WO1997017967A1 - ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a - Google Patents

ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a Download PDF

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Publication number
WO1997017967A1
WO1997017967A1 PCT/US1996/018321 US9618321W WO9717967A1 WO 1997017967 A1 WO1997017967 A1 WO 1997017967A1 US 9618321 W US9618321 W US 9618321W WO 9717967 A1 WO9717967 A1 WO 9717967A1
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WIPO (PCT)
Prior art keywords
cyano
hydrogen
alpha
compound
alkyl
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PCT/US1996/018321
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English (en)
Inventor
Mark G. Bock
Michael A. Patane
Rose Ann Ponticello
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Merck & Co., Inc.
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Publication date
Priority claimed from GBGB9603423.6A external-priority patent/GB9603423D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU77343/96A priority Critical patent/AU710337B2/en
Priority to EP96940465A priority patent/EP0865280A1/fr
Priority to JP9519091A priority patent/JPH11507395A/ja
Priority to CA 2235370 priority patent/CA2235370A1/fr
Priority to US09/066,477 priority patent/US5922722A/en
Publication of WO1997017967A1 publication Critical patent/WO1997017967A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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).
  • BPH benign prostatic hyperplasia
  • Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
  • Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla.
  • the binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol.
  • the binding affinity of these hormones is reversed for the beta receptors.
  • the functional responses such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
  • alpha and beta receptors were further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources.
  • alpha and beta adrenergic receptors were further subdivided into cq , oc2, Bl , and ⁇ 2 subtypes.
  • non ⁇ selective alpha-adrenergic blockers such as phenoxybenzamine and phentolamine
  • phenoxybenzamine and phentolamine are limited by their ⁇ 2 adrenergic receptor mediated induction of increased plasma catecholamine concentration and the attendant physiological sequelae (increased heart rate and smooth muscle contraction).
  • Benign prostatic hyperplasia also known as benign prostatic hypertrophy or BPH
  • BPH benign prostatic hypertrophy
  • the symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free ⁇ flow of fluids through the male urethra.
  • the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
  • the male hormone 5 ⁇ - dihydrotestosterone has been identified as the principal culprit.
  • the continual production of 5 ⁇ -dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
  • the effect of this compound is to inhibit the enzyme testosterone 5- alpha reductase, which converts testosterone into 5 ⁇ -dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass.
  • PROSCAR® bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently rapidly.
  • one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief.
  • Agents which induce relaxation of the urethral smooth muscle, by binding to alpha 1 adrenergic receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity.
  • one such agent is alf ⁇ zosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia.
  • the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the ⁇ l subtype was reported.
  • Non-selective alpha 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer).
  • prazosin Minipress, Pfizer
  • Terazosin Terazosin
  • doxazosin mesylate Cardura, Pfizer
  • identification of active compounds is accomplished through use of animal tissues known to be enriched in adrenergic receptors.
  • rat tissues have been used to screen for potential adrenergic receptor antagonists.
  • compounds which appear active in animal tissue may not be active or sufficiently selective in humans. This results in substantial wastage of time and effort, particularly where high volume compound - 5 -
  • Meperidine and normeperidine are known opioid receptor ligands useful as analgesics. [Janssen, P.A. et al, J. Med. Chem. 1(4), 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 reducing the acute symptoms of BPH without side effects caused by ancillary opioid receptor binding.
  • compounds of this invention may be used alone or in conjunction with a more long-term anti-BPH therapeutics, such as testosterone 5-alpha reductase inhibitors, including PROSCAR® (finasteride).
  • a more long-term anti-BPH therapeutics such as testosterone 5-alpha reductase inhibitors, including PROSCAR® (finasteride).
  • these compounds may be used to induce highly tissue-specific, localized ⁇ ic adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac arrhythmias, and possibly a host of alpha lc receptor mediated central nervous system events.
  • ⁇ i adrenergic receptor ⁇ i -AR
  • QT Adrenoceptor Classification Sha ⁇ ening Occam's Razor. Trends in Pharm. Sci. 1994, L5, 167-170
  • IUPHAR International Union of Pharmacology
  • This new naming system reflects the correspondence between the proteins encoded by the ⁇ ia and ⁇ ib genes (new IUPHAR nomenclature) and the receptors characterized by traditional pharmacological means as ⁇ iA and ⁇ i ⁇ , respectively, in the literature. Recombinant receptors and receptors characterized pharmacologically in tissues are distinguished by lowercase and uppercase subscripts, respectively.
  • 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 administering to the subject a therapeutically effective amount of a compound of the formula:
  • A is selected from C-R 2 or N;
  • X is C or N, provided that when X is N, then Rl is absent;
  • R l is selected from hydrogen, halogen, Cl -8 alkyl, mono-, di- or tri- halogenated Cl -8 alkyl, Cl -6 alkoxy, cyano, CONR 4 R 0 r C3-8 cycloalkyl;
  • R 2 is selected from hydrogen, cyano, CONR 4 R 5 or CO2R 4 ;
  • R3 is selected from hydrogen, cyano, CONR R5, CO2R 4 or SO2R 4 ; and R 4 and R5 are each independently selected from hydrogen, Cl -8 alkyl or C3-8 cycloalkyl; and the pharmaceutically acceptable salts thereof.
  • the compound used in the method is selected from
  • In one embodiment of the invention is the method of treating a condition which is susceptible to treatment by antagonism of the alpha 1 a adrenergic receptor wherein
  • R l is selected from hydrogen, halogen, Cl -6 alkyl, mono-, di- or tri- halogenated Cl -6 alkyl, Cl -4 alkoxy, cyano, CONH2 or
  • R3 is selected from hydrogen, cyano or CO2R 4 ; and R 4 and R ⁇ are each independently selected from hydrogen, Cl -6 alkyl or C3-6 cycloalkyl; and the pharmaceutically acceptable salts thereof.
  • a class of the invention is the method of treating a condition which is susceptible to treatment by antagonism of the alpha la adrenergic receptor wherein
  • X is C
  • Rl is selected from hydrogen, chloro, Cl-4 alkyl, tri-halogenated
  • R 2 is selected from hydrogen, cyano, CONH2 or CO2R 4 ;
  • R3 is selected from hydrogen, cyano or CO2CH2CH3;
  • R 4 is selected from hydrogen, Cl -4 alkyl or C3-6 cycloalkyl; and the pharmaceutically acceptable salts thereof.
  • R 4 is selected from hydrogen, Cl -4 alkyl or C3-6 cycloalkyl; and the pharmaceutically acceptable salts thereof.
  • R l is selected from hydrogen, chloro, methyl, trifiuoromethyl, methoxy, cyano or CONH2;
  • R 2 is selected from hydrogen, cyano, CONH2, CO2H, CO2CH3,
  • 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
  • R 2 is selected from hydrogen, cyano, CO2H or CO2NH2; and the pharmaceutically 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
  • Exemplifying the invention is the method 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.
  • Examples of conditions which are susceptible to treatment by antagonism of the alpha la adrenergic receptor include, but are not limited to, benign prostatic hype ⁇ lasia, urinary obstruction, impotence and high intraocular pressure.
  • the compounds useful in the methods of the present invention selectively antagonize the human alpha la adrenergic receptor at nanomolar concentrations while exhibiting at least five fold lower affinity for the alpha Id and alpha lb human adrenergic receptors and many other G-protein coupled receptors.
  • Use of selective alpha la adrenergic receptor antagonists in the methods of the instant invention results in reduced side effects related to peripheral adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc.
  • FIG. 1 Further illustrating the invention is a method of treating benign prostatic hype ⁇ lasia in a subject in need thereof which comprises administering 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 hype ⁇ lasia or relax urethral smooth muscle.
  • the testosterone 5-alpha reductase inhibitor is a type 1 , a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is a type 2 testosterone -alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is finasteride. 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 hype ⁇ lasia, or for relaxing urethral smooth muscle.
  • Another example of the invention is a drug which is useful for treating benign prostatic hype ⁇ lasia or for relaxing urethral smooth muscle, the effective ingredient of the said drug being any of the compounds descibed above.
  • 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 diastolic blood pressure.
  • Representative compounds utilized in the methods of this invention display submicromolar affinity for the human alpha la adrenergic receptor subtype while displaying at least five-fold lower affinity for the human alpha 1 d and alpha 1 b adrenergic receptor subtypes, and many other G-protein coupled human receptors.
  • Preferred compounds of this invention exhibit nanomolar affinity for the human alpha la adrenergic receptor subtype while displaying at least 10 fold lower affinity for the human alpha Id and alpha lb adrenergic receptor subtypes, opioid receptors and many other G-protein coupled human receptors.
  • salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: Acetate, Benzenesulf onate, Benzoate, Bicarbonate,
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
  • the compounds according to the invention may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymo ⁇ hs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
  • 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, etc.).
  • alkenyl shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
  • aryl refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it shall be inte ⁇ reted as including those limitations given above for "alkyl” and "aryl.”
  • Designated numbers of carbon atoms e.g., Ci-i ⁇ shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • halogen shall include iodine, bromine, chlorine and fluorine.
  • substituted shall be deemed to include multiple degrees of substitution by a named substitutent.
  • poly- substituted shall include di-, tri-, tetra- and penta- substitution by a named substituent.
  • substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • heterocycle or heterocyclic ring 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, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazohdinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, mo ⁇ holinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamo ⁇ holinyl, thiam
  • terapéuticaally effective amount 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.
  • compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • an insoluble salt of the active compound such as the decanoate salt
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be inco ⁇ orated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d- tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • 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 concemed. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the specificity of binding of compounds showing affinity for the alpha 1 a receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha 1 a receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha Id, alpha lb) or beta adrenergic receptors.
  • the human alpha adrenergic receptor of the la subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994, each of which is hereby inco ⁇ orated by reference.
  • the cloned human alpha la receptor when expressed in mammalian cell Iines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned human alpha Id, 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 selective human alpha 1 a 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 April 4, 1995, the contents of which are hereby inco ⁇ orated by reference].
  • 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.
  • compositions containing compounds of this invention 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.
  • the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
  • an effective but non-toxic amount of the compound desired can be employed as an alpha 1 a antagonistic agent.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • suitable pharmaceutical diluents, excipients or carriers 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.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • 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.
  • glycerin for parenteral administration, sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinyl ⁇ pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day.
  • 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, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 250 mg kg of body weight per day.
  • the range is from about 0.001 to 100 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha la adrenergic receptor while minimizing any potential toxicity.
  • co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable.
  • this includes administration of compounds of this invention and a human testosterone 5- ⁇ reductase inhibitor. Included with this embodiment are inhibitors of 5 -alpha reductase isoenzyme 2.
  • PROSCAR® also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071 , for example, hereby inco ⁇ orated by reference.
  • PROSCAR® which is principally active in prostatic tissue due to its selectivity for human 5- ⁇ reductase isozyme 2
  • combinations of compounds which are specifically active in inhibiting testosterone 5- alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2 are useful in combination with compounds of this invention.
  • the dosages of the alpha la adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined to achieve desired effects.
  • dosages of the 5-alpha reductase inhibitor and the alpha la adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone.
  • the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be inte ⁇ reted accordingly.
  • a method of treating BPH comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH.
  • the dosage of finasteride administered to the subject is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha la antagonist.
  • the dosage of finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day.
  • compounds of this invention exhibiting alpha la adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5 ⁇ -reductase 2 inhibitor, such as finasteride, in addition to a 5 ⁇ - reductase 1 inhibitor, such as 4,7 ⁇ -dimethyl-4-aza-5 ⁇ -cholestan-3- one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation.
  • a combined therapy can be employed wherein the alpha la adrenergic receptor antagonist and the 5 ⁇ - reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5 ⁇ -reductase inhibitors.
  • BOPC1 bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • EDCI l -(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
  • FABLRMS fast atom bombardment low resolution mass spectroscopy
  • HPLC high performance liquid chromatography
  • HOBt 1 -hydroxy benzotriazole hydrate
  • i-PrOH 2-propanol
  • NMP l-methyl-2-pynolidinone
  • PCTLC preparative centrifugal thin layer chromatography
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • the compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Unless 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 4-phenylpiperidines 3 were either: 1) N-Boc deprotected with HC1-
  • the commercially available amino alcohol 12 was converted to the corresponding chloride 13 via treatment with thionyl 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-Cl in dichloroethane followed by treatment with methanol supplying the cyano piperazine 16.
  • Piperazines 15 and 16 were separated easily utilizing chiral HPLC technology and each enantiomer was evaluated individually, 15a and 15b, and 16a and 16b, respectively.
  • R 1 R ⁇ R ⁇ R2/R3 a H H H C NA b H C0 2 CH 3 H C NA c H C0 C H 2 CH 3 H C NA d H C0 2 (CH 2 ) 3 CH 3 H C NA e H C0 2 cyclohexyl H C NA f H CN H C NA
  • 4-(2-ChlorophenylV4-cvanopiperidine hydrochloride (4j) A solution of EtOAc saturated with HCl (200 ml) was added to 4-(2-chlorophenyl)-4-cyano--V-(l ,l - dimethylethoxycarbonyl)piperidine, (880 mg, 2.74 mmol). The resulting 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.
  • N-Benzyl-N'- ⁇ henyl-1.2-diaminoethane hydrochloride (14) A solution of 13 (8.618 g, 42.0 mmol) and aniline (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. Recrystallization from ethanol (220 mL) afforded the title compound 14 as white crystals.
  • Enantiomers of 15 (15a and 15b).
  • the enantiomeric mixture was separated utilizing normal 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 utilizing similar HPLC conditions (Chiralcel OD, 4.6 mm x 25 cm, 65 hexanes/35 2-propanol/0.2 diethyl amine, 0.7 mL/min).
  • the enantiomeric mixture was separated utilizing normal phase chiral HPLC (Chiralcel OD, 2.0 cm x 25 cm, 65 hexanes/35 2- propanoI/0.2 diethyl amine, 2.5 mL/min). Each enantiomer possessed identical spectroscopic properties but opposite signs of optical rotation. Chiral purity was assessed utilizing similar HPLC conditions (Chiralcel OD, 4.6 mm x 25 cm, 65 hexanes/35 2-propanol/0.2 diethyl amine, 0.7 mL/min).
  • 100 mg of the compound of Example 3 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size
  • Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki).
  • the objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4. 38 -
  • Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (lOmM Tris-HCl/5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 ⁇ m) are resuspended in 50mM Tris-HCl pH 7.4 containing EDTA, MgCl[2], KCI, NaCl, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 ⁇ g membranes in a total volume of 500 ⁇ l containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 ⁇ M apomorphine. The assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.
  • the objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor
  • Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at 38,0OOXg for 30'.
  • the binding assay contains 0.25 nM [3H]8- OH-DPAT (8-hydroxy-2-dipropylamino-l ,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaC12 and lmg/ml ascorbate. Non-specific binding is defined using 10 ⁇ M propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters EXAMPLE 16
  • Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate.
  • Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution ovemight 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 hype ⁇ lasia are also stored ovemight in ice-cold Krebs solution if needed.
  • the tissue is placed in a Petri dish containing oxygenated
  • the tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder.
  • a cumulative concentration response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated.
  • EC50 values are calculated for each group using GraphPad Inplot software.
  • pA2 (-log Kb) values were obtained from Schild plot when three or more concentrations were tested.
  • Benign prostatic hype ⁇ lasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction.
  • Alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man.
  • these are non-selective alpha 1 receptor antagonists which also have pronounced vascular effects. Because we have identified the alpha 1 a receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without concomitant changes in the vasculature.
  • the following model is used to measure adrenergically mediated changes in intra-urethral pressure and arterial pressure in anesthetized dogs in order to evaluate the efficacy and potency of selective alpha adrenergic receptor antagonists.
  • the goals are to: 1) identify the alpha 1 receptor subtypes responsible for prostatic/urethral contraction and vascular responses, and 2) use this model to evaluate novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be evaluated in this manner.
  • the urethers are ligated and cannulated so that urine flows freely into beakers.
  • the dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra.
  • Umbilical tape is passed beneath the urethra at d e bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate.
  • the bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra.
  • the bladder incision is sutured with 2-0 or 3-0 silk (purse- string suture) to hold the transducer.
  • Phenylephrine an alpha 1 adrenergic agonist
  • Phenylephrine an alpha 1 adrenergic agonist
  • phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle).
  • the relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis.
  • the family of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant among curves.
  • the dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the ED5 ⁇ 's for the respective curves.
  • the Kb dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve
  • 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.
  • 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.
  • ⁇ H-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 > 6 ⁇ M.

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Abstract

L'invention concerne certains nouveaux composés et leur dérivés, leur synthèse et leur utilisation en tant qu'antagonistes du récepteur adrénergique alpha 1a. Le traitement de l'adénome prostatique constitue l'une des applications desdits composés. Ces composés sont sélectifs dans leur capacité à relaxer les tissus des muscles lisses enrichis en sous-type du récepteur alpha 1a sans pour autant provoquer une hypotension. L'un de ces tissus entoure la muqueuse urétrale. Par conséquent, ces composés peuvent servir par exemple à soulager de façon aiguë les hommes souffrant d'adénome prostatique, en permettant un flux urinaire moins entravé. En combinant ces composés avec un composé inhibiteur de la réductase 5-alpha humaine, on peut également les utiliser pour atténuer de façon chronique et aiguë les effets de l'adénome prostatique.
PCT/US1996/018321 1995-11-15 1996-11-12 ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a WO1997017967A1 (fr)

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AU77343/96A AU710337B2 (en) 1995-11-15 1996-11-12 Alpha 1a adrenergic receptor antagonists
EP96940465A EP0865280A1 (fr) 1995-11-15 1996-11-12 ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a
JP9519091A JPH11507395A (ja) 1995-11-15 1996-11-12 アルファ１ａ アドレナリン受容体拮抗薬
CA 2235370 CA2235370A1 (fr) 1995-11-15 1996-11-12 Antagonistes du recepteur adrenergique alpha 1a
US09/066,477 US5922722A (en) 1996-11-12 1996-11-12 Alpha 1a adrenergic receptor antagonists

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US676595P 1995-11-15 1995-11-15
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GBGB9603423.6A GB9603423D0 (en) 1996-02-19 1996-02-19 Alpha la adrenergic receptor antagonists
GB9603423.6 1996-02-19

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4661491A (en) * 1985-05-28 1987-04-28 Synthelabo Alfuzosine compositions and use
US5212176A (en) * 1990-06-29 1993-05-18 Abbott Laboratories R(+)-terazosin
US5403847A (en) * 1992-11-13 1995-04-04 Synaptic Pharmaceutical Corporation Use of α1C specific compounds to treat benign prostatic hyperlasia
US5580871A (en) * 1992-11-20 1996-12-03 The Dupont Merck Pharmaceutical Company 4-Heteroaryl- 1,4-dihydropyridine compounds with calcium agonist and alpha1 -antagonist activity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4661491A (en) * 1985-05-28 1987-04-28 Synthelabo Alfuzosine compositions and use
US5212176A (en) * 1990-06-29 1993-05-18 Abbott Laboratories R(+)-terazosin
US5403847A (en) * 1992-11-13 1995-04-04 Synaptic Pharmaceutical Corporation Use of α1C specific compounds to treat benign prostatic hyperlasia
US5580871A (en) * 1992-11-20 1996-12-03 The Dupont Merck Pharmaceutical Company 4-Heteroaryl- 1,4-dihydropyridine compounds with calcium agonist and alpha1 -antagonist activity

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