How to treat or prevent overactive bladder syndrome

Abstract

The present disclosure provides a method of treating a human subject (having normal renal function, mild renal impairment, or mild to moderate renal impairment) in need of treatment or prevention of overactive bladder syndrome (OBS), the method comprising administering to the human subject a therapeutically effective amount of a compound of formula (I): [Chemical 1] JPEG2025521597000054.jpg72165or a pharmaceutically acceptable salt thereof. In one embodiment, the method comprises administering a compound of formula (IA). [Chemical 2] JPEG2025521597000055.jpg66165

Description

[Background technology]

[0001] Overactive bladder syndrome (OBS) can occur when the bladder muscles begin to contract involuntarily, even when the amount of urine in the bladder is small. These muscle contractions necessitate emergency urination. Patients with overactive bladder syndrome (OBS) generally urinate more frequently than healthy individuals and often wake up at night more than once to urinate (nocturia). Many OBS patients experience urinary incontinence, which is defined as loss of urine.

[0002] OBS (Occlusive Bladder Spasm) results from abnormal and involuntary contractions of the detrusor muscle of the bladder, which is linked to muscarinic receptors. When the bladder is filled with urine, it begins to stretch. This stretch, sensed by afferent neurons, creates the urge to urinate. Nerves in the bladder's muscle wall release the neurotransmitter acetylcholine, which binds to muscarinic receptors in the bladder's muscle wall, causing the cells to contract and further intensifying the urge to urinate. When these muscarinic receptors are stimulated by acetylcholine, bladder contraction occurs, leading to urination. Normally, the detrusor muscle remains at rest when the bladder is filled with urine. However, in patients with OBS, the bladder contracts during the filling phase.

[0003] The common pharmacological treatment for ovarian stenosis (OBS) is the use of antimuscarinic agents (i.e., muscarinic receptor antagonists) that inhibit muscle stimulation by the neurotransmitter acetylcholine. Several antimuscarinic agents, including oxybutynin, tolterodine, throspium, solifenacin, and dalifenacin, are approved for use in the treatment of OBS. By blocking the effects of acetylcholine on muscle cells, antimuscarinic agents slow the increase in pressure in the bladder, reduce the urge to urinate, and prevent uncontrolled urination.

[0004] Administration of antimuscarinic agents affects the efferent pathways associated with muscle contractions that lead to urination. Treatments that affect the sensory (afferent) pathways associated with urination have not been very successful. Afferent nerve fibers are transmitted from the lower urinary tract to the spinal cord via the pelvic nerve, hypogastric nerve, and pudendal nerve. Afferent nerves in the lower urinary tract are made up of two fibers (A-δ and C- fibers) that are associated with the sensation of pressure and respond to bladder stretching when the bladder is filled with urine. Afferent neurons express different types of receptors and ion channels, including transient receptor potential channels, purinergic, muscarinic, endothelin, neurotrophic factor, and estrogen receptors. These receptors have various functions, many of which are involved in increasing or decreasing neuronal excitability. One role of these afferent fibers is to transmit information about bladder pressure to the central nervous system, thereby initiating the efferent pathways. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] There is a need for effective treatment of lower urinary tract disorders using small molecule drugs that can be administered orally. [Means for solving the problem]

[0006] This disclosure provides a method for treating or preventing overactive bladder syndrome (OBS) through the administration of a small molecule agonist of an analgesic opioid peptide receptor, also known as the ORL-1 receptor.

[0007] In one embodiment, the present disclosure relates to a method for administering treatment or prevention of OBS to a human subject identified as needing such treatment, comprising a therapeutically effective amount of a compound of formula (I): [ka] The present invention provides a method comprising administering a pharmaceutically acceptable salt thereof to a human subject. The compound of formula (I) includes all of its stereoisomers (including enantiomers) and polymorphs.

[0008] In some embodiments, the present disclosure provides a method of treating a human subject identified as needing treatment or prevention of overactive bladder syndrome (OBS), the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I’):

Chemical formula

[0009] In certain embodiments, the compound of formula (I) or formula (I’) is administered as the tosylate salt. For example, in certain embodiments, the present disclosure provides a method of treating a human subject identified as needing treatment or prevention of overactive bladder syndrome (OBS), the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA).

Chemical formula

[0010] In certain embodiments, the present disclosure provides a method of treating a human subject identified as needing treatment or prevention of one or more symptoms associated with OBS, the method comprising administering to the subject a compound of formula (I) or (I’), or a pharmaceutically acceptable salt thereof, wherein the one or more symptoms are selected from the group consisting of urinary incontinence, urgency, and increased urinary frequency. In some embodiments, the method comprises administering a compound of formula (IA).

[0011] In certain embodiments, compounds of formula (I) or (I'), or pharmaceutically acceptable salts thereof, are administered orally. As referred to below, the compounds of the Disclosure include compounds of formula (I) and (I') (including all stereoisomers), pharmaceutically acceptable salts thereof (e.g., compounds of formula (IA)), polymorphs, solvates, or hydrates. Appropriate effective doses of the compounds of the Disclosure as single doses for oral administration are about 0.001 mg to about 30 mg, about 0.10 mg to about 10 mg, about 0.50 mg to about 8 mg, about 1 mg to about 6 mg, or about 1 mg to about 3 mg. In some such embodiments, the compound administered is a compound of formula (IA).

[0012] In certain embodiments, the compounds of the Disclosure are administered orally. In certain embodiments, the administered compound is a compound of formula (IA). It is understood that oral administration of a compound of the Disclosure (e.g., a compound of formula (I), (I'), or (IA)) leads to an increase in the concentration of the compound in the bladder.

[0013] A special advantage of the methods of the present disclosure is that they can simultaneously treat patients suffering from both sleep disorders and lower urinary tract complications (e.g., OBS). Accordingly, in one embodiment, the present disclosure provides a method for treating or preventing OBS in a human subject also suffering from a sleep disorder, comprising administering a therapeutically effective amount of the compound of the present disclosure to the subject. In certain embodiments, the compound is a compound of formula (IA). In some embodiments, the human subject suffers from insomnia. In one embodiment, the human subject suffers from insomnia associated with alcohol abstinence. In some embodiments, the compound of the present disclosure is administered at night. [Brief explanation of the drawing]

[0014] [Figure 1A] This table shows the baseline rhythmic bladder contraction (RBC) frequency in female rats anesthetized after administration of a vehicle, the compound of formula (IA) (denoted as Cpd(IA)), or tolterodine. Results are expressed as mean ± sem. NSp > 0.05, one-way ANOVA. [Figure 1B] This table shows the baseline RBC amplitude in female rats anesthetized after administration of the vehicle, the compound of formula (IA), or tolterodine. Results are expressed as mean ± sem. NSp > 0.05, one-way ANOVA. [Figure 1C] A figure shows a study designed to evaluate the effect of intravenous administration of the compound of formula (IA) on bladder measurement parameters in an isovolumetric model of anesthetized female rats. [Figure 2A] This study shows the effect of vehicle (1 mL / kg, iv) on RBC frequency in anesthetized female rats. Results are expressed as mean ± sem. *p<0.05, **p<0.01, and ****p<0.0001, paired with baseline, paired Student's t-test or Wilcoxon test. [Figure 2B] This study shows the effect of the compound (3 mg / kg, iv) of formula (1A) on RBC frequency in anesthetized female rats. Results are expressed as mean ± sem. *p<0.05, **p<0.01, and ****p<0.0001, paired with baseline, corresponding Student's t-test or Wilcoxon test. [Figure 2C] This study shows the effect of tolterodine compounds (1 mg / kg, iv) on RBC frequency in anesthetized female rats. Results are expressed as mean ± sem. *p<0.05, **p<0.01, and ****p<0.0001, paired with baseline, paired Student's t-test or Wilcoxon test. [Figure 3] The effects of vehicle (1 mL / kg, iv), compound (1A) (3 mg / kg, iv), and tolterodine (1 mg / kg, iv) on RBC frequency in anesthetized female rats are shown as percentage changes from baseline. Results are expressed as mean ± sem. Post-hoc tests of NSp > 0.05 and ++++p < 0.0001 were performed against vehicle, Kruskal-Wallis, and then Dunn. [Figure 4A]This study shows the effect of vehicle (1 mL / kg, iv) on RBC amplitude in anesthetized female rats. Results are expressed as mean ± sem. *p<0.05, and **p<0.01, versus baseline, paired Student's t-test or Wilcoxon test. [Figure 4B] The effect of compound (3 mg / kg, iv) of formula (1A) on RBC amplitude in anesthetized female rats is shown. Results are expressed as mean ± sem. *p<0.05, and **p<0.01, versus baseline, corresponding Student's t-test or Wilcoxon test. [Figure 4C] This study shows the effect of tolterodine compounds (1 mg / kg, iv) on RBC amplitude in anesthetized female rats. Results are expressed as mean ± sem. *p<0.05, and **p<0.01, versus baseline, paired Student's t-test or Wilcoxon test. [Figure 5] The effects of vehicle (1 mL / kg, iv), compound (IA) (3 mg / kg, iv), and tolterodine (1 mg / kg, iv) on RBC amplitude in anesthetized female rats are shown as a percentage of variation from the baseline. RBC amplitude is expressed as a percentage of variation from the baseline. Results are expressed as mean ± sem. NSp > 0.05 and ++++p < 0.001, versus vehicle, one-way ANOVA, followed by Dunnett's post-hoc test. [Figure 6] The effects of vehicle (1 mL / kg, iv), compound (1A) (3 mg / kg, iv), and tolterodine (1 mg / kg, iv) on inhibition time in anesthetized female rats are shown. Results are expressed as mean ± sem. NSp > 0.05 and ++p < 0.01, one-way ANOVA against vehicle, followed by Dunnett's post-hoc test. [Figure 7A] Figure 7A shows the records of bladder measurement parameters analyzed for vehicle (1 mL / kg, iv). [Figure 7B] Figure 7B shows the records of bladder measurement parameters analyzed for compound (IA) (3 mg / kg, iv). [Figure 7C]Figure 7C shows the records of bladder measurement parameters analyzed for tolterodine (1 mg / kg, iv). [Figure 8] A general record of the analyzed bladder measurement parameters is shown. [Figure 9] This is a scheme for designing SCI trial protocols. [Figure 10] The bladder measurement parameters measured in the SCI test are presented. [Figure 11] A shows the effect of SCI on BC, a bladder measurement parameter. B shows the effect of SCI on ThP, a bladder measurement parameter. C shows the effect of SCI on AM, a bladder measurement parameter. D shows the effect of SCI on NVC frequency, a bladder measurement parameter. E shows the effect of SCI on NVC amplitude, a bladder measurement parameter. F shows the effect of SCI on bladder weight, a bladder measurement parameter. Results are expressed as mean ± sem. nsp>0.05, §§p<0.01, §§§p<0.001, §§§§p<0.0001, unpaired Student's t-test. [Figure 12] A shows the baseline value of the bladder measurement parameter, namely BC, in SCI experimental rats. B shows the baseline value of the bladder measurement parameter, namely ThP, in SCI experimental rats. C shows the baseline value of the bladder measurement parameter, namely AM, in SCI experimental rats. D shows the baseline value of the bladder measurement parameter, namely NVC frequency, in SCI experimental rats. E shows the baseline value of the bladder measurement parameter, namely NVC amplitude, in SCI experimental rats. F shows the baseline value of the bladder measurement parameter, namely bladder weight amplitude, in SCI experimental rats. Results are expressed as mean ± sem. NSp > 0.05, one-way ANOVA or Kruskal-Wallis test. [Figure 13A]Figure 13A shows the effect of vehicle (5 mL / kg, ig, n=12, 1 dose) on Siamese rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, **p < 0.01***p < 0.001, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman test, followed by Dunn's post-hoc test, compared to baseline. [Figure 13B] Figure 13B shows the effect of vehicle (5 mL / kg, ig, n=11, 1 dose) on baseline in SCI rats. Results are expressed as mean ± sem. NSp > 0.05, **p < 0.01***p < 0.001, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman's test, followed by Dunn's post-hoc test, versus baseline. [Figure 13C] Figure 13C shows the effect of mirabegron (10 mg / kg, ig, n=13, 1 dose) on baseline in SCI rats. Results are expressed as mean ± sem. NSp > 0.05, **p < 0.01***p < 0.001, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman test, followed by Dunn's post-hoc test, versus baseline. [Figure 13D] Figure 13D shows the effect of Cpd(IA) (30 mg / kg, ig, n=12, 1 dose) in SCI rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, **p < 0.01***p < 0.001, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman's test, followed by Dunn's post-hoc test, compared to baseline. [Figure 14A] Figure 14A shows the effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) on ​​BC (calcium glycyrrhizin) compared to vehicle (5 mL / kg, ig). Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, Kruskal-Wallis test followed by Dunn's post-hoc test, compared to vehicle. [Figure 14B]Figure 15B shows the effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) on ​​the vehicle (5 mL / kg, ig) in percentage change from baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, Kruskal-Wallis test followed by Dunn's post-hoc test, against the vehicle. [Figure 15A] Figure 15A shows the effect of vehicle (5 mL / kg, ig) on ​​THP in Siamese rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, one-way ANOVA with repeated measures or Friedman test, followed by Dunn's post-hoc test, compared to baseline. [Figure 15B] Figure 15B shows the effect of vehicle (5 mL / kg, ig) on ​​THP in SCI rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, one-way ANOVA with repeated measures or Friedman test, followed by Dunn's post-hoc test, compared to baseline. [Figure 15C] Figure 15C shows the effect of mirabegron (10 mg / kg, ig) on ​​THP in SCI rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, one-way ANOVA with repeated measures or Friedman test, followed by Dunn's post-hoc test, compared to baseline. [Figure 15D] Figure 15D shows the effect of Cpd(IA) (30 mg / kg, ig) on ​​THP in SCI rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, one-way ANOVA with repeated measures or Friedman test, followed by Dunn's post-hoc test, compared to baseline. [Figure 16A] Figure 16A shows the effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) on ​​ThP, expressed in mmHg, compared to the vehicle (5 mL / kg, ig). Results are expressed as mean ± sem. NSp > 0.05. Kruskal-Wallis test, compared to the vehicle. [Figure 16B]Figure 16B shows the effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) on ​​the vehicle (5 mL / kg, ig) in percentage change from baseline. Results are expressed as mean ± sem. NSp > 0.05. Kruskal-Wallis test, against vehicle. [Figure 17A] Figure 17A shows the effect of vehicle (5 mL / kg, ig) on ​​AM in Siamese rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, one-way ANOVA with repeated measures or Friedman test, compared to baseline. [Figure 17B] Figure 17B shows the effect of vehicle (5 mL / kg, ig) on ​​AM in SCI rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, one-way ANOVA with repeated measures or Friedman test, compared to baseline. [Figure 17C] Figure 17C shows the effect of mirabegron (10 mg / kg, ig) on ​​AM in SCI rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, one-way ANOVA with repeated measures or Friedman test, compared to baseline. [Figure 17D] Figure 17D shows the effect of Cpd(IA) (30 mg / kg, ig) on ​​AM in SCI rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, one-way ANOVA with repeated measures or Friedman test, compared to baseline. [Figure 18A] Figure 18A shows the effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) on ​​AM compared to vehicle (5 mL / kg, ig), expressed in mmHg. Results are expressed as mean ± sem. NSp > 0.05, Kruskal-Wallis test, followed by Dunn's post-hoc test, compared to vehicle. [Figure 18B]Figure 18B shows the effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) on ​​the vehicle (5 mL / kg, ig) in terms of percentage change from baseline. Results are expressed as mean ± sem. NSp > 0.05, Kruskal-Wallis test followed by Dunn's post-hoc test, against the vehicle. [Figure 19A] Figure 19A shows the effect of vehicle (5 mL / kg, ig) on ​​NVC frequency in Siamese rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, **p < 0.01, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman test, followed by Dunn's post-hoc test, compared to baseline. [Figure 19B] Figure 19B shows the effect of vehicle (5 mL / kg, ig) on ​​NVC frequency against baseline in SCI rats. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, **p < 0.01, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman test, followed by Dunn's post-hoc test, against baseline. [Figure 19C] Figure 19C shows the effect of mirabegron (10 mg / kg, ig) on ​​NVC frequency against baseline in SCI rats. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, **p < 0.01, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman test, followed by Dunn's post-hoc test, against baseline. [Figure 19D] Figure 19D shows the effect of Cpd(IA) (30 mg / kg, ig) on ​​NVC frequency in SCI rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, **p < 0.01, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman test, followed by Dunn's post-hoc test, compared to baseline. [Figure 20A]Figure 20A shows the effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) on ​​NVC frequency, expressed in NVC / min, compared to vehicle (5 mL / kg, ig). Results are expressed as mean ± sem. NSp > 0.05, one-way ANOVA, compared to vehicle. [Figure 20B] Figure 20B shows the effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) on ​​the vehicle (5 mL / kg, ig) in terms of percentage change from baseline. Results are expressed as mean ± sem. NSp > 0.05, one-way ANOVA, versus vehicle. [Figure 21A] Figure 21A shows the effect of vehicle (5 mL / kg, ig) on ​​NVC amplitude in Siamese rats compared to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, ***p < 0.01, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman test, followed by Dunn's post-hoc test, compared to baseline. [Figure 21B] Figure 21B shows the effect of vehicle (5 mL / kg, ig) on ​​NVC amplitude against baseline in SCI rats. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, ***p < 0.01, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman's test, followed by Dunn's post-hoc test, against baseline. [Figure 21C] Figure 21C shows the effect of mirabegron (10 mg / kg, ig) on ​​NVC amplitude in SCI rats relative to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, ***p < 0.01, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman test, followed by Dunn's post-hoc test, relative to baseline. [Figure 21D]Figure 21D shows the effect of Cpd(IA) (30 mg / kg, ig) on ​​NVC amplitude in SCI rats relative to baseline. Results are expressed as mean ± sem. NSp > 0.05, *p < 0.05, ***p < 0.01, one-way ANOVA with repeated measures, followed by Dunnett's post-hoc test or Friedman test, followed by Dunn's post-hoc test, relative to baseline. [Figure 22A] Figure 22A shows the effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) on ​​NVC amplitude, expressed in mmHg, relative to the vehicle (5 mL / kg, ig). Results are expressed as mean ± sem. NSp > 0.05, one-way ANOVA or Kruskal-Wallis test, relative to vehicle. [Figure 22B] Figure 22B shows the effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) on ​​vehicle (5 mL / kg, ig) in percentage change from baseline. Results are expressed as mean ± sem. NSp > 0.05, one-way ANOVA or Kruskal-Wallis test, versus vehicle. [Figure 23] A represents the baseline value of BC in all BOO experimental rats. B represents the baseline value of ThP in all BOO experimental rats. C represents the baseline value of AM in all BOO experimental rats. D represents the baseline value of NVC frequency in all BOO experimental rats. E represents the baseline value of NVC amplitude in all BOO experimental rats. F represents the baseline value of bladder weight in all BOO experimental rats. Results are expressed as mean ± sem. NSp > 0.05, unpaired Student's t-test. [Figure 24A] Figure 24A shows the effect of vehicle (1 mL / kg, iv) on BC in BOO rats over the entire period from 0 to 90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 24B]Figure 24B shows the effect of Cpd(IA) (3 mg / kg, iv) on BC in BOO rats over the entire period from 0 to 90 minutes, compared to the baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 25A] Figure 25A shows the effect of Cpd(IA) (3 mg / kg, iv) against vehicle (1 mL / kg, iv) on BC expressed in mL over the entire period from 0 to 90 minutes. Results are expressed as mean ± sem. nsp > 0.05 and ++ p < 0.01, unpaired Student's t-test or Mann-Whitney test, against vehicle. [Figure 25B] Figure 25B shows the effect of Cpd(IA) (3 mg / kg, iv) compared to vehicle (1 mL / kg, iv) in terms of percentage change from baseline over the entire period from 0 to 90 minutes. Results are expressed as mean ± sem. nsp > 0.05 and ++ p < 0.01, unpaired Student's t-test or Mann-Whitney test, compared to vehicle. [Figure 26A] Figure 26A shows the effect of vehicle (1 mL / kg, iv) on BC in BOO rats over the entire period of 60–90 minutes. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, against baseline. [Figure 26B] Figure 26B shows the effect of Cpd(IA) (3 mg / kg, iv) on BC in BOO rats over the entire period of 60–90 minutes. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, against baseline. [Figure 27A] Figure 27A shows the effect of Cpd(IA) (3 mg / kg, iv) on BC (expressed in mL) versus vehicle (1 mL / kg, iv) over the entire period of 60–90 minutes. Results are expressed as mean ± sem. nsp > 0.05, unpaired Student's t-test or Mann-Whitney test, versus vehicle. [Figure 27B]Figure 27B shows the effect of Cpd(IA) (3 mg / kg, iv) on vehicle (1 mL / kg, iv) versus vehicle (1 mL / kg, iv) in percentage change from baseline over the entire 60–90 minute period. Results are expressed as mean ± sem. nsp > 0.05, unpaired Student's t-test or Mann-Whitney U test, versus vehicle. [Figure 28A] Figure 28A shows the effect of vehicle (1 mL / kg, iv) on ThP in BOO rats over the entire period from 0 to 90 minutes, compared to the baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test, compared to baseline. [Figure 28B] Figure 28B shows the effect of Cpd(IA) (3 mg / kg, iv) on ThP in BOO rats over the entire period from 0 to 90 minutes, compared to the baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test, compared to baseline. [Figure 29A] Figure 29A shows the effect of Cpd(IA) (3 mg / kg, iv) on ThP (expressed in mmHg) compared to vehicle (1 mL / kg, iv) over the entire period from 0 to 90 minutes. Results are expressed as mean ± sem. nsp > 0.05, unpaired Student's t-test, vs. vehicle. [Figure 29B] Figure 29B shows the effect of Cpd(IA) (3 mg / kg, iv) on vehicle (1 mL / kg, iv) compared to vehicle (1 mL / kg, iv) in terms of percentage change from baseline over the entire period from 0 to 90 minutes. Results are expressed as mean ± sem. nsp > 0.05, unpaired Student's t-test, vs. vehicle. [Figure 30A] Figure 30A shows the effect of vehicle (1 mL / kg, iv) on ThP in BOO rats over the entire period of 60–90 minutes, compared to the baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test, compared to baseline. [Figure 30B] Figure 30B shows the effect of Cpd(IA) (3 mg / kg, iv) on ThP in BOO rats over the entire period of 60–90 minutes, compared to the baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test, compared to baseline. [Figure 31A] Figure 31A shows the effect of Cpd(IA) (3 mg / kg, iv) on ThP (expressed in mmHg) compared to vehicle (1 mL / kg, iv) over the entire period of 60-90 minutes. nsp > 0.05 and +p < 0.05, unpaired Student's t-test, vs. vehicle. [Figure 31B] Figure 31B shows the effect of Cpd(IA) (3 mg / kg, iv) compared to vehicle (1 mL / kg, iv) in terms of percentage change from baseline over the entire period of 60–90 minutes. nsp > 0.05 and +p < 0.05, unpaired Student's t-test, vs. vehicle. [Figure 32A] Figure 32A shows the effect of vehicle (1 mL / kg, iv) on AM in BOO rats over the entire period from 0 to 90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 32B] Figure 32B shows the effect of Cpd(IA) (3 mg / kg, iv) on AM in BOO rats over the entire period from 0 to 90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 33A] Figure 33A shows the effect of Cpd(IA) (3 mg / kg, iv) against vehicle (1 mL / kg, iv) on AM, expressed in mmHg, over the entire period from 0 to 90 minutes. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Mann-Whitney test, against baseline. [Figure 33B] Figure 33B shows the effect of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) in percentage change from baseline over the entire period from 0 to 90 minutes. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Mann-Whitney test, relative to baseline. [Figure 34A]Figure 34A shows the effect of vehicle (1 mL / kg, iv) on AM (amnesia) expressed in mmHg over the entire period of 60–90 minutes in BOO rats, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 34B] Figure 34B shows the effect of Cpd(IA) (3 mg / kg, iv) on AM (expressed in mmHg) in BOO rats over the entire period of 60–90 minutes, compared to the baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 35A] Figure 35A shows the effect of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) on AM, expressed in mmHg, over the entire period of 60–90 minutes. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Mann-Whitney test, relative to baseline. [Figure 35B] Figure 35B shows the effect of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) in percentage change from baseline over the entire 60-90 minute period. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Mann-Whitney test, relative to baseline. [Figure 36A] Figure 36A shows the effect of vehicle (1 mL / kg, iv) on NVC frequency in BOO rats over the entire period from 0 to 90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test, versus baseline. [Figure 36B] Figure 36B shows the effect of Cpd(IA) (3 mg / kg, iv) on NVC frequency in BOO rats over the entire period from 0 to 90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test, versus baseline. [Figure 37A]Figure 37A shows the effect of Cpd(IA) (3 mg / kg, iv) against vehicle (1 mL / kg, iv) on NVC frequency expressed in NVC / min over the entire period from 0 to 90 minutes. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Mann-Whitney test, against baseline. [Figure 37B] Figure 37B shows the effect of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) in percentage change from baseline over the entire period from 0 to 90 minutes. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Mann-Whitney test, relative to baseline. [Figure 38A] Figure 38A shows the effect of vehicle (1 mL / kg, iv) on NVC frequency in BOO rats over the entire period of 60–90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 38B] Figure 38B shows the effect of Cpd(IA) (3 mg / kg, iv) on NVC frequency in BOO rats over the entire period of 60–90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 39A] Figure 39A shows the effect of Cpd(IA) (3 mg / kg, iv) compared to vehicle (1 mL / kg, iv) on NVC frequency expressed in NVC / min over the entire period of 60-90 minutes. Results are expressed as mean ± sem. nsp > 0.05, one-way ANOVA followed by Dunnett's post-hoc test, compared to vehicle. [Figure 39B] Figure 39B shows the effect of Cpd(IA) (3 mg / kg, iv) on vehicle (1 mL / kg, iv) compared to vehicle (1 mL / kg, iv) in terms of percentage change from baseline over the entire period of 60-90 minutes. Results are expressed as mean ± sem. nsp > 0.05, one-way ANOVA followed by Dunnett's post-hoc test, compared to vehicle. [Figure 40A]Figure 40A shows the effect of vehicle (1 mL / kg, iv) on NVC amplitude in BOO rats over the entire period from 0 to 90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 40B] Figure 40B shows the effect of Cpd(IA) (3 mg / kg, iv) on NVC amplitude in BOO rats over the entire period from 0 to 90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 41A] Figure 41A shows the effect of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) on NVC amplitude, expressed in mmHg, over the entire period from 0 to 90 minutes. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Mann-Whitney test, relative to baseline. [Figure 41B] Figure 41B shows the effect of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) in percentage change from baseline over the entire period from 0 to 90 minutes. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Mann-Whitney test, relative to baseline. [Figure 42A] Figure 42A shows the effect of vehicle (1 mL / kg, iv) on NVC amplitude in BOO rats over the entire period of 60–90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 42B] Figure 42B shows the effect of Cpd(IA) (3 mg / kg, iv) on NVC amplitude in BOO rats over the entire period of 60–90 minutes, compared to baseline. Results are expressed as mean ± sem. nsp > 0.05, paired Student's t-test or Wilcoxon test, compared to baseline. [Figure 43A]Figure 43A shows the effect of Cpd(IA) (3 mg / kg, iv) against vehicle (1 mL / kg, iv) on NVC amplitude, expressed in mmHg, over the entire period of 60–90 minutes. Results are expressed as mean ± sem. nsp > 0.05, unpaired Student's t-test or Mann-Whitney U test, against vehicle. [Figure 43B] Figure 43B shows the effect of Cpd(IA) (3 mg / kg, iv) compared to vehicle (1 mL / kg, iv) in terms of percentage change from baseline over the entire 60-90 minute period. Results are expressed as mean ± sem. nsp > 0.05, unpaired Student's t-test or Mann-Whitney test, compared to vehicle. [Figure 44] The diagram shows the design of a Phase 1, non-randomized, open-label, parallel-group, single-dose trial. [Figure 45A] The mean plasma concentration-time profiles for subjects with normal renal function (n=10) and subjects with mild renal impairment (n=10) are shown on a linear scale. [Figure 45B] The mean plasma concentration-time profiles for subjects with normal renal function (n=10) and subjects with mild renal impairment (n=10) are shown on a semi-logarithmic scale over a linear scale. [Figure 46A] The plasma concentration-time profiles in individual subjects (n=10) with mild renal impairment are shown on a linear scale. [Figure 46B] The plasma concentration-time profiles in individual subjects (n=10) with mild renal impairment are shown on a semi-logarithmic scale. [Figure 47A] The plasma concentration-time profiles in individual subjects (n=10) with normal renal function are shown on a linear scale. [Figure 47B] The plasma concentration-time profiles for individual functional subjects (n=10) are shown on a semi-logarithmic scale. [Modes for carrying out the invention]

[0015] This disclosure provides a method for treating or preventing conditions associated with excessive stimulation of afferent nerves related to the lower urinary tract. These conditions include overactive bladder system (OBS), urinary urgency, increased urination frequency, nocturia, and urinary incontinence. Specifically, this disclosure provides a method for treating or preventing conditions associated with excessive stimulation of afferent nerves through the administration of an agonist of the nociceptin opioid peptide receptor, also known as the ORL-1 receptor.

[0016] The identification of the ORL-1 receptor, distinct from the three major opioid receptor classes in the central nervous system (mu, kappa, and delta), was achieved through experiments with these opioid receptor classes. Since the ORL-1 receptor did not exhibit pharmacological properties overlapping with classical mu opioid receptors, it was identified and classified as an opioid receptor based solely on amino acid sequence homology. Initially, it was demonstrated that non-selective ligands with high affinity for mu, kappa, and delta receptors had low affinity for the ORL-1 receptor. This characteristic, combined with the fact that an endogenous ligand has yet to be discovered, gave rise to the term "orphan receptor." See, for example, Henderson et al., “The orphan opioid receptor and its endogenous ligand - nociceptin / orphanin FQ,” Trends Pharmacol. Sci. 18(8):293-300 (1997). Subsequent investigations led to the isolation and structural determination of the endogenous ligand for the ORL-1 receptor (i.e., nociceptin; also known as orghanin FQ or OFQ), a 17-amino acid peptide structurally similar to members of the opioid peptide family. For a general discussion of the ORL-1 receptor, see Calo et al., “Pharmacology of nociceptin and its receptor: a novel therapeutic target,” Br.J.Pharmacol.129:1261-1283 (2000).

[0017] The endogenous ligand for the ORL-1 receptor is a 17-amino acid peptide called nociceptin. Through its interaction with ORL-1, nociceptin exhibits inhibitory activity of the micturition reflex in various animal models. Direct administration of nociception and nociception peptide analogs to the bladder has been studied as a means of alleviating urinary incontinence, which is presumed to be caused by a decrease in afferent signaling (Lazzeri et al., 2003 Urology; Lazzeri et al., 2006 J. Urology; and Popolo et al., 2011).

[0018] The inventors unexpectedly found that a pathological condition associated with excessive stimulation of afferent nerves related to the lower urinary tract is effectively treated with a compound of formula (I) in a therapeutically effective amount. [ka] It was discovered that improvement or treatment is possible through the administration of a pharmaceutically acceptable salt thereof. The compound of formula (I) includes all of its stereoisomers (including enantiomers) and polymorphs.

[0019] In certain embodiments, the compound of formula (I) is a single stereoisomer, i.e., the compound of formula (I') having the structure shown below. [ka] Compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts thereof, can be prepared as described in U.S. Patent No. 8,476,221, incorporated herein by reference.

[0020] Accordingly, in one embodiment, the Disclosure provides a method for administering treatment to a human subject in need of treatment or prevention of overactive bladder syndrome (OBS), comprising administering a therapeutically effective amount of a compound of the Disclosure, for example, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (for example, a compound of formula (IA)), to the subject. In certain embodiments, administration of a compound of the Disclosure also improves (e.g., reduces the severity of) symptoms associated with OBS, including but not limited to urinary urgency, increased urination frequency, nocturia, and urinary incontinence.

[0021] In one embodiment, administration of the compounds of the Disclosure increases the pressure threshold for urination by about 10% to about 99.5%. In another embodiment, administration of the compounds of the Disclosure increases the pressure threshold for urination by about 20% to about 90%. In yet another embodiment, administration of the compounds of the Disclosure increases the pressure threshold for urination by about 30% to about 80%.

[0022] In another embodiment, the Disclosure provides a method for administering a therapeutically effective dose of the compound of the Disclosure to a human subject who requires a reduction in the occurrence of nocturnal polyuria. In some embodiments, nocturnal administration refers to administering the compound before bedtime. In some embodiments, the compound of the Disclosure can be administered at any time from about three hours before bedtime to immediately before bedtime in a human subject. In one embodiment, after nightly administration of the compound of the Disclosure, the number of nightly urinations decreases from two or more times per night to less than two times per night. For example, the number of times a subject urinates at night may decrease from two or more times to zero or one time after nightly administration of the compound of the Disclosure.

[0023] In certain embodiments, the method of the Disclosure comprises administering a therapeutically effective dose of the Compound of the Disclosure to a human subject once every two nights. In other embodiments, the method comprises administering a therapeutically effective dose of the Compound of the Disclosure to a human subject once every three nights. In yet another embodiment, the method comprises administering a therapeutically effective dose of the Compound of the Disclosure to a human subject once a week. In yet another embodiment, the method comprises administering a therapeutically effective dose of the Compound of the Disclosure to a human subject once every three nights. In yet another embodiment, the method comprises administering a therapeutically effective dose of the Compound of the Disclosure to a human subject twice a week.

[0024] In another aspect, the Disclosure provides a method for administering to a human subject identified as needing treatment or prevention of urinary incontinence, the method comprising administering a therapeutically effective amount of the Compound of the Disclosure to the subject.

[0025] In another embodiment, the Disclosure provides a method for treating or preventing OBS in a human subject by administering a therapeutically effective amount of the Compound of the Disclosure, which acts by inhibiting the contraction of the detrusor muscle in the bladder of the human subject. In some embodiments, the contraction of the detrusor muscle in the bladder can be delayed by at least 20% (in time intervals) after administration of the Compound of the Disclosure. In other embodiments, the contraction of the detrusor muscle in the bladder can be delayed by at least 30% after administration of the Compound of the Disclosure. In other embodiments, the contraction of the detrusor muscle in the bladder can be delayed by at least 50% after administration of the Compound of the Disclosure. In other embodiments, the contraction of the detrusor muscle in the bladder can be delayed by at least 70% after administration of the Compound of the Disclosure. In other embodiments, the contraction of the detrusor muscle in the bladder can be delayed by at least 80% after administration of the Compound of the Disclosure. In other embodiments, the contraction of the detrusor muscle in the bladder can be delayed by at least 90% after administration of the Compound of the Disclosure. In other embodiments, after administration of the compounds of the present disclosure, the contraction of the detrusor muscle in the bladder may be delayed by about 20% to about 90%, about 30% to about 85%, about 40% to about 80%, or about 50% to about 70%.

[0026] In another embodiment, the Disclosure provides a method for treating or preventing OBS in a human subject by administering a compound of the Disclosure (e.g., a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof), the compound acting by reducing the frequency of detrusor contractions in the subject's bladder. In some embodiments, the frequency of detrusor contractions in the bladder is reduced by at least 20% after administration of a compound of the Disclosure. In other embodiments, the frequency of detrusor contractions in the bladder is reduced by at least 30% after administration of a compound of the Disclosure. In other embodiments, the frequency of detrusor contractions in the bladder is reduced by at least 50% after administration of a compound of the Disclosure. In other embodiments, the frequency of detrusor contractions in the bladder is reduced by at least 70% after administration of a compound of the Disclosure. In other embodiments, the frequency of detrusor contractions in the bladder is reduced by at least 80% after administration of a compound of the Disclosure. In other embodiments, the frequency of detrusor contractions in the bladder is reduced by at least 90% after administration of a compound of the Disclosure. In certain embodiments, the frequency of detrusor muscle contractions in the bladder decreases by about 20% to about 90%, about 30% to about 85%, about 40% to about 80%, or about 50% to about 70% after administration of the compounds of the Disclosure.

[0027] As used herein, the terms “treatment,” “to treat,” and related terms include improvement, relief, reduction, slowing, or cessation of a condition or its symptoms by administering an effective amount of the compounds of this disclosure, e.g., compounds of formula (I) or (I'), or pharmaceutically acceptable salts thereof (e.g., compounds of formula (IA)). In some embodiments, treating includes inhibiting an episode of a condition (e.g., OBS) or its symptoms (e.g., urinary incontinence or nocturia) (e.g., reducing its overall frequency), or reducing the severity of a condition or its symptoms.

[0028] As used herein, the terms “prevention of,” “prevention,” and related terms include avoiding the development of a condition or its symptoms by administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0029] When used in connection with the methods of this disclosure, the term “effective dose” means the amount of a compound that, when administered to an animal (e.g., a human subject), produces a partial or complete therapeutic effect desired by a person skilled in the art (e.g., a physician).

[0030] When used in connection with the methods of this disclosure, the term “therapeutic dose” refers to the amount of a compound administered to an animal (e.g., a human subject) that produces the desired therapeutic effect.

[0031] While we do not wish to be bound by any theory, the compounds of this disclosure are thought to exert beneficial effects by modulating ORL-1 receptors expressed at afferent nerve fibers / terminals in the lower urinary tract. The terms “modulate,” “to modulate,” and related terms used herein with respect to ORL-1 receptors mean mediating a pharmacodynamic response (e.g., OBS) in animals by (i) inhibiting or activating the receptor, or (ii) directly or indirectly affecting the normal regulation of receptor activity. Compounds that modulate receptor activity include agonists, partial agonists, biased agonists, antagonists, mixed agonist / antagonists, mixed partial agonist / antagonists, and compounds that directly or indirectly affect the regulation of receptor activity. Compounds of formulas (I) and (I'), and their pharmaceutically acceptable salts (e.g., compounds of formula (IA)), are partial agonists. As used herein, a compound that binds to a receptor and is only partially effective as an agonist compared to another agonist containing a natural ligand is defined as a “partial agonist.” The partial agonists disclosed herein are considered to be able to achieve desired therapeutic effects (e.g., treatment of OBS) with little to no side effects often associated with the administration of full agonists.

[0032] As used herein, the term "eGFR" refers to the estimated glomerular filtration rate (eGFR) calculated by the following formula: eGFR = 142 x min(standardized Scr / k,1)α x max(standardized Scr / k,1)-1200 x 0.9938Age x 1.012 [for females], where k is 0.7 for females and 0.9 for males, α is -0.241 for females and -0.302 for males, min represents the minimum value of Scr / k or 1, and max represents the maximum value of Scr / k or 1.

[0033] As used herein, "human subjects without renal impairment" or "human subjects with normal renal function" means human subjects having an eGFR of 90 mL / min or higher.

[0034] When used herein, "human subjects with mild renal impairment" means that the human subjects have an eGFR of approximately 60 mL / min to approximately 89 mL / min.

[0035] As used herein, "a human subject with mild to moderate renal impairment" means a human subject with an eGFR of approximately 45 mL / min to approximately 59 mL / min.

[0036] The compounds of this disclosure may be administered as components of a composition comprising a pharmaceutically acceptable carrier or excipient. Routes of administration include, but are not limited to, oral, intravesical, intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, epidural, transmucosal, buccal, gingival, sublingual, intraocular, intracerebral, vaginal, transdermal (e.g., via a patch), rectal, inhalation, or topical. In other embodiments, routes of administration include, but are not limited to, intravenous, intravesical, oral, or inhalation. In another embodiment, the route of administration is oral. In another embodiment, the route of administration is intravesical. In another embodiment, the route of administration is inhalation.

[0037] In yet another embodiment, the compounds of the Disclosure may be delivered by a controlled-release or sustained-release system. As is well understood in the art (e.g., the pharmaceutical industry), controlled-release or sustained-release pharmaceutical compositions can improve pharmacotherapy beyond what can be achieved by their non-controlled-release or non-sustained-release counterparts (e.g., immediate-release formulations). In one embodiment, the controlled-release or sustained-release composition comprises a therapeutically effective amount of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, for the long-term treatment or prevention of OBS or its symptoms. Advantages of controlled-release or sustained-release compositions include extended drug activity, reduced administration frequency, and increased compliance.

[0038] The compounds of this disclosure may be administered by controlled-release or sustained-release means, or by delivery devices known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Patents 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566 (each of which is incorporated herein by reference). Many other controlled-release or sustained-release delivery devices are known to those skilled in the art (see, for example, Goodson, “Dental Applications,” in Medical Applications of Controlled Release, Vol. 2, Applications and Evaluation, Langer and Wise, eds., CRC Press, Chapter 6, pp. 115-138 (1984) (hereinafter “Goodson”)). Other controlled-release or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) may be used.In one embodiment, a pump may be used (Langer, Science 249:1527-1533 (1990); Sefton, “Implantable Pumps,” in CRC Crit. Rev. Biomed. Eng. 14(3):201-240 (1987); Buchwald et al., “Long-term, Continuous Intravenous Heparin Administration by an Implantable Infusion Pump in Ambulatory Patients with Recurrent Venous Thrombosis,” Surgery 88:507-516 (1980); and Saudek et al., “A Preliminary Trial of the Programmable Implantable Medication System for Insulin Delivery,” New Engl. J. Med. 321:574-579 (1989)).In another embodiment, polymer materials may be used (Goodson; Smolen et al., “Drug Product Design and Performance,” Controlled Drug Bioavailability Vol.1, John Wiley and Sons, New York (1984); Langer et al., “Chemical and Physical Structure of Polymers as Carriers for Controlled Release of Bioactive Agents: A Review,” J.Macromol.Sci.Rev.Macromol.Chem.C23(1):61-126 (1983); Levy et al., “Inhibition of Calcification of Bioprosthetic Heart Valves by Local Controlled-Release Diphosphonate,” Science 228:190-192 (1985); During et al., “Controlled Release of Dopamine from a Polymeric Brain Implant: In Vivo Characterization,” Ann.Neurol.25:351-356 (1989); and Howard et al., “Intracerebral drug delivery in rats with See "leaf-induced memory deficits," J. Neurosurg. 71:105-112 (1989).

[0039] Using suitable dosage forms, for example, hydroxypropyl methylcellulose, ethylcellulose, other polymer matrices, gels, permeable membranes, permeable systems, multilayer coatings, microparticles, multiplicities, liposomes, microspheres, or combinations thereof, controlled or sustained release of one or more active ingredients can be achieved, providing desired release profiles in various proportions. Suitable controlled-release or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of this disclosure. Accordingly, this disclosure encompasses single-unit dosage forms suitable for oral administration adapted for controlled or sustained release (including, but not limited to, tablets, capsules, gel caps, and caplets).

[0040] The composition may optionally, but preferably, further contain a suitable amount of pharmaceutically acceptable excipients to provide a form suitable for appropriate administration to animals. Such pharmaceutically acceptable excipients may be diluents, suspending agents, solubilizers, binders, disintegrants, preservatives, colorants, lubricants, etc. The pharmaceutically acceptable excipients may be liquids such as water or oil (of petroleum, animal, plant, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). The pharmaceutically acceptable excipients may be physiological saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliary agents, stabilizers, thickeners, lubricants, and colorants may be used. In one embodiment, the pharmaceutically acceptable excipient is sterile when administered to animals. Water is a particularly useful excipient when the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered intravenously. Physiological saline solutions and aqueous solutions of dextrose and glycerol may also be used as liquid excipients (especially for injectable solutions). Suitable pharmaceutically acceptable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol. The composition may optionally contain small amounts of wetting agents or emulsifiers or pH buffers. Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients (Amer. Pharmaceutical Ass'n, Washington, DC, 1986), which is incorporated herein by reference. Other examples of suitable pharmaceutically acceptable excipients are incorporated herein by reference in Radebough et al., “Preformulation,” pp. 1447–1676 in Remington's Pharmaceutical Sciences Vol. 2 (Gennaro, ed., 19 th This is described in Ed., Mack Publishing, Easton, PA, 1995.

[0041] In one embodiment, the compounds of the Disclosure are formulated as compositions suitable for oral administration to humans according to routine procedures. The orally delivered compounds of the Disclosure may be in the form of, for example, tablets, capsules, gel caps, caplets, lozenges, aqueous or oily solutions, suspensions, granules, microparticles, multiplicities, powders, emulsions, syrups, or elixirs. When a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is incorporated into an oral tablet, such a tablet may be compressed, powdered, enteric-coated, sugar-coated, film-coated, multi-compressed, or multilayer. Techniques and compositions for producing solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman et al., eds., 2 nd This is described in (Ed., Marcel Dekker, Inc., 1989 and 1990). Techniques and compositions for preparing tablets (compressed and molded), capsules (rigid and soft gelatin), and pills are also described in King, “Tablets, Capsules, and Pills,” pp. 1553-1593 in Remington's Pharmaceutical Sciences (Osol, ed., 16 th This is described in Ed., Mack Publishing, Easton, PA, 1980.

[0042] Liquid oral dosage forms include aqueous and non-aqueous solutions, emulsions, suspensions, and solutions and / or suspensions reconstituted from non-foaming granules, and optionally contain one or more suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, colorants, flavoring agents, etc. Techniques and compositions for preparing liquid oral dosage forms are described in Pharmaceutical Dosage Forms: Disperse Systems (Lieberman et al., eds., 2) nd This is described in (Ed., Marcel Dekker, Inc., 1996 and 1998).

[0043] Oral pharmaceutical compositions comprising the compounds of the Disclosure (e.g., compounds of formula (I) or (I'), or pharmaceutically acceptable salts thereof) may include one or more excipients, such as sweeteners (e.g., fructose, aspartame, or saccharin); flavoring agents (e.g., peppermint, wintergreen oil, or cherry); colorants; and preservatives, to provide a pharmaceutically acceptable preparation. Furthermore, in tablet or pill form, the composition may be coated to slow down breakdown and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. Selectively permeable membranes surrounding osmotically active driving compounds are also suitable for oral administration compositions. In these latter platforms, fluids from the surrounding environment of the capsule are absorbed by the driving compound, which expands and pushes the drug or pharmaceutical composition through the opening. These delivery platforms may provide an essentially zero-order delivery profile, in contrast to the spiked profile of immediate-release formulations. Time-delaying materials such as glycerol monostearate or glycerol stearate may also be used. The oral composition may contain standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

[0044] The composition may take the form of a solution, suspension, emulsion, tablet (e.g., orally disintegrating tablet (ODT) or sublingual tablet), pill, pellet, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, suspension, fine particles, multiply particles, rapid-dissolving film, or other form for oral or mucosal administration, or any other form suitable for use. In one embodiment, the composition is in the form of an ODT (see, for example, U.S. Patents 7,749,533 and 9,241,910). In another embodiment, the composition is in the form of a sublingual tablet (see, for example, U.S. Patents 6,572,891 and 9,308,175). In yet another embodiment, the composition is in the form of a capsule (see, for example, U.S. Patent 5,698,155). In another embodiment, the composition is in a form suitable for buccal administration, for example, as a tablet, lozenge, gel, patch, or film formulated in a conventional manner (see, for example, Pater et al., “Current status and the future of buccal drug delivery systems,” Expert Opin. Drug Deliv. 5(5):531-542 (2008)). In another embodiment, the composition is in a form suitable for gingival administration, for example, as a polymer film containing polyvinyl alcohol, chitosan, polycarbophil, hydroxypropyl cellulose, or Eudragit S-100, as disclosed by Padula et al., “In Vitro Evaluation of Mucoadhesive Films for Gingival Administration of Lidocaine,” AAPS PharmSciTech 14(4):1279-1283 (2013). In another embodiment, the composition is in a form suitable for intraocular administration.

[0045] In one embodiment, the compounds of the Disclosure are formulated for parenteral administration. When the compounds of the Disclosure are administered parenterally, this may be, for example, in the form of an isotonic sterile solution.

[0046] When the compounds of this disclosure are administered parenterally, the parenteral formulation may be in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle. Such formulation may further contain one or more pharmaceutically necessary additives, such as stabilizers, suspenders, dispersants, or buffers. The compounds of this disclosure may also be in the form of a powder for reconstitution as an injectable formulation.

[0047] In another embodiment, the compounds of the Disclosure may be formulated for intravenous administration. In certain embodiments, the intravenous composition comprises a sterile isotonic aqueous buffer. If necessary, the composition may also include a solubilizer. The intravenous composition containing the compounds of the Disclosure may optionally include a local anesthetic, such as benzocaine or prilocaine, to relieve pain at the injection site. Generally, the components are supplied separately or mixed in unit dosage forms, for example, as lyophilized powder or anhydrous concentrate in a sealed container such as an ampoule or sachet indicating the amount of the active agent. When the compounds of the Disclosure are administered by infusion, they may be dispensed, for example, in an infusion bottle containing sterile pharmaceutical-grade water or saline. When the compounds of the Disclosure are administered by injection, ampoules of sterile water or saline for injection may be provided so that the components can be mixed before administration.

[0048] The compounds of this disclosure, for example, the compounds of formula (I) or (I'), are mostly excreted unchanged, primarily through urine (see Example 2 below). Therefore, the compounds of formula (I) or (I') are mostly concentrated in the bladder after administration. For example, when administered orally, the amount of the compound of formula (I) or (I') excreted in urine ranges from about 30% to about 95%, depending on the dose administered. Furthermore, the concentration of the compound of formula (I) or (I') in urine remains high for at least 24 hours after oral administration. In certain embodiments, the concentration of the compound of formula (I) or (I') is greater than 100 nM 12 hours after oral administration. In other embodiments, the concentration of the compound of formula (I) or (I') is greater than 500 nM 12 hours after oral administration. In other embodiments, the concentration of the compound of formula (I) or (I') is greater than 1,000 nM 12 hours after oral administration. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration is greater than 5,000 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration is greater than 10,000 nM. In certain embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration may be in the range of about 100 nM to about 30,000 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration may be in the range of about 500 nM to about 15,000 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration may be in the range of about 1,000 nM to about 10,000 nM.

[0049] In some embodiments, the compound of formula (I) or (I') is administered in the form of a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt (including both inorganic and organic salts) that can be prepared from the compound of formula (I). Examples of salts include, but are not limited to, sulfates, citrates, acetates, trifluoroacetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucoronates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts). In one embodiment, pharmaceutically acceptable salts are hydrochloride, sulfate, sodium salt, potassium salt, benzenesulfonate, p-toluenesulfonate, or fumarate. In another embodiment, pharmaceutically acceptable salts are hydrochloride or sulfate. In another embodiment, pharmaceutically acceptable salts are hydrochloride. In another embodiment, pharmaceutically acceptable salts are sulfate. In another embodiment, pharmaceutically acceptable salts are sodium salt. In another embodiment, pharmaceutically acceptable salts are potassium salt. In another embodiment, pharmaceutically acceptable salts are fumarate. In another embodiment, pharmaceutically acceptable salts are p-toluenesulfonate, i.e., p-toluenesulfonate (also known as "tosylate salt"). In another embodiment, pharmaceutically acceptable salts are choline salt.

[0050] In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains 1 equivalent of the compound of formula (I) or (I') and about 1.0 equivalent of p-toluenesulfonic acid, for example, about 0.8 to about 1.2 equivalents of p-toluenesulfonic acid in one embodiment, about 0.9 to about 1.1 equivalents of p-toluenesulfonic acid in another embodiment, about 0.93 to about 1.07 equivalents of p-toluenesulfonic acid in another embodiment, about 0.95 to about 1.05 equivalents of p-toluenesulfonic acid in another embodiment, about 0.98 to about 1.02 equivalents of p-toluenesulfonic acid in another embodiment, or about 0.99 to about 1.01 equivalents of p-toluenesulfonic acid in another embodiment. In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains about 1 equivalent of the compound of formula (I') and about 1 equivalent of p-toluenesulfonic acid (i.e., a monotosylate salt). In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains 1 equivalent of the compound of formula (I) (relative to the amount of p-toluenesulfonic acid). In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains 1 equivalent of the compound of formula (I'). The monotosylate salt of the compound of formula (I'), i.e., the compound of formula (IA), is as follows: [ka]

[0051] The methods of the disclosure provided herein also include the use of any solvates of the compound of formula (I) or (I') or any pharmaceutically acceptable salt thereof. “Solvate” is a term commonly known in the art and is hereby considered to be a combination, physical association, and / or solvation of the compound of formula (I) or (I') or any pharmaceutically acceptable salt thereof. This physical association may include varying degrees of ionic and covalent bonding, including hydrogen bonding. If the solvate is stoichiometric, the ratio of solvent molecules to the compound of formula (I) or (I') or any pharmaceutically acceptable salt thereof is constant. The compound of formula (I) or (I') or any pharmaceutically acceptable salt thereof may exist in solvated form with a pharmaceutically acceptable solvent, such as water (e.g., hydrate), methanol, or ethanol.

[0052] The methods of this disclosure provided herein also encompass the use of any crystalline form (or polymorph) of the compound of formula (I) or (I') or any pharmaceutically acceptable salt thereof. As used herein, the term “crystalline” and related terms, when used to describe a substance, component, or product, mean that the substance, component, or product is substantially crystalline as determined by X-ray diffraction, microscopy, polarized light microscopy, or other known analytical procedures known to those skilled in the art. As used herein, the term “polymorph” refers to the crystalline structure of a compound having different unit cell structures in the crystal, resulting from diverse molecular stereochemistry and molecular packing. Polymorphs of a single compound may have one or more different chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties from one another. Differences in physical properties exhibited by polymorphisms can affect pharmaceutical parameters such as storage stability, compressibility, density (important in the manufacture of compositions and products), dissolution rate (a key factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water absorption, compaction, and particle morphology. Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, where the dosage form discolors more rapidly when composed of one polymorph than when composed of another), mechanical changes (e.g., changes in crystals during storage, where a kinetically favorable polymorph is converted to a thermodynamically more stable polymorph), or both (e.g., one polymorph being more hygroscopic than another).

[0053] In certain embodiments, the compound of formula (IA) has crystalline forms referred to as form A, form B, form C, form D, or form E, as described in WO2020 / 157691, the contents of which are incorporated herein by reference. In some embodiments, the compound of formula (IA) is of crystalline form A. In other embodiments, the compound of formula (IA) is of crystalline form B. In other embodiments, the compound of formula (IA) is of crystalline form C. In other embodiments, the compound of formula (IA) is of crystalline form D. In other embodiments, the compound of formula (IA) is of crystalline form E.

[0054] As used herein, “dose,” “amount,” and related terms refer to the weight-based quantities of the compound of formula (I) or (I') in its free acid and free base forms, i.e., non-salt forms. For example, a 10.0 mg dose means that 10.0 mg of the non-salt form of the compound of formula (I) or (I') is actually administered. However, for example, a 10.0 mg dose of, for example, the monohydrochloride or 1:1 molar hydrochloride of the compound of formula (I) or (I') means that 10.84 mg of the compound is actually administered, which results in 10.00 mg of the non-salt form of the compound of formula (I) or (I') (0.0229 mmol) and 0.84 mg of hydrochloride (0.0229 mmol). Similarly, a dose of 10.00 mg of, for example, the monotosylate salt of the compound of formula (IA) (1:1 mole of p-toluenesulfonate) means that 13.93 mg of the above compound is actually administered, and this 13.93 mg results in 10.00 mg of the unsalted form of the compound of formula (I) or (I') (0.0229 mmol) and 3.93 mg of p-toluenesulfonic acid (0.0229 mmol).

[0055] With respect to methods for treating or preventing a condition or symptom in human subjects, preferred effective doses of the compounds of this disclosure are, in one embodiment, about 0.0002 mg / kg to about 10 mg / kg of body weight of the human subject per day; in another embodiment, about 0.00025 mg / kg / day to about 5 mg / kg / day; in another embodiment, about 1.5 mg / kg / day to about 3 mg / kg / day; in another embodiment, about 0.2 mg / kg / day to about 2 mg / kg / day; in another embodiment, about 2.5 mg / kg / day to about 10.0 mg / kg / day; and in another embodiment, about 3.0 mg / kg / day to about 5.0 mg / kg / day. In another embodiment, the effective dose is about 10 mg / kg / day or less. In certain embodiments, preferred effective doses of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, are about 0.0002 mg / kg / day to about 10 mg / kg / day, about 0.001 to about 10 mg / kg / day, about 0.002 mg / kg / day to about 10 mg / kg / day, about 0.003 mg / kg / day to about 10 mg / kg / day, about 0.0005 mg / kg / day to about 5.0 mg / kg / day, about 0.001 mg / kg / day to about 2.5 mg / kg / day, about 0.002 mg / kg / day to about 2.0 mg / kg / day, or about 0.002 mg / kg / day to about 1.0 mg / kg / day. In other embodiments, the effective dose is about 1.0 mg / kg / day or less. In certain other embodiments, preferred effective doses of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, are approximately 0.001 mg / kg / day to approximately 1.0 mg / kg / day, approximately 0.002 mg / kg / day to approximately 0.8 mg / kg / day, approximately 0.0025 mg / kg / day to approximately 0.5 mg / kg / day, approximately 0.003 mg / kg / day to approximately 0.15 mg / kg / day, approximately 0.006 mg / kg / day to approximately 0.12 mg / kg / day, or approximately 0.010 mg / kg / day to approximately 0.10 mg / kg / day. It should be understood that, with respect to these doses, the term “day” refers to a 24-hour cycle beginning from the time of administration of the compound of the present disclosure, e.g., the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof.

[0056] In embodiments in which a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (IA)), is administered orally, suitable effective doses of the compound as a single dose are approximately 0.001 mg to approximately 300 mg, approximately 0.005 mg to approximately 250 mg, approximately 0.01 mg to approximately 200 mg, approximately 0.05 mg to approximately 150 mg, approximately 0.075 mg to approximately 50 mg, or approximately 0.10 mg to approximately 10 mg. In one embodiment, the compound of the Disclosure is administered as a single dose in an uncontrolled-release or non-sustained-release formulation (e.g., an immediate-release formulation). In another embodiment, the effective dose of the compound of the Disclosure is administered as multiple doses in an uncontrolled-release or non-sustained-release formulation.

[0057] In specific uses, approximately 0.05 mg, approximately 0.06 mg, approximately 0.07 mg, approximately 0.08 mg, approximately 0.09 mg, approximately 0.100 mg, approximately 0.120 mg, approximately 0.125 mg, approximately 0.150 mg, approximately 0.175 mg, approximately 0.200 mg, approximately 0.225 mg, approximately 0.250 mg, approximately 0.275 mg, approximately 0.30 mg, approximately 0.35 mg, approximately 0.40 mg, approximately 0.45 mg, approximately 0.50 mg, approximately 0.55 mg, approximately 0.60 mg, approximately 0.65 mg, approximately 0.70 mg, approximately 0.75 mg, approximately 0.80 mg, approximately 0.85 mg, approximately 0.90 mg, approximately 0.95 mg, approximately 1.00 mg, approximately 1.25 mg, approximately 1.50 mg, approximately 1.75 mg, approximately 2.00 mg, approximately 2.25 mg, approximately 2.50 mg, approximately 2.75 mg, approximately 3.00 mg, approximately 3.25 mg, approximately 3.50 mg, approximately 3.75 mg, approximately 4.0 mg, approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, approximately 6.0 mg, approximately 6.5 mg, approximately 7.0 mg, approximately 7.5 mg, approximately 8.0 mg, approximately 9.0 mg, or approximately 10 mg of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (IA)), is administered orally to a human subject requiring it. In some embodiments, approximately 1 mg of a compound of formula (I) or (I'), or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered orally to a human subject requiring it. In some embodiments, approximately 1.5 mg of a compound of formula (I) or (I'), or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered orally to a human subject requiring it. As is known to those skilled in the art, in the case of human animals, a once-daily dose (in mg) can be converted to a mg / kg / day dose by dividing the mg dose by 60 kg, which is the average mass of human animals recognized in the art. For example, a once-daily dose of 12 mg for humans is thus converted to a dose of approximately 0.20 mg / kg / day.

[0058] In certain embodiments, a controlled-release composition containing a therapeutically effective amount of the compound of this disclosure is administered as a single dose or multiple doses. The controlled-release composition may contain up to 100 times the dose of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (IA)), used in an uncontrolled-release or non-sustained-release formulation.

[0059] In some embodiments, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered once daily. In some such embodiments, the compound of formula (I) or (I') is administered nightly (e.g., before bedtime). As shown in Example 2, daily administration of the compound of formula (I) or (I') results in urinary concentrations of Ki and EC. 50 The measured activity is several orders of magnitude greater than the in vitro activity of the compound of formula (IA).

[0060] In addition to the beneficial effects of treating or preventing conditions associated with overactive bladder, the compounds of this disclosure can also induce drowsiness and treat sleep disorders when administered at sufficient dose levels. See U.S. Patent Publication 2020 / 0345726, incorporated herein by reference. Patients suffering from symptoms associated with overactive bladder often experience poor sleep quality, insomnia, and / or nocturia. In some embodiments, the patient suffering from sleep disorders is a woman aged 50 years or older. In other embodiments, the patient suffering from sleep disorders is a man aged 50 years or older. Nightly administration of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, improves both sleep quality and symptoms associated with overactive bladder. In certain embodiments, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered by the patient nightly before sleep. For example, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered approximately 1 minute to 3 hours before sleep. In some embodiments, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered approximately 5 minutes to 60 minutes before sleep. In other embodiments, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered approximately 10 minutes to 30 minutes before sleep.

[0061] In one embodiment, an effective dose or dosage of the compound of this disclosure (e.g., a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof) is administered about 60 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 45 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 30 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 20 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered within about 20 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 15 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered within about 15 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 10 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered within approximately 10 minutes before the median of the human's habitual bedtime. In yet another embodiment, the effective dose or dosage is administered approximately 5 minutes before the median of the human's habitual bedtime.

[0062] In certain embodiments, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered multiple times a day. For example, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered twice or three times a day. In embodiments in which the compound is administered multiple times a day, each dose may be the same or different. In some embodiments, the dose of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered in a higher dose than any other dose provided at an earlier point in the day. In some embodiments, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered twice a day, approximately every 12 hours. In other embodiments, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered three times a day, approximately every 8 hours.

[0063] In certain embodiments, the compounds of the present disclosure are administered twice daily, with the second dose (i.e., the second therapeutically effective dose) being administered before bedtime as described above. In some such embodiments, the second dose is administered in a larger amount than the first dose. For example, the second dose may be administered in an amount approximately 1.5 times, 2 times, 3 times, 5 times, 10 times, 20 times, 50 times, 100 times, or 1000 times greater than the first dose. In some embodiments, the second dose may be administered in an amount approximately 1.5 times to approximately 10 times greater than the first dose. In other embodiments, the second dose may be administered in an amount approximately 1.5 times to approximately 100 times greater than the first dose. In other embodiments, the second dose may be administered in an amount approximately 1.5 times to approximately 1000 times greater than the first dose. In other embodiments, the second dose may be administered in an amount approximately 3 times to approximately 100 times greater than the first dose. In other embodiments, the second dose may be administered in amounts approximately 3 to 1000 times greater than the first dose. In other embodiments, the second dose may be administered in amounts approximately 5 to 100 times greater than the first dose. In other embodiments, the second dose may be administered in amounts approximately 5 to 1000 times greater than the first dose. Such a dosing schedule ensures that in human subjects, the first dose is effective in treating or preventing OBS and its associated symptoms without causing drowsiness, while the second dose is effective in treating or preventing OBS inflammation and its associated symptoms, and inducing drowsiness or sleep. In certain embodiments, both the first and second doses are administered through (the same or different) uncontrolled-release or non-sustained-release formulations. In other embodiments, the first dose is administered through a controlled-release or non-sustained-release formulation, and the second dose is administered through an uncontrolled-release or non-sustained-release formulation.

[0064] In another embodiment, compositions comprising the compounds of the present disclosure are useful as pharmaceuticals in the treatment of human subjects suffering from both OBS and certain sleep disorders. Such sleep disorders include, but are not limited to, insomnia, hypersomnia, circadian rhythm sleep-wake disorders, alcohol-induced sleep disorders, or any combination thereof. Other sleep disorders include alcohol-induced sleep disorders (e.g., insomnia-type alcohol-induced sleep disorder, daytime sleepiness-type alcohol-induced sleep disorder, parasomnia-type alcohol-induced sleep disorder, and mixed-type alcohol-induced sleep disorder); insomnia in alcohol use disorder, sleep disturbances associated with alcohol cessation (e.g., insomnia associated with alcohol abstinence), or any combination thereof. In one embodiment, the human subject suffers from both OBS and insomnia associated with alcohol abstinence.

[0065] A method for treating or preventing lower urinary tract disorders (e.g., OBS) in a human subject (e.g., a patient) requiring treatment or prevention of such disorders may further include co-administering a compound of the Disclosure (e.g., a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof) and a second therapeutic agent to the human subject. In one embodiment, the second therapeutic agent is administered in an effective amount to achieve the desired therapeutic effect by the method of the Disclosure. In one embodiment, the second therapeutic agent is an antimuscarinic agent. In some such embodiments, the antimuscarinic agent is oxybutynin. In other such embodiments, the antimuscarinic agent is tolterodine. In other such embodiments, the antimuscarinic agent is throspium. In a separate embodiment, the antimuscarinic agent is solifenacin. In a particular embodiment, the antimuscarinic agent is dalifenacin. In other such embodiments, the antimuscarinic agent is flavoxate. A method for treating overactive bladder syndrome in a human subject requiring treatment of such syndrome, comprising a therapeutically effective amount of a compound of formula (I): [ka] administering to a human subject the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the human subject has mild or mild to moderate renal impairment, is also disclosed herein. In some embodiments, a human subject having mild renal impairment may have an estimated glomerular filtration rate (eGFR) of from about 60 mL / min to about 89 mL / min. In some embodiments, a human subject having mild to moderate renal impairment may have an eGFR of from about 45 mL / min to about 59 mL / min.

[0066] In some embodiments, administering the compound of formula (I) to the subject results in an average AUC, C max , T max , T 1 / 2 , or no statistical difference in CL / F compared to that in a human subject under similar circumstances without renal insufficiency (or having normal renal function). In some embodiments, administering the compound of formula (I) to the subject results in an average AUC, C max , T max , T 1 / 2 , or CL / F that can be obtained at least. As used herein, a human subject is considered to be "under similar circumstances" if the human subject meets the same selection / exclusion criteria as other human subjects being treated by the methods of the present disclosure and also conforms to other relevant characteristics in clinical trials, such as gender, age, weight, and body mass index.

[0067] As used herein, "AUC" refers to the area under the concentration-time curve. As used herein, "C max " refers to the maximum observed plasma concentration. As used herein, "T max " refers to the time to reach the maximum observed plasma concentration. As used herein, "T 1 / 2 " refers to the apparent terminal half-life. As used herein, "CL / F" refers to the apparent total body clearance.

[0068] In some embodiments, administering the compound of formula (I) to a subject can yield at least an average AUC that does not differ statistically from the corresponding average AUC in human subjects under similar conditions without renal impairment (or with normal renal function). In some embodiments, administering the compound of formula (I) to a subject can yield the corresponding average C in human subjects under similar conditions without renal impairment max There is no statistical difference with the mean C max At least can be obtained. In some embodiments, administering a compound of formula (I) to a subject yields the corresponding mean T in human subjects under similar conditions without renal impairment. max There is no statistical difference with the mean T max At least can be obtained. In some embodiments, administering a compound of formula (I) to a subject yields the corresponding mean T in human subjects under similar conditions without renal impairment. 1 / 2 There is no statistical difference with the mean T 1 / 2 At least can be obtained. In some embodiments, administering a compound of formula (I) to a subject can at least obtain an average CL / F that does not show a statistically significant difference from the corresponding average CL / F in human subjects under similar conditions without renal impairment.

[0069] In some embodiments, administering a compound of formula (I) to human subjects resulted in the corresponding mean Ae, Fe, or CL levels in human subjects under similar conditions without renal impairment. R Average Ae, Fe, or CL that do not show a statistically significant difference from the above. R At least can be obtained. As used herein, "Ae" refers to the amount of drug excreted unchanged in the urine after administration of the test drug. As used herein, "Fe" refers to, for example, (Ae 0~96 This refers to the percentage of the test drug excreted in the urine, calculated as ( / dose). When used herein, "CL" refers to the percentage of the test drug excreted in the urine. R " for example, (Ae 0~96 / AUC inf This refers to the estimated renal clearance of the test drug over the entire collection interval (e.g., 0–96 hours), calculated as follows:

[0070] In some embodiments, administering the compound of formula (I) to human subjects can yield at least an average Ae that is statistically no different from the corresponding average Ae in human subjects under similar conditions without renal impairment. In some embodiments, administering the compound of formula (I) to human subjects can yield at least an average Fe that is statistically no different from the corresponding average Fe in human subjects under similar conditions without renal impairment. In some embodiments, administering the compound of formula (I) to human subjects can yield the corresponding average CL in human subjects under similar conditions without renal impairment. R There is no statistically significant difference from the average CL. R At least this can be obtained.

[0071] In some embodiments, the compound of formula (I) is the compound of formula (I'): [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the method may involve administering a pharmaceutically acceptable salt of the compound of formula (I), the salt being selected from the group consisting of sulfates, citrates, acetates, trifluoroacetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bicarbonates, ascorbicates, succinates, maleates, gentisinates, fumarates, glucons, gluconates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, and p-toluenesulfons.

[0072] In some embodiments, the method may involve administering a p-toluenesulfonic acid salt (i.e., p-toluenesulfonate salt), sulfate, phosphate, or hydrochloride of the compound of formula (I). In some embodiments, a p-toluenesulfonic acid salt of the compound of formula (I) may be administered.

[0073] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is the compound of formula (IA). [ka]

[0074] In some embodiments, the compound of formula (IA) may be administered orally, parenterally, intravenously, intramuscularly, buccally, or transdermally. In some embodiments, the compound of formula (IA) may be administered orally. In some embodiments, the effective dose of the compound of formula (IA) may be about 0.10 mg to about 10 mg. In some embodiments, the compound of formula (IA) may be administered once daily. In some embodiments, the compound of formula (IA) may be administered at night. In some embodiments, the compound of formula (IA) may be administered before bedtime. In some embodiments, the compound of formula (IA) may be administered twice daily. In some embodiments, the compound of formula (IA) may be administered about every 12 hours.

[0075] In some embodiments, the method may involve administering a first effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof during the day, and a second effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a human subject before bedtime at night. In some embodiments, the first effective amount may be a therapeutic effective amount and be the same as the second effective amount.

[0076] In some embodiments, the first effective amount and the second effective amount may be different. In some embodiments, the second effective amount may be about twice as much as the first effective amount. In some embodiments, the second effective amount may be about ten times as much as the first effective amount.

[0077] In some embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof may increase the voiding pressure threshold in human subjects by about 30% to 80%. In some embodiments, the method may further include administering an effective amount of an antimuscarinic agent to human subjects. In some embodiments, the antimuscarinic agent may be oxybutynin, tolterodine, trospium, solifenacin, dalifenacin, or a pharmaceutically acceptable salt of any of the foregoing.

[0078] This disclosure provides additional embodiments. A) A method for administering such treatment to a human subject in need of treatment or prevention of overactive bladder syndrome, wherein the compound of formula (I) is present in a therapeutically effective amount: [ka] The method comprising administering a pharmaceutically acceptable salt thereof to a human subject. B) The compound is the compound of formula (I'): [ka] The method according to Embodiment A, or a pharmaceutically acceptable salt thereof. C) The method according to Embodiment A or Embodiment B, wherein the method comprises administering a pharmaceutically acceptable salt of the compound, the salt being selected from the group consisting of sulfates, citrates, acetates, trifluoroacetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bicarbonates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, gluconates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, and p-toluenesulfons. D) The method according to any one of Embodiments A to C, wherein the method comprises administering a p-toluenesulfonate, sulfate, phosphate, or hydrochloride of the compound. E) The method according to any one of Embodiments A to D, wherein p-toluenesulfonate of the compound is administered. F) The method according to any one of Embodiments A to E, comprising administering a compound of formula (IA). [ka] G) The method according to any one of embodiments A to F, wherein the urination frequency of the human subject is reduced. H) The method according to any one of embodiments A to F, wherein episodes of nocturnal polyuria in the human subject are reduced. I) A method for administering such treatment to a human subject who needs to reduce nocturnal polyuria, wherein the human subject is given a therapeutically effective amount of a compound of formula (I): [ka] The method comprising administering a pharmaceutically acceptable salt thereof. J) The compound is the compound of formula (I'): [ka] The method according to Embodiment I, or a pharmaceutically acceptable salt thereof. K) The method according to Embodiment I or Embodiment J, wherein the method comprises administering a pharmaceutically acceptable salt of the compound, the salt being selected from the group consisting of sulfates, citrates, acetates, trifluoroacetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bicarbonates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, gluconates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, and p-toluenesulfons. L) The method according to any one of Embodiments I to K, wherein the method comprises administering a p-toluenesulfonate, sulfate, phosphate, or hydrochloride of the compound. M) The method according to any one of Embodiments I to L, wherein p-toluenesulfonate of the compound is administered. The method according to Embodiment M, comprising administering a compound of formula (IA) N. [ka] O) The method according to any one of Embodiments A to N, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally, parenterally, intravenously, intramuscularly, buccally, or transdermally. P) The method according to any one of Embodiments A to O, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally. Q) The method according to any one of Embodiments A to P, wherein the therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is about 0.001 mg to about 300 mg. R) The method according to any one of Embodiments A to Q, wherein the therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is about 0.10 mg to about 10 mg. S) The method according to Embodiment R, wherein the compound or a pharmaceutically acceptable salt thereof is a compound of formula (IA). [ka] T) The method according to any one of Embodiments A to S, wherein the compound or a pharmaceutically acceptable salt thereof is administered once daily. U) The method according to any one of Embodiments A to T, wherein the compound or a pharmaceutically acceptable salt thereof is administered at night. V) The method according to Embodiment U, wherein the compound or a pharmaceutically acceptable salt thereof is administered before bedtime. W) The method according to any one of embodiments P to S, wherein the compound or a pharmaceutically acceptable salt thereof is administered twice daily. X) The method according to embodiment W, wherein the compound or a pharmaceutically acceptable salt thereof is administered approximately every 12 hours. Y) The method of Embodiment W or Embodiment X, comprising administering a first therapeutically effective dose of the compound or a pharmaceutically acceptable salt thereof during the day and a second therapeutically effective dose at night before the human subject goes to bed. Z) The method according to embodiment Y, wherein the first effective therapeutic dose and the second effective therapeutic dose are the same. AA) The method according to embodiment Y, wherein the first therapeutic effective dose and the second therapeutic effective dose are different. BB) The method according to embodiment AA, wherein the second effective therapeutic dose is approximately twice as large as the first effective therapeutic dose. CC) The method according to embodiment AA, wherein the second effective therapeutic dose is about 10 times greater than the first effective therapeutic dose. DD) The method according to any one of Embodiments A to CC, wherein administration of the compound or a pharmaceutically acceptable salt thereof increases the urination pressure threshold in the human subject by approximately 30% to 80%. EE) The method according to any one of Embodiments A to DD, further comprising administering an effective amount of an antimuscarinic agent to the human subject. FF) The method according to Embodiment EE, wherein the antimuscarinic agent is oxybutynin, tolterodine, throspium, solifenacin, and dalifenacin, or a pharmaceutically acceptable salt of any of the above. GG) A method for administering such treatment to a human subject in need of treatment or prevention of overactive bladder syndrome, comprising a therapeutically effective amount of the compound of formula (I): [ka] The method comprising administering to a human subject a pharmaceutically acceptable salt thereof, wherein the patient also suffers from a sleep disorder. HH) The above compound is a compound of formula (I'): [ka] The method according to embodiment GG, or a pharmaceutically acceptable salt thereof. II) The method according to Embodiment GG or Embodiment HH, comprising administering a pharmaceutically acceptable salt of the compound, wherein the salt is selected from the group consisting of sulfates, citrates, acetates, trifluoroacetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bicarbonates, ascorbicates, succinates, maleates, gentisates, fumarates, glucons, gluconates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, and p-toluenesulfons. JJ) The method according to any one of Embodiments GG to II, wherein the pharmaceutically acceptable salt is p-toluenesulfonate, sulfate, phosphate, or hydrochloride. KK) The method according to any one of embodiments GG to JJ, wherein the pharmaceutically acceptable salt is p-toluenesulfonate. The method according to any one of embodiments GG to KK, comprising administering a compound of formula (IA) LL. [ka] MM) The method according to any one of embodiments GG to LL, wherein the human subject is a woman aged 50 years or older. A method for treating sleep disorders in NN patients, comprising a compound of formula (I) in a therapeutically effective amount: [ka] The method comprising administering to the patient a pharmaceutically acceptable salt thereof, wherein the patient also suffers from urinary incontinence. OO) The above compound is a compound of formula (I'): [ka] The method according to embodiment NN, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof. The method of Embodiment NN or Embodiment OO, comprising administering a compound of formula (IA) PP. [ka] QQ) The method according to any one of embodiments NN to PP, wherein the sleep disorder is insomnia, hypersomnia, circadian rhythm sleep-wake disorder, alcohol-induced sleep disorder, insomnia associated with alcohol abstinence, or any combination thereof. RR) A method for treating overactive bladder syndrome in human subjects requiring treatment of overactive bladder syndrome, comprising an effective amount of a compound of formula (I): [ka] or administering a pharmaceutically acceptable salt thereof to the human subject, The method wherein the human subject has mild or mild to moderate renal impairment. SS) The method according to Embodiment RR, wherein the human subject having mild renal impairment has an estimated glomerular filtration rate (eGFR) of approximately 60 mL / min to approximately 89 mL / min. TT) The method according to Embodiment RR, wherein the human subject having mild to moderate renal impairment has an eGFR of approximately 45 mL / min to approximately 59 mL / min. UU) By administering the compound of formula (I) to the subject, the corresponding mean AUC and C in human subjects under similar conditions without renal impairment were observed. max , T max , T 1 / 2 , or mean AUC, C, which does not show a statistical difference from CL / F max , T max , T 1 / 2 or the method according to any one of embodiments RR to TT, wherein CL / F is obtained at least. VV) By administering the compound of formula (I) to the aforementioned human subjects, the corresponding mean Ae, Fe, or CL levels in human subjects under similar conditions without renal impairment were increased. R Average Ae, Fe, or CL that do not show a statistically significant difference from the above. R A method according to any one of embodiments RR to UU, wherein at least is obtained. WW) The aforementioned compound is a compound of formula (I'): [ka] The method according to any one of embodiments RR to VV, or a pharmaceutically acceptable salt thereof. XX) The method according to any one of embodiments RR to WW, wherein the method comprises administering a pharmaceutically acceptable salt of the compound of formula (I), the salt being selected from the group consisting of sulfates, citrates, acetates, trifluoroacetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bicarbonates, ascorbicates, succinates, maleates, gentisinates, fumarates, glucons, gluconates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, and p-toluenesulfons. YY) The method according to any one of embodiments RR to XX, wherein the method comprises administering a p-toluenesulfonate, sulfate, phosphate, or hydrochloride of the compound of formula (I). ZZ) The method according to any one of embodiments RR to YY, wherein p-toluenesulfonate of the compound of formula (I) is administered. AAA) The method according to any one of embodiments RR to ZZ, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (IA). [ka] BBB) The method according to Embodiment AAA, wherein the compound of formula (IA) is administered orally, parenterally, intravenously, intramuscularly, buccally, or transdermally. The method according to Embodiment AAA or Embodiment BBB, wherein the compound of formula (IA) is administered orally (CCC). DDD) The method according to Embodiment CCC, wherein the effective amount of the compound of formula (IA) is about 0.10 mg to about 10 mg. EEE) The method according to any one of embodiments AAA to DDD, wherein the compound of formula (IA) is administered once daily. FFF) The method according to any one of embodiments AAA to EEE, wherein the compound of formula (IA) is administered at night. GGG) The method according to any one of embodiments AAA to FFF, wherein the compound of formula (IA) is administered before bedtime. HHH) The method according to any one of embodiments AAA to DDD, wherein the compound of formula (IA) is administered twice daily. III) The method according to Embodiment HHH, wherein the compound of formula (IA) is administered approximately every 12 hours. JJJ) The method according to Embodiment HHH or Embodiment III, comprising administering a first effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof during the daytime and administering a second effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the human subject at night before bedtime. KKK) The method according to Embodiment JJJ, wherein the first effective amount is a therapeutic effective amount and is the same as the second effective amount. LLL) The method according to Embodiment JJJ, wherein the first effective amount and the second effective amount are different. MMM) The method according to embodiment LLL, wherein the second effective amount is about twice as much as the first effective amount. NNN) The method according to Embodiment LLL, wherein the second effective amount is about 10 times greater than the first effective amount. OOO) The method according to any one of embodiments AAA to NNN, wherein administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof increases the urination pressure threshold in the human subject by approximately 30% to 80%. The method according to any one of embodiments AAA to OOO, further comprising administering an effective amount of an antimuscarinic agent to the human subject (PPP). QQQ) The method according to Embodiment PPP, wherein the antimuscarinic agent is oxybutynin, tolterodine, throspium, solifenacin, dalifenacin, or a pharmaceutically acceptable salt of any of the above. [Examples]

[0079] Example 1: Equivolute model for measuring the effect of compound of formula (IA) on OBS In rats, under isovolume conditions, bladder distension induced rhythmic bladder contractions (RBCs) (Aizawa et al, (2015) Effects of L-arginine, mirabegron, and oxybutynin on the primary bladder afferent nerve activities synchronized with reflexic, rhythmic bladder contractions in the rat. Neurology & Urodynamics 34:368-374). This isovolume model allows for the evaluation of compounds on RBCs. This is a closed system in which saline solution is slowly injected into the bladder via a urethral catheter until spontaneous rhythmic bladder contractions occur.

[0080] The purpose of this study was to evaluate the effect of intravenous administration of the compound of formula (IA) on bladder measurement parameters in an isovolumetric model of anesthetized female rats. The effect of the test substance was compared with that of tolterodine (a commercially available anti-muscarinic receptor for human overactive bladder) as a reference substance.

[0081] Test design protocol The animals were anesthetized with urethane (IP). The ureter was ligated and removed near the kidney. A bladder catheter was inserted into the bladder through the urethral opening. • The urethral opening was closed. A catheter was inserted into the jugular vein for the administration of the compound. The bladder was filled with saline solution until red blood cells (RBCs) were produced. After a 30-minute basal period, the compound was administered as described below. The effects of the test substance were tracked for one hour after administration.

[0082] Experimental group: The three experimental groups were as shown in Table 1 below. [Table 1]

[0083] Before the start of the experiment, animals were randomly assigned to treatment groups. The randomization was designed so that there was at least one animal in each group on each experimental day. At the end of the experiment, the excluded animals were replaced.

[0084] animal: All experiments were conducted in accordance with European Community Council Directive 2010 / 63 / UE and French Ministry of Agriculture, Agrifood and Forestry Decree 2013-118.

[0085] Female Sprague-Dawley rats were acclimated to laboratory conditions for at least three days prior to the start of the experiment. The animals were housed in groups of three in polysulfone-type Sealsafe Plus 1291H cages (Tecniplast, Lyon, France) with wood chip bedding (Souralit, Girona, Spain), and were given free access to food (Safe's Rodent Maintenance Diet A04 / 10) and water (0.2 μm filtered water). Species-appropriate environmental enrichment (Aspen brick, Plexx, Uden, Netherlands) was added to the cages. The animal housing room was maintained under artificial lighting (12 hours) from 7:00 AM to 7:00 PM, with an ambient temperature controlled at 22 ± 2°C and a relative humidity maintained at 55 ± 10%.

[0086] Test substance An appropriate amount of the compound of formula (I) was weighed and dissolved in a vehicle to obtain a drug solution with a target concentration of 3 mg / mL (as free base). The drug preparation (3 mL) was stored in a refrigerator for a maximum of 3 days. The mother liquor was used directly at a dose of 3 mg / kg.

[0087] A 20% (w / v) aqueous solution of 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) was prepared by dissolving 10 g of HP-β-CD (Sigma-Aldrich, Saint-Quentin Fallavier, France, batch number BCBV0722) in 50 mL of sterile water for injection (WFI). The vehicle was prepared over one week.

[0088] Tolterodine was freshly prepared on the day of administration to a final concentration of 1 mg / mL (free base form). An appropriate mass of tolterodine was weighed and dissolved in a vehicle (20% HP-β-CD) at room temperature.

[0089] I purchased polyurethane from Sigma-Aldrich. I purchased Dolethal® from Vetoquinol via Centravet (Lapalisse, France). I purchased saline solution from B-Braun via Centravet. I obtained WFI from Cooper (Melun, France).

[0090] Test protocol Rats were anesthetized by intraperitoneal administration of urethane (1 g / kg). The ureters were ligated and resected near the kidneys. Catheters (0.30 mm inner diameter and 0.70 mm outer diameter, respectively) were inserted into the bladder through the urethral orifice, and then the urethra was ligated. Another catheter (0.58 mm inner diameter and 0.96 mm outer diameter, respectively) was inserted into the jugular vein, and intravenous (IV) administration was performed.

[0091] In all groups, animals were treated via the IV route (1 mL / kg) (slow bolus) after the basal period.

[0092] Evaluation of bladder pressure measurement: A bladder catheter was connected to a strain gauge (for measuring intravesical pressure) and syringe via a T-tube. Isovolume bladder contractions were induced by stepwise injections of room temperature saline (100 μL every 5 minutes) until stable RBCs occurred. Bladder pressure was continuously recorded. After a 30-minute control period (baseline), the substance or vehicle was administered intravenously. The effects of the substance were tracked for 60 minutes after administration. At the end of the experiment, the animals were sacrificed by cervical dislocation.

[0093] Laboratory equipment: The animals were weighed using an LS620C balance (Precisa, Dietikon, Switzerland).

[0094] The surgery was performed using an SX45 binocular microscope (Fisher Scientific, Illkirch, France). A thermoregulation system (TCAT-2LV Controller, Physitemp Instruments, Clifton, NJ, USA) set to 37°C was used during the surgery.

[0095] For bladder pressure measurement, bladder pressure was measured using a strain gauge MX960P1 (Smiths Medical, Rungis, France) and continuously recorded using a PowerLab / 8-30 or 8-35 data acquisition system (AD Instruments Pty Ltd) and LabChart® software version 7.3.7.

[0096] Presentation and analysis of results The following parameters were analyzed. • Amplitude of RBC (mmHg) • Frequency of RBCs (number / 30 minutes) • Inhibition time (seconds)

[0097] As shown in Figure 8, bladder measurement parameters for each RBC were analyzed during the 30 minutes before administration (baseline) and the entire 60 minutes after administration. The percentage change from the baseline value for RBC frequency and amplitude was calculated.

[0098] Statistical analysis: Statistical analysis and graphing were performed using GraphPad Prism® (GraphPad Software Inc., La Jolla, CA, USA). A p-value < 0.05 was considered statistically significant. Baseline values ​​of RBC frequency and amplitude across all groups were compared using one-way ANOVA followed by Turkey's test. Baseline duration and treatment duration for RBC frequency and amplitude in each group were compared using a paired Student's t-test or Wilcoxon test. The percentage variation from baseline values ​​of RBC frequency, inhibition time, or inhibition amplitude for tolterodine and the compound of formula (IA) was compared with the vehicle group using Kruskal-Wallis or one-way ANOVA followed by Dunn's test or Dunnett's test.

[0099] result There were no significant differences in the baseline RBC frequency across all experimental groups (p>0.05, Figure 1A). The baseline RBC frequencies within 30 minutes were 25.90±1.91, 25.90±1.36, and 23.00±0.87 for the vehicle, compound (IA), and tolterodine groups, respectively (Tables 2-4).

[0100] There were no significant differences in the baseline RBC amplitude across all experimental groups (p>0.05, Figure 1B). The baseline RBC amplitudes were 29.13±3.02, 29.49±2.46, and 27.22±2.03 mmHg for the vehicle, compound (IA), and tolterodine groups, respectively (Tables 2-4). [Table 2] [Table 3] Note: In the Cpd(IA) group, there were no RBCs after administration, so only 8 rats were used to average the RBC amplitude. [Table 4]

[0101] Vehicle (1 mL / kg, iv), compound (IA) (3 mg / kg, iv), and tolterodine (1 mg / kg, iv) significantly reduced the frequency of RBCs (p<0.05 and p<0.0001, Figures 2A-B-C, Tables 2-4).

[0102] The RBC frequencies during the 0 / 60 minute post-treatment period were 18.50±2.42, 3.05±1.02, and 15.30±2.72 RBCs at 30 minutes after vehicle, compound (IA), and tolterodine treatment, respectively (Figures 2A-B-C, Tables 2-4).

[0103] After treatment with the compound of formula (IA) (3 mg / kg, iv), the RBC frequency was significantly reduced (p<0.0001, Figure 3, Table 3), but tolterodine (1 mg / kg, iv) did not significantly change the RBC frequency (p>0.05, Figure 3, Table 4). The reduction in RBC frequency after treatment with the compound of formula (IA) reached -88.57±3.68%, while the reductions after vehicle and tolterodine treatments were -28.18±7.30 and -33.93±10.93%, respectively (Figure 3, Tables 2-4).

[0104] Compared to baseline levels, vehicle and tolterodine significantly reduced RBC amplitude (p<0.05 and p<0.01, Figures 4A-4C, Tables 2-4). No significant effect on RBC amplitude was observed after administration of the compound of formula (IA) (p>0.05, Figure 4B, Table 3).

[0105] Compared to the vehicle, tolterodine (1 mg / kg, iv) significantly reduced RBC amplitude (p<0.001, Figure 5 and Tables 2-4), while the compound of formula (IA) (3 mg / kg) did not significantly alter RBC amplitude (p>0.05, Figure 5 and Tables 2-3). The percentage change from baseline in RBC amplitude after tolterodine was -5.18±2.12% in the vehicle group compared to -30.83±5.24% in the vehicle group.

[0106] Compared to the vehicle, the compound of formula (IA) (3 mg / kg, iv) significantly increased the inhibition time (p<0.01, Figure 6 and Table 3), but no significant difference in inhibition time was observed after tolterodine treatment (p>0.05, Figure 6 and Table 4). The inhibition times were 422.89±113.60, 2860.51±272.38, and 87.04±31.06 seconds for the vehicle, the compound of formula (IA), and the tolterodine group, respectively.

[0107] Typical records of the effects of the vehicle, the compound of formula (IA), and tolterodine are shown in Figures 7A, 7B, and 7C, respectively.

[0108] The results of Example 1 show that the compound of formula (IA) significantly reduced the afferent activity of the bladder. On the other hand, tolterodine did not affect afferent activity but effectively inhibited the centrifugal activity of the bladder.

[0109] Example 2: Pharmacokinetic study of the compound of formula (IA) The urinary concentrations of the compound of formula (IA) (also known as Cpd(IA)) in the form of a methylcellulose suspension were evaluated in humans (9 subjects in total) up to 48 hours after a single oral dose. Urine samples (sequential samples pooled from the entire urinated urine) were collected at the following time intervals to determine the concentration of the compound of formula (IA) for each subject: 0–8 hours, 8–16 hours, 16–24 hours, 24–32 hours, and 40–48 hours post-administration. A summary of the urinary concentrations of the compound of formula (IA) for each subject, treatment, and time interval is shown in Table 5 below. [Table 5] • In vitro activity on human pain receptors; Ki = 2.45 nM, EC 50 =4.0nM

[0110] Table 5 shows the mean urinary concentration levels and standard deviations of the compound of formula (IA) at specific time intervals after administration of specific doses (0.2 mg, 0.6 mg, 2 mg, and 10 mg). Table 5 shows that even at the lowest dose (0.2 mg) of the compound of formula (IA), Ki and EC are present. 50 Measurements show that the urinary concentration of the compound of formula (IA) is several orders of magnitude higher than its in vitro activity.

[0111] Example 3: Effect of compound of formula (IA) on bladder measurement parameters in female rats (SCI model) Spinal cord injury (SCI) results in significant changes in bladder function in several species, including rats and humans. In rats, SCI disrupts reflex pathways that regulate spontaneous urination and bladder and sphincter function, leading to an unreflexive bladder and dysuria. Two weeks after spinal cord injury, the micturition reflex reappears, but there is competition between the bladder and urethral sphincter, and bladder distension that induces hyperreflexia of the detrusor muscle. The development of spinal reflex pathways that enable rats to urinate demonstrates the regeneration of neurotransmission (Cheng et al., 1995, Yoshiyama et al., 1999).

[0112] Combined with coordination problems between the bladder and sphincter, abnormalities in the reflex pathway lead to bladder enlargement, inefficient urination, and detrusor hyperactivity (de Groat & Yoshimura, 2010). SCI in rats has been shown to increase the frequency of non-voiding contractions (NVCs) and bladder capacity at the thoracic level, while decreasing voiding efficiency (Yoshiyama et al., 1999, Kadekawa et al., 2017, Wada et al., 2017, Wada et al., 2018). SCI in rats is also characterized by bladder enlargement. As a result, this model is widely used to evaluate substances specific to neurogenic bladder dysfunction. Furthermore, the β3-adrenergic receptor agonists CL-316,243 have been shown to significantly increase bladder capacity and decrease the frequency of NVCs (Beauval et al., 2015).

[0113] The purpose of this study was to evaluate the effect of intragastric (ig) administration of the compound of formula (IA) ("Cpd(IA)") (30 mg / kg) on ​​bladder measurement parameters in conscious SCI rats. The effect of the test substance was compared to that of mirabegron, a commercially available reference substance for overactive bladder, which is a β3-adrenergic receptor agonist.

[0114] Test design Protocol design • In W-5, spinal cord injury was performed at the T8 level as described below. Rats were treated with gentamicin daily during weeks W-5. During weeks 5 and 4, the bladder was manually emptied once a day. From W-5 to W0, the animals' weight was measured once a week. • In D-2(W0), catheter implantation was performed under isoflurane anesthesia, as described below. • Bladder pressure was measured at D0 (W0).

[0115] The protocol design scheme is shown in Figure 9. Experimental group:

[0116] The four experimental groups were included as listed in the table below. [Table 6]

[0117] Before the start of the experiment, animals were randomly assigned to treatment groups. The randomization was designed so that there was at least one animal in each group on each experimental day. At the end of the experiment, follow-up surveys were completed for any missing animals.

[0118] Female Sprague-Dawley rats were acclimated to laboratory conditions for at least 3 days before the start of the experiment. The animals were housed individually in polysulfone-type Sealsafe Plus 1291H cages (Tecniplast, Lyon, France) with a wood chip (Souralit, Girona, Spain) bedding for 2 weeks after SCI surgery, then two animals per group until catheter implantation, and individually until cytometry. Food (Safe's Rodent Maintenance Diet A04 / 10) and water (0.2 μm filtered water) were available ad libitum. Appropriate environmental enrichment for the species (Aspen brick, Plexx, Uden, Netherlands) was added to the cages. The animal breeding room was maintained at a controlled ambient temperature of 22 ± 2 °C and a relative humidity of 55 ± 10% under artificial lighting (12 hours) from 7:00 am to 7:00 pm.

[0119] Preparation of test materials: A stock solution of the compound of formula (IA) was prepared in vehicle at a final concentration of 6 mg / mL (free base form). An appropriate amount of vehicle was slowly added to the weighed compound of formula (IA) in a porcelain mortar, and the powder was triturated with a pestle until a suspension was obtained. Aliquots of the suspension were made (1 aliquot / dose) and maintained at +4 °C for a maximum of 3 days. On each experimental day, the suspension was equilibrated to room temperature for at least 30 minutes before dosing.

[0120] The vehicle was 0.5% methylcellulose (MC). This was prepared in water for injection (WFI) and maintained at 4 °C for 1 week. MC (batch number SLBR8963V) was purchased from Sigma-Aldrich (Saint-Quentin Fallavier, France).

[0121] Mirabegron was freshly prepared on the dosing day at a final concentration of 2 mg / mL (free base form). An appropriate mass of mirabegron was weighed and dissolved in vehicle at room temperature.

[0122] Test protocol SCI surgery: Rats were anesthetized with isoflurane (3%). During surgery, the animals' body temperature was kept constant at 37°C by placing them on a temperature-controlled hot plate. A laminectomy was performed, and the spinal cord was resected at the T8 level using micro-scissors. Care was taken to ensure that the resection was complete by confirming that the two fragments had slightly contracted. The muscles were then sutured and the skin was fixed with staples. The scar was disinfected with Vetedine. The same surgery was performed on the Siamese group without spinal cord resection.

[0123] The bladder was compressed once daily for 14 days while gently massaging the abdomen until the micturition reflex recovered. In addition, gentamicin (2 mg / mL, 0.2 ml / rat) was administered intramuscularly daily for one week. Animals were euthanized when they reached a humane endpoint (weight loss exceeding 20% ​​of body weight and / or abnormal behavioral changes indicating the presence of pain and distress (weakness, self-injurious behavior, aggression)).

[0124] Surgery for cystomanometry: Rats were anesthetized with isoflurane (3%). During surgery, the animals' body temperature was kept constant at 37°C by placing them on a temperature-controlled hot plate. Polyethylene catheters (0.58 mm inner diameter and 0.96 mm outer diameter, respectively) were implanted in the bladder through the dome to record bladder pressure. Another catheter (0.58 mm inner diameter and 0.96 mm outer diameter, respectively) was implanted in the stomach for intragastric administration. The catheters were exited the body at the level of the scapula. After surgery, each rat was housed individually and given free access to food and water until the end of the protocol.

[0125] The animals were kept in a partially restrained state within a restraint device. Physiological saline was injected into the bladder of Siamese or SCI rats at a constant flow rate of 2 mL / hour or 6 mL / hour, respectively. At least 45 minutes later (three complete urination cycles corresponding to baseline), the test substance was administered via the intragastric route. Bladder pressure was then recorded for 90 minutes.

[0126] At the end of the experiment, the rats were sedated with Dolethal® (0.3-0.5 mL of pentobarbital sodium at 182.2 mg / mL per rat, iP), and then euthanized by cervical dislocation. Next, their bladders were collected and weighed.

[0127] Results and Analysis All raw data was entered into an Excel® spreadsheet. Before data analysis, all entered data was compared with the raw data by two individuals. The results are expressed as the mean ± standard error (SEM).

[0128] The following bladder measurement parameters were analyzed (see Figure 10): ·Mistration amplitude (AM, mmHg) ·Threshold pressure (ThP, mmHg) • Contraction interval (ICI, seconds): Time between basal pressure and ThP. ICI was not shown for Siamese rats and SCI rats due to differences in infusion rates. ICI was analyzed solely for the purpose of calculating bladder volume. ·Bladder capacity (BC, mL) BC=ICI×infusion rate • Amplitude of non-voiding contractions (NVC, mmHg) • Frequency of NVC (number per minute).

[0129] NVC was defined as an increase in intravesical pressure with an amplitude greater than 1.5 mmHg without urinary leakage.

[0130] Statistical analysis and graphing were performed using GraphPad Prism® (GraphPad Software Inc., La Jolla, CA, USA). Before performing any statistical tests, the data were tested for normality (Shapiro-Wilk normality test), and their variances were evaluated (F-test or Bartlett test for two or more groups, respectively). As a result, appropriate statistical tests were applied.

[0131] The following comparisons were made for each bladder measurement parameter and each period. The baseline values ​​of each bladder measurement parameter in the sham / vehicle group and the SCI / vehicle group were compared using an unpaired Student's t-test. We compared the baseline values ​​of each bladder measurement parameter across all SCI groups using one-way ANOVA or the Kruskal-Wallis test. Within the same group, three 30-minute intervals after treatment for each bladder measurement parameter were compared to the corresponding baseline values ​​using one-way ANOVA with repeated measures or Friedman test, followed by Dunnett or Dunn post-hoc tests. The three 30-minute interval periods after treatment for each bladder measurement parameter were compared among all SCI groups using one-way ANOVA or Kruskal-Wallis test, followed by Holm-Sidak or Dunn post-hoc tests against the vehicle, respectively.

[0132] Test results: Baseline values ​​for BC, AM, NVC frequency, NVC amplitude, and bladder weight were significantly higher in the SCI / vehicle group compared to the sham / vehicle group (p<0.01, Figure 11). In contrast, there was no significant difference in the baseline value of ThP (p>0.05, Figure 11).

[0133] Figure 12 shows that there were no significant differences in baseline values ​​for BC, ThP, AM, NVC frequency, and NVC amplitude across all experimental SCI groups (p>0.05).

[0134] In Siamese rats, the vehicle (5 mL / kg, ig) significantly decreased BC during the interval period from 0 to 30 minutes after administration, and significantly increased BC during the final interval period (60 to 90 minutes) (p<0.01 and p<0.001, respectively, Figure 13A).

[0135] In SCI rats, vehicle (5 mL / kg, ig) and mirabegron (10 mg / kg, ig) did not significantly alter BC (p>0.05, Figures 13B and C). In SCI rats, Cpd(IA) (30 mg / kg, ig) significantly reduced BC at intervals of 0-30 minutes and 30-60 minutes after administration (p<0.001, Figure 13D).

[0136] Figure 14A shows that there was no significant difference in BC between the mirabegron group and the Cpd(IA) group (p > 0.05, expressed in mL). Figure 14B shows that Cpd(IA) (30 mg / kg, i.g.) significantly decreased BC during the post-dose interval from 0 to 30 minutes (p < 0.05, expressed as % change from the basal value). In fact, the % change from the basal value of BC was -35 ± 7% and -0.4 ± 15% in the SCI / Cpd(IA) group and the SCI / vehicle group, respectively. After mirabegron treatment, BC did not change significantly (p > 0.05, Figure 14B).

[0137] In sham rats and SCI rats, vehicle (5 mL / kg, i.g.) did not significantly change ThP (p > 0.05, Figures 15A and 15B). In SCI rats, mirabegron (10 mg / kg, i.g.) significantly decreased ThP during the interval from 60 to 90 minutes after dosing (p < 0.05, Figure 15C). In SCI rats, no significant effect on ThP was observed after Cpd(IA) treatment (p > 0.05, Figure 15D).

[0138] Figures 16A - B show that ThP did not change significantly after mirabegron or Cpd(IA) treatment.

[0139] In sham rats and SCI rats, vehicle (5 mL / kg, i.g.) did not have a significant effect on AM (p > 0.05, Figures 17A - B). In SCI rats, mirabegron (10 mg / kg, i.g.) and Cpd(IA) (30 mg / kg, i.g.) did not significantly change AM (p > 0.05, Figures 17C - D). AM did not change significantly after mirabegron or Cpd(IA) treatment (p > 0.05, Figures 18A - B).

[0140] In Siamese rats, the vehicle (5 mL / kg, ig) did not significantly alter NVC frequency (p>0.05, Figure 19A). In SCI rats, the vehicle (5 mL / kg, ig) significantly reduced NVC frequency during intervals of 30–60 minutes and 60–90 minutes (p<0.05, Figure 19B). In SCI rats, mirabegron (10 mg / kg, ig) significantly reduced NVC frequency during intervals of 30–60 minutes and 60–90 minutes (p<0.01 and p<0.05, Figure 19C). In SCI rats, Cpd(IA) (30 mg / kg, ig) significantly reduced NVC frequency during intervals of 0–30 minutes and 60–90 minutes (p<0.05 and p<0.01, Figure 19D).

[0141] Figures 20A-B show that NVC frequency did not change significantly after mirabegron or Cpd(IA) treatment.

[0142] In Siamese rats, the vehicle (5 mL / kg, ig) did not significantly alter NVC amplitude (p>0.05, Figure 21A). In SCI rats, the vehicle (5 mL / kg, ig) significantly reduced NVC amplitude during the interval period of 60 to 90 minutes after administration (p<0.05, Figure 21B). In SCI rats, mirabegron (10 mg / kg, ig) did not significantly alter NVC amplitude (p>0.05, Figure 21C). In SCI rats, Cpd(IA) (30 mg / kg, ig) significantly reduced NVC amplitude during the interval period of 30 to 60 minutes and 60 to 90 minutes after administration (p<0.05 and p<0.001, Figure 21D).

[0143] Figures 22A-B show that NVC amplitude did not change significantly after mirabegron or Cpd(IA) treatment (p>0.05, expressed in mmHg or percentage change from baseline).

[0144] In Siamese rats, compared to the baseline, the vehicle (5 mL / kg, ig) decreased BC immediately after administration and increased BC during the 60-90 minute interval. The effect on BC immediately after administration was likely due to the vehicle itself, while the increase in BC during the 60-90 minute interval after administration was due to a time effect. In SCI rats, the vehicle (5 mL / kg, ig) affected NVC frequency and NVC amplitude during the final post-administration interval, supporting either an effect of the vehicle itself or a time effect.

[0145] As expected, mirabegron (10 mg / kg, ig) slightly but significantly reduced NVC frequency compared to the basal level (Beauval et al., 2015).

[0146] The compound of formula (IA) (30 mg / kg, ig) significantly reduced NVC frequency compared to baseline at intervals of 0–30 minutes and 60–90 minutes after administration. This is an effect expected from a substance specifically for overactive bladder (OAB). Cpd(IA) also significantly reduced BC compared to vehicle at intervals of 0–30 minutes after administration, but this is not a desirable effect for the treatment of OAB.

[0147] Example 4: Effect of compound of formula (IA) on bladder measurement parameters in female rats (BOO model) Bladder outlet obstruction (BOO) in rats is a well-known model of overactive bladder (OAB). According to the literature (Lluel et al., 1998), BOO induces bladder hypertrophy and bladder overactivity characterized by increased frequency and amplitude of BC, AM, and NVC. In this model, it has been previously demonstrated that mirabegron, a β3 receptor agonist, reduces the frequency of NVC (Gillespy et al., 2012).

[0148] The purpose of this study was to evaluate the effect of intragastric (ig) administration of the compound of formula (IA) ("Cpd(IA)") (30 mg / kg) on ​​bladder measurement parameters in conscious BOO rats. The effect of the test substance was compared with the effect of mirabegron, a commercially available reference substance for overactive bladder.

[0149] Design of a test protocol • Partial ligation of the urethra was performed at W-6. • In W-6, rats were treated daily with gentamicin and Ketofen® for three consecutive days. Their bladders were manually emptied once daily. From Week 6 to Week 1, the animals were monitored and their weight was measured once a week. • At W0 (D-2), the catheter was implanted under isoflurane anesthesia. • Bladder pressure was measured at D0.

[0150] Animals and test materials: Female Sprague-Dawley rats were acclimated to laboratory conditions for at least three days prior to the start of the experiment. The animals were housed in groups of two or three, and individually, in polysulfone-type Sealsafe Plus 1291H cages (Tecniplast, Lyon, France) with wood chip bedding (Souralit, Girona, Spain) until cytometry, with free access to food (Safe's Rodent Maintenance Diet A04 / 10) and water (0.2 μm filtered water). Species-appropriate environmental enrichment (Aspen brick, Plexx, Uden, Netherlands) was added to the cages. The animal housing room was maintained under artificial lighting (12 hours) from 7:00 AM to 7:00 PM, with an ambient temperature controlled at 22 ± 2°C and a relative humidity maintained at 55 ± 10%.

[0151] An appropriate amount of Cpd(IA) was weighed and dissolved in a vehicle to obtain a drug solution with a target concentration of 3 mg / mL (as free base). The mother liquor was used directly at a dose of 3 mg / kg.

[0152] The vehicle was 0.5% methylcellulose (MC). This was prepared in water for injection (WFI) and maintained at 4°C for one week. The MC (batch number SLBR8963V) was purchased from Sigma-Aldrich (Saint-Quentin Fallavier, France).

[0153] For intravenous administration, a 20% (w / v) aqueous solution of 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) was prepared by dissolving 10 g of HP-β-CD (Sigma-Aldrich, batch number BCBV0722) in 50 mL of WFI. Mirabegron (Kemprotec) was freshly prepared on the day of administration to a final concentration of 2 mg / mL (free base form). The appropriate mass of mirabegron was weighed and dissolved in a vehicle (0.5% MC) at room temperature.

[0154] The six experimental groups are shown in the table below. [Table 7]

[0155] Results of intragastric (ig) administration Baseline values ​​for BC, AM, NVC frequency, NVC amplitude, and bladder weight were significantly higher in the BOO / vehicle group compared to the sham / vehicle group (p<0.05). In contrast, there was no significant difference in the baseline value of ThP (p>0.05).

[0156] There were no significant differences in baseline values ​​for BC, ThP, AM, NVC frequency, NVC amplitude, and bladder weight across all experimental BOO groups, including vehicle (5 mL / kg, ig), mirabegron (10 mg / kg, ig), and Cpd(IA) (30 mg / kg, ig).

[0157] For the entire duration from 0 to 90 minutes: In Siamese rats and BOO rats, the vehicle did not have a significant effect on BC compared to the baseline. In BOO rats, mirabegron did not significantly change BC, but Cpd(IA) significantly reduced BC. Compared to the vehicle, no significant difference in BC was observed between the mirabegron group and the Cpd(IA) group, expressed in mL. Expressed as a percentage change from the baseline, Cpd(IA) significantly reduced BC. The percentage change in BC from the baseline was -13±6% and 11±6% in the BOO / Cpd(IA) group and the BOO / vehicle group, respectively. After mirabegron treatment, BC did not change significantly.

[0158] Compared to baseline levels, the vehicle did not have a significant effect on ThP in Siamese rats and BOO rats (p>0.05), while mirabegron and Cpd(IA) did not alter ThP (p>0.05). Compared to the vehicle, ThP, expressed in mmHg, did not change significantly after treatment with mirabegron or Cpd(IA) (p>0.05). Expressed as a percentage change from baseline, ThP decreased significantly after treatment with Cpd(IA) (p<0.05), but no significant effect was observed after treatment with mirabegron (p>0.05).

[0159] Compared to baseline, the vehicle significantly increased AM in Siamese rats (p<0.01). In BOO rats, the vehicle had no significant effect on AM (p>0.05), while mirabegron and Cpd(IA) did not significantly alter AM (p>0.05). Compared to the vehicle, AM did not significantly change after mirabegron or Cpd(IA) treatment, expressed as mmHg or percentage change from baseline (p>0.05).

[0160] Compared to baseline, the vehicle did not significantly alter NVC frequency in Siamese rats and BOO rats (p>0.05). In BOO rats, mirabegron significantly reduced NVC frequency (p<0.01). In BOO rats, Cpd(IA) did not affect NVC frequency (p>0.05). Compared to the vehicle, NVC frequency, expressed as NVCs / min or percentage change from baseline, did not significantly change after treatment with mirabegron or Cpd(IA) (p>0.05).

[0161] Compared to baseline, vehicle, mirabegron, and Cpd(IA) did not alter NVC amplitude in any experimental group (p>0.05). Compared to vehicle, NVC amplitude, expressed as mmHg values, did not significantly change after mirabegron or Cpd(IA) treatment (p>0.05). Expressed as a percentage change from baseline, NVC amplitude significantly decreased only after mirabegron treatment and remained unaffected by Cpd(IA) (p<0.05 and p>0.05).

[0162] For intervals of 60-90 minutes: Compared to baseline, in Siamese rats, the vehicle significantly increased BC (p<0.001). In BOO rats, the vehicle had no significant effect on BC (p>0.05). In BOO rats, mirabegron significantly increased BC (p<0.05), while Cpd(IA) significantly decreased BC (p<0.05, Figure 5D). Compared to the vehicle, no significant difference in BC was observed between the mirabegron group and the Cpd(IA) group, expressed in mL (p>0.05). Expressed as a percentage change from baseline, Cpd(IA) significantly decreased BC (p<0.05), but no significant difference was observed after mirabegron treatment (p>0.05).

[0163] Compared to baseline, the vehicle did not have a significant effect on ThP in Siamese rats and BOO rats (p>0.05). In BOO rats, mirabegron had no effect on ThP (p>0.05), but Cpd(IA) significantly reduced ThP (p<0.01). Compared to the vehicle, ThP, expressed in mmHg, did not change significantly after treatment with mirabegron or Cpd(IA) (p>0.05). Expressed as a percentage change from baseline, ThP was significantly reduced after treatment with mirabegron or Cpd(IA) (p<0.05).

[0164] In Siamese rats, the vehicle significantly increased AM compared to baseline (p<0.01). In BOO rats, the vehicle had no significant effect on AM (p>0.05), while mirabegron and Cpd(IA) did not significantly alter AM (p>0.05). Compared to the vehicle, no effect on AM was observed after treatment with mirabegron or Cpd(IA), expressed as mmHg or percentage change from baseline (p>0.05).

[0165] In Siamese and BOO rats, no significant effect on NVC frequency was observed after vehicle treatment compared to baseline (p>0.05). In BOO rats, mirabegron significantly reduced NVC frequency (p<0.01), while Cpd(IA) did not affect NVC frequency (p>0.05). Expressed relative to the vehicle, as NVCs / min or % change from baseline, NVC frequency was unaffected after mirabegron or Cpd(IA) treatment (p>0.05).

[0166] The vehicle did not significantly alter NVC amplitude in Siamese and BOO rats compared to baseline (p>0.05). In BOO rats, mirabegron significantly reduced NVC amplitude (p<0.05), while Cpd(IA) had no effect on NVC amplitude. Compared to the vehicle, NVC amplitude, expressed in mmHg, did not significantly change after treatment with mirabegron or Cpd(IA) (p>0.05). Expressed as a percentage change from baseline, NVC amplitude did not significantly change after Cpd(IA) treatment, but mirabegron significantly reduced NVC amplitude (p>0.05 and p<0.05).

[0167] Results of intravenous (iv) administration There were no significant differences in baseline values ​​for BC, ThP, AM, NVC frequency, NVC amplitude, and bladder weight between the two experimental BOO groups, including vehicle (1 mL / kg, iv) and Cpd(IA) (3 mg / kg, iv) (p>0.05, Figure 23). Results from the entire period from 0 to 90 minutes:

[0168] Compared to baseline values, vehicle and Cpd(IA) did not significantly alter BC in BOO rats (p>0.05, Figures 24A and 24B). Compared to vehicle, no significant difference in BC was observed in the Cpd(IA) group, expressed in mL (p>0.05, Figure 25A). Expressed as a percentage change from baseline, Cpd(IA) significantly reduced BC (p<0.01, Figure 25B).

[0169] Compared to baseline levels, no significant effect on ThP was observed after vehicle or Cpd(IA) treatment (p>0.05, 28A and 28B). Compared to vehicle levels, ThP, expressed in mmHg, did not change significantly after Cpd(IA) treatment (p>0.05, Figure 29A). Expressed as a percentage change from baseline, ThP decreased after Cpd(IA) treatment, with a nearly significant p-value (p=0.0504, Figure 29B).

[0170] Compared to baseline, vehicle and Cpd(IA) did not significantly alter AM in BOO rats (p>0.05, Figures 32A and 32B). Compared to vehicle, AM did not significantly change after Cpd(IA) treatment, expressed as mmHg or percentage change from baseline (p>0.05, Figures 33A and 33B).

[0171] Compared to baseline values, vehicle and Cpd(IA) did not affect NVC frequency in BOO rats (p>0.05, Figures 36A and 36B). Compared to vehicle, NVC frequency, expressed as NVCs / min or percentage change from baseline, did not change significantly after Cpd(IA) treatment (p>0.05, Figures 37A and 37B).

[0172] Compared to baseline, vehicle and Cpd(IA) did not alter NVC amplitude (p>0.05, Figures 40A and 40B). Compared to vehicle, NVC amplitude did not significantly change after Cpd(IA) treatment, expressed as the number of mmHg values ​​and the percentage change from baseline (p>0.05, Figures 41A and 41B).

[0173] Results from intervals of 60-90 minutes: Compared to baseline levels, neither vehicle nor Cpd(IA) had a significant effect on BC in BOO rats (p>0.05, Figures 26A and 26B). Compared to vehicle levels, no significant difference in BC was observed in the Cpd(IA) group, expressed as mL and percentage change from baseline levels (p>0.05, Figures 27A and 27B).

[0174] Compared to baseline levels, the vehicle did not significantly affect ThP in BOO rats (p>0.05, Figure 30A). In contrast, Cpd(IA) significantly reduced ThP (p<0.05, Figure 30B). Compared to the vehicle, ThP, expressed in mmHg, did not significantly change after Cpd(IA) treatment (p>0.05, Figure 31A). Expressed as a percentage change from baseline, ThP significantly decreased after Cpd(IA) treatment (p<0.05, Figure 31B).

[0175] Compared to baseline levels, vehicle and Cpd(IA) did not significantly alter AM in BOO rats (p>0.05, Figures 34A and 34B). Compared to vehicle levels, no effect on AM was observed after Cpd(IA) treatment, expressed as mmHg or percentage change from baseline (p>0.05, Figures 35A and 35B).

[0176] Compared to baseline levels, no significant effect on NVC frequency was observed in BOO rats after vehicle or Cpd(IA) (p>0.05, Figures 38A and 38B). Compared to vehicle levels, NVC frequency, expressed as NVCs / min or percentage change from baseline, was unaffected after Cpd(IA) treatment (p>0.05, Figures 39A and 39B).

[0177] Compared to baseline levels, vehicle and Cpd(IA) had no effect on NVC amplitude in BOO rats (p>0.05, Figures 42A and 42B). Compared to vehicle levels, NVC amplitude did not change significantly after Cpd(IA) treatment, expressed as mmHg and percentage change from baseline (p>0.05, Figures 43A and 43B).

[0178] Conclusion: In Siamese rats, compared to baseline, the vehicle (5 mL / kg, ig) increased BC only during the 60-90 minute interval period. These effects on BC after administration are thought to be due to the time effect. The vehicle also significantly increased AM over the entire period (90 minutes) and during the final interval period (60-90 minutes) compared to baseline. In BOO rats, the vehicle (5 mL / kg, ig) had no effect on any bladder measurement parameters, thus introducing a confounding factor for the evaluation of the test substance.

[0179] As expected, mirabegron (10 mg / kg, ig) significantly increased BC compared to baseline and decreased NVC amplitude and NVC frequency compared to vehicle and baseline, respectively (Gillespy et al., 2012).

[0180] As observed in the SCI model study, Cpd(IA)(ig) significantly reduced BC and ThP compared to the vehicle. Since urination occurs at lower intravesical pressures, the effect observed in ThP can be interpreted as a reduction in bladder capacity. The significant reduction in BC after treatment was similar to the results obtained in SCI rats.

[0181] In BOO rats, the vehicle (1 mL / kg, iv) had no effect on any bladder measurement parameters, thus introducing a confounding factor for the evaluation of the test substance. As observed in the SCI test and in BOO rats administered intragastricly, Cpd(IA)(iv) significantly reduced BC and ThP compared to the vehicle, and had no effect on any other bladder measurement parameters.

[0182] These results suggest that the differences in effects observed in SCI and BOO rats compared to normal rats (isovolume model) are likely due to different involvement of afferent fibers resulting from remodeling in the disease models (SCI and BOO rats) (De Groat, 1995, De Groat & Yoshimura, 2010, and Aizawa et al., 2017).

[0183] Example 5: A phase 1b blinded, placebo-controlled crossover study evaluating the effects of oral administration of compound (IA) in female human subjects with overactive bladder. This study includes a screening / washout period (up to 4 weeks), a single-blind placebo lan-in period (2 weeks), a double-blind treatment period (8 weeks), a single-blind placebo washout period (1 week), and a follow-up period (up to 1 week). The test design is summarized in Table 8: [Table 8]

[0184] Screening / Washout Period: Informed consent will be obtained from each participant before any study procedure is performed in this study. Assessment of study eligibility criteria will begin at the screening visit (visit 1), and will include medical history, physical examination, vital signs, clinical tests, urine culture, pregnancy test, and drug screening. If a washout for prohibited drugs is required, this washout will be completed during the screening / washout period.

[0185] Participants will discontinue their current drug treatment for OAB, but ongoing nonclinical therapies (which may include temporary voiding and behavioral modification, dietary restrictions, and stress reduction) will be continued in a similar and consistent manner throughout the study.

[0186] There is no minimum screening period; participants can enter the run-in period immediately if they meet the eligibility criteria.

[0187] Single-blind run-in period: Eligible subjects enter a single-blind run-in period (visit 2). Subjects must have experienced symptoms of overactive bladder after washing out previous overactive bladder medication. During the run-in period, subjects are instructed to take one tablet of the study drug each night at bedtime.

[0188] Participants will record their individual overall symptoms related to OAB using a voiding diary and other assessments. Participants will complete the Symptom Impact Sleep Questionnaire (SISQ) in the morning.

[0189] During the week prior to the next clinic visit (visit 3), participants will record the duration, type, and urgency of urination for a minimum of 3 to a maximum of 7 days for each episode.

[0190] At visit 3, eligibility for randomization will be assessed. Eligibility will be confirmed with the institution before randomization using an algorithm that takes into account urinary components recorded during the run-in period. In addition, the PI will confirm that the subject did not use any medications (other than the study drug) to treat OAB symptoms during the run-in period, and that all diaries were properly completed according to the protocol.

[0191] - Day 1 visit 3 marks the end of the single-blind run-in period and the start of the double-blind treatment period.

[0192] Double-blind treatment period: At visit 3, subjects who continue to meet eligibility criteria and meet all randomization eligibility criteria will be randomized to the study, given the double-blind study drug, and instructed to take the first dose at bedtime that night. Subjects will visit the clinic every two weeks for tolerability assessment and at least one telephone call on days 1 and 15, as well as each week between clinic visits, to review their diary / medication instructions.

[0193] In the week prior to each clinic visit (visits 4, 5, 6, 7, and 8), participants will record the duration, type, and urgency of urination for a minimum of 3 to a maximum of 7 days for each episode.

[0194] Upon visiting the clinic, participants will complete the efficacy / safety and other evaluations.

[0195] Single-blind washout period: Participants will follow the evaluation. During the week prior to clinic visit (visit 8), participants will record voiding time, type, and urgency for a minimum of 3 to a maximum of 7 days for each episode.

[0196] End of Treatment (EOT) / Early Termination (ET): Participants will undergo the EOT procedure at the end of double-blind treatment or if the trial is terminated early. Assessment calls at the time of EOT will be conducted on the same day as the completion of the trial or on the same day as the ET. If the study drug is not administered after these assessments, these assessments will not be repeated.

[0197] Follow-up period / End of study (EOS): Follow-up telephone contact will be completed approximately one week after the final dose of the study drug to monitor adverse events (AEs) and concomitant medications / therapies since the last visit.

[0198] Selection criteria: 1. A woman must be female, at least 18 years of age, and able to urinate on her own. A woman is eligible to participate if she is not pregnant, not breastfeeding, and meets at least one of the following criteria: She must be considered capable of bearing children, or capable of bearing children, unless she has had a hysterectomy, had a tubal ligation, or has been menopausal for at least one year. Female participants must consent to the use of a reliable method of contraception with a failure rate of less than 1% per year when used continuously and appropriately during the trial and for 30 days after the end of the trial (e.g., implants, injections, oral contraceptives, certain intrauterine devices (IUDs), sexual abstinence, or a vasectomy-treated partner). Regardless of whether or not urinary incontinence has lasted for 2-3 months, the patient has symptoms of overactive bladder, including urinary urgency and frequent urination. 3. Any ongoing nonclinical treatments (such as temporary voiding and behavioral modification, dietary restrictions, and stress reduction) may be continued in a similar and consistent manner throughout the study, while discontinuing any ongoing pharmacological treatments for overactive bladder (including anticholinergics and beta-3 antagonists) and other prohibited medications (including antipsychotics, opioids, GABA receptor analogs / modulators / agonists, and renal transport inhibitors). 4. Based on the opinion of the principal investigator at the clinical site, the patient is considered generally healthy, taking into account the medical history, physical examination, 12-lead electrocardiogram, and laboratory profile. 5. The candidate is able to understand the consent form and communicate effectively with the examination staff. 6. The subject willingly provides written informed consent and is willing and capable of completing all examination procedures, including electronic journals and examination-related questionnaires.

[0199] Exclusion criteria: 1. Having had a UTI, including bacterial cystitis, within the past 30 days, or a history of recurrent UTIs defined as three or more culture-documented episodes within the past 6 months. 2. Hematuria judged to be related to a malignant tumor of the bladder or other serious lesion. 3. You have undergone any surgical treatment affecting bladder function, bladder incontinence surgery, urethral surgery, or have received a botulinum toxin bladder injection within the past six months. 4. The patient has initiated use of a sacral and / or pudendal nerve neuromodulatory device (e.g., Interstim) within the past nine months. Patients with a history of transcutaneous nerve stimulation with an OAB are eligible if they initiated device use more than nine months prior to the present, have been in a stable environment for the past six months, and have permission from a medical monitor. 5. The patient has clinically significant outflow impairment (as determined by the principal investigator). 6. A catheter is in place, or intermittent self-catheterization is being performed. 7. Having abnormal detrusor activity and / or neurological causes of diabetic neuropathy, and / or having uncontrolled diabetes. Subjects with early-stage diabetes or controlled diabetes are eligible based on A1C records and permission for medical monitoring. 8. You have a history of chronic inflammation (e.g., interstitial cystitis), bladder stones, a history of pelvic radiation therapy, or a history of malignant disease of the pelvic organs (within the pelvic region). You have had cyclophosphamide cystitis or chemical cystitis or tuberculosis, received pelvic irradiation, or had active genital herpes or vaginitis. 9. The patient had grade III / IV pelvic organ prolapse with or without cystocele or urethral diverticulum. 10. Having moderate to severe liver impairment as defined by Child-Pugh classification B or C. 11. Any history and / or current evidence (including any surgical intervention for weight loss) of any other medical condition (e.g., cardiac, respiratory, gastrointestinal, renal, or malignant tumors other than basal cell carcinoma), neurological, or psychiatric condition that, in the opinion of the principal investigator, could affect the safety of the subject, interfere with the evaluation of the study, or interfere with the absorption, distribution, metabolism, or excretion of the drug. 12. Positive findings on the Columbia Suicide Severity Scale (C-SSRS), or current suicidal ideation / behavior, or a history thereof. Positive findings on the C-SSRS include, but are not limited to, suicidal ideation with actual attempts and methods or plans in the past year (answering "yes" to item 4 or 5 on the C-SSRS), a history of suicidal behavior in the past five years (answering "yes" to any item on the suicidal behavior section of the C-SSRS), or any lifetime history of serious or recurrent suicidal behavior. 13. You currently have a drug abuse or addiction, or a recent history of such abuse or addiction (within the past 6 months), or you have a diagnosis of a substance use disorder. 14. Current or past clinically significant kidney disease or renal dysfunction, or nephrolithiasis (findings or symptoms in the past 3 years), or 60 mL / min / 1.73 m 2 It has an estimated glomerular filtration rate (eGFR) of less than . 15. The patient received medication in a clinical drug trial within 30 days prior to their screening visit.

[0200] Randomization criteria At visit 3, subjects who meet the following randomization criteria will be eligible to participate in the double-blind treatment period: For at least 3 days in the voiding diary, subjects must (i) have urinated 8 or more times per 24-hour period, and (ii) have urinated at least once per 24-hour period with an urgency grade of ≥1.

[0201] Experimental treatment: Table 9 shows the details of the treatments administered. [Table 9]

[0202] Considerations regarding lifestyle: Sleep / Wake Pattern: Participants are encouraged to maintain a consistent sleep / wake pattern throughout the study period.

[0203] Diet and Dietary Restrictions: During the study, participants will be instructed to maintain a regular daily meal schedule and not make any changes to their usual diet (e.g., starting a weight loss program).

[0204] Caffeine, alcohol, and tobacco: Participants will be instructed to limit their intake of caffeine and alcohol. Smokers will be encouraged to maintain the same number of cigarettes smoked per day during the study.

[0205] Concomitant drugs / prohibited substances: During the screening / washout period, participants discontinued all current medications for OAB, while any ongoing behavioral therapy was continued in a similar / consistent manner throughout the trial. Any OAB medication was discontinued at least 7 days before the start of the single-blind run-in period.

[0206] Any prohibited substance must be discontinued at least 7 days before the start of the single-blind run-in period. If a substance does not fall into the listed substance class, consult a medical monitor to determine whether it is permitted.

[0207] Test endpoint: The objectives and endpoints of the study are listed in Table 10. [Table 10]

[0208] Example 6: Phase 1, non-randomized, open-label, parallel-group study to evaluate the effect of mild renal impairment on the single-dose pharmacokinetics and safety of the compound of formula (IA). Test design (methodology): This was a Phase 1, non-randomized, open-label, parallel-group, single-dose trial. A total of 20 subjects were tested (10 with mild renal impairment and 10 healthy controls with normal renal function).

[0209] During screening, participants were assigned to the test group according to their estimated glomerular filtration rate (eGFR), calculated using the 2021 Chronic Kidney Disease Collaboration (CKD-EPI 2021) formula, as shown in Table 11 below. [Table 11]

[0210] Healthy subjects (Group A) were matched with subjects with mild renal impairment (Group B) according to gender distribution, mean age (±10 years), mean weight (±15%), and mean body mass index (BMI; ±20%).

[0211] All subjects were screened up to 28 days prior to check-in, entered the clinical facility the day before administration of the study drug (-1 day), and received a single oral dose of the compound of formula (IA) on 1 day.

[0212] A single oral dose of the compound of formula (IA) in a 1.0 mg immediate-release tablet was administered with 240 mL of water the morning after fasting for at least 10 hours overnight. Subjects remained fasted for 4 hours after administration of the study drug (however, subjects with diabetes were permitted to have a light breakfast 2 hours after administration at the discretion of the principal investigator). Except as part of the study drug administration, subjects restricted their water intake 2 hours before and 2 hours after administration. At all other times during the study, subjects were free to drink water.

[0213] Participants underwent the End of Study (EOS) procedure and were discharged from the clinical facility on the 5th day (or in the case of early termination). Participants received a follow-up telephone call 7 to 10 days after the EOS. Figure 44 shows a diagram of the study design.

[0214] Selection / exclusion criteria: Males and females aged 18–70 years (including 18- and 70-year-olds) who are deemed suitable for participation in this clinical trial by the principal investigator and who have no clinically significant history of renal impairment or other stable comorbidities (except in the case of subjects with only renal impairment).

[0215] Drug concentration measurement: Blood samples were collected from all subjects to analyze the concentration of the compound of formula (IA) before administration and up to 96 hours after administration. To determine the plasma concentration of the compound of formula (IA), blood samples were collected before administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after administration.

[0216] Pharmacokinetic results: In all subjects, plasma concentrations at 72 and 96 hours were below the limit of quantification (concentration = 0 pg / mL); therefore, Figures 45-47 show plasma concentrations from 0 to 48 hours after treatment administration.

[0217] Figure 45A shows the mean plasma concentration-time profiles on a linear scale for subjects with normal renal function (n=10) and subjects with mild renal impairment (n=10). Figure 45B shows the mean plasma concentration-time profiles on a semi-logarithmic scale for subjects with normal renal function (n=10) and subjects with mild renal impairment (n=10).

[0218] Figure 46A shows the plasma concentration-time profile on a linear scale for individual subjects (n=10) with mild renal impairment. Figure 46B shows the plasma concentration-time profile on a semi-logarithmic scale for individual subjects (n=10) with mild renal impairment. Figure 47A shows the plasma concentration-time profile on a linear scale for individual subjects (n=10) with normal renal function. Figure 47B shows the plasma concentration-time profile on a semi-logarithmic scale for individual subjects (n=10) with normal renal function.

[0219] As shown in Figures 45-47, after administration of a single 1.0 mg immediate-release tablet of the compound of formula (IA), the time-course plasma concentrations in subjects with mild renal impairment were comparable to those in subjects with normal renal function.

[0220] While the subject matter of this disclosure has been described with reference to exemplary embodiments and examples, this description is not intended to be constrained. Various modifications of the exemplary embodiments and other embodiments of the invention will be apparent to those skilled in the art by reference to this description. Accordingly, the appended claims are intended to cover any such modifications or embodiments. The present invention also includes the following embodiments. <1> A method for administering such treatment to a human subject in need of treatment or prevention of overactive bladder syndrome, comprising a therapeutically effective amount of the compound of formula (I): [ka] The method comprising administering a pharmaceutically acceptable salt thereof to a human subject. <2> The aforementioned compound is the compound of formula (I'): [ka] The method according to item 1 above, or a pharmaceutically acceptable salt thereof. <3> The method according to 1 or 2 above, comprising administering a pharmaceutically acceptable salt of the compound, wherein the salt is selected from the group consisting of sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidic phosphate, isonicotinate, lactate, salicylate, acidic citrate, tartrate, oleate, tannate, pantothenate, bicarbonate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate. <4> The method according to any of the preceding descriptions, wherein the method comprises administering a p-toluenesulfonate, sulfate, phosphate, or hydrochloride of the compound. <5> The method according to any of the preceding descriptions, wherein p-toluenesulfonate of the aforementioned compound is administered. <6> The method described in any of the preceding descriptions, comprising administering a compound of formula (IA). [ka] <7> The method described above, wherein the urination frequency of the human subject is reduced. <8> The method described above, which reduces episodes of nocturnal polyuria in the aforementioned human subjects. <9> A method for administering such treatment to a human subject who requires a reduction in nocturnal polyuria, wherein the human subject is given a therapeutically effective amount of a compound of formula (I): [ka] The method comprising administering a pharmaceutically acceptable salt thereof. <10> The aforementioned compound is the compound of formula (I'): [ka] The method according to 9 above, or a pharmaceutically acceptable salt thereof. <11> The method according to 9 or 10 above, comprising administering a pharmaceutically acceptable salt of the compound, wherein the salt is selected from the group consisting of sulfates, citrates, acetates, trifluoroacetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bicarbonates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, gluconates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, and p-toluenesulfons. <12> The method according to any one of the above 9 to 11, wherein the method comprises administering a p-toluenesulfonate, sulfate, phosphate, or hydrochloride of the compound. <13> The method according to any one of 9 to 12 above, wherein p-toluenesulfonate of the aforementioned compound is administered. <14> The method according to 13 above, comprising administering a compound of formula (IA).

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[0221] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference in whole.

[0222] References: ·FDA 2019 Draft Guidance Document.Interstitial Cystitis / Bladder Pain Syndrome (IC / BPS): Establishing Effectiveness of Drugs for Treatment Guidance for Industry. ·Bosch PC.Examination of the Significant Placebo Effect in the Treatment of Interstitial Cystitis / Bladder Pain Syndrome. Urology 2014;84(2):321-325 ·Beauval JB et al., 2015. Comparison of the effects of β3 -adrenoceptor agonism on urinary bladder function in conscious, anesthetized, and spinal cord injured rats.Neurourol Urodyn. 34: 578-585. ·Cheng C et al., 1995. Effect of capsaicin on micturition and associated reflexes in chronic spinal rats. Brain Research 678: 40-48. ·De Groat WC, 1995.Mechanism underlying the recovery of lower urinary tract function following spinal cord injury. Paraplegia 33: 413-501. ·De Groat WC & Yoshimura N., 2010. Changes in afferent activity after spinal cord injury. Neurourol Urodyn. 29: 63-76. ·Kadekawa K et al., 2017. Effects of an alpha1A / D-adrenoceptor antagonist, naftopidil, and a phosphodiesterase type 5 inhibitor, tadalafil, on urinary bladder remodeling in rats with spinal cord injury. Neurourol Urodyn. 36: 1488-1495. ·Wada N et al., 2017. Combination effects of muscarinic receptor inhibition and β3-adrenoceptor stimulation on neurogenic bladder dysfunction in rats with spinal cord injury. Neurourol Urodyn. 36: 1039-1045. ·Wada N et al., 2018. Urodynamic effects of intravenous and intrathecal administration of E-series prostaglandin 1 receptor antagonist on detrusor overactivity in rats with spinal cord injury. Neurourol Urodyn. 37: 132-137. ·Yoshiyama M et al., 1999. Changes in micturition after spinal cord injury in conscious rats. Urology. 54: 29-933. ·Aizawa N et al., 2017. Characteristics of the Mechanosensitive Bladder Afferent Activities in Relation With Microcontractions in Male Rats With Bladder Outlet Obstruction. Sci Rep 7: 7646 ·De Groat WC, 1995.Mechanism underlying the recovery of lower urinary tract function following spinal cord injury. Paraplegia 33: 413-501. ·De Groat WC & Yoshimura N., 2010. Changes in afferent activity after spinal cord injury. Neurourol Urodyn. 29: 63-76. ·Gillespie J. et al., 2012 Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the β(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction.BJU International 110:132-142 ·Lluel P. et al., 1998. Experimental bladder instability following bladder outlet obstruction in the female rat.J Urol. 160:2253-2257.

Claims

1. (a) Treatment or prevention of overactive bladder syndrome in human subjects requiring treatment, (b) Reduction of nocturnal polyuria in human subjects requiring treatment, or (c) To treat sleep disorders in patients who also suffer from urinary incontinence, Compounds of formula (I) in therapeutically effective doses: 【Chemistry 1】 or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof.

2. The aforementioned compound is the compound of formula (I'): 【Chemistry 2】 The pharmaceutical composition according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound, the salt being selected from the group consisting of sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidic phosphate, isonicotinate, lactate, salicylate, acidic citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

4. The pharmaceutical composition is the pharmaceutical composition according to any one of claims 1 to 3, comprising a compound of formula (IA). 【Transformation 3】

5. The pharmaceutical composition according to any one of claims 1 to 3, for treating or preventing overactive bladder syndrome, wherein the frequency of urination in the human subject is reduced, or the episodes of nocturnal polyuria in the human subject is reduced.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally, parenterally, intravenously, intramuscularly, buccally, or transdermally.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is 0.10 mg to 10 mg.

8. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is administered once a day and / or at night or before bedtime.

9. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is administered twice a day or every 12 hours.

10. The pharmaceutical composition according to any one of claims 1 to 3, wherein the urination pressure threshold in the human subject increases by 30% to 80%.

11. The pharmaceutical composition according to any one of claims 1 to 3, comprising 1 mg or 1.5 mg of a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to any one of claims 1 to 3, further comprising an effective amount of an antimuscarinic agent.

13. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is for the treatment or prevention of overactive bladder syndrome, and the patient also suffers from a sleep disorder.

14. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is for treating a sleep disorder, the sleep disorder being insomnia, hypersomnia, circadian rhythm sleep-wake disorder, alcohol-induced sleep disorder, insomnia associated with alcohol abstinence, or any combination thereof.

15. The pharmaceutical composition is for the treatment of overactive bladder syndrome, and the human subject has mild renal impairment having an estimated glomerular filtration rate (eGFR) of 60 mL / min to 89 mL / min, according to any one of claims 1 to 3.

16. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is for the treatment of overactive bladder syndrome, and the human subject has mild to moderate renal impairment having an estimated glomerular filtration rate (eGFR) of 45 mL / min to 59 mL / min.

17. Administration of the aforementioned pharmaceutical composition results in the corresponding mean AUC and C in human subjects under similar conditions without renal dysfunction. ｍａｘ , T ｍａｘ , T １／２ , or mean AUC, C with no statistical difference from CL / F ｍａｘ , T ｍａｘ , T １／２ The pharmaceutical composition according to claim 15, wherein at least CL / F is obtained.

18. By administering the pharmaceutical composition, the corresponding mean Ae, Fe, or CL in human subjects under similar conditions without renal dysfunction Ｒ Mean Ae, Fe, or CL with no statistically significant difference Ｒ The pharmaceutical composition according to claim 15, wherein at least the following can be obtained.

19. The pharmaceutical composition according to claim 16, wherein administration of the pharmaceutical composition yields at least an average AUC, C max, T max, T 1 / 2, or CL / F that does not show a statistical difference from the corresponding average AUC, C max, T max, T 1 / 2, or CL / F in a human subject under similar conditions without renal failure.

20. The pharmaceutical composition according to claim 16, wherein administration of the pharmaceutical composition yields at least an average Ae, Fe, or CL R that does not differ statistically from the corresponding average Ae, Fe, or CL R in a human subject under similar conditions without renal failure.

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