Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-06-03
2000-07-18
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546209, A61K 31445, C07D41302, A61P 906, A61P 1714
Patent
active
060908254
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention is directed to pharmaceutically active organic compounds containing two heterocylic ring structures.
BACKGROUND OF THE INVENTION
Benign prostatic hyperplasia (BPH) is a benign neoplasm found primarily in older males, see H. Lepor, Urologic Clinics of North America, 17, No. 3, 651-659 (1990). BPH clinical manifestations include bladder outlet obstruction resulting from enlargement of the prostate gland. The condition is most often treated by transurethral prostatectomy, see H. Lepor, et al. The Journal of Urology, 148, 1467-1474 (1992).
The prostate has been demonstrated to be rich in alpha 1 (.varies.-1) adrenergic receptors, see s. Raz, et al, British Journal of Urology, 45, 663-667 (1973). It has been reported that BPH can be treated with an .varies.-1 adrenergic receptor blocker, which may act by relaxing the tension of prostate smooth muscle, thus relieving the symptoms of infravesical obstruction, see H. Lepor et al, supra at 1473 and Forray et al., Molecular Pharmacology, 45, 703-708 (1994). Recently the .varies.-1 adrenergic receptor mRNA from human prostate has been analyzed and three subtypes have been identified: .varies.-1B, .varies.-1C and .varies.-1D, with .varies.-1C comprising 70% of the mRNA. In August of 1994 the nomenclature of the .varies.-1B, .varies.-1C and .varies.-1D subtypes of the alpha adrenergic receptors were renamed as .varies.-1B, .varies.-1A and .varies.-1D respectively, see J. Med. Chem., vol. 38 No. 10, 1579-1581 (1995) and Ford et al. Trends Pharmacol. Sci., 1994, 15, 167-170. In the present invention, the old nomenclature .varies.-1C is used to define that subtype adrenergic receptor that is currently referred to as .varies.-1A under the aforementioned August 1994 nomenclature.
Different adrenergic receptors may account for the cardiovascular and central nervous system side effects caused by nondiscriminator blockage of .varies.-1 adrenergic receptor subtypes, see D. T. Price, et al, The Journal of Urology, 150, 546-551 (1993) and PCT Application WO 94/10989. .varies.-1 adrenergic antagonists which bind selectively to the .varies.-1C adrenergic receptor subtype preferentially over the .varies.-1B and .varies.-1D subtypes have been claimed as useful in the treatment of BPH, see PCT Application WO 94/10989, supra. Testosterone 5.varies.-reductase inhibitors such as Proscar.TM. (Merck) have been shown to be useful in the treatment of a variety of androgen responsive diseases such as BPH and prostate cancer, see Frye, et al, U.S. Pat. No. 5,302,589, PCT Application WO 94/10989, supra. Additionally, .varies.-1 adrenergic receptor antagonists and dopamine D.sub.2 antagonists in combination have been shown to be useful as an antipsychotic treatment, see Hrib, et al, J. Med. Chem., 37, 2308-2314 (1994). .varies.-1-adrenergic antagonists have also been shown to differentially control serotonin release in the hippocampus and striatum, see Rouquier, et al, Eur. J. Pharmacol., 261(1-2), 59-64 (1994), have an effect on susceptibility to malignant arrhythmias, see Billman, J. Cardiovasc. Pharmacol., 24(3), 394-402 (1994), to possess dopamine receptor agonist activity and 5-HT receptor antagonist activity, see PCT patent application WO 9305035, to effect hyperthermia and hyperglycemia, see Nonogaki K., et al, Eur. J. Pharmacol.,262(1-2):177-180 (1994), to have a role in treatment of obstructive detrusor instability, see C. R. Chapple, et al, Brit. J. of Urology, 73, 117-123 (1994), and to have hemodynamic effects in cirrhotic patients with portal hypertension, see Albillos A, et al, Hepatology, 20(3): 611-617 (1994). .varies.-1-adrenergic agonists have been shown to precondition rabbit ischemic myocardium independent of adenosine by direct activation of protein kinase, see Tsuchida, et al, Circ. Res., 75(3): 576-585 (1994).
Compounds which modulate .varies.-1-adrenergic subtype response have additionally been implicated as useful for treatment of conditions such as hypertension, see U.S. Pat. No. 4,440,769, ischemic heart disease, and psy
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Chemical Abstracts, vol. 91, No. 5, Jul. 30 1979, Columbus, OH, US, Abstract No. 39463g, p. 634.
Andrews Robert Carl
Brown Peter Jonathan
Cadilla Rodolfo
Drewry David Harold
Luzzio Michael Joseph
Brink Robert H.
Coleman Brenda
Glaxo Wellcome Inc.
Shah Mukund J.
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