Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-07
2002-10-15
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S366000
Reexamination Certificate
active
06465469
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of treating depression using S-hydroxynefazodone and pharmaceutical compositions containing S-hydroxynefazodone.
BACKGROUND OF THE INVENTION
Nefazodone, or 2- [3-[4-(3-chlorophenyl)1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(phenoxyethyl)-3H-1,2,4-triazol-3-one is approved for the treatment of depression by the United States Food and Drug Administration. It is available under the trade name SERZONE® from Bristol-Myers Squibb. Nefazodone has the structure of Formula I:
Studies have shown that nefazodone is extensively metabolized in the body. (See, for example, Green, D. S. and Barbhaiya, R. H.,
Drug Disposition
, 1997, 260-275 (1997)). One of these metabolites is the hydroxylated derivative 2-[3-[4-(3-chlorophenyl)1-piperazinyl]propyl]-5-(1-hydroxyethyl)-2,4-dihydro-4-(phenoxyethyl)-3H-1,2,4-triazol-3-one, II, CAS Registry Number 98159-82-1, also known as hydroxynefazodone.
The stereochemistry of the metabolite II has not to date been defined in the literature. It is believed that the hydroxy metabolite of nefazodone contributes to the therapeutic activity of nefazodone (Malik, K.,
Journal of Psychopharmacology
1-4 (1996). Use of hydroxynefazodone as an antidepressant is disclosed in U.S. Pat. No. 4,613,600. Neither hydroxynefazodone (racemic) nor either of its stereoisomers is commercially available at the present time.
Preclinical studies have shown that nefazodone inhibits neuronal uptake of serotonin and norepinephrine. Nefazodone occupies central 5-HT
2
receptors at nanomolar concentrations, and acts as an antagonist at this receptor.
Nefazodone has been shown to antagonize alpha
1
-adrenergic receptors, a property which may be associated with postural hypotension. In vitro binding studies showed that nefazodone had no significant affinity for the following receptors; alpha
2
and beta adrenergic, 5-HT
1A
, cholinergic, dopaminergic, or benzodiazepine.
Nefazodone hydrochloride is rapidly and completely adsorbed but because of the extensive metabolism discussed above, its absolute bioavailability is low, about 20%, and variable. Peak plasma concentrations occur at about one hour and the half-life of nefazodone is 2-4 hours.
Both nefazodone and hydroxynefazodone exhibit nonlinear kinetics for both dose and time, with AUC and C
max
increasing more than proportionally with dose increases and more than expected upon multiple dosing over time, compared to single dosing.
The primary clinical use of nefazodone is in the treatment of depression. Use of nefazodone for treatment of various psychiatric illnesses has been disclosed in the patent literature. The term “psychiatric illness” is defined herein to include depression, sleep disorder involving decreased REM sleep and/or decreased slow wave sleep, panic disorder, recurrent headache disorder, post traumatic stress disorder, affective disorder, cerebral function disorders and obesity and weight gain. Nefazodone for the treatment of headache disorders is described in U.S. Pat. No. 5,854,248, for the treatment of post traumatic stress disorder, in U.S. Pat. No. 5,852,020, for the treatment of sleep disorders in U.S. Pat. No. 5,116,852, and for treating panic disorders, in European Patent application EP 769 297.
While nefazodone can be an effective treatment for depression, sleep disorders, post traumatic stress disorder and panic disorders, it can give rise to certain adverse effects. The most frequently reported adverse effects associated with nefazodone are headaches, dry mouth, somnolence, nausea and dizziness. Other adverse affects are headache, asthenia, infection, flu syndrome, chills, fever, neck rigidity, hypotension, pruritus, rash, nausea, constipation, dyspepsia, diarrhea, increased appetite, nausea and vomiting, peripheral edema, thirst, arthralgia, insomnia, lightheadedness, confusion, memory impairment, paresthesia, vasodilatation, abnormal dreams, decreased concentration, ataxia, incoordination, psychomotor retardation, tremor, hypertonia, decreased libido, pharyngitis, cough, blurred vision, abnormal vision, tinnitus, taste perversion, visual field defect, urinary frequency, urinary tract infection, urinary retention, vaginitis and breast pain. In addition, nefazodone is known to cause sinus bradycardia and postural hypotension.
It is therefore desirable to find a compound with the advantages of nefazodone which does not have the above described adverse effects.
Formation of hydroxynefazodone occurs in the liver through the enzymes of the P450 system, specifically CYP3A4, and nefazodone is an inhibitor of CYP3A4. Other drugs which inhibit the CYP3A4 isozyme may interfere with the formation of this metabolite. In addition, coadministration of another drug metabolized by CYP3A4 may lead to elevated blood concentrations of one or both drugs. For example, known inhibitors of CYP3A4, such as erythromycin, ketoconazole, and cimetidine, may interfere with hydroxylation of nefazodone. On the other hand, the disposition of drugs metabolized by CYP3A4, such as terfenadine and haloperidol, may be interfered with by nefazodone, and compounds which are inducers of CYP3A4 may cause faster metabolism of nefazodone when coadministered.
It would be desirable to find a compound with the advantages of nefazodone, but with fewer drug-drug interactions.
SUMMARY OF THE INVENTION
It has now been discovered that the S-isomer of the hydroxy metabolite of nefazodone, S-hydroxynefazodone, is an effective treatment for depression which does not give rise to the adverse effects associated with nefazodone. Therefore, in one aspect, the present invention relates to a method of treating depression, comprising administering to a person a need of such therapy a therapeutically effective amount of S-hydroxynefazodone or a pharmaceutically acceptable salt thereof.
It has also been discovered that the S-isomer of hydroxynefazodone is useful in the treatment of sleep disorders. In another aspect, the present invention relates to a method of treating sleep disorders involving decreased REM sleep and/or decreased slow wave sleep. The method comprises administering to a person in need of such therapy a therapeutically effective amount of S-hydroxynefazodone. Particular sleep disorders of interest are nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dysomnia, night terrors, insomnias of depression, and sleep walking disorders.
It has also been discovered that the S-isomer of hydroxynefazodone is useful in the treatment of panic disorders. In another aspect, the present invention relates to a method for alleviation of panic disorders comprising administering to a person in need of such therapy a therapeutically effective amount of S-hydroxynefazodone or pharmaceutically acceptable salt thereof Panic disorders of interest are panic attacks, agoraphobia, and phobic anxiety.
It has also been discovered that the S-isomer of hydroxynefazodone is useful in the treatment of recurrent headache disorders. In another aspect, the present invention relates to a method of treating recurrent headache disorders comprising administering to a person in need of such therapy a therapeutically effective dose of S-hydroxy nefazodone or a pharmaceutically acceptable salt thereof Recurrent headache disorders of interest are vascular headache, migraine headache, and chronic daily headache.
It has also been discovered that the S-isomer of hydroxynefazodone is useful in the treatment of post traumatic stress disorder. In another aspect, the present invention relates to a method of treating post traumatic stress disorder, comprising administering to a person in need of such therapy a therapeutically effective dose of S-hydroxynefazodone or a pharmaceutically acceptable salt thereof Symptoms of post traumatic stress disorder alleviated by treatment with S-hydroxynefazodone are depression, hostility, and sleep disturbance.
It has also been discovered that the S-isomer of hydroxynefazodone is useful in the treatment of affective d
Barberich Timothy J.
Rubin Paul D.
Yelle William E.
Gioeni, Esq. Mary Louise
Heslin Rothenberg Farley & & Mesiti P.C.
Liu Hong
Sepracor Inc.
Shah Mukund J.
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