Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-08-09
2000-08-29
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548217, 548221, 548222, A61K 31421, A61K 314178, A61P 912, C07D26357, C07D26354
Patent
active
061109525
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to certain substituted (2-imidazolinylamino)benzoxazole compounds. The compounds have been found to be alpha-2 adrenoceptor agonists and are useful for treatment of disorders modulated by alpha-2 adrenoceptors.
BACKGROUND OF THE INVENTION
Therapeutic indications of alpha-2 adrenoceptor agonists have been discussed in the literature: Ruffolo, R. R., A. J. Nichols, J. M. Stadel, & J. P. Hieble, "Pharmacologic and Therapeutic Applications of Alpha-2 Adrenoceptor Subtypes", Annual Review of Pharmacology & Toxicology, Vol. 32 (1993) pp. 243-279.
Information regarding alpha adrenergic receptors, agonists and antagonists, in general, and regarding compounds related in structure to those of this invention are disclosed in the following references: Timmermans, P. B. M. W. M., A. T. Chiu & M. J. M. C. Thoolen, "12.1 .alpha.-Adrenergic Receptors", Comprehensive Medicinal Chemistry, Vol. 3, Membranes & Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185; Timmermans, P. B. M. W. M. & P. A. van Zwieten, ".alpha.-Adrenoceptor Agonists and Antagonists", Drugs of the Future, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F. H. L. Awouters & C. J. E. Niemegeers, "Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the .alpha..sub.1 and .alpha..sub.2 -Selectivity of Test Compounds: (2) .alpha.-Adrenoceptor Agonists", European Journal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, P. B. M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wilffert, H. Batink & P. A. van Zwieten, "Quantitative Relationships between .alpha.-Adrenergic Activity and Binding Affinity of .alpha.-Adrenoceptor Agonists and Antagonists", Journal of Medicinal Chemistry, Vol. 27 (1984) pp. 495-503; van Meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmermans & P. A. van Zwieten, "Selectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat", The Journal of Pharmacolocy and Experimental Therapeutics, Vol. 219, No. 3 (1981), pp. 760-767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M. Myers, C. F. C. Smith & M. R. Stillings, "Effect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard .alpha.-Adrenoreceptor Agents", European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622; Chapieo, C. B., R. C. M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings & I. F. Tulloch, "Heteroaromatic Analogues of the .alpha..sub.2 -Adrenoreceptor Partial Agonist Clonidine", Journal of Medicinal Chemistry, Vol. 32 (1989), pp. 1627-1630; Clare, K. A., M. C. Scrutton & N. T. Thompson, "Effects of .alpha..sub.2 -Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Platelets", British Journal of Pharmacology, Vol. 82 (1984), pp. 467-476; U. S. Pat. No. 3,890,319 issued to Danielewicz, Snarey & Thomas on Jun. 17, 1975; and U. S. Pat. No. 5,091,528 issued to Gluchowski on Feb. 25, 1992. However, many compounds related in structure to those of this invention do not provide the activity and specificity desirable when treating disorders modulated by alpha-2 adrenoceptors.
For example, many compounds found to be effective nasal decongestants are frequently found to have undesirable side effects, such as causing hypertension and insomnia at systemically effective doses. There is a need for new drugs which provide relief from nasal congestion without causing these undesirable side effects.
OBJECTS OF THE INVENTION
It is an object of the invention to provide compounds and compositions useful in treating disorders modulated by alpha-2 adrenoceptors.
It is an object of this invention to provide novel compounds having substantial activity in preventing or treating nasal congestion, otitis media, and sinusitis, without undesired side effects.
It is also an object of this invention to provide novel compounds for treating cough, chronic obstructive pulmonary disease (COPD) and/or asthm
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C.B. Chapleo, et al, "Heteroaromatic Analogues of the .alpha..sub.2 -Adrenoceptor Partial Agonist Clonidine", J. Med. Chem., vol. 32, pp. 1627-1630, (1989).
s.a. Munk, et al., "Synthesis and Evaluation of 2-[(5-Methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a Potent, Peripherally Acting .alpha..sub.2 Adrenoceptor Agonist", J. Med. Chem., vol. 39, pp. 3533-3538, (1996).
Timmermans, P.B.M.W.M, et al, "12.1 .alpha.-Adrenergic Receptors", Neurotransmitter and Autocoid Receptors, Comprehensive Medicinal Chemistry, vol. 3, Membranes & Receptors, P.G. Sammes & J.B. Taylor, eds., Pergamon Press, pp. 133-185 (1990).
Clare, K.A., et al., Effects of .alpha..sub.2 -Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Platelets, Br. J. Pharmac, vol. 82, pp. 467-476, (1984).
Chapleo, C.B., "Effect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard .alpha.-Adrenoreceptor Agents", Eur. J. Med. Chem., vol. 24, pp. 619-622, (1989).
Van Meel, J.C.A., "Selectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat.sup.1 ", The Journal of Pharmacology and Experimental Therapeutics, vol. 219, No. 3, pp. 760-767, (1981).
Timmerman, P.B.M.W.M., et al., "Quantitative Relationships Between .alpha.-Adrenergic Activity and Binding Affinity of .alpha.-Adrenoceptor Agonists and Antagonists", J. Med. Chem., vol. 27, pp. 495-503, (1984).
Megens, A.A.H.P., et al., "Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the .alpha..sub.2 /.alpha..sub.1 -selectivity of Test Compounds: (2) .alpha.-adrenoceptor Agonists", European Journal of Pharmacology, vol. 129, pp. 57-64, (1986).
Timmermans, P.B.M.W.M., et al., ".alpha.-Adrenoceptor Agonists and Antagonists", Drugs of the Future, vol. 9, No. 1, pp. 41-55, (1984).
Ruffolo, R.R., et al., "Pharmacological & Therapeutic Applications of Alpha-2 Adrenoceptor Subtypes", Annual Review of Pharmacology & Toxicology, vol. 32, pp. 243-279, (1993).
Henry Raymond Todd
Seibel William Lee
Sheldon Russell James
Kellerman James C.
McKane Joseph
Roof Carl J.
The Procter & Gamble & Company
Wright Sonya N
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