AU705661B2 - Alpha 1a adrenergic receptor antagonists - Google Patents

Description

Alpha la Adrenergic Receptor Antagonists 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 pharmacologial characterization of these receptors 20 from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into xl, a2, 11, and P2 subtypes. Functional differences between al and a2 receptors have been 00** 0 0 o• [N:\LIBZZ]00121:tab WO 96/39140 PCTIUS96/08672 -2recognized, and compounds which exhibit selective binding between these two subtypes have been developed. Thus, in WO 92/0073, the selective ability of the enantiomer of terazosin to selectively bind to adrenergic receptors of the alpha 1 subtype was reported. The al/a2 selectivity of this compound was disclosed as being significant because agonist stimulation of the U2 receptors was said to inhibit secretion of epinephrine and norepinephrine, while antagonism of the a2 receptor was said to increase secretion of these hormones. Thus, the use of nonselective alpha-adrenergic blockers, such as phenoxybenzamine and phentolamine, is limited by their a2 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 a-adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., a- Adrenoreceptors: Molecular Biology. Biochemistry and Pharmacology, (Progress in Basic and Clinical Pharmacology series. Karger, 1991), wherein the basis of al/a2 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 a-adrenergic receptor affinity was explored.

The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the al receptors into Ula, (Lomasney, et al., J. Biol. Chem., 266:6365-6369 (1991), rat ala; Bruno et al., BBRC, 179:1485-1490 (1991), human ala), aib (Cotecchia, et al., PNAS, 85;7159-7163 (1988), hamster alb; Libert, et al., Science, (1989), dog alb; Ramarao, et al., J. Biol.

Chem., 267:21936-21945 (1992), human alb), and most recently, in a study using bovine brain, a new alc 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 al c adrenergic receptor; Hoehe et al., WO 96/39140 PCT/US96/08672 -3- Human Mol. Genetics 1(5):349 (8/92) noted the existence of a two-allele Pstl restriction fragment polymorphism in the xlc adrenergic receptor gene; another study suggests that there may even be an alpha-I d receptor subtype, see Perez et al., Mol. Pharm., 40:876-883, 1992).

Each al receptor subtype exhibits its own pharmacologic and tissue specificities. Schwinn and coworkers noted that the cloned bovine alc receptor exhibited pharmacological properties proposed for the 1i a subtype. Nonetheless, based on its non-expression in tissues where the c1 a subtype is expressed, and its sensitivity to chloroethylclonidine, the receptor was given a new designation.

The differences in the oc-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 freeflow 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 dihydrotestosterone has been identified as the principal culprit. The continual production of 5oc-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 WO 96/39140 PCT/US96/08672 -4alpha reductase, which converts testosterone into 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 enantiomer of terazosin to bind to adrenergic receptors of the al subtype was reported. In addition, in WO 92/161213, hereby incorporated by reference, combinations of alpha-reductase inhibitory compounds and alpha 1-adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the acla, alb, or al c 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-I 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, 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 WO 96/39140 PCTIUS96/08672 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., 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 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 a 1 c subtype (ATCC CRL 11140) and the use of a screening assay which enables identification of compounds which specifically interact with the human alc 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 I c adrenergic receptor and a method for identifying compounds which bind the human allc receptor has now made possible the identification of selective human a lc adrenergic receptor antagonists useful for treating BPH. The instant patent disclosure discloses novel compounds which selectively WO 96/39140 PCT/US96/08672 -6bind to the human (lc 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 (alc 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 c ic 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-Ic receptor mediated central nervous system events.

NOMENCLATURE

Recently, a new al adrenergic receptor (cal-AR) classification scheme similar to that proposed by Ford, et al. [al- Adrenoceptor Classification: Sharpening Occam's Razor, Trends in Pharm. Sci. 1994, 15, 167-170] was adopted at the August, 1994 meeting of the International Union of Pharmacology (IUPHAR) in Montreal, Canada. The al-AR genes formerly known as ala/d, (Olb and a(lc were renamed ald, aflb and ala, respectively. This new naming system reflects the correspondence between the proteins encoded by the ala and alb genes (new IUPHAR nomenclature) and the receptors characterized by traditional pharmacological means as alA and alB, 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 ala/d, cxlb and alc); however, hereinafter, the new classification scheme will be utilized aid, alb and Cala). Thus, what was formerly referred to as the aclc WO 96/39140 PCTIUS96/08672 -7receptor (and alc receptor antagonists) will hereinafter be referred to utilizing the new nomenclature as the ala receptor (and Ua a receptor antagonists).

SUMMARY OF THE INVETON The present invention provides a method of treating a disease which is susceptible to treatment by antagonism of the alpha I a receptor which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the formula I 4 R R 1 T 1 NN 3 I (CH)n R 6 wherein R1 is independently selected from hydrogen, Cl-4 alkyl, R 2 (CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C1-4 alkyl, Cl-4 alkoxy, furanyl, pyridyl, thienyl or aryl;

R

2 is selected from cyano-, NH2CO-, (R 3 )2NCO-, R 3 CONMe-,

R

1 2 (CH2)p-OC(O)NH-, R 3 (CH2)mC(O)pNH-, R 3 CONMe-,

R

3 S(O)mNH- or het;

R

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

R

4 and R 5 taken together are or

R

4 is hydrogen, and R 5 is selected from hydrogen or hydroxy;

R

6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from WO 96/39140 PCT/US96/08672 halogen, nitro, amino, CI-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, C1-4 alkyl, C1-4 alkoxy or aryl; indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, C -4 alkoxy or aryl; or

R

13 is selected from hydrogen or Cl-4 alkyl; R1 4 is selected from hydrogen or COCH3;

R

15 is selected from hydrogen, N02 or CN; Z is selected from C=O 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

N-N

N

N

Me Me Me

N-NH

N

O-N

H

H

N-NH

oJNI)- >O NMe HNN, N

N

N-O

H

2 N

N

WO 96/39140 PCT/US96/08672 -9- °0-N o I N H 2 NlN, or CO 2 Me 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 4 R R N (CH2) n R6 wherein

R

6 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, C1-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, C1-4 alkyl, CI-4 alkoxy or aryl; or disubstituted 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 4 R R 'R 0 'R O (CH2)n R' WO 96/39140 PCT/US96/08672 wherein each R1 is independently selected from hydrogen, R 2 (CH2)nor unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, CI-4 alkyl, C1-4 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 1 a receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, 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 alpha reductase inhibitor is fminasteride.

More particularly illustrating the invention is a compound of the formula: WO 96/39140 PCT/US96/08672 -11- 8 R 4 R R 9 R 0 N 13 (CH)n R 6 wherein

R

9 is selected from hydrogen, C1-4 alkyl, R 2 (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, CI-4 alkoxy, furanyl, pyridyl, thienyl or aryl;

R

2 is selected from NC-, NH2CO-, (R 3 )2NCO-, R 3

CONH-,

R

3 CONMe-,

R

3 -S(0)mNH- or het;

R

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

R

4 and R 5 taken together are or

R

4 is hydrogen and R 5 is hydrogen or hydroxy;

R

6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C1-4 alkyl, C -4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is selected from halogen, Cl-4 alkyl, C1-4 alkoxy or aryl; indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, CI-4 alkoxy or aryl; or

R

15 R 14 WO 96/39140 PCT/US96/08672 12-

R

8 is selected from hydrogen, Cl-4 alkyl, R 1 I(CH2)n- or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C1-4 alkyl, Cl-4 alkoxy, furanyl, pyridyl, thienyl or aryl;

R

1 I is selected from cyano, R 12 -S(O)mNH-, RI2CONMe-, R 1 2 (CH2)p-OC(O)NH-, R 12 (CH2)pC(O)NH- or het; R 1 2 is selected from hydrogen, het or unsubstituted, mono-, di- or trisubstituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C1-4 alkyl or Cl-4 alkoxy;

R

13 is selected from hydrogen or Cl-4 alkyl;

R

14 is selected from hydrogen or COCH3;

R

15 is selected from hydrogen, N02 or CN; Z is selected from C=O 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 WO 96/39140 PCT/US96/08672 13 02 NM O e N- NH I' Me Me N 0rN N 0J-N N- NH NMe

-NN-

N aH2N or C0 2 Me 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 8 and R 9 are not simultaneously hydrogen; and provided further that when R 9 is hydrogen, and R 8 is

N

N where n is zero or one, then R 6 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, C1-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, Cl-4 alkyl, C1-4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, C1-4 alkyl, Cl-4 alkoxy or aryl; or

N

1

R

15

R

14 and WO 96/39140 PCT/US96/08672 14provided further that when R 9 is hydrogen,

R

8 is cyano, and n is two, then R 6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C1-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, C1-4 alkyl, Cl-4 alkoxy or aryl; or 2 ,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, C1-4 alkyl, C1-4 alkoxy or aryl; or

N

R

15

R

1 4 and the pharmaceutically acceptable salts thereof.

Preferably, the compound is of the formula B 4 R R N (CH2)n

R

6 wherein

R

6 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 indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, Cl-4 alkyl, C -4 alkoxy or aryl; and all other variables are as defined above; provided that R 8 and R 9 are not simultaneously hydrogen; and provided further that when R 9 is hydrogen, and R 8 is WO 96/39140 PCT/US96/08672 15 H 2),N N where n is zero or one, then R 6 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 R 9 is hydrogen, R 8 is cyano, and n is two, then R 6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C1-4 alkyl, Cl-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is halogen, C1-4 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

R

8 is selected from hydrogen, R 11(CH2)n- or unsubstituted, mono-, dior tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, Cl-4 alkyl, C1-4 alkoxy, furanyl, pyridyl, thienyl or aryl; and

R

9 is selected from hydrogen or R 2 (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 WO 96/39140 PCT/US96/08672 16

R

1

(H

2 )4R

R

N.

N (CH2) n R6 where all variables are as defined above; and the pharmaceutically acceptable salts thereof.

Exemplifying the invention is the compound of the formula 0 R 1 1 C H 2 f N

(CH

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

An example of the invention is the compound of the formula 4 R R R2-(CH2)n 0 N (CH2) n

R

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

Further illustrating the invention is the compound of the formula 0 02 1 C CH3 N 0C

H

N'(CH2)n R 6 mw WO 96/39140 PCT/US96/08672 -17 wherein

R

6 is selected from mono-, di- or tni-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, CI..-4 alkyl or CI-4 alkoxy; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substitutent is selected from halogen, C 1 -4 alkyl or Ci 1.4 alkoxy; or 2 ,5 -di substituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, CI-4 alkyl or Ci1 -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- I'-[2-(2-methyl-3indolyl )ethyl] spiro[ I -benzopy ran 2, 41 -pipe ri dine] -4 -one; 3 4 -Dihydro-7-methanesulfonamido. methoxyphenyl )ethyl]spiro I -benzopyran-2 ,4'-piperidine] -4-one; 3 4 -Dihydro-7-methanesulfonamido I I -naphthyl)ethyl]spiro[(2H).

Il-benzopyran-2,4..piperi dine].4-.one; 3 ,4-Dihydro-l'-[ 2 3 -indolyl)ethylp7.. methanesulfonamidospiro[(2H)-I benzopyran-2 4 1 -piperi dine] -4-one; 3 4 -Dihydro-7-methanesulfonamidol thianaphthyl)ethyl] spiro I -benzopyran-2,4 ?iieidine] -4-one; l'-r 2 2 -Ethoxyphenyl)ethyly.3,4.dihydro-7 methanesulfonamidospiro 1 -benzopyran-2,4 '-pipenidine] -4-one; 6 -Benzyloxycarbonylamido-3,4-dihydro. I naphthyl)ethyl] spiro I -benzopy ran -2,4'-piperi dine] -4-one; 3 ,4-Dihydro- 1 I -naphthyl)ethyl] -6-phenyl sulfonamidospiro 1 benzopyran-2 4 9 -piperi dine] -4-one; 3,4-Dihydro-6-( I -methyl-4-imidazolyl)acetamido. I 1naphthyl )ethyl] spiro[(2H)- I -benzopyran-2 4 1 -piperi dine] -4-one; 3 4 -Dihydro-6- (3,5 din.ethyl.4-isox azol yl)sulfonamido- 1naphthyl )ethyl] spiro I -benzopyran-2 49 -piperi dine] -4-one; 3 ,4-Dihydro-6-( I-methyl 4 -imidazolyl)sulfonamido. I 1naphthyl )ethyl] spiro I -benzopyran -2 4 '-pipefi dine] -4-one; WO 96/39140 PCT/US96/08672 18 3,4-Dihydro-6-( 1 -imidazolylmethyl)-1 1 -naphthyl)ethyl]spiro[(2H)l-benzopyran-2,4'-piperidine]-4-one; 3,4-Dihydro- -naphthyl)ethyl]-6-(1,2,4triazolylmethyl)spiro[(2H)- l-benzopyran-2,4'-piperidine]- 4 -one; 6 -Cyanomethyl-3,4-dihydro-l'-[2-(l -naphthyl)ethyl]spiro[(2H)- 1benzopyran-2,4'-piperidine]-4-one or 7 -Acetamido-3,4-dihydro-l'-[ 2 2 -fluorophenyl)ethyl]spiro[(2H) 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 alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 a three component combination comprising any of the compounds described above combined with both a type I testosterone reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type I 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 WO 96/39140 PCT/US96/08672 19relaxing 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 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.

WO 96/39140 PCT/US96/08672 20 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 I a adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alphald and alphalb adrenergic receptor subtypes, and many other Gprotein coupled human receptors. Particular representative compounds of this invention exhibit nanomolar affinity for the human alpha 1 a adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alpha I ld and alpha I lb 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; WO 96/39140 PCT/US96/08672 -21 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 WO 96/39140 PCT/US96/08672 22 invention may form solvates with water 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 methyl, ethyl, I-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 CI-10) 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 7membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from N, 0 or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. 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, WO 96/39140 PCT/US96/08672 23 oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.

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 WO 96/39140 PCT/US96/08672 24 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 incorporated 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.

WO 96/39140 PCT/US96/08672 25 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-dtartaric 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 a la receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the CIl a receptor and membranes from cell lines or tissues known to express other types of alpha aid, Ualb) or beta adrenergic receptors. Expression of the cloned human ald, Xlb, and ala 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 ala adrenergic receptor subtype may be functionally WO 96/39140 PCT/US96/08672 26 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 ala receptor makes them useful for the treatment of BPH. The specificity of binding of compounds showing affinity for the al a 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. W094/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994, each of which is hereby incorporated by reference. The cloned human a la 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, Oclb, and ala 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 c la 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. [See PCT International Application Publication No. W094/10989, published 26 May 1994; U.S. Patent No.

5,403,847, issued April 4, 1995]. Compounds which are both selective amongst the various human alphal adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the B-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 l adrenergic receptors.

WO 96/39140 PCT/US96/08672 27 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 WO 96/39140 PCT/US96/08672 28 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 incorporated 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 WO 96/39140 PCT/US96/08672 29 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 polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyleneoxidepolylysine 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 alpha la 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 WO 96/39140 PCT/US96/08672 30 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 a la 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-x 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 incorporated by reference). In addition to PROSCAR®, which is principally active in prostatic tissue due to its selectivity for human 5-a reductase isozyme 2, combinations of compounds which are specifically active in inhibiting testosterone alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes I and 2, are useful in combination with compounds of this invention. Compounds that are active as 5ox-reductase inhibitors have been described in W093/23420, EP 0572166; WO 93/23050; W093/23038,; W093/23048; W093/23041; W093/23040; W093/23039; W093/23376; W093/23419, EP 0572165; W093/23051, each of which is hereby incorporated 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 WO 96/39140 PCT/US96/08672 31 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 interpreted 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 ala 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 I to about 7 mg per subject to day, most preferably, about 5 mg per subject per day.

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

Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows: WO 96/39140 PCT/US96/08672 32- Ac acetyl Ar aryl Boc or BOC t-butyloxycarbonyl CBZ benzyloxycarbonyl Cbz-CI 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 WO 96/39140 PCT/US96/08672 33 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)-lbenzopyran-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 tbutyloxycarbonyl 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 HCI or trifluoroacetic acid, and extractive workup according to standard procedures affords IV. The piperidine IV is derivatized on N-I' 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.

WO 96/39140 PCTIUS96/08672 34 SCHEME 1 0 Me

OH

37%

CH

2

O

conc. HCI Me Nu, DMF

OH

O 0=7 NBOC

OH

N

H

0 O

SHCI

Nu 0

NBOC

Ar(CH 2 2 Br Nu

NH

Ar 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°C, and treated with crushed ice.

The resultant solid is collected and dried according to standard procedures to provide VI. The spiro[( 2 H)-l-benzopyran-2,4'piperidine]-4-one moiety is formed employing the methodology described above to afford VII. The piperidyl nitrogen is selectively WO 96/39140 PCT/US96/08672 35 liberated by treatment of VII with an acid, such as HCI 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 AcCI, AICI 3 0 O NBOC AcHN

OH

AcHN OH Q

N

VI H 0 HCI O 0 HCI. Ar(CH 2 2

B

r 0 o C rt 0 AcHN AcHN ONH

NBOC

VII

VIII

0 AcHN 0

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 HC1, 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 WO 96/39140 PCT/US96/08672 36 of the piperidine nitrogen (to afford XII) and subsequent alkylation (to afford XIII) are accomplished employing the methodology described above.

SCHEME 3 1- 1. HCI 02 'OH 2. MeSO 2 CI Me

S

'N

H

NBOC

N

H

AcHN 02 Me'S

HCI

NBOC

02 MeS 'N

H

Ar(CH 2 2 Br MeO 2

SHN

Other 7-position derivatives of the instant invention can be prepared according to Scheme 4. Both the acetamide and the tbutyloxycarbonyl group of VII can be removed by treatment with an acid, preferably HC1, 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, WO 96/39140 PCT/US96/08672 37 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 0 0 HCI Ar(CH 2 2 Br I O heat AcHN ONBOC H 2 N NH VII

XIV

RSO

2 CI or

H

2 N 0

RCOCI

N Ar

-R

XV

R'HN 0 R' is RSO 2 XVI or RCO WO 96/39140 PCT/US96/08672 38 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[( 2 H)-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 HC1. 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.

WO 96/39140 PCT/TJS96/08672 39 SCHEME o 0

H

2 N Cbz-Cl CBZHN 0< NBOC OH L OH

N

XVII XVIII H 0 CBZHN

HCI

0

NBOC

XIX

CH CBZHN N H 2 /Pd black CBZHNo Ar(CH2)2Br O0 N Ar NH

XXI

XX

0

H

2 N N

RSO

2 CIor R'HN

.N

RCOCI N

A

N V" Ar R' is RSO 2 XXII or RCO XXIII 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 WO 96/39140 PCT/US96/08672 40 (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 Ar O H

TMSCHN

2 Ar' O Me LiAIH 4 0 0 XXIV XXV AKOH ^BCBr 4 Ar., H CBr4 Ar Br PPh 3 XXVI XXVII Where a carboxylic acid chloride is needed, it is prepared from the corresponding carboxylic acid by standard synthetic WO 96/39140 PCT/US96/08672 -41 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-l 2 -(2-methyl-3indolvl)ethvllspiro[2H)-l -benzopvran-2.4'-piperidineI-4-one Step 1: A suspension of 10 g (66 mmol) 3 -acetamidophenol in 30 mL dichloromethane and 21 mL (240 mmol) 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 mmol) was added portion wise over 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 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 hydroxyphenyl)acetamide as a pale yellow solid.

Step 2: To a solution of 14 g (76 mmol) hydroxyphenyl)acetamide in 250 mL methanol was added 6.3 mL (76 mmol) pyrrolidine and 15.1 g (76 mmol) N-t-butyloxycarbonyl-4piperidone. The reaction mixture was heated on a sand bath to WO 96/39140 PCT/US96/08672 42 (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'-t-butyloxycarbonyl-3,4-dihydrospiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one.

Step 3: To a suspension of 15.2 g (40.6 mmol) of 7acetamido- l'-t-butyloxycarbonyl-3,4-dihydro-[(2H)- I -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 HC1. 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]-4one as a pale yellow solid.

Step 4: To a solution of dihydrochloride salt of 7-amino- 3,4-dihydro-[ l-benzopyran-2,4'-piperidine]-4-one (570 mg, 1.88 mmol) in DMF (5 mL) was added diisopropylethylamine (1.02 mL, 5.83 mmol), and 3 2 -bromoethyl)-2-methylindole (493 mg, 2.07 mmol). 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 Na2SO4 and concentrated under reduced pressure to give 7 -amino-3,4-dihydro-l'-[2-(2-methyl-3indolyl)ethyl]spiro[(2H)- I -benzopyran-2,4'-piperidine]-4-one.

HPLC: retention time 6.55 min WO 96/39140 PCT/US96/08672 43 Step 5: To a solution of 7 -amino -3,4-dihydro- F- methyl-3-indolyl)ethyl] spiro[(2H)-l1-benzopyran-2,4'-piperidine] -4-one (140 mg, 0.37 mmol) 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 mmol). After I 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 NaHCO3 solution (1 x 50 mL), brine (I x 50 mL), and dried over Na2SO4. 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 in chloroform saturated with NH3 to afford 3 4 -dihydro-7-methanesulfonajm 0 j 2 -(2-methyl- 3 -indolyl)ethyl]spiro[(2H). I-benzopy ran -2,4'-pip eri dine] -4-one as a pale yellow solid.

I H NMR HCI salt: (400 MHz, CD3OD) 7.79 J=8.73 Hz, IH), 7.76 J= 7.21 Hz, IH), 7.24 (dd, J=6.88, 1.00 Hz, IH), 7.07 J= 2.02 Hz, I 7.01 (in, 2H), 6.83 (dd, J=8.57, 2.19 Hz, I 3.64 (br d, J= 12.93 Hz, 2H), 3.46 (br d, J= 13.94 Hz, 2H), 3.3 8 (in, 2H), 3.21 (in, 2H), 3.10 3H), 2.84 2H), 2.42 3H), 2.39 J=14.78 Hz, 2H), 2.04 (bt, J= 12.93 Hz, 2H).

Analysis: C25H29N30 4 S, 0.8 H20, 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:mz =468 (M EXAMPLE 2 3 4 -Dihydro-7-methanesufonmid- methoxyphenyl)ethvlispio(H -benzopyran-2,4' 1iprdie4-one Step 1: To a solution of 1.0 g (5.2 inmol) of hydroxyphenyl)acetamide (prepared in above example. Step 1) in mL absolute ethanol was added 25 mL water and 25 mL 1 2N HCI. The reaction mixture was refluxed for 20 h when the volatiles were I I WO 96/39140 PCT/US96/08672 44 removed at reduced pressure and the residue was partitioned between 200 mL dichloromethane and 100 mL saturated NaHCO3 solution. The layers were separated and the aqueous layer extracted with dichloromethane (2 x 50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to provide 1-(4-amino-2hydroxyphenyl)ethanone.

HPLC: retention time 4.25 min, purity 100% Step 2: A solution of 1-( 4 -amino-2-hydroxyphenyl)ethanone (2.0 g, 10 mmol) 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 mmol). 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 HC1. 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 Na2SO4. The volatiles were removed under reduced pressure and the resulting solid was triturated and filtered from dichloromethane to afford N-(4-acetylas a purple solid.

HPLC: retention time 5.23 min FAB MS: m/z 230 (M H+) Step 3: To a solution of N-( 4 methanesulfonamide (1.4 g, 6.2 mmol) in 15 mL methanol was added pyrrolidine (0.52 mL, 6.2 mmol) and a solution of N-t-butyloxycarbonyl-4-piperidone (1.2 g, 6.2 mmol) 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 NaHCO3 solution.

The organic layer was washed with saturated NaHCO3 solution (2 x mL), with brine (1 x 50 mL), dried over Na2SO4 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 l'-t-butyloxycarbonyl-3,4-dihydro-7-methanesulfonamidospiro[(2H)-l-benzopyran-2,4'-piperidine]-4-one as a white solid.

M WO 96/39140 PCTIUS96/08672 45 HPLC: retention time 8.25 mlin FAB MS: m/z =411 (M Step 4: 1 t -t-Butyloxycarbonyl -3 4 -dihydro-7-methane.

sulfonamidospiro I -benzopyran -2,4'-piperi dine] 4.one (1.95 g, 4.8 mmol) was dissolved in 25 mL. isopropanol and 12 rnL 8N HCI 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-methanesu lfonamidospiro[ I1benzopyran-2,4'-piperi dine] 4-one.

FABMNS: mz=311l(M Step 5: To a solution of the hydrochloride salt of 3,4dihydro-7-methanesufonmidospiro[(2H)- I -benzopyran-2,4'piperi dine] -4-one (100 mg, 0.29 mmol) in DMF (2 miL) was added Li2C03 (47 mg, 0.64 mmol), KI catalytic amount), and 2-(2bromoethyl)methoxybenzene (75 mg, 0.35 mmol). 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 dichioromethane and 25 mL saturated NaHCO3 solution. The organic layer was washed with brine (I x 25 mE), dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was purified by pressurized silica gel chromatography, using a gradient elution of 1-4% methanol in dichioromethane containing 0.5% concentrated ammonium hydroxide to obtain 3 4 -dihydro-7-methanesulfonamido. methoxyphenyl)ethyl] spiro [(2H I -benzopyran-2 ,4'-piperi dine] -4-one.

Analysis: C23H28N205S, 1.7 H20: 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 EXAMPLE 3 3 4 -Dihydro-7-methanesulfonamido- I '-[2-(2-methyl-3indolvi )ethyl1liro[V2H).. I-benzolvrain-24'-Diperi dineI 4-one WO 96/39140 PCT/US96/08672 46 The compound of EXAMPLE I was also prepared according to the process described in Example 2 by substituting 3-(2bromoethyl) 2 -methylindole for 2 2 -bromoethyl)metho xybenzene 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- I I -naphthyl)ethyl]spiro[(2H)- 1 -benzonyran-24'pDiperi dine 4-on Following the procedure of EXAMPLE 2, but substituting

I-(

2 -bromoethyl)naphthalene for 2 2 -bromoethyl)methoxybenzene in Step 5, the title compound was obtained.

1 H NMR HCJ salt: (400 MHz, CD3 OD) 8.12 (br d, J= 8.22 Hz, I H), 7.92 (br d, J= 7.22 Hz, IH), 7.84 (br d, J= 7.21 Hz, IH), 7.80

J=

8.56 Hz, IH). 7.62 (bt, J= 6.89 Hz. IH) 7.52 (in, 3H), 7.08 (bs, 1H), 6.8 3 (dd, J= 8.73, 2.02 Hz, I 3.68 (in, 2H), 3.52 (in, 6H), 3. 10 (s, 3H), 2.86 (bs, 2H), 2.42 (in, 2H), 2.08 (in, 2H).

Analysis: C26H28N20 4 S HCI 1.00 H20: 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 mini, purity 96% FAB MS: m/z =465 (M EXAMPLE 3,4-Dihydro-l'[-3inoyIthl--etaeufoaio1io(Hbenzopyran -2.4'-ipe dine I -4-.one Following the procedure of EXAMPLE 2, but substituting 3-(2bromoethyl)indole for 2 2 -bromoethyl)inethoxybenzene in Example 2, Step 5, the title compound was obtained.

I H NMR (400 MHz. CDCI3) 8.02 (bs, I 7.84 1= 8.56, 1H), 7.62 J= 7.55 Hz, IlH), 7.37 J= 8.06 Hz, I 7.20 J= 7.22 Hz, I H), WO 96/39140 1PCT/US96/08672 47 7.12 J=7.89 Hz, I 7.05 1= 1.68 Hz, I 6.88 J=2.18 Hz, IH), 6.69 (dd, J= 8.56, 2.18 Hz, IH), 3.14 3H), 2.99 (bt, J= 7.56 Hz, 2H), 2.79 (in, 4H), 2.71 2H), 2.55 (bt, J= 11.42 Hz, 2H), 2.08 J= 13.09 Hz, 2H), 1. 81 (dt, J= 14.27, 3.69 Hz, 2H).

Analysis: C24H27N30 4 S 1.0 H20. caic: 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 CH2CI2:MeOH:NH 4

OH)

HPLC: retention time 6.36 min, purity 96% FAB MS: m/z =454 (M EXAMPLE 6 3 ,4-Dihydro-7 -methanesulfonami do-I thianaphthvl)ethyl] spiro.L(2H)- I-benzOpvran-2,4'-.pimeridinep-4- 0 n 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 1 H NMR HCI salt (400 MHz, CD3OD) 7.91 (dt, J= 7.89, 0.85 Hz, 2H), 7. 80 J= 8.56 Hz, I 7.49 I1H), 7.47 (dd, J= 7.05, 1.01 Hz, I1H), 7.43 (dd, J= 8.40, 1 .35 Hz. 1 H) 7.39 (br d, 1= 7.06 Hz, I 7.09 (bs, IH), 6.83 (dd, J= 8.56, 2.01 Hz, IH). 3.63 (in, 4H), 3.88 (in, 4H), 3.11 3H), 2.89 2H), 2.41 (br d, J=14.61 Hz, 2H), 2.11 (in, 2H).

Analysis: C24H26N20 4

S

2 HCI 0.65 H20.- caic: 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 CHCI3:MeOH:NJI 4

OH)

HPLC: retention time 7.32 min, purity 97% FAB MS: m/z =471 (M EXAMPLE 7

I'A[

2 2 -Ethoxyphenyl)ethyll-3,4-dhydr.7methanesulfonaiidoSpiro I -benizopvran-?. -ieidn n WO 96/391 40 PCTIUS96/08672 48 The title compound was prepared according to the procedure of EXAMPLE 2 by substituting 2 2 -bromoethyl)ethoxybenzene for 2 2 -bromoethyl)methoxybenzene in Step IH NMR HCI salt (400 MHz, CD3OD) 7.80 J= 8.56 HZ, IH), 7.26 (in, 2H), 7.06 J=1.85 Hz, IH), 6.98 8.05 Hz, IH), 6.92 (dt, J= 7.3 9 Hz, I 6.8 3 (dd, J= 8.57, 2.02 Hz, I 4.12 J=7.05 Hz, 2H), 3.61 (br d, J=13.09 Hz, 2H), 3.37 (in, 4H), 3.1 1 5H), 2.83 2H), 2.3 8 (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: C24H30N20 5 S HCl 1.9 H20. caic: C 54.46, Fl 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: mlz= 459 (M EXAMPLE 8 6 -Benzyloxycarbonylamido..3,4-.dhydro- I-112-(l naphthvl)ethvllspiror(2H)- I-benzopvyran-2,4'...ipridinel4one 1 -Amin o-2 -hydrox yphenyl )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 I -(5-amnino-2-hydroxyphenyl)> ethanone hydrochloride (1.5 g, 8.0 mmol) in 50 mL dichioromethane was treated with 50 mL saturated Na2CO3 and cooled on an ice-water bath when benzyl chloroformate (1.1 mL, 8.0 inmol) was added. The reaction mixture was stirred in the ice-water bath for 3 h when it was diluted with 50 mL dichioromethane and 50 mL water and the layers separated. The organic layer was then washed with water (1 x 50 mL), brine (I x 50 mL) and dried over sodium sulfate. The volatiles were removed under reduced pressure and I -(5-benzyloxycarbonylamido..2.

hydroxyphenyl)ethanone was obtained as a yellow solid.

WO 96/39140 PCT/US96/08672 49 HPLC: retention time 9.14 min, purity FAB MS: m/z 286 (M H+) Step 2: To a solution of 1-(5-benzyloxycarbonylamido-2hydroxyphenyl)ethanone (2.2 g, 7.5 mmol) in 50 mL methanol was added pyrrolidine (0.63 mL, 7.5 mmol) and a solution of N-t-butyloxycarbonyl-4-piperidone (1.5 g, 7.5 mmol) 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 NaHCO3 solution (100 mL). The organic layer was washed with saturated NaHCO3 solution (2 x 50 mL) and brine (1 x 50 mL), dried over Na2SO4 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'-tbutyloxycarbonyl-3,4-dihydrospiro[(2H)- I -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'-tbutyloxycarbonyl-3, 4 -dihydrospiro[(2H)- I -benzopyran-2,4'-piperidine]- 4-one (1.0 g, 2.1 mmol) 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 NaHCO3 solution (100 mL). The organic layer was washed with additional saturated NaHCO3 (2 x 50 mL), brine (1 x 50 mL) and dried over Na2SO4. Concentration under reduced pressure gave 6 -benzyloxycarbonylamido-3,4-dihydrospiro[(2H)- -benzopyran-2,4'-piperidine]-4-one as a yellow solid.

HPLC: retention time 6.77 min WO 96/39140 PCTIUS96/08672 50 Step 4: To a solution of 6 -benzyloxycarbonylamido-3,4dihydrospiro[(2H). I-benzopyran-2,4'-piperidine1 -4-one (0.62 g, 1.7 mmol) in DMF (10 mL) was added Li2CO3 (0.15 g, 2.0 mmol) KI (catalytic amount), and I 2 -bromoethyl)naphthalene (0.48 g, nimol). 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 NaHCO3 solution (50 mL). The organic layer was washed with additional saturated NaHCO3 solution (50 mL), brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was purified by pressurized silica gel chromatography, using a gradient elution of 1-5% methanol in dichioromethane containing concentrated ammonium hydroxide to obtain 6 -benzyloxycarbonyl.

amido-3,4-dihydro. I I -naphthyl)ethyl]spiro[(2H). I -benzopyran- 2 4 9 -piperi dine] -4 -one.

I H NMR (400 MHz, CDC13) 8.04 J= 7.39 Hz, IH), 7.85 (dd, J= 7.89, 1.51 Hz, IH), 7.72 J= 8.05 Hz, 2H), 7.67 J= 2.69 Hz, JH), 7.54- 7.45 (in, 2H), 7.42-7.31 (in, 6H), 6.98 J= 8.90 Hz, IH), 6.92 (in, 1H), 3.31- 3.27 (in, 2H), 2.94 2H), 2.87 2H), 2.76 (in, 4H), 2.55 J=9.91 Hz, 2H), 2.09 J=12.76 Hz, 2H), 1.79 (dt, J= 14.61, 4.37 Hz, 2H).

Analysis: C33H32N20 4 HCI, 0.8 H20. caic: 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 CH2CI2:MeOH:NH4OH) HPLC: retention time 9.15 min, purity 96% FAB MS:m/z =521 (M EXAMPLE 9 3 ,4-Dihydro-lI'-[2-( 1-naphthyl)ethyl] 6 -phenylsulfonamidospiro 1benzopvran-2.4'-nipe ridine 1 -4 -one Step 1: To a solution of 6 -benzyloxycarbonylamido.3,4dibydro-l1'-[2-( I-naphthyl)ethyl] spiro[(2H)-l1-benizopyran-2,4'- WO 96/39140 PCTIUS96/08672 -51 piperidine]-4-one (0.47 g, 0.89 mmol) in ethanol (50 mL) was added 12N HCI (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 6amino-3,4-dihydro- -naphthyl)ethyl] -spiro I -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- -naphthyl)ethyl]spiro[(2H)-l-benzopyran-2,4'piperidine]-4-one (0.10 g, 0.22 mmol) 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 mmol) was added. After I 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)- I -benzopyran- 2 ,4'-piperidine]- 4 -one.

IH NMR (400 MHz, CD30D) 8.11 J=8.06 Hz, 1H), 7.92 J= 7.55 Hz, 1H), 7.83 (dd, J=6.88, 1.67 Hz, 1H), 7.75 IH), 7.73 1H), 7.62- 7.43 8H), 7.36 (dd, J= 8.90, 2.69 Hz, 1H), 7.05 J=8.90 Hz, IH), 3.59-3.40 8H), 2.86 (bs, 2H), 2.31 2H), 2.17 2H).

Analysis: C31H30N20 4 S HCI 1.85 H20. 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 3,4-Dihydro-6-( 1 -methyl-4-imidazolyl)acetamido- 1 naphthvl)ethyvlspiro[(2H) l-benzopvran-2,4'-piperidine]-4-one WO 96/39140 PCTIUS96/08672 52 The title compound was prepared according to the procedure of EXAMPLE 9 by substituting 1 -methyl-4-imidazoleacetyl chloride for benzenesulfonyl chloride in Step 2.

1 H NMR (400 MHz, CD3OD) 8.84 I 8. 16 J= 8.40 Hz, I H), 8.09 J=2.68 Hz, 1H), 7.92 8.05 Hz, IH), 7.83 J= 7.89 Hz, IH), 7.77 (dd, J= 8.89, 2.68 Hz, IH), 7.61 (dt, J=6.89, 1.34 Hz, 1H), 7.54 J=8.06 Hz, I1H), 7.5 1-7.44 (in, 2H), 7.23- 7.10 (mn, 4H), 3.93 (s, 3H), 3.91 2H), 3.74- 3.43 (mn, 8H), 2.90 2H), 2.39 (mn, 2H), 2.14 (bt, J=1 1.75 Hz, 2H).

Analysis: C3 IH32N40 3 2 HCI, 1.2 H20 0.45 EtOAc. caic: 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% FABMNS:m/z =509 (M EXAMPLE I1 3 4 -Dihydro-6(3,5dimethyl4isoxazolyl)sulfonaiido- 1naphthv )ehsIro I -benzopvran-2,4:ppe dne4.one The title compound was prepared according to the procedure of EXAMPLE 9 by substituting 3 ,5-dimethylisoxazole-4sulfonyl chloride for benzenesulfonyl chloride in Step 2.

1 H NMR (400 MHz, CDCI3) 8.12 J=8.23 Hz, I 7.92 J= 8.06 Hz, I 7.83 (dd, J=7.22, 1.85 Hz, I 7.61 (in, I 7.54 (in, 3H), 7.48 J=8.89 Hz, IH), 7.37 (dd, J= 8.90, 2.86 Hz, 111), 7.14 (d, J=8.89 H-z, I 3.52 (mn, 7H), 2.91 2H), 2.78 (in, I 2.47 3H), 2.34 (in, 2H). 2.24 I 2.11 (in, 2H).

Analysis: C30H31IN30 5 S HCI 0.85 H20. caic: C 60.3 1, H 5.69, N 7.03. found: C 60.35, H 5.56, N 6.92.

HPLC: retention time 8.59 inin, purity 96% FABMNS:nijz =546 (M WO 96/39140 PCT/US96/08672 53 EXAMPLE 12 3,4-Dihydro-6-( 1-methyl- 4 -imidazolyl)sulfonamido-l 1naphthyl)ethvylspirof(2H)-l-benzopvran-2,4'-piperidine1-4-one The title compound was prepared according to the procedure of EXAMPLE 9 by substituting I-methyl-4imidazolesulfonyl chloride for benzenesulfonyl chloride in Step 2.

IH NMR (400 MHz, CD30D) 8.22 1H), 8.15 J= 8.39 Hz, 1H), 7.91 J= 8.06 Hz, 1H), 7.83 J= 8.90 Hz, 2H), 7.52 6H) 7.12 J 12.90 Hz, 2H), 3.79 3H). 3.64 4H), 3.47 4H), 2.87 (s, 2H), 2.35 (bt, J=l 1.25 Hz, 2H), 2.11 (bt, J=l 1.76 Hz, 2H).

Analysis: C29H30N40 4 S 2 HCI 1.5 H20. 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 FAB MS: m/z 531 (M H+) EXAMPLE 13 3,4-Dihydro-6-(l -imidazolylmethyl)- -naphthyl)ethyl]spiro[(2H)- 1 -benzopyran-2.4'-piperidine1-4-one Step 1: 1-(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 mmol) 2 -hydroxyphenyl)ethanone in DMF at room temperature was added 3.45 g (33 immol) anhydrous sodium carbonate followed by 1.2 g (18 mmol) 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 MgSO4, 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 WO 96/39140 PCTIUS96/08672 54 containing 0.5% concentrated ammonium hydroxide to obtain hydroxy-5-(1-imidazolylmethyl)phenyl]ethanone as a pale yellow solid.

HPLC: retention time 2.95 min Step 3: A solution of 2.6 g (12 mmol) 1-[(2-hydroxy-5-(1imidazolylmethyl)phenyl]ethanone in 30 mL methanol was treated with mL (12 mmol) pyrrolidine followed by 2.4 g (12 mmol) N-tbutyloxycarbonyl-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 l'-t-butyloxycarbonyl-3,4-dihydro-6-(1 -imidazolylmethyl)spiro[( 2 H)-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 mmol) l'-t-butyloxycarbonyl-3,4-dihydro-6-(l -imidazolylmethyl)spiro[(2H)- I -benzopyran- 2 4 '-piperidine]-4-one in 100 mL was treated with 90 mL 8N HCI 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 NaHCO3 solution. The layers were separated, the aqueous layer extracted with an additional 100 mL dichloromethane, the organic layers combined, dried over MgSO4, filtered and concentrated under reduced pressure to provide 3,4-dihydro-6-(l-imidazolylmethyl)-spiro[(2H)- -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 mmol) of 3,4dihydro-6-( -imidazolylmethyl)spiro[(2H)-1-benzopyran-2,4'piperidine]-4-one and 0.18 mL (1.0 mmol) diisopropylethylamine in mL dry DMF was added 174 mg (0.7 mmol) 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 mL dichloromethane, washed with saturated aqueous NaHCO3 (1 x mL), dried over MgSO4 and concentrated at reduced pressure. The oil WO 96/39140 PCTIUS96/08672 55 was purified by pressurized silica gel chromatography using an eluent of 3% methanol in dichioromethane containing 0.5% concentrated and then the HCI salt prepared and triturated with diethyl ether from methanol to provide the dihydrochloride salt of 3,4-dihydro-6-(1umdazolylmethyl)- I 1 -naphthyl)ethyljspiro[(2H). I -benzopyran- 2 4 1 -p iperi dine]I-4-one as an off-white solid.

Analysis:

C

29

H

29

N

3 0 9 2HCl; 2.35 H 2 0, caic: C 61.45, H 6.35, N 7.41.

found: C 61.45, H 5.99, IN 7.52.

HPLC: retention time 6.24 min, purity 99% FAB MS: m/z 452 (M H+) EXAMPLE 14 3,4-Dihydro- I I -naphthyl)ethyl]-6-( 1,2,4triaZollmethvl)spiro[(2H)- I -benzopvran-2,4'-piperidinel4one Following the procedure of EXAMPLE 13, but substituting I ,2,4-triazole for imidazole in Step 2, the title compound was obtained.

Analysis: C 2 8

H

28

N

4 0 2 3HCI; 0.35 H 2 0, caic: C 59.18. H- 5.62, N 9.86.

found: C 59.19, H5.65, N 9.81.

HPLC: retention time 6.9 min, purity 94% FAB MIS: m/z =453 (M H+) EXAMPLE 6 -Cyanomethyl-3,4-dihydro- I 1 -naphthyl)ethyllspiro[(2H)- I benzopyran-2 .4'-p2iperi dine I -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:

C

2 7

H-

2 4N 2 0 2 HCl; 0.7 H 2 0, caic: C 70.56. H 6.23, N 6. found: C 70.62, H 6.26, N 6.20.

HPLC: purity WO 96/39140 PCT/US96/08672 56 EXAMPLE 16 7 -Acetamido-3,4-dihydro- 2 2 -fluorophenyl)ethyl]spiro[(2H)-1benzopyran-2,4'-piperidine-4-one Step 1: A suspension of 7-acetamido-l'-tbutyloxycarbonyl-3, 4 -dihydrospiro -benzopyran-2,4'-piperidine]- 4 -one (4.3 g, 11.5 mmol)(prepared as shown n Example 1, Steps 1 2) in 200 mL ethyl acetate was cooled on an ice-water bath and HCI (g) bubbled through the suspension via a glass pipet for 10 min. The icewater bath was removed and the suspension stirred at room temperature I h when the volatiles were removed at reduced pressure and 7acetamido-3,4-dihydrospiro[(2H)- -benzopyran-2,4'-piperidine]-4-one obtained as a white powder.

Step 2: To a solution of 200 mg (0.6 mmol) of 7acetamido-3, 4 -dihydrospiro[(2H)- I -benzopyran-2,4'-piperidine]-4-one and 0.28 mL (1.6 mmol) diisopropylethylamine in 5 mL dry DMF was added 170 mg (0.8 mmol) 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 NaHCO3 (1 x mL). The aqueous layer was extracted with dichloromethane (3 x mL) and the combined organic layers dried over MgSO4 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 NH40H and then the HCI 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)-. -benzopyran-2,4'-piperidine]-4one as an off-white solid.

Analysis:

C

23

H

25

N

2 0 3 F HCI; 0.75 H 2 0, 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% WO 96/39140 PCTIUS96/08672 -57 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 mmol) of 2-methyl-3indole acetic acid in 3:1 methanol:chloroform (50 mL) was added a 2.0M solution of (trimethylsilyl)diazomethane in hexanes (2.7 mL, 5.4 mmol) and the mixture stirred at room temperature for I 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 mmol) of methyl 2methyl-3-indoleacetate in diethyl ether (50 mL) was added a 1 M solution of lithium aluminum hydride in tetrahydrofuran (13 mL, 13 mmol) 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 Na2SO4, filtered and concentrated to provide 3-(2hydroxyethyl)-2-methylindole.

Step 3: A solution of 3 2 -hydroxyethyl)-2-methylindole (0.92 g, 5.3, mmol) in dichloromethane (50 mL) was treated with carbon tetrabromide (2.3 g, 6.8 mmol) and cooled on an ice-water bath.

Triphenylphosphine (1.8 g, 6.8 mmol) 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 -bromoethvi)methoxybenzene -0000 WO 96/39140 PCT/US96/08672 -58 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 -42-bromoethyl naphthalene l-( 2 -bromoethyl)naphthalene was prepared according to EXAMPLE 17, Step 3 using 1-naphthaleneethanol instead of 3-(2hydroxyethyl)-2-methylindole.

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

EXAMPLE 21 2 -(2-bromoethyl)ethox vbenzene: Step 1: A solution of methyl 2 -hydroxyphenylacetate g, 6.0 mmol) in acetone. (30 mL) was treated with ethyl iodide (4.7 mL, mmol) and potassium carbonate (4.5 g, 33 mmol), 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 Na2SO4, filtered, concentrated and the resultant oil was purified by pressurized silica gel chromatography using a gradient of WO 96/39140 PCT/US96/08672 -59 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-bromoethyl)fluorobenzene 2 -(2-bromoethyl)fluorobenzene was prepared according to EXAMPLE 17, Step 3 using 2 -fluorophenethyl alcohol instead of 3-(2hydroxyethyl)- 2 -methylindole.

EXAMPLE 23 1 -Methyl-4-imidazoleacetyl chloride: Step 1: To a suspension of the hydrochloride salt of 1methyl-4-imidazole acetic acid (120 mg, 0.66 mmol) 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 I is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.

WO 96/39140 PCT/US96/08672 60 EXAMPLE Screening assay: Alpha la Adrenergic Receptor Binding Membranes prepared from the stably transfected human ala cell line (ATCC CRL 11140) were used to identify compounds that bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume 200 gl) contained 50 mM Tris-HCI pH. 7.4, 5 mM EDTA, 150 mM NaCI, 100 pM [125 I]-HEAT, membranes prepared from the ala 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 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 a ld and alb cell lines (ATCC CRL 11138 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 gl) contained 50 mM Tris-HCI pH. 7.4, 5 mM EDTA, 150 mM NaC1, 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).

WO 96/39140 PCT/US96/08672 -61 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 (10mM Tris-HCl/5mM Mg, pH Pellets obtained after centrifuging these membranes (15' at 24,450 rpm) are resuspended in Tris-HCI pH 7.4 containing EDTA, MgCI[2], KC1, NaC1, CaCI[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 gg membranes in a total volume of 500 gL containing 0.2 nM 3 H]-spiperone. Non-specific binding is defined using 10 4M apomorphine. 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-HCI pH 7.4.

2. Assay Title: Serotonin Objective of the Assay The objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTI a receptor Method: Modified from Schelegel and Peroutka Biochemical Pharmacology 35: 1943-1949 (1986).

WO 96/39140 PCT/US96/08672 62 Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCI 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at 100OXg for 30', and then the supernatant is centrifuged again at 38,00OXg 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 Img/mL ascorbate. Non-specific binding is defined using 10 [iM 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, 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 hyperplasia are also stored overnight in ice-cold Krebs solution if needed.

The tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCI, 118 mM; KCI, 4.7 mM; CaCI2, 2.5 mM; KH2PO 4 1.2 mM; MgSO4, 1.2 mM; NaHCO3, 2.0 mM; dextrose, 11 mM] warmed to 37°C. Excess lipid material and connective tissue are WO 96/39140 PCT/US96/08672 63 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 0 C, bubbled with 5% C02/95% 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 giM (for rat), 10 p[M (for dog) and 20 pM (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.

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 x-1 where x is the ratio of EC50 of agonist in the presence and absence of antagonist and is the antagonist concentration.

2. Measurement of Intra-Urethral Pressure in Anesthetized Dogs PURPOSE: Benign prostatic hyperplasia 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 WO 96/39140 PCTIUS96/08672 64 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-I 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 -1/2 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 WO 96/39140 PCT/US96/08672 65 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 ALLFIT 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 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 alphal a 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 I 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 Corp. (Japan).

WO 96/39140 PCTIUS96/08672 66 AcHI 0 1. HO! 2. RBr IR"COCI or

R"SO

2

CI

NBOC

ViI 0 RBr isy B r I 0

'RHN-

A' is R"00 or R"S0 2 0 B r

H

B r 0

H

'N2H Br

N

CNH

CNN0/- WO 96/39140 PCTIUS96IOS672 67 TABLE 1 0

CH

3

SO

2 H- 0

N-,R

R is N 0 CH N

CH

3

K

H

0

CH

3 K

NY

H

0

CH

3 K-o N CH

NN

C H 3 K-N

CH

3 K

N

CN 0CN H WO 96/39140 PCT/US96/08672 68 TABLE 2

O

CH

3 C-H 0 o o

N-R

R is CH N

OH

3

C

H

OH

3 K -N

CH

3

N

oH

NO

2 0 NO 2 CH3 loo N

CH

3

N

CO H 0 CN While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose 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 (35)

1. A compound which is of formula: R4 N "(CH2)nR6 or of formula: R4 R2-(CH2)n O N. (CH 2 )nR 6 wherein R 2 is selected from NC-, NH 2 CO-, (R 3 2 NCO-, R 3 CONH-, R 3 CONMe-, R 3 -S(O)mNH- or het; R 3 is selected from hydrogen, C 1 4 alkyl, het or aryl; lo R 4 and R 5 taken together are O0; or R 4 is hydrogen and R 5 is hydrogen or hydroxy; R 6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, :C1-4 alkyl, C1- 4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2- substituted indolyl where the substituent is selected from halogen, C 1 4 alkyl, C 1 -4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, C 1 4 alkyl, C 1 4 alkoxy or aryl; R 11 is selected from cyano, R 12 -S(0)mNH-, R 12 CONMe-, R1 2 (CH 2 )p-OC(0)NH-, R1 2 (CH 2 )pC(0)NH- or het; 20 R 12 is selected from het or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C1-4 alkyl or C 1 4 alkoxy; aryl is unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C1-4 alkyl, C 1 4 alkoxy, pyridyl, thienyl or furanyl; het is selected from [N:\LIBZZ]00121 :tab Me N/ 02 N-NH N N- N N) Me Me N O-N H 0 O N-NH O-NMe N-O0 H 0 N NN H 2 N N N S H 2 NS C N o S CO 2 Me or 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 when R 11 (CH 2 n is (CH 2 )n.N S. S N where n is zero or one, then R 6 is selected from mono-, di-, or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C 1 4 alkyl, C1-4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl;

2-substituted indolyl where the substituent is halogen, C 1 4 alkyl, CI 1 4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, C 1 -4 alkyl, C 1 4 alkoxy or aryl; and provided further that when R 1 l(CH 2 )n is cyano and (CH 2 )nR 6 is (CH 2 2 R 6 then R 6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C 1 4 alkyl, C 1 4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the 2° substituent is halogen, C 1 4 alkyl, C 1 4 alkoxy or aryl; or 2,5-disubstituted indolyl where 20 the substituents are independently selected from hydrogen, halogen, nitro, amino, C 1 -4 alkyl, C 1 4 alkoxy or aryl; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R 4 and R 5 taken together are =0; R 6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C 1 -4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl [N:\LIBZZ]00121:tab where the substituent is selected from halogen, C 1 4 alkyl, C 1 4 alkoxy or aryl; or disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, CI- 4 alkyl, C 1 4 alkoxy or aryl; provided that when R 11 (CH 2 n is (CH2)n- N N where n is zero or one, then R 6 is selected from naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substituent is halogen, C 1 -4 alkyl, C 1 4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, C 1 4 alkyl, C 1 4 alkoxy or aryl; and provided further that when R 11 (CH 2 )n is cyano and (CH 2 )nR 6 is (CH 2 2 R 6 then R 6 is selected from naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substituent is halogen, C 1 4 alkyl, C 1 4 alkoxy or aryl; or disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, C 1 4 alkyl, C 1 4 alkoxy or aryl; 15 or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein R 2 is selected from R 3 CONH- or R 3 -S(O) 2 NH-; R 3 is selected from hydrogen or C 1 4 alkyl; °R 6 is selected from mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen or C 1 4 alkoxy; naphthyl; thianaphthenyl; indolyl; or 2-substituted indolyl where the substituent is selected from halogen, C 1 4 alkyl, or C1-4 alkoxy; R 11 is selected from cyano, R12-S(O) 2 NH-, R 12 (CH 2 )p-OC(O)NH-, R1 2 (CH2)pC(O)NH- or het; R 12 is selected from het or unsubstituted phenyl; and Shet is selected from Me N/ N O N N-N N N N Me Me or provided that when R 11 (CH 2 )n is (CH2)n\, N [N:\LII3ZZ]00121 :tab where n is zero or one, then R 6 is selected from naphthyl; thianaphthenyl; indolyl; or 2-substituted indolyl where the substituent is halogen, C1-4 alkyl, or C 1 -4 alkoxy; and provided further that when R 11 (CH 2 )n is cyano and (CH 2 )nR 6 is (CH 2 2 R 6 then R 6 is selected from naphthyl; thianaphthenyl; indolyl; or 2-substituted indolyl where the substituent is halogen, C 1 4 alkyl, or C 1 4 alkoxy; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, of the formula R 4 >"CH 2 )nR6 or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4, of the formula S. S Ce. See. 0* 5. 0 0**g 0 5*55e5 C S. S *SS* RI 1 -(CH2)n, OSee S 0 5* 0* 5* p or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, of the formula S. S 55 S. 0 6555 S. S 0e N (CH2)nR6 or a pharmaceutically acceptable salt thereof. [N:\LIBZZ]00121:tab

7. The compound of claim 6, of the formula S0 N"(CH2)nR 6 wherein R 6 is selected from mono-, di- or tni-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C 1 -4 alkyl or CI- 4 alkoxy; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2-substituted indolyl where the substituent is halogen, CI- 4 alkyl or C 1 4 alkoxy; or 2 indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, C 1 4 alkyl or C 1 4 alkoxy; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 3 selected from 3 4 -Dihydro-7-methanesulfonamido-1 2 -(2-methyl-3 -indolyl)ethyljspiro[(2H) S. benzopyran-2 ,4 '-piperidine] -4-one; 3,4Dhyr--mtae1loamd-'-[ 2 2 -methoxyphenyl)ethyllspiro[(2H) benzopyran-2,4'-piperidine]-4oe; 3,4Dhyr--mtaeslo1m-' -naphthyl)ethyl] spiro [(2H)-l1-benzopyran-2 ,4 piperidinel-4-one; 3 ,4-Dihydro-l1'-[ 2 3 -indolyl)ethyl]-7-methanesulfonamidosp iro[(2H) 1 -benzopyran-2 piperidine]-4-one; 3,4Dhyr-7mtan1lfnmio -thianaphthyl)ethyll spiro [(2H)-l1-benzopyran- 2 4 '-piperidine]-4-one; 1-[ 2 2 -Ethoxyphenyl)ethyl]y3,4dhdr--ehaeufn1 opro(H--benzopyran- 2,4 '-piperidine]oe 6 -Benzyloxycarbonylamido-3 ,4-dihydro-l1'-[2-(l1-naphthyl)ethyl]spiro[(2H> 1 -benzopyran- 2,4'-piperidine] -4-one; 3, 4-Dihydro- l-naphthyl)ethyl] -6-phenyl sulfonamidospiro(211) 1 -benzopyran-2 ~Opiperidine] -4-one; 3,4-Dihydr-6-( -methyl-4-imidazolyl)acetamid 0 1 -naphthyl)ethyl] spiro[(2H-)- 1- benzopyran-2 ,4 iperidinel -4-one; 3 ,4-Dihydro-6-(3 ,5-iety--ioa1?lsufnmiol-[2-(1 -naphthyl)ethyl] spiro[(2J4)- 1 -benzopyran-2 ,4 '-pipenidine] -4-one; 3 ,4-Dihydro-6-(1 -methyl- 4 -imidazolyl)sulfonamido-1' -naphthyl)ethyl]spiro[(2H)- benzopyran-2 ,4 '-piperidine] -4-one; 3 ,4-Dihydro-6-(l1-imidazolylmethyl)-1 1-naphthyl)ethyl] spiro[(2H)-l1-benzopyran- 2,4 -piperidine] -4-one; [N:\LIBZZIOO121:tab 74 3,4-Dihydro- 1-[2-(l-naphthyl)ethyl]-6-(1,2, 4 -triazolylmethyl)spiro[(2H)-l-benzopyran- 2,4' -piperidine]-4-one; 6 -Cyanomethyl-3,4-dihydro- 1 -naphthyl)ethyl]spiro[(2H)- 1 -benzopyran-2,4' piperidine]-4-one; or 7-Acetamido-3,4-dihydro-1'-[2-(2-fluorophenyl)ethyl]spiro[(2H)-l-benzopyran-2,4'- piperidine]-4-one; and the pharmaceutically acceptable salts thereof.

9. A method of preparing a compound of claim 1 wherein the method is substantially as hereinbefore described with reference to the Examples.

10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

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

12. The composition of claim 11, wherein the testosterone 5-alpha reductase 15 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.

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

14. The composition of claim 13, wherein the testosterone 5-alpha reductase inhibitor is finasteride. a

15. A method of treating benign prostatic hyperplasia in a subject which method comprises administering to the subject a therapeutically effective amount of a comlSound of the formula R 4 .R I SRI 0N N (CH 2 )nR 6 wherein each RI is independently selected from hydrogen, C 1 -4 alkyl, R 2 (CH 2 or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C 1 -4 alkyl, CI-4 alkoxy, furanyl, pyridyl, thienyl or aryl; or R 2 is selected from cyano-, NH 2 CO-, (R 3 2 NCO-, R 3 CONMe-, R 12 (CH 2 )p OC(O)NH-, R 3 (CH 2 )mC(O)pNH-, R 3 S(O)mNH- or het; R 3 is selected from hydrogen, C 1 -4 alkyl, het or aryl; R 4 and R 5 taken together are 0; or R 4 is hydrogen, and R 5 is selected from hydrogen or hydroxy; [N:\LIBAA]O1 538:TAB3 R 6 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, CI- 4 alkyl, C 1 4 alkoxy or aryl; naphthyl; thianaphthenyl; benzofuranyl; indolyl; 2- substituted indolyl where the substituent is halogen, C 1 4 alkyl, C 1 4 alkoxy or aryl; or 2,5-disubstituted indolyl where the substituents are independently selected from hydrogen, halogen, nitro, amino, C 1 4 alkyl, C 1 -4 alkoxy or aryl; 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, C 1 4 alkoxy, pyridyl, thienyl or furanyl; het is selected from Me S 02 N N S N-N N N-NH N* NN Me Me "N 0. O-N H N-NH NMe N-0 H 0 N N H 2 N N N H 2 N N S CO2Me or 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; or a pharmaceutically acceptable salt thereof.

16. The method of claim 15, wherein the compound has the formula 0 RI N"(CH2)nR6 wherein each R 1 is independently selected from hydrogen, R 2 (CH 2 or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, nitro, amino, C 1 4 alkyl, C 1 4 alkoxy, furanyl, pyridyl, thienyl or aryl; and the pharmaceutically acceptable salts thereof. [N:\LIBAA)O1 538:TAB 76

17. The method of claim 15 or claim 16, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.

18. The method of claim 15 or claim 16, 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.

A method of treating benign prostatic hyperplasia in a subject, which method comprises administering to the subject a therapeutically effective amount of the composition of any one of claims 10 to 14.

21. A method of relaxing urethral smooth muscle in a subject, which method comprises administering to the subject a therapeutically effective amount of a compound defined in the method of claim 15 or claim 16.

22. The method of claim 21, wherein the compound has the formula R 4 R \(CH2)nR6 wherein each RI is independently selected from hydrogen, R2(CH2) n or unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyf are independently selected from halogen, nitro, amino, Cl-4 alkyl, C1-4 alkoxy, furanyl, pyridyl, thienyl or aryl; and the pharmaceutically acceptable salts thereof. 20

23. The method of claim 21 or claim 22, wherein the compound additionally does S. not cause a fall in blood pressure at dosages effective to relax urethral smooth muscle.

24. The method of claim 21 or claim 22, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.

The method of claim 24, wherein the testosterone 5-alpha reductase inhibitor is finasteride.

26. A method of treating a disease which is susceptible to treatment by antagonism of the alpha la receptor in a subject which method comprises administering to the subject an amount of a compound defined in the method of claim 15 effective to treat the disease.

27. A pharmaceutical composition made by combining a compound of claim 1 and a pharmaceutically acceptable carrier.

28. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier. [NA\UBAA]O1 538:TAB 77

29. The use of a compound of any one of claims 1 to 9 or of a composition of any one of claims 10 to 14 in the preparation of a medicament for the treatment of benign prostatic hyperplasia.

The use of a compound of any one of claims 1 to 9 or of a composition of any one of claims 10 to 14 in the preparation of a medicament for relaxing urethral smooth muscle.

31. The use of claim 29 or claim 30 wherein the effective ingredient of the medicament is the composition of claim 14.

32. A drug which is useful for treating benign prostatic hyperplasic in a mammal, 1 o the effective ingredient of the drug being the composition of claim 14.

33. A drug which is useful for relaxing urethral smooth muscle in a mammal, the effective ingredient of the drug being the composition of claim 14

34. A compound of any one of claims 1 to 9 or a composition of any one of claims 10 to 14 when used for treating benign prostatic hyperplasic in a mamnual. 15

35. A compound of any one of claims 1 to 9 or a composition of any one of claims 10 to 14 when used for relaxing urethral smooth muscle in a mammal. Dated 22 March, 1999 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person 20 SPRUSON FERGUSON o S (N:LIDAA)O1 538:TAB