EP1019052A1 - ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a - Google Patents

ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a

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Publication number
EP1019052A1
EP1019052A1 EP98931353A EP98931353A EP1019052A1 EP 1019052 A1 EP1019052 A1 EP 1019052A1 EP 98931353 A EP98931353 A EP 98931353A EP 98931353 A EP98931353 A EP 98931353A EP 1019052 A1 EP1019052 A1 EP 1019052A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
cycloalkyl
independently selected
alpha
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98931353A
Other languages
German (de)
English (en)
Other versions
EP1019052A4 (fr
Inventor
Michael A. Patane
Mark G. Bock
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9800231.4A external-priority patent/GB9800231D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1019052A1 publication Critical patent/EP1019052A1/fr
Publication of EP1019052A4 publication Critical patent/EP1019052A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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.

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Abstract

Cette invention concerne des composés hétérocycliques contenant de l'azote et des dérivés de ces derniers, leur synthèse ainsi que leur utilisation en tant qu'antagonistes de l'adrénorécepteur alpha 1a. Les composés de cette invention sont plus particulièrement utiles pour traiter l'hyperplaxie prostatique bénigne.
EP98931353A 1997-06-18 1998-06-18 ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a Withdrawn EP1019052A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US5096097P 1997-06-18 1997-06-18
US50960P 1997-06-18
GB9800231 1998-01-06
GBGB9800231.4A GB9800231D0 (en) 1998-01-06 1998-01-06 Alpha 1a adrenergic receptor antagonists
PCT/US1998/012672 WO1998057640A1 (fr) 1997-06-18 1998-06-18 ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a

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EP1019052A1 true EP1019052A1 (fr) 2000-07-19
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US6207444B1 (en) 1997-08-05 2001-03-27 Merck & Co., Inc. Enzymatic process of making alpha 1a adrenergic receptor antagonists using protease
AU5234899A (en) 1998-07-30 2000-02-21 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6319932B1 (en) 1998-11-10 2001-11-20 Merck & Co., Inc. Oxazolidinones useful as alpha 1A adrenoceptor antagonists
US6228870B1 (en) 1998-11-10 2001-05-08 Merck & Co., Inc. Oxazolidinones useful as alpha 1a adrenoceptor antagonists
US6358959B1 (en) 1999-01-26 2002-03-19 Merck & Co., Inc. Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists
WO2000063168A1 (fr) * 1999-04-16 2000-10-26 Coelacanth Chemical Corporation Synthese de derives d'azetidine
GB2355263A (en) 1999-09-30 2001-04-18 Merck & Co Inc Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
GB2355264A (en) 1999-09-30 2001-04-18 Merck & Co Inc Spirohydantoin derivatives useful as alpha 1a adrenoceptor antagonists
GB2355457A (en) 1999-09-30 2001-04-25 Merck & Co Inc Novel spirotricyclic substituted azacycloalkane derivatives useful as alpha 1a adrenoceptor antagonists
GB2355456A (en) 1999-09-30 2001-04-25 Merck & Co Inc Novel arylhydantoin derivatives useful as alpha 1a adrenoceptor antagonists
AR028110A1 (es) * 2000-06-02 2003-04-23 Astrazeneca Ab Nuevo proceso
WO2007053498A1 (fr) 2005-11-01 2007-05-10 Millennium Pharmaceuticals, Inc. Composés pouvant être employés en tant qu'antagonistes de ccr2
WO2007053499A2 (fr) 2005-11-01 2007-05-10 Millennium Pharmaceuticals, Inc. Composés pouvant être employés en tant qu'antagonistes de ccr2

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GB9206989D0 (en) * 1992-03-31 1992-05-13 Glaxo Group Ltd Chemical compounds
US5574044A (en) * 1994-10-27 1996-11-12 Merck & Co., Inc. Muscarine antagonists

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WO1998057640A1 (fr) 1998-12-23

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