The present invention relates to a compound of the formula ##STR1## and the pharmaceutically acceptable salts thereof wherein W is a bicyclic heterocyclic ring system. The compounds are .alpha.-1 adrenergic antagonists and are useful in the treatment of BPH; also disclosed are .alpha.-1 antagonist compositions and a method for antagonizing .alpha.-1 receptors and treating BPH.

TECHNICAL FIELD 
The present invention relates to novel organic compounds and compositions 
which are alpha-1 (.alpha.-1) adrenoreceptor antagonists, processes for 
making such compounds, synthetic intermediates employed in these 
processes, and a method for inhibiting alpha-1 adrenoceptors and treating 
benign prostatic hyperplasia (BPH), also called 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 
adrenoceptor sites within adrenergic nerves can initiate a variety of 
physiological responses, including vasoconstriction, vasodilation, and 
increased or decreased heart rate (chronotropic), contractility 
(inotropic) and metabolic activity. In the past, various 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 receptor 
sites. That is, these adrenergic compounds do not demonstrate a high 
degree of specificity for differing receptor types within adrenergic 
neurons in order to obtain a desired physiological response separate from 
other possible, and perhaps less desirable, responses of the system. 
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 in the 1970's (M. Caine, et al., Brit. J. Urol., 47: 193-202 
(1975)) of large numbers of alpha-adrenergic receptors 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. The static component derives from the 
progressive hyperplasia of the prostate with aging, leading to urethral 
narrowing which causes symptoms of urinary obstruction. Superimposed on 
this essentially mechanical problem is the variable degree of smooth 
muscle contraction controlled by the sympatheic nervous system and which 
is affected by 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 the surgical procedure of 
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 event (incontinence 2-4%, infection 5-10%, and 
impotence 5-10%). A non-invasive alternative treatment would thus 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 .alpha.-1 adrenoceptor 
blockade in diseases of the lower urinary tract. Subsequent studies by 
several groups have documented the functional role of .alpha.-1 
adrenoceptors relative to .alpha.-2 adrenoceptors in the stromal 
compartment of the prostate, thereby providing a putative molecular basis 
for the use of specific .alpha.-1 adrenoceptor 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 .alpha.-1 antagonists in BPH has been 
demonstrated with several non-selective .alpha.-1 blockers, including 
terazosin (Hytrin.RTM.), prazosin, and doxazosin. Treatment periods as 
short as two to four weeks with .alpha.-1 adrenoceptor 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: hypotension, dizziness, and muscle fatigue. There thus exists a 
need for a "uroselective" .alpha.-1 antagonist with reduced side effect 
liabilities. 
SUMMARY OF THE INVENTION 
In its principle embodiment, the present invention provides certain 
hexahydro-1H!-benze!isoindole compounds of the formula I: 
##STR2## 
or a pharmaceutically acceptable salt thereof wherein n is an integer from 
2 to 6. 
R.sub.1 and R.sub.2 are independently selected from the group consisting of 
hydrogen, alkyl of one to six carbon atom, alkoxy of one to six carbon 
atoms, hydroxy, halo, carboxy, and alkoxycarbonyl of two to eight carbon 
atoms. 
W is selected from the group consisting of 
##STR3## 
wherein R.sub.3 is selected from the group consisting of hydrogen, alkyl 
of one to six carbon atoms, unsubstituted phenyl and phenyl substituted 
with alkyl of one to six carbon atoms, and R.sub.4 is hydrogen or alkyl of 
one to six carbon atoms. 
U, taken together with the carbon atoms to which it is attached forms a 
ring selected from the group consisting of (a) an unsubstituted or 
substituted five membered ring having four carbon atoms, two double bonds 
and one heteroatom selected from the group consisting of --N(R.sub.5)--, 
--O-- and --S-- wherein R.sub.5 is hydrogen or alkyl of one to six carbon 
atoms and the ring substituent is selected from the group consisting of 
alkyl of one to six carbon atoms, phenyl, halo, cyano, nitro, carboxy, 
alkoxycarbonyl of two to eight carbon atoms and alkoxy of one to six 
carbon atoms; (b) an unsubstituted or substituted five membered ring 
having three carbon atoms, two double bonds and two heteroatoms selected 
from the group consisting of two nitrogen atoms, one oxygen atom and one 
nitrogen atom, and one sulfur atom and one nitrogen atom wherein the ring 
substituent is selected from the group consisting of alkyl of one to six 
carbon atoms, phenyl, halo, cyano, nitro, carboxy, alkoxycarbonyl of two 
to eight carbon atoms and alkoxy of one to six carbon atoms; (c) a benzene 
ring which is unsubstituted or substituted with a substitutent selected 
from the group consisting of alkyl of one to six carbon atoms, phenyl, 
halo, cyano, nitro, carboxy, alkoxycarbonyl of two to eight carbon atoms 
and alkoxy of one to six carbon atoms methylenedioxy and ethylenedioxy; 
and (d) an unsubstituted or substituted six membered ring having one to 
three double bonds and one or two nitrogen atoms, wherein the ring 
substituent is selected from the group consisting of alkyl of one to six 
carbon atoms, phenyl, halo, cyano, nitro, carboxy, alkoxycarbonyl of two 
to eight carbon atoms and alkoxy of one to six carbon atoms. 
In one embodiment, the present invention provides a compound of the formula 
##STR4## 
wherein R.sub.1, R.sub.2, n, R.sub.3 and U are as previously defined. 
In another embodiment, the present invention provides a compound of the 
formula 
##STR5## 
wherein R.sub.1, R.sub.2, n, R.sub.4 and U are as previously defined. 
Yet another embodiment of the present invention provides a compound of 
formula (I) wherein W is selected from the group consisting of 
##STR6## 
wherein X is selected from the group consisting of --N(R.sub.5)--, --O-- 
and --S-- wherein R.sub.5 is hydrogen or alkyl of one to six carbon atoms, 
R.sub.6 and R.sub.7 are the same or different and are independently 
selected from the group consisting of hydrogen, alkyl of one to six carbon 
atoms, phenyl, halo, cyano, nitro, carboxy, alkoxycarbonyl of two to eight 
carbon atoms and alkoxy of one to six carbon atoms, and R.sub.3 is as 
previously defined. 
In yet another embodiment of the present invention provides a compound of 
formula (I) wherein W is selected from the group consisting of 
##STR7## 
wherein X is selected from the group consisting of --N(R.sub.5)--, --O-- 
and --S-- wherein R.sub.5 is hydrogen or alkyl of one to six carbon atoms, 
R.sub.6 and R.sub.7 are the same or different and are independently 
selected from the group consisting of hydrogen, alkyl of one to six carbon 
atoms , phenyl, halo, cyano, nitro, carboxy, alkoxycarbonyl of two to 
eight carbon atoms and alkoxy of one to six carbon atoms, and R.sub.4 is 
as previously defined. 
Another embodiment of the present invention provides a compound of formula 
(I) wherein W is selected from the group consisting of 
##STR8## 
wherein X is selected from the group consisting of --N(R.sub.5)--, --O-- 
and --S-- wherein R.sub.5 is hydrogen or alkyl of one to six carbon atoms 
and R.sub.3 is as previously defined. 
Another embodiment of the present invention provides a compound of formula 
(I) wherein W is selected from the group consisting of 
##STR9## 
wherein X is selected from the group consisting of --N(R.sub.5)--, --O-- 
and --S-- wherein R.sub.5 is hydrogen or alkyl of one to six carbon atoms 
and R.sub.4 is as previously defined. 
Yet another embodiment of the present invention provides a compound of 
formula (I) wherein W is 
##STR10## 
wherein m is selected from 1, 2 and 3 and, when m is 2 or 3, R.sub.8 at 
each occurence is independently selected from the group consisting of 
hydrogen, alkyl of one to six carbon atoms, halo, cyano, nitro, carboxy, 
alkoxycarbonyl of two to eight carbon atoms, alkoxy of one to six carbon 
atoms and, when m is 2, methylenedioxy and ethylenedioxy, and R.sub.3 is 
as previously defined. 
Another embodiment of the present invention provides a compound of formula 
(I) wherein W is 
##STR11## 
wherein m is selected from 1, 2 and 3 and, when m is 2 or 3, R.sub.8 at 
each occurence is independently selected from the group consisting of 
hydrogen, alkyl of one to six carbon atoms, halo, cyano, nitro, carboxy, 
alkoxycarbonyl of two to eight carbon atoms, alkoxy of one to six carbon 
atoms and, when m is 2, methylenedioxy and ethylenedioxy, and R.sub.4 is 
as previously defined. 
In yet another embodiment, the present invention provides a compound of 
formula (I) wherein W is selected from the group consisting of 
##STR12## 
wherein p is selected from 1 and 2 and, when p is 2, R.sub.9 at each 
occurence is independently selected from the group consisting of hydrogen, 
alkyl of one to six carbon atoms, phenyl, halo, cyano, nitro, carboxy, 
alkoxycarbonyl of two to eight carbon atoms and alkoxy of one to six 
carbon atoms, and R.sub.3 is as previously defined. 
Another embodiment of the present invention provides a compound of formula 
(I) wherein W is selected from the group consisting of 
##STR13## 
wherein p is selected from 1 and 2 and, when p is 2, R.sub.9 at each 
occurence is independently selected from the group consisting of hydrogen, 
alkyl of one to six carbon atoms, phenyl, halo, cyano, nitro, carboxy, 
alkoxycarbonyl of two to eight carbon atoms, and alkoxy of one to six 
carbon atoms, and R.sub.4 is as previously defined. 
Another embodiment of the present invention provides a compound of formula 
(I) wherein W is selected from the group consisting of 
##STR14## 
wherein R.sub.10 is selected from the group consisting of hydrogen, alkyl 
of one to six carbon atoms, phenyl, halo, cyano, nitro, carboxy, 
alkoxycarbonyl of two to eight carbon atoms and alkoxy of one to six 
carbon atoms and R.sub.4 is as previously defined. 
Another embodiment of the present invention provides a compound of formula 
(I) wherein W is selected from the group consisting of 
##STR15## 
wherein R.sub.10 is selected from the group consisting of hydrogen, alkyl 
of one to six carbon atoms, phenyl, halo, cyano, nitro, carboxy, 
alkoxycarbonyl of two to eight carbon atoms, and alkoxy of one to six 
carbon atoms and R.sub.3 is as previously defined. 
A preferred embodiment of the present invention provides a compound of 
formula (I) wherein W is selected from the group consisting of 
##STR16## 
wherein R.sub.1, R.sub.2, n, m, R.sub.4, R.sub.6, R.sub.7 and R.sub.8 are 
as previously defined. 
A more preferred embodiment of the present invention is a compound of 
formula (I) wherein one of R.sub.1 and R.sub.2 is alkoxy of one to six 
carbon atoms and the other one is hydrogen, n is selected from an integer 
from 2 to 4 and W is selected from the group consisting of 
##STR17## 
wherein R.sub.1, R.sub.2, n, m, R.sub.4, R.sub.6, R.sub.7 and R.sub.8 are 
as previously defined. 
The present invention also relates to pharmaceutical compositions which 
comprise a therapeutically effective amount of a compound of claim 1 in 
combination with a pharmaceutically acceptable carrier. 
The invention further relates to a method of antagonizing .alpha.-1 
receptors in a host mammal in need of such treatment a therapeutically 
effective amount of a compound of claim 1. 
The invention still further relates to a method of treating BPH in a host 
mammal in need of such treatment a therapeutically effective amount of a 
compound of claim 1.