EP0998285A1 - ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a - Google Patents

ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a

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Publication number
EP0998285A1
EP0998285A1 EP98930356A EP98930356A EP0998285A1 EP 0998285 A1 EP0998285 A1 EP 0998285A1 EP 98930356 A EP98930356 A EP 98930356A EP 98930356 A EP98930356 A EP 98930356A EP 0998285 A1 EP0998285 A1 EP 0998285A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
cyclohexyl
pyrrolidin
oxo
difluorophenyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98930356A
Other languages
German (de)
English (en)
Other versions
EP0998285A4 (fr
Inventor
Michael A. Patane
Mark G. Bock
Harold G. Selnick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and 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 GBGB9719392.4A external-priority patent/GB9719392D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0998285A1 publication Critical patent/EP0998285A1/fr
Publication of EP0998285A4 publication Critical patent/EP0998285A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha la adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine. Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla.
  • the binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
  • alpha and beta receptors were further subdivided into alpha 1 ? alpha 2 y Bl, and &2 subtypes. Functional differences between alpha 1 and alpha 2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.
  • alpha adrenergic receptors the reader's attention is directed to Robert R. RufFolo, Jr., £ f Adrenorecentors: Molecular Biology. Biochemistry and Pharmacology.
  • alpha 1/alpha 2 subclassification the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3'- terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting alpha-adrenergic receptor affinity was explored.
  • the cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the alpha 1 receptors into alpha Id (formerly known as alpha la or la/Id), alpha lb and alpha la (formerly known as alpha lc) subtypes.
  • alpha 1 receptor subtype exhibits its own pharmacologic and tissue specificities.
  • the designation "alpha la” is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated “alpha lc” cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995).
  • the designation alpha la is used throughout this application to refer to this subtype.
  • the receptor formerly designated alpha la was renamed alpha Id.
  • the new nomenclature is used throughout this application.
  • Stable cell lines expressing these alpha 1 receptor subtypes are referred to herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature.
  • ATCC American Type Culture Collection
  • Benign prostatic hyperplasia also known as benign prostatic hypertrophy or BPH
  • BPH benign prostatic hypertrophy
  • the symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra.
  • the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
  • the male hormone ⁇ alpha- 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 lower urinary tract tissue, 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.
  • the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alphai subtype was reported.
  • non-selective antagonists suffer from side effects related to antagonism of the alpha Id and alpha lb receptors in the peripheral vasculature, e.g., hypotension and syncope.
  • the recent cloning of the human alpha la adrenergic receptor (ATCC CRL 11140) and the use of a screening assay utilizing the cloned human alpha la receptor enables identification of compounds which specifically interact with the human alpha la adrenergic receptor.
  • WO94/08040 published 14 April 1994 and WO94/10989, published 26 May 1994
  • a cloned human alpha la adrenergic receptor and a method for identifying compounds which bind the human alpha la receptor has now made possible the identification of selective human alpha la adrenergic receptor antagonists useful for treating BPH.
  • the instant patent disclosure discloses novel compounds which selectively bind to the human alpha la receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors (e.g., alpha 2), thus defining the specificity of the compounds of the present invention for the human alpha la adrenergic receptor.
  • the compounds of the present invention are alpha la adrenergic receptor antagonists.
  • the compounds of the present invention are useful for treating BPH in mammals. Additionally, it has been found that the alpha la adrenergic receptor antagonists of the present invention are also useful for relaxing lower urinary tract tissue in mammals.
  • the present invention provides compounds for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • the compounds antagonize the human alpha la adrenergic receptor at nanomolar and subnanomolar concentrations while exhibiting at least ten fold lower affinity for the alpha 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 hypotension, syncope, lethargy, etc.
  • the compounds of the present invention have the structure:
  • E, G, L and M are each independently selected from hydrogen, C ⁇ -8 alkyl, C3-8 cycloalkyl, (CH 2 ) ⁇ -4 ⁇ R6, (CH 2 ) ⁇ -4N(Rl9) 2 , (CH 2 ) ⁇ -4CN, (CH 2 )0-4CF 3 , (CH 2 )0-4CO2R 19 , (CH 2 ) ⁇ -4CON(Rl9) 2 , (CH 2 ) ⁇ -4S0 2 R 6 of
  • J is selected from hydrogen, C ⁇ -8 alkyl, C3-8 cycloalkyl, (CH2)l-4 ⁇ R ⁇ , (CH 2 )l-4N(Rl9)2, (CH 2 )l-4CN, (CH 2 ) ⁇ -4CF 3 , (CH2) ⁇ -4C0 2 R 19 , (CH2)0-4CON(Rl9) 2 , (CH ) ⁇ -4S ⁇ 2R 6 , or (CH 2 ) ⁇ -4S ⁇ 2N(Rl9) 2 ;
  • Rl is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , N(R 19 ) 2 , NR 19 COR 20 ,
  • R is selected from hydrogen, cyano, OR 6 , C02R 19 , CON(Rl9) 2 , tetrazole, isooxadiazole, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR 6 , (CH2) ⁇ -4C ⁇ 2R 19 , (CH2) ⁇ -4CON(R 19 ) 2 , N(R 19 ) 2 , NR 19 COR 6 , NR!9CON(R 20 )2, NR 19 S ⁇ 2R 6 , NR 19 SO2N(R 2 0) 2 ,
  • R 2 > R ⁇ and R 7 are each independently selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl, (CH2) ⁇ -4C0 R 19 , (CH 2 ) ⁇ -4CON(Rl9) 2 , (CH 2 ) ⁇ - 4COR 6 , (CH2)2-4 ⁇ R 6 , (CH2)l-4CF3, (CH2) ⁇ -4S ⁇ 2R 6 , (CH2) ⁇ -4S ⁇ 2N(R 19 ) 2 or (CH2)1-4CN;
  • R 4 is selected from hydrogen, (CH2) ⁇ -4COR 6 , (CH2) ⁇ -4CN, (CH2) ⁇ -4CF3, (CH 2 )0-4CO2R 19 , (CH2)0-4CON(R 19 ) 2 , (CH 2 ) ⁇ -4S ⁇ 2R 6 or (CH2)0-4SO2N(R 19 ) 2;
  • R 5 , R 8 , R 10 , R 15 , R 16 , R 17 and R 18 are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4 ⁇ R 6 or
  • R 6 is selected from hydrogen, C ⁇ -8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF 3 ;
  • R9 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, CO2R 6 , CON(R 6 )2, (CH2)l-4 ⁇ R 6 or (CH2) ⁇ -4CF3;
  • RU and R ⁇ 2 are each independently selected from hydrogen, Cl-8 alkyl or C3-8 cycloalkyl;
  • Rl3 and R ⁇ 4 are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4 ⁇ R 6 , (CH2) ⁇ -4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2)0-4CON(R 19 )2, (CH2) ⁇ -4C ⁇ 2R 19 or Ci-4 alkyl; or unsubstituted, mono- or poly-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR 6 , halogen, Cl-4 alkyl or C3-8 cycloalkyl;
  • Rl and R 2 ⁇ are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or (CH2)l-4CF3;
  • R 22 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2) ⁇ -4 ⁇ R 6 or (CH2)0-4CF3;
  • R 24 and R 26 are each independently selected from hydrogen or OR 28 ;
  • R 28 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or —
  • W is O or NR 11 ; each X is independently selected from halogen, cyano, nitro, Cl-8 alkyl, C3-8 cycloalkyl, (CH 2 ) ⁇ -4 ⁇ R 6 or (CH 2 ) ⁇ -4CF 3 ;
  • Y is C-R 6 or N
  • Z is hydrogen, oxygen or sulphur
  • n, o, s and t are each independently an integer of from zero to. four; v is an integer from zero to one; and the pharmaceutically acceptable salts thereof.
  • R ⁇ is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , N(R 19 )2, NR 19 COR 20 , NR19CON(R 2 0)2, NRl9S02R 6 , NRl9S ⁇ 2N(R 2 0) 2 , (CH2) ⁇ -4C ⁇ 2R 19 , (CH 2 )0-4CON(Rl9) 2 , (CH 2 )0-4S ⁇ 2N(Rl9)2,
  • (CH2) ⁇ -4S ⁇ 2 or C1.4 alkyl or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl, or naphthyl are independently selected from CF3, cyano, nitro, N(Rl9) 2 , (CH ) ⁇ -4C ⁇ 2R 19 , (CH 2 ) ⁇ -4CON(Rl9) 2 , (CH2)0-4S ⁇ 2N(Rl9) 2 , (CH2) ⁇ -4S ⁇ 2R 6 , phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl;
  • R 4 is selected from (CH 2 ) ⁇ -4COR 6 , (CH2) ⁇ -4CN, (CH2) ⁇ -4CF3, (CH2)0-4CO2R 19 , (CH2) ⁇ -4CON(R 19 ) 2 , (CH2) ⁇ -4S ⁇ 2R 6 or (CH2)0-4SO2N(R 1 9) ; and
  • R 9 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4 ⁇ R 6 or (CH 2 )0-4CF 3 ;
  • E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2) ⁇ -4CF3;
  • Ri is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , N(R 19 ) 2 , NR 19 COR 20 , NR!9CON(R 2 0)2, NRl9S02R 6 , N l9s ⁇ 2N( 20 )2, (CH2) ⁇ -4C ⁇ 2R 19 , (CH 2 )0-4CON(Rl9)2, (CH2) ⁇ -4S ⁇ 2N(R 1 9) 2 , (CH2) ⁇ -4S ⁇ 2R 6 or Ci-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyridyl N-oxide (N- 0), pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl where
  • R 2 , R3 and R 7 are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3;
  • Rl3 and R ⁇ 4 are each independently selected from hydrogen, C ⁇ -8 alkyl, C3-8 cycloalkyl, (CH2)l-4 ⁇ R 6 , (CH2) ⁇ -4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2)0-4CON(R 19 )2, (CH2) ⁇ -4C ⁇ 2R 19 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR 6 , halogen, Cl-4 alkyl or C3-8 cycloalkyl; and
  • n and t are each independently an integer from zero to two; and all other variables are as originally defined above [previously]; and the pharmaceutically acceptable salts thereof.
  • Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , N(R 19 )2, NR 19 COR 20 , NR!9CON(R 2 0)2, NRl9s ⁇ 2R 6 , NR 1 9SO2N(R 2 0) 2 , (CH2) ⁇ -4C ⁇ 2R 19 , (CH2)0-4CON(Rl9)2, (CH2) ⁇ -4S ⁇ 2N(Rl9) 2 , (CH2) ⁇ -4S ⁇ 2R 6 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl,
  • a first class of the invention is the compound selected
  • Ri is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2) ⁇ -2C ⁇ 2R 19 , (CH2) ⁇ -2CON(R 19 )2, (CH2)0-2SO2N(R 19 ) 2 , (CH2) ⁇ -2S ⁇ 2R 6 or Cl-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl or pyridyl N-oxide, wherein the substituents on the pyridyl or pyridyl N-oxide are independently selected from halogen, CF3, cyano, OR 6 ,
  • R is selected from hydrogen, cyano, OR 6 , C02R 19 , CON(R 19 )2, or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR 6 , (CH2)0-2CO2R 19 , (CH2) ⁇ -2CON(R 1 9) 2 or Cl-4 alkyl;
  • R 4 is selected from hydrogen, COR 6 , C02R 19 , SO2R 6 or CON(R 19 ) ;
  • R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2) ⁇ -3 ⁇ R 6 or (CH2)0-3CF 3 ;
  • R 6 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF 3 ;
  • R 8 and RlO are each independently selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH 2 )2-4 ⁇ R 6 or (CH2) ⁇ -3CF3;
  • R is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl,
  • Rl3 i s selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl,
  • Rl9 i selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH 2 )1-3CF 3 ;
  • R 22 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2) ⁇ -4 ⁇ R 6 or (CH2)0-3CF3;
  • R 24 and R 26 are each independently selected from hydrogen or OR 28 , wherein R 28 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)1-3CF3;
  • s is an integer from zero to three;
  • Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2) ⁇ -2C ⁇ 2R 19 , (CH2) ⁇ -
  • R 4 is selected from COR 6 , C02R 19 , SO2R 6 , or CON(Rl9) 2 ;
  • R is selected from hydrogen, OR 6 or cyano
  • A is selected from C-R 1 or N or N- 0;
  • Rl3 is selected from hydrogen, Cl-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , C02R 19 or Cl-4 alkyl;
  • each X is a halogen
  • each R 2 1 is independently selected from hydrogen, halogen, hydroxy, cyano, OCl-4 alkyl, OCF3, OCH2CF3, CO2-C1-4 alkyl, CONH2, SO2NH2 or SO2C1-4 alkyl;
  • R 24 and R 26 are each independently selected from hydrogen or OR 28 , wherein R 28 is selected from hydrogen, Cl-4 alkyl, or (CH2) ⁇ -2CF3;
  • r is an integer from zero to two; and all other variables are as defined in the first class above; and the pharmaceutically acceptable salts thereof.
  • A is selected from C-R 2 1 or N;
  • l3 is selected from hydrogen, Cl-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , C02R 19 or Cl-4 alkyl;
  • each X is a halogen
  • each R 2 1 is independently selected from hydrogen, halogen, hydroxy, cyano, OCi-4 alkyl, OCF3, OCH2CF3, CO2-C1-4 alkyl, CONH2, SO2NH2 or SO2C1-4 alkyl;
  • r is an integer from zero to two; all other variables are as defined in the second class above; and the pharmaceutically acceptable salts thereof.
  • R is selected from hydrogen, hydroxy or cyano
  • R 4 is C02R 19 ;
  • R 5 is (CH2)0-3 ⁇ R 6 ;
  • q is an integer from zero to one; and all other variables are as defined in the first subclass above; and the pharmaceutically acceptable salts thereof; provided that the compound is not (4S)-£r ⁇ ns-4-(3,4-difluorophenyl)-2-oxooxazolidine-3- carboxylic acid-[l-(4-hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)-pvrrolidin-3- yl] amide.
  • R is selected from hydrogen, hydroxy or cyano; R 4 is C ⁇ 2R 19 ;
  • R5 is (CH2)0-3 ⁇ R 6 ;
  • q is an integer from zero to one; and all other variables are as defined in the second subclass above; and the pharmaceutically acceptable salts thereof; provided that the compound is not (4S)- r ⁇ 7is-4-(3,4-difluorophenyl)-2-oxooxazolidine-3- carboxylic acid-[l-(4-hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3- yl] amide.
  • R is H or OH
  • R 4 is H or CO2CH3
  • R5 is H, CH3, or CH2OCH3;
  • R 9 is H, CH3, cyclopropyl, CONH2, CH2OH, or COOCH3;
  • q is an integer from zero to one; and all other variables are as defined in the first subclass above; and pharmaceutically acceptable salts thereof; provided that the compound is not (4S)-t ⁇ ns-4-(3,4-difluorophenyl)-2- oxooxazolidine-3-carboxylic acid-[l-(4-hydroxy-4-pyridin-2-yl-cyclohexyl)- (3R)-pyrrolidin-3-yl]amide hydrochloride.
  • One aspect of the invention is the compound having the formula:
  • R is H or OH
  • Ri is suitably unsubstituted pyridyl, unsubstituted pyridyl N-oxide, unsubstituted phenyl, or mono- or poly-substituted phenyl; typically unsubstituted pyridyl, unsubstituted pyridyl N-oxide, unsubstituted phenyl, or mono- or di-substituted phenyl; more typically 2-pyridyl, 2- pyridyl N-oxide, 4-substituted phenyl, 2-substituted phenyl, or 2,4- substituted phenyl; wherein the phenyl substituents are independently selected from fluorine, cyano, OH, OCH3, CO2CH2CH3, and CF3; and
  • R 4 is H or CO2CH3
  • R ⁇ is H, CH3, or CH2OCH3;
  • R9 is H, CH3, cyclopropyl, CONH2, CH2OH, or COOCH3; provided that the compound is not (4S)-- ⁇ s-4-(3,4-difluorophenyl)-2-oxooxazolidine-3- carboxylic acid-[l-(4-hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3- yl] amide hydro chloride.
  • Exemplifying the invention is the compound selected from
  • Also exemplifying the invention is the compound selected from (4S)-ir ns-4-(3-,4-difl oro-ph ⁇ nyl)-3-[l-[4-(2-fluoro-phenyl)-cyclohexyl]- (3R)-pyrroli--in-3-ylcarb--_moyl ⁇ -6-methoxy ethyl-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid methyl ester;
  • Another preferred embodiment is Compound A or a pharmaceutically acceptable salt thereof.
  • Another preferred embodiment is Compound B or a pharmaceutically acceptable salt thereof.
  • Still another preferred embodiment is Compound C or a pharmaceutically acceptable salt thereof.
  • An illustration of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier.
  • An example of the invention is a pharmaceutical composition made by 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.
  • More specifically illustrating the invention is a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
  • Another illustration of the invention is the method of treating benign prostatic hyperplasia wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is finasteride.
  • FIG. 1 Further illustrating the invention is a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
  • More specifically exemplifying the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) additionally does not cause a fall in blood pressures at dosages effective to inhibit contraction of prostate tissue. More particularly illustrating the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) is administered in combination with a testosterone 5-alpha reductase inhibitor; preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
  • More particularly exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the alpha la receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease.
  • Diseases which are susceptible to treatment by antagonism of the alpha la receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see, K.A. Vatz, Headache 1997:37: 107-108) and cardiac arrhythmia.
  • An additional illustration of the invention is the use of any of the compounds described above in the preparation of a medicament for: a) the treatment of benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof.
  • An additional example of the invention is the use of any of the alpha la antagonist compounds described above and a 5-alpha reductase inhibitor for the manufacture of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue which comprises an effective amount of the alpha la antagonist compound and an effective amount of 5-alpha reductase inhibitor, together or separately.
  • 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.
  • Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha la adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alpha Id and alpha lb adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors).
  • 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, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Pamoate (Embonate),
  • 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.
  • 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 polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present - invention may form solvates with water (i.e., hydrates) or common 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 interpreted as including those limitations given above for "alkyl” and "aryl.”
  • Designated numbers of carbon atoms e.g., Cl-io 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 substituent.
  • poly- substituted as used herein shall include di-, tri-, tetra- and penta- substitution by a named substituent.
  • a poly-substituted moiety is di-, tri- or tetra-substituted by the named substituents, most preferably, di- or tri-substituted.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below. 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.
  • 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, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl,
  • activated (+)-DHP refers to a N- 3-(activated)carbamate of the desired dihydropyrimidinone where the activating group is, for example, a p-nitrophenyloxy group.
  • a specific example of an activated (+)-DHP is 4-(3,4-difluorophenyl)-5- methoxycarbonyl-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine- 3-carboxylic acid (4-nitrophenyl ester), also referred to as the compound 15.
  • (S)-oxa refers to an oxazolidinone group of the formula
  • activated (S)-oxa refers to an N- (activated)carbamate of the desired oxazolidinone where the activating group is, for example, a p-nitrophenyloxy group.
  • a specific example of an activated (S)-oxa group is 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3- carboxylic acid 4-nitrophenyl ester (i.e., compound 16).
  • lower urinary tract tissue refers to and includes, but is not limited to, prostatic smooth muscle ⁇ the prostatic capsule, the urethra and the bladder neck.
  • 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.
  • selective alpha la adrenergic receptor antagonist refers to an alpha la antagonist compound which is at least ten fold selective for the human alpha la adrenergic receptor as compared to the human alpha lb, alpha Id, alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
  • 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.
  • the 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.
  • 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 preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • 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
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate
  • 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.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous 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 alpha la receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha la receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha Id, alpha lb) or beta adrenergic receptors.
  • alpha e.g., alpha Id, alpha lb
  • beta adrenergic receptors e.g., beta adrenergic receptors.
  • 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.
  • 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 hypotensive effects.
  • the ability of compounds of the present invention to specifically bind to the alpha la receptor makes them useful for the treatment of BPH.
  • the specificity of binding of compounds showing affinity for the alpha la receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors.
  • the human alpha adrenergic receptor of the la subtype was recently 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.
  • 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.
  • 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.
  • intravenous both bolus and infusion
  • intraperitoneal subcutaneous
  • topical with or without occlusion
  • 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 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 incorporated into the mixture.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • 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 targe table drug carriers.
  • Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled- to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per
  • 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 20 mg/kg of body weight per day.
  • the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha la adrenergic receptor while minimizing any potential toxicity.
  • co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable.
  • this includes administration of compounds of this invention and a human testosterone 5- reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2.
  • 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).
  • 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 interpreted accordingly.
  • a method of treating BPH comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH.
  • the dosage of finasteride administered to the subject is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha la antagonist.
  • the dosage of finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day.
  • compounds of this invention exhibiting alpha la adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5 ⁇ -reductase 2 inhibitor, such as finasteride, in addition to a 5 ⁇ - reductase 1 inhibitor, such as 4,7 ⁇ -dimethyl-4-aza-5 ⁇ -cholestan-3- - - one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation.
  • a combined therapy can be employed wherein the alpha la adrenergic receptor antagonist and the 5 ⁇ - reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5 ⁇ -reductase inhibitors.
  • BOPC1 bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • Cbz-Cl or CBZC1 benzyloxycarbonyl chloride
  • CSA 10-Camphorsulfonic acid
  • DAST diethylaminosulfurtrifluoride
  • DEAD diethylazodicarboxylate
  • DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • FABLRMS fast atom bombardment low resolution mass spectroscopy
  • HMPA hexamethylphosporamide
  • HOBt 1-hydroxy benzotriazole hydrate
  • i-PrOH 2-propanol
  • i-Pr2NEt diisopropylethylamine
  • LAH lithium aluminum hydride
  • LDA lithium diisopropyl amide
  • mCPBA meta-chloroperbenzoic acid
  • PEI polyethylenimine
  • 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.
  • 4-amino piperidine were prepared from isonipecotic acid via the sequence outlined in Scheme 2. Isonipecotic acid was converted to 4- (tertr-butoxycarbonyl)amino piperidine in three chemical steps. Reductive amination with 4-cyano 4-phenyl cyclohexanone provided a separable mixture of cis and trans products, which after Boc deprotection and acylation provided the desired antagonists.
  • the 3-amino piperidinyl bridged compounds were assembled in analogous fashion starting from nipecotic acid, Scheme 3. The corresponding 3-amino pyrroldinyl analogs were obtained by substituting the commercially available 3-( er -butoxycaronyl)amino pyrrolidine for the corresponding piperidinyl material as shown in Scheme 4.
  • the activated termini species comprising the "Q" groups are readily prepared by one of ordinary skill in the art.
  • unsubstituted, alkyl- and cycloalkyl-substituted oxazolidinones are prepared and activated in general by published and well developed chemistry, in particular, of Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13. 1 (1982)]
  • the starting materials, in general, are natural and unnatural amino acids.
  • some of the preferred compounds are prepared from substituted phenyl glycine derivatives, which after reduction of the carboxylate and a phosgene equivalent mediated cyclization provides the substituted oxazolidinone ring system.
  • Deprotonation with n-butyl lithium and addition to a THF solution of p- nitrophenylchloroformate produces the stable, isolable "activated'Oxazolidinone (oxa).
  • Oxazolidinones substituted with carboxylate, carboxamide, and hydroxymethyl are prepared by hydroxyamination of olefins to provide protected aminoalcohols, using procedures as described in Sharpless et al., Angew. Chem. Int. Ed. Engl., 35, 2813 (1996). Deprotection under standard conditions followed by a phosgene equivalent to mediate cyclization provides the substituted oxazolidinone ring system. Deprotonation with a strong base, for example, lithium bis(trimethylsilyl)amide, and addition to a THF solution of p- nitrophenylchloroformate produces the stable, isolatable "activated" oxazolidinone.
  • a strong base for example, lithium bis(trimethylsilyl)amide
  • Dihydropyrimidinones are prepared by condensation reaction of the aldehyde, urea and a 1,3-acetoacetate type derivative catalyzed by a Lewis Acid, a copper (I) species and acetic acid. Activation was accomplished by treatment with a strong base, for instance, LiN(TMS)2, followed by addition to a THF solution of p- nitrophenylchloroformate .
  • a strong base for instance, LiN(TMS)2
  • Hydantoins and cycloimide were prepared in two chemical steps from ketones as outlined in the literature. More specifically, hydantoins were prepared according to known methodology, e.g., J.J. Edmunds et al., J. Med. Chem. 1995, 38, pp. 3759-3771; J.H. Poupart et al., J. Chem. Res. 1979, pp. 174-175. Saccharins were prepared according to known methods, e.g., page 40 and Examples 21 and 22 of PCT International Application Publication No. W096/25934, published August 29, 1996.
  • the dihydropyrimidinones and the unsubstituted, alkyl- and cycloalkyl-substituted oxazolidinones were synthesized independently in racemic form, and then separated utilizing preparative chiral HPLC. Their optical rotations were recorded. Then they were activated and reacted with prerequisite amines. From the receptor binding studies, a preferred isomer was identified, the (+) rotational isomer in each case.
  • the absolute configurations were determined to be (S) for both the dihydropyrimidinones and oxazolidinones by correlating their optical rotations with x-ray crystal structures obtained of fragments involved in the production of the antagonists.
  • ketones were readily assembled following the sequence outlined in Scheme 6. For example, a substituted benzyl nitrile, sulphone, etc. could be added to methyl acrylate (or other substituted acrylates), submitted to Dieckman cyclization, hydrolyzed and decarboxylated providing appropriately substituted ketones.
  • ketones can be accomplished following the Dieckman cyclization, which provides the ⁇ -keto ester which can be either: (a) submitted to a reductive amination and carried on to final product, (b) enolized and alkylated then reductively aminated, deprotected and further manipulated providing further substituted analogs; or (c) hydrolyzed and decarboxylated and run through the above described conditions producing the desired antagonists.
  • the 4,4-diaryl cyclohex-2-en-l-ones could be subjected to Michael addition of selected nucleophiles, alkylation or aldolyzation of the enolate of the resulting ketone then reductively aminated and carried through the standard chemical transformation to provide further elaborated antagonists.
  • Schemes 8-17 describe the synthesis of the 3-aminomethyl-3-hydroxyazetidine and the 4-amino-3- hydroxypyrrolidine intermediates.
  • the 3-aminomethyl-3- hydroxyazetidine was assembled from the commercially available N- protected 3-hydroxyl azetidine as outlined Scheme 16. Swern oxidation of the alcohol with dimethylsulfoxide and oxalyl chloride provided the azetidinone.
  • the zinc iodide catalyzed addition of TMSCN produced the cyanohydrin.
  • R CN, S0 2 alk, others
  • R 21 H, CN, C0 2 Et, F, CF 3 , OMe,
  • Step A Tnfluoromethanesulfonic acid l,4-dioxa-spiro[4.5]dec-7-en-
  • reaction solution was warmed to r.t., poured onto saturated sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude material was passed through silica (3% methanol, dichloromethane) to give the product as an oil.
  • Step C 2-(l,4-Dioxaspiro[4.5]dec -8-yl)benzonitrile
  • Step E cis and trans 2-[4-(3R-3-Amino-pyrrolidin-l-yl)-cyclohexyl]- benzonitrile dihydrochloride
  • Step F 3- ⁇ l-[4-(2-Cyano-phenyl)-cyclohexyl]-3R-pyrrolidin-3- ylcarbamoyl]-4-(3,4-difluoro-phenyl)-6-methoxymethyl-2- oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride
  • Step A 8-(2-Methoxy-phenyl)-l,4-dioxa-spiro[4.5]decan-8-ol
  • Step B 4- (2-Methoxy-phenyl)-cyclohex-3-enone and 4-(2-Methoxy- phenyl)-cyclohex-2-enone
  • HCI 1.4 mL 6M, 8.4 mmol
  • the solution was heated to 80°C for 45 min, then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo.
  • Step A 8-(2-Pyridyl)-l,4-dioxaspiro[4,5]decan-8-ol
  • Step A 8-(2-Benxyloxy-phenyl)-l,4-dioxa-spiro[4.5]decan-8-ol
  • Step B 4-(2-Benzyloxy-phenyl)-4-hydroxy-cyclohexanone
  • Step C 4-(2-Benzyloxy-phenyl)-cyclohex-3-enone and 4-(2-Benzyloxy- phenyl)-cyclohex-2-enone
  • Example 21 was prepared from the product of step D by procedures identical to that described in EXAMPLE 1 Steps E + F Analysis Calcd. for C 31 H 36 F 2 N 5 0 6 • 0.9 H 2 0 • 0.4 CH 2 C1 2
  • Step A 8-(2-Fluorophenyl)-l,4-dioxa-spiro[4.5]decan-8-ol
  • Step B 4-(2-Fluorophenyl)-4-hydroxy-cyclohexanone
  • IM hydrogen chloride
  • Step C 4- (2-Fluorophenyl)-cyclohexanone:
  • Step D cis and trans -l-[4-(2-Fluorophenyl)-cyclohexyl]-pyrrolidin-
  • Step E trrat ⁇ s-4-(3-,4-Difluorophenyl)-3- ⁇ l-[4-(2-fluorophenyl)- cyclohexyl]-pyrrolidin-3-ylcarbamoyl ⁇ -6-methoxymethyl- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride
  • Step A 8-(4-Fluorophenyl)-l,4-dioxa-spiro[4.5]decan-8-ol
  • Step B 4-(4-Fluorophenyl)-4-hydroxy-cyclohexanone
  • Step D 4-[(3R)-3-Aminopyrrolidin-l-yl]-l-(4-fluorophenyl)- cyclohexanol dihydrochloride
  • Step E 4-(3,4-Difluorophenyl)-3- ⁇ l-[4-(4-fluorophenyl)-4-hydroxy- cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl ⁇ -6- methoxymethyl-l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride was prepared by a procedure substantially as described above for the preparation of Example 25
  • the reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate (2 X 200 mL). The organic extracts were washed with brine, and the organic layer was dried over Na 2 SO 4 . The solvent was removed after filtration, and the residue was purified by column chromatography on silica gel 30% ethyl acetate hexane. The material was rechromatographed on silica gel eluting with 2% acetone/ methylene chloride to give 1.2 g the product as a thick syrup which solidified upon standing.
  • StepD 5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic arid ⁇ l-[4-(2-fluorophenyl)-cyclohexyl]-py ⁇ oUdin-3-yl-a--nide
  • the title compound was prepared from the reaction of the product of Step C above and trans -l-[4-(2-fluoro-phenyl)-cyclohexyl]-pyrrolidin-3- ylamine dihydrochloride
  • This compound was prepared from the product of Example 35, Step D and the product of Example 43, Step C by a procedure similar to that described in Example 25, Step E.
  • the reaction vessel was fitted with an efficient reflux condenser and the reaction mixture was heated to 65° C for 30 minutes. The reaction mixture was subsequently heated to reflux for 30 minutes more. After one hour, an additional 5.33 mmole each of chlorotrimethylsilane and sodium iodide were added and then the same amount, once more, after three hours. The reaction was terminated after six hours. All volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and water. The organic phase was washed with water and brine, then dried (sodium sulfate) and concentrated to yield an amorphous solid.
  • Step A 2-(l,4-Dioxaspiro[4.5]dec-7-en-8-yl)pyridine
  • the reaction was quenched with the addition of 200 mL of saturated sodium bicarbonate solution. After stirring 5 minutes more, the phases were separated and the aqueous layer was extracted with ethyl acetate The combined organic extracts were washed with saturated sodium chloride, dried with sodium sulfate, and concentrated in vacuo. The crude material was chromatographed over silica gel eluting with 25% ethyl acetate/hexane to give 14.6 (76%) of homogeneous product.
  • Step B 2-(l,4-Dioxaspiro[4.5]dec-8-yl)pyridine
  • Step E 2-[t:r ⁇ ns-4-(3R-3-Aminopyrrolidin-l-yl)-cyclohexyl]pyridine
  • Step F tr ⁇ rcs-4S-(3,4-Difluorophenyl)-6-methyl-2-oxo-3- ⁇ l-[4-(l- oxopyridin-2-yl)-cyclohexyl]-3R-pyrrolidin-3-ylcarbamoyl ⁇ - l,2,3,4-tetrahydropyrimidine-5-carboxylic Add Methyl Ester Hydrochloride
  • the hydrochloride salt was prepared by dissolving the chromatographed product in ice cold ethyl acetate and treating this solution with a solution of ethyl acetate saturated with HCI gas. In this way, the title compound was obtained analytically pure as an off-white solid: m.p. 195-200°C.
  • Step A To a solution of (+)-DHP 17 (4.63 g, 14.7 mmol) in a methanol
  • Step B (alternative to Step A): To a solution of (+)-DHP 17 (5.36 g, 17.0 mmol) in a methanol (150 ml) was added IN NaOH (10 ml). The resulting mixture was refluxed at 90 °C for 16 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was dissolved in CH 2 C1 2 and H 2 0 then neutralized with 10% aqueous HCI solution. The organic layer was dried over Na 2 S0 4 , concentrated, and purified by PCTLC (7% MeOH in CHC1 3 with 2% NH 4 OH) to afford a 2.35 g mixture of 18 and 19 (54% yield). The ⁇ NMR is consistent with the assigned structure. MS (FAB) 255 (M+l)
  • Step C The title compound was prepared by reacting a mixture of 18 and 19 (1.93 g, 7.59 mmol) with 4-nitrophenoxycarbonyl chloride (1.5 equivalents) in LDA (1.1 equivalents) at -78°C until the reaction was completed as determined by GLC. 0.488 g (15% yield) of 20 was obtained.
  • the ⁇ NMR was consistent with the assigned structure.
  • Step D The title compound was obtained from 20 (0.119 g, 0.284 mmol) using the procedure described for step F in Example 1.
  • the ⁇ NMR was consistent with the assigned structure.
  • Step A t ⁇ - s-3,4-Difluorocinnamic acid methyl ester
  • Step B (2R, 3S)-N-Benzyloxycarbonyl-3-amino-3-(3,4- difluorophenyl)-2-hydroxypropionic add methyl ester
  • Step D (4S,5R)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester
  • Step F (4S,5R)-- ⁇ ns-4-(3,4-Difluorophenyl-3- ⁇ l-[4-(4-fluoro-2- methoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3- ylcarbamoyl ⁇ -2-oxo-oxazolidine-5-carboxylic acid methyl ester
  • reaction mixture was stirred at ambient temperature for 4 h.
  • the volatiles were removed under reduced pressure and residue dissolved in ethyl acetate, washed with 10% aqueous sodium carbonate solution (8 x 100 ml), brine (1 x 100 ml), dried over magnesium sulfate and filtered.
  • Step B (4S,5R) 4-(3,4-Difluorophenyl)-5-(tetrahydropyran-2- yloxymethyl)-oxazolidin-2-one
  • Step C (4S,5R)-4-(3,4-Difluorophenyl)-2-oxo-5-(tetrahydropyran-2- yloxymethyl)-oxazolidine-3-ca boxylic add 4-nitrophenyl ester
  • the p-nitrophenylchloroformate (586 mg, 2.9 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) under argon and cooled to -78°C. Then the above prepared anion solution was added via cannula to the chloroformate solution and reaction mixture was stirred 1 h at - 78°C. The reaction mixture was treated with ethyl acetate (150 mL). The resulting solution was washed with water (1 x 150 ml), brine (1 x 150 mL), dried over magnesium sulfate and filtered.
  • Step D (4S,5R)-t;r ⁇ tts-4-(3,4-Difluorophenyl)-5-(tetrahydropyran-2- yloxymethyl-2-oxo-oxazolidine-3-carboxylic acid ⁇ l-[4-(4- fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3-yl ⁇ amide
  • reaction mixture was stirred at ambient temperature for 18 h when the volatiles were removed under reduced pressure and residue dissolved in ethyl acetate (100 mL) and washed with 10% aqueous sodium carbonate solution (8 x 100 ml), brine (1 x 100 ml), dried over magnesium sulfate and filtered.
  • Step E (4S,5R)- rans-4-(3,4-Difluorophenyl)-5-hydroxymethyl-2-oxo- oxazolidine-3-carboxylic add ⁇ l-[4-(4- fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3-yl ⁇ amide
  • Example 75 The compound of Example 75 was prepared by procedures substantially as described above for Example 74, Steps E and F.
  • the title compound was prepared by the procedure described in Example 67, followed by pressurized silica gel chromatography using an elution system containing chloroform saturated with ammonia gas and methanol.
  • (+)-4-(3,4-difluorophenyl)-6-methoxymethyl- 2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (4.63 g, 14.7 mmol) in a methanol (100 ml) was added sodium hydroxide (2.94 g, 73.6 mmol).
  • the resulting mixture was refluxed at 90 °C for 16 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was dissolved in CH 2 C1 2 and H 2 0 then neutralized with 10% aqueous HCI solution.
  • (+)-4-(3,4-difluorophenyl)-6-methoxymethyl- 2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 5.36 g, 17.0 mmol
  • a methanol 150 ml
  • IN NaOH 10 ml
  • the resulting mixture was refluxed at 90 °C for 16 hours. After cooling to room temperature the solvent was removed in vacuo.
  • the solid was dissolved in CH 2 C1 2 and H 2 0 then neutralized with 10% aqueous HCI solution.
  • Example 80 The title compound was prepared by treating the mixture obtained from Example 80 or Example 81 (1.93 g, 7.59 mmol) with lithium diisopropylamide (2.0M THF solution, 1.1 equivalents) in THF at -78 °C for 20 minutes followed by the rapid addition of 4-nitrophenyl chloroformate (1.5 equivalents) in THF. 0.488 g of the title compound was obtained in a 15% yield.
  • the l R NMR was consistent with the assigned structure.
  • the title compounds were prepared from 4 ⁇ -4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester (5.0 g, 17.7 mmol) using the procedure described in Example 80. A mixture of 2.0 g of the title compounds was obtained in 50% yield. The ⁇ NMR was consistent with the assigned structure.
  • Compounds of the invention can be prepared by reacting the products obtained in Example 82 with an aminopiperidine, e.g., in accordance with Scheme 3.
  • Compounds of the invention can also be prepared by preparing a nitrophenoxy derivative of the compound of Example 83 in accordance with the procedure set forth in Example 82 and then reacting the derivative with an aminopiperidine in accordance with Scheme 3.

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Abstract

Cette invention concerne certains composés nouveaux et leurs dérivés, ainsi que leur synthèse et leur utilisation en tant qu'antagonistes de l'adrénorécepteur alpha 1a. Ces composés sont utiles pour traiter l'hypertrophie prostatique bénigne (HPB).
EP98930356A 1997-06-18 1998-06-17 ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a Withdrawn EP0998285A4 (fr)

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US4992197P 1997-06-18 1997-06-18
US49921P 1997-06-18
GB9719392 1997-09-11
GBGB9719392.4A GB9719392D0 (en) 1997-09-11 1997-09-11 Alpha la adrenergic receptor antagonists
PCT/US1998/012673 WO1998057641A1 (fr) 1997-06-18 1998-06-17 ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a

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AU5234899A (en) 1998-07-30 2000-02-21 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6319932B1 (en) 1998-11-10 2001-11-20 Merck & Co., Inc. Oxazolidinones useful as alpha 1A adrenoceptor antagonists
US6228870B1 (en) 1998-11-10 2001-05-08 Merck & Co., Inc. Oxazolidinones useful as alpha 1a adrenoceptor antagonists
US6358959B1 (en) 1999-01-26 2002-03-19 Merck & Co., Inc. Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists
US6828460B2 (en) 1999-03-22 2004-12-07 Pfizer Inc. Resorcinol derivatives
GB2355456A (en) 1999-09-30 2001-04-25 Merck & Co Inc Novel arylhydantoin derivatives useful as alpha 1a adrenoceptor antagonists
GB2355457A (en) 1999-09-30 2001-04-25 Merck & Co Inc Novel spirotricyclic substituted azacycloalkane derivatives useful as alpha 1a adrenoceptor antagonists
GB2355264A (en) 1999-09-30 2001-04-18 Merck & Co Inc Spirohydantoin derivatives useful as alpha 1a adrenoceptor antagonists
GB2355263A (en) 1999-09-30 2001-04-18 Merck & Co Inc Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
EA010027B1 (ru) 2002-11-27 2008-06-30 Инсайт Корпорейшн Производные 3-аминопирролидина в качестве модуляторов рецепторов хемокинов
US7166603B2 (en) 2003-07-23 2007-01-23 Bristol-Myers Squibb Co. Dihydropyrimidone inhibitors of calcium channel function
TW201033204A (en) 2008-12-10 2010-09-16 Janssen Pharmaceutica Nv 4-azetidinyl-1-heteroaryl-cyclohexanol antagonists of CCR2
CN102459226B (zh) 2009-04-17 2014-09-17 詹森药业有限公司 Ccr2的4-氮杂环丁烷基-1-杂原子连接的-环己烷拮抗剂
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TW201211027A (en) * 2010-06-09 2012-03-16 Janssen Pharmaceutica Nv Cyclohexyl-azetidinyl antagonists of CCR2
TWI537263B (zh) 2010-06-09 2016-06-11 健生藥品公司 使用作為β－分泌酶抑制劑之５，６－二氫－２Ｈ－［１，４］－３－基－胺衍生物
TW201204717A (en) 2010-06-17 2012-02-01 Janssen Pharmaceutica Nv Cyclohexyl-azetidinyl antagonists of CCR2
KR101866987B1 (ko) 2010-12-22 2018-07-19 얀센 파마슈티카 엔.브이. 베타-세크레타아제(ＢＡＣＥ) 저해제로 유용한 5,6-디하이드로-이미다조[1,2-ａ]피라진-8-일-아민 유도체
WO2012120023A1 (fr) 2011-03-09 2012-09-13 Janssen Pharmaceutica Nv Dérivés de 3,4-dihydro-pyrazolo[1,2-a]pyrazin-1-ylamine utiles en tant qu'inhibiteurs de bêta-sécrétase (bace)
US9187451B2 (en) 2011-11-18 2015-11-17 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
EP3008065B1 (fr) 2013-06-12 2019-01-30 Janssen Pharmaceutica NV Dérivés de 4-amino-6-phényl-6,7-dihydro[1,2,3]triazolo [1,5-a]pyrazine comme inhibiteurs de bêta-sécrétase (bace)
ES2697684T3 (es) 2013-06-12 2019-01-25 Janssen Pharmaceutica Nv Derivados de 4-amino-6-fenil-5,6-dihidroimidazo[1,5 a]pirazina como inhibidores de beta-secretasa (BACE)
US9834559B2 (en) 2013-06-12 2017-12-05 Janssen Pharmaceutica Nv 4-Amino-6-phenyl-5,6-dihydroimidazo[1,5-a]pyrazin-3(2H)-one derivatives as inhibitors of beta-secretase (BACE)
CN107108582B (zh) 2014-12-18 2019-10-18 詹森药业有限公司 β-分泌酶的2，3，4，5-四氢吡啶-6-胺化合物抑制剂
GB201513743D0 (en) 2015-08-03 2015-09-16 Heptares Therapeutics Ltd Muscarinic agonists
GB201617454D0 (en) 2016-10-14 2016-11-30 Heptares Therapeutics Limited Pharmaceutical compounds
US10259787B2 (en) 2016-10-14 2019-04-16 Heptares Therapeutics Limited Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
GB201810239D0 (en) 2018-06-22 2018-08-08 Heptares Therapeutics Ltd Pharmaceutical compounds
GB201819960D0 (en) 2018-12-07 2019-01-23 Heptares Therapeutics Ltd Pharmaceutical compounds
GB202020191D0 (en) 2020-12-18 2021-02-03 Heptares Therapeutics Ltd Pharmaceutical compounds

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