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WO1997018209A1 - ANTAGONISTES DE RECEPTEURS ADRENERGIQUES ALPHA 1a - Google Patents

ANTAGONISTES DE RECEPTEURS ADRENERGIQUES ALPHA 1a Download PDF

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Publication number
WO1997018209A1
WO1997018209A1 PCT/US1996/018346 US9618346W WO9718209A1 WO 1997018209 A1 WO1997018209 A1 WO 1997018209A1 US 9618346 W US9618346 W US 9618346W WO 9718209 A1 WO9718209 A1 WO 9718209A1
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WO
WIPO (PCT)
Prior art keywords
compound
alpha
compounds
testosterone
pharmaceutically acceptable
Prior art date
Application number
PCT/US1996/018346
Other languages
English (en)
Inventor
Mark G. Bock
Michael A. Patane
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9605165.1A external-priority patent/GB9605165D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU77344/96A priority Critical patent/AU7734496A/en
Publication of WO1997018209A1 publication Critical patent/WO1997018209A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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 hype ⁇ lasia (BPH).
  • BPH benign prostatic hype ⁇ lasia
  • 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 subdivided into i , c ⁇ 2, ttl , and B2 subtypes. Functional differences between i and cc2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.
  • WO 92/0073 the selective ability of the R(--) enantiomer of terazosin to selectively bind to adrenergic receptors of the alpha 1 subtype was reported.
  • the ⁇ i/ ⁇ 2 selectivity of this compound was disclosed as being significant because agonist stimulation of the cc2 receptors was said to inhibit secretion of epinephrine and norepinephrine, while antagonism of the ⁇ 2 receptor was said to increase secretion of these hormones.
  • non- selective alpha-adrenergic blockers such as phenoxybenzamine and phentolamine, is limited by their cc2 adrenergic receptor mediated induction of increased plasma catecholamine concentration and the attendant physiological sequelae (increased heart rate and smooth muscle contraction).
  • Benign prostatic hype ⁇ lasia 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 hype ⁇ lasia, 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.
  • 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 alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hype ⁇ lasia.
  • the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the ⁇ i 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 screening programs are employed.
  • compounds, which might be highly effective in humans would be missed because of their absence of appreciable affinity for the heterologous animal receptors.
  • even single amino acid changes between the sequence of biologically active proteins in one species may give rise to substantial pharmacological differences.
  • WO94/08040 published 14 April 1994 and WO94/10989, published 26 May 1994
  • a cloned human ⁇ ic adrenergic receptor and a method for identifying compounds which bind the human ⁇ ic receptor has now made possible the identification of selective human ⁇ ic adrenergic receptor antagonists useful for treating BPH.
  • the instant patent disclosure discloses novel compounds which selectively bind to the human ⁇ i c receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors, thus defining the specificity of the compounds of the present invention for the human ⁇ i c adrenergic receptor.
  • compounds of this invention are used to reduce the acute symptoms of BPH.
  • 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 ⁇ c 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 l c receptor mediated central nervous system events.
  • NOMENCLATURE Recently, a new ⁇ i adrenergic receptor ( ⁇ i -AR) classification scheme similar to that proposed by Ford, et al. [ ⁇ j ⁇ Adrenoceptor Classification: Sha ⁇ ening Occam's Razor. Trends in Pharm. Sci. 1994, 15, 167-170] was adopted at the August, 1994 meeting of the International Union of Pharmacology (IUPHAR) in Montreal, Canada.
  • the ⁇ i -AR genes formerly known as ⁇ ia/d, ⁇ lb and ⁇ i c were renamed ⁇ I d, otlb and ⁇ ia, respectively.
  • This new naming system reflects the correspondence between the proteins encoded by the ⁇ ia and ⁇ lb 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 compounds for the treatment of urinary obstruction caused by benign prostatic hype ⁇ lasia (BPH).
  • BPH benign prostatic hype ⁇ lasia
  • the compounds selectively antagonize the human alpha la adrenergic receptor at nanomolar and subnanomolar concentrations while exhibiting at least ten fold lower affinity for the alpha Id and alpha lb human adrenergic receptors and many other G-protein coupled receptors.
  • This invention has the advantage over non-selective alpha 1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include orthostatic hypotension, syncope, lethargy, etc.
  • the compounds of the present invention have the structure:
  • W is selected from unsubstituted, mono or di-substituted: phenyl, pyridyl, thienyl, furanyl or naphthyl where the substituents on the phenyl, pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR 4 , halogen, Cl -4 alkyl or C3-8 cycloalkyl;
  • R 1 and R2 are each independently selected from hydrogen, cyano, CONR4R5, CO2R 4 or SO2R 4 ;
  • R3 is selected from
  • R 4 and R ⁇ are each independently selected from hydrogen, Cl -8 alkyl or C3-8 cycloalkyl
  • R6 is selected from hydrogen or chloro
  • R 7 is selected from C ⁇ _g alkyl
  • T, U, X, Y and Z are each independently selected from hydrogen, halogen, Cl -8 alkyl, C3- cycloalkyl or OR 8 ;
  • A is selected from CH or N;
  • G is selected from H2, O or S;
  • E is selected from CH2, O or NR 8 ;
  • R 8 is selected from hydrogen, Cl -8 alkyl or C3-8 cycloalkyl, (CH2)mC02R 4 or (CH2)mCONH2;
  • each m is independently an integer of from zero to three; and n is an integer of from two to six; and the pharmaceutically acceptable salts thereof.
  • W is selected from unsubstituted or mono-substituted phenyl where the substituent on the phenyl is Cl -4 alkyl or halogen; 2-, 3- or 4-pyridyl; 2- or 3-thienyl; 2- or 3 -furanyl; or unsubstituted, mono- or di- substituted naphthyl where the substituent on the naphthyl is selected from CF3, phenyl, OR 4 , halogen, Cl -4 alkyl or C3- cycloalkyl;
  • R3 is selected from
  • R j is selected from hydrogen or cyano
  • W is selected from unsubstituted or mono-substituted phenyl where the substituent on phenyl is selected from methyl or halogen; and where R ⁇ is as defined above; and the pharmaceutically acceptable salts thereof.
  • W is selected from phenyl, 2-methylphenyl or 2-chlorophenyl; and where R ⁇ is as defined above; and the pharmaceutically acceptable salts thereof.
  • Exemplifying the invention is the compound selected from 4-(4-saccary lbuty l)-2-cyano- 1 -phenylpiperazine or 4-(propyl-ditolylacetamide)-2-cyano- 1 -phenylpiperazine; and the pharmaceutically acceptable salts thereof.
  • Another illustration of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier.
  • Another example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • the composition further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor.
  • 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 5 -alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is finasteride.
  • An example of 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 or pharmaceutical compositions described above. Further exemplifying the invention is the method of treating BPH wherein the compound or pharmaceutical composition additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH.
  • An additional illustration of the invention is the method of treating benign prostatic hype ⁇ lasia wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is finasteride.
  • a method of relaxing urethral smooth muscle in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. More specifically exemplifying the invention is the method of relaxing urethral smooth muscle wherein the compound or pharmaceutical composition additionally does not cause a fall in blood pressures at dosages effective to relax urethral smooth muscle.
  • More particularly illustrating the invention is the method of relaxing urethral smooth muscle wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor; preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
  • More specifically 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.
  • More particularly exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the alpha la receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease.
  • Diseases which are susceptible to treatment by antagonism of the alpha l a receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain and cardiac arrhythmia.
  • Another aspect of the invention is a compound of the formula
  • R l is selected from cyano, CONR 4 R5, CO2R 4 or SO2R 4 ;
  • R 4 and R ⁇ are each independently selected from hydrogen, Cl -8 alkyl or C3-8 cycloalkyl
  • R9 is selected from hydrogen, CF3, phenyl, OR 4 , halogen, Cl -4 alkyl or C3-8 cycloalkyl; and the pharmaceutically acceptable salts thereof.
  • R 1 is cyano; and R9 is selected from hydrogen, methyl or chloro.
  • 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 of this invention display submicromolar affinity for the human alpha la adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alpha Id and alpha lb adrenergic receptor subtypes, and many other G- protein coupled human receptors. These compounds are administered in dosages effective to antagonize the alpha la receptor where such treatment is needed, as in BPH.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • 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.
  • alkali metal salts e.g. sodium or potassium salts
  • alkaline earth metal salts e.g. calcium or magnesium salts
  • suitable organic ligands e.g. quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following:
  • 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., Cl -l ⁇ ) 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, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, mo ⁇ holinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamo ⁇ holinyl, thiam
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • 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.
  • it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistrv. 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 ⁇ ia receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the ia receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., ai , a lb) or beta adrenergic receptors.
  • Expression of the cloned human aid, alpha lb, and ⁇ ia receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
  • Antagonism by these compounds of the human alpha la adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting orthostatic hypotensive effects.
  • the cloned human alpha la receptor when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the 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. fSee e.g.. PCT International Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995, 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.
  • 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
  • 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.
  • 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 1 a adrenergic receptor is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1 ,000 mg per adult human per day.
  • 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-alpha 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 l a 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 l a 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.
  • Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
  • ACE-C1 alpha-chloroethylchloroformate
  • DMF N,N-dimethylformamide
  • EDCI l -(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
  • FABLRMS fast atom bombardment low resolution mass spectroscopy
  • HMPA hexamethylphosphoramide
  • HOBt 1-hydroxy benzotriazole hydrate
  • i-Prl isopropyliodide
  • i-PrOH 2-propanol
  • i-Pr2NEt diisopropylethylamine
  • PCTLC preparative centrifugal thin layer chromatography
  • PEI polyethylenimine
  • TMSC1 chlorotrimethylsilane
  • TMSCN trimethylsilyl cyanide
  • 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 commercially available amino alcohol 1 was converted to the corresponding chloride 2 via treatment with thionyl chloride.
  • the chloride 2 was displaced by aniline in toluene at 130 °C providing anilinoethylbenzyl amine 3.
  • Treatment of 3 with 2-chloroacrylonitrile in DMF provided the desired cyano piperazine 4 (Phillips, G. B. et al J. Med. Chem. 1992, 32, 743-750).
  • N-benzyl deprotection was accomplished using ACE-Cl in dichloroethane followed by treatment with methanol supplying 5.
  • the cyano piperazine 5 alkylated smoothly with bromobutyl saccharin 10 and bromide 7 providing 6 and 8, respectively (Scheme 1).
  • the saccharin or substituted saccharin (referred to as “the saccharin moiety") was prepared according to methods known in the art (see for example US Patents 4,818,756; 4,937,343; 4,988,809 and 5,187,276, hereby inco ⁇ orated by reference for this pu ⁇ ose).
  • the saccharin moiety was then alkylated with a reagent such as 1 ,4-dibromobutane, or a similar reagent, to form the butyl-saccharin moiety 10 (see e.g., Examples 9 and 10).
  • the bromoalkyl amide 7 was prepared via coupling of the acetic acid derivative 9 to bromopropyl or bromoethyl amine prior to alkylation.
  • Piperazines 4 and 5 were separated easily utilizing chiral HPLC technology and each enantiomer was evaluated individually, 4a and 4b, and 5a and 5b, respectively, Scheme 2.
  • the regioisomer of piperazine 4 was also prepared 11, 13, and 14 by following the literature procedures (Phillips, G. B. et al., J . Med. Chem. 1992, 32, 743-750) outlined in Scheme 3. Reaction of the previously described 3 with 2,3-dibromopropionamide provided 11 directly, which could be deprotected following the ACE-Cl procedure providing 12. The N-benzyl compound 11 could also be further modified at the carboxamido group via either dehydration providing nitrile 13a or hydrolysis followed by esterification to provide esters 14a. Reaction of the deprotected piperazines 12, 13b, or 14b with bromides 10 or 7 will furnish analogs 15 and 16, Scheme 3.
  • the phenyl acetic acetamide derivatives 20 were prepared (Scheme 4) via initial alkylation of the enolate of the appropriate phenyl acetic acid 17, derived from treatment of 17 with LiN(TMS)2, with the desired electrophile, for example, 2-iodopropane in THF/HMPA to form 18, followed by acylation with amine 19.
  • TMS LiN(TMS)2
  • the desired electrophile for example, 2-iodopropane in THF/HMPA
  • Some phenyl acetic acetamide derivatives, for example 23, were not accessible via this route and required the use of the modified Julia Olefination protocol outlined in Scheme 5.
  • R 7 H, C-,. g alkyl, C 3 . 8 cycloalkyl, aryl
  • 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- 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).
  • 100 mg of the compound of Example 5 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
  • 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.
  • 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 rpm) are resuspended in 50mM Tris-HCl pH 7.4 containing EDTA, MgCl[2], KCl, NaCl, CaCl[21 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 5 HT l a 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,OOOXg for 30'.
  • the binding assay contains 0.25 nM [3H]8- OH-DPAT (8-hydroxy-2-dipropylamino- 1 ,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaC12 and l mg/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
  • Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate.
  • Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary.
  • Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles.
  • Human prostate chips from transurethral surgery of benign prostate hype ⁇ lasia are also stored overnight in ice-cold Krebs solution if needed.
  • the tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCl, 1 18 mM; KCl, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgS ⁇ 4, 1.2 mM; NaHC ⁇ 3, 2.0 mM; dextrose, 1 1 mM] warmed to 37°C. Excess lipid material and connective tissue are carefully removed. Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% C ⁇ 2/95% O2.
  • 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.
  • Benign prostatic hyperplasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction.
  • Alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man.
  • 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 dogs are anesthetized with pentobarbital sodium (35 mg/kg, i.v. plus 4 mg/kg/hr iv infusion).
  • An endotracheal tube is inserted and the animal ventilated with room air using a Harvard instruments positive displacement large animal ventilator.
  • Catheters PE 240 or 260
  • Catheters are placed in the aorta via the femoral artery and vena cava via the femoral veins (2 catheters, one in each vein) for the measurement of arterial pressure and the administration of drugs, respectively.
  • a supra-pubic incision ⁇ l/2 inch lateral to the penis is made to expose the urethers, bladder and urethra.
  • the urethers are ligated and cannulated so that urine flows freely into beakers.
  • the dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra.
  • Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate.
  • the bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra.
  • the bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer.
  • 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 ED50'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.
  • one is able to confirm the selectivity of alpha 1 a adrenergic receptor antagonists that prevent the increase in intra- urethral pressure to phenylephrine without any activity at the vasculature.

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Abstract

L'invention concerne de nouveaux composés, et des dérivés de ces derniers, leur synthèse et leur utilisation comme antagonistes de récepteurs adrénergiques alpha 1a sélectifs. Une des applications de ces composés est leur utilisation dans le traitement de l'hypertrophie de la prostate. Ces composés présentent une capacité sélective pour relâcher les tissus des muscles lisses dont la teneur en sous-types de récepteurs alpha 1a est enrichie, sans induire en même temps de syndrome orthostatique. Un tissu de ce type entoure la muqueuse urétrale. Par conséquent, l'intérêt de ces composés instantanés est d'assurer un soulagement rapide chez l'homme souffrant d'hypertrophie de la prostate, en évitant l'obstruction de l'écoulement urinaire. Un autre intérêt de ces composés est leur association à un composé inhibiteur de la réductase 5-alpha humaine, permettant d'obtenir des soulagements rapides et à long terme des effets de l'hypertrophie de la prostate.
PCT/US1996/018346 1995-11-15 1996-11-12 ANTAGONISTES DE RECEPTEURS ADRENERGIQUES ALPHA 1a WO1997018209A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1014973A4 (fr) * 1997-06-18 2000-09-20 Merck & Co Inc ANTAGONISTES DES ADRENORECEPTEURS ALPHA 1a

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4110449A (en) * 1977-05-23 1978-08-29 E. R. Squibb & Sons, Inc. 2-substituted benzisothiazol-3-ones
US4760071A (en) * 1984-02-27 1988-07-26 Merck & Co., Inc. 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors
US5462942A (en) * 1993-07-05 1995-10-31 Duphar International Research B.V. 2,3-dihydro-1,4-benzodioxin-5-yl-piperazine derivatives having 5-HT 1A-antagonistic activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4110449A (en) * 1977-05-23 1978-08-29 E. R. Squibb & Sons, Inc. 2-substituted benzisothiazol-3-ones
US4760071A (en) * 1984-02-27 1988-07-26 Merck & Co., Inc. 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors
US5462942A (en) * 1993-07-05 1995-10-31 Duphar International Research B.V. 2,3-dihydro-1,4-benzodioxin-5-yl-piperazine derivatives having 5-HT 1A-antagonistic activity

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1014973A4 (fr) * 1997-06-18 2000-09-20 Merck & Co Inc ANTAGONISTES DES ADRENORECEPTEURS ALPHA 1a

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