UA28717U - Method for preventing or alleviating nausea or vomiting - Google Patents

Abstract

A method for preventing or alleviating the nausea or the vomiting provides for administering the effective amount of the substance of the general formula: where R1 is linear or branched, saturated or unsaturated alkylene, which comprises from one to eight carbon atoms, optionally substituted with one or several substitutes selected among halogen, primary or secondary amine, primary or secondary alcohol, or interrupted by one or several heteroatoms selected from the group comprising O, N and S; R2, R3, R4 and R5 each independently represent hydrogen, hydroxyl, linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkoxy, nitro, amino, cyano, sulfonyl, halogenalkyl, carboaryloxy, carboalkylaryloxy, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfate, arylsulfate, sulfonamide, thioalkyl, optionally substituted with halogen; AO represents physiologically acceptable anion, together with pharmaceutically acceptable carrier or diluent.

Description

Description of the invention

The present utility model relates to medicaments for the prevention or treatment of headache, nausea 2 or vomiting, more specifically for the relief of migraine symptoms, including but not limited to nausea and vomiting.

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 "Midgaiple Neadasne apa She Mapadei Sage Rogtshiagu" YuOgydz Vepeiyi Tgepaz (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

Neadasnev" Ogodz (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-HT10) adopiviv apa oiyeg adepiv ip askie tidgaiipe" Admapsez ip Neadasne, in (1997) 15 (13: 61-81. "- 7. Rgadaiiieg, "Tgeaytepi 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) Serpaiadia (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 (common 7 migraine) and it covers 85-95 of all sufferers. The second, most common type, called migraine with aura -k 70 (classic migraine), covers most of the remaining 15 95 sufferers. Aura is a disorder of the nervous system that often precedes a headache. "m 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 an 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 20 to 95 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. r. 425).

Commonly accepted treatment of migraine.

There are several approved therapeutic drugs. 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 2o Migraine medications are thought to initially relieve migraines by primarily 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 migraine sufferers and those who cannot tolerate the side effects of existing medications, there are no conventional pharmaceuticals that demonstrate therapeutic efficacy without severe side effects. --

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, ibuprofen, and other nonsteroidal anti-inflammatory agents, including naproxen and naproxen sodium. However, these agents, while 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 medications: 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 undesirable and potentially dangerous side effects. Ergotamines should not be used in patients with peripheral vascular disease

And disease, coronary heart disease, hypertension, impaired liver or kidney function, and severe itching or sepsis. They are also contraindicated in pregnant women or those who are planning to become pregnant. Nausea and vomiting have been reported in 10 to 95 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, so paresthesia and possibly convulsive attacks. Chronic ergotism is characterized by intermittent -I lameness, muscle aches, numbness, and cold extremities, as well as other gastrointestinal and central nervous system (CNS) side effects. There are methods of treatment that include - the introduction of high doses of caffeine with preparations of horns or other pharmacological agents. In addition, "M" drugs and caffeine are potentially addictive with well-documented withdrawal symptoms.

Triptan drugs (serotonin agonists): Another treatment option involves the administration of more novel therapeutic agents known as serotonin agonists or 5-hydroxytryptamine (5-HT) agonists. The first drug from this family, sumatriptan, is undoubtedly a significant improvement in the treatment of migraine. Sumatriptan succinate is sold under the trademark IMITKEH by SiIaho UUesote Ips. Despite the applicability of sumatriptan c 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 the 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.

In general, migraine care is complicated by the lack of a single therapy that is effective for all patients with 65 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

Antiemetic drugs.

A particularly important application 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 anticancer chemotherapy agents such as cisplatin. It causes serious problems with cancer chemotherapy, and in some patients the vomiting is so severe that therapy has to be stopped. Therefore, antiemetic agents are often taken to alleviate this side effect of an anticancer chemotherapy agent.

The antiemetic agents used are often benzamide derivatives such as methocpopramide, which has dopamine antagonist activity. In terms of dopamine antagonist activity, benzamide derivatives such as metoclopramine alone exhibit serious and undesirable side effects such as extrapyramidal effects such as tardive dyskinesia, acute dystonia, akathisia, and tremor.

Physiologically acceptable salts of carbazolones are described in US Pat. No. 5,578,628 as potent antiemetics that are selective antagonists of 5-hydroxytryptamine (5-HT) at neuronal 5-HT type 2o receptors located at the terminals of primary afferent nerves and believed to also be present in central nervous system.

Thus, there is a need for a safe and effective antiemetic agent and gastric motility stimulant, without the undesirable side effects of known antiemetic agents, that acts through various CNS receptors.

MU098/13036 discloses the use of 5-alkylisothiouronium derivatives, including some new compounds, as drugs for increasing arterial blood pressure or for protecting patients from hyperoxia. These compounds are proposed for the treatment of acute hypotension, such as shock states, and chronic arterial hypotension or oxygen poisoning. This invention is presented on the example of the hypertensive action of 3-ethylisothiouronium diethyl phosphate under different conditions. However, MU098/13036 does not describe or suggest the use of M zo Z-alkylisothiouronium derivatives for the treatment of headache, migraine or nausea and vomiting.

It was accidentally discovered that 5-alkylisothysuronium salts derivatives, which are known as hypertensive agents, are also highly effective in alleviating headaches in general and migraine symptoms in particular. When using this useful M model in practice, it was also found that these 5-alkylisothiouronium salt derivatives are effective in the treatment of nausea and vomiting. Migraine patients have been successfully treated with 3-ethylisothiouronium diethyl phosphate at doses c5 unexpectedly lower than those required for antihypertensive use. Treatment started at the peak of a migraine attack consistently shows relief within 60 minutes. after taking medication. In some cases, significant improvement is reported within about 15 minutes.

Thus, for the treatment of headache, migraine, nausea and vomiting, a pharmaceutical composition is presented, which includes as an active ingredient a compound of the general formula I:

Re - st v xz» KZ Feya dk t ha ko Formula (I) o 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 consisting of halogen, primary, secondary and tertiary amine, primary, secondary and tertiary 20 alcohol, or interrupted by one or more heteroatoms selected from the group consisting of O, M and 5;

In, 83, in and 2? each independently represents hydrogen, hydroxy, linear or branched lower alkyl, "M linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkyl, nitro, amino, cyano, sulfonyl, haloalkyl, carboaryloxy , carboalkylparyloxy, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, 22-alkylsulfate, arylsulfate, sulfonamide, thioalkyl, optionally substituted with halogen; c Av represents a physiologically acceptable anion; together with a pharmaceutically acceptable carrier or diluent.

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 headache, migraine or nausea is provided by the administration of a pharmaceutical composition comprising a therapeutically effective amount of a compound of the general formula (1): b5 c tm v!

AS sub

Y - re food

Formula (I) where VE! represents a linear or branched, saturated or unsaturated alkylene containing from one 70 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 an 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, 72 alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkoxy, 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.

The process of obtaining a medicinal product for headache, migraine or nausea includes the stage of mixing as an active ingredient the compound of the general formula (1): с тм в!

AC sub; ge - - eat

Formula (I) where B! represents a linear or branched, saturated or unsaturated alkylene containing from one to eight carbon atoms, optionally substituted by 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, M and 5; them-

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, co

C35 alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkyl, nitro, amino, cyano, sulfonyl, haloalkyl, Ha carboaryloxy, carboalkylaryloxy, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfate, arylsulfate, 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 - c, which includes the anion of phosphorus-containing acid, ester of phosphorus-containing acid, amide of phosphorus-containing acid, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bitartrate, bisulfate, "» butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, 2-hydroxyethanesulfonate, isothionate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthapinesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, pivalate, propionate, succinate, tartrate, thiocyanate, glutamate, CO bicarbonate, para-toluenesulfonate, chloride, bromide, iodide, and undecanoate.

According to the following, accepted best options of this useful model are physiologically acceptable

The Me anion represents an anion of a phosphorus-containing acid, more preferably a group consisting of anions of an ether -I or amide of phosphoric acid, most preferably an anion of a mono- or dialkyl ether of a phosphorus-containing 50 acid.

According to the features of other options, the drug is packaged and identified as having "and anti-headache, anti-migraine or anti-emetic activity."

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

Z-methylisothiouronium methyl phosphite;

Z-methylisothiouronium dimethyl phosphate;

C-ethylisothiouronium metaphosphate; c 3-ethylisothiouronium ethyl phosphite;

Z-ethylisotisuronium diethyl phosphate;

Z-propylisothiouronium propyl phosphite; 60 z-isopropylisothiouronium metaphosphate; z-isopropylisothiouronium isopropyl phosphite;

Z-butylisothiouronium dibutyl phosphate;

C-isobutypizotisuronium isobutyl phosphite.

According to features of other options, the anti-headache, anti-migraine, anti-nausea or 65 vomiting medicine is made for oral or parenteral administration. Among drugs for parenteral administration, the best drugs are suitable for injection, sublingual, transdermal, mucosal, or inhalation.

According to the features of other options, the anti-migraine medicine is made in the form of tablets or capsules.

According to features of other variants, each tablet or capsule includes from 10 to 300 mg of the compound.

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

According to features of other variants, each tablet or capsule includes from 30 to 80 mg of the compound.

The drug must be packaged and identified as having activity against headache, migraine, nausea, or vomiting.

According to the best options, the therapeutically effective amount is from 0.1 to 3 mg/kg of body weight. 70 According to other variants, a therapeutically effective amount is between 0.4 and 1.6 mg/kg of body weight.

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

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

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

Of course, because migraine is the most severe form of headache, the described treatment is also suitable for other types of headache and nausea, including, but not limited to, PMS or hangover-related headaches and nausea. This is particularly appropriate due to the few side effects observed in people using this beneficial model.

Compounds of formula (I) inhibit vomiting. Therefore, these compounds can also be used as antiemetic agents, for example to prevent vomiting induced by anticancer chemotherapeutic agents such as cisplatin. Also of particular note is the treatment of radiation-induced vomiting. Thus, the compounds of formula (I) can be used to prevent emesis induced by radiation therapy, for example radiation of 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 relief of acute symptoms. at,

According to the features of other variants, the stage of introduction of the compound is carried out during or before an attack of nausea.

It is understood by those skilled in the art that oral administration may be less desirable after the onset of nausea.

This useful model successfully corrects the shortcomings of currently known drugs, providing an effective compound for treating and/or alleviating the symptoms of nausea. This superior compound has no apparent side effects and has been shown to be potent at low doses and to provide a therapeutic/relieving effect - over a short period of time compared to currently marketed drugs. uh-

Description of the best options.

This utility model relates to the use of 5-alkylisothiouronium derivatives for the treatment of nausea and vomiting. co

The compositions of this utility model are effective in preventing or alleviating vomiting associated with migraine or with other medical conditions such as chemotherapy or radiotherapy. These compounds were previously known to affect arterial blood pressure in cases of acute hypotension (for example, after hemorrhage, trauma, shock, or poisoning).

Before explaining this useful model in detail, it should be understood that it is not limited in its application to the details specified in the following description or presented in the "Examples" section. This useful model can be implemented in practice or implemented 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;" restrictive

The term "migraine" used here is understood in a broad sense to include a type of headache that is characterized by an unusually strong, one-sided pulsating headache that lasts for 4-72 hours. and

GI which may include one or more of the following symptoms: nausea, vomiting, sensitivity to light and/or sound with or without a preceding "aura" and visual photophobia (eg, visual disturbances). According to this useful model, a medicine against headache, migraine, nausea or -I vomiting is provided, which includes as an active ingredient a compound of the general formula (1): - 50 he tm in! "7-reg de 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 or secondary amine, of a primary or secondary alcohol, or interrupted by one or more heteroatoms selected from the group consisting of isO, Mi 5; 60 822, 83, B and B, each independently representing hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower alkenyl , straight or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkoxy, nitro, amino, cyano, sulfonyl, haloalkyl, carboaryloxy, carboalkylaryloxy, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfate, arylsulfate, sulfonamide, thiasalkyl, neobo necessarily replaced by halogen, because Av represents a physiologically acceptable anion;

together with a pharmaceutically acceptable carrier or diluent.

Preferably, the physiologically acceptable anion is derived from, without limitation, 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, methanesulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmoate, pectinate, Z-phenylpropionate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, chloride, bromide, iodide and undecanoate. 70 According to other variants described below, the physiologically acceptable anion is an anion of a phosphorus-containing acid, more preferably a group consisting of ether or amide anions of phosphoric acid, most preferably an anion of a mono- or dialkyl ester of a phosphorus-containing acid.

As used in the description and in the formula of the 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 I-methyl-1-ethylallyl.

As used, the term "cycloalkyl" refers to cyclic radicals including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.

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, r.zo ethoxybutyl, n-propoxyethyl and iso-propoxyethyl.

The term "Alkoxy" is used to refer to an alkyl group attached to the original molecular group through an oxygen atom. uh-

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

The term "halogen" is used to refer to I, Bg, SI or GB. with

The term "carboxy" used refers to the radical -COOH. 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. z c Without excluding other options, which are given below, 5-ethylisothiouronium diethyl phosphate is the best at this time. a compound for the treatment of headaches, particularly migraines, and nausea or vomiting. Other examples of derivatives and? 3-Alkylisothiouronium compounds that can be used to treat migraine according to this utility model include, but are not limited to, 5-methylisothiouronium methyl phosphite, 5-methylisothiouronium dimethyl phosphate,

Z-ethylisothiouronium metaphosphate, Z-ethylisothiouronium ethyl phosphite, Z-ethylisothiouronium diethyl phosphate, co Z-propylisothiouronium propyl phosphite, Z-isopropylisothiouronium metaphosphate, 5-isopropylisothiouronium isopropyl phosphite, Z-butylisothiouronium dibutyl phosphate and 5-isobutylisothiouronium isobutyl phosphite. It is known that these compounds are safe for humans, because it is well known in this area that phosphorus-containing - and derivatives of 8-alkylisothiouronium have low toxicity, and their GO 5o (50 9o lethal dose) is in the range of 100-1000 mg/kg , which is significantly higher than the therapeutic doses of these compounds. - The anti-nausea or vomiting medicinals of this utility model are preferably packaged and identified "M" 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.

As used, the expression "pharmaceutical composition" refers to the preparation of one or more compounds described in c or their physiologically acceptable salts or prodrugs with other chemical components, such as physiologically acceptable carriers and excipients. The task of the pharmaceutical composition is to facilitate the introduction of the compound into the 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, 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, commonly known anti-migraine agents.

The pharmaceutical compositions of this utility model can be prepared by methods known in the art, for example by 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, the drug uses a wetting reagent suitable for penetration through this barrier. 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 compounds of this useful model 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 excipients are, in particular, sugar types 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 necessary, 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. A concentrated sugar solution may be used for this purpose, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, glaze solutions, and suitable organic solvents or solvent mixtures. To tablets or M

Dyes or pigments can be added to the dragee coating to identify or characterize different combinations of doses of active compounds. -

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

Hard capsules may contain the active ingredients in admixture with a filler such as lactose, binders such as starches, lubricating agents such as talc or magnesium stearate, optionally with 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 by conventional methods.

Compounds for use in accordance with this utility model that are 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

GI is determined by providing the container with a valve that delivers a measured quantity. Capsules and cartridges can be prepared, for example from gelatin for use in an inhaler or insufflator, containing a powder mixture of the compound and a suitable powder base such as lactose or starch. -I 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 appropriate 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 injection 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

They increase the solubility of these compounds and make it possible to obtain solutions with high concentrations.

Alternatively, the active ingredient may be in the form of a powder to be reconstituted prior to use with a suitable vehicle, such as sterile, pyrogen-free water.

The compounds of this useful model can also be prepared in the form of compositions for rectal administration, such as suppositories or retention enemas, using, for example, conventional bases for suppositories, such as cocoa butter or other glycerides.

Pharmaceutical compositions that are used to obtain these drugs may also contain a suitable solid carrier or gel phase filler. 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. 65 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 disease in a patient subject to treatment.

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 efficacy of the described compounds can be determined by standard pharmaceutical methods in cell cultures or on experimental animals, for example, by determining IC0 (the concentration that provides 50 95 inhibition) and I0 50 (the lethal dose that causes death in 50 96 test animals) for the considered compound. Data obtained from cell culture experiments and from 7/0 animal studies can be used in determining the dosage range for human use.

The dosage can be varied depending on the dosage form used and the method of administration. The exact composition, method of administration and dosage can be chosen by the doctor, taking into account the patient's condition, see, for example, Ripa! etc. 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 /5 times the introduction of the composition with a slow release of the active substance during the course of treatment from several days to several weeks or until healing or weakening of the painful condition 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-alkylisotisuronium, 2o Can be used before an attack, for example, 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. Also, a tablet or capsule can be prepared in such a way that part of the active ingredient is released immediately, providing initial migraine relief, and the other part is released SLOWLY and in measured amounts.

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 within approximately 10-60 minutes. after the introduction.

Each tablet or capsule of this useful model 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 (53-alkylisothiouronium derivative).

The expression "about" used means 20 90. -

The medicine against headache, migraine, nausea and vomiting is obtained by mixing as an active ingredient the compound of the general formula (1):

EV d) 35 tm in! with

AS sub "7 and " eat 40 de VE! represents a linear or branched, saturated or unsaturated alkylene containing from one o, c 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, M and 5;

In, 83, in and 2? each independently represents hydrogen, hydroxy, linear or branched lower alkyl, 45 linear or branched lower alkenyl, linear or branched lower alkynyl, lower alkoxy, o alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkyl, nitro, amino, cyano, sulfonyl, haloalkyl, o carboaryloxy, carboalkylaryloxy, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, alkyl sulfate, aryl sulfate, sulfonamide, thialkyl, optionally substituted with halogen;

She Av represents a physiologically acceptable anion; - 70 together with a pharmaceutically acceptable carrier or diluent. -h 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, migraine or nausea. c Treatment of headache, migraine or nausea is carried out by administering to the patient a therapeutically effective amount of the compound of the general formula (1): с тм в!

And suf-v "7 re eat 65 de V! 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 or secondary amine, primary or secondary alcohol, or interrupted by one or more heteroatoms selected from the group consisting of O, Mi 5; 22, 3, in Her Co each independently represents hydrogen, hydroxy, linear or branched lower alkyl, linear or branched lower apkenyl, linear or branched lower alkynyl, lower alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, lower thioalkyloxy, nitro, amino, cyano, sulfonyl, gapogenalkyl, 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; 70 together with a pharmaceutically acceptable carrier or diluent.

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 3-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 mg). In addition, this drug has been found to be effective in reducing migraine symptoms in a relatively short period of time, on average about 45 minutes, when the patient is at the peak of the 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 medicine has a quick and 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 work most quickly when administered parenterally. When taken orally, recognized drugs act much more slowly than when the headache is a continuation of the physiological chain of events that caused the original headache, or a new headache due to another or recurrent 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. what-

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 the 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 09 by narrowing of blood vessels). Thus, the striking therapeutic effect of 3-ethylisothiouronium diethyl phosphate "M" as an anti-migraine agent, together with the known ability to regulate abnormal blood flow, is the answer to the alleviation of migraine symptoms without the side effects of known anti-migraine agents.

In addition, 5-ethylisothiouronium diehyl phosphate can be combined with another anti-migraine agent, such as an ergotamine derivative or a sirtonergic agonist. Combined treatment requires less of each drug, while the addition of 5-ethylisothiouronium diethyl phosphate to known therapeutic agents reduces the side effects of known drugs and provides suffering patients with initial relief within minutes. As previously discussed, the compound is formulated for oral administration, injection, inhalation, or transdermal administration.

When taken orally, 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 clinical results, about 50 mg of the compound. Thus, the therapeutically effective amount of this compound is in the range of 0.1 to 3.0 mg/kg of body weight, preferably from 0.4 to 1.6 mg/kg of body weight, more preferably from 0.5 to 1.2 mg/kg body weight.

The above-mentioned ranges of therapeutically effective doses are chosen in such a way as to provide significant relief of migraine symptoms within 15-60 minutes. after the introduction. 20 In this useful model, the 5-alkylisothiouronium derivative is administered during or after the onset of migraine.

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

Examples.

We now turn to the following examples, which, together with the above descriptions, illustrate this useful c model without limiting It.

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

Research protocol for oral administration (tablets). 60 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 study.

The purpose of the following research protocol is to evaluate the safety and potential efficacy of Oigtecg (5-ethylisothiouronium diethyl phosphate) tablets at increasing doses starting at 10 mg and up to 50 mg in the treatment of a single 65 acute migraine attack. The study is characterized as an open study in a selected group of patients classified according to the IM5b criteria as suffering from migraine-induced headache of moderate to severe intensity without aura. Research is conducted according to established international 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 ten patients with migraine who are treated during an acute attack of migraine with Oiijig tablets in a hospital setting. The initial dose of Oigteishg is 10 mg (1 tablet), followed by an increase in the dose to 20 mg, 30 mg, 40 mg and 50 mg. The total number of patients participating in the study is 50. 7/0 patients are hospitalized and observed for at least 4 hours. to evaluate the safety, effectiveness and possible side effects of Oitekig. 3. Taking the medicine.

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 50 mg is given in the form of two tablets of 25 mg each. Tablets are individually /5 packed in a blister pack and have a label indicating the medicinal product as the study drug.

Each dose is given to 10 patients with increasing doses. 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 (grade 4), moderate (grade 3), weak (grade 2), absence of pain (grade 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. - caused by migraine (treatment begins during a migraine attack). t sh sing 16 - 1 p

Ch , , , p

Oitekshg dose 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. - c It has unexpectedly been discovered that low doses of Oiitesg, ineffective or less effective in relieving severe migraine headache, are effective in reducing or eliminating the symptoms of nausea. In addition, it was observed that the time interval to relief of nausea was reported to be shorter than the interval reported to relief of severe headache. This supports the use of these drugs as an antiemetic. yu s - p yu that 4 Dose Oiteig during treatment. 29 5 Percentage of patients showing a positive antiemetic response to Oitekig. s 6 The time after swallowing the medicine, after which the patient reports the end of vomiting.

Example 2.

Multiple doses of Oigteishg for headache relief. caused by migraine.

Medical history 1. bo 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 established medications with little or no success. Due to lack of response to drug treatment during migraine attacks, she tried alternative drug treatments. because 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 became significantly less severe. At this time, the patient experiences only about two migraine attacks per month,

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.

Past medical treatment: Medications used by the patient prior to alternative treatment methods include: Tetidgap, Midgaieme, Itygeh and 7otipd. These treatments were discontinued 7/0 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 5-ethylisothiouronium diegyl phosphate (2 tablets in/5 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 min. 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 2 tablets of Z-ethylisothiouronium diethyl phosphate (50 mg). This time, taking the pills coincided with the peak of the 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 (50 mg). After 15 min. the pain caused by the migraine disappeared.

The third attack (two and a half weeks after the second attack). The migraine attack started on the way to work. One 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 min. migraine symptoms disappeared. t

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

Example 2.

Medical history 2. Iso Previous 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. M

Until now, the patient did not use specific medical treatment and usually used well-known analgesics. co

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

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 3-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. c c Second attack (about four weeks after the first attack). A migraine attack started as a result. very hot weather conditions. The intensity of this attack was higher than usual migraine attacks. Is the patient in the morning?" took 2 tablets of Z-ethylisothiouronium diethyl phosphate (50 mg), which were taken on an empty stomach. Within 20 min. after taking 3-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. In this one

At that moment, the patient himself took an analgesic and the pain disappeared.

Side effects. The attending specialist did not find any side effects after taking 25 or 50 mg of 3-ethylisotisouronium diethyl phosphate. -I Discussion of the results.

Both case histories, and especially the first case, show an unexpected significant positive effect - Z-ethylisothiouronium diethyl phosphate taken during a migraine attack. The effective dose is about "M half of the effective dose used in the treatment of hypotension (which is about 50-100 mg). In addition, the drug has been found to be effective in relieving migraine symptoms for a period of less than 20 minutes, when the patient is at the peak of the attack migraines. In addition to eliminating the acute headache, the medicine also eliminates nausea and the unpleasant feeling of photophobia and corrects impaired visual focus. The shock effect of the medicine is repeated three times in the first patient and twice in the second patient. Apparently, this medicine is more effective if it is taken On an empty stomach.

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 quick effect, has a low effective dose and, according to the described case histories, does not give side effects.

Example 3.

Antiemetic in animal studies.

The effect of the studied compounds on vomiting in ferrets is studied and summarized below. According to the general method described by Riogeguk, Zspy!ygid apa Vgadpei (Sapseg Tgeaiytepi Kerogi, 1982 66(1) 187-9). Test compound 65 and cisplatin are prepared and administered in normal saline. a) Control - without the tested compound.

In group b, male ferrets weighing 1.5-2 kg were induced to vomit by intravenous cisplatin at a dose of 10 mg/kg. Vomiting begins after 30-75 minutes. after the injection and for a period of 2 hours. the number of cases of vomiting/urges (attacks) is 30-60 (on average 40 cases of vomiting/urges in 2 hours).

Behavioral changes characteristic of vomiting are also noted.

C) With the investigated compound.

A group of 6 male ferrets weighing 1.5-2 kg was 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 three hours. 70 The effect of the test compound on vomiting is also assessed 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 were injected with the studied compound at a dose of 1 mg/kg intraperitoneally for 3 min. before and 1 hour after intraperitoneal administration of cisplatin.

Example 4.

Clinical trials in the treatment of migraine attacks by intravenous administration of Oigeig 1.

Summary of the study.

The purpose of the following research protocol is to evaluate the safety and potential efficacy of Oitesig 10 95 solution for injection at a dose of 0.6 mg/kg in the treatment of a single acute migraine attack. The study is characterized as 2o Open study on 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 conducted according to established international criteria for assessing the safety and effectiveness of migraine treatment. 2. Administration of drugs.

Oitesg is presented as a 10 95 (100 mg/ml) solution in a 1 ml ampoule. Before treatment, it is dissolved in 100 ml of physiological saline in a device for intravenous administration. The dose of Oieig is 0.6 mg/kg when administered via a dropper over 10 minutes. t

C. Performance evaluation.

The severity of the headache is assessed verbally on a 5-point scale: very strong (score 4), strong (score 3), moderate (score 2), weak (score 1), no pain (score 0). A reduction in the severity of M. is considered a success

From Headache from very strong, severe or moderate (score 4-2) to weak or no pain (score 1-0). -- 4. Research results. M

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 a significant relief of pain

From HEADACHE. Effectiveness and time to effect are presented in Table 3. and 181vtyu11111111m and? 1 Success is considered relief of the severity of the headache from very strong, strong or moderate (score km 4-2) to weak or no pain (score 1-0). со 2 The time after the start of treatment, after which the patient reports a decrease in headache to a score of 1-0.

Although 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 formula are embraced. -l 20 All publications, patents, and patent applications mentioned in the description are incorporated into the description in their entirety by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually referenced to inclusion as a 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. with

Claims (14)

The formula of the invention 1. A method of preventing or alleviating nausea or vomiting, which includes the step of administering to a patient 60 therapeutically effective amounts of a compound of the general formula b5 V , t v A sub-ya p t ra de V! 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 one or more heteroatoms selected from the group consisting of O, 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, 19 carboaryloxy, carboalkylaryloxy, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfate, arylsulfate, sulfonamide, thialkyl, optionally substituted with halogen; where represents a physiologically acceptable anion, together with a pharmaceutically acceptable carrier or diluent. 2. The method according to claim 1, where the specified physiologically acceptable anion is selected from the group that includes an anion obtained from phosphoric acid, phosphoric acid ester, phosphoric acid amide, acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, bitartrate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, 2-hydroxyethanesulfonate, isothionate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmoate, lectinate, 3-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 3-methylisothiouronium methyl phosphite; Z-methylisothiouronium dimethyl phosphate; M zo Z-ethylisothiouronium metaphosphate; Z-ethylisothiouronium ethyl phosphite; -- Z-ethylisothiouronium diethyl phosphate; M Z-propylisothiouronium propylphosphite; z-isopropylisothiouronium metaphosphate; so z-isopropylisothiouronium isopropylphosphite; with 3-butylisothiouronium dibutylphosphate and 3-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 1, where the compound is prepared in the form of tablets, capsules or ampoules. with c b. The method according to claim 5, wherein each of said tablets, capsules or ampoules contains from 10 to 300 mg of said compound. with 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. 8. The method according to claim 5, where each of the specified tablets, capsules or ampoules contains from 3 to 80 mg of this GI 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. for 10. The method according to claim 1, where the indicated therapeutically effective amount is from 0.4 to 1.6 mg/kg body weight. 11. The method according to claim 1, where the specified therapeutically effective amount is from 0.5 to 1.2 mg/kg body weight. "M 12. The method according to claim 3, where the specified compound is 5-ethylisothiouronium diethyl phosphate. 13. The method according to claim 1, where the specified compound is administered simultaneously with, or before, the appointment of an anticancer agent or anticancer therapy. 14. The method of claim 1, wherein the anticancer agent or therapy is selected from the group consisting of chemotherapy and radiotherapy. 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. b5