WO2000027816A1 - Oxazolidinones useful as alpha 1a adrenoceptor antagonists - Google Patents
Oxazolidinones useful as alpha 1a adrenoceptor antagonists Download PDFInfo
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- WO2000027816A1 WO2000027816A1 PCT/US1999/026436 US9926436W WO0027816A1 WO 2000027816 A1 WO2000027816 A1 WO 2000027816A1 US 9926436 W US9926436 W US 9926436W WO 0027816 A1 WO0027816 A1 WO 0027816A1
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- 0 C*(C*(C)NC(N(C([C@](C(OC)=O)O1)C2=CC=*C(C)(C)C=C2)C1=O)=O)CN(CC1)CCC1(C1=CC(C)(*(C)(C)C)C=CC=*1)O Chemical compound C*(C*(C)NC(N(C([C@](C(OC)=O)O1)C2=CC=*C(C)(C)C=C2)C1=O)=O)CN(CC1)CCC1(C1=CC(C)(*(C)(C)C)C=CC=*1)O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- This invention relates to certain oxazolidinone compounds and pharmaceutically acceptable salts thereof, their synthesis, and their use as alpha 1 a 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.
- the functional responses such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding. Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources.
- alpha and beta adrenergic receptors were further subdivided into alpha 1, alpha 2 ? ⁇ i , and B>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 la was renamed alpha Id.
- the new nomenclature is used throughout this application. Stable cell lines expressing these alpha 1 receptor subtypes are referred to herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature.
- ATCC American Type Culture Collection
- Benign prostatic hyperplasia also known as benign prostatic hypertrophy or BPH
- BPH benign prostatic hypertrophy
- the symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. 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 5alpha- dihydrotestosterone has been identified as the principal culprit.
- the continual production of 5 ⁇ -dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
- one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief.
- Agents which induce relaxation of the lower urinary tract tissue, by binding to alpha 1 adrenergic receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity.
- one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia.
- the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alpha 1 subtype was reported.
- non-selective antagonists suffer from side effects related to antagonism of the alpha Id and alpha lb receptors in the peripheral vasculature, e.g., hypotension and syncope.
- the relatively recent cloning of the human alpha la adrenergic receptor (ATCC CRL 11140) and the use of a screening assay utilizing the cloned human alpha la receptor has enabled identification of compounds which specifically interact with the human alpha 1 a adrenergic receptor.
- ATCC CRL 11140 human alpha la adrenergic receptor
- a screening assay utilizing the cloned human alpha la receptor
- a cloned human alpha la adrenergic receptor and a method for identifying compounds which bind the human alpha la receptor has made possible the identification of selective human alpha la adrenergic receptor antagonists useful for treating BPH.
- WO 94/22829 discloses, for example, certain 4-(un)substituted phenyl-l,4-dihydropyridine derivatives which are described as potent, selective alpha la antagonists with weak calcium channel antagonistic activity and which are further described to be anticipated as useful for treating BPH.
- WO 96/14846, WO 97/17969 and WO 97/42956 each disclose certain dihydropyrimidine derivatives (e.g., certain l,2,3,6-tetrahydro-2- oxo-pyrimidine derivatives) which are selective antagonists for the human alpha 1 a receptor and useful for treatment of BPH, impotency, cardiac arrhythmia, and other diseases where antagonism of the alpha la receptor may be useful.
- WO 96/40135 discloses, inter alia, certain phenylpiperidinyl alkyl saccharin derivatives and their use as selective alpha la antagonists.
- the instant patent disclosure discloses novel oxazolidinone 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 and histamine HI), 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 (4-aryl-4-hydroxy piperidinyl) alkylcarbamoyl oxazolidinone 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 typically exhibiting at least about 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 present invention is a compound of formula (I):
- A is CX or N
- X is hydrogen, halo, nitro, cyano, Cl -C4 alkyl, fluorinated Cl -C4 alkyl, fluorinated C1-C4 alkoxy, (CH2)l-4ORa, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, N(Ra)CORa, N(Ra)CON(Ra)2, N(Ra)SO2R a , N(Ra)SO2N(Ra)2, (CH2)0-4CO2R a , (CH )0-4CON(Ra) 2 , (CH2) ⁇ -4SO 2 N(Ra) 2 , or (CH 2 )0-4SO2R a ; Y is hydrogen, halo, nitro, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1 -C4 alkyl, fluorinated C1 -C4 alkoxy, (
- Ra is hydrogen, C1 -C4 alkyl, or fluorinated C1-C4 alkyl
- n is an integer of from 1 to 3;
- q and r are each independently integers of from 0 to 3;
- the present invention also includes pharmaceutical compositions, methods of preparing pharmaceutical compositions, and methods of treatment.
- the present invention includes oxazolidinone compounds of Formula (I) above. These compounds and their pharmaceutically acceptable salts are useful as selective alpha 1 a antagonists.
- the present invention is a compound is of Formula (II)
- the present invention is a compound of Formula (I), wherein
- X is hydrogen, halo, nitro, cyano, C1-C4 alkyl, (CH2)l-3ORa, (CH2) ⁇ -3CF3, OCF3, N(Ra)CORa, N(Ra)CON(Ra)2, N(Ra)SO2R a , N(Ra)SO2N(Ra)2, (CH2) ⁇ -4C ⁇ 2R , (CH 2 )0-4CON(Ra) 2 , (CH 2 ) ⁇ -4SO 2 N(Ra) 2 , or (CH 2 ) ⁇ -4SO 2 R ;
- Y is hydrogen, halo, nitro, cyano, hydroxy, C1 -C4 alkyl, C1 -C4 alkoxy, (CH2)l- 3ORa (CH2)0-3CF3, OCF3, N(Ra) 2 , N(Ra)CORa, N(Ra)CON(Ra) 2 , N(Ra)SO2R a , N(Ra)S02N(Ra) 2 , (CH 2 )0-4CO2Ra (CH 2 ) ⁇ -4CON(Ra) 2 , (CH )0-4SO2N(Ra) 2 , or (CH 2 )0-4SO 2 R ;
- R a is hydrogen, C1 -C4 alkyl, or (CH2)0-3CF3;
- q and r are each independently integers of from 0 to 2;
- the present invention is a compound of Formula (I), wherein wherein A is CX;
- X is hydrogen, halo, nitro, cyano, methyl, ethyl, or CF3;
- Y is hydrogen, halo, nitro, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, or CF3;
- R is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, CF3, or CH2CF3;
- Ra is hydrogen, C1 -C4 alkyl, or (CH2) ⁇ -3CF3;
- n is an integer of from 1 to 3;
- q and r are each independently integers of from 0 to 2;
- X is hydrogen, fluoro or cyano; and Y is hydrogen or fluoro; and all other variables are as defined above for the third embodiment; or a pharmaceutically acceptable salt thereof.
- X is hydrogen, halo, nitro, cyano, methyl, ethyl, or CF3;
- Y is hydrogen, halo, nitro, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy or CF3; and R is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, CF3, or CH2CF3;
- Ra is hydrogen, C1 -C4 alkyl, or (CH2)0-3CF3;
- n is an integer of from 1 to 3;
- q and r are each independently integers of from 0 to 2;
- X is hydrogen, fluoro or cyano; and all other variables are as defined in the class; or a pharmaceutically acceptable salt thereof.
- Exemplifying the invention is a compound selected from the group consisting of:
- the present invention also includes a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier.
- a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
- the present invention further includes a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
- the present invention further includes a pharmaceutical composition as described in the preceding paragraph 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 suitably fmasteride.
- the present invention also includes 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 compound (or composition) does not cause a fall in blood pressure at dosages effective to alleviate BPH.
- the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
- a suitable testosterone 5-alpha reductase inhibitor for use in the method is fmasteride.
- the present invention also includes 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.
- the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to inhibit contraction of prostate tissue.
- the compound is administered in combination with a testosterone 5-alpha reductase inhibitor; the testosterone 5-alpha reductase inhibitor is suitably fmasteride.
- the present invention also includes 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 Vatz, Headache (1997), 37: 107-108) and cardiac arrhythmia.
- the present invention also includes the use of any of the compounds described above in the preparation of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof.
- the present invention further includes 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.
- C1 -C4 alkyl means linear or branched chain alkyl groups having from 1 to 4 carbon atoms and includes n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
- C1-C4 alkoxy means an -O-alkyl group wherein alkyl is Cl to C4 alkyl. Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and sec-butoxy.
- C3-C8 cycloalkyl means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
- C3-C6 cycloalkyl refers to a cyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- halo refers to fluoro, chloro, bromo, and iodo (alternatively fluorine, chlorine, bromine and iodine).
- fluorinated C1-C4 alkyl (which may alternatively be referred to as "C1-C4 fluoroalkyi”) means a C1 -C4 linear or branched alkyl group as defined above with one or more fluorine substituents.
- fluorooalkyls include the series (CH2)0-3CF3 (i.e., trifluoromethyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.), 1 -fluoroethyl, 2-fluoroethyl, 2,2- difluoroethyl, 3,3,3-trifluoroisopropyl, and 1,1,1,3,3,3-hexafluoroisopropyl.
- fluorinated C3-C8 cycloalkyl (which may alternatively be referred to as “C3-C8 fluoroocycloalkyl”) means a cycloalkyl group as defined above with one or more fluorine substituents. "Fluorinated C3-C6 cycloalkyl” has an analogous meaning.
- fluorocycloalkyls include all isomers of fluorocyclohexyl (i.e., 1-, 2-, 3-, and 4-fluorocyclohexyl), difluorocyclohexyl (e.g., 2,4-difluorocyclohexyl, 3,4-difluorocyclohexyl, etc.), fluorocyclopentyl, and so forth.
- fluorinated C1 -C4 alkoxy (which may alternatively be referred to as "C1 -C4 fluoroalkoxy”) means a C1 -C6 alkoxy group as defined above wherein the alkyl moiety has one or more fluorine substituents.
- Representative examples include the series O(CH2) ⁇ -3CF3 (i.e., trifluoromethoxy, 2,2,2- trifluoroethoxy, 3,3,3-trifluoro-n-propoxy, etc.), 1,1,1,3,3,3-hexafluoroisopropoxy, and so forth.
- aryl refers to phenyl and substituted phenyl.
- heteroaryl refers to pyridyl and substituted pyridyl.
- substituted includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution is defined herein and chemically allowed.
- a substituent e.g., (CH2) ⁇ - 4CO2R a
- variable e.g., R a
- Y can be any one of CO2H, CO2Me, CO2Et, CO2Pr, CH2CO2H, CH2CO2Me, CH2CO2Et, CH2CO2Pr, (CH2)2CO2H, etc.
- N(Ra)2 represents groups such as -NH2
- 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 the methods set forth below and, when viewed in the light of this disclosure, by techniques known in the art. 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.
- 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 typically displaying at least about 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 1 a adrenergic receptor subtype while displaying at least about 20 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.
- Still other representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha 1 a adrenergic receptor subtype while displaying at least about 100 fold lower affinity for the human alpha Id and alpha lb adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors). These compounds are administered in dosages effective to antagonize the alpha la receptor where such treatment is needed; e.g., treatment of BPH.
- 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 in the prepartion 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 combination with more long-term anti-BPH therapeutics, such as testosterone 5-a reductase inhibitors, including PROSCAR® (fmasteride).
- 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.
- selective alpha la adrenergic receptor antagonist refers to an alpha la antagonist compound which is at least about ten fold selective for the human alpha 1 a 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.
- 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 encompasses 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 flavored 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 chromato graphic 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 in the art.
- the specificity of binding of compounds showing affinity for the alpha la receptor is shown by comparing affinity to membranes obtained from transfected cell lines that express the alpha la receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha Id, alpha lb) or beta adrenergic receptors.
- alpha e.g., alpha Id, alpha lb
- beta adrenergic receptors e.g., beta adrenergic receptors.
- Expression of the cloned human alpha Id, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
- Antagonism by these compounds of the human alpha la adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may-be used to increase urine flow without exhibiting hypotensive effects.
- the ability of compounds of the present invention to specifically bind to the alpha la receptor makes them useful for the treatment of BPH.
- the specificity of binding of compounds showing affinity for the alpha la receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors.
- the human alpha adrenergic receptor of the la subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994.
- the cloned human alpha la receptor when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function.
- the present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.
- compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha la adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration.
- the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
- intravenous both bolus and infusion
- intraperitoneal subcutaneous
- topical with or without occlusion
- intramuscular form all using forms well known to those of ordinary skill in the pharmaceutical arts.
- An effective but non-toxic amount of the compound desired can be employed as an alpha la antagonistic agent.
- compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
- compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
- the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
- the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
- a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
- Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
- the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
- carrier suitable pharmaceutical diluents, excipients or carriers
- 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.
- biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required.
- the daily dosage of the products may be varied over a wide range; e.g., from about 0.01 to about 1000 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 about 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to about 7 mg/kg of body weight per day.
- the compounds may be administered on a regimen of 1 to 4 times per day.
- this invention is 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 fmasteride, a 4-Aza-steroid; see US 4377584 and 4760071, 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.
- 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 fmasteride effective to treat BPH.
- the dosage of fmasteride administered to the subject is from 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 fmasteride in the combination is from about 0.2 mg per subject per day to about 10 mg per subject per day, and, in another aspect, from about 1 to about 7 mg per subject to day (e.g., 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 fmasteride, in addition to a 5a-reductase 1 inhibitor, such as 4,7 ⁇ -dimethyl-4-aza-5a-cholestan-3- one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation.
- a combined therapy can be employed wherein the alpha la adrenergic receptor antagonist and the 5a-reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations.
- EDTA ethylenediamine tetraacetic acid
- HOBt 1 -hydroxy benzotriazole hydrate
- HPLC high performance liquid chromatography
- i-Pr2NEt diisopropylethylamine
- LDA lithium diisopropyl amide
- LiHMDS lithium bis(trimethylsilyl)amide
- THF tetrahydrofuran
- TsOH p-toluenesulfonic acid
- UV ultraviolet
- 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. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
- Scheme I describes the preparation of primary amines suitable for use in preparing many of the compounds of the present invention, wherein aryl or heteroaryl Grignard reagent is reacted with a Boc-protected piperidone to provide tertiary alcohols of type 2, which can be converted to amines of type 3.
- Oxazolidinones can be prepared by hydroxyamination of olefms to provide protected aminoalcohols, using procedures as described in Sharpless et al., Angew. Chem. Int. Ed. Engl. (1996), 35: 2813. 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 a stable, isolable "activated" oxazolidinone. These oxazolidinones were prepared in enantiomer-enriched form, and the configuration assignments were made in accordance with Sharpless et al., Angew. Chem. Int. Ed. Engl. (1996), 35: 2813.
- Oxazolidinones can also be prepared by condensation of carboxylic acids with aldehydes or ketones to form 1,2-hydroxycarboxylic acids and then cyclizing the hydroxy acids with diphenyldiphosphorylazide to form the oxazolidinones, which can then be activated by treatment with p- nitrophenylchloroformate.
- the oxazolidinones can be resolved into their optical isomers via chromatography prior to activation, or the unresolved material can be activated directly.
- Selective acylation of the primary amines can be accomplished by treatment of the amines with nearly equimolar quantities of the activated oxazolidinones.
- Scheme II provides further illustration of the preparation of the compounds of the present invention.
- a cinnamic acid is esterified with methanol in the presence of acid to form the corresponding methyl cinnamate, which is reacted with benzylcarbamate in the presence of t-butyl hypochlorite, base, an osmium catalyst, and a phthalazine ligand to form an asymmetric hydroxycarbamate.
- the hydroxycarbamate is deprotected via hydrogenation to the corresponding aminoalcohol, which is cyclized to the oxazolidinone 4 with triphosgene, deprotonated with lithium bis(trimethylsilyl)amide, and converted to the activated p- nitrophenyl analog 5 by reaction with p-nitrophenylchloroformate, which is coupled with primary amine 3 to give a methyl ester-containing compound of the invention 6.
- the methyl ester functional group in the coupled product can be converted to an carboxamide-containing compound of the invention 7 by dissolving the coupled amine product in chloroform saturated with ammonia gas and then treating with silica gel.
- Scheme II, part B describes the preparation of alkylcarbonyl oxazolidinone compounds 10 of the present invention.
- the amine-coupled oxazolidinone methyl ester 6 is converted to the corresponding oxazolidinone carboxylic acid 8 by contact with LiOH.
- the carboxylic acid intermediate 8 is then converted to alkylcarbonyl compound 10 by first converting the carboxylic acid to the N-methylmethoxyamide derivative 9, and then reacting 9 with the appropriate Grignard reagent.
- Scheme II, Part C describes the preparation of hydroxymethyl oxazolidinone compounds of the invention.
- the methylcarboxylate group of oxazolidinone 4 is reduced via LiBH4 to the hydroxymethyl-substituted oxazolidinone 11.
- Compound 17 is then coupled with primary amine 3 to form compound 18.
- Alkyl- and cycloalkyl-substituted oxazolidinone precursors can be prepared by treating arylacetic acid 19 with a base such as LDA, and then with alkyl- or cycloalkyl-carboxaldehyde to form the corresponding aryl (cyclo)alkyl-3-hydroxypropionic acid 20, which can be cyclized by treatment with DPP A to form aryl-substituted oxazolidinone 21.
- Racemate 21 can be activated as is or it can first be resolved on a chiral column to obtain, e.g., 22., and then treated with p-nitrophenylchloroformate to form activated 23., which is then coupled with primary amine 3 to form compound 24.
- Step A 2-(3,4-Difluorophenyl)-3-cyclopropyl-3-hydroxypropionic acid
- Step B 4-(3,4-Difluorophenyl)-5-cyclopropyloxazolidin-2-one
- (+)-4-(3,4-difluorophenyl)-5-cyclopropyl-oxazolidin- 2-one (2 g, 8.3 mmol) in 100 ml THF was added a solution of n-butyllithium in hexane (9.1 mmol) dropwise via a syringe under an argon atmosphere at -78°C. The resulting yellow solution was stirred at -78°C for 10 min. To this solution was then added dropwise via syringe 4-nitrophenylchloro formate (1.03 g, 5.1 mmol) in 20 ml of THF. The reaction was stirred at -78° for 10 min.
- the reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate (2 X 200 ml). The organic extracts were washed with brine, and the organic layer was dried over Na 2 SO 4 . The solvent was removed after filtration, and the residue was purified by column chromatography on silica gel 30% ethyl acetate hexane. The material was rechromatographed on silica gel eluting with 2% acetone/ methylene chloride to give 1.2 g of the product as a thick syrup which solidified upon standing.
- Step D (+)-(4S,5S)-5-Cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazoli-dine-3- carboxylic acid ⁇ 3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-l-yl]-propyl ⁇ amide hydrochloride
- Step B 4-(3,4-Difluorophenyl)-5-methyloxazolidin-2-one
- the resulting hydroxy acids without further purification, were dissolved in dry degassed DMF (50 ml) and treated with solid NaHCO3 (24.0 g, 278 mmol) and diphenylphosphorylazide (DPP A, 11.9 g, 41.7 mmol, 9.3 ml) at room temperature. Within minutes the reaction became very turbid and DMF was added (50 ml). After complete consumption of the starting acids (2 h), the heterogeneous mixture was filtered (the filter cake was washed with 100 ml DMF) and heated to 60 °C. Signs of nitrogen evolution were immediately apparent. After heating for 4 h the reaction mixture was concentrated in vacuo and purified by TLC (Si ⁇ 2, 8 mm, 0 -
- Enantiomers of the first (i.e. trans) diastereomeric mixture were separated by HPLC by using a Chiralcel OD column (4.6 x 250 mm) using 80% hexane/20%) isopropyl alcohol/ 0.1 % diethylamine as the eluting system (12 ml/min) under isothermal conditions (UN 254 nM).
- the (+)-enantiomer was used in the next step.
- Step C (+)-4-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-carboxylic acid-4- nitrophenyl ester
- (+)-4-(3,4-difluorophenyl)-5-methyl-oxazolidin-2-one (0.97 g, 4.55 mmol) in 60 ml THF was added a solution of n-butyllithium in hexane (3.06 ml, 4.9 mmol) dropwise via a syringe under an argon atmosphere at -78°C.
- the resulting yellow solution was stirred at -78 C for 40 min.
- Step D (+)-(4S,5S)-5-Methyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid ⁇ 3-[4-(4-fluorophenyl)-4-hydroxypiperidin-l -yl]-propyl ⁇ amide hydrochloride
- reaction mixture was stirred for one hour at room temperature, poured into saturated sodium bicarbonate (50 ml) and extracted with ethyl acetate (3 X 30 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil which was purified by flash chromatography on silica gel eluting with 3% methanol/dichloromethane.
- 100 mg of the compound of Example 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.
- 100 mg of the compound of Example 3 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 compounds of the present invention prepared in Examples 2 and 3 were respectively found to have alpha la Ki values of 0.11 nM and 0.19 nM, as determined via the screening assay described in Example 6.
- the binding selectivity of each of the compounds for the alpha la receptors versus the alpha lb and Id receptors was determined via the selective binding assay described in the preceding paragraph. The results were as follows:
- the binding affinity (Ki in nM) of the compounds of the present invention for histamine HI receptors can determined via the binding assay described in Chang et al., J. Neurochem. (1979), 32: 1653, or as described in US 5403847, or suitable modifications thereof known to those skilled in the art.
- the assay can be used to eliminate agents which specifically affect binding to hHl receptors.
- 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 5HT la receptor
- Mammalian cells expressing cloned human 5HT la 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/C filters
- 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.
- 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.
- pN2 (-log Kb) values were obtained from Schild plot when three or more concentrations were tested. When less than three concentrations of antagonist are tested, K values are calculated according
- [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.
- 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 inctsion ⁇ l/2 inch lateral to the penis is made to expose the urethers, bladder and urethra.
- the urethers are ligated and cannulated so that urine flows freely into beakers.
- the dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra.
- Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate.
- the bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra.
- the bladder incision is sutured with 2-0 or 3-0 silk (purse- string suture) to hold the transducer.
- the tip of the transducer is placed in the prostatic urethra and the position of the Millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure.
- Phenylephrine an alpha 1 adrenergic agonist, is administered (0.1-100 ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure.
- the dose ratios for the antagonist doses are calculated as the ratio of the EDso'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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