WO2003051397A1 - Antagonistes des recepteurs y5 des neuropeptides pour traiter la depression, l'anxiete et la demence - Google Patents

Antagonistes des recepteurs y5 des neuropeptides pour traiter la depression, l'anxiete et la demence Download PDF

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Publication number
WO2003051397A1
WO2003051397A1 PCT/US2002/040012 US0240012W WO03051397A1 WO 2003051397 A1 WO2003051397 A1 WO 2003051397A1 US 0240012 W US0240012 W US 0240012W WO 03051397 A1 WO03051397 A1 WO 03051397A1
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npy
antagonist
mammal
anxiety
depression
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PCT/US2002/040012
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English (en)
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Douglas J. Macneil
Lauren P. Shearman
Leonardus H. T. Van Der Ploeg
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Merck & Co., Inc.
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Priority to AU2002359706A priority Critical patent/AU2002359706A1/en
Publication of WO2003051397A1 publication Critical patent/WO2003051397A1/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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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

Definitions

  • This invention relates to the treatment and/or prevention of depression and/or anxiety disorders and/or dementia by the administration of a Neuropeptide Y Y5 antagonist.
  • a major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either 0 depressed mood or the loss of interest or pleasure in all, or nearly all activities.
  • the individual may also experience changes in appetite or weight, sleep and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating or making decisions; and recunent thoughts of death or suicidal ideation, plans or attempts.
  • One or more major depressive episodes may give rise to a 5 diagnosis of major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatric Association, 1994).
  • Treatment regimens commonly include the use of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), some psychotropic drugs, lithium carbonate, and electroconvulsive therapy (ECT) (see R. J. Baldessarini 0 in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, Chapter 19, McGraw-Hill, 1996 for a review). More recently, new classes of antidepressant drugs are being developed including selective serotonin reuptake inhibitors (SSRIs), specific monoamine reuptake inhibitors and 5-HTiA receptor agonists and antagonists. 5 The most established drug treatment for the management of depressive illness are the tricyclic antidepressants.
  • tricyclic antidepressants such as amitriptyline
  • amitriptyline for other patients, less sedating compounds such as imipramine or desipramine can be used.
  • tricyclic antidepressants also possess antagonist properties at a variety of neurotransmitter receptors, including muscarinic cholinergic receptors, -adrenoceptors and Hi-histamine receptors.
  • receptor antagonist effects account for much of the side-effect profile of the tricyclic antidepressants, and in particular, their anticholinergic side-effects which are 5 particularly troublesome in patients with prostatic enlargement or glaucoma.
  • Other side-effects include dry mouth, tachycardia, difficulty in visual accommodation, constipation, urinary retention, sexual dysfunction, cognitive impairment, postural hypotension, and weight gain.
  • Monoamine oxidase inhibitors are generally prescribed for patients who have failed to respond to tricyclic antidepressants or electroconvulsive therapy.
  • tricyclic antidepressants there are a number of side-effects associated with the use of MAOIs including dizziness, muscular twitching, insomnia, confusion, mania, tachycardia, postural hypotension, hypertension, dry mouth, blurred vision, impotence, peripheral edema, hepatocellular damage and leucopenia.
  • selective serotonin reuptake inhibitors are increasingly prescribed, particularly in patients where the use of tricyclic antidepressants is contraindicated because of their anticholinergic and cardiotoxic effects.
  • SSRIs such as fluoxetine, fluvoxamine, sertraline and paroxetine are generally non-sedating. Furthermore, SSRIs do not stimulate appetite and may therefore be appropriate in patients in whom weight gain would be undesirable. However, SSRIs are not without their own side-effects, including nausea, diarehea, dry mouth, reduced appetite, dyspepsia, vomiting, headache, nervousness, insomnia, anxiety, tremor, dizziness, fatigue, decreased libido, pharyngitis, dyspnea, skin rash and sexual dysfunction. Whatever drug is used, there is a delay of usually two, three or even four weeks before a therapeutic effect is observed. This period of delay may be particularly difficult for a patient suffering from a major depressive illness.
  • Anxiety is an emotional condition characterized by feelings such as apprehension and fear accompanied by physical symptoms such as tachycardia, increased respiration, sweating and tremor. It is a normal emotion but when it is severe and disabling it becomes pathological.
  • Anxiety disorders are generally treated using benzodiazepine sedative- antianxiety agents.
  • Potent benzodiazepines are effective in panic disorder as well as in generalized anxiety disorder, however, the risks associated with the drug dependency may limit their long-term use, 5-HTiA receptor partial agonists also have useful anxiolytic and other psychotropic activity, and less likelihood of sedation and dependence (See, e.g., RJ. Balderssarini in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, Chapter 18, McGraw-Hill, 1996, for a review).
  • Dementia is a syndrome due to disease of the brain, usually a chronic or progressive nature, in which there is a disturbance of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement. Consciousness is not clouded. Impairments of cognitive functioning are commonly accompanied, and occasionally preceded, by deterioration in emotional control, social behavior or motivation. This syndrome occurs in Alzheimer's disease, in cerebrovascular disease, and in other conditions primarily or secondarily affecting the brain.
  • Neuropeptide Y is a 36 amino acid peptide that is a member of the pancreatic polypeptide family, which also includes pancreatic polypeptide (PP) and peptide YY (PYY).
  • NPY is located throughout the central and peripheral nervous systems and affects a diverse range of biological functions, including central endocrine secretion, vascular and smooth muscle activity, appetite, memory, anxiety, blood pressure regulation and reproduction. See, e.g., Karla, et al., Phys. & Behavior 50, 5 (1991).
  • Endogenous receptor proteins that bind NPY and related peptides as ligands have been identified and distinguished, and several such proteins have been cloned and expressed.
  • Six different receptor subtypes [Yl, Y2, Y3, Y4(PP), Y5, Y6 (formerly designated as a Y5 receptor)] are recognized today based upon binding profile, pharmacology and/or composition if identity as known (Wahlestedt, C. et al. Ann. NYAcad. Sei. 1990, 611, 7; Larhammar, D. et al. J. Biol. Chem. 1992, 267, 10935; Wahlestedt, C. et al. Regul. Pept.
  • NPY receptor proteins belong to the family of so-called G-protein coupled receptors (GPCRs).
  • GPCRs G-protein coupled receptors
  • cAMP cyclic adenosine monophosphate
  • NPY inhibits forskolin-stimulated cAMP production/levels in a neuroblastoma cell line.
  • a Y5 ligand that mimics NPY in this fashion is an agonist wheras one that competitively reverses the NPY inhibition of forskolin-stimulated cAMP production is an antagonist.
  • Neuropeptide Y itself is the archetypal substrate for the NPY receptors and its binding can elicit a variety of pharmacological and biological effects in vitro and in vivo.
  • NPY When administered to the brain of live animals (intracerebroventricularly (icv) or into the amygdala), NPY produces anxiolytic effects in established animal models of anxiety such as the elevated plus-maze, Vogel punished drinking and Geller-Seifter's bar-pressing conflict paradigms (Hilor, M. et al. Psychopharmacology 1989, 98, 524; Heilig, M. et. al. Reg. Peptides 1992, 41, 61; Heilig M. et. al. Neuropsycho-pharmacology 1993, 8, 357).
  • compounds that mimic NPY are postulated to be useful for the treatment of anxiolytic disorders.
  • neuropeptide Y improves memory and performance scores in animal models of learning (Flood, J. F. et. al.
  • NPY neurodegenerative diseases
  • AD Alzheimer's Disease
  • AIDS-related and senile dementia Elevated plasma levels of NPY are present in animals and humans experiencing episodes of high sympathetic nerve activity such as surgery, newborn delivery and hemorrhage (Morris, M. J. et. al. Journal ofAutonomic Nervous System 1986, 17, 143).
  • chemical substances that alter the NPY-ergic system may be useful for alleviating migraine, pain and the condition of stress.
  • the present invention relates to the use of a NPY Y5 antagonist for treating depression in a mammal. Accordingly, the present invention provides a method for treating depression in a mammal comprising the administration of NPY Y5 antagonist. The present invention further provides a pharmaceutical composition for treating depression. The present invention further provides a method of manufacture of a medicament useful in the treatment or prevention of depression.
  • the present invention is further directed to the use of a NPY Y5 antagonist for treating anxiety in a mammal. Accordingly, the present invention provides a method for treating anxiety in a mammal comprising the administration of NPY Y5 antagonist. The present invention further provides a pharmaceutical composition for treating anxiety. The present invention further provides a method of manufacture of a medicament useful in the treatment or prevention of anxiety.
  • the present invention is further directed to the use of a NPY Y5 antagonist for treating dementia in a mammal. Accordingly, the present invention provides a method for treating dementia in a mammal comprising the administration of NPY Y5 antagonist. The present invention further provides a pharmaceutical composition for treating dementia. The present invention further provides a method of manufacture of a medicament useful in the treatment or prevention of dementia.
  • the present invention relates to the use of a NPY Y5 antagonist for treating depression in a mammal.
  • the present invention also relates to the use of a NPY Y5 antagonist for treating anxiety in a mammal.
  • the present invention also relates to the use of a NPY Y5 antagonist for treating dementia in a mammal.
  • Illustrating the invention is the use of a CNS penetrant NPY Y5 antagonist for the treatment of depression, anxiety and/or dementia.
  • NPY Y5 an orally active NPY Y5 antagonist for the treatment of depression, anxiety and/or dementia.
  • a non-peptidyl NPY Y5 antagonist for the treatment of depression, anxiety and/or dementia is the use of a non-peptidyl NPY Y5 antagonist for the treatment of depression, anxiety and/or dementia.
  • NPY Y5 antagonist for the treatment of major depressive disorder.
  • Exemplifying the invention is the use of a NPY Y5 antagonist for the treatment of depression including depressive disorders, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder.
  • depressive disorders for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression
  • melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation
  • atypical depression or reactive depression
  • bipolar disorders or manic depression for example, bipolar I disorder, bipolar II
  • NPY Y5 antagonist for the treatment of disorders of the central nervous system.
  • disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile
  • the present invention is also concerned with treatment and prevention of these conditions, and with the use of a NPY Y5 antagonist, combinations, and compositions thereof, for the manufacture of a medicament useful for treating or preventing these conditions.
  • the NPY Y5 antagonists of use in the present invention may be any
  • NPY Y5 antagonist known from the art.
  • the NPY Y5 antagonist may be peptidal or non-peptidal in nature, however, the use of a non-peptidal NPY Y5 antagonist is preferred. In addition, for convenience the use of an orally active NPY Y5 antagonist is preferred. In the present invention, it is preferred that the NPY Y5 antagonist active upon the central nervous system (CNS), such as the brain, following systemic administration, i.e. that it readily penetrates the CNS. Accordingly, a preferred NPY Y5 antagonist for use in the present invention is a CNS -penetrating NPY Y5 antagonist.
  • Non-limiting examples of NPY Y5 receptor antagonists include compounds of the formula:
  • A is selected from the group consisting of aryl or heteroaryl, wherein said aryl and heteroaryl groups may be optionally substituted on either the carbon or hetero atom, the substituent being selected from the group consisting of halogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylene optionally substituted with oxo, and a group represented by formula of -Q-D; D is selected from the group consisting of aryl or heteroaryl, wherein said aryl and heteroaryl groups may be optionally substituted, the substituent being selected from the group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,
  • n is an integer from 0 tol ;
  • Q is selected from the group consisting of a single bond or carbonyl
  • T, U, V and W are each independently selected from the group consisting of nitrogen or a methylene group, said nitrogen or methylene group may be optionally substituted with a substituent selected from the group consisting of: halogen, lower alkyl, hydroxy, and lower alkoxy;
  • X is selected from the group consisting of methylene or nitrogen
  • Y is selected from the group consisting of nitrogen and oxygen, wherein said nitrogen may be optionally substituted with lower alkyl or oxygen; and the pharmaceutically acceptable salts and esters thereof.
  • Non-limiting examples of NPY Y5 receptor antagonists include compounds of the formula:
  • V, W, X and Z are independently selected from CH and N;
  • Rl is H, Ci-3 alkyl, Ci-3 alkoxy, F, or Cl;
  • R2 is S(O)n R6, COR6 or CHO, wherein n is 0, 1 or 2; and R6 is N(R3)2 or C1.3 alkyl; R3 is independently H or Ci-3 alkyl; Ar is aryl or heteroaryl;
  • R4 and R5 are independently selected from:
  • Non-limiting examples of NPY Y5 receptor antagonists include compound L-152,804 of the formula:
  • NPY Y5 antagonists which are currently under investigation.
  • this listing of groups of compounds is not meant to be comprehensive, the methods of the present invention may employ any NPY Y5 antagonist and is not limited to any particular structural class of compound.
  • a suitable selection cascade for NPY Y5 antagonists of use according to the present invention is as follows:
  • NPY Y5 receptor antagonists of use in the present invention are the compounds described in US 6,191,160, US 6,313,298 and International Publication Number WO 01/14376 and WO 00/27845; and US Patent No. 6,258,837, all of which are hereby incorporated by reference in their entirety.
  • Further examples of NPY Y5 receptor antagonists of use in the present invention are the compounds described in J. Organic Chemistry, vol. 31, No. 5, p.
  • Suitable pharmaceutically acceptable salts of the NPY Y5 antagonists of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.
  • Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group.
  • the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
  • a compound as a NPY Y5 antagonist in particular a CNS penetrant NPY Y5 antagonist, and thus able to have utility in the present invention may be readily determined without undue experimentation by methodology well known in the art, such as the assays described herein.
  • NPY Y5 antagonist and one or more other pharmacologically active agents suitable for the treatment of the specific condition may be administered to a patient simultaneously, sequentially or in combination.
  • the present compound may employed directly in combination with the other active agent(s), or it may be administered prior, concunent or subsequent to the administration of the other active agent(s).
  • the cunently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
  • the NPY Y5 antagonist may be used in conjunction with other anti-depressant or anti- anxiety agents.
  • Suitable classes of anti-depressant agent include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, -adrenoreceptor antagonists and atypical anti-depressants.
  • SSRIs selective serotonin reuptake inhibitors
  • MAOIs monoamine oxidase inhibitors
  • RIMAs reversible inhibitors of monoamine oxidase
  • SNRIs noradrenaline reuptake inhibitors
  • CRF corticotropin releasing factor
  • Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics.
  • Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramdne, and pharmaceutically acceptable salts thereof.
  • Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
  • Another norepinephrine reuptake inhibitor of use in the present invention is reboxetine.
  • Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
  • Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.
  • Suitable reversible inhibitors of monoamine oxidase include: moclobemide, and pharmaceutically acceptable salts thereof.
  • Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof.
  • Suitable CRF antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.
  • Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
  • Another suitable atypical antidepressant is sibutramine.
  • antidepressants of use in the present invention include adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide combination, atipamezole, azamianserin, apelinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline,
  • Suitable classes of anti-anxiety agent include benzodiazepines and 5-HTiA agonists or antagonists, especially 5-HTiA partial agonists, and corticotropin releasing factor (CRF) antagonists.
  • benzodiazepines other suitable classes of anti-anxiety agent are nonbenzodiazepine sedative-hypnotic drugs such as zolpidem; mood-stabilizing drugs such as clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol and vigabatrin; and barbiturates.
  • Suitable benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.
  • Suitable 5-HTiA receptor agonists or antagonists include, in particular, the 5-HTiA receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising a compound of the present invention and an anti-depressant or anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.
  • the present invention further includes the use of a NPY Y5 antagonist in the manufacture of a medicament useful in the treatment or prevention of depression, anxiety, or dementia.
  • a product comprising a compound of the present invention and an anti- depressant or anti-anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and/or anxiety.
  • the compounds of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • compositions containing an the NPY Y5 antagonists of use according to the present invention are in unit dosage forms such as tablets, pills, capsules, wafers and the like.
  • the NPY Y5 antagonists of use according to the present invention may be presented as granules or powders for extemporaneous formulation as volume defined solutions or suspensions.
  • the NPY Y5 antagonists of use according to the present invention may be presented in ready- prepared volume defined solutions or suspensions. Preferred forms are tablets and capsules.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl- pyrrolidone or gelatin.
  • compositions of the present invention may also be administered via the buccal cavity using conventional technology, for example, absorption wafers.
  • compositions in the form of tablets, pills, capsules or wafers for oral administration are particularly preferred.
  • an appropriate dosage level will generally be about 0.01 ⁇ g to 50 mg per kg patient body weight per day which may be administered in single or multiple doses.
  • the dosage level will be about 0.1 ⁇ g to about 25 mg/kg per day; more preferably about 0.5 ⁇ g to about 10 mg/kg per day.
  • a suitable dosage level is about 0.1 ⁇ g to 25 mg/kg per day, preferably about 0.5 ⁇ g to 10 mg/kg per day, and especially about 1 ⁇ g to 5 mg/kg per day.
  • a typical indicated dose is about 300 ⁇ g to 400 mg orally.
  • a compound may be administered on a regimen of several times per day, for example 1 to 4 times per day, preferably once or twice per day.
  • a suitable dosage level is about 0.1 ⁇ g to 10 mg/kg per day, preferably about 0.5 ⁇ g to 5 mg/kg per day, and especially about 1 ⁇ g to 1 mg/kg per day. In larger mammals, for example humans, a typical indicated dose is about 100 ⁇ g to 100 mg i.v.
  • a compound may be administered on a regimen of several times per day, for example 1 to 4 times per day, preferably once or twice per day.
  • compositions of the present invention may be provided in a solid dosage formulation preferably comprising about 100 ⁇ g to 500 mg active ingredient, more preferably comprising about 100 ⁇ g to 250 mg active ingredient.
  • the pharmaceutical composition is preferably provided in a solid dosage formulation comprising about 100 ⁇ g, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient.
  • the amount of the NPY Y5 antagonist required for use in the treatment or prevention of major depressive disorders will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
  • depression includes major depressive episodes, major depressive disorder and seasonal affective disorder.
  • major depressive disorder includes single or recunent major depressive episodes, with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset and, in the case of recurrent episodes, with or without interepisode recovery and with or without seasonal pattern.
  • Major depressive disorder include dysthymic disorder with early or late onset and with or without atypical features; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, ***e, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood.
  • Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc.
  • a “major depressive episode” is defined as at least two weeks of depressed mood or loss of interest, which may be accompanied by other symptoms of depression. The symptoms must persist for most of the day (i.e. for at least two thirds of the patients' waking hours), nearly every day (i.e. for at least ten out of fourteen days) for at least two consecutive weeks.
  • a "depressed mood” is often described by the patient as feeling sad, hopeless, helpless or worthless. The patient may also appear sad to an observer, for example, through facial expression, posture, voice and tearfulness, hi children and adolescents, the mood may be irritable.
  • a "loss of interest” is often described by the patient as feeling less interested in hobbies or not feeling any enjoyment in activities that were previously considered to be pleasurable.
  • a major depressive episode may be accompanied by other symptoms of depression including significant weight loss when not dieting or weight gain (e.g. a change of more than 5% body weight in one month), or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation; fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate; or indecisiveness; and recunent thoughts of death, recunent suicidal ideation with or without a specific plan, or a suicide attempt.
  • weight gain e.g. a change of more than 5% body weight in one month
  • Signs and symptoms of the disorder include depression, loss of energy, anxiety, initability, headaches, increased sleep, loss of interest in sex, overeating (especially foods high in carbohydrates), weight gain, and difficulty concentrating and processing information.
  • the patient is usually free of the symptoms during spring and summer, but some patients do have exacerbated symptoms of depression in the spring. Others may experience periods of mania or hypomania, a less intense form of mania, during the summer. Characteristics of mania may include persistent elevated mood, hyperactivity, and inflated self-esteem.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
  • CNS -penetrating refers to a compound that is active upon the central nervous system (CNS), such as the brain, following systemic administration.
  • orally active refers to a compound which when given by mouth results in at least 5% of the dose being absorbed into the systemic circulation.
  • the cloned human Y5 receptor is used in the primary assay.
  • Vectors expressing either the 455 amino acid form (See, e.g., US 5,602,024) or a 10 amino acid, N-terminally shorter form (See, e.g., US 5,919,901) can be introduced into cell lines to obtain cells which express the human Y5 receptor.
  • Binding of [125 ⁇ ]p ⁇ (NEN) to membrane preparations from cells expressing the cloned human Y5 receptor are performed in 0.2 ml of 25 mM Tris buffer (pH 7.4) containing 10 mM MgCl2, 1 mM PMSF, 0.1% bacitracin and 0.5% bovine serum albumin.
  • the functional potency of Y5 antagonists can be determined using various assays which measure inhibition of second messenger pathways.
  • NPY increases intracellular Ca2+ concentration via activation of Y5 receptors through coupling to G qi5.
  • the potency of a Y5 antagonist in blocking NPY mediated Ca2+ increase can be used as a measure of its functional antagonist activity.
  • CHO cells expressing both NPY Y5 receptors and G qi5 are seeded (40,000 cells per well) into 96-well plate 24 hr before assay.
  • potent Y5 antagonists with a binding IC50 and/or functional IC50 of less than 1 ⁇ M can be identified.
  • Useful antagonists would also have to posses other characteristics such as selectivity over the other NPY receptors, good systemic exposure, sufficient half-life and brain penetration.
  • EXAMPLE 2 Effect of a Y5 antagonist on bovine pancreatic polypeptide ( bPP)-induced food intake in Sprague-Dawley rats. To affect depression or anxiety a Y5 antagonist must penetrate into the bovine pancreatic polypeptide (bPP)-induced food intake in Sprague-Dawley rats. To affect depression or anxiety a Y5 antagonist must penetrate into the bovine pancreatic polypeptide (bPP)-induced food intake in Sprague-Dawley rats. To affect depression or anxiety a Y5 antagonist must penetrate into the
  • This assay measures the ability of NPY Y5 antagonists to block the action of an ICV dose of bPP, a NPY Y5 agonist.
  • Rats Male Sprague-Dawley rats aged 7 weeks (Charles River, Japan) were maintained under the controlled temperature (23 ⁇ 3 °C), humidity (55 ⁇ 15%) and light-dark cycle (7:00-19:00 light on). Rats were housed individually with ad libitum access food (CE-2, Clea Japan) and tap water.
  • Rats were anesthetized with sodium pentobarbital (50 mg/kg, i.p., Dainabot, Japan).
  • a permanent stainless steel guide cannula for intracerebroventricular (ICV) injection (21 gauge, 10 mm long) was stereotaxically implanted into the right lateral ventricle.
  • the stereotaxic coordinates used were as follows : 0.9 mm posterior and 1.2 mm lateral to the bregma and 1.5 mm ventral to the brain surface. Animals were allowed at least 6-day recovery postoperatively before the start of feeding experiment. The day before the experiment, they were handled and underwent mock injection, and nocturnal food intake was measured. Rats which ate more than 15 g during the night before the experiment were used for the following experiment.
  • Test compounds were suspended in 0.5 % methylcellulose and orally administered by gavage. Administration of test compounds usually began at 10:00. Dosing volume was 5 ml/kg.
  • bovine pancreatic polypeptide PP, 5 ⁇ g/10 ⁇ l/1 min
  • PP bovine pancreatic polypeptide
  • the injector extended 2 mm beyond the end of the guide cannula.
  • Bovine PP was dissolved in 10 mM PBS containing 0.05 % BSA. Two hour post-injection food intake was measured for each rat.
  • a Y5 antagonist was orally administered 1 hour prior to the ICV- injection of bPP in satiated male Sprague-Dawley rats. Effective compounds suppressed bPP-induced food intake in a dose-dependent manner, with a minimum effective dose between 3 and 50 mg/kg.
  • mice Male and female guinea-pigs pups are housed in family groups with their mothers and littermates throughout the study. Experiments are commenced after weaning when the pups are 2 weeks old. Before entering an experiment, the pups are screened to ensure that a vigorous vocalization response is reproducibly elicited following maternal separation. The pups are placed individually in an observation cage (55cm x 39cm x 19cm) in a room physically isolated from the home cage for 15 minutes and the duration of vocalization during this baseline period is recorded. Only animals which vocalize for longer than 5 minutes are employed for drug challenge studies (approximately 50% of available pups may fail to reach this criterion). On test days each pup receives an oral dose or an s.c. or i.p.
  • test compound or vehicle injection of test compound or vehicle and is then immediately returned to the home cage with its mother and siblings for 30 to 60 minutes (or for up to 4 hours following an oral dose, dependent upon the oral pharmacokinetics of the test compound) before social isolation for 15 minutes as described above.
  • the duration of vocalization on drug treatment days is expressed as a percentage of the pre-treatment baseline value for each animal. The same subjects are retested once weekly for up to 6 weeks. Between 6 and 8 animals receive each test compound at each dose tested.
  • CNS-penetrant NPY Y5 receptor antagonists of use in the present invention are also effective in the attenuation of separation-induced vocalizations by guinea-pig pups as hereinafter defined.
  • a vocalization response in guinea-pig pups is induced by isolation from their mothers and littermates, which response is attenuated when a CNS-penetrant NPY Y5 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocalizations during the first 15 minutes of isolation are attenuated with an ID50 ⁇ 20mg/kg, preferably with an ID50 ⁇ 10mg/kg, and especially with an ID50 ⁇ 5mg/kg.
  • the NPY Y5 receptor antagonist is administered orally, 2 hours prior to isolation, wherein vocalizations during the first 15 minutes of isolation are attenuated with an ID50 ⁇ 20mg/kg, preferably with an ID50 ⁇ 10mg/kg, and especially with an IX>50 ⁇ 5mg/kg.

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Abstract

La présente invention concerne le traitement et/ou la prévention de la dépression, de l'anxiété et/ou de la démence par administration d'un antagoniste Y5 du neuropeptide Y. L'invention concerne également l'utilisation d'un médicament pour conduire cette thérapie.
PCT/US2002/040012 2001-12-17 2002-12-13 Antagonistes des recepteurs y5 des neuropeptides pour traiter la depression, l'anxiete et la demence WO2003051397A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030210A1 (fr) * 2003-09-26 2005-04-07 Pfizer Products Inc. Traitement des dereglements neurologiques lies a des troubles du sommeil paradoxal avec un antagoniste du recepteur y5 du npy
JP2012501962A (ja) * 2008-09-10 2012-01-26 田辺三菱製薬株式会社 芳香族含窒素六員環化合物及びその使用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997020820A1 (fr) * 1995-12-01 1997-06-12 Novartis Ag Composes heteroaryles
WO1999010330A1 (fr) * 1997-08-25 1999-03-04 Bayer Corporation Cetones heterocycliques en tant qu'antagonistes du recepteur y5 du neuropeptide y
EP0992239A1 (fr) * 1997-04-23 2000-04-12 Banyu Pharmaceutical Co., Ltd. Antagoniste de recepteur de neuropeptide y
WO2000027845A1 (fr) * 1998-11-10 2000-05-18 Merck & Co., Inc. Spiro-indolines en tant qu'antagonistes du recepteur y5
US6326375B1 (en) * 1999-08-20 2001-12-04 Banyu Pharmaceutical Co., Ltd. Spiro compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997020820A1 (fr) * 1995-12-01 1997-06-12 Novartis Ag Composes heteroaryles
EP0992239A1 (fr) * 1997-04-23 2000-04-12 Banyu Pharmaceutical Co., Ltd. Antagoniste de recepteur de neuropeptide y
WO1999010330A1 (fr) * 1997-08-25 1999-03-04 Bayer Corporation Cetones heterocycliques en tant qu'antagonistes du recepteur y5 du neuropeptide y
WO2000027845A1 (fr) * 1998-11-10 2000-05-18 Merck & Co., Inc. Spiro-indolines en tant qu'antagonistes du recepteur y5
US6326375B1 (en) * 1999-08-20 2001-12-04 Banyu Pharmaceutical Co., Ltd. Spiro compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030210A1 (fr) * 2003-09-26 2005-04-07 Pfizer Products Inc. Traitement des dereglements neurologiques lies a des troubles du sommeil paradoxal avec un antagoniste du recepteur y5 du npy
JP2012501962A (ja) * 2008-09-10 2012-01-26 田辺三菱製薬株式会社 芳香族含窒素六員環化合物及びその使用

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