WO1996039140A1 - ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS - Google Patents

Abstract

This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as selective alpha 1a adrenergic receptor antagonists. One application of these compounds is in the treatment of benign prostatic hyperplasia. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha 1a receptor subtype without at the same time inducing 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.

Description

TITLE OF THE INVENTION

ALPHA la ADRENERGIC RECEPTOR ANTAGONISTS

FIELD OF THE INVENTION: This application is a continuation-in-part of copending application U.S. Serial No. 08/470,164, filed June 6, 1995, the contents of which are hereby incorporated by reference.

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 αi , α2, βl , and ^β2 subtypes. Functional differences between c and α2 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 adreDergic receptors of the alpha 1 subtype was reported. The αi/α2 selectivity of this compound was disclosed as being significant because agonist stimulation of the α2 receptors was said to inhibit secretion of epinephrine and norepinephrine, while antagonism of the α2 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 α2 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 α-adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., α-

Adrenoreceptors: Molecular Biology. Biochemistry and Pharmacology. (Progress in Basic and Clinical Pharmacology series, Karger, 1991), wherein the basis of αι/oc2 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 α-adrenergic receptor affinity was explored.

The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the αi receptors into αia, (Lomasney, et al., J. Biol. Chem.. 266:6365-6369 (1991), rat αi_a; Bruno et al., BBRC. 179:1485-1490 (1991 ), human αia), αib (Cotecchia, et al., PNAS. 85;7159-7163 (1988), hamster lb; Libert, et al., Science. (1989), dog αib; Ramarao, et al., J. Biol. Chem.. 267:21936-21945 (1992), human αib), and most recently, in a study using bovine brain, a new αic 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 αi c adrenergic receptor; Hoehe et al., Human Mol. Genetics 1 (5^:349 (8/92) noted the existence of a two-allele Pstl restriction fragment polymo hism in the αic adrenergic receptor gene; another study suggests that there may even be an alpha- Id receptor subtype, see Perez et al., Mol. Pharm.. 40:876-883, 1992). Each αi receptor subtype exhibits its own pharmacologic and tissue specificities. Schwinn and coworkers noted that the cloned bovine αic receptor exhibited pharmacological properties proposed for the αia subtype. Nonetheless, based on its non-expression in tissues where the αia subtype is expressed, and its sensitivity to chloroethylclonidine, the receptor was given a new designation.

The differences in the α-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 5α- dihydrotestosterone has been identified as the principal culprit. The continual production of 5α-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 5α-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 αi subtype was reported. In addition, in WO 92/161213, hereby incorporated by reference, combinations of 5- alpha-reductase inhibitory compounds and alpha 1 -adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the αia, x lb, or αic 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 antagonism of the alpha- la and alpha- lb receptors in the peripheral vasculature, e.g., orthostatic hypotension and syncope. Typically, identification of active compounds is accomplished 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 were solved by cloning the human adrenergic receptor of the αi c subtype (ATCC CRL 1 1 140) and the use of a screening assay which enables identification of compounds which specifically interact with the human αic adrenergic receptor. [PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO94/10989, published 26 May 1994] As disclosed in the instant patent disclosure, a cloned human αic adrenergic receptor and a method for identifying compounds which bind the human αic receptor has now made possible the identification of selective human αic adrenergic receptor antagonists useful for treating BPH. The instant patent disclosure discloses novel compounds which selectively bind to the human ic 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 of the present invention for the human αic adrenergic receptor.

Compounds of this 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® (finasteride). Aside from their utility as anti-BPH agents, these compounds may be used to induce highly tissue-specific, localized αic 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- lc receptor mediated central nervous system events.

NOMENCLATURE

Recently, a new αl adrenergic receptor (αl -AR) classification scheme similar to that proposed by Ford, et al. fαl- Adrenoceptor Classification: Sharpening Occam's Razor. Trends in Pharm. Sci. 1994, l_5, 167-170] was adopted at the August, 1994 meeting of the International Union of Pharmacology (IUPHAR) in Montreal, Canada. The αl-AR genes formerly known as αia/d, αib and αic were renamed aid, alb and αia, respectively. This new naming system reflects the correspondence between the proteins encoded by the αia and αib genes (new IUPHAR nomenclature) and the receptors characterized by traditional pharmacological means as αiA and αiB, respectively, in the literature. Recombinant receptors and receptors characterized pharmacologically in tissues are distinguished by lowercase and uppercase subscripts, respectively.

The above discussion contained in the Background section used the former classification scheme (i.e., αia/d, αib ^arjd αic); however, hereinafter, the new classification scheme will be utilized (i.e., aid, cxib and αia). Thus, what was formerly referred to as the αic receptor (and αic receptor antagonists) will hereinafter be referred to utilizing the new nomenclature as the αia receptor (and αia receptor antagonists).

SUMMARY OF THE INVENTION

The present invention provides a method of treating a disease which is susceptible to treatment by antagonism of the alpha la receptor which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the formula I

wherein

Rl is independently selected from hydrogen, Cl -4 alkyl, R2(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl -4 alkyl, Cl -4 alkoxy, furanyl, pyridyl, thienyl or aryl;

R2 is selected from cyano-, NH2CO-, (R3)2NCO-, R3C0NMe-, Rl2(CH2)p-OC(0)NH-, R3(CH2) C(0)_pNH-, R3cONMe-, R3S(0)_mNH- or het;

R is selected from hydrogen, Cl -4 alkyl, het or aryl;

R4 and R^ taken together are =0; or

R4 is hydrogen, and R5 is selected from hydrogen or hydroxy;

R6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substituted is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; or

Rl3 i_s selected from hydrogen or Cl-4 alkyl;

R I⁴ is selected from hydrogen or COCH3;

Rl5 is selected from hydrogen, Nθ2 or CN;

Z is selected from C=0 or CH2;

aryl is unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl -4 alkoxy, pyridyl, thienyl or furanyl;

het is selected from

m is an integer of from zero to two; n is an integer of from zero to four; and p is an integer of from one to two; q is an integer of from one to four; and the pharmaceutically acceptable salts thereof.

Preferably, the compounds utilized in the methods of the present invention have the formula

wherein

R° is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substituted is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or 2,5- di substituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl -4 alkyl, Cl-4 alkoxy or aryl; wherein all other variables are as defined above; or a pharmaceutically acceptable salt thereof. More preferably, the compounds utilized in the methods of the present invention have the formula

(CH₂)_n R⁶ wherein each Rl is independently selected from hydrogen, R2(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy, furanyl, pyridyl, thienyl or aryl; wherein all other variables are as defined above; or a pharmaceutically acceptable salt thereof.

Examples of diseases which are susceptible to treatment by antagonism of the alpha la receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, npotency, sympathetically mediated pain and cardiac arrhythmia.

In one embodiment of the present invention is a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of formula I described above. In a second embodiment of the present invention is a method of inhibiting contraction of prostate tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of formula I described above. In a third embodiment of the present invention is a method of relaxing urethral smooth muscle in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of formula I described above. In preferred embodiments of the present invention, the compound additionally does not cause a fall in blood pressure when administered for treating BPH, inhibiting contraction of prostate tissue or relacing urethral smooth muscle.

In a class of the invention are any of the methods described above wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5- alpha reductase inhibitor is finasteride. More particularly illustrating the invention is a compound of the formula:

wherein

R9 is selected from hydrogen, Cl -4 alkyl, R2(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl -4 alkyl, Cl-4 alkoxy, furanyl, pyridyl, thienyl or aryl;

R2 is selected from NC-, NH2CO-, (R3)2NCO-, R3CONH-, R3C0NMe-, R3-S(0)_mNH- or het;

R3 is selected from hydrogen, Cl -4 alkyl, het or aryl;

R4 and R5 taken together are =0; or

R4 is hydrogen and R5 is hydrogen or hydroxy;

R6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl -4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is selected from halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; or

R⁸ is selected from hydrogen, Cl-4 alkyl, R¹ !(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy, furanyl, pyridyl, thienyl or aryl;

R^{1 1} is selected from cyano, Rl2-S(0)mNH-, Rl2cθNMe-, Rl2(CH2)p-OC(0)NH-, Rl2(CH2)pC(0)NH- or het;

Rl2 is selected from hydrogen, het or unsubstituted, mono-, di- or tri- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl or Cl-4 alkoxy;

Rl is selected from hydrogen or Cl-4 alkyl;

Rl4 is selected from hydrogen or COCH3;

Rl5 is selected from hydrogen, Nθ2 or CN;

Z is selected from C=0 or CH2;

aryl is unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy, pyridyl, thienyl or furanyl;

het is selected from

m is an integer of from zero to two; n is an integer of from zero to four; and p is an integer of from one to two;

provided that R^ and R^ are not simultaneously hydrogen; and

provided further that when R^ is hydrogen, and R^ is

where n is zero or one, then R6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl -4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl -4 alkyl, Cl -4 alkoxy or aryl; or

; and provided further that when R9 is hydrogen, R^ is cyano, and n is two, then R6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; or

and the pharmaceutically acceptable salts thereof.

Preferably, the compound is of the formula

wherein

R6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or

2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; and all other variables are as defined above;

provided that R^ and R9 are not simultaneously hydrogen; and

provided further that when R9 is hydrogen, and R^ is

where n is zero or one, then R6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl -4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl -4 alkyl, Cl -4 alkoxy or aryl; and

provided further that when R9 is hydrogen, R^ is cyano, and n is two, then R6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl -4 alkyl, Cl -4 alkoxy or aryl;

and the pharmaceutically acceptable salts thereof. Illustrative of the invention is the compound wherein

R8 is selected from hydrogen, Rl l(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl -4 alkoxy, furanyl, pyridyl, thienyl or aryl; and

R9 is selected from hydrogen or R2(CH2)n and all other variables are as defined above; and the pharmaceutically acceptable salts thereof. An illustration of the invention is the compound of the formula

where all variables are as defined above; and the pharmaceutically acceptable salts thereof.

Exemplifying the invention is the compound of the formula

R^

where all variables are as defined above; and the pharmaceutically acceptable salts thereof.

An example of the invention is the compound of the formula

where all variables are as defined above; and the pharmaceutically acceptable salts thereof..

Further illustrating the invention is the compound of the formula

(CH₂)_n R^£ wherein R6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl or Cl-4 alkoxy; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is selected from halogen, Cl-4 alkyl or Cl -4 alkoxy; or

2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl or

Cl-4 alkoxy; where all other variables are as defined above; and the pharmaceutically acceptable salts thereof. Another illustration of the invention is the compound selected from

3,4-Dihydro-7-methanesulfonamido-l'-[2-(2-methyl-3- indolyl)ethyl]spiro[(2H)-l -benzopyran-2,4'-piperidine]-4-one;

3,4-Dihydro-7-methanesulfonamido-l '-[2-(2- methoxyphenyl)ethyl]spiro[(2H)-l -benzopyran-2,4'-piperidine]-4-one;

3,4-Dihydro-7-methanesulfonamido- 1 '-[2-( 1 -naphthyl)ethyl]spiro[(2H)- l -benzopyran-2,4'-piperidine]-4-one;

3,4-Dihydro-l '-[2-(3-indolyl)ethyl]-7-methanesulfonamidospiro[(2H)-l - benzopyran-2,4'-piperidine]-4-one; 3,4-Dihydro-7-methanesulfonamido-l '-[2-(3- thianaphthyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one; l '-[2-(2-Ethoxyρhenyl)ethyl]-3,4-dihydro-7- methanesulfonamidospiro[(2H)- 1 -benzopyran-2,4'-piperidine]-4-one;

6-Benzyloxycarbonylamido-3,4-dihydro-l '-[2-(l- naphthyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one;

3 ,4-Dihy dro- 1 '- [2-( 1 -naphthy l)ethy 1 ] -6-pheny 1 su If onamidospiro [ (2H)- 1 • benzopyran-2,4'-piperidine]-4-one;

3,4-Dihydro-6-(l-methyl-4-imidazolyl)acetamido- -[2-(l - naphthyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one; 3,4-Dihydro-6-(3,5-dimethyl-4-isoxazolyl)sulfonamido-l'-[2-(l- naphthyl)ethyl]spiro[(2H)-l -benzopyran-2,4'-piperidine]-4-one;

3,4-Dihydro-6-( 1 -methyl-4-imidazolyl)sulfonamido- 1 '-[2-( 1 - naphthyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one; 3,4-Dihydro-6-(l-imidazolylmethyl)-l '-[2-(l -naphthyl)ethyl]spiro[(2H)- l-benzopyran-2,4'-piperidine]-4-one; 3,4-Dihydro- 1 '-[2-( 1 -naphthyl)ethyl]-6-(l ,2,4- triazolylmethyl)spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one; 6-Cyanomethyl-3,4-dihydro-l'-[2-(l-naphthyl)ethyl]spiro[(2H)-l- benzopyran-2,4'-piperidine]-4-one or

7-Acetamido-3,4-dihydro-l '-[2-(2-fluorophenyl)ethyl]spiro[(2H)-l- benzopyran-2,4'-piperidine]-4-one; and the pharmaceutically acceptable salts thereof. Another example of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier.

More specifically exemplifying the invention is the composition further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5- alpha reductase inhibitor is a type 1 , a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor.

More preferably, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5 -alpha reductase inhibitor. Most preferably, the testosterone 5-alpha reductase inhibitor is finasteride.

Another illustration of the invention are methods of treating benign prostatic hyperplasia, inhibiting contraction of prostate tissue or relaxing urethral smooth muscle in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the pharmaceutical compositions described above.

More specifically illustrating the invention are methods of treating benign prostatic hyperplasia, inhibiting contraction of prostate tissue or relaxing urethral smooth muscle in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds described above. Preferably, in the methods of treating BPH, inhibiting contraction of prostate tissue or relaxing urethral smooth muscle, the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH or inhibit contraction of prostate tissue.

Another example of the invention are methods of treating benign prostatic hyperplasia, inhibiting contraction of prostate tissue or relaxing urethral smooth muscle wherein any of the compounds described above are administered in combination with a testosterone 5- alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is finasteride. Still another example of the invention is a pharmaceutical composition made by combining any of the compounds described above with a pharmaceutically acceptable carrier.

More particularly illustrating the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier. More particularly exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for: the treatment of benign prostatic hyperplasia, inhibiting contraction of prostate tissue, or relaxing urethral smooth muscle in a subject in need thereof.

An additional illustration of the invention is a drug which is useful for: treating benign prostatic hyperplasia, inhibiting contraction of prostate tissue or relaxing urethral smooth muscle in a mammal in need thereof, the effective ingredient of the said drug being any of the compounds described above.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH). Representative compounds of the present invention exhibit high selectivity for the human alpha la adrenergic receptor. 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. Thus, one implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.

Representative compounds of this invention display submicromolar affinity for the human alpha la adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alphald and alphalb adrenergic receptor subtypes, and many other G- protein coupled human receptors. Particular representative compounds of this invention exhibit nanomolar affinity for the human alpha la adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alphald and alphalb adrenergic receptor subtypes, and many other G-protein coupled human receptors. Preferred compounds of this invention exhibit Ki's for human alphala adrenergic receptors which are more than 40 fold lower than for the human alphal d or alphalb adrenergic receptors, while exhibiting greater than 100 fold selectivity for the human alphala adrenergic receptor over all other human G-protein coupled receptors tested (including serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors). These compounds are administered in dosages effective to antagonize the alphala receptor where such treatment is needed, as in BPH. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate,

Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.

Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.

The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, t-butyl, etc.). The term "aryl" as used herein, except where otherwise specifically defined, refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl. Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Cl-lθ) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

The term "halogen" shall include iodine, bromine, chlorine and fluorine.

The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent.

Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. The term heterocycle, het, or heterocyclic ring, as used herein, represents an unsubstituted or substituted stable 5- to 7- membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidiήyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamo holinyl, thiamoφholinyl sulf oxide, thiamorpholinyl sulfone, and oxadiazolyl. Moφholino is the same as moφholinyl.

The term "subject," as used herein refers to an animal, preferably a mammal, most preferably a human, which has been the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.

Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incoφorated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d- tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic

Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. The specificity of binding of compounds showing affinity for the αia receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the αia receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., ai d, a lb) or beta adrenergic receptors. Expression of the cloned human aid, aib, and αia receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities. Antagonism by these compounds of the human αia adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be. used to increase urine flow without exhibiting orthostatic hypotensive effects.

The ability of compounds of the present invention to specifically bind to the αia receptor makes them useful for the treatment of BPH. The specificity of binding of compounds showing affinity for the αia receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors. The human alpha adrenergic receptor of the la subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994, each of which is hereby incoφorated by reference. The cloned human αia receptor, when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned human aid, a lb, and αia receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.

Compounds of this invention exhibiting selective human ia adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. fSee e.g.. PCT International Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995]. Compounds which are both selective amongst the various human alpha 1 adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the β-adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly preferred. The absence of these non-specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various human alpha 1 adrenergic receptors. Furthermore, functional biological tests are used to confirm the effects of identified compounds as alphala adrenergic receptor antagonists.

The present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alphala adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration. For example, the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an alphala antagonistic agent. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incoφorated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alphal a adrenergic receptor is required.

The daily dosage of the products may be varied over a wide range from 0.01 to 1 ,000 mg per adult human/per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 250 mg/kg of body weight per day. Preferably, the range is from about 0.001 to 100 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 7 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.

Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human αia adrenergic receptor while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this includes administration of compounds of this invention and a human testosterone 5 -α reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are now well known in the art and include such compounds as PROSCAR®, (also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071 , for example, hereby incoφorated by reference). In addition to PROSCAR®, which is principally active in prostatic tissue due to its selectivity for human 5-α reductase isozyme 2, combinations of compounds which are specifically active in inhibiting testosterone 5- alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in combination with compounds of this invention. Compounds that are active as 5α-reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050; WO93/23038, ; WO93/23048; WO93/23041 ; WO93/23040; WO93/23039; W093/23376; W093/23419, EP 0572165; WO93/23051 , each of which is hereby incoφorated by reference. The dosages of the alphala adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the 5-alpha reductase inhibitor and the alphal a adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be inteφreted accordingly. Thus, in one preferred embodiment of the present invention, a method of treating BPH is provided which comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH. The dosage of finasteride administered to the subject is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an αia antagonist. Preferably, the dosage of finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day.

For the treatment of benign prostatic hypeφlasia, compounds of this invention exhibiting alphala adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5α-reductase 2 inhibitor, such as finasteride, in addition to a 5α- reductase 1 inhibitor, such as 4,7β-dimethyl-4-aza-5α-cholestan-3- one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed wherein the alphala adrenergic receptor antagonist and the 5α- reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5α-reductase inhibitors.

Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows: Ac = acetyl Ar = aryl

Boc or BOC = t-butyloxycarbonyl CBZ = benzyloxycarbonyl

Cbz-Cl = benzyloxycarbonyl chloride or benzyl chloroformate DMF = N,N-dimethylformamide Et = ethyl

Et3N = triethylamine EtOAc = ethyl acetate

EtOH = ethanol het = heterocycle

HPLC = high pressure liquid chromatography HOAc = acetic acid i-PrOH = isopropanol

Me = methyl MeOH = methanol Nu = nucleophile

NMR = nuclear magnetic resonance PEI = polyethylenimine

Ph = phenyl

TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography

The compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.

The compounds and pharmaceutically acceptable salts of the present invention can be synthesized according to the general methods outlined in Schemes 1 -6. The 6-carbon substituted compounds of the instant invention can be prepared as shown in Scheme 1. Accordingly, compound I is prepared by the method of Acta Pharm. Suec, 15, 13 (1978). A solution of I in a polar, aprotic solvent, preferably N,N- dimethylformamide, is prepared following the usual techniques for the exclusion of moisture. To this solution is added a nucleophile, such as imidazole or 1,2,4-triazole, and an inorganic base, preferably sodium carbonate. Alternatively, a nucleophile such as potassium cyanide is added and the inorganic base is not needed. The reaction mixture temperature is maintained at 25°C. Extractive workup and purification according to standard procedures affords II. The spiro[(2H)-l- benzopyran-2,4'-piperidine]-4-one moiety is formed by treating a solution of II, following the usual techniques for the exclusion of moisture, in a protic solvent such as an alcohol, preferably methanol, with a dialkylamine base, preferably pyrrolidine, followed by a protected form of 4-piperidone, preferably protected as the t- butyloxycarbonyl derivative on nitrogen. The reaction mixture is maintained at 25°C when the volatiles are removed and purification according to standard procedures affords III. The piperidyl nitrogen is liberated by treatment of III with an acid, such as HCl or trifluoroacetic acid, and extractive workup according to standard procedures affords IV. The piperidine IV is derivatized on N-l ' following the usual techniques for the exclusion of moisture, by treatment of a solution of IV in a polar solvent, preferably N,N-dimethylformamide, with an alkylating agent, such as an alkyl bromide or iodide, preferably an arylethyl bromide, and the addition of a base like diisopropylethylamine or triethylamine. Alternatively, an inorganic base such as lithium carbonate can be used. The reaction mixture is maintained at an elevated temperature, preferably 70°C, and extractive workup and purification according to standard procedures affords V.

The 7-acetamide compounds of the instant invention can be prepared as shown in Scheme 2. Accordingly, 3-acetamidophenol is suspended in an aprotic organic solvent, preferably dichloromethane, and treated with an acylating agent such as acetyl chloride following the usual techniques for the exclusion of moisture. A strong Lewis acid, preferably aluminum trichloride, is added portionwise to keep the vigorous exothermic reaction under control at ambient temperature. The reaction mixture is .then heated and the volatiles are removed by distillation. The reaction mixture is then further heated, preferably to 140°C, until the reaction mixture is thick and stirring difficult. The mixture is then cooled, preferably to 0^βC, and treated with crushed ice. The resultant solid is collected and dried according to standard procedures to provide VI. The spiro[(2H)-l-benzopyran-2,4'- piperidine]-4-one moiety is formed employing the methodology described above to afford VII. The piperidyl nitrogen is selectively liberated by treatment of VII with an acid, such as HCl or trifluoroacetic acid, preferably at or below ambient temperature. Extractive workup according to standard procedures affords VIII. The piperidine VIII can be converted to IX employing the alkylating methodology described above.

SCHEME 2

VII VIII

IX

The 7-methylsulfonamide compounds of the instant invention can be prepared as shown in Scheme 3. The acetamide VI can be converted to the corresponding aniline by treatment with an acid, preferably HCl, in a protic solvent system such as a mixture of ethanol and water, at elevated temperature, followed by treatment with methanesulfonyl chloride and a tertiary amine base, preferably pyridine, in a polar aprotic solvent such as dichloromethane, following the usual techniques for the exclusion of moisture. Extractive workup and purification according to standard procedures affords X. The spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one moiety is formed employing the methodology described above to afford XI. Liberation of the piperidine nitrogen (to afford XII) and subsequent alkylation (to afford XIII) are accomplished employing the methodology described above.

SCHEME 3

Ar(CH₂)₂Br

Other 7-position derivatives of the instant invention can be prepared according to Scheme 4. Both the acetamide and the t- butyloxycarbonyl group of VII can be removed by treatment with an acid, preferably HCl, in a protic solvent system such as a mixture of ethanol and water, at elevated temperature to afford XIV after standard extractive procedures. The piperidine nitrogen N-l' can be alkylated selectively by treatment of a solution of XIV in a polar solvent, preferably N,N-dimethylformamide, with an alkylating agent, such as an alkyl bromide or iodide, and the addition of a base such as diisopropylethyl amine or triethylamine following the usual techniques for the exclusion of moisture. Alternatively, an inorganic base such as lithium carbonate can be used. The reaction mixture is maintained at an elevated temperature, preferably 70°C, and extractive workup and purification according to standard procedures affords XV. The aniline nitrogen is derivatized by dissolving XV in an aprotic organic solvent, preferably dichloromethane following the usual techniques for the exclusion of moisture. To this solution is then added a organic base such as pyridine followed by an acylating agent, such as a carboxylic acid chloride, carboxylic acid anhydride or sulfonic acid chloride, or the like. The reaction mixture temperature is maintained between 0°C and 27°C, preferably 24°C. Extractive workup and purification according to standard procedures affords XVI.

SCHEME 4

The 6-nitrogen substituted compounds of the instant, invention can be prepared as shown in Scheme 5. Aniline XVII (prepared according to that procedure described in J. M. Elliott et. al., J. Med. Chem. 1992, 35, 3973-3976) is dissolved in a polar aprotic solvent, preferably dichloromethane, treated with an equal volume of a saturated aqueous solution of an inorganic base such as sodium carbonate and the two-phase mixture stirred preferably at 0°C and treated with a suitable chloroformate, such as benzyl chloroformate. Extractive workup according to standard procedures affords XVIII. The spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one product XIX is formed employing the methodology described above as are the liberation of the piperidine nitrogen (to afford XX) and subsequent alkylation (to afford XXI). The carbobenzyloxy group in XXI is removed by dissolving XXI in a protic organic solvent such as an alcohol, preferably ethanol, containing a concentrated inorganic acid, preferably HCl. To this solution is added a catalyst to effect hydrogenolysis, preferably palladium black, and the mixture is shaken under a hydrogen atmosphere, preferably at 55 pounds/square inch (psi), in a Parr apparatus which affords XXII after removal of the catalyst by filtration. The aniline nitrogen is derivatized by dissolving XXII in an aprotic organic solvent, preferably dichloromethane, following the usual techniques for the exclusion of moisture. To this solution is then added a tertiary amine base such as pyridine followed by an acylating agent, such as a carboxylic acid chloride, carboxylic acid anhydride or sulfonic acid chloride, or the like. The reaction mixture temperature is maintained between 0°C and 27 °C, preferably 24°C. Extractive workup and purification according to standard procedures affords XXIII. SCHEME 5

CBZHN

XIX

The alkyl bromides used in the instant invention can be prepared according to the general methods outlined in Scheme 6. Accordingly, a carboxylic acid XXIV, preferably an aryl acetic acid, is converted to an alkyl ester, preferably the methyl ester. This can be accomplished by dissolving acid XXIV in a mixture of polar organic solvents, preferably methanol and chloroform, and treating with a solution of a diazomethane derivative, such as (trimethylsilyl)diazomethane, and the reaction mixture maintained at ambient temperature. The excess diazo compound is quenched with an organic acid, preferably acetic acid, and removal of volatiles affords ester XXV. Alternatively, esters can be prepared by dissolving the acid XXIV in an organic alcohol, such as methanol, treating with a catalytic amount of inorganic acid, preferably sulfuric acid, and maintaining the reaction temperature preferably above 65°C. Removal of the volatiles affords XXV. Conversion of the ester to the alcohol XXVI can be accomplished by treating a solution of ester XXV in a nonpolar organic solvent, such as diethyl ether or tetrahydrofuran, with a metal hydride reducing agent, such as lithium aluminum hydride, following the usual techniques for the exclusion of moisture. Extractive workup and purification according to standard procedures affords XXVI. Bromides XXVII can be prepared by dissolving the alcohol in an aprotic organic solvent, preferably dichloromethane, and treating the solution with a bromine source, preferably carbon tetrabromide, followed by a phosphine, such as triphenylphosphine, following the usual techniques for the exclusion of moisture. The reaction temperature is maintained between 0°C and 27°C, preferably 24°C. Removal of volatiles and purification according to standard procedures affords XXVII.

SCHEME 6 LiAIH_4|

XXV XXIV

Where a carboxylic acid chloride is needed, it is prepared from the corresponding carboxylic acid by standard synthetic methodology. Additionally, where an aromatic ether is needed, it is prepared from the corresponding phenol by standard synthetic methodology.

The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples.

EXAMPLE 1

3,4-Dihydro-7-methanesulfonamido- -[2-(2-methyl-3- indolvπethyllspiror(2H)-l -benzopyran-2.4'-piperidine]-4-one

Step 1 : A suspension of 10 g (66 mmoi) 3-acetamidophenol in 30 mL dichloromethane and 21 mL (240 mmoi) acetyl chloride in a 500 mL 3-neck round bottom flask was stirred by means of an overhead mechanical stirrer, affixed with an Ar inlet and a glass stopper. Aluminum trichloride (30.4 g, 230 mmoi) was added portion wise over 20 minutes, reaction was vigorously exothermic and evolves gas. After addition was complete, the reaction mixture was homogeneous, a heating mantle was affixed to the reaction and the stopper was removed to expose the reaction to the atmosphere. The reaction mixture was heated with stirring to evaporate the volatiles and then further heated to 140°C (mantle temperature) until reaction mixture was thick and stirring was difficult. Heating was continued for an additional 10 minutes when the heating mantle was removed and the reaction cooled to room temperature. The flask was then placed in an ice-water bath and crushed ice (300 mL) was added to the reaction mixture which facilitates stirring and causes a yellow solid to precipitate out. This solid was collected by filtration, rinsed with water and dried by azeotropic removal of toluene (2 x 200 mL) to provide N-(4-acetyl-5- hydroxyphenyl)acetamide as a pale yellow solid.

Step 2: To a solution of 14 g (76 mmoi) N-(4-acetyl-5- hydroxyphenyl)acetamide in 250 mL methanol was added 6.3 mL (76 mmoi) pyrrolidine and 15.1 g (76 mmoi) N-t-butyloxycarbonyl-4- piperidone. The reaction mixture was heated on a sand bath to 60°C (bath temperature) for 48 h when the reaction was cooled to room temperature and the volatiles removed by rotary evaporation to provide an insoluble precipitate in the methanol solution. The precipitate was collected and washed with methanol to give an off-white solid and the combined methanol washes concentrated at reduced pressure. The resultant oil was purified by pressurized silica gel chromatography, using a gradient elution of 50-70% ethyl acetate in hexane to obtain an additional foamy white solid, identical spectroscopically to the first solid. These solids were combined to give 7-acetamido-l'-r-butyloxy- carbonyl-3,4-dihydrospiro[(2H)- 1 -benzopyran-2,4'-piperidine]-4-one. Step 3: To a suspension of 15.2 g (40.6 mmoi) of 7- acetamido- -f-butyloxycarbonyl-3,4-dihydro-[(2H)-l-benzopyran-2,4'- piperidine]-4-one in 600 mL ethanol in a 2 L round bottom flask was added 300 mL water and 300 mL concentrated HCl. The flask was affixed with a water-cooled condenser and stirred while heating at reflux for 14 h. The reaction was then cooled to room temperature, the volatiles removed by rotary evaporation and the resulting solid azeotroped with toluene (3 x 200 mL) to provide the dihydrochloride salt of 7-amino-3,4-dihydrospiro[(2H)-l-benzopyran-2,4'-piperidine]-4- one as a pale yellow solid.

Step 4: To a solution of dihydrochloride salt of 7-amino- 3,4-dihydro-[(2H)-l-benzopyran-2,4'-piperidine]-4-one (570 mg, 1.88 mmoi) in DMF (5 mL) was added diisopropylethylamine (1.02 mL, 5.83 mmoi), and 3-(2-bromoethyl)-2-methylindole (493 mg, 2.07 mmoi). The reaction mixture was warmed to 65°C for 17 h. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and 10% aqueous citric acid solution. The layers were separated and the aqueous layer was diluted with saturated NaCl solution (25% by volume), basified with IN NaOH and extracted with dichloromethane (6 x 50 mL). The combined organic layers were then dried over Na2Sθ4 and concentrated under reduced pressure to give 7-amino-3,4-dihydro-l'-[2-(2-methyl-3- indolyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one. HPLC: retention time = 6.55 min Step 5: To a solution of 7-amino-3,4-dihydro-l '-[2-(2- methyl-3-indolyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one (140 mg, 0.37 mmoi) in dry dichloromethane (5 mL) and pyridine (0.3 mL), cooled on an ice-water bath under argon, was added methanesulfonyl chloride (32 mL, 0.41 mmoi). After 1 h, the ice-water bath was removed and reaction mixture warmed to room temperature. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane (100 mL) and washed with saturated NaHCθ3 solution (1 x 50 mL), brine (1 x 50 mL), and dried over Na2Sθ4. The volatiles were removed under reduced pressure and the resulting solid was purified by pressurized silica gel chromatography, using a gradient elution of methanol (1 -6%) in chloroform saturated with NH3 to afford 3,4-dihydro-7-methanesulfonamido-l '-[2-(2-methyl- 3-indolyl)ethyl]spiro[(2H)-l -benzopyran-2,4'-piperidine]-4-one as a pale yellow solid.

^ΪH NMR HCl salt: (400 MHz, CD3OD) 7.79 (d, J=8.73 Hz, IH), 7.76 (d, J= 7.21 Hz, IH), 7.24 (dd, J=6.88, 1.00 Hz, IH), 7.07 (d, J= 2.02 Hz, IH), 7.01 (m, 2H), 6.83 (dd, J=8.57, 2.19 Hz, IH), 3.64 (br d, J= 12.93 Hz, 2H), 3.46 (br d, J=13.94 Hz, 2H), 3.38 (m, 2H), 3.21 (m, 2H), 3.10 (s, 3H), 2.84 (s, 2H), 2.42 (s, 3H), 2.39 (d, J=14.78 Hz, 2H), 2.04 (bt, J= 12.93 Hz, 2H).

Analysis: C25H29N3O4 S, 0.8 H2O, calc: C 62.29, H 6.40, N 8.72. found: C 62.32, H 6.25, N 8.73. HPLC: retention time = 6.78 min, purity = 96% FAB MS: m/z = 468 (M + H+)

EXAMPLE 2

3,4-Dihydro-7-methanesulfonamido- 1 '-[2-(2- methoxyphenyl)ethynspiro[(2H)- 1 -benzopyran-2,4'-piperidine1-4-one

Step 1 : To a solution of 1.0 g (5.2 mmoi) of N-(4-acetyl-5- hydroxyphenyl)acetamide (prepared in above example, Step 1) in 50 mL absolute ethanol was added 25 mL water and 25 mL 12N HCl. The reaction mixture was refluxed for 20 h when the volatiles were removed at reduced pressure and the residue was partitioned between 200 mL dichloromethane and 100 mL saturated NaHC03 solution. The layers were separated and the aqueous layer extracted with dichloromethane (2 x 50 mL). The organic layers were combined, dried over Na2Sθ4, filtered and concentrated to provide 1 -(4-amino-2- hy droxypheny 1 )ethanone . HPLC: retention time = 4.25 min, purity = 100%

Step 2: A solution of 1 -(4-amino-2-hydroxyphenyl)- ethanone (2.0 g, 10 mmoi) in dry dichloromethane (100 mL) and pyridine (2.05 mL) was cooled in an ice-water bath under argon and treated with methanesulfonyl chloride (0.8 mL, 10.2 mmoi). After 1 h, the ice bath was removed and reaction mixture warmed to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and extracted with 50 mL IN HCl. The aqueous layer was washed with dichloromethane (50 mL) and the organic layers were combined, washed with brine ( 1 x 25 mL) and dried over Na2Sθ4. The volatiles were removed under reduced pressure and the resulting solid was triturated and filtered from dichloromethane to afford N-(4-acetyl- 5-hydroxyphenyl)methanesulfonamide as a puφle solid. HPLC: retention time = 5.23 min FAB MS: m/z = 230 (M + H+)

Step 3: To a solution of N-(4-acetyl-5-hydroxyphenyl)- methanesulfonamide (1.4 g, 6.2 mmoi) in 15 mL methanol was added pyrrolidine (0.52 mL, 6.2 mmoi) and a solution of N-t-butyloxy- carbonyl-4-piperidone (1.2 g, 6.2 mmoi) in 50 mL methanol. The reaction mixture was warmed to 65°C for 17 h. The volatiles were removed under reduced pressure and the residue was partitioned between 200 mL ethyl acetate and 100 mL saturated NaHCθ3 solution. The organic layer was washed with saturated NaHCθ3 solution (2 x 50 mL), with brine (1 x 50 mL), dried over Na2Sθ4 and concentrated under reduced pressure. The resultant oil was purified by pressurized silica gel chromatography, using 2:1 hexanes:ethyl acetate as the eluent to obtain 1 '-r-butyloxycarbonyl-3,4-dihydro-7-methanesulfonamido- spiro[(2H)-l -benzopyran-2,4'-piperidine]-4-one as a white solid. HPLC: retention time = 8.25 min FAB MS: m/z = 41 1(M + H⁺)

Step 4: l '-r-Butyloxycarbonyl-3,4-dihydro-7-methane- sulfonamidospiro[(2H)-l -benzopyran-2,4'-piperidine]-4-one (1.95 g, 4.8 mmoi) was dissolved in 25 mL isopropanol and 12 mL 8N HCl was added. The reaction mixture was stirred at room temperature for 17 h. The volatiles were removed under reduced pressure to afford the hydrochloride salt of 3,4-dihydro-7-methanesulfonamidosρiro[(2H)-l - benzopyran-2,4'-piperidine]-4-one. FAB MS: m/z = 311(M + H+)

Step 5: To a solution of the hydrochloride salt of 3,4- dihydro-7-methanesulfonamidospiro[(2H)- 1 -benzoρyran-2,4'- piperidine]-4-one (100 mg, 0.29 mmoi) in DMF (2 mL) was added Li2C03 (47 mg, 0.64 mmoi), KI ( catalytic amount), and 2-(2- bromoethyl)methoxybenzene (75 mg, 0.35 mmoi). The reaction mixture was warmed to 65°C for 17 h. The volatiles were removed under reduced pressure and the residue was partitioned between 50 mL dichloromethane and 25 mL saturated NaHC03 solution. The organic layer was washed with brine (1 x 25 mL), dried over Na2Sθ4 and concentrated under reduced pressure. The resultant oil was purified by pressurized silica gel chromatography, using a gradient elution of 1 -4% methanol in dichloromethane containing 0.5% concentrated ammonium hydroxide to obtain 3,4-dihydro-7-methanesulfonamido-l '-[2-(2- methoxyphenyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one. Analysis: C23H28N2O5S, 1.7 H2O: calc: C 53.99, H 5.83, N 5.63. found: C 53.99, H 6.38, N 5.48. HPLC: retention time = 6.51 min, purity = 98% FAB MS: m/z = 445 (M + H+)

EXAMPLE 3

3,4-Dihydro-7-memanesulfonamido- -[2-(2-methyl-3- indolyπethyllspiror(2H -l -benzopyran-2.4'-piperidinel-4-one The compound of EXAMPLE 1 was also prepared according to the process described in Example 2 by substituting 3-(2- bromoethyl)-2-methylindole for 2-(2-bromoethyl)methoxybenzene in Step 5 of EXAMPLE 2. The compound prepared in this manner was identical in all respects to that prepared according to EXAMPLE 1.

EXAMPLE 4

3,4-Dihydro-7-methanesulfonamido-l '-[2-(l -naphthyl)ethyl]spiro[(2H)- l -benzopyran-2.4'-piperidine1-4-one

Following the procedure of EXAMPLE 2, but substituting l-(2-bromoethyl)naphthalene for 2-(2-bromoethyl)methoxybenzene in Step 5, the title compound was obtained. IH NMR HCl salt: (400 MHz, CD3OD) 8.12 (br d, J= 8.22 Hz, IH), 7.92 (br d, J= 7.22 Hz, IH), 7.84 (br d, J= 7.21 Hz, IH), 7.80 (d, J= 8.56 Hz, IH), 7.62 (bt, J= 6.89 Hz, IH) 7.52 (m, 3H), 7.08 (bs, IH), 6.83 (dd, J= 8.73, 2.02 Hz, IH), 3.68 (m, 2H), 3.52 (m, 6H), 3.10 (s, 3H), 2.86 (bs, 2H), 2.42 (m, 2H), 2.08 (m, 2H). Analysis: C26H28N2O4S HCl 1.00 H2O: calc:C 60.16, H 6.02, N

5.40. found: C 60.13, H 5.89, H 5.30.

HPLC: retention time = 7.24 min, purity = 96%

FAB MS: m/z = 465 (M + H+)

EXAMPLE 5

3,4-Dihydro-l'-[2-(3-indolyl)ethyl]-7-methanesulfonamidosρiro[(2H)-l- benzopyran-2.4'-piperidine1-4-one

Following the procedure of EXAMPLE 2, but substituting 3-(2- bromoethyl)indole for 2-(2-bromoethyl)methoxybenzene in Example 2, Step 5, the title compound was obtained.

^JH NMR (400 MHz, CDCI3) 8.02 (bs, IH), 7.84 (d, J= 8.56,1H), 7.62 (d, J= 7.55 Hz, IH), 7.37 (d, J= 8.06 Hz, IH), 7.20 (t, J= 7.22 Hz, IH), 7.12 (t, J=7.89 Hz, IH), 7.05 (d, J= 1.68 Hz, IH), 6.88 (d, J=2.18 Hz, IH), 6.69 (dd, J= 8.56, 2.18 Hz, IH), 3.14 (s, 3H), 2.99 (bt, J= 7.56 Hz, 2H), 2.79 (m, 4H), 2.71 (s, 2H), 2.55 (bt, J= 11.42 Hz, 2H), 2.08 (d, J= 13.09 Hz, 2H), 1.81 (dt, J=14.27, 3.69 Hz, 2H).

Analysis: C24H27N3O4S 1.0 H2O. calc: C 54.60, H 6.15, N 7.96. found: C 54.56, H 5.80, N 7.95. TLC: Rf = 0.12 (95:5:0.5 CH2Cl2:MeOH:NH4θH) HPLC: retention time = 6.36 min, purity = 96% FAB MS: m z = 454 (M + H+)

EXAMPLE 6

3,4-Dihydro-7-methanesulfonamido- 1 '-[2-(3- thianaphthvDethyllspirolY2H - 1 -benzopyran-2.4'-piperidinel-4-one

The title compound was prepared according to the procedure of EXAMPLE 2 by substituting 3-(2-bromoethyl)- thianaphthene for 2-(2-bromoethyl)methoxybenzene in Step 5. *H NMR HCl salt (400 MHz, CD3OD) 7.91 (dt, J= 7.89, 0.85 Hz, 2H), 7.80 (d, J= 8.56 Hz, IH), 7.49 (s, IH), 7.47 (dd, J= 7.05, 1.01 Hz, IH), 7.43 (dd, J= 8.40, 1.35 Hz, IH) 7.39 (br d, J= 7.06 Hz, IH), 7.09 (bs, IH), 6.83 (dd, J= 8.56, 2.01 Hz, IH), 3.63 (m, 4H), 3.88 (m, 4H), 3.1 1 (s, 3H), 2.89 (s, 2H), 2.41 (br d, J=14.61 Hz, 2H), 2.11 (m, 2H). Analysis: C24H26N2O4S2 HCl 0.65 H2O . calc: C 55.56, H 5.50, N 5.40. found: C 55.53, H 5.39, N 5.35. TLC: Rf = 0.26 (95:5:0.5 CHCl3:MeOH:NH4θH) HPLC: retention time = 7.32 min, purity = 97% FAB MS: m/z = 471 (M + H+)

EXAMPLE 7

l '-[2-(2-Ethoxyphenyl)ethyl]-3,4-dihydro-7- methanesulfonamidospirorr2H - 1 -benzopyran-2.4'-piperidine1-4-one The title compound was prepared according to the procedure of EXAMPLE 2 by substituting 2-(2-bromoethyl)ethoxy- benzene for 2-(2-bromoethyl)methoxybenzene in Step 5. IH NMR HCl salt (400 MHz, CD3OD) 7.80 (d, J= 8.56 HZ, IH), 7.26 (m, 2H), 7.06 (d, J=1.85 Hz, IH), 6.98 (d, 8.05 Hz, IH), 6.92 (dt, J= 7.39 Hz, IH), 6.83 (dd, J= 8.57, 2.02 Hz, IH), 4.12 (q, J=7.05 Hz, 2H), 3.61 (br d, J=13.09 Hz, 2H), 3.37 (m, 4H), 3.1 1 (s, 5H), 2.83 (s, 2H), 2.38 (br d, J= 14.94 Hz, 2H), 2.03 (dt, J= 13.60, 4.36 Hz, 2H), 1.45 (t, J=6.88 Hz, 3H).

Analysis: C24H30N2O5S HCl 1.9 H2O. calc: C 54.46, H 6.63, N

5.29. found: C 54.50, H 6.07, N 5.22.

HPLC: retention time = 7.10 min, purity = 98%

FAB MS: m/z = 459 (M + H+)

EXAMPLE 8

6-Benzyloxycarbonylamido-3,4-dihydro- 1 '-[2-( 1 - naphth vDethyllspirolY2H)- 1 -benzopyran-2.4'-piperidinel-4-one

l -(5-Amino-2-hydroxyphenyl)ethanone hydrochloride was prepared according to the procedure described in J. M. Elliott et. al., J. Med. Chem. 1992, 35, 3973-3976.

Step 1 : A solution of 1 -(5-amino-2-hydroxyphenyl)- ethanone hydrochloride (1.5 g, 8.0 mmoi) in 50 mL dichloromethane was treated with 50 mL saturated Na2C03 and cooled on an ice-water bath when benzyl chloroformate (1.1 mL, 8.0 mmoi) was added. The reaction mixture was stirred in the ice-water bath for 3 h when it was diluted with 50 mL dichloromethane and 50 mL water and the layers separated. The organic layer was then washed with water (1 x 50 mL), brine (1 x 50 mL) and dried over sodium sulfate. The volatiles were removed under reduced pressure and 1 -(5-benzyloxycarbonylamido-2- hydroxyphenyl)ethanone was obtained as a yellow solid. HPLC: retention time = 9.14 min, purity = >95% FAB MS: m/z = 286 (M + H+)

Step 2: To a solution of l-(5-benzyloxycarbonylamido-2- hydroxyphenyl)ethanone (2.2 g, 7.5 mmoi) in 50 mL methanol was added pyrrolidine (0.63 mL, 7.5 mmoi) and a solution of N-t-butyloxy- carbonyl-4-piperidone (1.5 g, 7.5 m oi) in 50 mL methanol and the reaction mixture was warmed to 65 °C overnight. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate (250 mL) and saturated NaHCθ3 solution (100 mL). The organic layer was washed with saturated NaHCθ3 solution (2 x 50 mL) and brine (1 x 50 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was taken up in methanol and the resulting precipitate collected and washed with methanol to provide a yellow solid and the combined methanol washes concentrated at reduced pressure. The resultant oil was purified by pressurized silica gel chromatography, using 10% ethyl acetate in hexane as the eluent to obtain an additional white solid, identical spectroscopically to the first. These solids were combined to yield 6-benzyloxycarbonylamido-l '-?- butyloxycarbonyl-3,4-dihydrospiro[(2H)-l -benzopyran-2,4'-piperidine]- 4-one.

HPLC: retention time = 10.84 min FAB MS: m/z = 466(M + H+)

Step 3: To a solution of 6-benzyloxycarbonylamido-l '-r- butyloxycarbonyl-3,4-dihydrospiro[(2H)-l -benzopyran-2,4'-piperidine]- 4-one (1.0 g, 2.1 mmoi) in dichloromethane (60 mL) was added trifluoroacetic acid (30 mL) and the reaction mixture was stirred at room temperature for 2 h when the volatiles were removed under reduced pressure. The resulting oil was taken up in dichloromethane (200 mL) and carefully treated with saturated NaHCθ3 solution (100 mL). The organic layer was washed with additional saturated NaHC03 (2 x 50 mL), brine (1 x 50 mL) and dried over Na2Sθ4. Concentration under reduced pressure gave 6-benzyloxycarbonylamido-3,4-dihydro- spiro[(2H)-l -benzopyran-2,4'-piperidine]-4-one as a yellow solid. HPLC: retention time = 6.77 min Step 4: To a solution of 6-benzyloxycarbonylamido-3,4- d-hydrospiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one (0.62 g, 1.7 mmoi) in DMF (10 mL) was added Li2Cθ3 (0.15 g, 2.0 mmoi) , Kl (catalytic amount), and l-(2-bromoethyl)naphthalene (0.48 g, 2.0 mmoi). The reaction mixture was warmed to 65°C for 17 h. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane (100 mL) and saturated NaHCθ3 solution (50 mL). The organic layer was washed with additional saturated NaHC03 solution (50 mL), brine (50 mL), dried over Na2S04 and concentrated under reduced pressure. The resultant oil was purified by pressurized silica gel chromatography, using a gradient elution of 1 -5% methanol in dichloromethane containing 0.5% concentrated ammonium hydroxide to obtain 6-benzyloxycarbonyl- amido-3,4-dihydro-l '-[2-(l -naphthyl)ethyl]spiro[(2H)-l-benzopyran- 2,4'-piperidine]-4-one.

!H NMR (400 MHz, CDCI3) 8.04 (d, J= 7.39 Hz, IH), 7.85 (dd, J=

7.89, 1.51 Hz, IH), 7.72 (d, J= 8.05 Hz, 2H), 7.67 (d, J= 2.69 Hz, IH), 7.54- 7.45 (m, 2H), 7.42-7.31 (m, 6H), 6.98 (d, J= 8.90 Hz, IH), 6.92 (m, IH), 3.31- 3.27 (m, 2H), 2.94 (s, 2H), 2.87 (s, 2H), 2.76 (m, 4H), 2.55 (t, J=9.91 Hz, 2H), 2.09 (d, J= 12.76 Hz, 2H), 1.79 (dt, J= 14.61 , 4.37 Hz, 2H). Analysis: C33H32N2O4 HCl, 0.8 H2O. calc: C 69.35, H 6.10, N

4.90. found: C 69.38, H 6.09, N 5.08.

TLC: Rf = 0.34 (95:5:0.5 CH2Cl2:MeOH:NH4θH) HPLC: retention time = 9.15 min, purity = 96% FAB MS: m/z = 521 (M + H+)

EXAMPLE 9

3,4-Dihydro-l'-[2-(l -naphthyl)ethyl]-6-phenylsu benzopyran-2.4'-piperidinel-4-one

Step 1 : To a solution of 6-benzyloxycarbonylamido-3,4- dihydro- 1 '-[2-( 1 -naphthyl)ethyl]spiro[(2H)- 1 -benzopyran-2,4'- piperidine] -4-one (0.47 g, 0.89 mmoi) in ethanol (50 mL) was added 12N HCl (2 mL) and palladium black (76 mg). The reaction mixture was shaken at 55 psi hydrogen gas in a Parr apparatus for 25 h when the reaction mixture was flushed with argon, filtered through celite and washed with copious amounts of warm methanol. The volatiles were removed under reduced pressure to give the hydrochloride salt of 6- amino-3,4-dihydro- -[2-(l-naphthyl)ethyl]-spiro[(2H)-l -benzopyran- 2,4'-piperidine]-4-one. HPLC: retention time = 9.29 min FAB MS: m/z =387(M + H+)

Step 2: A solution of the hydrochloride salt of 6-amino- 3,4-dihydro- 1 '-[2-( 1 -naphthyl)ethyl]spiro[(2H)- 1 -benzopyran-2,4'- piperidine]-4-one (0.10 g, 0.22 mmoi) in dry dichloromethane (2 mL) and pyridine (0.3 mL) was cooled on an ice-water bath under argon and benzenesulfonyl chloride (34 mL, 0.26 mmoi) was added. After 1 h, the bath was removed and reaction mixture warmed to room temperature when the volatiles were removed under reduced pressure. The resultant oil was purified by pressurized silica gel chromatography, using 1 % methanol in dichloromethane containing 0.5% concentrated ammonium hydroxide as the eluent to obtain 3,4-dihydro-l '-[2-(l -naphthyl)ethyl]- 6-phenylsulfonamidospiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one. ! H NMR (400 MHz, CD3OD) 8.1 1 (d, J=8.06 Hz, IH), 7.92 (d, J= 7.55 Hz, IH), 7.83 (dd, J=6.88, 1.67 Hz, IH), 7.75 (s, IH), 7.73 (m, IH), 7.62- 7.43 (m, 8H), 7.36 (dd, J= 8.90, 2.69 Hz, IH), 7.05 (d, J=8.90 Hz, IH), 3.59-3.40 (m, 8H), 2.86 (bs, 2H), 2.31 (m, 2H), 2.17 (m, 2H). Analysis: C31H30N2O4S HCl 1.85 H2O. calc: C 62.42, H 5.86, N 4.70. found: C 62.45, H 6.83, N 4.57. HPLC: retention time = 8.09 min, purity = 96% FAB MS: m/z = 527(M + H+)

EXAMPLE 10

3,4-Dihydro-6-( 1 -methyl-4-imidazolyl)acetamido- 1 '-[2-( 1 - naphthyDethyllspiror(2Hy 1 -benzopyran-2.4'-piperidinel-4-one The title compound was prepared according to the procedure of EXAMPLE 9 by substituting l-methyl-4-imidazoleacetyl chloride for benzenesulfonyl chloride in Step 2. lH NMR (400 MHz, CD3OD) 8.84 (s, IH), 8.16 (d, J= 8.40 Hz, IH), 8.09 (d, J=2.68 Hz, IH), 7.92 (d, 8.05 Hz, IH), 7.83 (d, J= 7.89 Hz, IH), 7.77 (dd, J= 8.89, 2.68 Hz, IH), 7.61 (dt, J=6.89, 1.34 Hz, IH), 7.54 (d, J=8.06 Hz, IH), 7.51-7.44 (m, 2H), 7.23- 7.10 (m, 4H), 3.93 (s, 3H), 3.91 (s, 2H), 3.74- 3.43 (m, 8H), 2.90 (s, 2H), 2.39 (m, 2H), 2.14 (bt, J=11.75 Hz, 2H).

Analysis: C31H32N4O3 2 HCl, 1.2 H2O 0.45 EtOAc. calc: C 62.38, H 6.27, N 8.72. found: C 61.28, H 6.22, N 8.65 HPLC: retention time = 6.44 min, purity = 92% FAB MS: m z = 509 (M + H+)

EXAMPLE 1 1

3,4-Dihydro-6-(3,5-dimethyl-4-isoxazolyl)sulfonamido-l'-[2-(l* naphthyltethvπspiror(2HV 1 -benzopyran-2.4'-piperidinel-4-one

The title compound was prepared according to the procedure of EXAMPLE 9 by substituting 3,5-dimethyϊisoxazole-4- sulfonyl chloride for benzenesulfonyl chloride in Step 2. IH NMR (400 MHz, CDC13) 8.12 (d, J=8.23 Hz, IH), 7.92 (d, J= 8.06 Hz, IH), 7.83 (dd, J=7.22, 1.85 Hz, IH), 7.61 (m, IH), 7.54 (m, 3H), 7.48 (d, J=8.89 Hz, IH), 7.37 (dd, J= 8.90, 2.86 Hz, IH), 7.14 (d, J=8.89 Hz, IH), 3.52 (m, 7H), 2.91 (s, 2H), 2.78 (m, IH), 2.47 (s, 3H), 2.34 (m, 2H), 2.24 (s, IH), 2.11 (m, 2H). Analysis: C30H31N3O5S HCl 0.85 H2O. calc: C 60.31, H 5.69, N 7.03. found: C 60.35, H 5.56, N 6.92.

HPLC: retention time = 8.59 min, purity = 96% FAB MS: m/z = 546 (M + H+) EX AMPLE 12

3 ,4-Dihydro-6-( 1 -methyl-4-imidazoly l)sulfonamido- 1 '-[2-( 1 - naphthyl ethyl1spirol(2H -l-benzopyran-2.4'-piperidine1-4-one

The title compound was prepared according to the procedure of EXAMPLE 9 by substituting 1 -methyl-4- imidazolesulfonyl chloride for benzenesulfonyl chloride in Step 2. l H NMR (400 MHz, CD3OD) 8.22 (s, IH), 8.15 (d, J= 8.39 Hz, IH), 7.91 (d, J= 8.06 Hz, IH), 7.83 (d, J= 8.90 Hz, 2H), 7.52 (m, 6H) 7.12

(d, J = 12.90 Hz, 2H), 3.79 (s, 3H), 3.64 (m, 4H), 3.47 (m, 4H), 2.87 (s,

2H), 2.35 (bt, J=l 1.25 Hz, 2H), 2.1 1 (bt, J=1 1.76 Hz, 2H).

Analysis: C29H30N4O4S 2 HCl 1.5 H2O. calc: C 55.23, H 5.59, N

8.89. found: C 55.25, H 5.49, N 8.90. HPLC: retention time = 6.69 min, purity = 95%

FAB MS: m/z = 531 (M + H+)

EXAMPLE 13

3,4-Dihydro-6-( l -imidazolylmethyl)-l '-[2-(l -naphthyl)ethyl]spiro[(2H)- l -benzopyran-2.4'-piperidinel-4-one

Step 1 : l-(5-chloromethyl-2-hydroxyphenyl)ethanone was prepared by the method of Acta Pharm. Suec, 15, 13 (1978). Step 2: To a solution of 3 g (16 mmoi) l -(5-chloromethyl-

2-hydroxyphenyl)ethanone in DMF at room temperature was added 3.45 g (33 mmoi) anhydrous sodium carbonate followed by 1.2 g (18 mmoi) imidazole. The solution was stirred 4 h when the volatiles were removed by rotary evaporation and the crude reaction mixture partitioned between 200 mL dichloromethane and 100 mL water. The layers were separated, the organic layer washed with 100 mL brine, dried over MgS04, filtered and concentrated under reduced pressure. The resultant oil was purified by pressurized silica gel chromatography, using a gradient elution of 3-5% methanol in dichloromethane containing 0.5% concentrated ammonium hydroxide to obtain l-[(2- hydroxy-5-(l-imidazolylmethyl)phenyl]ethanone as a pale yellow solid. HPLC: retention time = 2.95 min

Step 3: A solution of 2.6 g (12 mmoi) l-[(2-hydroxy-5-(l- imidazolylmethyl)phenyl]ethanone in 30 mL methanol was treated with 1.0 mL (12 mmoi) pyrrolidine followed by 2.4 g (12 mmoi) N-t- butyloxycarbonyl-4-piperidone. The reaction mixture was stirred at room temperature for 20 h when the volatiles were removed by rotary evaporation. The resultant oil was purified by pressurized silica gel chromatography, using a gradient elution of 3-4% methanol in dichloromethane containing 0.5% concentrated ammonium hydroxide to obtain 1 '-r-butyloxycarbonyl-3,4-dihydro-6-( 1 -imidazolylmethyl)- spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one as a pale yellow foam. HPLC: retention time = 6.9 min Step 4: A solution of 4.4 g (11 mmoi) l'-r-butyloxy- carbonyl-3,4-dihydro-6-( 1 -imidazolylmethyl)spiro[(2H)- 1 -benzopyran- 2,4'-piperidine]-4-one in 100 mL was treated with 90 mL 8N HCl and the mixture stirred at room temperature 3 h when the volatiles were removed by rotary evaporation. The resultant oil was partitioned between 200 mL dichloromethane and 100 mL saturated NaHCθ3 solution. The layers were separated, the aqueous layer extracted with an additional 100 mL dichloromethane, the organic layers combined, dried over MgS04, filtered and concentrated under reduced pressure to provide 3,4-dihydro-6-(l-imidazolylmethyl)-spiro[(2H)-l-benzopyran- 2,4'-piperidine]-4-one as an off-white solid. HPLC: retention time = 2.75 min

Step 5: To a solution of 200 mg (0.7 mmoi) of 3,4- dihydro-6-(l-imidazolylmethyl)spiro[(2H)-l-benzopyran-2,4'- piperidine]-4-one and 0.18 mL (1.0 mmoi) diisopropylethylamine in 5 mL dry DMF was added 174 mg (0.7 mmoi) 1 -(2-bromoethyl)- naphthalene and the reaction warmed to 70°C for 23 h. The volatiles were removed at reduced pressure and the resultant oil taken up in 50 mL dichloromethane, washed with saturated aqueous NaHCθ3 (1 x 25 mL), dried over MgS04 and concentrated at reduced pressure. The oil was purified by pressurized silica gel chromatography using an eluent of 3% methanol in dichloromethane containing 0.5% concentrated NH4OH and then the HCl salt prepared and triturated with diethyl ether from methanol to provide the dihydrochloride salt of 3,4-dihydro-6-(l- imidazolylmethyl)- 1 '-[2-( 1 -naphthyl)ethyl]spiro[(2H)- 1 -benzopyran- 2,4'-piperidine]-4-one as an off-white solid.

Analysis: C29H₂9N₃O₂ 2HC1; 2.35 H₂0, calc: C 61.45, H 6.35, N 7.41. found: C 61.45, H 5.99, N 7.52. HPLC: retention time = 6.24 min, purity = 99% FAB MS: m/z = 452 (M + H+)

EXAMPLE 14

3,4-Dihydro-l'-[2-( l-naphthyl)ethyl]-6-(l ,2,4- triazolylmethyDspirolY2Hy 1 -benzopyran-2.4'-piperidine1-4-one

Following the procedure of EXAMPLE 13, but substituting 1 ,2,4-triazole for imidazole in Step 2, the title compound was obtained. Analysis: C₂₈-H28N4O2 3HC1; 0.35 H₂0, calc: C 59.18, H 5.62, N 9.86. found: C 59.19, H 5.65, N 9.81.

HPLC: retention time = 6.9 min, purity = 94% FAB MS: m/z = 453 (M + H+)

EXAMPLE 15

6-Cyanomethyl-3,4-dihydro- 1 '-[2-(l -naphthyl)ethyl]spiro[(2H)-l- benzopyran-2.4'-piperidine]-4-one

Following the procedure of EXAMPLE 13, but substituting potassium cyanide for imidazole and sodium carbonate in Step 2, the title compound was obtained.

Analysis: C₂₇H₂₆N₂O₂ HCl; 0.7 H₂0, calc: C 70.56, H 6.23, N 6.10. found: C 70.62, H 6.26, N 6.20. HPLC: purity = 95% EX AMPLE 16

7-Acetamido-3,4-dihydro- 1 '-[2-(2-fluorophenyl)ethyl]spiro[(2H)-l - benzopyran-2.4'-piperidine]-4-one

Step 1 : A suspension of 7-acetamido-l'-/- butyloxycarbonyl-3,4-dihydrospiro[(2H)-l-benzopyran-2,4'-piperidine]- 4-one (4.3 g, 1 1.5 mmol)(prepared as shown n Example 1 , Steps 1 & 2) in 200 mL ethyl acetate was cooled on an ice-water bath and HCl (g) bubbled through the suspension via a glass pipet for 10 min. The ice- water bath was removed and the suspension stirred at room temperature 1 h when the volatiles were removed at reduced pressure and 7- acetamido-3,4-dihydrospiro[(2H)-l -benzopyran-2,4'-piperidine]-4-one obtained as a white powder.

Step 2: To a solution of 200 mg (0.6 mmoi) of 7- acetamido-3,4-dihydrospiror(2H)-l -benzopyran-2,4'-piperidine]-4-one and 0.28 mL (1.6 mmoi) diisopropylethylamine in 5 mL dry DMF was added 170 mg (0.8 mmoi) 2-(2-bromoethyl)fluorobenzene and the reaction warmed to 60°C for 65 h. The volatiles were removed at reduced pressure and the resultant oil taken up in 50 mL dichloromethane and washed with saturated aqueous NaHCθ3 (1 x 25 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL) and the combined organic layers dried over MgS04 and concentrated at reduced pressure. The resultant oil was purified by pressurized silica gel chromatography using a gradient of 0.5-4% methanol in dichloromethane containing 0.5% concentrated NH4OH and then the HCl salt prepared and triturated with diethyl ether from methanol to provide the hydrochloride salt of 7-acetamido-3,4-dihydro- -[2-(2-fluorophenyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4- one as an off-white solid.

Analysis: C₂₃H₂₅N₂O₃F HCl; 0.75 H₂0, calc: C 61.88, H 6.21 , N 6.27. found: C 61.85, H 6.10, N 6.22. HPLC: retention time = 6.31 min, purity = 98% FAB MS: m/z = 397 (M + H⁺)

EXAMPLE 17

3-(2-bromoethyl -2-methylindole

Step 1 : To a solution of 1.0 g (5.3 mmoi) of 2-methyl-3- indole acetic acid in 3:1 (v:v) methano chloroform (50 mL) was added a 2.0M solution of (trimethylsilyl)diazomethane in hexanes (2.7 mL, 5.4 mmoi) and the mixture stirred at room temperature for 1 h when the yellow color of the solution was quenched by careful dropwise addition of concentrated HOAc. The volatiles were removed under reduced pressure to provide methyl 2-methyl-3-indoleacetate.

Step 2: To a solution of 1.1 g (5.3 mmoi) of methyl 2- methyl-3-indoleacetate in diethyl ether (50 mL) was added a 1M solution of lithium aluminum hydride in tetrahydrofuran (13 mL, 13 mmoi) and the reaction stirred at room temperature 2 h. The reaction is treated carefully with a saturated solution of sodium potassium tartrate (150 mL total) and diluted with 100 mL ether. The two-phase mixture was stirred 30 min and then the layers separated, the organic layer dried over Na2S04, filtered and concentrated to provide 3-(2- hydroxyethyl)-2-methylindole.

Step 3: A solution of 3-(2-hydroxyethyl)-2-methylindole (0.92 g, 5.3, mmoi) in dichloromethane (50 mL) was treated with carbon tetrabromide (2.3 g, 6.8 mmoi) and cooled on an ice-water bath. Triphenylphosphine (1.8 g, 6.8 mmoi) is added slowly and the reaction warmed to room temperature overnight when the volatiles are removed and the resultant solids were purified by pressurized silica gel chromatography using a gradient of 1 -10% ethyl acetate in hexane to provide 3-(2-bromoethyl)-2-methylindole as a colorless oil which was used immediately as it readily decomposes upon storage.

EXAMPLE 18

2-(2-bromoethyl methoxybenzene 2-(2-bromoethyl)methoxybenzene was prepared according to EXAMPLE 17, Step 3 using 2-methoxyphenethyl alcohol instead of 3-(2-hydroxyethyl)-2-methylindole.

EXAMPLE 19

1 -(2-bromoethyl)naphthalene

l-(2-bromoethyl)naphthalene was prepared according to

EXAMPLE 17, Step 3 using 1 -naphthaleneethanol instead of 3-(2- hydroxyethyl)-2-methylindole.

EXAMPLE 20

3-(2-bromoethyl)thianaphthene

3-(2-bromoethyl)thianaphthene was prepared according to EXAMPLE 17, Steps 1 -3 using thianaρhthele-3-acetic acid instead of 2- methyl-3-indole acetic acid.

EXAMPLE 21

2-(2-bromoethyl ethoxybenzene:

Step 1 : A solution of methyl 2-hydroxyphenylacetate (1.0 g, 6.0 mmoi) in acetone. (30 mL) was treated with ethyl iodide (4.7 mL, 60 mmoi) and potassium carbonate (4.5 g, 33 mmoi), the flask affixed with a water-cooled condenser and the mixture reluxed 17 h. The mixture is cooled to room temperature, concentrated at reduced pressure and the resultant oil partitioned between dichloromethane (150 mL) and brine (75 mL). The layers were separated, the organic layer dried over Na2Sθ4, filtered, concentrated and the resultant oil was purified by pressurized silica gel chromatography using a gradient of 10-50% ethyl acetate in hexane to provide methyl 2-ethoxyphenylacetate as a colorless oil.

2-(2-bromoethyl)ethoxybenzene was prepared according to EXAMPLE 17, Steps 2 and 3 using methyl 2-ethoxyphenylacetate instead of methyl 2-methyl-3-indoleacetate.

EXAMPLE 22

2-(2-bromoethyDfluorobenzene

2-(2-bromoethyl)fluorobenzene was prepared according to EXAMPLE 17, Step 3 using 2-fluorophenethyl alcohol instead of 3-(2- hydroxyethyl)-2-methylindole.

EXAMPLE 23

1 -Methyl-4-imidazoleacetyl chloride:

Step 1 : To a suspension of the hydrochloride salt of 1- methyl-4-imidazole acetic acid (120 mg, 0.66 mmoi) in dichloromethane (2 mL) cooled on an ice-water bath was added oxalyl chloride (0.12 mL) and dry DMF (1 drop). The reaction was stirred in the ice-water bath 30 min then warmed to room temperature and allowed to stir until the mixture was homogeneous when the volatiles were removed under reduced pressure. The resultant oil was used immediately in EXAMPLE 9, Step 2 instead of benzenesulfonyl chloride to provide the title compound.

EXAMPLE 24

As a specific embodiment of an oral composition, 100 mg of the compound of EXAMPLE 1 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule. EXAMPLE 25

Screening assav: Alpha la Adrenergic Receptor Binding

Membranes prepared from the stably transfected human αia cell lin (ATCC CRL 11140) were used to identify compounds that bind to the human alphala adrenergic receptor. These competition binding reactions (total volume = 200 μl) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [¹²⁵ I] -HEAT, membranes prepared from the αia cell line and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki). Representative compounds of the present invention were found to have Ki values < 5 nM.

EXAMPLE 26

Selective Binding assays

Membranes prepared from stably transfected human aid and al b cell lines (ATCC CRL 11 138 and CRL 11139, respectively) were used to identify compounds that selectively bind to the human alphala adrenergic receptor. These competition binding reactions (total volume = 200 μl) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [¹²⁵ I]-HEAT, membranes prepared from cell lines transfected with the respective alpha 1 subtype expression plasmid and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki). EXAMPLE 27

EXEMPLARY COUNTERSCREENS

1. Assay Title: Dopamine D2, D3, D4 in vitro screen

Objective of the Assay:

The objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4.

Method:

Modified from VanTol et al (1991 ); Nature (Vol 350) Pg 610-613. Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 mL lysing buffer (lOmM Tris-HCl/5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 φ ) are resuspended in 50mM Tris-HCl pH 7.4 containing EDTA, MgCl[2], KCl, NaCl, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 μg membranes in a total volume of 500 μL containing 0.2 nM [3H] -spiperone. Non-specific binding is defined using 10 μM apomoφhine. The assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.

2. Assay Title: Serotonin 5HT la

Objective of the Assay The objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor

Method:

Modified from Schelegel and Peroutka Biochemical Pharmacology 35: 1943-1949 (1986). Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at 38,OOOXg for 30'. The binding assay contains 0.25 nM [3H]8- OH-DPAT (8-hydroxy-2-dipropylamino- 1 ,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaC12 and lmg/mL ascorbate. Non-specific binding is defined using 10 μM propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters

EXAMPLE 28

EXEMPLARY FUNCTIONAL ASSAYS

In order to confirm the specificity of compounds for the human alphala adrenergic receptor and to define the biological activity of the compounds, the following functional tests may be performed:

1. In vitro Rat, Dog and Human Prostate and Dog Urethra

Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate. Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary. Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles. Human prostate chips from transurethral surgery of benign prostate hypeφlasia are also stored overnight in ice-cold Krebs solution if needed.

The tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCl, 1 18 mM; KCl, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgS04, 1.2 mM; NaHCθ3, 2.0 mM; dextrose, 11 mM] warmed to 37°C. Excess lipid material and connective tissue are carefully removed. Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% Cθ2/95% 02- The tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder.

After a single priming dose of 3 μM (for rat), 10 μM (for dog) and 20 μM (for human) of phenylephrine, a cumulative concentration response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated.

EC50 values are calculated for each group using GraphPad Inplot software. pA2 (-log Kb) values were obtained from Schild plot when three or more concentrations were tested. When less than three concentrations of antagonist are tested, Kb values are calculated according to the following formula Kb = TB1. x-1 where x is the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration.

2. Measurement of Intra-Urethral Pressure in Anesthetized Dogs

PURPOSE: Benign prostatic hypeφlasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction. Alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man. However, these are non-selective alpha- 1 receptor antagonists which also have pronounced vascular effects. Because we have identified the alpha- la receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without concomitant changes in the vasculature. The following model is used to measure adrenergically mediated changes in intra-urethral pressure and arterial pressure in anesthetized dogs in order to evaluate the efficacy and potency of selective alpha adrenergic receptor antagonists. The goals are to: 1) identify the alpha- 1 receptor subtypes responsible for prostatic/urethral contraction and vascular responses, and 2) use this model to evaluate novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be evaluated in this manner.

METHODS: Male mongrel dogs (7-12 kg) are used in this study.

The dogs are anesthetized with pentobarbital sodium (35 mg/kg, i.v. plus 4 mg/kg/hr iv infusion). An endotracheal tube is inserted and the animal ventilated with room air using a Harvard instruments positive displacement large animal ventilator. Catheters (PE 240 or 260) are placed in the aorta via the femoral artery and vena cava via the femoral veins (2 catheters, one in each vein) for the measurement of arterial pressure and the administration of drugs, respectively. A supra-pubic incision ~l/2 inch lateral to the penis is made to expose the urethers, bladder and urethra. The urethers are ligated and cannulated so that urine flows freely into beakers. The dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra. Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate. The bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra. The bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer. The tip of the transducer is placed in the prostatic urethra and the position of the Millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure. Phenylephrine, an alpha- 1 adrenergic agonist, is administered (0.1-100 ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure. Following administration of increasing doses of an alpha adrenergic antagonist (or vehicle), the effects of phenylephrine on arterial pressure and intra-urethral pressure are re-evaluated. Four or five phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle). The relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis. The family of averaged curves are fit simultaneously (using ALLFTT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant among curves. The dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the ED50's for the respective curves. These dose-ratios are then used to construct a Schild plot and the Kb (expressed as ug/kg, iv) determined. The Kb (dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve) is used to compare the relative potency of the antagonists on inhibiting phenylephrine responses for intra-urethral and arterial pressure. The relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure Kb's. Effects of the alpha- 1 antagonists on baseline arterial pressure are also monitored. Comparison of the relative antagonist potency on changes in arterial pressure and intra-urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing intra-urethral pressure is also present in the systemic vasculature. According to this method, one is able to confirm the selectivity of alphala adrenergic receptor antagonists that prevent the increase in intra-urethral pressure to phenylephrine without any activity at the vasculature.

In addition to the compounds specifically exemplified above, the compounds shown below in Tables 1 and 2 are readily prepared by one of ordinary skill in the art by following the teaching described herein. Preparation of the bromides, RBr, are described in European Patent Application EP 0600675-A to Kissei Coφ. (Japan).

TABLE 1

TABLE 2

While the foregoing specification teaches the principles of the present invention, with examples provided for the puφose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula:

wherein

R9 is selected from hydrogen, Cl -4 alkyl, R2(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl -4 alkyl, Cl-4 alkoxy, furanyl, pyridyl, thienyl or aryl;

R2 is selected from NC-, NH2CO-, (R3)2NCO-, R3CONH-, R3C0NMe-, R3-S(0)_mNH- or het;

R3 is selected from hydrogen, Cl -4 alkyl, het or aryl;

R4 and R^ taken together are =0; or

R4 is hydrogen and R^ is hydrogen or hydroxy;

R6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is selected from halogen, Cl-4 alkyl, Cl -4 alkoxy or aryl; 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; or

R8 is selected from hydrogen, Cl-4 alkyl, R¹ l(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl -4 alkyl, Cl-4 alkoxy, furanyl, pyridyl, thienyl or aryl;

R¹1 is selected from cyano, Rl2-S(0)_mNH-,

Rl2(CH2)p-OC(0)NH-, Rl2(CH2)pC(0)NH- or het;

R l2 i selected from hydrogen, het or unsubstituted, mono-, di- or tri- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl or Cl -4 alkoxy;

R l 3 is selected from hydrogen or Cl -4 alkyl;

R ¹⁴ is selected from hydrogen or COCH3;

Rl5 is selected from hydrogen, Nθ2 or CN;

Z is selected from C=0 or CH2;

aryl is unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl -4 alkoxy, pyridyl, thienyl or furanyl;

het is selected from

m is an integer of from zero to two; n is an integer of from zero to four; and p is an integer of from one to two;

provided that R^ and R9 are not simultaneously hydrogen; and

provided further that when R9 is hydrogen, and R^ is

elected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl -4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl -4 alkyl, Cl -4 alkoxy or aryl; or

; and provided further that when R9 is hydrogen, R^ is cyano, and n is two, then R6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; or

and the pharmaceutically acceptable salts thereof.

2. The compound of Claim 1 of the formula:

wherein

R6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or

2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; and

provided that R^ and R9 are not simultaneously hydrogen; and rovided further that when R9 is hydrogen, and R^ is

elected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Ci _4 alkyl,

Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl -4 alkyl, Cl-4 alkoxy or aryl; and

provided further that when R9 is hydrogen, R^ is cyano, and n is two, then R° is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl -4 alkyl, Cl -4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl -4 alkyl, Cι _4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl -4 alkyl, Cl -4 alkoxy or aryl;

and the pharmaceutically acceptable salts thereof.

3. The compound of Claim 2, wherein

R8 is selected from hydrogen, R^l l(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl -4 alkoxy, furanyl, pyridyl, thienyl or aryl; and

R9 is selected from hydrogen or R2(CH2)nS and the pharmaceutically acceptable salts thereof.

4. The compound of Claim 3, of the formula

and the pharmaceutically acceptable salts thereof.

5. The compound of Claim 4, of the formula

and the pharmaceutically acceptable salts thereof.

6. The compound of Claim 3, of the formula

and the pharmaceutically acceptable salts thereof.

7. The compound of Claim 6, of the formula

wherein R6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl or Cl-4 alkoxy; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl or Cl-4 alkoxy; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl or Cl-4 alkoxy; and the pharmaceutically acceptable salts thereof.

8. The compound of Claim 3 selected from

3,4-Dihydro-7-memanesulfonamido-l '-[2-(2-methyl-3- indolyl)ethyllspiro[(2H)-l -benzopyran-2,4'-piperidinel-4-one;

3,4-Dihydro-7-methanesulfonamido-l '-[2-(2- methoxyphenyl)ethyl]spiro[(2H)-l -benzopyran-2,4'-piperidine]-4-one; 3,4-Dihydro-7-methanesulfonamido- 1 '-[2-( 1 -naphthyl)ethyl]spiro[(2H)- l -benzopyran-2,4'-piperidine]-4-one;

3,4-Dihydro-l '-[2-(3-indolyl)ethyl]-7-methanesulfonamidospiro[(2H)-l- benzopyran-2,4'-piperidine]-4-one;

3,4-Dihydro-7-methanesulfonamido-l '-[2-(3- thianaphthyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one; l '-[2-(2-Ethoxyρhenyl)ethyl]-3,4-dihydro-7- methanesulfonamidospiro[(2H)- 1 -benzopyran-2,4'-piperidine]-4-one;

6-Benzyloxycarbonylamido-3,4-dihydro- 1 '-[2-( 1 - naphthyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one; 3,4-Dihydro- 1 '-[2-( 1 -naphthyl)ethyl]-6-phenylsulfonamidospiro[(2H)- 1 - benzopyran-2,4'-piperidine]-4-one;

3 ,4-Dihydro-6-( 1 -methyl-4-imidazolyl)acetamido- 1 '-[2-( 1 - naphthyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one;

3,4-Dihydro-6-(3,5-dimethyl-4-isoxazolyl)sulfonamido- -[2-(l- naphthyl)ethyl]spiro[(2H)-l -benzopyran-2,4'-piperidine]-4-one;

3,4-Dihydro-6-( 1 -methyl-4-imidazolyl)sulfonamido- 1 '-[2-( 1 - naphthyl)ethyl]spiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one;

3,4-Dihydro-6-(l -imidazolylmethyl)- 1 '-[2-(l -naphthyl)ethyl]spiro[(2H)- l -benzopyran-2,4'-piperidine]-4-one; 3,4-Dihydro-l ^*-[2-(l -naphthyl)ethyl]-6-(l ,2,4- triazolylmethyI)spiro[(2H)- 1 -benzopyran-2,4'-piperidine]-4-one; 6-Cyanomethyl-3,4-dihydro- 1 ^*-[2-( 1 -naphthyl)ethyl]spiro[(2H)- 1 - benzopyran-2,4'-piperidine]-4-one or 7-Acetamido-3,4-dihydro-l'-[2-(2-fluorophenyl)ethyI]spiro[(2H)-l- benzopyran-2,4'-piperidine]-4-one; and the pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier.

10. The composition of Claim 9 further comprising a therapeutically effective amount of a testosterone 5 -alpha reductase inhibitor.

11. The composition of Claim 10, wherein the testosterone 5-alpha reductase inhibitor is a type 1 , a type 2, both a type 1 and a type 2 or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor.

12. The composition of Claim 11 , wherein the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor.

13. The composition of Claim 12, wherein the testosterone 5-alpha reductase inhibitor is finasteride.

14. A method of treating benign prostatic hypeφlasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of the formula

wherein

Rl is independently selected from hydrogen, Cl-4 alkyl, R2(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl -4 alkyl, Cl -4 alkoxy, furanyl, pyridyl, thienyl or aryl;

R2 is selected from cyano-, NH2CO-, (R3)2NCO-, R3cONMe-, Rl2(CH2)p-OC(0)NH-, R3(CH2)_mC(0)_pNH-, R3C0NMe-, R3S(0)_mNH- or het;

R is selected from hydrogen, Cl -4 alkyl, het or aryl;

R4 and R5 taken together are =0; or

R4 is hydrogen, and R5 is selected from hydrogen or hydroxy;

R6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl;

2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; or

Rl is selected from hydrogen or Cl-4 alkyl;

Rl4 i_s selected from hydrogen or COCH3;

Rl5 is selected from hydrogen, Nθ2 or CN;

Z is selected from C=0 or CH2;

aryl is unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy, pyridyl, thienyl or furanyl;

het is selected from

m is an integer of from zero to two; n is an integer of from zero to four; and p is an integer of from one to two; q is an integer of from one to four; and the pharmaceutically acceptable salts thereof.

15. The method of Claim 14 wherein the compound has the formula

wherein R6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl -4 alkyl, Cl -4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, Cl-4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy or aryl; and the pharmaceutically acceptable salts thereof.

16. The method of Claim 15, wherein the compound has the formula

wherein each Rl is independently selected from hydrogen, R2(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy, furanyl, pyridyl, thienyl or aryl; and the pharmaceutically acceptable salts thereof.

17. The method of Claim 14, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hypeφlasia.

18. The method of Claim 14, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.

19. The method of Claim 18, wherein the testosterone 5- alpha reductase inhibitor is finasteride.

20. A method of treating benign prostatic hypeφlasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the composition of Claim 9.

21. The method of Claim 20, wherein the composition further comprises a therapeutically effective amount of a testosterone 5 -alpha reductase inhibitor.

22. A method of relaxing urethral smooth muscle in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 14.

23. A method of relaxing urethral smooth muscle in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 15.

24. The method of Claim 23, wherein the compound has the formula

^■(CH₂)_n R^f wherein each R^l is indepently selected from hydrogen, R2(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, Cl-4 alkoxy, furanyl, pyridyl, thienyl or aryl; and the pharmaceutically acceptable salts thereof.

25. The method of Claim 22, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to relax urethral smooth muscle.

26. The method of Claim 22, wherein the compound is administered in combination with a testosterone 5 -alpha reductase inhibitor.

27. The method of Claim 26, wherein the testosterone

5-alpha reductase inhibitor is finasteride.

28. A method of treating a disease which is susceptible to treatment by antagonism of the alpha 1 a receptor which comprises administering to a subject in need thereof an amount of the compound of Claim 14 effective to treat the disease.

29. A pharmaceutical composition made by combining a compound of Claim 1 and a pharmaceutically acceptable carrier.

30. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.

31. The use of the compound of Claim 14 in the preparation of a medicament for the treatment of benign prostatic hypeφlasia in a subject in need thereof.

32. The use of the compound of Claim 14 in the preparation of a medicament for relaxing urethral smooth muscle in a subject in need thereof.

33. A drug which is useful for treating benign prostatic hypeφlasia in a mammal in need thereof, the effective ingredient of the said drug being the compound of Claim 14.

34. A drug which is useful for relaxing urethral smooth muscle in a mammal in need thereof, the effective ingredient of the said drug being the compound of Claim 14.