Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-12-27
1997-12-09
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514345, 514585, 514598, 514617, 514631, 514634, 546297, 546298, 546360, 564 28, 564 52, 564170, 564237, 564247, C07D21336, C07C23329, A61K 31165
Patent
active
056961383
DESCRIPTION:
BRIEF SUMMARY
The present application is a U.S. national application filed under 35 USC 371 of PCT/EP/94/01008, filed Mar. 30, 1994, which in turn is based upon the priority of Danish application 0411/93, filed Apr. 7, 1995.
The present invention relates to novel urea derivatives, a method of preparing the same, a method of treatment with the novel urea derivatives, and to pharmaceutical compositions comprising the same.
OBJECT OF THE INVENTION
It is an object of the present invention to provide novel urea compounds which are useful in the treatment of disorders or diseases of a living animal body, including a human, and especially in the treatment of disorders or diseases which can be treated by opening cell membrane potassium channels of such a living animal body.
Another object of the present invention is to provide a method of treating disorders or diseases of a living animal body, including a human, which disorders or diseases are responsive to opening of potassium channels and which comprises administering to such a living animal body in need thereof a compound of the invention.
A third object of the present invention is to provide novel pharmaceutical compositions for the treatment of disorders or diseases of a living animal body, including a human, which disorders or diseases are responsive to the opening of potassium channels.
Other objects will be apparent to the person skilled in the art hereinafter.
BACKGROUND OF THE INVENTION
European patent application Publication No 477 819 discloses that certain compounds are openers of BK channels.
It is generally well known that opening of potassium (K.sup.+) channels leads to a hyperpolarization and relaxation of cells. The presently known K.sup.+ channel openers (e.g. cromakalim and pinacidil) exert their effect primarily by interaction with the K.sup.+ channel subtype K.sub.ATP, These compounds have a high affinity for vascular smooth muscle cells and are thus mostly vasodilators. Recent studies indicate, however, that K.sup.+ channel openers hyperpolarizing neuronal cells also have anticonvulsive and antiischemic effects in the central nervous system (the CNS), European Journal of Pharmacology 167, 181-183 (1989), Neuroscience Letters 115, 195-200 (1990), Neuroscience 37(1), 55-60 (1990), The Journal of Pharmacology and Experimental Therapeutics 251(1), 98-104 (1989). Furthermore recent studies demonstrate that potassium channel openers acting on airways smooth muscle (tracheal smooth muscle) cells will have anti-asthmatic effects (Williams et al., The Lancet 336, 334-336 (1990)).
There exist other K.sup.+ channel sybtypes than K.sub.ATP, and one such subtype is the BK channel, also called the maxi-K channel or large-conductance Ca.sup.2+ dependent K.sup.+ channel. The BK channel is present in many cells including most central and peripheral nerve cells, striated muscle cells, smooth muscle cells of the airways, the vasculature, the gastrointestinal tract and bladder, in endo- and exocrine glands including pancreatic .beta.-cells and in kidney tubules (R. Latorre et al., Annu. Rev. Physiol. 51, 385 (1989)).
A scorpion toxin peptide, charybdotoxin, which blocks the BK channel fairly specific has been used to demonstrate that the BK channel plays an important role as a relaxing negative feed-back when the cells in these tissues become highly active or spastic (J. E. Brayden and M. T. Nelson, Science 256, 532 (1992); T. R. Jones et al., J. Pharmacol. Exp. Thor. 255, 697 (1990); R. Robiteille and M. P. Charlton, J. Neurosci. 12, 297 (1992); G. Suarez-Kurtz et al., J. Pharmacol. Exp. Ther. 259, (1991)).
SUMMARY OF THE INVENTION
The invention then, inter alia, comprises the following, alone or in combination:
A compound having the formula ##STR2## or a pharmaceutically acceptable salt thereof, wherein being C;
R.sup.1 and R.sup.4 each independently are hydrogen, halogen, CF.sub.3, COOH, COO-alkyl, COO-aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
R.sup
REFERENCES:
patent: 3331874 (1967-07-01), Stecker
patent: 3689550 (1972-09-01), Schellenbaum et al.
patent: 3935262 (1976-01-01), Lestina et al.
Mohsen, A. et al., "Synthesis and Evaluation of Novel N-Substituted N'-(3-Hydroxy-17-oxoestra-1,3,5(10)-trien-2-and -4-yl)thiourea Derivatives for Binding to the Estrogen Receptor and Cytotoxic Activity on MCF-7 Cells", Journal of Pharmaceutical Sciences, 73 (12), 1984, pp. 1871-1873.
Yamana, T., et al., "Stabilization of Drugs. I. The Quantitative Prediction of the pH-Dependency of Amide and Anilide Hydrolyses By Neighboring Hydroxyl Groups", Chem. Pharm. Bull., 21 (4), 1973, pp. 721-728.
European Search Report, Aug. 18, 1994.
Gandolfo, G., et al., "K+ channel openers descrease seizures in genetically epileptic rats", European Journal of Pharmacology, 167 (1989) pp. 181-183.
Abele, A., et al., "Potassium Channel Activators Abolish Excitotoxicity in Cultured Hippocampal Pyramidal Neurons", Neuroscience Letters, 115 (1990) pp. 195-200.
Ben-Ari, Y., et al., "Activators of ATP-Sensitive K+ Channels Reduce Anoxic Depolarization in CA3 Hippocampal Neurons", Neuroscience, 37 (1) (1990) pp. 55-60.
Grover, G., et al., "Anti-Ischemic Effects of the Potassium Channel Activators Pinacidil and Cromakalim and the Reversal of these Effects with the Potassium Channel Blocker Glybudrie", The Journal of Pharmacology and Experimental Therapeutics, 251(1) (1989) pp. 98-104.
Williams, A., et al., "Attenuation of Nocturnal Asthma by Cromakalim", The Lancet, 336 (1990) pp. 334-336.
Latorre, R., et al. "Varieties of Calcium-Activated Potassium Channels", Annu, Rev. Physiol., 51 (1989) pp. 385-399.
Brayden, J., et al., "Regulation of Arterial Tone by Activation of Calcium-Dependent Potassium Channels", Science, 256 (1992) pp. 532-535.
Jones, T., et al., "Selective Inhibition of Relaxation of Guinea-Pig Trachea by Charybdotoxin, a Potent Ca++-Activated K+ Channel Inhibitor", J. Pharmacol, Exp. Ther., 255 (1990) pp. 697-706.
Robitaille, R., et al., "Presynaptic Calcium Signals and Transmitter Release Are Modulated by Calcium-Activated Potassium Channels", J. Neurosci, 2 (1) (1992) pp. 297-305.
Suarez-Kurtz, G., et al., "Charybdotoxin and Iberiotoxin on the Spontaneous Tonus of Different Guinea Pig Smooth Muscle", J. Pharmacol. Exp. Ther., 259 (1991) pp. 439-443.
Moldt Peter
Olesen S.o slashed.ren-Peter
Pedersen Ove
Davis Zinna Northington
NeuroSearch A/S
LandOfFree
Urea derivatives and their use does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Urea derivatives and their use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Urea derivatives and their use will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1608050