WO1998057640A1 - Alpha 1a adrenergic receptor antagonists - Google Patents

Alpha 1a adrenergic receptor antagonists Download PDF

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Publication number
WO1998057640A1
WO1998057640A1 PCT/US1998/012672 US9812672W WO9857640A1 WO 1998057640 A1 WO1998057640 A1 WO 1998057640A1 US 9812672 W US9812672 W US 9812672W WO 9857640 A1 WO9857640 A1 WO 9857640A1
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Prior art keywords
alkyl
hydrogen
cycloalkyl
independently selected
alpha
Prior art date
Application number
PCT/US1998/012672
Other languages
French (fr)
Inventor
Michael A. Patane
Mark G. Bock
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Merck & Co., Inc.
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Filing date
Publication date
Priority claimed from GBGB9800231.4A external-priority patent/GB9800231D0/en
Priority to CA002294346A priority Critical patent/CA2294346A1/en
Priority to AU81501/98A priority patent/AU8150198A/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP50478099A priority patent/JP2002508764A/en
Priority to EP98931353A priority patent/EP1019052A4/en
Publication of WO1998057640A1 publication Critical patent/WO1998057640A1/en

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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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.
  • alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenoL
  • the binding affinity of these hormones is reversed for the beta receptors.
  • the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
  • alpha and beta receptors were further subdivided into alpha 1, alpha 2 ⁇ ⁇ ⁇ 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:
  • E, G, L and M are each independently selected from hydrogen, C ⁇ -8 alkyl, C3-8 cycloalkyl, (CH 2 ) ⁇ -4 ⁇ R6, (CH2)0-4N(Rl9)2, (CH2) ⁇ -4CN, (CH 2 )0-4CF 3 , (CH 2 )0-4CO2R 19 , (CH 2 ) ⁇ -4CON(Rl9) 2 , (CH 2 ) ⁇ -4S ⁇ 2R 19 , or J is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4 ⁇ R 6 , (CH 2 )l-4N(Rl9)2, (CH2)l-4CN, (CH 2 ) ⁇ -4CF 3 , (CH2) ⁇ -4C0 2 R 19 , (CH2)0-4CON(Rl9) 2 , (CH2) ⁇ -4S ⁇ 2 19 , or (CH2) ⁇ -4S ⁇ 2N(Rl9) 2 ;
  • RI is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl9) 2 , NR ⁇ COR 20 , NR1 CON(R20) 2 , NR19S02R 20 , NR19S02N(R20)2, OR6, (CH2) ⁇ -4C ⁇ 2R 19 , oxadiazolyl-, Cl- 4 alkyl oxadiazolyl-, (CH2) ⁇ -4CON(Rl9) 2 , (CH2) ⁇ -4S ⁇ 2N(Rl9) 2 , (CH2) ⁇ - 4SO2R 6 or C1.4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents
  • R17 and R 18 are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2) 2-40R 6 or (CH2) ⁇ -4CF3;
  • R 4 is selected from hydrogen, (CH2) ⁇ -4COR6, (CH2) ⁇ -4CN, (CH2)0-4CF3, (CH2)0-4CO2R 19 , (CH2)0-4CON(Rl9) 2 , (CH 2 ) ⁇ -4S ⁇ 2R 6 or
  • R5 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4 ⁇ R6 or (CH 2 )0-4CF 3 ;
  • R6 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or (CH 2 )0-4CF 3 ;
  • R ⁇ is selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R 19 , (CH2) ⁇ -4CON(Rl9) 2 , (CH2) ⁇ -4CORl9, (CH2)2-4 ⁇ R6, (CH2)1-4CF3, (CH 2 )0-4SO2R 6 , (CH2) ⁇ -4S ⁇ 2N(Rl9) 2 or (CH2)l-4CN;
  • R is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, CO2R 6 , CON(R6)2, (CH2)l-4 ⁇ R 6 or (CH2) ⁇ -4 CF3;
  • RU and R ⁇ 2 are each independently selected from hydrogen, Cl-8 alkyl or C3-8 cycloalkyl;
  • Rl3 and R ⁇ - 4 are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4 ⁇ R 6 , (CH2) ⁇ -4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , (CH2)0-4CON(R 19 )2, (CH2)0-4CO2R 19 or Ci-4 alkyl; or unsubstituted, mono- or poly-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR 6 , halogen, Ci-4 alkyl or C3-8 cycloalkyl;
  • Rl9 and R 2 ⁇ are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or (CH2)l-4CF3;
  • R 22 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2) ⁇ -4 ⁇ R 6 or (CH2)0-4CF3;
  • R 24 and R 26 are each independently selected from hydrogen or OR 28 ;
  • R 28 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH 2 )0-4CF 3 ;
  • W is O or NRH
  • each X is independently selected from halogen, cyano, nitro, Cl-8 alkyl, C3-8 cycloalkyl, (CH 2 ) ⁇ -4 ⁇ R 6 or (CH 2 ) ⁇ -4CF3;
  • Y is C-R 19 or N;
  • Z is hydrogen, oxygen or sulphur;
  • n, o, and s are each independently an integer from zero to four; and v is an integer from zero to one;
  • 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 19 )2, NR 19 COR 20 , NR 1 9CON(R 2 0) 2 , NR 19 S ⁇ 2R 20 , NRl9s ⁇ 2N(R 2 0)2, OR 6 , (CH2) 0-
  • R 4 is selected from (CH2) ⁇ -4COR 6 , (CH2) ⁇ -4CN, (CH2) ⁇ -4CF3, (CH2)0-4CO2R 19 , (CH2) 0-4CON(Rl9) 2 , (CH2) ⁇ -4S ⁇ 2R 6 or
  • R 5 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4 ⁇ R 6 or (CH 2 )0-4CF 3 ;
  • R 9 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4 ⁇ R 6 or (CH2)0-4CF3;
  • E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2) ⁇ -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(Rl9) 2 , NRl 9 COR 2 0, NR 19 CON(R 2 0) 2 , NR19S02R 20 , NR19S02N(R 2 0)2, OR 6 , (CH2)0-4CO2R 19 , oxadiazolyl-, C1-4 alkyloxadiazolyl, (CH2) ⁇ -4CON(Rl9) 2 , (CH2) ⁇ -4S ⁇ 2N(Rl9) 2 , (CH2) ⁇ - 4SO2R 6 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl
  • R7 is selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH 2 )l-4CF 3 ;
  • Rl3 and R ⁇ 4 are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4 ⁇ R 6 , (CH2) ⁇ -4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , (CH2)0-4 CON(R 19 ) 2 , (CH2) ⁇ -4C ⁇ 2R 19 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF
  • n is an integer from zero to two; and all other variables are as originally defined above; and the pharmaceutically acceptable salts thereof.
  • E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2) ⁇ -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 19 ) 2 , NR 19 COR 20 , NR 19 CON(R 20 )2, NR 19 S ⁇ 2R 20 , NR 19 SO2N(R 20 )2, OR 6 , (CH2)0-4CO2R 19 , (CH 2 )0-4CON(Rl 9 )2, (CH 2 ) ⁇ -4S ⁇ 2N(R 19 )2, (CH2)0-4SO2R 6 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazin
  • ⁇ is selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH 2 )l-4CF 3 ;
  • Rl3 and R ⁇ are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4 ⁇ R 6 , (CH2) ⁇ -4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , (CH2)0-4CON(R 19 )2, (CH2) ⁇ -4C ⁇ 2R 19 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR 6 , halogen, Cl-4 alkyl or C3-8 cycloalkyl;
  • n is an integer from zero to two; and all other variables are as defined in the first embodiment; and the pharmaceutically acceptable salts thereof.
  • a first class of the invention is the compound 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, OR 6 , (CH2) ⁇ -2C ⁇ 2R 19 , (CH2) 0-2CON(R 19 )2, (CH2)0-2SO2N(R 19 )2, (CH2) ⁇ -2S0 2 R 6 , Cl-4 alkyl oxadiazolyl- or Cl-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2) ⁇ -2C ⁇ 2R 19 , (CH2) ⁇ -2CON(Rl 9 )2, (CH2)0-2SO2N(R 19 )2_ (CH2) ⁇ -2S ⁇ 2R 6 or Cl-4 alkyl;
  • R 4 is selected from hydrogen, COR 6 , CO2R 19 , SO2R 6 or CON(R 19 )2;
  • R 5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)l-3 ⁇ R 6 or (CH 2 )0-3CF 3 ;
  • R 6 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH 2 )0-3CF 3 ;
  • R 8 and RlO are each independently selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)2-4 ⁇ R 6 or (CH2) ⁇ -3CF3;
  • R 9 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, CO2R 6 , CON(R 6 )2, (CH2)l-4 ⁇ R 6 or (CH2) ⁇ -3CF 3 ;
  • Rl3 i s selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)2-4 ⁇ R 6 , (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 6 , CO2 9 or Cl-4 alkyl;
  • RI is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)1-3CF 3 ;
  • R 22 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2) ⁇ -4 ⁇ R 6 or (CH 2 )0-3CF 3 ;
  • R 28 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, or (CH 2 )0-3CF3;
  • q is an integer from zero to two; and s is an integer from zero to three; and all other variables are as defined previously in the second embodiment; and the pharmaceutically acceptable salts thereof.
  • RI is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2) O-2CO2R 19 , (CH2) ⁇ -2CON(Rl 9 )2, (CH2)0-2SO2N(R 19 )2, (CH2) ⁇ -2S ⁇ 2R 6 or C1-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, OR 6 ,
  • R 4 is selected from COR 6 , C02R 19 , SO2R 6 or CON(R 19 )2;
  • R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)l-3 ⁇ R 6 or (CH 2 )o-3CF 3 ;
  • R 6 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH 2 )o-3CF 3 ;
  • R 8 , R 9 and R l O are each independently selected from hydrogen, C ⁇ -6 alkyl, C3-6 cycloalkyl, (CH2)2-4 ⁇ R 6 or (CH2) ⁇ -3CF3;
  • Rl3 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)2-4 ⁇ R 6 , (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 6 , C ⁇ 2R ⁇ 9 or Cl-4 alkyl;
  • RI 9 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or
  • R 22 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2) ⁇ -4 ⁇ R 6 or (CH2)0-3CF 3 ;
  • Rl3 is selected from hydrogen, Cl-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 6 ,
  • each X is a halogen; and all other variables are as defined previously in the first class; and the pharmaceutically acceptable salts thereof.
  • Rl3 is selected from hydrogen, Cl-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , CO2R 19 or Cl-4 alkyl;
  • each X is a halogen; and all other variables are as defined previously in the second class; and the pharmaceutically acceptable salts thereof.
  • A is C-R 2 1 or N;
  • each R 2 1 is independently selected from hydrogen, halogen, cyano, OCl-4 alkyl, OCF3, OCH2CF3, C02CH3, CONH2, SO2NH2 or SO2C1-4 alkyl;
  • R 24 and R 26 are each independently selected from hydrogen or OR 28 , wherein R 28 is hydrogen or Cl-4 alkyl;
  • each X is fluorine
  • r is an integer from zero to two; and q is an integer from zero to one; and all other variables are as defined previously in the first subclass; and the pharmaceutically acceptable salts thereof.
  • A is C-R 1 or N;
  • each R 2 1 is independently selected from hydrogen, halogen, cyano, OCi- 4 alkyl, OCF3, OCH2CF3, CO2CH3, CONH2, SO2NH2 or SO2C1-4 alkyl;
  • each X is fluorine
  • R 4 is C02R 19 ;
  • R5 is (CH2)l-3 ⁇ R 6 ; and all other variables are as defined previously in the first illustration; and the pharmaceutically acceptable salts thereof.
  • R 4 is C02R 19 ;
  • R 5 is (CH2)l-3 ⁇ R 6 ; and all other variables are as defined previously in the second illustration; 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.
  • 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 illustration of the invention is the method of treating benign prostatic hyperplasia wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is finasteride.
  • FIG. 1 Further illustrating the invention is a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
  • More specifically exemplifying the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) additionally does not cause a fall in blood pressures at dosages effective to inhibit contraction of prostate tissue.
  • More particularly illustrating the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) is administered in combination with a testosterone 5-alpha reductase inhibitor; preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
  • More particularly exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the alpha la receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease.
  • Diseases which are susceptible to treatment by antagonism of the alpha la receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see, K.A. Vatz, Headache 1997:37: 107-108) and cardiac arrhythmia.
  • An additional illustration of the invention is the use of any of the compounds described above in the preparation of a medicament for: a) the treatment of benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof.
  • Representative compounds of the present invention exhibit selectivity for the human alpha la adrenergic receptor.
  • 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).
  • G-protein coupled human receptors e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,
  • 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).
  • 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 m vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
  • the compounds according to the invention may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
  • alkyl shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
  • alkenyl shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
  • aryl refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it shall be interpreted as including those limitations given above for "alkyl” and "aryl.”
  • Designated numbers of carbon atoms e.g., Ci-io shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • halogen shall include iodine, bromine, chlorine and fluorine.
  • substituted shall be deemed to include multiple degrees of substitution by a named substituent.
  • poly- substituted as used herein shall include di-, tri-, tetra- and penta- substitution by a named substituent.
  • a poly-substituted moiety e.g., phenyl
  • a poly-substituted moiety is di-, tri- or tetra- substituted by the named substituents, most preferably, di- or tri-substituted.
  • - N(Rl9)2 represents -NH 2 , -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, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl,
  • activated (+)-DHP refers to a N- 3-(activated)carbamate of the desired dihydropyrimidinone where the activating group is, for example, a p-nitrophenyloxy group.
  • a specific example of an activated (+)-DHP is 4-(3,4-difluorophenyl)-5- methoxycarbonyl-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine- 3-carboxylic acid (4-nitrophenyl ester), also referred to as the compound 8.
  • (S)-oxa refers to an oxazolidinone group of the formula
  • activated (S)-oxa refers to an JV- (activated)carbamate of the desired oxazolidinone where the activating group is, for example, a p-nitrophenyloxy group.
  • a specific example of an activated (S)-oxa group is 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3- carboxylic acid 4-nitrophenyl ester (i.e., compound 19).
  • 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.
  • therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto- injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • 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
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • Other dispersing agents which may be employed include glycerin and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day.
  • the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 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 4,7B-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.
  • Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
  • BOPC1 bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • DPPA diphenylphosphoryl azide
  • EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • PCTLC preparative centrifugal thin layer chromatography
  • PEI polyethylenimine
  • TEBAC benzyltriethylammonium chloride
  • the compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Unless otherwise indicated, all variables are as defined above.
  • the preparation of some desired compounds are described in Schemes 1-11. 3-(_er£-Butyloxycarbonyl)amino piperidine was prepared from nipecotic acid in three steps, Scheme 1.
  • the 3-aminopyrrolidinyl analogs were constructed by reductive amination of 3-( er£-butoxycarbonyl)amino pyrrolidine and a piperidone derivative, Scheme 3. Acidic deprotection of the carbamate produced the 3-amino pyrrolidinyl intermediate which was acylated under standard conditions.
  • Antagonists with cycloalkyl linking chains can be " assembled by reductive amination of the prerequisite amino alcohol and a ketone, for example, N-(2-cyanophenyl)piperidin-4-one, Scheme 9. Conversion of the hydroxy to a tosylate with tosyl anhydride, followed by displacement by the sodium or lithium salt of the desired Q group completes the synthesis of the targeted antagonists.
  • the activated termini species comprising the "Q" groups are readily prepared by one of ordinary skill in the art.
  • unsubstituted, alkyl- and cycloalkyl-substituted oxazolidinones are prepared and activated in general by published and well developed chemistry, in particular, of Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13, 1 (1982)]
  • the starting materials, in general, are natural and unnatural amino acids.
  • some of the preferred compounds are prepared from substituted phenyl glycine derivatives, which after reduction of the carboxylate and a phosgene equivalent mediated cyclization provides the substituted oxazolidinone ring system.
  • Oxazolidinones substituted with carboxylate, carboxamide, and hydroxymethyl are prepared by hydroxyamination of olefins to provide protected aminoalcohols, using procedures as described in Sharpless et al., Angew. Chem. Int. Ed. EngL, 35, 2813 (1996). Deprotection under standard conditions followed by a phosgene equivalent to mediate cyclization provides the substituted oxazolidinone ring system. Deprotonation with a strong base, for example, lithium bis(trimethylsilyl)amide, and addition to a THF solution of p- nitrophenylchloroformate produces the stable, isolatable "activated" oxazolidinone.
  • a strong base for example, lithium bis(trimethylsilyl)amide
  • Dihydropyrimidinones are prepared by condensation reaction of the aldehyde, urea and a 1,3-acetoacetate type derivative catalyzed by a Lewis Acid, a copper (I) species and acetic acid. Activation was accomplished by treatment with a strong base, for instance, LiN(TMS)2, followed by addition to a THF solution of p- nitrophenylchloroformate.
  • a strong base for instance, LiN(TMS)2
  • Hydantoins and cycloimide were prepared in two chemical steps from ketones as outlined in the literature. More specifically, hydantoins were prepared according to known methodology, e.g., J.J.
  • the dihydropyrimidinones and the unsubstituted, alkyl- and cycloalkyl-substituted oxazolidinones were synthesized independently in racemic form, and then separated utilizing preparative chiral HPLC. Their optical rotations were recorded. Then they were activated and reacted with prerequisite amines. From the receptor binding studies, a preferred isomer was identified, the (+) rotational isomer in each case.
  • the absolute configurations were determined to be (S) for both the dihydropyrimidinones and oxazolidinones by correlating their optical rotations with x-ray crystal structures obtained of fragments involved in the production of the antagonists.
  • the title compound was prepared from 15 (1.0 g, 4.9 mmol) and 3 (1.0 g, 4.3 mmol) using the procedure described for the preparation of 6 to give the title compound.
  • the title compound was prepared from 17 (1.0 g, 3.9 mmol) and 8 (520 mg, 1.1 mmol) using the procedure described for 9.
  • the title compound was prepared from 24 (560 mg, 1.73 mmol) and triphenylphosphine (900 mg, 3.4mmol) using the procedure described for 13.
  • the title compound was prepared from 35 using the procedure described for the preparation of l ⁇ .
  • the title compound was prepared from 36 using the procedure described for the preparation of 16.
  • the title compound was prepared from 37 using the procedure desrcibed for the preparation of 17.
  • the title compound 39 was prepared from 38 using the procedure described for the preparation of 18.
  • Calc. for 0.05CHCl3;0.55EtOAc Solvate mol. wt. 736.00g/mole
  • trans-3,4-difluorocinnamic acid (10 g, 54 mmol) in 300 mL methanol was added concentrated sulfuric acid (2 mL). The solution was stirred 48 h at ambient temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (2 x 100 mL), brine (1 x 100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide trans-3,4-difluorocinnamic acid methyl ester (10.7 g, 54 mmol, 100%) as a white solid.
  • Step B (2R, 3S)-N-Benzyloxycarbonyl-3-amino-3-(3,4- difluorophenyl)-2-hydroxypropionic acid methyl ester
  • a solution of NaOH (4.1 g, 103 mmol) was prepared in 175 mL water. Potassium osmate dihydrate (491 mg, 1.3 mmol) was dissolved in 35 mL of this NaOH solution, resulting in a dark pink homogeneous mixture.
  • To a 1000 mL round bottom flask is added the remaining NaOH solution prepared above, 135 mL n-propanol and benzyl cabamate (9.8 g, 110 mmol). The suspension was stirred at ambient temperature for 30 min wherein the mixture was nearly homogeneous.
  • the reaction flask was placed in a room temperature water bath and the surrounding lights were turned off.
  • Step D (4S, 5R)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-5- carboxylic acid methyl ester
  • Step E (4S, 5R)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3,5- dicarboxylic acid methyl ester 3-(4-nitrophenyl) ester
  • Step F (4S, 5R)-4-(3,4-Difluorophenyl-3-(l- ⁇ l-[4-fluoro-2-(3- methyl[l,2,4]oxadiazol-5-yl)phenyl]-piperidin-4-yl ⁇ -(3R)- pyrrolidin-3-ylcarbamoyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester
  • the reaction mixture was stirred at ambient temperature for 1 h when the volatiles were removed under reduced pressure.
  • the residue was dissolved in ethyl acetate (100 mL) and washed with 10% aqueous sodium carbonate solution (8 x 100 mL), brine (1 x 100 mL), dried over magnesium sulfate and filtered.
  • the volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (2% methanol in ethyl acetate) to give a foam.
  • hydrochloride salt was prepared according to standard procedures to afford (4S, 5R)trans-4-(3,4- difluorophenyl-3-(l- ⁇ l-[4-fluoro-2-(3-methyl-[l,2,4]oxadiazol-5-yl)phenyl]- piperidin-4-yl ⁇ -(3R)-pyrrolidin-3-ylearbamoyl)-2-oxo-oxazolidine-5- carboxylic acid methyl ester as a solid.
  • Step C (4S, 5R)-4-(3,4-Difluorophenyl)-2-oxo-5-(tetrahydropyran-2- yloxymethyl)-oxazolidine-3-carboxylic acid 4-nitrophenyl ester
  • the p-mtrophenylchloroformate (586 mg, 2.9 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) under argon and cooled to -78°C.
  • the above prepared anion solution was added via cannula to the chloroformate solution and reaction mixture was stirred 1 h at -78°C.
  • the reaction mixture was treated with ethyl acetate (150 mL).
  • the resulting solution was washed with water (1 x 150 ml), brine (1 x 150 mL), dried over magnesium sulfate and filtered.
  • Step D (4S, 5R)-4-(3,4-Difluorophenyl)-2-oxo-5-(tetrahydropyran-2- yloxymethyl)oxazolidine-3-carboxylic acid ⁇ l-[l-(2- cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-yl ⁇ amide
  • reaction mixture was stirred at room temperature for 4 h when the volatiles were removed under reduced pressure, the residue dissolved in ethyl acetate (100 mL), washed with 10% aqueous sodium carbonate solution (8 x 100 mL), brine (1 x 100 mL), dried over magnesium sulfate and filtered.
  • Step E (4S, 5R)-4-(3,4-Difluorophenyl)-5-hydroxymethyl-2-oxo- oxazolidine-3-carboxylic acid ⁇ l-[l-(2-cyanophenyl)piperidin- 4-yl]-(3R)-pyrrolidin-3-yl ⁇ amide
  • Examples 34 and 35 were prepared by procedures described in Example 30 Steps A-F, followed by pressurized silica gel chromatography using an elution system containing chloroform saturated with ammonia gas and methanol.
  • (+)-4-(3,4-difluorophenyl)-6-methoxymethyl- 2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (4.63 g, 14.7 mmol) in a methanol (100 ml) was added sodium hydroxide (2.94 g, 73.6 mmol). The resulting mixture was refluxed at 90 °C for 16 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was dissolved in CH 2 C1 2 and H 2 0 then neutralized with 10% aqueous HCl solution.
  • (+)-4-(3,4-difluorophenyl)-6-methoxymethyl- 2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 5.36 g, 17.0 mmol
  • a methanol 150 ml
  • IN NaOH 10 ml
  • the resulting mixture was refluxed at 90 °C for 16 hours. After cooling to room temperature the solvent was removed in vacuo.
  • the solid was dissolved in CH 2 C1 2 and H 2 0 then neutralized with 10% aqueous HCl solution.
  • the title compound was prepared by treating the mixture obtained from Example 36 or Example 37 (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 38 in accordance with procedures and schemes described above.
  • the compound of Example 38 can, for example, be reacted with an aminopiperidine or aminoalkylpiperidine as set forth in Schemes 1 and 2 to obtain the desired compounds.
  • Compounds of the invention can also be prepared by preparing a nitrophenoxy derivative of the compound of Example 39 in accordance with the procedure set forth in Example 38 and then reacting the derivative with an aminopiperidine or aminoalkylpiperidine as set forth in Schemes 1 and 2 to obtain compounds of the invention.
  • EXAMPLE 56 (3jR,-_?S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid ⁇ l-[l-(2- (N-3-dimethylsulfonamido)aminophenyl)-piperidin-4-yl]pyrrolidin-3-yl ⁇ - amide
  • EXAMPLE 66 (Racemic @ pyrrolidine) (4 ⁇ S)-3- ⁇ l-[l-(2-Cyanophenyl)piperidin-4-yl]-3- hydroxy-pyrrolidin-4-ylcarbamoyl ⁇ -4-(3,4-difluorophenyl)-6- methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
  • 100 mg of the compound of Example 6 (i.e., Compound 2) 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.
  • 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 contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [I 25 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).
  • the objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4.
  • Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (lOmM Tris-HCl/5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 rpm) are resuspended in 50mM Tris-HCl pH 7.4 containing EDTA, MgCl[2], KC1, NaCl, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 ⁇ g membranes in a total volume of 500 ⁇ l containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 ⁇ M apomorphine. The assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.
  • the objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor
  • Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at 38,000Xg for 30'.
  • the binding assay contains 0.25 nM [3HJ8-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; KCl, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgS ⁇ 4, 1.2 mM; NaHC ⁇ 3, 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. After a single priming dose of 3 ⁇ M (for rat), 10 ⁇ M (for dog) and 20 ⁇ M (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.
  • 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.
  • the tip of the transducer is placed in the prostatic urethra and the position of the Millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure.
  • Phenylephrine an alpha 1 adrenergic agonist
  • Phenylephrine is administered (0.1-100 ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure.
  • an alpha adrenergic antagonist or vehicle
  • the effects of phenylephrine on arterial pressure and intra-urethral pressure are re-evaluated.
  • Four or five phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle).
  • the relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis.
  • the family of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant among curves.
  • the dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the ED ⁇ o's for the respective curves. These dose-ratios are then used to construct a Schild plot and the Kb (expressed as ug/kg, iv) determined.
  • the Kb dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve
  • the relative selectivity is 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 nitrogen containing heterocyclic compounds and derivatives thereof, their synthesis, and their use as alpha 1a adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia.

Description

TITLE OF THE INVENTION
ALPHA la ADRENERGIC RECEPTOR ANTAGONISTS
This application claims the benefit of U.S. Provisional Application No. 60/050,960, 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} βχ} 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., a Adrenoreceptors: Molecular Biology, Biochemistrv and Pharmacology, (Progress in Basic and Clinical Pharmacology 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., Nαunyn- 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:
Figure imgf000007_0001
wherein Q is selected from
Figure imgf000008_0001
E, G, L and M are each independently selected from hydrogen, Cι-8 alkyl, C3-8 cycloalkyl, (CH2)θ-4θR6, (CH2)0-4N(Rl9)2, (CH2)θ-4CN, (CH2)0-4CF3, (CH2)0-4CO2R19, (CH2)θ-4CON(Rl9)2, (CH2)θ-4Sθ2R19, or
Figure imgf000008_0002
J is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θR6, (CH2)l-4N(Rl9)2, (CH2)l-4CN, (CH2)θ-4CF3, (CH2)θ-4C02R19, (CH2)0-4CON(Rl9)2, (CH2)θ-4Sθ2 19, or (CH2)θ-4Sθ2N(Rl9)2;
RI is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl9)2, NR^COR20, NR1 CON(R20)2, NR19S02R20, NR19S02N(R20)2, OR6, (CH2)θ-4Cθ2R19, oxadiazolyl-, Cl- 4 alkyl oxadiazolyl-, (CH2)θ-4CON(Rl9)2, (CH2)θ-4Sθ2N(Rl9)2, (CH2)θ- 4SO2R6 or C1.4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, (CH2)θ-4Cθ2R19, (CH2)θ-4CON(Rl9)2, (CH2)θ-4Sθ2N(Rl9)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, C1.4 alkyl or C3-8 cycloalkyl;
R2, R3, R8, RIO, Rl5f Rl6? R17 and R18 are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2) 2-40R6 or (CH2)θ-4CF3;
R4 is selected from hydrogen, (CH2)θ-4COR6, (CH2)θ-4CN, (CH2)0-4CF3, (CH2)0-4CO2R19, (CH2)0-4CON(Rl9)2, (CH2)θ-4Sθ2R6 or
Figure imgf000009_0001
R5 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θR6 or (CH2)0-4CF3;
R6 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3;
R^ is selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R19, (CH2)θ-4CON(Rl9)2, (CH2)θ-4CORl9, (CH2)2-4θR6, (CH2)1-4CF3, (CH2)0-4SO2R6, (CH2)θ-4Sθ2N(Rl9)2 or (CH2)l-4CN; R is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, CO2R6, CON(R6)2, (CH2)l-4θR6 or (CH2)θ-4 CF3;
RU and R^2 are each independently selected from hydrogen, Cl-8 alkyl or C3-8 cycloalkyl;
Rl3 and R^-4 are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θR6, (CH2)θ-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, (CH2)0-4CON(R19)2, (CH2)0-4CO2R19 or Ci-4 alkyl; or unsubstituted, mono- or poly-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR6, halogen, Ci-4 alkyl or C3-8 cycloalkyl;
Rl9 and R2^ are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or (CH2)l-4CF3;
R22 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)θ-4θR6 or (CH2)0-4CF3;
R24 and R26 are each independently selected from hydrogen or OR28;
R28 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3;
W is O or NRH;
each X is independently selected from halogen, cyano, nitro, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)θ-4θR6 or (CH2)θ-4CF3;
Y is C-R19 or N; Z is hydrogen, oxygen or sulphur;
m, p and q are each independently an integer from zero to two, provided that when q is zero, R26 is hydrogen; n, o, and s are each independently an integer from zero to four; and v is an integer from zero to one;
and the pharmaceutically acceptable salts thereof.
In a first embodiment of the invention is the compound having the structure
Figure imgf000011_0001
wherein 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(R19)2, NR19COR20, NR19CON(R20)2, NR19Sθ2R20, NRl9sθ2N(R20)2, OR6, (CH2) 0-
4C02R19, (CH2) 0-4CON(Rl9)2, (CH2)θ-4Sθ2N(Rl9)2, (CH2)θ-4Sθ2R6 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, (CH2)0-4CO2R19, (CH2)θ-4CON(Rl9)2, (CH2)θ-4Sθ2N(Rl9)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, Ci-4 alkyl or C3-8 cycloalkyl;
R4 is selected from (CH2)θ-4COR6, (CH2)θ-4CN, (CH2)θ-4CF3, (CH2)0-4CO2R19, (CH2) 0-4CON(Rl9)2, (CH2)θ-4Sθ2R6 or
Figure imgf000011_0002
R5 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4θR6 or (CH2)0-4CF3; R9 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4θR6 or (CH2)0-4CF3; and
all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
In a second embodiment of the invention is the compound of the formula
Figure imgf000012_0001
wherein
E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2)θ-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(Rl9)2, NRl9COR20, NR19CON(R20)2, NR19S02R20, NR19S02N(R20)2, OR6, (CH2)0-4CO2R19, oxadiazolyl-, C1-4 alkyloxadiazolyl, (CH2)θ-4CON(Rl9)2, (CH2)θ-4Sθ2N(Rl9)2, (CH2)θ- 4SO2R6 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, (CH2)θ-4Cθ2R19, (CH2)θ-4CON(Rl9)2, (CH2)θ-4Sθ2N(Rl9)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
R7 is selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3; Rl3 and R^4 are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θR6, (CH2)θ-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, (CH2)0-4 CON(R19)2, (CH2)θ-4Cθ2R19 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR6, halogen, Cl-4 alkyl or C3-8 cycloalkyl; and
n is an integer from zero to two; 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
Figure imgf000013_0001
wherein E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2)θ-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(R19)2, NR19COR20, NR19CON(R20)2, NR19Sθ2R20, NR19SO2N(R20)2, OR6, (CH2)0-4CO2R19, (CH2)0-4CON(Rl9)2, (CH2)θ-4Sθ2N(R19)2, (CH2)0-4SO2R6 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, (CH2)0-4CO2R19 (CH2)θ-4CON(R19)2, (CH2)θ-4Sθ2N(Rl9)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
Ε is selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3;
Rl3 and R^ are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θR6, (CH2)θ-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, (CH2)0-4CON(R19)2, (CH2)θ-4Cθ2R19 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR6, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
n is an integer from zero to two; and all other variables are as defined in the first embodiment; and the pharmaceutically acceptable salts thereof.
In a first class of the invention is the compound selected from
Figure imgf000014_0001
wherein Q is selected from
Figure imgf000015_0001
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, OR6, (CH2)θ-2Cθ2R19, (CH2) 0-2CON(R19)2, (CH2)0-2SO2N(R19)2, (CH2)θ-2S02R6, Cl-4 alkyl oxadiazolyl- or Cl-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, OR6, (CH2)θ-2Cθ2R19, (CH2)θ-2CON(Rl9)2, (CH2)0-2SO2N(R19)2_ (CH2)θ-2Sθ2R6 or Cl-4 alkyl;
R4 is selected from hydrogen, COR6, CO2R19, SO2R6 or CON(R19)2;
R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)l-3θR6 or (CH2)0-3CF3;
R6 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3;
R8 and RlO are each independently selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)2-4θR6 or (CH2)θ-3CF3;
R9 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, CO2R6, CON(R6)2, (CH2)l-4θR6 or (CH2)θ-3CF3; Rl3 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)2-4θR6, (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, OR6, CO2 9 or Cl-4 alkyl;
RI is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)1-3CF3;
R22 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)θ-4θR6 or (CH2)0-3CF3;
R28 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, or (CH2)0-3CF3;
q is an integer from zero to two; and s is an integer from zero to three; and all other variables are as defined previously in the second embodiment; and the pharmaceutically acceptable salts thereof.
In a second class of the invention is the compound selected from
Figure imgf000016_0001
Figure imgf000016_0002
wherein Q is selected from
Figure imgf000017_0001
RI is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR6, (CH2) O-2CO2R19, (CH2)θ-2CON(Rl9)2, (CH2)0-2SO2N(R19)2, (CH2)θ-2Sθ2R6 or C1-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, OR6,
(CH2)0-2CO2R19 (CH2)0-2CON(Rl9)2, (CH2)θ-2Sθ2N(Rl9)2, (CH2)0-2Sθ2R6 or Cl-4 alkyl;
R4 is selected from COR6, C02R19, SO2R6 or CON(R19)2;
R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)l-3θR6 or (CH2)o-3CF3;
R6 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)o-3CF3;
R8, R9 and RlO are each independently selected from hydrogen, Cι-6 alkyl, C3-6 cycloalkyl, (CH2)2-4θR6 or (CH2)θ-3CF3;
Rl3 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)2-4θR6, (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, OR6, Cθ2R^9 or Cl-4 alkyl;
RI9 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or
(CH2)l-3CF3;
R22 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)θ-4θR6 or (CH2)0-3CF3;
q 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 third embodiment; and the pharmaceutically acceptable salts thereof.
In a first subclass of the invention is the compound wherein Q is selected from
Figure imgf000018_0001
Rl3 is selected from hydrogen, Cl-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6,
CO2R19 or Cl-4 alkyl;
each X is a halogen; 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 wherein Q is selected from
Figure imgf000019_0001
Rl3 is selected from hydrogen, Cl-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, CO2R19 or Cl-4 alkyl;
each X is a halogen; and all other variables are as defined previously in the second class; and the pharmaceutically acceptable salts thereof.
In a first illustration of the invention is the compound selected from
Figure imgf000019_0002
Figure imgf000020_0001
wherein A is C-R21 or N;
each R21 is independently selected from hydrogen, halogen, cyano, OCl-4 alkyl, OCF3, OCH2CF3, C02CH3, CONH2, SO2NH2 or SO2C1-4 alkyl;
R24 and R26 are each independently selected from hydrogen or OR28, wherein R28 is hydrogen or Cl-4 alkyl;
each X is fluorine;
r is an integer from zero to two; and q is an integer from zero to one; and all other variables are as defined previously in the first subclass; and the pharmaceutically acceptable salts thereof.
In a second illustration of the invention is the compound selected from
Figure imgf000020_0002
Figure imgf000021_0001
wherein A is C-R 1 or N;
each R21 is independently selected from hydrogen, halogen, cyano, OCi- 4 alkyl, OCF3, OCH2CF3, CO2CH3, CONH2, SO2NH2 or SO2C1-4 alkyl;
each X is fluorine;
r is an integer from zero to two; q is an integer from zero to one; and all other variables are as defined previously in the second subclass; and the pharmaceutically acceptable salts thereof.
In a first exemplification of the invention is the compound wherein Q is selected from
Figure imgf000021_0002
R4 is C02R19;
R5 is (CH2)l-3θR6; and all other variables are as defined previously in the first illustration; and the pharmaceutically acceptable salts thereof.
In a second exemplification of the invention is the compound wherein Q is selected from
Figure imgf000022_0001
R4 is C02R19;
R5 is (CH2)l-3θR6; and all other variables are as defined previously in the second illustration; 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.
Another example of 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 illustration of the invention is the method of treating benign prostatic hyperplasia wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. 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.
DETAILED DESCRIPTION OF THE INVENTION Representative compounds of the present invention exhibit 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 m 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 "cycloalkyl" 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., Ci-io) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
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 (e.g., phenyl) 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^9, R2^) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, - N(Rl9)2 represents -NH2, -NHCH3, -NHC2H5, -N(CH3)C2Hδ, etc. and
represents for m=2
Figure imgf000027_0001
OH
Figure imgf000027_0002
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 "Z is hydrogen," when refering to the "Q" group
Figure imgf000028_0001
refers to the moiety
Figure imgf000028_0002
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, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. 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
Figure imgf000029_0001
The terms "(+)-DHP" and "DHP" as used herein, refer to a dihydropyrimidinone group of the formula
Figure imgf000029_0002
for example:
Figure imgf000029_0003
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-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine- 3-carboxylic acid (4-nitrophenyl ester), also referred to as the compound 8. The term "(S)-oxa" as used herein, refers to an oxazolidinone group of the formula
Figure imgf000030_0001
or example,
Figure imgf000030_0002
The term "activated (S)-oxa" as used herein, refers to an JV- (activated)carbamate of the desired oxazolidinone where the activating group is, for example, a p-nitrophenyloxy group. A specific example of an activated (S)-oxa group is 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3- carboxylic acid 4-nitrophenyl ester (i.e., compound 19).
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 4,7B-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:
AcOH or HOAc = acetic acid BCE = bromochloroethane Boc or BOC = t-butyloxycarbonyl
BOC2O = di-tert-butyl dicarbonate
BOPC1 = bis(2-oxo-3-oxazolidinyl)phosphinic chloride
BuOH = butanol
Cbz-Cl = benzyloxycarbonyl chloride DAST = diethylaminosulfurtrifluoride
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 FABMS = fast atom bombardment mass spectroscopy HMPA = hexamethylphosporamide HPLC = high performance liquid chromatography
HOBt = 1-hydroxy benzotriazole hydrate i-Pr or iPr = isopropyl i-PrOH = 2-propanol i-Pr2NEt = diisopropylethylamine LAH = lithium aluminum hydride mCPBA = meta-chloroperbenzoic acid
Me = methyl
MeOH = methanol n-BuLi = n-butyl lithium NMR = nuclear magnetic resonance
PCTLC = preparative centrifugal thin layer chromatography
PEI = polyethylenimine
Ph = phenyl RT = retention time
TEBAC = benzyltriethylammonium chloride
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography TMS = trimethylsilyl
Tos2θ or TOS2O = p-toluenesulfonic anhydride
The compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Unless otherwise indicated, all variables are as defined above. The preparation of some desired compounds are described in Schemes 1-11. 3-(_er£-Butyloxycarbonyl)amino piperidine was prepared from nipecotic acid in three steps, Scheme 1. Subsequent reductive amination with a piperidone derivative, followed by Boc deprotection provided the desired acylation/alkylation precursor which after treatment with activated (+)-DHP, (S)-oxa, or difluorophenyl acetic acid derivatives produced the alpha la antagonists. When desired, the ketone starting materials can be further elaborated, for instance, via enolate alkylation to provide the alpha substituted ketones. The 3-aminomethyl piperidinyl derivatives were assembled as outlined in Scheme 2 starting with reductive amination of 3-hydroxy methyl piperidine and a piperidone derivative. The hydroxy group was converted to a tosylate, displaced with azide and reduced to the amino compound. Acylation or alkylation under standard conditions produced the targeted analogs.
The 3-aminopyrrolidinyl analogs were constructed by reductive amination of 3-( er£-butoxycarbonyl)amino pyrrolidine and a piperidone derivative, Scheme 3. Acidic deprotection of the carbamate produced the 3-amino pyrrolidinyl intermediate which was acylated under standard conditions.
In Scheme 4, the 3-aminomethyl pyrrolidinyl analogs were assembled in an analogous manner to the 3-aminomethyl piperidinyl analogs illustrated in Scheme 2.
Similarly, Scheme 5 describes the preparation of the 3- aminoazetidinyl analogs.
Examples of the preparation of some desired compounds are outlined in Scheme 6. Selective Boc protection of 4-aminomethyl piperidine (1) on the piperidine nitrogen provided (2) and CBZ protection of the primary amine resulted in (3). TFA treatment of (3) produced (4) which after reductive amination with ketone (5) yielded (6).
Hydrogenolysis of (6) left the primary amine (7) which clearly acylated with (8) which produced the DHP derivative (9). Amine (7) was also acylated with the oxazolidinone (19) producing (28).
Other derivatives were prepared via the route outlined in Schemes 7 to 8. N -protected 3-hydroxy azetidine (10) was tosylated providing (11). Azide displacement produced (12) followed by reduction with PPI13/H2O resulted in N-protected 3-amino azetidine (13). Boc protection provided (14) which after hydrogenation produced (15). Reductive amination with (5) yielding (16), followed by TFA treatment set up the requisite amine (17). Acylation with activated DHP (8), oxa (19) and acids (29) and (31) produced (18), (20), (30) and (32), respectively.
The synthesis of some 3-substituted piperidinyl analogs was accomplished starting with reductive amination of 3-hydroxymethyl piperidine (21) and (5) providing (22) as shown in Scheme 8. Tosylation, azide displacement and subsequent reduction provided the 3- aminomethyl piperidinyl intermediate (25). Acylation with activated DHP (8) and oxa (19) produced (26) and (27). These diastereomeric mixtures were separated using a Chiracel AD column providing the pairs (26a) & (26b) and (27a) & (27b). Antagonists with cycloalkyl linking chains can be " assembled by reductive amination of the prerequisite amino alcohol and a ketone, for example, N-(2-cyanophenyl)piperidin-4-one, Scheme 9. Conversion of the hydroxy to a tosylate with tosyl anhydride, followed by displacement by the sodium or lithium salt of the desired Q group completes the synthesis of the targeted antagonists.
The 3-aminomethyl azetidine analogs were assembled starting from the N-protected 3-cyanoazetidine (33) by LAH (lithium aluminum hydride) reduction (34), amine protection with BOC2O (35) and azetidine deprotection (36) under catalytic hydrogenation conditions, Scheme 10. Reductive amination with (5) produced (37), which after Boc deprotection with TFA liberated the required amine (38) for coupling with activated species (8) and (19) providing (39) and (40), respectively.
Selective acylation of the primary amines was accomplished by treatment of the amines with nearly equimolar quantities of the activated termini species (i.e., the "Q" groups). The activated termini species comprising the "Q" groups are readily prepared by one of ordinary skill in the art. For example, unsubstituted, alkyl- and cycloalkyl-substituted oxazolidinones are prepared and activated in general by published and well developed chemistry, in particular, of Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13, 1 (1982)] The starting materials, in general, are natural and unnatural amino acids. 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).
Oxazolidinones substituted with carboxylate, carboxamide, and hydroxymethyl are prepared by hydroxyamination of olefins to provide protected aminoalcohols, using procedures as described in Sharpless et al., Angew. Chem. Int. Ed. EngL, 35, 2813 (1996). Deprotection under standard conditions followed by a phosgene equivalent to mediate cyclization provides the substituted oxazolidinone ring system. Deprotonation with a strong base, for example, lithium bis(trimethylsilyl)amide, and addition to a THF solution of p- nitrophenylchloroformate produces the stable, isolatable "activated" oxazolidinone.
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 the unsubstituted, alkyl- and cycloalkyl-substituted oxazolidinones were synthesized independently in racemic form, and then separated utilizing preparative chiral HPLC. Their optical rotations were recorded. Then they were activated and reacted with prerequisite amines. From the receptor binding studies, a preferred isomer was identified, the (+) rotational isomer in each case. The absolute configurations were determined to be (S) for both the dihydropyrimidinones and oxazolidinones by correlating their optical rotations with x-ray crystal structures obtained of fragments involved in the production of the antagonists.
The oxazolidinones substituted with carboxylate, carboxamide, and hydroxymethyl were prepared in enantiomer- enriched form and the assignments of (4S,5R) were made in accordance with Sharpless et al., Angew. Chem. Int. Ed. EngL, 35, 2813 (1996)
SCHEME 1
Figure imgf000045_0001
SCHEME 1 (CONT'D)
Figure imgf000046_0001
SCHEME 2
Figure imgf000047_0001
SCHEME 2 (Cont'd)
Figure imgf000048_0001
Figure imgf000049_0001
SCHEME 4
Figure imgf000050_0001
Figure imgf000050_0002
SCHEME 4 (Cont'd)
Figure imgf000051_0001
SCHEME 5
Figure imgf000052_0001
Figure imgf000053_0001
SCHEME 6
Cbz-CI
Figure imgf000054_0001
Figure imgf000054_0002
SCHEME 6 (cont'd)
Figure imgf000055_0001
SCHEME 7
Figure imgf000056_0001
BOC O
Figure imgf000056_0002
Figure imgf000056_0003
Figure imgf000056_0004
SCHEME 7 (cont'd)
Figure imgf000057_0001
SCHEME 8
Figure imgf000058_0001
21
Figure imgf000058_0002
26a Diastereomer A 26b Diastereomer B SCHEME 8 (cont'd)
Figure imgf000059_0001
31a Diastereomer A 31b Diastereomer B
SCHEME 9
Figure imgf000060_0001
SCHEME 9 (cont'd)
Figure imgf000061_0001
SCHEME 10
BOCoO
Figure imgf000062_0001
Figure imgf000062_0002
NaCNBH.
Figure imgf000062_0003
Figure imgf000062_0004
SCHEME 10 (Cont'd)
Figure imgf000063_0001
Figure imgf000064_0001
H2
Figure imgf000064_0002
Scheme 11 (cont'd)
Figure imgf000065_0001
The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples.
EXAMPLE 1
4-Aminomethyl-piperidine-l-carboxylic acid er -butyl ester (2)
A solution of C-piperidin-4-yl-methylamine (1) (5.0 g, 44 mmol) and triethylamine (12 ml 88 mmol) in 150 ml of chloroform was cooled to 0 C. To this solution was added dropwise ditertbutyldicarbonate (8.6 g, 40 mmol) in 100 ml of chloroform. After stirring at room temperature for 24 hours the solution was washed with water, dried over MgS04, filtered and the solvents removed in vacuo to give the title compound 1H NMR (CDCI3, 400 MHz) 4.20-4.00 (br m, 2H), 2.75-2.62 (br t, 2H), 2.60 (d, 2H), 1.75-1.65 (br m, 2H), 1.50-1.30 (m, 3H), 1.63 (s, 9H), 1.20-1.00 (m, 2H).
EXAMPLE 2
4-(Benzyloxycarbonylamino-methyl)-piperidine-l-carboxylic acid tert- butyl ester (3)
To a solution of 2 (2.4 g, 11.8 mmol) in 60 ml of ethyl acetate was added 60 ml of saturated K2CO3. To this biphasic solution was added benzyl chloroformate (2.03 ml, 14.23 mmol) dropwise. After stirring at room temperature for 3 hours the layers were separated and the organic layer dried over MgSθ4, filtered, and the solvents removed in vacuo. The crude product was purified by chromatography on silica gel (3:1 hexane:ethyl acetate) to give the title compound.
!H NMR (CDCI3, 400 MHz) 7.39-7.30 (m, 5H), 5.09 (s, IH),
4.90-4.80 (m, IH), 4.15-4.05 (m, 2H), 3.09 (br t, 2H J=5.62 Hz), 2.66 (m, 2H), 1.70-1.62 (m, 3H), 1.45 (s, 9H), 1.20-1.00 (m, 2H).
EXAMPLE 3
Piperidin-4-ylmethyl-carbamic acid benzyl ester (4)
To a solution of 3 (4.4 g, 13 mmol) in 90 ml of methylene chloride was added 45 ml of TFA. After stirring at room temperature for 24 hours, the solvents were removed in vacuo and the residue partitioned between chloroform and 10% Na2Cθ3. The organics were dried over MgSθ4, filtered, and the solvent removed in vacuo to give the title compound. IH NMR (CDCI3, 400 MHz) 7.35 (s, 5H), 5.09 (s, 2H), 4.97 (br s, IH), 3.36 (br s, IH), 3.20-3.00 (m, 3H), 2.60 (t, 2H, J=11.96 Hz), 1.75-1.50 (m, 3H), 1.25-1.05 (m, 3H).
EXAMPLE 4 [l'-(2-Cyano-phenyl)-[l,4']bipiperidinyl-4-ylmethyl]-carbamic acid benzyl ester (6)
To a solution of 2-(4-oxo-piperidin-l-yl)-benzonitrile (5} (653 mg, 3.26 mmol) and 4 (890 mg, 3.58 mmol) in 40 ml of methanol was added 4 g of powdered 4A molecular sieves. The resulting suspension was stirred at room temperature for 24 hours. The suspension was subsequently acidified to pH 5 with acetic acid and a 1M solution of NaCNBH3 in THF (6.0 ml 5.6 mmol) was added slowly with a syringe pump over 24 hours. When the addition was complete, the solvent was removed in vacuo and the residue taken up in chloroform and filtered. The solution was then washed with 10% Na2Cθ3, dried over MgSθ4, and the solvent removed in vacuo to give the crude amine. The crude product was purified by chromatography on silica gel (5% MeOH/CHCl3) to give the title compound.
IH NMR (CDCI3, 400 MHz) 7.54 (dd IH, J=7.5Hz, J=1.46Hz),
7.45 (m, IH), 7.40-7.30 (m, 5H), 7.0-6.95 (m, 2H), 5.09 (s, 2H), 4.89 (m, IH), 3.65 (d, 2H, J=11.9 Hz), 3.10 (t, 2H, J=6.4Hz) 2.99 (d, 2H, J=10.62Hz)2.80 (t, 2H, J=10.8Hz), 2.52 (br t, IH, J=11.16Hz), 2.27 (t, 2H, J=10.81Hz), 1.98-1.70 (m, 6H), 1.60-1.45 (m, IH), 1.40-1.25 (m, 2H).
EXAMPLE 5
2-(4-Aminomethyl-ri.4'lbipiperidinyl-l'-yl)-benzonitrile (7) A suspension of 6 (100 mg, 0.232 mmol) and 10% Pd/C (30 mg) in 50 ml of ethyl acetate was hydrogenated at atmospheric pressure for 6 days. The suspension was subsequently filtered through celite and the solvent removed in vacuo to give the title compound.
!H NMR (CDCI3, 400 MHz) 7.53 (dd, IH, J=7.69Hz, J=1.4Hz) 7.45, (m, IH), 7.05-6.90 (m, 2H), 3.66 (d, 2H, J=11.71Hz), 2.98 (d, 2H, J=11.36 Hz), 2.80 (t, 2H, J=11.9Hz), 2.59 (d, 2H, J=5.86Hz), 2.50-2.40 (m, IH), 2.30-2.15 (m, 2H), 2.00-1.75 (m, 6H), 1.35-1.10 (m, 4H).
EXAMPLE 6 3-{[l'-(2-Cyano-phenyl)-[l,4']bipiperidinyl-4-ylmethyl]-carbamoyl}-4-(3,4- difluoro-phenvl)-6-methoxvmethvl-2-oxo- 1.2.3.4-tetrahvdro-pyrimidine-5- carboxylic acid methyl ester trifluoroacetic acid salt (9)
To a solution of 7 in 30 ml of chloroform was added dropwise 8 (100 mg, 0.232 mmol) in 10 ml of chloroform. The resulting solution was stirred for 20 minutes and the crude material purified by chromatography on silica gel (5% MeOH/CHCl3).
IH NMR (CD3OD, 400 MHz) 9.15 (br s, IH), 7.70-7.55 (m, 2H), 7.30-7.10 (m, 5H), 6.63 (s, IH), 4.66 (AB q, 2H, J=39Hz, J=15.02), 3.72 (s, 3H), 3.80-3.60 (m, 3H), 3.50-3.30 (m, 3H), 3.44 (s, 3H), 3.07 (t, 2H,
J=10.8Hz), 2.90 (t, 2H, J=11.54Hz), 2.23 (d, 2H, J=9.89 Hz), 2.10-2.80 (m, 6H), 1.60-1.42 (m, 2H). MS (FAB) 637 (M+l)
Analysis calculated for C33 H38 Nβ O5 F2 0.80 H20, 1.40
TFA: C, 53.03; H, 5.10; N, 10.37 Found: C 53.03 H 5.12 N 10.37.
EXAMPLE 7
Toluene-4-sulfonic acid l-benzhvdryl-azetidin-3-yl ester (11)
To a cooled (0°C) solution of 10 (7 g, 29 mmol) in 100 ml of chloroform was added paratoluene sulfonic anhydride (11.5 g,
35.2mmol), and triethylamine (12 ml, 88mmol). The resulting solution was stirred at room temperature for 24 hours. The solution was subsequently washed with water, dried over MgSθ4, filtered, and the solvent removed in vacuo. The crude material was purified by chromatography on silica gel to give the desired product as an oil.
IH NMR (CDCI3, 400 MHz) 7.75 (d, 2H, J=8.3Hz), 7.35-7.15
(m, 12H), 4.95-4.82 (m, IH), 4.32 (s, IH), 3.50-3.40 (m, 2H), 3.10-3.00 (m, 2H), 2.43 (s, 3H).
EXAMPLE 8
3-Azido-l-benzhvdryl-azetidine (12)
A solution of 11 (11.5 g, 31.8 mmol) and sodium azide (4.12 g, 64 mmol) in 250 ml of DMF was heated to 70°C for 24 hours. After cooling to room temperature the solvent was removed in vacuo and the residue partitioned between chloroform and water. The organics were dried over. MgSθ4, filtered and the solvent removed in vacuo. The crude product was purified by chromatography on silica gel (8:1 hexane: ethyl acetate) to give the title compound. lH NMR (CDCI3, 400 MHz) 7.41-7.15 (m, 10H), 4.33 (s, IH),
4.02-3.95 (m, IH) 3.50-3.41 (m, 2H), 3.07-3.00 (m, 2H).
EXAMPLE 9
l-Benzhvdryl-azetidin-3-ylamine (13)
A solution of 12 (5.7 g, 21.6 mmol), triphenylphosphine (11.3 g, 43 mmol) and water (5 ml) was heated to reflux for 24 hours. After cooling to room temperature the solvent was removed in vacuo and the residue purified by chromatography on silica gel (90:9:1 CHCI3: MeOH:NH4θH).
IH NMR (CDCI3. 400 MHz) 7.41-7.15 (m, 10H), 4.27 (s, IH), 3.65-3.55 (m, IH), 3.55-3.50 (m, 2H), 2.65-2.60 (m, 2H) 1.44 (br s, 2H).
EXAMPLE 10
(l-Benzhvdryl-azetidin-3-yl)-carbamic acid ter£-butyl ester (14)
A solution of 13. (3.5 g, 14.7 mmol) di-_et -butyl dicarbonate (3.8 g, 17.6 mmol) and triethyl amine (4.0 ml, 29 mmol) in 100 ml of chloroform was stirred at room temperature for 24 hours. The solution was subsequently washed with water, dried over MgSθ4, filtered and the solvent removed in vacuo. The crude product was purified by chromatography on silica gel (3:1 hexane:ethyl acetate) to give the title compound.
IH NMR (CDCI3, 400 MHz) 7.38-7.15 (m, 10H), 4.81-4.90 (br s, IH), 4.28 (s, IH), 3.52 (t, 2H, J=6.96Hz) 2.81 (m, 2H), 1.42 (s, 9H).
EXAMPLE 11
Azetidin-3-yl-carbamic acid _er.-butyl ester acetic acid salt (15)
A suspension of 14 (4.6 g, 13.6 mmol) and 10% Pd/C (2.0 g) in 200 ml of 10:2:1 ethanol:water:acetic acid was hydrogenated at 50 psi for 24 hours. The suspension was subsequently filtered through celite and the solvents removed in vacuo to give the title compound.
IH NMR (CD3OD, 400 MHz) 4.55-4.45 (m, IH), 4.20-4.10 (m,
2H), 4.10-4.00 (m, 2H), 1.91 (s, 3H), 1.44 (s, 9H).
EXAMPLE 12
{l-[l-(2-Cyano-phenyl)-piperidin-4-yl]-azetidin-3-yl}-carbamic acid tert- butyl ester (16)
The title compound was prepared from 15 (1.0 g, 4.9 mmol) and 3 (1.0 g, 4.3 mmol) using the procedure described for the preparation of 6 to give the title compound.
!H NMR (CDCI3, 400 MHz) 7.54-7.51 (m, IH,), 7.46-7.40 (m,
IH), 7.00-6.92 (m, 2H), 5.00-4.85 (br s, IH), 4.35-4.21 (br s, IH), 3.64 (t, 2H, J=6.83Hz), 3.55-3.42 (m, 2H), 2.95-2.80 (m, 4H), 2.25-2.10 (m, IH), 1.90-1.75 (m, 2H), 1.62-1.50 (m, 2H), 1.45 (s, 9H). EXAMPLE 13
2-r4-(3-Amino-azetidin-l-yl)-piperidin-l-yll-benzonitrile (17)
The title compound was prepared from 16 (1.5 g) using the procedure described for the preparation of 4. lH NMR (CDCI3, 400 MHz) 7.53 (dd, IH, J=7.57Hz, 1.46Hz),
7.50-7.37 (m, IH), 7.05-6.90 (m, 2H), 3.70-3.55 (m, 3H), 3.55-3.45 (m, 2H), 2.95-2.85 (m, 2H), 2.70-2.60 (m, 2H), 2.20-2.10 (m, IH), 1.90-1.77 (m, 2H), 1.70-1.30 (m, 4H).
EXAMPLE 14
3-{l-[l-(2-Cyano-phenyl)-piperidin-4-yl]-azetidin-3-ylcarbamoyl}-4-(3,4- difluoro-phenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro-pyrimidine-f carboxylic acid methyl ester (18)
The title compound was prepared from 17 (1.0 g, 3.9 mmol) and 8 (520 mg, 1.1 mmol) using the procedure described for 9.
IH NMR (CDCI3, 400 MHz) 9.04 (d, IH, J=6.6Hz), 7.72 (s,
IH), 7.55-7.50 (m, IH), 7.40-7.50 (m, IH), 7.21-6.90 (m, 5H), 6.65 (s, IH), 4.68 (s, 2H), 4.55-4.50 (m, IH), 3.75-3.65 (m, 2H), 3.71 (s, 3H), 3.55-3.42 (m, 2H), 3.50 (s, 3H), 2.95-2.82 (m, 4H), 2.30-2.15 (m, IH), 2.87-2.75 (m, 2H), 1.63-1.45 (m, 2H).
MS (FAB) 595 (M+l).
Analysis calculated for C30 H22 Nβ O5 F2 OO H2O: C, 58.81; H, 5.59, N, 13.72. Found: C, 58.58; H, 5.20; N, 13.59.
EXAMPLE 15
4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2-cyano- phenyl)-piperidin-4-yl]-azetidin-3-yl}-amide triflouroacetic acid salt (20)
The title compound was prepared from 17 (100 mg, 0.4 mmol) and 19 (171 mg, 0.48 mmol) using the procedure described for 9. lH NMR (CD3OD, 400 MHz) 7.65-7.55 (m, 2H), 7.35-7.25 (m,
2H) 7.15-7.20 (m, 3H), 5.45-5.50 (m, IH), 4.85-4.78 (m, IH), 4.75-4.62 (br s, IH), 4.50-4.35 (m, 4H), 4.32-4.22 (m, IH), 3.63 (d, 2H, J=12.27Hz), 3.50-3.40 (m, IH), 2.88 (t, 2H, J= 12.27), 2.16 (d, 2H, J=10.99Hz), 1.75-1.60 (m, 2H).
MS (FAB) 482 (M+l).
Analysis calculated for C25 H25 N5 O3 F2 1.05 H20, 1.35
TFA: C, 50.84; H, 4.38; N, 10.70. Found: C, 50.83; H, 4.29; N, 11.09.
EXAMPLE 16
2-(3-Hvdroxymethyl-rL4'1bipiperidinyl-l'-yl)-benzonitrile (22)
The title compound was prepared from 21 (1.13 g, 5.6 mmol) and 5 (750 mg, 3.75 mmol) using the procedure described in 16 to give the title compound. lH NMR (CDCI3, 400 MHz) 7.37-7.35 (m, IH), 7.50-7.41 (m,
IH), 7.20-6.93 (m, 2H), 3.77-3.55 (m, 4H), 2.98-2.90 (m, IH), 2.90-2.67 (m, 3H), 2.57-2.23 (m, 4H), 1.98-1.50 (m, 8H), 1.27-1.08 (m, IH).
EXAMPLE 17
p-Tolyl-methanesulfonic acid l'-(2-cyano-phenyl)-[l,4']bipiperidinyl-3- ylmethyl ester (23) The title compound was prepared from 22 (1.1 g, δ.Ommol) and para-toluene sulfonic anhydride (2.48 g, 7.58 mmol) using the procedure described in 11.
!H NMR (CDCI3, 400 MHz) 7.80 (d, 2H, J=8.24Hz), 7.55-7.53
(m, IH), 7.45 (m, IH), 7.40-7.32 (m, 2H), 7.02-6.95 (m, 2H), 3.95-3.85 (m, 2H), 3.63 (d, 2H, J=11.71Hz), 2.82-2.70 (m, 3H), 2.45 (s, 3H), 2.45-2.35 (m, IH), 2.27-2.18 (m, IH), 2.07-1.90 (m, 2H), 1.85-1.57 (m, 7H), 1.57-1.45 (m, IH), 1.10-0.97 (m, IH).
EXAMPLE 18
2-(3-Azidomethyl-[1.4'lbipiperidinyl-l'-yl)-benzonitrile (24)
The title compound was prepared from 23 (1.37 g, 3.0 mmol) and sodium azide (0.4 g, 6.0 mmol) according to the procedure described in 12 to give the title compound. lH NMR (CDCI3, 400 MHz) 7.55-7.52 (m, IH), 7.50-7.42 (m,
IH), 7.02-6.94 (m, 2H), 3.66 (d, 2H, J=11.97Hz), 3.30-3.15 (m, 2H), 2.95-2.75 (m, 5H), 2.55-2.40 (m, IH), 2.30-2.20 (m, IH), 2.06 (t, IH, J=10.01Hz), 1.95- 1.65 (m, 6H), 1.65-1.50 (m, IH), 1.10-0.95 (m, IH).
EXAMPLE 19
2-(3-Aminomethyl-ri.4'lbipiperidinyl-l'-yl)-benzonitrile (25)
The title compound was prepared from 24 (560 mg, 1.73 mmol) and triphenylphosphine (900 mg, 3.4mmol) using the procedure described for 13.
!H NMR (CDCI3, 400 MHz) 7.55-7.53 (m, IH), 7.47-7.43 (m,
IH), 7.00-6.95 (m, 2H), 3.66 (d, 2H, J=11.72Hz), 3.02 (d, IH, J=10.25Hz), 2.91 (d, IH, J=10.98Hz), 2.81 (t, 2H, J=11.9Hz), 2.62 (br s, 2H), 2.60-2.45 (m, IH), 2.30-2.20 (m, IH), 2.05-1.52 (m, 11H), 1.00-0.87 (m, IH).
EXAMPLE 20
3-{[l'-(2-Cyano-phenyl)-[l,4']bipiperidinyl-3-ylmethyl]-carbamoyl}-4-(3,4- difluoro-phenyl)-6-methoxymethvl-2-oxo-1.2.3.4-tetrahvdro-pyrimidine-5- carboxylic acid methyl ester trifluoroacetic acid salt (26)
The title compound was prepared from 25 (175 mg, 0.58 mmol) and 8 (140 mg, 0.29 mmol) using the procedure described for 9. IH NMR (CD3OD, 400 MHz) 9.20-9.10 (m, IH), 7.67-7.55 (m,
2H), 7.25-7.10 (m, 5H), 6.61-6.59 (m, IH), 4.66 (AB q, 2H, J=39.37Hz, J=15.2Hz), 3.72 (s, 3H), 3.70-3.20 (m, 4H), 3.00-2.73 (m, 5H), 2.25-1.70 (m, 10H), 1.35-1.20 (m, IH).
MS (FAB) 637 (M+l).
Analysis calculated for C33 H38 Nβ O5 F2 0.35 H2O, 1.65
TFA: C, 52.45; H, 4.89; N, 10.11. Found: C, 52.45; H, 4.88; N, 10.13.
EXAMPLE 21
4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid [l'-(2-cyano- phenyl)-ri.4'1bipiperidinyl-3-ylmethvn-amide trifluoroacetic acid salt (27) The title compound was prepared from 25 (175 g, 0.58 mmol) and 19 (105 mg, 0.28 mmol) using the procedure described for 9.
IH NMR (DMSO-d6, 400 MHz) 8.10-8.00 (m, IH), 7.78-7.70 (m, IH), 7.65-7.57 (m, IH), 7.50-7.37 (m, 2H), 7.21-7.08 (m, 3H), 5.47-5.39 (m, IH), 4.76 (t, IH, J=8.79Hz), 4.23-4.13 (m, IH), 3.70-2.60 (m, 12H), 2.25- 1.57 (m, 8H), 1.23-1.03 (m, IH).
MS (FAB) 524 (M+l).
Analysis calculated for C28 H31 N5 O3 F2 1.30 TFA:
C, 54.70; H, 4.85; N, 10.43. Found: C, 54.72; H, 4.77; N, 10.11. EXAMPLE 22
4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid [l'-(2-cyano- phenyl)-ri.4'1bipiperidinyl-4-ylmethyll-amide triflouroacetic acid salt (28) The title compound was prepared from 7 (140 mg, 0.47 mmol) and 19 (170 mg, 0.47 mmol) using the procedure described for 9. !H NMR (CD3OD, 400 MHz) 7.65-7.52 (m, 2H), 7.35-7.25 (m,
2H), 7.20-7.15 (m, 3H), 5.27-5.20 (m, IH), 4.77 (t, IH, J=8.97Hz), 4.27-4.20 (m, IH), 3.74-3.58 (m, 4H), 3.40-3.30 (m, IH), 3.25-3.15 (m, 2H), 3.10-3.00 (m, 2H), 2.95-2.82 (t, 2H, J=11.71Hz), 2.24 (d, 2H, J=11.54), 2.10-1.80 (m, 5H), 1.58-1.42 (m, 2H).
MS (FAB) 524 (M+l).
Analysis calculated for C28 H31 N5 O3 F2 0.30 H20, 1.85
TFA: C, 51.45; H, 4.56; N, 9.47. Found: C, 51.47; H, 4.58; N, 9.36.
EXAMPLE 23
Figure imgf000075_0001
3-Aminomethyl N-diphenylmethyl azetidine. (34)
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 33 (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. *H NMR (CDClg, 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 24
Figure imgf000076_0001
3-N-( l,l-dimethylethoxycarbonyl)aminomethyl N-diphenylmethyl azetidine. (35)
The title compound was prepared from 34 using the procedure described for the preparation of 14- NMR (CDCI3, 300 MHz) 7.40-7.14 (m, 10 H), 4.84 (s, 1 H),
4.31 (s, 1 H), 3.50-3.21 (m, 4 H), 2.85 (t, 2 H), 2.59-2.48 (m, 1 H), 1.44 (s, 9 H).
EXAMPLE 25
BOCHN^ A NH
3-N-[(l.l-dimethvIethoxycarbonyl)methyl1aminomethyl azetidine. (36)
The title compound was prepared from 35 using the procedure described for the preparation of lϋ.
!H NMR (CD3OD, 300 MHz) 4.92-4.85 (m, 4 H), 4.05 (br m, 2 H), 3.88-3.86 (br m, 2 H), 1.94-1.90 (m, 1 H), 1.46 (s, 9 H)
EXAMPLE 26
Figure imgf000077_0001
2-[4-(3-N-(l,l-Dimethylethoxycarbonyl)aminomethyl-azetidin-l-yl)- piperidin-1-yll-benzonitrile. (37)
The title compound was prepared from 36 using the procedure described for the preparation of 16.
IH NMR (CDClg, 300 MHz) 7.57-7.40 (m, 2 H), 7.05-6.92 (m, 2
H), 4.89 (s, 1 H), 3.53-3.46 (m, 3 H), 3.39-3.27 (m, 4 H), 2.95-2.85 (m, 4 H), 2.64-2.58 (m, 1 H), 2.25-2.19 (m, 1 H), 1.85-1.79 (m, 2 H), 1.60-1.44 (m, 10 H).
EXAMPLE 27
Figure imgf000077_0002
2-r4-(3-Aminomethyl-azetidin-l-yl)-piperidin-l-yll-benzonitrile. (38)
The title compound was prepared from 37 using the procedure desrcibed for the preparation of 17.
!H NMR (CDC13, 300 MHz) 7.54-7.40 (m, 2 H), 7.00-6.91 (m, 2
H), 3.55-3.46 (m, 2 H), 3.44-3.38 (m, 2 H), 2.93-2.83 (m, 6 H), 2.58-2.46 (m, 1 H), 2.23-2.14 (m, 1 H), 1.85-1.80 (m, 2 H), 1.60-1.48 (m, 2 H), 1.01-0.95 (br s, 2 H).
EXAMPLE 28
Figure imgf000078_0001
Compound (39)
The title compound 39 was prepared from 38 using the procedure described for the preparation of 18.
IH NMR (CDC13, 400 MHz) 8.98-8.95 (t, 1 H), 7.72 (s, 1 H),
7.54-7.52 (dd, 1 H), 7.46-7.42 (m, 1 H), 7.09-7.06 (m, 2 H), 6.99-6.93 (m, 2 H), 6.66 (s, 1 H), 4.68 (s, 2 H), 3.71 (s, 3 H), 3.55-3.39 (m, 10 H), 3.02-2.98 (t, 2 H), 2.88-2.73 (m, 3 H), 2.28-2.26 (m, 1 H), 1.83-1.80 (m, 2 H), 1.61,1.56(m, 2 H).
MS (FAB) 609 (M+l)
EXAMPLE 29
Figure imgf000078_0002
Compound (40) The title compound 40 was prepared from 38 using the procedure described for the preparation of 20.
IH NMR (CDCI3, 400 MHz) 8.01-7.98 (s, 1 H), 7.53-7.51 (d, 1
H), 7.45-7.41 (t, 1 H), 7.22-7.12 (m, 1 H), 7.07-7.00 (m, 1 H), 6.98-6.92 (m, 2 H), 5.41-5.40 (m, 1 H), 4.74-4.70 (t, 1 H), 4.27-4.23 (m, 1 H), 3.52-3.44 (m, 3 H), 3.40-3.31 (m, 3 H), 2.91-2.86 (m, 4 H), 2.67-2.64 (m, 1 H), 2.21 (br s, 1 H), 1.81-1.78 (m, 2 H), 1.58-1.53(m, 2 H). Anal. Calcd for C26H27N5θ3F2 • 0.25 CHC13 + 0.20 H20 : C =
61.94, H = 5.48, N = 13.87. Found: C = 61.97, H = 5.55, N = 13.50. MS (FAB) 496 (M+l)
Utilizing the methodology described in detail herein, the following additional compounds shown in Tables 1 and 2 were made. In Tables 1 and 2, (+)DHP is
Figure imgf000079_0001
TABLE 1
Figure imgf000080_0001
FABLRMS HPLC Elemental R.T. Analysis l-*< 385.23g/mole 8.27 min. N/A
H 285.21 g/mole 5.60 min. Calc. for 2.4HC1;0.50 EtOAc Solvate mol. t.=515.98g/mole Calc:C=54.86%H=7.37%N=13.47% Obs:C=54.82%H=7.59%N=13.50%
(+)DHP diast.(A) 623.396g/mole 8.98 min. Calc. for 0.40CHCl3;070EtOAc Solvate mol. wt.=734.12g/mole CaIc:C=57.59%H=6.04%N=l 1.45% Obs:C=57Jl%H=5.61%N=l 1.36%
(+)DHP diast.(B) 623.64g/mole 8J2 min. Calc. for 1.80HCl;0.40EtOAc Solvate mol. wt.=725.59g/mole Calc:C=55.62%H=5.97%N=l 1.58%
TABLE 1 (cont.)
Obs:C=55.55%H=5J6%N=11.51%
*πχ 439.24g/mole 8.62 min. Calc. for 1.0HCl;0.80H2O;0.20EtOAc
Solvate mol.wt.=474.99g/mole Calc:C=61.12%H=6.40%N=11.05% Obs:C=61.08%H=6.32%N=11.06%
TABLE 2
Figure imgf000082_0001
FABLRMS HPLC Elemental R.T. Analysis
Figure imgf000082_0002
371 g/mole 7.231 min. Calc. for 0.25CHCl3;0.20H2O Solvate mol. wt.=403.95/mole Calc:C=63.19%H=7.65%N=13.87% Obs:C=63.23%H=7.60%N=14.22%
H 271.14/mole 4.87 min. Calc. for 3.0HC1;0.90 EtOAc;1.0H2θ;
OJOCHCI3
Solvate mol. wt.=560.64g/mole
Calc:C=43.49%H=6.27%N=9.99%
Obs:C=43.51%H=6.65%N=10.21%
(+)DHP 5:7 (A:B) 609.17g/mole 9.431min. Calc. for 0.05CHCl3;0.55EtOAc Solvate mol. wt.=736.00g/mole Calc:C=54.26%H=5.54%N=l 1.42% Obs:C=54.07%H=5.54%N=l 1.45%
TABLE 2 (cont.)
Y ; 425.00g/mole 7.43 min. Calc. for 1.0HCl;0.80CHC_3;0.55EtOAc
Solvate mol.wt.=509.99g/mole Calc:C=58.64%H=5.63%N=10.99% Obs:C=58J9%H=5.98%N=10.99%
I
EXAMPLE 30 (4S, 5R)-4-(3,4-Difluorophenyl-3-(l-{l-[4-fluoro-2-(3-methyl- [l,2,4]oxadiazol-5-yl)phenyl]piperidin-4-yl}-(3R)-pyrrolidin-3- ylcarbamoyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester
Figure imgf000084_0001
Step A: trans-3,4-Difluorocinnamic acid methyl ester
To a solution of trans-3,4-difluorocinnamic acid (10 g, 54 mmol) in 300 mL methanol was added concentrated sulfuric acid (2 mL). The solution was stirred 48 h at ambient temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (2 x 100 mL), brine (1 x 100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide trans-3,4-difluorocinnamic acid methyl ester (10.7 g, 54 mmol, 100%) as a white solid.
Η NMR dH (400 MHz, CDC13) 7.59 (d, IH, J = 15.9), 7.34 (m, IH), 7.24 (m, IH) 7.18 (dd, IH, J = 9.9, 2.0), 6.35 (d, IH, J = 16.1), 3.81 (s, 3H).
Step B: (2R, 3S)-N-Benzyloxycarbonyl-3-amino-3-(3,4- difluorophenyl)-2-hydroxypropionic acid methyl ester
A solution of NaOH (4.1 g, 103 mmol) was prepared in 175 mL water. Potassium osmate dihydrate (491 mg, 1.3 mmol) was dissolved in 35 mL of this NaOH solution, resulting in a dark pink homogeneous mixture. To a 1000 mL round bottom flask is added the remaining NaOH solution prepared above, 135 mL n-propanol and benzyl cabamate (9.8 g, 110 mmol). The suspension was stirred at ambient temperature for 30 min wherein the mixture was nearly homogeneous. The reaction flask was placed in a room temperature water bath and the surrounding lights were turned off. Freshly prepared t-butylhypochlorite (11.2 mL, 103 mmol) was added dropwise with vigorous stirring, and the reaction stirred an additional 15 min. In a separate 250 mL round bottom flask was suspended trans-3,4-difluorocinnamic acid methyl ester (6.6 g, 33.3 mmol) and (DHQ)2PHAL (1.3 g, 1.7 mmol) in 100 mL n-propanol. The suspension was added to the above reaction mixture and the residue rinsed into the reaction flask (2 x 10 mL). To the reaction was added the above prepared solution of potassium osmate dihydrate. The resulting green solution became amber/brown over 1 h. Sodium metabisulfite (66 g, 347 mmol) was added and the resulting suspension stirred 3 h when it was poured into a separatory funnel containing ethyl acetate (200 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (150 mL) and the combined organics washed with brine (100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide a pale yellow solid. The crude material was passed through silica (25% ethyl acetate/hexane) to give (2R, 3S)-N-benzyloxycarbonyl-3-amino-3- (3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester contaminated with benzyl carbamate.
Step C: (2R, 3S)-3-Amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester
(2R, 3S)-N-Benzyloxycarbonyl-3-a_nino-3-(3,4-difluorophenyl)-2- hydroxypropionic acid methyl ester (>12.2 g, 33.3 mmol maximum) was dissolved in 750 mL ethanol. The flask was purged and filled with argon three times. Palladium on carbon (2 g, 10% wt) was added under argon and the suspension was again purged and filled with argon three times. The suspension was then purged, filled with hydrogen, and stirred 16 h. The suspension was purged, filled with argon three times, filtered through celite and concentrated in vacuo to give (2R, 3S)-3-amino-3-(3,4- difluorophenyl)-2-hydroxypropionic acid methyl ester (5.8 g, 25 mmol, 75% from trans-3,4-difluorocinnamic acid methyl ester). Η NMR dH (400 MHz, CDC13) 7.26 (m, IH), 7.15-7.08 (m, 2H), 4.28 (s, 2H), 3.82 (s, 3H), 2.48 (bs, 2H).
Step D: (4S, 5R)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-5- carboxylic acid methyl ester
To a solution of (2R, 3S)-3-amino-3-(3,4-difluorophenyl)-2- hydroxypropionic acid methyl ester (5.8 g, 25 mmol) in 250 mL tetrahydrofuran at 0°C was added N,N-diisopropylethylamine (8.75 mL, 50 mmol) and triphosgene (2.48 g, 8.4 mmol). The reaction was stirred at 0°C for 30 min when it was poured over ethyl acetate (200 mL) and saturated sodium carbonate solution (100 mL). The layers were separated, the organic layer washed with saturated sodium carbonate solution (1 x 100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide a pale yellow oil. The material was triturated with 25% ethyl acetate/hexane from dichloromethane to provide (4S, 5R)-4- (3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester. The recovered mother liqour was passed through silica (50% ethyl acetate/hexane) to give an additional 1.1 g (4.8 g total, 18 mmol, 75%) Η NMR dH (400 MHz, CDC13) 7.25-7.20 (m, 2H), 7.15 (m, IH), 6.33
(bs, IH), 4.98 (d, IH, J = 5.1), 4.72 (d, IH, J = 5.3), 3.89 (s, 3H). FABMS M+H = 258
Step E: (4S, 5R)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3,5- dicarboxylic acid methyl ester 3-(4-nitrophenyl) ester
To a solution of (4S, 5R)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5- carboxylic acid methyl ester (910 mg, 3.5 mmol) in anhydrous tetrahydrofuran (50 mL), cooled to -78°C under argon, was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.5 mL, 3.5 mmol) dropwise. The reaction mixture was warmed to 0°C in an ice bath, stirred 30 minutes, then returned to -78°C. In a separate flask, p- nitrophenylchloroformate (714 mg, 3.54 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) under argon and cooled to -78°C. The above prepared anion solution was added via cannula to the chloroformate solution and the reaction mixture was stirred 1 h at - 78°C. The reaction mixture was treated with ethyl acetate (150 mL) and the resulting solution was washed with water (1 x 150 ml), brine (1 x 150 ml) and dried over magnesium sulfate and filtered. The volitiles were removed under reduced pressure and the resulting oil was triturated with diethyl ether. Ether was twice decanted from the resulting pale yellow solid to give (4S, 5R)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3,5- dicarboxylic acid methyl ester 3-(4-nitrophenyl) ester (1.3 g, 3.1 mmol, 87%). FAB MS: m/z=423 (M+H)
Step F: (4S, 5R)-4-(3,4-Difluorophenyl-3-(l-{l-[4-fluoro-2-(3- methyl[l,2,4]oxadiazol-5-yl)phenyl]-piperidin-4-yl}-(3R)- pyrrolidin-3-ylcarbamoyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester
To a solution of l-{l-[4-fluoro-2-(3-methyl[l,2,4]oxadiazol-5- yl)phenyl]piperidin-4-yl}-(3R)-pyrrolidin-3-ylamine (105 mg, 0.23 mmol) in dry, degassed N,N-dimethylformamide (2 mL) was added N,N- diisopropylethylamine (120 μL, 0.69 mmol) followed by (4S, 5R)-4-(3,4- difluorophenyl)-2-oxo-oxazolidine-3,5-dicarboxylic acid methyl ester 3-(4- nitrophenyl) ester (98 mg, 0.23 mmol). The reaction mixture was stirred at ambient temperature for 1 h when the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with 10% aqueous sodium carbonate solution (8 x 100 mL), brine (1 x 100 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (2% methanol in ethyl acetate) to give a foam. The hydrochloride salt was prepared according to standard procedures to afford (4S, 5R)trans-4-(3,4- difluorophenyl-3-(l-{l-[4-fluoro-2-(3-methyl-[l,2,4]oxadiazol-5-yl)phenyl]- piperidin-4-yl}-(3R)-pyrrolidin-3-ylearbamoyl)-2-oxo-oxazolidine-5- carboxylic acid methyl ester as a solid.
HPLC retention time = 8.59 min, purity= 94% FAB MS: m/z=629 (M+H) Analysis: Calcd for C30H31N6O6F3«2HCl»0.2EtOAc
C 51.44, H 4.85, N 11.69. Found: C 51.83, H 5.11, N 11.68.
The compounds in Examples 31 and 32 were prepared by procedures substantially as described above for Example 30, Step F.
EXAMPLE 31 (4S, 5R)-4-(3,4-Difluorophenyl-3-{l-[l-(4-fluoro-2- methoxyphenyl)piperidin-4-yl]-(3R)-pvrrolidin-3-ylcarbamoyl}-2-oxo- oxazolidine-5-carboxylic acid methyl ester
Figure imgf000088_0001
FAB MS: m z=577 (M+H)
Analysis: Calcd for C28H31N406F3-2F3CC02H
C 45.81, H 4.42, N 6.68. Found: C 45.85, H 4.54, N 6.62.
EXAMPLE 32
(4S, 5R)3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3- ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester
Figure imgf000088_0002
FAB MS: m z=554 (M+H)
Analysis: Calcd for C28H29N5O5F2«HCl»0.25H2O«0.75dioxane
C 56.36, H 5.57, N 10.60. Found: C 56.33, H 5.39, N 10.61.
EXAMPLE 33 (4S, 5R)-4-(3,4-Difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine-3- carboxylic acid {l-[l-(2-cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3- yljamide
Figure imgf000089_0001
Step A: (4S, 5R) 4-(3,4-Difluorophenyl)-5-hydroxymethyl-oxazolidin-
2-one
To a solution of (4S, 5R)-4-(3,4-difluorophenyl)-2-oxo- oxazolidine-5-carboxylic acid methyl ester [(200 mg, 0.8 mmol) product of Example 30 Step D] in tetrahydrofuran (10 mL) at 0°C was added a 2 M solution of lithium borohydride in tetrahydrofuran (0.4 mL, 0.8 mmol). After stirring for 20 min at 0°C, saturated sodium bicarbonate (20 mL) was added and the mixture stirred at ambient temperature for 20 min. Ethyl acetate (50 mL) was added and the layers separated. The organic layer was washed with brine (1 x 10 mL), dried with magnesium sulfate, filtered and concentrated in vacuo to provide (4S, 5R) 4-(3,4- difluorophenyl)-5-hydroxymethyl-oxazolidin-2-one as a white solid (180 mg, 0.8 mmol, 100%)
Η NMR dH (400 MHz, CDC13) 7.23-7.15 (m, 2H), 7.10-7.07 (m, IH), 6.48 (bs, IH), 4.89 (d, IH, J = 6.8), 4.31 (dt, IH, J = 6.6, 2.9), 3.96 (dd, IH, J = 12.82, 2.75), 3.70 (bdd, IH, J = 12.1, 2.2), 3.53 (bs, IH). Step B: (4S, 5R) 4-(3,4-Difluorophenyl)-5-(tetrahydropyran-2- yloxymethyl)-oxazolidin-2-one
To a solution of (4S, 5R) 4-(3,4-difluorophenyl)-5-hydroxymethyl- oxazolidin-2-one (695 mg, 3.0 mmol) in dry dichloromethane (30 mL) was added 2,3-dihydropyran (0.3 mL, 3.6 mmol) and camphorsulfonic acid (70 mg, 0.3 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate solution (2 x 100 ml), brine (1 x 100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting solid was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate :hexane) to afford (4S, 5R)-4- (3,4-difluorophenyl)-5-(tetrahydropyran-2-yloxymethyl)-oxazolidin-2-one as a colorless oil (750 mg, 2.4 mmol, 80%). FAB MS: m/z=314 (M+H)
Step C: (4S, 5R)-4-(3,4-Difluorophenyl)-2-oxo-5-(tetrahydropyran-2- yloxymethyl)-oxazolidine-3-carboxylic acid 4-nitrophenyl ester
To a solution of (4S, 5R)-4-(3,4-difluorophenyl)-5-(tetrahydropyran- 2-yloxymethyl)-oxazolidin-2-one (910 mg, 2.9 mmol) in anhydrous tetrahydrofuran (60 mL) cooled to -78°C under argon, was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.9 mL, 2.9 mmol) dropwise. The reaction mixture was warmed to 0°C in an ice bath, stirred 45 min, and then returned to -78°C. Meanwhile, in a separate dried flask, the p-mtrophenylchloroformate (586 mg, 2.9 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) under argon and cooled to -78°C. The above prepared anion solution was added via cannula to the chloroformate solution and reaction mixture was stirred 1 h at -78°C. The reaction mixture was treated with ethyl acetate (150 mL). The resulting solution was washed with water (1 x 150 ml), brine (1 x 150 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure to give (4S, 5R)-4-(3,4- difluorophenyl)-2-oxo-5-(tetrahydropyran-2-yloxymethyl)-oxazolidine-3- carboxylic acid 4-nitrophenyl ester as a yellow foam (1.3g, 2.8 mmol, 96%).
FAB MS: m/z=479 (M+H)
Step D: (4S, 5R)-4-(3,4-Difluorophenyl)-2-oxo-5-(tetrahydropyran-2- yloxymethyl)oxazolidine-3-carboxylic acid {l-[l-(2- cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-yl}amide
To a solution of 2-[4-(3-amino-(3R)-pyrrolidin-l-yl)piperidin-l- yl]benzonitrile (166 mg, 0.44 mmol) in dry, degassed N,N- dimethylformamide (4 mL) was added N,N-diisopropylethylamine (230 μL, 1.3 mmol) followed by (4S, 5R)-4-(3,4-difluorophenyl)-2-oxo-5- (tetrahydropyran-2-yloxymethyl)-oxazolidine-3-carboxylic acid 4- nitrophenyl ester (210 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 4 h when the volatiles were removed under reduced pressure, the residue dissolved in ethyl acetate (100 mL), washed with 10% aqueous sodium carbonate solution (8 x 100 mL), brine (1 x 100 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S, 5R)-4-(3,4-difluorophenyl)-2-oxo-5- (tetrahydropyran-2-yloxymethyl)oxazolidine-3-carboxylic acid {l-[l-(2- cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-yl}amide as a white foam (156 mg, 0.26 mmol, 59%).
FAB MS: m/z=610 (M+H)
Step E: (4S, 5R)-4-(3,4-Difluorophenyl)-5-hydroxymethyl-2-oxo- oxazolidine-3-carboxylic acid {l-[l-(2-cyanophenyl)piperidin- 4-yl]-(3R)-pyrrolidin-3-yl}amide
To a solution of (4S, 5R)-4-(3,4-difluorophenyl)-2-oxo-5- (tetrahydropyran-2-yloxvmethyl)oxazolidine-3-carboxylic acid {l-[l-(2- cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-yl}amide (156 mg, 0.26 mmol) in methanol (5 mL) was added p-toluenesulfonic acid (50 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 17 h. The volatiles were removed under reduced pressure, the residue taken up in ethyl acetate (100 mL), washed with saturated sodium carbonate solution (3 x 100 mL), brine (1 x 100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure to afford (4S, 5R)-4-(3,4-difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine- 3-carboxylic acid {l-[l-(2-cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3- yl}amide. The hydrochloride salt was prepared according to standard procedures to provide a white solid (123 mg, 0.22 mmol, 84%) HPLC: retention time= 7.20 min, purity=95%
FAB MS: m z=526 (M+H)
Η NMR HCl salt dH (400 MHz, CD30D) 7.97 (d, J= 7.33 Hz, IH), 7.53 (d, J= 7.69 Hz, 1 H), 7.45 (t, J= 8.61, IH), 7.16 (m, 2H), 7.04 (m, IH), 6.96 (m, 2H), 5.26 (d, J=4.58 Hz, IH), 4.39 (d, J=4.21, IH), 4.25 (m, IH), 3.95 (dd, J=8.61, 3.11, IH), 3.82 (dd, J=9.16, 3.48, IH), 3.57 (m, 2H), 2.88 (m. 3H), 2.77 (m, IH), 2.68 (m, IH), 2.47 (m, IH), 2.22 (m, 3H), 1.95 (m, 2H), 1.78 (bm, 2H), 1.68 (bm, IH)
Analysis: Calcd for C27 H29 N5 04 F2-0.35 H20 C 60.97, H 5.63, N 13.17.
Found: C 61.02, H 5.59, N 13.12.
The compounds of Examples 34 and 35 were prepared by procedures described in Example 30 Steps A-F, followed by pressurized silica gel chromatography using an elution system containing chloroform saturated with ammonia gas and methanol.
Figure imgf000092_0001
EXAMPLE 34 (4S, 5R)3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3- ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxamide
Figure imgf000093_0001
FAB MS: m z=539 (M+H)
Analysis: Calcd for C27H28N6O4F2»HCl»0.9H2O
C 54.85, H 5.25, N 14.22. Found: C 54.83, H 5.02, N 14.05.
EXAMPLE 35 (4S, 5R)-4-(3,4-Difluorophenyl-3-{l-[l-(4-fluoro-2- methoxyphenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-ylcarbamoyl}-2-oxo- oxazolidine-5-carboxamide
Figure imgf000093_0002
FAB MS: m z=562 (M+H) Analysis: Calcd for C27H30N5O5F3»0.85H2O C 56.21, H 5.54, N 12.14. Found: C 56.20, H 5.20, N 12.05.
EXAMPLE 36
Mixture of4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine and 4iS-4-(3,4-difluorophenyl)-6-methoxymethyl-2- oxo-2, 3,4, 5-tetrahydropyrimi dine
Figure imgf000094_0001
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 HCl 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 37 Mixture of4<S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine and 4_S-4-(3,4-difluorophenyl)-6-methoxymethyl-2- oxo-2,3,4,5-tetrahydropyrimidine
Figure imgf000094_0002
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 HCl 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 Η NMR was consistent with the assigned structure. MS (FAB) 255 (M+l)
EXAMPLE 38
4_S-4-(3,4-Difluorophenyl)-6-methoxymethyl-3-(4-nitrophenoxycarbonyl)-2- oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000095_0001
The title compound was prepared by treating the mixture obtained from Example 36 or Example 37 (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 39 Mixture of 4i?-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
Figure imgf000096_0001
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 36. 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 38 in accordance with procedures and schemes described above. The compound of Example 38 can, for example, be reacted with an aminopiperidine or aminoalkylpiperidine as set forth in Schemes 1 and 2 to obtain the desired compounds. Compounds of the invention can also be prepared by preparing a nitrophenoxy derivative of the compound of Example 39 in accordance with the procedure set forth in Example 38 and then reacting the derivative with an aminopiperidine or aminoalkylpiperidine as set forth in Schemes 1 and 2 to obtain compounds of the invention.
The following compounds were prepared in accordance with procedures set forth in the foregoing Schemes and Examples.
EXAMPLE 40
N-(l-(l-(2-Cyanophenyl)piperidin-4-yl)azetidin-3-yl)-2-(3,4- difluorophenyDacetamide
Figure imgf000097_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 411 g/mole (M++H, C23H24F2N4O1 = 410.47 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.
Anal. Calcd for C23H24F5N5O3 • 1.20 TFA: C = 55.74, H = 4.64, N = 10.24. Found: C = 55.75, H = 4.65, N = 10.34.
EXAMPLE 41 (2+)-N-(l-(l-(2-Cyanophenyl)piperidin-4-yl)azetidin-3-yl)-2-(3,4- difluorophenyl)-2-(2-propyl)acetamide
Figure imgf000097_0002
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 453 g/mole (M++H, C26H3θF2N4θ! = 452.23 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.
Anal. Calcd for C26H30F2N4O1 • 1.15 TFA • 0.15 H20: C = 57.96, H = 5.41, N = 9.56. Found: C = 57.98, H = 5.19, N = 9.73.
EXAMPLE 42 (4jS)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2- cyanophenyl)-piperidin-4-yl]azetidin-3-yl}-amide
Figure imgf000098_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 482 g/mole (M++H, C25H25F2N5O3 = 481.51 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >99% pure.
Anal. Calcd for C25H25F2N5O3 1.35 TFA and 1.05 H20: C =
50.84, H = 4.38, N = 10.70. Found: C = 50.83, H = 4.29, N = 11.09.
EXAMPLE 43 (4ιS)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]azetidin-3-ylcarbamoyl}-4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylic acid methyl ester
Figure imgf000099_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 595 g/mole (M++H, C3oH32F2N6θ5 = 594.62 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >97% pure.
Anal. Calcd for C30H32F2N6O5 • 1.55 TFA and 1.30 H20: C = 50.02, H = 4.58, N = 10.58. Found: C = 49.99, H = 4.55, N = 10.59.
EXAMPLE 44 N-(l-(l-(2-Cyanophenyl)piperidin-4-yl)azetidin-3-ylmethyl)-2-(3,4- difluorophenyl)acetamide
Figure imgf000099_0002
!H NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m/e 425 g/mole (M++H, C24H26F2N4O1 = 424.49 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 99% pure.
Anal. Calcd for C24H26 2N4O1 • 0.05 CH2C12: C = 67.37, H
= 6.14, N = 13.07. Found: C = 67.53, H = 6.15, N = 13.40.
EXAMPLE 45 N-(l-(l-(2-Cyanophenyl)piperidin-4-yl)azetidin-3-ylmethyl)-2,2- spirocyclopropyl-2-(3,4-difluorophenyl)acetamide
Figure imgf000100_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 451 g/mole (M++H, C26H28F2N4O1 = 450.53 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 98% pure.
Anal. Calcd for C26H28F2N4O1 • 1.9 HCl and 0.15 Hexane:
C = 60.64, H = 6.05, N = 10.52. Found: C = 60.63, H = 6.45, N = 10.78.
EXAMPLE 46 (4S)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]azetidin-3-ylmethylcarbamoyl}- 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000101_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 609.26 g/mole (M++H, C3iH34F2N6θ5 = 608.64 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 93.4% pure.
EXAMPLE 47
(4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2- cyanophenyl)-piperidin-4-yl]azetidin-3-ylmethyl}-amide
Figure imgf000101_0002
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 496.26 g/mole (M++H, C26H27F2N5O3 =
495.53 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 94.8% pure. Anal. Calcd for C29H32F5N5O5 • 0.05 CHCI3 and 0.2 H 0: C = 61.94, H = 5.48, N = 13.87. Found: C = 61.97, H = 5.55, N = 13.50.
EXAMPLE 48 (4_S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2- cyanophenyl)-piperidin-4-yl]-3-hydroxy-azetidin-3-ylmethyl}-amide
Figure imgf000102_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 512 g/mole (M++H, C26H27F2N5O4 = 511.52 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95% pure.
EXAMPLE 49 (4iS)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]-3-hydroxy-azetidin-3- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000102_0002
iH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 625 g/mole (M++H, C3iH34F2N606 = 624.64 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure.
Anal. Calcd for C3iH34F2N606 • 1.65 HCl and 0.2 Et20: C
= 54.59, H = 5.42, N = 12.01. Found: C = 54.65, H = 5.25, N = 11.99.
EXAMPLE 50 (3RI>iV-(l-(l-(2-Nitrophenyl)piperidin-4-yl)pyrrolidin-3-yl)-2-(3,4- difluorophenyl)acetamide
Figure imgf000103_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 445 g/mole (M++H, C23H26F2N4O3 = 444.485 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 98% pure.
Anal. Calcd for C23H26F2N4O3 • 1.75 HCl: C = 54.35, H =
5.50, N = 11.02. Found: C = 54.29, H = 5.51, N = 10.63.
EXAMPLE 51
(Dias A) r3i?J-N-(l-(l-(2-Nitrophenyl)piperidin-4-yl)pyrrolidin-3-yl)-2-(3,4- difluorophenyl)acetamide
Figure imgf000104_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 487 g/mole (M++H, C26H32F2N4O3 = 486.567 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
Anal. Calcd for C26H32F2N4O3 • 1.4 HCl: C = 58.08, H = 6.26, N = 10.42. Found: C = 58.34, H = 6.22, N = 10.55.
EXAMPLE 52 (Dias A) (3R! _v"-(l-(l-(2-Cyanophenyl)piperidin-4-yl)pyrrolidin-3-yl)-2- (3,4-difluorophenyl)acetamide
Figure imgf000104_0002
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 467 g/mole (M++H, C27H32F2N4O1 = 466.577 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95.4% pure.
EXAMPLE 53 (Diast B) 3JR>iV-(l-(l-(2-Cyanophenyl)piperidin-4-yl)pyrrolidin-3-yl)-2- (3,4-difluorophenyl)acetamide
Figure imgf000105_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 467 g/mole (M++H, C27H32F2N4O1 = 466.577 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 95.8% pure.
EXAMPLE 54 (3R, 4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2- nitrophenyl)-piperidin-4-yl]pyrrolidin-3-yl}-amide
Figure imgf000105_0002
T-H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 516 g/mole (M++H, C25H27F2N5O5 = 515.522 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 100% pure. Anal. Calcd for C25H27F2N5O5 • 1.35 HCl: C = 53.17, H = 5.06, N = 12.40. Found: C = 53.26, H = 5.09, N = 12.08.
EXAMPLE 55 (3_R,-_-S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2- [N-l-(N-3-methylureyl)]phenyl)-piperidin-4-yl]pyrrolidin-3-yl}-amide
Figure imgf000106_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m/e 543 g/mole (M++H, C27H32F2N604 = 542.591 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 95% pure. Anal. Calcd for C27H32F2N6θ4 • 2.15 HCl: C = 52.22, H =
5.54, N = 13.53. Found: C = 52.20, H = 5.50, N = 13.22.
EXAMPLE 56 (3jR,-_?S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2- (N-3-dimethylsulfonamido)aminophenyl)-piperidin-4-yl]pyrrolidin-3-yl}- amide
Figure imgf000107_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 593 g/mole (M++H, C27H3 F2N6θ5S = 592.666 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.1% pure.
Anal. Calcd for C27H34F2N605S • 1.90 HCl: C = 48.99, H = 5.47, N = 12.70. Found: C = 49.06, H = 5.76, N = 12.69.
EXAMPLE 57 (3_R,4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2- (N-l-methanesulfonyl)aminophenyl)-piperidin-4-yl]pyrrolidin-3-yl}- amide
Figure imgf000107_0002
1-H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 564 g/mole (M++H, C26H31F2N5O5S = 563.624 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 100% pure.
Anal. Calcd for C26H31F2N5O5S • 2.0 HCl: C = 49.05, H = 5.23, N = 11.00. Found: C = 49.03, H = 5.18, N = 10.93.
EXAMPLE 58 (3i?,4_S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2- (N-l-acetyl)aminophenyl)-piperidin-4-yl]pyrrolidin-3-yl}-amide
Figure imgf000108_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 528 g/mole (M++H, C27H31F2N5O4 = 527.576 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 95.7% pure.
EXAMPLE 59
(4<S)-3-{l-[l-(2-Nitrophenyl)piperidin-4-yl]-pvrrolidin-3-ylcarbamoyl}-4- (3 ,4-difluorophenyl )-6-methoxymethyl-2-oxo- 1 ,2 ,3 ,4- tetrahydropyrimidine- 5 -carboxylic acid methyl ester
Figure imgf000109_0001
iH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 629 g/mole (M++H, C3oH34F2N607 = 628.64 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 60
(4S)-3-{l-[l-(2-[iV-l-(iv'-3-methylureyl)]phenyl)piperidin-4-yl]-pyrrolidin-3- ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxvmethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000109_0002
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 656 g/mole (M++H, C32H39F2N7θ6 = 655.709 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96.8% pure.
EXAMPLE 61 (4iS)-3-{l-[l-(2-(N-3-dimethylsulfonamido)aminophenyl)piperidin-4-yl]- pyrrolidin-3-ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000110_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 706 g/mole (M++H, C32H41 F2N7O7S =
705.783 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.1% pure.
Anal. Calcd for C32H41F2N7O7 • 2.10 HCl: C = 49.12, H =
5.55, N = 12.53. Found: C = 49.12, H = 5.60, N = 12.44.
EXAMPLE 62
(4S)-3-{l-[l-(2-(N-l-acetyl)aminophenyl)piperidin-4-yl]-pyrrolidin-3- ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000111_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 641 g/mole (M++H, C32H38F2N606 = 640.693 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 63
(4S)-3-{l-[l-(2-(N-l-methanesulfonyl)aminophenyl)piperidin-4-yl]- pyrrolidin-3-ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000111_0002
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 677 g/mole (M++H, C31H38F2N6θ7S =
676.747 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.9% pure.
EXAMPLE 64 (Diast A) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{l-[l-(2-cyanophenyl)piperidin-4-yl]-3-hydroxy-pyrrolidin-4-yl}amide
Figure imgf000112_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 512 g/mole (M++H, C26H27 2N5O4 = 511.52 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; 96% pure.
EXAMPLE 65 (Diast B) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{l-[l-(2-cyanophenyl)piperidin-4-yl]-3-hydroxy-pyrrolidin-4-yl}amide
Figure imgf000112_0002
iH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 512 g/mole (M++H, C26H27F2N5O4 = 511.52 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure.
EXAMPLE 66 (Racemic @ pyrrolidine) (4<S)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]-3- hydroxy-pyrrolidin-4-ylcarbamoyl}-4-(3,4-difluorophenyl)-6- methoxymethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000113_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 625.4 g/mole (M++H, C3iH34F2N606 =
624.64 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 67 (Dias A) (4<S)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]-3-hydroxy-pvrrolidin- 4-ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000114_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 625.4 g/mole (M++H, C3ιH34F2N606 = 624.64 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 68
(Dias B) (4<S)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]-3-hydroxy-pyrrolidin- 4-ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000114_0002
lH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 625.4 g/mole (M++H, C3iH34F2N606 =
624.64 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
EXAMPLE 69 (racemic) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2-cyanophenyl)-piperidin-4-yl]pyrrolidin-3-ylmethyl}-amide
Figure imgf000115_0001
iH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 510.34 g/mole (M++H, C27H29F2N5O3 =
509.55 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96% pure.
EXAMPLE 70 (racemic) (4S)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]pyrrolidin-3- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000115_0002
^-H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 623.5 g/mole (M++H, C32H36F2N6θ5 =
622.67 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 92% pure.
EXAMPLE 71 Diast A (4S)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]pyrrolidin-3- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000116_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 623.5 g/mole (M++H, C32H36F2N6θ5 =
622.67 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 92% pure.
EXAMPLE 72 (Diast B) ( S)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]pyrrolidin-3- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000117_0001
^-H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 623.5 g/mole (M++H, C32H36F2N605 = 622.67 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 92% pure.
EXAMPLE 73
(Racemic) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2-cyanophenyl)-piperidin-4-yl]piperidin-3-ylmethyl}-amide
Figure imgf000117_0002
iH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 524 g/mole (M++H, C28H31F2N5O3 = 523.58 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; >95% pure. EXAMPLE 74 (Dias A) (4ιS)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2-cyanophenyl)-piperidin-4-yl]piperidin-3-ylmethyl}-amide
Figure imgf000118_0001
iH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 524 g/mole (M++H, C28H31 F2N5O3 = 523.58 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; >95% pure.
EXAMPLE 75 (Dias B) (4<S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1- [l-(2-cyanophenyl)-piperidin-4-yl]piperidin-3-ylmethyl}-amide
Figure imgf000118_0002
iH NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m e 524 g/mole (M++H, C28H31F2N5O3 = 523.58 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.
EXAMPLE 76 (racemic) (4„_ -3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]piperidin-3- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000119_0001
iH NMR (CDCI3, 400 MHz) consistent with assigned structure. FABLRMS m e 637 g/mole (M++H, C33H38F2N6θ5 = 622.67 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; >95% pure.
EXAMPLE 77
(Diast A) (4S)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]piperidin-3- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000120_0001
iH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m e 637 g/mole (M++H, C33H38F2N605 = 622.67 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; >95% pure.
EXAMPLE 78 (Diast B) (4S)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]piperidin-3- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000120_0002
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 637 g/mole (M++H, C33H38F2N6θ5 = 622.67 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.
EXAMPLE 79 (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2- cyanophenyl)-piperidin-4-yl]piperidin-4-ylmethyl}-amide
Figure imgf000121_0001
!H NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 524 g/mole (M++H, C28H31F2N5θ3 = 523.58 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; >95% pure.
EXAMPLE 80 (4ιS)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]piperidin-4- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester
Figure imgf000122_0001
iH NMR (CDCI3, 400 MHz) consistent with assigned structure.
FABLRMS m/e 637 g/mole (M++H, C33H38F2N6θ5 = 622.67 g/mole.)
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml min flow rate) focus = 215 nm; >99% pure.
EXAMPLE 81
(3R, 4iS,5S)-4-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-carboxylic acid {l-[l-(2-carboxymethylphenyl)-piperidin-4-yl]pyrrolid-3-yl}-amide
Figure imgf000122_0002
iH NMR (CDCI3, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.
Anal. Calcd for C28H32F2N4θ5 • 1.25 EtOAc and 1.85 H20: C = 57.77, H = 6.71, N = 8.17. Found: C = 57.75, H = 6.95, N = 8.16. EXAMPLE 82 (3i?,4S,5i?)-5-Carboxymethyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3- carboxylic acid {l-[l-(2-carboxymethylphenyl)-piperidin-4-yl]pyrrolid-3- yl} -amide
Figure imgf000123_0001
iH NMR (CDC13, 400 MHz) consistent with assigned structure.
HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96% pure.
Anal. Calcd for C29H32F2N4O7 • 2.1 HCl and 0.7 Et20: C
53.41, H = 5.79, N = 7.84. Found: C = 53.39, H = 5.56, N = 7.82.
EXAMPLE 83
As a specific embodiment of an oral composition, 100 mg of the compound of Example 6 (i.e., Compound 2) 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 84
Screening assay: 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 I]-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 85
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 86
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 [3HJ8-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 87
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; KCl, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgSθ4, 1.2 mM; NaHCθ3, 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 K = 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 -1/2 inch lateral to the penis is made to expose the urethers, bladder and urethra. The urethers are ligated and cannulated so that urine flows freely into beakers. The dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra. Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate. The bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra. The bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer. The tip of the transducer is placed in the prostatic urethra and the position of the Millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure.
Phenylephrine, an alpha 1 adrenergic agonist, 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:
Figure imgf000130_0001
wherein Q is selected from
Figure imgf000130_0002
Figure imgf000131_0001
E, G, L and M are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH )θ-4θR6, (CH2)θ-4N(Rl9)2, (CH2)θ-4CN, (CH2)0-4CF3, (CH2)0-4CO2R19, (CH )θ-4CON(Rl9)2, (CH2)θ-4S0 Rl9, or
Figure imgf000131_0002
J is selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, (CH2)l-40R6, (CH2)l-4N(Rl9)2, (CH2)l-4CN, (CH2)θ-4CF3, (CH2)θ-4Cθ2R19, (CH2)0-4CON(R19)2, (CH2)0-4SO2R19, or (CH2)θ-4Sθ2N(R19)2;
RI is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro,
Figure imgf000131_0003
NR1 CON(R20)2, NRl9S02R20, NRl9sθ2N(R20)2, OR6, (CH2)θ-4Cθ2R19, oxadiazolyl-, Cl- 4 alkyl oxadiazolyl-, (CH2)θ-4CON(Rl9)2, (CH2)θ-4Sθ2N(R19)2, (CH2)θ- 4Sθ2R^ 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, (CH2)θ-4Cθ2R19, (CH2)θ-4CON(R19)2, (CH2)θ-4Sθ2N(R19)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
R2, R3, R8, R!0, Rl5, Rlβ ^ R17 and R18 are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4θR6 or (CH2)θ-4CF3;
R4 is selected from hydrogen, (CH2)θ-4COR6, (CH2)θ-4CN, (CH2)θ-4CF3, (CH2)0-4CO2R19, (CH2)θ-4CON(R19)2, (CH2)θ-4Sθ2R6 or
Figure imgf000131_0004
R5 is selected from hydrogen, Cι-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θR6 or (CH )0-4CF3;
R6 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3;
Η is selected from hydrogen, Ci-8 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)θ-4CORl9, (CH2)2-4θR6, (CH2)1-4CF3, (CH2)θ-4Sθ2R6, (CH2)θ-4Sθ2N(Rl9)2 or (CH2)l-4CN;
R9 is selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, CO2R6, CON(R6)2, (CH2)l-4θR6 or (CH2)θ-4 CF3;
RU and R^2 are each independently selected from hydrogen, Ci-8 alkyl or C3-8 cycloalkyl;
Rl3 and R^4 are each independently selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θR6, (CH2)θ-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, (CH2)0-4CON(R19)2, (CH2)θ-4Cθ2R19 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, phenyl, OR6, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
Rl9 and R2^ are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl or (CH2)l-4CF3;
R22 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)θ-4θR6 or (CH2)0-4CF3;
R24 and R26 are each independently selected from hydrogen or OR2^; R2^ is selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3;
W is O or NR11;
each X is independently selected from halogen, cyano, nitro, Ci-8 alkyl, C3-8 cycloalkyl, (CH )θ-4θR6 or (CH )0-4CF3;
Y is C-R19 or N;
Z is hydrogen, oxygen or sulphur;
m, p and q are each independently an integer from zero to two, provided that when q is zero, R26 is hydrogen; n, o, and s are each independently an integer from zero to four; and v is an integer from zero to one;
or a pharmaceutically acceptable salt thereof.
The compound of Claim 1, of the formula
Figure imgf000133_0001
wherein 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(R19)2, NRJ^COR20, NR19CON(R 0)2, NRl9sθ2R20, NRl9sθ2N(R20)2, OR6, (CH2)0- 4C02R19, (CH2)0-4CON(Rl9)2, (CH2)θ-4Sθ2N(Rl9)2, (CH2)0-4SO2R6 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, (CH2)0-4CO2R19, (CH2)θ-4CON(Rl9)2, (CH2)θ-4Sθ2N( l9)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
R4 is selected from (CH2)θ-4COR6, (CH2)θ-4CN, (CH2)θ-4CF3,
(CH2)0-4CO2R19, (CH2)0-4CON(Rl9)2, (CH2)θ-4Sθ2R6 or
Figure imgf000134_0001
R5 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4θR6 or (CH2)0-4CF3;
R9 is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)2-4θR6 or (CH2)0-4 CF3;
or a pharmaceutically acceptable salt thereof.
3. The compound of Claim 1, of the formula
Figure imgf000134_0002
wherein
E, G, L, M and J are each independently selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, or (CH2)θ-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,
Figure imgf000134_0003
NR!9S02R20, NR!9SO2N(R20)2, OR6, (CH2)θ-4Cθ2R19, oxadiazolyl-, Cl-4 alkyl oxadiazolyl-, (CH2)θ-4CON(R19)2, (CH2)θ-4Sθ2N(R19)2, (CH2)0-4SO2R6 or C1.4 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, (CH2)θ-4Cθ2R19, (CH2)θ-4CON(Rl9)2, (CH2)0- 4Sθ2N(R19)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, Cl-4 alkyl or C3-8 cycloalkyl;
R is selected from hydrogen, Cl-8 alkyl, C4-8 cycloalkyl or (CH2)1-4CF3;
Rl3 and R^4 are each independently selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, (CH2)l-4θR6, (CH2)θ-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, (CH2)0-4CON(R19)2, (CH2)θ-4Cθ2R19 or Cl-4 alkyl; or unsubstituted, mono-, di- or tri-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR6, halogen, Cl-4 alkyl or C3-8 cycloalkyl; and
n is an integer from zero to two;
or a pharmaceutically acceptable salt thereof.
4. The compound of Claim 3, selected from
Figure imgf000136_0001
wherein Q is selected from
Figure imgf000136_0002
RI is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR6, (CH2)θ-2Cθ2R19, (CH2)θ-2CON(Rl9)2, (CH2)0-2Sθ2N(Rl9)2, (CH2.O-2SO2R6, C1.4 alkyloxadiazolyl or Cχ.4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, OR6, (CH2)θ-2Cθ2R19, (CH2)θ-2CON(R19)2, (CH2)0-2SO2N(Rl9)2, (CH2)θ-2S02R6 or Ci-4 alkyl;
R4 is selected from hydrogen, COR6, C02R19, SO2R6 or CON(Rl9)2; R5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)θ-3θR6 or (CH2)l-3CF3;
R6 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3;
R8 and RlO are each independently selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH )2-4θR6 or (CH2)θ-3CF3;
R9 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, CO2R6, CON(R6)2, (CH2)l-4θR6 or (CH2)θ-3CF3;
Rl3 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)2-4θR6, (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, OR6,
Figure imgf000137_0001
or Cl-4 alkyl;
Rl9 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)1-3CF3;
R22 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH2)θ-4θR6 or (CH2)0-3CF3;
R2^ is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, or (CH2)0-3CF3;
q is an integer from zero to two; s is an integer from zero to three; and
or a pharmaceutically acceptable salt thereof.
5. The compound of Claim 4, wherein Q is selected from
Figure imgf000138_0001
Rl3 is selected from hydrogen, Cl-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, C02R19 or Cl-4 alkyl;
each X is a halogen;
or a pharmaceutically acceptable salt thereof.
6. The compound of Claim 5, selected from
Figure imgf000138_0002
Figure imgf000139_0001
wherein A is C-R21 or N;
each R21 is independently selected from hydrogen, halogen, cyano, OCi-4 alkyl, OCF3, OCH2CF3, C02CH3, CONH2, SO2NH2 or SO2C1-4 alkyl;
R24 and R26 are each independently selected from hydrogen or OR2°, wherein R2^ is hydrogen or Cl-4 alkyl;
each X is fluorine;
r is an integer from zero to two; and q is an integer from zero to one;
or a pharmaceutically acceptable salt thereof.
7. The compound of Claim 5, wherein Q is selected from
Figure imgf000140_0001
R4 is C02R19; and
R5 is (CH2)l-3θR6; or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition made by combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
10. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
11. The composition of Claim 8 further comprising a testosterone 5-alpha reductase inhibitor.
12. The composition of Claim 11, 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.
13. The composition of Claim 12, wherein the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor.
14. The composition of Claim 13, wherein the testosterone 5-alpha reductase inhibitor is finasteride.
15. 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.
16. The method of Claim 15, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
17. The method of Claim 15, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
18. The method of Claim 17, wherein the testosterone 5- alpha reductase inhibitor is finasteride.
19. 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 8.
20. The method of Claim 19, wherein the composition further comprises a therapeutically effective amount of a testosterone 5- alpha reductase inhibitor.
21. 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.
22. The method of Claim 21, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue.
23. The method of Claim 21, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
24. The method of Claim 23, wherein the testosterone 5- alpha reductase inhibitor is finasteride.
25. 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.
26. 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.
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000043374A1 (en) * 1999-01-26 2000-07-27 Merck & Co., Inc. Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists
WO2000063168A1 (en) * 1999-04-16 2000-10-26 Coelacanth Chemical Corporation Synthesis of azetidine derivatives
US6228870B1 (en) 1998-11-10 2001-05-08 Merck & Co., Inc. Oxazolidinones useful as alpha 1a adrenoceptor antagonists
US6316437B1 (en) 1999-09-30 2001-11-13 Merck & Co., Inc. Spirohydantoin compounds and uses thereof
US6319932B1 (en) 1998-11-10 2001-11-20 Merck & Co., Inc. Oxazolidinones useful as alpha 1A adrenoceptor antagonists
US6320049B1 (en) 1997-08-05 2001-11-20 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6326372B1 (en) 1999-09-30 2001-12-04 Merck & Co., Inc. Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
US6339090B1 (en) 1998-07-30 2002-01-15 Merck & Co., Inc. Alpha 1A adrenergic receptor antagonists
US6387893B1 (en) 1999-09-30 2002-05-14 Merck & Co., Inc. Spirotricyclic substituted azacycloalkane derivatives and uses thereof
US6436962B1 (en) 1999-09-30 2002-08-20 Merck & Co., Inc. Arylhydantoin derivatives and uses thereof
EP1760066A2 (en) * 2000-06-02 2007-03-07 AstraZeneca AB Processes for the preparation of cyclopropyl carboxylic acid derivatives and intermediates provided by these processes
US8067415B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2
US8067457B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5574044A (en) * 1994-10-27 1996-11-12 Merck & Co., Inc. Muscarine antagonists
US5618827A (en) * 1992-03-31 1997-04-08 Glaxo Group Limited Substituted phenylcarbamates and phenylureas, their preparation and their use as 5-HT antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5618827A (en) * 1992-03-31 1997-04-08 Glaxo Group Limited Substituted phenylcarbamates and phenylureas, their preparation and their use as 5-HT antagonists
US5574044A (en) * 1994-10-27 1996-11-12 Merck & Co., Inc. Muscarine antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1019052A4 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6320049B1 (en) 1997-08-05 2001-11-20 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6339090B1 (en) 1998-07-30 2002-01-15 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
WO2000043374A1 (en) * 1999-01-26 2000-07-27 Merck & Co., Inc. Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists
WO2000063168A1 (en) * 1999-04-16 2000-10-26 Coelacanth Chemical Corporation Synthesis of azetidine derivatives
US6316437B1 (en) 1999-09-30 2001-11-13 Merck & Co., Inc. Spirohydantoin compounds and uses thereof
US6326372B1 (en) 1999-09-30 2001-12-04 Merck & Co., Inc. Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
US6387893B1 (en) 1999-09-30 2002-05-14 Merck & Co., Inc. Spirotricyclic substituted azacycloalkane derivatives and uses thereof
US6436962B1 (en) 1999-09-30 2002-08-20 Merck & Co., Inc. Arylhydantoin derivatives and uses thereof
EP1760066A2 (en) * 2000-06-02 2007-03-07 AstraZeneca AB Processes for the preparation of cyclopropyl carboxylic acid derivatives and intermediates provided by these processes
EP1760066A3 (en) * 2000-06-02 2008-09-10 AstraZeneca AB Processes for the preparation of cyclopropyl carboxylic acid derivatives and intermediates provided by these processes
US7906662B2 (en) 2000-06-02 2011-03-15 Astrazeneca Ab Process for the preparation of cyclopropyl carboxylic acid esters and derivatives
EP2292582A3 (en) * 2000-06-02 2011-11-02 AstraZeneca AB 2-substituted 1-(3,4-difluorophenyl)cyclopropane derivatives
EP2292591A3 (en) * 2000-06-02 2011-11-02 AstraZeneca AB Process for the preparation of cyclopropyl derivatives
US8183412B2 (en) 2000-06-02 2012-05-22 Astrazeneca Ab Process for the preparation of cyclopropyl carboxylic acid esters and derivatives
US8067415B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2
US8067457B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2

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EP1019052A4 (en) 2001-05-16

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