RU2275905C2 - Pharmaceutical compositions against headache, migraine, sickness, and retch - Google Patents

Abstract

FIELD: medicine and pharmacology.

SUBSTANCE: compositions against headache, migraine, sickness, and retch contain S-alkylisothiouronium. Disclosed are method for production of drug and treatment methods.

EFFECT: pharmaceutical composition of improved effectiveness.

48 cl, 3 tbl, 4 ex

Description

Field of Invention

The present invention relates to the use of, but not limited to, S-alkylisothiouronium derivatives of S-ethylisothiouronium diethylphosphate for the prevention or treatment of headaches, including but not limited to migraines, and for the prevention or treatment of vomiting, and more particularly to alleviate migraine symptoms, including headache, nausea and vomiting, but not limited to this.

BACKGROUND OF THE INVENTION

The term “headache” is used to describe various sets of symptoms that vary in intensity from mild discomfort to a very severe syndrome known as migraine.

While the most severe and debilitating form of headache is migraine, there are several other types of headaches that justify the discussion in terms of prevalence, including, but not limited to, premenstrual syndrome (PMS) associated with headaches and the condition in the morning after drinking alcohol, commonly called a hangover. Symptoms such as headache, fever, chills, nausea, muscle and nervous pain, lethargy, and others, are often manifested in a syndrome known as a hangover.

Without presenting a threat to life, PMS and a hangover can be very unpleasant, as well as harmful at work and at home. Currently, most common treatments for these conditions include self-administration of NSAIDs (non-steroidal anti-inflammatory drugs), painkillers and other prescription and over-the-counter drugs.

The following publications represent the previous level of knowledge regarding headaches in general and migraines, in particular, their causes and methods for their treatment:

1. Capobianco "An overview of the diagnosis and pharmacologic treatment of migraine" Mayo Clin. Proc. (1996) 71: 1055-1066.

2. Cohen "Migraine Headache and the Managed Care Formulary" Drugs Benefit Trends (1996) 8 (8) 28-30, 33-34, 41.

3. Diamond, "Do Non-Steroidal Anti-Inflammatory Agents Have a Role in the Treatment of Migraine Headaches" Drugs (1989) 37: 755-760.

4. Klapper, "Toward a standard drug fonnulary for the treatment of headache" Headache (1995) Apr., 225-227.

5. Kumar, "Recent advances in the acute management of migraine and cluster headaches" Journal of General Internal Medicine (1994) 9: 339-348.

6. Matthew, "Serotonin 1D (5-HT1D) agonists and other agents in acute migraine" Advances in Headache, (1997) 15 (1): 61-81.

7. Pradalier, "Treatment Review: Non-Steroid Anti-Inflammatory Drugs in the Treatment and Long-Term Prevention of Migraine Attacks" Headache (1988) 28: 550-557.

8. Pryse-Phillips, "Guidelines for the diagnosis and management of migraine in clinical practice" Can. Med. Assoc. J. (1997) 156 (9): 1273-1287.

9. Wilkinson, "Migraine and cluster headache-their management with sumatriptan: a critical review of the current clinical experience" Cephalalgia (1995) 15: 337-357.

Below is the current knowledge regarding migraines and their treatment.

Symptoms and diagnosis of migraine

Migraine headache is a severe episodic headache characterized by one-sided intense throbbing headache, nausea, vomiting, the appearance of sparks of light, the appearance of rainbow colors, empty spots in the field of vision and other sensations and sensitivity to light and sounds [Larson, E. David, M.D. Editor-in-Chif "Mayo Clinic Family Health Book" 1994, pp. 502-503]. Migraine refers to a group of symptoms that can occur together. The most famous is a headache with disability, on the one hand or throughout the head, which can last from 2 to 72 hours. This pain is usually described as throbbing. Such headaches are usually, but not always, associated with a feeling of nausea in the stomach or sensitivity to light, sound, or body movement. The pain is very severe and often a person with a migraine should stay in bed. Nutritional factors, emotional, hormonal and environmental factors can cause an attack.

In practice, there are two types of migraine. The most common type is called migraine without aura (common migraine) and it covers 85% of all suffering. The second, most common type is called migraine with aura (classical migraine), it covers most of the remaining 15% of sufferers. An aura is a disturbance of the nervous system that often precedes a headache.

People suffering from migraines sometimes get a warning signal before an attack. Some experience an “aura,” a brain dysfunction that occurs twenty to thirty minutes before an attack. It is characterized by visual disturbances, such as flashes of light and darkened vision, or sensation in the body of injections and needles acting on one limb or in one side. These violations are usually short-term and almost invariably pass, without leaving long-term effects. Others with migraines feel a “precursor” that appears several hours or even the day before the onset of an attack. Symptoms may include yawning, fatigue, mood changes, desire to eat, and sensitivity to light (photophobia), sound (phonophobia), touch, and / or smells. In most of those who have a precursor, the type and location of the headache remains the same for every migraine attack. Other common symptoms include numbness or tingling around the lips or hands, hallucinations, speech loss, symptoms of depression, irritability (some people tend to retire in a dark room), anxiety, nausea, or loss of appetite, which occur in about 20% of migraine sufferers. The same percentage of migraine sufferers lose their vision in specific areas (called a blind spot or scotoma) or see uneven, flickering or flashing light. Less commonly, images are distorted, for example, objects appear smaller or larger than they are.

Migraine is a chronic incurable disorder. There are no laboratory tests to help diagnose a migraine, but it is usually easy to identify by a specific type of headache. Headaches are not life threatening and there is no evidence that they lead to other disorders [Larson, E., David M.D. Editor-in-Chif "Mayo Clinic Family Health Book" 1994, pp. 503]. Often they do not pay attention to the importance of migraine for public health, probably due to its episodic nature and low mortality due to this violation. However, migraine often disables, causing a significant blow to social activity and work.

Prevalence

The prevalence of migraine is relatively high and is said to be approximately 6% in the male population and 18% in the female population. The predominance of migraine in women appears after puberty; in many patients, migraine appears during menstruation, and during pregnancy there is an improvement. It is estimated that in the United States alone, approximately 35 million people suffer from migraines. In some people, migraine attacks can occur weekly; others may have less than one episode per year [Griffith, H.Winter, M.D. "All-New Third Edition Complete Guide to Symptoms, Illness & Surgery", July 1995, p. 425].

Common Migraine Treatment

There are several approved therapeutic drugs for migraine. The treatment of many patients with recurrent migraines usually involves simple analgesics (usually in combination with an antiemetic, but such drugs are of limited value), non-steroidal anti-inflammatory agents, or specific agents such as ergotamines or triptans. Being nothing more than sporadically effective, traditional practice recognizes that anti-migraine medications are believed to first relieve migraines, primarily causing vasoconstriction. Unfortunately, this traditional practice recognizes that medications for migraine are accompanied by significant negative side effects that are associated with excessive vasoactivity in areas of the body that are not included in the pathogenesis of migraine. This remote vasoactivity is an effect that has no therapeutic benefit for the treatment of migraine. Such vasoactive drugs are indeed contraindicated in patients with cardiovascular diseases or at risk of cardiovascular diseases such as hypertension, coronary arterial disease or peripheral vascular diseases. Other known significant side effects are chest pain or pressure, hot flashes, a common sensation of tinnitus, nausea, vomiting, pain in the legs and arms, asthenia, drowsiness, and dizziness. Prophylactic agents such as beta blockers, tricyclic antidepressants and sodium valproate can reduce, but not eliminate, migraine attacks in some patients. For the rest of the people suffering from migraine, and for those who cannot tolerate the side effects of the available drugs, there are no conventional pharmaceutical preparations that demonstrate a therapeutic effect without severe side effects. Thus, there remains a great need for drugs specific for migraine.

OTC analgesics: It has been found that in some forms of migraine, some patients experience general or partial relief from the use of non-prescription analgesics such as acetaminophen, aspirin, ibuprofen and other non-steroidal anti-inflammatory agents, including naproxen and naproxenatrium. However, these agents, taken on their own, are rarely effective in providing complete and quick relief of all the symptoms of migraine, especially if the symptoms of the attack already include nausea and vomiting. In addition, the onset of their action is slowed, so that relief sometimes does not occur for at least several hours.

Ergotamine drugs: One of the known treatments for migraine is to take compounds with vasoconstrictive properties, such as ergotamines or ergotamine-like agents. However, ergotamine is a non-selective vasoconstrictor agent that constricts blood vessels throughout the body and has unwanted and potentially dangerous side effects. Ergotamines should not be used in patients with peripheral vascular disease, coronary heart disease, hypertension, impaired liver or kidney function, severe itching or sepsis. They are also contraindicated in pregnant women or those who are about to become pregnant. Nausea and vomiting have been reported in 10% of patients taking therapeutic doses of ergotamine. Acute ergotism is an extremely severe side effect of ergot drugs and is characterized by severe central and peripheral vasoconstriction, sometimes leading to amputation of the affected limbs and / or fingers, nausea, vomiting, diarrhea, colic, headache, dizziness, paresthesia, and possibly convulsive seizures. Chronic ergotism is characterized by intermittent claudication, muscle pain, numbness and cold limbs, as well as other gastrointestinal side effects and effects on the central nervous system (CNS). There are treatment methods that include administering a high dose of caffeine with ergot drugs or other pharmacological agents. In addition, ergot drugs and caffeine are potentially addictive with well-confirmed withdrawal symptoms.

Triptan drugs (serotonin agonists): Another treatment option is to administer newer therapeutic agents known as serotonin agonists or 5-hydroxytryptamine agonists (5-HT). The first of the family, sumatriptan, is without a doubt a significant improvement in migraine therapy. Sumatriptan succinate is sold under the trademark IMITREX from Glaxo Wellcome Inc. Despite the applicability of sumatriptan in the treatment of migraine, it has some limitations, for example, low bioavailability when taken orally, frequent relapses of headache and contraindication for patients with coronary arterial disease.

The main mechanism of action of triptans for migraine is the narrowing of dilated cranial extracerebral blood vessels. In addition, triptans can reduce the release of neuropeptides and the transudation of plasma proteins through the dural vessels and centrally inhibit the passage of the pulse inside the trigeminovascular system.

In general, help with migraines is complicated by the lack of a single therapy that is effective for all patients with the same type of migraine, and the need to choose a suspension or prophylactic treatment for such migraines. Additional complications include the common use of drugs that, with prolonged use, are addictive, such as the ergot alkaloid, ergotamine. Another important consideration is that, in common use, more effective anti-migraine agents, for example, ergot drugs, metisergide, with prolonged use give severe side effects that limit the use.

Thus, there is a need for an effective medicament for alleviating or treating the symptoms of migraine, which can be used either before the attack, for example in the aura phase, or during the attack, so as to quickly alleviate the symptoms of migraine during the attack, and which does not give side effects.

Antiemetic drugs

A particularly important use of antiemetic agents is the prevention and treatment of nausea and vomiting associated with cancer chemotherapy. Vomiting is a well-known and common side effect of anti-cancer chemotherapeutic agents such as cisplatin. It causes serious problems with cancer chemotherapy, and in some patients vomiting is so severe that therapy has to be interrupted. Therefore, antiemetic agents are often taken to alleviate this side effect of the anticancer chemotherapeutic agent. Antiemetic agents used are often benzamide derivatives, such as metoclopramide, which has dopamine antagonist activity. In terms of dopamine antagonist activity, benzamide derivatives, such as metoclopramine, themselves exhibit serious and undesirable side effects, such as extrapyramidal effects, such as delayed dyskinesia, acute dystonia, akathisia, and tremor.

Physiologically acceptable carbazolone salts are described in US Pat. No. 5,587,628 as potent antiemetics that are selective antagonists of 5-hydroxytryptamine (5-HT) on neural 5-HT receptors of the type located at the ends of primary afferent nerves and which are also believed to be present in the central nervous system.

Thus, there is a need for a safe and effective antiemetic agent and a stimulator of gastric mobility in the absence of undesirable side effects of known antiemetic agents, which exerts its effect through various CNS receptors.

WO 98/13036 discloses the use of S-alkylisothiouronium derivatives, including some new compounds, as medicaments for increasing blood pressure or for protecting patients from hyperoxia. These compounds are provided for the treatment of acute hypotension, for example, shock conditions, and chronic arterial hypotension or oxygen poisoning. The present invention is illustrated by the hypertensive effect of S-ethylisothiouronium diethylphosphate under various conditions. However, WO 98/13036 does not describe or suggest the use of S-alkylisothiouronium derivatives for the treatment of headache, migraine or nausea and vomiting.

Summary of invention

It has been unexpectedly disclosed that derivatives of S-alkyl isothiouronium salts, which are known as hypertensive agents, are also highly effective in relieving headaches in general and migraine symptoms in particular. Using the present invention, it has also been found in practice that these derivatives of S-alkylisothiouronium salts are effective in treating nausea and vomiting. Patients with migraine successfully underwent treatment with S-ethylisothiouronium diethylphosphate with unexpectedly lower doses than required for antihypertensive use. Treatment started at the peak of a migraine attack steadily shows relief within 60 minutes after taking the medicine. In some cases, significant improvement has been reported for approximately 15 minutes.

Thus, according to one aspect of the present invention, there is provided a pharmaceutical composition for treating headache, migraine, nausea and vomiting, comprising, as an active ingredient, a compound of general formula I:

where R ¹ represents a linear or branched, saturated or unsaturated alkylene, comprising from one to eight carbon atoms, optionally substituted with one or more substituents selected from the group consisting of halogen, primary, secondary and tertiary amine, primary, secondary and tertiary alcohol, or interrupted by one or more heteroatoms selected from the group consisting of O, N and S;

R ² , R ³ , R ⁴ and R ⁵ each independently represent hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkoxy, nitro, amino, cyano, sulfonyl, haloalkyl, carboaryloxy, carboalkylaryloxy, alkyl sulfoxide, arylsulfoxide, alkyl sulfone, arylsulfone, alkyl sulfate, arylsulfate, sulfonamide, thioalkyl optionally substituted with halogen;

представляет физиологически приемлемый анион;

represents a physiologically acceptable anion;

together with a pharmaceutically acceptable carrier or diluent.

According to the preferred embodiments of the invention described below, a physiologically acceptable anion is an anion derived from a phosphoric acid, more preferably a group consisting of an anion derived from a phosphoric acid ester or amide, most preferably an anion derived from a phosphoric acid mono- or dialkyl ester.

According to another aspect of the present invention, there is provided a method of treating a patient suffering from headache, migraine or nausea, said method comprising the step of administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I):

where R ¹ represents a linear or branched, saturated or unsaturated alkylene, comprising from one to eight carbon atoms, optionally substituted with one or more substituents selected from the group consisting of halogen, primary, secondary and tertiary amine, primary, secondary and tertiary alcohol, or interrupted by one or more heteroatoms selected from the group consisting of O, N and S;

R ² , R ³ , R ⁴ and R ⁵ each independently represent hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkoxy, nitro, amino, cyano, sulfonyl, haloalkyl, carboaryloxy, carboalkylaryloxy, alkyl sulfoxide, arylsulfoxide, alkyl sulfone, arylsulfone, alkyl sulfate, arylsulfate, sulfonamide, thioalkyl optionally substituted with halogen;

представляет физиологически приемлемый анион.

represents a physiologically acceptable anion.

According to another aspect of the present invention, there is provided a method for preparing a medicament for headache, migraine or nausea, said method comprising the step of mixing, as an active ingredient, a compound of general formula (I):

where R ¹ represents a linear or branched, saturated or unsaturated alkylene, comprising from one to eight carbon atoms, optionally substituted with one or more substituents selected from the group consisting of halogen, primary, secondary and tertiary amine, primary, secondary and tertiary alcohol, or interrupted by one or more heteroatoms selected from the group consisting of O, N and S;

R ² , R ³ , R ⁴ and R ⁵ each independently represent hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkoxy, nitro, amino, cyano, sulfonyl, haloalkyl, carboaryloxy, carboalkylaryloxy, alkyl sulfoxide, arylsulfoxide, alkyl sulfone, arylsulfone, alkyl sulfate, arylsulfate, sulfonamide, thioalkyl optionally substituted with halogen;

представляет физиологически приемлемый анион;

represents a physiologically acceptable anion;

with a pharmaceutically acceptable carrier or diluent.

In accordance with other features of preferred embodiments of the invention, the physiologically acceptable anion is selected from the group consisting of phosphoric acid anion, phosphoric acid ester, phosphoric acid amide, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bitartarate, bisulfate, butyrate, butyrate , camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, 2-hydroxyethanesulfonate, isothionate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, o lettuce, palmoate, pectinate, 3-phenylpropionate, pivalate, propionate, succinate, tartrate, thiocyanate, glutamate, bicarbonate, p-toluenesulfonate, chloride, bromide, iodide and undecanoate.

According to the preferred embodiments of the invention described below, the physiologically acceptable anion is a phosphoric acid anion, more preferably a group consisting of phosphoric acid ester or amide anions, most preferably a phosphoric acid mono- or dialkyl ester anion.

In accordance with other features of the described preferred embodiments, the medicament is packaged and identified as having anti-headache, anti-migraine or anti-vomiting activity.

In accordance with other features of the described preferred options, the compound is selected from the group including:

S-methylisothiouronium methylphosphite;

S-methylisothiouronium dimethyl phosphate;

S-ethyl isothiouronium metaphosphate;

S-ethylisothiouronium ethyl phosphite;

S-ethylisothiouronium diethyl phosphate;

S-propylisothiouronium propylphosphite;

S-isopropylisothiouronium metaphosphate;

S-isopropylisothiouronium isopropyl phosphite;

S-butylisothiouronium dibutyl phosphate;

S-isobutyl isothiouronium isobutyl phosphite.

In accordance with other features of the described preferred options, the drug for headache, anti-migraine, anti-nausea or vomiting is prepared for oral or parenteral administration. Among preparations for parenteral routes of administration, particularly preferred preparations are suitable for injection, sublingual, transdermal administration, administration through the mucous membrane or by inhalation.

In accordance with other features of the described preferred embodiments, the anti-migraine drug is prepared in the form of tablets or capsules.

In accordance with other features of the described preferred options, each tablet or capsule comprises from 10 to 300 mg of the compound.

In accordance with other features of the described preferred options, each tablet or capsule comprises from 20 to 200 mg of the compound.

In accordance with other features of the described preferred options, each tablet or capsule comprises from 30 to 80 mg of the compound.

In accordance with other features of the described preferred options, the method also includes the steps of packaging the drug and identifying the drug as having activity against headache, migraine, nausea or vomiting.

In preferred embodiments, the therapeutically effective amount is from 0.1 to 3 mg / kg body weight.

In other preferred embodiments, the therapeutically effective amount is from 0.4 to 1.6 mg / kg body weight.

According to the most preferred embodiments, the therapeutically effective amount is from 0.5 to 1.2 mg / kg body weight.

In accordance with other features of the described preferred embodiments, the therapeutically effective amount is selected so that within a period of less than 60 minutes after administration, significant relief of the symptoms of migraine occurs.

In some preferred embodiments, the compound is taken after the onset of symptoms of a headache, in particular migraine, or nausea.

In other preferred embodiments, the compound is taken for an attack of a headache, in particular migraine, or nausea.

It is understood that since migraine is the most severe form of headache, the methods of treatment of the present invention are also suitable for other types of headaches and nausea, including but not limited to PMS or hangover-related headaches and nausea. This is particularly suitable due to minor side effects observed in people using the compositions and methods of the present invention.

The compounds of formula (I) inhibit vomiting. Therefore, these compounds are also useful as antiemetic agents, for example, for preventing vomiting induced by anticancer chemotherapeutic agents such as cisplatin. Also, treatment of vomiting induced by radiation can be particularly noted. Thus, the compounds of formula (I) can be used to prevent vomiting induced by radiation therapy, for example by irradiating the chest or abdomen, as in the treatment of cancer; or in the treatment of radiation sickness. It is understood that the compounds of formula (I) can be used prophylactically, and in this description, references to treatment include both prophylactic treatment and alleviation of acute symptoms.

In accordance with other features of the described preferred embodiments, the step of administering the compound is carried out during or before an attack of nausea. Those skilled in the art will appreciate that oral administration may be less desirable after the onset of nausea.

The present invention successfully corrects the disadvantages of currently known drugs by providing an effective compound for treating and / or alleviating the symptoms of a headache, in particular migraine, or nausea. This preferred compound has no obvious side effects and is shown to be potent at low doses and provides a therapeutic / alleviating effect in a short period of time compared to currently available drugs.

Description of Preferred Options

The present invention relates to the use of S-alkylisothiouronium derivatives for the treatment of headache, in particular migraine, or nausea and vomiting. The compositions of this invention are effective in preventing or alleviating vomiting associated with migraine or other medical conditions, such as chemotherapy or radiotherapy, as well as other symptoms of migraine, including phonophobia and photophobia. It was previously known that these compounds affect arterial blood pressure in cases of acute hypotension (for example, after hemorrhage, trauma, shock, or poisoning).

Before a detailed explanation of at least one embodiment of the invention, it should be understood that the invention is not limited in its application to the details indicated in the following description or presented in the Examples section. The present invention may have other variations or may be practiced or carried out in other ways. It should also be understood that the phraseology and terminology used here are for descriptive purposes and should not be construed as limiting.

The term “migraine” as used herein is understood broadly as including a type of headache characterized by an unusually strong, unilateral throbbing headache lasting for 4-72 hours, and which may include one or more of the following symptoms: nausea, vomiting, sensitivity to light and / or sounds with or without previous “aura” and visual photophobia (eg, visual impairment).

According to one aspect of the present invention, there is provided a medicament for headache, migraine, nausea or vomiting, comprising, as an active ingredient, a compound of general formula (I):

where R ¹ represents a linear or branched, saturated or unsaturated alkylene, comprising from one to eight carbon atoms, optionally substituted by one or more substituents selected from the group consisting of halogen, primary or secondary amine, primary or secondary alcohol, or interrupted by one or more heteroatoms selected from the group consisting of O, N and S;

R ² , R ³ , R ⁴ and R ⁵ each independently represent hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkoxy, nitro , amino, cyano, sulfonyl, haloalkyl, carboaryloxy, carboalkylaryloxy, alkyl sulfoxide, arylsulfoxide, alkyl sulfone, arylsulfone, alkyl sulfate, arylsulfate, sulfonamide, thioalkyl optionally substituted with halogen;

представляет физиологически приемлемый анион;

represents a physiologically acceptable anion;

together with a pharmaceutically acceptable carrier or diluent.

Preferably, a physiologically acceptable anion is obtained, without limitation, from phosphoric acid, a group containing an anion derived from phosphoric acid, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bitartarate, bisulfate, butyrate, camphorite, camphorsulfonate, diglyconfonate , hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate, isothionate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, pivalate, propylate, propylate t, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, chloride, bromide, iodide and undecanoate.

According to the preferred embodiments of the invention described below, the physiologically acceptable anion is a phosphoric acid anion, more preferably a group consisting of phosphoric acid ester or amide anions, most preferably a phosphoric acid mono- or dialkyl ester anion.

Used in the description and in the claims, the term "alkylene" means a saturated or unsaturated hydrocarbon chain, including linear or branched alkyl, alkenyl or alkynyl.

The term “alkyl” as used means a saturated hydrocarbon chain containing from 1 to 30, preferably from 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, n-pentyl, n-hexyl and the like. The term “alkyl” as used is also read in haloalkyls which contain halogen atoms. Alkyl also includes heteroalkyl with heteroatoms of sulfur, oxygen and nitrogen.

The terms "alkenyl" and "alkynyl" are used to mean linear or branched hydrocarbon groups having from 2 to 12 carbon atoms with an unsaturated double or triple bond, respectively, such as vinyl, allyl, propargyl, 1-methylvinyl, but-1-enyl , but-2-enyl, but-2-ynyl, 1-methylbut-2-enyl, pent-1-enyl, pent-3-enyl, 3-methylbut-1-ynyl, 1,1-dimethylallyl, hex-2 phenyl and 1-methyl-1-ethylallyl.

As used herein, “cycloalkyl” refers to cyclic radicals including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like.

As used herein, “cycloalkylalkyl” refers to cycloalkyl groups attached to a lower alkyl radical, including, but not limited to, cyclohexylmethyl.

The term “alkoxyalkyl” as defined for R-substituents preferably means a group containing only 1-22 carbon atoms. Examples include methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, n-propoxyethyl and iso-propoxyethyl.

As used herein, “alkoxy” refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.

As used herein, “alkoxyalkoxy” refers to an alkoxy group attached to the parent molecular moiety through an alkoxy group.

Used the term "halogen" refers to I, Br, Cl or F.

The term “carboxy” as used refers to the —COOH radical. The term “ether” refers to —COOR; the term amide refers to —CONH ₂ , —CONHR or —CONR ₂ . The term “cyano” refers to the —CN radical.

Phosphorus-containing and other salts of S-alkylisothiouronium are synthesized by various methods well known in the art, for example, by alkylation of thiourea with suitable trialkyl phosphates or dialkyl phosphites when heated in an organic solvent.

Without excluding the other options below, S-ethylisothiouronium diethylphosphate is currently the preferred compound for treating headaches, particularly migraines, and nausea or vomiting. Other examples of S-alkylisothiouronium derivatives that can be used to treat migraine according to the present invention include, but are not limited to, S-methylisothiouronium methylphosphate, S-methylisothiouronium dimethylphosphate, S-ethylisothiouronium metaphosphate, S-ethylisothiouronium ethylphosphite, S-ethylisothiouronium ethylphosphite, S-ethylisothiouronium ethylphosphite, -propylisothiouronium propylphosphite, S-isopropylisothiouronium metaphosphate, S-isopropylisothiouronium isopropyl phosphite, S-butylisothiouronium dibutyl phosphate and S-isobutylisothiouronium isobutyl phosphite.

It is known that these compounds are safe for humans, since it is well known in the art that phosphorus derivatives of S-alkyl isothiouronium have low toxicity, and their LD ₅₀ (50% lethal dose) is in the range of 100-1000 mg / kg, which is significantly higher therapeutic doses of these compounds.

The medicaments of the present invention for headache, anti-migraine, anti-nausea or vomiting are preferably packaged and identified as having the indicated activity. Such identification may be printed, for example, on a package insert of a drug product or on a bag or container that contains the drug.

The compound of the present invention can be administered to the patient alone or in the form of a pharmaceutical composition, where it is mixed with suitable carriers or excipients.

The expression "pharmaceutical composition" as used refers to the preparation of one or more of the described compounds or their physiologically acceptable salts or prodrugs with other chemical components, such as physiologically acceptable carriers and excipients. The objective of the pharmaceutical composition is to facilitate the administration of the compound to the body.

The term "prodrug" refers to an agent that is converted in vivo to the active parent drug. Prodrugs are often useful, as in some cases they can be easier to administer than the original drug. For example, they may be bioavailable when taken orally, whereas the starting drugs are not. A prodrug may also have better solubility compared to the parent drug in the pharmaceutical composition.

The term “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Pharmaceutical compositions may also include one or more additional ingredients, such as, but not limited to, well-known anti-migraine agents.

The pharmaceutical compositions of the present invention can be obtained by methods known in the art, for example, by conventional mixing, dissolving, granulating, grinding, spraying, dragee, grinding, emulsifying, capsule preparation, capturing or lyophilization.

Thus, pharmaceutical compositions for use in accordance with the present invention can be prepared in a conventional manner using one or more physiologically acceptable carriers, including excipients and excipients, which facilitate the processing of the active compounds into a preparation that can be used pharmaceutically. The exact composition depends on the chosen method of administration.

For injection, the compounds of this invention can be prepared in an aqueous solution, preferably in physiologically compatible buffers, such as Hank's solution, Ringer's solution or saline buffer. For administration through the mucous membrane, a wetting agent is used in the preparation, suitable for penetration through this barrier. Such wetting agents, for example DMSO or polyethylene glycol, are well known in the art.

Compounds for oral administration can be easily prepared by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers make it possible to prepare the compounds of this invention in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, pastes, suspensions and the like for swallowing by a patient. Pharmacological preparations for oral administration can be obtained using a solid excipient, optionally grinding the resulting mixture and processing the mixture of granules, then adding suitable auxiliary agents, if necessary, and obtaining tablets or dragee cores. Suitable excipients are, in particular, excipients such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropyl methyl cellulose, sodium carbomethyl cellulose and / or physiologically acceptable polymers such as polyvinyl pyrrolide. If desired, disintegrants, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts, such as sodium alginate, can be added.

Appropriate coatings are applied to the dragee cores. For this purpose, you can use a concentrated sugar solution, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, glaze solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings to identify or characterize various combinations of doses of the active compounds.

Pharmaceutical compositions that can be administered orally include push-fit gelatin capsules as well as soft, closed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Hard (push-fit) capsules may contain the active ingredients in admixture with an excipient such as lactose, binders such as starches, lubricating agents such as talc or magnesium stearate, optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, you can add stabilizers. All preparations for oral administration should be dosed in an appropriate manner for the chosen route of administration.

Compositions for buccal administration may take the form of tablets or lozenges formulated in the usual manner.

Compounds administered by inhalation for use in accordance with the present invention are usually delivered in the form of an aerosol spray from a pressurized container or a nebulizer using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit can be determined by providing the container with a valve supplying a metered amount. Capsules and cartridges can be prepared, for example, from gelatin for use in an inhaler or insufflator, containing a powder mixture of a compound and a suitable powder base, such as lactose or starch.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active drug in a water-soluble form. In addition, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or carriers include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspensions may also contain suitable stabilizers or agents that increase the solubility of these compounds, allowing to obtain solutions with high concentrations.

Alternatively, the active ingredient may be in powder form to prepare, before use, a composition with a suitable carrier, for example, sterile pyrogen-free water.

The compounds of the present invention can also be obtained in the form of compositions for rectal administration, such as suppositories or retention enemas, using, for example, conventional suppository bases, such as cocoa butter or other glycerides.

The described pharmaceutical compositions may also contain a suitable solid of a carrier or gel phase excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.

Pharmaceutical compositions suitable for use in the context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount is an amount of a compound effective to prevent, alleviate, or alleviate the symptoms of a disease of a patient being treated.

The determination of a therapeutically effective amount is completely within the capabilities of a person skilled in the art, especially in light of the detailed description presented.

The toxicity and therapeutic efficacy of the described compounds can be determined by standard pharmaceutical methods in cell cultures or in experimental animals, for example, by determining IC ₅₀ (concentration providing 50% inhibition) and LD ₅₀ (lethal dose causing death in 50% of the studied animals) for the subject connections. Data from cell culture experiments and animal studies can be used to determine the dosage range for human use. The dosage can vary depending on the dosage form used and the method of administration. The exact composition, method of administration and dosage may be selected by the attending physician, taking into account the patient's condition (see, for example, Fingl et al., 1975 in The Pharmacological Basis of Therapeutics, Ch.1, p.1).

Depending on the severity and susceptibility of the condition to be treated, the dosage can also be a single administration of the composition with a slow release of the active substance in the course of treatment from several days to several weeks or until healing or amelioration of the disease state is achieved.

The amount of the composition to be taken, of course, depends on the patient being treated, the severity of the disease, the route of administration, the opinions of the attending physician, etc.

Slow-release tablets or capsules of the active substance that contain S-alkyl isothiouronium can be used before the attack, for example, people who are about to undergo chemotherapy or other treatments that are known to cause nausea or vomiting, women who know that their premenstrual the period is usually accompanied by nausea or migraine, or patients who experience an “aura” and can identify it as a previous migraine condition. Also, a tablet or capsule can be prepared so that part of the active ingredient is released immediately, providing initial relief of migraines, and the other part is released slowly and in measured amounts.

As used herein, the term “initial relief of migraine” refers to the reduction or elimination of migraine symptoms within a predetermined period of time after administration, in particular in the present invention, for about 10-60 minutes after administration.

Each tablet or capsule of the present invention preferably contains from 10 to 300 mg, more preferably from 20 to 200 mg, most preferably from 30 to 80 mg of the active compound (S-alkylisothiouronium derivative). Used the expression "approximately" means ± 20%.

According to another aspect of the present invention, there is provided a method of preparing a medicament for headache, migraine, nausea and vomiting. The method corresponding to this aspect of the present invention is carried out by mixing as an active ingredient a compound of the general formula (I):

where R ¹ represents a linear or branched, saturated or unsaturated alkylene, comprising from one to eight carbon atoms, optionally substituted by one or more substituents selected from the group consisting of halogen, primary or secondary amine, primary or secondary alcohol, or interrupted by one or a large number of heteroatoms selected from the group consisting of O, N and S;

R ² , R ³ , R ⁴ and R ⁵ each independently represent hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkoxy, nitro, amino, cyano, sulfonyl, haloalkyl, carboaryloxy, carboalkylaryloxy, alkyl sulfoxide, arylsulfoxide, alkyl sulfone, arylsulfone, alkyl sulfate, arylsulfate, sulfonamide, thioalkyl optionally substituted with halogen;

представляет физиологически приемлемый анион;

represents a physiologically acceptable anion;

together with a pharmaceutically acceptable carrier or diluent.

According to a preferred embodiment of the present invention, the method further comprises the step of packaging and identifying the drug as having activity against headache, migraine, nausea and vomiting, as described above. The identification of the drug as an agent against headache, in particular against migraine or vomiting, is a new indication for derivatives of S-alkyl isothiouronium, which are known as hypertensive agents and have not previously been used to treat or alleviate symptoms of headache, migraine or nausea.

In another aspect of the present invention, there is provided a method of treating headache, migraine or nausea. The method corresponding to this aspect of the present invention is carried out by introducing to the patient a therapeutically effective amount of a compound of general formula (I):

where R ¹ represents a linear or branched, saturated or unsaturated alkylene, comprising from one to eight carbon atoms, optionally substituted by one or more substituents selected from the group consisting of halogen, primary or secondary amine, primary or secondary alcohol, or interrupted by one or more heteroatoms selected from the group consisting of O, N and S;

R ² , R ³ , R ⁴ and R ⁵ each independently represent hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkoxy, nitro, amino, cyano, sulfonyl, haloalkyl, carboaryloxy, carboalkylaryloxy, alkyl sulfoxide, arylsulfoxide, alkyl sulfone, arylsulfone, alkyl sulfate, arylsulfate, sulfonamide, thioalkyl optionally substituted with halogen;

представляет физиологически приемлемый анион;

represents a physiologically acceptable anion;

together with a pharmaceutically acceptable carrier or diluent.

In this regard, it should be noted that clinical trials, which are described in detail later in the examples section, evaluate the response of human patients and the beneficial effects of S-ethylisothiouronium diethylphosphate. Unexpectedly, these patients show a significant positive effect of this drug, which is administered during a migraine attack. The administered dose is significantly lower than the effective oral dose used to treat hypotension (which is usually about 100 mg). In addition, it was found that this drug is potent in reducing the symptoms of migraine in a relatively short period of time, on average about 45 minutes, when the patient is at the peak of a migraine attack.

In addition to eliminating acute headache, this drug also eliminates the unpleasant feeling of nausea, photophobia and improves impaired focus of vision. It is shown that this drug has a quick and prolonged effect. In addition, the fast type of action involves the rapid absorption of the drug. There are also no obvious side effects.

These results are extremely unexpected. In this regard, it is understood that recognized migraine medications act most rapidly when administered by the parenteral route. Also, regardless of the route of administration, therapeutic relief of migraines is often not obtained using recognized migraine medications. With oral administration, recognized migraine medications act much slower than with parenteral administration, so that pain relief, if achieved, may not occur within 2-3 hours after administration.

The term “therapeutically effective amount” or “therapeutically effective” as used in relation to the dosage of a drug refers to a dose that provides a specific pharmacological response for which the drug is administered to a sufficiently large number of patients requiring such treatment. A “therapeutically effective amount” may vary, for example, depending on the physical condition of the patient, the age of the patient, and the severity of the disease. It is emphasized that a headache caused by a migraine is not well understood, and the etiology of individual migraines is changing, which gives a response to specific medicines. Thus, the expression “a specific pharmacological response for which a drug is administered to a sufficiently large number of patients requiring such treatment” is a recognition that the “therapeutically effective amount” administered to a particular patient in a particular case does not always relieve a migraine attack or alleviate an acute headache pain caused by migraine, even if specialists consider this dose to be a “therapeutically effective amount”.

The expression "sustained action" in relation to S-ethylisothiouronium diethylphosphate refers to its pharmacokinetic half-life. In this regard, it should be noted that in the case histories described in the next section of the examples, a migraine attack is eliminated within minutes after drug administration and in the above cases no additional treatment is required.

A preliminary clinical trial found two other important points that relate to the “relapse” of headache and the side effects of currently available anti-migraine medications within a few hours of administration. Relapse of headache after successful initial treatment is another drawback of some of the currently available anti-migraine drugs. Indeed, after administering to the patient a dose of a known therapeutic agent in an amount effective for the initial treatment of a migraine attack, relief of migraine is observed, migraine symptoms appear again after a period of 1-8 hours after the first relief until 12-24 hours. Headache that occurs in the described the above circumstances, in different ways and interchangeably called "rebound", "recurrent", "recurring", "subsequent" or "secondary" headache. These terms do not contradict each other, it is not currently known whether this later headache is a continuation of the physiological chain of events that caused the initial headache, or a new headache due to another or repeated, but unrelated hidden pathology. It is also possible that after a headache there should be a reaction to therapeutic agents that first successfully act to treat the initial symptoms of migraine. The terms "ricochet", "recurrent", "recurring", "subsequent" or "secondary" (as defined below) are considered synonyms that are used without implying a mechanism or cause of a migraine headache.

According to the reports, this phenomenon is not observed when taking S-ethylisothiouronium diethylphosphate.

In this regard, it should be noted that migraine attacks are associated with the expansion of blood vessels in the head, and the relief of headache during migraines is associated, among other things, with the weakening of such expansion of blood vessels. As a side effect, anti-migraine agents can cause abnormal blood flow (either with expansion or narrowing of blood vessels). Thus, the astounding therapeutic effect of S-ethylisothiouronium diethylphosphate as an anti-migraine agent, together with the known ability to regulate abnormal blood flow, is a response to alleviate the symptoms of migraine without the side effects of known anti-migraine agents.

In addition, S-ethylisothiouronium diethylphosphate can be combined with another anti-migraine agent, such as an ergotamine derivative or a serotonergic agonist. Co-treatment requires a smaller amount of each drug, while adding S-ethylisothiouronium diethylphosphate to known therapeutic agents reduces the side effects of known drugs and provides suffering patients with initial relief in a few minutes.

As discussed previously, the compound is formulated for oral administration, injection, inhalation, or percutaneous administration.

For oral administration, tablets or capsules are used where the preferred dose is from 10 to 200 mg of the compound, preferably from 20 to 70 mg of the compound, and according to the clinical results, about 50 mg of the compound. Thus, a therapeutically effective amount of this compound is in the range of 0.1 to 3.0 mg / kg body weight, preferably 0.4 to 1.6 mg / kg body weight, more preferably 0.5 to 1, 2 mg / kg body weight.

The above ranges of therapeutically effective doses are selected so as to provide significant relief of migraine symptoms within 15-60 minutes after administration.

In a preferred embodiment of the present invention, administration of the S-alkylisothiouronium derivative is carried out during or after the onset of migraine.

Additional objectives, advantages, and new features of the present invention will be apparent to those skilled in the art after studying the following examples, which are not restrictive. In addition, each of the various examples and aspects of the present invention presented in the description and claimed in the claims finds experimental confirmation in the following examples.

EXAMPLES

We now turn to the following examples, which together with the above descriptions illustrate the invention, without limiting it.

Example 1

Clinical trial results for treating a migraine attack with Difetur for oral use (tablets)

Study protocol

Dose-increase research on the safety and efficacy of Difetur tablets for the treatment of an acute migraine attack.

1. The purpose of the study

The goal of the following research protocol is to evaluate the safety and potential effectiveness of Difetur tablets (S-ethylisothiouronium diethylphosphate) at increasing doses, ranging from 10 mg to 50 mg, in the treatment of a single acute migraine attack. The study is characterized as an open study on a selected group of patients classified according to IHS criteria as suffering from migraine-induced headaches with moderate to severe intensity, without aura. The study is carried out in accordance with established international criteria for assessing the safety and effectiveness of migraine treatment.

2. Research plan

This study is conducted as a study on 5 branches (groups). Only female patients classified as suffering from migraine without an aura according to IHS criteria are participating in this study. Each group includes ten patients with migraine who are treated during an acute migraine attack with Difetur tablets during hospitalization. The initial dose of Difetur is 10 mg (1 tablet), followed by a dose increase to 20 mg, 30 mg, 40 mg and 50 mg. The total number of patients participating in the study is 50. Patients are hospitalized and monitored for at least 4 hours to evaluate the safety, efficacy and possible side effects of Difetur.

3. Taking a medicine

In the first group, each of 10 patients takes an initial dose of 10 mg of the study drug in the form of one tablet. A dose of 50 mg is given in two tablets of 25 mg each. The tablets are individually packaged in blister packs and have a label indicating the drug as the study drug. Each dose is given to 10 patients with an increase in dose. The drug is swallowed with a glass of water under the supervision of a physician.

4. Evaluation of effectiveness

4.1 The primary goal of effectiveness is to reduce headaches

The severity of headache is assessed verbally on a 4-digit scale: strong (grade 4), moderate (grade 3), mild (grade 2), no pain (grade 1). Success is considered to be a reduction in the severity of headaches from severe or moderate (grade 3-4) to mild or no pain (grade 1-2).

4.2 Secondary exposure targets - reduction of nausea, vomiting and sensitivity to light and sounds

Assess their presence, absence or disappearance, as documented by patients.

Research results

Table 1
A summary of the results of treating a headache caused by a migraine (treatment begins during a migraine attack) No. Dose ¹ (mg) Percentage of patients benefiting from treatment ² Time to effect ³ (min) one 10 0 - 2 twenty 70 43 3 thirty 70 58

¹ Dose of Difetur for Treatment

² Headache relief is considered effective if the patient reports a decrease in the severity of the headache from severe or moderate (grade 3-4) to mild or no pain (grade 1-2). [Headache severity scale: 1 - no pain, 2 - weak, 3 - moderate, 4 - severe pain].

³ Time after swallowing the medication, after which the patient reports a decrease in headache to a score of 1-2.

It has been unexpectedly discovered that low doses of Difetur, ineffective or less effective in relieving severe headaches caused by migraines, are effective in reducing or eliminating the symptoms of nausea. In addition, it has been observed that the time interval to alleviate nausea is reported to be shorter than the interval recorded before the reduction of severe headache. This reinforces the use of this drug as an antiemetic.

table 2
Summary of treatment for vomiting during a migraine attack) No. Dose ⁴ (mg) Percentage of patients benefiting from treatment ⁵ Time to effect ⁶ (min) one 10 70 28 2 twenty one hundred 25 3 thirty one hundred 29th

⁴ Dose of Difetur for Treatment

⁵ Percentage of patients who experience a positive antiemetic response to Difetur.

⁶ Time after ingestion of the medication through which the patient reports the end of vomiting

Example 2

Multiple doses of Difetur to relieve migraine headache

Medical history 1

The previous medical history: the patient smokes, a woman of 30 years old was first diagnosed as suffering from classical migraine at the age of 17. Other than that, she is completely healthy. Two years ago and earlier, the frequency of migraine attacks was seven cases per month. Over the past two years, with little or no success, she has been treated with various types of recognized medications. Due to the lack of response to drug treatment during migraine attacks, she tried alternative methods of drug treatment.

As a result of treatment with S-ethylisothiouronium diethylphosphate, the frequency of migraine attacks she suffered from decreased to about three per month. In addition, the nature of migraine attacks has changed, they have become weaker. The reported effect of treatment with S-ethylisothiouronium diethylphosphate on migraine pain is that it has become significantly weaker. Currently, the patient experiences only about two migraine attacks per month, mainly in the premenstrual period, in hot weather or with a sharp change in weather. Migraine attacks during the premenstrual period are usually longer and more acute than other migraine attacks. The duration of each attack is 24-72 hours.

Past medical treatment: Medications used by the patient before alternative treatment options include: Temigran, Migraleve, Imitrex and Zoming. These treatments were interrupted due to various severe side effects, including hand tremors, trembling, dry mouth, nausea, and vomiting.

Diethyl Phosphate Treatment for S-Ethylisothiouronium

First attack. The patient suffered from an acute attack of migraine, which lasted for 72 hours. Despite taking the prescribed medication every two hours, the intensity of pain caused by migraine did not change. The next day, the patient took a single dose of 50 mg of S-ethylisothiouronium diethylphosphate (2 tablets of 25 mg each). The medicine was taken on an empty stomach; the patient did not eat or drink anything before swallowing the medicine. Over the next 10-15 minutes after ingestion, the pain suddenly disappeared, like other symptoms that appeared during a migraine attack.

The second attack (three weeks later). The second migraine attack began at night. The next day, the patient again took 2 tablets of S-ethylisothiouronium diethylphosphate (50 mg). This time, the pill was taken at the peak of a migraine attack after eating. Within 20 minutes, the headache subsided, the patient was able to focus his eyes, and photophobia disappeared. A mild headache was present, but its intensity decreased. Three hours later, the patient took two more tablets of S-ethylisothiouronium diethylphosphate (50 mg). After 15 minutes, the pain caused by migraine disappeared.

The third attack (two and a half weeks after the second attack). A migraine attack began on the way to work. One hour after the onset and at the peak of a migraine attack, the patient took 2 tablets of S-ethylisothiouronium diethylphosphate (25 mg each). The medicine was taken on an empty stomach. After 11 minutes, the symptoms of migraine disappeared.

Side effects. No side effects were observed after taking S-ethylisothiouronium diethylphosphate.

Example 2

Medical history 2

Previous medical history: the patient does not smoke, a 34-year-old woman suffering from migraine attacks in the last two years. The frequency of migraine attacks once a month in the premenstrual period. The pain appeared in the temples, sinuses and spread down to the lower jaw. The duration of photophobia was approximately 48 hours. Until now, the patient has not applied specific medical treatment and usually used well-known analgesics.

Past medical treatment: Well-known pain relievers (analgesics).

Diethyl Phosphate Treatment for S-Ethylisothiouronium

First attack. An acute migraine attack began in the morning, during the day the symptoms intensified. Before noon, the patient took one tablet of S-ethylisothiouronium diethylphosphate (25 mg). There was no significant change in pain caused by migraine. Two hours later, the patient took two more tablets of S-ethylisothiouronium diethylphosphate (each 25 mg). Ten minutes later, the pain caused by migraine disappeared.

Second attack (approximately four weeks after the first attack). A migraine attack began as a result of very hot weather conditions. The intensity of this attack was higher than regular migraine attacks. In the morning, the patient took 2 tablets of S-ethylisothiouronium diethylphosphate (50 mg), which were taken on an empty stomach. Within 20 minutes after taking S-ethylisothiouronium diethylphosphate, there was a significant relief of migraine-induced pain. Fifteen minutes later, the pain disappeared. On the same afternoon, the patient experienced mild pain. At this point, the patient himself took the analgesic and the pain disappeared.

Side effects. The curator did not find any side effects after taking 25 or 50 mg of S-ethylisothiouronium diethyl phosphate.

The discussion of the results

Both medical histories and especially the first case show an unexpected significant positive effect of S-ethylisothiouronium diethylphosphate taken with a migraine attack. The effective dose is about half the effective dose used in the treatment of hypotension (which is approximately 50-100 mg). In addition, it was found that the drug is potent in eliminating the symptoms of migraine for a period of less than 20 minutes, when the patient is at the peak of a migraine attack. In addition to eliminating acute headache, the medicine also eliminates nausea and an unpleasant sensation of photophobia and corrects impaired focus of vision. The shock effect of the drug is repeated three times in the first patient and twice in the second patient. This drug seems to be more effective if taken on an empty stomach.

Thus, we can conclude that S-ethylisothiouronium diethylphosphate is a potent drug for the treatment and alleviation of migraine symptoms. It has a fast action, has a low effective dose and, according to the described medical histories, does not give side effects.

Example 3

Antiemetic in animal studies

The effect of the test compounds on vomiting on ferrets was studied and summarized according to the general method described by Florezyk, Schurig and Bradnet (Cancer Treatment Report, 1982, 66 (1), 187-9). The test compound and cisplatin are prepared and administered in normal saline.

a) Control - without test compound

In a group of 6 male ferrets weighing 1.5-2 kg, vomiting is induced by intravenous administration of cisplatin at a dose of 10 mg / kg. Vomiting begins 30-75 minutes after injection and over a period of 2 hours the number of cases of vomiting / urging (seizures) is 30-60 (an average of 40 cases of vomiting / urging in 2 hours). Behavioral changes characteristic of vomiting are also noted.

b) With test compound

A group of 6 male ferrets weighing 1.5-2 kg is administered the test compound intravenously in doses of 0.01, 0.1 and 1 mg / kg immediately before the administration of cisplatin, as described above. Animals are observed for 3 hours.

The effect of the test compound on vomiting is also evaluated after intraperitoneal administration using a procedure similar to that described above. Thus, cisplatin is administered intraperitoneally to a group of male ferrets at a dose of 5-10 mg / kg and the time of onset of vomiting and the number of episodes of vomiting are recorded. In the second group, male ferrets are given the test compound at a dose of 1 mg / kg intraperitoneally 30 minutes before and 1 hour after intraperitoneal administration of cisplatin.

Example 4

Clinical trials in the treatment of a migraine attack by intravenous administration of Difetur

1. Summary of the study

The goal of the following research protocol is to evaluate the safety and potential efficacy of a 10% Difetur injection solution at a dose of 0.6 mg / kg in the treatment of a single acute migraine attack. The study is characterized as an open study on a selected group of patients classified according to IHS criteria as suffering from moderate or severe intensity migraine-induced headaches without aura. The study is carried out in accordance with established international criteria for assessing the safety and effectiveness of migraine treatment.

2. Drug Administration

Difetur is presented as a 10% (100 mg / ml) solution in a 1 ml ampoule. Before treatment, it is dissolved in 100 ml of saline in an intravenous device. The dose of Difetur is 0.6 mg / kg when administered via a dropper for 10 minutes.

3. Evaluation of effectiveness

The severity of headache is assessed verbally on a 5-digit scale: very strong (grade 4), strong (grade 3), moderate (grade 2), mild (grade 1), no pain (grade 0). Success is considered to be a reduction in the severity of the headache from very strong, strong or moderate (score 4-2) to mild or no pain (score 1-0).

4. Research results

This study included 13 patients with headaches of varying severity. With the exception of one patient who did not experience a reduction in headache, all the others experienced significant headache relief. Efficiency and time to effect are presented in table 3.

Table 3
The results of treatment of headache caused by migraine with IV treatment Headache score Patient count Percentage of patients who benefited from treatment ¹ The average time to effect ² (min) four one one hundred% fifty 3 four one hundred% 25.5 2 8 87% 13.7

¹ Success is considered to be the relief of headache severity from very strong, strong or moderate (grade 4-2) to mild or no pain (grade 1-0).

² Time after the start of treatment, after which the patient reports a decrease in headache until a score of 1-0.

Although the invention has been described in connection with its specific variations, it is obvious that many alternatives, modifications and variations are understood by those skilled in the art. Therefore, it is understood that all alternatives, modifications, and variations are embraced that are consistent with the spirit and wide scope of the appended claims. All publications, patents and patent applications referred to in the description are included in the description in their entirety by reference, to the same extent as if each individual publication, patent or patent application were specifically and individually indicated for inclusion by reference . In addition, citing or identifying any link in this application does not constitute recognition that such a link is suitable as a prototype of the present invention.

Claims (48)

1. A pharmaceutical composition for treating headache, migraine, nausea or vomiting, comprising, as an active ingredient, a compound of the general formula

where R ¹ , R ² , R ³ , R ⁴ each independently represents hydrogen and R ⁵ represents a linear or branched C1-C4 alkyl;

represents a physiologically acceptable anion, together with a pharmaceutically acceptable carrier or diluent. 2. The pharmaceutical composition according to claim 1, wherein said physiologically acceptable anion is selected from the group consisting of an anion derived from phosphoric acid, phosphoric acid ester, phosphoric acid amide, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bitartrate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate, isothionate, lactate, maleate, methanesulfonate, nicotinate, 2-nephthalsulfonate palmoate, pectinate, 3-phenylpropionate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, chloride, bromide, iodide and undecanoate. 3. The pharmaceutical composition according to claim 1, which is packaged and designated as having activity against headache, migraine, nausea or vomiting. 4. The pharmaceutical composition according to claim 1, where the compound is selected from the group including S-methylisothiouronium methylphosphite; S-methylisothiouronium dimethyl phosphate; S-ethyl isothiouronium metaphosphate; S-ethylisothiouronium ethyl phosphite; S-ethylisothiouronium diethyl phosphate; S-propylisothiouronium propylphosphite; S-isopropylisothiouronium metaphosphate; S-isopropylisothiouronium isopropyl phosphite; S-butylisothiouronium dibutyl phosphate and S-isobutyl isothiouronium isobutyl phosphite. 5. The pharmaceutical composition according to claim 1, prepared for oral administration, administration by injection, inhalation, through the mucous membrane or percutaneous administration. 6. The pharmaceutical composition according to claim 5, prepared in the form of tablets, capsules or ampoules for injection. 7. The pharmaceutical composition according to claim 6, where each of these tablets or capsules contains from 10 to 300 mg of this compound. 8. The pharmaceutical composition according to claim 6, where each of these tablets, capsules or ampoules contains from 20 to 200 mg of this compound. 9. The pharmaceutical composition according to claim 6, where each of these tablets, capsules or ampoules contains from 40 to 80 mg of this compound. 10. Use for the manufacture of a medicament for the treatment of headache, migraine, nausea or vomiting, a compound of the general formula

where R ¹ , R ² , R ³ , R ⁴ each independently represents hydrogen and R ⁵ represents a linear or branched C1-C4 alkyl;

represents a physiologically acceptable anion, together with a pharmaceutically acceptable carrier or diluent. 11. The use of claim 10, wherein said physiologically acceptable anion is selected from the group consisting of an anion derived from phosphoric acid, phosphoric acid ester, phosphoric acid amide, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bitartrate, bisulfate , butyrate, camphorite, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, 2-hydroxyethanesulfonate, isothionate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate pene palto, pionate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, chloride, bromide, iodide and undecanoate. 12. The use of claim 10, further comprising the steps of packaging the drug and identifying the drug as having activity against headache, migraine, nausea, or vomiting. 13. The use of claim 10, where the compound is selected from the group including S-methylisothiouronium methylphosphite; S-methylisothiourononium di methylphosphate; S-ethyl isothiouronium metaphosphate; S-ethylisothiouronium ethyl phosphite; S-ethylisothiouronium diethyl phosphate; S-propylisothiouronium propylphosphite; S-isopropylisothiouronium metaphosphate; S-isopropylisothiouronium isopropyl phosphite; S-butylisothiouronium dibutyl phosphate and S-isobutyl isothiouronium isobutyl phosphite. 14. The use of claim 10, where the anti-migraine drug is prepared for oral administration, injection, inhalation, through the mucous membrane or percutaneous administration. 15. The application of clause 14, where the drug is prepared in the form of tablets, capsules or ampoules. 16. The application of clause 15, where each of these tablets, capsules or ampoules contains from 10 to 300 mg of the compounds. 17. The application of clause 15, where each of these tablets, capsules or ampoules contains from 20 to 200 mg of the compounds. 18. The application of clause 15, where each of these tablets, capsules or ampoules contains from 40 to 80 mg of the indicated compound. 19. A method of treating a headache or migraine, comprising the step of administering to the patient a therapeutically effective amount of a compound of general formula

where R ¹ , R ² , R ³ , R ⁴ each independently represents hydrogen and R ⁵ represents a linear or branched C1-C4 alkyl;

represents a physiologically acceptable anion, together with a pharmaceutically acceptable carrier or diluent. 20. The method according to claim 19, where the specified physiologically acceptable anion is selected from the group comprising an anion derived from phosphoric acid, phosphoric acid ester, phosphoric acid amide, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bitartarate, bisulfate butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulphate, heptanoate, hexanoate, fumarate, 2-hydroxyethanesulfonate, isothionate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate phenyl palmo, palate at, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, chloride, bromide, iodide and undecanoate. 21. The method according to claim 19, where the compound is selected from the group including S-methylisothiouronium methylphosphite; S-methylisothiouronium dimethyl phosphate; S-ethyl isothiouronium metaphosphate; S-ethylisothiouronium ethyl phosphite; S-ethylisothiouronium diethyl phosphate; S-propylisothiouronium propylphosphite; S-isopropylisothiouronium metaphosphate; S-isopropylisothiouronium isopropyl phosphite; S-butylisothiouronium dibutyl phosphate and S-isobutyl isothiouronium isobutyl phosphite. 22. The method according to claim 19, where the compound is prepared for oral administration, administration by injection, inhalation, through the mucous membrane or percutaneous administration. 23. The method according to item 22, where the compound is prepared in the form of tablets, capsules or ampoules for injection. 24. The method according to item 23, where each of these tablets, capsules or ampoules contains from 10 to 300 mg of the specified compound. 25. The method according to item 23, where each of these tablets, capsules or ampoules contains from 20 to 200 mg of the specified compound. 26. The method according to item 23, where each of these tablets, capsules or ampoules contains from 30 to 80 mg of this compound. 27. The method according to claim 19, where the specified therapeutically effective amount is from 0.1 to 3 mg / kg of body weight. 28. The method according to claim 19, where the specified therapeutically effective amount is from 0.4 to 1.6 mg / kg of body weight. 29. The method according to claim 19, where the specified therapeutically effective amount is from 0.5 to 1.2 mg / kg of body weight. 30. The method according to item 21, where the specified compound is S-ethylisothiouronium diethylphosphate. 31. The method according to claim 19, where the specified therapeutically effective amount is selected so that a significant relief of migraine symptoms is observed for a period of less than one hour after administration. 32. The method according to claim 19, where the specified stage of the introduction of the compounds is carried out after the onset of headache or migraine. 33. The method according to claim 19, where the specified stage of the introduction of the compounds is carried out simultaneously with the onset of headache or migraine. 34. A method of preventing or alleviating nausea or vomiting, comprising the step of administering to the patient a therapeutically effective amount of a compound of general formula

where R ¹ , R ² , R ³ , R ⁴ each independently represents hydrogen and R ⁵ represents a linear or branched C1-C4 alkyl;

represents a physiologically acceptable anion, together with a pharmaceutically acceptable carrier or diluent. 35. The method according to clause 34, where the specified physiologically acceptable anion is selected from the group comprising an anion derived from phosphoric acid, phosphoric acid ester, phosphoric acid amide, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bitartrate, bisulfate butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulphate, heptanoate, hexanoate, fumarate, 2-hydroxyethanesulfonate, isothionate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate phenyl palmo, palate at, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, chloride, bromide, iodide and undecanoate. 36. The method according to clause 34, where the compound is selected from the group including S-methylisothiouronium methylphosphite; S-methylisothiouronium dimethyl phosphate; S-ethyl isothiouronium metaphosphate; S-ethylisothiouronium ethyl phosphite; S-ethylisothiouronium diethyl phosphate; S-propylisothiouronium propylphosphite; S-isopropylisothiouronium metaphosphate; S-isopropylisothiouronium isopropyl phosphite; S-butylisothiouronium dibutyl phosphate and S-isobutyl isothiouronium isobutyl phosphite. 37. The method according to clause 34, where the compound is prepared for oral administration, administration by injection, inhalation, through the mucous membrane or percutaneous administration. 38. The method according to clause 34, where the compound is prepared in the form of tablets, capsules or ampoules. 39. The method according to § 38, where each of these tablets, capsules or ampoules contains from 10 to 300 mg of the compound. 40. The method according to § 38, where each of these tablets, capsules or ampoules contains from 20 to 200 mg of the compound. 41. The method according to § 38, where each of these tablets, capsules or ampoules contains from 30 to 80 mg of this compound. 42. The method according to clause 34, where the specified therapeutically effective amount is from 0.1 to 3 mg / kg of body weight. 43. The method according to clause 34, where the specified therapeutically effective amount is from 0.4 to 1.6 mg / kg of body weight. 44. The method according to clause 34, where the specified therapeutically effective amount is from 0.5 to 1.2 mg / kg of body weight. 45. The method according to clause 36, where the specified compound is S-ethylisothiouronium diethyl phosphate. 46. The method according to clause 34, where the specified nausea or vomiting associated with anti-cancer therapy. 47. The method according to item 46, where the specified compound is administered together or before anticancer therapy. 48. The method according to item 46, where the anticancer therapy is selected from the group comprising chemotherapy or radiotherapy.