Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-22
2002-06-25
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S324000, C514S648000
Reexamination Certificate
active
06410565
ABSTRACT:
FIELD OF THE INVENTION
The current invention pertains to the fields of medicinal chemistry, pharmacology, and medicine. Further, the current invention identifies compounds which are antagonists of the &agr;
1
-adrenergic receptor.
BACKGROUND OF THE INVENTION
The sympathetic nervous system is a critical system in mammals, including humans. It's major activity is to regulate and maintain homeostasis of a wide variety of functions throughout the body. For example, the sympathetic nervous system provides control and coordinated regulation of several major cell types, among these; smooth muscle, liver, skeletal muscle, nerve, and adipoetic cells.
As a result of the system's effect on smooth muscle cells (constriction or dilation), the sympathetic nervous system is critical in the control (flow and pressure) of fluids in the body, such as air, blood, urine, food, waste, and the like. Similarly, system effects on hepaticytes and adipocytes have a major regulatory function on energy production and utilization. For further details on the function and effects of the sympathetic nervous system, see: “Goodman and Gilman's The Pharmacological Basis of Therapy”, Eds. Gilman, A. E., Rall, T. W., Nies, A. S., and Taylor, P., 8th Ed., Pergamon Press, New York, 1990, Ch. 5, pp. 84-95.
On a molecular level, the sympathetic nervous system is primarily activated by the catecholamine neurotransmitters (primarily epinephrine and norepinephrine, and to a much lesser extent, outside the central nervous system, dopamine). For further information see: ibid., Chap. 10 and references cited therein. The action or response of a particular cell type to catecholamine stimuli is dependent on the type of receptor on that cell. Germane to the current invention, are the receptors of the sympathetic nervous system known as adrenergic receptors. Most germane to the current invention are the actions of the &agr; receptor and more specifically the &agr;
1
receptor.
The &agr;
1
receptor is a major regulatory element on smooth muscle cells. Thus, tissues containing large numbers of these cells are often highly effected by agonist or antagonists to this receptor. Such tissues would include the arterioles, veins, sphincter, trigone, skin, male ejaculatory system, and the like. In general, activation of the &agr;
1
receptor causes the smooth muscle cells to contract. Thus, activation may have the effect of constricting the vasculature and raising blood pressure, constricting the urinary tract and restricting urine flow, and the like. Compounds which block the &agr;
1
receptor have the opposing effects, i.e., vasodilatation, etc.
Thus, &agr;
1
receptor antagonists are potential therapeutic agents for hypertension, congestive heart failure, and other cardiovascular diseases. Additionally, &agr;
1
antagonists have been used successfully in increasing urinary flow in patients suffering from benign prostatic hyperplasia (BPH), see: “Pharmacological Options in the Treatment of Benign Prostatic Hyperplasia”, Kenny, B., et al., J. Med. Chem., 40(9), pp. 1293-1315 (1997).
Currently, the most widely used compounds which block the &agr;
1
receptor are a series of piperazinyl quinazolines, e.g., prazosin, terazosin, doxazosin, and trimazosin. Of these, the most commonly used compound is prazosin (Minipress™). Although, this compound is quite beneficial in lowering blood pressure, it can also cause postural hypotension and syncopal episodes. (For further information, see: “Physician's Desk Reference”, 47th Ed., Medical Economics Co., Montvale N.J., 1993, pp. 1834-5). Thus, a need currently exists for new &agr;
1
antagonists.
SUMMARY OF THE INVENTION
The current invention relates to a method for antagonizing &agr;
1
-adrenergic receptors which includes administering, to a mammal in need thereof, an effective amount of a compound of formula I:
or an N-oxide or pharmaceutical salt or solvate thereof; wherein A is a moiety selected from the group consisting of:
wherein:
R and R
1
are independently hydrogen, hydroxy, chloro, bromo, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, OCOC
1
-C
6
alkyl, OCO(phenyl), or OCO(substituted phenyl);
X is oxygen or sulfur; and
Y is oxygen, CH
2
, or CO.
The present invention further relates to a method of inhibiting the pathological states or sequelae resulting from inappropriate activation of &agr;
1
-adrenergic receptors comprising administering, to a mammal in need thereof, an effective amount of a compound of formula I.
Moreover, the present invention relates to the use of a compound of formula I for the manufacture of a medicament useful as an antagonist of the &agr;
1
-adrenergic receptor.
In addition, the present invention relates to the use of a compound of formula I for the manufacture of a medicament for the inhibition of pathological states or sequelae resulting from inappropriate activation of the &agr;
1
-adrenergic receptor.
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Franco L.G., et al., “Tomixifen a new proposed treatment for scleroderma and Raynaud's disease preliminary study using fingertip temperature measurements” Database Biosis “Online”,Biosciences Information Service and Revista Argentina De Dermatologica69(3) pp. 168-176 (1988).
Grese, Timothy A., et al., “Molecular determinants of tissue selectivity in estrogen receptor modulators”National Academy of Sciences94 pp. 14105-14110 (1997).
Hoffman, Brian B., et al. “Adrenergic Receptor Antagonists”The Pharmacological Basis of Therapeutics, Eighth Edition, pp 221-229 (1990).
Kenny, Barry et al., “Pharmacological Options in the Treatment of Benign Prostatic Hyperplasia”Journal of Medicinal Chemistry40(9) pp. 1293-1315 (1997).
Palkowitz, Alan D. “Discovery and Synthesis of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxyl-2-(4-hydroxyphenyl)]benzo [b]thiophene: A Novel, Highly Potent, Selective Estrogen Receptor Modulator”Journal of Medicinal Chemistry40(10) pp. 1407-1416 (1997).
Eli Lilly and Company
Henley III Raymond
Voy Gilbert T.
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