EP0812196A1 - ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS - Google Patents
ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTSInfo
- Publication number
- EP0812196A1 EP0812196A1 EP96905575A EP96905575A EP0812196A1 EP 0812196 A1 EP0812196 A1 EP 0812196A1 EP 96905575 A EP96905575 A EP 96905575A EP 96905575 A EP96905575 A EP 96905575A EP 0812196 A1 EP0812196 A1 EP 0812196A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- oxo
- mono
- dioxido
- benzisothiazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- This invention relates to certain novel compounds, their synthesis, and their use as a selective alpha la adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating 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 subdivided into eel, ⁇ X2, Bl, and ⁇ 2 subtypes. Functional differences between a ⁇ and ⁇ 2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.
- WO 92/0073 the selective ability of the R(+) enantiomer of terazosin to selectively bind to adrenergic receptors of the alpha 1 subtype was reported.
- the ⁇ / ⁇ 2 selectivity of this compound was disclosed as being significant because agonist stimulation of the oc2 receptors was said to inhibit secretion of epinephrine and norepinephrine, while antagonism of the ⁇ 2 receptor was said to increase secretion of these hormones.
- non- selective alpha-adrenergic blockers such as phenoxybenzamine and phentolamine, is limited by their cx2 adrenergic receptor mediated induction of increased plasma catecholamine concentration and the attendant physiological sequelae (increased heart rate and smooth muscle contraction).
- Adrenoreceptors Molecular Biology. Biochemistry and Pharmacology. (Progress in Basic and Clinical Pharmacology series, Karger, 1991), wherein the basis of ⁇ i/ ⁇ 2 subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3'-terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting ⁇ -adrenergic receptor affinity was explored.
- 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.
- 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 ⁇ i subtype was reported.
- combinations of 5- alpha-reductase inhibitory compounds and alpha 1 -adrenergic receptor blockers terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin
- no information as to the ⁇ i A, ⁇ iB, or ⁇ ic subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known.
- Non-selective alpha 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer).
- prazosin Minipress, Pfizer
- Terazosin Terazosin
- doxazosin mesylate Cardura, Pfizer
- identification of active compounds is accomplished through use of animal tissues known to be enriched in adrenergic receptors.
- rat tissues have been used to screen for potential adrenergic receptor antagonists.
- compounds which appear active in animal tissue may not be active or sufficiently selective in humans. This results in substantial wastage of time and effort, particularly where high volume compound screening programs are employed.
- compounds, which might be highly effective in humans would be missed because of their absence of appreciable affinity for the heterologous animal receptors.
- even single amino acid changes between the sequence of biologically active proteins in one species may give rise to substantial pharmacological differences.
- WO94/08040 published 14 April 1994 and WO94/10989, published 26 May 1994
- a cloned human ⁇ ic adrenergic receptor and a method for identifying compounds which bind the human ⁇ ic receptor has now made possible the identification of selective human ⁇ ic adrenergic receptor antagonists useful for treating BPH.
- the instant patent disclosure discloses novel compounds which selectively bind to the human ⁇ ic receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors, thus defining the specificity of the compounds of the present invention for the human ⁇ ic adrenergic receptor.
- 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-alpha reductase inhibitors, including PROSCAR® (finasteride).
- a more long-term anti-BPH therapeutics such as testosterone 5-alpha reductase inhibitors, including PROSCAR® (finasteride).
- these compounds may be used to induce highly tissue-specific, localized ⁇ ic adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac a ⁇ hythmias, and possibly a host of alpha lc receptor mediated central nervous system events.
- ⁇ i-AR ⁇ i adrenergic receptor
- This new naming system reflects the correspondence between the proteins encoded by the ⁇ ia and ⁇ ib genes (new IUPHAR nomenclature) and the receptors characterized by traditional pharmacological means as ⁇ iA and ⁇ iB, respectively, in the literature. Recombinant receptors and receptors characterized pharmacologically in tissues are distinguished by lowercase and uppercase subscripts, respectively.
- the present invention provides novel compounds for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH).
- BPH benign prostatic hyperplasia
- the compounds selectively antagonize the human ⁇ ia adrenergic receptor at subnanomolar concentration while exhibiting at least 100 fold lower affinity for the aid and ⁇ ib human adrenergic receptors and many other G-protein coupled receptors.
- This invention has the advantage over non-selective ⁇ i 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:
- X is selected from N-Rl or O;
- Rl is selected from the group consisting of hydrogen, C3-6 cycloalkyl, unsubstituted or substituted Ci-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Ci-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring or aryl, and unsubstituted or substituted C2-6 alkenyl where the substituent on the alkenyl is selected from mono-, di- or tri-halogen, Ci-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring or aryl;
- R2 is independently one or more of hydrogen, halogen, Ci-4 alkoxy, mono-, di- or tri-halogenated Ci-4 alkoxy, or unsubstituted or substituted Cl-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring or aryl;
- R 3 is selected from hydrogen, cyano, C02R , CONH2, CONHR 1 , CON (R 1)2, C3-6 cycloalkyl or C3-6 cycloalkyl wherein one of the carbon atoms is replaced with a heteroatom selected from O or NH, or unsubstituted or substituted mono- or di-Cl-6 alkyl wherein the substituent on the mono- or di-alkyl is selected from hydroxy, Ci-4 alkoxy, amino or mono-, di- or tri-halogen;
- R is independently one or more of hydrogen, Cl-6 alkyl, halogen, Ci-4 alkoxy, mono-, di- or tri-halogenated Cl-4 alkoxy, nitro, amino, mono-, di- or tri-halogenated Cl-6 alkyl, Cl-6 alkylsulfonyl, Cl-4 alkylenedioxy, unsubstituted or substituted aryl where the substituent on the aryl is selected from halogen, unsubstituted Cl-3 alkyl, mono-, di- or tri-halogenated Cl-3 alkyl or Cl-4 alkoxy- Ci-3 alkyl, or unsubstituted or substituted heterocyclic ring where the substituent on the heterocyclic ring is selected from halogen, unsubstituted Cl-3 alkyl, mono-, di- or tri-halogenated Cl-3 alkyl or Cl-4 alkoxy-Ci-3 alkyl;
- R5 is independently one or more of hydrogen, cyano, Cl-6 alkyl, CO2R 1 , CONH2, CONHRl , CON(Rl )2;
- n is an integer of from 2 to 4;
- R 3 and R5 are both hydrogen, then X is N-R where Rl is selected from C3-6 cycloalkyl; unsubstituted C2-6 alkyl or substituted Cl-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring or aryl; or unsubstituted or substituted C2-6 alkenyl where the substituent on the alkenyl is selected from mono-, di- or tri- halogen, Cl-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring or aryl; and the pharmaceutically acceptable salts thereof.
- R2 is independently one or more of hydrogen, halogen, Cl-4 alkoxy or unsubstituted or substituted Cl-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring or aryl;
- R4 is independently one or more of hydrogen, Cl-6 alkyl, halogen, Cl-4 alkoxy, nitro, amino, mono-, di- or tri-halogenated Cl-6 alkyl, Cl-6 alkylsulfonyl, Cl-4 alkylenedioxy, unsubstituted or substituted aryl where the substituent on the aryl is selected from halogen, unsubstituted Cl-3 alkyl, mono-, di- or tri-halogenated Cl-3 alkyl or Cl-4 alkoxy-Cl-3 alkyl, or unsubstituted or substituted heterocyclic ring where the substituent on the heterocyclic ring is selected from halogen, unsubstituted Cl-3 alkyl, mono-, di- or tri-halogenated Cl-3 alkyl or Cl-4 alkoxy-Cl-3 alkyl; and all other variables are as defined above;
- X is N-Rl where Rl is unsubstituted C2-6 alkyl or substituted Cl-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring or aryl.
- Rl is unsubstituted C2-6 alkyl or substituted Cl-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring or aryl.
- R is selected from the group consisting of hydrogen, unsubstituted or substituted Cl-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, a heterocyclic ring or phenyl, and unsubstituted or substituted
- R2 is independently one, two or three of hydrogen, halogen or C 1-6 alkyl
- R 3 is selected from hydrogen, cyano, Cl-4 alkoxycarbonyl, CONH2 or unsubstituted or substituted mono- or di-Cl-6 alkyl wherein the substituent on the mono- or di-alkyl is mono-, di- or tri-halogen;
- R is independently one, two or three of hydrogen, Cl-6 alkyl, halogen, Cl-4 alkoxy, mono-, di- or tri-halogenated Cl-4 alkoxy, nitro or Cl-4 alkylenedioxy;
- R5 is independently one, two or three of hydrogen, cyano, Cl-6 alkyl or C ⁇ 2Rl ; and where all other variables are as defined above;
- X is N-Rl where Rl is selected from unsubstituted C2-6 alkyl or substituted
- Cl-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, a heterocyclic ring or phenyl; or unsubstituted or substituted C2-6 alkenyl where the substituent on the alkenyl is selected from mono-, di- or tri-halogen; and the pharmaceutically acceptable salts thereof.
- R4 is independently one, two or three of hydrogen, Cl-6 alkyl, halogen, Cl-4 alkoxy, nitro or Cl-4 alkylenedioxy; and all other variables are as defined above; provided that when R 3 and R ⁇ are both hydrogen, then X is N-Rl where Rl is selected from unsubstituted C2-6 alkyl or substituted
- Rl is selected from hydrogen, Cl-6 alkyl, mono-, di- or tri-halogenated Cl-6 alkyl, benzyl, C2-6 alkenyl or mono-, di- or tri-halogenated C2-6 alkenyl;
- R3 is selected from hydrogen, cyano or mono- or di-Ci-6 alkyl;
- R4 is independently one, two or three of hydrogen, Cl-6 alkyl, halogen, Cl-4 alkoxy, mono-, di- or tri-halogenated Cl-4 alkoxy or Cl-4 alkylenedioxy; and where all other variables are as defined above;
- R 3 and R ⁇ are both hydrogen, then X is N-R where Rl is selected from unsubstituted C2-6 alkyl, mono-, di- or tri- halogenated Cl-6 alkyl, benzyl, C2-6 alkenyl or mono-, di- or tri- halogenated C2-6 alkenyl; and the pharmaceutically acceptable salts thereof.
- R4 is independently one, two or three of hydrogen, Cl-6 alkyl, halogen or Ci-4 alkylenedioxy; and all other variables are as defined above; provided that when R 3 and R ⁇ are both hydrogen, then X is N-Rl where Rl is selected from unsubstituted C2-6 alkyl, mono-, di- or tri-halogenated Cl-6 alkyl or benzyl.
- Rl is selected from hydrogen, Cl-4 alkyl, C2-6 alkenyl, benzyl, trifluoroethyl or fluoroethyl;
- R2 is selected from hydrogen, chlorine, fluoriqe or methyl
- R3 is selected from hydrogen, methyl or dimethyl
- R is selected from hydrogen, chlorine, ethoxy, trifluoromethoxy or ethylenedioxy; and R5 is selected from hydrogen, cyano, methyl or methoxycarbonyl; and where all other variables are as defined above;
- R 3 and R5 are both hydrogen, then X is N-R 1 where R is selected from unsubstituted C2-4 alkyl, C2-6 alkenyl, benzyl, trifluoroethyl or fluoroethyl; and the pharmaceutically acceptable salts thereof.
- R4 is independently one or more of hydrogen, chlorine or ethylenedioxy; and all other variables are as defined above; provided that when ⁇ and R5 are both hydrogen, then X is N-Rl where Rl is selected from unsubstituted C2-4 alkyl, C2-6 alkenyl, benzyl, trifluoroethyl or fluoroethyl.
- Rl is selected from unsubstituted C2-4 alkyl, C2-6 alkenyl, benzyl, trifluoroethyl or fluoroethyl; and the pharmaceutically acceptable salts thereof.
- An illustration of the invention is the compound of the formula
- Rl is selected from ethyl, trifluoroethyl or fluoroethyl
- R2 is selected from chlorine, fluorine or methyl
- R4 is selected from hydrogen, chlorine, ethoxy, methoxy or trifluoromethoxy; and the pharmaceutically acceptable salts thereof.
- Exemplifying the invention is the compound selected from:
- An example of the invention is the compound selected from
- a phaimaceutical composition comprising a therapeutically effective amount of 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.
- Another illustration of the invention is a method of treating benign prostatic hyperplasia, relaxing urethral smooth muscle, relaxing prostatic smooth muscle and/or improving urine flow 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 pharmaceutical compositions described above.
- More particularly illustrating the invention are the methods of treating BPH, relaxing urethral smooth muscle, relaxing prostatic smooth muscle and/or improving urine flow wherein the compound or pharmaceutical composition additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH, relax urethral smooth muscle, relax prostatic smooth muscle and/or improve urine flow.
- the testosterone 5-alpha reductase inhibitor is a type 1 , a type 2, both a type 1 and a type 2 or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. More preferably, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5- alpha reductase inhibitor. Most preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
- More specifically exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the alpha la adrenergic receptor which comprises administering to a subject in need thereof an amount of any of the compounds or pharmaceutical compositions 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, glaucoma, high cholesterol, impotency, sympathetically mediated pain and cardiac arrhythmia.
- An additional example of the invention is a drug which is useful for treating BPH, relaxing urethral smooth muscle, relaxing prostatic smooth muscle and/or improving urine flow in a mammal in need thereof, the effective ingredient of the said drug being any of the compounds descibed above.
- More specifically illustrating the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment of BPH, relaxing urethral smooth muscle, relaxing prostatic smooth muscle and/or improving urine flow in a mammal in need thereof.
- Another aspect of the invention is a method of preparing any of the compounds described above which comprises alkylating a halogenated butyl saccharin with a deprotected benzimidazolyl piperidine or a deprotected benzoxazolinyl piperidine.
- the method comprises reacting a butyl saccharin moiety with a piperidinylbenzimidazolinone moiety.
- the compounds of the present invention exhibit high selectivity for the human alpha la adrenergic receptor.
- One implication of this selectivity is that the compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.
- the compounds of the present invention are useful for relaxing urethral smooth muscle; additionally, the compounds claimed herein are useful for relaxing prostatic smooth muscle.
- the ability of the compounds of the present invention to relax urethral and prostatic smooth muscle results in improved urine flow in patients suffering from impaired urine flow (i.e., difficulty in urination) due to enlargement of the prostate gland.
- impaired urine flow i.e., difficulty in urination
- the compounds of the present invention are useful for treating BPH.
- Representative compounds of this invention display submicromolar affinity for the human ⁇ ia adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human aid and ⁇ ib 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 ⁇ ia adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human ai and ⁇ ib adrenergic receptor subtypes, and many other G-protein coupled human receptors.
- the most preferred compounds of this invention exhibit a Ki for human ⁇ ia adrenergic receptors which is more than 100 fold lower than for the human aid or aib adrenergic receptors, while exhibiting greater than 50 fold selectivity for the human ⁇ ia adrenergic receptor over all other human G-protein coupled receptors tested (including serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors).
- Representative compounds of the present invention are also potent opioid agonists useful as analgesics to eliminate or ameliorate pain and suffering in animals, preferably mammals, especially humans, without loss of consciousness. More particularly, the opioid agonist compounds described herein are selective for the mu opioid receptor over the kappa and delta opioid receptors.
- Opioids are a class of drugs which are, to varying degrees, opium-like or morphine-like in their properties.
- the opium group of narcotic drugs are among the most powerfully acting and clinically useful drugs producing depression of the central nervous system (CNS). Drugs of this group are used principally as analgesics, but possess numerous other useful properties.
- Morphine for example, is used to induce sleep in the presence of pain, relieve diarrhea, suppress cough, ease dyspnea and facilitate anesthesia.
- Analgesia is defined as the reduction of awareness of pain and suffering without loss of consciousness.
- Analgesic compounds are agents which produce a state of analgesia, and thus, analgesics are compounds which alleviate and are useful for treating pain without loss of consciousness.
- mo ⁇ hine agonists mo ⁇ hine-like drugs
- mixed mo ⁇ hine agonist-antagonists could best be explained by postulating the existence of more than one type of cellular receptor for the opioids, and for related drugs.
- the rigid alkaloid opiates typified by mo ⁇ hine, are believed to produce their major effects on the CNS and the bowel by acting as agonists, particularly at the mu receptors; however, mo ⁇ hine also has appreciable affinity for kappa and delta receptors. [Jaffe, J.H.; Martin, W.R., Opioid Analgesics and Antagonists, in Goodman & Gilman's The Pharmacological Basis of Therapeutics (8th ed. 1990)].
- ligands which are highly selective for a single opioid receptor type or subtype have the potential of minimizing or eliminating unwanted side effects mediated by the other opioid receptor types. It has now been found that compounds of the present invention are highly selective for the mu opioid receptor and are therefore useful as analgesic agents.
- opioid agonists are primarily employed as analgesics, the compounds described herein are also useful as antitussives, antidiarrhea agents, anesthetics and tranquilizers.
- a method of treating a condition which is susceptible to treatment by agonism of a mu opioid receptor which comprises administering to a subject in need thereof an amount of a compound effective to treat the condition wherein the compound has the formula:
- X is selected from N-Rl or O;
- Rl is selected from the group consisting of hydrogen, C3-6 cycloalkyl, unsubstituted or substituted Cl-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring or aryl, and unsubstituted or substituted C2-6 alkenyl where the substituent on the alkenyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring or aryl;
- R2 is independently one or more of hydrogen, halogen, Cl-4 alkoxy, mono-, di- or tri-halogenated Cl-4 alkoxy or unsubstituted or substituted Cl-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, SO2NH2, a heterocyclic ring
- R3 is selected from hydrogen, cyano, CO2R 1 , CONH2, CONHR 1 , CON(Rl)2, C3-6 cycloalkyl, C3-6 cycloalkyl wherein one of the carbon atoms is replaced with a heteroatom selected from O or NH, or unsubstituted or substituted mono- or di-Ci-6 alkyl wherein the substituent on the mono- or di-alkyl is selected from hydroxy, Cl-4 alkoxy, amino or mono-, di- or tri-halogen;
- R4 is independently one or more of hydrogen, Cl-6 alkyl, halogen, Ci-4 alkoxy, mono-, di- or tri-halogenated Cl-4 alkoxy, nitro, amino, mono-, di- or tri-halogenated Cl-6 alkyl, Cl-6 alkylsulfonyl, Cl-4 alkylenedioxy, unsubstituted or substituted aryl where the substituent on the aryl is selected from halogen, unsubstituted Cl-3 alkyl, mono-, di- or tri-halogenated Cl-3 alkyl or Cl-4 alkoxy-Cl-3 alkyl, or unsubstituted or substituted heterocyclic ring where the substituent on the heterocyclic ring is selected from halogen, unsubstituted Cl-3 alkyl, mono-, di- or tri-halogenated Cl-3 alkyl or Cl-4 alkoxy-Cl-3 alkyl;
- R5 is independently one or more of hydrogen, cyano, Cl- alkyl, CO2R , CONH2, CONHR 1 , CON(R 1)2;
- n is an integer of from 2 to 4; and the pharmaceutically acceptable salts thereof.
- n is an integer of from 2 to 4; and the pharmaceutically acceptable salts thereof.
- R3 is selected from cyano, C ⁇ 2Rl, CONH2, CONHRl, CON(Rl)2, C3- 6 cycloalkyl, C3-6 cycloalkyl wherein one of the carbon atoms is replaced with a heteroatom selected from O or NH, or unsubstituted or substituted mono- or di-Ci-6 alkyl wherein the substituent on the mono- or di-alkyl is selected from hydroxy, Cl-4 alkoxy, amino or mono-, di- or tri-halogen; and
- R4 is independently one or more of hydrogen, Cl-6 alkyl, halogen, Cl-4 alkoxy, mono-, di- or tri-halogenated Cl-4 alkoxy, nitro or Ci-4 alkylenedioxy; and wherein all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
- R 1 is selected from the group consisting of hydrogen, unsubstituted or substituted Cl-6 alkyl where the substituent on the alkyl is selected from mono-, di- or tri-halogen, Cl-4 alkoxy, carboxy, CONH2, a heterocyclic ring or phenyl, and unsubstituted or substituted C2-6 alkenyl where the substituent on the alkenyl is mono-, di- or tri-halogen;
- R2 is independently one or more of hydrogen, halogen or Cl-6 alkyl
- R is selected from cyano, Cl-4 alkoxycarbonyl, CONH2 or unsubstituted or substituted mono- or di-Ci-6 alkyl wherein the substituent on the mono- or di-alkyl is mono-, di- or tri-halogen;
- R is independently one or more of hydrogen or halogen; and R5 is independently one or more of hydrogen, cyano, Cl-6 alkyl or CO2R 1 ; and wherein all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
- Illustrative of this aspect of the invention is the method of alleviating pain wherein
- Rl is selected from hydrogen, Cl-6 alkyl, mono-, di- or tri-halogenated Cl- alkyl, benzyl, C2-6 alkenyl or mono-, di- or tri-halogenated C2-6 alkenyl;
- R3 is selected from cyano or mono- or di-Ci-6 alkyl
- R4 is independently one or more of hydrogen or chlorine; and wherein all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
- Rl is selected from hydrogen, Cl-4 alkyl, C2-6 alkenyl, benzyl, trifluoroethyl or fluoroethyl;
- R2 is independently one or more of hydrogen, chlorine, fluorine or methyl
- R3 is selected from hydrogen, methyl or dimethyl
- R5 is independently one or more of hydrogen, cyano, methyl or methoxycarbonyl; and wherein all other variables are as defined above; and the pharmaceutically acceptable salts thereof. Exemplifying this aspect of the invention is the method of alleviating pain wherein the compound has the formula
- An example of this aspect of the invention is the method of alleviating pain wherein the compound is selected from the group consisting of
- the compound is selected from l,l-dioxido-2-(4-(4-(2-oxo-l -benzimidazoliny] )piperidin-l -yl)pentyl)- 1 ,2-benzisothiazol-3(2H)-one; l ,l-dioxido-2-(4-(4-(3-ethyl-2-oxo-l-benzimidazolinyl)piperidin-l- yl)pentyl)- 1 ,2-benzisothiazol-3(2H)-one;
- the compound is selected from
- Another illustration of this aspect of the invention is a drug which is useful for alleviating pain or inducing analgesia in a mammal in need thereof, the effective ingredient of the said drug being any of the compounds descibed above.
- the compounds of the present invention are administered in dosages effective to antagonize the alpha 1 a receptor where such treatment is needed, as in BPH, or in dosages effective to agonize the mu opioid receptor where such treatment for pain is needed.
- the salts of the compounds of this invention refer to non-toxic
- 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, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g.
- salts include the following:
- Glycollylarsanilate Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate .Tosylate, Triethiodide and Valerate.
- 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 polymo ⁇ hs 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 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 shall mean phenyl, napthyl or fluorenyl.
- 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 inte ⁇ reted as including those limitations given above for "alkyl” and "aryl.”
- Designated numbers of carbon atoms e.g., Cl-l ⁇ shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
- halogen shall include iodine, bromine, chlorine and fluorine.
- substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
- the substituents on the piperidine ring (i.e., R ⁇ ) and the fused benzene rings of the benzimidazolone (or benzoxazolinone) and saccharin rings, i.e., R2 and R , respectively, can be one or more of the named substituents. That is, the piperidine ring and the benzene rings can be mono-, di-, tri- or tetra-substituted by any of the substituents listed in the definitions of R ⁇ , R4 and R ⁇ . Moreover, where the piperidine or benzene rings are poly- substituted, the substitutents can be the same or different.
- 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-R6 (R6 ⁇ S hydrogen, Cl-6 alkyl or absent), O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized.
- 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 are 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, mo ⁇ holinyl, thiazglyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamo ⁇ holinyl,
- the term "mono- or di-Ci-6 alkyl” shall mean that the R3 bound carbon can be mono- or di- substituted with a Cl-6 alkyl group.
- the Cl-6 alkyl groups can be the same or different.
- C3-6 cycloalkyl shall mean that the methylene group and the R substituent can together form a C3-6 cycloalkyl ring.
- Cl-4 alkylenedioxy shall mean that phenyl ring containing the R4 substituent contains a Ci-4 alkylenedioxy bridge connecting two adjacent carbon atoms of the benzene ring.
- analgesia is defined as the reduction of awareness of pain and suffering without loss of consciousness.
- Analgesic compounds are agents which produce a state of analgesia (i.e., induce analgesia), and thus, analgesics are compounds which alleviate and are useful for treating pain without loss of consciousness.
- 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.
- a variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- the liquid forms in which the novel compositions of the present invention may be inco ⁇ orated 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.
- 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
- 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 ⁇ ia receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the ⁇ ia receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., aid, a lb) or beta adrenergic receptors.
- the ability of compounds of the present invention to specifically bind to the ⁇ ia receptor makes them useful for the treatment of BPH.
- the specificity of binding of compounds showing affinity for the ⁇ ia 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, each of which is hereby inco ⁇ orated by reference.
- the cloned human ⁇ ia 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 aid, alb, and ⁇ ia 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 selective human ⁇ ia 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 and U.S. Patent No. 5,403,847, issued April 4, 1995, the contents of which are hereby inco ⁇ orated by reference].
- 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 and/or in the alleviation of pain 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, veterinarian or clinician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
- Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
- the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
- carrier suitable pharmaceutical diluents, excipients or carriers
- the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
- suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
- Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
- the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
- suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
- Other dispersing agents which may be employed include glycerin and the like.
- sterile suspensions and solutions are desired.
- Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
- the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
- Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
- the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues.
- the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required and/or whenever relief from pain is required.
- the daily dosage of the products may be varied over a wide range from 0.
- 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 250 mg/kg of body weight per day.
- the range is from about 0.001 to 100 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 ⁇ ia 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, hereby inco ⁇ orated by reference).
- 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.
- 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 1 a adrenergic receptor may be independently optimized and combined to achieve a 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 inte ⁇ reted 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 in the combination is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an ⁇ ia 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 perferably, 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.
- Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
- 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.
- the compounds of the present invention are prepared by a two step alkylation process beginning with a saccharin or substituted saccharin (referred to as "the saccharin moiety") prepared according to methods known in the art (see for example US Patents 4,818,756; 4,937,343; 4,988,809 and 5,187,276, hereby inco ⁇ orated by reference for this pu ⁇ ose).
- the saccharin moiety is alkylated with a reagent such as 1 ,4-dibromobutane, or a similar reagent, to form the butyl-saccharin moiety (see Scheme 1 and Examples 21 and 22 below).
- the butyl saccharin is then alkylated with a piperidinyl benzoxazolinone (prepared as shown in Examples 17-19 which follow) or with a piperidinyl benzimidazolinone (prepared as shown in Schemes 1 - 4 below) to form the active compounds of this invention.
- Various ⁇ -substituted benzimidazolinone-piperidine derivatives are prepared by alkylating the Boc-protected benzimidazolinone-piperidine as shown in Scheme 1 and Example 1, steps 1-3 below).
- the benzimidazolinone-piperidine derivatives with substituents on the benzene ring are prepared as shown in Schemes 4 and 5 using procedures described in J. Med.
- Compound A is prepared according to Scheme 5 and the procedure of Example 27.
- Step 1 To a partial suspension of 4-(2-oxo-l -benzimidazolinyl) piperidine (1.085 gm, 5.0 mmol), which is commercially available, in 30 mL of methylene chloride under an argon atmosphere was added 1.37 gm (6.3 mmol) of di-t-butyl dicarbonate. After reaction was stirred at ambient temp, for 1 hour, the solvent was removed and the residue triturated with diethyl ether to give l-t-butoxycarbonyl-4-(2- oxo-l-benzimidazolinyl)piperidine as an off-white solid, melting point 161-163°C.
- Step 2 To a solution of l-t-butoxycarboxyl-4-(2-oxo-l- benzimidazolinyl)-piperidine (542 mg, 1.7 mmol) in dry dimethyl- formamide (5 mL) under an argon atmosphere was added 86 mg (2.0 mmol) of 60% sodium hydride in mineral oil. The mixture was warmed at 50°C until gas evolution ceased ( ⁇ l/2 hour) and then cooled to room temperature. Iodopropane (0.29 mL, 3.0 mmol) was added by syringe and the reaction was stirred for 20-48 hours. Water was added to the reaction mixture and the product extracted into ethyl acetate.
- Step 3 A solution of l-t-butoxycarbonyl-4-(3-propyl-2-oxo-l- be ⁇ _zimidazolinyl)piperidine (540 mg, 1.5 mmol) in chloroform (7 mL) containing trifluoroacetic acid (1 mL) was allowed to stir at ambient temperature for 15-25 hours. The solvent was removed on a rotary evaporator, the residue dissolved in chloroform and washed with aq. Na2C ⁇ 3. The dried (Na2S04) chloroform extract was evaporated to give 4-(3-propyl-2-oxo-l-benzimidazolinyl)piperidine as an oil which was used as is.
- Step 4 To a solution of 4-(3-propyl-2-oxo-l-rjenzimidazolinyl)- piperidine (440 mg, 1.7 mmol) in dry dimethylformamide (6 mL), under an argon atmosphere was added l,l-dioxido-2-(4-bromobutyl)-5- chloro-1.2-benzisothiazol-3(2H)-one (615 mg, 1.74 mmol, prepared as shown in Example 22) followed by triethylamine (0.25 mL, 1.8 mmol). This solution was heated at 50°C for four hours and then cooled to room temperature as water was added. The product was extracted, dried (Na2S ⁇ 4) and evaporated.
- Step 1 A mixture of 12.8 gm (77 mmol) of 5-bromo-2-pentanone, which was obtained as described by ApSimon and Sequin in Synthetic Communications. J_0, 897 (1980), and 12 mL of ethylene glycol in 100 mL of benzene containing 0.84 gm of p-toluenesulfonic acid was refluxed with a Dean-Stark trap until the required water was azeotroped off. The solution was poured into saturated NaHC ⁇ 3 and the product extracted into ethyl acetate. The dried (Na2S ⁇ 3) solution was evaporated to give the ethylene ketal of 5-bromo-2-pentanone which was used as is.
- Step 2 A mixture of the above ketal (3.2 gm, 15 mmol) and sodium saccharin (3.1 gm, 14 mmol) in dimethylformamide (15 mL) was heated at 170°C for 5 hours. The cooled reaction mixture was poured into water and the crude product extracted into ethyl acetate. The dried extract was evaporated and the crude product was chromotographed on a column of silica gel eluting with a gradient of 20-40% EtOAc/hexane to give crystalline l ,l -dioxido-2-(4-oxo-pentyl)-l ,2-benzisothiazol- 3(2H)-one, melting point 90-93°C.
- Step 3 A mixture of 4-(3-ethyl-2-oxo-l -benzimidazolinyl)piperidine (319 mg, 1.0 mmol) and l ,l -dioxido-2-(4-oxo-pentyl)-l ,2- benzisothiazol-3-(2H)-one (267 mg, 1.0 mmol) in isopropanol (0.4 mL) containing titanium (IV) isoproproxide (0.4 mL, 1.3 mmol) was heated at 55°C under an argon atmosphere for one hour to give a yellow solution. This solution was cooled to room temperature and diluted with absolute EtOH (4 mL).
- Step 4 Compound L was chromatographed on a chiral HPLC column (Chiralcel OD®, Chiral Technologies Inc., Exton, Pa.) eluting under isocratic conditions with a 90%hexane/ 10% 1 -butanol/ 0.1 % diethylamine solvent mixture to afford the two enantiomers, designated as Enantiomer 1 and Enantiomer 2.
- a chiral HPLC column Chiralcel OD®, Chiral Technologies Inc., Exton, Pa.
- Step 1 A solution of 5-(benzyloxycarbonylamino)-2-methyl-2- pentylamine (1.59 gm, 6.3 mmol) [prepared as described by Nagarajan and Ganem, J. Org. Chem.. 51.
- Step 2 An equivalent of phenylene diamine (1 18 mg, 1.09 mmol) was added to a solution of N-(5-benzyloxycarbonylamino-2-methyl-2- pentyl)-4-piperidone (345 mg, 1.04 mmol) in methanol (5 mL) containing acetic acid (0.065 mL, 1.15 mmol). After stirring this reaction mixture for one hour, solid sodium cyanoborohydride (82 mg. 1.3 mmol) was added in one portion and stirring was continued overnight at ambient temperature. The reaction was cooled in an ice bath and acetaldehyde (0.06 mL, 1.0 mmol) was added by syringe. The reaction was stirred for an additional 20 hours.
- Step 3 The above mixture was dissolved in ethyl acetate (8 mL), saturated aq. Na2 ⁇ 3 (6 mL) was added, and the biphase mixture cooled in an ice bath as 1.9M phosgene/toluene (1 mL) was added dropwise. After 4-20 hours, the reaction mixture was diluted with water and the crude product extracted into ethyl acetate.
- Step 4 A solution of l-(5-benzyloxycarbonylamino-2-methyl-2- pentyl)-4-(3-ethyl-2-oxo- l-benzimidazolinyl)piperidine (93 mg, 0.19 mmol) in methanol (8 mL) containing chloroform (0.04 mL,
- Step 5 A solution of l-(5-amino-2-methyl-2-pentyl)-4-(3-ethyl-2-oxo- l -benzimidazolinyl)piperidine (67 mg, 0.19 mmol) in methylene chloride (4 mL) was cooled in an ice bath and methyl 2-chlorosulfonyl benzoate (5.5 mg, 0.25 mmol) and triethylamine (0.04 mL, 0.3 mmol) were added. After one hour aq. Na2C03 was added to the reaction mixture and the product extracted into methylene chloride, dried (Na2S04) and evaporated.
- Step 1 A mixture of 15.4 g 4-piperidone hydrochloride hydrate, 200 mL ether, 100 mL saturated aqueous Na2C ⁇ 3 solution and 21.8 g di-t- butyldicarbonate was vigorously stirred for 48 h. The layers were separated and the organic layer was washed with two 150 mL portions of 10% aqueous citric acid, dried over MgS04. Removal of solvents under reduced pressure gave N-t-butyloxycarbonyl-4-piperidone as a white solid.
- Step 2 A mixture of 6.0 g N-t-butyloxycarbonyl-4-piperidone, 3.3 g of 2-aminophenol, 25 mL of 1 ,2-dichloroethane, 25 mL of glacial acetic acid, and 500 mg powdered 4A molecular sieves was stirred under inert atmosphere. After 30 min, 6.4 g sodium triacetoxyborohydride was added stirring was continued for 38 h. The reaction mixture was poured into 400 mL ethyl acetate and 200 mL saturated aqueous NaHC03 and the layers separated. The organic layer was washed with brine (2 x 100 mL), dried over MgS ⁇ 4, filtered and concentrated under reduced pressure.
- Step 3 To a stirred solution of 6.95 g 1 -t-butyloxycarbonyl-4-(2- hydroxyphenylamino)piperidine and 6.2 mL diisopropylethylamine in 120 mL tetrahydrofuran cooled to 0°C was added 3.0 g triphosgene. The reaction was stirred 30 min at 0°C and then at room temperature 2 h. The precipitate was removed by filtration, the filtrate concentrated at reduced pressure and partitioned between 250 mL ethyl acetate and 100 mL saturated aqueous Na2C03.
- Step 4 A stirred solution of 6.0 g (19 mmol) 1 -(( 1 -t-butyloxy- carbonyl)piperidin-4-yl)-3-benzoxazolin-2-one in 120 mL ethyl acetate was cooled to -78°C and a stream of hydrogen chloride gas was introduced with a fritted dispersion tube for 15 min. The mixture was allowed to warm to 0°C for 1 h, then room temperature for 2 h. The resulting precipitate was collected by filtration. Drying at reduced pressure for 8 h gave the hydrochloride salt of l-(4-piperidinyl)-3- benzoxazolin-2-one as an off-white solid.
- Step 5 From l-(4-piperidinyl)-3-benzoxazolin-2-one and 1 ,1-dioxido- 2-(4-oxo-pentyl)-l,2-benzisothiazol-3(2H)-one using the procedures of Example 2 there was obtained a white solid upon formation of the HCl salt (from isopropanol and methanol), melting point 273-274°C. Analysis calculated for C24H27N3O5S ⁇ CI : C, 56.96; H, 5.58; N, 8.30; found: C, 56.59; H, 5.67, N, 8.01. The NMR was consistent with the structure.
- Step 1 4-(6-methyl-2-oxo-3-benzoxazolinyl)piperidine was obtained as a white solid from the reaction of 6-amino-m-cresol and N-t- butyloxycarbonyl-4-piperidone according to Steps 2-4 of Example 17.
- Step 2 From 4-(6-methyl-2-oxo-3-benzoxazolinyl)piperidine and 1 , 1 - dioxido-2-(4-oxo-pentyl)-l ,2-benzisothiazol-3(2H)-one using the procedures of Example 2 there was obtained a white solid upon formation of the HCl salt (from ethanol and diethyl ether), melting point 234-236°C. Analysis calculated for C25H29N3O5S-HC1-.0.4 H20: C, 56.95; H, 5.89; N, 7.97; found: C, 56.92; H, 5.75, N, 7.79. The NMR was consistent with the structure.
- Step 1 From phenylene diamine and methyl N-t-butoxycarbonyl-4- oxo-3-piperidinecarboxylate ( obtained by reaction of methyl 4-oxo-3- piperidinecarboxylate with di-t-butyl dicarbonate as described in Example 1 , Stepl ) using the procedures described in Example 3, Step 2 (except that the acetaldehyde was omitted) and Step 3, followed by removal of the t-butoxycarbonyl group with HCl gas in ethyl acetate there was obtained (+) cis/trans-4-(2-oxo- 1 -benzimidazoliny l)-3- methoxycarbonyl-piperidine which was used as is.
- Step 2 From ( ⁇ ) cis/trans-4-(2-oxo-l -benzimidazolinyl)-3- methoxycarbonyl -piperidine and l ,l-dioxido-2-(4-bromobutyl)-5- chloro-l,2-benzisothiazol-3(2H)-one (prepared as shown in Example 22) using the procedures described in Example 1 , Step 3, there was obtained a white solid from methylene chloride, melting point 170- 176°C. Analysis calculated for C25H27CIN4O6S: C, 54.89; H, 4.98; N, 10.24; found: C, 54.65; H, 4.98; N, 10.22. The NMR was consistent with the structure.
- Step 1 To a cloudy solution of 4-(3-n-propyl-2-oxo-l - benzimidazolinyl)- piperidine (420 mg, 1.62 mmol) [obtained in Example 1 , step 3] in diethyl ether (4 mL) which was cooled in an ice bath was added t-butyl hypochlorite (0.53 mL, 4.4 mmol) in three portions by syringe over a two hour period. When the starting amine had disappeared by tic, the diluted etheral mixture was washed with water and the organic solution dried (Na2S04).
- this etheral solution was added to a suspension of potassium superoxide (253 mg, 3.56 mmol) in diethyl ether (10 mL) containing 18-crown-6 ether (10 mg) and stirred vigorously for 15 - 20 hours. This mixture was filtered and the etheral filtrate was added dropwise to a solution of tri-methylsilyl cyanide (0.50 mL, 3.56 mmol) in diethyl ether (5 mL) cooled in an ice bath. After one hour the solution was washed with water and brine and then dried (Na2S ⁇ 4) and evaporated.
- Step 2 From ( ⁇ ) cis/trans-2-cyano-4-(3-n-propyl-2-oxo-l- benzimidazolinyl)- piperidine and l ,l-dioxido-2-(4-bromobutyl)-5- chloro-l ,2-benzisothiazol-3(2H)-one using a modification of the procedure described in Example 1 , Step 4, wherein one equivalent of potassium iodide was added and the reaction was warmed at 80°C for 24 hours, there was obtained a white solid after chromatographic purification, melting point 159-160 °C. The NMR was consistent with structure.
- Step 1 Chlorosulfonic acid (6 mL, 90 mmol) was added dropwise to an ice cooled solution of 1 ,4-benzodioxane ( 12 gm, 88 mmol) in chloroform (40 mL). After allowing the reaction mixture to warm to 20°C (about 15 min.), this solution was poured jon to ice (400 gm) and the product extracted into chloroform. This extract was dried (MgS04) and the solvent evaporated to give the 6-chlorosulfonyl-l ,4- benzodioxane as a white crystalline solid.
- This sulfonyl chloride was dissolved in methylene chloride ( 100 mL) and added to an ice cooled solution of 4-amino- 1 -butanol ( 10 gm, 1 12 mmol) and excess triethylamine (25 mL) in methylene chloride (250 mL). After stirring for 24 hours and gradually warming to ambient temp., the reaction mixture was washed with 6N HCl (100 mL), dried (MgS ⁇ 4) and filtered.
- the separated THF layer was washed with diluted Na2C ⁇ 3 (2 x 100 mL).
- the combined Na2C ⁇ 3 extracts were carefully acidified with cone. HCl and the product was extracted into diethyl ether (3 x 200 mL).
- the ether extracts were dried (MgS ⁇ 4) and the solvent evaporated to give the carboxylic acid as a glassy foam.
- This material was dissolved in methylene chloride (200 mL), cooled to 0°C, and triethylamine (7 mL) added followed by the dropwise addition of methyl chloroformate (2 mL).
- Step 2 To a solution of l , l-dioxido-2-(4-hydroxybutyl)-4,5- ethylenedioxy- 1 ,2-benzisothiazol-3(2H)-one (313 mg, 1 mmol) and carbon tetrabromide (432 mg, 1.3 mmol) in methylene chloride (2 mL) cooled in an ice bath under a nitrogen atomosphere was added dropwise a solution of triphenylphosphine (341 mg, 1.3 mmol) in methylene chloride (3.5 mL).
- Steps 1 -4 are based on modifications of procedures described by R.Henning et.al., JMed.Chem. 30, 14-819 (1987): Step 1 : A solution of ethyl 4-amino-l -piperidine carboxylate (9.0 g, 52 mmol.) and 2-chloro-5-fluoronitrobenzene (10.3g, 58 mmol.) in cyclo- hexanol (30 mL) containing powdered sodium carbonate (6.1 g, 57 mmol.) was refluxed (>160°C) for 30 hours or until no further reaction was indicated by tlc( 30% EtOAc/hexane).
- Step 2 This l -ethoxycarbonyl-4-(4-fluoro-2-nitroanilino)piperidine (5.7g, 18.3 mmol.) was dissolved in THF (50 mL) and diluted with ethanol (100 mL). After addition of 5% platinum/carbon catalyst
- Step 3 The crude l -ethoxycarbonyl-4-(2-amino-4-fluoroanilino)piperi- dine above was dissolved in EtOAc (100 mL) and saturated aq. Na CO (100 mL) was then added to give a two-phase system. After cooling in an ice bath, phosgene in toluene (25 mL, 1.9N ) was added in portions with stirring. After one hour, the reaction mixture was warmed to room temp, and diluted with EtOAc. The organic layer was separated and washed with more NaHC ⁇ 3/Na2CO ⁇ solution, dried (Na2S ⁇ 4), and filtered through a pad of charcoal.
- Step 4 A suspension of l -ethoxycarbonyl-4-(5-fluoro-2-oxo- l -benz- imidazoliny piperidine (5.22g, 17 mmol.) in 2 N NaOH (55 mL) was refluxed for twelve hours. The clear amber solution was cooled to room temp, and solid NH4CI (5.9g, 1 10 mmol.) was added to neutralized the hydroxide. After addition of aq. Na2C ⁇ and 5 N NaOH (2 mL), the product was extracted into chloroform.
- Step 5 This crude 4-(5-fluoro-2-oxo-l-benzimidazolinyl)piperidine was dissolved in chloroform (70 mL), cooled in an ice bath and di-tert- butyl dicarbonate (4.13g, 19 mmol.) was added. After stirring for two hours, the solvent was evaporated and the residue triturated with Et2 ⁇ to give 1 -tert-butoxycarbonyl-4-(5-fluoro-2-oxo-l-benzimidazolinyl)- piperidine as an off-white solid.
- Step 6 Solid l-tert-butoxycarbonyl-4-(5-fluoro-2-oxo-l - benzimidazolinyl)piperidine (9.7 g, 28.9 mmol.) was dissolved in anhydrous DMF (72 mL) under an inert atmosphere and cesium carbonate ( 10.6 g, 32.5 mmol.) was added followed by excess 2,2,2-trifluoroethyl iodide ( 14.3 mL, 145 mmol.).
- This reaction mixture was gently warmed at 40 -50°C for an extended period ( 1 -2 days), periodically adding additional 2,2,2-trifluoroethyl iodide (4 mL, 4 mmol in four portions) to drive the alkylation to completion.
- the cooled reaction mixture was diluted with EtOAc and washed with aq. NaHC03 and water (3x).
- the organic layer was dried (Na2S ⁇ 4) and filtered through a pad of charcoal and the solvent then evaporated.
- Step 7 A solution of l -tert-butoxycarbonyl-4-(5-fluoro-3-(2,2,2-tri- fluoroethyl)-2-oxo-l -benzimidazolinyl)piperidine (4.17g, 10 mmol.) in chloroform (50 mL) containing trifluoroacetic acid (5.5 mL) was stirred at room temp, under an inert atmosphere for 6 -12 hours until reaction was complete. The solvent and excess TFA were removed and the residue redissolved in chloroform. This solution was washed with Na2C ⁇ 3/NaOH solution.
- Step 8 The 4-(5-fluoro-3-(2,2,2-trifluoroethyl)-2-oxo-l -benzimidazol- inyOpiperidine (-10 mmol.) above was dissolved in anhydrous DMF (25 mL) followed by the addition of l,l -dioxido-2-(4-bromobutyl)-5- chloro-l ,2-benzisothiazol-3(2H)-one (3.54 g, 10 mmol.) and triethylamine (1.4 mL, 10 mmol.) and allowed to stir at 50°C under an inert atmosphere for three hours or until reaction was complete.
- 100 mg of the compound of Example 27 (i.e., Compound A) 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 [ ⁇ H] spiperone to cells expressing human dopamine receptors D2, D3 or D4.
- the assay is initiated by adding 50-75 ⁇ g membranes in a total volume of 500 ⁇ l containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 ⁇ M apomorphine.
- the assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.
- the objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor
- Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at 38,OOOXg for 30'.
- the binding assay contains 0.25 nM [3H]8- OH-DPAT (8-hydroxy-2-dipropylamino- 1 ,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaC12 and lmg/ml ascorbate. Non-specific binding is defined using 10 ⁇ M propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters
- Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate.
- Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary.
- Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles.
- Human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored overnight in ice-cold Krebs solution if needed.
- the tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCl, 118 mM; KCl, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgS04, 1.2 mM; NaHC ⁇ 3, 2.0 mM; dextrose, 1 1 mM] warmed to 37°C. Excess lipid material and connective tissue are carefully removed.
- Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% C ⁇ 2/95% 02-
- the tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder.
- 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
- Kb [Bl. x-1 where x is 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.
- 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
- Catheters 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.
- Phenylephrine an alpha 1 adrenergic agonist
- Phenylephrine an alpha 1 adrenergic agonist
- phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle).
- the relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis.
- the family of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant among curves.
- the dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the ED50's for the respective curves.
- the Kb dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve
- the relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure Kb's. Effects of the alpha 1 antagonists on baseline arterial pressure are also monitored.
- ⁇ H-Naloxone binds with high affinity to opiate receptors in brain tissue (Creese and Snyder, J. Pharm Expt. Ther., 194: 205-219,
- ⁇ H-Naloxone binding in rat brain membranes was performed as described by Creese and Snyder (J. Pharm. Expt. Ther.. 194. 205-219, 1975) using Tris buffer alone or in the presence of 150 mM NaCl.
- Naloxone binding for representative examples of the present invention are given below in Table 6.
- Opioid mu and delta receptor binding assays were performed with rat brain membranes using ⁇ H-DAMGO ([D-Ala2, Me- Phe 4 , Gly-ol5]enkephalin, InM) and 3H-DPDPE ([D-Pen2, D- Pen ⁇ jenkephalin, 3 nM) as the selective radioligand, respectively (Slater and Cross, 1991 , Methods in Neurosciences ed. P.M. Conn. Academic Press, vol. 5 pp.459-478).
- ⁇ H-DAMGO [D-Ala2, Me- Phe 4 , Gly-ol5]enkephalin, InM
- 3H-DPDPE [D-Pen2, D- Pen ⁇ jenkephalin, 3 nM
- Kappa receptor binding assays were performed with guinea pig brain membranes using 3H-U69593 (5 alpha, 7 alpha, 8 beta)-(+)-N-Methyl-N-[7-(l -pyrrolinyl)- l -oxaspiro[4,5]dec- 8-yl]benzene-acetamide, 5 nM) as the radioligand.
- Brain membrane preparation and radioligand binding assays were performed similarly to those for ⁇ H-naloxone binding assay with the exception as noted below.
- protease inhibitors (bacitracin 20 ⁇ g/ml, soybean trypsin inhibitor 50 ⁇ g/ml and leupeptin 10 ⁇ g/ml) were added to the binding assay buffer for 3H-DAMGO and ⁇ H-DPDPE binding assays. Binding assays were carried out at 25 ⁇ >C for 1 hour (3H-DAMGO and 3H-U69593) and 3 hours (3H-DPDPE). Nonspecific binding was determined in the presence of 1 ⁇ M of naloxone.
- the selectivity of representative compounds of the present invention on opioid receptor subtypes are shown below in Table 7.
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Abstract
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US39269995A | 1995-02-23 | 1995-02-23 | |
US392699 | 1995-02-23 | ||
US253495P | 1995-08-18 | 1995-08-18 | |
GBGB9603457.4A GB9603457D0 (en) | 1996-02-19 | 1996-02-19 | |
GB9603457 | 1996-02-19 | ||
PCT/US1996/002534 WO1996025934A1 (en) | 1995-02-23 | 1996-02-23 | ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS |
US2534 | 1998-01-02 |
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EP (1) | EP0812196A4 (en) |
JP (1) | JPH11508536A (en) |
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CA (1) | CA2213192A1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4110449A (en) * | 1977-05-23 | 1978-08-29 | E. R. Squibb & Sons, Inc. | 2-substituted benzisothiazol-3-ones |
WO1995028397A1 (en) * | 1994-04-14 | 1995-10-26 | Merck & Co., Inc. | Alpha1c adrenergic receptor antagonists |
US5462942A (en) * | 1993-07-05 | 1995-10-31 | Duphar International Research B.V. | 2,3-dihydro-1,4-benzodioxin-5-yl-piperazine derivatives having 5-HT 1A-antagonistic activity |
-
1996
- 1996-02-23 JP JP8525855A patent/JPH11508536A/en active Pending
- 1996-02-23 EP EP96905575A patent/EP0812196A4/en not_active Ceased
- 1996-02-23 CA CA002213192A patent/CA2213192A1/en not_active Abandoned
- 1996-02-23 AU AU49301/96A patent/AU700559B2/en not_active Ceased
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4110449A (en) * | 1977-05-23 | 1978-08-29 | E. R. Squibb & Sons, Inc. | 2-substituted benzisothiazol-3-ones |
US5462942A (en) * | 1993-07-05 | 1995-10-31 | Duphar International Research B.V. | 2,3-dihydro-1,4-benzodioxin-5-yl-piperazine derivatives having 5-HT 1A-antagonistic activity |
WO1995028397A1 (en) * | 1994-04-14 | 1995-10-26 | Merck & Co., Inc. | Alpha1c adrenergic receptor antagonists |
Non-Patent Citations (1)
Title |
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See also references of WO9625934A1 * |
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EP0812196A4 (en) | 1998-05-20 |
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