WO2008106659A2 - Méthodes de traitement du trouble bipolaire, ainsi que du trouble de la mémoire et/ou de la déficience cognitive qui lui sont associés - Google Patents

Méthodes de traitement du trouble bipolaire, ainsi que du trouble de la mémoire et/ou de la déficience cognitive qui lui sont associés Download PDF

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Publication number
WO2008106659A2
WO2008106659A2 PCT/US2008/055562 US2008055562W WO2008106659A2 WO 2008106659 A2 WO2008106659 A2 WO 2008106659A2 US 2008055562 W US2008055562 W US 2008055562W WO 2008106659 A2 WO2008106659 A2 WO 2008106659A2
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WIPO (PCT)
Prior art keywords
calcium channel
disorder
bipolar
channel modulator
lercanidipine
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PCT/US2008/055562
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English (en)
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WO2008106659A3 (fr
Inventor
David Lowe
Christopher J. Leonard
Michael De Vivo
Geoffrey Tombaugh
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Memory Pharmaceuticals Corporation
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Publication of WO2008106659A2 publication Critical patent/WO2008106659A2/fr
Publication of WO2008106659A3 publication Critical patent/WO2008106659A3/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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to methods of treating bipolar I disorder and memory and/or cognitive impairment associated therewith by administering an effective amount of at least one calcium channel modulator selected from (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of certain 1 ,4- dihydropyridine compounds.
  • at least one calcium channel modulator selected from (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of certain 1 ,4- dihydropyridine compounds.
  • Bipolar I disorder is one of the most common, severe, and persistent mental illnesses. It is characterized by periods of deep, prolonged, and profound depressions that alternate with periods of excessively elevated and/or irritable mood (mania).
  • bipolar I disorder such as lithium
  • Known treatments of bipolar I disorder have a number of drawbacks. Lithium is often prescribed to control mania or prevent the recurrence of both manic and depressive episodes. However, many patients with mania do not react well to treatment with lithium (e.g., rapid cyclers). Furthermore lithium is not suitable for pregnant women as it has been associated with an increased incidence of Ebstein's anomaly, a heart malformation in newborns. Some patients cannot tolerate the side effects of lithium which can include, for example, nausea, stomach cramps, diarrhea, muscle weakness, and feelings of being somewhat tired, dazed, or sleepy. Mild hand tremors may also emerge as lithium dose is increased.
  • the present invention is a method of treating or preventing mixed and/or manic episodes associated with bipolar I disorder or memory and/or cognitive impairment associated therewith in a patient by administering a therapeutically effective amount of at least one calcium channel modulator ("CCM") selected from (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of a 1 ,4-dihydropyridine compound, other than (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l ,4- dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate.
  • CCM calcium channel modulator
  • R 1 is methyl or -CN
  • R 2 is Ci-C 4 alkyl optionally substituted with Ci-C 4 alkoxy, NR 5 R 6 , or -OC(O)- (Ci-C 4 alky 1)
  • R 3 is Ci-C 4 alkyl
  • R 4 is (i) phenyl substituted with one or more substituents selected from halogen and NO 2 or (ii) benzofused heterocyclic group;
  • R 5 and R 6 are independently Ci-C 4 alkyl, aryl, or aryl(C]-C 4 alkyl), or R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted by one or two CpC 4 alkyl or aryl groups.
  • the CCM is the R-enantiomer of amlodipine, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, nimodipine, nifedipine, nicardipine or nitrendipine.
  • Patients administered the R-enantiomer of one of the aforementioned dihydropyridines can be treated for the disorders without inducing cardiovascular effects commonly associated with racemic calcium channel blockers, such as for example, hypotension or myocardial infarction. Patients who do not have hypertension or other cardiovascular symptoms may therefore be treated without adverse side effects.
  • the invention also relates to a method of prophylactically treating the recurrence of mixed or manic episodes associated with bipolar I disorder or memory and/or cognitive impairment associated therewith in a patient by administration of an effective amount of at least one CCM.
  • the patient may be in remission and not currently experiencing symptoms associated with bipolar I disorder.
  • the invention further relates to a method of treating depressive episodes associated with bipolar I disorder in a patient by administration of an effective amount of at least one CCM.
  • the invention further relates to a method of maintenance treatment of bipolar I disorder in a patient by administration of an effective amount of at least one CCM.
  • the treatment delays the time to occurrence of mood episodes (such as depression, mania, hypomania, and mixed episodes).
  • the invention further relates to a method of relapse prevention in patients with bipolar I disorder by administration of an effective amount of at least one CCM.
  • the patient may be of any age, such as a child, an adolescent, or an adult, or may be elderly. Furthermore, the CCM is effective in treatment-refractory patients.
  • the duration of the treatment is preferably at least 3 weeks.
  • patients treated with a therapeutically effective amount of at least one CCM have at least a 30% reduction in the Young Mania Rating Scale after about 3 weeks of treatment.
  • the CCM may be administered as the sole active ingredient, in combination with psychotherapy, or in combination with one or more second therapeutic agents.
  • a preferred second therapeutic agent is another bipolar I disorder-treating agent, such as lithium, a manic episode-treating agent, or a mixed episode treating agent.
  • anticonvulsants e.g., carbamazepine (Tegretol ® ), oxcarbazepine (Trileptal ® ), ethosuximide (Zarontin ® ), felbamate (Felbatol ® ), gabapentin (Neurontin ® ), lamotrigine (Lamictal ® ), phenobarbital (Luminal ® ), phenytoin (Dilantin ® ), topiramate (Topamax ® ), valproate, valproic acid, and divalproex sodium (Depakote ® )); mood stabilizers (e.g., lithium (Lithobid ® and Eskalith ® )); antidepressants, such as bupropion (Wellbutrin ® ), trazodone (Dresyrel ® ), serotonin-norepinep
  • This list of secondary agents is not limiting; it is contemplated that other mood stabilizers, antidepressants, anticonvulsants, calcium channel blockers, antipsychotics, and other psychotropic drugs can be administered with the CCM in the treatment methods of the present invention.
  • the CCM can be administered by any route of administration known in the art. Oral administration is preferred. DETAILED DESCRIPTION OF THE INVENTION
  • the R-enantiomers of the dihydropyridines described herein have an optical purity of at least 98, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% (by weight) (i.e., the weight percentage of R-enantiomer of the dihydropyridine based on the total weight of R and S enantiomers of the dihydropyridine).
  • the dihydropyridines and their optically pure enantiomers may be prepared by methods known in the art.
  • the dihydropyridines described herein may be administered in their free base form or, when appropriate, as pharmaceutically acceptable salts (e.g., acid addition salts such as hydrochloride salts, besylate salts, and maleate salts) of the dihydropyridine.
  • pharmaceutically acceptable salts e.g., acid addition salts such as hydrochloride salts, besylate salts, and maleate salts
  • halogen refers to F, Cl, Br, and I. Preferred halogens are F and Cl. More preferred is Cl.
  • alkyl refers to a straight-chain or branched- chain aliphatic hydrocarbon radical. Suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
  • alkoxy refers an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are - OCH 3 and -OC 2 H 5 .
  • aryl refers to an aromatic carbocyclic radical containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl.
  • alkyl refers to a divalent alkylene group having 1 to 4 carbon atoms.
  • a preferred aryKCpCj alkyl) group is benzyl.
  • heterocyclic ring refers to a 5- or 6- membered non-aromatic, saturated or partially unsaturated, cyclic group containing at least one hetero-ring atom, preferably nitrogen.
  • a preferred heterocyclic ring is piperidinyl.
  • benzofused heterocyclic group refers to a phenyl group fused to a heterocyclic ring, such as a benzo[c][l,2,5]oxadiazole.
  • the term "patient” refers to a human, such as a man, woman, child, adolescent, adult, or elderly person.
  • the term "treating” refers to (1) preventing or delaying the appearance of clinical symptoms of a disease or condition in a patient that may be afflicted with or predisposed to the disease or condition, but does not yet experience or display clinical or subclinical symptoms of the disease or condition; (2) relieving the disease or condition, i.e., causing regression of the disease or condition or at least one of its clinical or sub-clinical symptoms; and (3) inhibiting the progression of the disease or condition, i.e., arresting or reducing its development or at least one clinical or sub-clinical symptom thereof.
  • the benefit to a patient to be treated is either statistically significant or at least perceptible to the patient and/or the physician.
  • bipolar [ disorder,” “manic episode.” ''mixed episode,” and “major depressive disorder,” and other clinical terms have the definitions provided for them in DSM-IV-TR (4 th Fd.. 2000).
  • DSM-IV-TR the essential feature of bipolar I disorder is a clinical course that is characterized by the occurrence of one or more manic episodes or mixed episodes. Often individuals have also had one or more major depressive episodes.
  • a manic episode is defined by a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week
  • the criteria for a manic episode are: A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary).
  • the mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
  • the symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatments) or a general medical condition (e.g., hyperthyroidism).
  • a substance e.g., a drug of abuse, a medication, or other treatments
  • a general medical condition e.g., hyperthyroidism.
  • Manic-like episodes that are clearly caused by somatic antidepressant treatment e.g., medication, electroconvulsive therapy, light therapy
  • a Mixed Episode is characterized by a period of time (lasting at least 1 week) in which the criteria are met both for a manic episode and for a major depressive episode nearly every day.
  • the criteria for a mixed episode are:
  • the mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
  • the symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).
  • a substance e.g., a drug of abuse, a medication, or other treatment
  • a general medical condition e.g., hyperthyroidism
  • somatic antidepressant treatment e.g., medication, electroconvulsive therapy, light therapy
  • somatic antidepressant treatment e.g., medication, electroconvulsive therapy, light therapy
  • Signs and symptoms of depression include, but are not limited to: lasting sad, anxious, or empty mood; feelings of hopelessness or pessimism; feelings of guilt, worthlessness, or helplessness; loss of interest or pleasure in activities once enjoyed, including sex; decreased energy, a feeling of fatigue or of being slowed down; difficulty concentrating, remembering, making decisions; restlessness or irritability; hypersomnolence, or insomnia; changes in appetite and/or unintended weight loss or gain; chronic pain or other persistent bodily symptoms that are not caused by physical illness or injury; thoughts of death or suicide, or suicide attempts agitation (DSM-IV-TR, 349-351).
  • YMRS Young Mania Rating Scale
  • the 1 1 items are elevated mood, increased motor activity energ> . sexual interest, sleep, irritability, speech (rate and amount), language-thought disorder, content, disruptive-aggressive behavior, appearance, and insight.
  • YMRS features operationally- defined anchor points and the normal expected score is greater than or equal to 20 (Young, et al.. Br. J. Psychiatry, 133:429-435 ( 1978)).
  • the term ''memory and/or cognitive impairment refers to difficulty w ith, or abnormality or loss (partial or complete) of: memory, perception, problem-solving abilities, conceptualization, spatial or temporal orientation, and/or problems with attention deficit.
  • Memory and/or cognitive impairment can be present before, during, or after episodes associated with bipolar I disorder, and may be present before, during, or after any treatment for bipolar I disorder.
  • Memory and/or cognitive impairment can manifest as confusion, inappropriate behavior, irritability, aggression, or other behaviors indicative of improper thought process.
  • signs or symptoms of memory and/or cognitive impairment can be chronic, acute, continuous, non-continuous (i.e., sporactic or intermittant), mild, or severe.
  • treatment refractory refers to patients who have failed at least one treatment other than a CCM of the present invention for their disorder. See, for example, Vo, D., and Dunner, D. L., Treatment resistant bipolar disorder: a comparison of rapid cyclers and non-rapid cyclers, CNS Spectrums, 8:948-952 (2003).
  • All weight amounts of CCM described herein are provided based upon a molar equivalent of the free base unless otherwise indicated.
  • the CCM is typically administered in an amount sufficient for the desired effect.
  • the amount can be determined by methods known in the art.
  • the amount of the CCM is less than that which causes a significant hypotensive effect.
  • the CCM may be administered by any route.
  • the CCM may be administered parenterally, such as by one or multiple injection.
  • the CCM is administered orally, such as in the form of a tablet or capsule.
  • the oral dosage form can be formulated for immediate release or controlled release of the CCM.
  • the CCM may be administered as the sole active ingredient, in combination with psychotherapy, or in combination with one or more second therapeutic agents.
  • a preferred second therapeutic agent is another bipolar I disorder-treating agent, such as lithium, a manic episode-treating agent, or a mixed episode treating agent.
  • anticonvulsants e.g., carbamazepine (Tegretol ® ), oxcarbazepine (Trileptal ® ), ethosuximide (Zarontin ® ), felbamate (Felbatol ® ), gabapentin (Neurontin ® ), lamotrigine (Lamictal ® ), phenobarbital (Luminal ® ), phenytoin (Dilantin ® ), topiramate (Topamax ® ), valproate, valproic acid, and divalproex sodium (Depakote )); mood stabilizers (e.g., lithium (Lithobid ® and Eskalith ® )); antidepressants, such as bupropion (Wellbutrin ® ), trazodone (Dresyrel ® ), serotonin-norepinephrine
  • anticonvulsants e.g., carbamaz
  • This list of secondary agents is not limiting; it is contemplated that other mood stabilizers, antidepressants, anticonvulsants, calcium channel blockers, antipsychotics, and other psychotropic drugs can be administered with the CCM in the treatment methods of the present invention.
  • the second agent may be administered with the CCM in a unitary dosage form (i.e., a dosage form containing both the CCM and the second agent), or concurrently in separate dosage forms, which may be administered by the same or different routes of administration.
  • the CCM and optionally the second agent can be administered by any route including, but not limited to, orally, nasally, parenterally (subcutaneously, intraveneously, intramuscularly, intrasternally and by infusion), rectally, vaginally, topically and by ocular administration.
  • the CCM and optionally the second agent can be incorporated into a dosage form, such as a solid or liquid oral dosage form, suppository, vaginal dosage form, and topical dosage form.
  • dosage forms typically contain one or more pharmaceutically acceptable carriers, diluents, and/or excipients.
  • Suitable solid oral dosage forms include, but are not limited to, tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
  • the CCM can be incorporated into the dosage form alone or in combination with one or more pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, and starches) and excipients, including but not limited to, suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, and lubricants.
  • the dosage form can provide controlled release of the CCM and optionally the second agent.
  • the dosage form can be a time release capsule, tablet or gel.
  • Suitable liquid oral dosage forms include, but are not limited to, aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain one or more suitable inert diluents, such as water, and excipients, such as preservatives, wetting agents, sweeteners, flavorants, and agents for emulsifying and/or suspending the CCM and/or the second agent.
  • the dosage form can be injected, for example, intravenously, in the form of an isotonic sterile solution.
  • Suppositories for rectal administration of the CCM and optionally the second agent can be prepared by mixing the CCM and/or second agent with a suitable excipient, such as cocoa butter, salicylates or a polyethylene glycol.
  • a suitable excipient such as cocoa butter, salicylates or a polyethylene glycol.
  • Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing the active ingredient(s) and one or more carriers.
  • the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose.
  • the topical formulation may be in the form of a transdermal patch.
  • the CCM and/or optional second agent can be present in these preparations in a concentration of 0.1 to 99.5% by weight and preferably at 0.5 to 95% by weight of the total formulation.
  • the amount of CCM is provided in the equivalent weight of the free base.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une méthode qui permet de traiter ou de prévenir chez un patient des épisodes mixtes et/ou maniaques liés au trouble bipolaire, ainsi qu'au trouble de la mémoire et/ou à la déficience qui lui sont associés. La méthode consiste à administrer audit patient une quantité efficace d'au moins un modulateur du canal calcique sélectionné dans le groupe constitué par: (1) amlodipine, bépridil, clévidipine, félodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, ou nitrendipine; ou 2) l'énantiomère R d'un composé de 1,4-dihydropyridine autre que (+)-isopropyl-2-méthoxyéthyl-4-(2-chloro-3-cyano-phényl)-1,4-dihydro-2,6-diméthyl-pyridine-3,5-dicarboxylate.
PCT/US2008/055562 2007-03-01 2008-02-29 Méthodes de traitement du trouble bipolaire, ainsi que du trouble de la mémoire et/ou de la déficience cognitive qui lui sont associés WO2008106659A2 (fr)

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US89245507P 2007-03-01 2007-03-01
US60/892,455 2007-03-01

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7820691B2 (en) 2006-08-28 2010-10-26 Medipropharma, Inc. Indoloquinoline compounds as calcium channel blockers
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
WO2014052849A1 (fr) * 2012-09-28 2014-04-03 Elan Pharmaceuticals, Inc. Traitements combinés de troubles bipolaires
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules

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US6458808B1 (en) * 2000-12-20 2002-10-01 Osmotica Corp. Pharmaceutical composition for the treatment of cognitive cerebrovascular disease

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US4567271A (en) * 1977-06-20 1986-01-28 Sandoz Ltd. Benzoxadiazoles and benzothiadiazoles
US6458808B1 (en) * 2000-12-20 2002-10-01 Osmotica Corp. Pharmaceutical composition for the treatment of cognitive cerebrovascular disease

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7820691B2 (en) 2006-08-28 2010-10-26 Medipropharma, Inc. Indoloquinoline compounds as calcium channel blockers
WO2014052849A1 (fr) * 2012-09-28 2014-04-03 Elan Pharmaceuticals, Inc. Traitements combinés de troubles bipolaires
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US8889190B2 (en) 2013-03-13 2014-11-18 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10363224B2 (en) 2013-03-13 2019-07-30 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9555005B2 (en) 2013-03-15 2017-01-31 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10172878B2 (en) 2013-03-15 2019-01-08 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules

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