NPY antagonists

Details NPY antagonists NPY antagonists

1998-10-26

2000-10-03

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514539, 514586, 514595, 514616, 514618, 514619, 514620, 560 25, 560 27, 560 28, 560 34, 562439, 564 47, 564 56, 564147, 564153, 564154, 564157, A01N 3710, A01N 3712, A01N 3744, A61K 31235, A61K 3124

Patent

active

061274143

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to new pharmaceutically-useful compounds, in particular antagonists of neuropeptide Y, the use of such compounds as medicaments, pharmaceutical compositions containing them and synthetic routes to their production.


BACKGROUND

Neuropeptide Y (NPY) is a peptide consisting of 36 amino acids. In recent years it has been established that NPY is an important co-transmitter in the peripheral sympathetic nervous system.
It has been postulated (see Pharmacological Reviews (1996) 48, 113) that the effects of sympathetic nerve activation are not only due to the neuronal release of noradrenaline but may also be the result of a simultaneous release of NPY from the sympathetic nerve terminal.
Released NPY is known to elicit marked constriction of blood vessels in both the heart (coronary arteries) and in most peripheral organs. This vasoconstrictive effect of NPY is believed to be mediated by a receptor sub-type known as Y.sub.1.
Released NPY may also act on autonomic nerve endings to inhibit the release of neurotransmitters and, in doing so, reduce the cardiac vagal tone as a result of decreased acetylcholine release. This effect of NPY is believed to be mediated by a receptor sub-type known as Y2.
Other NPY-receptor sub-types, including the Y.sub.3, Y.sub.4, Y.sub.5 and Y6 sub-receptors, have been identified. The precise functions of these sub-receptors have not been identified in any detail, but the Y.sub.5 sub-receptor is thought to be involved in feeding and eating regulation (see Exp. Opin. Invest. Drugs, 6, 437 (1997)).
Increased plasma concentrations of NPY have been found in several cardiovascular diseases including angina pectoris, myocardial infarction and hypertension. Further, emotional stress has been shown to cause a significant increase in plasma NPY levels (see Circulation (1994) 90, I-268, Abstract No. 1445). Such observations suggest a significant pathogenic role for NPY in myocardial ischemic heart disease and hypertension. Moreover, by causing coronary vasoconstriction and reduced vagal tone, NPY may predispose a patient to ventricular fibrillation and sudden cardiac death.
Effective NPY antagonists would therefore be expected to be useful in the treatment of inter alia cardiovascular diseases.


PRIOR ART

Non-peptide antagonists of NPY have been disclosed in European Patent Applications 614 911, 747 357, 747 356 and 747 378, International Patent Applications WO 94/17035, WO 97/19911, WO 97/19913, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822 and WO 97/20823 and U.S. Pat. Nos. 5,552,411 and 5,567,714.
European Patent Applications 747 357, 747 356 and 747 378 disclose dihydropyridine derivatives as Y.sub.1 sub-receptor antagonists.
International Patent Applications WO 96/12490, WO 97/09308 and U.S. Pat. No. 5,567,714 disclose benzothiophene and indole derivatives as Y.sub.1 sub-receptor antagonists.
International Patent Application WO 96/40660 discloses benzylamine derivatives as Y.sub.1 sub-receptor antagonists or partial Y.sub.1 sub-receptor agonists.
U.S. Pat. No. 5,552,411 discloses quinoline derivatives as Y.sub.1 sub-receptor antagonists.
International Patent Applications WO 97/20820, WO 97/20821, WO 97/20822 and WO 97/20823 disclose quinazoline derivatives as Y.sub.5 sub-receptor antagonists and are thus indicated for use in the treatment of eating disorders.
The compounds disclosed in International Patent Application WO 96/22305 are disclosed as Y.sub.2 sub-receptor antagonists and are also indicated for use in the treatment of eating disorders. Amongst the compounds specifically disclosed are phenylalaninamide derivatives of N-(diphenylpropionyl)-arginine.
Whether the compounds disclosed in European Patent Application 614 911 and International Patent Application WO 94/17035 are Y.sub.1 or Y2 sub-receptor antagonists is not mentioned.
International Patent Application WO 94/17035 discloses certain amino acid derivatives, including (R)-N.sup.2 -(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl

REFERENCES:
patent: 5779631 (1998-07-01), Chance
patent: 5889016 (1999-03-01), Bruce et al.
patent: 5962455 (1999-10-01), Blum et al.

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