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WO1996025934A1 - ANTAGONISTES DU RECEPTEUR ALPHA-1a-ADRENERGIQUE - Google Patents

ANTAGONISTES DU RECEPTEUR ALPHA-1a-ADRENERGIQUE Download PDF

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Publication number
WO1996025934A1
WO1996025934A1 PCT/US1996/002534 US9602534W WO9625934A1 WO 1996025934 A1 WO1996025934 A1 WO 1996025934A1 US 9602534 W US9602534 W US 9602534W WO 9625934 A1 WO9625934 A1 WO 9625934A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
oxo
mono
dioxido
benzisothiazol
Prior art date
Application number
PCT/US1996/002534
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English (en)
Inventor
Ben E. Evans
Gerald S. Ponticello
Jacob M. Hoffman
Raymond S. L. Chang
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
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to US08/860,314 priority Critical patent/US5952351A/en
Priority to JP8525855A priority patent/JPH11508536A/ja
Priority to EP96905575A priority patent/EP0812196A4/fr
Priority to AU49301/96A priority patent/AU700559B2/en
Publication of WO1996025934A1 publication Critical patent/WO1996025934A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS
  • This invention relates to certain novel compounds, their synthesis, and their use as a selective alpha la adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating 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 adrenergic receptors were further subdivided into ⁇ 1, ⁇ 2, ß1, and ß2 subtypes. Functional differences between a1 and ⁇ 2 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 ⁇ 1/ ⁇ 2 selectivity of this compound was disclosed as being significant because agonist stimulation of the ⁇ 2 receptors was said to inhibit secretion of epinephrine and norepinephrine, while antagonism of the ⁇ 2 receptor was said to increase secretion of these hormones.
  • nonselective alpha-adrenergic blockers such as phenoxybenzamine and phentolamine, is 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).
  • Adrenoreceptors Molecular Biology, Biochemistry and Pharmacology, (Progress in Basic and Clinical Pharmacology series, Karger, 1991), wherein the basis of ⁇ i/ ⁇ 2 subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3'-terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting ⁇ -adrenergic receptor affinity was explored.
  • the cloned bovine ⁇ 1c receptor exhibited pharmacological properties proposed for the ⁇ 1a subtype. Nonetheless, based on its non-expression in tissues where the ⁇ 1a subtype is expressed, and its sensitivity to chloroethylclonidine, the receptor was given a new designation.
  • Benign prostatic hyperplasia also known as benign prostatic hypertrophy or BPH
  • BPH benign prostatic hypertrophy
  • 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 hyperplasia.
  • adrenergic receptors of the ⁇ i subtype was reported.
  • combinations of 5- alpha-reductase inhibitory compounds and alpha 1-adrenergic receptor blockers terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin
  • terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin were disclosed.
  • no information as to the ⁇ i A, ⁇ 1B, or ⁇ 1c subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known.
  • 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.
  • 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 In this regard, it has been noted that even single amino acid changes between the sequence of biologically active proteins in one species may give rise to substantial
  • the instant patent disclosure discloses novel compounds which selectively bind to the human ⁇ 1c 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 ⁇ 1c 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).
  • PROSCAR® farnesoic acid
  • compounds may be used to induce highly tissue-specific, localized ⁇ 1c 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 1c receptor mediated central nervous system events.
  • ⁇ 1 adrenergic receptor ⁇ 1-AR
  • ⁇ 1-Adrenoceptor Classification Sharpening Occam's Razor. Trends in Pharm. Sci. 1994, 15, 167-170
  • IUPHAR International Union of Pharmacology
  • This new naming system reflects the correspondence between the proteins encoded by the ⁇ 1a and ⁇ 1b genes (new IUPHAR nomenclature) and the receptors characterized by traditional pharmacological means as ⁇ 1A and ⁇ 1B, respectively, in the literature. Recombinant receptors and receptors characterized pharmacologically in tissues are
  • the new classification scheme will be utilized (i.e., ⁇ 1d, ⁇ 1b and ⁇ 1a).
  • ⁇ 1d ⁇ 1d
  • ⁇ 1b ⁇ 1a
  • ⁇ 1a receptor ⁇ 1a receptor antagonists
  • the present invention provides novel compounds for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • adrenergic receptor at subnanomolar concentration while exhibiting at least 100 fold lower affinity for the a1d and ⁇ 1b human adrenergic receptors and many other G-protein coupled receptors.
  • This invention has the advantage over non-selective ⁇ 1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc.
  • the compounds of the present invention have the structure:
  • R 1 is selected from the group consisting of hydrogen, C 3-6 cycloalkyl, unsubstituted or substituted C 1 -6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 , SO 2 NH 2 , a heterocyclic ring or aryl, and unsubstituted or substituted C 2-6 alkenyl where the substituent on the alkenyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 ,
  • R 2 is independently one or more of hydrogen, halogen, C 1 -4 alkoxy, mono-, di- or tri-halogenated C 1 -4 alkoxy, or unsubstituted or substituted C 1 -6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 , SO 2 NH 2 , a heterocyclic ring or aryl;
  • R 3 is selected from hydrogen, cyano, CO 2 R 1 , CONH 2 , CONHR 1 , CON (R 1 ) 2 , C 3-6 cycloalkyl or C 3-6 cycloalkyl wherein one of the carbon atoms is replaced with a heteroatom selected from O or NH, or unsubstituted or substituted mono- or di-C 1 -6 alkyl wherein the substituent on the mono- or di-alkyl is selected from hydroxy,
  • R 4 is independently one or more of hydrogen, C 1 -6 alkyl, halogen, C 1 -4 alkoxy, mono-, di- or tri-halogenated C 1 -4 alkoxy, nitro, amino, mono-, di- or tri-halogenated C 1 -6 alkyl, C 1 -6 alkylsulfonyl,
  • C 1 -3 alkyl mono-, di- or tri-halogenated C 1 -3 alkyl or C 1 -4 alkoxy-C 1 -3 alkyl, or unsubstituted or substituted heterocyclic ring where the substituent on the heterocyclic ring is selected from halogen, unsubstituted C 1 -3 alkyl, mono-, di- or tri-halogenated C 1 -3 alkyl or C 1 -4 alkoxy-C 1 -3 alkyl;
  • R 5 is independently one or more of hydrogen, cyano, C 1 -6 alkyl, CO 2 R 1 , CONH 2 , CONHR 1 , CON(R 1 ) 2 ; and n is an integer of from 2 to 4; provided that when R 3 and R 5 are both hydrogen, then X is N-R 1 where R 1 is selected from C 3-6 cycloalkyl; unsubstituted C 2-6 alkyl or substituted C 1 -6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 , SO 2 NH 2 , a heterocyclic ring or aryl; or unsubstituted or substituted C 2-6 alkenyl where the substituent on the alkenyl is selected from mono-, di- or tri- halogen, C 1 -4 alkoxy, carboxy, CONH 2 , SO 2 NH 2 , a heterocyclic ring or aryl;
  • R 2 is independently one or more of hydrogen, halogen, C 1 -4 alkoxy or unsubstituted or substituted C 1 -6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 , SO 2 NH 2 , a heterocyclic ring or aryl;
  • R 4 is independently one or more of hydrogen, C 1 -6 alkyl, halogen, C 1 -4 alkoxy, nitro, amino, mono-, di- or tri-halogenated C 1 -6 alkyl, C 1 -6 alkylsulfonyl, C 1 -4 alkylenedioxy, unsubstituted or substituted aryl where the substituent on the aryl is selected from halogen, unsubstituted C 1 -3 alkyl, mono-, di- or tri-halogenated C 1 -3 alkyl or C 1 -4 alkoxy-C 1 -3 alkyl, or unsubstituted or substituted heterocyclic ring where the substituent on the heterocyclic ring is selected from halogen, unsubstituted C 1 -3 alkyl, mono-, di- or tri-halogenated
  • R 1 is selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 , a
  • R 2 is independently one, two or three of hydrogen, halogen or C 1 -6 alkyl;
  • R 3 is selected from hydrogen, cyano, C 1 -4 alkoxycarbonyl, CONH 2 or unsubstituted or substituted mono- or di-C 1 -6 alkyl wherein the substituent on the mono- or di-alkyl is mono-, di- or tri-halogen;
  • R 4 is independently one, two or three of hydrogen, C 1 -6 alkyl, halogen, C 1 -4 alkoxy, mono-, di- or tri-halogenated C 1 -4 alkoxy, nitro or C 1 -4 alkylenedioxy;
  • R 5 is independently one, two or three of hydrogen, cyano, C 1 -6 alkyl or CO 2 R 1 ; and where all other variables are as defined above; provided that when R 3 and R 5 are both hydrogen, then X is N-R 1 where R 1 is selected from unsubstituted C 2-6 alkyl or substituted
  • C 1 -6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 , a heterocyclic ring or phenyl; or unsubstituted or substituted C 2-6 alkenyl where the
  • substituent on the alkenyl is selected from mono-, di- or tri-halogen; and the pharmaceutically acceptable salts thereof.
  • R 4 is independently one, two or three of hydrogen, C 1 -6 alkyl, halogen, C 1 -4 alkoxy, nitro or
  • R 3 and R 5 are both hydrogen, then X is N-R 1 where R 1 is selected from unsubstituted C 2-6 alkyl or substituted
  • C 1 -6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 , a heterocyclic ring or phenyl.
  • R 1 is selected from hydrogen, C 1 -6 alkyl, mono-, di- or tri-halogenated C 1 -6 alkyl, benzyl, C 2-6 alkenyl or mono-, di- or tri-halogenated C 2-6 alkenyl;
  • R 3 is selected from hydrogen, cyano or mono- or di-C 1 -6 alkyl;
  • R 4 is independently one, two or three of hydrogen, C 1 -6 alkyl, halogen, C 1 -4 alkoxy, mono-, di- or tri-halogenated C 1 -4 alkoxy or
  • R 1 is selected from unsubstituted C 2-6 alkyl, mono-, di- or tri-halogenated C 1 -6 alkyl, benzyl, C 2-6 alkenyl or mono-, di- or tri-halogenated C 2-6 alkenyl;
  • R 4 is independently one, two or three of hydrogen, C 1 -6 alkyl, halogen or C 1 -4 alkylenedioxy; and all other variables are as defined above; provided that when R 3 and R 5 are both hydrogen, then X is N-R 1 where R 1 is selected from unsubstituted C 2-6 alkyl, mono-, di- or tri-halogenated C 1 -6 alkyl or benzyl.
  • R 1 is selected from hydrogen, C 1 -4 alkyl, C 2-6 alkenyl, benzyl, trifluoroethyl or fluoroethyl;
  • R 2 is selected from hydrogen, chlorine, fluoriqe or methyl; and
  • R 3 is selected from hydrogen, methyl or dimethyl;
  • R 4 is selected from hydrogen, chlorine, ethoxy, trifluoromethoxy or ethylenedioxy; and R 5 is selected from hydrogen, cyano, methyl or methoxycarbonyl; and where all other variables are as defined above; provided that when R 3 and R 5 are both hydrogen, then X is N-R 1 where R 1 is selected from unsubstituted C 2-4 alkyl, C 2-6 alkenyl, benzyl, trifluoroethyl or fluoroethyl;
  • R 4 is independently one or more of hydrogen, chlorine or ethylenedioxy; and all other variables are as defined above; provided that when R 3 and R 5 are both hydrogen, then X is N-R 1 where R 1 is selected from unsubstituted
  • R 1 is selected from
  • R 1 is selected from ethyl, trifluoroethyl or fluoroethyl
  • R 2 is selected from chlorine, fluorine or methyl
  • R 4 is selected from hydrogen, chlorine, ethoxy, methoxy or
  • Exemplifying the invention is the compound selected from:
  • An example of the invention is the compound selected from
  • a phaimaceutical composition comprising a therapeutically effective amount of 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 a 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 a type 2 testosterone 5-alpha reductase inhibitor.
  • testosterone 5-alpha reductase inhibitor is finasteride.
  • Another illustration of the invention is a method of treating benign prostatic hyperplasia, relaxing urethral smooth muscle, relaxing prostatic smooth muscle and/or improving urine flow in a subject in need thereof which comprises administering to the subject a
  • More particularly illustrating the invention are the methods of treating BPH, relaxing urethral smooth muscle, relaxing prostatic smooth muscle and/or improving urine flow wherein the compound or pharmaceutical composition additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH, relax urethral smooth muscle, relax prostatic smooth muscle and/or improve urine flow.
  • the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. More preferably, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5- alpha reductase inhibitor. Most preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
  • More specifically exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the alpha la adrenergic receptor which comprises administering to a subject in need thereof an amount of any of the compounds or pharmaceutical compositions described above effective to treat the disease.
  • Diseases which are susceptible to treatment by antagonism of the alpha la receptor include, but are not limited to, BPH, high intraocular pressure, glaucoma, high cholesterol, impotency, sympathetically mediated pain and cardiac arrhythmia.
  • An additional example of the invention is a drug which is useful for treating BPH, relaxing urethral smooth muscle, relaxing prostatic smooth muscle and/or improving urine flow in a mammal in need thereof, the effective ingredient of the said drug being any of the compounds descibed above.
  • 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 BPH, relaxing urethral smooth muscle, relaxing prostatic smooth muscle and/or improving urine flow in a mammal in need thereof.
  • Another aspect of the invention is a method of preparing any of the compounds described above which comprises alkylating a halogenated butyl saccharin with a deprotected benzimidazolyl
  • the method comprises reacting a butyl saccharin moiety with a
  • the compounds of the present invention exhibit high selectivity for the human alpha la adrenergic receptor.
  • One implication of this selectivity is that the compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.
  • the compounds of the present invention are useful for relaxing urethral smooth muscle; additionally, the compounds claimed herein are useful for relaxing prostatic smooth muscle.
  • the ability of the compounds of the present invention to relax urethral and prostatic smooth muscle results in improved urine flow in patients suffering from impaired urine flow (i.e., difficulty in urination) due to enlargement of the prostate gland.
  • impaired urine flow i.e., difficulty in urination
  • the compounds of the present invention are useful for treating BPH.
  • Representative compounds of this invention display submicromolar affinity for the human ⁇ 1a adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human aid and ⁇ ib adrenergic receptor subtypes, and many other G-protein coupled human receptors.
  • Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human ⁇ 1a adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human aid and ⁇ ib adrenergic receptor subtypes, and many other G-protein coupled human receptors.
  • the most preferred compounds of this invention exhibit a Ki for human ⁇ 1a adrenergic receptors which is more than 100 fold lower than for the human aid or aib adrenergic receptors, while exhibiting greater than 50 fold selectivity for the human ⁇ 1a adrenergic receptor over all other human G-protein coupled receptors tested (including serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors).
  • Representative compounds of the present invention are also potent opioid agonists useful as analgesics to eliminate or ameliorate pain and suffering in animals, preferably mammals, especially humans, without loss of consciousness. More particularly, the opioid agonist compounds described herein are selective for the mu opioid receptor over the kappa and delta opioid receptors.
  • Opioids are a class of drugs which are, to varying degrees, opium-like or morphine-like in their properties.
  • the opium group of narcotic drugs are among the most powerfully acting and clinically useful drugs producing depression of the central nervous system (CNS). Drugs of this group are used principally as analgesics, but possess numerous other useful properties.
  • Morphine for example, is used to induce sleep in the presence of pain, relieve diarrhea, suppress cough, ease dyspnea and facilitate anesthesia.
  • Analgesia is defined as the reduction of awareness of pain and suffering without loss of consciousness.
  • Analgesic compounds are agents which produce a state of analgesia, and thus, analgesics are compounds which alleviate and are useful for treating pain without loss of consciousness.
  • morphine agonists morphine-like drugs
  • mixed morphine agonist-antagonists could best be explained by postulating the existence of more than one type of cellular receptor for the opioids, and for related drugs.
  • the rigid alkaloid opiates typified by morphine, are believed to produce their major effects on the CNS and the bowel by acting as agonists, particularly at the mu receptors; however, morphine also has appreciable affinity for kappa and delta receptors.
  • morphine also has appreciable affinity for kappa and delta receptors.
  • ligands which are highly selective for a single opioid receptor type or subtype have the potential of minimizing or eliminating unwanted side effects mediated by the other opioid receptor types. It has now been found that compounds of the present invention are highly selective for the mu opioid receptor and are therefore useful as analgesic agents.
  • opioid agonists are primarily employed as analgesics, the compounds described herein are also useful as antitussives, antidiarrhea agents, anesthetics and tranquilizers.
  • a method of treating a condition which is susceptible to treatment by agonism of a mu opioid receptor which comprises administering to a subject in need thereof an amount of a compound effective to treat the condition wherein the compound has the formula:
  • R 1 is selected from the group consisting of hydrogen, C 3-6 cycloalkyl, unsubstituted or substituted C 1 -6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 , SO 2 NH 2 , a heterocyclic ring or aryl, and unsubstituted or substituted C 2-6 alkenyl where the substituent on the alkenyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 ,
  • R 2 is independently one or more of hydrogen, halogen, C 1 -4 alkoxy, mono-, di- or tri-halogenated C 1 -4 alkoxy or unsubstituted or
  • substituted C 1 -6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 , SO 2 NH 2 , a heterocyclic ring or aryl;
  • R 3 is selected from hydrogen, cyano, CO 2 R 1 , CONH 2 , CONHR 1 , CON(R 1 ) 2 , C 3-6 cycloalkyl, C 3-6 cycloalkyl wherein one of the carbon atoms is replaced with a heteroatom selected from O or NH, or unsubstituted or substituted mono- or di-C 1 -6 alkyl wherein the substituent on the mono- or di-alkyl is selected from hydroxy, C 1 -4 alkoxy, amino or mono-, di- or tri-halogen;
  • R 4 is independently one or more of hydrogen, C 1 -6 alkyl, halogen, C 1 -4 alkoxy, mono-, di- or tri-halogenated C 1 -4 alkoxy, nitro, amino, mono-, di- or tri-halogenated C 1 -6 alkyl, C 1 -6 alkylsulfonyl, C 1 -4 alkylenedioxy, unsubstituted or substituted aryl where the substituent on the aryl is selected from halogen, unsubstituted C 1 -3 alkyl, mono-, di- or tri-halogenated C 1 -3 alkyl or C 1 -4 alkoxy-C 1 -3 alkyl, or
  • R 5 is independently one or more of hydrogen, cyano, C 1 -6 alkyl, CO 2 R 1 , CONH 2 , CONHR 1 , CON(R 1 ) 2 ; and n is an integer of from 2 to 4;
  • this aspect of the invention is a method of alleviating pain in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound described above.
  • R 3 is selected from cyano, CO 2 R 1 , CONH 2 , CONHR 1 , CON(R 1 ) 2 , C 3 - 6 cycloalkyl, C 3-6 cycloalkyl wherein one of the carbon atoms is replaced with a heteroatom selected from O or NH, or unsubstituted or substituted mono- or di-C 1 -6 alkyl wherein the substituent on the mono- or di-alkyl is selected from hydroxy, C 1 -4 alkoxy, amino or mono-, di- or tri-halogen; and
  • R 4 is independently one or more of hydrogen, C 1 -6 alkyl, halogen, C 1 -4 alkoxy, mono-, di- or tri-halogenated C 1 -4 alkoxy, nitro or C 1 -4 alkylenedioxy;
  • R 1 is selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, C 1 -4 alkoxy, carboxy, CONH 2 , a
  • heterocyclic ring or phenyl and unsubstituted or substituted C 2-6 alkenyl where the substituent on the alkenyl is mono-, di- or
  • R 2 is independently one or more of hydrogen, halogen or C 1 -6 alkyl
  • R 3 is selected from cyano, C 1 -4 alkoxycarbonyl, CONH 2 or
  • R 4 is independently one or more of hydrogen or halogen; and R 5 is independently one or more of hydrogen, cyano, C 1 -6 alkyl or CO 2 R 1 ; and wherein all other variables are as defined above;
  • Illustrative of this aspect of the invention is the method of alleviating pain wherein R 1 is selected from hydrogen, C 1 -6 alkyl, mono-, di- or tri-halogenated C 1 -6 alkyl, benzyl, C 2-6 alkenyl or mono-, di- or tri-halogenated C 2-6 alkenyl; R 3 is selected from cyano or mono- or di-C 1 -6 alkyl; and
  • R 4 is independently one or more of hydrogen or chlorine
  • R 1 is selected from hydrogen, C 1 -4 alkyl, C 2-6 alkenyl, benzyl, trifluoroethyl or fluoroethyl;
  • R 2 is independently one or more of hydrogen, chlorine, fluorine or methyl;
  • R 3 is selected from hydrogen, methyl or dimethyl;
  • R 5 is independently one or more of hydrogen, cyano, methyl or methoxycarbonyl; and wherein all other variables are as defined above; and the pharmaceutically acceptable salts thereof. Exemplifying this aspect of the invention is the method of alleviating pain wherein the compound has the formula
  • An example of this aspect of the invention is the method of alleviating pain wherein the compound is selected from the group consisting of
  • the compound is selected from:
  • the compound is selected from
  • Another illustration of this aspect of the invention is a drug which is useful for alleviating pain or inducing analgesia in a mammal in need thereof, the effective ingredient of the said drug being any of the compounds descibed above.
  • the compounds of the present invention are administered in dosages effective to antagonize the alpha 1 a receptor where such treatment is needed, as in BPH, or in dosages effective to agonize the mu opioid receptor where such treatment for pain is needed.
  • the salts of the compounds of this invention refer to non-toxic
  • 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
  • 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
  • salts formed with suitable organic ligands e.g. quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following:
  • Glycollylarsanilate Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,
  • Methylbromide Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,
  • 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.
  • the term “administering” shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • 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.
  • crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the present invention may form solvates with water 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 shall mean phenyl, napthyl or fluorenyl.
  • 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., C 1 -10 ) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • halogen shall include iodine, bromine, chlorine and fluorine.
  • substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • R 4 can be one or more of the named substituents. That is, the piperidine ring and the benzene rings can be mono-, di-, tri- or tetra-substituted by any of the substituents listed in the definitions of R 2 ,
  • R 4 and R 5 are poly-substituted.
  • the substitutents can be the same or different.
  • 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-R 6 (R 6 is hydrogen, C 1 -6 alkyl or absent), O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl,
  • oxoazepinyl azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazglyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl,
  • Morpholino is the same as morpholinyl.
  • the term "mono- or di-C 1 -6 alkyl” shall mean that the R 3 bound carbon can be mono- or di- substituted with a C 1 -6 alkyl group.
  • R 3 when R 3 is di- methyl, then shall mean Moreover, when R 3 is di-C 1 -6 alkyl, the C 1 -6 alkyl groups can be the same or different.
  • C 3-6 cycloalkyl shall mean that the methylene group and the R 3 substituent can together form a C 3-6 cycloalkyl ring.
  • C 1 -4 alkylenedioxy shall mean that phenyl ring containing the R 4 substituent contains a C 1 -4 alkylenedioxy bridge connecting two adjacent carbon atoms of the benzene ring.
  • analgesia as used herein is defined as the reduction of awareness of pain and suffering without loss of
  • Analgesic compounds are agents which produce a state of analgesia (i.e., induce analgesia), and thus, analgesics are compounds which alleviate and are useful for treating pain without loss of
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • therapeutically 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. water, to form a solid
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid
  • preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • 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 compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-dtartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
  • 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
  • the specificity of binding of compounds showing affinity for the ⁇ 1a receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the ⁇ 1a receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., ⁇ 1d, ⁇ lb) or beta adrenergic receptors.
  • Expression of the cloned human aid, aib, and ⁇ 1a 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 1 a adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting hypotensive effects.
  • the ability of compounds of the present invention to specifically bind to the ⁇ 1a receptor makes them useful for the treatment of BPH.
  • the specificity of binding of compounds showing affinity for the ⁇ 1a receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors.
  • the human alpha adrenergic receptor of the la subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. 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 ⁇ 1a receptor when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned human aid, alb, and ⁇ 1a 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
  • Compounds of this invention exhibiting selective human ⁇ 1a 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
  • the present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical
  • compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha la adrenergic receptors and/or in the alleviation of pain can be administered in a wide variety of therapeutic dosage forms in
  • 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.
  • they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • An effective but non-toxic amount of the compound desired can be employed as an alpha la 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, veterinarian or clinician 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
  • 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, com sweeteners, natural and
  • carboxymethylcellulose polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium
  • 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.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl-amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residues.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid,
  • polyepsilon caprolactone polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required and/or whenever relief from pain 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 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active 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
  • 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 ⁇ 1a 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.
  • Many such compounds are now well known in the art and include such compounds as PROSCAR®, (also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071, for example, hereby 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.
  • Compounds that are active as 5 ⁇ -reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050;
  • adrenergic receptor may be independently optimized and combined to achieve a 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
  • 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 in the combination is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an ⁇ 1a 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
  • 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 4,7ß-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,
  • PEI polyethylenimine
  • Ph phenyl
  • the compounds of the present invention are prepared by a two step alkylation process beginning with a saccharin or substituted saccharin (referred to as “the saccharin moiety") prepared according to methods known in the art (see for example US Patents 4,818,756;
  • the saccharin moiety is alkylated with a reagent such as 1 ,4-dibromobutane, or a similar reagent, to form the butyl-saccharin moiety (see Scheme 1 and Examples 21 and 22 below).
  • the butyl saccharin is then alkylated with a piperidinyl benzoxazolinone (prepared as shown in Examples 17-19 which follow) or with a piperidinyl benzimidazolinone (prepared as shown in Schemes 1 - 4 below) to form the active compounds of this invention.
  • benzimidazolinone-piperidine derivatives are prepared by alkylating the Boc-protected benzimidazolinone-piperidine as shown in Scheme 1 and Example 1, steps 1-3 below).
  • the benzimidazolinone-piperidine derivatives with substituents on the benzene ring are prepared as shown in Schemes 4 and 5 using procedures described in J. Med. Chem., 30, 814-819 (1987) and U.S. Patent No. 3,910,930, hereby inco ⁇ orated by reference.
  • Compound A is prepared according to Scheme 5 and the procedure of Example 27.
  • Step 1 To a partial suspension of 4-(2-oxo-1-benzimidazolinyl) piperidine (1.085 gm, 5.0 mmol), which is commercially available, in 30 mL of methylene chloride under an argon atmosphere was added 1.37 gm (6.3 mmol) of di-t-butyl dicarbonate. After reaction was stirred at ambient temp, for 1 hour, the solvent was removed and the residue triturated with diethyl ether to give 1-t-butoxycarbonyl-4-(2-oxo-1-benzimidazolinyl)piperidine as an off-white solid, melting point 161-163°C.
  • Step 2 To a solution of 1-t-butoxycarboxyl-4-(2-oxo-1-benzimidazolinyl)-piperidine (542 mg, 1.7 mmol) in dry dimethyl-formamide (5 mL) under an argon atmosphere was added 86 mg (2.0 mmol) of 60% sodium hydride in mineral oil. The mixture was warmed at 50°C until gas evolution ceased ( ⁇ 1/2 hour) and then cooled to room temperature. Iodopropane (0.29 mL, 3.0 mmol) was added by syringe and the reaction was stirred for 20-48 hours. Water was added to the reaction mixture and the product extracted into ethyl acetate.
  • Step 3 A solution of 1-t-butoxycarbonyl-4-(3-propyl-2-oxo-1-benzimidazolinyl)piperidine (540 mg, 1.5 mmol) in chloroform (7 mL) containing trifluoroacetic acid (1 mL) was allowed to stir at ambient temperature for 15-25 hours. The solvent was removed on a rotary evaporator, the residue dissolved in chloroform and washed with aq. Na 2 CO 3 . The dried (Na2SO 4 ) chloroform extract was evaporated to give 4-(3-propyl-2-oxo-1-benzimidazolinyl)piperidine as an oil which was used as is.
  • Step 4 To a solution of 4-(3-propyl-2-oxo-1-benzimidazolinyl)-piperidine (440 mg, 1.7 mmol) in dry dimethylformamide (6 mL), under an argon atmosphere was added 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1 ,2-benzisothiazol-3(2H)-one (615 mg, 1.74 mmol, prepared as shown in Example 22) followed by triethylamine (0.25 mL, 1.8 mmol). This solution was heated at 50°C for four hours and then cooled to room temperature as water was added. The product was extracted, dried (Na 2 SO 4 ) and evaporated.
  • 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1 ,2-benzisothiazol-3(2H)-one 615 mg, 1.74 mmol, prepared as shown in Example 22
  • triethylamine (0.25
  • Step 1 A mixture of 12.8 gm (77 mmol) of 5-bromo-2-pentanone, which was obtained as described by ApSimon and Sequin in Synthetic Communications, 10, 897 (1980), and 12 mL of ethylene glycol in 100 mL of benzene containing 0.84 gm of p-toluenesulfonic acid was refluxed with a Dean-Stark trap until the required water was
  • Step 2 A mixture of the above ketal (3.2 gm, 15 mmol) and sodium saccharin (3.1 gm, 14 mmol) in dimethylformamide (15 mL) was heated at 170°C for 5 hours. The cooled reaction mixture was poured into water and the crude product extracted into ethyl acetate. The dried extract was evaporated and the crude product was chromotographed on a column of silica gel eluting with a gradient of 20-40% EtOAc/hexane to give crystalline 1 ,1-dioxido-2-(4-oxo-pentyl)-1 ,2-benzisothiazol-3(2H)-one, melting point 90-93°C.
  • Step 3 A mixture of 4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine (319 mg, 1.0 mmol) and 1,1 -dioxido-2-(4-oxo-pentyl)-1,2-benzisothiazol-3-(2H)-one (267 mg, 1.0 mmol) in isopropanol (0.4 mL) containing titanium (IV) isoproproxide (0.4 mL, 1.3 mmol) was heated at 55°C under an argon atmosphere for one hour to give a yellow solution. This solution was cooled to room temperature and diluted with absolute EtOH (4 mL).
  • Step 1 A solution of 5-(benzyloxycarbonylamino)-2-methyl-2-pentylamine (1.59 gm, 6.3 mmol) [prepared as described by Nagarajan and Ganem, J. Org. Chem., 51 , 4856 (1986) except that a benzyloxycarbonyl protecting group was used in place of a t-butoxycarbonyl group] in ethanol (14 mL) containing potassium carbonate (101 mg, 0.7 mmol) was heated at 80°C and a solution of methyl ethylpiperidonium iodide (2.54 gm, 9.45 mmol) [obtained by a dropwise addition of one equivalent of methyl iodide to n-ethyl-4-piperidone in acetone] in water (45 mL) was added dropwise over a 2 hour period. After heating the reaction mixture for 4 more hours, the reaction was cooled, diluted with water and aq. Na 2 CO 3 and the
  • Step 2 An equivalent of phenylene diamine (1 18 mg, 1.09 mmol) was added to a solution of N-(5-benzyloxycarbonylamino-2-methyl-2-pentyl)-4-piperidone (345 mg, 1.04 mmol) in methanol (5 mL) containing acetic acid (0.065 mL, 1.15 mmol). After stirring this reaction mixture for one hour, solid sodium cyanoborohydride (82 mg. 1.3 mmol) was added in one portion and stirring was continued overnight at ambient temperature. The reaction was cooled in an ice bath and acetaldehyde (0.06 mL, 1.0 mmol) was added by syringe. The reaction was stirred for an additional 20 hours.
  • Step 3 The above mixture was dissolved in ethyl acetate (8 mL), saturated aq. Na 2 O 3 (6 mL) was added, and the biphase mixture cooled in an ice bath as 1.9M phosgene/toluene (1 mL) was added dropwise. After 4-20 hours, the reaction mixture was diluted with water and the crude product extracted into ethyl acetate. The dried (Na 2 SO 4 ) ethyl acetate solution was evaporated and the residue chromatographed on a column of silica gel eluting with a gradient of 0.25-3%
  • Step 4 A solution of 1-(5-benzyloxycarbonylamino-2-methyl-2-pentyl)-4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine (93 mg, 0.19 mmol) in methanol (8 mL) containing chloroform (0.04 mL,
  • Step 5 A solution of 1-(5-amino-2-methyl-2-pentyl)-4-(3-ethyl-2-oxo- 1-benzimidazolinyl)piperidine (67 mg, 0.19 mmol) in methylene chloride (4 mL) was cooled in an ice bath and methyl 2-chlorosulfonyl benzoate (5.5 mg, 0.25 mmol) and triethylamine (0.04 mL, 0.3 mmol) were added. After one hour aq. Na 2 CO 3 was added to the reaction mixture and the product extracted into methylene chloride, dried (Na 2 SO 4 ) and evaporated.
  • Step 1 A mixture of 15.4 g 4-piperidone hydrochloride hydrate, 200 mL ether, 100 mL saturated aqueous Na 2 CO 3 solution and 21.8 g di-t-butyldicarbonate was vigorously stirred for 48 h. The layers were separated and the organic layer was washed with two 150 mL portions of 10% aqueous citric acid, dried over MgSO 4 . Removal of solvents under reduced pressure gave N-t-butyloxycarbonyl-4-piperidone as a white solid.
  • Step 2 A mixture of 6.0 g N-t-butyloxycarbonyl-4-piperidone, 3.3 g of 2-aminophenol, 25 mL of 1 ,2-dichloroethane, 25 mL of glacial acetic acid, and 500 mg powdered 4A molecular sieves was stirred under inert atmosphere. After 30 min, 6.4 g sodium triacetoxyborohydride was added stirring was continued for 38 h. The reaction mixture was poured into 400 mL ethyl acetate and 200 mL saturated aqueous
  • Step 3 To a stirred solution of 6.95 g 1-t-butyloxycarbonyl-4-(2-hydroxyphenylamino)piperidine and 6.2 mL diisopropylethylamine in 120 mL tetrahydrofuran cooled to 0°C was added 3.0 g triphosgene. The reaction was stirred 30 min at 0°C and then at room temperature 2 h. The precipitate was removed by filtration, the filtrate concentrated at reduced pressure and partitioned between 250 mL ethyl acetate and 100 mL saturated aqueous Na 2 CO 3 . The layers were separated, the organic layer washed with 100 mL of saturated aqueous Na 2 CO 3 , 100 mL of water, 100 mL of brine, dried over MgSO 4 , and
  • Step 4 A stirred solution of 6.0 g (19 mmol) 1 -((1-t-butyloxycarbonyl)piperidin-4-yl)-3-benzoxazolin-2-one in 120 mL ethyl acetate was cooled to -78°C and a stream of hydrogen chloride gas was introduced with a fritted dispersion tube for 15 min. The mixture was allowed to warm to 0°C for 1 h, then room temperature for 2 h. The resulting precipitate was collected by filtration. Drying at reduced pressure for 8 h gave the hydrochloride salt of 1-(4-piperidinyl)-3-benzoxazolin-2-one as an off-white solid.
  • Step 5 From 1-(4-piperidinyl)-3-benzoxazolin-2-one and 1,1-dioxido-2-(4-oxo-pentyl)-1,2-benzisothiazol-3(2H)-one using the procedures of Example 2 there was obtained a white solid upon formation of the HCl salt (from isopropanol and methanol), melting point 273-274°C.
  • Step 1 4-(6-methyl-2-oxo-3-benzoxazolinyl)piperidine was obtained as a white solid from the reaction of 6-amino-m-cresol and N-t-butyloxycarbonyl-4-piperidone according to Steps 2-4 of Example 17.
  • Step 2 From 4-(6-methyl-2-oxo-3-benzoxazolinyl)piperidine and 1 ,1 - dioxido-2-(4-oxo-pentyl)-1 ,2-benzisothiazol-3(2H)-one using the procedures of Example 2 there was obtained a white solid upon formation of the HCl salt (from ethanol and diethyl ether), melting point 234-236°C. Analysis calculated for C 25 H 29 N 3 O 5 S•HCl•.0.4 H2O: C, 56.95; H, 5.89; N, 7.97; found: C, 56.92; H, 5.75, N, 7.79. The NMR was consistent with the structure.
  • Step 1 From phenylene diamine and methyl N-t-butoxycarbonyl-4-oxo-3-piperidinecarboxylate ( obtained by reaction of methyl 4-oxo-3-piperidinecarboxylate with di-t-butyl dicarbonate as described in Example 1, Stepl) using the procedures described in Example 3, Step 2 (except that the acetaldehyde was omitted) and Step 3, followed by removal of the t-butoxycarbonyl group with HCl gas in ethyl acetate there was obtained ( ⁇ ) cis/trans-4-(2-oxo-1-benzimidazolinyl)-3-methoxycarbonyl-piperidine which was used as is.
  • Step 2 From ( ⁇ ) cis/trans-4-(2-oxo-1-benzimidazolinyl)-3-methoxycarbonyl-piperidine and 1 ,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 22) using the procedures described in Example 1, Step 3, there was obtained a white solid from methylene chloride, melting point 170-176°C. Analysis calculated for C 25 H 27 CIN 4 O 6 S: C, 54.89; H, 4.98; N, 10.24; found: C, 54.65; H, 4.98; N, 10.22. The NMR was consistent with the structure.
  • Step 1 To a cloudy solution of 4-(3-n-propyl-2-oxo-1 -benzimidazolinyl)- piperidine (420 mg, 1.62 mmol) [obtained in
  • Example 1 step 3] in diethyl ether (4 mL) which was cooled in an ice bath was added t-butyl hypochlorite (0.53 mL, 4.4 mmol) in three portions by syringe over a two hour period.
  • t-butyl hypochlorite (0.53 mL, 4.4 mmol)
  • the starting amine had disappeared by tic
  • the diluted etheral mixture was washed with water and the organic solution dried (Na2SO 4 ). After concentration to about 4 mL, this etheral solution was added to a suspension of potassium superoxide (253 mg, 3.56 mmol) in diethyl ether (10 mL) containing 18-crown-6 ether (10 mg) and stirred vigorously for 15 - 20 hours.
  • Step 2 From ( ⁇ ) cis/trans-2-cyano-4-(3-n-propyl-2-oxo-1-benzimidazolinyl)- piperidine and 1 ,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one using a modification of the procedure described in Example 1, Step 4, wherein one equivalent of potassium iodide was added and the reaction was warmed at 80°C for 24 hours, there was obtained a white solid after chromatographic
  • Step 1 Chlorosulfonic acid (6 mL, 90 mmol) was added dropwise to an ice cooled solution of 1 ,4-benzodioxane ( 12 gm, 88 mmol) in
  • the separated THF layer was washed with diluted Na 2 CO 3 (2 ⁇ 100 mL).
  • the combined Na 2 CO 3 extracts were carefully acidified with cone. HCl and the product was extracted into diethyl ether (3 ⁇ 200 mL).
  • the ether extracts were dried (MgSO 4 ) and the solvent evaporated to give the carboxylic acid as a glassy foam.
  • This material was dissolved in methylene chloride (200 mL), cooled to 0°C, and triethylamine (7 mL) added followed by the dropwise addition of methyl chloroformate (2 mL).
  • Step 2 To a solution of 1 ,1-dioxido-2-(4-hydroxybutyl)-4,5-ethylenedioxy-1,2-benzisothiazol-3(2H)-one (313 mg, 1 mmol) and carbon tetrabromide (432 mg, 1.3 mmol) in methylene chloride (2 mL) cooled in an ice bath under a nitrogen atomosphere was added dropwise a solution of triphenylphosphine (341 mg, 1.3 mmol) in methylene chloride (3.5 mL).
  • Steps 1-4 are based on modifications of procedures described by
  • Step 1 A solution of ethyl 4-amino-1-piperidine carboxylate (9.0 g, 52 mmol.) and 2-chloro-5-fluoronitrobenzene (10.3g, 58 mmol.) in cyclohexanol (30 mL) containing powdered sodium carbonate (6.1 g, 57 mmol.) was refluxed (>160°C) for 30 hours or until no further reaction was indicated by tlc( 30% EtOAc/hexane).
  • Step 2 This 1-ethoxycarbonyl-4-(4-fluoro-2-nitroanilino)piperidine (5.7g, 18.3 mmol.) was dissolved in THF (50 mL) and diluted with ethanol (100 mL). After addition of 5% platinum/carbon catalyst
  • Step 3 The crude 1 -ethoxycarbonyl-4-(2-amino-4-fluoroanilino)piperidine above was dissolved in EtOAc (100 mL) and saturated aq. NazCO 3 (100 mL) was then added to give a two-phase system. After cooling in an ice bath, phosgene in toluene (25 mL, 1.9N ) was added in portions with stirring. After one hour, the reaction mixture was warmed to room temp, and diluted with EtOAc. The organic layer was separated and washed with more NaHCO 3 /Na2CO 3 solution, dried (Na2SO 4 ), and filtered through a pad of charcoal. The filtrate was evaporated and the residue triturated with Et 2 O to give purified 1-ethoxycarbonyl-4-(5-fluoro-2-oxo-1-benzimidazolinyl)piperidine as an off-white solid.
  • Step 4 A suspension of 1 -ethoxycarbonyl-4-(5-fluoro-2-oxo-1-benzimidazolinyl)piperidine (5.22g, 17 mmol.) in 2 N NaOH (55 mL) was refluxed for twelve hours. The clear amber solution was cooled to room temp, and solid NH 4 CI (5.9g, 1 10 mmol.) was added to
  • Step 5 This crude 4-(5-fluoro-2-oxo-1-benzimidazolinyl)piperidine was dissolved in chloroform (70 mL), cooled in an ice bath and di-tert-butyl dicarbonate (4.13g, 19 mmol.) was added. After stirring for two hours, the solvent was evaporated and the residue triturated with Et 2 O to give 1 -tert-butoxycarbonyl-4-(5-fluoro-2-oxo-1-benzimidazolinyl)-piperidine as an off-white solid.
  • Step 6 Solid 1-tert-butoxycarbonyl-4-(5-fluoro-2-oxo-1-benzimidazolinyl)piperidine (9.7 g, 28.9 mmol.) was dissolved in anhydrous DMF (72 mL) under an inert atmosphere and cesium carbonate (10.6 g, 32.5 mmol.) was added followed by excess
  • Step 7 A solution of 1 -tert-butoxycarbonyl-4-(5-fluoro-3-(2,2,2-tri ⁇ fluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine (4.17g, 10 mmol.) in chloroform (50 mL) containing trifluoroacetic acid (5.5 mL) was stirred at room temp, under an inert atmosphere for 6 -12 hours until reaction was complete. The solvent and excess TFA were removed and the residue redissolved in chloroform. This solution was washed with Na 2 CO 3 /NaOH solution.
  • Step 8 The 4-(5-fluoro-3-(2,2,2-trifluoroethyl)-2-oxo-1 -benzimidazolinyl)piperidine ( ⁇ 10 mmol.) above was dissolved in anhydrous DMF (25 mL) followed by the addition o1 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1 ,2-benzisothiazol-3(2H)-one (3.54 g, 10 mmol.) and
  • 100 mg of the compound of Example 27 (i.e., Compound A) 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 [ 3 H] spiperone to cells expressing human dopamine receptors D 2 , D 3 or D 4 .
  • Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (10mM Tris-HCl/5mM Mg, pH 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], KCl, 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 [ 3 H]-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.
  • 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 1000Xg for 30', and then the supernatant is centrifuged again at 38,000Xg for 30'.
  • the binding assay contains 0.25 nM [3H]8-OH-DPAT (8-hydroxy-2-dipropylamino-1 ,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaCl2 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
  • Taconic Farms Sprague-Dawley male rats, weighing 250-400 grams are sacrificed by cervical dislocation under anesthesia
  • the tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCl, 118 mM; KCl, 4.7 mM; CaCl 2 , 2.5 mM;
  • 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.
  • Kb [B].
  • x is the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration.
  • 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 la receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without 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 -1/2 inch lateral to the penis is made to expose the urethers, bladder and urethra.
  • the urethers are ligated and cannulated so that urine flows freely into beakers.
  • the dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra.
  • Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1 -2 cm distal to the prostate.
  • the bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra.
  • the bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer.
  • the tip of the transducer is placed in the prostatic urethra and the position of the Millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure.
  • Phenylephrine an alpha 1 adrenergic agonist
  • Phenylephrine is administered (0.1-100 ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure.
  • an alpha adrenergic antagonist or vehicle
  • the effects of phenylephrine on arterial pressure and intra-urethral pressure are re-evaluated.
  • Four or five phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle).
  • the relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis.
  • the family of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant among curves.
  • the dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the ED 50 's for the respective curves. These dose-ratios are then used to construct a Schild plot and the Kb (expressed as ug/kg, iv) determined.
  • the Kb dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve
  • the relative selectivity is
  • 3H-Naloxone binds with high affinity to opiate receptors in brain tissue (Creese and Snyder, J. Pharm Expt. Ther., 194: 205-219,
  • 3H-Naloxone binding in rat brain membranes was performed as described by Creese and Snyder (J. Pharm. Expt. Ther.. 194, 205-219, 1975) using Tris buffer alone or in the presence of 150 mM NaCl.
  • Naloxone binding for representative examples of the present invention are given below in Table 6.
  • Opioid mu and delta receptor binding assays were performed with rat brain membranes using 3 H-DAMGO ([D-Ala 2 , Me-Phe 4 , Gly-ol 5 ]enkephalin, 1nM) and 3 H-DPDPE ([D-Pen 2 , D-Pen 5 ]enkephalin, 3 nM) as the selective radioligand, respectively (Slater and Cross, 1991 , Methods in Neurosciences ed. P.M. Conn. Academic Press, vol. 5 pp.459-478).
  • 3 H-DAMGO [D-Ala 2 , Me-Phe 4 , Gly-ol 5 ]enkephalin, 1nM
  • 3 H-DPDPE [D-Pen 2 , D-Pen 5 ]enkephalin, 3 nM
  • Kappa receptor binding assays were performed with guinea pig brain membranes using 3 H-U69593 (5 alpha, 7 alpha, 8 beta)-(+)-N-Methyl-N-[7-(1-pyrrolinyl)-1-oxaspiro[4,5]dec-8-yl]benzene-acetamide, 5 nM) as the radioligand.
  • Brain membrane preparation and radioligand binding assays were performed similarly to those for 3 H-naloxone binding assay with the exception as noted below.
  • protease inhibitors (bacitracin 20 ⁇ g/ml, soybean trypsin inhibitor 50 ⁇ g/ml and leupeptin 10 ⁇ g/ml) were added to the binding assay buffer for 3H-DAMGO and 3 H-DPDPE binding assays. Binding assays were carried out at 25 oC for 1 hour (3H-DAMGO and 3 H-U69593) and 3 hours (3H-DPDPE). Nonspecific binding was determined in the presence of 1 ⁇ M of naloxone.
  • the selectivity of representative compounds of the present invention on opioid receptor subtypes are shown below in Table 7.
  • Guinea pig ileum longitudinal muscles with attached myenteric plexus were removed by the method of Paton and Zar (J. PhysioL, 194, 13-33, 1968) and were mounted in organ baths (5 ml) containing Krebs-Ringer-bicarbonate solution under 0.5g tension. The strips were stimulated by supramaximal electrical stimulation via two platinum electrodes at 0.15Hz and 1.5 msec pulse duration.

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Abstract

Cette invention se rapporte à de nouveaux composés, à leur synthèse, et à leur utilisation comme antagonistes sélectifs du récepteur α1a-adrénergique. Une première application de ces composés est le traitement de l'hyperplasie bénigne de la prostate. Ces composés sont sélectifs du point de vue de leur capacité à relâcher les tissus des muscles lisses enrichis en récepteur adrénergique de sous-type α1a, sans qu'une hypotension soit en même temps provoquée. On trouve de tels tissus autour de la membrane tapissant l'urèthre. Par conséquent, une première utilité de ces composés est d'entraîner un soulagement immédiat des sujets mâles souffrant d'hyperplasie bénigne de la prostate, en permettant un écoulement d'urine moins entravé. Une seconde utilité de ces composés est obtenue par combinaison avec un composé inhibiteur de 5-alpha-réductase humaine, pour que soit obtenu un soulagement à la fois immédiat et chronique des effets de l'hyperplasie bénigne de la prostate.
PCT/US1996/002534 1995-02-23 1996-02-23 ANTAGONISTES DU RECEPTEUR ALPHA-1a-ADRENERGIQUE WO1996025934A1 (fr)

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US08/860,314 US5952351A (en) 1995-02-23 1996-02-23 Alpha 1a adrenergic receptor antagonists
JP8525855A JPH11508536A (ja) 1995-02-23 1996-02-23 アドレナリン性α▲下１ａ▼受容体アンタゴニスト
EP96905575A EP0812196A4 (fr) 1995-02-23 1996-02-23 ANTAGONISTES DU RECEPTEUR ALPHA-1a-ADRENERGIQUE
AU49301/96A AU700559B2 (en) 1995-02-23 1996-02-23 Alpha 1a adrenergic receptor antagonists

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US6096763A (en) * 1995-02-23 2000-08-01 Merck & Co., Inc. α1a adrenergic receptor antagonists
WO2001027104A1 (fr) * 1999-10-13 2001-04-19 Banyu Pharmaceutical Co., Ltd. Derives d'imidazolidinone a substitution
US6326372B1 (en) 1999-09-30 2001-12-04 Merck & Co., Inc. Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
EP1379246A4 (fr) * 2001-04-18 2005-09-28 Euro Celtique Sa Analogues de la nociceptine

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US4470989A (en) * 1981-06-20 1984-09-11 Hoechst Aktiengesellschaft Neuroleptic n-oxacyclyl-alkylpiperidine derivatives
FR2621588A1 (fr) * 1987-10-08 1989-04-14 Roussel Uclaf Nouveaux derives de la 1,1-dioxo 1,2-benzoisothiazol 3-one, leur procede de preparation et leur application comme medicaments
US5143923A (en) * 1991-04-29 1992-09-01 Hoechst-Roussel Pharmaceuticals Inc. Benzoisothiazole- and benziosoxazole-3-carboxamides
WO1992016213A1 (fr) * 1991-03-20 1992-10-01 Merck & Co., Inc. Combinaison pharmaceutique pour le traitement de l'hyperplasie de la prostate renfermant un inhibiteur de 5 alpha-reductase et un antiandrogene

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Publication number Priority date Publication date Assignee Title
US4470989A (en) * 1981-06-20 1984-09-11 Hoechst Aktiengesellschaft Neuroleptic n-oxacyclyl-alkylpiperidine derivatives
FR2621588A1 (fr) * 1987-10-08 1989-04-14 Roussel Uclaf Nouveaux derives de la 1,1-dioxo 1,2-benzoisothiazol 3-one, leur procede de preparation et leur application comme medicaments
WO1992016213A1 (fr) * 1991-03-20 1992-10-01 Merck & Co., Inc. Combinaison pharmaceutique pour le traitement de l'hyperplasie de la prostate renfermant un inhibiteur de 5 alpha-reductase et un antiandrogene
US5143923A (en) * 1991-04-29 1992-09-01 Hoechst-Roussel Pharmaceuticals Inc. Benzoisothiazole- and benziosoxazole-3-carboxamides
US5143923B1 (en) * 1991-04-29 1993-11-02 Hoechst-Roussel Pharmaceuticals Incorporated Benzoisothiazole-and benzisoxazole-3-carboxamides

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6096763A (en) * 1995-02-23 2000-08-01 Merck & Co., Inc. α1a adrenergic receptor antagonists
US6326372B1 (en) 1999-09-30 2001-12-04 Merck & Co., Inc. Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
WO2001027104A1 (fr) * 1999-10-13 2001-04-19 Banyu Pharmaceutical Co., Ltd. Derives d'imidazolidinone a substitution
US6699880B1 (en) 1999-10-13 2004-03-02 Banyu Pharmaceutical Co., Ltd. Substituted imidazolidinone derivatives
EP1379246A4 (fr) * 2001-04-18 2005-09-28 Euro Celtique Sa Analogues de la nociceptine
EP1598339A1 (fr) * 2001-04-18 2005-11-23 Euro-Celtique S.A. Derivés de la 1-(4-amino-cyclohexyl)-1,3-dihydro-2h-benzimidazole-2-one et composés similaires pour l'utilisation comme analogues du nociceptin et ligandes du orl1 pour le traitement de la douleur
EP1598340A1 (fr) * 2001-04-18 2005-11-23 Euro-Celtique S.A. Derivés de la 1-(4-piperidinyl)-1,3-dihydro-2h-benzoxazole-2-one et composés similaires pour l'utilisation comme analogues du nociceptin et ligands du orl1 pour le traitement de la douleur
EP1930322A1 (fr) * 2001-04-18 2008-06-11 Euro-Celtique S.A. Dérivés de la 1-(4-piperidinyl)-1,3-dihydro-2H-benzoxazole-2-one et composés similaires en tant que analogues de la nociceptine et ligands ORL1 pour le traitement de la douleur

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