UA28715U - Method for treating headache or migraine - Google Patents

Abstract

A method for treating headache or migraine is effective in preventing the vomiting in migraine or other conditions as well as for alleviating other symptoms of migraine including phonophobia and photophobia.

Description

Description of the invention

The present utility model relates to methods of preventing or treating headache, including but not limited to migraine, 2 more specifically for alleviating the symptoms of migraine, including but not limited to headache.

The term "headache" is used to describe a diverse set of symptoms that vary in intensity from mild discomfort to a very severe syndrome known as a "migraine."

While migraine is the most severe and debilitating form of headache, there are several other 710 types of headache that warrant 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, usually called a hangover. Symptoms such as headache, fever, chills, nausea, muscle and nerve pain, lethargy, and others often appear in the syndrome known as a hangover.

While not life-threatening, PMS and hangovers can be very unpleasant as well as harmful 12 at work and at home. Currently, most common treatments for these conditions include self-medication of NSAIDs (nonsteroidal anti-inflammatory drugs), pain relievers, and other prescription and over-the-counter medications.

The following publications represent the preliminary level of knowledge concerning headaches in general and migraines, in particular, their causes and methods of their treatment: 1. Saroriapso "Ap omegmiem/u oi She aiadpovziz apia rpagtasoiodis (heaitepi oi tidgaiiple" Mauo Siip. Rgos. (1996) 71:1055-1066. 2. Sopep "Midgaviple Neadasne apa (She Mapadei Sage Rogtshiagu) Yugidvs Vepeii Tgepiaz (1996) 8(8) 28-30, 33-34, 41.

Z. Oiatopa, "for Mop-e(egoida! Apii-Ipyattaigu Adepiv Name a Koie ip (Pe Tgeaytepi oi Midgaiipe

Neadaspev" Ogydv (1989) 37:755-760. - 4. KiIarreg, "Tomjaga a viapadaga agad togtiyagu Tog (Pe igeaitepi oi pPeadasne" Neadasne (1995) Arg., 225-227. 5. Kitag, "Kesepi admapsevz ip ( te askie tapadetepi oi tidgaiipe apa siivieg peadaspev" doigpa! oi Sepegai

Ipiegpa! Meadisipe (1994) 9:339-348. b. Manipem, "Zegoiopip 10 (5-NT10) adopiviv apa oiyeg adepiv ip askie tidgaiipe" Admapsez ip Neadasne, o (1997) 15 (13: 61-81. "- 7. Rgadaiiieg, "Tgeaitepi Kemiem: Mop-5(egoii Apii - Ipattayugu YuOgodv ip (Pe Tgeaytepi apa Iopd-Tegt

Rgemepiyop oi Midgaipe AbasKe" Neadasne (1988) 28: 550-557. in 8. Rguze-RpNyirve, "Scydeipev og (She diadpoziv apa tapadetepi oi tidgaipe ip siipisai rgasise" Sap. so

Honey. Azzos. . (1997) 156 (9): 1273-1287. 3o 9. UMiKipvop, "Midgaipe apa siivieg peadaspe (peiig tapadetepi m/yy zitayigiriap: a sgyisa! gemiemzhm oi (Pe sch sitepi siipisa! ehregiepse) Serpaiidia (1995) 15:337-357.

Presented below is the current knowledge about migraines and their treatment.

Symptoms and diagnosis of migraine. "

Migraine is a severe episodic headache, characterized by a one-sided intense throbbing headache, nausea, vomiting, the appearance of sparks of light, the appearance of rainbow colors, empty with spots in the field of vision and other premonitions and sensitivity to light and sounds (Agzop, E. YuOamiy, M.O.

From" Eaiyug-ip-Spieyi, "Mauo Siipis Gatiu Neaky Vook" 1994. pp. 502-503).

A migraine refers to a group of symptoms that can occur together. The most well-known is a disabling headache, on one side or the whole 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 strong and often a person with a migraine must stay in

Ge | the bed Nutritional, emotional, hormonal, and environmental factors can trigger an attack.

In practice, there are two types of migraine. The most common type is called migraine without aura (a total of 7 migraines) and it covers 8,595 of all sufferers. The second, most common type, called migraine with aura -k 70 (classic migraine), covers most of the remaining 15,956 sufferers. Aura is a disorder of the nervous system that often precedes a headache. Migraine sufferers sometimes get a warning signal before an attack. Some experience an "aura," a disturbance in brain function that occurs twenty to thirty minutes before the attack.

They are characterized by visual disturbances, such as flashes of light and blurred vision, or a feeling of pins and needles in the body, acting on one limb or on one side. These disturbances are usually short-lived and almost invariably pass without leaving long-term effects. Others who suffer from migraines feel a "harbinger" that appears several hours or even a day before the onset of the attack. Symptoms may include yawning, fatigue, mood changes, food cravings, and sensitivity to light (photophobia), sound (phonophobia), touch, and/or smells. In most of those who have a harbinger, the type and location of the headache remains the same with each migraine attack. Other common symptoms include numbness or tingling around the lips or hands, hallucinations, loss of speech, symptoms of depression, irritability (some people seek solitude in a dark room), anxiety, nausea, or loss of appetite, which occur in about 2,095 migraine sufferers.

The same percentage of migraine sufferers lose vision in specific areas (called a blind spot or scotoma) or see uneven, flickering, or flashing lights. Less often, images are distorted, for example 62 objects appear smaller or larger than they are.

Migraine is a chronic incurable disorder. There are no laboratory tests that help diagnose migraine, but it is usually easily identified by a certain type of headache. Headaches are not life-threatening, and there is no evidence that they lead to other disorders (agsop, E. Yuamidy, M.O.

Eaiyug-ip-Spieyi, "Mauo Siipis Gatyu Neaiky Vook" 1994. rr. 502-503). The public health importance of migraine is often overlooked, presumably because of its episodic nature and low mortality from the disorder. However, migraine is often incapacitating, causing a significant blow to social activity and work.

Prevalence.

The prevalence of migraine is relatively high and is said to be approximately 695 in the male population and 1895 in 7/0 of the female population. Predominance of migraine in women appears after puberty; in many patients, migraines appear during menstruation, and during pregnancy there is an improvement. It has been determined that in the US alone, approximately 35 million people suffer from migraines. Some people may have migraine attacks every week; others may have less than one episode per year (Shiyyi, N. M/ipieg, M. O., "API-Mezh Triga Eyop

Sotrieie Scide o butrioptzv, PShpevzz 5 Zygdegu" UshShu 1995. p. 425).

Commonly accepted treatment of migraine.

There are several approved therapeutic drugs for migraine. Treatment for many patients with recurrent migraine usually includes simple analgesics (usually in combination with an antiemetic, but such agents are of limited value), nonsteroidal anti-inflammatory agents, or specific agents such as ergotamines or triptans. While only modestly effective, traditional practice recognizes that migraine medications are thought to initially relieve migraines primarily by causing vasoconstriction. Unfortunately, this traditional practice recognizes that migraine medications are accompanied by significant negative side effects, which are associated with excessive vasoactivity in areas of the body that are not included in the pathogenesis of migraine. This remote vasoactivity represents an effect that has no therapeutic benefit for the treatment of migraine. Such vasoactive drugs are strictly contraindicated in patients with cardiovascular disease or at risk of cardiovascular disease, such as hypertension, coronary artery disease, or peripheral vascular disease. Other known significant side effects are chest pain or pressure, flushing, generalized ringing in the ears, nausea, vomiting, leg and arm pain, asthenia, drowsiness, and dizziness. Preventive agents such as beta-blockers, tricyclic antidepressants, and sodium valproate can reduce, but not eliminate, migraine attacks in some patients. For other chronic migraine sufferers and those who cannot tolerate the side effects of existing medications, there are no conventional pharmaceuticals that demonstrate a therapeutic effect without severe side effects. Thus, -- there remains a greater need for drugs specific to migraine. M

OTC analgesics: In some forms of migraine, some patients have been found to experience total or partial relief with over-the-counter analgesics such as acetaminophen, aspirin, co-ibuprofen, and other nonsteroidal anti-inflammatory agents, including naproxen and naproxen sodium. However, these agents, acceptable on their own, are rarely effective in providing complete and rapid relief of all migraine symptoms, especially if the attack symptoms already include nausea and vomiting. In addition, the onset of their action is delayed, so that relief sometimes does not occur for at least several hours.

Ergotamine drugs: One known way to treat migraines is to take compounds that have 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. disease, coronary heart disease, hypertension, impaired liver or kidney function, severe pruritus, or sepsis. They are also contraindicated for pregnant women or those who are about to

Become pregnant. Nausea and vomiting have been reported in 1095 patients receiving therapeutic doses of ergotamine. Acute ergotism is a side effect of ergot preparations, which is extremely difficult and is characterized by severe central and peripheral vasoconstriction, which sometimes leads to amputation of affected limbs and/or fingers, nausea, vomiting, diarrhea, colic, headache, dizziness, - And paresthesias and, perhaps, convulsive attacks. Chronic ergotism is characterized by intermittent lameness, muscle pain, numbness, and cold extremities, as well as other gastrointestinal and central nervous system (CNS) side effects. There are treatments that include co-administration of high doses of caffeine with horn preparations or other pharmacological agents. Additionally, cloves and caffeine are potentially addictive with well-documented withdrawal symptoms.

Triptan drugs (serotonin agonists): Another treatment option is the administration of more than two new therapeutic agents known as serotonin agonists or 5-hydroxytryptamine (5-HT) agonists. The first of this family, sumatriptan, is without a doubt a significant improvement in migraine therapy. Sumatriptan succinate is sold under the trademark IMITKEH by SiIaho UUesote Ips. Despite the applicability of sumatriptan in the treatment of migraine, it has some limitations, such as low oral bioavailability, frequent headache recurrences, and contraindications for patients with coronary artery disease.

The main mechanism of action of triptans in migraine is narrowing of expanded cranial extracerebral blood vessels. In addition, triptans can reduce the release of neuropeptides and transudation of plasma proteins through dural vessels and centrally inhibit impulse conduction within the trigeminovascular system. 65 In general, migraine care 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 suspending or prophylactic treatment for such migraines. Additional complications include the common use of drugs that, with long-term use, cause addiction, such as the clove alkaloid - ergotamine. Another important consideration is that with conventional use, more effective anti-migraine agents, such as ergot preparations, methysergide, with long-term use produce severe side effects that limit their use.

Thus, there is a need for an effective medicament for the relief or treatment of migraine symptoms, which can be administered either before an attack, such as in the aura phase, or during an attack, so as to rapidly relieve migraine symptoms during an attack, and which does not produce side effects effects

Summary of useful model. 70 Incidentally, 5-alkylisothysuronium salts, known as hypertensive agents, have also been found to be highly effective in relieving headache in general and migraine symptoms in particular. Migraine patients were successfully treated with 5-ethylisothiouronium diethyl phosphate at doses unexpectedly lower than those required for antihypertensive use. Treatment started at the peak of a migraine attack consistently shows relief over the course of two weeks. after taking medication. In some cases, significant improvement is reported within about 15 minutes.

Thus, for the treatment of headaches and migraines, a pharmaceutical composition is presented, which includes as an active ingredient a compound of the general formula I:

And FoS-8 sho

Kk -- x ra

Formula (I) where B" represents a linear or branched, saturated or unsaturated alkylene containing 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 isO, M and 5;

In, 83, in and 2? each independently represents hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkyl, nitro, amino, cyano, sulfonyl, haloalkyl, -carboaryloxy , carboalkyparyloxy, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, alkyl sulfate, aryl sulfate, sulfonamide, thialkyl, optionally substituted with halogen;

Av represents a physiologically acceptable anion; together with a pharmaceutically acceptable carrier or diluent. with

A physiologically acceptable anion is an anion derived from a phosphorus-containing acid, more preferably a group consisting of an anion derived from a complex ester or amide of phosphoric acid, most preferably an anion derived from a mono- or dialkyl ester of a phosphorus-containing acid. "

Treatment of a patient suffering from a headache or migraine is provided by the administration of a pharmaceutical composition that includes a therapeutically effective amount of a compound of the general formula (1): - c ve

Kk ;z» ei -M ra

And Fos-8 --" 5 yu x ra shki Formula (I) - where VE! represents a linear or branched, saturated or unsaturated alkylene containing from one to 20 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 sl alcohol, or interrupted by one or more heteroatoms selected from the group consisting of isO, M and 5;

In, 83, in and 2? each independently represents 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, c carboaryloxy, carboalkylaryloxy, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfate, arylsulfate, sulfonamide, thialkyl, optionally substituted with halogen;

Av represents a physiologically acceptable anion.

The process of obtaining a medicinal product from a headache or migraine includes the stage of mixing as an active ingredient the compound of the general formula (1): b5 e5 c --- h5yzhyx 7 c! - Oh well

A -Sh-eoS- 8 and in--kh« x ra

Formula (I) where B! represents a linear or branched, saturated or unsaturated alkylene containing 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 zo, M and 5; 22, 3, in Her Co each independently represents hydrogen, hydroxy, linear or branched lower alkyl, 75 linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkyloxy, nitro, amino, cyano , sulfonyl, haloalkyl, carboaryloxy, carboalkylaryloxy, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, alkyl sulfate, aryl sulfate, sulfonamide, thialkyl, optionally substituted with halogen;

Av represents a physiologically acceptable anion; with a pharmaceutically acceptable carrier or diluent.

According to the features of other variants of this useful model, the physiologically acceptable anion is selected from the group consisting of the anion of a phosphoric acid, a phosphoric acid ester, a phosphoric acid amide, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bitartrate, bisulfate, butyrate, camphorate ) tartrate, thiocyanate, glutamate, bicarbonate, para-toluenesulfonate, chloride, bromide, iodide, and undecanoate.

According to the below-described, accepted best variants of this useful model, the physiologically acceptable anion is an anion of a phosphorus-containing acid, more preferably a group consisting of anions of a phosphoric acid ester or amide, most preferably an anion of a mono- or dialkyl ester of a phosphorus-containing acid.

According to the features of other options, the medicine is packaged and identified as having and - activity against headache or migraine. co

According to features of other options, the compound is selected from the group including:

Z-methylisothiouronium methyl phosphite; with

Z-methylisothiouronium dimethyl phosphate;

Z-ethylisotisouronium metaphosphate;

Z-ethylisothiouronium ethyl phosphite; "

Z-ethylisotisuronium diethyl phosphate;

Z-propylisothiouronium propyl phosphite; t c z-isopropylisothiouronium metaphosphate; h z-isopropylisothiouronium isopropyl phosphite; » Z-butylisothiouronium dibutyl phosphate;

C-isobutypizotisuronium isobutyl phosphite.

According to the features of other options, the drug against headache or migraine is made for co-oral or parenteral administration. Among drugs for parenteral methods of administration, especially the best drugs are suitable for injection, sublingual, transdermal administration, administration through the mucous membrane or by inhalation. - According to the indications of other options, the anti-migraine medicine is made in the form of tablets or capsules. -oUu 70 According to the features of other variants, each tablet or capsule includes from 10 to 300 mg of the compound.

According to the features of other options, each tablet or capsule includes from 20 to 200 mg of the compound. According to the features of other variants, each tablet or capsule includes from 30 to 8Omg of the compound.

The drug must be packaged and identified as having activity against headache, migraine, nausea or vomiting. 22 According to preferred embodiments, the therapeutically effective amount is from 0.1 to Zmg/kg of body weight. c According to other options, the therapeutically effective amount is from 0.4 to 1.bmg/kg of body weight.

According to other most acceptable options, the therapeutically effective amount is from 0.5 to 1.2 mg/kg of body weight.

According to the indications of other options, the therapeutically effective amount is chosen in such a way that during the 60 period of the smaller bOhv. after administration, there was a significant relief of migraine symptoms.

In some preferred embodiments, the compound is administered after the onset of headache symptoms, particularly migraine.

According to other options, the compound is taken during an attack of a headache, in particular, a migraine.

Of course, because migraines represent the most severe form of headache, the described treatment 65 is also suitable for other types of headache and nausea, including, but not limited to, PMS or hangover-related headaches and nausea. It is particularly suitable due to the minor side effects,

observed in people using the method of this useful model.

This useful model successfully overcomes the shortcomings of currently known drugs, providing an effective compound for the treatment and/or relief of headache symptoms, in particular migraine. This compound has no apparent side effects and has been shown to be potent at low doses and to provide therapeutic/relieving effects over a short period of time compared to currently marketed drugs.

Description of the best options.

This utility model relates to the use of 5-alkylisothiouronium derivatives for the treatment of headache, in particular migraine. The compositions of this utility model are effective in preventing or alleviating vomiting associated with migraine or other medical conditions, as well as other symptoms of migraine, including phonophobia and photophobia. These compounds were previously known to 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 variant of this useful model, it should be understood that this useful model is not limited in its application to the details specified in the further description or /5 presented in the "Examples" section. This utility model may have other variants or may be implemented or implemented in other ways. It is also worth understanding the phraseology used here. and terminology are for descriptive purposes and should not be construed as limiting.

As used here, the term "migraine" is understood in a broad sense to include a type of headache characterized by an unusually severe, unilateral throbbing headache lasting 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 a preceding "aura" and visual photophobia (eg, visual impairment).

According to one aspect of this utility model, there is provided a headache or migraine medication comprising as an active ingredient a compound of general formula (1): e5

A - 5 4 and in! - oh

А -Щ-еоС- 8 2nd x va yuyu where B" represents a linear or branched, saturated or unsaturated alkylene, which includes from one to eight carbon atoms, optionally substituted by one or more substituents selected from the group that - consists of a halogen, a primary or secondary amine, a primary or secondary alcohol, or interrupted by one or more heteroatoms selected from the group consisting of isO, Mi 5; so 822, 83, B and B, each independently representing hydrogen, hydroxy, linear or branched lower alkyl, es! linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkyl, nitro, amino, cyano, sulfonyl, haloalkyl, carboaryloxy, carboalkylaryloxy, alkylsulfoxide, arylsulfoxide, alkylsulfone , aryl sulfone, " alkyl sulfate, aryl sulfate, sulfonamide, thialkyl, optionally substituted with halogen;

Av represents a physiologically acceptable anion; t c together with a pharmaceutically acceptable carrier or diluent. h» Preferably, the physiologically acceptable anion is derived, without limitation, from a phosphorus-containing acid, the group "containing anion derived from a phosphorus-containing acid, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bitartrate, bisulfate, butyrate, camphorate, camphorsulfonate , digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate, isothionate, lactate, maleate, im)methanesulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, pivalate, opropionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, chloride, bromide, iodide, and undecanoate.- According to the other variants described below, the physiologically acceptable anion represents the anion of Х--U 20 of a phosphorus-containing acid, more preferably a group consisting of from the anions of the ether or amide of phosphoric acid, most preferably the anion of the mono- or dialkyl ether of a phosphorous-containing acid. sl Used in the description and in the formula utility model, the term "alkylene" refers to a saturated or unsaturated hydrocarbon chain, including linear or branched alkyl, alkenyl or alkynyl.

As used, the term "alkyl" refers to a saturated hydrocarbon chain containing from 1 to 30, preferably from 1 to b, 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" used is also read in haloalkyls, which contain halogen atoms. Alkyl also includes heteroalkyl with sulfur, oxygen, and nitrogen heteroatoms.

As used, the terms "alkenyl" and "alkynyl" refer to 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-enyl and 1-methyl-1-ethylallyl.

As used, the term "cycloalkyl" refers to cyclic radicals including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. 65 As used, the term "cycloalkylalkyl" refers to cycloalkyl groups attached to a lower alkyl radical, including, but not limited to, cyclohexylmethyl.

The term "Alkoxyalkyl" specified for K-substituents preferably denotes a group containing only 1-22 carbon atoms. Examples include methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, n-propoxyethyl and iso-propoxyethyl.

As used, the term "Alkoxy" refers to an alkyl group attached to the parent molecular group through an oxygen atom.

As used, the term "alkoxyapkoxy" refers to an alkoxy group attached to the parent molecular group through an apkoxy group.

The term "halogen" is used to refer to I, Bg, SI or GB. 70 The term "carboxy" used refers to the -COOH radical. The term "ether" refers to -SOOC; the term amide refers to -SOMN", -"SOMNE or -SOME". The term "cyano" refers to the -CM radical.

Phosphorus-containing and other 3-alkylisothiouronium salts are synthesized by various methods well known in the field, for example, by alkylation of thiourea with suitable trialkylphosphates or dialkylphosphites under heating in an organic solvent.

Without excluding the other options listed below, 5-ethylisothiouronium diethyl phosphate is currently the preferred compound for the treatment of headache, particularly migraine, and nausea or vomiting. Other examples of 3-alkylisothiouronium derivatives that can be used in the treatment of migraine according to the present invention include, but are not limited to, 5-methylisothiouronium methyl phosphite, 5-methylisothiouronium dimethyl phosphate, 3-ethylisothiouronium metaphosphate, 5-ethylisothiouronium ethyl phosphite, 5-ethylisothiouronium diethyl phosphate, 5-propylisothiouronium propyl phosphite, z-isopropylisothiouronium metaphosphate, z-isopropylisothiouronium isopropyl phosphite,

C-butylisothiouronium dibutylphosphate and 5-isobutylisothiouronium isobutylphosphite.

It is known that these compounds are safe for humans, because it is well known in this field that phosphorus-containing derivatives of 8-alkylisothiouronium have low toxicity, and their GO 5o (5095 lethal dose) is in the range of 100-1000 mg/kg, which is much higher therapeutic doses of these compounds.

The headache or migraine medications of this utility model are preferably packaged and identified as having the claimed activity. Such identification may be printed, for example, on the package insert of the medicinal product or on the package or container containing the medicinal product.

A compound of this useful model can be administered to a patient by itself or in the form of a pharmaceutical composition where it is mixed with suitable carriers or excipients. The term "pharmaceutical composition" 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 fillers. The task of the pharmaceutical composition is to facilitate the introduction of the compound into M's body.

The term "prodrug" refers to an agent that is converted into the active parent drug. Prodrugs are often useful because in some cases they can be administered more easily than the parent drug. For example, they may be bioavailable when taken orally, whereas the parent drug is not. Prodrugs may also have better solubility compared to parent drugs in a pharmaceutical formulation.

The term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Non-limiting examples of fillers include calcium carbonate, phosphate

Calcium, 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, commonly known anti-migraine agents. The pharmaceutical compositions of this utility model can be prepared by methods known in the art, such as conventional mixing, dissolving, granulating, grinding, spraying, dragee preparation, trituration, emulsification, capsule preparation, entrapment or lyophilization. Thus, pharmaceutical compositions for use in accordance with this utility model can be prepared in a conventional manner using one or more physiologically acceptable carriers, including excipients and excipients that facilitate 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 useful model can be prepared in aqueous solution, preferably in physiologically compatible buffers, such as Hank's solution, Ringer's solution, or saline buffer. For introduction through the mucous membrane in the drug, a wetting agent suitable for penetration through this barrier is used. Such wetting reagents, such as DMSO or polyethylene glycol, are widely known in the art.

Compounds for oral administration can be readily 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 ingestion by the patient. Pharmacological preparations for oral administration can be prepared using a solid excipient, optionally grinding the resulting mixture and processing the mixture into granules, then adding suitable excipients, if necessary, and obtaining tablets or dragee cores. Suitable for 6. in particular, such fillers as types of sugar, 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 polyvinylpyrrolidone. If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts such as sodium alginate can be added.

Suitable coatings are applied to the dragee cores. For this purpose, you can use a concentrated solution of sugar,

which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, glaze solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings to identify or characterize different combinations of doses of active compounds.

Pharmaceutical compositions that can be administered orally include hard capsules made of gelatin, as well as soft, closed capsules made of gelatin and a plasticizer such as glycerin or sorbitol.

Hard (rice-yO) capsules may contain the active ingredients in a mixture with a filler such as lactose, binders such as starches, lubricating agents such as talc or magnesium stearate, optionally 70 stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, petroleum jelly or liquid polyethylene glycols. In addition, stabilizers can be added. All drugs for oral administration must be dosed in a manner suitable for the chosen method of administration.

Compositions for transbuccal use may be in the form of tablets or cakes obtained /5 in a conventional manner.

Compounds for use in accordance with this utility model, administered by inhalation, are typically delivered as an aerosol spray from a pressurized container or nebulizer using a suitable propellant, such as 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 that delivers a metered amount. Capsules and cartridges, for example from gelatin for use in an inhaler or insufflator, can be prepared containing a powder mixture of the 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, it is possible to obtain suspensions of active compounds in the form of suitable oil suspensions for injections. 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 suspensions for injections may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, suspensions may also contain suitable stabilizers or agents that increase the solubility of these compounds and allow obtaining solutions with high concentrations. Alternatively, the active ingredient may be in the form of a powder to be reconstituted with a suitable vehicle, such as pyrogen-free sterile water, prior to use. -

The compounds of this utility model can also be prepared 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. co

Pharmaceutical compositions, which are used to obtain these medicinal products, may also contain a suitable solid substance of the carrier or filler of the gel phase. Examples of such carriers or fillers 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 this utility model include "

Compositions where the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount refers to an amount of a compound effective in preventing, ameliorating, or ameliorating the symptoms of a patient's disease to be treated. ;" Determination of a therapeutically effective amount is fully within the capabilities of one skilled in the art, especially in light of the detailed description provided.

The toxicity and therapeutic effectiveness of the described compounds can be determined according to the standards

GI by pharmaceutical methods in cell cultures or experimental animals, for example, by determining IC0 (concentration that provides 5095 inhibition) and IC050 (lethal dose that causes death in so 5096 test animals) for the compound under consideration. Data obtained from cell culture experiments and animal studies can be used to determine the dosage range for human use. 5p The dosage can be varied depending on the dosage form used and the method of administration. The exact composition - the method of administration and dosage can be chosen by the doctor, taking into account the patient's condition | see, for example, Ripa! etc. sp 1975, in "Tpe Riagtasoiiodisa! Vaviz oi Tpegaretsiisv", SA.1, r.I).

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

The amount of the composition taken, of course, depends on the patient being treated, the severity of the disease, the method of administration, the doctor's opinion, etc.

Sustained-release tablets or capsules containing 3-alkylisothysuronium can be used before an attack, for example, by people about to undergo chemotherapy or other treatments known to cause nausea or vomiting, women who know that their premenstrual period is usually accompanied by nausea or migraine, or patients who experience an "aura" and can identify it as a condition preceding a migraine. A tablet or capsule can also be formulated so that part of the active ingredient is released immediately, providing initial migraine relief, and the other part is released slowly and in measured amounts. 65 As used, the term "initial migraine relief" refers to the reduction or elimination of migraine symptoms within a predetermined period of time after administration, particularly according to the invention within about 10 minutes. after the introduction.

Each tablet or capsule of this useful model preferably contains from 10 to Zb0Omg, more preferably from 20 to 200Omg, most preferably from 30 to 8Omg of the active compound (5-alkylisothiouronium derivative).

The expression "approximately" used refers to 20,965.

A medicine against headaches, in particular migraines, is obtained by mixing, as an active ingredient, compounds of the general formula (1): е5 в --- х5ижых 7 в! 70 - A k

A -Sh-eoS- 8 2nd x ra de VE! represents a linear or branched, saturated or unsaturated alkylene containing from one to eight carbon atoms, optionally substituted with 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, M and 5; 22, 3, in Her Co each independently represents hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkyloxy, nitro, amino, cyano, sulfonyl, haloalkyl, carboaryloxy, carboalkylaryloxy, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, alkyl sulfate, aryl sulfate, sulfonamide, thialkyl, optionally substituted with halogen;

Av represents a physiologically acceptable anion; together with a pharmaceutically acceptable carrier or diluent. -

The medicinal product must be packaged and identified as having activity against headache, migraine, nausea and vomiting as described above. The identification of the drug as an anti-headache agent, particularly anti-migraine or anti-emetic, is a new indication for 5-alkylisothiouronium derivatives, which are known as hypertensive agents and have not previously been used to treat or alleviate the symptoms of headache, it) migraine or nausea. "-

Treatment of headaches, in particular migraines, is carried out by administering to the patient a therapeutically effective amount of the compound of the general formula (1): o

ЕЗ со в --- ч5ижых 7 в! -8 A K p

А -Щ-еоС- 8 2nd x vz "where B" represents a linear or branched, saturated or unsaturated alkylene, which includes from one c) c to eight carbon atoms, optionally substituted by one or more substituents selected from the group , which "consists of a halogen, a primary or secondary amine, a primary or secondary alcohol, or interrupted by one or more heteroatoms selected from the group consisting of O, Mi 5; 22, 3, in Her Ko each independently represents hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower apkenyl, linear or branched lower alkynyl, lower alkoxy, di alkoxyalkyl, cycloalkyl, cycloalkyl alkyl, lower thioalkyl, nitro, amino, cyano, sulfonyl, gapogenalkyl, (oo)carboaryloxy, carboalkylaryloxy, alkylsulfoxide , aryl sulfoxide, alkyl sulfone, aryl sulfone, alkyl sulfate, aryl sulfate, sulfonamide, thialkyl, optionally substituted by halogen; and Av represents a physiologically acceptable anion; - 70 together with pharmaceutically clear carrier or diluent. sp In this regard, it should be noted that the clinical trials conducted and described in detail below in the examples section evaluate the response of human patients and the beneficial effects of 5-ethylisothiouronium diethyl phosphate.

Unexpectedly, these patients show a significant positive effect of this drug administered during a migraine attack. The administered dose is substantially lower than the effective oral dose used to treat hypotension (which is usually about 100 Ωg). In addition, this drug has been found to be effective in reducing migraine symptoms in a relatively short period of time, averaging about 45 minutes, when the patient is at the peak of a migraine attack.

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

These results are extremely unexpected. In this regard, it is clear that recognized drugs for migraine act most quickly when administered parenterally. Also, regardless of the route of administration, therapeutic migraine relief is often not obtained with established migraine medications. When taken orally, recognized migraine medications act much more slowly than when the 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 underlying pathology. It is also possible that the headache is followed by a response to therapeutic agents that are initially effective in treating the initial symptoms of migraine. The terms "rebound", "recurrent", "recurrent", "next" or "secondary" (as defined below) are considered synonyms used without referring to the mechanism or cause of the migraine headache.

According to the above reports, this phenomenon is not observed when taking 3-ethylisothiouronium diethyl phosphate.

In this regard, it should be noted that migraine attacks are associated with dilation of blood vessels in the head, and 7/0 relief of migraine headaches is associated, among other things, with the weakening of such dilation of blood vessels. As a side effect, anti-migraine agents can cause abnormal blood flow (either by dilation or by narrowing of blood vessels). Thus, the striking therapeutic effect of 5-ethylisothysuronium diethyl phosphate as an anti-migraine agent, together with its known ability to regulate abnormal blood flow, is the answer to alleviating migraine symptoms without the side effects of known anti-migraine agents.

In addition, 5-ethylisothiouronium diegyl phosphate can be combined with another antimigraine agent, such as an ergotamine derivative or a sirtonergic agonist. Combined treatment requires less of each drug, while the addition of 5-ethylisotisuronium diegyl phosphate to known therapeutic agents reduces the side effects of known drugs and provides suffering patients with initial relief within minutes.

As discussed earlier, the compound is manufactured as a preparation for oral administration, injection, inhalation, or transdermal administration.

When taken orally, tablets or capsules are used, where the best dose is from 10 to 200mg of the compound, preferably from 20 to 7Omg of the compound, and according to clinical results approximately 5Omg of the compound. Thus, the therapeutically effective amount of this compound is in the range from 0.1 to 3.0 mg/kg of body weight, preferably from 0.4 to 1.0 mg/kg of body weight, more preferably from 0.5 to 1.2 mg/ kg of body weight.

The ranges of therapeutically effective doses indicated above are chosen in such a way as to provide significant relief of migraine symptoms within 15-6 hours. after the introduction. t

In a preferred embodiment of this useful model, the 5-alkylisotisuronium derivative is administered during or after the onset of migraine.

Additional purposes, advantages, and novel features of this useful model will be apparent to those skilled in the art after examining some of the following non-limiting examples. In addition, each of the various examples and aspects of this useful model presented in the description and claimed in the claims is experimentally confirmed in the following examples. uh-

Examples

Now let's turn to the following examples, which, together with the above descriptions, illustrate this useful so

With the Model, without limiting It. with

Example 1. Results of a clinical trial in the treatment of a migraine attack using the drug Oigesg.

Research protocol for oral administration (tablets).

A dose-escalation study to study the safety and efficacy of Oiteig tablets for the treatment of an acute migraine attack. « 1. The purpose of the research. The purpose of the following research protocol is to evaluate the safety and potential effectiveness of Oigtecg tablets. (5-ethylisothiouronium diethyl phosphate) at increasing doses, starting from 1 Ωg and up to 5 Ωg, in the treatment of a separate и? acute migraine attack. The study is characterized as an open-label study of a selected group of patients classified according to the INJ criteria as suffering from migraine-induced headache of moderate to severe intensity without aura. Research is conducted in accordance with established international co-criteria for assessing the safety and effectiveness of migraine treatment. 2. Research plan. This study is conducted as a study of 5 directions (groups). Only female patients classified as suffering from migraine without aura according to IN5 criteria participate in this study. Each group includes 5 or ten patients with migraine, who are treated during an acute migraine attack with tablets Oieishg in the conditions of hospitalization. sp The initial dose of Oigteig is 1Omg (1 tablet) with subsequent dose increases to 2Omg, ZOmg, 4Omg and

BOmg. The total number of patients participating in the study is 50. Patients are hospitalized and observed for at least 4 hours. to assess the safety, effectiveness and possible side effects of Rigeimg. 3. Taking the medicine. c In the first group, each of the 10 patients takes an initial dose of 10 mg of the studied medicinal product in the form of one tablet. A dose of 5Omg is given in the form of two tablets of 25 mg each. The tablets are individually packed in a blister pack and have a label indicating the drug as the study drug. because Each dose is given to 10 patients with an increase in the dose. The drug is swallowed with a glass of water under the supervision of a doctor. 4. Evaluation of efficiency. 4.1. The primary goal of effectiveness is to reduce headache.

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

4.2. Secondary goals of influence - reduction of nausea, vomiting and sensitivity to light and sounds.

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

Research results (treatment starts during migraine attack)

LETTER TO TO PO

1 dose of Oiteig during treatment. 2 Headache relief is considered effective if the patient reports a reduction in headache severity from severe or moderate (score 3-4) to mild or no pain (score 1-2). Headache severity scale: 1 - no pain, 2 - weak, C - moderate, 4 - severe pain).

Q The time after taking the medicine, during which the patient reports a decrease in headache to a score of 1-2.

Unexpectedly, low doses of Oiitesg, ineffective or less effective in relieving severe migraine headaches, were found to be effective in reducing or eliminating the symptoms of nausea. In addition, it has been observed that the time interval to relief of nausea is reported to be shorter than the interval reported to relief of severe headache. This supports the use of these drugs as an antiemetic.

Z yu zo - cha 4 Dose Oiteshg during treatment. co 5 Percentage of patients who show a positive antiemetic reaction to taking Oitekig. 6 The time after ingestion of the medication, after which the patient reports the end of vomiting. with

Example 2. Multiple doses of Oitesshg for headache relief. caused by migraine.

Medical history 1

Previous medical history: the patient smokes, a 30-year-old woman was first diagnosed as suffering from "classic migraine" at the age of 17. Other than that, she is perfectly healthy. Two years ago and earlier, the frequency of migraine attacks was seven cases per month. For the past two years she has been treated with various types of recognized drugs with little or no success. Due to lack of response to medication during migraine attacks, she tried alternative drug treatments.

As a result of treatment with 5-ethylisothiouronium diethyl phosphate, the frequency of migraine attacks from which she suffered 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 5-ethylisothiouronium diethyl phosphate on migraine pain is that it has become significantly weaker. At this time, the patient experiences only about two migraine attacks per month,

Ho) mainly, in the premenstrual period, in hot weather conditions or with a sudden change in weather. Premenstrual migraine attacks are usually longer and more severe than other migraine attacks. - The duration of each attack is 24-72 hours. - 70 Past medical treatment: Medicines used by the patient before using alternative treatment methods include: Tetidgap, Midgaieme, Itygeh and 7otipd. These treatments have been discontinued due to various severe side effects, including hand tremors, tremors, dry mouth, nausea, and vomiting.

Treatment of 5-ethylisothiouronium with diethyl phosphate.

The first attack. The patient suffered from an acute migraine attack that lasted for 72 hours. Despite taking the proposed medicinal product every two hours, the intensity of the pain caused by the migraine did not change. The next day, the patient took a single dose of 50 mg of Z-ethylisothiouronium diethyl phosphate (2 tablets of 25 mg each). Medicines were taken on an empty stomach; the patient did not eat or drink anything before swallowing the medicine. During the next 10-15 minutes. after taking the pain suddenly disappeared, as well as other symptoms that appeared during a migraine attack.

The second attack (after three weeks). The second migraine attack started at night. The next day, the patient again took 60 2 tablets of Z-ethylisothiouronium diegyl phosphate (5Omg). This time, the pills were 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 slight headache was present, but its intensity was decreasing. Three hours later, the patient took two more tablets of 5-ethylisothiouronium diethyl phosphate (5Omg). After 15 minutes the pain caused by the migraine disappeared. because the Third attack (two and a half weeks after the second attack). The migraine attack started on the way to work. An hour after the onset and at the peak of the migraine attack, the patient took 2 tablets of 5-ethylisothiouronium diethyl phosphate (25 mg each). Medicines were taken on an empty stomach. After 11 minutes migraine symptoms disappeared.

Side effects. No side effects were found after taking 5-ethylisotisuronium diethyl phosphate.

Example 2

Medical history 2

Past medical history: The patient is a non-smoker, a 34-year-old woman who has been suffering from migraine attacks for the past 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. 7/0 Until now, the patient did not use specific medical treatment and usually used well-known analgesics.

Past medical treatment: Commonly used pain relievers (analgesics).

Treatment of 5-ethylisothiouronium with diethyl phosphate.

The first attack. An acute migraine attack began in the morning, during the day the symptoms intensified. Before noon, the patient took one tablet of 5-ethylisothiouronium diethyl phosphate (25 mg). No significant change in migraine-induced pain was observed. Two hours later, the patient took two more tablets of 5-ethylisothiouronium diethyl phosphate (25 mg each). After ten minutes, the migraine pain disappeared.

A second attack (about four weeks after the first attack). The migraine attack started as a result of very hot weather conditions. The intensity of this attack was higher than usual migraine attacks. In the morning, the patient took 2 tablets of 5-ethylisothiouronium diethyl phosphate (5Omg), which were taken on an empty stomach. During 20 min. after taking 5-ethylisothiouronium diethyl phosphate, there was a significant relief of pain caused by migraine. After fifteen minutes, the pain disappeared. On the same day, in the afternoon, the patient experienced mild pain. At that moment, the patient himself took an analgesic and the pain disappeared.

Side effects. The supervising specialist did not find any side effects after taking 25 or 500 mg of 3-ethylisothiouronium diethyl phosphate.

Discussion of results. t

Both case histories and especially the first case show an unexpected significant positive effect

C-Ethylisothiouronium of diethyl phosphate taken during migraine attack. The effective dose is about half of the effective dose used in the treatment of hypotension (which is about 50-10Omg). In addition, the drug has been found to be effective in relieving migraine symptoms in less than 20 minutes, when the patient is at the peak of a migraine attack. In addition to eliminating an acute headache, the medicine also eliminates nausea and the unpleasant feeling of photophobia and corrects impaired visual focus. The shock effect of drug M is repeated three times in the first patient and twice in the second patient. Obviously, this medicine is more effective if it is taken on an empty stomach. co

Thus, it can be concluded that 5-ethylisothiouronium diethyl phosphate is a potent drug for the treatment and relief of migraine symptoms. It has a rapid effect, has a low effective dose and, according to the described case histories, does not give side effects.

Example C

Clinical trials in the treatment of a migraine attack by intravenous administration of Origekg « 1. Summary of the study. The purpose of the following research protocol is to evaluate the safety and potential effectiveness of 1095 Oekshg injection solution at a dose of 0.bmg/kg in the treatment of a single acute migraine attack. Research is characterized as;" an open study in a selected group of patients classified according to IM5 criteria as suffering from migraine-induced headache of moderate or severe intensity without aura. Research is being conducted

According to established international criteria for evaluating the safety and effectiveness of migraine treatment. ko 2. Administration of drugs.

Oitesg is presented as a 1095 (100mg/ml) solution in a ml ampoule. Before treatment, it is dissolved in 100 ml of physiological saline in a device for intravenous administration. The dose of Oiiiig is 0.bmg/kg when administered through a dropper within 10 minutes.

C. Performance evaluation. - Severity of headache is assessed verbally on a 5-digit scale: very strong (score 4), strong (score sp 3), moderate (score 2), weak (score 1), absence of pain (score 0). A reduction in headache severity from very severe, severe, or moderate (score 4-2) to mild or no pain (score 1-0) is considered success. 4. Research results.

This study included 13 patients with headaches of varying degrees of severity. With the exception of one patient who did not experience a decrease in headache, all others experienced significant headache relief. Efficiency and time to effect are presented in Table 3. о b5 а 181втю11111111м

1 Success is considered relief of headache severity from very severe, severe, or moderate (score 4-2) to mild or no pain (score 1-0). 2 Time after initiation of treatment after which the patient reports a decrease in headache to a score of 1-0.

While this utility model is described in connection with specific embodiments thereof, it is intended that all alternatives, modifications, and variations that are within the spirit and scope of the attached utility model formulation be embraced.

All publications, patents, and patent applications referred to in the specification are incorporated into the specification in their entirety by reference to the same extent as if each individual publication, patent, or patent application had been specifically and individually referenced prior to incorporation. link. In addition, the citation or identification of any reference in this application is not an admission that such reference is suitable as a prototype of a given utility model.

Claims (15)

15 Formula of the invention 1. A method of treating a headache or migraine, which includes the stage of administering to the patient a therapeutically effective amount of a compound of the general formula в Ж в - А Кк А -Щ-еоС- 8 в-- кт х ра - де ВЕ! represents a linear or branched, saturated or unsaturated alkylene containing from one to eight carbon atoms, optionally substituted with 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, M and 5; at 22, 3, in Her Co each independently represents hydrogen, hydroxy, linear or branched lower alkyl, "-- linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkyloxy, nitro, amino, cyano, sulfonyl, haloalkyl, v carboaryloxy, carboalkylaryloxy, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, c alkylsulfate, arylsulfate, sulfonamide, thialkyl, optionally substituted with halogen; Ab represents a physiologically acceptable anion, together with a pharmaceutically acceptable carrier or diluent. 2. The method according to claim 1, where the indicated physiologically acceptable anion is selected from the group that includes an anion obtained from phosphoric acid, phosphoric acid ester, phosphoric acid amide, diacetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bitartrate, bisulfate, butyrate, z camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, c 2-hydroxyethanesulfonate, isothionate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, :z» palmoate, pectinate , Z-phenylpropionate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, chloride, bromide, iodide, and undecanoate. 3. The method according to claim 1, where the compound is selected from the group that includes 5-methylisothiouronium methyl phosphite; with 15 Z-methylisothiouronium dimethyl phosphate; Z-ethylisothiouronium metaphosphate; (ee) Z-ethylisothiouronium ethyl phosphite; - Z-ethylisothiouronium diethyl phosphate; C-propylisothiouronium propyl phosphite; - z-isopropylisothiouronium metaphosphate; sl 3-isopropylisothiouronium isopropylphosphite; What is 3-butylisothiouronium dibutylphosphate and 5-isobutylisothiouronium isobutylphosphite. 4. The method according to claim 1, where the compound is prepared for oral administration, administration by injection, inhalation, mucosal or transdermal administration. 5. The method according to claim 4, where the compound is prepared in the form of tablets, capsules or ampoules for injections. with b. The method according to claim 5, wherein each of said tablets, capsules or ampoules contains from 10 to 300 mg of said compound. 7. The method according to claim 5, where each of the indicated tablets, capsules or ampoules contains from 20 to 200 mg of the indicated compound. because . . . . . 8. The method according to claim 5, where each of the indicated tablets, capsules or ampoules contains from 3 to 80 mg of this compound. 9. The method according to claim 1, where the indicated therapeutically effective amount is from 0.1 to 3 mg/kg of body weight. 10. The method according to claim 1, where the indicated therapeutically effective amount is from 0.4 to 1.6 mg/kg of body weight. b5; . . . . 11. The method according to claim 1, where the specified therapeutically effective amount is from 0.5 to 1.2 mg/kg of body weight. 12. The method according to claim 3, where the specified compound is 5-ethylisothiouronium diethyl phosphate. 13. The method according to claim 1, wherein the indicated therapeutically effective amount is selected in such a way that a significant relief of migraine symptoms is observed for a period of less than one hour after administration. 14. The method according to claim 1, where the specified stage of administration of the compound is carried out after the onset of a headache or migraine. 15. The method according to claim 1, where the specified stage of administration of the compound is carried out simultaneously with the onset of a headache or migraine. 0. and and and and. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 21, 25.12.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. with with IF) "- in (ee) p - and? ime) (ee) -i - 70 sl 60 b5