Alpha IC adrenergic receptor antagonists

This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as selective alpha-1C adrenergic receptor antagonists. One application of these compounds is in the treatment of benign prostatic hypertrophy. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha1C receptor subtype without at the same time inducing orthostatic hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to certain novel compounds and derivatives thereof, 
their synthesis, and their use as selective alpha-1c adrenoceptor 
antagonists. One application of these compounds is in the treatment of 
benign prostatic hypertrophy. These compounds are selective in their 
ability to relax smooth muscle tissue enriched in the alpha1C receptor 
subtype without at the same time inducing orthostatic hypotension. One 
such tissue is found surrounding the urethral lining. Therefore, one 
utility of the instant compounds is to provide acute relief to males 
suffering from benign prostatic hyperplasia, by permitting less hindered 
urine flow. Another utility of the instant compounds is provided by 
combination with a human 5-alpha reductase inhibitory compound, such that 
both acute and chronic relief from the effects of benign prostatic 
hyperplasia are achieved. Other advantages of the instant compounds are 
appreciated from the complete disclosure. 
2. Background 
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 .alpha..sub.1, .alpha..sub.2, .beta..sub.1, and 
.beta..sub.2 subtypes. Functional differences between .alpha..sub.1 and 
.beta..sub.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 (.alpha..sub.1 /.alpha..sub.2 selectivity of this compound 
was disclosed as being significant because agonist stimulation of the 
.alpha..sub.2 receptors was said to inhibit secretion of epinephrine and 
norepinephrine, while antagonism of the .alpha..sub.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 .alpha..sub.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 .alpha.-adrenergic receptors, the reader's 
attention is directed to Robert R. Ruffolo, Jr., .alpha.-Adrenoreceptors: 
Molecular Biology, Biochemistry and Pharmacology, (Progress in Basic and 
Clinical Pharmacology series, Karger, 1991), wherein the basis of 
.alpha..sub.1 /.alpha..sub.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 
.alpha.-adrenergic receptor affinity was explored. 
The cloning, sequencing and expression of alpha receptor subtypes from 
animal tissues has led to the subclassification of the .alpha..sub.1 
receptors into .alpha..sub.1A, (Lomasney, et al., J. Biol. Chem., 
266:6365-6369 (1991), rat .alpha..sub.1A ; Bruno et al., BBRC, 
179:1485-1490 (1991), human .alpha..sub.1A), .alpha..sub.1B (Cotecchia, et 
al., PNAS, 85;7159-7163 (1988), hamster a.sub.1B ; Libert, et al., 
Science, (1989), dog .alpha..sub.1B ; Ramarao, et al., J. Biol. Chem., 
267:21936-21945 (1992), human .alpha..sub.1B), and most recently, in a 
study using bovine brain, a new .alpha..sub.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 .alpha..sub.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 .alpha..sub.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 .alpha..sub.1 receptor subtype exhibits its own pharmacologic 
and tissue specificities. Schwinn and coworkers noted that the cloned 
bovine .alpha..sub.1C receptor exhibited pharmacological properties 
proposed for the .alpha..sub.1A subtype. Nonetheless, based on its 
non-expression in tissues where the .alpha..sub.1A subtype is expressed, 
and its sensitivity to chloroethylclonidine, the receptor was given a new 
designation. 
The differences in the .alpha.-adrenergic receptor subtypes have relevance 
in pathophysiologic conditions. Benign prostatic hypertrophy, 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 limted to, increased difficulty in urination and sexual 
dysfunction. These symptoms are induced by enlargement, or hypertrophy, 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. 
The mechanism of prostatic hypertrophy is well understood. The male 
hormone, 5.alpha.-dihydrotestosterone has been identified as the principal 
culprit. The continual production of 5.alpha.-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.RTM. (finasteride). The effect of 
this compound is to inhibit the enzyme testosterone 5-alpha reductase, 
which converts testosterone into 5.alpha.-dihydrotesterone, resulting in a 
reduced rate of prostatic enlargement, and often reduction in prostatic 
mass. 
The development of such agents as PROSCAR.RTM. 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-i 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 hypertrophy. Likewise, 
in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin 
to bind to adrenergic receptors of the .alpha..sub.1 subtype was reported. 
In addition, in WO 92/161213, hereby incorporated by reference, 
combinations of 5-alpha-reductase inhibitory compounds and 
alpha-adrenergic receptor blockers (terazosin, doxazosin, prazosin, 
bunazosin, indoramin, alfuzosin) were disclosed. However, no information 
as to the .alpha..sub.1A, .alpha..sub.1B, or .alpha..sub.1C subtype 
specificity of these compounds was provided as these refinements were not 
yet available. Current therapy for BPH uses existing non-selective alpha-1 
antagonists such as prazosin (Minipress, Pfizer) or Terazosin (Hytrin, 
Abbott). These non-selective antagonists suffer from side effects related 
to antagonism of the alpha-1a and alpha-1b receptors in the peripheral 
vasculature, eg., orthostatic hypotension and syncope. 
Typically, identification of active compounds is through use of animal 
tissues known to be enriched in adrenergic receptors. Thus, rat tissues 
have been used to screen for potential adrenergic receptor antagonists. 
However, because of species variability, compounds which appear active in 
animal tissue may not be active or sufficiently selective in humans. This 
results in substantial wastage of time and effort, particularly where high 
volume compound screening programs are employed. There is also the danger 
that compounds, which might be highly effective in humans, would be missed 
because of their absence of appreciable affinity for the heterologous 
animal receptors. In this regard, it has been noted that even single amino 
acid changes between the sequence of biologically active proteins in one 
species may give rise to substantial pharmacological differences. Thus, 
Fong et al., (J. Biol. Chem., 267:25668-25671, 1992) showed that there are 
22 divergent amino acid residues between the sequence of the human 
neurokinin-1 receptor and the homologous rat receptor. They further 
showed, in studies with mutant receptors, that substitution of only two 
amino acid residues was both necessary and sufficient to reproduce the rat 
receptor's antagonist binding affinity in the human receptor. Oksenberg et 
al., (Nature 360:161-163, 1992) showed that a single amino-acid difference 
confers major pharmacological variation between the human and the rodent 
5-hydroxytryptamine receptors. Likewise, Kuhse et al., (Neuron, 5:867-873, 
1990) showed that a single amino-acid exchange alters the pharmacology of 
the neonatal rat glycine receptor subunit. This difficulty and 
unpredictability has resulted in a need for a compound screen which will 
identify compounds that will be active in humans. 
These problems are solved by cloning the human adrenergic receptor of the 
.alpha..sub.1C subtype and the use of a screening assay which enables 
identification of compounds which specifically interact with the human 
.alpha.1C adrenergic receptor. Marshall et al (Br. J. Pharm., 107:327 
(1992)) speculated that compounds which specifically interact with the 
.alpha.1C adrenergic receptor may be responsible for contraction of the 
human prostate. As disclosed in the instant patent disclosure, a cloned 
human .alpha..sub.1C adrenergic receptor and a method for identifying 
compounds which bind the human .alpha..sub.1C receptor has now made 
possible the identification of specific human .alpha..sub.1C adrenergic 
receptor antagonists. In the instant patent disclosure, we reveal novel 
compounds which we have discovered specifically bind the human 
.alpha..sub.1C receptor. These compounds are further tested for binding to 
other human alpha 1 receptor subtypes, as well as counterscreened against 
other types of receptors, thus defining the specificity of the compounds 
for the human .alpha..sub.1C adrenergic receptor. 
Compounds of his invention are used to reduce the acute symptoms of BPH. 
Thus, compounds of this invention may be used alone or in conjunction with 
a more long-term anti-BPH therapeutics, such as testosterone 5-alpha 
reductase inhibitors, including PROSCAR.RTM. (finasteride). Aside from 
their utility as anti-BPH agents, these compounds may be used to induce 
highly tissue-specific, localized .alpha..sub.1C adrenergic receptor 
blockade whenever this is desired. Effects of this blockade include 
reduction of intra-ocular pressure, control of cardiac arrhythmias, and 
possibly a host of alpha-1C receptor mediated central nervous system 
events. 
SUMMARY OF THE INVENTION 
This invention provides compounds for the treatment of urinary obstruction 
caused by benign prostatic hypertropy (also known as benign prostatic 
hyperplasia or BPH). The compounds selectively antagonize the human 
alpha-1C adrenergic receptor at nanomolar and subnanomolar concetrations 
while exhibiting at least ten fold lower affinity for the alpha1A and 
alpha1B human adrenergic receptor and many other G-protein coupled 
receptors. This invention has the advantage over non-selective alpha-1 
adrenoceptor antagonists of reduced side effects related to peripheral 
adrenergic blockade. Such side effects include orthostatic hypotension, 
syncope, lethargy etc. These compounds have the structure: 
##STR1## 
and a pharmaceutically acceptable salt, prodrug, polymorph, or metabolite 
thereof wherein: 
n is an integer from 3 to 5; 
Y represents carbonyl, sulphonyl, --CO--CH.sub.2 --, or --CO--NR.sup.12 --; 
R.sup.12 is hydrogen, substituted or unsubstituted lower alkyl, substituted 
or unsubstituted phenyl; 
E is carbonyl or sulphonyl; 
A, B, G, D are independently carbon or nitrogen; 
R.sup.1 -R.sup.4 are independently selected from the group consisting of 
hydrogen; halogen; nitro; amino; substituted or unsubstituted lower alkyl; 
perhalogenated lower alkyl; substituted or unsubstituted lower alkoxy; 
sulfonyl alkyl; and substituted or unsubstituted aryl or heteroaryl; with 
the proviso that if any of A, B, G, or D is a nitrogen, then the 
substituent R group is not present; 
Q is, independently, (--CH.sub.2 --).sub.r, --NH--, S, or O; 
r is 0-3; and 
X is 
##STR2## 
T is nitrogen, carbon, lower alkylene of one to three carbons or lower 
alkenylene of one to three carbons; 
R.sup.7 -R.sup.10 are independently selected from the group consisting of 
hydrogen, lower alkyl, lower alkenyl, and lower alkoxy; and 
Z is O, S, CH.sub.2, CH.sub.2 O, OCH.sub.2, SCH.sub.2, lower alkylene, 
lower alkenylene, NH, or NMe. 
In one embodiment of the invention, the compound has the structure: 
##STR3## 
and a pharmaceutically acceptable salt, prodrug, polymorph or metabolite 
thereof, wherein all substituents are as defined above. 
These compounds may be used to advantage whenever specific blockade of the 
alpha1C adrenergic receptor is desirable, and are particularly useful in 
the treatment of benign prostatic hyperplasia (BPH) and for inhibiting 
contraction of prostate tissue, either alone or in combination with other 
active compounds. One preferred combination therapy includes the use of 
compounds described herein in conduction with a compound effective to 
inhibit testosterone 5-alpha reductase.