Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-07
2002-04-23
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S101000
Reexamination Certificate
active
06376488
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel organic compounds and compositions which are &agr;
1
adrenoreceptor antagonists, a method for inhibiting &agr;
1
adrenoreceptors and a method for treating benign prostatic hyperplasia (BPH), bladder outlet obstruction (BOO), neurogenic bladder, and gynecological syndromes such as dysmenorrhea (benign prostatic hypertrophy).
BACKGROUND OF THE INVENTION
Adrenergic neurons play a major role in the innervation of heart, blood vessel and smooth muscle tissue. Compounds capable of interacting with adrenoreceptor sites within adrenergic nerves can initiate physiological responses including vasoconstriction, vasodilation and increased or decreased heart rate (chronotropic), contractility (inotropic) and metabolic activity. Adrenergic compounds have been employed to affect these and other physiological responses, however, many adrenergic compounds do not possess significant selectivity to enable desirable interactions with adrenergic adrenoreceptor sites. That is, these adrenergic compounds do not demonstrate a high degree of specificity for differing adrenoreceptor types within adrenergic neurons in order to obtain a desired physiological response separate from other possible, and perhaps less desirable, responses of the system under treatment.
Benign prostatic hyperplasia (BPH) is a condition which develops in middle-aged and elderly males and refers to the benign overgrowth of the stromal and epithelial elements of the prostate associated with aging. Symptoms of BPH include increased frequency of urination, nocturia, a weak urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
Typically, BPH begins at an age in the mid-fifties and is the most common cause of urinary tract problems of men of this age. BPH is apparently rare in men prior to age 40, but at age 60, approximately 50% of men have histological evidence of BPH. The prevalence of BPH continues to increase with age until, at age 80, approximately 80% of men have pathological evidence of BPH.
Although prostatic hyperplasia is a common finding in older men, the presence of urinary symptoms is the essential feature that distinguishes simple anatomic enlargement of the prostate from prostatism, which is the clinical syndrome whereby the patient experiences significant obstruction of urinary flow. It is not uncommon in older men to have a palpably enlarged prostate without showing the symptoms of prostatism. From the patient's perspective, however, the incidence and progression of urinary symptoms are more important than the mere presence of an enlarged prostate.
The discovery of large numbers of alpha-adrenergic adrenoreceptors in the smooth muscle of the prostatic capsule and bladder neck led to the conclusion that there is both a static and a dynamic component to bladder outlet obstruction associated with BPH (M. Caine, et al., Brit. J. Urol., 47: 193-202 (1975)). The static component derives from progressive hyperplasia of the aging prostate and leads to urethral narrowing with symptoms of urinary obstruction. Superimposed on this essentially mechanical problem is the variable degree of smooth muscle contraction controlled by the sympatheic nervous system which is affected by factors such as stress, cold and sympathomimetic drugs. It is this dynamic component which explains the often rapid fluctuations in symptoms observed in patients with prostatism.
The currently most effective treatment for BPH is surgical transurethral resection of the prostate (TURP). Since it removes the obstructing tissue (C. Chapple, Br. Med. Journal 304: 1198-1199 (1992)), it is a treatment which is directed to the static and dynamic components of BPH. However, this surgical treatment is associated with rates of mortality (1%) and adverse events (incontinence (2-4%), infection (5-10%), and impotence (5-10%)). A non-invasive alternative treatment would therefore be highly desirable.
The incidental clinical observation that urinary incontinence developed in women during antihypertensive treatment with prazosin (T. Thien, K. P. Delacre, F. M. J. Debruyne, R. A. P. Koene, Br. Med. Journal, 622-623 (1978)) and the experimental work of Caine (op cit.) contributed to the recognition of the potential role of selective a, adrenoreceptor blockade in diseases of the lower urinary tract. Subsequent studies by several groups have documented the functional role of &agr;
1
adrenoreceptors relative to &agr;
2
adrenoreceptors in the stromal compartment of the prostate, thereby providing a putative molecular basis for the use of specific &agr;
1
adrenoreceptor blockers in the non-surgical management of BPH (C. R. Chapple, M. L. Aubry, S. James, M. Greengrass, G. Burnstock, R. T. Turner-Warwick, Br. J. Urol. 63: 487-496 (1989)). Clinical efficacy of &agr;
1
antagonists in BPH has been demonstrated with several non-selective &agr;
1
blockers, including terazosin (Hytrin®), prazosin, and doxazosin. Treatment periods as short as two to four weeks with &agr;
1
adrenoreceptor blockers have shown objective improvements in the mean and maximum urinary flow rates (14-96%) with subjective improvements in patients'symptom scores (R. A. Janknegt, C. R. Chapple, Eur. Urol. 24: 319-326 (1993)). Longer term studies with terazosin, indoramin, prazosin and doxazosin have similarly demonstrated significant improvements in urinary flow rates and subjective symptom scores (R. A. Janknegt, op. cit., H. Lepor, G. Knapp-Maloney, J. Urol. 145: 263A (1991), W. Chow, D. Hahn, D. Sandhu, Br. J. Urol. 65: 36-38 (1990) and C. R. Chapple, T. J. Christmas, E. J. G. Milroy, Urol. Int. 45: 47-55 (1990)). However, these agents possess similar dose-limiting side effects including hypotension, dizziness and muscle fatigue.
In recent years, it has become clear that BPH and bladder outlet obstruction (BOO) are clinically differentiable, and that the severity of clinical BPH is related to many factors in addition to BOO (Lepor, H., Alpha Blockade for the Treatment of Benign Prostatic Hyperplasia, Urol. Clin. N. Amer., 22: 375-386, 1995.). For example, BOO may be related to other urological symptoms such as detrusor instability (Rosier, P. F. W. M., J. J. M. C. H. de la Rosette, H. Wijkstra, Ph.E. V. Van Kerrebroeck and F. M. J. Debruyne, Is Detrusor Instability in Elderly Males Related to the Grade of Obstruction?, Neurourol. Urodynam., 14: 625-633, 1995). Additionally, the role of extraprostatic &agr;
1
adrenoreceptors has been postulated as important in the etiology of lower urinary tract symptoms, such that antagonism of these receptors in spinal cord, ganglia, nerve terminals, bladder and bladder neck or the external urethral sphincter could be important in pharmacotherapy of urological conditions such as BOO or neurogenic bladder (Andersson, K-E., Prostatic and Extraprostatic a adrenoceptors Contributions to the Lower Urinary Tract Symptoms in Benign Prostatic Hyperplasia, Scand. J. Urol. and Nephrol., 30: 105-111, 1996). The recognition that women possess paraurethral glands which have anatomical, histological and biochemical similarities to the male prostate (Gittes, R. F. and R. M. Nakamura, Female urethral syndrome: A female prostatitis?, Western J. Medicine, 164: 435-438, 1996) suggests a potential role for &agr;
1
adrenoreceptor antagonist pharmacotherapy for amelioration of some symptoms of female urethral syndromes. In addition, &agr; adrenoreceptors are functionally important to smooth muscle contraction in the uterus (Miller, M. D. and J. M. Marshall, Uterine Response to Nerve Stimulation: Relation to Hormonal Status and Catecholamines, Am. J. Physiol., 209: 859-863, 1965) and the modulation of sympathetic responses to catecholamines is enhanced by elevations in the levels of estrogens (Miller and Marshall, Uterine Response to Nerve Stimulation: Relation to Hormonal Status and Catecholamines, Am. J. Physiol., 209: 859-863, 1965). Consistent w
Basha Fatima Z.
Pratt John K.
Wendt Michael D.
Abbott Laboratories
Ford John M.
Ward Michael J.
LandOfFree
Benzoxazine &agr;-1 adrenergic compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzoxazine &agr;-1 adrenergic compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzoxazine &agr;-1 adrenergic compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2856797