WO1998057632A1 - ANTAGONISTES DES ADRENORECEPTEURS ALPHA 1a - Google Patents

ANTAGONISTES DES ADRENORECEPTEURS ALPHA 1a Download PDF

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Publication number
WO1998057632A1
WO1998057632A1 PCT/US1998/012573 US9812573W WO9857632A1 WO 1998057632 A1 WO1998057632 A1 WO 1998057632A1 US 9812573 W US9812573 W US 9812573W WO 9857632 A1 WO9857632 A1 WO 9857632A1
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Prior art keywords
phenyl
alkyl
cyano
independently selected
cycloalkyl
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PCT/US1998/012573
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English (en)
Inventor
Michael A. Patane
Mark G. Bock
Dhanapalan Nagarathnam
Bharat Lagu
Wai C. Wong
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Merck & Co., Inc.
Synaptic Pharmaceutical Corporation
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Priority claimed from GBGB9800219.9A external-priority patent/GB9800219D0/en
Application filed by Merck & Co., Inc., Synaptic Pharmaceutical Corporation filed Critical Merck & Co., Inc.
Priority to EP98931320A priority Critical patent/EP1014973A4/fr
Priority to CA002294591A priority patent/CA2294591A1/fr
Priority to JP50472099A priority patent/JP2002511086A/ja
Priority to AU81474/98A priority patent/AU8147498A/en
Publication of WO1998057632A1 publication Critical patent/WO1998057632A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha la adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine. Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla.
  • the binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
  • alpha and beta receptors were further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources.
  • alpha and beta adrenergic receptors were further subdivided into alpha l f alpha 2 ? ⁇ i, and ⁇ 2 subtypes. Functional differences between alpha 1 and alpha 2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.
  • alpha 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 5 ⁇ -dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
  • 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 5 ⁇ -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, Ci-8 alkyl, C3-8 cycloalkyl, (CH2) ⁇ -4 ⁇ R 15 , (CH 2 ) ⁇ -4N(Rl6) 2 , (CH 2 )0-4CN, (CH2)0-4CF3, (CH 2 )0-4CO2R 16 , (CH 2 ) ⁇ -4CON(Rl6) 2 , (CH2)0-4SO2R 15 or (CH2)0-4SO2N(R!6)2;
  • J is selected from hydrogen, Cl-8 alkyl, C3-8 cycloalkyl, (CH2)l-4 ⁇ R 1 5, (CH2)1-4N(R 16 )2, (CH 2 )l-4CN, (CH 2 )0-4CF3, (CH2)0-4CO2R 16 , (CH2) ⁇ -4CON(Rl6) 2 , (CH2)0-4SO2 15 or
  • Rl is selected from unsubstituted, mono- or poly- substituted phenyl wherein the substitutents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R 16 )2, NR 16 COR 18 , NR16CON(R!8)2, NR 1 6S02R 18 , NR 16 S02N(R 1 8) 2 , ORl ⁇ , (CH2)0-4CO2R 16 , (CH2)0-4CON(Rl6)2, (CH2)0-4SO2N(Rl6) 2 , (CH2)0-4SO2R 15 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,
  • R is selected from hydrogen, cyano, OR 15 , CO2R 15 , CON(R 16 )2, SO2R 15 , tetrazole, isooxadiazole, unsubstituted, mono- or poly- substituted phenyl wherein the substitutents on the phenyl are independently selected from halogen, cyano, OR ⁇ , (CH2)0-4CO2R-'- ⁇ , (CH2)0-4CON(Rl6) 2 , N(Rl6) 2 , NR16COR!5, NR 1 6C0N(R 18 )2, NRI6SO2R 15 , NR 1 6S02N(R 18 )2, (CH2)0-4SO2N(R 1 6) 2 , (CH2)0-4SO2R- ⁇ or Cl-4 alkyl; or unsubstituted, mono- or poly- substituted pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl
  • R 2 and R? are each independently selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R 16 , (CH 2 )0-4CON(Rl6) 2 , (CH2)0-4CORl5, (CH2)2-4 ⁇ R 15 , (CH2)l-4CF3, (CH2)0-4SO2R 15 , (CH2)0-4SO2N(R 16 )2 or (CH2)l-4CN;
  • RU and Rl2 are each independently selected from hydrogen, C ⁇ -8 alkyl or C3-8 cycloalkyl;
  • Rl3 and Rl4 are each independently selected from hydrogen, C ⁇ -8 alkyl,
  • 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, OR15, halogen, C ⁇ -4 alkyl or C3-8 cycloalkyl;
  • Rl5 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH 2 )0-4CF 3 ;
  • Rl6 an d Rl8 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)l-4CF3;
  • Rl9 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-4 ⁇ R 15 or (CH2) ⁇ - CF3;
  • W is O or NR 11 ;
  • each X is independently selected from halogen, cyano, nitro, C1-8 alkyl, C3-8 cycloalkyl, (CH ) ⁇ -4 ⁇ R 24 or (CH 2 ) ⁇ -4CF 3 ;
  • R is selected from hydrogen, C ⁇ .g alkyl, 03.3 cycloalkyl or (C ⁇ CF ;
  • Y is C-Rl ⁇ or N
  • Z is hydrogen, oxygen or sulphur
  • n, p and q are each independently an integer from zero to four; o is an integer from one to four;
  • E, G, L, M and J are each independently selected from hydrogen, Ci-8 alkyl, C3-8 cycloalkyl, (CH2)0-4CO2R 16 or (CH )0-4CF3;
  • Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substitutents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6) 2 , NR16COR18, NR16C0N(R18) 2 ,
  • R is selected from hydrogen, cyano, OR 1 ⁇ , CO2R 15 , CON(R 16 )2, SO2R 15 , SO2N(Rl6)2 or unsubstituted, mono- or di-substituted phenyl wherein the substitutents on the phenyl are independently selected from halogen, cyano, ORl ⁇ , (CH2)0-4CO2R 16 , (CH2) ⁇ -4CON(Rl6)2, N(Rl6) 2 , Rl ⁇ cORl ⁇ , NRl6CON(Rl8)2, NRI6SO2R 15 , NRl6S02N(Rl8) 2 , (CH2) ⁇ - 4SO2N(Rl6)2, (CH2)0-4SO2R 15 or Cl-4 alkyl; or unsubstituted, mono- or di-substituted pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thien
  • R 2 and R ⁇ are each independently selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl or (CH2)l-4CF3;
  • Rl3 and Rl4 are each independently selected from hydrogen
  • E and J are each independently selected from hydrogen or CO2-C1-6 alkyl
  • Rl is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substitutents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6) 2 , ORl5, (CH2)0-2CO2R 16 , (CH2) ⁇ -2CON(Rl6)2 or Cl-4 alkyl; or unsubstituted, mono- or di- substituted pyridyl wherein the substitutents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, N(Rl6)2, ORl5, (CH2)0-2CO2R 16 , (CH2)0-2CON(Rl6) 2 or Cl-4 alkyl;
  • R is selected from hydrogen, cyano, OR 15 , CO2R 15 , CON(R 16 )2, SO2R 15
  • R 2 and R ⁇ are each independently selected from hydrogen, C1-6 alkyl, C4-6 cycloalkyl or (CH2)l-4CF3;
  • R8, R9 and RlO are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-4 ⁇ Rl5 or (CH2) ⁇ -2CF3;
  • Rl3 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-4 ⁇ Rl5, (CH2) ⁇ -2CF3, or imsubstituted, mono-, or di- substituted phenyl wherein the substitutents on the phenyl are independently selected from halogen, CF3, cyano, CO2R 6 , 0R15 or Cl-4 alkyl;
  • Rl5 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)0-2CF 3 ;
  • Rl6 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl or (CH2)l-2CF 3 ;
  • Rl9 is selected from hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, (CH 2 )0-4 ⁇ Rl 5 or (CH 2 ) ⁇ -2CF3;
  • each X is independently selected from halogen or C1-4 alkyl
  • A is C-RI 7 or N; R is selected from hydrogen, cyano, hydroxy, CON(Rl6)2,
  • each Rl? is independently selected from hydrogen, halogen, CO2R 6, cyano, nitro, CON(Rl6) 2 , SO2R 15 , SO2N(Rl6) 2 or ORl ⁇ ;
  • each X is independently selected from flourine or methyl
  • s is an integer from zero to two; and all other variables are as defined above;
  • Illustrative of the invention is the compound selected from
  • An illustration of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier.
  • An example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • the composition further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is finasteride.
  • More specifically illustrating the invention is a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
  • Another example of the invention is the method of treating benign prostatic hyperplasia wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
  • the testosterone 5-alpha reductase inhibitor is finasteride.
  • FIG. 1 Further illustrating the invention is a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
  • More specifically exemplifying the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) additionally does not cause a fall in blood pressures at dosages effective to inhibit contraction of prostate tissue.
  • Diseases which are susceptible to treatment by antagonism of the alpha la receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see, K.A.
  • Vatz, Headache 1997:37: 107-108) and cardiac arrhythmia An additional illustration of the invention is the use of any of the compounds described above in the preparation of a medicament for: a) the treatment of benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof.
  • An additional example of the invention is the use of any of the alpha la antagonist compounds described above and a 5-alpha reductase inhibitor for the manufacture of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue which comprises an effective amount of the alpha la antagonist compound and an effective amount of 5-alpha reductase inhibitor, together or separately.
  • Representative compounds of the present invention exhibit high selectivity for the human alpha la adrenergic receptor.
  • One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.
  • Representative compounds of this invention display submicromolar affinity for the human alpha la adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alpha Id and alpha lb adrenergic receptor subtypes, and many other G- protein coupled human receptors.
  • Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha la adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alpha Id and alpha lb adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors).
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • alkali metal salts e.g. sodium or potassium salts
  • alkaline earth metal salts e.g. calcium or magnesium salts
  • suitable organic ligands e.g. quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following:
  • 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 ⁇ -reductase inhibitors, including PROSCAR® (finasteride).
  • these compounds may be used to induce highly tissue-specific, localized alpha la adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac arrhythmias, and possibly a host of alpha la receptor mediated central nervous system events.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
  • the compounds according to the invention may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
  • alkyl shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
  • alkenyl shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
  • aryl refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl.
  • 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 substitutent.
  • poly- substituted shall include di-, tri-, tetra- and penta- substitution by a named substituent.
  • any substituent or variable e.g., X, Rl6, Rl8 at a particular location in a molecule be independent of its definitions elsewhere in that molecule.
  • - N(Rl6)2 represents -NEt ⁇ , -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.
  • Z is hydrogen
  • 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 (S)-oxa refers to an N-(activated)carbamate of the desired oxazolidinone where the activating group is, for example, a p-nitrophenyloxy group.
  • a specific example of an activated (S)-oxa group is 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3- carboxylic acid 4-nitrophenyl ester (i.e., compound 2).
  • selective alpha la adrenergic receptor antagonist refers to an alpha la antagonist compound which is at least ten fold selective for the human alpha la adrenergic receptor as compared to the human alpha lb, alpha Id, alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
  • lower urinary tract tissue refers to and includes, but is not limited to, prostatic smooth muscle, the prostatic capsule, the urethra and the bladder neck.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • the present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
  • compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto- injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the specificity of binding of compounds showing affinity for the alpha la receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha la receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha Id, alpha lb) or beta adrenergic receptors.
  • alpha e.g., alpha Id, alpha lb
  • beta adrenergic receptors e.g., beta adrenergic receptors.
  • Expression of the cloned human alpha Id, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
  • Antagonism by these compounds of the human alpha la adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting hypotensive effects.
  • the ability of compounds of the present invention to specifically bind to the alpha la receptor makes them useful for the treatment of BPH.
  • the specificity of binding of compounds showing affinity for the alpha la receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors.
  • the human alpha adrenergic receptor of the la subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994.
  • the cloned human alpha la receptor when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned human alpha Id, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
  • Compounds of this invention exhibiting human alpha la adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. fSee e.g.. PCT International Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995].
  • Compounds which are both selective amongst the various human alphal adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the ⁇ - adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly preferred.
  • the present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha la adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration.
  • the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
  • intravenous both bolus and infusion
  • intraperitoneal subcutaneous
  • topical with or without occlusion
  • intramuscular form all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • An effective but non-toxic amount of the compound desired can be employed as an alpha la antagonistic agent.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • suitable pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • Other dispersing agents which may be employed include glycerin and the like.
  • glycerin for parenteral administration, sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day.
  • the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg kg to about 20 mg/kg of body weight per day.
  • the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha la adrenergic receptor while minimizing any potential toxicity.
  • co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable.
  • this includes administration of compounds of this invention and a human testosterone 5 ⁇ -reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2.
  • Many such compounds are now well known in the art and include such compounds as PROSCAR®, (also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071, for example).
  • PROSCAR® which is principally active in prostatic tissue due to its selectivity for human 5 ⁇ -reductase isozyme 2
  • combinations of compounds which are specifically active in inhibiting testosterone 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2 are useful in combination with compounds of this invention.
  • dosages of the 5-alpha reductase inhibitor and the alpha la adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone.
  • the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • a method of treating BPH comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH.
  • the dosage of finasteride administered to the subject is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha la antagonist.
  • the dosage of finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day.
  • compounds of this invention exhibiting alpha la adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5 ⁇ -reductase 2 inhibitor, such as finasteride, in addition to a 5 ⁇ - reductase 1 inhibitor, such as 4,7 ⁇ -dimethyl-4-aza-5 ⁇ -cholestan-3- one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation.
  • a combined therapy can be employed wherein the alpha la adrenergic receptor antagonist and the 5 ⁇ - reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5 ⁇ -reductase inhibitors.
  • EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • FABLRMS fast atom bombardment low resolution mass spectroscopy
  • HPLC high performance liquid chromatography
  • HOBt 1-hydroxy benzotriazole hydrate
  • i-PrOH 2-propanol
  • i-Pr2NEt diisopropylethylamine
  • LAH lithium aluminum hydride
  • mCPBA meta-chloroperbenzoic acid
  • Me methyl
  • PCTLC preparative centrifugal thin layer chromatography
  • PEI polyethylenimine
  • Ph phenyl
  • TEBAC benzyltriethylammonium chloride
  • TFA trifluoroacetic acid
  • Tos2 ⁇ p-toluenesulfonicanhydride
  • Triton B N-benzyltrimethylammonium hydroxide
  • 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.
  • Scheme 2 depicts a more specific series of compounds derived from Michael addition of substituted benzyl nitriles to methyl acrylate, Dieckman cyclization, providing the ⁇ -keto ester which can be either: (a) submitted to a reductive amination and carried on to final products, (b) enolized and alkylated then reductively aminated, deprotected and further manipulated providing further substituted analogs; or (c) hydrolyzed and decarboxylated and run through the above described conditions producing the desired antagonists.
  • Some examples were prepared by first assembling the appropriately substituted amino bearing cycloalkyl, then allylating the amino moiety. This approach is described in Scheme 4. Starting with a cycloalkanone, for instance, 4-cyano 4-phenyl piperidone, reductive amination with ammonium acetate and sodium cyanoborohydride provides both the cis and trans 1-amino cyclohexanes. The ratio of these isomers is modulated by the choice of an appropriate reducing reagent, The incipient amino group could be protected, alkylated, deprotected and alkylated again providing more funtionalized analogs.
  • Antagonists with alkyl can be assembled by reductive amination of the prerequisite aminoalcohol and a cycloketone, for example, 4-cyano 4-phenylcyclohexanone, Scheme 5. Boc protection of the amine, followed by tosylation of the hydroxy and displacement by the lithium or sodium salt of the desired Q group completes the synthesis of the targeted antagonists.
  • the selective acylation of the primary amines was accomplished by treatment 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.
  • oxazolidinones are prepared and activated in general by published and well developed chemistry, in particular, of Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13, 1 (1982)]
  • the starting materials, in general, are natural and unnatural amino acids.
  • some of the preferred compounds are prepared from substituted phenyl glycine derivatives, which after reduction of the carboxylate and a phosgene equivalent mediated cyclization provides the substituted oxazolidinone ring system.
  • Deprotonation with n-butyl lithium and addition to a THF solution of p- nitrophenylchloroformate produces the stable, isolable "activated'Oxazolidinone (oxa).
  • 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. WO96/25934, published August 29, 1996.
  • a B A 5-nitrilo-4-o-tolyl-pentanoic acid methyl ester
  • (+)-2-Oxo-4-(3,4-difluorophenyl)-oxazolidine-3-carboxylic acid [2- (4-phenyl-4-methoxycarbonyl-cyclohexylamino)-ethyl] amide (cis isomer) and (+)-2-Oxo-4-(3,4-difluorophenyl)-oxazolidine-3-carboxylic acid [2-
  • This oil (5.98 g, 17.9 mmol) was dissolved in dry toluene (50 mL), cooled by an ice water bath and treated with NaH (60% oil dispersion, 804 mg,
  • reaction mixture was stirred for 15 minutes and then was treated with 5 mL of 10% potassium carbonate solution.
  • the reaction mixture was extracted with ethyl acetate (2X). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated to give the crude product as an oil.
  • Column chromatography of the reaction product on silica gel (methanol/ methylene chloride gradient elution (1 to 4%)) afforded the title compound which was converted to its salt form with HCl in dioxane: m.p. 140° C (d);
  • Example 19139 mg (0.38 mmole) of (+)-4-(3,4-difluorophenyl)-2-oxo- oxazolidine-3-carboxylic acid 4-nitrophenyl ester in 2 mL of tetrahydrofuran was converted to the title compound by reacting it with 100 mg (0.38 mmole) of 2- ⁇ [4-cyano-4-(2-fluoro)phenyl] cyclohexylaminolethyl.
  • the chromatographed product was converted to the HCl salt and lyophilized:
  • Example 21 122 mg (0.34 mmole) of (+)-4-(3,4-difluorophenyl)-2-oxo- oxazolidine-3-carboxylic acid 4-nitrophenyl ester in 5 mL of N,N- dimethylformamide was converted to the title compound by reacting it with 129 mg (0.34 mmole) of 2- ⁇ [4-cyano-4-(2-trifluoromethyl)phenyl] cyclohexylaminolethyl amine hydrochloride and 204 ⁇ L (1.2 mmole) of diisopropylethylamine. Extractive workup, followed by flash chromatography of the crude reaction product, and lyophilization gave the title compound as a white powder:
  • Example 21 130 mg (0.36 mmole) of (+)-4-(3,4-difluorophenyl)-2-oxo- oxazolidine-3-carboxylic acid 4-nitrophenyl ester in 5 mL of N,N- dimethylformamide was converted to the title compound by reacting it with 138 mg (0.36 mmole) of 2- ⁇ [4-cyano-4-(2-trifluoromethyl)phenyl] cyclohexylaminolethyl amine hydrochloride and 219 ⁇ L (1.26 mmole) of diisopropylethylamine. Extractive workup, followed by flash chromatography of the crude reaction product, and lyophilization gave the title compound as a white powder:
  • Example 21 172 mg (0.47 mmole) of (+)-4-(3,4-difluorophenyl)-2-oxo- oxazolidine-3-carboxylic acid 4-nitrophenyl ester in a solvent mix of 8 mL of N,N-dimethylformamide and 2 mL of tetrahydrofuran was converted to the title compound by reacting it with 175 mg (0.47 mmole) of 2-[(4- methansulfonyl-4-phenyl) cyclohexylaminolethyl amine hydrochloride and 288 ⁇ L (1.66 mmole) of diisopropylethylamine.
  • Example 21 153 mg (0.42 mmole) of (+)-4-(3,4-difluorophenyl)-2-oxo- oxazolidine-3-carboxylic acid 4-nitrophenyl ester in 2 mL of N,N- dimethylformamide was converted to the title compound by reacting it with 155 mg (0.42 mmole) of 2-[(4-methansulfonyl-4-phenyl) cyclohexylaminolethyl amine hydrochloride and 256 ⁇ L (1.47 mmole) of diisopropylethylamine.
  • 100 mg of the compound of Example 5 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
  • the objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4.
  • 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 Method:
  • Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at 38,000Xg for 30'.
  • the binding assay contains 0.25 nM [3H]8-OH- DPAT (8-hydroxy-2-dipropylamino-l,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaC12 and lmg/ml ascorbate. Non-specific binding is defined using 10 ⁇ M propranolol.
  • the assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters
  • Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate.
  • Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary.
  • Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles.
  • Human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored overnight in ice-cold Krebs solution if needed.
  • the tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCl, 118 mM; KC1, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgSO4, 1.2 mM; NaHCO3, 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% CO2/95% O2. The tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram
  • 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.
  • K IB1.
  • x the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration.
  • Benign prostatic hyperplasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction.
  • Alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man.
  • these are non-selective alpha 1 receptor antagonists which also have pronounced vascular effects. Because we have identified the alpha la receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without concomitant changes in the vasculature.
  • the following model is used to measure adrenergically mediated changes in intra-urethral pressure and arterial pressure in anesthetized dogs in order to evaluate the efficacy and potency of selective alpha adrenergic receptor antagonists.
  • the goals are to: 1) identify the alpha 1 receptor subtypes responsible for prostatic/urethral contraction and vascular responses, and 2) use this model to evaluate novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be evaluated in this manner.
  • mice 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
  • 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 se rapporte à certains nouveaux composés et dérivés de ces composés, à leur synthèse et à leur utilisation en tant qu'antagonistes des adrénorécepteurs alpha 1a. L'une des applications de ces composés se fait dans le traitement de l'hyperplasie prostatique bénigne. Ces composés sont sélectifs du point de vue de leur capacité à provoquer la détente de tissus des muscles lisses enrichis par un récepteur du sous-type alpha 1a et ce, sans entraîner d'hypotension. L'un de ces tissus entoure la tunique urétrale. Par conséquent, les composés selon l'invention peuvent être utilisés pour induire un soulagement prononcé chez les hommes souffrant de l'hyperplasie prostatique bégnigne du fait qu'ils permettent un écoulement de l'urine plus facile. Les composés selon la présente invention peuvent également être utilisés en combinaison avec un composé inhibiteur de la réductase 5-alpha humaine et ce, de manière à induire un soulagement prononcé et chronique concernant les effets de l'hyperplasie prostatique bénigne.
PCT/US1998/012573 1997-06-18 1998-06-17 ANTAGONISTES DES ADRENORECEPTEURS ALPHA 1a WO1998057632A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98931320A EP1014973A4 (fr) 1997-06-18 1998-06-17 ANTAGONISTES DES ADRENORECEPTEURS ALPHA 1a
CA002294591A CA2294591A1 (fr) 1997-06-18 1998-06-17 Antagonistes des adrenorecepteurs alpha 1a
JP50472099A JP2002511086A (ja) 1997-06-18 1998-06-17 α１ａアドレナリン受容体拮抗薬
AU81474/98A AU8147498A (en) 1997-06-18 1998-06-17 Alpha 1a adrenergic receptor antagonists

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US5013697P 1997-06-18 1997-06-18
US60/050,136 1997-06-18
GBGB9800219.9A GB9800219D0 (fr) 1998-01-07 1998-01-07
GB9800219.9 1998-01-07

Publications (1)

Publication Number Publication Date
WO1998057632A1 true WO1998057632A1 (fr) 1998-12-23

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Application Number Title Priority Date Filing Date
PCT/US1998/012573 WO1998057632A1 (fr) 1997-06-18 1998-06-17 ANTAGONISTES DES ADRENORECEPTEURS ALPHA 1a

Country Status (5)

Country Link
EP (1) EP1014973A4 (fr)
JP (1) JP2002511086A (fr)
AU (1) AU8147498A (fr)
CA (1) CA2294591A1 (fr)
WO (1) WO1998057632A1 (fr)

Cited By (9)

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Publication number Priority date Publication date Assignee Title
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
US6320049B1 (en) 1997-08-05 2001-11-20 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
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
US6358959B1 (en) 1999-01-26 2002-03-19 Merck & Co., Inc. Polyazanaphthalenone 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

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US5231179A (en) * 1986-01-27 1993-07-27 Sumitomo Pharmaceuticals Company, Limited Heterocyclic compounds and their production
US5380737A (en) * 1989-05-04 1995-01-10 Sterling Winthrop Inc. Saccharin derivative proteolytic enzyme inhibitors

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AU7734496A (en) * 1995-11-15 1997-06-05 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
WO1997017969A1 (fr) * 1995-11-16 1997-05-22 Synaptic Pharmaceutical Corporation Dihydropirimidines et leurs emplois

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US4593024A (en) * 1985-08-15 1986-06-03 International Minerals & Chemical Corp. Dihydroisoxazole compounds and anthelmintic use
US5231179A (en) * 1986-01-27 1993-07-27 Sumitomo Pharmaceuticals Company, Limited Heterocyclic compounds and their production
US5380737A (en) * 1989-05-04 1995-01-10 Sterling Winthrop Inc. Saccharin derivative proteolytic enzyme inhibitors

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See also references of EP1014973A4 *

Cited By (9)

* 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
US6228870B1 (en) 1998-11-10 2001-05-08 Merck & Co., Inc. Oxazolidinones useful as alpha 1a adrenoceptor antagonists
US6319932B1 (en) 1998-11-10 2001-11-20 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
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

Also Published As

Publication number Publication date
JP2002511086A (ja) 2002-04-09
EP1014973A1 (fr) 2000-07-05
EP1014973A4 (fr) 2000-09-20
AU8147498A (en) 1999-01-04
CA2294591A1 (fr) 1998-12-23

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