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(12) United States Patent (10) Patent No.: US 6,469,008 B2 Currie Et Al

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(12) United States Patent (10) Patent No.: US 6,469,008 B2 Currie Et Al USOO6469008B2 (12) United States Patent (10) Patent No.: US 6,469,008 B2 Currie et al. (45) Date of Patent: Oct. 22, 2002 (54) (R)-HYDROXYNEFAZODONE FOREIGN PATENT DOCUMENTS ANTIPSYCHOTIC THERAPY EP O769297 A1 4/1997 (75) Inventors: Mark G. Currie, Sterling, MA (US); OTHER PUBLICATIONS Thomas P. Jerussi, Framingham, MA (US); Paul D. Rubin, Sudbury, MA Green et al. “Clinical Pharmacokinetics of Nefazodone” (US) Clin. Pharmacokinet. 33, 260–275 (1997). Barbahaiya et al. “Single and Multiple Dose Pharmacoki (73) Assignee: Sepracor Inc., Marlborough, MA (US) netics of Nefazodone in Subjects Classified . .” Br. J. Clin. Pharm. 42,573–581 (1996). (*) Notice: Subject to any disclaimer, the term of this Cyr et al. “Nefazodone: Its Place Among Antidepressants' patent is extended or adjusted under 35 Ann. Pharmacother 30, 1006-12 (1996). U.S.C. 154(b) by 0 days. Malik “Nefazodone: structure, mode of action and pharma cokinetics”. J. Psychopharm. 10, 1-4 (1996). (21) Appl. No.: 09/992, 197 S.A. Montgomery “Efficacy of nefazodone in the treatment of depression” J. Psychopharm. 10, 5-10 (1996). (22) Filed: Nov. 14, 2001 Nacca et al. “Brain-to-blood partition and in vivo inhibition O O of 5-hydroxytryptamine reuptake . .” Br. J. Pharmac. 125, (65) Prior Publication Data 1617–1623 (1998). US 2002/0058675 A1 May 16, 2002 von Moltke et al. “Nefazodone, meta-chlorophenylpipera zine, and their metabolites . Psychopharma. 145, Related U.S. Application Data 113–122 (1999). Eison et a. “Nefazodone: Preclinical Pharmacology of a (63) Continuation-in-part of application No. 09/545,602, filed on New Antidepressant’ Psychopharma. Bulletin 26, No. 3, Apr. 7, 2000, now Pat. No. 6,384,037. 311-315 (1990) (60) 1999.Provisional application No. 60/128,479, filed on Apr. 9, Joffe et al. "Adjunctive nefazodone in neuroleptic-treated 7 Schizophrenic patients with predominantly . ” Intl. Clin. (51) Int. C. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - A61K 31/50 Psychopharma. 14, 233-238 (1999). (52) U.S. Cl. .................................................. 514/254.05 Rosenberg et al. “Nefazodone in the Adjunctive Therapy of (58) Field of Search ..................................... 514/254.05 Schizophrenia: An Open-Label . Clin. Neuropharma. 23, 222-225 (2000). (56) References Cited Primary Examiner William R. A. Jarvis U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm-Heslin Rothenberg Farley 4.338,317. A 7/1982 Temple et al. .............. 424,250 & Mesiti P.C. 4,613,600 A 9/1986 Gammans et al. .......... 514/252 5,116,852 A 5/1992 Gammans ............ ... 514/359 (57) ABSTRACT 5,256,664 A 10/1993 Mayol et al. ... 514/252 Treatment of psychoses with (R)-hydroxynefazodone is 5,691,324 A 11/1997 Sandyk ......... ... 514/159 disclosed. 5,788.986 A 8/1998 Dodman ....... ... 424/451 5,852,020 A 12/1998 Marcus et al. .... ... 514/252 5,854.248 A 12/1998 Marcus et al. .............. 514/255 7 Claims, No Drawings US 6,469,008 B2 1 2 (R)-HYDROXYNEFAZODONE ary Symptoms of Schizophrenia, many perSons with Schizo ANTIPSYCHOTIC THERAPY phrenia also suffer with disturbances of mood and affect that can be clinically significant. As a result, many perSons with CROSS-REFERENCE TO RELATED Schizophrenia and Schizoaffective disorder are treated with APPLICATIONS antidepressants for the mood Symptoms. Psychiatric disorders other than psychoses, Such as This application is a continuation-in-part of U.S. appli depression, anxiety, Social phobia and panic disorder are cation Ser. No. 09/545,602, filed Apr. 7, 2000, now U.S. Pat. treated with drugs that inhibit the neuronal reuptake of No. 6,384,037, which claims the benefit of U.S. Provisional monoamines (e.g. Serotonin, norepinephrine and dopamine). Application 60/128,479, filed Apr. 9, 1999. The entire dis These reuptake inhibitors are referred to collectively as closures of both are incorporated herein by reference. MRI’s (monoamine reuptake inhibitors). Selective serotonin reuptake inhibitors (SSRI's) are a particularly preferred FIELD OF THE INVENTION subclass of MRIs. The most widely known SSRIs, in The present invention relates to methods of treating addition to nefazodone, are fluoxetine, Venlafaxine, psychoses using (R)-hydroxynefazodone. 15 milnacipran, citalopram, fluvoxamine, paroxetine, and Ser traline. BACKGROUND OF THE INVENTION Nefazodone, the metabolic parent of hydroxynefazodone, Clinicians recognize a distinction among mental is approved for the treatment of depression by the United illnesses-in particular, between psychoses (e.g. States Food and Drug Administration. It is available under Schizophrenia, dementia, obsessive-compulsive disorder, the trade name SERZONE(R) from Bristol-Myers Squibb. Tourette's disorder, bipolar disorder and schizoaffective Studies have shown that nefazodone is extensively metabo disorder) and psychiatric disorders (e.g. depression, anxiety, lized in the body. See, for example, Green, D. S. and Social phobia and panic disorder). The two types of mental Barbhaiya, R. H., Drug Disposition, 1997, 260–275 (1997)). illnesses are treated quite differently. Psychoses are treated One of these metabolites is the hydroxylated derivative with D2 antagonists, the “typical' antipsychotics and "atypi 25 2-3-4-(3-chlorophenyl)1-piperazinylpropyl-5-(1- cal' antipsychotics. Psychiatric disorders, i.e. mental ill hydroxyethyl)-2,4-dihydro-4-(phenoxyethyl)-3H-1,2,4- neSSes other than psychoses, are treated with drugs that triazol-3-one, I, CAS Registry Number 98159-82-1, also inhibit the neuronal reuptake of monoamines, particularly of known as hydroxynefazodone. serotonin, Such as SSRIs. Antipsychotic agents are employed in the treatment of psychoses. All of the common antipsychotic agents are OH antagonists at post-Synaptic D receptors, and this is accepted in the art as the mechanism by which they exert their antipsychotic activity. Antipsychotic agents are com monly considered to fall into one of two classes: “typical” 35 Ol -- N and "atypical'. O Y \ / Haloperidol is the archetype of the “typical' antipsy O C chotic. It is an antagonist at post-Synaptic D2 receptors, but it is indiscriminate. Dopamine receptors are distributed 40 The stereochemistry of the metabolite I has not to date throughout the nervous System, and in addition to being in been defined in the literature. Use of hydroxynefazodone as cortical areas, both in neocortex and paleocortex (limbic an antidepressant is disclosed in U.S. Pat. No. 4,613,600. areas), they are also present in areas associated with motor Neither hydroxynefazodone (racemic) nor either of its ste functions, Such as the striatum. Blockade of dopamine reoisomers is commercially available at the present time. receptors in the striatum gives rise to many of the Side effects 45 Nefazodone has been shown to antagonize alpha asSociated with the use of haloperidol, the So-called extrapy adrenergic receptors, a property which may be associated ramidal side effects. Other “typical' antipsychotics include with postural hypotension. In vitro binding Studies showed fluphenazine, perphenazine and trifluoperazine. that nefazodone had no significant affinity for the following “Atypical' antipsychotics are differentiated from “typi receptors, alpha2, and beta adrenergic, 5-HT1A, cholinergic, cal' by their less acute extrapyramidal side effects, espe 50 dopaminergic, or benzodiazepine. Nefazodone hydrochlo cially dystonias. Clozapine is the prototypical atypical antip ride is rapidly and completely absorbed, but because of Sychotic. Other atypical antipsychotics include: olanzapine, extensive metabolism, its absolute bioavailability is low, risperidone, Sertindole, quetiapine and Ziprasidone. Neither about 20%, and variable. Peak plasma concentrations occur nefazodone nor hydroxynefazodone has been reported to be at about one hour, and the half-life of nefazodone is 2-4 effective as an antipsychotic. 55 hours. Nefazodone and hydroxynefazodone exhibit nonlin The core Symptoms of Schizophrenia are considered to ear kinetics for both dose and time, with AUC and C. include hallucinations, agitation and delusions. Typical increasing more than proportionally with dose increases and antipsychotics purely block the D2 receptor and work fairly more than expected upon multiple dosing over time, com well for core symptoms. They do very little for the so-called pared to Single dosing. negative or Secondary Symptoms of Schizophrenia, which 60 While nefazodone can be an effective treatment psychi include apathy, the lack of ability to experience pleasure and atric disorders, it can give rise to certain adverse effects. The the lack of motivation. In fact, these Secondary Symptoms most frequently reported adverse effects associated with may be more significant to the overall morbidity of the nefazodone are headaches, dry mouth, Somnolence, nausea illness in terms of loSS productivity and quality of life than and dizziness. Other adverse affects are headache, asthenia, the core Symptoms. Because they appear more effective 65 infection, flu Syndrome, chills, fever, neck rigidity, against the Secondary Symptoms, the atypical antipsychotics hypotension, pruritus, rash, nausea, constipation, dyspepsia, are often preferred. In addition to both the core and Second diarrhea, increased appetite, nausea and Vomiting, peripheral US 6,469,008 B2 3 4 edema, thirst, arthralgia, insomnia, lightheadedness, ramidal Symptoms, elevated Serum prolactin levels, Sexual confusion, memory impairment, paresthesia, Vasodilatation, dysfunction (decreased libido,
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