Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-08
2001-07-10
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06258837
ABSTRACT:
FIELD OF THE INVENTION
The present invention is useful in the field of medicines. More specifically, medicines containing compounds represented by the formula [I] of the present invention as active ingredients are useful as neuropeptide Y receptor antagonists and as agents for the treatment of various diseases of circulatory organs, central nervous system and metabolic system.
BACKGROUND OF THE INVENTION
Neuropeptide Y (hereinafter abbreviated as NPY) is a peptide consisting of 36 amino acids, which was isolated from porcine brain for the first time by Tatemoto et al. in 1982 [Nature, vol.296, p.659 (1982)]. NPY is broadly distributed in central and peripheral nervous systems and has various in vivo functions as one of the peptides most abundantly present in the nervous systems. That is, in the central nervous system, NPY acts as an aperitive and significantly promotes a fat accumulation associated with the lowering of a basal metabolism via secretion of various hormones and actions of the nervous systems. It is known that a continuous intracerebroventricular administration of NPY induces obesity and insulin resistance based on the above actions. And, it is known that in rodents showing hereditary or dietary obesity, NPY concentration in the brain is increased. Further, the increase in expression of the NPY receptor is reported. NPY is also associated with the control of mood and functions of the central autonomic nervous system. In addition, in the peripheral nervous system, NPY is present together with norepinephrine in the sympathetic nerve terminal and associated with the tension of the sympathetic nervous system [International Journal of Obesity, vol.19, p.517 (1995); Endocrinology, vol.133, p.1753 (1993); Neuropeptide Y and drug development, p.15 (1997); Brain Research, vol.744, p.1 (1997); The biology of neuropeptide Y, p.315 (1993)].
The function of NPY is expressed when it is bound to an NPY receptor present in the central or peripheral nervous system. Therefore, the expression of the function of NPY can be prevented if the binding of NPY to the NPY receptor is inhibited. Consequently, it is expected that compounds capable of antagonizing the binding of NPY to the NPY receptor are useful in the prevention or treatment of various diseases associated with NPY, for example, diseases of circulatory organs such as hypertension, nephropathy, cardiopathy and angiospasm; diseases of central nervous system such as bulimia, depression, epilepsy and dementia; metabolic diseases such as obesity, diabetes and dysendocrisiasis, or glaucoma [Trends in Pharmacological Sciences, vol.15, p.153 (1994)].
Compounds structurally similar to the compounds related to the present invention are disclosed in Eur. J. Med. Chem., vol.23, No.2, p.111 (1988); J. Organic Chemistry, vol.31, No.5, p.1639 (1966); JP-49125364A; U.S. Pat. Nos. 3,414,587, 3,454,577, 3,536,757 and 3,539,590; and etc. Especially, J. Organic Chemistry, vol.31, No.5, p.1639 (1966) clearly discloses the compound related to the present invention.
However, an antagonistic action to NPY of the compound in question is not described at all therein.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a new medicine having an antagonistic action to NPY.
The present inventors have found that a compound represented by the formula [I]:
has an antagonistic action to NPY.
Since the compound [I] related to the present invention has the antagonistic action to NPY, it is useful as an agent for the treatment of various diseases associated with NPY, for example, diseases of circulatory organs such as hypertension, nephropathy, cardiopathy and angiospasm, diseases of central nervous system such as bulimia, depression, epilepsy and dementia, metabolic diseases such as obesity, diabetes and dysendocrisiasis, or glaucoma.
Especially, the compound [I] related to the present invention is useful as an agent for the treatment of bulimia, obesity, diabetes or the like.
The present invention relates to a neuropeptide Y receptor antagonist and an agent for the treatment of bulimia, obesity or diabetes comprising the compound represented by the formula [I] as an active ingredient.
The term “agent for the treatment” as used herein means a drug to be used for the treatment and/or prevention of various diseases.
Although the compounds represented by the formula [I] may exists in optical isomers or tautomers, all of the optical isomers and tautomers and their mixtures are also included in the present invention.
As the above tautomer, the compound represented by the formula [I-1]:
can be exemplified.
The compound related to the present invention can be prepared by, for example, the method as described in the aforementioned publication (J. Organic Chemistry, vol. 31, No.5, p.1639 (1966)) or the method as illustrated in the following Preparation Examples.
An optically active compound represented by the formula [I] can be prepared by passing a racemate corresponding thereto through an optically active column or by adding an optically active amine such as cinchonidine to the racemate to form a salt and then subjecting to the fractional recrystllization.
The usefulness of the compound related to the present invention as a medicine is demonstrated by showing its antagonistic activity to NPY in the following pharmacological test examples.
Pharmacological Test Example 1 (test of inhibition of NPY binding)
cDNA Sequence encoding a human NPY Y5 receptor [International Publication WO 96/16542] was cloned into expression vectors pcDNA3, pRc/RSV (manufactured by Invitrogen) and pCI-neo (manufactured by Promega). Using the cationic lipid method [see Proceedings of the National Academy of Science of the United States of America, vol.84, p.7413 (1987)], host cells COS-7, CHO and LM(tk-) (American Type Culture Collection) were transfected with the thus prepared expression vectors to obtain cells in which the NPY Y5 receptor had been expressed.
Each of the membrane preparations thus prepared from the cells in which the NPY Y5 receptor had been expressed was incubated together with each compound to be tested and 20,000 cpm of [
125
I] peptide YY (manufactured by Amersham) at 25° C. for 2 hours in an assay buffer solution (25 mM HEPES buffer, pH 7.4, containing 10 mM magnesium chloride, 1 mM phenylmethylsulfonyl fluoride and 0.1% bacitracin) and then, the reaction mixture was filtered through a glass filter GF/C. After washing with 50 mM Tris buffer, pH 7.4, containing 0.3% BSA, radioactivity on the glass filter was measured using a gamma counter. Non-specific binding was measured in the presence of 1 &mgr;M of peptide YY to calculate a concentration of each compound to be tested which concentration is needed to inhibit 50% of the specific binding of the peptide YY (IC
50
value) [see Endocrinology, vol.131, p.2090 (1992)]. As the result, IC
50
value of the compound was calculated to be 27 nM.
As shown in the above, the compound related to the present invention strongly inhibited the binding of the peptide YY (a homologue of NPY) to the NPY Y5 receptor.
Pharmacological Test Example 2 (test of inhibition of feeding behavior induced by bPP)
Under pentobarbital anesthesia (single intraperitoneal injection of 50 mg/kg), a chronic guide cannula (outer diameter 0.8 mm; inner diameter 0.5 mm; length 10 mm) was stereotactically inserted in a right lateral cerebral ventricle of each of SD male rats (7 to 8-week-old; 200 to 300 g) and fixed using a dental resin. A tip of the guide cannula was positioned 0.9 mm behind a bregma, 1.2 mm at the right of a median line and in the depth of 1.5 mm from the brain surface. An inner needle was inserted such that its tip projected from the tip of the guide cannula by about 2 mm and arrived to a lateral cerebral ventricle. After a recovery period of about one week, a bovine pancreatic polypeptide (bpp, 5 &mgr;g/head/10 &mgr;l) was administered to the lateral cerebral ventricle.
Fukami Takehiro
Fukuroda Takahiro
Ihara Masaki
Kanatani Akio
Okabe Takayoshi
Banyu Pharmaceutical Co. Ltd.
Jones Dwayne C.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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