JP2015509931A - Pharmaceutical combination - Google Patents

Abstract

The present application provides pharmaceutical combinations comprising β-3 adrenergic receptor agonists and muscarinic receptor antagonists, and methods for their use. Also provided are methods using pharmaceutical combinations for the treatment of one or more symptoms associated with overactive bladder (OAB), such as impending urinary frequency, nocturia, and urinary incontinence. [Selection figure] None

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority based on US Provisional Patent Application No. 61 / 596,893, filed February 9, 2012. This application is also filed by US application 13/370, filed August 2, 2011, which claims the benefit of priority based on US Provisional Patent Application 61 / 370,171, filed August 3, 2010. Claims priority based on 196,068. All of the above-mentioned applications are hereby incorporated by reference in their entirety.

  The present invention relates to pharmaceutical combinations and methods for their use. In particular, the present invention relates to a pharmaceutical combination comprising a β-3 adrenergic receptor agonist and a muscarinic acetylcholine receptor antagonist (hereinafter also referred to as “muscarinic receptor antagonist” or “antimuscarinic”), and for example imminent It relates to the use of such a combination in the treatment of one or more symptoms associated with overactive bladder such as frequent urination, frequent urination, nocturia.

  The International Urinary Control Society (ICS) has defined overactive bladder (OAB) as a group of urgent symptoms with frequent urination and nocturia with or without urge incontinence. Symptoms of overactive bladder are usually associated with involuntary contraction of the micturition (bladder) muscle, which creates a state of bladder hyperactivity. OABs are generally classified into neurological, idiopathic, and obstructive subtypes. Neurogenic OAB is due to coexistence with neurological disorders such as Parkinson's disease, multiple sclerosis, spinal cord injury or stroke. The underlying pathology is an interruption of the different regular control of urination, resulting in the above mentioned syndrome. Idiopathic OAB is not well defined; changes in signaling in the bladder are implicated. Finally, OAB can be associated with anatomical changes in the lower urinary tract in patients suffering from subvesical urethral obstruction, which can be the result of, for example, benign prostatic hyperplasia. Finally, OAB can be associated with anatomical changes in the lower urinary tract, for example in patients suffering from subvesical urethral obstruction that may be the result of benign prostatic hyperplasia.

  In general, the incidence of OAB increases with age. The ratio of men to women depends on age group, but women generally tend to be more susceptible than men. OAB imposes a significant burden on patients in terms of quality of life (QOL).

  As muscarinic receptor antagonists (antimuscarinic or anticholinergics) such as Detrol (R) LA (tolterodine), Ditropan XL (TM) (oxybutynin), and Vesicare (TM) (solifenacin succinate) Also represent the major pharmacological options currently approved and marketed for the treatment of OBA. Antimuscarinic drugs are thought to reduce bladder hyperactivity by interfering with the contractility of bladder smooth muscle. Physicians and patients are unsatisfied with current therapies and want medicines with improved efficacy and tolerability. In particular, unacceptable side effects such as dry mouth and constipation associated with these drugs occur. Also, current medications do not have a sufficient effect on impending frequent urination, one of the most troublesome symptoms of OAB.

  Thus, in addition to the currently available uses, there is a need for new drugs and treatment methods that have improved efficacy and tolerability in the treatment of symptoms associated with overactive bladder.

  A method of treating one or more symptoms associated with overactive bladder using a new synergistic treatment combination has been discovered. According to the invention, the treatment combination comprises a β-3 adrenergic receptor agonist and a muscarinic receptor antagonist. The inventors have shown that this combination unexpectedly increases efficacy and efficacy against one or more symptoms associated with OAB.

  That is, the present invention encompasses a therapeutic combination comprising (i) a therapeutically effective amount of a β-3 adrenergic receptor agonist, and (ii) a therapeutically effective amount or a sub-therapeutically effective muscarinic receptor antagonist, This combination is useful to relieve one or more symptoms associated with overactive bladder (OAB), synergistically to the individual components (i) and (ii). Symptoms associated with overactive bladder are selected from the group consisting of urgency, urinary frequency, nocturia, and urinary incontinence. The invention also encompasses a method of treating one or more symptoms associated with overactive bladder in a mammal using (i) and (ii) in a single dosage form or in separate states. Use of the combination for the treatment of one or more symptoms associated with overactive bladder, use of the combination in pharmaceutical therapy, and use of the combination in the manufacture of a medicament for the treatment of one or more symptoms associated with overactive bladder Provided.

  β-3 adrenergic receptor agonists are solveglone, CL-316,243, mirabegron, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and solvents with pharmaceutically acceptable solvents thereof. A compound selected from the group consisting of the pharmaceutically acceptable salts thereof can be included.

  Muscarinic receptor antagonists include oxybutynin, tolterodine, solifenacin, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceutical agents solvated with pharmaceutically acceptable solvents thereof. And a compound selected from the group consisting of acceptable salts.

  In a preferred embodiment, the combination comprises (i) a solvent with a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount or sub-therapeutically effective tolterodine, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Or a pharmaceutically acceptable salt solvated with a pharmaceutically acceptable solvent thereof, the combination synergistically with the individual components (i) and (ii) Useful to relieve one or more symptoms associated with (OAB).

  Another aspect of the invention includes administering to a mammal a (i) a therapeutically effective amount of a β-3 adrenergic receptor agonist, and (ii) a therapeutically effective amount or a subtherapeutically effective muscarinic receptor antagonist. A method of treating one or more symptoms associated with overactive bladder in a mammal.

  In one embodiment of the above method, the β-3 adrenergic receptor agonist is solavegron, CL-316,243, mirabegron, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, and a medicament thereof A compound selected from the group consisting of pharmaceutically acceptable salts solvated with a pharmaceutically acceptable solvent.

  In further embodiments of the above methods, the muscarinic receptor antagonist is oxybutynin, tolterodine, solifenacin, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable solvents thereof. A compound selected from the group consisting of pharmaceutically acceptable salts thereof solvated with:

  Further embodiments are solvated with (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount or sub-therapeutically effective amount of tolterodine, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or A method of treating one or more symptoms associated with overactive bladder in a mammal comprising administering to the mammal a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent.

  Said method may comprise co-administering components (i) and (ii). In one embodiment, components (i) and (ii) are included in a single dosage form. In other embodiments, co-administration includes administering components (i) and (ii) formulated separately.

  The method may comprise administering components (i) and (ii) separately. When administered separately, there may be a time delay between the administration of components (i) and (ii).

  In a further embodiment, the salt of solabegron comprises the hydrochloride salt.

  Another embodiment is a pharmaceutical composition comprising a combination of components (i) and (ii) and further comprising one or more pharmaceutically acceptable carriers, diluents or excipients.

  Further embodiments include the step of administering to the mammal in need a therapeutically effective amount of a combination of components (i) and (ii) as defined above for one or more symptoms associated with overactive bladder in the mammal It is a treatment method.

  Another embodiment is the method wherein component (i) comprises solabegron, wherein component (i) further comprises a compound of formula (III).

FIG. 1 shows a graph of the experimental protocol of Example 3. Figure 2 shows the effect of various antimuscarinic drugs on EFS-induced contractions (% inhibition from basal) in combination with various β-3 adrenergic receptor agonists. Show. FIG. 3 shows the effect of various antimuscarinic agents on CL-316,243 inhibition of EFS-induced contraction of rat isolated bladder. FIG. 4 shows the effect of antimuscarinic drugs on CL-316,243 inhibition of EFS-induced contraction of isolated rat bladder, including previous results. FIG. 5 shows the effect of various antimuscarinic agents on sorabegron inhibition of EFS-induced contraction of rat isolated bladder. FIG. 6 shows the effect of various antimuscarinic agents on mirabegron inhibition of EFS-induced contraction of rat isolated bladder. FIG. 7 shows the E _max and pIC ₅₀ values of various β-3 adrenergic receptor agonists alone (vehicle) or in the presence of various 10 nM antimuscarinic agents. FIG. 8 shows the E _max and IC ₅₀ values of various β-3 adrenergic receptor agonists alone (vehicle) or in the presence of various 10 nM antimuscarinic drugs.

  Unexpectedly, a new synergistic drug combination (combined formulation) has been shown to be useful in the treatment of one or more symptoms associated with OAB. These combinations include (i) a β-3 adrenergic receptor agonist, and (ii) a muscarinic receptor antagonist. These combinations have been shown to surprisingly increase efficacy and efficacy for the treatment of at least one symptom associated with OAB.

  That is, one embodiment of the invention is a therapeutic comprising (i) a therapeutically effective amount of a β-3 adrenergic receptor agonist, and (ii) a therapeutically effective amount or a subtherapeutically effective muscarinic receptor antagonist. Includes combinations. Sub-therapeutically effective doses of muscarinic antagonists can be used for combination synergism. In particular, one embodiment includes a synergistic combination comprising (i) a therapeutically effective amount of a β-3 adrenergic receptor agonist; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of a muscarinic receptor antagonist. However, this combination is useful to alleviate one or more symptoms associated with overactive bladder (OAB) synergistically for individual components (i) and (ii).

  Further embodiments include administering to a mammal (i) a therapeutically effective amount of a β-3 adrenergic receptor agonist; and (ii) a therapeutically effective amount or a subtherapeutically effective muscarinic receptor antagonist; Included are methods of treating one or more symptoms associated with mammalian overactive bladder. Administering a combination of both (i) and (ii) synergistically alleviates one or more symptoms associated with overactive bladder (OAB) for individual components (i) and (ii) Useful for.

  Thus, in one embodiment, the combination of (i) and (ii) can be used to treat one or more symptoms associated with overactive bladder. In another embodiment, the combination of (i) and (ii) can be used in pharmaceutical therapy. In further embodiments, the combination of (i) and (ii) can be used in the manufacture of a medicament for the treatment of one or more symptoms associated with OAB.

  In further embodiments, components (i) and (ii), or medicaments containing them, can be administered separately for the treatment of one or more symptoms associated with OAB, during administration There may be a time delay.

  As used herein, the term “effective amount” refers to, for example, the amount of a drug or pharmaceutical agent or the biological or medical response of a tissue, system, animal or human that is sought by a researcher or clinician. Means the amount of drug or drug combination that induces. Furthermore, the term “therapeutically effective amount” means any amount, and improved as compared to a corresponding subject not receiving such amount, as is known in the art on the day of the present invention. By an amount that results in treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, a decrease in the rate of progression of the disease or disorder.

  Thus, the term “subtherapeutically effective amount” refers to any amount of a muscarinic receptor antagonist, as known in the art on the day of the present invention, and is not therapeutically effective or treated alone. Although effective in minimal amounts, it exhibits a synergistic therapeutic effect in combination with a therapeutically effective amount of a β-3 adrenergic receptor agonist. In certain embodiments of the combinations and methods in the claims of the present application, the low dose (sub-therapeutic dose) of the antimuscarinic agent is due to the synergistic effect of the two compounds while avoiding or minimizing the side effects of the antimuscarinic agent. Can be used to produce a superior effect of the combination.

  In a further embodiment of the invention, as of the date of the present invention, as defined in the art for a single agent, a β-3 adrenergic receptor agonist or muscarinic receptor antagonist, or both, is therapeutically effective. Combinations that can be combined in sub-amounts and that are therapeutically useful due to the synergistic therapeutic effects of the drug combinations are also provided.

  As used herein, the term “synergistic” or “synergistically” or the term “synergistic method” refers to the interaction of two or more drugs in vitro or in vivo, and thus The combined effect when administered together is better than the sum of the effects observed when each is administered individually. That is, the effect of administering the combination of (i) and (ii) defined above is better than the sum of the effects of administering (i) and (ii) alone at a given dose.

One aspect of the invention includes a method of treating one or more symptoms associated with OAB,
(I) a therapeutically effective amount of a β-3 adrenergic receptor agonist represented by formula (I),

Or a pharmaceutically acceptable salt thereof (eg, hydrochloride), a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof; and,
(Ii) a muscarinic receptor antagonist represented by formula (II) at or below a therapeutically effective amount;

Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. Including.

  The compound of formula (I) is 3 ′-[(2-{[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino} ethyl) -amino]-[1,1′biphenyl]- It has the chemical name 3-carboxylic acid and is known as solabegron. Solabegron may be administered as a salt, which may be an anhydride, hydrate or solvate with a pharmaceutically acceptable solvent such as ethanol. In certain embodiments, solabegron is administered as the hydrochloride salt. In a preferred embodiment, solabegron hydrochloride is anhydrous hydrochloride.

  Free bases and pharmaceutically acceptable salts of solabegron (formula (I)), such as the hydrochloride salt, are filed, for example, on June 9, 1999 and on December 23, 1999, WO 99/65877. International patent application PCT / EP99 / 03958, published as PCT / GB00 / 04697, filed on December 8, 2000 and published as WO01 / 42195 on June 17, 2001, and 2001-12 It can be prepared according to the procedures disclosed in International Patent Application PCT / US01 / 49355, filed on May 17 and published as WO 2006/113649 on August 29, 2002.

  In a further embodiment of the invention, when component (i) is solabegron, it may contain the main active human metabolite of solabegron shown in formula (III).

  The compound of formula (II) has the genus name oxybutynin.

  The chemical name of the compound of formula (II) is 4-diethylaminobut-2-ynyl-2-cyclohexyl-2-hydroxy-2-phenyl -ethanoate) and 4- (diethylamino) -2-butynyl-α-cyclohexyl-α-hydroxybenzeneacetate (4- (diethylamino) -2-butynyl- · -cyclohexyl- · -hydroxybenzeneacetate), 4- (diethylamino) Also known as 2-butyn-1-yl-cyclo-hexyl- (hydroxy) phenyl acetate. Compounds of formula (II) may be prepared, for example, according to the procedure described in British Patent Specification GB 940,540, filed July 25, 1961 and published October 30, 1963 . The (S) optical isomer of oxybutynin can be prepared according to the procedure described in EP 0806948 B1. The (R) -enantiomer of oxybutynin can be prepared according to the procedure of US 6,123,961. Oxybutynin has been shown to be safe and effective in treating patients with overactive bladder, and side effects are known (see above) but are sold worldwide.

  In a further embodiment, for example, but not limited to, taught in International Patent Application No. PCT / EP99 / 03958, filed on June 9, 1999 and published as WO 1999/65877 on December 23, 1999. Or, for example, Amibegron (SR-58611, sanofi-aventis), ritobegron (KUC-7483, Kissei), KRP204 (N-5984, Kyorin Pharmaceutical), GS-332 ( Mitsubishi Tanabe), YM-178 (Astellas Pharma), or the compound disclosed in US2011 / 0028481 published on February 3, 2011 (Merck), or US2012 / published on June 21, 2012 0157432, disclosed in US Pat. No. 8,354,403 published on Jan. 15, 2013 (Merck), or 20 What is disclosed in the international publication WO2009 / 124167 (Merck) published on October 10, 1997, or disclosed in the international publication WO2011 / 025690 published on March 3, 2011 (Merck) The present invention encompasses compositions, methods and uses comprising other or additional β-3 adrenergic receptor agonists.

  One class of other or additional β-3 adrenergic receptor agonists is represented by the general structure:

  This is disclosed in the above-mentioned Merck patents and patent publications. One specific compound has the following structure:

  All of the above patents and patent applications are hereby incorporated by reference in their entirety.

  In further embodiments, suitable muscarinic receptor antagonists other than oxybutynin can also be used in accordance with the present invention. Such antimuscarinic agents include, but are not limited to tolterodine, solifenacin, trospium, darifenacin, propiverine, and fesoterodine.

Accordingly, the therapeutic combinations encompassed by the present invention include (i) a therapeutically effective amount of a β-3 adrenergic receptor agonist, and (ii) a therapeutically effective amount or a sub-therapeutically effective muscarinic receptor antagonist. This combination is useful to relieve one or more symptoms associated with overactive bladder (OAB) synergistically for individual components (i) and (ii). Symptoms associated with overactive bladder include, but are not limited to, urgency, urinary frequency, nocturia, and urinary incontinence. The combinations (i) and (ii) of the present invention can be used to treat various combinations of symptoms associated with OAB. Such combinations of OAB symptoms include, but are not limited to:
Urgent frequency and nocturia; or Urinary frequency and urinary incontinence; or Nocturia and urinary incontinence; or Urgent frequency and nocturia and urinary incontinence; Frequency and urgency frequency; or urinary frequency and urinary incontinence; or urinary frequency and urgency frequency and nocturia; or urinary frequency and urgency frequency and urinary incontinence; Urinary and urinary incontinence; or urinary frequency and nocturia and urinary incontinence and urgency.

  The invention also encompasses a method of treating one or more symptoms associated with overactive bladder in a mammal, using (i) and (ii) in a single dosage form or separately. Use of the combination for the treatment of one or more symptoms associated with overactive bladder, use of the combination in pharmaceutical therapy, and use of the combination in the manufacture of a medicament for the treatment of one or more symptoms associated with overactive bladder It is an embodiment of the invention.

  In one embodiment of the invention, the beta-3 adrenergic receptor agonist is solavegron, CL-316,243, mirabegron, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceuticals thereof. A compound selected from the group consisting of pharmaceutically acceptable salts thereof solvated with a pharmaceutically acceptable solvent. In a preferred embodiment, the beta-3 adrenergic receptor agonist comprises solabegron at a daily total oral dose of about 50 to about 800 mg, preferably about 100 to about 500 mg, more preferably about 200 to about 400 mg. In other preferred embodiments, the β-3 adrenergic receptor agonist comprises mirabegron at a daily total oral dosage of about 25 to about 200 mg, preferably about 25 to about 100 mg, more preferably about 25 to about 50 mg. . In yet another preferred embodiment, the β-3 adrenergic receptor agonist is at a total daily oral dosage of about 0.5 to about 500 mg, preferably about 1 to about 100 mg, more preferably about 5 to about 50 mg, CL-316 and 243 are included. These drugs can be administered bis in die (BID), ie twice a day.

  In one embodiment of the invention, the muscarinic receptor antagonist is oxybutynin, tolterodine, solifenacin, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable solvents thereof. A compound selected from the group consisting of pharmaceutically acceptable salts thereof solvated with: In preferred embodiments, the muscarinic receptor antagonist comprises oxybutynin at a daily total oral dosage of about 1 to about 40 mg, preferably about 1 to about 20 mg, more preferably about 2.5 to about 10 mg. In other preferred embodiments, the muscarinic receptor antagonist comprises tolterodine at a daily total oral dosage of about 1 to about 10 mg, preferably about 1 to about 8 mg, more preferably about 1 to about 4 mg. In yet another preferred embodiment, the muscarinic receptor antagonist is at a daily total oral dose of about 1 to about 20 mg, preferably about 2.5 to about 15 mg, more preferably about 2.5 to about 10 mg, Contains solifenacin. These drugs can be administered divis, that is, twice a day.

  In a preferred embodiment, the combination comprises (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt thereof solvated with; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of tolterodine, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof. Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. This combination is useful to relieve one or more symptoms associated with overactive bladder (OAB), synergistically to the individual components (i) and (ii).

  In another preferred embodiment, the combination comprises (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof, or a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt thereof solvated with; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of oxybutynin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof. Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. The above combination is useful to relieve one or more symptoms associated with overactive bladder (OAB), synergistically to the individual components (i) and (ii).

  In yet another preferred embodiment, the combination comprises (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt thereof solvated with a solvent that can be treated; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of solifenacin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. The above combination is useful to relieve one or more symptoms associated with overactive bladder (OAB), synergistically to the individual components (i) and (ii).

  In one preferred embodiment, the combination comprises (i) a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt thereof solvated with a solvent; and (ii) a therapeutically effective amount or sub-therapeutically effective amount of tolterodine, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A solvate, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. The above combination is useful to relieve one or more symptoms associated with overactive bladder (OAB), synergistically to the individual components (i) and (ii).

  In another preferred embodiment, the combination comprises (i) a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt thereof solvated with a solvent capable of being treated; and (ii) a therapeutically effective amount or sub-therapeutically effective amount of oxybutynin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. The above combination is useful to relieve one or more symptoms associated with overactive bladder (OAB), synergistically to the individual components (i) and (ii).

  In another preferred embodiment, the combination comprises (i) a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt thereof solvated with a solvent that can be treated; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of solifenacin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. The above combination is useful to relieve one or more symptoms associated with overactive bladder (OAB), synergistically to the individual components (i) and (ii).

  In another preferred embodiment, the combination comprises (i) a therapeutically effective amount of CL-316,243, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or A pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of tolterodine, or a pharmaceutically acceptable salt thereof, or a thereof A pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. The above combination is useful to relieve one or more symptoms associated with overactive bladder (OAB), synergistically to the individual components (i) and (ii).

  In another preferred embodiment, the combination comprises (i) a therapeutically effective amount of CL-316,243, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or A pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or sub-therapeutically effective amount of oxybutynin, or a pharmaceutically acceptable salt thereof, or A pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. The above combination is useful to relieve one or more symptoms associated with overactive bladder (OAB), synergistically to the individual components (i) and (ii).

  In another preferred embodiment, the combination comprises (i) a therapeutically effective amount of CL-316,243, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or A pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a sub-therapeutically effective amount of solifenacin, or a pharmaceutically acceptable salt thereof, or A pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. The above combination is useful to relieve one or more symptoms associated with overactive bladder (OAB), synergistically to the individual components (i) and (ii).

  Another aspect of the present invention is to administer to a mammal (i) a therapeutically effective amount of a β-3 adrenergic receptor agonist; and (ii) a therapeutically effective amount or a subtherapeutically effective muscarinic receptor antagonist; A method of treating one or more symptoms associated with overactive bladder in a mammal.

  In one embodiment of said method, the beta-3 adrenergic receptor agonist is solavegron, CL-316,243, mirabegron, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceuticals thereof A compound selected from the group consisting of pharmaceutically acceptable salts thereof solvated with a pharmaceutically acceptable solvent. In a preferred embodiment, the beta-3 adrenergic receptor agonist comprises solabegron at a daily total oral dose of about 50 to about 800 mg, preferably about 100 to about 500 mg, more preferably about 200 to about 400 mg. In other preferred embodiments, the β-3 adrenergic receptor agonist comprises mirabegron at a daily total oral dosage of about 25 to about 200 mg, preferably about 25 to about 100 mg, more preferably about 25 to about 50 mg. . In yet another preferred embodiment, the β-3 adrenergic receptor agonist is at a total daily oral dosage of about 0.5 to about 500 mg, preferably about 1 to about 100 mg, more preferably about 5 to about 50 mg, CL-316 and 243 are included. These drugs can be administered bis in die (BID), ie twice a day.

  In one embodiment of said method, the muscarinic receptor antagonist is oxybutynin, tolterodine, solifenacin, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable solvents thereof. A compound selected from the group consisting of pharmaceutically acceptable salts thereof solvated with: In preferred embodiments, the muscarinic receptor antagonist comprises oxybutynin at a daily total oral dosage of about 1 to about 40 mg, preferably about 1 to about 20 mg, more preferably about 2.5 to about 10 mg. In another preferred embodiment, the muscarinic receptor antagonist comprises tolterodine at a daily total oral dosage of about 1 to about 10 mg, preferably about 1 to about 8 mg, more preferably about 1 to about 4 mg. In yet another preferred embodiment, the muscarinic receptor antagonist is at a total daily oral dosage of about 1 to about 20 mg, preferably about 2.5 to about 15 mg, more preferably about 2.5 to about 10 mg, Contains solifenacin. These drugs can be administered bis in die (BID), ie twice a day.

  In a preferred form, a method of treating one or more symptoms associated with overactive bladder in a mammal comprises: (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof. Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of tolterodine, or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof;

  In another preferred form, a method of treating one or more symptoms associated with overactive bladder in a mammal comprises (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of oxybutynin, or a pharmaceutically acceptable salt thereof. Administering to a mammal an acceptable salt, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof.

  In another preferred form, a method of treating one or more symptoms associated with overactive bladder in a mammal comprises (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of solifenacin, or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof;

  In another preferred form, a method of treating one or more symptoms associated with overactive bladder in a mammal comprises (i) a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of tolterodine, or a pharmaceutically acceptable salt thereof. Administering to a mammal an acceptable salt, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof.

  In another preferred form, a method of treating one or more symptoms associated with overactive bladder in a mammal comprises (i) a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of oxybutynin, or a pharmaceutically acceptable salt thereof. Administering to a mammal an acceptable salt, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof.

  In another preferred form, a method of treating one or more symptoms associated with overactive bladder in a mammal comprises (i) a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of solifenacin, or a pharmaceutically acceptable salt thereof. Administering to a mammal an acceptable salt, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof.

  In a preferred form, a method of treating one or more symptoms associated with overactive bladder in a mammal comprises: (i) a therapeutically effective amount of CL-316,243, or a pharmaceutically acceptable salt thereof, or a pharmaceutically An acceptable solvate, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a subtherapeutically effective tolterodine, or a pharmaceutical thereof A pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof; Including.

  In a preferred form, a method of treating one or more symptoms associated with overactive bladder in a mammal comprises: (i) a therapeutically effective amount of CL-316,243, or a pharmaceutically acceptable salt thereof, or a pharmaceutically An acceptable solvate, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a sub-therapeutically effective amount of oxybutynin, or a medicament thereof A pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof; Including.

  In a preferred form, a method of treating one or more symptoms associated with overactive bladder in a mammal comprises: (i) a therapeutically effective amount of CL-316,243, or a pharmaceutically acceptable salt thereof, or a pharmaceutically An acceptable solvate, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent; and (ii) a therapeutically effective amount or a subtherapeutically effective amount of solifenacin, or a medicament thereof A pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof; Including.

  Said method may comprise co-administering components (i) and (ii). In one embodiment, components (i) and (ii) are included in a single or unit dosage form. In another embodiment, co-administration comprises administering components (i) and (ii) formulated separately.

  The method can also include administering components (i) and (ii) separately. When administered separately, there may be a time delay between the administration of components (i) and (ii).

  In one preferred embodiment, the solabegron salt comprises the hydrochloride salt.

  Another embodiment is a pharmaceutical composition comprising a combination of components (i) and (ii) and further comprising one or more pharmaceutically acceptable carriers, diluents or excipients. One preferred pharmaceutical composition is (i) solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a solvated thereof with a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt, (ii) tolterodine, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a solvated thereof with a pharmaceutically acceptable solvent thereof A pharmaceutically acceptable salt; and (iii) one or more pharmaceutically acceptable carriers, diluents or excipients. One preferred pharmaceutical composition is (i) mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a solvated thereof with a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt, (ii) tolterodine, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a solvated thereof with a pharmaceutically acceptable solvent thereof A pharmaceutically acceptable salt; and (iii) one or more pharmaceutically acceptable carriers, diluents or excipients. Another preferred pharmaceutical composition is solvated with (i) solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. Or a pharmaceutically acceptable salt thereof, (ii) oxybutynin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt thereof; and (iii) one or more pharmaceutically acceptable carriers, diluents or excipients. Another preferred pharmaceutical composition is solvated with (i) mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. Or a pharmaceutically acceptable salt thereof, (ii) oxybutynin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt thereof; and (iii) one or more pharmaceutically acceptable carriers, diluents or excipients. Another preferred pharmaceutical composition is solvated with (i) solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. Or a pharmaceutically acceptable salt thereof, (ii) solifenacin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt thereof; and (iii) one or more pharmaceutically acceptable carriers, diluents or excipients. Yet another preferred pharmaceutical composition is solvated with (i) mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. Solvated with a pharmaceutically acceptable salt thereof, (ii) solifenacin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof A pharmaceutically acceptable salt thereof; and (iii) one or more pharmaceutically acceptable carriers, diluents or excipients.

  Further embodiments provide for overactive bladder in a mammal comprising administering to a mammal in need a therapeutically effective amount of a combination of components (i) and (ii) as defined above, or a pharmaceutical composition thereof. A method of treating one or more associated symptoms.

  Another embodiment of the above therapeutic methods relates to a method comprising solabegron, wherein component (i) further comprises an in vivo primary metabolite of solabegron of formula (III).

  In certain embodiments of the invention, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable solvents of components (i) and (ii) are solvated. Use of pharmaceutically acceptable salts. As used herein, the term “solvate” or “solvated salt” refers to a solute (in this invention, a compound of formula (I) or (II) (or a salt thereof). And a variable stoichiometric complex formed by a solvent. For the purposes of the present invention, such solvents do not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to water, methanol, ethanol and acetic acid. In a preferred embodiment, the solvent is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. In a more preferred embodiment, the solvent is water providing a “hydrate”.

  β-3 adrenergic receptor agonists and muscarinic receptor antagonists are either (1) a single pharmaceutical composition comprising both compounds (single dosage form) or (2) each composition is They can be used in combination by simultaneous administration as separate pharmaceutical compositions containing one of the compounds. The combination may also include separate administration of the compounds in a sequential manner, for example, first administering either a β-3 adrenergic receptor agonist or a mumuscarinic receptor antagonist, and then the other half. Is administered. Such sequential administration may be administered at short time intervals or at long time intervals, i.e. the administration may have a time delay.

  In general, the salts according to the invention are pharmaceutically acceptable salts. Salts including “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of the invention. The salt of the compound concerning this invention may contain the acid addition salt derived from nitrogen in the substituent of the compound concerning this invention. Representative pharmaceutically acceptable salts include: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, acid tartrate, borate, bromide, edetic acid Calcium, cansylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edicateate, estrate, esylate, fumarate, glucoceptate, gluconate , Glutamate, glycolylarsanilate, hexyl-resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, Lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, monopotassium maleate Salt, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate , Polygalacturonate, potassium, salicylate, sodium, stearate, basic acetate, succinate, tannate, tartrate, theocrate, tosylate, tosylate, trimethylammonium and yoshi Contains herbate. Other salts that are not pharmaceutically acceptable can be used to prepare the compounds of the invention and they constitute a further aspect of the invention.

  With β-3 adrenergic receptor agonist, muscarinic receptor antagonist, or pharmaceutically acceptable salt thereof, pharmaceutically acceptable solvate thereof, or pharmaceutically acceptable solvent thereof for pharmaceutical therapy Although solvated pharmaceutically acceptable salts can be administered as the chemical compound itself, the active ingredient or ingredient can also be presented as a pharmaceutical composition. Accordingly, the present invention further provides a therapeutically effective amount of a β-3 adrenergic receptor agonist, and a therapeutically effective amount or sub-therapeutically effective amount of a muscarinic receptor antagonist, or a pharmaceutically acceptable salt thereof, a pharmaceutical agent thereof Or a pharmaceutically acceptable salt solvated with a pharmaceutically acceptable solvent and one or more pharmaceutically acceptable carriers, diluents or excipients A composition is provided. The carrier, diluent or excipient must be acceptable in the sense that it is compatible with other pharmaceutical ingredients, is capable of pharmaceutical formulation (pharmaceutical formulation), and is not harmful to the receptor itself. The present invention also relates to a β-3 adrenergic receptor agonist, muscarinic receptor antagonist, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. Provided is a method of preparing a pharmaceutical formulation comprising admixing a solvated pharmaceutically acceptable salt with one or more pharmaceutically acceptable carriers, diluents or excipients.

  The pharmaceutical formulation may be in unit dosage form containing a predetermined amount of active ingredient per unit dose. As is known to those skilled in the art, the amount of active ingredient per dose depends on the treatment situation, the route of administration and the age, weight and situation of the patient, or the pharmaceutical formulation is a pre-determined active ingredient per unit dose. It can be present in a unit dosage form containing an amount. Preferred unit dose formulations are those containing a daily dose or sub-dose of the active ingredient, or an appropriate fraction thereof. Furthermore, such pharmaceutical formulations may be prepared by any method known to those skilled in the art.

  The β-3 adrenergic receptor agonist and muscarinic receptor antagonist can be administered by any suitable route. Suitable routes include oral, rectal, nasal, and parenteral (including intravesical, subcutaneous, intramuscular, intravenous, transdermal, intradermal, intrathecal and epidural). Administration can also take place by means of a bladder pump or sustained release within the bladder.

  It goes without saying that the preferred route depends on, for example, the situation of the combination of receptors. It will also be appreciated that each administered drug can be administered by the same or different routes, and that β-3 adrenergic receptor agonists and muscarinic receptor antagonists can be formulated together in a pharmaceutical composition / formulation.

  The methods of the present invention may also be used in conjunction with other therapies to treat one or more symptoms associated with overactive bladder. Thus, the combination therapy according to the present invention includes administration of β-3 adrenergic receptor agonists and muscarinic receptor antagonists, as well as other therapeutic agents including other β-3 adrenergic receptor agonists and / or muscarinic receptor antagonists. Includes optional use. Such combinations of agents may be administered together or individually, and if administered separately, may be administered simultaneously or administered in short or long time intervals in any order. May be. In order to achieve the desired combination of therapeutic effects, the amount and relative timing of administration of the complex of β-3 adrenergic receptor agonist, muscarinic receptor antagonist and any other pharmaceutically active agent can be selected.

Furthermore, the combinations and methods according to the invention provide that the isotopes of components (i) and / or (ii) (ie β-3 adrenergic receptor agonists and / or muscarinic receptor antagonists are isotopically labeled). Can be included). In one embodiment, the isotopically labeled compound has one or more hydrogen atoms substituted with either deuterium or tritium. In another embodiment, the isotopically labeled compound has one or more carbon atoms replaced with ¹¹ C, ¹³ C or ¹⁴ C. In one preferred embodiment, the β-3 adrenergic receptor agonist comprises deuterated solabegron.

  Pharmaceutical formulations for oral administration include, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water emulsions or water-in-oil milk It may be present in a separate unit such as a suspension.

  For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. . Powders are prepared by comminuting the compound to an appropriate fineness and mixing with a pharmaceutical carrier, such as edible carbohydrates (eg, starch or mannitol), as well as finely divided. Flavoring agents, preservatives, dispersants and coloring agents can also be added.

  Capsules are produced by preparing the powder mixture described above and filling a shaped gelatin sheath. For example, lubricants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. Disintegrants or solubilizers such as agar, calcium carbonate or sodium carbonate can also be added to increase the effectiveness of the drug when the capsule is ingested.

  In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be used in the granulation. The powder mixture may be passed through a tablet machine, and if the formed slug is insufficient, they may be granulated, and the granules can be lubricated and reincorporated into the mixture. . Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn syrup, natural and synthetic gums such as arabic, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like. Tablets are made, for example, by preparing a powder mixture, granulating or agglomerating, and pressing a lubricant and disintegrant into the tablet. A powder mixture is prepared by mixing the above comminuted compound with the diluent or base described above, a binder such as carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone, a dissolution retardant such as paraffin, a quaternary salt. Such as absorption enhancers and / or absorbents such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting with a syrup, starch paste, gum arabic mucus or a binder such as cellulose or polymeric material and passing through a screen. Another way to prevent sticking to the tablet mold is to add stearic acid, stearate, talc or mineral oil. The lubricated mixture is then compressed into a tablet. The compounds according to the invention can be combined with a free-flowing inert carrier and compressed into tablets without granulating or agglomerating steps. A transparent or opaque protective layer consisting of a shellac seal coat layer, a sugar or polymer material coat layer, and a wax coating of wax can be applied. Dyestuffs can be added to these coat layers to distinguish them from different unit formulations.

  For example, oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form to have a given quantity including a predetermined quantity of the compound. Syrups are prepared by dissolving the compound in a suitably flavored aqueous solution, whereas elixirs can be prepared by using a non-toxic alcohol vehicle. Suspensions can be prepared by dispersing the compound in a non-toxic medium. Solubilizing and emulsifying agents such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, peppermint oil, natural sweeteners, saccharin or other artificial sweeteners and other flavoring additives can also be added.

  Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be manufactured to extend or maintain release, for example, by coating or incorporating particulate material in polymers, waxes, and the like.

  Agents used in accordance with the present invention can also be administered in the form of liposome delivery systems such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

  Agents for use in accordance with the present invention can also be delivered by using monoclonal antibodies as individual carriers to which the compound molecules are bound. The compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers include, but are not limited to, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylasparto-amide-phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds include, for example, biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanos. Acrylates and hydrogels can be bonded to crosslinked or amphiphilic block polymers.

  Pharmaceutical formulations suitable for transdermal administration may be individual patches intended to maintain intimate contact with the recipient's epidermis for an extended period of time. For example, the active ingredient can be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

  Pharmaceutical formulations suitable for rectal administration can also be provided as suppositories or enemas.

  Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostatic agents, and salts that render the formulation isotonic with the blood of the intended recipient; Includes aqueous and non-aqueous sterile suspensions which may include turbidity and thickening agents. The formulation may be contained in unit-dose or multi-dose containers, such as sealed ampoules and vials, and freeze-dried (lyophilized) requiring only the addition of a sterile liquid carrier (eg, water for injection) just prior to use. ) May be saved in the state. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

  In addition to the components described above, it should be understood that the formulation may include other agents commonly used in the art with respect to the type of formulation (eg, formulations suitable for oral administration may include flavoring agents). It is.

  Also contemplated by the present invention are drug combinations comprising β-3 adrenergic receptor agonists and muscarinic receptor antagonists. In other embodiments, it comprises a β-3 adrenergic receptor agonist, a muscarinic receptor antagonist, and optionally at least one additional β-adrenergic receptor agonist or muscarinic receptor antagonist. The β-3 adrenergic receptor agonist, muscarinic receptor antagonist, and additional β-3 adrenergic receptor agonist or muscarinic receptor antagonist are as described above.

  A therapeutically effective amount of a β-3 adrenergic receptor agonist, a therapeutically effective amount or a subtherapeutically effective amount of a muscarinic receptor antagonist, and optionally an additional β-3 adrenergic receptor agonist or muscarinic receptor antagonist Is administered to a mammal. Typically, one therapeutically effective amount of an agent of the invention administered will be, for example, the age and weight of the mammal, the exact condition in need of treatment, the severity of the condition, the nature of the formulation, and the administration Depends on a number of factors, including routes. Ultimately, the therapeutically effective amount will be at the discretion of the attending physician or veterinarian. Furthermore, the antimuscarinic agent can be administered at a lower dose (sub-therapeutic dose) in order to provide the superior effect of the combination while controlling the side effects of the antimuscarinic agent. .

  The present invention relates to any situation that is susceptible to receptor activation of the beta-3 adrenergic receptor (agonism) or antagonism of the muscarinic receptor (antagonism), or beta-3 adrenergic receptor Treatment of conditions susceptible to both agonistic activity and antagonism of muscarinic receptors.

  Without being bound to any particular theory, for example, β-3 adrenergic receptor agonists, such as sorabeclone, are effective by binding to β-3 adrenergic receptors, resulting in relaxation of bladder smooth muscle. Conceivable. Also, for example, muscarinic receptor antagonists such as oxybutynin are thought to act through blocking parasympathetic nerve-mediated bladder contractions. Agents that provide these two different mechanisms of action provide a synergistic effect that has never been known and unexpected.

  Examples of situations associated with smooth muscle over-activity suitable for treatment using a combination comprising a β-3 adrenergic receptor agonist and a muscarinic receptor antagonist of the present invention include OAB, hypersensitive colon Gastrointestinal syndrome such as syndrome (IBD), ulcerative colitis and the like. Thus, the pharmaceutical combination of the present invention may be effective for the treatment of such situations. The β-3 adrenergic receptor has already been found in heart tissue. Accordingly, the pharmaceutical combination of the present invention may be effective in the treatment of cardiovascular diseases.

  The following examples are intended to illustrate particular embodiments of the present invention and are in no way intended to limit the scope of the invention.

The symbols and conventions used in these methods, schemes, and examples herein are consistent with those used in modern chemical literature such as, for example, Journal of the American Chemical Society and Journal of Biological Chemistry. Unless otherwise noted, all raw materials were obtained from commercial sources and used without further purification. Specifically, the following abbreviations are used in the specification and examples:
BID twice a day, ECG ECG, g (gram), mg (milligram), IR immediate release, L (liter), mL (milliliter), μL (microliter) mol (mol)
M (molar concentration, molar), mM (millimolar), N (normative), Kg (kilogram), mmol (mmol), RT (room temperature), min (minute), h (hour), QID 4 times a day, XL Extended release
Example 1. Drug interaction test in healthy human subjects Drug interaction test was conducted in healthy human volunteers using multiple oral doses of solabegron and oxybutynin alone or in combination with each other, and the residual amount after urination Pharmacokinetic and pharmacodynamic parameters were evaluated by measuring (post void residual, PVR). PVR was measured in subjects treated with each single agent and combinations thereof under steady state conditions.

  The study was a two-group randomized, open-label, double-dose, 3-way crossover study in healthy adult subjects. Two commercial formulations of oxybutynin were used during the test: i) Ditropan IR®, an immediate release (IR) type oxybutynin; and ii) Ditropan XL®, a sustained release (XL) type oxybutynin. ). The total daily dose was 20 mg. Sorabegron was administered as a tablet. Details of the solabegron tablet composition used are shown in Table 1 (Composition A).

  For the first group (n = 14 subjects), first sorbegron is administered at 200 mg BID (100 mg × 2) for 5 days, then for 5 days in the second phase, oxybutynin IR is administered at 5 mg QID, and finally 5 days, a combination of solavegron 200 mg BID (100 mg × 2) and oxybutynin IR 5 mg QID was administered for 5 days.

  For the second group (n = 12 subjects), sorabegron is first administered at 200 mg BID (100 mg × 2) for 5 days, then oxybutynin XL is administered at 10 mg BID for 5 days in the second stage, and finally In the administration stage, a combination of 200 mg BID (100 mg × 2) solavegron and 10 mg BID oxybutynin was administered for 5 days.

  Each test session was separated by a washout period of at least 5 days. Safety assessments include vital signs, ambulatory blood pressure monitoring (ABPM) physical examination, clinical safety studies, 12-lead ECGs, PVR levels to assess urinary retention and potential adverse events It was. PVR can also be used to determine bladder smooth muscle relaxation in healthy subjects to determine whether sorabegron combined with oxybutynin has a better effect on relaxation than when each compound is administered alone. It was also used as a biomarker.

Finally, blood samples were collected as needed for pharmacokinetic analysis of plasma concentrations:
-Sorabegron and primary active metabolites as shown below;
-R-oxybutynin, S-oxybutynin and R-desethyloxybutynin metabolites and S-desethyloxybutynin metabolites shown below.

  Sorabegron primary active metabolite, chemical formula (III):

  The primary active metabolite of oxybutynin is desethyloxybutynin, chemical formula (IV):

Sorabegron tablet composition A
Composition A was prepared by blending and wet granulating components (a)-(e) shown in Table 1 with a suitable high shear mixer / granulator. Ingredients (f)-(h) were added to the dry granules, mixed and compressed. The compressed tablets were coated with an aqueous film layer.

Results of drug-drug interaction test-PVR level To measure the PVR level, an ultrasound scan of the bladder was performed on the first day (one day prior to the dosing period) and the sixth day (dosing period) of each test period. On the 6th day).

  Subjects who received sorabegron alone or oxybutynin IR alone in the PVR amount showed mean increases of 4.4 mL and 45.7 mL, respectively, from baseline, whereas the combination of sorabegron and oxybutynin IR was administered. The test subjects surprisingly showed an average increase of 79.8 mL from baseline. Subjects who received oxybutynin XL alone in PVR dose showed an average increase of 20.2 from baseline, while subjects who received the combination of solavegron and oxybutynin XL surprisingly Showed an average increase of 50.8. These data are shown in Table 2.

  These data show that in healthy subjects, sorabegron alone showed minimal changes in PVR levels, and oxybutynin IR or XL alone showed modest changes in PVR levels. It can be seen that there was a greater increase in the amount of PVR when administered in combination with either oxybutynin IR or oxybutynin XL compared to the sum of the expected effects of each of these two active ingredients. . When oxybutynin IR is used as an antimuscarinic agent, the PVR for combination therapy is 79.8 mL, whereas the total PVR when administered alone is 50.1 mL. Similarly, when oxybutynin XL is used as an antimuscarinic agent, the PVR for combination therapy is 50.8 mL, whereas the total PVR when administered alone is 24.6 mL. The latter comparison shows an increase of more than 100% in the effect of the combination treatment over the single treatment.

  This is interpreted as evidence of a pharmacological synergy in combination therapy. That is, this test shows enhanced efficacy in the treatment of one or more symptoms of OAB, as it shows that more fluid is retained in the PVR test and the bladder muscles are more relaxed, thereby increasing bladder capacity. Show.

Example 2 Effect of β-receptor agonist and antimuscarinic agent combination on rat bladder contractility Efferent nerve stimulation to the bladder leads to the release of acetylcholine (ACh), thereby post-junction in bladder smooth muscle Of muscarinic (M3) receptors, resulting in contraction and subsequent urination. The M2 receptor is functionally expressed in human bladder smooth muscle and may also play a role in bladder contractility, but this probably indirectly enhances M3-mediated contraction and is a beta-3 adrenergic receptor. By inhibiting mediated relaxation. Antimuscarinic agents are thought to work primarily by blocking the M3 receptor and thus suppress contractions associated with overactive bladder.

  Other approaches to the treatment of overactive bladder include targeting β-3 adrenergic receptors located on bladder smooth muscle. Stimulation of the post-junction β-3 adrenergic receptor results in the production of cAMP and the induction of smooth muscle direct relaxation.

  To study possible pharmacological synergies in the combination of muscarinic and beta receptor pathways, the muscarinic antagonist oxybutynin and the β-3 adrenergic receptor agonist CL-316,243 (a highly selective and potent antagonist) A combination of dental β3-AR agonists was tested against the EFS-induced response of rat urinary bladder strips.

Rat detrusor longitudinal strips were suspended in an organic bath chamber containing oxygenated Krebs solution (pH 7.4, supplied with 95% O ₂ and 5% CO ₂ gas at 37 ° C.). To block the α1-adrenergic receptor, prazosin (1 μM) was added into the Krebs solution. Bladder response was measured using an isometric transducer and recorded using a data acquisition system. The tissue was equilibrated for 60 minutes under a static tension of 1.0 g. After the equilibration period, the strips were exposed to KCL (80 mM) to measure their viability. Tissue was washed and allowed to equilibrate for an additional 45 minutes. The bladder strips were then subjected to EFS using the following parameters: maximum current 800 mA, 15 Hz frequency, 0.1 ms square pulse, 4 s trains every minute. After about 15 minutes (when EFS contraction was stabilized), the selective β-adrenergic receptor antagonist ICI-118551 (30 nM) was incubated for 15 minutes. After the contractile response is stabilized, a concentration response curve corresponding to each bladder strip is obtained by adding CL-316,243 or oxybutynin (1 nM to 10 μM) (or a corresponding vehicle) to increase the concentration in log units. Was obtained.

  In the first series of experiments, oxybutynin gave a minimal value (about 15% inhibition of EFS-induced bladder strip contraction) at a concentration of 10 nM.

  In the second series of experiments, a single concentration of 10 nM oxybutynin (determined in the first series of experiments) was added into the bath chamber followed by different doses of CL-316,243 using CL Concentration response curves for -316,243 were obtained.

In the presence of the minimum effective amount of oxybutynin, there was a shift of about 3.5-fold on the left side of the concentration response curve for CL-316,243. _{EC 50} for inhibition of bladder contractions by CL-316,243 has been a 7.2 nM, in the presence of oxybutynin (10 nM), the _{EC 50} of was 2.1 nM.

  In addition, the maximum inhibition of EFS-induced contraction by CL-316,243 alone was 65%, but the inhibition by CL-316,243 in the presence of oxybutynin (10 nM) reached 80%. .

The difference in EC ₅₀ value and inhibition of maximal response is statistically significant (p <0.05).

  These data suggested that the combination of an antimuscarinic agent and a selective beta-3 adrenergic receptor agonist had a significant pharmaceutical synergistic effect on the suppression of bladder contraction.

Example 3 Effects of combinations of various β-adrenergic receptor agonists and antimuscarinic drugs on rat bladder contractions induced by EFS (electric field stimulation),
In this study, various combinations of β3-adrenergic receptor agonists and antimuscarinic agents were tested in isolated rat bladder pieces.

Bladder smooth muscle strips were obtained from female rats (Sprague-Dawley strain, body weight 240-360 grams). Two strips were made for each bladder and connected to tension transducers in a 5 ml bath containing Krebs-Henseleit solution (37 ° C, kept at pH 7.4, 95 Aeration with% O ₂ /5% CO ₂ ). Prazosin (1 μM) was added to the Krebs solution to block the β1-adrenergic receptor. The strips were equilibrated for at least 60 minutes with a static tension of 1.0 g while the tissue was washed every 15 minutes. Each strip was then exposed to 80 mM KCl to confirm its viability. After a further 45-minute wash-out period, the strip was subjected to EFS (electrical field stimulation parameters: constant current 800 mA, 15 Hz frequency, 0.1 ms square pulse, 2 minutes Every 4 s trains). After stabilization, the β2-adrenergic receptor antagonist, ICI-118551 (30 nM) was incubated for 15 minutes. Oxybutynin, tolterodine, solifenacin, or their common solvent (vehicle control) was then added to the strip for an additional 15 minutes. Subsequently, cumulative concentrations of solabegron (10 nM-10 μM), mirabegron (10 nM-10 μM) and CL-316243 (10 nM-10 μM) were added in half-log increments. At the end of CRC's, 10 μM forskolin (FSK) was added to determine maximal relaxation (FIG. 1).

Each CRC was fitted using non-linear regression (GraphPad Prism® software) to obtain Emax and pIC ₅₀ (−log IC ₅₀ ) values. The average CRC of the vehicle and the treated strips were fitted in parallel and statistically compared. The first fit is used to compare E _max values, and when these values are not statistically different, the second fit is used to obtain a pIC ₅₀ value for each pair of curves. , E _max shared. The difference is considered statistically significant when the null hypothesis can be eliminated with a risk α (riskα) of less than 0.05.

As evidenced by the data shown in the figure, the E _max value of CL-316243 was significantly increased in the presence of oxybutynin and tolterodine. Furthermore, in the presence of oxybutynin, the IC _{50 of} CL-316243 was greatly reduced.

For solabegron, oxybutynin, is E _max value by tolterodine and solifenacin increased substantially. Furthermore, the IC ₅₀ value of solabegron was significantly lower in the presence of oxybutynin and tolterodine.

For mirabegron, the Emax value appears to be significantly increased in the presence of tolterodine. Furthermore, IC ₅₀ values of Mirabegron are oxybutynin, tolterodine, and were significantly lower in the presence of solifenacin.

  Thus, it is clear that antimuscarinic drugs can affect both the potency and efficacy of β-3 adrenergic receptor agonists.

  All references cited herein are hereby incorporated in their entirety.

Claims (32)

(I) a therapeutically effective amount of a β-3 adrenergic receptor agonist; and
(Ii) a therapeutically effective amount or a sub-therapeutically effective muscarinic receptor antagonist;
A synergistic combination to relieve one or more symptoms associated with overactive bladder (OAB).   The combination of claim 1, wherein the one or more symptoms associated with overactive bladder are selected from the group consisting of impending urinary frequency, urinary frequency, nocturia, and urinary incontinence.   The β-3 adrenergic receptor agonist is solabegron, CL-316,243, mirabegron, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable solvent thereof. 3. A combination according to claim 1 or 2 comprising a compound selected from the group consisting of solvated pharmaceutically acceptable salts thereof.   The β-3 adrenergic receptor agonist is solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutical solvated with the pharmaceutically acceptable solvent thereof. 4. A combination according to claim 3 comprising a pharmaceutically acceptable salt.   The β-3 adrenergic receptor agonist is mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutical solvated with the pharmaceutically acceptable solvent thereof 4. A combination according to claim 3 comprising a pharmaceutically acceptable salt.   The muscarinic receptor antagonist is solvated with oxybutynin, tolterodine, solifenacin, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable pharmaceuticals thereof 6. The combination according to any one of claims 1 to 5, comprising a compound selected from the group consisting of:   The muscarinic receptor antagonist is pharmaceutically but solvated with oxybutynin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. 7. A combination according to claim 6 comprising an acceptable salt.   The muscarinic receptor antagonist is tolterodine, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable solvent thereof. 7. A combination according to claim 6 comprising an acceptable salt.   The muscarinic receptor antagonist is solifenacin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or pharmaceutically solvated with a pharmaceutically acceptable solvent thereof. 7. A combination according to claim 6 comprising an acceptable salt. (I) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. A salt that can be made; and
(Ii) Solvate with a therapeutically effective amount or a sub-therapeutically effective amount of tolterodine, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt thereof;
A synergistic combination to relieve one or more symptoms associated with overactive bladder (OAB). (I) a therapeutically effective amount of a β-3 adrenergic receptor agonist; and
(Ii) a therapeutically effective amount or a sub-therapeutically effective muscarinic receptor antagonist;
A method of treating one or more symptoms associated with overactive bladder in a mammal comprising administering to the mammal.   12. The method of claim 11, wherein the one or more symptoms associated with the overactive bladder are selected from the group consisting of impending urinary frequency, urinary frequency, nocturia, and urinary incontinence.   The β-3 adrenergic receptor agonist is solabegron, CL-316,243, mirabegron, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable solvent thereof. 13. A method according to claim 11 or 12, comprising a compound selected from the group consisting of solvated pharmaceutically acceptable salts thereof.   The β-3 adrenergic receptor agonist is solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutical solvated with the pharmaceutically acceptable solvent thereof. 14. The method of claim 13, comprising a pharmaceutically acceptable salt.   The β-3 adrenergic receptor agonist is mirabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutical solvated with the pharmaceutically acceptable solvent thereof 14. The method of claim 13, comprising a pharmaceutically acceptable salt.   The muscarinic receptor antagonist is oxybutynin, tolterodine, solifenacin, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, and a pharmaceutical solvated with the pharmaceutically acceptable solvent thereof 16. A method according to any one of claims 11 to 15, comprising a compound selected from the group consisting of pharmaceutically acceptable salts.   The muscarinic receptor antagonist is pharmaceutically but solvated with oxybutynin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. 17. A method according to claim 16, comprising an acceptable salt.   The muscarinic receptor antagonist is tolterodine, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable solvent thereof. 17. A method according to claim 16, comprising an acceptable salt.   The muscarinic receptor antagonist is solifenacin, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or pharmaceutically solvated with a pharmaceutically acceptable solvent thereof. 17. A method according to claim 16, comprising an acceptable salt. (I) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof solvated with a pharmaceutically acceptable solvent thereof. A salt that can be made; and
(Ii) Solvate with a therapeutically effective amount or a sub-therapeutically effective amount of tolterodine, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvent thereof. A pharmaceutically acceptable salt thereof;
A method of treating one or more symptoms associated with overactive bladder (OAB) in a mammal comprising administering to the mammal.   21. A method according to any one of claims 11 to 20, wherein components (i) and (ii) are administered simultaneously.   22. A method according to any one of claims 11 to 21, wherein components (i) and (ii) are included in a single dosage form.   21. A method according to any one of claims 11 to 20, wherein components (i) and (ii) are administered separately.   24. A method according to any one of claims 11 to 20 or 23, wherein there is a time delay between administration of components (i) and (ii).   5. The combination of claim 4, wherein the solabegron salt comprises a hydrochloride salt.   15. The method of claim 14, wherein the solabegron salt comprises a hydrochloride salt.   26. A pharmaceutical composition comprising a combination according to any one of claims 1-10 or 25 and further comprising one or more pharmaceutically acceptable carriers, diluents or excipients.   26. Use of a combination according to any one of claims 1 to 10 or 25 in the manufacture of a medicament for treating one or more symptoms associated with overactive bladder.   26. One or more symptoms associated with overactive bladder in a mammal comprising the step of administering to the mammal in need thereof a therapeutically effective amount of the combination of any one of claims 1-10 or 25. Method of treatment.   28. A method of treating one or more symptoms associated with overactive bladder in a mammal comprising the step of administering to the mammal in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 27. 27. A method according to claim 14 or 26, wherein component (i) further comprises a compound of formula (III).
  26. A combination according to any one of claims 1 to 10 or 25 for the treatment of overactive bladder (OAB).