CA2235370A1 - Alpha 1a adrenergic receptor antagonists - Google Patents

Abstract

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

Description

CA 0223~370 1998-04-20 TIT~E OF THE INVENTION
ALPHA la ADRENERGIC RECEPTOR ANTAGONISTS

~l~;LD OF THE INVENTION:
This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as selective alpha la adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH).
BACKGROUND OF THE INVENTION
Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the 15 peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
Norepinephrine is produced by adrenergic nerve en~ling.s, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of 2 0 the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are 2 5 opposed to responses in~ ced by beta receptor bin~lin~.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various ~nim~l and tissue sources. As a result, alpha and beta adrenergic 3 0 receptors were further subdivided into al, a2, ~1, and ~2 subtypes.
Functional differences between al and a2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed. Thus, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to selectively bind CA 02235370 l998-04-20 to adrenergic receptors of the alpha 1 subtype was reported. The al/a2 selectivity of this compound was disclosed as being significant because agonist stin~ tion of the a2 receptors was said to inhibit secretion of epinep~rine and norepinephrine, while antagonism of the a2 receptor was saicl to increase secretion of these hormones. Thus, the use of non-selective alpha-adrenergic blockers, such as phenoxyben7~min~ and phentol~lmine, is limited by their a2 adrenergic receptor me~ t~l induction of increased plasma catechol~mine concentration and the attendant physiological sequelae (increased heart rate and smooth muscle 10 contraction).
For a general background on the a-adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., a-Adrenoreceptors: Molecular Biolo~y~ Biochemistry and Pharmacolo~y.
(Pro~ress in Basic and Clinical Pharmacolo~y series, Karger, 1991), 15 wherein the basis of al/a2 subclassification, the molecular biology, signal tr;msduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3'-termimls of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds 2 o exhibiting a-adrenergic receptor affinity was explored.
The cloning, sequencing and expression of alpha receptor subtypes from ~nim~l tissues has led to the subclassification of the al receptors into a1a, (Lomasney, et al., J. Biol. Chem.. 266:6365-6369 (1991), rat a1a; Bruno et al., BBRC, 179:1485-1490 (1991), hllm~n 25 ala)~ a1b (Cotecchia, et al., PNAS~ 85;7159-7163 (1988), hamster a1b;
Libert, et al., Science. (1989), dog alb; Ramarao, et al., J. Biol.
Chem.. 267:21936-21945 (19'32), hl-m~n alb)~ and most recently, in a study using bovine brain, a new alc subtype was proposed (Schwinn, et al.. J. Biol. Chem.. 265:8183-X189 (1990); Hirasawa et al., BBRC
3 0 195:902-909 (1993), described the cloning, functional expression and tissue distribution of a human alC adrenergic receptor; Hoehe et al., Human Mol. Genetics 1(5):349 (8/92) noted the existence of a two-allele Pstl restriction fragment polymorphism in the a1C adrenergic receptor gene; another study suggests that there may even be an alpha ld CA 0223~370 1998-04-20 W O 97/17967 PCT~US96118321 receptor subtype, see Perez et al., Mol. Pharm., 40:876-883, 1992).
Each a1 receptor subtype exhibits its own pharmacologic and tissue specificities. Schwinn and coworkers noted that the cloned bovine a1C
receptor exhibited pharmacological properties proposed for the a1a subtype. Nonetheless, based on its non-expression in tissues where the ala subtype is expressed, and its sensitivity to chloroethylclonidine, the receptor was given a new designation.
The differences in the a-adrenergic receptor subtypes have relevance in pathophysiologic conditions. Benign prostatic hyperylasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction.
These synlytollls 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. Conco~ nil~ltly~ 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.
2 0 In benign prostatic hypelplasia, the male hormone 5a-dihydrotestosterone has been identified as the principal culprit. The continual production of Sa-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 2 5 enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
The elucidation of the mech~ni~m s-lmm~rized 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 3 0 these agents is Merck & Co., Inc.s' product PROSCAR~) (finasteride).
The effect of this compound is to inhibit the en~yme testosterone 5-alpha reductase, which converts testosterone into Sa-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass.

CA 0223~370 1998-04-20 W O 97/1796'~ PCT~US96/18321 The development of such agents as PROSCAR(~) bodes wel]
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 5 suffer, .md may in fact lose hope that the agents are working sufficiently rapidly In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation 10 of the urethral smooth muscle, by binding to alpha 1 adrenergic receptorLs, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity. Thus, one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/0073, the 1 c, selective ability of the R(+) enantiomer of terazosin to bind to adrener.gic receptors of the a1 subtype was reported. In addition, in WO 921'161213, hereby incorporated by reference, combinations of 5-alpha-reductase inhibitory compounds and alpha l-adrenergic receptor blockers (terazosin, doxazosi~n, prazosin, bunazosin, indoramin, 2C alfuzosin) were disclosed. However, no information as to the a1a, a or a1C subtype specificity of these compounds was provided as ~is data and its relevancy to the treatment of BPH was not known. Current therapy for BPH uses existing non-selective alpha 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin 2 5 mesylate (Cardura, Pfizer). These non-selective antagonists suffer from side effects related to antagonism of the alpha 1 a and alpha lb receptors in the peripheral vasculature, e.g., orthostatic hypotension and syncope.
Typically, identification of active compounds is accomplished through use of ~nim~l tissues known to be enriched in 3 0 adrenergic receptors. Thus, rat tissues have been used to screen for potential adrenergic receptor antagonists. However, because of species variability, compounds which appear active in ~nim~l tissue may not be active or sufficiently selective in hllm~n~. This results in subst~n~
wastage of time and effort, particularly where high volume compound W O 97117967 PCT~US96/1832 screening programs are employed. There is also the danger that compounds, which might be highly effective in hllm~n.s, would be missed because of their absence of appreciable affinity for the heterologous ~nim~l receptors. In this regard, it has been noted that 5 even single amino acid changes between the se4uence of biologically active proteins in one species may give rise to substantial pharmacological differences. Thus, Fong et al., (J. Biol. Chem..
267:25668-25671, 1992) showed that there are 22 divergent amino acid residues between the sequence of the human neurokinin-l receptor and 1 CI the homologous rat receptor. They further showed, in studies with mutant receptors, that substitution of only two arnino acid residues was both necessary and sufficient to reproduce the rat receptor's antagonist binding affinity in the hl~m~n receptor. Oksenberg et al., (Nature~
360:161-163, 1992) showed that a single amino-acid difference confers 1 ~ major ph~rm~cological variation between the human and the rodent 5-hydroxytrypt~min~ receptors. Likewise, Kuhse et al., (Neuron. 5:867-873, 1990) showed that a single amino-acid exchange alters the pharmacology of the neonatal rat glycine receptor subunit. This difficulty and unpredictability has resulted in a need for a compound 2 o screen which will identify compounds that will be active in hllm~n~.
These problems were solved by cloning the hllm7~n adrenergic receptor of the alC subtype (ATCC CRL 11140) and the use of a screening assay which enables identification of compounds which specifically interact with the hllm~n alc adrenergic receptor. [PCT
2 5 International Application Publication Nos. W094/08040, published 14 April 1994 and WO94/10989, published 26 May 1994] As disclosed in the instant patent disclosure, a cloned human a1C adrenergic receptor and a method for identifying compounds which bind the hllm~n a1C
receptor has now made possible the identification of selective hllm~n 3 0 a1 C adrenergic receptor antagonists useful for treating BPH. The instant patent disclosure discloses novel compounds which selectively bind to the hllm~n alC receptor. These compounds are further tested for binding to other hllm~n alpha 1 receptor subtypes, as well as counterscreened against other types of receptors, thus defining the W O 97/1796'7 PCTrUS96/18321 specific:ity of the compounds of the present invention for the hllm~n alC adrenergic receptor.
Meperidine and normeperidine are known opioid receptor ligands useful as analgesics. LJanssen, P.A. et al, J. Med. Chem. 1(4), c; 309 (1959)]. It has now been found that the compounds of the present invention, which represent structurally modified normeperidine derivatives, are selective alpha la receptor antagonists devoid of opioid binding properties.
Compounds of this invention are thereful useful for 1 C reducin,g the acute symptoms of BPH without side effects caused by ancillary opioid receptor binding. Thus, compounds of this invention may be used alone or in conjunction with a more long-term anti-BPH
therapeutics, such as testosterone S-alpha reductase inhibitors, including PROSCAR(~) (finasteride). Aside from their utility as anti-BPH agents, 15 these compounds may be used to induce highly tissue-specific, localized a1C adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac arrhythmias, and possibly a host of alpha lc receptor mediated central nervous system events.
NOMENCLATURE
Recently, a new a1 adrenergic receptor (a1-AR) classification scheme similar to that proposed by Ford, et al. [~1-Adrenoc eptor Classification: Sharpening Occam's Razor. Trends in 2 5 Pharm ,Sci. 1994, 15, 167-170] was adopted at the August, 1994 meeting of the International lJnion of Pharmacology (IUPHAR) in MontreaLI, C~n~ . The al-AR genes formerly known as ala/d~ alb and alC were renamed a1d, alb and ala, respectively. This new naming system reflects the correspondence between the proteins 3 0 encoded by the ala and alb genes (new IUPHAR nomenclature) and the receptors characterized by traditional pharmacological means as a1A and a1g, respectively, in the literature. Recombinant receptors and receptors characterized ph~ cologically in tissues are distingu.ished by lowercase and uppercase subscripts, respectively.

The above discussion contained in the Background section used the former classification scheme (i-e-, a1a/d, alb and a1c);
however, hereinafter, the new classification scheme will be utilized (i.e., ald, alb and ala)- Thus, what was formerly referred to as the alC
5 receptor (and alC receptor antagonists) will hereinafter be referred to tili7.in~ the new nomenclature as the a1a receptor (and ala receptor antagonists).
SUMMARY OF THE ~VENTION
The present invention provides a method of treating a condition which is susceptible to treatment by antagonism of the alpha la adrenergic receptor which comprises a(l-nini~tering to the subject a therapeutically effective amount of a compound of the formula:

,X~
A~R3 1 5 wherein A is selected from C-R2 or N;

X is C or N, provided that when X is N, then Rl is absent;
R l is selected from hydrogen, halogen, C1 8 alkyl, mono-, di- or tri-halogenated Cl ~s alkyl, C1 6 alkoxy, cyano, CoNR4R5 or C3-8 cycloalkyl;

2 5 R2 is selected from hydrogen, cyano, CoNR4R5 or C02R4;

R3 is selected from hydrogen, cyano, CoNR4R5, C02R4 or S02R4;
and WO 97117g67 PCT/USg6/18321 R4 and RS are each independently selected from hydrogen, C1 8 alkyl or C3-8 cycloalkyl;
and the pharmaceutically acceptable salts thereof. Preferably, the 5 compound used in the method is selected from ?~ or [~
H H
wherein X, Rl and R3 are as defined above.
In one embodiment of the invention is the method of treating a condition which is susceptible to treatment by antagonism of 10 the alpha la adrenergic receptor wherein R l is selected from hydrogen, halogen, C'l -6 alkyl, mono-, di- or tri-halogenated Cl 6 alkyl, Cl 4 alkoxy, cyano, CONH2 or C3-6 cycloaLkyl;
R3 is selected from hydrogen, cyano or C02R4; and 15 R4 and ]RS are each independently selected from hydrogen, C1 6 alkyl or C3-6 cycloalkyl;
and the pharmaceutically acceptable salts thereof.
In a class of the invention is the method of treating a condition which is susceptible to treatment by antagonism of the alpha 20 la adrenergic receptor wherein xisC;
Rl is selected from hydrogen, chloro, Cl 4 alkyl, tri-halogenated Cl 4 aLkyl, Cl 4 alkoxy, cyano or CONH2;
R2 is se]lected from hydrogen, cyano, CONH2 or C02R4;
2 5 R3 is selected from hydrogen, cyano or Co2cH2cH3; and R4 is se;lected from hydrogen, Cl 4 alkyl or C3-6 cycloaLkyl;
and the pharmaceutically acceptable salts thereof.

In a subclass of the invention is the method of treating a condition which is susceptible to treatment by antagonism of the alpha la adrenergic receptor wherein the compound has the formula 1R~
,J~ R3 5 wherein R 1 is selected from hydrogen, chloro, methyl, trifluoromethyl, methoxy, cyano or CONH2; and R2 is selected from hydrogen, cyano, CONH2, C02H, C02CH3, C02CH2CH3, C02(CH2)3CH3 or C02cyclohexyl;
10 and the pharmaceutically acceptable salts thereof.
Illustrative of the invention is the method of treating a condition which is susceptible to treatment by antagonism of the alpha la adrenergic receptor wherein the compound is selected from 1RJ~ 1RJ~R2 ~,CN ~

15 wherein R2 is selected from hydrogen, cyano, C02H or C02NH2;
and the ph~ reutically acceptable salts thereof.
An illustration of the invention is the method of treating a condition which is susceptible to treatment by antagonism of the alpha la adrenergic receptor wherein the compound has the structure W 0 97/1796'1 PCTAUS96/18321 R~

H~R2 and the ph~rm~ceutically acceptable salts thereof.
Exemplifying the invention is the method wherein the compound is selected from 5 4-cyano-4-(2-trifluoromethylphenyl)piperidine;

4-cyano-4-(2-methylphenyl)piperidine;
4-(2-chlorophenyl)-4-cyanopiperidine or 4-(2-chlorophenyl)-4-(methoxycarbonyl)piperidine and the pharmaceutically acceptable salts thereof.
Examples of conditions which are susceptible to treatment by antagronism of the alpha la adrenergic receptor include, but are not limited lo, benign prostatic h;yperplasia, urinary obstruction, impotence and high intraocular pressure The compounds useful in the methods of the present invention selectively antagonize the hllm~n alpha la 15 adrenergic receptor at nanomolar concentrations while exhibiting at least five fold lower affinity for the alpha l d and alpha lb hllm~n adrenergic receptors and many other G-protein coupled receptors. Use of selective alpha la adrener~;ic receptor antagonists in the methods of the instant invention results in reduced side effects related to peripheral 2 0 adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc.
Further illustrating the invention is a method of treating benign prostatic hyperplasia in a subject in need thereof which comprise s ~lmini~tering to the subject a therapeutically effective 2 5 amount of any of the compounds desribed above.
Further exemplifying the invention is a method of relaxing urethral smooth muscle in a subject in need thereof which comprises CA 0223~370 1998-04-20 W O 97/17967 PCT~US96/18321 ~lmini~tering to the subject a therapeutically effective amount of any of the compounds desribed above.
Additional illustrations of the invention are the methods of treating BPH or of relaxing urethral smooth muscle wherein the ', compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia or relax ul~lh smooth muscle.
More specifically exemplifying the invention are the methods of treating BPH or of relaxing urethral smooth muscle wherein the compound is ~lmini~tered in combination with a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type I testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. More preferably, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. Most preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
2 0 More particularly illustrating the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment of benign prostatic hyperplasia, or for relaxing urethral smooth muscle.
Another example of the invention is a drug which is useful 2 5 for treating benign prostatic hyperplasia or for relaxing urethral smooth muscle, the effective ingredient of the said drug being any of the compounds descibed above.

DETAILED DESCRIPTION OF THE ~VENTION
3 0 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 subst~nti~lly affecting diastolic blood pressure.

W O 97/17967 PCT~US96/18321 Representative compounds l-tili7ed in the methods of this invention display submicrornolar affinity for the hum~n alpha la adrenergic receptor subtype while displaying at least five-fold lower affinity for the human alpha ld and alpha lb adrenergic receptor subtypes, and many other G-protein coupled hnm~n receptors.
Preferred compounds of this invention exhibit nanomolar affinity for the hl1rn~n alpha la adrenergic receptor subtype while displaying at least 10 fold lower affinity for the hnm~n alpha ld and alpha lb adrenergic recepto,r subtypes, opioid receptors and many other G-protein coupled hl~m~n receptors.
These compounds are a~lmini~tered in dosages effective to antagonize the alpha la receptor where such tre~tment is n~e~le~l, as in BPH. For use in medicine, 1he salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention ~,vith a 2 () solution of a pharmaceutically acceptable acid such as hydrochloric acid,sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable ph~rm~ceutically acceptable salts 2 ~, thereof may include alkali metal salts, e.g. sodium or potassium salts;
~Ik~line earth metal salts, e.g. calcium or m~nesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
Thus, r~presentative ph~rm~ceutically acceptable salts include the followillg:
3 C Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clav~ n~t~, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glllt~m~te, Glycoll~ylars~nil~te, Hexylresorcinate, Hydrabamine, Hydrobromide, CA 0223~370 1998-04-20 W O 97/17967 PCTrUS96/18321 Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, LauMte, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate~ N-methylglllc~mine ammonium salt, Oleate, Oxalate, Pamoate s j (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be 10 functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H.
Bundgaard, Elsevier, 1985. Metabolites of these compounds include 15 active species produced upon introduction of compounds of this invention into the biological milieu.
Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers.
Where the compounds according to the invention possess two or more 2 0 chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymoIphs and as such are intended to be included in the 2 ~ present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
The term "alkyl" shall mean straight or branched chain 3 C ~lk~nes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, l-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).

CA 0223~370 1998-04-20 W O 9711796'7 PCTAUS96/18321 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 ', 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).
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., araL~coxyaryloxy) it shall be interpreted as including those limit~tions given above for "alkyl" and "aryl." Design~ted numbers of carbon atoms (e.g., C1-10) shall re~fer independently to Ihe number of carbon atoms in an alkyl or 1', cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The term "halogen" shall include iodine, bromine, chlorine and fluorine.
The term "substituted" shall be deemed to include multiple 2 C degrees of substitution by a named subs~ilulellt. The term "poly-substituted" as used herein shall include di-, tri-, tetra- and penta-substitution by a named substituent.
Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently sub~~iluled by 2 5 one or nnore of the disclosed or claimed substituent moieties, singly or plurally.
The term heterocycle or heterocyclic ring, as used herein, represents an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system which may be saturated or Im~tllrated, and 3 0 which consists of carbon atoms and from one to three heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroat~ms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon ,atom which results in the creation of a CA 0223~370 1998-04-20 W O 97/1796~ PCTAUS96/18321 stable structure. Examples of such heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thi~ 701yl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and o~ 7.olyl. Morpholino is the same as morpholinyl.
The term "subject," as used herein refers to an ~nim~l, preferably a m~mm~l, most preferably a hllm~n, who has been the object of treatment, observation or experiment.
The term "therapeutically effective amount" as used herein means that amount of active compound or ph~rm~ceutical 15 agent that elicits the biological or medicinal response in a tissue, system, ~nim~l 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.
The present invention also provides pharmaceutical 2 0 compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or 25 suppositories; for oral, parenteral, intr~n~l, sublingual or rectal ?~lmini.ctration, or for ~-lmini~tration by inh~l~tion or insufflation.
Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly ~llrnini.~tration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted 3 0 to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and CA 0223~370 1998-04-20 WO 9711796'7 PCT/US96118321 other pharmaceutical diluents, e.g. water, to form a solid preformulation composition cont~ining a homogeneous mixture of a compolmd of the present invention, or a ph~rm~ceutically acceptable salt thereof. When referling to these preformulation compositions as ', homogeneous, it is meant that the active ingredient is dispersed evenly through,out the composition so that the composition may be readily subdivilded into equally effective unit dosage forms such as tablets, pills and caplsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above cont~ining from 0.1 l(J to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage c omponent, the latter being in the for~n of 1~ an envelope over the former. The two components can be separated by an entelic layer which serves to resist tli~integration in the stomach and permits the inner component to pass intact into the duo~len-lm 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 2 0 acids and mixtures of polymeric acids with such materials as shellac, cetyl alc ohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for ~lmini.stration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous 2 5 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 sim-ilar pharmaceut;ical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tr~g~C~ntll~ acacia, alginate, dextran, sodium carboxymethylcellulose, 3 o methylcellulose, polyvinyl-pyrrolidone or gelabin.
Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in CA 0223~370 1998-04-20 WO 97tl7967 PCT/US96118321 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 5 formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional cryst~lli7.~tion 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 10 chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules 15 concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Or~anic Chemistry~ ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Or anic Synthesis. John Wiley &
Sons, lg91. The protecting groups may be removed at a convenient 2 0 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 25 of alpha (e.g., alpha ld, alpha lb) or beta adrenergic receptors.
Expression of the cloned hllm~n alpha ld, alpha lb, and alpha la receptors and comparison of their binding properties with kno~vn selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable ph~rm~cological 3 0 activities. Antagonism by these compounds of the human alpha la adrenergic receptor subtype may be functionally demonstrated in anesthetized ~nim~l~. These compounds may be used to increase urine flow without exhibiting orthostatic hypotensive effects.

W O 97/1796'7 PCT~US96/18321 The ability of compounds of the present invention to specifically bind to the alpha la receptor makes them useful for the tre~tment 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 identified, cloned and expressed as described in PCT International Application Publication Nos. W094/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994, each of which is 1 0 hereby mcorporated by reference. The cloned human alpha la receptor, when expressed in m~mm~ n cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned hllm~n alpha ld, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists 1 5 provides a rational way for selection of compounds and discovery of new compounds with predictable ph~rm~cological activities.
Compounds of this invention exhibiting selective hl-m~n alpha 1a adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in 2 o the art using other receptors responsible for me~ ting diverse biological functions. rSee e.~., PCT Intemational Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No.
5,403,847, issued April 4, 1995, the contents of which are hereby incorporated by reference]. Compounds which are both selective 2 5 amongs1 the various hllm~n alpha 1 adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the ~-adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly ~r~felled. The absence of these non-specific activities may be 3 o con~rmed by using cloned and expressed receptors in an analogous fashion l:o the method disclosed herein for identifying compounds which have hig;h affinity for the various hllm~n alpha 1 adrenergic receptors.
Furthermore, functional biological tests are used to co-lrilln the effects of identified compounds as alpha la adrenergic receptor antagonists.

CA 0223~370 1998-04-20 The present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical form~ tions for use in the novel methods of treatment of the present invention. The compositions cont~ining compounds of this invention 'j as the active ingredient for use in the specific antagonism of h~ n alpha la adrenergic receptors can be ~-lmini.~tered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic ?~lmini~tration. For example, the compounds can be ~-lmini.ctered in such oral dosage forms as tablets, capsules (each including timed 10 release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injectiom. Likewise, they may also be ~ inistered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well 15 known to those of ordinary skill in the ph~ ceutical arts. An effective but non-toxic amount of the compound desired can be employed as an alpha 1 a antagonistic agent.
Advantageously, compounds of the present invention may be ~(lmini~tered in a single daily dose, or the total daily dosage 2 o may be ~lmini~tered in divided doses of two, three or four times daily. Purthermore, compounds for the present invention can be ~-~mini~tered in intranasal fonn via topical use of suitable intranasal vehicles, or via transderrnal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be 25 ~lmini~tered in the form of a transdermal delivery system, the dosage ~ mini~tration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The dosage regimen lltili7:ing the compounds of the present invention is selected in accordance with a variety of factors 3 0 including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of ~mini~tration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective CA 0223~370 1998-04-20 WO 97/17967' PCT/US96/18321 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 5 availability to target sites. This involves a consideration of the distribution, equilibrium, and elimin~tion of a drug.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically ~(lmini~tered in admixture with suitable pharmaceutical 10 diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the inten~le-l form of adrnini.ctration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral ~(lministration 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 2 0 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, tr~g~c~nth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
Lubricants used in these dosage forms include, without limit~tion, sodium oleate, sodium stearate, m~gnP.sium stearate, sodium ben70~te, sodium acetate, sodium chloride and the like.
Disintegrators include, without limit~tion, starch, methyl cellulose, agar, bentonite, x~nth~n gum and the like.
3 0 The li~uid 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 di~ye~sillg agents which may be employed include glycerin and the like. For parenteral ~tlmini~tration, sterile suspensions and solutions are desired.

CA 0223~370 1998-04-20 Isotonic preparations which generally contain suitable preservatives are employed when intravenous ~-lmini~tration is desired.
The compounds of the present invention can also be nini.~tered in the form of liposome delivery systems, such as small ~i lmil~mPllar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers 1 C to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl-~mitlephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl-15 eneoxidepolylysine substituted with palmitoyl residues.Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, 2 0 polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be ~ ni~ctered in any of the foregoing compositions and according to dosage regimens established in ~e art whenever specific blockade of the hnm~n alpha 25 la adrenergic receptor is required.
The dai~y dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult hllm~n per day. For oral ~mini~tration, the compositions are preferably provided in the form of tablets cont~ining 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 3 0 50.0, 100 and 500 milligrams of the active ingredient for the s~lnptolllatic adjustment of the dosage to ~e patient to be treated. A
medicament typically contains from about 0.01 mg to about 500 mg of ~e active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. An effective amount of ~e drug is ordinarily 6'7 PCT/US96/18321 supplield at a dosage level of from about 0.0002 mg/kg to about 250 m~/kg of body weight per day. Preferably, the range is from about 0.001 to 100 mg/kg of body weight per day, and especially from about 0.001 mg/lcg to 7 m~/kg of body weight per day. The compounds may S be ~llmini.ctered on a regimen of 1 to 4 times per day.
Compounds of this patent disclosure may be used alone at a~l~ro~iate dosages defined by routine testing in order to obtain optimal antagonism of the hllm~n alpha la adrenergic receptor while minimi7ing any potential toxicity. In addition, co-~-lmini~tration or 10 sequential ~ ini.~tration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this includes ~lmini~tration of compounds of this invention and a hllm~n testosterone 5-a reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are now well 1 c; known in the art and include such compounds as PROSCAR(~), (also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071, for example, hereby incorporated by reference). In addition to PROSCAR@~), which is principally active in prostatic tissue due to its selectivity for hllm~n 5-a reductase isozyme 2, combinations of 2 o compounds which are specifically active in inhibiting testosterone 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in combination with compounds of this invention. Compounds that are active as Sa-reductase inhibitors have been described in W093/23420, EP 0572166; WO 93/23050;
25 W093/~!3038,; W093/23W8; WO93/23041; W093/23040;
W093/23039; W093/23376; WO93/23419, EP 0572165; WO93/23051, each of which is hereby incorporated by reference.
The dosages of the alpha la adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined 3 0 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 optimi7s~1 and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In CA 0223~370 1998-04-20 W O 97/1796'7 PCT~US96118321 accordance with the method of the present invention, the individual components of the combination can be ~-lministered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is 5 therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "~flmini~tering" is to be interpreted accordingly.
Thus, in one preferred embodiment of the present invention, a method of treating BPH is provided which comprises 1 C ~lmini.~tering to a subject in need of tre~tment any of the compounds of the present invention in combination with finasteride effective to treat BPH. The dosage of finasteride ~dministered to the subject is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha la antagonist. Preferably, the 15 dosage of finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day.
For the treatment of benign prostatic hyperplasia, 2 0 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 4,7~-dimethyl-4-aza-Sa-cholestan-3-one, in a single oral, systemic, or parenteral pharmaceutical dosage 2 5 formulation. Alternatively, a combined therapy can be employed wherein the alpha la adrenergic receptor antagonist and the 5a-reductase 1 or 2 inhibitor are ~lmini~tered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and 3 0 formulal:ions for Sa-reductase inhibitors.
Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:

ACE-Cl = alpha-chloroethylchloroformate W O 97/1796,' PCT~US96/18321 Boc or BOC = t-butyloxycarbonyl BOPCI = bis(2-oxo-3-oxazolidinyl)phosphinic chloride Cbz-CI = benzyloxycarbonyl chloride DAST = diethylaminosulfurtrifluoride DEAD = diethylazodicarboxylate DMF = N,N-dimethylformamide EDCI= 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride Et = ethyl Et3N = triethylamine EtOAc = ethyl acetate EtOH = ethanol FABLRMS = fast atom bombardment low resolution mass spectroscopy HPLC = high performance liquid chromatography HOAc = acetic acid HOBt = l-hydroxy benzotriazole hydrate i-PrOH= 2-propanol i-Pr2NEt = diisopropylethylamine 2 o Me = methyl MeOH = methanol NMP = 1-methyl-2-pyrrolidinone NMR = nuclear m~ tic resonance PCTLC = preparative centrifugal thin layer 2 5 chromatography PEI = polyethyle~ le Ph = phenyl RT = retention time TFA = trifluoroacetic acid 3 0 THF = tetrahydrofuran TLC = thin layer chromatography The compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or 7' PCT/US96/18321 modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possib~e to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater 5 detail. IJnless otherwise indicated, all variables are as defined above.
The preparation of 4,4-disubstituted piperidines 4 was accomplished via spiro annulation of substituted acetonitrile derivatives 1 with N-Boc bischloroethyl amine under basic conditions, typically NaH in DMF at 80 ~C in good yields, Scheme 1. The resulting 4-cyano 10 4-phenylpiperidines 3 were either: 1) N-Boc deprotected with HCl-EtOAc or 2) the nitrile hydrolyzed to the corresponding carboxylic acid with concomitant N-Boc deprotection with concentrated aqueous HCl and converted to esters and ~mitles via simple coupling reactions to targeted derivatives 4. In some instances the amino acids derived from 15 treatment of 3 with concentrated aqueous HCl required N-Boc protection prior to the coupling reactions to limit oligomerization.
Scheme 1.
Cl CN
C~ + NBOC THF/DMF e~NBOC
R1 Cl 2 60~C R1 3 (R2=CN) ~2 C~NBOC Q{~NH-HCI

(R =CO2R Or CONH2) 4 3 1 ) COnC aq HCI
2) ROH/tlCI(9~
Or ROH/BOPCI
Or NH3/BOPCI

CA 02235370 l998-04-20 W O 97117967 PCTrUS96/18321 The preparation of 3,4-disubstituted piperidines 8 and 10 was accomplished in a simple two step fashion, Scheme 2. The vinyl triflate 6, derived from N-Boc 3-carboxyethyl 4-piperidinone was coupled under Pd catalysis to aryl boronic acids and aryl st~nn~n~s in , excellent yields. The resulting a,~-unsaturated esters 7 were reduced with hydrogen and Pd-C providing the (t)-cis enantiomeric pair 8. At this stage several pathways were pursued: (1) the (+)-cis racemate 8 was deprotected yielding 9, (2) the (i)-cis enantiomeric pair 8 was converted to (+)-trans 10 via epimerization to the diequitorial isomer 10 wi~ the use of sodium ethoxide, then the resulting 10 (+)-trans was deprotected providing 11, (3) the mixture (+)-cis enantiomers 8 was separated using normal phase chiral HPLC providing 8a (-)-cis and 8b (+)-cis and 8a was then deprotected providing 9a.
Scheme 2.
, ~ CO2CH2CH3 1~ 31 CO2CH2CH3 TfO~ K PO ~
B(O H)2 + ~ 4 , ~ NBOC
or NR THFlreflux -SnMe3 or - - Pd(OAc)2 7 5a Ar(BOH2) 6 R=BOC NMP/-15-0 C
5b .ArSnMe3 H2 l~jl CO2CH2CH3 ~ CO2CH2CH3 10 % Pd-C ~ NaOEt ~
7 EtOH . ~1 EtOH ~ ~ NR

Chiralcel OD R=BOC
HCI ~ 8 R=BOC 8a (-)-cis 10 (+)-trans R=BOC
EtOAc ¦~ g R=H-Hcl 8b (+)-cis HCI
R=H-HCI 11 R=H-HCI EtOAc 9a (-)-cis 9b (+)-cis The commercially available amino alcohol 12 was converted to the corresponding chloride 13 via treatment with thionyl W O 97117967 PCT~US96118321.

chloride, Scheme 3. The chloride 13 was displaced by aniline in toluene at 180 ~C providing anilinoethylbenzyl amine 14. Treatment of 14 with 2-chloroacrylonitrile in DMF provided the desired cyano piperazine 15. N-benzyl deprotection was accomplished using ACE-CI
~, in dichloroethane followed by treatment wi~ methanol supplying the cyano piperazine 16. Piperazines 15 and 16 were separated easily tili7.ing chiral HPLC technology and each enantiomer was evaluated individually, 15a and 15b, and 16a and 16b, respectively.

Scheme 3 ~~ CHCI3 ~~ H ~HCI ~NH2 12 13 Toluene, 130~C

WO 97/17967 PCT/US96/18.321 =( N CN ~Cl 1 C813CoHC2CH2CI~
~NHHCl .~N~ + ~=O 2. MeOH, r.t. ~N~CN

N~ DMF, (i-Pr)2NEt ~13 Cl lN6 . HCI

14 ~ Chiralcel OD ~

~N~,CN ~N~CN

15a~l 15C
¢~ ~
N C N Chiralcel OD ~ ~ +

16 16a 16b rj Preferred compounds of the present invention are shown below im Table 1. The compounds of the present invention can be prepared by one of ordinary skill in the art following the schemes and examples set forth herein, substituting the a~lo~-iate readily available starting materials.
lCI

W O 97/17967 PCTrUS96/18321 R~r~R2 ~A~,~,~ R3 4a H H H C NA
4b H CO2CH 3 H C NA
4c H CO2CH2CH3 H C NA
4d H C02(CH2)3CH3 H C NA
4e H CO2cyclohexyl H C NA
4f H CN H C NA
4g H CONH2 H C NA
4h H CO2H H C NA
4i CH3 CN H C NA
4; Cl C N H C NA
4k Cl CO2CH3 H C NA

4m OCH3 C N H C NA
4n CN CN H C NA

9 H H CO2CH2CH3 C (i)-cis 11 H H CO2CH2CH3 C (+)-trans W O 97/1796'7 PCTAUS96/18321 gb H H CO2CH2CI 13 C (+)-cis 9a H H CO2CH2CH3 C (-)-cis 1 6a H - C N N isomer A
16b H - C N N isomer B
In addition to the compounds disclosed above in Table 1, 4-cyano4-(2-pyridyl)piperidine was also prepared.
The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples.

1~ Bis(2-c:hloroethyl)-N-(l~1-dimethylethoxy)carbonyl amine (2) A solution of N-(2,2'-bischloro)diethyl amine (23.0 g, 0.130 mol) and di-tert-butyl dicarbonate (28.8 g, 0.130 mol) in CH2CI,~
(150 mL) was treated with N,N-diisopropylethylamine (22.52 ml, 0.720 mol) at room temperature (1.5 h). The solvent was removed in vacuo and the residue was triturated with ether (300 ml). The ether solution was collected and concentrated in vac~lo affording N42,2'-bischloro)-diethyl-N-(1,1-dimethylethoxy)carbonyl amine as a clear oil.
lH NMR (CDCl3, 400 MHz) d 3.65 (m, 8H), 1.52 (s, 9H) FABLRMS (3:1 mixture of dithiothreitol and dithioerythritol in MeOH) m/e 242 g/mole (M++ H, C25H29N205SCl -242.2 gJmole.) 2';
4-Cyano-N-( 1 ~1 -dimethylethoxy)carbonyl-4-(2-methylphenyl)piperidine A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (1.438 g, 5.94 mmol) and 2-3 0 methylphenyl acetonitrile (600 mg, 3.96 mmol) in a 4:1 mixture of CA 02235370 l998-04-20 WO 97/1796'7 PCTAUS9G/18321 THF/DMF (15 mL) was treated with NaH (357.9 mg, 8.7 mmol) at 60 ~C (3 d). The solvent was removed in vacuo, the residue dissolved in EtOAc (200 ml) and washed with saturated NaHCO3 (50 ml), H20 (2 x 50ml), and saturated aqueous NaCI (50 ml), dried (Na2S04) and 5 concentrated in vacuo. PCTLC (SiO2, 6mm, 100% hexane) afforded 4-cyano-. \7-(1,1 -dimethyletho~cy)carbonyl-4-(2-methylphenyl) piperidine as a yellow/orange oil.
1H NMR (CDCl3, 400 MHz) d 7.25 (m,4H), 4.28 (br s, 2H), 3.28 (br t, 2H), 2.65 (s, 3H), 2.32 (d, 2H, J = 13.0 Hz), 2.32 (dt 1~~ 2H, J = 4.1, 13.0 Hz), 1.48 (s, 9H).
HPLC (Vydac; C18; diameter = 4.6 mm; length = 15 cm;
gradient = CH3CN [0.1% TFA] - H20 [0.1% TFA], S~o - 95%, 95 - 5%
over 20 min. 1.5 ml/min flow rate; RT = 11.730 min; focus = 215 nm;
75% pure.
11~

4-Cyano-4-(2-methylphenyl)piperidine hydrochloride (4i) 2 () A solution of EtOAc saturated with HCl (200 ml) was added to 4-cyano-N-(I,l-dimethylethoxy)carbonyl-4-(2-methylphenyl)piperidine (31 mg, 0.097 mmol). The resulting mixt~lre was allowed to react for 1 hour at room temperature. The EtOAc was removed in vacuo affording 4-cyano4-(2-methylphenyl)piperidine 2 '; hydrochloride (4i) as a white solid.
lH NMR (CD30D, 400 MHz) d 7.37 (m, lH), 7.32 (m, 3H), 3.64 (dd, 2H, J = 2.2, 11.4 Hz), 3.46 (t, 2H, J = 13.5 Hz), 2.64 (m, 2H'I, 2.65 (s, 3H), 2.28 (t d, 2H, J = 3.7 Hz, 13.5 Hz).
FABLRMS (3:1 mixture of dithiothreitol and 3 0 dithioerythritol in MeOH) m/e 201 g/mole (M++ H, C13H16N2 = 201.3 g/mole.) HPLC (Vydac; C18; ~ meter = 4.6 mm; length =15 cm;
gradienlt = CH3CN [0.1% TFA] - H20 [0.1% TFAI, 5% - 95%, 95 5%

over 20 min. 1.5 ml/min flow rate; RT = 5.82 min; focus = 215 nm;
100% pure.
Anal. Calcd for Cl3Hl6N2. HCl and 0.30 H20 and 0.25 CH2C12: C = 60.42, H = 6.93, N = 10.64. Found: C = 60.37, H = 6.83, 5 N= 1l.09.

4-(2-Chlorophenyl)-4-cyano-N-(I .1 -dimethylethoxycarbonyl)piperidine A solution of bis(2-chloroethyl)-N-(l,l-dimethylethoxy)carbonyl amine (9.298 g, 38.4 mmol) and 2-chlorophenylacetonitrile (5.0 g, 32.0 mmol) in a 4:1 mixture of THF/
DMF (15 mL) was treated with NaH (2.82 g, 70.4 mmol) at 60 ~C (7 1 5 d). The solvent was removed in vaclw, the residue dissolved in EtOAc (200 ml) and washed with saturated NaHCO3 (50 ml), H20 (2 x 50ml), and saturated aqueous NaCI (50 ml), dried (Na2SO4) and concentrated in vac~o. Trituration of the residue with 100% MeOH afforded 4-(2-chlorophenyl)-4-cyano-N-(1,1-dimethylethoxy) carbonyl piperidine as a 2 l~ white solid.
1H NMR (CD30D, 400 MHz) d 7.53 (m, 2H), d 7.41 (m, 2H), 4.28 (br dd, 2H, J = 13.4 Hz), 3.26 (m, 2H), 2.52 (dd, 2H, J = 2.2, 11.2 H;z), 2.03 (dt, 2H, J = 4.0, 9.2 Hz), 2.03 (s, 9H).
FABLRMS (3:1 mixture of dithiothreitol and 2 5 dithioel~thritol in MeOH) m/e 321 g/mole (M++ H, C17H21N202CI =
320.8 glmole.) HPLC (Vydac; C18; diameter = 4.6 mm; leng~ = 15 cm;
gradient = CH3CN [0.1% TFA] - H20 [0.1% TFA], 5% - 95%, 95 - 5%
over 20 min. 1.5 ml/min flow rate; RT = 11.70 min; focus = 215 nm;
3 ~ 97.4% pure.

4-(2-Chlorophenyl)-4-cyanopiperidine hydrochloride (4j) 3c;

W O 97/1796'7 PCTAUS96/18321 A solution of EtOAc saturated with HCI (200 ml) was added l:o 4-(2-chlorophenyl)-4-cyano-N-(l,l-dimethylethoxycarbonyl)piperidine, (880 mg, 2.74 mmol). The resultinLg mixture was allowed to react for 1 hour at room temperature.
, The EtOAc was removed in vacuo affording 4-(2-Chlorophenyl)4-cyanopiperidine hydrochloride (4j) as a white solid.
lH NMR (CD30D, 400 MHz) d 7.53 (dd, lH, J = 2.0, 4.3 Hz), 7.:5 (dd, lH, J = 2.0, 5.3 Hz), 7.40 (ddd, 2H, J = 2.0, 6.0, 7.9 Hz), 3.14 (dldd, 4H, J = 2.2, 10.8, 12.4 Hz), 2.51 (dd, 2H, J = 2.2, 13.5 Hz), 10 2.00 (dt, 2H, J = 3.4, 13.5 Hz).
FABLRMS (3:1 mixture of dithiothreitol and dithioelythritol in MeOH) rnJe 221 ~/mole (M++ H, C13H16N2 =
220.7 ~Jmole.) HPLC (Vydac; C18; diameter - 4.6 mm; length =1 5 cm;
15 gradient = CH3CN [0.1% TFA] - H20 [0.1% TFA], 5% - 95%, 95 - 5 over 20 min. 1.5 ml/min flow rate; RT = 5.744 min; focus = 215 nm;
99.04% pure.
Anal. Calcd for C12H13N2Cl. HCI and 0.60 H2O: C =
62.26,H=6.18,N= 12.10. Found:C=62.29,H=5.69,N= 11.71.
2() N-Benzyl-N-(2-chloroethyl)arnine hydrochloride (13) 2 ', A solution of N-benzyl-2-aminoethanol (12, 79.05 g, 0.523 mole) in chlorofolm (400 mL) was treated with thionyl chloride (80 mL, 1.09 mole) at room temperature. The resulting mixture was heated to reflu ~ (6 h). The solvent was removed in vacuo, the residue dissloved in hot ethanol (1.3 L) and cooled overnight. The solids were 3 0 collected via suction f1ltration and dried in vacuo at 65~C (24 h) to afford t]he title compound 13 as white plates.

35 N-Benzyl-N'-phenyl-1.2-~ rninoethane hydrochloride (14) WO 97/17967 PCTrUS96/18321 A solution of 13 (8.618 g, 42.0 mmol) and ~niline (11.75 g, 126 mmol) in toluene (40 mL) was heated to 130~C (1.5 h). The mixture was triturated with dichloromethane (200 mL) and filtered.
Recryst~11i7-~tion from ethanol (220 mI,) afforded the title compound 14 as white crystals.
lH NMR (DMSO, 400 MHz) ~ 7.59 (dd, 2H, J = 1.93, 7.64 Hz), 7.42 (m, 3H), 7.10 (t, 2H, 7.98 Hz), 6.59 (m, 3H), 5.95 (s, lH), 4.17 (s. 2H), 3.41 (t, 2H, J = 6.38 Hz), 3.04 (t, 2H, J = 6.55 Hz).
FABLRMS m/e 241 g/mole (M++H, Cl6H2"N2=241 g/mole ) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm;
gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 7.371 min; focus = 215 nm; 99.3%
1 ', pure.

4-Benzyl-2-cyano- 1 -phenylpiperazine (15) 2() A solution of 14 (5.07 g, 17.0 mmol) and diisopropylethylamine (4.97 g, 38.4 mmol) in DMF (40 mL) was treated with a solution of 2-cyanoacrylonitrile (2.30 g, 26.3 mmol) in DMF (40 mL) at room temperature (14 d). The solvent was removed 2 'i in vacuo and the residue dissolved in dichloromethane alld washed with water, brine, and dried (Na2SO4). Concentrated in vac~o, the residue was reclystallized from e~anol to afford 15 as white crystals.
IH NMR (CDCl3, 400 MHz) ~ 7.34 (m, 7H), 7.00 (t, 3H, J
= 8.31 Hz), 4.53 (s, lH), 3.72 (d, lH, J = 13.26 Hz), 3.59 (d, lH, 13.43 3C Hz), 3.40 (d, lH, J = 11.91 Hz), 3.28 (td, lH, J = 3.13, 11.59 Hz), 3.13 (dt, lH, J = 2.26, 11.42 Hz), 3.01 (dq, lH, J = 2.43, 11.08 Hz), 2.53 (dd, lH, J = 3.19, 11.41 Hz), 2.39 (td, lH, J = 3.36, 11.25 Hz).
FABLRMS mte 278 g/mole (M++H, Cl8H20N3 = 278 g/mole. ) W O 97/17967 PCT~US96/18321 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm;
gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minllte~" 2 ml/min flow rate) RT = 7.936 min; focus = 215 nm; 100%
pure.
S Anal. Calcd for Cl8HIgN3 ~ 0.15 H2O: C = 77.19, H = 6.95 N = 15 00. Found: C = 77.14, H = 6.90, N = 14.88.

2-Cyano-1-phenylpiperazine (16) A solution of 15 (3.40 g, 12.25 mmol) in 1,2-dichloroethane (60 mL) was treated with alpha-chloroethyl-chloroformate (3.78 g, 26.44 mmol) at 0~C. The reaction mixtllre was 1c, heated to 100~C (8 h). The solvent was removed in vacuo and the residue dissolved in methanol (80 mL) at room temperature (overnight). The solvent was removed in vacllo and the residue was recrystallized from ethanol (160 mL) to afford crystalline 16.
IH NMR (DMSO, 400 MHz) ~ 9.74 (s, lH), 7.36 (m, 2H), 7.12(d,2H,J=7.89Hz),7.()3(t, lH,J=7.31 Hz),5.48(d, lH,J=
4.03 Hz), 3.75 (d, 2H, J = 13.09 Hz), 3.43 (dd, lH, J = 4.53, 13.43 Hz), 3.38 (d, 2H, J = 10.74 Hz), 3.07 (m, 2H).
FABLRMS m/e 188 g/mole (M++H, Cl,HI4N3= 188 g/mole.') HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm;
gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minlltes, 2 ml/min flow rate) RT = 3.563 min; focus = 215 nm; 100%
pure.
Anal. Calcd for ClIHl3N3 ~ 1.00 HCl: C = 59.06, H = 6.31, N = 18.'79. Found: C = 59.27, H = 6.37, N = 18.42.

Enantioxners of 15 (15~ and 1 5h).

WO 97tl796'' PCTtUS96/18321 The enantiomeric mixture was separated lltili7ing norrnal phase chiral HPLC (Chiralcel OD~ 2.0 cm x 25 cm, 65 hexanes/35 2-propanol/0.2 diethyl amine, 2.5 mL/min). Each enantiomer possessed identical spectroscopic properties but opposite signs of optical rotation.
~, Chiral purity was assessed lltili7in~ similar HPLC conditions (Chiralcel OD, 4.6 mm x 25 cm, 65 hexanes/35 2-propanol/0.2 die~yl amine, 0.7 mL/min).

EXAMPLE 1 l 1() Fn~ntiomers of 16 (16~ and 16h).

The enantiomeric mixture was separated ~ ing normal phase chiral HPLC (Chiralcel OD, 2.0 cm x 25 cm, 65 hexanes/35 2-15 propanol/0.2 diethyl amine, 2.5 mL/min). Each enantiomer possessedidentica,l spectroscopic properties but opposite signs of optical rotation.
Chiral purity was assessed lltili~ing similar HPLC conditions (Chiralcel OD, 4.6 mm x 25 cm, 65 hexanes/35 2-propanol/0.2 diethyl amine, 0.7 mL/min).
2~3 As a specific embodiment of an oral composition, 100 mg of the compound of Example 3 is formulated with sufficient finely 2 5 divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

3 C Screening assay: Alpha la Adrenergic Receptor Bin¢lin~
Membranes prepared from the stably transfected hllm~n alpha la cell line (ATCC CRL 11140) were used to identify compounds that bind to the hllm~n alpha la adrenergic receptor. These competition binding reactions (total volume = 200 ~l) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCI, 1()0 pM [125 I]-HEAT, membr;mes prepared from the alpha la cell line and increasing amounts of unlalbeled ligand. Reactions were incubated at room temperature for one hour with ~h~king Reactions were filtered onto Wh~tm~n GF/C
t, glass fiber filters with a Inotec 96 well cell harvester. Pilters 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 ~ 500 nM.

Selective Bindin,~ assays Membranes prepared from stably transfected hllm~n alpha ld and alpha lb cell lines (ATCC CRL 11 138 and CRL 11139, 15 respectively) were used to identify compounds that selectively bind to the hllm~n alpha la adrenergic receptor. These competition binding reactions (total volume = 20() ,ul) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 I~-HEAT, membranes prepared from cell lines transfected with the respective alpha 1 subtype 2 C expressiion plasmid and increasing amounts of unlabeled ligand.
Reactions were incubated at room temperature for one hour with sh~kin~. Reactions were filtered onto Whatnn~n GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki).

EXEMPLARY COIJNTERSCREENS

3 o 1. Assay Title: Dopamine D2, D3, D4 in vitro screen Objective of the Assay:
The objective of this assay is to elimin~te agents which specifically affect binding of [3H] spiperone to cells expressing hl-m~n dopamine receptors D2, D3 or D4.

W O g7/17967 PCT~US96118321 Method;
Modified from VanTol et al (1991); Nature (Vol 350) Pg 610-613.
Frozen pellets cont~ining specific dopamine receptor 5 subtypes stably expressed in clonal cell lines are Iysed in 2 ml Iysing buffer (lOmM Tris-HCV5mM Mg, pH 7.4). Pellets obtained after centrifilging these membranes (lS' at 24,450 rpm) are resuspended in 50mM Tris-HCI pH 7.4 cont~ining EDTA, MgCI[2~, KCI, NaCI, CaCI[2]
and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by 1 ~ ~dding 50-75 ,ug membranes in a total volume of 500 ,ul con~ining 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 ,uM
apomorphine. The assay is termin~ted after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.
l''j 2. Assay Title: Serotonin SHTla Objective of the Assay The objective of this assay is to elimin~te agents which specifically affect binding to cloned human SHTla receptor 2() Method:
Modified from Schelegel and Peroutka Biochemical Pharmacology 35: 1943- 1949 (1986).
mm~ n cells expressing cloned hllm~n SHTla receptors 2 'j are lysed in ice-cold 5 mM Tris-HCl, 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at 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 ) 3 CI in 50 mM Tris-HCl, 4 mM CaCl2 and lmg/ml ascorbate. Non-specific binding is defined using 10 ,uM propranolol. The assay is tern~in~ted after a 11 hour incubation at room temperature by rapid filtration over GF/Cfilters EXEMPLARY FUNCTIONAL ASSAYS
In order to confirm the specificity of compounds for the hllm~n alpha la adrenergic receptor and to define the biological activity of the compounds, the following functional tests may be performed:

1. In vitro Rat, Dog and Human Prostate and Dog Urethra Taconic Farms Sprague-Dawley male rats, weighing 250-1~ 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate. Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary. Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles. Human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored overnight in ice-cold Krebs solution if needed.
2 0 The tissue is placed in a Petri dish cont~ining oxygenated Krebs solution [NaCl, 118 mM; KCI, 4.7 mM; CaCl2, 2.5 mM;
KH2PC)4, 1.2 mM; MgSO4, 1.2 mM; NaHCO3, 2.0 mM; dextrose, 11 mM] warmed to 37~C. Excess lipid material and connective tissue are carefully removed. Tissue segments are attached to glass tissue holders 2 ', with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath cont~in-in~ Krebs buffer at 37~C, bubbled with 5% C02/95% O2. The tissues are connected to a St~th~m-Gould force transducer; 1 gram (rat, hllm~n) or 1.5 gram (dog) of tension is applied and the tissues are allowedl to equilibrate for one hour. Contractions are recorded on a 3 () Hewletli-Packard 7700 series strip chart recorder.
After a single priming dose of 3 ~uM (for rat), 10 ~M (for dog) and 20 ~M (for hllm~n) of phenylephrine, a cumulative concentration response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added CA 0223~370 1998-04-20 W O 97/17967 PCTfUS96/18321 to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated.
EC50 values are calculated for each group using GraphPad Inplot software. pA2 (-log Kb) values were obtained from Schild plot 5 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 = rBl, x-l where x is the ratio of EC50 of agonist in the presence and absence of 10 antagonist and [B3 is the antagonist concentration.

2. Measurement of ~tra-Urethral Pressure in Anesthetized Dogs PURPOSE: Benign prostatic hyperplasia causes a decreased urine flow rate that may be produced by both passive physical 15 obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction. Alpha adrenergic receptorantagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man. However, these are non-selective alpha l 2 0 receptor antagonists which also have pronounced vascular effects.
Because we have identified the alpha la receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without concolllila,lt changes in the vasculature. The following model is used to 2 5 measure adrenergically mediated changes in intra-urethral pressure and arterial pressure in anesthetized dogs in order to evaluate the efficacy and potency of selective alpha adrenergic receptor antagonists. The goals are to: 1) identify the alpha 1 receptor subtypes responsible for prostati~/urethral contraction and vascular responses, and 2) use this 3 o model to evaluate novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be ev~ ted in this m~nner.
METHODS: Male mongrel dogs (7-12 kg) are used in this study. The dogs are anesthetized with pentobarbital sodium (35 CA 0223~370 l998-04-20 W O 97/1796" PCTAUS96/18321 mglkg, i.v. plus 4 mg/kglhr iv infusion). An endotracheal tube is inserted and the ~nim~l ventilated with room air using a Harvard instruments positive displacement large ~nim~l ventilator. C~theters (PE 240 or 260) are placed in the aorta via the femoral artery and vena cava via the femoral veins (2 catheters, one in each vein) for the measurement of arterial pressure and the ~lmini.~tration 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 c~nn~ ted so that urine flows freely into beakers. The 1 () dome of the bladder is retracted to facilitate dissection of the proximaland distal urethra. Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate. The bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra. The bladder incision is sutured with 2-0 or 3-0 silk (purse-string s-uture) 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.
2 o Phenylephrine, .m alpha 1 adrenergic agonist, is lmini~tered (0.1-100 ug/kg, iv; 0.05 mllkg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure. Following ~11mini.~tration of increasing doses of an alpha adrenergic antagonist (or vehicle), the effects of phenylephrine on 2 ~, arterial pressure and intra-urethral pressure are re-evaluated. Four or five phenylephrine dose-response curves are generated in each ~nim~l (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 farnily 3 C of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining ~e slope, mi~ response, and maximllm response to be constant among curves. The dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the CA 0223~370 1998-04-20 W O 97/1796~ PCT~US96/1832:1 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 c~l-sing a 2-fold rightward shift of the phenylephrine dose-response curve) is used to compare the relative potency of the antagonists on inhibiting phenylephrine responses for intra-urethral and arterial pressure. The relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure Kb's. Effects of the alpha 1 antagonists on baseline arterial pressure are also monitored. Comparison of the relative antagonist potency on changes in arterial pressure and intra-urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing intra-urethral pressure is also present in the systemic vasculature.
According to this method, one is able to confirm the selectivity of alpha la adrenergic receptor antagonists that prevent the increase in intra-urethral pressure to phenylephrine without any activity at the vasculature.

2 0 Opioid receptor binding assay 3H-Naloxone binds with high affinity to opiate receptors in brain tissue (Creese and Snyder, J. Pharm Expt. Ther., 194: 205-219, 1975). The potency of a compound to inhibit the specific binding of this radioligand gives a measure of the affinity for these receptors.
2 5 3H-Naloxone binding in rat brain membranes was performed as described by Creese and Snyder (J. Pharm. Expt. Ther., 194, 205-219, 1975) using Tris buffer alone or in the presence of 150 mM NaCl.
Naloxone binding for representative examples of the present invention are 2 6 ~M.
3 0 While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come wi~in the scope of the following claims and their equivalents.

Claims (23)

WHAT IS CLAIMED IS:

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

wherein A is selected from C-R2 or N;

X is C or N, provided that when X is N, then R1 is absent;

R1 is selected from hydrogen, halogen, C1-8 alkyl, mono-, di- or tri-halogenated C1-8 alkyl, C1-6 alkoxy, cyano, CONR4R5 or C3-8 cycloalkyl;

R2 is selected from hydrogen, cyano, CONR4R5 or CO2R4;

R3 is selected from hydrogen, cyano, CONR4R5, CO2R4 or SO2R4;
and R4 and R5 are each independently selected from hydrogen, C1-8 alkyl or C3-8 cycloalkyl;
and the pharmaceutically acceptable salts thereof.

2. The method of Claim 1, wherein R1 is selected from hydrogen, halogen, C1-6 alkyl, mono-, di- or tri-halogenated C1-6 alkyl, C1-4 alkoxy, cyano, CONH2 or C3-6 cycloalkyl;
R3 is selected from hydrogen, cyano or CO2R4; and R4 and R5 are each independently selected from hydrogen, C1-6 alkyl or C3-6 cycloalkyl;
and the pharmaceutically acceptable salts thereof.

3. The method of Claim 2, wherein X is C;
R1 is selected from hydrogen, chloro, C1-4 alkyl, tri-halogenated C1-4 alkyl, C1-4 alkoxy, cyano or CONH2;
R2 is selected from hydrogen, cyano, CONH2 or CO2R4;
R3 is selected from hydrogen, cyano or CO2CH2CH3; and R4 is selected from hydrogen, C1-4 alkyl or C3-6 cycloalkyl;
and the pharmaceutically acceptable salts thereof.

4. The method of Claim 3, wherein the compound has the formula wherein R1 is selected from hydrogen, chloro, methyl, trifluoromethyl, methoxy, cyano or CONH2; and R2 is selected from hydrogen, cyano, CONH2, CO2H, CO2CH3, CO2CH2CH3, CO2(CH2)3CH3 or CO2cyclohexyl;
and the pharmaceutically acceptable salts thereof.

5. The method of Claim 4, wherein the compound is selected from or wherein R2 is selected from hydrogen, cyano, CO2H or CO2NH2;
and the pharmaceutically acceptable salts thereof.

6. The method of Claim 5, wherein the compound has the structure and the pharmaceutically acceptable salts thereof.

7. The method of Claim 6, wherein the compound is selected from 4-cyano-4-(2-trifluoromethylphenyl)piperidine;
4-cyano-4-(2-methylphenyl)piperidine;
4-(2-chlorophenyl)-4-cyanopiperidine or 4-(2-chlorophenyl)-4-(methoxycarbonyl)piperidine and the pharmaceutically acceptable salts thereof.

8. The method of Claim 1, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.

9. The method of Claim 1, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.

10. The method of Claim 9, 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.

11. The method of Claim 10, wherein the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor.

12. The method of Claim 11, wherein the testosterone 5-alpha reductase inhibitor is finasteride.

13. A method of relaxing urethral smooth muscle in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1.

14. The method of Claim 13, wherein R1 is selected from hydrogen, halogen, C1-6 alkyl, mono-, di- or tri-halogenated C1-6 alkyl, C1-4 alkoxy, cyano, CONH2 or C3-6 cycloalkyl;
R3 is selected from hydrogen, cyano or CO2R4; and R4 and R5 are each independently selected from hydrogen, C1-6 alkyl or C3-6 cycloalkyl;
and the pharmaceutically acceptable salts thereof.

15. The method of Claim 14, wherein X is C;
R1 is selected from hydrogen, chloro, C1-4 alkyl, tri-halogenated C1-4 alkyl, C1-4 alkoxy, cyano or CONH2;
R2 is selected from hydrogen, cyano, CONH2 or CO2R4;
R3 is selected from hydrogen, cyano or CO2CH2CH3; and R4 is selected from hydrogen, C1-4 alkyl or C3-6 cycloalkyl;
and the pharmaceutically acceptable salts thereof.

16. The method of Claim 15, wherein the compound has the formula wherein R1 is selected from hydrogen, chloro, methyl, trifluoromethyl, methoxy, cyano or CONH2; and R2 is selected from hydrogen, cyano, CONH2, CO2H, CO2CH3, CO2CH2CH3, CO2(CH2)3CH3 or CO2cyclohexyl;
and the pharmaceutically acceptable salts thereof.

17. The method of Claim 16, wherein the compound is selected from or wherein R2 is selected from hydrogen, cyano, CO2H or CO2NH2;
and the pharmaceutically acceptable salts thereof.

18. The method of Claim 17, wherein the compound has the structure and the pharmaceutically acceptable salts thereof.

19. The method of Claim 18, wherein the compound is selected from 4-cyano-4-(2-trifluoromethylphenyl)piperidine;
4-cyano-4-(2-methylphenyl)piperidine;
4-(2-chlorophenyl)-4-cyanopiperidine or 4-(2-chlorophenyl)-4-(methoxycarbonyl)piperidine and the pharmaceutically acceptable salts thereof.

20. The method of Claim 13, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to relax urethral smooth muscle.

21. The method of Claim 13, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.

22. The method of Claim 21, wherein the testosterone 5-alpha reductase inhibitor is finasteride.

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