant differences with control, P <0.05

The experiments were conducted on male rats. There were 8 rats in the control group (1st column of the table). The 2nd column of the table shows the average values that characterize the pain threshold. Rats from the control group were injected intraperitoneally with physiological saline. 11 rats were injected with comenic acid in the form of a standard Hanks solution containing up to 40 mg of comenic acid / kg rat weight (daily dose) in one injection (3 column of the table). The 4th column of the table shows the average values characterizing the pain threshold in this group of rats. In both series of experiments, two types of pain were observed: 1) acute pain - the first phase, lasting less than 5 minutes; 2) tonic pain - observation time 90 min (therefore, different values in the columns are “average”). Between acute and tonic interphase pain ~ 10 min: no answers at all.

Comenic acid injection (intraperitoneal, daily doses from 33.7 to 40.18 mg / kg rat mass) completely suppressed the response in the formalin test in 3 out of 11 rats; in other animals, it caused a suppression of either the first or second phase of the response (see table) both in the flexion + shake patterns (7/3) and in the lick patterns (6/4).

At the spinal level (flexion + shaking, 7/3): in rats included in the statistics, i.e. having both phases of the response (n = 4), pain sensitivity decreased compared with the control (n = 8). At the supraspinal level (licking), animals that had both phases of response were absent. In 1 out of 7 experimental rats, 1 phase was observed (in 6 animals it was completely absent), the second phase was observed only in 3 experimental animals out of 11. The statistics included 3 animals in which both phases were present.

The loss of phases 1 and 2 of the formalin test in animals that received an injection of comenic acid at both the spinal and supraspinal levels demonstrates a profound change in the coding of nociceptive information, due to which the nociceptive signal is modulated, as a result, the analgesic effect of the claimed drug is realized.

The results obtained reliably indicate a powerful analgesic effect of the proposed drug at both the peripheral and central levels.

Similar results were obtained when rats were introduced with meconic and methyl-comenic acids. The daily derivative dose of gamma-pyron fit into the range of 33-40 mg / kg of rat mass.

Thus, under the conditions of the formalin test, it was found that the test agent exhibits a pronounced analgesic effect (modulates the nociceptive signal both on the periphery and in the central structures).

Statistical processing of the experimental results showed their complete reliability.

It should be emphasized that in all the studied animals that received injections of the above gamma-pyrone derivatives, there were no negative side effects characteristic of opiates when they were studied under the formalin test [Abbott F., Guy E. Effects of morphine, pentobarbital and amphetamine on formalin-induced behaviors in infant rats: sedation verses specific suppression of pain Pain 62 (1995). P.303-312; Dubuisson D., Dennis S.G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats // Pain. 1977. V.4. P.161-174].

Example 4. Confirmation of the analgesic effect in the test "hot plate".

The analgesic effect of a non-narcotic synthetic analgesic agent was determined in mice using the “hot plate” method. This test characterizes the pain signal at the peripheral level. The reflex of withdrawing limbs from the hot is unconditional and closes at the level of the spinal cord.

The experimental plate was heated to 52 ° C.

The latent period of the appearance of jerking of the legs in animals, motor anxiety, and hopping activity using a stopwatch was measured. The experiments were carried out after 30, 60 and 120 minutes after administration of the drug for a group of 20 animals. The proposed drug and analogues used for comparison were administered intraperitoneally.

The analgesic activity of comenic acid was compared with the most commonly used and effective drugs for the relief of pain, including cancer. Comparators in this series of experiments were analgin and morphine hydrochloride.

The experimental results are presented in Table 2.

Comenic acid in all doses showed a pronounced analgesic effect. Efficiency was dose-dependent in the range from 5 to 50 mg / kg.

The analgesic effect of comenic acid significantly exceeded the effect of analginum by 10 times and was not inferior to morphine in analgesic efficacy (see Table 2).

table 2 Drug dose Latent period, seconds 30 minutes 60 min 120 min Control (1.1% soda solution) 10.5 ± 0.9 10.8 ± 0.6 11.1 ± 0.8 Comenic acid, 5 mg / kg 22.0 ± 1.G 21.7 ± 0.7 * 22.3 ± 0.8 * Comenic acid, 10 mg / kg 31.8 ± 0.7 * 32.5 ± 1.4 * 33.7 ± 1.2 * Comenic acid, 50 mg / kg 37.0 ± 1.6 * 37.2 ± 1.9 * 38.2 ± 1.8 * Analgin 50 mg / kg 20.07 ± 0.6 * 22.1 ± 1.8 * 22.5 ± 0.9 * Morphine hydrochloride, 10 mg / kg 35.8 ± 0.6 * 30.5 ± 1.7 * 27.8 ± 1.2 * * - significant differences with control, P <0.05

A comparative analysis of the results obtained under the conditions of the formalin test and in the “hot plate” test made it possible to prove that the analgesic properties of the claimed substances at the periphery are realized at a dose of 5 mg / kg, and at a dose of 50 mg / kg, the claimed substances stop the pain syndrome in general - periphery and in the center. Thus, when using the drug, depending on the etiology of the pain syndrome, the dose of the active substance necessary to block the nociceptive signal can be clearly calculated.

Additionally, the dynamics of the thresholds of thermonociceptive reactions as a marker of the analgesic effect of the claimed drug at the stage of discontinuation of morphine was also studied in morphine-dependent rats. The proposed tool was administered intraperitoneally at the rate of 50 mg / kg weight once a day. In morphine-dependent rats, as well as in ordinary animals, a pronounced analgesic effect of the substance was revealed, which manifests itself in an increase in thermonociceptive thresholds after administration of the indicated agent (the effective dose of the analgesic agent was higher than in intact mice, which was associated with a change in the pain threshold of animals during morphination) .

In this case, the analgesic effect of the claimed drug was stronger than that of morphine. The latter is in good agreement with the data obtained on intact mice (see table 2). Similar results were obtained when rats were introduced with meconic and methyl-comenic acids. The daily dose of gamma-pyron fit in the range of 30-50 mg / kg of rat mass. The strength of the analgesic effect of the derivatives of gamma-pyrone studied by the authors does not decrease during their prolonged use, addiction does not develop.

According to these properties, derivatives of gamma-pyron compares favorably with morphine and its analogues, which, as you know, get used to is developing very quickly.

The analgesic effect of the claimed drug lasts at least 24 hours. The latter compares favorably with the chosen prototype - tramadol, the analgesic effect of which lasts for 3-5 hours after intravenous injection.

Example 5. Confirmation of experimental results in the methodology of stimulation of the lateral hypothalamus (method of self-stimulation) to determine the effect of derivatives of gamma-pyrone on possible mechanisms of formation of physical dependence

The reaction of self-stimulation (SS) of brain structures included in the system of positive reinforcement is a recognized model for the experimental evaluation of positive emotional behavior in animals [Zvartau E.E. The effect of chronic administration of morphine on the reward system in rats. Pharmacology and Toxicology, 1978, 3, p. 529-535; Zvartau E.E. The effect of naloxone on the emotionally positive and antinociceptive effects of stimulation of the hypothalamus in rats. Bull. expert. biol. and honey., 1979, 88, N 11, p. 43-45; Zvartau E.E., Patkina N.A. Motivational components and self-stimulation during behavioral reactions caused by electrical stimulation of the hypothalamus. Zhurn. higher nervous activ., 1974, N 3, S. 529-535; Bespalov A., Lebedev A., Panchenko G., Zvartau E. Effects of abused drugs on thresholds and breaking points of intracranial self-stimulation in rats. Eur. Neuropsychopharmacol., 1999, 9, N 5, p. 377-383; Carlezon W.A., Wise R.A. Morphine-induced potentiation of brain stimulation reward is enhanced by MK-801. Brain Res., 1993, 620, N 2, p. 339-342; Knapp C.M., Kornetsky C. Low-dose apomorphine attenuates morphine-induced enhancement of brain stimulation reward. Pharmacol Biochem. Behavior, 1996, 55, N 1, p. 87-91; Pellegrino L.J., Pellegrino A.S., Cushman L.J. A stereotaxic atlas of the rat brain. Plenum. Press NY. London 1979; Sundstrom J.M., Hall F.S., Stellar J.R., Waugh E.J. Effects of isolation-rearing on intracranial self-stimulation reward of the lateral hypothalamus: baseline assessment and drug challenges. Life Sci, 2002, 70, N 23, p. 2799-2810]. The lateral hypothalamus, participating in the natural regulation of positive emotional states, is most often used in experiments as a structure, the stimulation of which causes the animals to independently press the lever to obtain a positive reinforcing effect, that is, self-stimulation - SS [Valdman A.V., Babayan E. A., Zvartau E.E. Psychopharmacological and medico-legal aspects of substance abuse. M .: Medicine, 1988, 288 p .; Zvartau E.E. The effect of naloxone on the emotionally positive and antinociceptive effects of stimulation of the hypothalamus in rats. Bull. expert. biol. and honey., 1979, 88, N 11, p. 43-45 .; Diotte M., Miguelez M., Miliaressis E., Bielajew C. Interactions between rewarding lateral hypothalamic and aversive nucleus reticularis gigantocellularis stimulation. Behavior Brain Res., 2000, 116, N 2, p. 149-156; Hatcher J.P., Hagan J.J. The effects of dopamine D3 / D2 receptor agonists on intracranial self stimulation in the rat. Psychopharmacology (Berl), 1998, 140, N 4, p. 405-410; Knapp C.M., Kornetsky C. Low-dose apomorphine attenuates morphine-induced enhancement of brain stimulation reward. Pharmacol Biochem. Behav., 1996, 55, N 1, p. 87-91; Pellegrino L.J., Pellegrino A.S., Cushman L.J. A stereotaxic atlas of the rat brain. Plenum. Press NY. London 1979; Sundstrom J.M., Hall F.S., Stellar J.R., Waugh E.J. Effects of isolation-rearing on intracranial self-stimulation reward of the lateral hypothalamus: baseline assessment and drug challenges. Life Sci, 2002, 70, N 23, p. 2799-2810].

The SS reaction parameters, in particular, the number of lever presses for a certain period of time, characterizes the intensity of the "reward" effect [Zvartau E.E., Patkina N.A. Motivational components and self-stimulation during behavioral reactions caused by electrical stimulation of the hypothalamus. Zhurn. higher nervous activ., 1974, N 3, S. 529-535; Touzani K., Velley L. Electrical self-stimulation in the central amygdaloid nucleus after ibotenic acid lesion of the lateral hypothalamus. Behav Brain Res 1998, 90, N 2, p. 115-124; Zimmermann P., Privou C., Huston J.P. Differential sensitivity of the caudal and rostral nucleus accumbens to the rewarding effects of a H1-histaminergic receptor blocker as measured with place-preference and self-stimulation behavior. Neuroscience, 1999, 94, N 1, p. 93-103.]. Using this model, we studied the effect of pharmacological drugs of different nature that affect emotional behavior [Burov Yu.V., Borisenko S.A. Features of the influence of neurotropic substances on the self-stimulation reaction at the hypothalamic level. Bull. expert. biol. and honey., 1976, 81, p. 43-45; Waldman A.V., Babayan E.A., Zvartau E.E. Psychopharmacological and medical-legal aspects of substance abuse. M .: Medicine, 1988, 288 s; Zvartau E.E. The effect of chronic administration of morphine on the reward system in rats. Pharmacology and Toxicology, 1978, 3, p. 529-535; Touzani K., Velley L. Electrical self-stimulation in the central amygdaloid nucleus after ibotenic acid lesion of the lateral hypothalamus. Behav. Brain Res 1998, 90, N 2, p. 115-124; Zimmermann P., Privou C., Huston J.P. Differential sensitivity of the caudal and rostral nucleus accumbens to the rewarding effects of a H1-histaminergic receptor blocker as measured with place-preference and self-stimulation behavior. Neuroscience, 1999, 94, N 1, p. 93-103]. It was found that a common property of drugs that cause drug dependence is the intensification of the SS reaction [Burov Yu.V., Borisenko S.A. Features of the influence of neurotropic substances on the self-stimulation reaction at the hypothalamic level. Bull. expert. biol. and honey., 1976, 81, p. 43-45 .; Waldman A.V., Babayan E.A., Zvartau E.E. Psychopharmacological and medical-legal aspects of substance abuse. M .: Medicine, 1988, 288 s; Zvartau E.E. The effect of chronic administration of morphine on the reward system in rats. Pharmacology and Toxicology, 1978, 3, p. 529-535; Zvartau E.E. The effect of naloxone on the emotionally positive and antinociceptive effects of stimulation of the hypothalamus in rats. Bull. expert. biol. and honey., 1979, 88, N 11, p. 43-45 .; Zvartau E.E., Patkina N.A. Motivational components and self-stimulation during behavioral reactions caused by electrical stimulation of the hypothalamus. Zhurn. higher nervous activ., 1974, N 3, S. 529-535; Shabanov P.D., Stackelberg O.Yu. Addiction. Pathopsychology, clinic, rehabilitation. St. Petersburg, Doe, 2001, 460 p .; Bespalov A., Lebedev A., Panchenko G., Zvartau E. Effects of abused drugs on thresholds and breaking points of intracranial self-stimulation in rats. Eur. Neuropsychopharmacol., 1999, 9, N 5, p. 377-383].

The experiments were carried out in compliance with the rules of the Helsinki Convention.

The experiments were performed on 13 rats of males of the Wistar line (of which 3 were control). Animals weighing 150-250 g under anesthesia (ketamine, 0.3 mg / 100 g weight and Nembutal, 3 mg / 100 g weight) were placed in a stereotactic device. Subject to sterile conditions, in the region of the lateral hypothalamus (A 1.5 mm, L 1.5 mm, H 8.5 mm) according to the coordinates of the rat brain atlas [Pellegrino L.J., Pellegrino A.S., Cushman L.J. A stereotaxic atlas of the rat brain. Plenum. Press NY. London 1979] implanted bipolar concentric electrodes.

5-7 days after the operation, the rats were placed in an experimental chamber (40 × 40 × 60 cm) with a lever, pressing which closed the current circuit and applying a pulse train to the electrode (pulse duration - 0.5 ms, repetition rate - 100 Hz, current strength 90-300 μA, in one rat - 500 μA). Pulses were supplied from the ESA-1 stimulator for 0.5 s. Developing a stable SS reaction skill took 2-3 days. The current strength, causing a stable frequency of pressing the lever, was conventionally taken as a threshold. The number of clicks in 10 minutes was recorded. The SS reaction was tested with the introduction of three doses of the claimed funds "(1, 10 and 30 mg / kg) intraperitoneally. Three control rats were injected with a Hanks solution of 1.5 ml pH 7.0-7.4. On the computer using a special program during the experiment, a histogram and a table of the number of lever presses were built for 10 minutes before the injection of the inventive agent from the group of gamma-pyrons, immediately and 30 and 60 minutes after the injection with simultaneous processing of the average value. We observed a change in the threshold of the SS reaction. The significance of differences in the data obtained was determined by the Student-Fisher criterion. After completion of the experiments, coagulation of CC sites was performed (2 mA, DC, 10 sec). The brain was placed in a 10% formalin solution. The localization of the electrode tip was determined histologically on sections (60 μm) by freezing using a rat brain atlas [Pellegrino L.J., Pellegrino A.S., Cushman L.J. A stereotaxic atlas of the rat brain. Plenum. Press NY. London 1979]. The results of histological analysis confirmed the localization of the tip of the stimulating electrode in the lateral hypothalamus.

It was found that derivatives of gamma-pyrone (meconic, methyl-comenic acid and comenic acid) in proportion to the dose cause inhibition of the self-stimulation reaction of the literal hypothalamus. The weakening of the reaction of self-stimulation caused by the claimed drug was manifested immediately after injection. The effect was most pronounced after the introduction of the claimed drug in a daily dose of 30-40 mg / kg of weight and was manifested in a decrease in the number of clicks on the lever relative to the threshold value for the reaction of self-stimulation. Further, a complete cessation of self-stimulation was observed. A similar inhibitory effect of these gamma pyrone derivatives on the self-stimulation reaction was obtained with repeated injections.

In control rats that received an injection of saline, significant changes in the frequency of pressing the lever (the average number of pressing the lever for 10 minutes was 295 ± 13) were not observed in the reaction threshold.

The results of this study indicate that the proposed tool causes inhibition of the SS reaction of the lateral hypothalamus. The observed decrease in the rewarding effect of SS after an intraperitoneal injection of the studied substances (from the group of gamma-pyrone derivatives listed above) was proportional to its dose. The effect of the effects of comenic acid was most clearly observed at a dose of 28.8-30 mg / kg and was manifested in a decrease in the number of presses on the lever at a threshold current strength or in an increase in the threshold of the SS reaction and its complete cessation. One of the two rats studied at a dose of 10 mg / kg had a decrease in the frequency of pressing the lever and an increase in the SS threshold. Weakening of SS caused by drugs, in most cases, manifested immediately after injection. Similar results were obtained when rats were given both comenic acid and other derivatives of gamma-pyrone — meconic and methyl-comenic acids. The daily dose of gamma-pyrone derivatives was within the range of 30-40 mg / kg of rat mass.

It should be noted that in the present work, the neurotoxic effect of gamma-pyrone derivatives, which is expressed in unlocking the mechanism of the self-stimulation reaction, was manifested at a dose of 30 mg / kg. The animal moved away from the pedal. According to the literature [Burov Yu.V., Borisenko S.A. Features of the influence of neurotropic substances on the self-stimulation reaction at the hypothalamic level. Bull. expert. biol. and honey., 1976, 81, p. 43-45; Zvartau E.E. The effect of chronic administration of morphine on the reward system in rats. Pharmacology and Toxicology, 1978, 3, p. 529-535; Carlezon W.A., Wise R.A. Morphine-induced potentiation of brain stimulation reward is enhanced by MK-801. Brain Res., 1993, 620, N 2, p.339-342] when studying the effect of morphine on the intensity of the “reward” effect of the lateral hypothalamus, catatonia appears at a dose of 120 mg / kg, but even in this state, SS continues, with a higher frequency compared to the background. A comparison of the doses of comenic acid and other substances studied by the authors and morphine, at which catatonia appears in rats, allows us to conclude that the effect of the drugs studied by the authors on the system of positive reinforcement of the lateral hypothalamus is four times stronger than the effect of the latter. However, comenic acid and other compounds claimed by the authors, unlike morphine, do not cause an increase in the SS reaction, but, on the contrary, suppress it. The same inhibitory effect of the studied drug on SS was obtained by the authors with repeated injections.

Thus, the proposed non-narcotic analgesic synthetic agent in contrast to morphine [Burov Yu.V., Borisenko S.A. Features of the effect of neurotropic substances on the self-stimulation reaction at the hypothalamic level. Bull. expert. biol. and honey., 1976, 81, p. 43-45; Zvartau E.E. The effect of chronic administration of morphine on the reward system in rats. Pharmacology and Toxicology, 1978, 3, p. 529-535; Shabanov P.D., Stackelberg O.Yu. Addiction. Pathopsychology, clinic, rehabilitation. St. Petersburg, Doe, 2001, 460 p .; Carlezon W.A., Wise R.A. Morphine-induced potentiation of brain stimulation reward is enhanced by MK-801. Brain Res., 1993, 620, N 2, p.339-342] does not cause activation of the system of positive reinforcement of the lateral hypothalamus, that is, it does not cause dependence and addiction to it.

The proposed tool, in contrast to morphine and its analogues, including tramadol, breaks the positive connection formed in the experiment that occurs during electrical stimulation of the pleasure center of the lateral hypothalamus.

It was found that the proposed tool does not cause physical dependence and addiction. The last property of the analgesic fundamentally distinguishes it from opiates.

Example 6. A study of the course of withdrawal symptoms in morphinated rats while receiving the claimed non-narcotic analgesic agent.

The relief of the algic component of withdrawal symptoms was studied in morphine-dependent rats. Comenic acid was administered intraperitoneally at a rate of 30-40 mg / kg of weight once a day. Throughout the experiment, symptoms of withdrawal were recorded daily: “shaking a wet dog”, diarrhea, cramps, shaking with the front paws, ptosis, sawing, humping, sneezing, grinding teeth. The significance of the differences was evaluated using the nonparametric Wilcoxon-Mann-Whitney test.

It was found that the introduction of the proposed drug to morphinated rats has a therapeutic effect (due to the relief of the algic component of the withdrawal syndrome). In this case, an easier course of withdrawal syndrome is observed (an indicator of the syndrome of 7.28 instead of 9.12, the absence of dead rats). Withdrawal syndrome as a whole disappears in a shorter time frame (8-12 days instead of 15-22). The proposed tool, as shown earlier, is not addictive and addictive: the algae component, and due to this, the withdrawal syndrome as a whole disappeared while taking the claimed substance, and after its withdrawal there were no relapse syndrome (animals were observed up to 50 days after cancellation therapy of the claimed agent). Signs of the formation of dependence on the administration of the claimed drug in animals during the treatment of morphine withdrawal syndrome were not observed.

In parallel, morphine rats assessed the level of fear and anxiety. We used the tests "cruciform labyrinth" and "open field". Stabilization of the level of fear and anxiety, in most cases, even the normalization of the psychoemotional state in rats that were administered the proposed tool, was achieved in 9 days (control group - 45 days).

It was shown that the proposed tool normalizes the levels of depression (Porsolt forced swimming test) and orientational research activity (the same tests as for assessing the level of fear) in morphine-dependent rats at the stage of morphine withdrawal, which indicates that the proposed tool does not have psychotropic effect (as in the case of the use of morphine analogues) and acts on the body by a mechanism that is fundamentally different from the molecular mechanism of action of opiates.

Similar results were obtained when rats were introduced with meconic and methyl-comenic acids. The daily dose of gamma-pyron fit into the range of 33-50 mg / kg of rat mass.

The results can not be explained from the point of view of the traditional mechanism of action of drugs of the group of large analgesics (morphine and its analogues) and confirm a fundamentally different mechanism of action of the claimed drug in comparison with the known opiate receptor agonists.

The analgesic effect of the claimed drugs is realized due to their effect on the molecular mechanism of membrane signaling, including a new membrane receptor, Na / K-ATPase (its alpha three isoform) as a signal transducer and tetrodotoxin-resistant sodium channels. In this capacity, Na / K-ATPase is involved in the encoding of nociceptive information. The mechanism of action of the claimed synthetic analgesic agent based on derivatives of gamma-pyrone is fundamentally different from the effects of analgesics containing morphine as an active substance, since G-proteins are not involved in its implementation. Evidence from [Biser P.S., Thayne K.A., Fleming W.W., Taylor D.A. Na, K-ATPase alpha-subunit isoform distribution and abundance in guinea-pig longitudinal muscle / mienteric plexus after exposure to morphine. Brain Res. 2002 Mar. 29; 931 (2): 186-93] indicate that morphine blocks the work of Na / K-ATPase neurons. As a result of this, irreversible morphological changes in cells, tissues and organs occur, which ultimately can lead to death.

Studies have shown that the use of funds from the claimed group of derivatives of gamma-pyrone increase, but not reduce, the activity of Na / K-ATPase of nerve cells. Thus, the proposed analgesic agent exhibits a pronounced analgesic activity and, unlike the "large" analgesics, does not cause mental and physical dependence. The effect of the drug at the molecular level is associated with the activation of the membrane receptor, Na / K-ATPase (its alpha three isoform), which acts as a signal transducer and modulation of tetrodotoxin-resistant sodium channels.

Example 7. A method of treating pain of various etiologies.

When conducting research, the following synthetic analgesic agents obtained by the method specified in example 1 were used.

Recalculation of the doses of the proposed analgesic recommended for human administration was carried out taking into account the methodology described in the Guide to the experimental (preclinical) study of new pharmacological substances. Ministry of Health of the Russian Federation. Pharmaceutical Committee of the Russian Federation. M., 2000. It is assumed that the daily dose used for a rat weighing 250 g, for translation into a dose for a person weighing 70 kg, should be divided by a factor of 7. As mentioned above, the optimal daily dose of 34 was used in the experiment with rats up to 40 mg gamma-pyrone / kg rat mass. In experiments on mice, the threshold dose of the claimed drug was 5 mg / kg

Additional studies conducted by the authors made it possible to clarify the calculations and showed that the upper limit of the daily dose (allows you to enter an initial reference point safe for people with experience with other analgesics to conduct further preclinical tests on the effect and concentrations in one direction or another) for a person - up to 300 mg of gamma-pyron per day.

A further increase in the dose of the drug does not affect analgesic activity.

This approach correlates with data on analgesics obtained in [Leeling J.L., Evans J.V., Helms R.J., Ryerson B.A. Disposition and metabolism of codorphone in the rat, dog, and man // Drug Metab Dispos. 1982. Nov-Dec. V.10 (6) P.649-653], which shows doses for humans 10 times lower than in animals, due to the faster metabolism of animals.

Comparison with the prototype agent (tramadol), as well as with analginum, morphine hydrochloride and the method of treatment using this known agent was carried out both on the basis of literature data - the description given in [Mashkovsky M.D. Medicines 14th edition. M .: New wave, 2003.V.1. P.157] and in the text of the present description - see above when describing analogues, and based on our own experimental data.

The compositions described in example 1 were tested on animals - rats and mice - in single doses and daily doses determined in the above experiments. Allergic reactions were not observed.

The effect of stopping the pain syndrome of various etiologies (including the algic component of the opiate withdrawal syndrome) after each use of the proposed drug lasted at least 24 hours. It should be noted that after an intravenous injection of tramadol, taken as a prototype, the analgesic effect lasts from 3 to 5 hours.

In experiments on morphinated rats, a stable therapeutic effect of the inventive non-narcotic analgesic agent was shown, which persisted after application of the inventive agent for a month - 50 days and even more without drug dependence.

In the treatment with animals obtained by treatment, there were no signs characteristic of chronic administration of drugs of the group of large analgesics. Inhibition of respiration, vomiting, blocking the cough center, diarrhea, hair loss, changes in the condition of the skin, even with long-term up to 60 days of taking drugs in animals were not observed.

The preferred dose is from 0.05 to 300 mg in one or more daily doses throughout the day. The dose determined by the doctor can be received by the patient in one or several doses, as well as in the form of long-term use, depending on the diagnosis and severity of the disease.

When taking an analgesic agent in a dose of more than 300 mg per day, the drugs can show a mild sedative effect, while the analgesic effect does not increase. The latter indicates the inappropriateness of increasing the upper limit of the dose of the drug.

The administration of an analgesic may be prescribed to the patient in the form of injections or intranasally.

It should be emphasized that the dose of the claimed drug does not exceed the dose of known analogues - tramadol, morphine hydrochloride, analgin. Daily doses within the claimed can be prescribed in a wide range in accordance with individual characteristics and recommendations of doctors.

The possibility of implementing the invention is not limited to the above examples.

According to the test results, a highly effective non-narcotic synthetic analgesic agent was obtained that does not have negative side pharmacological effects characteristic of the group of "large analgesics", which is primarily not addictive and addictive inherent to known analogues (morphine, tramadol, in some cases, analgin), and a method for treating pain syndrome of various etiologies with the help of this tool, leading to long-term withdrawal of the pain syndrome, creating the possibility of conducting better ennoy therapy for the underlying disease, including cancer patients and patients with drug addiction.

Repeated experiments showed good reproducibility of the results.

Claims (9)

1. Non-narcotic synthetic analgesic agent containing an active principle - a gamma-pyrone derivative selected from the group consisting of meconic acid, methyl-comenic acid, comenic acid - in an amount of from 0.05 to 300 mg for a single dose and a pharmacologically compatible liquid filler in the following ratio of components, wt.%: active start 0.5-95 liquid filler rest, and representing a form intended for systematic administration. 2. The tool according to claim 1, characterized in that the liquid filler is selected from the series: water, ethanol, glycerol, saline. 3. The tool according to claim 1, characterized in that it further comprises an emulsifying agent and / or a buffering agent. 4. The tool according to claim 1, characterized in that it is presented in a dosage form for parenteral or intranasal administration. 5. The tool according to claim 4, characterized in that the form for parenteral or intranasal administration is a solution or suspension. 6. A method of treating a pain syndrome of various etiologies, which consists in parenteral or intranasal administration of a non-narcotic synthetic analgesic agent according to claims 1-5 in a dose of 0.05 to 300 mg of active principle 1 to 2 times a day, every day for 7- 14 days depending on the diagnosis and severity of the patient's condition until a therapeutic effect is achieved. 7. The method according to claim 6, characterized in that the agent is administered intranasally. 8. The method according to claim 6, characterized in that the agent is administered invasively in the form of an injection course. 9. The treatment method according to claim 6, characterized in that in cancer patients, the course of treatment can be extended to 30 days or more.