EP1003511A1 - ALPHA 1aADRENERGIC RECEPTOR ANTAGONISTS - Google Patents

ALPHA 1aADRENERGIC RECEPTOR ANTAGONISTS

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Publication number
EP1003511A1
EP1003511A1 EP98930349A EP98930349A EP1003511A1 EP 1003511 A1 EP1003511 A1 EP 1003511A1 EP 98930349 A EP98930349 A EP 98930349A EP 98930349 A EP98930349 A EP 98930349A EP 1003511 A1 EP1003511 A1 EP 1003511A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
cycloalkyi
alpha
independently selected
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Withdrawn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
EP98930349A
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German (de)
French (fr)
Inventor
Michael A. Patane
Mark G. Bock
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
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Filing date
Publication date
Priority claimed from GBGB9800456.7A external-priority patent/GB9800456D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1003511A1 publication Critical patent/EP1003511A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • 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
    • 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
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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 highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources.
  • alpha and beta adrenergic receptors were further subdivided into alpha 1 ? alpha 2 ⁇ ⁇ i, and B2 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 1 receptor subtypes 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. Each alpha 1 receptor subtype exhibits its own pharmacologic and tissue specificities.
  • 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).
  • alpha la is used throughout this application to refer to this subtype.
  • alpha 1 adrenoceptor subtypes were renamed alpha Id.
  • 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. Concommitantly, 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 5a-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.
  • 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.
  • combinations of 5a-reductase inhibitory compounds and alphal- adrenergic receptor blockers terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin
  • 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:
  • Rl is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R 17 )2, NR ⁇ COR 1 ⁇ NR1 C0N(R18) 2 , NR17S02R 7 , NR 17 S02N(R!8)2, OR 7 , (CH2)0-4CO2R 17 ,
  • E, G, L and M are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyi, (CH 2 ) ⁇ -4 ⁇ R 7 , (CH 2 ) ⁇ -4N(Rl 7 ) 2 , (CH2)0-4CN, (CH 2 )0-4CF3, (CH 2 ) ⁇ -4C ⁇ 2R 7 , (CH 2 ) ⁇ -4CON(Rl 7 )2, (CH 2 )0-4S ⁇ 2R 17 or (CH2) ⁇ -4S ⁇ 2N(Rl 7 )2;
  • J is selected from hydrogen, C ⁇ -8 alkyl, C3-8 cycloalkyi, (CH2)l-4 ⁇ R 7 , (CH 2 )l-4N(Rl 7 )2, (CH 2 )l-4CN, (CH 2 ) ⁇ -4CF 3 , (CH ) ⁇ -4C ⁇ 2R 7 , (CH )0-4CON(Rl )2, (CH ) ⁇ -4S0 2 R 17 or (CH 2 ) ⁇ -4S0 2 N(Rl 7 )2;
  • R2, R3 and R ⁇ are each independently selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyi, (CH 2 ) ⁇ -4C ⁇ 2R 7 , (CH 2 ) ⁇ -4CON(Rl 7 )2, (CH ) ⁇ - 4COR 7 , (CH 2 )2-4 ⁇ R 7 , (CH2)1-4CF 3 , (CH 2 )l-4S ⁇ 2R 7 , (CH2)0-4SO2N(Rl 7 )2 or (CH2)l-4CN;
  • R4 is selected from hydrogen, COR 7 , (CH2) ⁇ -4CN, (CH2) ⁇ -4CF3, (CH2)0-4CO2R 17 , (CH2) ⁇ -4CON(Rl 7 )2, (CH2) ⁇ -4S ⁇ 2R 7 or
  • R5 is selected from hydrogen, C ⁇ -8 alkyl, C3-8 cycloalkyi, (CH 2 )l-4 ⁇ R 7 or (CH 2 ) ⁇ -4CF 3 ;
  • R 7 is selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyi or (CH 2 )0-4CF 3 ;
  • R8, R9, R10 ? R14 ? R15 and R16 ar e each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)2-4 ⁇ R 7 or (CH2)0-4CF 3 ;
  • RU and Rl2 are each independently selected from hydrogen, Cl-8 alkyl or C3-8 cycloalkyi;
  • Rl3 i selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)2-4 ⁇ R 7 > OR 7 or (CH2)0-4CF3;
  • Rl 7 and Rl are each independently selected from is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi or (CH2)l-4CF3;
  • R20 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)l-4 ⁇ R 7 , (CH2) ⁇ -4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 7 , (CH2) ⁇ -4CON(R 17 )2, (CH2) ⁇ -4C ⁇ 2R ⁇ - 7 or Cl-4 alkyl; or unsubstituted, mono- or poly- substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR 7 , halogen, Cl-4 alkyl or C3-8 cycloalkyi;
  • R21 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH 2 )0-4OR 7 or (CH 2 ) ⁇ -4CF 3 ;
  • R26 is selected from hydrogen or OR28
  • R28 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH 2 )0-4OR 7 or (CH 2 ) ⁇ -4CF 3 ;
  • W is O or NR 11 ;
  • each X is independently selected from halogen, cyano, nitro, Cl-8 alkyl, C3-8 cycloalkyi, (CH 2 ) ⁇ -4 ⁇ R 7 or (CH 2 ) ⁇ -4CF 3
  • n, o, s and t are each independently an integer of from zero to four;
  • R 4 is selected from COR 7 , (CH2) ⁇ -4CN, (CH2) ⁇ -4CF3, (CH2)0-4CO2R 17 , (CH 2 ) ⁇ -4CON(Rl 7 ) 2 , (CH 2 ) ⁇ -4S ⁇ 2R 7 or
  • l3 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyi, (CH2)2-4 ⁇ R 7 or (CH 2 )0-4CF3;
  • 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, N(R 17 )2, NR 17 COR 18 , NR 17 CON(R 18 )2, NR 17 S ⁇ 2R 7 , NR 17 S ⁇ 2N(R 18 )2, OR 7 , (CH2) ⁇ -4C ⁇ 2R 17 ,
  • E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi or (CH2) ⁇ -4CF3;
  • R3 and R ⁇ are each independently selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyi, (CH 2 )0-4CO 2 R 7 , (CH2) ⁇ -4CON(Rl 7 )2, (CH2) ⁇ - 4COR 7 , (CH2)2-4 ⁇ R 7 , (CH2)l-4CF3, (CH2)l-4S ⁇ 2R 7 , (CH2)0-4S ⁇ 2N(Rl 7 ) 2 or (CH2)l-4CN;
  • R 8 , R 9 , R 10 , R 14 , R!5 and R 16 are each independently selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4 ⁇ R 7 or (CH 2 )0-4CF 3 ;
  • R 1 ⁇ is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4 ⁇ R 7 > OR 7 or (CH2)0-4CF3;
  • R20 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi,
  • R28 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH 2 )2-4 ⁇ R 7 or (CH2) ⁇ -4CF 3 ;
  • n, q and t are each independently an integer from zero to two, provided that when q is zero, R26 i s hydrogen; and p is an integer from zero to one; and all other variables are as originally defined above; 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, N(R 17 )2, NR 17 COR 18 , NR 17 CON(R 18 ) 2 , NR 17 S ⁇ 2R 7 , NRl 7 S02N(Rl8)2, OR 7 , (CH2) ⁇ -4C ⁇ 2R 17 , (CH2)0-4CON(R 17 )2, (CH2) ⁇ -4S ⁇ 2N(Rl 7 )2, (CH2) ⁇ -4S ⁇ 2R 7 or
  • R is selected from hydrogen, cyano, OR 7 , CO2R 17 , CON(R 17 )2, SO2R 7 , S ⁇ 2N(Rl 7 )2, tetrazole, isooxadiazole, unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR 7 , (CH2)0-4CO2R 17 , (CH2)0-4CON(Rl 7 )2, N(R 17 )2, NR 17 COR 7 , NR 17 CON(R 18 ) 2 , NR 17 S02R 7 , NR 17 S ⁇ 2N(R 18 )2, (CH2)0-4SO2N(R 17 )2, (CH2) ⁇ -4S ⁇ 2R 7 or Cl-4 alkyl;
  • E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi or (CH2) ⁇ -4CF3;
  • R2, R3 and R" are each independently selected from hydrogen
  • R 8 , R9, R10 ⁇ R13 ? R14 ? R15 an d R 16 are each independently selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4 ⁇ R 7 or (CH 2 )0-4CF3;
  • R20 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)l-4 ⁇ R 7 , (CH2)0-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 7 ,
  • R21 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH 2 )0-4OR 7 or (CH 2 ) ⁇ -4CF 3 ;
  • n, q and t are each independently an integer from zero to two; p is an integer from zero to one; and all other variables are as defined previously in the first embodiment; and the pharmaceutically acceptable salts thereof.
  • R2 is selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyi or (CH 2 )1-4CF 3 ;
  • R 4 is selected from hydrogen, COR 7 , (CH2) ⁇ -2C ⁇ 2R 17 , SO2R 7 or
  • R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH 2 )l-3 ⁇ R 7 or (CH 2 )0-3CF 3 ;
  • R 7 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi or (CH 2 )0-3CF 3 ;
  • Rl3 is hydrogen or OR 7 ;
  • RI 7 and Rl are each independently selected from is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi or (CH2)l-4CF3;
  • R ⁇ O is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4 ⁇ R 7 , (CH2) ⁇ -2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2RI 7 , CON(R 17 )2 or Cl-4 alkyl;
  • R26 is hydrogen or OR ⁇ , wherein R ⁇ 8 i s hydrogen or Cl-6 alkyl;
  • R2 is selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyi or (CH 2 )l-4CF 3 ;
  • R 4 is selected from COR 7 , (CH2) ⁇ -2C ⁇ 2R 17 , SO2R 7 or
  • R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)l-3 ⁇ R 7 or (CH 2 ) ⁇ -3CF3;
  • R 7 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi or (CH2)0-3CF3;
  • Rl 7 and Rl8 are each independently selected from is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi or (CH2)l-4CF3;
  • R20 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4 ⁇ R 7 , (CH2) ⁇ -2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 7 , CON(R 17 )2 or Cl-4 alkyl;
  • A is C-R19 or N
  • R is selected from hydrogen, cyano, hydroxy, C ⁇ 2R ⁇ 7 , CON(Rl 7 )2, SO2R 7 , S ⁇ 2N(R 17 )2;
  • R2 is selected from hydrogen or CH2CF3;
  • Rl3 is selected from hydrogen or hydroxy
  • each Rl 9 i independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 17 , CON(R 17 )2 or C1-4 alkyl;
  • R20 is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 17 , CON(R 17 )2 or Cl-4 alkyl;
  • R26 is selected from hydrogen or hydroxy
  • each X is halogen
  • q is an integer from zero to one, provided that when q is zero, R ⁇ 6 is hydrogen; and r is an integer from zero to two; s is an integer from zero to three; and all other variables are as defined previously in the first class; and the pharmaceutically acceptable salts thereof.
  • A is C-R ⁇ 9 or N
  • R is selected from hydrogen, cyano, hydroxy, C ⁇ 2R ⁇ 7 , CON(Rl 7 )2, SO2R 7 , S ⁇ 2N(R 17 )2;
  • R2 is selected from hydrogen or CH2CF3;
  • each Rl 9 is independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 17 , CON(R 17 )2 or C1-4 alkyl;
  • R ⁇ O is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 7 , CO2R 17 , CON(R 17 )2 or Cl-4 alkyl;
  • each X is halogen
  • R is selected from hydrogen or cyano
  • R 4 is selected from COR 7 , CO2R 17 or CON(Rl 7 )2;
  • R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH 2 )l-2 ⁇ R 7 or (CH 2 ) ⁇ -2CF 3 ;
  • Rl9 is selected from hydrogen, halogen, Cl-6 alkyl or CF3; each X is fluoro; and
  • 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.
  • Exemplifying the invention is 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.
  • the method of treating BPH wherein the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH.
  • Another example 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.
  • alkali metal salts e.g. sodium or potassium salts
  • alkaline earth metal salts e.g. calcium or magnesium salts
  • suitable organic ligands e.g. quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate,
  • 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-a reductase inhibitors, including PROSCAR® (finasteride).
  • a more long-term anti-BPH therapeutics such as testosterone 5-a reductase inhibitors, including PROSCAR® (finasteride).
  • these compounds may be used to induce highly tissue-specific, localized alpha la 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 la receptor mediated central nervous system events.
  • 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.
  • cycloalkyi 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-l ⁇ shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • halogen shall include iodine, bromine, chlorine and fluorine.
  • substituted shall be deemed to include multiple degrees of substitution by a named 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.
  • any substituent or variable e.g., X, R ⁇ 7 , Rl
  • - N(Rl 7 )2 represents -NH2, -NHCH3, -NHC2H5, -N(CH3)C2H ⁇ , etc.
  • 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, 0 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-methoxvmethyl-2-oxo-l, 2,3,4- tetrahydropyrimidine- 3-carboxylic acid (4-nitrophenyl ester).
  • (S)-oxa refers to an oxazolidinone group of the formula
  • activated (S)-oxa refers to an ⁇ -(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.
  • 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.
  • 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.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • the present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
  • 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.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • 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.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the specificity of binding of compounds showing affinity for the alpha 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. Expression of the cloned human alpha Id, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
  • Compounds of this invention exhibiting human alpha la adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. fSee e.g.. PCT International Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995].
  • Compounds which are both selective amongst the various human alphal adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the ⁇ - adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly preferred.
  • 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
  • suitable pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be 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.
  • glycerin for parenteral administration, sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day.
  • the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 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-a 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-a 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 5a-reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050; WO93/23038, ; WO93/23048; WO93/23041; WO93/23040; WO93/23039; W093/23376; W093/23419, EP 0572165; WO93/23051.
  • 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 5a-reductase 2 inhibitor, such as finasteride, in addition to a 5a- reductase 1 inhibitor, such as 4,7 ⁇ -dimethyl-4-aza-5a-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 5a- 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 5a-reductase inhibitors.
  • BOPC1 bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • Cbz benzyloxycarbonyl
  • DMSO dimethylsulfoxide
  • DPPA diphenylphosphoryl azide
  • EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • FABLRMS fast atom bombardment low resolution mass spectroscopy
  • HPLC high performance liquid chromatography
  • HOAc acetic acid
  • HOBt 1-hydroxy benzotriazole hydrate
  • i-PrOH 2-propanol
  • i-Pr2NEt diisopropylethylamine
  • KOtBu potassium t ⁇ / -butoxide
  • LAH lithium aluminum hydride
  • mCPBA meta-chloroperbenzoic acid
  • PCTLC preparative centrifugal thin layer chromatography
  • PEI polyethylenimine
  • TEBAC benzyltriethylammonium chloride
  • TMSCN trimethylsilyl cyanide
  • the compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Unless otherwise indicated, all variables are as defined above. In general, compounds claimed within this invention are readily accessible from an appropriately substituted cyclic alkanone via reductive amination with a mono blocked diamino equivalent, Scheme 1. Protection of the incipient amino group may be required, followed by deprotection of the terminal amino group. Acylation or alkylation provides the desired analog.
  • ketones were readily assembled following the sequence outlined in Scheme 4. 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 b-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-aryl 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.
  • the activated termini species comprising the "Q" groups are readily prepared by one of ordinary skill in the art.
  • 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.
  • 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.
  • 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.
  • R CN, S0 2 alk, others
  • (+)-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.
  • Example 7 The title compound was prepared by treating the mixture obtained from Example 7 or Example 8 (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 ! H NMR was consistent with the assigned structure.
  • Compounds of the invention can be prepared by reacting the products obtained in Example 9 in accordance with procedures and schemes described above.
  • the compound of Example 9 can, for example, be reacted with an aminocyclohexylpiperidine or aminocyclohexylpyrrolidine in accordance with Schemes 1 and 3 to obtain the desired compounds.
  • Compounds of the invention can also be prepared by preparing a nitrophenoxy derivative of the compound of Example 10 in accordance with the procedure set forth in Example 9 and then reacting the derivative with an aminocyclohexylpiperidine or aminocyclohexylpyrrolidine as set forth in Schemes 1 and 3 to obtain compounds of the invention.
  • 100 mg of the compound of Example 6 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
  • the objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4.
  • the assay is initiated by adding 50-75 ⁇ g membranes in a total volume of 500 ⁇ l containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 ⁇ M apomorphine.
  • the assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.
  • the objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor
  • Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at 38,000Xg for 30'.
  • the binding assay contains 0.25 nM [3H]8-OH- DPAT (8-hydroxy-2-dipropylamino-l,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaC12 and lmg/ml ascorbate. Non-specific binding is defined using 10 ⁇ M propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters
  • Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate.
  • Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary.
  • Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles.
  • Human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored overnight in ice-cold Krebs solution if needed.
  • the tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCl, 118 mM; KC1, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgS ⁇ 4, 1.2 mM; NaHC03, 2.0 mM; dextrose, 11 mM] warmed to 37°C. Excess lipid material and connective tissue are carefully removed.
  • Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% C ⁇ 2/95% 02-
  • the tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder.
  • Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated.
  • EC50 values are calculated for each group using GraphPad Inplot software.
  • Benign prostatic hyperplasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction.
  • Alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man.
  • these are non-selective alpha 1 receptor antagonists which also have pronounced vascular effects. Because we have identified the alpha 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 urethers are ligated and cannulated so that urine flows freely into beakers.
  • the dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra.
  • Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate.
  • the bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra.
  • the bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer.
  • Phenylephrine an alpha 1 adrenergic agonist
  • Phenylephrine an alpha 1 adrenergic agonist
  • phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle).
  • the relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis.
  • the family of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant among curves.
  • the dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the ED ⁇ o's for the respective curves.
  • the Kb dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve
  • the relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure Kb's. Effects of the alpha 1 antagonists on baseline arterial pressure are also monitored.
  • Comparison of the relative antagonist potency on changes in arterial pressure and intra-urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing intra-urethral pressure is also present in the systemic vasculature. According to this method, one is able to confirm the selectivity of alpha la adrenergic receptor antagonists that prevent the increase in intra-urethral pressure to phenylephrine without any activity at the vasculature.

Abstract

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

Description

TITLE OF THE INVENTION
ALPHA la ADRENERGIC RECEPTOR ANTAGONISTS
This application claims the benefit of U.S. Provisional Application No. 60/050,137, filed June 18, 1997.
FIELD OF THE INVENTION:
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).
BACKGROUND OF THE INVENTION Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the 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.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into alpha 1? alpha 2} βi, and B2 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.
For a general background on the alpha adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., Ά-. Adrenorecentors: Molecular Biology. Biochemistry and Pharmacologv. (Progress in Basic and Clinical Pharmacologv series, Karger, 1991), wherein the basis of 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. Each 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. At the same time, 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. For a review of the classification of alpha 1 adrenoceptor subtypes, see, Martin C. Michel, et al., Naunyn- Schmiedeberg's Arch. Pharmacol. (1995) 352:1-10.
The differences in the alpha adrenergic receptor subtypes have relevance in pathophysiologic conditions. Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These 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. Concommitantly, 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.
In benign prostatic hyperplasia, the male hormone δalpha- dihydrotestosterone has been identified as the principal culprit. The continual production of 5a-dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
The elucidation of the mechanism summarized above has resulted in the recent development of effective agents to control, and in many cases reverse, the pernicious advance of BPH. In the forefront of these agents is Merck & Co., Inc.s' product PROSCAR® (finasteride). The effect of this compound is to inhibit the enzyme testosterone 5-a reductase, which converts testosterone into 5a-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass.
The development of such agents as PROSCAR® bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently rapidly. In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation 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. Thus, one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alphai subtype was reported. In addition, in WO 92/161213, combinations of 5a-reductase inhibitory compounds and alphal- adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the alpha Id, alpha lb, or alpha la subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known. Current therapy for BPH uses existing non-selective alpha 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer). These 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. [PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO94/10989, published 26 May 1994] As disclosed in the instant patent disclosure, 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.
It is an object of the present invention to identify compounds which bind to the alpha la adrenergic receptor. It is a further object of the invention to identify compounds which act as antagonists of the alpha la adrenergic receptor. It is another object of the invention to identify alpha la adrenergic receptor antagonist compounds which are useful agents for treating BPH in animals, preferably mammals, especially humans. Still another object of the invention is to identify alpha la adrenergic receptor antagonists which are useful for relaxing lower urinary tract tissue in animals, preferably mammals, especially humans.
It has now been found that the compounds of the present invention are alpha la adrenergic receptor antagonists. Thus, 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.
SUMMARY OF THE INVENTION The present invention provides compounds for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH). 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:
wherein Q is selected from
Rl is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R17)2, NR^COR1^ NR1 C0N(R18)2, NR17S02R7, NR17S02N(R!8)2, OR7, (CH2)0-4CO2R17,
(CH2)0-4CON(Rl7)2, (CH2)θ-4Sθ2N(Rl7)2, (CH2)θ-4Sθ2R7 or Ci-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(Rl7) , (CH2)θ-4Cθ2R17, (CH2)θ-4CON(Rl7)2, (CH2)0-4Sθ2N(R7)2, (CH2)θ-4Sθ2R7, phenyl, OR7, halogen, Ci- alkyl or C3-8 cycloalkyi; R is selected from hydrogen, cyano, OR7, CO2R17, CON(Rl7)2, SO2R7, Sθ2N(Rl7)2, tetrazole, isooxadiazole, unsubstituted, mono- or poly- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR7, (CH2)0-4Cθ2R17, (CH2)0-4CON(Rl7)2, N(Rl7)2, NRl COR7, NRl7CON(Rl8)2, NRl7S02R7, NR17Sθ2N(Rl8)2, (CH2)0-4SO2N(R17)2, (CH2)θ-4Sθ2R7 or C1.4 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, (CH2)θ-4Cθ2R17, (CH2)0-4CON(Rl7)2, (CH2)θ-4Sθ2N(Rl7)2, (CH2)θ-4Sθ2R7, phenyl, OR7, halogen, Cχ-4 alkyl or C3.8 cycloalkyi;
E, G, L and M are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyi, (CH2)θ-4θR7, (CH2)θ-4N(Rl7)2, (CH2)0-4CN, (CH2)0-4CF3, (CH2)θ-4Cθ2R7, (CH2)θ-4CON(Rl7)2, (CH2)0-4Sθ2R17 or (CH2)θ-4Sθ2N(Rl7)2;
J is selected from hydrogen, Cχ-8 alkyl, C3-8 cycloalkyi, (CH2)l-4θR7, (CH2)l-4N(Rl7)2, (CH2)l-4CN, (CH2)θ-4CF3, (CH )θ-4Cθ2R7, (CH )0-4CON(Rl )2, (CH )θ-4S02R17 or (CH2)θ-4S02N(Rl7)2;
R2, R3 and R^ are each independently selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyi, (CH2)θ-4Cθ2R7, (CH2)θ-4CON(Rl7)2, (CH )θ- 4COR7, (CH2)2-4θR7, (CH2)1-4CF3, (CH2)l-4Sθ2R7, (CH2)0-4SO2N(Rl7)2 or (CH2)l-4CN;
R4 is selected from hydrogen, COR7, (CH2)θ-4CN, (CH2)θ-4CF3, (CH2)0-4CO2R17, (CH2)θ-4CON(Rl7)2, (CH2)θ-4Sθ2R7 or
R5 is selected from hydrogen, Cχ-8 alkyl, C3-8 cycloalkyi, (CH2)l-4θR7 or (CH2)θ-4CF3; R7 is selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyi or (CH2)0-4CF3;
R8, R9, R10? R14? R15 and R16 are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)2-4θR7 or (CH2)0-4CF3;
RU and Rl2 are each independently selected from hydrogen, Cl-8 alkyl or C3-8 cycloalkyi;
Rl3 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)2-4θR7> OR7 or (CH2)0-4CF3;
Rl7 and Rl are each independently selected from is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi or (CH2)l-4CF3;
R20 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)l-4θR7, (CH2)θ-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR7, (CH2)θ-4CON(R17)2, (CH2)θ-4Cθ2R^-7 or Cl-4 alkyl; or unsubstituted, mono- or poly- substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR7, halogen, Cl-4 alkyl or C3-8 cycloalkyi;
R21 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)0-4OR7 or (CH2)θ-4CF3;
R26 is selected from hydrogen or OR28;
R28 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)0-4OR7 or (CH2)θ-4CF3; W is O or NR11;
each X is independently selected from halogen, cyano, nitro, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)θ-4θR7 or (CH2)θ-4CF3
m, p and q are each independently an integer of from zero to two, provided that when q is zero, R^β is hydrogen; n, o, s and t are each independently an integer of from zero to four;
and the pharmaceutically acceptable salts thereof.
In a first embodiment of the invention is the compound having the structure
wherein R4 is selected from COR7, (CH2)θ-4CN, (CH2)θ-4CF3, (CH2)0-4CO2R17, (CH2)θ-4CON(Rl7)2, (CH2)θ-4Sθ2R7 or
l3 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyi, (CH2)2-4θR7 or (CH2)0-4CF3;
and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
In a second embodiment of the present invention is the compound of the formula:
wherein
Q is selected from
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, N(R17)2, NR17COR18, NR17CON(R18)2, NR17Sθ2R7, NR17Sθ2N(R18)2, OR7, (CH2)θ-4Cθ2R17,
(CH2)0-4CON(R17)2, (CH2)θ-4Sθ2N(R17)2, (CH2)0-4SO2R7 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, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, (CH2)θ-4Cθ2R17, (CH2)θ-4CON(R17)2, (CH2)0-4SO2N(R7)2, (CH2)θ-4Sθ2R7, phenyl, OR7, halogen, Cl-4 alkyl or C3-8 cycloalkyi; R is selected from hydrogen, cyano, OR7, CO2R17, CON(R17)2, SO2R7, Sθ2N(Rl7)2, tetrazole, isooxadiazole, unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR7, (CH2)0-4CO2R17, (CH2)θ-4CON(Rl7)2, N(Rl7)2, NRl7COR7, NRl7CON(Rl8)2, NRl7S02R7, NRl7Sθ2N(Rl8)2, (CH2)0-4SO2N(Rl7)2, (CH2)θ-4Sθ2R7 or Cl-4 alkyl;
E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi or (CH2)θ-4CF3;
2, R3 and R^ are each independently selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyi, (CH2)0-4CO2R7, (CH2)θ-4CON(Rl7)2, (CH2)θ- 4COR7, (CH2)2-4θR7, (CH2)l-4CF3, (CH2)l-4Sθ2R7, (CH2)0-4Sθ2N(Rl7)2 or (CH2)l-4CN;
R8, R9, R10, R14, R!5 and R16 are each independently selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4θR7 or (CH2)0-4CF3;
R1^ is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4θR7> OR7 or (CH2)0-4CF3;
R20 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi,
(CH2)l-4θR7, (CH2)θ-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR7,
(CH2)0-4CON(Rl7)2, (CH2)θ-4Cθ2R17 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, cyano, nitro, amino, phenyl, OR7, halogen, Cl-4 alkyl or C3-8 cycloalkyi; R21 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)0-4θR7 or (CH2)θ-4CF3;
R28 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4θR7 or (CH2)θ-4CF3;
m, n, q and t are each independently an integer from zero to two, provided that when q is zero, R26 is hydrogen; and p is an integer from zero to one; and all other variables are as originally defined above; and the pharmaceutically acceptable salts thereof.
In a third embodiment of the invention is the compound of the formula
wherein Q is selected from
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, N(R17)2, NR17COR18, NR17CON(R18)2, NR17Sθ2R7, NRl7S02N(Rl8)2, OR7, (CH2)θ-4Cθ2R17, (CH2)0-4CON(R17)2, (CH2)θ-4Sθ2N(Rl7)2, (CH2)θ-4Sθ2R7 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, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, (CH2)θ-4Cθ2R17, (CH2)θ-4CON(R17)2,
(CH2)0-4SO2N(R7)2, (CH2)θ-4Sθ2R7, phenyl, OR7, halogen, Cl-4 alkyl or C3-8 cycloalkyi;
R is selected from hydrogen, cyano, OR7, CO2R17, CON(R17)2, SO2R7, Sθ2N(Rl7)2, tetrazole, isooxadiazole, unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR7, (CH2)0-4CO2R17, (CH2)0-4CON(Rl7)2, N(R17)2, NR17COR7, NR17CON(R18)2, NR17S02R7, NR17Sθ2N(R18)2, (CH2)0-4SO2N(R17)2, (CH2)θ-4Sθ2R7 or Cl-4 alkyl;
E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi or (CH2)θ-4CF3;
R2, R3 and R" are each independently selected from hydrogen,
Cl-6 alkyl, C4-6 cycloalkyi, (CH2)θ-4Cθ2R7, (CH2)θ-4CON(Rl7)2, (CH2)θ- 4COR7, (CH2)2-4θR7, (CH2)1-4CF3, (CH2)l-4S02R7, (CH2)0-4SO2N(Rl7)2 or (CH2)l-4CN;
R8, R9, R10} R13? R14? R15 and R16 are each independently selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4θR7 or (CH2)0-4CF3;
R20 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)l-4θR7, (CH2)0-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR7,
(CH2)0-4CON(R17)2, (CH2)θ-4Cθ2R17 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, cyano, nitro, amino, phenyl, OR7, halogen, Cl-4 alkyl or C3-8 cycloalkyi;
R21 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)0-4OR7 or (CH2)θ-4CF3;
m, n, q and t are each independently an integer from zero to two; p is an integer from zero to one; and all other variables are as defined previously in the first embodiment; and the pharmaceutically acceptable salts thereof.
In a first class of the invention is the compound of the formula
wherein Q is selected from
R2 is selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyi or (CH2)1-4CF3;
R4 is selected from hydrogen, COR7, (CH2)θ-2Cθ2R17, SO2R7 or
R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)l-3θR7 or (CH2)0-3CF3; and
R7 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi or (CH2)0-3CF3;
Rl3 is hydrogen or OR7;
RI7 and Rl are each independently selected from is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi or (CH2)l-4CF3;
R^O is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4θR7, (CH2)θ-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR7, CO2RI7, CON(R17)2 or Cl-4 alkyl;
R26 is hydrogen or OR^ , wherein R^8 is hydrogen or Cl-6 alkyl;
and all other variables are as defined above in the second embodiment; and the pharmaceutically acceptable salts thereof.
In a second class of the invention is the compound of the formula
wherein Q is selected from
R2 is selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyi or (CH2)l-4CF3;
R4 is selected from COR7, (CH2)θ-2Cθ2R17, SO2R7 or
R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)l-3θR7 or (CH2)θ-3CF3; and
R7 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi or (CH2)0-3CF3;
Rl7 and Rl8 are each independently selected from is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi or (CH2)l-4CF3;
R20 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4θR7, (CH2)θ-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR7, CO2R 7, CON(R17)2 or Cl-4 alkyl;
and all other variables are as defined above in the third embodiment; and the pharmaceutically acceptable salts thereof.
In a first subclass of the invention is the compund of the formula
wherein A is C-R19 or N;
R is selected from hydrogen, cyano, hydroxy, Cθ2R^7, CON(Rl7)2, SO2R7, Sθ2N(R17)2;
R2 is selected from hydrogen or CH2CF3;
Rl3 is selected from hydrogen or hydroxy;
each Rl9 is independently selected from halogen, CF3, cyano, nitro, amino, OR7, CO2R17, CON(R17)2 or C1-4 alkyl;
R20 is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR7, CO2R17, CON(R17)2 or Cl-4 alkyl;
R26 is selected from hydrogen or hydroxy;
each X is halogen;
q is an integer from zero to one, provided that when q is zero, R^6 is hydrogen; and r is an integer from zero to two; s is an integer from zero to three; and all other variables are as defined previously in the first class; and the pharmaceutically acceptable salts thereof.
In a second subclass of the invention is the compound of the formula
wherein A is C-R^9 or N;
R is selected from hydrogen, cyano, hydroxy, Cθ2R^7, CON(Rl7)2, SO2R7, Sθ2N(R17)2;
R2 is selected from hydrogen or CH2CF3;
each Rl9 is independently selected from halogen, CF3, cyano, nitro, amino, OR7, CO2R17, CON(R17)2 or C1-4 alkyl;
R^O is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR7, CO2R17, CON(R17)2 or Cl-4 alkyl;
each X is halogen;
q is an integer from zero to one; r is an integer from zero to two; s is an integer from zero to three; and all other variables are as defined previously in the second class; and the pharmaceutically acceptable salts thereof.
Illustrative of the invention is the compound selected from wherein Q is selected from
wherein R is selected from hydrogen or cyano;
R4 is selected from COR7, CO2R17 or CON(Rl7)2;
R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)l-2θR7 or (CH2)θ-2CF3;
Rl9 is selected from hydrogen, halogen, Cl-6 alkyl or CF3; each X is fluoro; and
and all other variables are as defined previously in the second subclass; and the pharmaceutically acceptable salts 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. Exemplifying the invention is the composition further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 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. 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 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.
Further exemplifying the invention is the method of treating BPH wherein the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH. Another example 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. Preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
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.
DETAILED DESCRIPTION OF THE INVENTION
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).
These compounds are administered in dosages effective to antagonize the alpha la receptor where such treatment is needed, as in BPH. For use in medicine, 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. Furthermore, where the compounds of the invention carry an acidic moiety, 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. Thus, 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), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate.
Compounds of this invention are used to reduce the acute symptoms of BPH. Thus, compounds of this invention may be used alone or in conjunction with a more long-term anti-BPH therapeutics, such as testosterone 5-a reductase inhibitors, including PROSCAR® (finasteride). Aside from their utility as anti-BPH agents, these compounds may be used to induce highly tissue-specific, localized alpha la 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 la receptor mediated central nervous system events.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, 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. Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more 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.
The term "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.).
The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
The term "aryl" as used herein, except where otherwise specifically defined, refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl.
The term "cycloalkyi" shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Cl-lθ) 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.
The term "halogen" shall include iodine, bromine, chlorine and fluorine. The term "substituted" shall be deemed to include multiple degrees of substitution by a named substituent. The term "poly- substituted" as used herein shall include di-, tri-, tetra- and penta- substitution by a named substituent. Preferably, a poly-substituted moiety is di-, tri- or tetra-substituted by the named substituents, most preferably, di- or tri-substituted.
It is intended that the definition of any substituent or variable (e.g., X, R^7, Rl ) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, - N(Rl7)2 represents -NH2, -NHCH3, -NHC2H5, -N(CH3)C2Hδ, etc. It is understood that 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.
The term heterocycle or heterocyclic ring, as used herein, represents an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from N, 0 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. Examples of such heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The term "thienyl," as used herein, refers to the group
The terms "(+)-DHP" and "DHP" as used herein, refer to a dihydropyrimidinone group of the formula
for example:
The term "activated (+)-DHP," as used herein, 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-methoxvmethyl-2-oxo-l, 2,3,4- tetrahydropyrimidine- 3-carboxylic acid (4-nitrophenyl ester).
The term "(S)-oxa" as used herein, refers to an oxazolidinone group of the formula
for example,
The term "activated (S)-oxa" as used herein, refers to an Λ -(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.
The term "selective alpha la adrenergic receptor antagonist," as used herein, 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.
The term "lower urinary tract tissue," as used herein, refers to and includes, but is not limited to, prostatic smooth muscle, the prostatic capsule, the urethra and the bladder neck. The term "subject," as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term "therapeutically effective amount" as used herein means that amount of active compound or 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. The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto- injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, 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. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and 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. When referring to these 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. For example, 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. A variety of materials can be used for such 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.
As used herein, the term "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.
The 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.
Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in 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.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The specificity of binding of compounds showing affinity for the alpha 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. 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. Expression of the cloned human alpha Id, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
Compounds of this invention exhibiting human alpha la adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. fSee e.g.. PCT International Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995]. Compounds which are both selective amongst the various human alphal adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the β- adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly preferred. The absence of these non-specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various human alphal adrenergic receptors. Furthermore, functional biological tests are used to confirm the effects of identified compounds as alpha la adrenergic receptor antagonists.
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. The 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. For example, 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. Likewise, 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.
Advantageously, 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. Furthermore, 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. To be administered in the form of a transdermal delivery system, 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.
In the methods of the present invention, 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. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and 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. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required. The daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day. For oral administration, 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 20 mg/kg of body weight per day. Preferably, 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. In addition, co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this includes administration of compounds of this invention and a human testosterone 5-a 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). In addition to PROSCAR®, which is principally active in prostatic tissue due to its selectivity for human 5-a 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 5a-reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050; WO93/23038, ; WO93/23048; WO93/23041; WO93/23040; WO93/23039; W093/23376; W093/23419, EP 0572165; WO93/23051. The dosages of the alpha la adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the 5-alpha reductase inhibitor and the alpha la adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of the present invention, 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.
Thus, in one preferred embodiment of the present invention, a method of treating BPH is provided which 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. Preferably, 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. For the treatment of benign prostatic hyperplasia, compounds of this invention exhibiting alpha la adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5a-reductase 2 inhibitor, such as finasteride, in addition to a 5a- reductase 1 inhibitor, such as 4,7β-dimethyl-4-aza-5a-cholestan-3- one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed wherein the alpha la adrenergic receptor antagonist and the 5a- 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 5a-reductase inhibitors.
Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
Aq = aqueous
BCE = bromochloroethane
Boc or BOC = t-butyloxycarbonyl
BOC2O = di-terz butyl dicarbonate
BOPC1 = bis(2-oxo-3-oxazolidinyl)phosphinic chloride Cbz = benzyloxycarbonyl
Cbz-Cl = benzyloxycarbonyl chloride
DEAD = diethylazodicarboxylate
DMF = N,N-dimethylformamide
DMSO = dimethylsulfoxide DPPA = diphenylphosphoryl azide
EDCI = l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Et = ethyl
Et3N = triethylamine EtOAc = ethyl acetate EtOH = ethanol
FABLRMS = fast atom bombardment low resolution mass spectroscopy HPLC = high performance liquid chromatography HOAc = acetic acid
HOBt = 1-hydroxy benzotriazole hydrate i-PrOH = 2-propanol i-Pr2NEt = diisopropylethylamine
KOtBu = potassium tø/ -butoxide LAH = lithium aluminum hydride mCPBA = meta-chloroperbenzoic acid
Me = methyl
MeOH = methanol
NMR = nuclear magnetic resonance Nu" = nucleophile
PCTLC = preparative centrifugal thin layer chromatography
PEI = polyethylenimine
Ph = phenyl RT = retention time tBuOH = tert-butanol
TEBAC = benzyltriethylammonium chloride
TFA = trifluoroacetic acid
THF = tetrahydrofuran TLC = thin layer chromatography
TMS = trimethylsilyl
TMSCN = trimethylsilyl cyanide
The compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Unless otherwise indicated, all variables are as defined above. In general, compounds claimed within this invention are readily accessible from an appropriately substituted cyclic alkanone via reductive amination with a mono blocked diamino equivalent, Scheme 1. Protection of the incipient amino group may be required, followed by deprotection of the terminal amino group. Acylation or alkylation provides the desired analog. An example of this strategy is outlined starting with an aryl cyano cycloalkanone and .N-protected 3- aminoazetidine, which after reductive amination, Boc protection and hydrogenation produces the acylation precursor. Treatment with an activated Q species (e.g., activated (+)-DHP, activated (S)-oxa) and HC1- EtOAc provides the final product.
Some of the examples described within this invention were prepared as outlined in Scheme 2. Reductive amination of 4-cyano 4- phenylcyclohexanone and ammonium acetate provided both cis and trans isomers (~9:1) of l-amino-4-cyano-4-phenylcyclohexanone, which after reductive amination with piperidonyl amides A and B furnished the targeted alpha la antagonists.
The 3-amino piperidinyl analogs were prepared from reductive amination of 3-aminopiperidine and 4-cyano-4-phenyl cyclohexanone, followed by Boc protection and hydrogenation of the CBZ protecting group. Acylation with an activated Q species provided the final products, Scheme 3.
Some of the required ketones were readily assembled following the sequence outlined in Scheme 4. 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. Further modifications of the ketones can be accomplished following the Dieckman cyclization, which provides the b-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. Another strategy for the synthesis of some geminally disubstituted cyclic ketones, in particular, 4,4-disubstituted cyclohexanones was accomplished as outlined in Scheme 5 starting from benzophenone derivatives and substituted methyl vinyl ketones which under basic conditions lead to the 4,4-aryl cyclohex-2-en-l-ones in good yield. Subsequent hydrogenation, reductive amination and deprotection provided the appropriate acylation/alkylation precursors. Alternatively, the 4,4-aryl 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.
The synthesis of some additional compounds of the present invention is described in Schemes 7 and 8. 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. Subsequent LAH reduction of the nitrile yielded the key intermediate required for the reductive aminations with the cyclohexanones. Deprotection of the N-dibenzylidine group and acyclation with preferred activated "Q"- groups furnished the final targets.
The synthesis of the 4-amino-3-hydroxy-pyrrolidine intermediate began with 3,4-pyrroline. BOC protection of the amine followed by mCPBA oxidation provided the epoxidation. Subsequent sodium azide opening of the epoxide and triphenylphosphine/water mediated reduction produced 4-amino-N-l-(l,l-dimethylethoxycarbonyl)- 3-hydroxypyrrolidine. This key amino intermediate was then alkylated by reductive amination reactions with cyclohexanones. Following the cleavage of the BOC protecting group acyclation with preferred activated "Q"-groups furnished the final targets.
The activated termini species comprising the "Q" groups are readily prepared by one of ordinary skill in the art. For example, 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. For instance, 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). 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.
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 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. Scheme 1
Scheme 1 (cont'd)
Scheme 1 (cont'd)
Scheme 3 (cont'd)
Scheme 4
For example,
C02Me
R = CN, S02alk, others
or heteroaryl A
Scheme 5
or heteroaryl or heteroaryl
Nu-, ,, for example, cuprates
Scheme 6
KOtBu
THF
5aR )1199 = Me 6a 5bR19 = 0Me 6bR19 = OMe
7bR19 = 0Me 8bR19 = 0Me
10bR19 = OMe Scheme 7
Swern TMSCN Oxidatn Znls
Final Products
Scheme 8
mCPBA NaHCO,
HO
Final Products d or (S)-OXA
The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples.
EXAMPLE 1
e
A B
A: 5-nitrilo-4-o-tolyl-pentanoic acid methyl ester B: 4-cvano-4-o-tolyl-hentanedioic acid dimethyl ester. (6a)
A solution of 2-methylbenzyl nitrile (25.0 g), methyl acrylate
(75 mL) and Triton-B (40 mL) in t-butanol (90 mL) was refluxed (12 h). The solvent was removed in vacuo and submitted to SGC (Siθ2> 10 cm x 30 cm, 0 - 15% EtOAc - hexane) affording the mono addition product and the desired bis addition compound (6a). A : iH NMR (CDC13, 300 MHz) 7.42 (m, 1 H, ArH), 7.20 (m, 3 H,
ArH), 4.34 (dd, 1 H, CHCN), 3.69 (s, 3 H, OMe), 2.57 (m, 2 H), 2.37 (s, 3 H, Me), 2.16 (m, 2 H). B: !H NMR (CDCI3, 300 MHz) 7.42 (m, 1 H, ArH), 7.20 (m, 3 H,
ArH), 3.62 (s, 6 H, OMe), 2.57 (m, 4 H), 2.54 (s, 3 H, Me), 2.31 (m, 2 H).
EXAMPLE 2
5-cyano-2-oxo-5-o-tolyl-cyclohexanecarboxylic acid methyl ester. (7a)
A solution of the diester (9.38 g, 29.4 mmol) in THF (200 mL) was treated with KOt-Bu (6.6 g, 58.74 mmol) at 0°C then heated to reflux (20 min). The solvent was removed in vacuo and submitted to SGC (Siθ2,
6 cm x 20 cm, 15% EtOAc - hexane) affording desired product and some decarboxylated material.
!H NMR (CDCI3, 300 MHz) consistent with assigned structure.
FABLRMS m/e 272.22 g/mole (M++H, C16H17NO3 = 272 g/mole.)
EXAMPLE 3
4-cvano(2-methylphenyl)-cvclohexan-l-one. (8a)
A solution of the ketoester (5.0 g, 18.4 mmol) in AcOH (100 mL) was treated with 10% aqueous H2SO4 (10 mL) at 0°C then heated to reflux (24 h). The solvent was removed in vacuo, diluted with EtOAc (100 mL) and water (100 mL), partitioned, washed with brine (75 mL), dried (Na2Sθ4), filtered and concentrated in vacuo and submitted to SGC (Siθ2, 5 cm x 20 cm, 0 - 15% EtOAc - hexane) affording the ketone. iH NMR (CDCI3, 300 MHz) 7.24 (m, 4H, ArH), 2.95 (ddd, 1 H, CHCN), 2.70 (s, 3 H, Me), 2.60 (m, 4 H), 2.20 (ddd, 2 H).
EXAMPLE 4
3-Aminomethyl N-diphenylmethyl azetidine. (12) To a cooled solution of aluminum chloride (0.33 g, 2.41 mmol) in ether (50 mL) at -78 C was added lithium aluminum hydride (2.41 ml, 2.41 mmol). After stirring 15 minutes at -78 C the slurry was added a solution of 11(0.50 g, 2.01 mmol) in ether (10 mL) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The solution was cooled to 0 C and quenched with water (10 mL) dropwise followed by 25% NaOH solution (10 mL). The aqueous layer was extracted with EtOAc. The organics were dried over Na2Sθ4, filtered, and removed in vacuo. The crude product was not purified. iH NMR (CDCI3, 300 MHz) 7.41-7.13 (m, 10 H), 4.32 (s, 1 H), 3.28 (t, 2 H), 2.88-2.79 (m, 4 H), 2.52-2.42(m, 1 H), 1.28 (s, 1 H).
EXAMPLE 5
Compound (9b)
A solution ofthe ketone _3b (prepared in an analogous manner to 8a) (0.25 g, 1.09 mmol), amine 12 (0.275 g, 1.09 mmol) and acetic acid (0.327 g, 5.45 mmol) in MeOH (7 mL) was treated with NaBH3CN (1.19 mL, 1.19 mmol, 1.0 M THF solution) at room temperature over a 1 hour period. The solvent was removed (12 h) in vacuo , diluted with DCM (25 mL) and saturated aqueous sodium bicarbonate (25 mL), partitioned, extracted with DCM (2 x 25 mL), washed with saturated aqueous sodium bicarbonate (2 x 25 mL) and brine (50 mL), dried (Na2Sθ4), filtered and concentrated in vacuo and submitted to PCTLC (Si02, 4 mm, 90/10/1 CHCl3-MeOH-NH4θH) the titled amine.
!H NMR (CDCI3, 400 MHz) 7.41-7.38 (m, 4 H), 7.33-7.28 (m, 4
H), 7.22 (s, 2 H), 7.19-7.14 (m, 2 H), 6.98-6.90 (m, 2 H), 4.33 (s, 1 H), 3.91 (s, 3 H), 3.36-3.31 (t, 2 H), 2.88-2.74 (m, 5 H), 2.60-2.55 (m, 2 H), 1.89-1.80 (m, 2
H), 1.72-1.64 (m, 2 H).
Anal. Calcd for C31H35N3O1 • 0.15 CHCI3 : C = 77.37, H =
7.33, N = 8.69. Found: C = 77.54, H = 7.43, N = 9.08. MS (FAB) 466 (M+l)
EXAMPLE 6
4-{l-[4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carbonyrj-piperidin-4- ylaminol-1-phenyl-cvclohexanecarbonitrile a. 4-(l-Benzyl-piperidin-4-ylamino)-l-Phenyl-cyclohexanecarbo-nitrile
A mixture of 4-cyano-4-phenyl-cyclohexanone (1.5 g, 7.5 mmol) and 4-amino-N-benzylpiperidine (1.5 g, 7.9 mmol) in 50 ml of benzene was stirred at reflux for 2 h in presence of catalytic amount of p- toluenesulfonic acid. The reaction mixture was concentrated in vacuo to provide a white solid, which was redissolved in 50 ml of EtOH and stirred with NaBH4 (0.60 g, 160 mmol) for 12 h at 25 °C. Reaction mixture was diluted with 200 ml of EtOAc and washed with brine several times. Organic layer was dried over M Sθ and concentrated in vacuo, to provide oily residue, which was identified as the desired product by NMR analysis and subjected to the following reaction without any further purification.
b. (4-cyano-4-phenyl-cyclohexyl)-piperidin-4-yl-carbamic acid ert-butyl ester
A solution of the amine and di-£er£-butyl dicarbonate (1.6 g, 7.3 mmol) was dissolved in 30 ml of DMF and stirred at 80 °C for 12 h. The reaction mixture was diluted in EtOAc and washed with brine several times. Organic layer was separated and concentrated in vacuo, to provide oily residue, which was subjected to column chromatography (50% Hexane/EtOAc) to yield (4-cyano-4-phenyl-cyclohexyl)-l-benzyl- piperidin-4-yl-carbamic acid tert -butyl ester as an oil. The amine obtained was dissolved in 100 ml of MeOH and stirred with catalytic amount of 10% Pd/C under atmosphere pressure of H . The reaction mixture was filtered and concentrated in vacuo to provide the desired product as an oil.
c. 4-{l-[4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carbonyl]-piperidin-4- ylamino}-l-phenyl-cyclohexanecarbonitrile
To a solution of 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3- carboxylic acid 4-nitrophenyl ester (80 mg, 0.21 mmol) in 5 ml of THF was added (4-cyano-4-phenyl-cyclohexyl)-piperidin-4-yl-carbamic acid tert -butyl ester (150 mg, 0.40 mmol) in a portion and the resulting solution was stirred for 12 h at 25 C. Reaction mixture was concentrated in vacuo, yielding a yellow oil, which was subjected to column chromatography (50% Hexane/EtOAc) to provide the tert -butyl ester of the desired product as a colorless oil. The product obtained was dissolved in 5 ml of EtOAc and 1 ml of IN HCl-Et2θ to afford a white solid of the product as the HCI salt: mp 181-192 C; Anal. Calc. For 27H28F2N4°3 1 0HC1 requires C, 61.70; H, 5.73; N, 10.28.
Found: C, 59.48; H, 5.41; N, 10.34.
Following the schemes and examples described herein, the compounds shown in Table 1 were prepared.
Table 1
Compound cis/trans
1 CIS H
CIS CBZ
trans CBZ
Compound 1:
FABLRMS: 284.09 g/mole
HPLC R.T.: 5.73 min.
Elemental Analysis: Calc. for 2.0HC1
Solvate mol. wt.=613.14g/mole
Calc:C=60.67%H=7.82%N=11.79%
Obs:C=60.34%H=7.58%N=11.56%
Compound 2:
FABLRMS: 438.03 g/mole
HPLC R.T.: 9.25 min.
Elemental Analysis: Calc. for 1.0HCl;0.45H2θ;0.15EtOAc
Solvate mol.wt.=495.32g/mole
Calc:C=64.50%H=6.53%N=8.48%
Obs:C=64.47%H=6.47%N=8.46% Compound 3:
FABLRMS: 418.22 g/mole
HPLC R.T.: 8.71 min.
Elemental Analysis: Calc. for 1.0HCl;0.95H2θ;0.45EtOAc
Solvate mol.wt.=528.34/mole
Calc:C=63.20%H=6.91%N=7.95%
Obs:C=63.10%H=6.60%N=8.01%
Compound 4:
FABLRMS: 418.17 g/mole
HPLC R.T.: 8.50 min.
Elemental Analysis: Calc. for 1.0HC1
Solvate mol.wt.=454.02g/mole
Calc:C=68.78%H=7.10%N=9.26%
Obs:C=68.84%H=7.26%N=8.86%
EXAMPLE 7 Mixture of (4jS)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine and 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2- oxo-2,3,4,5-tetrahydropyrimidine
To a solution of (+)-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 CH2C12 and H20 then neutralized with 10% aqueous HCI solution. The organic layer was dried over Na2S04, concentrated, and purified by PCTLC (7% MeOH in CHC13 with 2% NH4OH) to afford a 2.65 g mixture of the title compounds (71% yield). The Η NMR was consistent with the assigned structure. MS (FAB) 255 (M+l)
EXAMPLE 8 Mixture of (4jS)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine and 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2- oxo-2 ,3 ,4, 5-tetrahydropyrimidine
To a solution of (+)-4-(3,4-difluorophenyl)-6-methoxymethyl-
2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (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 CH2C12 and H20 then neutralized with 10% aqueous HCI solution. The organic layer was dried over Na2S04, concentrated, and purified by PCTLC (7% MeOH in CHC13 with 2% NH4OH) to afford a 2.35 g mixture of the title compounds (54% yield). The !H NMR was consistent with the assigned structure. MS (FAB) 255 (M+l)
EXAMPLE 9 (4<S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-3-(4-nitrophenoxycarbonyl)- 2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
The title compound was prepared by treating the mixture obtained from Example 7 or Example 8 (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 !H NMR was consistent with the assigned structure.
EXAMPLE 10 Mixture of (4_R)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine and 4β-4-(3,4-difluorophenyl)-6-methoxymethyl-2- oxo-2,3,4,5-tetrahydropyrimidine
The title compounds were prepared from 4R-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 7. A mixture of 2.0 g of the title compounds was obtained in 50% yield. The !H NMR was consistent with the assigned structure.
MS (FAB) 255 (M+l)
Compounds of the invention can be prepared by reacting the products obtained in Example 9 in accordance with procedures and schemes described above. The compound of Example 9 can, for example, be reacted with an aminocyclohexylpiperidine or aminocyclohexylpyrrolidine in accordance with Schemes 1 and 3 to obtain the desired compounds. Compounds of the invention can also be prepared by preparing a nitrophenoxy derivative of the compound of Example 10 in accordance with the procedure set forth in Example 9 and then reacting the derivative with an aminocyclohexylpiperidine or aminocyclohexylpyrrolidine as set forth in Schemes 1 and 3 to obtain compounds of the invention.
EXAMPLE 11
As a specific embodiment of an oral composition, 100 mg of the compound of Example 6 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.
EXAMPLE 12
Screening assav: Alpha la Adrenergic Receptor Binding
Membranes prepared from the stably transfected human alpha la cell line (ATCC CRL 11140) were used to identify compounds that bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume = 200 μl) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 l]-HEAT, membranes prepared from the alpha la cell line and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki). Representative compounds of the present invention were found to have Ki values < 50 nM.
EXAMPLE 13
Selective Binding assays
Membranes prepared from stably transfected human alpha Id and alpha lb cell lines (ATCC CRL 11138 and CRL 11139, respectively) were used to identify compounds that selectively bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume = 200 μl) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [I25 IJ-HEAT, membranes prepared from cell lines transfected with the respective alpha 1 subtype expression plasmid and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki).
EXAMPLE 14
EXEMPLARY COUNTERSCREENS
1. Assay Title: Dopamine D2, D3, D4 in vitro screen
Objective of the Assay:
The objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4.
Method:
Modified from VanTol et al (1991); Nature (Vol 350) Pg 610- 613. Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (lOmM Tris-HCl/5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 rpm) are resuspended in 50mM Tris-HCl pH 7.4 containing EDTA, MgCl[2], KC1, NaCl, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 μg membranes in a total volume of 500 μl containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 μM 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.
2. Assay Title: Serotonin 5HT la
Objective of the Assay
The objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor
Method: Modified from Schelegel and Peroutka Biochemical
Pharmacology 35: 1943-1949 (1986).
Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at 38,000Xg for 30'. The binding assay contains 0.25 nM [3H]8-OH- DPAT (8-hydroxy-2-dipropylamino-l,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaC12 and lmg/ml ascorbate. Non-specific binding is defined using 10 μM propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters
EXAMPLE 15
EXEMPLARY FUNCTIONAL ASSAYS In order to confirm the specificity of compounds for the human alpha la adrenergic receptor and to define the biological activity of the compounds, the following functional tests may be performed:
1. In vitro Rat, Dog and Human Prostate and Dog Urethra
Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate. Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary. Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles. Human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored overnight in ice-cold Krebs solution if needed.
The tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCl, 118 mM; KC1, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgSθ4, 1.2 mM; NaHC03, 2.0 mM; dextrose, 11 mM] warmed to 37°C. Excess lipid material and connective tissue are carefully removed. Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% Cθ2/95% 02- The tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder.
After a single priming dose of 3 μM (for rat), 10 μM (for dog) and 20 μM (for human) of phenylephrine, a cumulative concentration response curve to an agonist is generated; the tissues are washed every
10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated.
EC50 values are calculated for each group using GraphPad Inplot software. pA2 (-log Kb) values were obtained from Schild plot when three or more concentrations were tested. When less than three concentrations of antagonist are tested, Kb values are calculated according to the following formula Kb = FBI. x-1 where x is the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration.
2. Measurement of Intra-Urethral Pressure in Anesthetized Dogs
PURPOSE: 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. However, 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.
METHODS: Male mongrel dogs (7-12 kg) are used in this study. 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) are placed in the aorta via the femoral artery and vena cava via the femoral veins (2 catheters, one in each vein) for the measurement of arterial pressure and the administration of drugs, respectively. A supra-pubic incision ~l/2 inch lateral to the penis is made to expose the urethers, bladder and urethra. The urethers are ligated and cannulated so that urine flows freely into beakers. The dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra. Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate. The bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra. The bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer. 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, 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. Following administration of increasing doses of 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 EDδo'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) is used to compare the relative potency of the antagonists on inhibiting phenylephrine responses for intra-urethral and arterial pressure. The relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure Kb's. Effects of the alpha 1 antagonists on baseline arterial pressure are also monitored. Comparison of the relative antagonist potency on changes in arterial pressure and intra-urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing intra-urethral pressure is also present in the systemic vasculature. According to this method, one is able to confirm the selectivity of alpha la adrenergic receptor antagonists that prevent the increase in intra-urethral pressure to phenylephrine without any activity at the vasculature.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula:
wherein Q is selected from
R1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R17)2, NR17COR18, NR17CON(R18)2, NR17S02R7, N l7S02N(R!8)2, OR7, (CH2)θ-4Cθ2R17, (CH2)0-4CON(Rl7)2, (CH2)θ-4Sθ2N(R1 )2, (CH2)θ-4Sθ2R7 or Cl-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(R17)2, (CH2)θ-4Cθ2R17, (CH2)θ-4CON(R17)2,
(CH2)0-4SO2N(R7)2, (CH2)θ-4Sθ2R7, phenyl, OR7, halogen, Cl-4 alkyl or C3-8 cycloalkyi;
R is selected from hydrogen, cyano, OR7, CO2R17, CON(R17)2, SO2R7, Sθ2N(Rl7)2, tetrazole, isooxadiazole, unsubstituted, mono- or poly- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR7, (CH2)0-4CO2R17, (CH2)θ-4CON(Rl7)2, N(R17)2, NR17COR7, NRl7CON(R18)2, NR17Sθ2R7, NRl7Sθ2N(R18)2, (CH2)0-4SO2N(R17)2, (CH2)θ-4Sθ2R7 or Cl-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, (CH2)θ-4Cθ2Rl7, (CH2)0-4CON(R17)2, (CH2)θ-4Sθ2N(Rl7)2, (CH2)0-4SO2R7, phenyl, OR7, halogen, Cl-4 alkyl or C3-8 cycloalkyi;
E, G, L and M are each independently selected from hydrogen, Cι-8 alkyl, C3-8 cycloalkyi, (CH2)θ-4θR7, (CH2)θ-4N(Rl7)2, (CH2)0-4CN, (CH2)0-4CF3, (CH2)θ-4C02R7, (CH2)θ-4CON(Rl7)2, (CH2)0-4SO2R17 or (CH2)θ-4Sθ2N(Rl )2;
J is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)l-4θR7, (CH2)l-4N(Rl7)2, (CH2)1-4CN, (CH2)θ-4CF3, (CH2)θ-4Cθ2R7, (CH2)0-4CON(R17)2, (CH2)θ-4Sθ2R17 or (CH2)θ-4Sθ2N(R17)2; R2, R3 and R^ are each independently selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyi, (CH2)θ-4Cθ2R7, (CH2)θ-4CON(Rl7)2, (CH2)θ- 4COR7, (CH2)2-4θR7, (CH2)1-4CF3, (CH2)l-4S02R7, (CH2)0-4Sθ2N(Rl7)2 or (CH2)l-4CN;
R4 is selected from hydrogen, COR7, (CH2)θ-4CN, (CH2)θ-4CF3, (CH2)0-4CO2R17, (CH2)0-4CON(Rl7)2, (CH2)θ-4Sθ2R7 or
R5 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)l-4θR7 or (CH2)θ-4CF3;
R7 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi or (CH2)0-4CF3;
R8, R9, RlO^ R14? R15 and R16 are eacn independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)2-4θR7 or (CH2)0-4CF3;
RU and R 2 are each independently selected from hydrogen, Cl-8 alkyl or C3-8 cycloalkyi;
Ri3 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)2-4θR7, OR7 or (CH2)0-4CF3;
Ri7 and Rl8 are each independently selected from is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi or (CH2)l-4CF3;
R20 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi,
(CH2)l-4θR7, (CH2)θ-4CF3, unsubstituted, mono- or poly- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR7, (CH2)θ-4CON(Rl7)2, (CH2)θ-4Cθ2Rl7 or Cl-4 alkyl; or unsubstituted, mono- or poly- substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR7, halogen, Cl-4 alkyl or C3-8 cycloalkyi;
R2i is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)0-4θR7 or (CH2)θ-4CF3;
R 6 is selected from hydrogen or OR28;
R28 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)0-4θR7 or (CH )0-4CF3;
W is 0 or NRll;
each X is independently selected from halogen, cyano, nitro, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)θ-4θR7 or (CH2)θ-4CF3
m, p and q are each independently an integer of from zero to two, provided that when q is zero, R2^ is hydrogen; n, o, s and t are each independently an integer of from zero to four;
or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1 of the formula:
wherein R4 is selected from COR7, (CH2)θ-4CN, (CH2)θ-4CF3, (CH2)0- 4CO2R17, (CH2)0-4CON(R17)2, (CH2)θ-4Sθ2R7 or (CH2)θ-4Sθ2N(Rl7)2; Ri3 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi, (CH2)2-4θR7 or (CH2)θ-4CF3; or a pharmaceutically acceptable salt thereof.
The compound of Claim 1 of the formula:
wherein
Q is selected from
R1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R17)2, NR17CORl8, NR17CON(R18)2, NRl7S02R7, NRl7S02N(R18)2, OR7, (CH2)θ-4Cθ2R17, (CH2)0-4CON(R17)2, (CH2)θ-4Sθ2N(R17)2, (CH2)θ-4Sθ2R7 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, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, (CH2)θ-4Cθ2R17, (CH2)θ-4CON(Rl )2, (CH2)0-4SO2N(R7)2, (CH2)θ-4Sθ2R7, phenyl, OR7, halogen, Cl-4 alkyl or C3-8 cycloalkyi;
R is selected from hydrogen, cyano, OR7, CO2R17, CON(R17)2, SO2R7, Sθ2N(Rl7)2, tetrazole, isooxadiazole, unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR7,
(CH2)0-4CO2R17, (CH2)0-4CON(Rl7)2, N(Rl7)2, NRl7COR7, NR17CON(R18)2, NR17Sθ2R7, NRl7Sθ2N(R18)2, (CH2)0-4SO2N(Rl7)2, (CH2)θ-4Sθ2R7 or Cl-4 alkyl;
E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi or (CH2)θ-4CF3;
R2, R3 and R^ are each independently selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyi, (CH2)θ-4Cθ2R7, (CH2)θ-4CON(Rl7)2, (CH )θ- 4COR7, (CH2)2-4θR7, (CH2)l-4CF3, (CH2)l-4Sθ2R7, (CH2)0-4SO2N(Rl7)2 or (CH2)l-4CN;
R8, R9, R10, R14, R15 and R16 are each independently selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4θR7 or (CH )0-4CF3;
Rl3 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4θR7> OR7 or (CH2)0-4CF3;
R20 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyi,
(CH2)l-4θR7, (CH2)θ-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR7,
(CH2)0-4CON(Rl7)2, (CH2)θ-4Cθ2R17 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, cyano, nitro, amino, phenyl, OR7, halogen, Cl-4 alkyl or C3-8 cycloalkyi;
R i is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)0-4θR7 or (CH2)θ-4CF3;
R28 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4θR7 or (CH2)θ-4CF3;
m, n, q and t are each independently an integer from zero to two, provided that when q is zero, R2^ is hydrogen; and p is an integer from zero to one;
or a pharmaceutically acceptable salt thereof.
4. The compound of Claim 3, of the formula
wherein Q is selected from
R2 is selected from hydrogen, Cl-6 alkyl, C4-6 cycloalkyi or (CH2)1-4CF3; R4 is selected from hydrogen, COR7, (CH2)θ-2Cθ2R17, SO2R7 or
R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)l-3θR7 or (CH2)θ-3CF3; and
R7 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi or (CH2)0-3CF3;
Rl3 is hydrogen or OR7;
Rl7 and R^8 are each independently selected from is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi or (CH2)l-4CF3;
R20 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)2-4θR7 . (CH2)θ-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR7, CO2RI7, CON(R17)2 or Cl-4 alkyl;
R2^ is hydrogen or OR28, wherein R28 is hydrogen or Cl-6 alkyl;
or a pharmaceutically acceptable salt thereof.
The compound of Claim 4, of the formula
wherein A is C-R 9 or N; R is selected from hydrogen, cyano, hydroxy, C02R*7, CON(Rl7)2, SO2R7, Sθ2N(R17)2;
R2 is selected from hydrogen or CH2CF3;
Rl8 is selected from hydrogen or hydroxy;
each Rl is independently selected from halogen, CF3, cyano, nitro, amino, OR7, CO2R17, CON(R17)2 or C1-4 alkyl;
R2^ is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR7, CO2R17, CON(R17)2 or Cl-4 alkyl;
R 6 is selected from hydrogen or hydroxy;
each X is halogen;
q is an integer from zero to one, provided that when q is zero, R2^ is hydrogen; and r is an integer from zero to two; s is an integer from zero to three; or a pharmaceutically acceptable salt thereof.
6. The compound of Claim 5, selected from
wherein Q is selected from
wherein R is selected from hydrogen or cyano;
R4 is selected from COR7, CO2R17 or CON(R17)2;
R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyi, (CH2)l-2θR7 or (CH2)0-2CF3; Rl9 is selected from hydrogen, halogen, Cl-6 alkyl or CF3;
each X is fluoro; or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition made by combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
9. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
10. The composition of Claim 7 further comprising a testosterone 5-alpha reductase inhibitor.
11. The composition of Claim 10, wherein the testosterone 5- alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor.
12. The composition of Claim 11, wherein the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor.
13. The composition of Claim 12, wherein the testosterone 5-alpha reductase inhibitor is finasteride.
14. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1.
15. The method of Claim 14, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
16. The method of Claim 15, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
17. The method of Claim 16, wherein the testosterone 5- alpha reductase inhibitor is finasteride.
18. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering a therapeutically effective amount of the composition of Claim 7.
19. The method of Claim 18, wherein the composition further comprises a therapeutically effective amount of a testosterone 5- alpha reductase inhibitor.
20. A method of relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1.
21. The method of Claim 20, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue.
22. The method of Claim 20, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
23. The method of Claim 22, wherein the testosterone 5- alpha reductase inhibitor is finasteride.
24. A method of treating a condition which is susceptible to treatment by antagonism of the alpha la receptor which comprises administering to a subject in need thereof an amount of the compound of Claim 1 effective to treat the condition.
25. A method of eliciting an alpha la antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of Claim 1.
EP98930349A 1997-06-18 1998-06-17 ALPHA 1aADRENERGIC RECEPTOR ANTAGONISTS Withdrawn EP1003511A1 (en)

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US6207444B1 (en) 1997-08-05 2001-03-27 Merck & Co., Inc. Enzymatic process of making alpha 1a adrenergic receptor antagonists using protease
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
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
GB2355263A (en) 1999-09-30 2001-04-18 Merck & Co Inc Lactam and cyclic urea 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
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