Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-30
2002-12-03
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S339000
Reexamination Certificate
active
06489341
ABSTRACT:
1. FIELD OF THE INVENTION
The invention relates to methods of using, and compositions comprising, sertindole derivatives such as nor-sertindole, 5-oxo-sertindole, dehydro-sertindole, and dehydro-nor-sertindole.
2. BACKGROUND OF THE INVENTION
Sertindole, chemically named 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinone, is an antipsychotic drug with high affinity for serotonin 5-HT
2
, dopamine D
2
and &agr;
1
,-adrenergic receptors. Samkamoto, K., et al.,
Xenobiotica
25(12):1327-1343 (1995). Sertindole, the synthesis of which is disclosed by U.S. Pat. No. 4,710,500 and WO 98/51685, has the following structure:
Most research directed at the therapeutic effectiveness of sertindole has focused on its use in the treatment of schizophrenia. See, e.g., U.S. Pat. No. 5,112,838; Brown, L. A., et al.,
Pharmocotherapy
18(1):69-83 (1993); Samara, E. and Granneman, R.,
Clin. Pharmacol. & Therapeutics
59(2):187 (1996); and Tamminga, C. A., et al.,
International Clin. Psychopharmacol
. 12(suppl. 1):S29-S35 (1997). Some have claimed, however, that sertindole can be effective in the treatment of other disorders such as: psychosis, including drug induced psychosis (U.S. Pat. No. 5,238,945); anxiety (U.S. Pat. No. 5,439,922); memory impairment (U.S. Pat. No. 5,444,073); substance dependency (U.S. Pat. No. 5,462,948); and depression, hypertension, and extrapyramidal side effects of other antipsychotic drugs (U.S. Pat. No. 5,703,087).
The metabolism of sertindole is complex, and varies between rat, dog, monkey and human subjects, although rat and human metabolisms of the drug are reportedly similar. Samkamoto, K., et al.,
Xenobiotica
25(12):1327-1343 (1995). Analysis of the in vivo metabolism of sertindole in rats reveals that at least six metabolites are formed. Id. Three of these, 5-oxo-sertindole, nor-sertindole and dehydro-sertindole, are also formed by the human metabolism of sertindole and are shown in Scheme 1:
Two major human metabolites of sertindole formed after oral administration of the drug are dehydro-sertindole and nor-sertindole. Menacherry, S. D., et al.,
J. Liq. Chrom. & Rel. Technol
. 20(14):2241-2257 (1997); Wong, S. L., et al.,
Clin. Pharmacol. Ther
. 62:157-164 (1997).
When administered, sertindole reportedly has fewer adverse effects than antipsychotics such as haloperidol, fluphenazine and chlorpromazine. Brown, L. A., et al.,
Pharmocotherapy
18(1):69-83 (1993). This is reportedly due to the limited binding of sertindole to histaminergic, muscarinic and &agr;
2
-adrenergic receptors, and to an unusual regional electrophysicologic characteristic of the drug. Specifically, sertindole does not induce depolarization inactivation in A9 dopamine neurons (the nigrostriatal pathway), although the drug retains activity in A10 neurons (the mesolimbic and mesocortical pathways). The mesolimbic dopamine neurons are believed to mediate antipsychotic actions of neuroleptics, while the nigrostriatal neurons are believed to mediate motor side effects. Tamminga, C. A., et al.,
International Clin. Psychopharmacol
. 12(suppl. 1):S29-S35 (1997).
Despite its advantages, sertindole does cause some adverse effects when administered to humans. These are reportedly due to antagonism of the &agr;
1
-adrenergic receptor and include, but are not limited to, nasal congestion, decreased ejaculatory volume not associated with retrograde ejaculation, loss of libido, erectile dysfunction, anorgasmia, dizziness, drymouth, tachycardia, elevation in the amounts of liver enzymes, and prolongation of the QT interval. The potentially severe consequences of QT prolongation, which include development of life-threatening cardiac (ventricular) arrhythmias such as torsades de pointes, have been of particular concern, and delayed approval of the drug by the United States Food and Drug Administration. Brown, L. A., et al.,
Pharmocotherapy
18(1):69-83 (1993).
Administration of sertindole can also cause some extrapyramidal side effects, although their severity is reportedly less than is typical of those associated with other antipsychotics such as haloperidol. Id. Extrapyramidal symptoms include acute dystonia, akathisia, parkinsonism, neuroleptic malignant syndrome, perioral tremor, and tardive dyskinesia.
Goodman & Gilman's The Pharmacological Basis of Therapeutics
, Hardman, J. G., et al., eds., 414-417 (9
th
ed. 1996).
A further disadvantage of sertindole is its potential interaction with other drugs. Sertindole interacts with a variety of isoenzyme systems, such as CYP450 2D6, 3A and 1A2, that are affected by, or aid in the metabolism of other drugs. Brown, L. A., et al.,
Pharmocotherapy
18(1):69-83 (1993). It has further been reported that a significant pharnmacodynamic interaction occurs upon concomitant administration of sertindole and other &agr;
1
-adrenergic receptor antagonists such as prazosin. Of even greater concern are problems that can arise upon concomitant administration of sertindole and other drugs known to prolong the QT interval. Id. Examples of such drugs include, but are not limited to: methylxanthines such as theophylline; antihistimines such as terfenadine and astemizole; antibiotics such as erythromycin; antiprotozoals such as pentamidine; antipsychotics such as thioridazine; and tricyclic antidepressants. Goodman & Gilman's
The Pharmacological Basis of Therapeutics
, Hardman, J. G., et al., eds., 856 (9
th
ed. 1996).
In view of the advantages and disadvantages of sertindole, pharmaceutical compositions are desired which exhibit therapeutic benefits of sertindole, but possesses fewer of its adverse effects and/or drug interactions.
3. SUMMARY OF THE INVENTION
This invention relates to novel methods using, and pharmaceutical compositions and dosage forms comprising, sertindole derivatives such as 5-oxo-sertindole, nor-sertindole, dehydro-sertindole, and dehydro-nor-sertindole. The methods of the invention are directed to the treatment and prevention of neuroleptic and related disorders. Examples of such disorders include, but are not limited to, psychotic disorders, depression, anxiety, substance addiction, memory impairment and pain. Examples of particular types of pain include, but are not limited to, acute, chronic, somatogenic (i.e., nociceptive or neuropathic), and psychogenic.
According to the invention, the methods and compositions disclosed herein allow the treatment and prevention of neuroleptic and related disorders while reducing or avoiding adverse effects associated with sertindole. The compositions of the invention further allow the treatment and prevention of neuroleptic and related disorders while reducing or avoiding drug-drug interactions that can occur as a result of the administration of sertindole. The invention thus provides methods of treating diseases and conditions using a wide range of novel drug combinations.
Finally, the invention encompasses novel pharmaceutical compositions and/or unit dosage forms of sertindole derivatives which can be administered by oral, mucosal, parenteral, sublingual, transdermal, buccal, or topical routes.
3.1. Definitions
As used herein, the term “sertindole metabolite” means a human metabolite of sertindole, and includes, but is not limited to, nor-sertindole, 5-oxo-sertindole, and dehydro-sertindole.
As used herein, the term “sertindole derivative” means a chemical derivative of sertindole or a chemical derivative of a sertindole metabolite. Examples of sertindole derivatives include, but are not limited to, sertindole metabolites and dehydro-nor-sertindole, which has the following structure:
As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic organic or inorganic acids. Examples of suitable non-toxic acids include, but are not limited to, maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citr
Pennie & Edmonds LLP
Sepracor Inc.
Spivack Phyllis G.
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