AU7975998A - Alpha 1aadrenergic receptor antagonists - Google Patents

Description

WO 98/57639 PCT/US98/12659 TITLE OF THE INVENTION ALPHA la ADRENERGIC RECEPTOR ANTAGONISTS This application claims the benefit of U.S. Provisional 5 Application No. 60/050,137, filed June 18, 1997. FIELD OF THE INVENTION: This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha la 10 adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH). BACKGROUND OF THE INVENTION 15 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. 20 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 25 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 30 beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into alpha 1, alpha 2, 131, and B2 subtypes. Functional differences between alpha 1 and alpha 2 receptors -1- WO 98/57639 PCT/US98/12659 have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed. For a general background on the alpha adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., a 5 Adrenoreceptors: Molecular Biolovgy, Biochemistry and Pharmacologyv, (Progress in Basic and Clinical Pharmacologv series, Karger, 1991), wherein the basis of alpha 1/alpha 2 subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3' 10 terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting alpha-adrenergic receptor affinity was explored. The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the 15 alpha 1 receptors into alpha ld (formerly known as alpha la or la/ld), alpha lb and alpha la (formerly known as alpha 1c) subtypes. Each alpha 1 receptor subtype exhibits its own pharmacologic and tissue specificities. The designation "alpha la" is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously 20 designated "alpha 1c" cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation alpha la is used throughout this application to refer to this subtype. At the same time, the receptor formerly designated alpha la was renamed alpha ld. The new nomenclature is used 25 throughout this application. Stable cell lines expressing these alpha 1 receptor subtypes are referred to herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature. For a review of the classification of alpha 1 adrenoceptor subtypes, see, Martin C. Michel, et al., Naunyn 30 Schmiedeberg's Arch. Pharmacol. (1995) 352:1-10. The differences in the alpha 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 35 severity with increasing age. The symptoms of the condition include, -2- WO 98/57639 PCT/US98/12659 but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. 5 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 5alpha 10 dihydrotestosterone has been identified as the principal culprit. The continual production of 5a-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 15 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). 20 The effect of this compound is to inhibit the enzyme testosterone 5-a reductase, which converts testosterone into 5a-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass. The development of such agents as PROSCAR® bodes well 25 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. 30 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 lower urinary tract tissue, by binding to alpha 1 adrenergic receptors, thus reducing the increased adrenergic tone due to the 35 disease, would be good candidates for this activity. Thus, one such agent -3- WO 98/57639 PCT/US98/12659 is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alphal subtype was reported. In addition, in WO 92/161213, 5 combinations of 5a-reductase inhibitory compounds and alphal adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the alpha ld, alpha lb, or alpha la subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was 10 not known. Current therapy for BPH uses existing non-selective alpha 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer). These non-selective antagonists suffer from side effects related to antagonism of the alpha ld and alpha lb receptors in the peripheral vasculature, e.g., hypotension 15 and syncope. The recent cloning of the human alpha la adrenergic receptor (ATCC CRL 11140) and the use of a screening assay utilizing the cloned human alpha la receptor enables identification of compounds which specifically interact with the human alpha la adrenergic 20 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 alpha la adrenergic receptor and a method for identifying compounds which bind the human alpha la receptor has now made possible the identification of 25 selective human alpha la adrenergic receptor antagonists useful for treating BPH. The instant patent disclosure discloses novel compounds which selectively bind to the human alpha la receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of 30 receptors (e.g., alpha 2), thus defining the specificity of the compounds of the present invention for the human alpha la adrenergic receptor. It is an object of the present invention to identify compounds which bind to the alpha la adrenergic receptor. It is a further object of the invention to identify compounds which act as antagonists of the 35 alpha la adrenergic receptor. It is another object of the invention to -4- WO 98/57639 PCT/US98/12659 identify alpha la adrenergic receptor antagonist compounds which are useful agents for treating BPH in animals, preferably mammals, especially humans. Still another object of the invention is to identify alpha la adrenergic receptor antagonists which are useful for relaxing 5 lower urinary tract tissue in animals, preferably mammals, especially humans. It has now been found that the compounds of the present invention are alpha la adrenergic receptor antagonists. Thus, the compounds of the present invention are useful for treating BPH in 10 mammals. Additionally, it has been found that the alpha la adrenergic receptor antagonists of the present invention are also useful for relaxing lower urinary tract tissue in mammals. SUMMARY OF THE INVENTION 15 The present invention provides compounds for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH). The compounds antagonize the human alpha la adrenergic receptor at nanomolar and subnanomolar concentrations while exhibiting at least ten fold lower affinity for the alpha ld and alpha lb 20 human adrenergic receptors and many other G-protein coupled receptors. This invention has the advantage over non-selective alpha 1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc. The compounds of the present invention have the 25 structure: M 2 R1 n6 nER R2 R N C N Q O n Rq R3 I2 I R1 J 6q L G R13 R wherein Q is selected from -5- WO 98/57639 PCT/US98/12659 (X)s (X)s (X)s XX I I I R4 N R8 9

R

8 N R N O N R O O RO R9 H ' Rio (X)s (X)s 0 R1 1 R12 N N W W 0 N R 11 O N H R 12 H o (X)s A20W R2 N (X)s \ t NR" or R5 N O H

R

1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R 17 )2, NR 17

COR

18 , NR 17

CON(R

18 )2, 5 NR 17 SO2R 7 , NR 17 SO2N(R 1 8 )2, OR 7 , (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 or C1-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, 10 quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, N(R 17 )2, (CH2)0-4CO2Rl 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2N(R 7 )2, (CH2)0-4SO2R 7 , phenyl, OR 7 , halogen, C1-4 alkyl or C3-8 cycloalkyl; -6- WO 98/57639 PCT/US98/12659 R is selected from hydrogen, cyano, OR 7 , CO2R 1 7 , CON(R 1 7 )2, SO2R 7 , SO2N(R 1 7 )2, tetrazole, isooxadiazole, unsubstituted, mono- or poly substituted phenyl wherein the substituents on the phenyl are 5 independently selected from halogen, cyano, nitro, OR 7 , (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 1 7 )2, N(R 1 7 )2, NR 1 7

COR

7 ,

NR

1 7

CON(R

1 8 )2, NR 1 7 SO2R 7 , NR 1 7 SO2N(R 1 8 )2, (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 or C1-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, thienyl, furanyl or naphthyl wherein 10 the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 , phenyl, OR 7 , halogen, C1-4 alkyl or C3-8 cycloalkyl; 15 E, G, L and M are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-4OR 7 , (CH2)0-4N(R 1 7 )2, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2R 1 7 or (CH2)0-4SO2N(R 1 7 )2; 20 J is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 7 , (CH2)1-4N(R 1 7 )2, (CH2)1-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2R 1 7 or (CH2)0-4SO2N(R 1 7 )2;

R

2 , R 3 and R 6 are each independently selected from hydrogen, 25 C1-8 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0 4COR 7 , (CH2)2-40R 7 , (CH2)1-4CF3, (CH2)1-4SO2R 7 , (CH2)0-4SO2N(R 1 7 )2 or (CH2)1-4CN;

R

4 is selected from hydrogen, COR 7 , (CH2)0-4CN, (CH2)0-4CF3, 30 (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R1 7 )2, (CH2)0-4SO2R 7 or (CH2)0-4SO2N(R 1 7 )2;

R

5 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 7 or (CH2)0-4CF3; 35 -7- WO 98/57639 PCT/US98/12659

R

7 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3;

R

8 , R 9 , R 1 0 , R 14 , R 1 5 and R 1 6 are each independently selected from 5 hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 7 or (CH2)0-4CF3;

R

1 1 and R 1 2 are each independently selected from hydrogen, C1-8 alkyl or C3-8 cycloalkyl; 10

R

1 3 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 7 ,

OR

7 or (CH2)0-4CF3;

R

1 7 and R 1 8 are each independently selected from is selected from 15 hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)1-4CF3;

R

2 0 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 7 , (CH2)0-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently 20 selected from halogen, CF3, cyano, nitro, OR 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4CO2R 1 7 or C1-4 alkyl; or unsubstituted, mono- or poly substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR 7 , halogen, C1-4 alkyl or 25 C3-8 cycloalkyl;

R

2 1 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-40R 7 or (CH2)0-4CF3; 30 R 2 6 is selected from hydrogen or OR 2 8 ;

R

2 8 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-4OR 7 or (CH2)0-4CF3; -8- WO 98/57639 PCT/US98/12659 W is 0 or NR 1 1 ; each X is independently selected from halogen, cyano, nitro, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-40R 7 or (CH2)0-4CF3 5 m, p and q are each independently an integer of from zero to two, provided that when q is zero, R 2 6 is hydrogen; n, o, s and t are each independently an integer of from zero to four; 10 and the pharmaceutically acceptable salts thereof. In a first embodiment of the invention is the compound having the structure R16 mO R'

S

G R13 R wherein R 4 is selected from COR 7 , (CH2)0-4CN, (CH2)0-4CF3, 15 (CH2)0-4CO2R 17 , (CH2)0-4CON(R 1 7)2, (CH2)0-4SO2R 7 or (CH2)0-4SO2N(R 1 7 )2;

R

1 3 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 7 or (CH2)0-4CF3; 20 and all other variables are as defined above; and the pharmaceutically acceptable salts thereof. In a second embodiment of the present invention is the compound of the formula: -9- WO 98/57639 PCT/US98/12659 1Z16 M R mO n ER R3 R R N C I R.. J R'--c p . R ', /j \R I2.. LG R13 R 14 wherein Q is selected from (X)s (X) (X)s

R

9 IX" or ,

R

1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from 4 R8 R8 LR 9 halogen, CF3, cyano, nitro, N(R 17 )2, NR 17 C R 18 , NR 17

CON(R

18 )2, 10 NR 1 7 S02R 7 , NR 1 7 SO2N(R 1 8 )2, OR 7 , (CH2)Ro 4CO 2R 1 7 , 5 H '1 R9 orI R1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R17)2, NR17COR18, NR17CON(R18)2, 10 NR17SO2R7, NR17SO2N(R18)2, OR7, (CH2)0-4CO2R17, (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 or C1-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, 15 quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, (CH2)0-4CO2R 17 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2N(R 7 )2, (CH2)0-4SO2R 7 , phenyl, OR 7 , halogen, C1-4 alkyl or C3-8 cycloalkyl; - 10 - WO 98/57639 PCT/US98/12659 R is selected from hydrogen, cyano, OR 7 , CO2R 1 7 , CON(R 1 7 )2, SO2R 7 , SO2N(R 1 7 )2, tetrazole, isooxadiazole, unsubstituted, mono- or di substituted phenyl wherein the substituents on the phenyl are 5 independently selected from halogen, cyano, nitro, OR 7 , (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 1 7 )2, N(R 1 7 )2, NR 1 7

COR

7 , NR1 7

CON(R

1 8 )2, NR 1 7 SO2R 7 , NR1 7 SO2N(R 1 8 )2, (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 or C1-4 alkyl; 10 E, G, L, M and J are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3;

R

2 , R 3 and R 6 are each independently selected from hydrogen, C1-6 alkyl, C4-6 cycloalkyl, (CH2)0-4CO2R 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0 15 4COR 7 , (CH2)2-40R 7 , (CH2)1-4CF3, (CH2)1-4SO2R 7 , (CH2)0-4SO2N(R 1 7 )2 or (CH2)1-4CN;

R

8 , R 9 , R 1 0 , R 1 4 , R 1 5 and R 1 6 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-40R 7 or 20 (CH2)0-4CF3;

R

1 3 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-40R 7 ,

OR

7 or (CH2)0-4CF3; 25 R 2 0 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-4OR 7 , (CH2)0-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 7 , (CH2)0-4CON(R1 7 )2, (CH2)0-4CO2R 1 7 or C1-4 alkyl; or unsubstituted, 30 mono-, di- or tri-substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, cyano, nitro, amino, phenyl, OR 7 , halogen, C1-4 alkyl or C3-8 cycloalkyl; 35 - 11- WO 98/57639 PCT/US98/12659

R

2 1 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)0-40R 7 or (CH2)0-4CF3;

R

2 8 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 5 (CH2)2-40R 7 or (CH2)0-4CF3; m, n, q and t are each independently an integer from zero to two, provided that when q is zero, R 2 6 is hydrogen; and p is an integer from zero to one; 10 and all other variables are as originally defined above; and the pharmaceutically acceptable salts thereof. In a third embodiment of the invention is the compound of the formula M 2 R1 m O n 3 R N C N Q J 6 L G R13 R 15 wherein Q is selected from (X)s (Xs (X)s RR N N R O 5 N R5 O O R1io , O R9 H 'Rio (X)s or t - 12- WO 98/57639 PCT/US98/12659

R

1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R 17 )2, NR 17

COR

18 , NR 17

CON(R

18 )2,

NR

17 SO2R 7 , NR 17 SO2N(R 18 )2, OR 7 , (CH2)0-4CO2R 17 , 5 (CH2)0-4CON(R 17 )2, (CH2)0-4SO2N(R 17 )2, (CH2)0-4SO2R 7 or C1-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, 10 nitro, amino, (CH2)0-4CO2R 17 , (CH2)0-4CON(R 17 )2, (CH2)0-4SO2N(R 7 )2, (CH2)0-4SO2R 7 , phenyl, OR 7 , halogen, C1-4 alkyl or C3-8 cycloalkyl; R is selected from hydrogen, cyano, OR 7 , CO2R 17 , CON(R 17 )2, SO2R 7 , 15 SO2N(R 17 )2, tetrazole, isooxadiazole, unsubstituted, mono- or di substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR 7 , (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 17 )2, N(R 17 )2, NR 17

COR

7 ,

NR

17

CON(R

18 )2, NR 17 SO2R 7 , NR 17 SO2N(R 18 )2, 20 (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 or C1-4 alkyl; E, G, L, M and J are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3; 25 R 2 , R 3 and R 6 are each independently selected from hydrogen, C1-6 alkyl, C4-6 cycloalkyl, (CH2)0-4CO2R 7 , (CH2)0-4CON(R 17 )2, (CH2)0 4COR 7 , (CH2)2-4OR 7 , (CH2)1-4CF3, (CH2)1-4SO2R 7 , (CH2)0-4SO2N(R 17 )2 or (CH2)1-4CN; 30 R 8 , R 9 , R 10 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-4OR 7 or (CH2)0-4CF3;

R

20 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, - 13 - WO 98/57639 PCT/US98/12659 (CH2)1-40R 7 , (CH2)0-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4CO2R 1 7 or C1-4 alkyl; or unsubstituted, 5 mono-, di- or tri-substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, cyano, nitro, amino, phenyl, OR 7 , halogen, C1-4 alkyl or C3-8 cycloalkyl; 10

R

2 1 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)0-40R 7 or (CH2)0-4CF3; m, n, q and t are each independently an integer from zero to two; 15 p is an integer from zero to one; and all other variables are as defined previously in the first embodiment; and the pharmaceutically acceptable salts thereof. In a first class of the invention is the compound of the formula R-2 qmO R CH 2 q RQ2

R

1 j " /,- P 20 R13 wherein Q is selected from (X)s (X)s

R

20

R

2 Ns ~N R OO R9 or t X H - 14- WO 98/57639 PCT/US98/12659

R

2 is selected from hydrogen, C1-6 alkyl, C4-6 cycloalkyl or (CH2)1-4CF3;

R

4 is selected from hydrogen, COR 7 , (CH2)0-2CO2R 1 7 , SO2R 7 or 5 (CH2)0-2CON(R 1 7)2;

R

5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)1-30R 7 or (CH2)0-3CF3; and 10 R 7 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3;

R

1 3 is hydrogen or OR 7 ; 15 R 1 7 and R 1 8 are each independently selected from is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)1-4CF3;

R

2 0 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-4OR 7 , (CH2)0-2CF3 or unsubstituted, mono- or di-substituted 20 phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 1 7 ,

CON(R

1 7 )2 or C1-4 alkyl;

R

2 6 is hydrogen or OR 2 8 , wherein R 2 8 is hydrogen or C1-6 alkyl; 25 and all other variables are as defined above in the second embodiment; and the pharmaceutically acceptable salts thereof. In a second class of the invention is the compound of the formula R 2 q \ M 0

H

2 mO 30 RP - 15- WO 98/57639 PCT/US98/12659 wherein Q is selected from (X)s (X)s (X) 4 R8 R20 R2 N N R R9 O N RO

R

10 or t H

R

2 is selected from hydrogen, C1-6 alkyl, C4-6 cycloalkyl or (CH2)1-4CF3; 5

R

4 is selected from COR 7 , (CH2)0-2CO2R 1 7 , SO2R 7 or (CH2)0-2CON(R 1 7 )2;

R

5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 10 (CH2)1-30R 7 or (CH2)0-3CF3; and

R

7 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3; 15 R 1 7 and R 1 8 are each independently selected from is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)1-4CF3;

R

2 0 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-40R 7 , (CH2)0-2CF3 or unsubstituted, mono- or di-substituted 20 phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 1 7 ,

CON(R

1 7 )2 or C1-4 alkyl; and all other variables are as defined above in the third embodiment; 25 and the pharmaceutically acceptable salts thereof. In a first subclass of the invention is the compund of the formula - 16- WO 98/57639 PCT/US98/12659 (R 9 )r 2 6 'R qR26 R 0 O wherein A is C-R 1 9 or N; R is selected from hydrogen, cyano, hydroxy, C02R 1 7 , CON(R 1 7 )2, 5 SO2R 7 , SO2N(R 1 7 )2;

R

2 is selected from hydrogen or CH2CF3;

R

1 3 is selected from hydrogen or hydroxy; 10 each R 1 9 is independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 1 7 , CON(R 1 7 )2 or C1-4 alkyl;

R

2 0 is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di 15 substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 1 7 , CON(R 1 7 )2 or C1-4 alkyl;

R

2 6 is selected from hydrogen or hydroxy; 20 each X is halogen; q is an integer from zero to one, provided that when q is zero, R 2 6 is hydrogen; and 25 r is an integer from zero to two; s is an integer from zero to three; and all other variables are as defined previously in the first class; and the pharmaceutically acceptable salts thereof. In a second subclass of the invention is the compound of the 30 formula - 17 - WO 98/57639 PCT/US98/12659 (R 1 9 )r (,A 2 mNr P O 0 wherein A is C-R 19 or N; R is selected from hydrogen, cyano, hydroxy, CO2R 1 7 , CON(R 1 7 )2, 5 SO2R 7 , SO2N(R 17 )2;

R

2 is selected from hydrogen or CH2CF3; each R 19 is independently selected from halogen, CF3, cyano, nitro, 10 amino, OR 7 , CO2R 17 , CON(R 17 )2 or C1-4 alkyl;

R

2 0 is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , 15 CO2R 17 , CON(R 1 7 )2 or C1-4 alkyl; each X is halogen; q is an integer from zero to one; 20 r is an integer from zero to two; s is an integer from zero to three; and all other variables are as defined previously in the second class; and the pharmaceutically acceptable salts thereof. Illustrative of the invention is the compound selected from - 18 - WO 98/57639 PCT/US98/12659 (R19)r~ H N Q A 0 0

(R

19 )r RN-H 0 R N oj-oC o, or

(R

19 )r H A q R N"

(R'

9 )r H N\Q 'A Y~ 0 wherein Q is selected from (X)s (X)s N(X) R4 R/ N N O N Rs O JO o R 20 H wherein R is selected from hydrogen or cyano; 5

R

4 is selected from COR 7 , C02R 1 7 or CON(R 17 )2;

R

5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)1-20R 7 or (CH2)0-2CF3; 10

R

19 is selected from hydrogen, halogen, C1-6 alkyl or CF3; - 19- WO 98/57639 PCT/US98/12659 each X is fluoro; and and all other variables are as defined previously in the second subclass; 5 and the pharmaceutically acceptable salts thereof. An illustration of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier. An example of the invention is a pharmaceutical composition made by 10 combining any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier. 15 Exemplifying the invention is the composition further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described 20 above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. More preferably, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. Most preferably, the 25 testosterone 5-alpha reductase inhibitor is finasteride. More specifically illustrating the 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 any of the compounds (or any of the compositions) described 30 above. Further exemplifying the invention is the method of treating BPH wherein the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH. Another example of the invention is the method of treating 35 benign prostatic hyperplasia wherein the compound is administered in -20 - WO 98/57639 PCT/US98/12659 combination with a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is finasteride. Further illustrating the invention is a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a 5 subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above. More specifically exemplifying the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary 10 tract tissue wherein the compound (or composition) additionally does not cause a fall in blood pressures at dosages effective to inhibit contraction of prostate tissue. More particularly illustrating the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract 15 tissue wherein the compound (or composition) is administered in combination with a testosterone 5-alpha reductase inhibitor; preferably, the testosterone 5-alpha reductase inhibitor is finasteride. More particularly exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the 20 alpha la receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease. Diseases which are susceptible to treatment by antagonism of the alpha la receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically 25 mediated pain, migraine (see, K.A. Vatz, Headache 1997:37: 107-108) and cardiac arrhythmia. An additional illustration of the invention is the use of any of the compounds described above in the preparation of a medicament for: a) the treatment of benign prostatic hyperplasia; b) relaxing lower 30 urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof. An additional example of the invention is the use of any of the alpha la antagonist compounds described above and a 5-alpha reductase inhibitor for the manufacture of a medicament for: a) treating 35 benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) -21- WO 98/57639 PCT/US98/12659 inhibiting contraction of prostate tissue which comprises an effective amount of the alpha la antagonist compound and an effective amount of 5-alpha reductase inhibitor, together or separately. 5 DETAILED DESCRIPTION OF THE INVENTION Representative compounds of the present invention exhibit high selectivity for the human alpha la adrenergic receptor. One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting 10 diastolic blood pressure. Representative compounds of this invention display submicromolar affinity for the human alpha la adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alpha ld and alpha lb adrenergic receptor subtypes, and many other G 15 protein coupled human receptors. Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha la adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alpha ld and alpha lb adrenergic receptor subtypes, and many other G-protein coupled human receptors 20 (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors). These compounds are administered in dosages effective to antagonize the alpha la receptor where such treatment is needed, as in BPH. For use in medicine, the salts of the compounds of this invention 25 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 30 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, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic 35 moiety, suitable pharmaceutically acceptable salts thereof may include -22- WO 98/57639 PCT/US98/12659 alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: 5 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, 10 Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, 15 Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate. 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, 20 such as testosterone 5-a reductase inhibitors, including PROSCAR® (finasteride). Aside from their utility as anti-BPH agents, these compounds may be used to induce highly tissue-specific, localized alpha la adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac 25 arrhythmias, and possibly a host of alpha la receptor mediated central nervous system events. 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 30 readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in 35 vivo after administration to the patient Conventional procedures for the -23 - WO 98/57639 PCT/US98/12659 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. 5 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 10 encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common 15 organic solvents. Such solvates are also encompassed within the scope of this invention. The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, 20 etc.). The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range. The term "aryl" as used herein, except where otherwise 25 specifically defined, refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl. The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). 30 Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., C1-10) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl -24- WO 98/57639 PCT/US98/12659 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. 5 The term "substituted" shall be deemed to include multiple degrees of substitution by a named substituent. The term "poly substituted" as used herein shall include di-, tri-, tetra- and penta substitution by a named substituent. Preferably, a poly-substituted moiety is di-, tri- or tetra-substituted by the named substituents, most 10 preferably, di- or tri-substituted. It is intended that the definition of any substituent or variable (e.g., X, R 1 7 , R 1 8 ) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, N(R 1 7 )2 represents -NH2, -NHCH3, -NHC2H5, -N(CH3)C2H5, etc. It is 15 understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below. 20 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 or heterocyclic ring, as used herein, 25 represents an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from N, 0 or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom 30 may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, 35 thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, -25 - WO 98/57639 PCT/US98/12659 imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 5 and oxadiazolyl. Morpholino is the same as morpholinyl. The term "thienyl," as used herein, refers to the group S The terms "(+)-DHP" and "DHP" as used herein, refer to a dihydropyrimidinone group of the formula (X)q 0 N

R

4 0 N R 5 10 H for example: F F O O N 0 O~N H The term "activated (+)-DHP," as used herein, refers to a N 3-(activated)carbamate of the desired dihydropyrimidinone where the 15 activating group is, for example, a p-nitrophenyloxy group. A specific example of an activated (+)-DHP is 4-(3,4-difluorophenyl)-5 -26- WO 98/57639 PCT/US98/12659 methoxycarbonyl-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine 3-carboxylic acid (4-nitrophenyl ester). The term "(S)-oxa" as used herein, refers to an oxazolidinone group of the formula (X)q O R8 R9 N Rio 5 O for example, F F O N The term "activated (S)-oxa" as used herein, refers to an N-(activated)carbamate of the desired oxazolidinone where the activating 10 group is, for example, a p-nitrophenyloxy group. A specific example of an activated (S)-oxa group is 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid 4-nitrophenyl ester. The term "selective alpha la adrenergic receptor antagonist," as used herein, refers to an alpha la antagonist compound 15 which is at least ten fold selective for the human alpha la adrenergic receptor as compared to the human alpha lb, alpha ld, alpha 2a, alpha 2b and alpha 2c adrenergic receptors. The term "lower urinary tract tissue," as used herein, refers to and includes, but is not limited to, prostatic smooth muscle, the 20 prostatic capsule, the urethra and the bladder neck. -27 - WO 98/57639 PCT/US98/12659 The term "subject," as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The term "therapeutically effective amount" as used 5 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. 10 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 15 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 20 example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, 25 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 30 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 35 about 500 mg of the active ingredient of the present invention. The -28 - WO 98/57639 PCT/US98/12659 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 5 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 10 acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. 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 15 indirectly, from combination of the specified ingredients in the specified amounts. 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 20 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 25 carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as 30 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 35 formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric -29- WO 98/57639 PCT/US98/12659 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 5 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 10 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 15 subsequent stage using methods known from the art. The specificity of binding of compounds showing affinity for the alpha la receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha la receptor and membranes from cell lines or tissues known to express other types of 20 alpha (e.g., alpha Id, alpha lb) or beta adrenergic receptors. Expression of the cloned human alpha ld, alpha lb, and alpha la 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 25 these compounds of the human alpha la adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting hypotensive effects. The ability of compounds of the present invention to 30 specifically bind to the alpha la receptor makes them useful for the treatment of BPH. The specificity of binding of compounds showing affinity for the alpha la 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 35 identified, cloned and expressed as described in PCT International -30- WO 98/57639 PCT/US98/12659 Application Publication Nos. WO94/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994. The cloned human alpha 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 5 cloned human alpha ld, alpha lb, and alpha la 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 human alpha la 10 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 e.g., PCT International Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued 15 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 20 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 alphal adrenergic receptors. Furthermore, functional biological tests are used to confirm the effects of identified compounds as alpha la adrenergic 25 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 30 as the active ingredient for use in the specific antagonism of human alpha la 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 35 release and sustained release formulations), pills, powders, -31- WO 98/57639 PCT/US98/12659 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 5 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 alpha la antagonistic agent. Advantageously, compounds of the present invention 10 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 15 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 20 present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian 25 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 30 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 35 diluents, excipients or carriers (collectively referred to herein as -32- WO 98/57639 PCT/US98/12659 "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. 5 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 10 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. 15 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. 20 The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are 25 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 30 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 35 present invention may also be coupled with soluble polymers as -33 - WO 98/57639 PCT/US98/12659 targetable drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residues. 5 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 10 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. 15 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 20 of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 20 mg/kg of body weight per day. 25 Preferably, the range is from about 0.001 to 10 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 30 appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha 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 35 administration of compounds of this invention and a human -34- WO 98/57639 PCT/US98/12659 testosterone 5-a 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 5 4,760,071, for example). 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 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in 10 combination with compounds of this invention. Compounds that are active as 5a-reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050; W093/23038,; W093/23048; WO93/23041; WO93/23040; WO93/23039; W093/23376; WO93/23419, EP 0572165; W093/23051. 15 The dosages of the alpha la 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 alpha la adrenergic receptor antagonist may be independently optimized 20 and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in 25 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 30 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 35 combination with an alpha la antagonist. Preferably, the dosage of - 35 - WO 98/57639 PCT/US98/12659 finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day. 5 For the treatment of benign prostatic hyperplasia, compounds of this invention exhibiting alpha la adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5a-reductase 2 inhibitor, such as finasteride, in addition to a 5a reductase 1 inhibitor, such as 4,7B-dimethyl-4-aza-5a-cholestan-3 10 one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed wherein the alpha la adrenergic receptor antagonist and the 5a reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent 15 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: 20 Aq = aqueous BCE = bromochloroethane Boc or BOC = t-butyloxycarbonyl BOC20 = di-tert-butyl dicarbonate BOPC1 = bis(2-oxo-3-oxazolidinyl)phosphinic chloride 25 Cbz = benzyloxycarbonyl Cbz-Cl = benzyloxycarbonyl chloride DEAD = diethylazodicarboxylate DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide 30 DPPA = diphenylphosphoryl azide EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et = ethyl Et3N = triethylamine 35 EtOAc = ethyl acetate -36- WO 98/57639 PCT/US98/12659 EtOH = ethanol FABLRMS = fast atom bombardment low resolution mass spectroscopy HPLC = high performance liquid chromatography 5 HOAc = acetic acid HOBt = 1-hydroxy benzotriazole hydrate i-PrOH = 2-propanol i-Pr2NEt = diisopropylethylamine KOtBu = potassium tert-butoxide 10 LAH = lithium aluminum hydride mCPBA = meta-chloroperbenzoic acid Me = methyl MeOH = methanol NMR = nuclear magnetic resonance 15 Nu- = nucleophile PCTLC = preparative centrifugal thin layer chromatography PEI = polyethylenimine Ph = phenyl 20 RT = retention time tBuOH = tert-butanol TEBAC = benzyltriethylammonium chloride TFA = trifluoroacetic acid THF = tetrahydrofuran 25 TLC = thin layer chromatography TMS = trimethylsilyl TMSCN = trimethylsilyl cyanide The compounds of the present invention can be prepared 30 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. 35 Unless otherwise indicated, all variables are as defined above. -37 - WO 98/57639 PCT/US98/12659 In general, compounds claimed within this invention are readily accessible from an appropriately substituted cyclic alkanone via reductive amination with a mono blocked diamino equivalent, Scheme 1. Protection of the incipient amino group may be required, followed by 5 deprotection of the terminal amino group. Acylation or alkylation provides the desired analog. An example of this strategy is outlined starting with an aryl cyano cycloalkanone and N-protected 3 aminoazetidine, which after reductive amination, Boc protection and hydrogenation produces the acylation precursor. Treatment with an 10 activated Q species (e.g., activated (+)-DHP, activated (S)-oxa) and HC1 EtOAc provides the final product. Some of the examples described within this invention were prepared as outlined in Scheme 2. Reductive amination of 4-cyano 4 phenylcyclohexanone and ammonium acetate provided both cis and 15 trans isomers (~9:1) of 1-amino-4-cyano-4-phenylcyclohexanone, which after reductive amination with piperidonyl amides A and B furnished the targeted alpha la antagonists. The 3-amino piperidinyl analogs were prepared from reductive amination of 3-aminopiperidine and 4-cyano-4-phenyl 20 cyclohexanone, followed by Boc protection and hydrogenation of the CBZ protecting group. Acylation with an activated Q species provided the final products, Scheme 3. Some of the required ketones were readily assembled following the sequence outlined in Scheme 4. For example, a substituted 25 benzyl nitrile, sulphone, etc. could be added to methyl acrylate (or other substituted acrylates), submitted to Dieckman cyclization, hydrolyzed and decarboxylated providing appropriately substituted ketones. Further modifications of the ketones can be accomplished following the Dieckman cyclization, which provides the b-keto ester which can be 30 either: (a) submitted to a reductive amination and carried on to final product, (b) enolized and alkylated then reductively aminated, deprotected and further manipulated providing further substituted analogs; or (c) hydrolyzed and decarboxylated and run through the above described conditions producing the desired antagonists. -38 - WO 98/57639 PCT/US98/12659 Another strategy for the synthesis of some geminally disubstituted cyclic ketones, in particular, 4,4-disubstituted cyclohexanones was accomplished as outlined in Scheme 5 starting from benzophenone derivatives and substituted methyl vinyl ketones 5 which under basic conditions lead to the 4,4-aryl cyclohex-2-en-l-ones in good yield. Subsequent hydrogenation, reductive amination and deprotection provided the appropriate acylation/alkylation precursors. Alternatively, the 4,4-aryl cyclohex-2-en-l-ones could be subjected to Michael addition of selected nucleophiles, alkylation or aldolyzation of 10 the enolate of the resulting ketone then reductively aminated and carried through the standard chemical transformation to provide further elaborated antagonists. The synthesis of some additional compounds of the present invention is described in Schemes 7 and 8. The 3-aminomethyl-3 15 hydroxyazetidine was assembled from the commercially available N protected 3-hydroxyl azetidine as outlined Scheme 16. Swern oxidation of the alcohol with dimethylsulfoxide and oxalyl chloride provided the azetidinone. The zinc iodide catalyzed addition of TMSCN produced the cyanohydrin. Subsequent LAH reduction of the nitrile yielded the key 20 intermediate required for the reductive aminations with the cyclohexanones. Deprotection of the N-dibenzylidine group and acyclation with preferred activated "Q"-groups furnished the final targets. The synthesis of the 4-amino-3-hydroxy-pyrrolidine 25 intermediate began with 3,4-pyrroline. BOC protection of the amine followed by mCPBA oxidation provided the epoxidation. Subsequent sodium azide opening of the epoxide and triphenylphosphine/water mediated reduction produced 4-amino-N-1-(1,1-dimethylethoxycarbonyl) 3-hydroxypyrrolidine. This key amino intermediate was then alkylated 30 by reductive amination reactions with cyclohexanones. Following the cleavage of the BOC protecting group acyclation with preferred activated "Q"-groups furnished the final targets. The activated termini species comprising the "Q" groups are readily prepared by one of ordinary skill in the art. For example, 35 oxazolidinones are prepared and activated in general by published and -39- WO 98/57639 PCT/US98/12659 well developed chemistry, in particular, of Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13, 1 (1982)] The starting materials, in general, are natural and unnatural amino acids. For instance, some of the preferred compounds are prepared from substituted phenyl 5 glycine derivatives, which after reduction of the carboxylate and a phosgene equivalent mediated cyclization provides the substituted oxazolidinone ring system. Deprotonation with n-butyl lithium and addition to a THF solution of p-nitrophenylchloroformate produces the stable, isolable "activated"oxazolidinone (oxa). 10 Dihydropyrimidinones are prepared by condensation reaction of the aldehyde, urea and a 1,3-acetoacetate type derivative catalyzed by a Lewis Acid, a copper (I) species and acetic acid. Activation was accomplished by treatment with a strong base, for instance, LiN(TMS)2, followed by addition to a THF solution of p 15 nitrophenylchloroformate. Hydantoins and cycloimide were prepared in two chemical steps from ketones as outlined in the literature. More specifically, hydantoins were prepared according to known methodology, e.g., J.J. Edmunds et al., J. Med. Chem. 1995, 38, pp. 3759-3771; J.H. Poupart et 20 al., J. Chem. Res. 1979, pp. 174-175. Saccharins were prepared according to known methods, e.g., page 40 and Examples 21 and 22 of PCT International Application Publication No. WO96/25934, published August 29, 1996. The dihydropyrimidinones and oxazolidinones were 25 synthesized independently in racemic form, and then separated utilizing preparative chiral HPLC. Their optical rotations were recorded. Then they were activated and reacted with prerequisite amines. From the receptor binding studies, a preferred isomer was identified, the (+) rotational isomer in each case. The absolute 30 configurations were determined to be (S) for both the dihydropyrimidinones and oxazolidinones by correlating their optical rotations with x-ray crystal structures obtained of fragments involved in the production of the antagonists. - 40- WO 98/57639 PCT/US98/12659 Scheme 1 m q (R19)(NH 2 CN BOCN NI2 C // n9 ) 91 (

R

r (R

'

9)r q m o ( O AcOH/MeOH o ( N NBOC A NaCNBH 3 H ( p CN O O N HOI (R19 (r q m LG Q EtOAc 0 N LG = leaving group, for p example ONn 0 2 NO (R19 r q m 0 or HO- + S N EDCl/HOBt p - 41 - WO 98/57639 PCT/US98/12659 Scheme 1 (cont'd) CN CN Ph (n AcOH/MeOH n h R19r NaCNBH 3 (R)r N Ph o( O o N A Ph H A-N --NH2 1) Boc 2 0 Ph 2) H 2 /Pd-C 1) Tos 2 0 CN 2) NaN 3 n 3) PPh 3

/H

2 0 (R19)(r NH Ph / o N N OH Boc Ph O LGK Q (CN O (R19 )r _J I 0 o N

'

C I Boc HCI/EtOAc CN O 19 e (Rl9)r NQ o N H -42- WO 98/57639 PCT/US98/12659 Scheme 1 (cont'd) C CN O.N AcOH/MeOH / O n (R19)r NaCNBH 3 (R19) 0 N o o o N Ph A Ph Y Ph LAH Ph _ Ph

-

CN CN (Ri9r 1) Boc 2 0 r 2) H 2 °Ooc NH /Pd-C Bo 1)O LG0 2) HCI- EtOAc LG SCN (Ri9)r H N Q 0 -43 - WO 98/57639 PCT/US98/12659 Scheme 2 F F Cl F 0 F N O iPr 2 NEt A NH F CI F N F iPr 2 NEt B F CN NH 4 OAc CN NB NaCNBH 3 NaCNBH 3 O MeOH NH 2 AcOH/MeOH CN O N NJ XF F H F CN F NN H -44- WO 98/57639 PCT/US98/12659 Scheme 3 1)Boc20 N NaCNBH3 CN 2) H 2 CNMeOH "- a Pd-C CNCBZ N NCBZ 0 H NH 1) Cbz-CI NH 2 2)DPPA CN CO2H Et3N 3) HCI/EtOAc N NCBZ H 1) OH F CN N NH EDOCI N HOBt BOC 2) HCI/EtOAc CN NNN F H F ~2CN H N NCBZ Pd-C N NH H -45 - WO 98/57639 PCT/US98/12659 Scheme 3 (cont'd) F F 0 2 N,/ CN ON 0yNyo N NH 0 0 H F F HH N 0 0 O NO FF 'thIIII1 N J N N, 0 HH O 0 0 N 0 0 NI HH ON 0 0 F F -46- WO 98/57639 PCT/US98/12659 Scheme 4 For example, R ' CO 2 Me 1 R KOtBu R * /Z /.. l' CO2Me, (R19)r Triton-B (R 19 )r THF tBuOH THF or heteroaryl or heteroaryl

CO

2 Me R = CN, SO 2 alk, others R R Me AcOH 19 R19)( CO 2 Me (R19 )r

(

R 19 )r Aq HCI o or heteroaryl 0O or heteroaryl A Scheme 5 I

S

(

R19r / \ (19)r a))0 0 H 2 /Pd-C Base 0

(R

19 )r O (R9)r or heteroaryl or heteroaryl Nu-, for example, cuprates S _ (R19)r (R19) r 0 O 470 0 0 0 Nu

O-(R

1 9 )r -- (R 19 )r -47 - WO 98/57639 PCT/US98/12659 Scheme 6

CO

2 Me CO2M e KOtBu . CN O Triton-B R9 THF

R

19 tBuOH 5a R 19 = Me 6a R 19 = Me CO 2 Me 5b R 19 = OMe 6b R 19 = OMe CN

CO

2 Me AcOH CN R 9 Aq HCI R19 7a R 19 = Me 8a R 19 = Me O 7b R 19 = OMe 8b R 19 = OMe CN AcOH ., NaBH 3 CN T MeOH

R

19 1) BOC20 " N 3 2) H 2 /Pd-C H NCHPh 2 H NCHPh 2 3) activated NC h 9._ga R 19 = Me carbamates H2 2 and

LAH/AICI

3

R

19 = OMe acids 4) HCI - EtOAc NC NCHPh 2 CN

R

19 N H tNCOQ 10a R 19 = Me 10b Ri 9 = OMe -48 - WO 98/57639 PCT/US98/12659 Scheme 7 HO Swern O TMSCN N Ph li N Ph O Oxidatn Y Znl2 Ph Ph NC. 9HLAH HN -~ - H 2 N N N yPh AACl3 yPh Ph Ph +o INaCNBH 3 CN O AcOH, MeOH I0 \1)

H

2 /Pd-C Final H0. Products CN 2) Activated Products H N Ph (+)-DHP y or Ph (S)-OXA -49 - WO 98/57639 PCT/US98/12659 Scheme 8

BOC

2 0 mCPBA NH NBOC NaHCO 3 HO q NaN 3 PPh 3 NBOC DMF N3 NBOC H 2 0 HO NaCNBH 3 H2N NBOC CN AcOH,MeOH SHO , 1) HCI Final CN NH NBOC 2) Activated Products (+)-DHP or (S)-OXA 5 The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples. 10 EXAMPLE 1 CN CN- CO 2 Me

CO

2 Me C(O 2 Me A B A: 5-nitrilo-4-o-tolyl-pentanoic acid methyl ester -50 - WO 98/57639 PCT/US98/12659 B: 4-cvano-4-o-tolv1-heptanedioic acid dimethyl ester, (6a) A solution of 2-methylbenzyl nitrile (25.0 g), methyl acrylate (75 mL) and Triton-B (40 mL) in t-butanol (90 mL) was refluxed (12 h). The solvent was removed in vacuo and submitted to SGC (SiO 2 , 10 cm x 5 30 cm, 0 - 15% EtOAc - hexane) affording the mono addition product and the desired bis addition compound (6a). A: 1 H NMR (CDC1 3 , 300 MHz) 7.42 (m, 1 H, ArH), 7.20 (m, 3 H, ArH), 4.34 (dd, 1 H, CHCN), 3.69 (s, 3 H, OMe), 2.57 (m, 2 H), 2.37 (s, 3 H, Me), 2.16 (m, 2 H). 10 B: 1 H NMR (CDC1 3 , 300 MHz) 7.42 (m, 1 H, ArH), 7.20 (m, 3 H, ArH), 3.62 (s, 6 H, OMe), 2.57 (m, 4 H), 2.54 (s, 3 H, Me), 2.31 (m, 2 H). EXAMPLE 2 CN SCO 2 Me 0 15 5-cvano-2-oxo-5-o-tolyl-cyclohexanecarboxylic acid methyl ester, (7a) A solution of the diester (9.38 g, 29.4 mmol) in THF (200 mL) was treated with KOt-Bu (6.6 g, 58.74 mmol) at 0 0 C then heated to reflux (20 min). The solvent was removed in vacuo and submitted to SGC (SiO 2 , 6 cm x 20 cm, 15% EtOAc - hexane) affording desired product and some 20 decarboxylated material. 1 H NMR (CDC1 3 , 300 MHz) consistent with assigned structure. FABLRMS m/e 272.22 g/mole (M++H, C 1 6

H

1 7

NO

3 = 272 g/mole.) 25 EXAMPLE 3 -51- WO 98/57639 PCT/US98/12659 iCN 10 4-cvano(2-methylphenyl)-cyclohexan- 1-one, (8a) A solution of the ketoester (5.0 g, 18.4 mmol) in AcOH (100 mL) was treated with 10% aqueous H2S04 (10 mL) at 0 0 C then heated to 5 reflux (24 h). The solvent was removed in vacuo, diluted with EtOAc (100 mL) and water (100 mL), partitioned, washed with brine (75 mL), dried (Na2SO4), filtered and concentrated in vacuo and submitted to SGC (SiO 2 , 5 cm x 20 cm, 0 - 15% EtOAc - hexane) affording the ketone. 1 H NMR (CDC1 3 , 300 MHz) 7.24 (m, 4H, ArH), 2.95 (ddd, 1 10 H, CHCN), 2.70 (s, 3 H, Me), 2.60 (m, 4 H), 2.20 (ddd, 2 H). EXAMPLE 4

H

2 N, N 3-Aminomethyl N-diphenylmethyl azetidine, (12) 15 To a cooled solution of aluminum chloride (0.33 g, 2.41 mmol) in ether (50 mL) at -780 C was added lithium aluminum hydride (2.41 ml, 2.41 mmol). After stirring 15 minutes at -780 C the slurry was added a solution of Jj(0.50 g, 2.01 mmol) in ether (10 mL) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The 20 solution was cooled to 0 0 C and quenched with water (10 mL) dropwise followed by 25% NaOH solution (10 mL). The aqueous layer was extracted with EtOAc. The organics were dried over Na2SO4, filtered, and removed in vacuo. The crude product was not purified. - 52- WO 98/57639 PCT/US98/12659 1 H NMR (CDC1 3 , 300 MHz) 7.41-7.13 (m, 10 H), 4.32 (s, 1 H), 3.28 (t, 2 H), 2.88-2.79 (m, 4 H), 2.52-2.42(m, 1 H), 1.28 (s, 1 H). EXAMPLE 5 CN OMe NN N H N 5 Compound (9b) A solution of the ketone 8b (prepared in an analogous manner to 8a) (0.25 g, 1.09 mmol), amine 12 (0.275 g, 1.09 mmol) and acetic acid (0.327 g, 5.45 mmol) in MeOH (7 mL) was treated with 10 NaBH3CN (1.19 mL, 1.19 mmol, 1.0 M THF solution) at room temperature over a 1 hour period. The solvent was removed (12 h) in vacuo , diluted with DCM (25 mL) and saturated aqueous sodium bicarbonate (25 mL), partitioned, extracted with DCM (2 x 25 mL), washed with saturated aqueous sodium bicarbonate (2 x 25 mL) and 15 brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo and submitted to PCTLC (SiO 2 , 4 mm, 90/10/1 CHC13-MeOH-NH4OH) the titled amine. 1 H NMR (CDC1 3 , 400 MHz) 7.41-7.38 (m, 4 H), 7.33-7.28 (m, 4 H), 7.22 (s, 2 H), 7.19-7.14 (m, 2 H), 6.98-6.90 (m, 2 H), 4.33 (s, 1 H), 3.91 (s, 20 3 H), 3.36-3.31 (t, 2 H), 2.88-2.74 (m, 5 H), 2.60-2.55 (m, 2 H), 1.89-1.80 (m, 2 H), 1.72-1.64 (m, 2 H). Anal. Calcd for C 3 1

H

3 5

N

3 0 1 * 0.15 CHC13: C = 77.37, H = 7.33, N = 8.69. Found: C = 77.54, H = 7.43, N = 9.08. MS (FAB) 466 (M+1) 25 EXAMPLE 6 -53 - WO 98/57639 PCT/US98/12659 F F N. 0. CNN0 NN N H 0 4- {1-[4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carbonyl]-piperidin-4 v1amino}l-1-henyl-cyclohexanecarbonitrile a. 4-(1-Benzyl-piperidin-4-ylamino)- 1-Phenyl-cyclohexanecarbo-nitrile 5 A mixture of 4-cyano-4-phenyl-cyclohexanone (1.5 g, 7.5 mmol) and 4-amino-N-benzylpiperidine (1.5 g, 7.9 mmol) in 50 ml of benzene was stirred at reflux for 2 h in presence of catalytic amount of p toluenesulfonic acid. The reaction mixture was concentrated in vacuo to provide a white solid, which was redissolved in 50 ml of EtOH and 10 stirred with NaBH4 (0.60 g, 160 mmol) for 12 h at 25 0 C. Reaction mixture was diluted with 200 ml of EtOAc and washed with brine several times. Organic layer was dried over MgSO 4 and concentrated in vacuo, to provide oily residue, which was identified as the desired product by NMR analysis and subjected to the following reaction without 15 any further purification. b. (4-cyano-4-phenyl-cyclohexyl)-piperidin-4-yl-carbamic acidtert-butyl ester A solution of the amine and di-tert-butyl dicarbonate (1.6 g, 20 7.3 mmol) was dissolved in 30 ml of DMF and stirred at 80 0 C for 12 h. The reaction mixture was diluted in EtOAc and washed with brine several times. Organic layer was separated and concentrated in vacuo, to provide oily residue, which was subjected to column chromatography (50% Hexane/EtOAc) to yield (4-cyano-4-phenyl-cyclohexyl)-l1-benzyl 25 piperidin-4-yl-carbamic acid tert-butyl ester as an oil. The amine obtained was dissolved in 100 ml of MeOH and stirred with catalytic amount of 10% Pd/C under atmosphere pressure of H 2 . The reaction -54 - WO 98/57639 PCT/US98/12659 mixture was filtered and concentrated in vacuo to provide the desired product as an oil. c. 4-{1-[4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carbonyl]-piperidin-4 5 ylaminol- 1-phenyl-cyclohexanecarbonitrile To a solution of 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid 4-nitrophenyl ester (80 mg, 0.21 mmol) in 5 ml of THF was added (4-cyano-4-phenyl-cyclohexyl)-piperidin-4-yl-carbamic acid tert-butyl ester (150 mg, 0.40 mmol) in a portion and the resulting 10 solution was stirred for 12 h at 25 oC. Reaction mixture was concentrated in vacuo, yielding a yellow oil, which was subjected to column chromatography (50% Hexane/EtOAc) to provide the tert-butyl ester of the desired product as a colorless oil. The product obtained was dissolved in 5 ml of EtOAc and 1 ml of 1N HC1-Et 2 0 to afford a white solid 15 of the product as the HC1 salt: mp 181-192 C; Anal. Calc. For

C

27

H

2 8

F

2

N

4 0 3 .1.0HC1 requires C, 61.70; H, 5.73; N, 10.28. Found: C, 59.48; H, 5.41; N, 10.34. Following the schemes and examples described herein, the 20 compounds shown in Table 1 were prepared. -55 - WO 98/57639 PCT/US98/12659 Table 1 ~CN N N'A H Compound cis/trans A 1 cis H F 2 cis 0 F 3 cis CBZ 4 trans CBZ Compound 1: FABLRMS: 284.09 g/mole 5 HPLC R.T.: 5.73 min. Elemental Analysis: Calc. for 2.0HC1 Solvate mol. wt.=613.14g/mole Calc:C=60.67%H=7.82%N=11.79% Obs:C=60.34%H= 7.58%N=11.56% 10 Compound 2: FABLRMS: 438.03 g/mole HPLC R.T.: 9.25 min. Elemental Analysis: Calc. for 1.0HC1;0.45H20;0.15EtOAc 15 Solvate mol.wt.=495.32g/mole Calc:C=64.50%H=6.53%N=8.48% Obs:C=64.47%H=6.47%N=8.46% -56- WO 98/57639 PCT/US98/12659 Compound 3: FABLRMS: 418.22 g/mole HPLC R.T.: 8.71 min. Elemental Analysis: Calc. for 1.0HC1;0.95H20;0.45EtOAc 5 Solvate mol.wt.=528.34/mole Calc:C=63.20%H=6.91%N=7.95% Obs:C=63.10%H=6.60%N=8.01% Compound 4: 10 FABLRMS: 418.17 g/mole HPLC R.T.: 8.50 min. Elemental Analysis: Calc. for 1.0HC1 Solvate mol.wt.=454.02g/mole Calc:C=68.78%H=7.10%N=9.26% 15 Obs:C=68.84%H=7.26%N=8.86% EXAMPLE 7 Mixture of (4S)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine and 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2 20 oxo-2,3,4,5-tetrahydropyrimidine F F F F HN HN OHAN O O N Oq H To a solution of (+)-4-(3,4-difluorophenyl)-6-methoxymethyl 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (4.63 g, 25 14.7 mmol) in a methanol (100 ml) was added sodium hydroxide (2.94 g, 73.6 mmol). The resulting mixture was refluxed at 90 OC for 16 hours. After cooling to room temperature the solvent was removed in vacuo. -57 - WO 98/57639 PCT/US98/12659 The solid was dissolved in CH 2 C1 2 and H20 then neutralized with 10% aqueous HC1 solution. The organic layer was dried over Na2SO4, concentrated, and purified by PCTLC (7% MeOH in CHC13 with 2%

NH

4 OH) to afford a 2.65 g mixture of the title compounds (71% yield). 5 The 1 H NMR was consistent with the assigned structure. MS (FAB) 255 (M+1) EXAMPLE 8 Mixture of (4S)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 10 tetrahydropyrimidine and 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2 oxo-2,3,4,5-tetrahydropyrimidine F F F F O N HN H 15 To a solution of (+)-4-(3,4-difluorophenyl)-6-methoxymethyl 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (5.36 g, 17.0 mmol) in a methanol (150 ml) was added 1N NaOH (10 ml). The resulting mixture was refluxed at 90 oC for 16 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was 20 dissolved in CH 2 C1 2 and H20 then neutralized with 10% aqueous HC1 solution. The organic layer was dried over Na 2

SO

4 , concentrated, and purified by PCTLC (7% MeOH in CHC1 3 with 2% NH 4 OH) to afford a 2.35 g mixture of the title compounds (54% yield). The 'H NMR was consistent with the assigned structure. 25 MS (FAB) 255 (M+1) EXAMPLE 9 -58 - WO 98/57639 PCT/US98/12659 (4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-3-(4-nitrophenoxycarbonyl) 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester F F 0 2 N O N OSN H 5 The title compound was prepared by treating the mixture obtained from Example 7 or Example 8 (1.93 g, 7.59 mmol) with lithium diisopropylamide (2.0M THF solution, 1.1 equivalents) in THF at -78 °C for 20 minutes followed by the rapid addition of 4-nitrophenyl chloroformate (1.5 equivalents) in THF. 0.488 g of the title compound 10 was obtained in a 15% yield. The 1 H NMR was consistent with the assigned structure. EXAMPLE 10 Mixture of (4R)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 15 tetrahydropyrimidine and 4R-4-(3,4-difluorophenyl)-6-methoxymethyl-2 oxo-2,3,4,5-tetrahydropyrimidine F F F F H HN O1N O ON H The title compounds were prepared from 4R-4-(3,4 20 difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylic acid methyl ester (5.0 g, 17.7 mmol) using the procedure -59- WO 98/57639 PCT/US98/12659 described in Example 7. A mixture of 2.0 g of the title compounds was obtained in 50% yield. The 1 H NMR was consistent with the assigned structure. MS (FAB) 255 (M+1) 5 Compounds of the invention can be prepared by reacting the products obtained in Example 9 in accordance with procedures and schemes described above. The compound of Example 9 can, for example, be reacted with an aminocyclohexylpiperidine or 10 aminocyclohexylpyrrolidine in accordance with Schemes 1 and 3 to obtain the desired compounds. Compounds of the invention can also be prepared by preparing a nitrophenoxy derivative of the compound of Example 10 in accordance with the procedure set forth in Example 9 and then reacting the derivative with an aminocyclohexylpiperidine or 15 aminocyclohexylpyrrolidine as set forth in Schemes 1 and 3 to obtain compounds of the invention. EXAMPLE 11 20 As a specific embodiment of an oral composition, 100 mg of the compound of Example 6 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule. 25 EXAMPLE 12 Screening assay: Alpha la Adrenergic Receptor Binding Membranes prepared from the stably transfected human alpha la cell line (ATCC CRL 11140) were used to identify compounds 30 that bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume = 200 ptl) contained 50 mM Tris-HC1 pH. 7.4, 5 mM EDTA, 150 mM NaC1, 100 pM [125 I]-HEAT, membranes prepared from the alpha la cell line and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for 35 one hour with shaking. Reactions were filtered onto Whatman GF/C -60- WO 98/57639 PCT/US98/12659 glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki). Representative compounds of the present invention were found to have Ki values < 50 nM. 5 EXAMPLE 13 Selective Binding assays Membranes prepared from stably transfected human alpha 10 ld and alpha lb cell lines (ATCC CRL 11138 and CRL 11139, respectively) were used to identify compounds that selectively bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume = 200 pl) contained 50 mM Tris-HC1 pH. 7.4, 5 mM EDTA, 150 mM NaC1, 100 pM [125 I]-HEAT, membranes prepared from cell lines 15 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 20 bound radioactivity was determined (Ki). EXAMPLE 14 EXEMPLARY COUNTERSCREENS 25 1. Assay Title: Dopamine D2, D3, D4 in vitro screen Objective of the Assay: The objective of this assay is to eliminate agents which 30 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 35 613. -61- WO 98/57639 PCT/US98/12659 Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (10mM Tris-HC1/5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 rpm) are resuspended in 5 50mM Tris-HC1 pH 7.4 containing EDTA, MgCl[2], KC1, NaC1, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 jig membranes in a total volume of 500 p l containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 p.M apomorphine. The assay is terminated after a 2 hour incubation at room 10 temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HC1 pH 7.4. 2. Assay Title: Serotonin 5HT1a 15 Objective of the Assay The objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor Method: 20 Modified from Schelegel and Peroutka Biochemical Pharmacology 35:1943-1949 (1986). Mammalian cells expressing cloned human 5HT1a receptors are lysed in ice-cold 5 mM Tris-HC1 , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is 25 centrifuged at 1000Xg for 30', and then the supernatant is centrifuged again at 38,000Xg 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-HC1, 4 mM CaC12 and lmg/ml ascorbate. Non-specific binding is defined using 10 pM propranolol. The assay is terminated after a 1 30 hour incubation at room temperature by rapid filtration over GF/Cfilters EXAMPLE 15 EXEMPLARY FUNCTIONAL ASSAYS -62- WO 98/57639 PCT/US98/12659 In order to confirm the specificity of compounds for the human alpha la adrenergic receptor and to define the biological activity of the compounds, the following functional tests may be performed: 5 1. In vitro Rat, Dog and Human Prostate and Dog Urethra Taconic Farms Sprague-Dawley male rats, weighing 250 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate. Each prostate 10 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 15 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 [NaC1, 118 mM; KC1, 4.7 mM; CaC12, 2.5 mM; KH2PO4, 1.2 mM; MgSO4, 1.2 mM; NaHCO3, 2.0 mM; dextrose, 11 mM] warmed 20 to 37 0 C. Excess lipid material and connective tissue are carefully removed. Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37 0 C, bubbled with 5% CO2/95% 02. The tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram 25 (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 pM (for rat), 10 gM (for dog) and 20 gM (for human) of phenylephrine, a cumulative concentration 30 response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated. EC50 values are calculated for each group using GraphPad 35 Inplot software. pA2 (-log Kb) values were obtained from Schild plot -63- WO 98/57639 PCT/US98/12659 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 =_Bl_, x-1 5 where x is the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration. 2. Measurement of Intra-Urethral Pressure in Anesthetized Dos 10 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 15 contraction, thus improve urine flow rate and provide symptomatic relief in man. However, these are non-selective alpha 1 receptor antagonists which also have pronounced vascular effects. Because we have identified the alpha la receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this 20 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) 25 identify the alpha 1 receptor subtypes responsible for prostatic/urethral contraction and vascular responses, and 2) use this model to evaluate novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be evaluated in this manner. 30 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 35 placed in the aorta via the femoral artery and vena cava via the femoral -64- WO 98/57639 PCT/US98/12659 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 5 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 10 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. 15 Phenylephrine, an alpha 1 adrenergic agonist, is administered (0.1-100 ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure. Following administration of increasing doses of an alpha adrenergic antagonist (or vehicle), the effects of phenylephrine on 20 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 25 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 30 the ED50's for the respective curves. These dose-ratios are then used to construct a Schild plot and the Kb (expressed as ug/kg, iv) determined. The Kb (dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve) is used to compare the relative potency of the antagonists on inhibiting phenylephrine responses for 35 intra-urethral and arterial pressure. The relative selectivity is -65 - WO 98/57639 PCT/US98/12659 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 5 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 alpha la adrenergic receptor antagonists that prevent the increase in intra-urethral pressure to phenylephrine without any 10 activity at the vasculature. 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 15 encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. -66 -

Claims (25)

1. A compound of the formula: M 2 3 Ri mO n ER R2 R NC N Q I L G R13 R14 5 wherein Q is selected from (X)s (X)s (X)s R4 R8 R8 "N R N R 9 O4N R 5 10 o S% O N Rs O O R0 O R H ' Rio (X)s (X)s O R" 1 12 N NV W W O N R11 O N (X)Ns (X)s t' NR 8 or R5 N O H -67 - WO 98/57639 PCT/US98/12659 R 1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R 1 7 )2, NR 1 7 COR 1 8 , NR 1 7 CON(R 1 8 )2, NR 1 7 SO2R 7 , NR 1 7 SO2N(R 1 8 )2, OR 7 , (CH2)0-4CO2R 1 7 , 5 (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 or C1-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, 10 nitro, N(R 1 7 )2, (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2N(R 7 )2, (CH2)0-4SO2R 7 , phenyl, OR 7 , halogen, C1-4 alkyl or C3.8 cycloalkyl; R is selected from hydrogen, cyano, OR 7 , CO2R 1 7 , CON(R 1 7 )2, SO2R 7 , 15 SO2N(R1 7 )2, tetrazole, isooxadiazole, unsubstituted, mono- or poly substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR 7 , (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 1 7 )2, N(R 1 7 )2, NR 1 7 COR 7 , NR 1 7 CON(R 1 8 )2, NR 1 7 SO2R 7 , NR 1 7 SO2N(R 1 8 )2, 20 (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 or C1-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 , phenyl, OR 7 , 25 halogen, C1-4 alkyl or C3-8 cycloalkyl; E, G, L and M are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-4OR 7 , (CH2)0-4N(R 1 7 )2, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 7 , (CH2)0-4CON(R 1 7 )2, 30 (CH2)0-4SO2R 1 7 or (CH2)0-4SO2N(R 17 )2; J is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-4OR 7 , (CH2)1-4N(R17)2, (CH2)1-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2R 1 7 or (CH2)0-4SO2N(R 1 7 )2; - 68 - WO 98/57639 PCT/US98/12659 R 2 , R 3 and R 6 are each independently selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R 7 , (CH2)0-4CON(R 1 7)2, (CH2)0 4COR 7 , (CH2)2-40R 7 , (CH2)1-4CF3, (CH2)1-4SO2R 7 , 5 (CH2)0-4SO2N(R 1 7 )2 or (CH2)1-4CN; R 4 is selected from hydrogen, COR 7 , (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2R 7 or (CH2)0-4SO2N(R 1 7 )2; 10 R 5 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 7 or (CH2)0-4CF3; R 7 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or 15 (CH2)0-4CF3; R 8 , R 9 , R 1 0 , R 1 4 , R 1 5 and R 1 6 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 7 or (CH2)0-4CF3; 20 R 1 1 and R 1 2 are each independently selected from hydrogen, C1-8 alkyl or C3-8 cycloalkyl; R 1 3 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 7 , 25 OR 7 or (CH2)0-4CF3; R 1 7 and R 1 8 are each independently selected from is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)1-4CF3; 30 R 2 0 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 7 , (CH2)0-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4CO2R 1 7 or 01-4 alkyl; or unsubstituted, mono- or poly 35 substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the - 69 - WO 98/57639 PCT/US98/12659 substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR 7 , halogen, C1-4 alkyl or C3-8 cycloalkyl; 5 R 2 1 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-4OR 7 or (CH2)0-4CF3; R 2 6 is selected from hydrogen or OR 2 8 ; 10 R 2 8 is selected from hydrogen, C 1-8 alkyl, C3-8 cycloalkyl, (CH2)0-4OR 7 or (CH2)0-4CF3; W is 0 or NR 1 1 ; 15 each X is independently selected from halogen, cyano, nitro, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-40R 7 or (CH2)0-4CF3 m, p and q are each independently an integer of from zero to two, provided that when q is zero, R 2 6 is hydrogen; 20 n, o, s and t are each independently an integer of from zero to four; or a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1 of the formula: 184 16 n E 2 R R N C N Q R1 jmO 2 L G R13 R14 25 L R wherein R 4 is selected from COR 7 , (CH2)0-4CN, (CH2)0-4CF3, (CH2)0 4CO2R 1 7 , (CH2)0-4CON(R 1 7)2, (CH2)0-4SO2R 7 or (CH2)0-4SO2N(R 1 7)2; - 70 - WO 98/57639 PCT/US98/12659 R 1 3 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 7 or (CH2)0-4CF3; or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 of the formula: 1016 M 2 R mO n ERl 3 R >N C 6 R ' J R - ,-k , 5 L G R13 R 1 4 wherein Q is selected from (X)s (X)s (X)s 4 R 8 R 8 R 9 NN R N O N0s R1o , Oj 9 H '1 Ro R9 (X)s or 10 R 1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R 1 7)2, NR 1 7 COR 1 8 , NR 1 7 CON(R 1 8 )2, NR 1 7 SO2R 7 , NR 1 7 SO2N(R 1 8 )2, OR 7 , (CH2)0-4CO2R 1 7 , 15 (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 or C1-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein -71- WO 98/57639 PCT/US98/12659 the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4SO2N(R 7 )2, (CH2)0-4SO2R 7 , phenyl, OR 7 , halogen, 5 C1-4 alkyl or C3-8 cycloalkyl; R is selected from hydrogen, cyano, OR 7 , CO2R 1 7 , CON(R 1 7 )2, SO2R 7 , SO2N(R 1 7 )2, tetrazole, isooxadiazole, unsubstituted, mono- or di substituted phenyl wherein the substituents on the phenyl are 10 independently selected from halogen, cyano, nitro, OR 7 , (CH2)0-4CO2R 1 7 , (CH2)0-4CON(R 1 7 )2, N(R 1 7 )2, NR 1 7 COR 7 , NR 1 7 CON(R 1 8 )2, NR 1 7 SO2R 7 , NR 1 7 SO2N(R 1 8 )2, (CH2)0-4SO2N(R 1 7 )2, (CH2)0-4SO2R 7 or C1-4 alkyl; 15 E, G, L, M and J are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3; R 2 , R 3 and R 6 are each independently selected from hydrogen, C1-6 alkyl, C4-6 cycloalkyl, (CH2)0-4CO2R 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0 20 4COR 7 , (CH2)2-40R 7 , (CH2)1-4CF3, (CH2)1-4SO2R 7 , (CH2)0-4SO2N(R 1 7 )2 or (CH2)1-4CN; R 8 , R 9 , R 1 0 , R 1 4 , R 1 5 and R 1 6 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-40R 7 or 25 (CH2)0-4CF3; R 1 3 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-4OR 7 , OR 7 or (CH2)0-4CF3; 30 R 2 0 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-4OR 7 , (CH2)0-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 7 , (CH2)0-4CON(R 1 7 )2, (CH2)0-4CO2R 1 7 or C1-4 alkyl; or unsubstituted, 35 mono-, di- or tri-substituted: pyridyl, pyrazinyl, thienyl, furanyl or - 72 - WO 98/57639 PCT/US98/12659 naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, cyano, nitro, amino, phenyl, OR 7 , halogen, C1-4 alkyl or C3-8 cycloalkyl; 5 R 2 1 is selected from hydrogen, 01-6 alkyl, C3-6 cycloalkyl, (CH2)0-40R 7 or (CH2)0-4CF3; R 2 8 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 10 (CH2)2-40R 7 or (CH2)0-4CF3; m, n, q and t are each independently an integer from zero to two, provided that when q is zero, R 2 6 is hydrogen; and p is an integer from zero to one; 15 or a pharmaceutically acceptable salt thereof.

4. The compound of Claim 3, of the formula R2 qmO R CH2 N Q R 1 J/---p R 13 20 wherein Q is selected from (X)s (X)s S4 R 20 R 2 (X)s R IN O N Rs O OXo o R1 or tI H R 2 is selected from hydrogen, 01-6 alkyl, C4-6 cycloalkyl or (CH2)1-4CF3; - 73 - WO 98/57639 PCT/US98/12659 R 4 is selected from hydrogen, COR 7 , (CH2)0-2CO2R 1 7 , SO2R 7 or (CH2)0-2CON(R 1 7 )2; 5 R 5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)1-30R 7 or (CH2)0-3CF3; and R 7 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3; 10 R 1 3 is hydrogen or OR 7 ; R 1 7 and R 1 8 are each independently selected from is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)1-4CF3; 15 R 2 0 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-40R 7 , (CH2)0-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 1 7 , 20 CON(R 1 7 )2 or C1-4 alkyl; R 2 6 is hydrogen or OR 2 8 , wherein R 2 8 is hydrogen or C1-6 alkyl; or a pharmaceutically acceptable salt thereof. 25

5. The compound of Claim 4, of the formula (R19)r R R26 N A R 2 L R: 13 /PY 0 wherein A is C-R 1 9 or N; -74- WO 98/57639 PCT/US98/12659 R is selected from hydrogen, cyano, hydroxy, C02R 17 , CON(R 17 )2, SO2R 7 , SO2N(R 17 )2; R 2 is selected from hydrogen or CH2CF3; 5 R 1 3 is selected from hydrogen or hydroxy; each R 19 is independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 17 , CON(R 17 )2 or C1-4 alkyl; 10 R 2 0 is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 1 7 , CON(R 1 7 )2 or C1-4 alkyl; 15 R 2 6 is selected from hydrogen or hydroxy; each X is halogen; 20 q is an integer from zero to one, provided that when q is zero, R 2 6 is hydrogen; and r is an integer from zero to two; s is an integer from zero to three; or a pharmaceutically acceptable salt thereof. 25

6. The compound of Claim 5, selected from - 75 - WO 98/57639 PCT/US98/12659 q R NN (R19)r A O O (R' 9 )r NQ 0 R N N Q (R 19 )r H O Aq R N (R 9 )r.\ H N Q wherein Q is selected from (X)s (X)s N Ns X 0 N R 5 O0 or R20 H 5 wherein R is selected from hydrogen or cyano; R 4 is selected from COR 7 , CO2R 1 7 or CON(R 1 7 )2; R 5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 10 (CH2)1-20R 7 or (CH2)0-2CF3; -76- WO 98/57639 PCT/US98/12659 R 1 9 is selected from hydrogen, halogen, C1-6 alkyl or CF3; each X is fluoro; 5 or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable carrier. 10

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

9. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically 15 acceptable carrier.

10. The composition of Claim 7 further comprising a testosterone 5-alpha reductase inhibitor. 20

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

12. The composition of Claim 11, wherein the 25 testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor.

13. The composition of Claim 12, wherein the testosterone 5-alpha reductase inhibitor is finasteride. 30

14. 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 Claim 1. - 77 - WO 98/57639 PCT/US98/12659

15. The method of Claim 14, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. 5

16. The method of Claim 15, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.

17. The method of Claim 16, wherein the testosterone 5 10 alpha reductase inhibitor is finasteride.

18. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering a therapeutically effective amount of the composition of Claim 7. 15

19. The method of Claim 18, wherein the composition further comprises a therapeutically effective amount of a testosterone 5 alpha reductase inhibitor.

20 20. A method of relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1.

21. The method of Claim 20, wherein the compound 25 additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue.

22. The method of Claim 20, wherein the compound is administered in combination with a testosterone 5-alpha reductase 30 inhibitor.

23. The method of Claim 22, wherein the testosterone 5 alpha reductase inhibitor is finasteride. - 78 - WO 98/57639 PCT/US98/12659

24. A method of treating a condition which is susceptible to treatment by antagonism of the alpha la receptor which comprises administering to a subject in need thereof an amount of the compound of Claim 1 effective to treat the condition. 5

25. A method of eliciting an alpha la antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of Claim 1. - 79-