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WO2002053139A2 - Combinaison d'antagoniste de recepteur d'acide amine excitateur et d'agoniste 5-ht1f : methode de traitement de troubles neurologiques - Google Patents

Combinaison d'antagoniste de recepteur d'acide amine excitateur et d'agoniste 5-ht1f : methode de traitement de troubles neurologiques Download PDF

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Publication number
WO2002053139A2
WO2002053139A2 PCT/US2001/045863 US0145863W WO02053139A2 WO 2002053139 A2 WO2002053139 A2 WO 2002053139A2 US 0145863 W US0145863 W US 0145863W WO 02053139 A2 WO02053139 A2 WO 02053139A2
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Prior art keywords
antagonist
receptor
compound
agonist
excitatory amino
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WO2002053139A3 (fr
WO2002053139A8 (fr
Inventor
Kirk Willis Johnson
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Eli Lilly and Co
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Eli Lilly and Co
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Priority to AU2002241565A priority Critical patent/AU2002241565A1/en
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Publication of WO2002053139A3 publication Critical patent/WO2002053139A3/fr
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Publication of WO2002053139A8 publication Critical patent/WO2002053139A8/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • 5-HTi The diverse physiological activity exhibited by the neurotransmitter serotonin (5-HT) is mediated by at least seven receptor classes: 5-HT ⁇ , 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7.
  • 5-HTiF 5-HTi subclass
  • Kao and coworkers Proc. Natl. Acad. Sci. USA, 90, 408-412 (1993)
  • This 5-HTIF receptor has been ⁇ hown to exhibit a pharmacological profile distinct from any serotonergic receptor yet described.
  • This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids at a dose similar to that required to treat acute migraine in humans. While this blockade of neurogenic protein extravasation, one aspect of neurogenic inflammation, is believed to be mediated by 5-HTID receptors, the effective dosages of 5-HTID selective compounds do not correlate with in vitro binding at the 5-HTID binding site. The lack of correlation suggests that a receptor subtype other than 5-HTID may mediate the effects of sumatriptan (Neurology, 43(suppl. 3), S16-S20 (1993)).
  • the transmission of nerve impulses in the mammalian central nervous system is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron.
  • L-Glutamate which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathways in mammals, and is referred to as an excitatory amino acid (EAA).
  • EAA receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol.
  • Excitatory amino acid receptors are classified into two general types; “ionotropic” and “metabotropic”. “Ionotropic” receptors are directly coupled to the opening of cation channels in the cell membrane of neurons. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate ( ⁇ MDA), -amino-3-hydroxy- 5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). Molecular biological studies have established that AMPA receptors are composed of subunits (GluRi - GIUR4), which can assemble to form functional ion channels. Five kainate receptors have been identified which are classified as either High Affinity (KA1 and KA2) or Low Affinity (GIUR5, GluRg, and GluR ). Bleakman et al., Molecular
  • the "metabotropic" excitatory amino acid receptors are G-protein or second messenger-linked receptors. This type of receptor is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in cAMP formation, and changes in ion channel function.
  • Schoepp and Conn Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also to participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
  • excitotoxicity has been implicated in the pathophysiology of numerous neurological disorders. For example, excitotoxicity has , been linked with the etiology of cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord lesions resulting from trauma or inflammation, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. In addition, excitotoxicity has been implicated in chronic neurodegenerative conditions including Alzheimer's Disease, Huntington's Chorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateral sclerosis, idiopathic and drug-induced Parkinson's Disease, as well as ocular damage and retinopathy.
  • Other neurological disorders implicated with excitotoxicity and/or glutamate dysfunction include muscular spasticity including tremors, drug tolerance and withdrawal, brain edema, convulsive disorders including epilepsy, depression, anxiety and anxiety related disorders such as post-traumatic stress syndrome, tardive dyskinesia, and psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxication or addiction.
  • excitatory amino acid excitotoxicity participates in the etiology of acute and chronic pain states including severe pain, intractable pain, neuropathic pain, and post-traumatic pain.
  • a neuroprotective agent such as an excitatory amino acid receptor antagonist
  • an excitatory amino acid receptor antagonist is believed to be useful in treating or preventing these disorders and/or reducing the amount of neurological damage associated with these disorders.
  • AMPA receptor antagonists are neuroprotective in focal and global ischemia models.
  • the competitive AMPA receptor antagonist is believed to be useful in treating or preventing these disorders and/or reducing the amount of neurological damage associated with these disorders.
  • NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[ ]quinoxaline) has been reported effective in preventing global and focal ischemic damage. Sheardown et al, Science,
  • AMPA receptor antagonists and, as such, are useful in the treatment of a multitude of disorders conditions, including pain and migraine headache.
  • WO 98/45270 discloses that certain decahydroisoquinoline derivative compounds are selective antagonists of the iGluR5 receptor and are useful for the treatment of various types of pain, including; severe, chronic, intractable, and neuropathic pain.
  • Excitatory amino acid receptor antagonists may also be useful as analgesic agents.
  • an excitatory amino acid receptor antagonist such as a selective antagonist of the iGluR5 receptor
  • an agonist of the 5HT ] ⁇ f receptor provides a synergistic and efficacious response in an animal model of neurogenic inflammation and, thus, could be useful for the treatment of migraine.
  • Such a combination could address a long felt need for a safe and effective treatment for migraine, without attending side effects.
  • the treatment of neurological disorders is hereby furthered.
  • the present invention provides a method of treating a neurological disorder or a neurodegenerative disease, comprising administering to a patient in need thereof an effective amount of an excitatory amino acid receptor antagonist, in combination with an effective amount of a 5HTi receptor agonist.
  • the present invention provides a method of treating a neurological disorder or a neurodegenerative disease, comprising administering to a patient in need thereof an effective amount of a selective iGluR5 receptor antagonist, in combination with an effective amount of a 5HTif receptor agonist.
  • the present invention provides a method of treating migraine, comprising administering to a patient in need thereof an effective amount of a selective iGluR5 receptor antagonist in combination with an effective amount of a 5HTif receptor agonist.
  • the present invention provides a method of treating a neurological disorder or a neurodegenerative disease comprising administering to a patient in need thereof an effective amount of a compound which possesses the combined activities of a selective iGluR5 receptor antagonist and a 5HT ⁇ f receptor agonist.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a selective iGluR5 receptor antagonist and a 5HTif receptor agonist, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the present invention further provides the use of a selective iGluR5 receptor antagonist in combination with a 5HTif receptor agonist for the manufacture of a medicament for treating a neurological disorder.
  • Figure 1 is a comparison of dose-response curves for Compound I (382884) and Compound II (344864) when administered intravenously, either individually, or in combination, in the rat model of dural protein extravasation. This figure depicts the dose of each compound administered and the resulting effect on extravasation ratio. This figure also depicts the ID50 values for Compound II when administered alone, and when administered in combination with a dose of Compound I which produced no change in extravasation ratio when administered individually.
  • the present invention provides a method for the treatment of a neurological disorder or neurodegenerative disease. Specifically, the present invention provides a method for the treatment of migraine which can be demonstrated by a particular mechanism of action, inhibition of neurogenic dural protein extravasation.
  • an excitatory amino acid receptor antagonist such as a selective iGluR5 receptor antagonist
  • a selective iGluR5 receptor antagonist in combination with a 5HTif receptor agonist, or a single compound possessing the combined activities of a selective iGluR5 receptor antagonist and a 5HTif receptor agonist
  • the neurogenic extravasation which mediates migraine is inhibited without the attending side effects of agents designed to optimize the 5-HTi-like mediated vasoconstrictive activity of sumatriptan.
  • pharmaceutically acceptable salt refers to salts of the compounds employed in the present invention which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds employed in the methods of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as /7-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as /7-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the potassium and sodium salt forms are particularly preferred.
  • the particular counterion forming a part of any salt employed in the methods of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • iGluR5 refers to the kainate ionotropic glutamate receptor, subtype 5, of the larger class of excitatory amino acid receptors.
  • the term "selective iGluR5 antagonist” or “selective iGluR5 receptor antagonist” refers those excitatory amino acid receptor antagonists which selectively bind to the iGluR5 kainate receptor subtype, relative to the iGluR.2 AMPA receptor subtype.
  • the selective iGluR5 antagonist for use according to the method of the present invention has a binding affinity at least 10 fold greater for iGluR5 than for iGluR2, more preferably at least 100 fold greater. It is further understood that any selective iGluR5 antagonist, as appreciated by one of ordinary skill in the art, is included within the scope of the methods of the present invention.
  • selective iGluR5 receptor antagonists are readily available to, or are readily prepared by, one of ordinary skill in the art following recognized procedures.
  • Examples of selective iGluR5 receptor antagonists include, but are not limited to, the compounds provided in WO 98/45270, the entire contents of which is herein incorporated by reference.
  • the selective iGluR5 antagonists for use according to the methods of the present invention may be a single compound or a combination of compounds capable of functioning as a selective iGluR5 receptor antagonist.
  • it may be a combination of a compound capable of functioning as an antagonist at the iGluR5 receptor and one or more other glutamate receptors, in combination with one or more compounds capable of blocking its actions at the iGluR2 receptor.
  • the selective iGluR antagonist for use in the methods of the present invention is preferably a single compound.
  • the term "5HTi agonist” refers to a full or partial agonist which may be composed of one or more agents which, individually or together, are selective agonists of 5-HTIF receptors relative to other serotonin receptors which produce unwanted effects like vasoconstriction. It is understood, however, that the 5HT ⁇ f agonist for use in the methods of the present invention, is preferably a single compound. A compound which is a partial agonist at the 5-HTIF receptor must exhibit sufficient agonist activity to inhibit neurogenic meningeal extravasation at an acceptable dose.
  • partial agonists of at least about 50% agonist effect (E ma ⁇ ) are preferred and partial agonists of at least about 80% agonist effect (E ma ⁇ ) are more preferred.
  • Full agonists at the 5-HTIF receptor are most preferred. Examples of 5HTif agonists include, but are not limited to, the compounds described in United
  • the selective iGluR5 antagonists, and the 5HTlf receptor agonists, employed in the methods of the present invention may exist as pharmaceutically acceptable salts and, as such, that the use of such salts are included within the scope of the present invention.
  • prodrug refers to a compound which has been structurally modified such that in vivo the prodrug is converted, for example, by hydrolytic, oxidative, reductive, or enzymatic cleavage into the parent compound (e.g. the carboxylic acid (drug), or as the case may be the parent dicarboxylic acid).
  • parent compound e.g. the carboxylic acid (drug), or as the case may be the parent dicarboxylic acid.
  • prodrugs may be, for example, metabolically labile mono- or di-ester derivatives of the parent compounds having a carboxylic acid group.
  • the present invention includes any such prodrugs, such as metabolically labile ester or diester derivatives of compounds useful in the methods of the present invention.
  • prodrugs such as metabolically labile ester or diester derivatives of compounds useful in the methods of the present invention.
  • the use of the compounds described herein as prodrugs is contemplated, and often is preferred, and thus, the prodrugs of the compounds employed are encompassed in the names of the compounds herein.
  • Preferred prodrugs include, for example, the diester derivatives of Compound I. Conventional procedures for the selection and preparation of suitable prodrugs are well known to one of ordinary skill in the art.
  • neurological disorder refers a disorder of the nervous system including but not limited to cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, global and focal cerebral ischemia, spinal cord lesions resulting from trauma or inflammation, perinatal hypoxia, hypoxia-induced nerve cell damage resulting from cardiac arrest, hypoglycemic neuronal damage, neonatal distress, and the like.
  • neurological disorders contemplated include muscular spasticity including tremors, drug tolerance and withdrawal, brain edema, convulsive disorders including epilepsy, depression, anxiety and anxiety related disorders such as post-traumatic stress syndrome, tardive dyskinesia, and psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxication or addiction, and acute and chronic pain states including severe pain, intractable pain, neuropathic pain, and post-traumatic pain.
  • neurodegenerative disease refers to Alzheimer's Disease, Huntington's Chorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateral sclerosis(ALS), idiopathic and drug-induced Parkinson's Disease, ocular damage and retinopathy, and the like.
  • ALS amyotrophic lateral sclerosis
  • idiopathic and drug-induced Parkinson's Disease ocular damage and retinopathy, and the like.
  • chronic means a deteriorating condition of slow progress and long continuance. As such, a chronic neurodegenerating condition is treated when it is diagnosed and continued throughout the course of the disease.
  • migraine refers a neurological disorder characterized by recurrent attacks of head pain (which are not caused by a structural brain abnormalitiy such as those resulting from tumor or stroke), gasrointestinal disturbances, and possibly neurological symptoms such as visual distortion. Characteristic headaches of migraine usually last one day and are commonly accompanied by nausea, emesis, and photophobia.
  • Migraine may be a "chronic" or "acute” condition.
  • chronic means a condition of slow progress and long continuance. As such, a chronic condition is treated when it is diagnosed and treatment continued throughout the course of the disease. Conversely, the term “acute” means an exacerbated event or attack, of short course, followed by a period of remission.
  • acute means an exacerbated event or attack, of short course, followed by a period of remission.
  • the treatment of migraine contemplates both acute events and chronic conditions. In an acute event, compound is administered at the onset of symptoms and discontinued when the symptoms disappear. As described above, a chronic condition is treated throughout the course of the disease.
  • patient refers to a mammal, such a mouse, gerbil, guinea pig, rat, dog or human. It is understood that the preferred patient is a human.
  • the terms “treating” or “to treat” each mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder.
  • the methods of this invention encompass both therapeutic and prophylactic administration.
  • the term "effective amount” refers to the amount or dose of the compound, upon single or multiple dose administration to the patient, either alone or in combination with another agent, which provides the desired effect in the patient under diagnosis or treatment.
  • an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • determining the effective amount or dose of compound administered a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific neurological disorder involved; the degree of or involvement or the severity of the neurological disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • a typical daily dose will contain from about 0.001 mg/kg to about 100 mg/kg of each compound used in the present adjunctive therapy.
  • daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
  • the adjunctive therapy of the present invention is carried out by administering an excitatory amino acid receptor antagonist, particularly a selective iGluR5 antagonist, together with a 5HTlf receptor agonist in any manner which provides effective levels of the particular compounds in the body at the same time.
  • the excitatory amino acid receptor antagonist and the 5HTlf receptor agonist may be administered together, in a single dosage form, or may be administered separately.
  • Oral administration is a preferred route, however, oral administration is not the only route, nor even the only preferred route.
  • other routes of administration include, but are not limited to, transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, pulmonary, sublingual, or intrarectal routes of administration.
  • one of the compounds may be administered by one route, such as oral, and the other may be administered by the transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, pulmonary, sublingual, or intrarectal route, in particular circumstances.
  • the route of administration may be varied in any way, limited by the physical properties of the compounds and the convenience of the patient and the caregiver.
  • the adjunctive combination may be administered as a single pharmaceutical composition, and so pharmaceutical compositions incorporating both compounds are important embodiments of the present invention.
  • Such compositions may take any physical form that is pharmaceutically acceptable, but orally usable pharmaceutical compositions are particularly preferred.
  • Such adjunctive pharmaceutical compositions contain an effective amount of each of the compounds, which effective amount is related to the daily dose of the compounds to be administered.
  • Each adjunctive dosage unit may contain the daily doses of all compounds, or may contain a fraction of the daily doses, such as one-third of the doses. Alternatively, each dosage unit may contain the entire dose of one of the compounds, and a fraction of the dose of the other compounds. In such case, the patient would daily take one of the combination dosage units, and one or more units containing only the other compounds.
  • the amounts of each compound to be contained in each dosage unit depends on the identity of the compounds chosen for the therapy, and other factors such as the indication for which the adjunctive therapy is being given.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg of each compound individually or in a single unit dosage form, more preferably about 5 mg to about 300 mg (for example 25 mg).
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for a patient, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • compositions contain from about 0.5% to about 50% of the compounds in total, depending on the desired doses and the type of composition to be used.
  • the amount of the compounds is best defined as the "effective amount", that is, the amount of each compound which provides the desired dose to the patient in need of such treatment.
  • the activity of the adjunctive combinations do not depend on the nature of the composition, so the compositions are chosen and formulated solely for convenience and economy. Any of the combinations may be formulated in any desired form of composition.
  • Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules.
  • suitable diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
  • Tablets are often coated with sugar as a flavor and sealant.
  • the compounds may also be formulated as chewable tablets, by using large amounts of pleasant- tasting substances such as mannitol in the formulation, as is now well-established practice.
  • Instantly dissolving tablet-like formulations are also now frequently used to assure that the patient consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some patients.
  • a lubricant is often necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Tablet disintegrators are substances which swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.
  • Enteric formulations are often used to protect an active ingredient from the strongly acid contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.
  • Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly.
  • Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use, also.
  • Transdermal patches have become popular recently. Typically they comprise a resinous composition in which the drugs will dissolve, or partially dissolve, which is held in contact with the skin by a film which protects the composition. Many patents have appeared in the field recently. Other, more complicated patch compositions are also in use, particularly those having a membrane pierced with innumerable pores through which the drugs are pumped by osmotic action.
  • Prodrugs have also become preferred recently, thus, it should also be understood by the skilled artisan that some of the compounds useful for the methods of the present invention are available for prodrug formualtion.
  • Prodrug includes metabolically labile ester or diester derivatives of the functional parent acid compounds (drugs) employed in the methods of, the present invention. When administered to a patient, the prodrug undergoes enzymatic and/or chemical hydrolytic cleavage in such a manner that the parent carboxylic acid (drug), or as the case may be the parent dicarboxylic acid, is released.
  • the use of the compounds described herein as prodrugs is contemplated, and often is preferred, and thus, the prodrugs of the compounds employed are encompassed in the names of the compounds herein.
  • Active Ingredient as it is used in the following table means either a 5HTlf agonist or a selective iGluR5 antagonist, or in the alternative, a single compound possessing the activities of a 5HTlf agonist and a selective iGluR5 antagonist.
  • the following is provided only to illustrate the invention and should not be interpreted as limiting the present invention in any way.
  • Hard gelatin capsules are prepared using the following ingredients:
  • Formulation 2 A tablet is prepared using the ingredients below:
  • the components are blended and compressed to form tablets each weighing 665 mg.
  • An aerosol solution is prepared containing the following components:
  • Propellant 22 70.00 (Chlorodifluoromethane)
  • the active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
  • Tablets each containing 60 mg of active ingredient are made as follows:
  • the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Capsules each containing 80 mg medicament are made as follows:
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities.
  • Suppositories each containing 225 mg of active ingredient may be made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
  • the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • An intravenous formulation may be prepared as follows:
  • the above procedures can be applied to a method of treating a neurological disorder or a neurodegenerative disease comprising administering to a patient in need thereof, an effective amount of a selective iGluR5 receptor antagonist in combination with an effective amount of a 5HTi receptor agonist. It is further understood that the above procedures can also be applied to a method of treating a neurological disorder or a neurodegenerative disease comprising administering to a patient in need thereof an effective amount of a compound which possesses the combined activities of a selective iGluR5 receptor antagonist and a 5HTlf receptor agonist.
  • the following compounds are representative of the excitatory amino acid receptor antagonists and the 5HTlf agonists, useful in the methods of the present invention. These compounds are intended to be illustrative only, and are under no circumstances to be interpreted as limiting the methods of the present invention in any way.
  • Compound I (382884) as an excitatory amino acid receptor antagonist, selective for the iGluR5 receptor subtype.
  • I may be prepared by following recognized general procedures as described in United States Patent No. 5,446,051 (Issued August 29, 1995), and more specifically as described in WO 98/45270 (published October 15, 1998), the entire contents of which are both herein incorporated by reference.
  • Compound U (344864) as an agonist of the 5-HTIF receptor.
  • Compound II may be prepared by following recognized general procedures as described in United States Patents No. 5,708,187 and 5,814,653, the entire contents of which are both herein incorporated by reference.
  • the ability of the compound to bind to the 5HTlf receptor or the iGluR5 receptor may be determined according to the following procedures.
  • A. 5HT1F Receptor Binding The ability of the compounds employed in the present invention to bind to the 5HT1F receptor subtype can be measured essentially as described in N. Adham, et al, Proceedings of the National Academy of Sciences (USA), 90, 408-412 (1993), as taught in United States Patents No. 5,708,187, the entire contents of which is herein incorporated by reference.
  • the binding affinities of compounds to other serotonin receptors can also be determined essentially as described below except that different cloned receptors are employed in place of the 5-HTIF receptor clone described herein.
  • [ ⁇ H 5-Hr] binding is performed using slight modifications of the 5-HTID assay conditions reported by Herrick-Davis and Knier (J. Neurochem., 50, 1624-1631 (1988)) with the omission of masking ligands. Radioligand binding studies are achieved at 37°C in a total volume of 250 ⁇ L of buffer (50 mM Tris, 10 mM MgCl2,
  • the 5-HTIF receptor is functionally coupled to a G-protein as measured by the ability of serotonin and serotonergic drugs to inhibit forskolin stimulated cAMP production in NIH3T3 cells transfected with the 5-HTIF receptor.
  • Adenylate cyclase activity is determined using standard techniques.
  • a maximal effect is achieved by serotonin.
  • An E m ax is determined by dividing the inhibition of a test compound by the maximal effect and determining a percent inhibition.
  • Drug concentration-effect curves are then conducted by adding 6 different final concentrations of drug, followed immediately by the addition of forskolin (10 D D Subsequently, the cells are incubated for an additional 10 minutes at 37°C, 5% CO2- The medium is aspirated and the reaction is stopped by the addition of 100 mM HC1.
  • a concentration-response curve for 5-HT is measured in parallel, using a fixed dose of methio ' thepin (0. D D D D
  • the plates are stored at 4°C for 15 minutes and then centrifuged for 5 minutes at 500 x g to pellet cellular debris, and the supernatant is aliquoted and stored at -20°C before assessment of cAMP formation by radioimmunoassay (cAMP radioimmunoassay kit; Advanced Magnetics, Cambridge, MA). Radioactivity is quantified using a Packard COBRA Auto Gamma counter, equipped with data reduction software.
  • Compounds useful in the methods of the present invention are found to be agonists at the 5-HT ⁇ receptor in the cAMP assay.
  • the binding affinity of the selective iGluR5 antagonist compounds of the present invention, to the iGluR5 receptor is first measured using standard methods.
  • the activity of compounds acting at the iGluR5 receptor can be determined by radiolabelled ligand binding studies at the cloned and expressed human iGluR5 receptor (Korczak et al., 1994, Recept. Channels 3; 41-49), and by whole cell voltage clamp electrophysiological recordings of currents in acutely isolated rat dorsal root ganglion neurons (Bleakman et al., 1996, Mol. Pharmacol. 49; 581-585).
  • the selectivity of compounds acting at the iGluR5 receptor subtype can then be determined by comparing antagonist activity at the iGluR5 receptor with antagonist activity at other AMPA and kainate receptors.
  • Methods useful for such comparison studies include: receptor-ligand binding studies and whole-cell voltage clamp electrophysiological recordings of functional activity at human GluRj, GluR2,GluR3 and GIUR4 receptors (Fletcher et al., 1995, Recept. Channels 3; 21-31); receptor- ligand binding studies and whole-cell voltage clamp electrophysiological recordings of functional activity at human GluRg receptors (Hoo et al., Recept. Channels 2;327-
  • the iGluR5 antagonist binding profile for compounds of the present invention is determined essentially as described in WO98/45270.
  • Cell lines HEK293 cells
  • stably transfected with human iGluR receptors are employed.
  • Displacement of 3[H] AMPA by increasing concentrations of antagonist is measured on iGluRj , iGluR2, iGluR3, and iGluR4 expressing cells, while displacement of 3[H] kainate (KA) is measured on iGluR5, iGluR ⁇ , iGluR , and KA2-expressing cells.
  • Kj antagonist binding activity in ⁇ M is determined for Compound I.
  • the ratio of binding affinity to the iGluR2 AMPA receptor subtype, versus the binding affinity to iGluR5 kainate receptor subtype is also determined.
  • Compounds useful in the methods of the present invention displayed a greater binding affinity for iGluR5 receptor subtype (lower Kj) versus that for iGluR2, preferably at least 10 fold greater for iGluR5 than that for iGluR2, and more preferably at least 100 fold.
  • the following animal model may be employed to determine the ability of the compounds of the present invention, to inhibit dural protein extravasation, a functional assay for the neuronal mechanism of migraine.
  • the results of this assay, employing Compound I and Compound ⁇ , individually and in combination, are summarized in Figure 1 and Table 1 (infra).
  • Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles River Laboratories (225-325 g) are anesthetized with sodium pentobarbital intraperitoneally (65 mg/kg or 45 mg/kg respectively) and placed in a stereotaxic frame (David Kopf Instruments) with the incisor bar set at -3.5 mm for rats or -4.0 mm for guinea pigs.
  • two pairs of bilateral holes are drilled through the skull (6 mm posterially, 2.0 and 4.0 mm laterally in rats; 4 mm posteriorly and 3.2 and 5.2 mm laterally in guinea pigs, all coordinates referenced to bregma).
  • Pairs of stainless steel stimulating electrodes, insulated except at the tips are lowered through the holes in both hemispheres to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) from dura.
  • test compound or test compounds
  • test compound is injected intravenously (i.v.) at a dosing volume of lml/Kg or, in the alternative, test compound may be administered orally (p.o) via gavage at a volume of 2.0ml/Kg .
  • a 50 mg/Kg dose of Evans Blue a fluorescent dye, is also injected intravenously.
  • the Evans Blue complexes with proteins in the blood and functions as a marker for protein extravasation.
  • the left trigeminal ganglion is stimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msec duration) with a Model 273 potentiostat/ galvanostat (EG&G Princeton Applied Research).
  • the animals are euthanized by exsanguination with 20 mL of saline.
  • the top of the skull is removed to facilitate the collection of the dural membranes.
  • the membrane samples are removed from both hemispheres, rinsed with water, and spread flat on microscopic slides. Once dried, the tissues are coverslipped with a 70% glycerol/water solution.
  • a fluorescence microscope (Zeiss) equipped with a grating monchromator and a spectrophotometer is used to quantify the amount of Evans Blue dye in each sample.
  • An excitation wavelength of approximately 535 nm is utilized and the emission intensity at 600 nm is determined.
  • the microscope is equipped with a motorized stage and also interfaced with a personal computer. This facilitates the computer-controlled movement of the stage with fluorescence measurements at 25 points (500 mm steps) on each dural sample. The mean and standard deviation of the measurements are determined by the computer.
  • the extravasation induced by the electrical stimulation of the trigeminal ganglion is an ipsilateral effect (i.e. occurs only on the side of the dura in which the trigeminal ganglion is stimulated). This allows the other (unstimulated) half of the dura to be used as a control.
  • the ratio of the amount of extravasation in the dura from the stimulated side, over the amount of extravasation in the unstimulated side, is calculated ("extravasation ratio").
  • Control animals dosed with only with saline yield an extravasation ratio of approximately 2.0 in rats and apprximately 1.8 in guinea pigs.
  • a compound which effectively completely prevents the extravasation in the dura from the stimulated side would yield an extravasation ratio of approximately 1.0.
  • a dose-response curve is generated for the 5HTlf agonist of Compound II and the dose that inhibits the protein extravasation ratio by 50% (ID50) is approximated.
  • the dose-response curve for Compound II is then repeated in the presence of the iGluR5 antagonist of Compound I which was administered at a dose that produced no change in extravasation ratio when administered alone.
  • These dose response curves are depicted in Figure I (rats).
  • the administration of the selective iGluR5 antagonist, in combiniation with the 5HTlf agonist shifted the dose response curve for the 5HTlf agonist to left, resulting in a 50 fold reduction in the resulting ED50 value.
  • the respective ID50 values, for the individual and combinations of compounds employed in the methods of the present invention, are summarized in Table I below.

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Abstract

L'invention concerne une méthode de traitement de trouble neurologique, en particulier de la migraine, qui consiste à administrer à un patient une quantité efficace d'un antagoniste de récepteur d'acide aminé excitateur combiné à un agoniste 5HT1f.
PCT/US2001/045863 2001-01-05 2001-12-20 Combinaison d'antagoniste de recepteur d'acide amine excitateur et d'agoniste 5-ht1f : methode de traitement de troubles neurologiques Ceased WO2002053139A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012048710A1 (fr) * 2010-10-15 2012-04-19 Concit Pharma Aps Combinaisons d'agonistes de récepteurs de sérotonine pour le traitement de troubles du mouvement
US10561618B2 (en) 2012-04-18 2020-02-18 Contera Pharma Aps Orally available pharmaceutical formulation suitable for improved management of movement disorders
US11975104B2 (en) 2016-07-11 2024-05-07 Contera Pharma A/S Pulsatile drug delivery system for treating morning akinesia

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521196A (en) * 1994-10-05 1996-05-28 Eli Lilly And Company 5-HT1F agonists for the treatment of migraine
US6242462B1 (en) * 1997-04-07 2001-06-05 Eli Lilly And Company Pharmacological agents
DZ3209A1 (fr) * 1999-07-06 2001-01-11 Lilly Co Eli Antagonistes selectifs du recepteur iGLuR5 utilises dans le traitement de la migraine.

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012048710A1 (fr) * 2010-10-15 2012-04-19 Concit Pharma Aps Combinaisons d'agonistes de récepteurs de sérotonine pour le traitement de troubles du mouvement
US9186359B2 (en) 2010-10-15 2015-11-17 Contera Pharma Aps Combinations of serotonin receptor agonists for treatment of movement disorders
US10632116B2 (en) 2010-10-15 2020-04-28 Contera Pharma A/S Combinations of serotonin receptor agonists for treatment of movement disorders
US10561618B2 (en) 2012-04-18 2020-02-18 Contera Pharma Aps Orally available pharmaceutical formulation suitable for improved management of movement disorders
US11975104B2 (en) 2016-07-11 2024-05-07 Contera Pharma A/S Pulsatile drug delivery system for treating morning akinesia

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