TWI404528B - Use of benzo-fused heterocycle sulfamide derivatives for the treatment of migraine - Google Patents

Description

Use of a benzodiazepine diamine derivative for the treatment of migraine

The present application claims priority to U.S. Provisional Application Serial No. 60/773,764, filed on Jan.

The present invention relates to the use of a benzocycloheterosulfonyl diamine derivative for the manufacture of a medicament for the treatment or prevention of migraine.

Migraine is a chronic, occasional, and weak physical condition that is diagnosed by the presence of moderate to severe rhythmic unilateral headaches that last between 4 and 72 hours. In addition, this headache is sometimes accompanied by temporary sensations (phobia and fear) and/or gastrointestinal (nausea, vomiting) disorders. Migraine can exist with or without warning.

A migraine without warning is defined as the following criteria for at least five seizures: (a) the headache episode lasts for 4-72 hours and the headache has at least two of the following characteristics: unilateral position, rhythmic nature, moderate or severe intensity Directly affects daily activities and deteriorates through going upstairs or similar daily routines; (b) At least one of the following occurs during headache: nausea and/or vomiting, fear of light or fear of hearing (headache disorder, brain neuralgia) And classification and diagnostic criteria for facial pain, International Headache Association's Headache Classification Committee, Cephalalgia 1988; 8 Suppl 7: 1-96).

A premeditated migraine is defined as at least two episodes accompanied by three of the following four characteristics: (a) one or more fully reversible signs of aura; (b) at least one symptom is gradually developed over four minutes or Two or more symptoms occur in sequence; (c) symptoms without warning continue for more than 60 minutes; (d) headaches start before, at the same time as, or after, and the free interval between omen and headache is less than about 60 minutes (headache disorder, Classification and diagnostic criteria for neuropathic pain and facial pain, International Headache Association's Headache Classification Committee, Cephalalgia 1988; 8 Suppl 7: 1-96).

The clinical situation of patients with migraine is represented by migraine without warning (about 70% of migraine patients) and migraine with warning (about 30% of migraine patients). Migraine without warning is also known as a common migraine and usually lasts for an average of about 18 to 24 hours. The pain at the time of onset is often one-sided, but it can also be alternating on both sides or on both sides. Migraine with signs can be associated with visual impairment and the cues usually develop over 5-20 minutes and usually last less than 60 minutes. Migraine with signs can be associated with episodes without warning. The most common form of migraine with aura is a typical migraine migraine, also known as classical migraine. A headache started within 60 minutes after the end of the omen. Other less common forms of migraine exist and include, but are not limited to, migraine with prolonged omen, associated with prognostic symptoms lasting more than 60 minutes; migraine signs without headache; migraine with acute onset; and dizziness , gait disorders and/or loss of consciousness related brain migraine; eye muscle acupuncture migraine associated with eye acupuncture, diplopia and prolapse; retinal migraine; and familiality associated with hemiplegia or hemiplegia Hemiplegia migraine (Migraine.Cognos.Decision Resources, 2000).

Pharmacological interventions for medical management of migraine can be divided into two general strategies: prevention methods and treatments to eliminate pain and related syndromes or frustration.

The goal of preventive care is to reduce the frequency of migraine attacks, reduce severity, and/or shorten the duration of attacks. Prophylactic treatment of migraine includes anticonvulsants, antidepressants, beta blockers, calcium channel group preparations, non-cholesterol anti-inflammatory agents (NSAIDs), and serotonin receptor antagonists. Many of these agents are used outside the scope of drug indications in migraine prophylaxis (Migraine. Cognos. Decision Resources, 2000).

According to clinical studies, specific agents within the classification of antidepressants and beta -blockers have been shown to have the greatest efficacy and optimal side effect effects.

Anticonvulsants used in the prevention of migraine include, but are not limited to, topiramate (Ortho-McNeil's TOPAMAX), valproic acid (Abbott's DEPAKENE), divalproex sodium (Abbott's DEPAKENE), And gabapentin (Warner-Lambert's NEURONTIN).

Antidepressants used in migraine prophylaxis include, but are not limited to, tricyclic antidepressants such as amitriptyline (Schering's ETRAFON, ICN's LIMBITROL, Banyu's TRYPTANOL, Bayer's SAROTEN, Roche's LAROxYL, Astra Zeneca's ELAVIL, and generic drugs ), nortriptyline (Novartis'PAMELOR, and generic drugs), clomipramine (Novartis' ANAFRANIL, and generic drugs), imipramine (Novartis' TOFRANIL, and generic drugs) ), doxepin (Pfizer's SINEQUAN, and generic drugs); monoamine oxidase inhibitors such as phenelzine (Parke-Davis' NARDIL); selective serotonin reuptake inhibitors such as fluoxetine (EliLilly's PROZAC, SARAFEM and generic drugs), fluvoxamine (Solvay's LUVOX), citalopram (Lundbeck's CIPRAMIL and Forest's CELEXA); and selective serotonin norepinephrine reuptake inhibitors such as Venlafaxine (Wyeth-Ayerst's EFFEXORXR).

Beta blockers used in the prevention of migraine include, but are not limited to, metoprolol (Astra Zeneca's TOPROL-XR, Novartis' LOPRESSOR, and generic drugs), atenolol (Astra Zeneca's TENORMIN, TEMORETIC) , and scientific name), propanolol (Wyeth-Ayerst's INDERAL, and scientific name), timolol (Merck, Sharp and Dohme's BLOCADREN, Falcon's TIMOLOL, and scientific name), and nadolol (nadolol) (Bristol-Myers Squibb's Monarch's CORGARD/SOLGOL, Dainippon's NADIC, and the scientific name).

Calcium channel blockers used in the prevention of migraine include, but are not limited to, verapamil (Knoll's ISOPTIN, Schwarz's Verelan, Searle's Covera and CALAN, and generic drugs), lomerizine (from Nippon Organon's) TERRANAS), flunarizine (SIBELIUM from Janssen Pharmaceutica), sulfur nitrogen Diltiazem (Biovail CARDIZEM, and generic drugs), nimodipine (Bayer, NIMOTOP and ESTEVE), zucapsaicin (Civamide from Winston Laboratories) and dotarizine (from Mylan) /Ferrer).

Non-steroidal anti-inflammatory agents used in the prevention of migraine include, but are not limited to, naproxen (Roche Laboratories 'Naprosyn and scientific name) and ketoprofen (Wyeth-Ayerst's ORUDIS and ORUVAIL and generic drugs) ).

The serotonin receptor antagonists used in the prevention of migraine include, but are not limited to, pizotifen (Novartis's SANOMIGRAN/PIZOTYLINE), methyrphine (Novartis'SANSERT/DESERIL and generic drugs), And cyproheptadine (Merck's PERIACTIN).

The treatment of depression in migraine management (elimination of pain and/or related syndromes) includes analgesics and combinations, antiemetics, ergot derivatives, non-steroidal anti-inflammatory agents, and triptans. Neuropeptide antagonists have also been studied (Migraine. Cognos. Decision Resources, 2000).

Painful painkillers and combinations for migraine (including combinations with other agents such as antiemetics) include, but are not limited to, aspirin, acetaminophen, paracetamol, meperidine , codeine, hydrocodone, Novartis' FIORICET or Forests' ESGIC or generic drug (combination of acetaminophen with butalbital and caffeine), FIORINAL or generic drug (aspirin) , combination of barbital and caffeine, Novartis), MIGPRIV or generic drug (combination of aspirin and metoclopramide; Sanofi-Synthelabo), MIDRIN/MIDRID or generic drug (acetaminophen and dichlorinated a combination of dichloralphenazone; Carnick), Sanofi-Synthelabo's PARAMAX or Dolorgiet's MIGRAENERTON or a generic drug (combination of paracetamol and metoclopramide), Abbott's VICODIN or a generic drug (combination of acetaminophen and hydrocodone) , STADOL NS (butorphanol nasal spray; Bristol-Myerssquibb), Boehringer Ingelheim's LONARID or Pfizer's MIGRALEVE or generic drug (combination of paracetamol and codeine).

Antiemetic agents for migraine headaches include, but are not limited to, sputum (SmithKline Beecham's MAXOLON, Robin's REGLAN, and generic drugs), domperidone (Janssen Pharmaceutica's MOTILIUM, and generic drugs), meperazine Prochlorperazine (SmithKline Beecham's COMPAZINE, and generic drugs), and promethazine (Wyeth-Ayerst's PHENERGAN/MEPERGAN, and generic drugs).

The ergot derivatives used in migraine include, but are not limited to, dihydroergotamine (Novartis DHE-45, MIGRANAL nasal spray), ergotamine (Lotus Biochemical's ERGOMAR, and generic drugs). ), and a combination of ergotamine and caffeine (Novartis' CAFERGOT, Organon's WIGRAINE, and a generic drug).

Non-steroidal anti-inflammatory agents for the treatment of migraine include, but are not limited to, aspirin, ibuprofen, diclofenac (Novartis' VOLTAREN, and generic drugs), naproxen ( Naproxen) (Roche's NAPROSYN, and generic drugs), and ketoprofen (Wyeth-Ayerst's ORUDIS and ORUVAIL, and generic drugs).

The three types of medical treatments for migraine include, but are not limited to, sumatriptan (IMITREX/IMIGRAN from Glaxo Wellcome), naratriptan (AMERGE from Glaxo Wellcome), and Rila III Rizatriptan (MAXALT, from Merck), zolmitriptan (ZOMIG, from Astra Zeneca), eletriptan (RELPAX, from Pfizer), frovatriptan (MIGUARD, From Vernalis/Elan/Menarini) and almotriptan (AXERT from Pharmacia).

Neuropeptide antagonists that can be used in the prevention of migraine and in frustration treatment include, but are not limited to, the following agents: calcitonin gene-related peptide antagonists (BIBN 4096 from Boehringer Ingelheim) and substance P antagonists such as darbitene ( Dapitant) (Aventis's ERISPANT), lanepitant (Lilly's LY-303870) and FK-888 from Fujisawa.

Agents for migraine treatment must be administered daily and many are associated with unwanted side effects. For example, the use of methimactyride poses a risk of retroperitoneal fibrosis. For non-steroidal anti-inflammatory agents, the high dose required to achieve an effect is a disadvantage. Tricyclic antidepressants are associated with multiple side effects, including sedation, weight gain, and anticholinergic effects including dry mouth, blurred vision, constipation, impaired identification, and closed urine. Monoamine oxidase inhibitors are often associated with side effects including orthostatic hypotension, hypertension risk, weight gain, insomnia, and sexual dysfunction. Side effects of selective serotonin reuptake inhibitors include nausea, diarrhea, constipation, sleep impairment, sexual dysfunction, anxiety, and the risk of serotonin syndrome. Venlafaxine may be associated with unwanted cardiovascular effects, sedation, anticholinergic effects, gastrointestinal disorders, and sexual dysfunction. Side effects of valproic acid include drowsiness, nausea, fatigue, trembling, and weight gain. In many cases, side effects are the cause of non-compliance and automatic withdrawal of medication. In addition, the probability of success of any of the existing prophylactic anti-migraine agents is about 60-70% (Harrison's Principles of Internal Medicine, eds. Isselbacher et al., McGraw-Hill, Inc., New York, 1994, p/). 69).

There is still a need to provide effective treatment and prevention of migraine.

Summary of invention

The present invention relates to the use of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment and/or prevention of migraine, Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and lower alkyl; R ⁴ is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; , , , , , and a group consisting of; wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halo, lower alkyl and nitro; Is when Yes or , then a is 1.

The invention further relates to the use of a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the manufacture and/or prevention of migraine.

Illustrating the invention is a method of treating or preventing migraine comprising administering a medically effective amount of any of the above disclosed compounds or pharmaceutical compositions to a subject in need thereof.

The invention also relates to a method for treating nausea, vomiting, phobia, and/or fear of dysphoria (preferably for nausea, phobia, and/or fear) associated with migraine, including medical treatment An effective amount of a compound of formula (I) or formula (II) is administered to a subject in need thereof.

In a specific embodiment of the invention, a method for treating and/or preventing migraine comprises co-medicating with a therapeutically effective amount of a compound of formula (I) or formula (II) and an anti-migraine agent, The anti-migraine agent is a prophylactic agent. In another embodiment of the present invention, a method for treating and/or preventing migraine comprises co-medicating with a therapeutically effective amount of a compound of formula (I) or formula (II) and an anti-migraine agent Wherein the anti-migraine agent is an agent that terminates the course of the disease.

In a specific embodiment of the invention, the anti-migraine agent is triptan. Preferably, the tripartite is selected from the group consisting of sumatriptan (IMITREX/IMIGRAN from Glaxo Wellcome), naratriptan (AMERGE from Glaxo Wellcome), and rizatriptan (MAXALT). From Merck), zolmitriptan (ZOMIG from Astra Zeneca), eletriptan (RELPAX from Pfizer), frovatriptan (MIGUARD from Vernalis/Elan/Menarini) And Almotriptan (AXERT from Pharmacia).

In a specific embodiment of the invention, a method for the treatment and/or prevention of migraine comprises administering a therapeutically effective amount of a compound of formula (I) or formula (II) and an exogenous agent comprising an analgesic, antiemetic Agents, ergot derivatives, non-steroidal anti-inflammatory agents, tritans, neuropeptide antagonists, anticonvulsants, antidepressants, beta-blockers, calcium channel blockers and serotonin receptor antagonists Co-medication of compounds.

In a particular embodiment of the invention, the benzoheterocyclic sulfonamide derivative is a medicament for the manufacture of a medicament for the treatment of migraine comprising a therapeutically effective amount of a compound of formula (I) or formula (II) Co-medication with a compound selected from the group consisting of analgesics, antiemetics, ergot derivatives, non-steroidal anti-inflammatory agents, tritans, and neuropeptide antagonists.

In a particular embodiment of the invention, the benzocycloheterocyclic sulfonamide derivative is a medicament for the manufacture of a medicament for the prevention of migraine, comprising the use of a therapeutically effective amount of a compound of formula (I) or formula (II) Co-medication with a compound selected from the group consisting of an anti-inflammatory agent, an antidepressant, a beta-blocker, a calcium channel blocker, a non-steroidal anti-inflammatory agent, and a serotonin receptor antagonist.

In a particular embodiment of the invention, the benzoheterocyclic sulfonamide derivative is a medicament for the manufacture of a medicament for the treatment and/or prevention of migraine, comprising the use of a therapeutically effective amount of formula (I) or formula (II) A compound medical treatment with a compound selected from the group consisting of an antidepressant, a β-blocker, and a tritan.

Detailed description of the invention

The present invention relates to a medically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment and/or prevention of migraine/migraine attacks among them , a, R ¹ , R ² and R ⁴ are as defined herein. More specifically, the invention relates to the use of reducing the severity or duration of migraine and/or occasional seizures. Moreover, the invention relates to the use of preventing recurrent migraine or occasional seizures.

The invention further relates to a compound of formula (I) or formula (II) and one or more, more preferably one, anti-migraine agent for use in the manufacture of a medicament for the treatment and/or prevention of migraine.

As used herein, the term "migraine" refers to a clinical situation in which a chronic, occasional, and weak physical condition is diagnosed by the presence of a moderate to severe rhythmic unilateral headache that lasts between 4 and 72 hours. Includes migraine without warning and migraine with signs.

As used herein, “the omnidirectional head features: unilateral position, rhythmic nature, moderate or severe intensity directly affects daily activities, and deteriorates through upstairs or similar daily work; (b) at least during headaches One of the following occurs: nausea and / or vomiting, fear of light and fear of sound.

As used herein, the term "predictive migraine" means that at least two episodes are accompanied by three of the following four characteristics: (a) one or more fully reversible omen symptoms; (b) at least one omen Symptoms are progressively more than four minutes or two or more symptoms in sequence; (c) symptoms without warning continue for more than 60 minutes; (d) headaches start before, at the same time as, or after, a free interval between omen and headache Less than about 60 minutes.

As used herein, the term "prevention" includes preventing migraine attacks (headaches), reducing the frequency of migraine attacks (headaches), reducing the severity of migraine attacks (headaches), and/or reducing migraine attacks (headaches). Duration of time.

As used herein, the term "preventive agent" refers to any agent that can be used to prevent or prevent migraine. Suitable examples include, but are not limited to, agents in the classes of anticonvulsants, antidepressants, beta blockers, calcium channel group formulations, non-cholesterol anti-inflammatory agents (NSAIDs), and serotonin receptor antagonists.

As used herein, the term "dumping agent" refers to any agent that can be used to treat migraine. Suitable examples include, but are not limited to, agents in the classification of analgesics and combinations, antiemetics, ergot derivatives, non-steroidal anti-inflammatory agents (NSAIDs), tritans and neuropeptide antagonists.

As used herein, the term "anti-migraine" includes any agent that can be used to treat or prevent migraine attacks (i.e., any agent that can be used to treat or prevent migraine). Suitable examples include, but are not limited to, anti-caries agents, anti-depressants, beta blockers, calcium channel group formulations, non-cholesterol anti-inflammatory agents, serotonin receptor antagonists, serotonin reuptake inhibitors, serotonin An agent for the classification of adrenaline reuptake inhibitors, analgesics, antiemetics, ergot derivatives, triptans, neuropeptide antagonists, and riboflavin (vitamin B2).

As used herein, anti-caries agents include, but are not limited to, valproic acid (usually a daily oral dose of 10 to 60 mg) (Abbott's DEPAKENE), divalproex sodium (usually a daily oral dose is 10 to 60 mg) (Abbott's DEPAKENE), and gabapentin (usually oral daily doses of 300 to 1800 mg for adults, lower dose range for children) (Warner-Lambert's NEURONTIN).

As used herein, antidepressants include, but are not limited to, tricyclic antidepressants such as amitriptyline (usually a daily oral dose of 150-300 mg) (Schering's ETRAFON, ICN's LIMBITROL, Banyu's TRYPTANOL, Bayer's SAROTEN , Roche's LAROXYL, Astra Zeneca's ELAVIL, and the scientific name), nortriptyline (usually oral daily oral dose is 50-150 mg) (Novartis' PAMELOR, and generic drugs), clomipramine (usually daily oral medical dose is 100-250 mg) (Novartis' ANAFRANIL, and generic drugs), imipramine (usually oral daily medical dose is 150-300 mg) (Novartis' TOFRANIL, and generic drugs ), doxepin (usually daily oral medical dose is 150-300 mg) (Pfizer's SINEQUAN, and generic drugs); monoamine oxidase inhibitors such as phenelzine (usually oral daily oral dose is 45-) 90 mg) (Parke-Davis' NARDIL); selective serotonin reuptake inhibitors such as fluoxetine (usually a daily oral dose of 20-60 mg) (Eli Lilly's PROZAC, SARAFE M and generic drugs), fluvoxamine (usually oral daily medical dose is 100-300 mg) (Solvay's LUVOX), citalopram (usually oral daily medical dose is 20-40 mg) (Lundbeck's CIPRAMIL and Forest's CELEXA); and selective serotonin norepinephrine reuptake inhibitors such as venlafaxine (usually a daily oral medical dose of 125-375 mg) (Wyeth-Ayerst's EFFEXOR).

Beta blockers include, but are not limited to, metoprolol (usually a daily oral medical dose of about 200 mg) (Astra Zeneca's TOPROL-XR, Novartis' LOPRESSOR, and the scientific name), and atenolol ( Usually daily oral medical dose is about 100 mg) (Astra Zeneca's TENORMIN, TEMORETIC, and generic drugs), propanolol (usually oral daily medical dose is about 160 mg) (Wyeth-Ayerst's INDERAL, and generic drugs) , timolol (usually oral daily oral dose is about 20 mg) (Merck, Sharp and Dohme's BLOCADREN, Falcon's TIMOLOL, and generic drugs), and nadolol (usually daily oral medical dose is About 160 mg) (Bristol-Myers Squibb's Monarch's CORGARD/SOLGOL, Dainippon's NADIC, and a generic drug).

Calcium channel blockers include, but are not limited to, verapamil (usually oral doses of 120 to 480 mg per day) (Knoll's ISOPTIN, Schwarz's Verelan, Searle's Covera and CALAN, and generic drugs), lomerizine (from Nippon Organon's TERRANAS), flunarizine (from SIBELIUM of Janssen Pharmaceutica), sulfur nitrogen Diltiazem (usually oral doses of 120 to 360 mg per day) (Biovail CARDIZEM, and generic drugs), nimodipine (usually oral doses of 60 to 240 mg per day) (Bayer, NIMOTOP and ESTEVE) , zucapsaicin (from Civamide of Winston Laboratories) and dotarizine (from Mylan/Ferrer).

Non-steroidal anti-inflammatory agents include, but are not limited to, aspirin, ibuprofen, diclofenac (usually oral doses of 50 to 200 mg per day) (Novartis' VOLTAREN and scientific name), naphthalene Naproxen (usually daily oral doses of 500 to 1000 mg) (Roche Laboratories 'Naprosyn and generic drugs) and ketoprofen (usually oral doses of 150 to 300 mg per day) (Wyeth-Ayerst's) ORUDIS and ORUVAIL and scientific name drugs).

As used herein, serotonin receptor antagonists include, but are not limited to, pizotifen (Novartis's SANOMIGRAN/PIZOTYLINE), methimylglycine (Novartis' SANSERT/DESERIL and generic drugs), and Cyproheptadine (usually a daily oral dose of 4 to 20 mg) (Merck's PERIACTIN).

Analgesics and combinations (including combinations with other agents such as antiemetics) include, but are not limited to, aspirin, acetaminophen, paracetamol, meperidine, codeine, hydrocadone , Novartis' FIORICET or Forests' ESGIC or generic drug (acetaminophen combined with butalbital and caffeine), FIORINAL or generic drug (aspirin, barbital and caffeine combination, Novartis ), MIGPRIV or a generic drug (a combination of aspirin and metoclopromide; Sanofi-Synthelabo), MIDRIN/MIDRID or a generic drug (combination of acetaminophen and dichloralphenazone; Carnick), Sanofi-Synthelabo's PARAMAX or Dolorgiet's MIGRAENERTON or a generic drug (combination of paracetamol and metoclopramide), Abbott's VICODIN or a generic drug (combination of acetaminophen and hydrocodone), STADOL NS (butorphanol nasal spray); Bristol-Myers Squibb), Boehringer Ingelheim's LONARID or Pfizer's MIGRALEVE or a generic drug (combination of paracetamol and codeine).

When used herein, antiemetic agents include, but are not limited to, metoclopramide (usually oral doses of 10 to 15 mg qid) (SmithKline Beecham's MAXOLON, Robin's REGLAN, and generic drugs), domperidone (Janssen Pharmaceutica's) MOTILIUM, and the scientific name), prochlorperazine (usually oral dose is 5 to 20 mg qid) (SmithKline Beecham's COMPAZINE, and generic drugs), and promethazine (usually oral dose is 12.5 to 50 mg) (Wyeth-Ayerst's PHENERGAN/MEPERGAN, and the generic drug).

Ergot derivatives include, but are not limited to, dihydroergotamine (Novartis DHE-45, MIGRANAL nasal spray), ergotamine (Lotus Biochemical's ERGOMAR, and generic drugs), and combinations of ergotamine and caffeine (Novartis' CAFERGOT, Organon's WIGRAINE, and the scientific name).

Tritans include, but are not limited to, Sumatan (usually a medical oral dose of approximately 50 mg) (IMITREX/IMIGRAN, Glaxo Wellcome), naratriptan (usually a medical oral dose of approximately 2.5 mg) (AMERGE, Glaxo Wellcome), rizatriptan (usually medical oral doses are 5-10 mg) (MAXALT, Merck), zolmitriptan (usually medical oral dose is about 2.5 mg) (ZOMIG, Astra Zeneca) And newer tripartites including but not limited to eletriptan (RELPAX, Pfizer), frovatriptan (MIGUARD, Vernalis/Elan/Menarini) and almotriptan (almotriptan) AXERT, Pharmacia).

As used herein, neuropeptide antagonists include, but are not limited to, the following agents: calcitonin gene-related peptide antagonists (BIBN 4096 from Boehringer Ingelheim) and substance P antagonists such as dapitant (Aventis's ERISPANT) , lanepitant (Lilly's LY-303870) and FK-888 from Fujisawa.

Antispasmodic, antidepressant, beta blocker, calcium channel group preparation, non-cholesterol anti-inflammatory agent, serotonin receptor antagonist, analgesic, antiemetic, ergot derivative, triptan, neuropeptide antagonism The medically effective dosage range and dosage regimen of the agents and other agents disclosed herein can be readily determined by those skilled in the art. For example, the public can obtain the medical amount and regimen of the approved drug for sale, such as labeling on the packaging label, standard dosing guidelines, standard dosing reference such as the Physician's Desk Reference (Medical Economics Company or at http://www.pdrel. Com online) and other sources.

As used herein, the term "subject" refers to an animal, preferably a mammal, and most preferably a human, which is the subject of treatment, observation or experimentation.

The term "medically effective amount" as used herein refers to the amount of active compound or agent that is sought by a researcher, veterinarian, doctor or other clinician for the biological or medical response that appears in a tissue system, animal or human. It includes the prevention and/or alleviation of the symptoms of the condition or disorder being treated. Wherein the present invention relates to co-medication comprising administering one or more compounds of formula (I) and one or more anti-migraine agents, and "medically effective amount" means the dosage of the combination agent such that the effect of the combination can reveal the desired biological or medical reaction. For example, a medically effective amount comprising co-medication of a compound of formula (I) or formula (II) and an anti-migraine agent, wherein the amount of the compound of formula (I) or formula (II) is the same as the amount of anti-migraine agent or When administered sequentially, it is a medically effective combination effect. Moreover, it will be apparent to those skilled in the art that in the case of a medically effective amount of co-medication, such as the above, the amount of the individual compound of formula (I), formula (II) and/or the amount of anti-migraine agent may have Or no effect.

As used herein, the term "common medical" refers to a subject in need of treatment by administering one or more compounds of formula (I) or formula (II) and one or more anti-migraine agents, wherein Or a compound of formula (II) and an anti-migraine agent are administered simultaneously, sequentially, separately or in separate pharmaceutical formulations via any suitable method. When the compound of the formula (I) or formula (II) and the anti-migraine agent are administered in separate administration forms, the number of administrations of the various compounds per day may be the same or different. The compound of formula (I) or formula (II) and the anti-migraine agent can be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, and rectal. The compounds can also be administered directly to the nervous system including, but not limited to, intracerebral, intraventricular, intraventricular, intrathecal, intracisternal, intraspinal, and/or perioral routes of administration, with or without pumping devices. Needle and/or catheter delivery within the intracranial or spinal column. The compound of formula (I) and the anti-migraine agent can be administered in separate or separate forms according to simultaneous or interactive parenting, at the same or different times in the medical procedure.

In a particular embodiment of the invention, R ¹ is selected from the group consisting of hydrogen and methyl. In another embodiment of the invention, R ² is selected from the group consisting of hydrogen and methyl. In still another embodiment of the present invention, R ¹ and R ^{2 are} each hydrogen or R ¹ and R ^{2 are} each a methyl group.

In a particular embodiment of the invention, -(CH ₂ )a- is selected from the group consisting of -CH ₂ - and -CH ₂ -CH ₂ -. In another embodiment of the invention, -(CH ₂ ) _a - is -CH ₂ -.

In a particular embodiment of the invention, R ⁴ is selected from the group consisting of hydrogen and methyl, and preferably R ⁴ is hydrogen.

In a specific embodiment of the invention, a is one.

In a specific embodiment of the invention, b is an integer from 0 to 2. In another embodiment of the invention, c is an integer from 0 to 2. In another embodiment of the invention, b is an integer from 0 to 1. In another embodiment of the invention, c is an integer from 0 to 1. In still another embodiment of the invention, the sum of b and c is an integer from 0 to 2, preferably an integer from 0 to 1. In another embodiment of the invention, b is an integer from 0 to 2 and c is zero.

In a specific embodiment of the invention, Freedom of choice , , , and Become a group base. In another embodiment of the invention, Is selected from , and The base of the composition.

In a specific embodiment of the invention, Is selected from 2-(2,3-dihydro-benzo[1,4]dioxanyl), 2-(benzo[1,3] Methoxy), 3-(3,4-dihydro-benzo[1,4]dioxinyl), 2-(6-chloro-2,3-dihydro-benzo[1,4]dioxo Mercapto), 2-(6-fluoro-2,3-dihydro-benzo[1,4]dioxanyl), 2-( , 2-(5-fluoro-2,3-dihydro-benzo[1,4]dioxanyl), 2-(7-chloro-2,3-dihydro-benzo[1,4 Dioxinyl), 2-(6-chloro-benzo[1,3] Methoxy), 2-(7-nitro-2,3-dihydro-benzo[1,4]dioxanyl), 2-(7-methyl-2,3-dihydro-benzo[1] , 4]dioxanyl), 2-(5-chloro-2,3-dihydro-benzo[1,4]dioxanyl), 2-(6-bromo-2,3-dihydro- Benzo[1,4]dioxanyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxanyl), 2-(8-chloro- 2,3-dihydro-benzo[1,4]dioxanyl), 2-(2,3-dihydro-naphtho[2,3-b][1,4]dioxanyl) and 2-(4-methyl-benzo[1,3] The base of the group consisting of.

In another embodiment of the invention, Is selected from 2-(benzo[1,3] Methoxy), 2-(2,3-dihydro-benzo[1,4]dioxanyl), 2-(6-chloro-2,3-dihydro-benzo[1,4]dioxime , 2-(7-chloro-2,3-dihydro-benzo[1,4]dioxanyl), 2-(7-methyl-2,3-dihydro-benzo[1, 4]dioxanyl), 2-(6-bromo-2,3-dihydro-benzo[1,4]dioxanyl) and 2-(6,7-dichloro-2,3-di A group consisting of hydrogen-benzo[1,4]dioxanyl). In another embodiment of the invention, Is selected from 2-(2,3-dihydro-benzo[1,4]dioxanyl), 2-(7-methyl-2,3-dihydro-benzo[1,4]dioxo A group consisting of fluorenyl) and 2-(6-bromo-2,3-dihydro-benzo[1,4]dioxanyl).

In a particular embodiment of the invention, R ⁵ is selected from the group consisting of halo and lower alkyl. In another embodiment of the present invention, R ⁵ is selected from chloro, fluoro, bromo and methyl.

In a particular embodiment of the invention, the stereocenter in the compound of formula (I) is an S-configuration. In another embodiment of the invention, the stereocenter in the compound of formula (I) is an R-configuration.

In a particular embodiment of the invention, the compound of formula (I) is present in a mixture which is enriched in palm torsion, wherein the % palme heterogeneity (%ee) is greater than about 75%, more preferably greater than about 90%, more preferably greater than about 95%, and most preferably greater than about 98%.

Other specific embodiments of the invention, including those wherein the substituents are selected for one or more of the variables defined herein (ie, R ¹ , R ² , R ³ , R ⁴ , X-Y, and A) are Any subset of any independent substituent or substituent is independently selected from the entire list as defined herein.

Representative compounds of the invention for use in the methods of the invention are listed in Table 1 below. The other compounds of the present invention are listed in Table 3. In Tables 1 and 2 below, the column "Clarity" of the heading is a stereoscopic configuration defining a heterocyclic carbon atom attached to the asterisk bond. When not specified, the compound is a mixture of preparative configurations. When "R" or "S" is specified, the stereo configuration is based on a stereoisomerically rich starting material.

As used herein, unless otherwise stated, "halo" means chloro, bromo, fluoro and iodo.

As used herein, unless otherwise indicated, the term "alkyl" is used alone or as part of a substituent, including both straight and branched chains. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl, pentyl and the like. Unless otherwise stated, "low carbon" when used with an alkyl group means that the carbon chain contains from 1 to 4 carbon atoms.

As used herein, unless otherwise specified, "alkoxy" refers to an oxygen ether group of the above straight or branched alkyl group. For example, methoxy, ethoxy, n-propoxy, second butoxy, tert-butoxy, n-hexyloxy and the like.

As used herein, the symbol " ^* " refers to the presence of a stereogenic center.

When a particular group is "substituted" (eg, alkyl, aryl, etc.), the group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably One to two substituents are independently selected from the list of substituents.

With respect to a substituent, the term "independently" means that when there may be more than one such group, the substituents may be the same or different from each other.

In the standard nomenclature used throughout the specification, the end portion of the side chain is indicated first, followed by the adjacent functional group towards the point of attachment, whereby, for example, "phenyl-alkyl-amino-carbonyl-alkyl" Substituent

The following are abbreviations used in this specification, particularly in the drawings and examples: DCC = dicyclohexylcarbodiimide DCE = dichloroethane DCM = dichloromethane DIPEA or DIEA = diisopropylethylamine DMF = N,N-dimethylformamide DMSO = dimethyl hydrazine EDC = ethyl carbodiimide Et ₃ N or TEA = triethylamine Et ₂ O = diethyl ether EA or EtOAc = ethyl acetate EtOH = ethanol IPA = 2-propanol Hept=heptane HOBT=1-hydroxybenzotriazole HPLC=high pressure liquid chromatography LAH=lithium aluminum hydride M or MeOH=methanol NMR=nuclear magnetic resonance Pd-C=palladium catalyst RP on carbon HPLC=reverse phase high pressure liquid chromatography RT or rt=room temperature TEA=triethylamine TFA=trifluoroacetic acid THF=tetrahydrofuran TLC=thin layer chromatography

When the compound according to the present invention has at least one center of the palm, it may be present as a palmomer, and when the compound has two or more pairs of palm centers, it may be present as a non-palomer And, of course, all such isomers and mixtures thereof are included in the scope of the present invention, and a part of the crystalline form of the compound may be present as a polymorph and is also included in the scope of the present invention. Solvents (e.g., hydrates) are formed from water or a common organic solvent, and such solvates are also included in the scope of the present invention.

When used in a medicament, the salt of the compound of the present invention means a non-toxic "pharmaceutically acceptable salt". However, other salts can be used in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may be, for example, by solution of the compound with a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, A solution of acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid is mixed. Moreover, when the compound of the present invention bears an acidic group, suitable pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; Salts formed by organic ligands, such as quaternary ammonium salts. Accordingly, representative pharmaceutically acceptable salts include the following: acetate, besylate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, edetic acid Calcium, dextrocamphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, ethanedisulfonate, ylide, ethanesulfonate, Fumarate, glucoheptonate, gluconate, glutamate, ethanol oxalate, hexyl resorcin, hydrabamine, bromate, chlorate , hydroxynaphthoate, iodide, isocyanate, lactate, lacturonate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, nitrate Ester, methyl sulfate, mucic acid salt, naphthalene sulfonate, nitrate, N-methyl reduced glucosamine ammonium salt, oleate, bamo acid salt (hydroxyl naphate), palmitate, pan Acid salts, phosphates/hydrogen phosphates, polygalacturonates, salicylates, stearates, sulfates, basic acetates, succinates, tannins, tartaric acid , Teoclate (teoclate), tosylate, triethiodide and valerate.

Representative acids and bases which may be employed in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroacetic acid, thiolated amino acids, adipic acid, alginic acid, ascorbic acid , L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-ethylguanidinobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, Capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexylamine sulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, Formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, d-gluconic acid, d-glucuronic acid, levo-glutamic acid, α-keto-glutaric acid, glycolic acid, Hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactulic acid, maleic acid, (-)-L-malic acid, malonic acid, (± DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, citric acid, oleic acid, orotic acid, Oxalic acid, palmitic acid, balmoic acid, phosphoric acid, levorotatory-focal Aminic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and Undecylenic acid; and the base includes ammonia, L-arginine, benzylamine, ethylenedibenzylamine, calcium hydroxide, choline, dansyl alcohol, diethanolamine, diethylamine, 2-(diethylamino)- Ethanol, ethanolamine, ethylenediamine, N-methyl-reduced glucosamine, seabamine, 1H-imidazole, levo-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, Hexahydropyr , potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

Compounds of formula (I) can be prepared according to the methods outlined in Scheme 1.

Accordingly, an appropriately substituted compound of the formula (X), which is a known compound or a compound prepared by a known method, is reacted with a sulfonium diamine which is a known compound, preferably a sulfonium sulfonate thereof. The diamine is present in an amount of from about 2 to about 5 equivalents in an organic solvent such as THF, The alkane, preferably at a temperature in the range of from about 50 ° C to about 100 ° C, more preferably at about reflux temperature, provides the corresponding compound of formula (Ia).

Alternatively, an appropriately substituted compound of the formula (X), which is a known compound or a compound prepared by a known method, is reacted with an appropriately substituted compound of the formula (XI), which is a known compound or The compound prepared by a known method is carried out in the presence of a base such as TEA, DIPEA, pyridine and the like in an organic solvent such as DMF, DMSO and the like to give the corresponding compound of the formula (I).

among them Yes The compound of formula (X) can be prepared according to the method outlined in Figure 2.

Accordingly, an appropriately substituted compound of the formula (XII), which is a known compound or a compound prepared by a known method (for example, as illustrated in Figure 3), is reacted with NH ₄ OH, which is known The compound is optionally subjected to an organic solvent such as acetonitrile and its phase to give the corresponding compound of formula (XIII).

The compound of the formula (XIII) is reacted with a suitably selected reducing agent such as LAH and its analogs in an organic solvent such as THF, diethyl ether and the like to give the corresponding compound of the formula (Xa).

among them Yes The compound of formula (X) can be prepared according to the method outlined in Figure 3.

Accordingly, an appropriately substituted compound of the formula (XIV), which is a known compound or a compound prepared by a known method, is reacted with NH ₄ OH in the presence of a coupling agent such as DCC and its analogs, etc. It is required to carry out in an organic solvent such as acetonitrile and its phase to give the corresponding compound of the formula (XV).

The compound of the formula (XV) is reacted with a suitably selected reducing agent such as LAH and its analogs in an organic solvent such as THF, diethyl ether and the like to give the corresponding compound of the formula (Xb).

among them Yes And the compound of formula (X) wherein a is 2 can be prepared according to the method outlined in Figure 4.

Accordingly, an appropriately substituted compound of the formula (XVI) wherein J ¹ is a suitable cleavage group such as Br, Cl, I, toluenesulfonyl, methylsulfonyl, trifluoromethylsulfonyl and their phases a compound or the like, which is a known compound or a compound prepared by a known method (for example, by activating a corresponding compound in which J ¹ is OH), and a cyanide such as potassium cyanide, sodium cyanide, and the like thereof. Reaction in an organic solvent such as DMSO, DMF, THF and its phase gives the corresponding compound of formula (XVII).

The compound of formula (XVII) is reduced according to known methods, for example by reaction with a suitable reducing agent such as LAH, borane and its analogs, to give the corresponding compound of formula (Xc).

among them Yes And the compound of formula (X) wherein a is 1 can be prepared according to the method outlined in Figure 5.

Accordingly, an appropriately substituted compound of the formula (XVIII), which is a known compound or a compound prepared by a known method, is obtained according to a known method, to give a corresponding compound of the formula (XIX), wherein J ² is suitable Release groups such as toluenesulfonyl, Cl, Br, I, methanesulfonyl, trifluoromethylsulfonyl and their analogs.

The compound of the formula (XIX) is reacted with a quinone imide salt such as potassium sulfoxide, sodium sulfoxide, and the like in an organic solvent such as DMF, DMSO, acetonitrile and the like, preferably in a The temperature is raised from 50 ° C to about 200 ° C, more preferably at about reflux temperature, to give the corresponding compound of formula (XX).

The compound of the formula (XX) is reacted with a known compound of N ₂ H ₄ in an organic solvent such as ethanol, methanol and the like, preferably at a temperature ranging from about 50 ° C to about 100 ° C, more preferably at about The reaction is carried out at reflux temperature to give the corresponding compound of formula (Xd).

Those skilled in the art will be able to understand Is selected from The compound of the formula (X) can be similarly prepared according to known methods or, for example, according to the methods outlined in the above Schemes 2 to 5, by selecting and substituting the corresponding naphthyl-fused compound for the benzo-fused starting material. .

Those skilled in the art will also be aware of the single palmar isomers of the desired compound of formula (X) (or one of the mixtures of palmitic isomers), as illustrated in Figures 1 through 5 above. The process can be carried out by replacing the appropriate starting materials with the corresponding single palmier isomers (or one of the mixtures of the palmier isomers).

It is also understood by those skilled in the art that one of the reaction steps of the present invention can be carried out in a variety of solvents or solvent systems, and the reaction step can also be carried out in a suitable solvent or mixture of solvent systems.

When a mixture of stereoisomers is produced by the process for the preparation of a compound according to the invention, these isomers can be separated by convenient techniques such as preparative chromatography. The compounds can be prepared in the form of racemates, or individual palmomerisomers can be prepared via stereospecific synthesis or via dissociation. The compound can be dissociated into its constituents, for example via standard techniques, for example via an optically active acid such as (-)-di-p-tolyl-D-tartaric acid and/or (+)-di-p-toluene. The sulfhydryl-L-tartaric acid salt is formed to form a non-palphaliomer pair, followed by gradual crystallization and regeneration of the free base. The dissociated compound can also be dissociated via the formation of a palmitic HPLC column via the formation of a non-palphalinic isomer or a guanamine, followed by separation and removal of the palmitic adjuvant by chromatography.

In any method for preparing a compound of the invention, it may be necessary and/or necessary to protect the susceptibility or reactivity of the relevant molecule via a conventional protecting group, for example disclosed in Protective Groups in Organic Chemistry , ed. JFW McOmie. , Plenum Press, 1973 and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis , John Wiley & Sons, 1991, protecting groups can be removed at a convenient subsequent stage using methods known in the art.

The invention also includes pharmaceutical compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical composition comprising the one or more compounds described herein as an active ingredient can be prepared by intimately mixing the compound or group of compounds with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques. Depending on the desired route of administration (eg, oral, parenteral), the carrier can take a wide variety of forms. Accordingly, suitable suitable carriers and additives for liquid oral preparations such as suspensions, elixirs and solutions include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, and the like; For example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, adhesives, decomposing agents and the like. Solid oral preparations may also be coated with a substance such as a sugar or an enteric coating to adjust the main site of adsorption. For parenteral administration, carriers typically include sterile water and other ingredients added to increase solubility or preservative properties. The injected suspension or solution can also be prepared using aqueous carriers and suitable additives.

In the preparation of the pharmaceutical composition of the present invention, one or more of the compounds of the present invention as an active ingredient are intimately mixed with a pharmaceutical carrier according to a conventional pharmaceutical mixing technique, depending on the desired route of administration, and the carrier may be in various forms. In preparing a composition for oral administration, any of the usual pharmaceutical media can be used. Accordingly, suitable liquid carriers and additives for liquid oral preparations such as suspensions, elixirs and solutions include water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, etc.; Formulations such as powders, capsules, caplets, capsules and tablets, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, adhesives, decomposing agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous form of oral administration unit, in which case it is apparent that solid pharmaceutical carriers are employed. If desired, the tablet may be sugar coated or enteric coated via standard techniques. For parenteral agents, the carrier will usually comprise sterile water, although other ingredients may be added, for example for the purpose of aiding solubility or preservation. It is also possible to prepare an injectable suspension, in which case a suitable liquid carrier, suspending agent or the like can be employed. Each of the administration units of the pharmaceutical compositions herein, such as tablets, capsules, powders, injections, teaspoons, and the like, will contain an amount of the active ingredient required to deliver the above effective amount. Each of the administration units of the pharmaceutical compositions herein, such as tablets, capsules, powders, injections, teaspoons, and the like, will contain from about 0.1 to 1000 mg and may be administered at a dose of from about 0.01 to 150.0 mg/kg/day. Preferably, it is from about 0.1 to 100 mg/kg/day, more preferably from about 0.5 to 50 mg/kg/day, more preferably from about 1.0 to 25.0 mg/kg/day or any range therein. However, depending on the needs of the patient, the severity of the condition to be treated, and the compound used, the dosage can be varied. It can be administered daily or after a period of time.

Preferably, these compositions are in unit dosage form, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered sprays or liquid sprays, drops, elixirs Agent, autoinjector device or suppository; for oral, parenteral, intranasal, sublingual or rectal administration, or by inhalation or insufflation. Alternatively, the composition may be in the form of a suitable weekly or monthly administration; for example, an insoluble salt of the active compound, such as a decanoate, may be provided to provide a depot preparation for intramuscular injection. For the preparation of a solid composition such as a tablet, the main active ingredient and a pharmaceutical carrier such as conventionally manufactured tablet ingredients such as corn starch, lactose, sucrose, mannitol, talc, stearic acid, magnesium stearate, dicalcium phosphate Alternatively, the colloid and other pharmaceutical diluents, such as water, are combined to form a solid pre-formulated composition comprising a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. When it is mentioned that these pre-modulated compositions are homogeneous, it means that the active ingredients are dispersed evenly throughout the composition so that the composition is easily subdivided into equally effective administration forms such as tablets, pills and capsules. This solid pre-formulated composition is then subdivided into a form of administration in the form described above containing from 0.1 to about 1000 mg of the active ingredient of the present invention. Tablets or pills of the novel compositions may be coated or mixed to provide a form of administration which provides the advantage of prolonged activity. For example, a tablet or pill may contain both internal and external administration ingredients, the latter coating the former in the form of an envelope. The two components can be isolated by an enteric layer which acts in the stomach as a barrier to decomposition and allows the internal components to pass intact into the duodenum or to be delayed in release. A variety of materials can be used as the enteric layer or coating, including a variety of polymeric acids and such materials as shellac, cetyl alcohol, and cellulose acetate.

Liquid forms in which the novel compositions of the present invention may be incorporated for oral or via injection include aqueous solutions, suitably flavored slurries, aqueous or oily suspensions, and edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, and alfalfa. Flavored suspension of the agent and a similar pharmaceutical vehicle. Suitable dispersing or suspending agents for aqueous suspensions, including synthetic and natural colloids such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyethylene Base-pyrrolidone or gelatin.

The methods of the invention can also be carried out using a pharmaceutical composition comprising any of the compounds defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 1000 mg of the compound, preferably about 50 to 500 mg, and may be formulated in any form suitable for the chosen mode of administration. Carriers include the required and inert pharmaceutical excipients including, but not limited to, adhesives, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms such as tablets, pills, caplets, capsules (each comprising immediate release, timed release and sustained release formulations), granules and powders, and liquid forms such as solutions , slurries, tinctures, lotions, and suspensions. Forms which can be used for parenteral administration include sterile solutions, emulsions and suspensions.

The compounds of the invention are advantageously administered at a single daily dose, or the total daily dose is divided into two, three or four doses per day. Moreover, the compounds of the present invention can be administered in the nasal form or via a transdermal skin patch via topical use of a suitable intranasal vehicle, as is well known to those skilled in the art. In order to administer the drug in the form of a system for transdermal delivery, the dose administered throughout the dosing regimen is of course continuous rather than intermittent.

For example, for oral administration in the form of a tablet or capsule, the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, suitable adhesives, lubricants, decomposers and colorants can also be incorporated into the mixture when necessary or desired. Suitable adhesives include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, yellow gum or sodium oleate, sodium stearate, stearic acid. Magnesium, sodium benzoate, sodium acetate, sodium chloride, and the like. Decomposers include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The liquid is formed in a suitably flavored suspending or dispersing agent, such as synthetic and natural gums such as tragacanth, acacia, methylcellulose, and the like. For parenteral administration, sterile suspensions and solutions are required. When intravenous administration is desired, isotonic preparations which usually contain a suitable preservative are employed.

Whether it is desired to treat or prevent migraine, the compounds of the invention can be administered in any of the above compositions and according to the administration regime established in the art.

The daily dose of this product can vary from 0.01 to 150 mg/kg per adult per day. For oral administration, the composition is preferably in the form of a tablet containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 mg of the active ingredient. Provides a dose for adjusting the patient to be treated according to the symptoms. An effective amount of the agent is usually supplied in a dosage range from about 0.01 mg/kg to about 1500 mg/kg body weight per day. Preferably, the range is from about 0.1 to about 100.0 mg/kg body weight per day, more preferably from about 0.5 mg/kg to about 50 mg/kg per day, and even more preferably from about 1.0 to about 25.0 mg/kg body weight per day. This compound can be administered in a regimen of 1 to 4 times per day.

Those skilled in the art can readily determine the optimal dosage to be administered and will vary with the particular compound employed, the mode of administration, the strength of the formulation, and the condition of the disease. In addition, the factors associated with the particular patient being treated, including the patient's age, weight, diet, and time of administration, will result in the need to adjust the dose.

Those skilled in the art will be aware of in vivo and in vitro tests using suitable, known and generally accepted cell and/or animal models that are expected to be capable of treating or preventing a particular condition.

Those skilled in the art can also learn about human clinical trials, including the first in humans, dose ranges, and efficacy tests, in health practitioners and/or those with specific diseases, which can be done according to methods well known in the clinical and medical arts.

Example 1

((3,4-dihydro-2H-benzo[b][1,4]2 Gyn-3-yl)methyl)sulfonamide (Compound #3)

Catechol (5.09 g, 46.2 mmol) and potassium carbonate were mixed in acetonitrile and heated under reflux for 1 hour. 2-Chloromethyl-3-chloro-1-propene (5.78 g, 46.2 mmol) was added and the reaction was refluxed for 24 h. The solution was allowed to cool to room temperature and filtered. The filtrate was evaporated and the residue was diluted with EtOAc EtOAc. The combined organic solution was dried over MgSO ₄ and concentrated. Chromatography (2% diethyl ether in hexane) gave 3-methylene-3,4-dihydro-2H-benzo[b][1,4] Glucan is a colorless oil.

MS (ESI): 163.2 (M + H +) 1 H NMR (300 MHz, CDCl 3), δ: 6.94 (m, 4H), 5.07 (s, 2H), 4.76 (s, 4H).

3-Methylene-3,4-dihydro-2H-benzo[b][1,4] Geng (5.00 g, 30.8 mmol) was dissolved in dry THF (100 mL). Borane-THF (1.0 M in THF, 10.3 mL) was added at 0 °C. The reaction was stirred at room temperature for 5 hours. Aminosulfonic acid (6.97 g, 61.6 mmol) was added. The reaction was heated at reflux overnight. The reaction was cooled to room temperature and aqueous sodium hydroxide (3.0 M, 100 mL) was then evaporated. The reaction was extracted with ethyl acetate (3×100 mL). The combined organic solution was dried through MgSO _4. The solution was concentrated under reduced pressure and obtained by chromatography (2% to 8% methanol in dichloromethane) ((3,4-dihydro-2H-benzo[b][1,4] Colorless oil of hept-3-yl)methyl)amine.

MS (ESI): 180.1 (M+H ⁺ ) ^: NMR (M.s., MH), NMR (M, MH), δ: 6. s (m, 4H), 4.21 (m, 2H), 4.07 (m, 2H), 3.33 (b. , 3.16 (d, J = 4 Hz, 1H), 2.72 (d, J = 4 Hz, 1H), 2.30 (m, 1H).

Will ((3,4-dihydro-2H-benzo[b][1,4]) Gyn-3-yl)methyl)amine (2.90 g, 16.2 mmol) and sulfonamide (3.11 g, 32.4 mmol) in anhydrous The mixture was stirred in hexane (60 mL) and heated at reflux overnight. Chloroform was added and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure EtOAc (EtOAc)

258.8(M+H ⁺ ) ¹ H NMR (300 MHz, DMSO), δ: 6.92 (m, 4H), 6.71 (b, s, 1H), 6.59 (b, s, 2H), 4.19 (m, 2H), 4.04 (m) , 2H), 3.00 (m, 2H), 2.39 (m, 1H).

Example 2

N-(2,3-Dihydro-benzo[1,4]dioxo-2-ylmethyl)-sulfonamide (Compound #1)

Racemic 2,3-dihydro-benzo[1,4]dioxo-2-ylmethylamine (4.4 g, 26 mmol) and sulfonamide (5.1 g, 53 mmol) Ear) in 1,4-two The mixture was mixed with an alkane (100 ml) and heated under reflux for 2 hours. The reaction was allowed to cool to room temperature and a small amount of solid was filtered and discarded. The filtrate was evaporated in vacuo <RTI ID=0.0> The solid was recrystallized from DCM toiel

Melting point: 97.5-98.5 ° C Elemental analysis: C, 44.25; H, 4.95; N, 11.47; S, 13.13 Elemental analysis: C, 44.28; H, 4.66; N, 11.21; S, 13.15 ¹ H NMR ( DMSO d6), δ: 6.85 (m, 4H), 6.68 (bd s, 3H, NH), 4.28 (m, 2H), 3.97 (dd, J = 6.9, 11.4 Hz, 1H), 3.20 (m, 1H) , 3.10 (m, 1H).

Example 3

(Benzo[1,3] II Methyl-2-ylmethyl)sulfonamide (Compound #2)

Catechol (10.26 g, 93.2 mmol), sodium methoxide (25 wt% in methanol, 40.3 g, 186 mmol) and methyl dichloroacetate (13.3 g, 93.2 mmol) in anhydrous methanol Mix in (100 ml). The solution was heated to reflux overnight. The reaction was allowed to cool to room temperature, acidified by addition of concentrated hydrochloric acid and then reduced to about 50 mL under reduced pressure. Water was added and the mixture was extracted with diethyl ether (3×100 mL). The combined organic solution was dried over MgSO _4, concentrated to a brown solid, and chromatographed (2% ethyl acetate in hexanes) to give benzo [1,3] After A colorless oil of methyl 2-carboxylate.

MS (ESI): 195.10 (M + H +) 1 H NMR (300 MHz, CDCl 3), δ: 6.89 ( br, 4H), 6.29 (s, 1H), 4.34 (q, J = 7 Hz, 2H), 1.33 (t, J = 7 Hz, 3H).

In benzo[1,3] Ammonium hydroxide (7.21 g, 40.0 mmol) was added with ammonium hydroxide (29% in water, 10 mL) and sufficient acetonitrile to make the mixture homogeneous (~5 mL). The solution was stirred at room temperature for 2 hours and then distilled water was added. Benzo[1,3] The phthalamide 2-carboxylic acid decylamine was precipitated as a white solid which was collected via filtration and was purified without further.

MS (ESI): 160.00 (M+H ⁺ ) ^: NMR (3, MH), δ: 7.79 (s, broad, 1H), 7.72 (s, broad, 1H), 6.94 (m, 2H), 6.86 (m, 2H), 6.30 (s, 1H).

Benzo[1,3] Methyl-2-carboxylic acid decylamine (5.44 g, 32.9 mmol) was dissolved in tetrahydrofuran (THF, 100 mL). Lithium aluminum hydride (LAH, 1 M in THF, 39.5 mL, 39.5 mmol) was slowly added to a solution at room temperature. The reaction was stirred at room temperature for 24 hours. Distilled water was added to destroy excess LAH. Aqueous sodium hydroxide (3.0 M, 100 mL) was added and the solution was extracted ethyl acetate (3×100 mL). The combined organic solution was washed with water and dried by MgSO _4. Evaporating the solvent to give C-benzo[1,3] A colorless oil of phthal-2-yl-methylamine.

MS (ESI): 152.1 (M+H ⁺ ) ¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.87 (m, 4H), 6.09 (t, J = 4 Hz, 1H), 3.13 (d, J = 4 Hz , 2H).

C-benzo[1,3] Methyl-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfonamide diamine (3.74 g, 38.9 mmol) in anhydrous Acetone (50 mL) was added and the solution was heated at reflux overnight. The reaction was concentrated and the residue was crystallisjjjjjjjjj

MS (ESI): 230.0 (M + H +) 1 H NMR (300 MHz, CDCl 3), δ: 6.87 (m, 4H), 6.25 (t, J = 4 Hz, 1H), 4.79 ( br, 1H), 4.62 (wide peak, 1H), 3.64 (d, J = 4 Hz, 2H).

Example 4

(2S)-(-)-N-(2,3-Dihydro-benzo[1,4]dioxo-2-ylmethyl)-sulfonamide (Compound #4)

Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-toluenesulfonic acid glycidyl ester (22.8 g, 0.10 mol) The reaction was stirred at 60 ° C for 24 hours. The reaction was cooled to rt and diluted with EtOAc (EtOAc) (EtOAc) The combined organic solution was washed 3 times with 10% EtOAc (EtOAc) EtOAc (EtOAc) After purification, a solid of ((2S)-2,3-dihydro-benzo[1,4]dioxo-2-yl)-methanol was obtained.

The solid (13.3 g, 68 mmol) was dissolved in pyridine (85 mL), cooled to 0 &lt;0&gt;C, p-toluenesulfonium chloride (13.0 g, 68 mM) was added and the mixture was stirred at room temperature for 20 hr. . The reaction was diluted with diethyl ether (1 L) and 1N HCl (1. The organic layer was separated and washed twice with 1N HCl (500 ml), washed with water (150 ml) four times, with brine once, dried (MgS04 ₄₎ and to give a white solid after vacuum evaporation, via flash column layer After purification (heptane: ethyl acetate-2:1), toluene-4-sulfonic acid (2S)-2,3-dihydro-benzo[1,4]dioxo-2-ylmethyl ester was obtained. White solid.

The white solid was mixed with potassium sulfinamide (14.4 g, 78 mmol) in DMF (250 mL) and heated under reflux for 1 hour, cooled to room temperature and poured into vigorously stirred water (1.5 L) and stirred. 30 minutes. The white solid was filtered and the solid was washed several times with water, 2% NaOH, washed again with water and air dried to give (2S)-2-(2,3-dihydro-benzo[1,4]dioxane- A white powdery solid of 2-methylmethyl)-isoindole-1,3-dione.

A powdery white solid was mixed with hydrazine (2.75 g, 86 mmol) in EtOH (225 mL) and warmed to reflux for 2 hr, cooled to room temperature and 1N HCl was added to pH 1.0 and stirred for 15 min. The white solid was filtered and washed with EtOAc (EtOAc)EtOAc. The ether solution was dried (Na ₂ SO _4), and the evaporated in vacuo to give a pale yellow oil. The oil was purified via flash column chromatography (DCM: MeOH-10:1) to afford oil. A portion of the oil (4.82 g, 29 mmol) was taken in EtOAc (EtOAc) (EtOAc) After 3 hours, the mixture was ice-cooled for 2 hours. The white flake solid (corresponding HCl salt of (2S)-C-(2,3-dihydro-benzo[1,4]dioxo-2-yl)-methylamine) was filtered and then again from 2 - Propanol was recrystallized to give a white solid.

[ α ] _D = -69.6 (c = 1.06, EtOH). White solid was partitioned between DCM and diluted NaOH. DCM was dried (Na ₂ SO ₄ ) and evaporated in vacuo to yield (2S)-C- (2, An oil of 3-dihydro-benzo[1,4]dioxo-2-yl)-methylamine.

[ α ] _D = -57.8 (c = 1.40, CHCl ₃ ) oil (2.1 g, 12.7 mmol) and sulfonamide (2.44 g, 25.4 mmol) in two The title compound was obtained as a white crystalline solid. m. m. .

Mp _{102-103 ℃ [α] D = -45.1} ° (c = 1.05, M) 1 H NMR (DMSOd6), δ: 6.86 (m, 4H), 6.81 (bd s, 3H, NH), 4.3 (m, 2H), 3.97 (dd, J=6.9, 11.4 Hz, 1H), 3.20 (dd, J=5.5, 13.7 Hz, 1H), 3.10 (dd, J=6.9, 13.7 Hz, 1H) Elemental analysis: C , 44.25; H, 4.95; N, 11.47; S, 13.13 Elemental analysis: C, 44.20; H, 4.69; N, 11.40; S, 13.22.

Example 5

N-(2,3-Dihydro-benzo[1,4]dioxo-2-ylmethyl)-N',N'-dimethylsulfonamide (Compound #6)

Racemic 2,3-dihydro-1,4-benzodioxo-2-ylmethylamine (8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) Mix in DMF (10 mL) and cool in an ice-bath and add dimethylamine sulfonium chloride (1.44 g, 10 mmol). The reaction mixture was then stirred for 3 hours under continuous cooling. The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate solution was washed with brine, dried (MgSO ₄₎ and evaporated to give an oil in vacuo. The oil was purified by EtOAc EtOAc EtOAc:EtOAc

Melting point: 76-78 ° C. MS 273 (MH ⁺ ). </RTI></RTI></RTI></RTI></RTI></RTI> C, 48.52; H, 5.92; N, 10.29; S, 11.78 Elemental analysis: C, 48.63; H, 5.62; N, 10.20; , 11.90 ¹ H NMR (CDCl ₃ ), δ: 6.87 (m, 4H), 4.59 (bd m, 1H, NH), 4.35 (m, 1H), 4.27 (dd, J = 2.3, 11.4 Hz, 1H), 4.04 (dd, J = 7.0, 11.4 Hz, 1H), 3.36 (m, 2H), 2.82 (s, 6H).

Example 6

N-(2,3-Dihydro-benzo[1,4]dioxo-2-ylmethyl)-N-methylsulfonyldiamine (Compound #7)

The racemic 2,3-dihydro-1,4-benzodioxo-2-ylmethylamine (825 mg, 5 mmol) was dissolved in ethyl formate (15 mL) and refluxed for 30 min. And evaporation in vacuo gave N-(2,3-dihydro-benzo[1,4]dioxo-2-ylmethyl)-carboxamide as an oil.

The oil was treated with 1 M EtOAc (EtOAc EtOAc. The reaction was cooled in an ice-bath and quenched with water (0.50 mL). The mixture was then stirred at room temperature for 1 hour. The solid was filtered and the filtrate was evaporated in vacuo to give crystall The aqueous layer was basified with 1 N NaOH and extracted with diethyl ether. The organic layer was dried (MgSO ₄₎ and with (2,3-dihydro - benzo [1,4] dioxin-2-ylmethyl) - methyl-evaporated in vacuo after - the oleylamine.

MS 180 (MH ⁺ ) ¹ H NMR (CDCl ₃ ), δ: 6.85 (m, 4H), 4.30 (m, 2H), 4.02 (dd, J = 7.9, 11.6 Hz, 1H), 2.85 (m, 2H) , 2.50 (s, 3H).

Oil (380 mg, 2.1 mmol) and sulfonamide (820 mg, 8.5 mmol) in two The mixture was stirred with EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

Melting point: 97-98 ° CMS 257 (M ^-1 ) Elemental analysis: C, 46.50; H, 5.64; N, 10.85; S, 12.41 Elemental analysis: C, 46.48; H, 5.65; N, 10.90; S, 12.07 ¹ H NMR (CDCl ₃ ), δ: 6.86 (m, 4H), 4.52 (bs, 2H), 4.46 (m, 1H), 4.29 (dd, J = 2.3, 11.5 Hz, 1H), 4.05 ( Dd, J = 6.5, 11.5 Hz, 1H), 3.51 (dd, J = 6.7, 14.9 Hz, 1H), 3.40 (dd, J = 5.9, 14.9 Hz, 1H), 2.99 (s, 3H).

Example 7

(2S)-(-)-N-(6-Chloro-2,3-dihydro-benzo[1,4]dioxo-2-ylmethyl)-sulfonamide (Compound #8)

According to the method outlined in the above Example 4, 4-chlorocatechol was reacted to give (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4]dioxo-2-yl) a mixture of methylamine and (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4]dioxo-2-yl)-methylamine (ca. 3:1 Proportion of 6-chloro: 7-chloro isomer via RP HPLC).

The mixture was dissolved in 2-propanol (100 mL) and 1N HCl in diethyl ether was added until pH = 1.0. The precipitated hydrochloride was filtered (2.65 g) and recrystallised from methanol/IPA to give white crystals. White crystals were dispensed in DCM and diluted NaOH. The purified (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4]dioxo-2-yl)-methylamine oil was obtained after drying DCM and evaporation in vacuo. .

[ α ] _D = -67.8 (c = 1.51, CHCl ₃ ) oil (7.75 mmol) and sulfonamide (1.50 g, 15.5 mmol) in The mixture was stirred and refluxed for EtOAc (EtOAc)EtOAc. The product was purified by flash column chromatography eluting elut elut

MS 277(M ^-1 )[ α ] _D = -59.9° (c = 1.11, M) ¹ H NMR (CDCl ₃ ), δ: 6.90 (d, H = 2.2 Hz, 1H), 6.81 (m, 2H) , 4.76 (m, 1H), 4.55 (s, 2H), 4.40 (m, 1H), 4.29 (dd, J = 2.4, 11.5 Hz, 1H), 4.05 (dd, J = 7.1, 11.5 Hz, 1H), 3.45 (m, 2H) Elemental analysis: C, 38.78; H, 3.98; N, 10.05 Elemental analysis: C, 38.80; H, 3.67; N, 9.99.

Recovery of the filtrate of the crystalline hydrochloride of (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4]dioxo-2-yl)-methylamine prepared above (Ca. 1:1 6-Chloro: 7-chloroisomer) and evaporated in vacuo to give a solid, which was partitioned from DCM (200 mL) and diluted NaOH (0.5 M, 50 mL). The DCM solution was purified once washed with brine, dried (Na ₂ SO ₄₎ and evaporated in vacuo to give an oil, after which was (containing 0.20% TFA in water containing 0.16% TFA sum of ACN 10-50%) via reverse phase HPLC The residue of (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4]dioxo-2-yl)-methylamine was obtained.

The residue and sulfonium diamine (0.90 g, 9.4 mmol) in two The mixture was stirred and refluxed for 2.5 h, cooled to rt and evaporated in vacuo. The oil was purified by flash column chromatography using DCM/methanol 10:1 to give (2S)-(-)-N-(7-chloro-2,3-dihydro-benzo[1,4]diox. A white solid of indole-2-ylmethyl)-sulfonamide.

MS 277(M ^-1 ) ¹ H NMR (CDCl ₃ /CD ₃ OD), δ: 6.88 (d, H = 0.7 Hz, 1H), 6.81 (m, 2H), 4.37 (m, 1H), 4.30 (dd , J=2.3, 11.6 Hz, 1H), 4.04 (dd, J=7.0, 11.6 Hz, 1H), 3.38 (m, 2H)

Example 8

-2-ylmethylsulfonamide diamine (compound #10)

will 2-carboxylic acid (4.5 g, 25 mmol) and HOBT (3.86 g, 25 mmol) were combined in DCM (40 mL) and DMF (10 mL). Dimethylaminopropylethylcarbodiimide (EDC, 4.84 g, 25 mmol) was added at room temperature and the reaction mixture was stirred for 30 min. Ammonium hydroxide (2.26 mL, 33.4 mmol) was added and the mixture was stirred 16 h. The reaction mixture was diluted with DCM (50 mL) and water (50 mL). The DCM was separated and the aqueous layer was extracted twice with DCM. The combined DCM layers dried (Na ₂ SO ₄₎ and evaporated in vacuo to give an oil, after which was obtained via an oil (ethyl acetate) was purified by flash column chromatography.

The oil (5.35 g, 30 mmol) was stirred in EtOAc (EtOAc) (EtOAc) The reaction was quenched with water, stirred for 2 hours, the solution was decanted, dried (Na ₂ SO ₄ ) and evaporated in vacuo to give C- An oily amine of 2-yl-methylamine.

Oily amine (1.63 g, 10 mmol) and sulfonamide (1.92 g, 20 mmol) in two The mixture was stirred and refluxed for 2 hours in hexanes (50 mL). The solution was cooled and the oil was evaporated in vacuo. The solid was recrystallized from ethyl acetate/hexane to give a white solid of -2-ylmethylsulfonamide.

Melting point 100-101 ° C. MS 241 (M ^-1 ) Elemental analysis: C, 49.57; H, 5.82; N, 11.56; S, 13.23 Elemental analysis: C, 49.57; H, 5.80; N, 11.75; , 13.33

Example 9

2-(2,3-Dihydro-benzo[1,4]dioxo-2-yl)-ethylsulfonyldiamine (Compound #16)

Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-(2,3-dihydrobenzo[1,4]dioxane in DMSO (90 mL) (6.87 g) , 30 millimoles) and stirred at ambient temperature for 20 hours. The reaction mixture was then diluted with water (250 mL) and brine. The ether was washed with water, then washed twice with brine, dried (Na ₂ SO ₄₎ and methyl 2-cyano-evaporated in vacuo after - (2,3-dihydrobenzo [1,4] dioxin) White solid.

¹ H NMR (CDCl ₃ ) δ 6.89 (m, 4H), 4.50 (m, 1H), 4.31 (dd, J = 2.3, 11.5 Hz, 1H), 4.08 (dd, J = 6.2, 11.6 Hz, 1H), 2.78 (d, J = 6.1 Hz, 2H).

Methyl 2-cyano - (2,3-dihydrobenzo [1,4] dioxin) was dissolved in THF (50 ml) and added of 1M BH ₃ THF (80 mL, 80 mmol) The reaction mixture was refluxed for 5 hours and then stirred at ambient temperature for 16 hours. Cool with an ice bath and add 2N HCl until pH = 1.0 is achieved. The reaction mixture was then stirred at rt for 1 h and evaporated in vacuo. It will be partitioned between 3 N NaOH and diethyl ether, and the ether solution is washed with brine, dried (Na ₂ SO ₄ ) and evaporated in vacuo to give crude 2-(2,3-dihydrobenzo[1,4]dioxane. -2-yl)ethylamine.

MS (M+H) ⁺ 180.

Crude 2-(2,3-dihydrobenzo[1,4]dioxo-2-yl)ethylamine in two Acetone (100 ml) was mixed with sulfonamide diamine (3.0 g, 31 mmol) and heated to reflux for 2 hours. The solution was cooled and evaporated to dryness crystals crystals crystals The solid was recrystallized from DCM to give the title compound.

MS (M-1) 257 MP 101-103 ° C (corr) ¹ H NMR (CDCl ₃ ) δ 6.86 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 4.30 (m, 2H) , 3.94 (dd, J = 7.4, 11.3 Hz, 1H), 3.43 (dd, J = 6.4, 12.9 Hz, 2H), 1.94 (dd, J = 6.5, 12.9 Hz, 2H). The theoretical value of elemental analysis: C, 46.48; H, 5.60; N, 10.81; S, 12.41 Elemental analysis: C, 46.50; H, 5.46; N, 10.85; S, 12.41

Example 10

(2S)-(-)-N-(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxo-2-ylmethyl)-sulfonyldiamine (Compound # 29)

4,5-Dichlorocatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-glycidyl sulfonate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 ° C for 24 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc EtOAc (EtOAc) The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO ₄₎ and to give (2S) evaporated in vacuo 2- (6,7-dichloro-2,3- A viscous oil of hydrogen-benzo[1,4]dioxo)-methanol.

(2S)-2-(6,7-Dichloro-2,3-dihydro-benzo[1,4]dioxan-methanol oil (6.4 g, 27 mmol) dissolved in pyridine (50 (ml) and cooled to 0 °C. Then p-toluenesulfonium chloride (5.2 g, 27 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with diethyl ether and 1N HCl (750 mL) and the organic layer was separated and washed twice with 1N HCl (250 mL), washed with water (150 ml) and washed once with brine twice, dried (MgSO ₄₎ and After evaporation in vacuo, toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxan-2-ylmethyl ester as a pale yellow solid was obtained.

¹ H NMR (CDCl ₃ ), δ: 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 6.83 (s, 1H), 4.37 ( m, 1H), 4.2 (m, 3H), 4.03 (dd, J = 6.3, 11.7 Hz, 1H), 2.47 (s, 3H).

Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxan-2-ylmethyl ester (8.0 g, 20.5 mmol) It was mixed with potassium hydrazide (6.1 g, 33 mmol) in DMF (75 ml) and heated under reflux for 1 hour, cooled to room temperature and poured into vigorously stirred water (0.5 liter) and stirred for 30 minutes. The white solid was filtered and the solid was washed several times with water, 2% NaOH, washed again with water and then air dried to give (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1] , 4]dioxo-2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%) as a white powdery solid.

The white powdery solid was mixed with hydrazine (1.06 g, 33 mmol) in EtOH (EtOAc) The pH of the reaction mixture was adjusted to pH 1.0 by the addition of 1N HCl and then the mixture was stirred for 15 min. The white solid was filtered and washed with EtOAc (EtOAc)EtOAc. The ether solution was dried (Na ₂ SO ₄ ) and evaporated in vacuo to give (2S)-2-aminomethyl-(6,7-dichloro-2,3-dihydro-benzo[1, 4] Dioxins).

¹ H NMR (CDCl ₃ ), δ: 6.98 (s, 1H), 6.96 (s, 1H), 4.25 (dd, J = 2.0, 11.2 Hz, 1H), 4.15 (m, 1H), 4.0 (m, 1H) ), 2.97 (d, J = 5.5 Hz, 2H).

A portion of the oil (3.8 grams, 16 millimoles) and sulfonamide (3.1 grams, 32.4 millimoles) in two The alkane (100 ml) was heated with EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The title compound was obtained as a white crystalline solid.

MS[M-H] ^- 311.0 mp 119-121 ° C [ α ] _D = -53.4 (c = 1.17, M) ¹ H NMR (DMSO d6), δ: 7.22 (s, 1H), 7.20 (s, 1H) ), 6.91 (bd s, 1H), 6.68 (bd s, 2H), 4.35 (m, 2H), 4.05 (dd, J = 6.5, 11.5 Hz, 1H), 3.15 (m, 2H) Elemental analysis: C, 34.52; H, 3.22; N, 8.95; Cl, 22.64; S, 10.24 Elemental analysis: C, 34.64; H, 2.68; N, 8.87; Cl, 22.94; S, 10.35.

Example 11

(2S)-(-)-N-(7-Amino-2,3-dihydro-benzo[1,4]dioxo-2-ylmethyl)-sulfonamide (Compound #36)

Preparation of (2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1,4]dioxan-2 from 4-nitrocatechol according to the method outlined in Example 4. -ylmethyl)-sulfonamide (1.2 g, 4.15 mmol), then (2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1, 4] Dioxin-2-ylmethyl)-sulphonium diamine was mixed with 10% Pd/C in methanol (120 ml) and shaken at room temperature under a hydrogen pressure (39 psi) for 3 hours. The solid was filtered and washed with EtOAc (EtOAc) The crude product was dissolved in 0.2N EtOAc (2.5 mL).

^{MS (M + H) + 260} 1 H NMR (DMSO d6), δ: 10.2 (bd s, 3H), 6.86 (m, 1H), 6.85 (s, 1H), 6.74 (dd, J = 2.5,8.4 Hz, 1H ), 4.22 (m, 2H), 3.88 (dd, J = 6.7, 11.4 Hz, 1H), 3.04 (m, 2H).

Example 12

(2S)-(-)-N-(7-Methyl-2,3-dihydro-benzo[1,4]dioxo-2-ylmethyl)-sulfonamide (Compound #19)

The title compound was obtained from EtOAc (EtOAc):

MS[M-H] ^- 257 ¹ H NMR (CDCl ₃ ), δ: 6.76 (m, 1H), 6.66 (m, 2H), 4.80 (m, 1H), 4.57 (bd s, 1H), 4.40 (m) , 1H), 4.28 (m, 1H), 4.03 (dd, J = 6.9, 11.4 Hz, 1H), 3.45 (m, 2H), 2.25 (s, 3H).

The theoretical value of the elemental analysis: C, 46.50; H, 5.46; N, 10.85; S, 12.41 Elemental analysis: C, 46.65; H, 5.60; N, 10.84; S, 12.61.

Example 13

Cortical dissemination testing as a migraine model involves cortical spreading depression (CSD) and headache in migraine and can be triggered in experimental animals via electronic or chemical stimulation (Kunkler & Kraig, 2003; Lauritzen et al) .1982; Moskowitz, 1984). Moreover, migraine prophylactic agents have been shown to increase the CSD threshold and thus reduce the number of CSD, which is seen as a useful mechanism for reducing migraine attacks (Ayata et al., Ann Neurol in press).

Adult male Sprague-Dawley rats (250-600 g) were divided into two treatment groups: vehicle (0.5% methylcellulose; n=13) and compound #8 (100 mg/kg/day, orally). , n=7). The results were compared with a historically positive control group of propylvaleric acid administered intravenously at 200 mg/kg/day.

The vehicle or compound #8 was orally administered once a day for 35 days. On the last day of treatment, rats continued to receive food and water without restriction and provided their daily oral dose of vehicle or Compound #8 approximately 1.5 hours prior to CSD testing. Rats were anesthetized with isoflurane and intubated via a tracheotomy for mechanical ventilation. Body temperature, blood pressure, and heartbeat were monitored throughout the procedure to confirm a constant state. Rats were placed in the stereometric configuration of the brain and three small washer holes (millimeters from the anterior bony) were drilled in the following coordinates of the right hemisphere under saline cooling: (1) posterior 4.5, lateral 2.0 (occipital cortex): KCL application; (2) posterior 0.5, lateral 2.0 (cranial cortical bone): position 1 for recording; ventral surface 2, lateral 2 (frontal cortex): position 2 for recording. The dura mater on the occipital cortex is slowly removed. Stable (DC) voltage and cortical brain waves (EcoG) were recorded at 300 micrometers below the surface of the dura mater using a glass micropipette filled with 200 millimolar NaCl. The Ag/AgCl reference electrode was placed under the skin of the neck. After the surgery was prepared, the cortex was allowed to recover for 30 minutes under saline lavage. Cortical dissemination was reduced by placing a cotton ball filled with 1 M KCl on the surface of the soft membrane. The number of CSDs induced by KCl was counted for 2 hours. The propagation speed is calculated from the distance (mm) between the recording electrodes 1 and 2 divided by the latency (minutes) between the CSDSs recorded at these positions.

According to Table 3 below, the number of cortical dissemination reductions induced by topical KCl application was 16 ± 3 and 14 ± 3 for animals treated with vehicle and Compound #8, respectively. Although there was a difference between the vehicle group and the test compound group, these results did not reach statistical significance (p=0.12, Kruskal-Wallis One Way Analysis of Variance on Ranks). Moreover, the propagation speed decreased from about 3.2 ± 1 mm/min (vehicle) to 2.7 ± 0.4 mm/min (compound #8) (p = 0.06, Kruskal-Wallis One Way Analysis of Variance on Ranks). Physiological monitoring, including arterial pH, pCO ₂ , pO _{2 ,} and blood pressure, did not differ between groups.

As a positive control group, amyl propionate (200 mg/kg/day, intravenously) was administered for 4 weeks according to a previous report (Ayata et al., Ann Neurol, in press). Brine was used as a vehicle control. The number of cortical spreads in saline and amyl propionate were 18 and 14 respectively (p < 0.05, Mann-Whitney Rank Sum Test).

Based on these results, the inventors believe that Compound #8 will become more effective in long-term treatment or at higher doses, especially in view of the tendency of the rate of propagation to decrease.

Example 14

As a specific embodiment of the oral composition, 100 mg of the compound #8 prepared according to Example 7 was formulated with a sufficiently finely divided amount of lactose to obtain a total amount of 580 to 590 mg and filled in a hard capsule of size O.

While the above description discloses the principles of the invention, the examples of the invention are intended to be illustrative, and the invention is intended to cover all such modifications, adaptations and/or modifications of the scope of the invention.

Claims (11)

A use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutically effective amount of a medicament for the treatment of a migraine, Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and a C ₁ -C ₄ alkyl group; R ⁴ is selected from the group consisting of hydrogen and a C ₁ -C ₄ alkyl group; a is from 1 to An integer of 2; Yes Wherein b is an integer from 0 to 4; and each R ⁵ is independently selected from a group consisting of a halogen group and a C ₁ -C ₄ alkyl group. The use according to the first aspect of the invention, wherein R ¹ and R ^{2 are} each independently selected from the group consisting of hydrogen and a C ₁ -C ₄ alkyl group; and R ⁴ is selected from the group consisting of hydrogen and methyl; Is an integer from 1 to 2; Is selected from 2-(2,3-dihydro-benzo[1,4]dioxanyl), 2-(6-chloro-2,3-dihydro-benzo[1,4]dioxane , 2-(6-fluoro-2,3-dihydro-benzo[1,4]dioxanyl), 2-(5-fluoro-2,3-dihydro-benzo[1,4 Dioxinyl), 2-(7-chloro-2,3-dihydro-benzo[1,4]dioxanyl), 2-(7-methyl-2,3-dihydro-benzene And [1,4]dioxanyl), 2-(5-chloro-2,3-dihydro-benzo[1,4]dioxanyl), 2-(6-bromo-2,3- Dihydro-benzo[1,4]dioxanyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxanyl) and 2-(8) -Chloro-2,3-dihydro-benzo[1,4]dioxanyl) or a pharmaceutically acceptable salt thereof. The use according to claim 2, wherein R ¹ and R ^{2 are} each independently selected from the group consisting of hydrogen and methyl; R ⁴ is selected from the group consisting of hydrogen and methyl; a is from 1 to 2. Integer Is selected from 2-(2,3-dihydro-benzo[1,4]dioxanyl), 2-(6-chloro-2,3-dihydro-benzo[1,4]dioxane , 2-(7-chloro-2,3-dihydro-benzo[1,4]dioxanyl), 2-(7-methyl-2,3-dihydro-benzo[1, 4]dioxo), 2-(6-bromo-2,3-dihydro-benzo[1,4]dioxanyl) and 2-(6,7-dihydro-2,3-di a group consisting of hydrogen-benzo[1,4]dioxanyl); or a pharmaceutically acceptable salt thereof. The use according to the first aspect of the patent application, wherein the compound of the formula (I) is selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4] a group consisting of oxon-2-ylmethyl)-sulphonyldiamine; and a pharmaceutically acceptable salt thereof. According to the use of item 4 of the scope of patent application, migraine is a migraine with signs. According to the application of the fourth scope of the patent application, migraine is a migraine without warning. According to the use of item 4 of the scope of the patent application, migraine is characterized by a moderate to severe rhythmic unilateral headache between 4 and 72 hours with or without warning. According to the use of item 4 of the scope of patent application, migraine is associated with nausea, vomiting, photophobia or fear. According to the use of claim 4, wherein treating migraine comprises reducing the severity or persistence of migraine. According to the use of the fourth aspect of the patent application, wherein (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxo-2-ylmethyl) The sulfonamide diamine or a pharmaceutically acceptable salt thereof is administered in a daily dose ranging from about 0.01 mg/kg to about 1500 mg/kg body weight. According to the use of the fourth aspect of the patent application, wherein (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxo-2-ylmethyl) The sulfonamide or a pharmaceutically acceptable salt thereof is administered in a dose ranging from about 0.5 mg/kg to about 50 mg/kg body weight from 1 to 4 times a day.