Compounds and methods which modulate feeding behavior and...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C544S280000

Reexamination Certificate

active

06187777

ABSTRACT:

BACKGROUND OF THE INVENTION
Neuropeptide Y (“NPY”) is a 36 amino acid peptide related to and a member of the “PP” peptide family which includes peptide YY (“PYY”) and pancreatic peptide (“PP”) (See, Tatemoto, et al.
Nature
, 296, 659 (1982); Tatemoto,
Proc. Natl. Acad. Sci USA
, 79, 5485 (1982)). NPY is named for the presence of an N-terminal tyrosine and a C-terminal tyrosine amide and is the most abundant peptide neurotransmitter in the brain and central nervous system. NPY is found also in various parts of the peripheral nervous system. This peptide mediates several important biological activities through various receptors and receptor subtypes as discussed below.
In the brain, high NPY levels are found in the cerebral cortex, hippocampus, thalamus, hypothalamus and brainstem. Dense NPY staining occurs in the hypothalamic, brainstem and some limbic regions suggesting that NPY plays a role in somatic, sensory or cognitive brain function. Studies have suggested, also that NPY plays a role in the regulation of food intake, particularly in eating disorders including, for example, obesity, anorexia and bulemia, and memory retention and other cognitive functions, as well as anxiolysis and depression.
Additionally, NPY is found in both peripheral nerves and in the circulation. NPY appears to be a co-transmitter with norepinephrine, playing a role in vasoconstriction and hypertension, cardiac contractility, analgesia and hyperalgesia, as well as control of secretory activity in the intestine.
As noted, NPY and NPY analogs, mediate the noted biological functions through a family of closely related receptor and receptor subtypes. Presently, five receptor subtypes have been identified and are designated Y1 through Y5. Each receptor subtype generally is associated with different biological activities.
For example, the Y1 receptor is believed to be responsible for mediating many of the central and peripheral activities of NPY, including the anxiolytic and sedative effects, as well as the observed vasoconstrictive activities.
The Y2 receptor is predominant in the brain, particularly in the hippocampus. The Y2 receptor mediated effects are associated with inhibition of adenylate cyclase and inhibition of transmitter release. The Y2 receptor effects include vasoconstriction in some blood vessels, antisecretory effects in the intestine, enhanced memory retention, and inhibition of lipolysis.
The Y3 receptor effects are associated with inhibition of adenylate cyclase and elevation of intracellular calcium ion concentrations. Biological effects observed for Y3 include hypotension and bradycardia, inhibition of cardiac contractile force, inhibition of glutamate responsiveness and baroreceptor reflex, inhibition of catecholamine release and release of aldosterone.
The Y4 receptor(also referred to as “PP1” receptor) may be involved in pancreatic exocrine secretion and hormonal control and may be important in diabetes or conditions associated with diabetes.
The most recently identified receptor is Y5 (sometimes referred to as “Y1-like” or “Feeding” receptor) (See, Gerald et al.,
Nature
, 382, 168 (1996) and Hu et al.,
J. Biol. Chem
., 271, 26315 (1996)). This receptor is associated with food intake and may mediate eating disorders such as obesity, bulemia and anorexia. Recently, Y5 has been implicated in the mediation of epileptic states and thus, NPY may be an endogenous anticonvulsant agent (See, e.g. Woldbye et al.
Nat. Med
., 3, 761 (1997)).
For several articles describing NPY, NPY analogs and receptors, see, for example, Hipskind, P. and Gehler, D., “Annual Reports in Medicinal Chemistry,” 31, pp. 1-10, Robertson ed., (1996); Grunemar, L. and H{dot over (a)}kanson, R., “TiPS Reviews,” Vol. 15, p. 153, Elsevier Science Ltd. (1994); Munglani, R. et al., “Drugs,” 52(3), 371 (1996); and Balasubramaniam, A., “Peptides”, 18(3), 445 (1997), and references cited therein.
Because of the biological importance of NPY and the receptors with which it interacts, researchers have sought mediators, particularly antagonists, as novel therapeutic agents. A variety of peptide derivatives and analogs have been prepared in which amino acid modifications, substitutions, and deletions have been made relative to NPY. See, e.g., Hipskind, supra.
Although it would be preferable to have an easily synthesized, physically and metabolically stable and perhaps orally active NPY modulating compound, only a few non-peptide antagonists have been prepared. For example, a few non-peptidyl antagonists include the following:
See Doughty, M. B. et al.,
Eur. J. Pharmacol
., 185, 113 (1990);
J. Pharmacol. Exp. Ther
., 265, 172 (1993);
See, Chaurasia, C.,
J. Med. Chem
., 37, 2242 (1994);
See, Rudolf, K., et al.,
Eur. J. Pharmacol
., 271, R11-R13 (1994); Sautel, M., et al.,
Mol. Pharmacol
., 50, 285 (1996);
See, Serradeil-Le Gal, C., et al.,
FEBS Lett
., 362, 192 (1995); Serradeil-Le Gal, C., et al.,
Soc. Neurosci. Abstr
. 376.14 (1994);
See, Wright, J. L., et al.,
Bioorg. Med. Chem. Lett
., 6, 1809 (1996); Wright, J. L., et al., 211
th
ACS National Meeting, New Orleans, La. (1996);
See, for example, Bruns, R. et al., PCT publications, WO 96/12489 and 96/12490; U.S. Pat. No. 5,504,094 (Apr. 2, 1996); and,
See Peterson, J. M., et al., PCT Publication WO 96/14307.
Additionally, compounds of the following general structure, described in PCT publication, WO 97/34873 (published Sep. 25, 1997), are noted to be useful in the treatment of hyperphagia, obesity or diabetes:
Further, the following compound and related compounds are noted to be useful in NPY5 associated disorders and are disclosed in PCT publications, WO 97/20823, WO 97/20820, WO 97/20821. and WO 97/20822:
and WO 98/35944 and WO 98/35957 disclose substituted alkylamide NPY5 receptor antagonists.
See, also, L. Criscione, et al., Society for Neuroscience, 23, Abstract No. 231.2, (1997).
Other published compounds include the following general formulae:
(See, respectively, PCT publication, WO 96/35689, published Nov. 14, 1996—CRF1 receptor agonist or antagonist compounds useful for treating and diagnosis of stress related disorders; and PCT publication, WO 97/29110, published Aug. 14, 1997—CRF receptor antagonist compounds useful for treating disorders relating to hypersecretion of CRF); and,
(See, PCT Publication, WO 95/33748, published Dec. 14, 1995—endothelin receptor antagonists).
Obesity, defined as an excess of body fat relative to lean body mass, is associated with important psychological and medical morbidities, the latter including hypertension, elevated blood lipids, and Type II or non-insulin dependent diabetes mellitus (“NIDDM”). There are over 6 million individuals with NIDDM in the United States, including approximately 20% of the population 65 years or older. See, Harris et al.,
Int. J. Obes
., 11, 275 (1987). Approximately 45% of males and 70% of females with NIDDM are obese, and their diabetes is substantially improved or eliminated by weight reduction. See, Harris,
Diabetes Care
, 14(3), 639 (1991).
The assimilation, storage and utilization of nutrient energy is a complex system central to survival of a warm-blooded animal. Among land-dwelling mammals, storage in adipose tissue of large quantities of metabolic fuel as triglycerides is crucial for surviving through periods of food deprivation. The need to maintain a fixed level of energy stores without continual alteration in the size and shape of an organism requires the achievement of a balance between energy intake and expenditure.
Models of obesity which use animals with mutations in the ob and db gene indicate that the animals have an altered metabolism of carbohydrates resembling Type II diabetes in humans. These animals show effects which resemble other aspects of obesity. In particular, mice with these mutations eat more food and expend less energy than lean control animals. The phenotype is similar to that observed in animals with lesions of the ventromedial hypothalamus which indicates that the noted mutations may interfere with the ability to properly integrate or respond to nu

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