Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-20
2004-11-16
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130
Reexamination Certificate
active
06818639
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the prophylaxis or treatment of a 5-HT
2C
and a 5-HT
6
receptor-related disease. In addition, the invention provides a pharmaceutical composition containing a 5-HT
2C
receptor agonist and a 5-HT
6
receptor antagonist for therapeutic use.
BACKGROUND ART
Serotonin (5-hydroxytryptamine or 5-HT) is a key neurotransmitter of the peripheral and central nervous system (PNS and CNS) and has been implicated in a variety of sensory, motor and behavioral functions such as regulation of eating, sleeping, body temperature, blood pressure, emotions and cognition. At least 14 distinct serotonin receptor subtypes are expressed in the mammalian PNS and CNS and have been formally classified; see Glennon, et al.,
Neurosci. Biobehav. Rev.
1990, 14, 35-37; and D. Hoyer, et al.,
Pharmacol. Rev.
1994, 46, 157-203. Serotoninergic agonists and antagonists have been suggested for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, drug abuse and addiction, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinsonism, and Huntington's chorea), and chemotherapy-induced vomiting.
The 5-HT
2
subfamily of receptors is composed of three subtypes, the 5-HT
2A
, 5-HT
2B
and 5-HT
2C
receptors. Serotonin 5-HT
2C
receptors are expressed in many brain regions and have been implicated in the regulation of food intake (Dourish, C. T.
Obes. Res.
1995, 3,
Suppl.
4, 449S-462S; Bickerdike, M. J., et al.
Diabetes, Obes. Metab.
1999, 1, 207-214). It has been demonstrated that the non-specific 5-HT
2C
receptor agonist m-chlorophenylpiperazine (m-CPP), which has some preference for the 5-HT
2C
receptor, reduces food intake in mice that express the normal 5-HT
2C
receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT
2C
receptor (Tecott, L. H., et al.
Nature
1995, 374, 542-546).
Moreover, it has been reported that m-CPP and the azepinoindole U-22394A, the latter recently identified to be a 5-HT
2C
receptor agonist (unpublished observation), reduce body weight in humans following two and nine weeks of treatment, respectively (Walsh, A. E. S.,
Psychopharmacology
1994, 116, 120-122; Sargent, P. A., et al.
Psychopharmacology
1997, 133, 309-312 and Gallant, D. M., et al.
Curr. Ther. Res.
1967, 9, 579-581).
Recently, a series of pyrrolo[3,2,1-ij]quinoline derivatives was identified to be 5-HT
2C
receptor agonists having selectivity over the 5-HT
2A
receptor (Isaac M., et al.,
Bioorg. Med. Chem. Lett.
2000, 10, 919-921). The compounds are said to offer a novel approach to the treatment of obesity and epilepsy.
The 5-HT
2C
receptor subtype has also been suggested to be involved in CNS disorders, such as depression and anxiety (Jenck, F., et al.
Expert Opin. Invest. Drugs
1998, 7,1587-1599; Leysen, D. C. M.
IDrugs
1999, 2, 109-120). The 5-HT
2C
receptor subtype has further been suggested to be involved in urinary disorders such as urinary incontinence (Leysen, D. C. M.
IDrugs
1999, 2, 109-120).
Also the 5-HT
6
receptor (identified in 1993-Monsma et al.,
Mol. Pharmacol.
1993, 43, 320-327 and Ruat, M. et al.
Biochem. Biophys. Res. Commun.
1993, 193, 269-276) has been implicated in the regulation of food intake and CNS disorders.
Thus, for example, Bentley, J. C., et al.,
Br. J. Pharmacol.
1999, 126, 66P describes food intake reduction in rats by the administration of a 5-HT
6
antagonist. Also, several antidepressants and atypical antipsychotics display high affinity for the 5-HT
6
receptor which have suggested the involvement of the 5-HT
6
receptor in schizophrenia (Roth et al.
J. Pharmacol. Exp. Ther.
1994, 268, 1403-1410; Sleight et al.
Expert Opin. Ther. Patents
1998, 8, 1217-1224; Bourson et al.
Br. J. Pharm.
1998, 125, 1562-1566; Boess et al.
Mol. Pharmacol.
1998, 54, 577-583; Sleight et al.
Br. J. Pharmacol.
1998, 124, 556-562). In addition, the 5-HT
6
receptor has been linked to generalized stress and anxiety states (Yoshioka et al.
Life Sci.
1998, 17/18, 1473-1477).
SUMMARY OF THE INVENTION
According to the present invention it has now unexpectedly been found that the combined administration of a 5-HT
2C
receptor agonist and a 5-HT
6
receptor antagonist reduces food intake by more than the administration of either agonist or antagonist alone. Such combined administration of a 5-HT
2C
receptor agonist and a 5-HT
6
receptor antagonist may offer therapeutic advantages as compared to treatment with either agonist or antagonist alone.
One aspect of the present invention therefore provides a pharmaceutical composition comprising an effective amount of a combination of a 5-HT
2C
receptor agonist and a 5-HT
6
receptor antagonist, and optionally a pharmaceutically acceptable carrier.
Another aspect of the invention provides a method of preventing or treating a disease, in particular obesity, related to the 5-HT
2C
receptor and the 5-HT6 receptor, comprising administering to a human or animal subject in need thereof a 5-HT
2C
receptor agonist and a 5-HT
6
receptor antagonist (simultaneously or sequentially) in sufficient amounts to provide a therapeutic effect.
Still another aspect of the invention provides the use of a 5-HT
2C
receptor agonist and a 5-HT
6
receptor antagonist for the manufacture of a medicament for the treatment of a disease related to the 5-HT
2C
receptor and the 5-HT
6
receptor.
Another aspect of the invention provides a process for preparing a pharmaceutical composition, wherein a 5-HT
2C
receptor agonist and a 5-HT
6
receptor antagonist in a combined therapeutic amount are intimately mixed with a pharmaceutically acceptable carrier.
Yet another aspect of the invention provides a product containing a 5-HT
2C
receptor agonist and a 5-HT
6
receptor antagonist as a combined preparation for simultaneous, separate or sequential use in therapy of a disease, in particular obesity, related to the 5-HT
2C
receptor and the 5-HT
6
receptor.
REFERENCES:
patent: WO 98/27081 (1998-06-01), None
patent: WO 99/65906 (1999-12-01), None
patent: WO 00/12510 (2000-03-01), None
Dourish, “Multiple Serotonin Receptors: Opportunities for New Treatments for Obesity?,” Obesity Research, 3(Supp. 4):449S-462S, Nov. 1995.
Kordik et al., “Pharmacological Treatment of Obesity: Therapeutic Strategies,” Journal of Medicinal Chemistry, 42(2):181-201, Jan. 28, 1999.
Nilsson Björn M.
Sakariassen Kjell S.
Sukhwinder Jossan
Svartengren Jan
Biovitrum AB
Fay Zohreh
Fish & Richardson P.C.
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