Classifications

• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• • 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
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism

Definitions

• Quetiapine fumarate is described in U.S. Patent Number 4,879,288, which is incorporated herein by reference. Quetiapine fumarate is able to treat both the positive (hallucinations, delusions) and negative symptoms (emotional withdrawal, apathy) of psychosis and is associated with fewer neurological and endocrine related side effects compared to older agents. Quetiapine fumarate has also been associated with a reduction in hostility and aggression.
• Quetiapine fumarate is associated with fewer side effects such as EPS, acute dystonia, acute dyskinesia, as well as tardive dyskinesia. Quetiapine fumarate has also helped to, enhance patient compliance with treatment, ability to function and overall quality of life, while reducing recidivism.
• P. Weiden et al. Atypical antipsychotic drugs and long-term outcome in schizophrenia, 11 J Clin. Psychiatry, 53-60, 57 (1996).
• quetiapine fumarate' s enhanced tolerability profile its use is particularly advantageous in the treatment of patients that are hypersensitive to the adverse effects of antipsychotic (such as elderly patients). Metabolites of quetiapine fumarate have been identified, E.
• a method of treating at least one symptom or condition associated with schizophrenia, dementia, anxiety, depression, mood disorders, bipolar disorders, bipolar mania, bipolar depression, cognitive disorders, psychosis and neurodegenerative disorders comprising administering to a mammal an effective amount of the compound of Formula I or its pharmaceutically acceptable salt.
• a pharmaceutical composition comprising an effective amount of the compound of Formula I or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier.
• a method of treating the symptoms or condition provided herein comprising administering to a mammal an effective amount of the above-mentioned pharmaceutical composition.
• the use of the compound of Formula I and/or the above- mentioned pharmaceutical composition in the treatment of the symptoms or conditions provided herein in mammals.
• the compound of Formula I is a dibenzothiazepine that has shown antidopaminergic activity. It has been shown to interact with a broad range of neurotransmitter receptors but has a higher affinity for serotonin (5-HT 2 ) receptors relative to dopamine (D 2 ) receptors in the brain.
• the compound of Formula I may be used as an antipsychotic with a reduction in the potential to cause side effects such as acute dystonia, acute dyskinesia, as well as tardive dyskinesia. Further the compound of Formula I may be used to treat patients of all ages and is advantageous in the treatment of elderly patients.
• the term "mammal” means a warm-blooded animal, preferably a human.
• the compound of Formula I may be made by a variety of methods known in the chemical arts.
• the compound of Formula I may be prepared by starting from known compounds or readily prepared intermediates including taking the lactam of Formula II:
• the immino chloride of Formula III may also be generated with other agents such as thionyl chloride or phosphorous pentachloride.
• the immino chloride is then reacted with piperazine to give the compound of Formula I.
• the compound of Formula I provided herein is useful as a free base, but may also be provided in the form of a pharmaceutically acceptable salt, and/or in the form of a pharmaceutically acceptable hydrate.
• pharmaceutically acceptable salts of Formula I include those derived from mineral acids such as for example: hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydro iodic acid, nitrous acid, and phosphorous acid, pharmaceutically acceptable salts may also be developed with organic acids including aliphatic mono dicarboxylates and aromatic acids.
• Other pharmaceutically acceptable salts of Formula I include but are not limited to hydrochloride, sulfate, pyrosulfate, bisulfate, bisulfite, nitrate, and phosphate.
• a clinician may determine the effective amount by using numerous methods already known in the art, an example of which is the BPRS cluster score that can be used to assess levels of hostility and positive symptoms.
• treating within the context of the present invention encompasses to administer an effective amount of the compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring symptom or condition.
• This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders. Particularly, the symptoms and conditions that may be treated by the administration of
• Formula I or its pharmaceutically acceptable salt or a pharmaceutical composition of Formula I include but are not limited to anxiety, agitation, hostility, panic, eating disorders, affective symptoms, mood symptoms, negative and positive psychotic symptoms commonly associated with psychosis and neurodegenerative disorders.
• the compound of Formula I may be administered comprising a predetermined dosage of the compound of Formula I to a mammal between one and four times a day, wherein the predetermined dosage is between 1 mg and 600 mg.
• the present invention also provides a method of treating the symptoms or conditions provided herein comprising the step of administering an initial predetermined dosage of a compound of Formula I to a human patient twice a day, wherein the predetermined dosage is between 1 mg and 30 mg with increases in increments of 1-50 mg twice daily on the second and third day as tolerated. Thereafter, further dosage adjustments can be made at intervals of no less than 2 days.
• the pharmaceutical composition comprises up to
• the pharmaceutical composition may comprise between 100 mg and 400 mg per day of the compound of Formula I or a pharmaceutically acceptable salt thereof.
• the pharmaceutical composition of the invention may accordingly be obtained by conventional procedures using conventional pharmaceutical excipients.
• pharmaceutical compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
• inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
• composition of the invention may be administered by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
• amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
• the size of the dose for therapeutic or prophylactic purposes of a compound of the Formulal will naturally vary according to the nature and severity of the symptoms or conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
• Another aspect of the invention provides a compound of Fo ⁇ nula I, or its pharmaceutically acceptable salt or solvate thereof, for use in treating the symptoms or conditions provided herein.
• the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in treating the symptoms or conditions provided herein.
• the present invention relates to methods of treating at least one symptom or condition associated with schizophrenia, dementia, anxiety, depression, mood disorders, bipolar disorders, bipolar mania, bipolar depression, cognitive disorders, psychosis and neurodegenerative disorders comprising administering to a mammal an effective amount of the compound of Formula I or its pharmaceutically acceptable salt and one or more of other therapeutically active agents, benzodiazepines, 5-HT JA ligands, 5-HTIB ligands, 5-HT ID ligands, mGluR2A agonists, mGluR5 antagonists, antipsychotics, NKl receptor antagonists, antidepressants, or serotonin reuptake inhibitors administered in combination as part of the same pharmaceutical composition, as well as to methods in which such active agents are administered separately as part of an appropriate dose regimen designed to obtain the benefits of combination therapy.
• the appropriate dose regimen, the amount of each dose of an active agent administered, and the specific intervals between doses of each active agent will depend upon the subject being treated, the specific active agent being administered and the nature and severity of the specific disorder or condition being treated.
• the compounds of this invention when used as either a single active agent or when used in combination with another active agent, will be administered to a subject in an amount up to about 750 mg per day, in single or divided doses.
• Such compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day. Variations may nevertheless occur depending upon the subject being treated and the individual response to the treatment, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
• benzodiazepines may include but are not limited to adinazolam, alprazolam, bromazepam, clonazepam, chlorazepate, chlordiazepoxide, diazepam, estazolam, flurazepam, balezepam, lorazepam, midazolam, nitrazepam, oxazepam, quazepam, temazepam, triazolam and equivalents thereof.
• Exemplary 5-HT IA and/or 5HT JB ligands may include but are not limited to buspirone, alnespirone, elzasonan, ipsapirone, gepirone, zopiclone and equivalents thereof.
• Exemplary mGluR 2 agonists may include (lS,3R)-l-aminocyclopentane-l,3- dicarboxylic acid, (2S,3S,4S)alpha-(carboxycyclopropyl)gIycine, and 3,5- dihydroxyphenylglycine.
• Exemplary antidepressants may include but are not limited to maprotiline, amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortryptyline, protriptyline, trimipramine, SSRIs and SNRIs such as fluoxetine, paroxetine, citalopram, escitalopram, sertraline, venlafaxine, fluoxamine, and reboxetine.
• Exemplary antipsychotics may include but are not limited to clozapine, risperidone, quetiapine, olanzapine, amisulpride, sulpiride, zotepine, chlorpromazine, haloperidol, ziprasidone, and sertindole.
• the following examples provided are not meant to limit the invention in any manner and are intended for illustrative purposes only.
• the reaction mixture was stripped down on the rotary evaporator under high vacuum to remove the xylene. The residue was partitioned between IN NaOH (400ml) and CH C1 2 (200ml). The layers were separated, and the aqueous phase further extracted with CH 2 C1 2 (3 X 200ml).

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• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Psychiatry (AREA)
• Epidemiology (AREA)
• Pain & Pain Management (AREA)
• Hospice & Palliative Care (AREA)
• Psychology (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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Publications (2)

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Cited By (13)

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• 2004
  • 2004-06-28 KR KR1020057025264A patent/KR20060082037A/ko not_active Withdrawn
  • 2004-06-28 CA CA002531284A patent/CA2531284A1/en not_active Abandoned
  • 2004-06-28 ES ES04743131T patent/ES2349091T3/es not_active Expired - Lifetime
  • 2004-06-28 WO PCT/GB2004/002783 patent/WO2005002586A1/en not_active Ceased
  • 2004-06-28 JP JP2006518324A patent/JP2007516193A/ja not_active Ceased
  • 2004-06-28 BR BRPI0412127-9A patent/BRPI0412127A/pt not_active IP Right Cessation
  • 2004-06-28 AT AT04743131T patent/ATE477803T1/de not_active IP Right Cessation
  • 2004-06-28 DE DE602004028739T patent/DE602004028739D1/de not_active Expired - Lifetime
  • 2004-06-28 EP EP04743131A patent/EP1644005B1/en not_active Expired - Lifetime
  • 2004-06-28 AU AU2004253334A patent/AU2004253334A1/en not_active Abandoned
  • 2004-06-28 CN CN2004800188710A patent/CN1816339B/zh not_active Expired - Fee Related
  • 2004-06-28 RU RU2005141060/15A patent/RU2005141060A/ru not_active Application Discontinuation
  • 2004-06-28 MX MXPA05013869A patent/MXPA05013869A/es not_active Application Discontinuation
  • 2004-07-01 US US10/883,024 patent/US20050026900A1/en not_active Abandoned
  • 2004-07-02 UY UY28400A patent/UY28400A1/es not_active Application Discontinuation
  • 2004-07-02 AR ARP040102345A patent/AR045004A1/es not_active Application Discontinuation
  • 2004-07-02 TW TW093120058A patent/TW200509944A/zh unknown
• 2005
  • 2005-12-15 IL IL172616A patent/IL172616A0/en unknown
• 2006
  • 2006-02-01 IS IS8283A patent/IS8283A/is unknown
  • 2006-02-02 NO NO20060556A patent/NO20060556L/no not_active Application Discontinuation

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