Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-30
2001-08-14
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S380000, C544S381000, C544S393000, C544S396000, C544S400000
Reexamination Certificate
active
06274583
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as selective alpha-la adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH).
BACKGROUND OF THE INVENTION
Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into &agr;
1
, &agr;
2
, &bgr;
1
, and &bgr;
2
subtypes. Functional differences between &agr;
1
and &agr;
2
receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed. Thus, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to selectively bind to adrenergic receptors of the alpha 1 subtype was reported. The &agr;
1
/&agr;
2
selectivity of this compound was disclosed as being significant because agonist stimulation of the &agr;
2
receptors was said to inhibit secretion of epinephrine and norepinephrine, while antagonism of the &agr;
2
receptor was said to increase secretion of these hormones. Thus, the use of non-selective alpha-adrenergic blockers, such as phenoxybenzamine and phentolamine, is limited by their &agr;
2
adrenergic receptor mediated induction of increased plasma catecholamine concentration and the attendant physiological sequelae (increased heart rate and smooth muscle contraction).
For a general background on the &agr;-adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., &agr;-
Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology,
(
Progress in Basic and Clinical Pharmacology
series, Karger, 1991), wherein the basis of &agr;
1
/&agr;
2
subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3′-terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting &agr;-adrenergic receptor affinity was explored.
The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the &agr;
1
receptors into &agr;
1a
, (Lomasney, et al.,
J. Biol. Chem.,
266:6365-6369 (1991), rat &agr;
1a
; Bruno et al.,
BBRC,
179:1485-1490 (1991), human &agr;
1a
), (&agr;
1b
(Cotecchia, et al.,
PNAS,
85;7159-7163 (1988), hamster &agr;1
b
; Libert, et al.,
Science,
(1989), dog &agr;
1b
; Ramarao, et al.,
J. Biol. Chem.,
267:21936-21945 (1992), human &agr;
1b
, and most recently, in a study using bovine brain, a new &agr;
1c
subtype was proposed (Schwinn, et al.,
J. Biol. Chem.,
265:8183-8189 (1990); Hirasawa et al.,
BBRC
195:902-909 (1993), described the cloning, functional expression and tissue distribution of a human &agr;
1c
adrenergic receptor; Hoehe et al.,
Human Mol. Genetics
1 (5):349 (8/92) noted the existence of a two-allele Pst1 restriction fragment polymorphism in the &agr;
1c
adrenergic receptor gene; another study suggests that there may even be an alpha-1d receptor subtype, see Perez et al.,
Mol. Pharm.,
40:876-883, 1992). Each &agr;
1
receptor subtype exhibits its own pharmacologic and tissue specificities. Schwinn and coworkers noted that the cloned bovine &agr;
1c
receptor exhibited pharmacological properties proposed for the &agr;
1a
subtype. Nonetheless, based on its non-expression in tissues where the &agr;
1a
subtype is expressed, and its sensitivity to chloroethylclonidine, the receptor was given a new designation.
The differences in the &agr;-adrenergic receptor subtypes have relevance in pathophysiologic conditions. Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
In benign prostatic hyperplasia, the male hormone 5&agr;-dihydrotestosterone has been identified as the principal culprit. The continual production of 5&agr;-dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
The elucidation of the mechanism summarized above has resulted in the recent development of effective agents to control, and in many cases reverse, the pernicious advance of BPH. In the forefront of these agents is Merck & Co., Inc.s' product PROSCAR® (finasteride).
The effect of this compound is to inhibit the enzyme testosterone 5-alpha reductase, which converts testosterone into 5&agr;-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass.
The development of such agents as PROSCAR® bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently rapidly.
In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation of the urethral smooth muscle, by binding to alpha-1 adrenergic receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity. Thus, one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the &agr;
1
subtype was reported. In addition, in WO 92/161213, hereby incorporated by reference, combinations of 5-alpha-reductase inhibitory compounds and alpha1-adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the &agr;
1a
, &agr;
1b
, or &agr;
1c
subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known. Current therapy for BPH uses existing non-selective alpha-1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer). These non-selective antagonists suffer from side effects related to a
Bock Mark G.
Newton Randall C.
Patane Michael A.
Chang Ceila
Fitch Catherine D.
Merck & Co. , Inc.
Walton Kenneth R.
Winokur Melvin
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