HK1058009B - Pharmaceutical compositions for headache, migraine, nausea and emesis - Google Patents

Description

Pharmaceutical composition for headache, migraine, nausea and vomiting

Technical Field

The present invention relates to the use of S-alkylisothiouronium (isothiouronium) derivatives, including, but not limited to, S-ethylisothiouronium, for the prevention or treatment of headache, including, but not limited to, migraine, and for the prevention or treatment of emesis, and more particularly to the alleviation of migraine symptoms, including, but not limited to, pain, nausea and vomiting.

Background of the invention

Headache is a term used to describe a range of different symptoms ranging from a moderately ill-fitting to a very severe syndrome known as migraine.

While the most severe and debilitating form of headache is migraine headache, there are other types of headache that are generally noteworthy and include, without limitation, premenstrual syndrome (PMS) associated with headache and a condition associated with post-alcohol consumption, commonly referred to as hangover. Symptoms such as headache, fever, chills, nausea, muscle and nerve pain, lethargy, and other symptoms are often manifested in the known hangover syndrome.

Although there are no life-threatening situations, PMS and hangover make people very uncomfortable and harmful to work or home life. Currently, the most common methods of treating these conditions include the use of NSAIDs, analgesics, and other prescription and OTC drugs.

The following publications give some background concerning headaches in general and migraine in particular, their causes and methods of treatment:

capobianco, "summary of diagnosis and pharmacological treatment of migraine", Mayo clin. 1055-1066.

Cohen, "migraine headache and treatment set", Drugs Benefitttrends (1996)8(8)28-30, 33-34, 41.

Diamond, "role non-steroidal anti-inflammatory Drugs play in migraine headaches," Drugs (1989) 37: 755-760.

Klaper, "Standard drug prescription for treatment of Headache," Headeache (1995) Apr., 225-.

Kumar, "recent progress in acute management of migraine and headache clusters", Journal of general Internal Medicine (1994) 9: 339-348.

Matthew, "serotonin 1D (5-HT1D) agonists and other agents in the treatment of acute migraine", Advances in headaches, (1997)15 (1): 61-81.

Pradalier, "therapeutic review: nonsteroidal anti-inflammatory drugs in the treatment and long-term prevention of migraine attacks, "Headache (1988) 28: 550-557.

Pryse-Phillips, "guidelines for diagnosis and control of migraine in clinical practice", can.med.assoc.j. (1997)156 (9): 1273-1287.

Wilkinson, "migraine and headache group-treatment thereof with sumatriptan: important review of current clinical experience ", cephaloalgia (1995) 15: 337-357.

The following paragraphs emphasize the prior art relating to migraine and its treatment.

Migraine symptoms and diagnosis

Migraine is a severe intermittent headache characterized by unilateral, intense, throbbing headaches, nausea, vomiting, visual flicker, rainbow-like color, blank spots, or other precursors and sensitivities to light and sound [ Larson, e.david, m.d. editor-in-Chief, "Mayo clinical Family Health Book", 1994, page 502-503 ]. Migraine refers to a group of symptoms that can occur together. One of the most significant symptoms is an incapacitating headache, pain on one side or the whole head, which can last from 2 to 72 hours. The pain is generally described as throbbing pain. These headaches are often, but not always, associated with feeling discomfort in the stomach or sensitivity to light, sound, or body activity. The pain is severe and patients with migraine often have to remain in bed. Dietary, mood, hormonal and environmental factors can trigger migraine attacks.

In practice there are two types of migraine. The most common is the so-called migraine without aura (common migraine), which accounts for 85% of all patients. The second most common type is the so-called migraine with aura (classic migraine), which is predominant in the remaining 15% of patients. Aura is a disorder of the nervous system that often precedes headache.

Migraine sufferers sometimes gain a prognostic sign before an attack. Some patients develop "aura" -a disruption of brain function twenty to thirty minutes before onset. It is characterized by visual disturbances such as light flicker and visual blurring or physical sensations affecting needle sticks and needle sticks on one limb or side. These disorders are usually short lasting and almost always do not produce long lasting effects after cessation. Other migraine sufferers experience a "prodromal symptom" that begins to appear hours or even a day before the headache attack. The symptoms may include yawning, fatigue, mood changes, overeating, and sensitivity to light (photophobia), sound (phonophobia), touch and/or smell. In most patients with prodrome symptoms, the headache pattern and location remains the same as in the case of the various migraine attacks. Other common symptoms include a sensation of numbness or tingling around the lips or hands, hallucinations, loss of speech, symptoms of depression, irritability (some people wish to stay in a dark room), restlessness, nausea, or loss of appetite, which occur in about 20% of migraine sufferers. A similar percentage of migraine sufferers lose vision in specific areas (so-called blind or scotomas) or see jagged, faint light, or flashing lights. Less common is image distortion; for example objects that appear smaller or larger than they originally were

Migraine is an incurable chronic condition. There is no effective laboratory test to help diagnose migraine, but the different patterns of headache often make it easy to identify. Headache is not life threatening and there is no evidence that it can lead to other conditions [ Larson, E.David, MD.Editor-in-Chief, "Mayo clinical Family Health Book", 1994, page 503 ]. The significance of migraine headache to public health is often overlooked, perhaps due to its episodic nature and mortality that does not affect the disease. However, migraine headache has a great impact on social activities and work, often disabling them.

Incidence of disease

The incidence of migraine is relatively high and it is said that about 6% of the male population and 18% of the female population suffer from migraine. Female migraine headache occurs mostly after puberty, and in most patients migraine headaches attack during the menstrual period and improve upon pregnancy. It is estimated that thirty-five million people in the united states alone have migraine headaches. For some people, intermittent episodes of migraine may occur once a week; other people may be less than once a year [ Griffith, H.winter, MD., "All-New Third Edition Complete Guide to Symptoms, Illness & Surgery" month 7 1995, page 425 ].

Current treatment for migraine:

there are several recognized drugs for the treatment of migraine. For many patients with sporadic migraine, treatment usually involves the simple use of analgesics (usually in combination with antiemetics, but such treatments have only limited value), non-steroidal anti-inflammatory drugs, or specific agents such as ergotamines or triptans. Although effective at best only occasionally, it is believed that the recognized prior art anti-migraine drugs can significantly alleviate migraine by causing vasoconstriction. Unfortunately, such recognized prior art migraine medications have some noticeable side effects associated with excessive vasoactivity in other areas of the body other than the general headache affliction area. This remote vasoactivity is effective but does not have any beneficial therapeutic effect on migraine. In fact, these vasoactive drugs are contraindicated for patients who are also suffering from, or may be suffering from, cardiovascular disease, such as hypertension, coronary artery disease, or peripheral vascular disease. Some other important side effects reported are chest pain or tightness, flushing, diffuse tingling, nausea, vomiting, leg and arm pain, weakness, drowsiness, and dizziness. For some patients, prophylactic agents such as beta blockers, tricyclic antidepressants, and sodium valproate can reduce, but not eliminate, migraine attacks. In the remaining migraine sufferer population, and in patients with intolerable side effects to the available drugs, there is a lack of a conventional pharmaceutical formulation with therapeutic effect without serious side effects. Thus, there remains a great need for drugs that are specific for migraine.

OTC analgesics: in some forms of migraine, it has been found that some patients are relieved in whole or in part by the use of over-the-counter analgesics, such as paracetamol, aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs including naproxen and naproxen sodium. However, when used alone, these substances rarely provide complete and rapid relief from all migraine symptoms, especially when the symptoms of the attack already include nausea or vomiting. Furthermore, their action is so slow that relief sometimes does not occur for at least a few hours.

Ergotamine drugs: one common method of treating migraine is the use of compounds with vasoconstrictive properties such as ergotamine or ergotamine analogs. However, ergotamine is a non-selective vasoconstrictor that constricts blood vessels throughout the body and thus has undesirable and potentially dangerous side effects. Ergotamines cannot be used in patients with peripheral vascular disease, coronary heart disease, hypertension, impaired liver or kidney function, severe pruritus or sepsis. Ergotamine cannot be used by women who are or may be pregnant. Nausea and vomiting have been reported in up to 10% of patients receiving therapeutic doses of ergotamine. Acute ergotoxemia is a particularly harmful side effect of ergot drugs, characterized by severe central and peripheral vasoconstriction, sometimes leading to the need to sever the affected limb and/or finger, nausea, vomiting, diarrhea, colic, headache, dizziness, paresthesia, and sometimes convulsive seizures. Chronic ergotoxemia is characterized by intermittent claudication, muscle pain, numbness, and cold limbs as well as other gastrointestinal and Central Nervous System (CNS) side effects. Some treatments include the administration of high doses of caffeine together with ergot or other pharmacological agents. In addition, many withdrawal symptoms are well documented as possible addictive ergot drugs and caffeine.

Triptan drugs (serotonin agonists): another treatment is the use of novel therapeutic agents known as serotonin agonists or 5-hydroxytryptamine (5-HT) agonists. The first substance of this family, sumatriptan, is undoubtedly an important advance in the treatment of migraine. Sumatriptan succinate is sold under the trade name IMITREX by Glaxo Wellcome Inc. Nevertheless, the use of sumatriptan in the treatment of migraine has certain limitations; such as low oral bioavailability, high headache recurrence rate and contraindication for patients with coronary artery disease.

The main mechanism of action of Triptans in migraine is the constriction of dilated cranial external blood vessels. In addition, triptans reduce neuropeptide release and plasma protein extravasation through the dura mater, and inhibit impulse transmission within the central trigeminal nervous system.

In general, the management of migraine is a complex matter due to the lack of simple treatments that need to be effective in all patients with the same type of migraine and the choice to forego treatment of these migraines or to choose a prophylactic treatment for these migraines. Furthermore, in the current use of drugs such as ergot alkaloid-ergotamine, which causes dependency when used for a long period of time, another important consideration is that the more potent anti-migraine drugs used in the current use, such as the ergot-like substance, mexican, cause serious side effects that limit their use when used for a long period of time.

Thus, there is a need for a drug that is effective in alleviating or treating the symptoms of migraine, which can be used either before the onset, e.g., during the aura, or during the onset, so that the symptoms of migraine can be quickly alleviated during the migraine attack and there are no side effects.

Antiemetic

One particularly important application of antiemetics is the prevention and treatment of nausea and vomiting associated with chemotherapy for cancer. Emesis is a well-known and common side effect of chemotherapeutic agents such as cisplatin. It can cause serious problems in cancer chemotherapy, and some patients vomit so severely that treatment must be stopped. Therefore, in order to alleviate such side effects of cancer chemotherapeutic drugs, it is often necessary to use antiemetics. The antiemetic agent used is generally a benzamide derivative, such as metoclopramide, which has dopamine antagonist activity. Due to their dopamine antagonist activity, benzamide derivatives such as metoclopramide themselves exhibit serious and undesirable side effects such as extrapyramidal effects, i.e. tardive dyskinesia, acute distonia, akathisia and tremor. Physiologically acceptable salts of carbazolones are described in US 5,578,628 as potent antiemetics, which are selective 5-hydroxytryptamine (5-HT) antagonists of 5-HT receptor-type neurons located at the terminal ends of primary afferents, and this type of neurons are also believed to be present in the central nervous system.

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

WO 98/13036 discloses the use of S-alkylisothiouronium derivatives, including some novel compounds, as a medicament for increasing arterial blood pressure or for protecting an individual from the effects of hyperoxia in tissues. These compounds are suggested for the treatment of acute hypotension, such as shock conditions and chronic arterial hypotension or oxygen poisoning. This invention illustrates the hypertensive effects of S-ethylisothiouronium diethylphosphate in each case. However, WO 98/13036 does not teach or suggest that S-alkylisothiouronium derivatives may be used to treat headache, migraine, or nausea and vomiting.

Summary of the invention

It has now been unexpectedly disclosed that S-alkylisothiouronium salt derivatives known as hypertensives also have a very potent effect in relieving pain in general, and in particular migraine symptoms. These S-alkylisothiouronium salt derivatives have also been found to be effective in the treatment of nausea and vomiting when the present invention is applied in practice. The unexpectedly low dose of S-ethylisothiouronium diethylphosphate allows for successful treatment of individuals suffering from migraine compared to the dose required for hypotensive applications. Treatment initiated at the apex of the migraine attack continued to exhibit relief within 60 minutes after administration. In some cases, significant improvement was reported to occur in about 15 minutes.

Accordingly, in one aspect, the present invention provides a pharmaceutical composition for treating headache, migraine, nausea or vomiting, comprising a compound having a structure represented by the general formula (I):

formula (I)

Wherein the content of the first and second substances,

R₁is a linear or branched, saturated or unsaturated alkylene group containing from 1 to 8 carbon atoms, which may optionally be substituted by one or more substituents selected from halogen, primary, secondary or tertiary amine, primary, secondary or tertiary alcohol, or which may be interrupted by one or more heteroatoms selected from O, N, and S;

R₂、R₃、R₄and R₅Each independently is 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, aryloxycarbonyl (carboaryloxy), alkylaryloxycarbonyl (carboalkoxyloxy), alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfate, arylsulfate, sulfonamide, thioalkyl, which may be optionally substituted with halogen;

A^-is a physiologically acceptable anion;

the composition further comprises a pharmaceutically acceptable carrier or diluent.

According to a generally preferred embodiment of the invention described below, the physiologically acceptable anion is an anion derived from a phosphoric acid, more preferably an anion derived from a phosphoric acid ester or amide, most preferably an anion derived from a mono-or di-alkyl ester of a phosphorous containing acid.

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

formula (I)

Wherein

R₁Is a linear or branched, saturated or unsaturated alkylene group containing from 1 to 8 carbon atoms, which may optionally be substituted with one or more substituents selected from halogen, primary, secondary or tertiary amine, primary, secondary or tertiary alcohol, or may be interrupted by one or more heteroatoms selected from O, N, and S;

R₂、R₃、R₄and R₅Each independently 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, aryloxycarbonyl, alkylaryloxycarbonyl, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfone, arylsulfonamide, thioalkyl, which may be optionally substituted with halogen;

A^-is a physiologically acceptable anion.

In another aspect of the present invention, there is provided a method for preparing a medicament for pain, migraine or nausea, which comprises the step of mixing a compound having the general formula (I) as an active ingredient with a pharmaceutically acceptable carrier or diluent:

formula (I)

Wherein the content of the first and second substances,

R₁is a linear or branched, saturated or unsaturated alkylene group containing from 1 to 8 carbon atoms, optionally substituted with one or more substituents selected from halogen, primary, secondary or tertiary amine, primary, secondary or tertiary alcohol, or may be interrupted by one or more heteroatoms selected from O, N, and S;

R₂、R₃、R₄and R₅Each independently 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, aryloxycarbonyl, alkylaryloxycarbonyl, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfone, arylsulfonamide, thioalkyl, which may be optionally substituted with halogen;

A^-is a physiologically acceptable anion.

In accordance with still further features in preferred embodiments of the invention the physiologically acceptable anion is selected from the group consisting of anions derived from phosphorous-containing acids, phosphites, amides, acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bitartrates, bisulfates, butyrates, camphorates, camphorsulfonates, digluconates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, 2-hydroxyethanesulfonates, isothionates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmitates, pectinates, 3-phenylpropionates, pivalates, propionates, succinates, tartrates, thiocyanates, glutamates, bicarbonates, p-toluenesulfonates, citrates, Chloride, bromide, iodide and undecabonate anions.

According to a preferred embodiment of the invention described below, the physiologically acceptable anion is an anion derived from a phosphorus-containing acid, more preferably an anion derived from a phosphite or an amide, most preferably an anion derived from a mono-or di-alkyl ester of a trivalent phosphorus-containing acid.

The preferred embodiments of the present invention are further characterized in that the medicament is packaged and identified as having anti-headache, anti-migraine or anti-emetic activity.

In a preferred embodiment of the invention, the compound is selected from:

s-methylisothiouronium methylphosphite;

dimethyl S-methylisothiouronium phosphate;

s-ethylisothiouronium metaphosphate;

ethyl phosphite S-ethyl isothiuronium salt;

diethyl S-ethylisothiouronium phosphate;

s-propylisothiuronium propylphosphite;

s-isopropylisothiuronium metaphosphate;

s-isopropylisothiouronium isopropyl phosphite;

s-butylisothiuronium dibutylphosphate; and

isobutyl phosphite S-isobutyl isothiouronium salt.

According to still further features in the described preferred embodiments the anti-headache, anti-migraine, anti-nausea or anti-emetic agent is formulated for oral, or parenteral administration. Particularly preferred formulations in the parenteral route are those suitable for injection, sublingual, transdermal, transmucosal or inhalation administration.

According to still further features in the described preferred embodiments the anti-migraine agent is formulated as a tablet or capsule.

According to still further features in preferred embodiments of the invention each tablet or capsule includes 10 to 300mg of the compound described above.

According to still further features in preferred embodiments of the invention each tablet or capsule includes between 20 and 200mg of the compound described above.

According to still further features in preferred embodiments of the invention each tablet or capsule includes 30 to 80mg of the compound described above.

According to still further features in the described preferred embodiments the method further comprises the step of packaging the medicament and identifying the medicament as having anti-headache, anti-migraine, anti-nausea or anti-emetic activity.

In a preferred embodiment, the therapeutically effective amount ranges from 0.1 to 3mg/kg body weight.

In a more preferred embodiment, the therapeutically effective amount ranges from 0.4 to 1.6mg/kg body weight.

In a presently most preferred embodiment, the therapeutically effective amount ranges from 0.5 to 1.2mg/kg body weight.

According to still further features in the described preferred embodiments the therapeutically effective amount is selected to be an amount effective to alleviate symptoms of migraine in less than 60 minutes after administration.

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

According to another preferred embodiment, the compound is administered at the onset of headache, in particular migraine, or nausea.

It should be clear that while migraine is the most severe form of headache, the treatment of the present invention is also applicable to other types of headache and nausea, including without limitation PMS or hangover associated with headache and nausea. This is particularly true because negligible side effects are observed in human subjects when using the compositions and methods of the present invention.

The compounds of formula (I) inhibit emesis. Thus, the compounds are also useful as antiemetics, i.e., for the prevention and treatment of nausea and vomiting. The compounds are of particular value in the prevention of emesis induced by cancer chemotherapeutic agents such as cisplatin. It is particularly contemplated that it may also be used for emesis induced by radiotherapy treatment. Accordingly, the compounds of formula (I) may be used for the prevention of emesis induced by radiotherapy, for example emesis induced by thoracic or abdominal radiation as in the treatment of cancer; or may be used in the treatment of radiation disorders. It will be appreciated that the compounds of formula (I) may be used prophylactically and that references herein to treatment include prophylactic treatment as well as alleviation of acute symptoms.

According to still further features in the described preferred embodiments the step of administering the compound is performed at or before the onset of nausea. One skilled in the art will recognize that oral administration after the onset of nausea is less than ideal.

The present invention successfully overcomes the disadvantages of known drugs by providing a compound which is effective in treating and/or alleviating headache, in particular migraine symptoms, or nausea. Presently, the preferred compounds have no significant side effects and show strong effects at low doses and produce therapeutic/palliative effects in a short period of time, as compared to the currently marketed drugs.

Description of the preferred embodiments

The present invention relates to the use of S-alkylisothiouronium derivatives for the treatment of headache, in particular migraine, or nausea and vomiting. The compositions of the present invention are effective in preventing or alleviating emesis associated with migraine or other medical conditions such as chemotherapy or radiation therapy and other migraine symptoms including phonophobia and photophobia. These compounds have previously been known to affect arterial blood pressure in cases of acute hypotension (e.g. after bleeding, trauma, shock or poisoning).

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified in the examples section. The invention is capable of being carried out or carried out in various ways by other embodiments. It is also to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

As used herein, the definition of "migraine" is to be understood broadly to include the group of headaches characterized by an unusually severe, unilateral, palpitations, headache duration of 4-72 hours, and may also include one or more of the following symptoms: nausea, vomiting, pre-emptive "or" pre-emptive "hypersensitivity to light and/or sound, and photophobia (e.g., visual impairment).

In one aspect of the present invention there is provided an anti-headache, anti-migraine, anti-nausea or anti-emesis medicament comprising as an active ingredient a compound having the general formula (I):

wherein the content of the first and second substances,

R₁is a linear or branched, saturated or unsaturated alkylene group containing from 1 to 8 carbon atoms, which may optionally be substituted with one or more substituents selected from halogen, primary or secondary amine, primary or secondary alcohol, or may be interrupted by one or more heteroatoms selected from O, N, and S;

R₂、R₃、R₄and R₅Each independently 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, aryloxycarbonyl, alkylaryloxycarbonyl, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfone, arylsulfonamide, thioalkyl, which may be optionally substituted with halogen;

A^-is a physiologically acceptable anion.

Preferably, the physiologically acceptable anion is derived, without limitation, from a phosphorus-containing acid selected from the group consisting of phosphorus-containing acids, acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bitartrates, bisulfates, butyrates, camphorates, camphorsulfonates, digluconates, glycerophosphates, hemisulfates, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate, isothionate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, 3-phenylpropionate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, chloride, bromide, iodide and undecanoate.

According to a generally preferred embodiment of the invention described below, the physiologically acceptable anion is an anion derived from a phosphorus-containing acid, more preferably an anion derived from a phosphate ester or amide, most preferably an anion derived from a mono-or di-alkyl ester of a trivalent phosphorus-containing acid.

As used herein and in the claims, the definition of "alkylene" refers to a saturated or unsaturated hydrocarbon chain containing straight or branched alkyl, alkenyl or alkynyl groups.

As used herein, the term "alkyl" is defined to mean a saturated hydrocarbon chain containing from 1 to 30, preferably from 1 to 6, carbon atoms, such as, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The definition of "alkyl" as used herein also refers to haloalkyl groups, which may contain halogen atoms. Alkyl also includes heteroalkyl with sulfur, oxygen, and nitrogen heteroatoms.

"alkenyl" and "alkynyl" as used herein refer to straight or branched chain hydrocarbon groups having 2 to 12 carbons and each having an unsaturated double or triple bond, such as vinyl, allyl, propargyl, 1-methylvinyl, but-1-enyl, but-2-ynyl, 1-methylbut-2-enyl, pent-1-enyl, pent-3-enyl, 3-methylbut-1-ynyl, 1-dimethylallyl, hex-2-enyl and 1-methyl-1-ethylallyl.

The term "cycloalkyl" as used herein is defined to mean a cyclic group including, without limitation, cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a lower alkyl group, including, but not limited to cyclohexylmethyl.

The "alkoxyalkyl" groups used herein for the R substituent are preferably groups containing a total of from 1 to 22 carbon atoms. Mention may be made, for example, of methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, n-propoxyethyl and i-propoxyethyl.

The term "alkoxy" as used herein, is defined as an alkyl group attached to the parent molecular moiety through an oxygen atom.

The term "alkoxyalkoxy" as used herein, is defined to mean an alkoxy group attached to the parent molecular moiety through an alkoxy group.

The term "halo" or "halogen" as used herein is defined to mean I, Br, Cl or F.

The term "carboxy" as used herein is defined as-COOH. The term "ester" as used herein is defined to mean-COOR; and the term "amide" refers to-CONH₂or-CONHR or-CONR₂. The term "cyano" as used herein is defined as meaning-CN.

As is well known in the art, phosphorus-containing and other salts of S-alkylisothiouronium may be synthesized in a variety of ways, for example by alkylating thiourea with the appropriate trialkyl phosphate or dialkyl phosphite by heating in an organic solvent.

Without excluding the other options listed below, S-ethylisothiouronium diethylphosphate is the currently preferred compound for the treatment of headache, in particular migraine, and nausea or vomiting. Other examples of S-alkylisothiouronium derivatives useful for treating migraine according to the present invention include, but are not limited to, S-methylisothiouronium methylphosphite; dimethyl S-methylisothiouronium phosphate; s-ethylisothiouronium metaphosphate; ethyl phosphite S-ethyl isothiuronium salt; diethyl S-ethylisothiouronium phosphate; s-propylisothiuronium propylphosphite; s-isopropylisothiuronium metaphosphate; s-isopropylisothiouronium isopropyl phosphite; s-butylisothiuronium dibutylphosphate; and isobutyl phosphite S-isobutyl isothiouronium salt.

These compounds are known to be safe for humans and are well known in the art as derivatives of phosphorus-containing S-alkylisothiouronium with low toxicity, the LD of which₅₀(50% lethal dose) is 100-1000mg/kg, well above the therapeutic dose of these compounds.

The anti-headache, anti-migraine, anti-nausea and anti-emetic agents of the present invention are preferably packaged and preferably identified as having such activity. Such a confirmation may be printed, for example, on a package into which the medicament is inserted, a package or container containing the medicament.

The compounds of the present invention may be administered to the subject to be treated as such or may be administered in the form of a pharmaceutical composition in admixture with a suitable carrier or excipient.

The definition of "pharmaceutical composition" as used herein refers to the formulation of one or more of the compounds described herein, or a physiologically acceptable salt or prodrug thereof, with other ingredients such as physiologically suitable carriers or excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compound to an organism.

The term "prodrug" is defined to mean an agent that is converted in vivo to the active parent drug. Prodrugs are often used because they may be easier to administer than the parent drug in some cases. For example, they are bioavailable when administered orally, whereas the parent drug is not bioavailable when administered orally. Prodrugs in a composition may also have improved solubility compared to the parent drug in the pharmaceutical composition.

The term "excipient" is defined herein to mean an inert substance added to the composition to further facilitate administration of the compound. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

The pharmaceutical composition may also include one or more additional active ingredients, such as, by way of non-limiting example, conventional anti-migraine agents.

The pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, for example, by means of conventional mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions used in the present invention can thus be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Suitable formulations depend on the chosen route of administration.

For injection, the compounds of the invention may be prepared as aqueous solutions, preferably as solutions in physiologically compatible buffers such as Hank's solution, ringer's solution, or physiological saline buffer. For transmucosal administration, a suitable penetrant or penetrants appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and are, for example, DMSO, or polyethylene glycol.

For oral administration, the compounds can be readily formulated by combining the compounds with pharmaceutically acceptable carriers well known in the art. Such carriers ensure that the compounds of the invention can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, suitable for oral ingestion by a patient. Pharmaceutical preparations for oral use can be prepared using solid excipients, the resulting mixture being ground or not, the mixture of granules being processed, if desired with the addition of suitable auxiliaries, after which tablets or dragee cores are obtained. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added thereto.

Dragee cores may be suitably coated. For this purpose, concentrated sugar solutions may be used, which may or may not contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings in order to identify or characterize different combinations of active compound doses.

Pharmaceutical compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and may or may not contain stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Further, a stabilizer may be added thereto. All formulations for oral administration should be in dosages suitable for the chosen route of administration.

For buccal administration, the composition may be in the form of tablets or lozenges formulated in a conventional manner.

For administration by inhalation, the compounds for use in the present invention are typically delivered in the form of an aerosol spray presentation in pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit is measured by a valve delivering a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agents in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or substances that increase the solubility of the compound to give a highly concentrated solution.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

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

The pharmaceutical compositions described herein may also contain solids of suitable gel phase carriers or excipients. Examples of such carriers or excipients include, without limitation, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

Pharmaceutical compositions for use in the context of the present invention include compositions wherein the active ingredient is contained in an amount effective to achieve the desired purpose. More specifically, a therapeutically effective amount refers to an amount of a compound that is effective to prevent, alleviate or ameliorate symptoms of disease in the subject being treated.

Determination of a therapeutically effective amount is well within the skill of those in the art, especially in light of the detailed disclosure herein.

Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures using cell cultures or experimental animals, e.g., by determining the IC of the test compound₅₀(concentration providing 50% inhibition) and LD₅₀(lethal dose causing 50% of the test animals to die) was performed. The data obtained from these cell culture assays and animal studies can be used to generate a range of dosage ranges for use in humans. The dosage may vary depending on the dosage form and route of administration used. The exact formulation, route of administration and dosage can be selected by the individual physician in accordance with the patient's circumstances. (see, e.g., Fingl et al, 1975, "Pharmacological Basis of therapy (The Pharmacological Basis of Therapeutics)", Chapter 1, page 1).

Depending on the severity and responsiveness of the condition being treated, administration may be a single administration of the sustained release composition, the course of which may last from several days to several weeks or until cure or diminution of the disease condition occurs.

The amount of the composition to be administered will, of course, depend on the individual being treated, the severity of the affliction, the mode of administration, the judgment of the prescribing physician, and the like.

Sustained release tablets or capsules containing S-alkylisothiouronium may be used prior to an attack, for example in patients who are about to undergo chemotherapy or other treatment known to cause nausea or vomiting, women who are typically followed by nausea or migraine headaches in the premenstrual phase, or migraine sufferers who experience "aura" and may be identified as a pre-migraine stage. The tablet or capsule may also be formulated such that a portion of the active ingredient is released immediately to provide an initial migraine-relieving effect, while the other portion is released slowly and quantitatively.

The term "initial migraine relief" as used herein is defined as the relief or disappearance of symptoms of migraine headache within a predetermined time frame after administration, and in the present invention specifically means the relief or disappearance of symptoms of migraine headache within about 10 to 60 minutes after administration.

Each tablet or capsule of the invention preferably contains from 10 to 300mg, preferably from 20 to 200mg, more preferably from 30 to 80mg of the active compound (S-alkylisothiouronium derivative). The term "about" as used herein means ± 20%.

In another aspect, the invention provides a method of preparing an anti-headache, anti-migraine, anti-nausea or anti-emetic agent. The process of the invention is carried out by mixing a compound having the general formula (I) as an active ingredient with a pharmaceutically acceptable carrier or diluent:

wherein

R₁Is a linear or branched, saturated or unsaturated alkylene radical comprising from 1 to 8 carbon atoms, which may optionally be substitutedSubstituted with one or more substituents selected from halogen, primary or secondary amine, primary or secondary alcohol, or may be interrupted by one or more heteroatoms selected from O, N, and S;

R₂、R₃、R₄and R₅Each independently 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, aryloxycarbonyl, alkylaryloxycarbonyl, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfone, arylsulfonamide, thioalkyl, which may be optionally substituted with halogen;

A^-is a physiologically acceptable anion.

According to a preferred embodiment of the invention, the method further comprises the steps of packaging the medicament and determining that the medicament has anti-headache, anti-migraine, anti-nausea and anti-emetic activity as described above. The identification of this drug as an anti-headache agent, and in particular an anti-migraine substance, is a novel indication of the S-alkylisothiouronium derivatives known as hypertensives, and there has been no previous suggestion that they could be used to treat or alleviate the symptoms of headache, migraine or nausea.

In another aspect, the invention provides a method of treating headache, migraine or nausea. According to this aspect of the invention, the method is accomplished by administering to the subject a therapeutically effective amount of a compound having the general formula (I):

wherein

R₁Is straight-chain or branched, saturated or containing 1 to 8 carbon atomsAn unsaturated alkylene group which may be optionally substituted with one or more substituents selected from halogen, primary or secondary amine, primary or secondary alcohol, or may be interrupted by one or more heteroatoms selected from O, N, and S;

R₂、R₃、R₄and R₅Each independently 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, aryloxycarbonyl, alkylaryloxycarbonyl, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, alkylsulfone, arylsulfonamide, thioalkyl, which may be optionally substituted with halogen;

A^-is a physiologically acceptable anion.

It should be noted in this regard that the reaction of human subjects to and the beneficial effects of S-ethylisothiouronium diethylphosphate were evaluated in ongoing clinical trials as described in the examples section below. Unexpectedly, these subjects administered during a migraine attack exhibited significant beneficial drug effects. It is administered at a dose well below the effective oral dose for the treatment of hypotension (which is typically about 100 mg). In addition, the drug was found to be effective in reducing headache symptoms in a relatively short period of time, averaging about 45 minutes, when the subject was at the apex of a migraine attack.

In addition to eliminating acute headache, the medicine can eliminate unpleasant feeling of nausea and photophobia, and improve impaired vision focusing. The drug appears to have a rapid and long-lasting effect. In addition, its rapid mode of action also indicates that the drug is absorbed very rapidly. In addition, no side effects were shown.

These results are quite unexpected. It will be appreciated in this regard that migraine drugs are generally recognized as having the fastest onset when administered by parenteral routes. However, therapeutic relief from migraine is often difficult to achieve with these recognized migraine medications, regardless of how they are administered. When administered orally, the accepted migraine drugs have a significantly slower onset of action than when administered parenterally, such that no relief of the headache occurs for as long as 2-3 hours after administration.

The term "therapeutically effective amount" or "therapeutically effective" as used herein in reference to a dosage of a drug means that the dosage provides a particular pharmacological response when the drug is administered to a significant number of subjects in need of such treatment. The "therapeutically effective amount" may vary depending on, for example, the physical condition of the patient, the age of the patient, and the severity of the disease. It is emphasized that the understanding of migraine headaches is not yet complete and that there are differences in the etiology of particular migraines, as well as differences in their response to particular drugs. Thus, it will be understood by those skilled in the art that the phrase "administering a particular pharmacological response to a significant number of subjects in need of such treatment" is an admission that "a therapeutically effective amount" although the dosage is indeed a "therapeutically effective amount", administration to a particular subject in a particular situation is not always capable of halting the onset of migraine or alleviating the actual migraine headache.

The definition relating to the "long-acting" of the S-ethylisothiouronium diethylphosphate relates to its pharmacokinetic half-life. It should be noted in this regard that in the case described in the examples section below, the migraine attack was eliminated within minutes after administration and no additional treatment was required in the reported cases.

Preclinical trials have shown two other important problems relating to the "recurrence" of headache several hours after administration and the side effects of current commercial anti-migraine drugs. After successful treatment has been initiated, the recurrence of headache is another disadvantage of the currently available anti-migraine preparations. That is, at the onset of treatment for a migraine attack, after a dose of a known therapeutic agent is administered to a subject in an effective amount and relief from the migraine has been observed, the symptoms of the migraine attack once more occur after about 1-8 hours to about 12 to 24 hours after the first relief. Headache occurring in the above-mentioned cases can have a variety of definitions and can be interchanged between the definitions, these being "rebound", "relapse", "recurrence", "continuation" or "secondary" headache. This definition has not been refined, and it is currently unknown whether such a later headache is a continuation of the physiological chain of events that caused the original headache or a new headache due to other or repeated, but unrelated, underlying pathologies. Secondary headaches may also be in response to an initially successful therapeutic agent treating the initial migraine symptoms. As used herein, the terms "rebound", "relapse", "recurrence", "continuation", and "secondary" (as defined below) are considered synonymous with no inference as to the mechanism or cause of migraine headache.

According to the case report described here, this phenomenon is not observed when S-ethylisothiouronium diethylphosphate is accepted.

It should be noted in this respect that migraine attacks are associated with vasodilation of the head, and that relief of migraine headaches is particularly associated with a reduction in this type of vasodilation. As a side effect, anti-migraine agents can cause abnormal blood flow (through vasodilation or vasoconstriction). Thus, the surprising efficacy of S-ethylisothiouronium diethylphosphate as an antimigraine agent and its efficacy in controlling abnormal blood flow are answers to attenuate migraine symptoms without causing the side effects of known antimigraine agents.

In addition, S-ethylisothiouronium diethylphosphate may be advantageously used in combination with other antimigraine agents, such as ergotamine derivatives, or serotonin agonists. The addition of S-ethylisothiouronium diethylphosphate to known therapeutic agents reduces the side effects of known drugs and provides initial relief to the patient in a matter of minutes, with lower amounts of each drug required for the combination therapy.

As discussed above, the compounds can be formulated for oral, injectable, inhaled or transdermal administration.

Oral administration is by tablet or capsule, with a preferred dose range of 10 to 200mg of compound, preferably 20 to 70mg of compound, and about 50mg of compound according to clinical trial results. Thus, a therapeutically effective amount of the compound ranges from 0.1 to 3.0mg/kg body weight, preferably from 0.4 to 1.6mg/kg body weight, more preferably from 0.5 to 1.2mg/kg body weight.

The therapeutically effective dose range is selected so that a substantial relief of migraine symptoms is achieved within 15-60 minutes after administration.

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

Additional objects, advantages, and novel features of the present invention will become more apparent to those skilled in the art from the following examples, which are not intended to be limiting. Furthermore, each of the various embodiments of the present invention, as well as the aspects of the present invention described above and in the claims below, can be supported experimentally in the following embodiments.

Examples

Reference is now made to the following examples, which together with the above description illustrate the invention in a non-limiting manner.

Example 1

Results of clinical trials for migraine treatment with Difetur oral formulations (tablets)

Study protocol

Dose escalation studies the safety and efficacy of Difetur tablets for the treatment of acute migraine attacks.

1. Purpose of study

The purpose of the following review protocol is to evaluate the safety and potential efficacy of Difetur (S-ethylisothiouronium diethylphosphate) tablets in the treatment of simple acute migraine attacks at increasing doses starting from 10mg and up to 50 mg. The study was an open study with a selected population of patients with moderate or severe migraine headaches without aura classified according to IHS criteria. The study was conducted according to established international standards for assessing the safety and efficacy of migraine.

2. Study protocol

The study was conducted as a 5 team (group) study. Only female patients with migraine headaches without aura classified according to IHS criteria were used in the study. Each group consisted of 10 migraine patients treated with Difetur in the hospital during an acute migraine attack. The initial dose of Difetur was 10mg (1 tablet) and subsequently increased to 20mg, 30mg, 40mg, and 50 mg. The total number of patients enrolled was 50. These patients are hospitalized for treatment and evaluated after at least 4 hours for safety, efficacy and possible side effects of Difetur.

3. Dosing regimens

The first group of 10 patients each received study drug in a single dose tablet form with an initial dose of 10 mg. The 50mg dose is administered as two tablets of 25mg each. The tablets were individually packaged in blister packs and the study drugs were labeled as test drugs. Each dose was given to 10 patients in a gradual increase. The medication was swallowed with a glass of water under the supervision of the attending physician.

4. Efficacy assessment

4.1 first efficacy objective is to reduce headache

Headache severity was scored orally on a 4 point scale: severe (grade 4), moderate (grade 3), mild (grade 2) and no pain (grade 1). It is believed that reducing the severity of headache from severe or moderate (grade 3-4) to mild or no pain (grade 1-2) is successful.

4.2 second efficacy goal is to reduce nausea, vomiting and sensitivity to light and sound

The presence, absence or disappearance is confirmed by patient certification.

Results of the study

TABLE 1Summary of treatment results for migraine headache (treatment started during migraine attack)

Serial number	Dosage form(mg)	Percentage of patients who benefited by treatment	Disappearance of action(min)
				1	10	0
2	20	70	43
				3	30	70	58

1. Difetur doses for each treatment.

2. Headache relief is considered effective if the patient reports a reduction in the severity of the headache from severe or moderate (grade 3-4) to mild or no pain (grade 1-2). [ headache severity score: 1 is painless; 2 is mild; 3-medium; 4-severe pain ].

3. Patients reported a time to grade 1-2 headache relief after taking the medication.

Unexpectedly, it has now been found that low doses of Difetur, which are ineffective or ineffective in relieving the severity of migraine headaches, are effective in reducing or eliminating the symptoms of nausea. In addition, it was found that nausea was alleviated for a shorter period of time than was recorded in headache severity relief. This supports its use as an antiemetic.

TABLE 2Summary of emesis treatment results during migraine attack

Serial number	Dosage form(mg)	Patients affected by the treatmentPercentage of	The time until onset(min)
				1	10	70	28
2	20	100	25
				3	30	100	29

4. The dose for each treatment.

5. Percentage of patients who showed a positive response to diffeur administration.

6. The patient reported the time required to eliminate vomiting after dosing.

Example 2

Multidose Difetur for relieving migraine headaches

Case report 1

Previous history of drugs: the patient was a 30 year old female smoking, first diagnosed with a typical migraine at age 17, and otherwise quite healthy. Until two years ago, the frequency of migraine attacks was seven attacks per month. In the last two years, they were treated with different types of well-known drugs, but with little or no effect. Due to the lack of response to drug treatment during migraine attacks, they have tried to select other drugs for treatment.

As a result, the frequency of migraine attacks was reduced to about 3 per month after treatment with S-ethylisothiouronium diethylphosphate. In addition, the nature of the migraine attack has shifted to weaker intensity. The reported therapeutic effect of S-ethylisothiouronium diethylphosphate on migraine headache is to make the pain very weak. Currently, she experiences migraine attacks about twice a month, mostly before the menstrual period, when the weather conditions are very hot, or when the weather changes greatly. Premenstrual migraine attacks are generally longer and more acute than other migraine attacks. The duration of each migraine attack is 24-72 hours.

Past drug treatments: before choosing to use alternative therapeutic drugs, she had used the following: temigran, migrleve, sumatriptan and zolmiter. These treatments are terminated by a variety of strong side effects including hand tremor, shivering, dry mouth, nausea and vomiting.

Treatment with S-ethylisothiouronium diethylphosphate:

first attack: the patient suffered acute migraine headaches lasting 72 hours. Although she took the prescribed medication every two hours, the intensity of migraine headache with pain did not change. The patient used a 50mg dose of S-ethylisothiouronium diethylphosphate (25mg per tablet, two tablets) on the following day. The medicine is administered on an empty stomach; the patient did not eat or drink anything before taking the medication. Within 10 to 15 minutes after administration, the pain suddenly disappeared, as did all other symptoms that appeared during the migraine attack.

Second episode (three weeks later): the second migraine attack begins at night. The next day the patient took 2 additional tablets of S-ethylisothiouronium diethylphosphate (50 mg). This time the tablet was taken at the apex of the migraine attack after the meal. Within 20 minutes the headache is relieved, the patient is able to concentrate his vision and the photophobia disappears. Some light headaches but with reduced intensity. After three hours the patient took two additional tablets of S-ethylisothiouronium diethylphosphate (50 mg). Within 15 minutes, the migraine pain disappeared.

The third episode: migraine headache occurs (two and a half weeks after the second attack) on his way to work. 1 hour after the onset of the most severe migraine attack, the patient took 2 tablets of S-ethylisothiouronium diethylphosphate (25mg per tablet). The medicine is administered on an empty stomach. The migraine symptoms disappeared within 11 minutes.

Side effects: no side effects were observed after administration of S-ethylisothiouronium diethylphosphate.

Example 2

Case report 2

Previous history of drugs: the patient was a non-smoking 34 year old female with migraine attacks in the last two years. Migraine attacks before menstruation, with a frequency of once a month. Pain occurs at the temples, sinoatrial node and extends down to the mandible. The duration of photophobia was about 48 hours. To date, the patient has not received specific medical treatment and has often taken general analgesic medications in the past.

Past drug treatments: conventional pain relief drugs (analgesics).

Treatment with S-ethylisothiouronium diethylphosphate:

first attack: an acute migraine attack begins in the morning and the symptoms become more and more intense the day. Just before noon, the patient took one tablet of S-ethylisothiouronium diethylphosphate (25 mg). No significant change in migraine pain was observed. After two hours, the patient used 2 additional tablets of S-ethylisothiouronium diethylphosphate (25mg each). After ten minutes, the migraine pain disappeared.

The second attack: migraine attacks (about four weeks after the first attack) due to very hot weather. This attack is more intense than a typical migraine attack. In the morning, the patient took 2 tablets of S-ethylisothiouronium diethylphosphate (50mg) on an empty stomach. Migraine headache was significantly alleviated within 20 minutes after taking S-ethylisothiouronium diethylphosphate. Pain disappeared after fifteen minutes. In the afternoon of the day, the patient experienced light pain. This time the patient took some pain medication himself, and the pain disappeared.

Side effects: no side effects were observed after 25 or 50mg of S-ethylisothiouronium diethylphosphate was taken by the guardian.

Discussion of results

Significant and unexpected beneficial effects were shown in both case reports of the administration of S-ethylisothiouronium diethylphosphate during migraine, especially in the first case report. This effective dose is about half the effective dose (about 50-100mg) for treating hypotension. In addition, the patient found that the drug was effective in eliminating the migraine symptoms in less than 20 minutes at the peak of the migraine attack. In addition to eliminating acute migraine headache, the drug also eliminates nausea and unpleasant photophobia and improves impaired visual focus. The surprising effect of the drug was repeated three times for the first patient and twice for the second patient. The drug appears to be more effective when administered in the open abdomen. In addition, no side effects were found.

Therefore, it can be concluded that S-ethylisothiouronium diethylphosphate is a very effective drug for treating and alleviating the symptoms of migraine. It has a rapid mode of action, an effective low dose, and it is reported to be completely free of side effects according to the described cases.

Example 3

Antiemetic test with test animals

The effect of ferrets on emesis for test compounds was tested according to the method described by Florezyk, schuricg and Bradnet (cancer treatment report, 198266(1)187-9) and is summarized below. Test compounds and cisplatin were prepared and administered in physiological saline.

a) control-No test Compound

Emesis was induced in groups of 6 male ferrets weighing 1.5-2kg per group by intravenous administration of cisplatin at a dose of 10 mg/kg. Emesis began to occur within 30 to 70 minutes after injection, with the number of vomits/retches (intermittently) occurring within a 2 hour period ranging from 30 to 60 (an average of 40 vomits/retches per hour). Changes in emesis behavioral characteristics were also noted.

b) Using test compounds

Groups of 6 male ferrets (1.5-2kg) were administered intravenously with test compounds at doses of 0.01, 0.1 and 1mg/kg prior to cisplatin administration as described above. The test animals were observed for 3 hours.

The effect of test compounds on emesis was also evaluated by intraperitoneal administration in a similar manner to that described above. Cisplatin is therefore administered intraperitoneally to a group of male ferrets at a dose of 5-10mg/kg, and the time to onset of emesis and the number of intermittent retches are recorded. Test compound was administered intraperitoneally at a dose of 1mg/kg in a second group of male ferrets 30 minutes before and 1 hour after the intraperitoneal administration of cisplatin.

Example 4

Clinical trials for intravenous Difetur treatment of migraine attacks

1. Overview of the study

The purpose of the protocol below is to evaluate the safety and potential efficacy of Difetur 10% solution for injection at a dose of 0.6mg/kg in the treatment of simple acute migraine attacks. The study was an open study with a selected population of patients with moderate to severe migraine headache-associated pain, acutely classified according to IHS criteria. The study was conducted according to established international standards for assessing the safety and effectiveness of migraine treatment.

2. Drug delivery

Difetur is in the form of a 10% solution (100mg/mL) in a 1mL ampoule. Before treatment, it was dissolved in 100mL of physiological saline solution in an intravenous set. The dosage was 0.6mg/kg by intravenous drip over 10 minutes.

3. Evaluation of effectiveness

The severity of headache was rated orally with a 5 point scoring system: very severe (grade 4), severe (grade 3), moderate (grade 2), mild (grade 1), no pain (grade 0). Reducing the severity of headache from very severe, severe or moderate (grade 4-2) to mild or no pain (grade 1-0) is considered successful.

4. Results of the study

The study included 13 patients suffering from various severity levels. Headache was significantly alleviated in all patients except one patient who was observed to have no relief. Efficacy and onset of action are listed in the following table:

TABLE 3Summary of migraine headache IV treatment results

Grade of headache	Number of patients	Percentage of patients benefited by treatment	Mean time required for onset (min)
				4	1	100％	50
3	4	100％	25.5
				2	8	87％	13.7

1. Reducing the severity of headache from very severe, severe or moderate (grade 4-2) to mild or no pain (grade 1-0) is considered successful.

2. Patients reported the time after treatment began when the headache had decreased to a severity level of 1-0.

While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and scope of the appended claims. All publications, patents and patent applications cited in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this specification shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims (17)

1. A medicament for the treatment of headache, migraine, nausea or vomiting comprising as an active ingredient a compound having the formula:

wherein the content of the first and second substances,

R₁is a linear or branched, saturated or unsaturated alkylene radical containing from 1 to 8 carbon atoms,which may be optionally substituted with one or more substituents selected from halogen, primary, secondary or tertiary amines, primary, secondary or tertiary alcohols, or may be interrupted by one or more heteroatoms selected from O, N, and S;

R₂、R₃、R₄and R₅Each independently is 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, aryloxycarbonyl, alkylaryloxycarbonyl, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, arylsulfonamide, thioalkyl, which may optionally be substituted with halogen, with the proviso that R is 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, aryloxyca₂、R₃、R₄And R₅Not hydrogen at the same time;

A^-is a physiologically acceptable anion.

2. The medicament of claim 1, wherein the physiologically acceptable anion is selected from the group consisting of acid esters derived from phosphoric acid, phosphorous acid, amides, acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bitartrates, bisulfates, butyrates, camphorates, camphorsulfonates, digluconates, glycerophosphates, hemisulfates, heptanoates, caproates, fumarates, hydrochlorides, 2-hydroxyethanesulfonates, isothionates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmitates, pectinates, 3-phenylpropionates, pivalates, propionates, succinates, tartrates, thiocyanates, phosphates, glutamates, bicarbonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmitates, pectinates, 3-phenylpropionates, pivalates, propionates, succinates, tartrates, thiocyanates, phosphates, glutam, P-toluenesulfonate, chloride, bromide, iodide and undecabonate anions.

3. The medicament of claim 1, wherein the medicament is packaged and identified as having anti-headache, anti-migraine, anti-nausea or anti-emetic activity.

4. The medicament of claim 1, which is prepared into a formulation for oral administration, injection administration, inhalation administration, transmucosal administration, or transdermal administration.

5. The medicament of claim 4, which is formulated as a tablet, capsule or ampoule for injection.

6. A medicament as claimed in claim 5, wherein each tablet or capsule contains from 10 to 300mg of said compound.

7. The medicament of claim 5, wherein each of the tablets, capsules or ampoules comprises between 20 and 200mg of the compound.

8. The medicament of claim 5, wherein each of the tablets, capsules or ampoules comprises between 40 and 80mg of the compound.

9. Use of a compound having the formula:

wherein the content of the first and second substances,

R₁is a linear or branched, saturated or unsaturated alkylene group containing from 1 to 8 carbon atoms, which may optionally be substituted by one or more substituents selected from halogen, primary, secondary or tertiary amines, primary, secondary or tertiary alcohols or may be interrupted by one or more heteroatoms selected from O, N, and S;

R₂、R₃、R₄and R₅Each independently is hydrogen, hydroxy, straight chainOr 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, aryloxycarbonyl, alkylaryloxycarbonyl, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, sulfonamide, thioalkyl which may be optionally substituted by halogen;

A^-is a physiologically acceptable anion.

10. The use according to claim 9, wherein the physiologically acceptable anion is selected from the group consisting of anions derived from phosphoric acid, esters of phosphoric acid, amides of phosphoric acid, acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bitartrates, bisulfates, butyrates, camphorates, camphorsulfonates, digluconates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, 2-hydroxyethanesulfonates, isothionates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmitates, pectinates, 3-phenylpropionates, pivalates, propionates, succinates, tartrates, thiocyanates, phosphates, glutamates, bicarbonates, p-toluenesulfonates, salts of benzoic acid, and mixtures thereof, Chloride, bromide, iodide and undecabonate anions.

11. The use of claim 9, further comprising the step of packaging the medicament and confirming that the medicament has anti-headache, anti-migraine, anti-nausea or anti-emetic activity.

12. The use according to claim 9, wherein the compound is selected from the group consisting of:

s-methylisothiouronium methylphosphite;

dimethyl S-methylisothiouronium phosphate;

s-ethylisothiouronium metaphosphate;

ethyl phosphite S-ethyl isothiuronium salt;

diethyl S-ethylisothiouronium phosphate;

s-propylisothiuronium propylphosphite;

s-isopropylisothiuronium metaphosphate;

s-isopropylisothiouronium isopropyl phosphite;

s-butylisothiuronium dibutylphosphate; and

isobutyl phosphite S-isobutyl isothiouronium salt.

13. The use according to claim 9, wherein the anti-migraine agent is formulated for oral, injectable, inhaled, transmucosal or transdermal administration.

14. The use according to claim 13, wherein the medicament is formulated as a tablet, capsule or ampoule.

15. The use according to claim 14, wherein each of said tablets, capsules or ampoules comprises between 10 and 300mg of the compound.

16. Use according to claim 14, wherein each of said tablets, capsules or ampoules comprises between 20 and 200mg of the compound.

17. The use according to claim 14, wherein each of said tablets, capsules or ampoules comprises between 40 and 80mg of the compound.