Methods of treating or preventing overactive bladder syndrome

Abstract

The present disclosure provides a method of treating or preventing overactive bladder syndrome (OBS) in a human subject (normal renal function, mild impaired renal function, or mild to moderate impaired renal function) in need of such treatment, the method comprising administering to the human subject a therapeutically effective amount of Compound of Formula (I) # imgabs0 # or a pharmaceutically acceptable salt thereof. In one embodiment, the method comprises administering a compound of formula (IA) # imgabs1 #

Description

Background of the Invention

[0002] Overactive bladder syndrome occurs when the muscles of the bladder begin to contract involuntarily, even when there is little urine in the bladder. These muscle contractions create an urgent need to urinate. Patients with overactive bladder syndrome (OBS) typically urinate more frequently than healthy individuals and often wake up one or more times at night to urinate (nocturia). Many patients with OBS experience urinary incontinence, which is defined as the involuntary leakage of urine.

[0003] OBS is caused by abnormal and involuntary contractions of the detrusor muscle of the bladder, which has muscarinic receptors embedded in it. As the bladder fills with urine, it begins to stretch. This stretch is sensed by afferent neurons, which results in the urge to urinate. Nerves in the bladder muscle wall release the neurotransmitter acetylcholine, which binds to muscarinic receptors on the bladder muscle wall and causes the cells to contract, further increasing the urge to urinate. Stimulation of these muscarinic receptors by acetylcholine causes the bladder to contract, which results in urination. Under normal circumstances, the detrusor muscle remains at rest as the bladder fills with urine. However, in patients with OBS, the bladder contracts during the filling phase.

[0004] Common drug treatments for OBS are antimuscarinics (i.e., muscarinic receptor antagonists), which inhibit the stimulation of the neurotransmitter acetylcholine on muscles. Several antimuscarinics have been approved for the treatment of OBS, including oxybutynin, tolterodine, trospium, solifenacin, and darifenacin. By blocking the effects of acetylcholine on muscle cells, antimuscarinics slow the buildup of pressure in the bladder, reduce the sensation of urination, and prevent uncontrolled urination.

[0005] Administration of antimuscarinics affects the efferent pathways associated with muscle contraction, leading to urination. Treatments that affect the sensory (afferent) pathways associated with urination have achieved less success. Afferent nerve fibers travel from the lower urinary tract to the spinal cord via the pelvic, hypogastric, and pudendal nerves. The afferent nerves in the lower urinary tract are composed of two types of fibers (A-delta and C-fibers) that are associated with the sensation of pressure and respond to the stretching of the bladder as it fills with urine. Afferent neurons express different types of receptors and ion channels, including transient receptor potential channels, purinergic receptors, muscarinic receptors, endothelin receptors, neurotrophin receptors, and estrogen receptors. These receptors have a variety of functions, many of which involve 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.

[0006] There is a need for effective treatments of lower urinary tract disorders using orally administrable small molecule therapeutics. Summary of the invention

[0007] The present disclosure provides a method of treating or preventing overactive bladder syndrome (OBS) by administering a small molecule agonist of the pain opioid peptide receptor (also known as the ORL-1 receptor).

[0008] In one aspect, the present disclosure provides a method of treating or preventing OBS in a human subject identified as being in need of such treatment, the method comprising administering to the human subject a therapeutically effective amount of a compound of formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof. The compound of formula (I) includes all its stereoisomers (including enantiomers) and polymorphic forms thereof.

[0011] In some embodiments, the present disclosure provides a method of treating or preventing overactive bladder syndrome (OBS) in a human subject identified as being in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I'):

[0012]

[0013] or a pharmaceutically acceptable salt thereof. As is well known to those skilled in the art, the compound of formula (I') is a stereoisomer of the compound of formula (I).

[0014] In certain embodiments, the compound of formula (I) or formula (I') is administered in the form of a tosylate salt. For example, in certain embodiments, the present disclosure provides a method for treating or preventing overactive bladder syndrome (OBS) in a human subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA):

[0015]

[0016] In certain embodiments, the present disclosure provides a method for treating or preventing one or more symptoms associated with OBS in a human subject identified as needing such treatment by administering a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof, wherein the one or more symptoms are selected from the group of urinary incontinence, urinary urgency, and increased urinary frequency. In some embodiments, the method comprises administering a compound of formula (IA).

[0017] In certain embodiments, the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof is administered orally. As mentioned below, the compounds of the present disclosure include compounds of formula (I) and (I') (including all stereoisomers), pharmaceutically acceptable salts thereof (e.g., compounds of formula (IA)), polymorphic forms, solvates or hydrates. Suitable effective doses of the compounds of the present disclosure administered orally as a single dose are from about 0.001 mg to about 30 mg, from about 0.10 mg to about 10 mg, from about 0.50 mg to about 8 mg, from about 1 mg to about 6 mg, or from about 1 mg to about 3 mg. In some such embodiments, the compound to be administered is a compound of formula (IA).

[0018] In certain embodiments, the compounds of the present disclosure are administered orally. In certain embodiments, the compound to be administered is a compound of formula (IA). It should be understood that oral administration of a compound of the present disclosure (e.g., a compound of formula (I), (I') or (IA)) results in high compound concentrations in the bladder.

[0019] A particular advantage of the disclosed methods is that they are able to simultaneously treat patients suffering from sleep disorders and lower urinary tract complications (e.g., OBS). Therefore, in one aspect, the present disclosure provides a method for treating or preventing OBS in a human subject who also suffers from sleep disorders, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. 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 withdrawal. In some embodiments, the compounds of the present disclosure are administered at night. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 A shows the basal values ​​of rhythmic bladder contraction (RBC) frequency in anesthetized female rats after administration of vehicle, compound of formula (IA) (labeled as Cpd(IA)) or tolterodine; Figure 1 B shows the basal values ​​of RBC amplitude in anesthetized female rats after administration of vehicle, compound of formula (IA) or tolterodine. Results are expressed as mean ± sem. N.S. p>0.05, one-way ANOVA.

[0021] Figure 1C Graph showing a study designed to evaluate the effect of intravenous administration of the compound of formula (IA) in anesthetized female rats on cystometric parameters in an isovolumetric model.

[0022] Figure 2A shows the effect of vehicle (1 mL / kg, iv) on RBC frequency in anesthetized female rats; Figure 2 B shows the effect of the compound of formula (1A) (3 mg / kg, iv) on RBC frequency in anesthetized female rats; Figure 2 C shows the effect of tolterodine compound (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, relative to basal values, paired Student's t-test or Wilcoxon test.

[0023] Figure 3 Shown are the effects of vehicle (1 mL / kg, iv), compound of formula (1A) (3 mg / kg, iv) and tolterodine (1 mg / kg, iv) on RBC frequency (expressed as % change from basal levels) in anesthetized female rats. Results are expressed as mean ± sem. N.S. p>0.05 and ++++ p<0.0001 vs. vehicle, Kruskal Wallis test followed by Dunn's post-test.

[0024] Figure 4 A shows the effect of vehicle (1 mL / kg, iv) on RBC amplitude in anesthetized female rats; Figure 4 B shows the effect of the compound of formula (1A) (3 mg / kg, iv) on RBC amplitude in anesthetized female rats; Figure 4 C shows the effect of tolterodine compound (1 mg / kg, iv) on RBC amplitude in anesthetized female rats. Results are expressed as mean±sem, *p<0.05 and **p<0.01, relative to basal values, paired Student's t-test or Wilcoxon test.

[0025] Figure 5 The effects of vehicle (1 mL / kg, iv), compound of formula (IA) (3 mg / kg, iv) and tolterodine (1 mg / kg, iv) on RBC amplitude (expressed as % change relative to basal levels) in anesthetized female rats are shown. RBC amplitude is expressed as % change relative to basal values. Results are expressed as mean ± sem. N.S. p>0.05 and ++++ p<0.001 vs. vehicle, one-way ANOVA followed by Dunnett's post-test.

[0026] Figure 6 Shown are the effects of vehicle (1 mL / kg, iv), compound of formula (1A) (3 mg / kg, iv) and tolterodine (1 mg / kg, iv) on inhibition time in anesthetized female rats. Results are expressed as mean ± sem. N.S. p>0.05 and ++ p<0.01 vs. vehicle, one-way ANOVA followed by Dunn's post hoc test.

[0027] Figure 7 Recordings of analyzed cystometric parameters are shown for vehicle (1 mL / kg, iv) (7A); compound of formula (IA) (3 mg / kg, iv) (7B); and tolterodine (1 mg / kg, iv) (7C).

[0028] Figure 8 A typical recording of the analyzed cystometric parameters is shown.

[0029] Fig. 9 It is a plan for SCI research program design.

[0030] Fig.10 Cystometry parameters measured in SCI studies are presented.

[0031] Fig.11 The effects of SCI on the following cystometric parameters are presented: BC (11A), ThP (11B), AM (11C), NVC frequency (11D) and NVC amplitude (11E), and bladder weight (11F). Results are expressed as mean ± sem. ns p>0.05, §§ p<0.01, §§§ p<0.001, §§§§ p<0.0001, unpaired Student's t-test.

[0032] Fig.12 Baseline values ​​of cystometric parameters for all SCI experimental rats are shown: BC (12A), ThP (12B), AM (12C), NVC frequency (12D) and NVC amplitude (12E); and bladder weight (12F). Results are expressed as mean ± sem. NS p>0.05, one-way ANOVA or Kruskal-Wallis test.

[0033] Fig.13Shown are the effects of vehicle (5 mL / kg, ig, n=12, once) in sham-operated rats (13A), vehicle (5 mL / kg, ig, n=11, once) in SCI rats (13B), mirabegron (10 mg / kg, ig, n=13, once) in SCI rats (13C), and Cpd(IA) (30 mg / kg, ig, n=12, once) in SCI rats (13D) relative to basal values. Results are expressed as mean ± sem. NS p>0.05, ** p<0.01 *** p<0.001, repeated measures one-way ANOVA followed by Dunn's post hoc test or Friedman test followed by Dunn's post hoc test, relative to basal values.

[0034] Fig.14 The effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) relative to vehicle (5 mL / kg, ig) on ​​BC expressed in mL (14A) and as % change from basal values ​​(14B) are shown. Results are expressed as mean ± sem. NS p>0.05, * p<0.05, Kruskal Wallis test followed by Dunn's post hoc test, versus vehicle.

[0035] Fig.15 The effects of vehicle (5 mL / kg, ig) in sham-operated rats (15A) and SCI rats (15B), mirabegron (10 mg / kg, ig) in SCI rats (15C), and Cpd(IA) (30 mg / kg, ig) in SCI rats (15D) on THP relative to basal values ​​are shown. Results are expressed as mean ± sem. NS p>0.05, * p < 0.05, repeated measures one-way ANOVA or Friedman test followed by Dunn's post hoc test, relative to basal values.

[0036] Fig.16 The effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) relative to vehicle (5 mL / kg, ig) on ​​ThP expressed in mmHg (16A) and as % change from basal values ​​(16B) are shown. Results are expressed as mean ± sem. NSp>0.05 Kruskal Wallis test, versus vehicle.

[0037] Fig.17 The effects of vehicle (5 mL / kg, ig) in sham-operated rats (17A) and SCI rats (17B), mirabegron (10 mg / kg, ig) in SCI rats (17C), and Cpd(IA) (30 mg / kg, ig) in SCI rats (17D) on AM are shown relative to basal values. Results are expressed as mean ± sem. NS p>0.05, * p < 0.05, repeated measures one-way ANOVA or Friedman test, relative to basal values.

[0038] Fig.18 The effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) relative to vehicle (5 mL / kg, ig) on ​​AM expressed in mmHg (18A) and as % change from basal values ​​(18B) are shown. Results are expressed as mean ± sem. NS p>0.05, Kruskal Wallis test followed by Dunn's post hoc test, versus vehicle.

[0039] Fig.19 The effects of vehicle (5 mL / kg, ig) in sham-operated rats (19A) and SCI rats (19B), mirabegron (10 mg / kg, ig) in SCI rats (19C), and Cpd(IA) (30 mg / kg, ig) in SCI rats (19D) on NVC frequency relative to basal values ​​are shown. Results are expressed as mean ± sem. NS p>0.05, * p<0.05, * *p<0.01, repeated measures one-way ANOVA followed by Dunn's post hoc test or Friedman's test followed by Dunn's post hoc test, relative to basal values.

[0040] Fig. 20 The effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) relative to vehicle (5 mL / kg, ig) on ​​the frequency of NVCs expressed as NVC / min (20A) and as % change from basal values ​​(20B) are shown. Results are expressed as mean ± sem. NS p>0.05, one-way ANOVA, versus vehicle.

[0041] Fig.21The effects of vehicle (5 mL / kg, ig) in sham-operated rats (21A) and SCI rats (21B), mirabegron (10 mg / kg, ig) in SCI rats (21C), and Cpd(IA) (30 mg / kg, ig) in SCI rats (21D) on NVC amplitude relative to basal values ​​are shown. Results are expressed as mean ± sem. NS p>0.05, * p<0.05, * **p < 0.01, repeated measures one-way ANOVA followed by Dunn's post hoc test or Friedman's test followed by Dunn's post hoc test, relative to basal values

[0042] Fig. 22 The effects of mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) relative to vehicle (5 mL / kg, ig) on ​​NVC amplitude expressed in mmHg (22A) and as % change from basal values ​​(22B) are shown. Results are expressed as mean ± sem. NS p>0.05, one-way ANOVA or Kruskal Wallis test, versus vehicle.

[0043] Fig.23 AF show the basal values ​​of cystometric parameters and bladder weight for all BOO experimental rats. The results are expressed as mean ± sem. NS p>0.05, unpaired Student's t-test.

[0044] Fig.24 Shown are the effects of vehicle (1 mL / kg, iv) (24A) and Cpd(IA) (3 mg / kg, iv) (24B) on BC in BOO rats over the entire period of 0-90 minutes relative to basal values. Results are expressed as mean ± sem. ns p>0.05, paired Student's t test or Wilcoxon test, relative to basal values.

[0045] Fig.25 Shown are the effects of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) over the entire period of 0-90 minutes on BC expressed in mL (25A) and as % change from basal values ​​(25B). Results are expressed as mean ± sem. ns p>0.05 and ++ p<0.01, unpaired Student's t-test or Mann-Whitney test, versus vehicle.

[0046] Fig.26 Shown are the effects of vehicle (1 mL / kg, iv) (26A) and Cpd(IA) (3 mg / kg, iv) (26B) on BC in BOO rats over a period of 60-90 minutes relative to basal values. Results are expressed as mean ± sem. ns p>0.05, paired Student's t test or Wilcoxon test, relative to basal values.

[0047] Fig. 27 The effect of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) over a period of 60-90 minutes on BC expressed in mL (27A) and as % change from basal values ​​(27B) is shown. Results are expressed as mean ± sem. ns p>0.05, unpaired Student's t test or Mann-Whitney test, relative to vehicle.

[0048] Fig.28 Shown are the effects of vehicle (1 mL / kg, iv) (28A) and Cpd(IA) (3 mg / kg, iv) (28B) on ThP in BOO rats over the entire period of 0-90 minutes relative to basal values. Results are expressed as mean ± sem. ns p>0.05, paired Student's t-test, relative to basal values.

[0049] Fig.29 Shown are the effects of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) over the period 0-90 min on ThP expressed in mmHg (29A) and as % change from basal values ​​(29B). Results are expressed as mean ± sem. ns p>0.05, unpaired Student's t-test, relative to vehicle.

[0050] Fig.30 Shown are the effects of vehicle (1 mL / kg, iv) (30A) and Cpd(IA) (3 mg / kg, iv) (30B) on ThP in BOO rats over a period of 60-90 minutes relative to basal values. Results are expressed as mean ± sem. ns p>0.05, paired Student's t-test, relative to basal values.

[0051] Fig.31Shown are the effects of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) over a period of 60-90 minutes on ThP expressed in mmHg (31A) and as % change from basal values ​​(31B). ns p>0.05 and + p<0.05, unpaired Student's t-test, versus vehicle.

[0052] Fig.32 Shown are the effects of vehicle (1 mL / kg, iv) (32A) and Cpd(IA) (3 mg / kg, iv) (32B) on AM in BOO rats over the entire period of 0-90 minutes relative to basal values. Results are expressed as mean ± sem. ns p>0.05, paired Student's t test or Wilcoxon test, relative to basal values.

[0053] Fig.33 Shown are the effects of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) over the entire period of 0-90 minutes on AM expressed in mmHg (33A) and as % change from basal values ​​(33B). Results are expressed as mean ± sem. ns p > 0.05, paired Student's t test or Mann-Whitney test, relative to basal values.

[0054] Fig.34 Shown are the effects of vehicle (1 mL / kg, iv) (34A) and Cpd(IA) (3 mg / kg, iv) (34B) on AM expressed in mmHg over a period of 60-90 minutes in BOO rats relative to basal values. Results are expressed as mean ± sem. ns p>0.05, paired Student's t test or Wilcoxon test, relative to basal values.

[0055] Fig.35 Shown are the effects of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) over a period of 60-90 minutes on AM expressed in mmHg (35A) and as % change from basal values ​​(35B). Results are expressed as mean ± sem. ns p > 0.05, paired Student's t test or Mann-Whitney test, relative to basal values.

[0056] Fig.36Shown are the effects of vehicle (1 mL / kg, iv) (36A) and Cpd(IA) (3 mg / kg, iv) (36B) on NVC frequency in BOO rats over the entire period of 0-90 minutes relative to basal values. Results are expressed as mean ± sem. ns p>0.05, paired Student's t-test, relative to basal values.

[0057] Fig.37 The effect of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) over the entire period of 0-90 minutes on the frequency of NVCs expressed as NVC / min (37A) and as % change from basal values ​​(37B) is shown. Results are expressed as mean ± sem. ns p > 0.05, paired Student's t test or Mann-Whitney test, relative to basal values.

[0058] Fig.38 Shown are the effects of vehicle (1 mL / kg, iv) (38A) and Cpd(IA) (3 mg / kg, iv) (38B) on NVC frequency in BOO rats over a period of 60-90 minutes relative to basal values. Results are expressed as mean ± sem. ns p>0.05, paired Student's t test or Wilcoxon test, relative to basal values.

[0059] Fig.39 The effect of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) over a period of 60-90 minutes on NVC frequency expressed as NVC / min (39A) and as % change from basal values ​​(39B) is shown. Results are expressed as mean ± sem. ns p > 0.05, one-way ANOVA followed by Dunn's post hoc test, relative to vehicle.

[0060] Fig.40 Shown are the effects of vehicle (1 mL / kg, iv) (40A) and Cpd(IA) (3 mg / kg, iv) (40B) on NVC amplitude in BOO rats over the entire period of 0-90 minutes relative to basal values. Results are expressed as mean ± sem. ns p>0.05, paired Student's t test or Wilcoxon test, relative to basal values.

[0061] Fig.41Shown are the effects of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) over the entire period of 0-90 minutes on NVC amplitude expressed in mmHg (41A) and as % change from basal values ​​(41B). Results are expressed as mean ± sem. ns p > 0.05, paired Student's t test or Mann-Whitney test, relative to basal values.

[0062] Fig.42 Shown are the effects of vehicle (1 mL / kg, iv) (42A) and Cpd(IA) (3 mg / kg, iv) (42B) on NVC amplitude in BOO rats over a period of 60-90 minutes relative to basal values. Results are expressed as mean ± sem. ns p>0.05, paired Student's t test or Wilcoxon test, relative to basal values.

[0063] Fig.43 The effect of Cpd(IA) (3 mg / kg, iv) relative to vehicle (1 mL / kg, iv) over a period of 60-90 minutes on NVC amplitude expressed in mmHg (43A) and as % change from basal values ​​(43B) is shown. Results are expressed as mean ± sem. ns p>0.05, unpaired Student's t test or Mann-Whitney test, relative to vehicle.

[0064] Fig.44 Diagram showing the Phase 1, non-randomized, open-label, parallel-group, single-dose study design.

[0065] Fig.45A Shown are mean plasma concentration versus time curves on a linear scale for subjects with normal renal function (n=10) and subjects with mild renal impairment (n10).

[0066] Fig.45B Mean plasma concentration versus time curves for subjects with normal renal function (n=10) and subjects with mild renal impairment (n=10) are shown on a linear scale and on a semi-logarithmic scale.

[0067] Fig.46A Shown are plasma concentration versus time curves on a linear scale for individual subjects (n=10) with mild renal impairment. Fig.46B Shown are plasma concentration versus time curves on a semi-logarithmic scale for individual subjects (n=10) with mild renal impairment.

[0068] Fig.47A Plasma concentration versus time curves on a linear scale are shown for individual subjects (n=10) with normal renal function.

[0069] Fig.47B Plasma concentration versus time curves for individual subjects with normal renal function (n=10) are shown on a semi-logarithmic scale. DETAILED DESCRIPTION

[0070] The present disclosure provides methods for treating or preventing pathological conditions associated with overstimulation of afferent nerves associated with the lower urinary tract. Such pathological conditions include overactive bladder system (OBS), urinary urgency, increased urination frequency, nocturia, and urinary incontinence. Specifically, the present disclosure provides methods for treating or preventing pathological conditions associated with overstimulation of afferent nerves by administering agonists of nociceptin opioid peptide receptors (also known as ORL-1 receptors).

[0071] The identification of the ORL-1 receptor, which is distinct from the three long-known major classes of opioid receptors in the central nervous system (μ, κ, and δ), stems from experiments with these opioid receptor classes. The ORL-1 receptor was identified and classified as an opioid receptor based solely on amino acid sequence homology, as the ORL-1 receptor does not exhibit pharmacology that overlaps with the classical μ opioid receptor. Initially, it was demonstrated that non-selective ligands with high affinity for the μ, κ, and δ receptors had low affinity for the ORL-1 receptor. This feature, coupled with the fact that no endogenous ligand has been found, gave rise to the term "orphan receptor." See, e.g., Henderson et al., "The orphan opioid receptor and its endogenous ligand-nociceptin / orphanin FQ," Trends Pharmacol. Sci. 18(8) :293-300 (1997). Subsequent studies have led to the isolation and structure of the endogenous ligand for the ORL-1 receptor (i.e., nociceptin; also known as orphanin FQ or OFQ), a 17 amino acid peptide with a structure 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).

[0072] The endogenous ligand of the ORL-1 receptor is a 17 amino acid peptide called nociceptin. Through its interaction with ORL-1, nociceptin has inhibitory activity on the micturition reflex in various animal models. Direct administration of nociceptin and peptide analogs of nociceptin into the bladder has been studied as a means of alleviating urinary incontinence, presumably by reducing afferent signaling (Lazzeri et al., 2003 Urology; Lazzeri et al., 2006 J. Urology; and Del Popolo et al., 2011).

[0073] The inventors have surprisingly discovered that pathological conditions associated with overstimulation of afferent nerves associated with the lower urinary tract can be treated by administering a therapeutically effective amount of a compound of formula (I):

[0074]

[0075] or a pharmaceutically acceptable salt thereof to improve or treat. The compound of formula (I) includes all its stereoisomers (including enantiomers) and polymorphic forms thereof.

[0076] In certain embodiments, the compound of Formula (I) is a single stereoisomer, ie, a compound of Formula (I') having the structure depicted below:

[0077]

[0078] Compounds of Formula (I) and Formula (I') or pharmaceutically acceptable salts thereof may be prepared as described in US Pat. No. 8,476,221, which is hereby incorporated by reference.

[0079] Thus, in one aspect, the present disclosure provides a method for treating or preventing overactive bladder syndrome (OBS) in a human subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, e.g., a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (IA)). In certain embodiments, administration of a compound of the present disclosure also improves symptoms associated with OBS (e.g., reduces its severity), including but not limited to urinary urgency, increased urination frequency, nocturia, and urinary incontinence.

[0080] In one embodiment, the administration of a compound of the present disclosure increases the pressure threshold for urination by about 10% to about 99.5%. In another embodiment, the administration of a compound of the present disclosure increases the pressure threshold for urination by about 20% to about 90%. In another embodiment, the administration of a compound of the present disclosure increases the pressure threshold for urination by about 30% to about 80%.

[0081] On the other hand, the present disclosure provides a method for reducing the occurrence of nocturia in a human subject in need of this treatment, the method comprising administering a therapeutically effective amount of a compound of the present disclosure to the subject. In some embodiments, nighttime administration refers to administering the compound before bedtime. In some embodiments, the compound of the present disclosure may be administered from about three hours before bedtime of the human subject until any time before bedtime. In one embodiment, after administering the compound of the present disclosure every night, the situation of nocturnal urination is reduced from 2 times or more per night to less than 2 times. For example, after administering the compound of the present disclosure every night, the number of times the subject urinates at night may be reduced from 2 times or more to 0 or 1 time.

[0082] In certain embodiments, the methods of the present disclosure include administering a therapeutically effective amount of a compound of the present disclosure to a human subject once every two nights. In other embodiments, the methods include administering a therapeutically effective amount of a compound of the present disclosure to a human subject once every three nights. In another embodiment, the methods include administering a therapeutically effective amount of a compound of the present disclosure to a human subject once a week. In other embodiments, the methods include administering a therapeutically effective amount of a compound of the present disclosure to a human subject once every three nights. In another embodiment, the methods include administering a therapeutically effective amount of a compound of the present disclosure to a human subject twice a week.

[0083] In another aspect, the present disclosure provides methods of treating or preventing urinary incontinence in a human subject identified in need of such treatment, the methods comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0084] On the other hand, the present disclosure provides a method for treating or preventing OBS in a human subject by administering a therapeutically effective amount of a compound of the present disclosure, wherein the compound acts by inhibiting the contraction of the bladder detrusor of the human subject. In some embodiments, after administering a compound of the present disclosure, the contraction of the bladder detrusor may be delayed (at a time interval) by at least 20%. In other embodiments, after administering a compound of the present disclosure, the contraction of the bladder detrusor may be delayed by at least 30%. In other embodiments, after administering a compound of the present disclosure, the contraction of the bladder detrusor may be delayed by at least 50%. In other embodiments, after administering a compound of the present disclosure, the contraction of the bladder detrusor may be delayed by at least 70%. In other embodiments, after administering a compound of the present disclosure, the contraction of the bladder detrusor may be delayed by at least 80%. In other embodiments, after administering a compound of the present disclosure, the contraction of the bladder detrusor may be delayed by at least 90%. In other embodiments, after administering a compound of the present disclosure, the contraction of the bladder detrusor 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%.

[0085] On the other hand, the present disclosure provides a method for treating or preventing OBS in a human subject by administering a compound of the present disclosure (e.g., a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof), wherein the compound acts by reducing the contraction frequency of the subject's bladder detrusor muscle. In some embodiments, after administering a compound of the present disclosure, the contraction frequency of the bladder detrusor muscle is reduced by at least 20%. In other embodiments, after administering a compound of the present disclosure, the contraction frequency of the bladder detrusor muscle is reduced by at least 30%. In other embodiments, after administering a compound of the present disclosure, the contraction frequency of the bladder detrusor muscle is reduced by at least 50%. In other embodiments, after administering a compound of the present disclosure, the contraction frequency of the bladder detrusor muscle is reduced by at least 70%. In other embodiments, after administering a compound of the present disclosure, the contraction frequency of the bladder detrusor muscle is reduced by at least 80%. In other embodiments, after administering a compound of the present disclosure, the contraction frequency of the bladder detrusor muscle is reduced by at least 90%. In certain embodiments, the frequency of contractions of the bladder detrusor muscle is reduced by about 20% to about 90%, about 30% to about 85%, about 40% to about 80%, or about 50% to about 70% following administration of a compound of the disclosure.

[0086] As used herein, the terms "treatment of", "treating" and related terms include improving, alleviating, mitigating, slowing down or stopping a disorder or symptom thereof by administering an effective amount of a compound of the present disclosure, such as a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (IA)). In some embodiments, treatment includes inhibiting the onset of a disorder (e.g., OBS) or a symptom thereof (e.g., urinary incontinence or nocturia) (e.g., reducing its overall frequency), or reducing the severity of a disorder or symptom thereof.

[0087] As used herein, the terms "prevention of", "preventing" and related terms include avoiding the onset of a disorder or its symptoms by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0088] When used in conjunction with the methods of the present disclosure, the term "effective amount" refers to the amount of a compound that, when administered to an animal (e.g., a human subject), provides the partial or complete therapeutic effect desired by the skilled artisan (e.g., a physician) by such administration.

[0089] When used in conjunction with the methods of the present disclosure, the term "therapeutically effective amount" refers to the amount of a compound administered to an animal (eg, a human subject) to provide the desired therapeutic effect.

[0090] Without being bound by any theory, it is believed that the compounds of the present disclosure exert their beneficial effects by modulating the ORL-1 receptor expressed on the afferent nerve fibers / terminals of the lower urinary tract. As used herein with respect to the ORL-1 receptor, the terms "modulate", "modulating" and related terms refer to mediating a pharmacodynamic response (e.g., OBS) in an animal 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 agonists / antagonists, mixed partial agonists / antagonists, and compounds that directly or indirectly affect the regulation of receptor activity. Compounds of formula (I) and (I') and pharmaceutically acceptable salts thereof (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, including a natural ligand, is defined as a "partial agonist". It is believed that the partial agonists of the present disclosure can achieve the desired therapeutic effect (eg, treatment of OBS) without any or with only a reduced number of concurrent side effects typically associated with the administration of full agonists.

[0091] As used herein, the term "eGFR" refers to estimated glomerular filtration rate (eGFR), which is calculated using the formula shown below:

[0092] eGFR = 142 x min(normalized Scr / k, 1) α x max(normalized Scr / k, 1) - 1200 x 0.9938 age x 1.012 [if female], where k for females is 0.7 and k for males is 0.9, α for females is -0.241 and α for males is -0.302, min represents the minimum value of Scr / k or 1, and max represents the maximum value of Scr / k or 1.

[0093] As used herein, a human subject with "no renal insufficiency" or "normal renal function" refers to a human subject with an eGFR of 90 mL / min or more.

[0094] As used herein, a human subject with "mild renal impairment" refers to a human subject with an eGFR of about 60 mL / min to about 89 mL / min.

[0095] As used herein, a human subject with "mild to moderate renal impairment" refers to a human subject with an eGFR of about 45 mL / min to about 59 mL / min.

[0096] The compounds of the present disclosure can be used as components of compositions comprising pharmaceutically acceptable carriers or excipients. The route of administration includes but is not limited to oral, intravesical, intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, epidural, transmucosal, buccal, gingival, sublingual, intraocular, intracerebral, intravaginal, transdermal (e.g., by patch), rectal, by inhalation or topical. In another embodiment, the route of administration includes but is not limited to intravenous, intravesical, oral or by 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 intravenous. In another embodiment, the route of administration is by inhalation.

[0097] In another embodiment, the compounds of the present disclosure can be delivered in a controlled release system or a sustained release system. As is well known in the art (e.g., the pharmaceutical industry), controlled or sustained release pharmaceutical compositions can improve drug therapy over drug therapy achieved by their non-controlled or non-sustaining counterparts (e.g., immediate release formulations). In one embodiment, a controlled or sustained release composition comprises a therapeutically effective amount of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof to treat or prevent OBS or its symptoms for an extended period of time. The advantages of a controlled or sustained release composition include extended drug activity, reduced dosing frequency, and increased compliance.

[0098] The administration of the disclosed compounds may be 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. Pat. Nos. 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, e.g., Goodson, "Dental Applications," Medical Applications of Controlled Release, Vol. 2, Applications and Evaluation, Langer and Wise, eds., CRC Press, Chapter 6, pp. 115-138 (1984), hereinafter "Goodson"). The devices described in Langer, Science 249 : 1527-1533 (1990) in the review of other controlled release or sustained release systems discussed. In one embodiment, a pump can be used (Langer, Science 249:1527-1533(1990); Sefton, "Implantable Pumps," CRCCrit.Rev.Biomed.Eng. 14(3) :201-240(1987); Buchwald et al., "Long-term, ContinuousIntravenous Heparin Administration by an Implantable Infusion Pump inAmbulatory 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, polymeric materials can be used (see 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 lesion-induced memory deficits," J. Neurosurg. 71 :105-112(1989)).

[0099] Suitable dosage forms can be used to provide controlled or sustained release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, ethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, multiparticles, liposomes, microspheres, or combinations thereof, to provide desired release profiles in varying proportions. Suitable controlled 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 the present disclosure. The present disclosure therefore encompasses single unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps, and caplets suitable for controlled or sustained release.

[0100] The composition may optionally but preferably also include an appropriate amount of pharmaceutically acceptable excipients to provide a form suitable for application to animals. Such pharmaceutical excipients may be diluents, suspending agents, solubilizing agents, binders, disintegrants, preservatives, colorants, lubricants, etc. Pharmaceutical excipients may be liquids, such as water or oils, including those oils from petroleum, animals, plants or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical excipients may be saline, gum arabic, gelatin, starch paste, talcum, keratin, colloidal silica, urea, etc. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants may be used. In one embodiment, when applied to animals, pharmaceutically acceptable excipients are sterile. When intravenously administering formula (I) compound or its pharmaceutically acceptable salt, water is a particularly useful excipient. Saline solutions and aqueous dextrose solutions and glycerol solutions may also be used as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. If necessary, the composition may also contain a small amount of wetting agent or emulsifier or pH buffer. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to prepare oral dosage forms are described in Handbook of Pharmaceutical Excipients (Amer. Pharmaceutical Ass'n, Washington, DC, 1986), which is incorporated herein by reference. Radebough et al., "Preformulation," pp. 1447-1676, Remington's Pharmaceutical Sciences Vol. 2 (Gennaro ed., 19th ed., Mack Publishing, Easton, PA, 1995) describes other examples of suitable pharmaceutical excipients, which are incorporated herein by reference.

[0101] In one embodiment, the compounds of the present invention are formulated into compositions suitable for oral administration to humans according to conventional procedures. The compounds of the present invention to be delivered orally may be in the form of, for example, tablets, capsules, capsule tablets, lozenges, aqueous or oily solutions, suspensions, particles, microparticles, multi-particles, powders, emulsions, syrups or elixirs. When the compounds of formula (I) or (I') or their pharmaceutically acceptable salts are incorporated into oral tablets, such tablets may be compressed, tablet ground, enteric coated, sugar coated, film coated, multiple compressed or multiple layered. The techniques and compositions for preparing solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman et al., ed., 2nd ed., Marcel Dekker, Inc., 1989 and 1990). King, "Tablets, Capsules, and Pills," pp. 1553-1593, Remington's Pharmaceutical Sciences (Osol, ed., 16th ed., Mack Publishing, Easton, PA, 1980) also describes techniques and compositions for making tablets (compression and molding), capsules (hard and soft gelatin), and pills.

[0102] Liquid oral dosage forms include aqueous and non-aqueous solutions, emulsions, suspensions, and solutions and / or suspensions reconstituted from non-effervescent granules, optionally containing 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., ed., 2nd ed., Marcel Dekker, Inc., 1996 and 1998).

[0103] Oral pharmaceutical compositions containing a compound of the present disclosure (e.g., a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof) may contain one or more excipients, such as sweeteners, such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, wintergreen oil or cherry; coloring agents; and preservatives to provide a pharmaceutically palatable formulation. In addition, in the case of tablet or pill form, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over an extended period of time. Selectively permeable membranes surrounding osmotically active driving compounds are also suitable for compositions for oral administration. In these latter platforms, fluid from the environment surrounding the capsule is absorbed by the driving compound, which swells to displace the agent or agent composition through the pores. These delivery platforms can provide a substantially zero-order delivery profile, in contrast to the tapered profile of an immediate release formulation. Time-delay materials such as glyceryl monostearate or glyceryl stearate may also be used. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

[0104] The composition can take the form of a solution, suspension, emulsion, tablet such as an orally disintegrating tablet (ODT) or a sublingual tablet, pill, pill, capsule, capsule containing a liquid, powder, sustained release formulation, suppository, emulsion, aerosol, spray, suspension, microparticles, multi-particles, fast dissolving film or other forms 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, e.g., U.S. Patent Nos. 7,749,533 and 9,241,910). In another embodiment, the composition is in the form of a sublingual tablet (see, e.g., U.S. Patent Nos. 6,572,891 and 9,308,175). In another embodiment, the composition is in the form of a capsule (see, e.g., U.S. Patent No. 5,698,155). In another embodiment, the composition is in a form suitable for buccal administration formulated in a conventional manner, for example in the form of a tablet, lozenge, gel, patch or film (see, e.g., Pather et al., "Current status and the future of buccaldrug 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, in the form of a polymer film comprising polyvinyl alcohol, chitosan, polycarbophil, hydroxypropyl cellulose or Eudragit S-100, as described in Padula et al., "In Vitro Evaluation of Mucoadhesive Films for Gingival Administration of Lidocaine," AAP S Pharm Sci Tech 14(4) : 1279-1283 (2013). In another embodiment, the composition is in a form suitable for intraocular administration.

[0105] In one embodiment, the compounds of the present disclosure are formulated for parenteral administration. When the compounds of the present disclosure are to be injected parenterally, they may, for example, be in the form of an isotonic sterile solution.

[0106] When the compounds of the present disclosure are administered parenterally, the preparations for parenteral administration may be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles. Such preparations may also contain pharmaceutically necessary additives, such as one or more stabilizers, suspending agents, dispersants, buffers, etc. The compounds of the present disclosure may also be in powder form to be reconstituted into injectable preparations.

[0107] In another embodiment, the compounds of the present disclosure may be formulated for intravenous administration. In certain embodiments, the composition for intravenous administration comprises a sterile isotonic aqueous buffer. If necessary, the composition may also comprise a solubilizing agent. The intravenous composition containing the compounds of the present disclosure may optionally comprise a local anesthetic, such as benzocaine or prilocaine, to relieve pain at the injection site. Typically, the components are provided separately or mixed together in unit dosage form, for example, in a sealed container, such as an ampoule or a sachet indicating the amount of the active agent as a dry lyophilized powder or anhydrous concentrate. In the case of a compound of the present disclosure to be administered by infusion, the compound may be, for example, dispensed with an infusion bottle containing pharmaceutical grade sterile water or saline. In the case of a compound of the present disclosure administered by injection, an ampoule of sterile water for injection or saline may be provided so that the components may be mixed before administration.

[0108] The compounds of the present disclosure (e.g., compounds of formula (I) or (I')) are mainly excreted from urine in a substantially unchanged form (see Example 2 below). Therefore, the compounds of formula (I) or (I') are mainly concentrated in the bladder after administration. For example, when orally administered, the compounds of formula (I) or (I') excreted in urine are in the range of about 30% to about 95%, depending on the dose administered. In addition, the concentration of the compounds of formula (I) or (I') in urine remains high for at least 24 hours after oral administration. In a specific embodiment, the concentration of the compounds of formula (I) or (I') is greater than 100 nM 12 hours after oral administration. In other embodiments, the concentration of the compounds of formula (I) or (I') is greater than 500 nM 12 hours after oral administration. In other embodiments, the concentration of the compounds 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') is greater than 5,000 nM 12 hours after oral administration. In other embodiments, the concentration of the compound of formula (I) or (I') is greater than 10,000 nM 12 hours after oral administration. In specific embodiments, the concentration of the compound of formula (I) or (I') may be in the range of about 100 nM to about 30,000 nM 12 hours after oral administration. In other embodiments, the concentration of the compound of formula (I) or (I') may be in the range of about 500 nM to about 15,000 nM 12 hours after oral administration. In other embodiments, the concentration of the compound of formula (I) or (I') may be in the range of about 1,000 nM to about 10,000 nM 12 hours after oral administration.

[0109] In some embodiments, the compound of formula (I) or formula (I') is administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein is any pharmaceutically acceptable salt (including inorganic and organic salts) that can be prepared from a compound of formula (I). Illustrative 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, bitartrates, ascorbates, succinates, maleates, gentisates, fumarates, gluconates, glucuronates, sugarates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). In one embodiment, the pharmaceutically acceptable salt is a hydrochloride, a sulfate, a sodium salt, a potassium salt, a benzenesulfonate, a p-toluenesulfonate, or a fumarate. In another embodiment, the pharmaceutically acceptable salt is a hydrochloride or a sulfate. In another embodiment, the pharmaceutically acceptable salt is a hydrochloride. In another embodiment, the pharmaceutically acceptable salt is a sulfate. In another embodiment, the pharmaceutically acceptable salt is a sodium salt. In another embodiment, the pharmaceutically acceptable salt is a potassium salt. In another embodiment, the pharmaceutically acceptable salt is a fumarate. In another embodiment, the pharmaceutically acceptable salt is a p-toluenesulfonate, i.e., a salt of p-toluenesulfonic acid (also referred to as "toluenesulfonate"). In another embodiment, the pharmaceutically acceptable salt is a choline salt.

[0110] In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains one equivalent of formula (I) or (I') compound 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 one equivalent of formula (I') compound and about one equivalent of p-toluenesulfonic acid, that is, it is a monotoluenesulfonate. In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains one equivalent (relative to the amount of p-toluenesulfonic acid) of formula (I) compound. In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains one equivalent of formula (I') compound. The monotoluenesulfonate salt of the compound of formula (I'), ie, the compound of formula (IA), is as follows:

[0111]

[0112] The methods of the present disclosure provided herein also encompass the use of any solvate of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof. "Solvate" is generally known in the art and is considered herein to be a combination, physical association and / or solvation of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof. Such physical association may involve varying degrees of ionic bonding and covalent bonding, including hydrogen bonding. When the solvate is of stoichiometric type, there is a fixed ratio of solvent molecules to a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof. A compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof may exist in a solvated form with a pharmaceutically acceptable solvent such as water (e.g., hydrate), methanol, ethanol, etc.

[0113] The methods of the present disclosure provided herein also encompass the use of any crystalline form (or polymorphic form) of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof. The term "crystalline" and related terms used herein, when used to describe a substance, component or product, refers to a substance, component or product that 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. The term "polymorph" as used herein refers to a crystalline form of a compound having different unit cell structures in a crystal, which is derived from a variety of molecular conformations and molecular packing. Polymorphs of a single compound may have one or more chemical, physical, mechanical, electrical, thermodynamic and / or biological properties that are different from each other. The differences in physical properties exhibited by polymorphs may affect drug parameters such as storage stability, compressibility, density (important in composition and product manufacturing), dissolution rate (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water absorption, compactability and particle morphology. Differences in stability may be due to changes in chemical reactivity (e.g., differential oxidation, causing a dosage form to change color more quickly when composed of one polymorph than when composed of another polymorph) or mechanical changes (e.g., crystal changes when a kinetically favored polymorph is converted to a thermodynamically more stable polymorph upon storage) or both (e.g., one polymorph is more hygroscopic than another).

[0114] In certain embodiments, the compound of formula (IA) has a crystalline form referred to as Form A, Form B, Form C, Form D, or Form E, as described in WO 2020 / 157691, the contents of which are incorporated herein by reference. In some embodiments, the compound of formula (IA) has Form A. In other embodiments, the compound of formula (IA) has Form B. In other embodiments, the compound of formula (IA) has Form C. In other embodiments, the compound of formula (IA) has Form D. In other embodiments, the compound of formula (IA) has Form E.

[0115] As used herein, the amount by weight of "dose", "dosage" and related terms administered refers to the free acid and free base forms, i.e., non-salt forms, of the compound of formula (I) or (I'). 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, a monohydrochloride salt or a 1:1 hydrochloride salt on a molar basis of a compound of formula (I) or (I') means that 10.84 mg of the compound is actually administered, wherein 10.84 mg provides 10.00 mg of the non-salt form of the compound of formula (I) or (I') (0.0229 mmol) and 0.84 mg of hydrochloric acid (0.0229 mmol). Likewise, a 10.00 mg dose of, for example, the monotosylate salt of the compound of formula (IA) (1:1 p-toluenesulfonate salt on a molar basis) means that 13.93 mg of the compound is actually administered, where 13.93 mg provides 10.00 mg of the non-salt form of the compound of formula (I) or (I') (0.0229 mmol) and 3.93 mg p-toluenesulfonic acid (0.0229 mmol).

[0116] For methods of treating or preventing a disorder or symptom in a human subject, a suitable effective dose of a compound of the present disclosure is from about 0.0002 mg / kg to about 10 mg / kg of human subject body weight / day in one embodiment, from about 0.00025 mg / kg / day to about 5 mg / kg / day in another embodiment, from about 1.5 mg / kg / day to about 3 mg / kg / day in another embodiment, from about 0.2 mg / kg / day to about 2 mg / kg / day in another embodiment, from about 2.5 mg / kg / day to about 10.0 mg / kg / day in another embodiment, and from about 3.0 mg / kg / day to about 5.0 mg / kg / day in another embodiment. In another embodiment, the effective dose is about 10 mg / kg / day or less. In certain embodiments, a suitable effective dose of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof is about 0.0002 mg / kg / day to about 10 mg / kg / day, about 0.001 mg / kg / day 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 another embodiment, the effective dose is about 1.0 mg / kg / day or less. In certain other embodiments, a suitable effective dose of a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof is from about 0.001 mg / kg / day to about 1.0 mg / kg / day, from about 0.002 mg / kg / day to about 0.8 mg / kg / day, from about 0.0025 mg / kg / day to about 0.5 mg / kg / day, from about 0.003 mg / kg / day to about 0.15 mg / kg / day, from about 0.006 mg / kg / day to about 0.12 mg / kg / day, or from about 0.010 mg / kg / day to about 0.10 mg / kg / day. It should be understood that for these doses, the term "day" refers to a 24-hour period starting from the time of administration of a compound of the present disclosure, e.g., a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof.

[0117] In embodiments where a compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (IA)) is administered orally, a suitable effective dose of the compound as a single dose is from about 0.001 mg to about 300 mg, from about 0.005 mg to about 250 mg, from about 0.01 mg to about 200 mg, from about 0.05 mg to about 150 mg, from about 0.075 mg to about 50 mg, or from about 0.10 mg to about 10 mg. In one embodiment, the compounds of the present disclosure are administered in a single dose in the form of a non-controlled or non-sustaining release formulation (e.g., an immediate release formulation). In another embodiment, the effective dose of the compounds of the present disclosure is administered in multiple doses in the form of a non-controlled or non-sustaining release formulation.

[0118] In certain embodiments, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.100 mg, about 0.120 mg, about 0.125 mg, about 0.150 mg, about 0.175 mg, about 0.200 mg, about 0.225 mg, about 0.250 mg, about 0.275 mg, about 0.30 mg, about 0.35 mg, about 0.40 mg, about 0.45 mg, about 0.50 mg, about 0.55 mg, about 0.60 mg, about 0.65 mg, about 0.70 mg, about 0.75 mg, about 0.80 mg, about 0.85 mg, about 0.90 In some embodiments, about 1 mg of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (IA)) is orally administered to a human subject in need thereof. In some embodiments, about 1 mg of a compound of formula (I) or (I') or an equivalent amount of a pharmaceutically acceptable salt thereof is orally administered to a human subject in need thereof. In some embodiments, about 1.5 mg of a compound of formula (I) or (I') or an equivalent amount of a pharmaceutically acceptable salt thereof is orally administered to a human subject in need thereof. As known to those skilled in the art, for human animals, a single daily dose (mg) can be converted to a mg / kg / day dose by dividing the mg dose by 60 kg (the average mass of human animals recognized in the art). For example, a single daily human dose of 12 mg is thus converted to a dose of about 0.20 mg / kg / day.

[0119] In certain embodiments, a controlled release composition comprising a therapeutically effective amount of a compound of the present disclosure is administered in a single dose or multiple doses. A controlled release composition may contain up to 100 times the dose of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (IA)) used in a non-controlled or non-sustained release formulation.

[0120] In some embodiments, the compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof can be administered once daily. In some such embodiments, the compound of Formula (I) or (I') is administered every night (e.g., before bedtime). As shown in Example 2, daily administration of the compound of Formula (I) or (I') results in urine concentrations that are higher than those measured by Ki and EC. 50 The measured in vitro activity of the compound of formula (IA) is several orders of magnitude greater.

[0121] In addition to its beneficial effects in treating or preventing diseases associated with overactive bladder, when administered at sufficient dosage levels, the compounds of the present disclosure can also induce sleepiness and treat sleep disorders. See U.S. Publication No. 2020 / 0345726, which is hereby incorporated by reference. Patients with symptoms associated with overactive bladder often suffer from poor sleep quality, insomnia and / or nocturia. In some embodiments, the patient with sleep disorder is a woman aged 50 or above. In other embodiments, the patient with sleep disorder is a man aged 50 or above. Applying formula (I) or (I') compound or its pharmaceutically acceptable salt every night improves sleep quality and symptoms associated with overactive bladder. In certain embodiments, formula (I) or (I') compound or its pharmaceutically acceptable salt is applied by the patient every night before going to bed. For example, formula (I) or (I') compound or its pharmaceutically acceptable salt can be applied from about 1 minute to about 3 hours before going to bed. In some embodiments, formula (I) or (I') compound or its pharmaceutically acceptable salt can be applied from about 5 minutes to about 60 minutes before going to bed. In other embodiments, the compound of Formula (I) or (I') or a pharmaceutically acceptable salt thereof may be administered from about 10 minutes to about 30 minutes before bedtime.

[0122] In one embodiment, an effective dose or dose of a compound of the present disclosure (e.g., a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof) is administered about 60 minutes before the median habitual bedtime of a person. In another embodiment, an effective dose or dose is administered about 45 minutes before the median habitual bedtime of a person. In another embodiment, an effective dose or dose is administered about 30 minutes before the median habitual bedtime of a person. In another embodiment, an effective dose or dose is administered about 20 minutes before the median habitual bedtime of a person. In another embodiment, an effective dose or dose is administered about 20 minutes or less before the median habitual bedtime of a person. In another embodiment, an effective dose or dose is administered about 15 minutes before the median habitual bedtime of a person. In another embodiment, an effective dose or dose is administered about 15 minutes or less before the median habitual bedtime of a person. In another embodiment, an effective dose or dose is administered about 10 minutes before the median habitual bedtime of a person. In another embodiment, an effective dose or dose is administered about 10 minutes or less before the median habitual bedtime of a person. In another embodiment, the effective dose or dose is administered about 5 minutes before the human's median habitual bedtime.

[0123] In certain embodiments, the compound of formula (I) or (I') or its pharmaceutically acceptable salt may be administered multiple times a day. For example, the compound of formula (I) or (I') or its pharmaceutically acceptable salt may be administered twice a day or three times a day. In embodiments where the compound is administered multiple times a day, each dose may be administered in the same amount or in a different amount. In some embodiments, the dose of the compound of formula (I) or (I') or its pharmaceutically acceptable salt is administered at a higher dose than other doses provided earlier in the day. In some embodiments, the compound of formula (I) or (I') or its pharmaceutically acceptable salt is administered twice a day, approximately once every 12 hours. In other embodiments, the compound of formula (I) or (I') or its pharmaceutically acceptable salt is administered three times a day, approximately once every 8 hours.

[0124] In certain embodiments, the compounds of the present disclosure are administered twice a day, wherein the second dose (i.e., the second therapeutically effective amount) is administered before bedtime, as described above. In some such embodiments, the second dose is administered in an amount higher than the first dose. For example, the second dose can be administered in an amount about 1.5 times, 2 times, 3 times, 5 times, 10 times, 20 times, 50 times, 100 times or 1000 times higher than the first dose. In some embodiments, the second dose can be administered in an amount about 1.5 times to about 10 times higher than the first dose. In other embodiments, the second dose can be administered in an amount about 1.5 times to about 100 times higher than the first dose. In other embodiments, the second dose can be administered in an amount about 1.5 times to about 1000 times higher than the first dose. In other embodiments, the second dose can be administered in an amount about 3 times to about 100 times higher than the first dose. In other embodiments, the second dose can be administered in an amount about 3 times to about 1000 times higher than the first dose. In other embodiments, the second dose can be administered in an amount about 5 times to about 100 times higher than the first dose. In other embodiments, the second dose can be administered in an amount about 5 times to about 1000 times higher than the first dose. Such a dosing schedule ensures that the first dose effectively treats or prevents OBS and symptoms associated with OBS without causing residual drowsiness, while the second dose effectively treats or prevents OBS and symptoms associated with OBS and causes drowsiness or induces sleep in human subjects. In certain embodiments, both the first dose and the second dose are administered by (the same or different) non-controlled or non-sustaining release formulations. In other embodiments, the first dose is administered by a controlled or non-sustaining release formulation, and the second dose is administered by a non-controlled or non-sustaining release formulation.

[0125] In another embodiment, a composition comprising a compound of the present disclosure can be used as a drug for treating a human subject suffering from OBS and a specific sleep disorder. Such sleep disorders include, but are not limited to, insomnia disorders, hypersomnia disorders, 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 disorders, daytime sleepiness-type alcohol-induced sleep disorders, parasomnia-type alcohol-induced sleep disorders, and mixed alcohol-induced sleep disorders); insomnia in alcohol use disorders; sleep disorders associated with alcohol withdrawal (e.g., insomnia associated with alcohol withdrawal); or any combination thereof. In one embodiment, a human subject suffers from OBS and insomnia associated with alcohol withdrawal.

[0126] Methods for treating or preventing lower urinary tract disorders (e.g., OBS) in human subjects (e.g., patients) in need thereof may also include co-administering a compound of the present 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, according to the methods of the present disclosure, the second therapeutic agent is administered in an effective amount to achieve the desired therapeutic effect. 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 trospium chloride. In separate embodiments, the antimuscarinic agent is solifenacin. In certain embodiments, the antimuscarinic agent is darifenacin. In other such embodiments, the antimuscarinic agent is flavoxate. Also disclosed herein is a method for treating overactive bladder syndrome in a human subject in need thereof, the method comprising administering to the human subject an effective amount of a compound of formula (I):

[0127]

[0128] Or a pharmaceutically acceptable salt thereof, wherein the human subject suffers from mild or mild to moderate renal impairment. In some embodiments, a human subject suffering from mild renal impairment may have an estimated glomerular filtration rate (eGFR) of about 60 mL / min to about 89 mL / min. In some embodiments, a human subject suffering from mild to moderate renal impairment may have an eGFR of about 45 mL / min to about 59 mL / min.

[0129] In some embodiments, administration of a compound of Formula (I) to a subject can result in at least a mean AUC, C max , T max , T 1 / 2 or CL / F and the corresponding mean AUC, C max , T max , T 1 / 2 As used herein, human subjects are considered "similarly situated" when they meet the same inclusion / exclusion criteria as other human subjects treated with the methods of the present disclosure and are also matched for other relevant characteristics in clinical studies (such as sex, age, weight, and body mass index).

[0130] As used herein, "AUC" refers to the area under the concentration-time curve. Cmax ” 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 systemic clearance.

[0131] In some embodiments, administration of a compound of Formula (I) to a subject may result in at least a mean AUC that is statistically indistinguishable from the corresponding mean AUC of a similarly situated human subject without renal insufficiency (or with normal renal function). In some embodiments, administration of a compound of Formula (I) to a subject may result in at least a mean C max The corresponding mean C of similarly situated human subjects without renal impairment max In some embodiments, administration of a compound of Formula (I) to a subject may result in a mean T of at least max The corresponding mean T values ​​for similarly situated human subjects without renal impairment were max In some embodiments, administration of a compound of Formula (I) to a subject may result in a mean T of at least 1 / 2 The corresponding mean T values ​​for similarly situated human subjects without renal impairment were 1 / 2 Statistically Not Different. In some embodiments, administration of a compound of Formula (I) to a subject can result in at least a mean CL / F that is not statistically different from the corresponding mean CL / F of similarly situated human subjects without renal insufficiency.

[0132] In some embodiments, administration of a compound of Formula (I) to a human subject can result in an average Ae, Fe or CL of at least R The corresponding mean Ae, Fe or CL of similarly situated human subjects without renal impairment R There was no statistical difference. As used herein, "Ae" refers to the amount of study drug excreted unchanged in the urine after administration of the study drug. As used herein, "Fe" refers to the fraction of study drug excreted in the urine, calculated as, for example (Ae 0-96 / dose). As used herein, "CL R ” refers to the estimated renal clearance of the study drug over the total collection interval (e.g., 0-96 hours), calculated as, for example (Ae 0-96 / AUC inf ).

[0133] In some embodiments, administration of a compound of Formula (I) to a human subject may result in at least a mean Ae that is not statistically different from the corresponding mean Ae of similarly situated human subjects without renal insufficiency. In some embodiments, administration of a compound of Formula (I) to a human subject may result in at least a mean Fe that is not statistically different from the corresponding mean Fe of similarly situated human subjects without renal insufficiency. In some embodiments, administration of a compound of Formula (I) to a human subject may result in at least a mean CL RThe corresponding mean CL in similarly situated human subjects without renal impairment R There was no statistical difference.

[0134] In some embodiments, the compound of formula (I) is a compound of formula (I'):

[0135]

[0136] or a pharmaceutically acceptable salt thereof. In some embodiments, the method may include administering a pharmaceutically acceptable salt of a compound of formula (I), wherein the salt is selected from the group consisting of sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

[0137] In some embodiments, the method may include administering a p-toluenesulfonic acid salt (ie, p-toluenesulfonate), sulfate, phosphate, or hydrochloride salt of a compound of formula (I). In some embodiments, a p-toluenesulfonic acid salt of a compound of formula (I) may be administered.

[0138] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IA):

[0139]

[0140] In some embodiments, the compound of formula (IA) can be administered orally, parenterally, intravenously, intramuscularly, buccally or transdermally. In some embodiments, the compound of formula (IA) can be administered orally. In some embodiments, the effective amount of the compound of formula (IA) can be from about 0.10 mg to about 10 mg. In some embodiments, the compound of formula (IA) can be administered once a day. In some embodiments, the compound of formula (IA) can be administered at night. In some embodiments, the compound of formula (IA) can be administered before bedtime. In some embodiments, the compound of formula (IA) can be administered twice a day. In some embodiments, the compound of formula (IA) can be administered approximately every 12 hours.

[0141] In some embodiments, the method may include administering a first effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof during the day, and administering a second effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof at night before the bedtime of the human subject. In some embodiments, the first effective amount may be a therapeutically effective amount and is the same as the second effective amount.

[0142] In some embodiments, the first effective amount and the second effective amount can be different. In some embodiments, the second effective amount can be about 2 times of the first effective amount. In some embodiments, the second effective amount can be about 10 times of the first effective amount.

[0143] In some embodiments, the administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof can increase the urination pressure threshold of a human subject by about 30% to 80%. In some embodiments, the method may further comprise administering to the human subject an effective amount of an antimuscarinic agent. In some embodiments, the antimuscarinic agent may be oxybutynin, tolterodine, trospium chloride, solifenacin, darifenacin, or a pharmaceutically acceptable salt of any of the foregoing.

[0144] The present disclosure provides additional embodiments.

[0145] A) A method of treating or preventing overactive bladder syndrome in a human subject in need of such treatment, said method comprising administering to said human subject a therapeutically effective amount of a compound of formula (I):

[0146]

[0147] or a pharmaceutically acceptable salt thereof.

[0148] B) A method according to embodiment A, wherein the compound is a compound of formula (I'):

[0149]

[0150] or a pharmaceutically acceptable salt thereof.

[0151] C) A method as described in embodiment A or embodiment B, wherein the method comprises 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, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate.

[0152] D) A method as described in any one of embodiments AC, wherein the method comprises administering a p-toluenesulfonate salt, sulfate salt, phosphate salt or hydrochloride salt of the compound.

[0153] E) The method according to any one of embodiments AD, wherein the p-toluenesulfonic acid salt of the compound is administered.

[0154] F) A method according to any one of embodiments AE, wherein the method comprises administering a compound of formula (IA):

[0155]

[0156] G) The method of any one of embodiments AF, wherein the human subject has a reduced frequency of urination.

[0157] H) The method of any one of embodiments AF, wherein the human subject experiences reduced episodes of nocturia.

[0158] I) A method of reducing nocturia in a human subject in need of such treatment, said method comprising administering to said human subject a therapeutically effective amount of a compound of formula (I):

[0159]

[0160] or a pharmaceutically acceptable salt thereof.

[0161] J) A method as described in embodiment I, wherein the compound is a compound of formula (I'):

[0162]

[0163] or a pharmaceutically acceptable salt thereof.

[0164] K) A method as described in embodiment I or embodiment J, wherein the method comprises 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, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate.

[0165] L) A method as described in any one of embodiments 1K, wherein the method comprises administering a p-toluenesulfonate, sulfate, phosphate or hydrochloride salt of the compound.

[0166] M) A method as described in any of embodiments IL, wherein the p-toluenesulfonate salt of the compound is administered.

[0167] N) A method according to embodiment M, wherein the method comprises administering a compound of formula (IA):

[0168]

[0169] O) A method as described in any one of embodiments AN, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally, parenterally, intravenously, intramuscularly, buccally or transdermally.

[0170] P) A method as described in any one of embodiments AO, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally.

[0171] Q) A method as described in any of embodiments AP, wherein the therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is about 0.001 mg to about 300 mg.

[0172] R) A method as described in any of embodiments AQ, wherein the therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is about 0.10 mg to about 10 mg.

[0173] S) A method according to embodiment R, wherein the compound or a pharmaceutically acceptable salt thereof is a compound of formula (IA):

[0174]

[0175] T) The method according to any one of embodiments AS, wherein the compound or a pharmaceutically acceptable salt thereof is administered once a day.

[0176] U) A method as described in any one of embodiments AT, wherein the compound or a pharmaceutically acceptable salt thereof is administered at night.

[0177] V) A method according to embodiment U, wherein the compound or a pharmaceutically acceptable salt thereof is administered before bedtime.

[0178] W) A method as described in any of embodiments PS, wherein the compound or a pharmaceutically acceptable salt thereof is administered twice a day.

[0179] X) A method as described in embodiment W, wherein the compound or a pharmaceutically acceptable salt thereof is administered approximately every 12 hours.

[0180] Y) A method as described in embodiment W or embodiment X, wherein the method comprises administering a first therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof during the day and administering a second therapeutically effective amount at night before the bedtime of the human subject.

[0181] Z) A method as described in embodiment Y, wherein the first therapeutically effective amount and the second therapeutically effective amount are the same.

[0182] AA) A method as described in embodiment Y, wherein the first therapeutically effective amount and the second therapeutically effective amount are different.

[0183] BB) A method as described in embodiment AA, wherein the second therapeutically effective amount is about 2 times the first therapeutically effective amount.

[0184] CC) A method as described in embodiment AA, wherein the second therapeutically effective amount is about 10 times the first therapeutically effective amount.

[0185] DD) The method of any one of embodiments A-CC, wherein administration of the compound or a pharmaceutically acceptable salt thereof increases the urination pressure threshold of the human subject by about 30% to 80%.

[0186] EE) The method of any one of embodiments A-DD, further comprising administering to the human subject an effective amount of an antimuscarinic agent.

[0187] FF) A method as described in embodiment EE, wherein the antimuscarinic agent is oxybutynin, tolterodine, trospium chloride, solifenacin and darifenacin or a pharmaceutically acceptable salt of any one of the foregoing.

[0188] GG) A method of treating or preventing overactive bladder syndrome in a human subject in need of such treatment, said method comprising administering to said human subject a therapeutically effective amount of a compound of formula (I):

[0189]

[0190] or a pharmaceutically acceptable salt thereof, wherein the patient also suffers from a sleep disorder.

[0191] HH) A method according to embodiment GG, wherein the compound is a compound of formula (I'):

[0192]

[0193] or a pharmaceutically acceptable salt thereof.

[0194] II) A method as described in embodiment GG or embodiment HH, wherein the method comprises 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, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate.

[0195] JJ) A method as described in any of embodiments GG-II, wherein the pharmaceutically acceptable salt is toluenesulfonate, sulfate, phosphate or hydrochloride.

[0196] KK) A method as described in any of embodiments GG-JJ, wherein the pharmaceutically acceptable salt is p-toluenesulfonate.

[0197] LL) A method as described in any one of embodiments GG-KK, wherein the method comprises administering the compound of formula (IA):

[0198]

[0199] MM) A method as described in any of embodiments GG-LL, wherein the human subject is a female 50 years of age or older.

[0200] NN) A method for treating a sleep disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I):

[0201]

[0202] or a pharmaceutically acceptable salt thereof, wherein the patient also suffers from urinary incontinence.

[0203] OO) A method according to embodiment NN, wherein the compound is a compound of formula (I'):

[0204]

[0205] or a pharmaceutically acceptable salt thereof.

[0206] PP) A method according to embodiment NN or embodiment OO, wherein the method comprises administering a compound of formula (IA):

[0207]

[0208] QQ) A method as described in any of embodiments NN-PP, wherein the sleep disorder is insomnia disorder, hypersomnia disorder, circadian rhythm sleep-wake disorder, alcohol-induced sleep disorder, insomnia related to alcohol withdrawal, or any combination thereof.

[0209] RR) A method of treating overactive bladder syndrome in a human subject in need thereof, the method comprising administering to the human subject an effective amount of a compound of formula (I):

[0210]

[0211] or a pharmaceutically acceptable salt thereof,

[0212] wherein the human subject suffers from mild or mild to moderate renal impairment.

[0213] SS) A method as described in embodiment RR, wherein the human subject with mild renal impairment has an estimated glomerular filtration rate (eGFR) of about 60 mL / min to about 89 mL / min.

[0214] TT) A method according to embodiment RR, wherein the human subject with mild to moderate renal impairment has an eGFR of about 45 mL / min to about 59 mL / min.

[0215] UU) A method as described in any of embodiments RR-TT, wherein administration of the compound of formula (I) to the subject results in at least a mean AUC, C max , T max , T 1 / 2 or CL / F and the corresponding mean AUC, C max , T max , T 1 / 2 There was no statistical difference in CL / F.

[0216] VV) A method as described in any of embodiments RR-UU, wherein administration of the compound of formula (I) to the human subject results in at least an average Ae, Fe or CL R The corresponding mean Ae, Fe or CL of similarly situated human subjects without renal impairment R There was no statistical difference.

[0217] WW) A method as described in any one of embodiments RR-VV, wherein the compound is a compound of formula (I'):

[0218]

[0219] or a pharmaceutically acceptable salt thereof.

[0220] XX) A method as described in any of embodiments RR-WW, wherein the method comprises administering a pharmaceutically acceptable salt of the compound of formula (I), wherein the salt is selected from the group consisting of sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate.

[0221] YY) A method as described in any of embodiments RR-XX, wherein the method comprises administering a p-toluenesulfonate, sulfate, phosphate or hydrochloride salt of the compound of formula (I).

[0222] ZZ) A method as described in any of embodiments RR-YY, wherein the p-toluenesulfonate salt of the compound of formula (I) is administered.

[0223] AAA) A method as described in any of embodiments RR-ZZ, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IA):

[0224]

[0225] BBB) A method according to embodiment AAA, wherein the compound of formula (IA) is administered orally, parenterally, intravenously, intramuscularly, buccally or transdermally.

[0226] CCC) A method as described in Embodiment AAA or Embodiment BBB, wherein the compound of Formula (IA) is administered orally.

[0227] DDD) A method as described in embodiment CCC, wherein the effective amount of the compound of formula (IA) is about 0.10 mg to about 10 mg.

[0228] EEE) A method as described in any of embodiments AAA-DDD, wherein the compound of formula (IA) is administered once a day.

[0229] FFF) A method as described in any of embodiments AAA-EEE, wherein the compound of formula (IA) is administered at night.

[0230] GGG) The method of any one of embodiments AAA-FFF, wherein the compound of formula (IA) is administered before bedtime.

[0231] HHH) A method as described in any of embodiments AAA-DDD, wherein the compound of formula (IA) is administered twice a day.

[0232] III) A method according to embodiment HHH, wherein the compound of formula (IA) is administered approximately every 12 hours.

[0233] JJJ) A method as described in embodiment HHH or embodiment III, wherein the method comprises administering a first effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof during the day, and administering a second effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof at night before the bedtime of the human subject.

[0234] KKK) A method as described in embodiment JJJ, wherein the first effective amount is a therapeutically effective amount and is the same as the second effective amount.

[0235] LLL) A method as described in embodiment JJJ, wherein the first effective amount and the second effective amount are different.

[0236] MMM) A method as described in embodiment LLL, wherein the second effective amount is about 2 times the first effective amount.

[0237] NNN) A method as described in embodiment LLL, wherein the second effective amount is about 10 times the first effective amount.

[0238] OOO) A method as described in any of embodiments AAA-NNN, wherein the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof increases the urination pressure threshold of the human subject by about 30% to 80%.

[0239] PPP) The method of any one of embodiments AAA-OOO, further comprising administering to the human subject an effective amount of an antimuscarinic agent.

[0240] QQQ) The method of embodiment PPP, wherein the antimuscarinic agent is oxybutynin, tolterodine, trospium chloride, solifenacin, darifenacin, or a pharmaceutically acceptable salt of any one of the foregoing.

[0241] Example

[0242] Example 1: Isochromic model for measuring the effect of the compound of formula (IA) on OBS

[0243] In rats, under isovolumetric conditions, bladder distension causes rhythmic bladder contractions (RBC) (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 isovolumetric model allows the evaluation of compounds on RBC. This is a closed system in which saline is slowly infused into the bladder through a urethral catheter until spontaneous rhythmic bladder contractions occur.

[0244] The aim of this study was to evaluate the effect of intravenous administration of compounds of formula (IA) on cystometric parameters in an isovolumetric model in anesthetized female rats. The effect of the test substance was compared with that of the reference substance tolterodine, an antimuscarinic receptor, marketed for the treatment of overactive bladder in humans.

[0245] Study Design

[0246] plan:

[0247] The animals were anesthetized with urethane (ip).

[0248] The ureters are ligated and cut close to the kidneys.

[0249] An intravesical catheter is inserted into the bladder through the urethra.

[0250] Seal the urethra.

[0251] - The jugular vein was cannulated for compound administration.

[0252] Fill the bladder with saline until RBCs appear.

[0253] After a 30-minute basal period, compounds were administered as follows

[0254] The effect of the test substance appears 1 hour after administration.

[0255] Experimental Group:

[0256] Three (3) experimental groups were included, as described in Table 1 below:

[0257] Table 1

[0258] Group Treatment (iv) n 1 Vehicle (20% 2-hydroxypropyl-β-cyclodextrin) 10 2 Compound of formula (IA) (3 mg / kg) 10 3 Tolterodine (1 mg / kg) 10

[0259] 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.

[0260] animal:

[0261] All experiments were performed in accordance with European Communities Council Directive 2010 / 63 / UE and French Ministry of Agriculture, Agro-products and Forestry Decree 2013-118.

[0262] Female Sprague-Dawley rats were adapted to laboratory conditions for at least 3 days before the start of the experiment. The animals were housed in polysulfone Sealsafe plus 1291H cages (Tecniplast, Lyon, France) on wood chip beds (Souralit, Girona, Spain) in groups of 3 with free access to food (rodent maintenance diet A04 / 10 from Safe) and water (0.2 μm filtered water). Appropriate environmental enrichment species (Aspen brick, Plexx, Uden, Netherlands) were added to the cages. The animal room was kept artificially lit (12 h) at a controlled ambient temperature of 22°C ± 2°C between 7:00am and 7:00pm, and the relative humidity was maintained at 55% ± 10%.

[0263] Test substance

[0264] Weigh an appropriate amount of the compound of formula (I) and dissolve it in a vehicle to obtain a dosing solution with a target concentration of 3 mg / mL (free base form). The dosing preparation (3 mL) was stored in a refrigerator for up to 3 days. The mother solution was used as is for a 3 mg / kg dose.

[0265] A 20% (w / v) HP-β-CD aqueous solution was prepared by dissolving 10 g 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) (Sigma-Aldrich, Saint-Quentin Fallavier, France, batch number BCBV0722) in 50 mL water for injection (WFI). The vehicle was prepared one week.

[0266] Tolterodine was prepared fresh on the day of administration at a final concentration of 1 mg / mL (free base form). An appropriate amount of tolterodine was weighed and dissolved in vehicle (20% HP-β-CD) at room temperature.

[0267] Urethane was purchased from Sigma-Aldrich. Purchased from Vetoquinol via Centravet (Lapalisse, France). Saline purchased from B-Braun via Centravet. WFI was supplied by Cooper (Melun, France).

[0268] Study plan

[0269] Rats were anesthetized by intraperitoneal administration of urethane (1 g / kg). The ureters were ligated and cut near the kidneys. Before urethral ligation, a catheter (internal and external diameters of 0.30 mm and 0.70 mm, respectively) was inserted into the bladder through the urethral orifice. Another catheter (internal and external diameters of 0.58 mm and 0.96 mm, respectively) was inserted into the jugular vein for intravenous (iv) administration.

[0270] For all groups, animals were treated by iv route (1 mL / kg) (slow bolus) after a basal period.

[0271] Cystometry assessment:

[0272] The bladder catheter is connected to a strain gauge (to measure the intravesical pressure) and a syringe via a T-tube. Isovolumetric bladder contraction is induced by gradually injecting room temperature saline (100 μL every 5 minutes) until stable RBCs appear. Bladder pressure is continuously recorded. After a 30-minute control period (basal value), the substance or vehicle is administered iv. The effect of the substance is tracked during 60 minutes after administration. At the end of the experiment, the animals are killed by cervical dislocation.

[0273] Laboratory Equipment:

[0274] Animals were weighed using a LS620C balance (Precisa, Dietikon, Switzerland).

[0275] Surgery was performed using a SX45 binocular microscope (Fisher Scientific, Illkirch, France). A temperature control system set at 37°C was used during surgery (TCAT-2LV controller, Physitemp Instruments, Clifton, NJ, USA).

[0276] For cystometry, intravesical pressure was measured using a strain gauge MX960P1 (Smiths Medical, Rungis, France) and a PowerLab / 8-30 or 8-35 data acquisition system (ADInstruments Pty Ltd) and Software version 7.3.7 continues to log.

[0277] Results presentation and analysis

[0278] The following parameters were analyzed:

[0279] RBC amplitude (mmHg)

[0280] RBC frequency (number / 30 minutes)

[0281] Suppression time (seconds)

[0282] like Figure 8 As shown, cystometric parameters were analyzed for each RBC during a 30-minute period before administration (basal values) and during a full 60-minute period after administration. The % change from basal values ​​was calculated for RBC frequency and amplitude.

[0283] Statistical analysis:

[0284] Using GraphPad (GraphPad Software Inc., La Jolla, CA, USA) for statistical analysis and graphs. p values ​​< 0.05 were considered statistically significant. One-way ANOVA followed by Turkey's test was used to compare the basal values ​​of RBC frequency and amplitude for all groups. Paired Student's t-test or Wilcoxon test was used to compare the basal and treatment periods of RBC frequency and amplitude for each group. Kruskal Wallis or one-way ANOVA followed by Dunn's or Dunn's test was used to compare the % change in RBC frequency, inhibition time or inhibition amplitude relative to basal values ​​for tolterodine and compound of formula (IA) with the vehicle group.

[0285] result

[0286] There was no significant difference in the basal values ​​of RBC frequency among all experimental groups (p>0.05, Figure 1A). Within 30 minutes, the basal values ​​of RBC frequency in the vehicle group, the compound of formula (IA) group, and the tolterodine group were 25.90±1.91, 25.90±1.36, and 23.00±0.87, respectively (Tables 2 to 4).

[0287] There was no significant difference in the basal values ​​of RBC amplitude among all experimental groups (p>0.05, Figure 1 B). The basal values ​​of RBC amplitude in the vehicle group, the compound of formula (IA) group, and the tolterodine group were 29.13±3.02, 29.49±2.46, and 27.22±2.03 mmHg, respectively (Tables 2 to 4).

[0288] Table 2: Effects of vehicle (1 mL / kg, iv, n=10) on RBC frequency, RBC amplitude and inhibition time in anesthetized female rats

[0289]

[0290] Table 3: Effects of Cpd(IA) (3 mg / kg, iv, n=8-10) on RBC frequency, RBC amplitude and inhibition time in anesthetized female rats

[0291]

[0292] Note: For the Cpd(IA) group, since there were no RBCs after administration, the RBC amplitudes of only 8 rats were averaged.

[0293] Table 4: Effects of tolterodine (1 mg / kg, iv, n=10) on RBC frequency, RBC amplitude and inhibition time in anesthetized female rats

[0294]

[0295] Vehicle (1 mL / kg, iv), compound of formula (IA) (3 mg / kg, iv) and tolterodine (1 mg / kg, iv) significantly reduced RBC frequency (p<0.05 and p<0.0001, Figure 2 ABC, Table 2-4).

[0296] After treatment with vehicle, compound of formula (IA) and tolterodine, the RBC frequency values ​​during 0 / 60 minutes after the treatment period were 18.50±2.42, 3.05±1.02 and 15.30±2.72 RBC / 30 minutes, respectively ( Figure 2 ABC, Table 2-4).

[0297] After treatment with the compound of formula (IA) (3 mg / kg, iv), RBC frequency was significantly decreased (p<0.0001, Figure 3 , Table 3), while tolterodine (1 mg / kg, iv) did not significantly change the RBC frequency (p>0.05, Figure 3 , Table 4). After treatment with the compound of formula (IA), the reduction in RBC frequency reached -88.57±3.68%, while the reductions after vehicle and tolterodine treatment were -28.18±7.30% and -33.93±10.93%, respectively ( Figure 3 , Tables 2 to 4).

[0298] Compared with basal values, vehicle and tolterodine significantly reduced RBC amplitude (p<0.05 and p<0.01, Figure 4 A-4C, Tables 2 to 4). No significant effect on RBC amplitude was observed after administration of the compound of formula (IA) (p>0.05, Figure 4 B, Table 3).

[0299] Tolterodine (1 mg / kg, iv) significantly reduced RBC amplitude compared with vehicle (p<0.001, Figure 5 and Tables 2 to 4), while the compound of formula (IA) (3 mg / kg) did not significantly change the RBC amplitude (p>0.05, Figure 5 and Tables 2-3). The percentage change of RBC amplitude relative to the basal value after tolterodine was -30.83±5.24%, while that of the vehicle group was -5.18±2.12%.

[0300] Compared with vehicle, the compound of formula (IA) (3 mg / kg, iv) significantly increased the inhibition time (p<0.01, Figure 6 and Table 3), while no significant difference in inhibition time was observed after tolterodine treatment (p>0.05, Figure 6 and Table 4). The inhibition times of the vehicle group, the compound of formula (IA) group, and the tolterodine group were 422.89±113.60 seconds, 2860.51±272.38 seconds, and 87.04±31.06 seconds, respectively.

[0301] Typical records of the effects of vehicle, compound of formula (IA) and tolterodine are presented in Figure 7 A, 7B and 7C.

[0302] The results of Example 1 show that the compound of formula (IA) significantly reduces bladder afferent activity. On the other hand, tolterodine has no effect on afferent activity but effectively inhibits bladder efferent activity.

[0303] Example 2: Pharmacokinetic study of the compound of formula (IA)

[0304] Urine concentrations of humans (9 humans in total) were evaluated up to 48 hours after administration of a single oral dose of the compound of formula (IA) in the form of a methylcellulose suspension (also known as Cpd (IA)). Urine samples of individual subjects (combined serial samples of all excreted urine) were collected at the following time intervals for determination of the concentration of the compound of formula (IA): 0 to 8 hours, 8 to 16 hours, 16 to 24 hours, 24 to 32 hours, and 40 to 48 hours after administration. A summary of urine concentrations of the compound of formula (IA) for individual subjects and by treatment and time interval is provided in Table 5 below.

[0305] Table 5: Summary of individual subjects and urine concentrations of Cpd(IA)

[0306]

[0307] LLOQ = 100 ng / mL = 229 nM

[0308] In vitro activity against human pain receptors; Ki = 2.45 nM, EC 50 =4.0nM

[0309] Table 5 shows the mean urine 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) of the compound of formula (IA). Table 5 shows that even at the lowest dose (0.2 mg) of the compound of formula (IA), the urine concentration was higher than that measured by Ki and EC. 50 The measured in vitro activity of the compound of formula (IA) is several orders of magnitude greater.

[0310] Example 3: Effects of the compound of formula (IA) on cystometric parameters in female rats (SCI model)

[0311] Spinal cord injury (SCI) causes significant changes in bladder function in multiple species including rats and humans. In rats, SCI interrupts the reflex pathways for voluntary urination and control of bladder and sphincter function, resulting in bladder reflex anisocoria and inability to urinate. Two weeks after spinal cord injury, the urination reflex reappears, but there is competition between the bladder and the urethral sphincter and there is bladder expansion that causes detrusor hyperreflexia. The development of spinal reflex pathways enables rats to urinate, proving that neurotransmission reappears (Cheng et al., 1995, Yoshiyama et al., 1999).

[0312] Abnormal reflex pathways coupled with coordination problems between the bladder and the sphincter lead to bladder hypertrophy, poor urination, and detrusor overactivity (de Groat & Yoshimura., 2010). Studies have shown that SCI at the thoracic level of rats increases non-voiding contractions (NVC) frequency and bladder capacity, and reduces urination efficiency (Yoshiyama et al., 1999, Kadekawa et al. 2017, Wada et al., 2017, Wada et al., 2018). Rat SCI is also characterized by bladder hypertrophy. Therefore, this model is widely used to evaluate substances specifically for neurogenic bladder dysfunction. In addition, the β3-adrenergic receptor agonist CL-316,243 was shown to significantly increase bladder capacity and reduce the frequency of NVC (Beauval et al., 2015).

[0313] The aim of this study was to evaluate the effects of intragastric (ig) administration of the compound of formula (IA) ("Cpd(IA)") (30 mg / kg) on ​​cystometric parameters in conscious SCI rats. The effects of the test substance were compared with those of the reference substance, the β3-adrenergic receptor agonist mirabegron (marketed for the treatment of overactive bladder).

[0314] Study Design

[0315] Solution Design

[0316] At W-5, a spinal cord injury was performed at the T8 level as described below.

[0317] During W-5, rats were treated with gentamicin daily.

[0318] · During W-5 and W-4, manually empty your bladder once a day.

[0319] • From W-5 to W0, animals were weighed once a week.

[0320] On D-2 (W0), catheter implantation was performed under isoflurane anesthesia as described below.

[0321] On D0 (W0), perform cystometry

[0322] The planned scheme of the scheme design is provided in Fig. 9 middle.

[0323] Experimental Group:

[0324] There are four (4) experimental groups as described in the following table:

[0325] Table 6

[0326] Group Operation Treatment (ig) n 1 Sham operation Vehicle (5 mL / kg) 12 2 SCI Vehicle (5 mL / kg) 11 3 SCI Cpd(IA)(30mg / kg) 12 4 SCI Mirabegron (10 mg / kg) 13

[0327] Before the start of the experiment, animals were randomly assigned to treatment groups. The randomization design was such that there was at least one animal in each group on each experimental day. At the end of the experiment, the animals were tracked, but some were lost.

[0328] Female Sprague-Dawley rats were adapted to laboratory conditions for at least 3 days before the start of the experiment. Animals were housed individually for two weeks after SCI surgery, then housed in polysulfone Sealsafe plus 1291H cages (Tecniplast, Lyon, France) on wood chip beds (Souralit, Girona, Spain) in groups of 2 (until catheter implantation) and individually (until cystometry), with free access to food (rodent maintenance diet A04 / 10 from Safe) and water (0.2 μm filtered water). Appropriate environmental enrichment species (Aspen brick, Plexx, Uden, Netherlands) were added to the cage. Artificial lighting (12 h) was maintained in the animal room at a controlled ambient temperature of 22 ° C ± 2 ° C between 7:00 am and 7:00 pm, and relative humidity was maintained at 55% ± 10%.

[0329] Preparation of test materials:

[0330] A stock solution of the compound of formula (IA) was prepared in the vehicle at a final concentration of 6 mg / mL (free base form). An appropriate volume of the vehicle was slowly added to the weighed compound of formula (IA) in a porcelain mortar and the powder was ground with a pestle until a suspension was obtained. Aliquots of the suspension were prepared (1 aliquot / application) and stored at +4°C for up to 3 days. On each experimental day, the suspension was equilibrated to room temperature for at least 30 minutes before application.

[0331] The vehicle was 0.5% methylcellulose (MC). It was prepared in water for injection (WFI) and stored at 4°C for 1 week. MC (lot number SLBR8963V) was purchased from Sigma-Aldrich (Saint-Quentin Fallavier, France).

[0332] Mirabegron was prepared fresh on the day of administration at a final concentration of 2 mg / mL (free base form). An appropriate mass of mirabegron was weighed and dissolved in the vehicle at room temperature.

[0333] Study plan

[0334] SCI surgery:

[0335] Rats were anesthetized with isoflurane (3%). The body temperature was kept constant at 37°C throughout the operation by placing the animals on a temperature-controlled hot plate. Laminectomy was performed and the spinal cord was cut at the T8 level with micro scissors. Care was taken to ensure that the section was intact by verifying that a slight retraction occurred in both segments. The muscles were then sutured and the skin was fixed with staples. The scar was cleaned with Vetedine. For the sham group, the same operation was performed, but the spinal cord was not cut.

[0336] The bladder was squeezed once a day for 14 days, and the abdomen was gently massaged until the urination reflex was restored. In addition, they were given gentamicin (2 mg / mL, 0.2 ml / rat) intramuscularly every day for one week. Animals were euthanized if they reached the humane endpoint: weight loss of more than 20% of their body weight and / or abnormal behavioral changes indicating pain and distress (prostration, self-mutilation, aggression).

[0337] Procedure for cystomanometry:

[0338] Rats were anesthetized with isoflurane (3%). The body temperature was kept constant at 37°C throughout the operation by placing the animals on a temperature-controlled hot plate. A polyethylene catheter (inner and outer diameters of 0.58 mm and 0.96 mm, respectively) was implanted into the bladder through the bladder dome to record intravesical pressure. Another catheter (inner and outer diameters of 0.58 mm and 0.96 mm, respectively) was implanted into the stomach for intragastric administration. The catheter was externalized at the level of the scapula. After surgery, each rat was housed individually until the end of the program with free access to food and water.

[0339] Animals were kept in partial restraints in restraint devices. For sham-operated or SCI rats, saline was infused into the bladder at a constant flow rate of 2 or 6 mL / h, respectively. At least 45 minutes later (corresponding to 3 complete urination cycles of the basal value), the test substance was administered by the intragastric route. Then, the intravesical pressure was recorded for 90 minutes.

[0340] At the end of the experiment, Rats were sedated with sodium pentobarbital (0.3–0.5 mL / rat, 182.2 mg / mL; ip) and then euthanized by cervical dislocation. The bladders were then collected and weighed.

[0341] Results and Analysis

[0342] Enter all raw data into All data entered were compared with the original data by two people before data analysis. Results are expressed as mean ± standard error of the mean (sem).

[0343] The following cystometric parameters were analyzed (see Fig.10 ):

[0344] ·Mid-urination amplitude (AM, mmHg)

[0345] Threshold pressure (ThP, mmHg)

[0346] • Inter-contraction interval (ICI, seconds): the time between basal pressure and ThP. Due to the different infusion rates between sham and SCI rats, ICI did not occur. Only ICI was analyzed to calculate bladder capacity.

[0347] Bladder capacity (BC, mL) BC = ICI x infusion rate

[0348] Non-voiding contraction amplitude (NVC, mmHg)

[0349] Frequency of NVC (number per minute).

[0350] NVC is defined as an increase in intravesical pressure exceeding 1.5 mmHg without urine leakage.

[0351] Using GraphPad Statistical analysis and graphs were performed using GraphPad Software Inc., La Jolla, CA, USA. Before any statistical test, the data were tested for normal distribution (Shapiro-Wilk normality test) and their variances were assessed (F test or Bartlett test for two or more groups, respectively). Appropriate statistical tests were therefore applied.

[0352] For each cystometric parameter and each time period, comparisons were made as follows:

[0353] ○ Unpaired Student's t test was used to compare the basal values ​​of each cystometric parameter between the sham / vehicle group and the SCI / vehicle group.

[0354] ○ Baseline values ​​of each cystometric parameter were compared across all SCI groups using one-way ANOVA or Kruskal-Wallis test

[0355] ○ The three 30-min intervals after treatment were compared with the corresponding baseline values ​​for each cystometric parameter within the same group using repeated measures one-way analysis of variance or Friedman's test followed by Dunn's or Dunn's post hoc test, respectively.

[0356] o The three 30-min intervals after treatment were compared between all SCI groups for each cystometric parameter relative to vehicle using one-way ANOVA or Kruskal Wallis test followed by Holm-Sidak or Dunn's post hoc test, respectively.

[0357] Research findings:

[0358] The basal values ​​of BC, AM, NVC frequency, NVC amplitude, and bladder weight in the SCI / vehicle group were significantly higher than those in the sham / vehicle group (p<0.01, Fig.11 In contrast, there was no significant difference in the basal value of ThP (p>0.05, Fig.11 ).

[0359] Fig.12 The results showed that there were no significant differences in the basal values ​​of BC, ThP, AM, NVC frequency and NVC amplitude among all experimental SCI groups (p>0.05).

[0360] In sham-operated rats, vehicle (5 mL / kg, ig) significantly decreased BC in the 0-30 min interval and significantly increased BC in the last interval (60-90 min) after administration (p<0.01 and p<0.001, respectively, Fig.13 A).

[0361] In SCI rats, vehicle (5 mL / kg, ig) and mirabegron (10 mg / kg, ig) did not significantly alter BC (p>0.05, Fig.13 B and C). In SCI rats, Cpd(IA) (30 mg / kg, ig) significantly reduced BC at the 0-30 and 30-60 min intervals after administration (p<0.001, Fig.13 D).

[0362] Fig.14 A shows that no significant difference in BC was observed between the mirabegron and Cpd(IA) groups (p>0.05, expressed in mL). Fig.14 B shows that Cpd(IA) (30 mg / kg, ig) significantly reduced BC in the 0-30 min interval after administration (p<0.05, expressed as % change relative to basal values). In fact, the % change of BC relative to basal values ​​in the SCI / Cpd(IA) group and the SCI / vehicle group was -35±7% and -0.4±15%, respectively. After mirabegron treatment, BC did not change significantly (p>0.05, Fig.14 B).

[0363] In sham-operated and SCI rats, vehicle (5 mL / kg, ig) did not significantly alter ThP (p>0.05, Fig.15 A and 15B). In SCI rats, mirabegron (10 mg / kg, ig) significantly reduced ThP in the 60-90 min interval after administration (p<0.05, Fig.15 C). In SCI rats, no significant effect on ThP was observed after Cpd(IA) treatment (p>0.05, Fig.15 D).

[0364] Fig.16 AB showed that ThP did not change significantly after mirabegron or Cpd(IA) treatment.

[0365] In sham-operated and SCI rats, vehicle (5 mL / kg, ig) had no significant effect on AM (p>0.05, Fig.17 AB). In SCI rats, mirabegron (10 mg / kg, ig) and Cpd(IA) (30 mg / kg, ig) did not significantly change AM (p>0.05, Fig.17 There was no significant change in AM after mirabegron or Cpd(IA) treatment (p>0.05, Fig.18 AB).

[0366] In sham-operated rats, vehicle (5 mL / kg, ig) did not significantly alter NVC frequency (p>0.05, Fig.19 A). In SCI rats, vehicle (5 mL / kg, ig) significantly reduced NVC frequency in the 30-60 and 60-90 min intervals (p<0.05, Fig.19 B). Mirabegron (10 mg / kg, ig) significantly reduced the frequency of NVCs in the 30-60 and 60-90 min intervals in SCI rats (p<0.01 and p<0.05, Fig.19 C). In SCI rats, Cpd(IA) (30 mg / kg, ig) significantly decreased the NVC frequency in the 0-30 and 60-90 min intervals (p<0.05 and p<0.01, Fig.19 D).

[0367] Fig. 20 AB showed that the frequency of NVC did not change significantly after treatment with mirabegron or Cpd(IA).

[0368] In sham-operated rats, vehicle (5 mL / kg, ig) did not significantly alter NVC amplitude (p>0.05, Fig.21A). In SCI rats, vehicle (5 mL / kg, ig) significantly reduced NVC amplitude in the 60-90 min interval after administration (p<0.05, Fig.21 B). Mirabegron (10 mg / kg, ig) did not significantly change the NVC amplitude in SCI rats (p>0.05, Fig.21 C). In SCI rats, Cpd(IA) (30 mg / kg, ig) significantly decreased the NVC amplitude at the 30-60 and 60-90 min intervals after administration (p<0.05 and p<0.001, Fig.21 D).

[0369] Fig. 22 AB showed that NVC amplitude did not change significantly after mirabegron or Cpd(IA) treatment (p>0.05, expressed as mmHg or as % change from basal value).

[0370] In sham-operated rats, vehicle (5 mL / kg, ig) decreased BC immediately after administration and increased BC during the 60-90 minute interval compared to basal values. The effect on BC after administration may be due to the effect of the vehicle itself, while the increase in BC during the 60-90 minute interval after administration is due to a time effect. In SCI rats, vehicle (5 mL / kg, ig) had an effect on NVC frequency and NVC amplitude during the last post-administration interval, confirming an effect of the vehicle itself or a time effect.

[0371] As expected, mirabegron (10 mg / kg, ig) slightly but significantly reduced NVC frequency compared to basal values ​​(Beauval et al., 2015).

[0372] The compound of formula (IA) (30 mg / kg, ig) significantly reduced the frequency of NVCs in the 0-30 and 60-90 minute intervals after administration compared to basal values. This is an expected effect for a substance specifically used for overactive bladder (OAB). Cpd (IA) also significantly reduced BC in the 0-30 minute interval after administration compared to vehicle, which is not an expected effect for the treatment of OAB.

[0373] Example 4: Effects of the compound of formula (IA) on cystometric parameters in female rats (BOO model)

[0374] Bladder outlet obstruction (BOO) in rats is a well-known model of overactive bladder (OAB). According to the literature (Lluel et al., 1998), BOO causes bladder hypertrophy and overactive bladder, which is characterized by an increase in the frequency and amplitude of BC, AM, and NVC. In this model, it has been previously shown thatβ3 The receptor agonist mirabegron reduces the frequency of NVCs (Gillespy et al., 2012).

[0375] The aim of this study was to evaluate the effect of intragastric (ig) administration of the compound of formula (IA) ("Cpd(IA)") (30 mg / kg) on ​​cystometric parameters in conscious BOO rats. The effect of the test substance was compared with that of the reference substance, mirabegron (marketed for the treatment of overactive bladder).

[0376] Study design

[0377] At W-6, a partial ligation of the urethra was performed.

[0378] On W-6, gentamicin and Treated Rats. Manual bladder emptying once daily.

[0379] From W-6 to W-1, animals were monitored and weighed weekly.

[0380] On W0 (D-2), the catheter was implanted under isoflurane anesthesia.

[0381] On D0, cystometry was performed.

[0382] Animals and Test Substances:

[0383] Female Sprague-Dawley rats were acclimated to laboratory conditions for at least 3 days before the start of the experiment. Animals were housed in polysulfone Sealsafe plus 1291H cages (Tecniplast, Lyon, France) on wood chip beds (Souralit, Girona, Spain) in groups of 2 or 3 and individually (until cystometry) with free access to food (rodent maintenance diet A04 / 10 from Safe) and water (0.2 μm filtered water). Appropriate environmental enrichment species (Aspenbrick, Plexx, Uden, Netherlands) were added to the cages. The animal room was kept artificially lit (12 h) at a controlled ambient temperature of 22°C ± 2°C between 7:00am and 7:00pm, and relative humidity was maintained at 55% ± 10%.

[0384] An appropriate amount of Cpd(IA) was weighed and dissolved in vehicle to give a dosing solution with a target concentration of 3 mg / mL (free base form). The stock solution was used as is for the 3 mg / kg dose.

[0385] The vehicle was 0.5% methylcellulose (MC). It was prepared in water for injection (WFI) and stored at 4°C for 1 week. MC (lot number SLBR8963V) was purchased from Sigma-Aldrich (Saint-Quentin Fallavier, France).

[0386] For intravenous administration, 20% (w / v) HP-β-CD aqueous solution was prepared by dissolving 10 g 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) (Sigma-Aldrich, batch number BCBV0722) in 50 mL of WFI. Mirabegron (from Kemprotec) was freshly prepared on the day of administration at a final concentration of 2 mg / mL (free base form). An appropriate amount of Mirabegron was weighed and dissolved in a vehicle (0.5% MC) at room temperature.

[0387] The following table provides six (6) experimental groups:

[0388] Table 7

[0389] Group Operation treat n 1 Sham operation Vehicle (5 mL / kg, ig) 10 2 BOO Vehicle (5 mL / kg, ig) 10 3 BOO Cpd(IA)(30mg / kg, ig) 10 4 BOO Mirabegron (10 mg / kg, ig) 10 5 BOO Vehicle (1 mL / kg, iv) 9 6 BOO Cpd(IA)(3mg / kg, iv) 9

[0390] Results of intragastric (ig) administration

[0391] The basal values ​​of BC, AM, NVC frequency, NVC amplitude and bladder weight in the BOO / vehicle group were significantly higher than those in the sham / vehicle group (p<0.05). In contrast, there was no significant difference in the basal values ​​of ThP (p>0.05).

[0392] There were no significant differences in the basal values ​​of BC, ThP, AM, NVC frequency, NVC amplitude, and bladder weight among all experimental BOO groups, including vehicle (5 mL / kg, ig), mirabegron (10 mg / kg, ig), and Cpd(IA) (30 mg / kg, ig).

[0393] For the entire period 0-90 minutes:

[0394] In sham and BOO rats, we noted no significant effect of vehicle on BC compared to basal values. In BOO rats, mirabegron did not significantly alter BC, whereas Cpd(IA) significantly reduced BC. No significant differences in BC were observed in the mirabegron and Cpd(IA) groups compared to vehicle, expressed in mL. Cpd(IA) significantly reduced BC, expressed as % change from basal values. The % change in BC from basal values ​​in the BOO / Cpd(IA) group and the BOO / vehicle group were -13±6% and 11±6%, respectively. BC did not change significantly after mirabegron treatment.

[0395] Compared with basal values, vehicle had no significant effect on THP in sham-operated and BOO rats (p>0.05), while mirabegron and Cpd(IA) did not change THP (p>0.05). Compared with vehicle, THP, expressed in mmHg, did not change significantly after mirabegron or Cpd(IA) treatment (p>0.05). Expressed as % change from basal values, THP was significantly reduced after Cpd(IA) treatment (p<0.05), while no significant effect was observed after mirabegron treatment (p>0.05).

[0396] In sham-operated rats, vehicle significantly increased AM compared with basal values ​​(p<0.01). In BOO rats, vehicle had no significant effect on AM (p>0.05), while mirabegron and Cpd(IA) did not significantly alter AM (p>0.05). AM was not significantly altered after mirabegron or Cpd(IA) treatment compared with vehicle, expressed in mmHg or as % change from basal values ​​(p>0.05).

[0397] Vehicle did not significantly alter NVC frequency compared to basal values ​​in sham and BOO rats (p>0.05). Mirabegron significantly reduced NVC frequency in BOO rats (p<0.01). Cpd(IA) did not affect NVC frequency in BOO rats (p>0.05). NVC frequency was not significantly altered following mirabegron or Cpd(IA) treatment compared to vehicle, expressed as number of NVCs / min or as % change from basal values ​​(p>0.05).

[0398] In all experimental groups, vehicle, mirabegron and Cpd(IA) did not change NVC amplitude compared to basal values ​​(p>0.05). NVC amplitude, expressed in mmHg, did not change significantly after mirabegron or Cpd(IA) treatment compared to vehicle (p>0.05). Expressed as % change from basal values, NVC amplitude was significantly reduced only after mirabegron treatment and remained unaffected by Cpd(IA) (p<0.05 and p>0.05).

[0399] For 60-90 minute intervals:

[0400] In sham-operated rats, vehicle significantly increased BC compared with basal values ​​(p<0.001). In BOO rats, 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). No significant differences in BC were observed in the mirabegron and Cpd(IA) groups, expressed in mL, compared to vehicle (p>0.05). Cpd(IA) significantly reduced BC (p<0.05), expressed as % change from basal values, while no significant differences were observed after mirabegron treatment (p>0.05).

[0401] In sham and BOO rats, vehicle had no significant effect on THP compared with basal values ​​(p>0.05). In BOO rats, mirabegron had no effect on THP (p>0.05), whereas Cpd(IA) significantly reduced THP (p<0.01). Compared with vehicle, THP, expressed in mmHg, did not change significantly after mirabegron or Cpd(IA) treatment (p>0.05). Expressed as % change from basal values, THP was significantly reduced after mirabegron or Cpd(IA) treatment (p<0.05).

[0402] In sham-operated rats, vehicle significantly increased AM compared with basal values ​​(p<0.01). In BOO rats, vehicle had no significant effect on AM (p>0.05), while mirabegron and Cpd(IA) did not significantly alter AM (p>0.05). No effect on AM was observed after mirabegron or Cpd(IA) treatment compared with vehicle, expressed as mmHg or as % change from basal values ​​(p>0.05).

[0403] In sham and BOO rats, no significant effect on NVC frequency was observed after vehicle compared to basal values ​​(p>0.05). In BOO rats, mirabegron significantly reduced NVC frequency (p<0.01), whereas Cpd(IA) did not affect NVC frequency (p>0.05). NVC frequency, expressed as number of NVCs / min or as % change from basal values, was not affected after mirabegron or Cpd(IA) treatment compared to vehicle (p>0.05).

[0404] In sham and BOO rats, vehicle did not significantly alter NVC amplitude compared to basal values ​​(p>0.05). In BOO rats, mirabegron significantly reduced NVC amplitude (p<0.05), while Cpd(IA) had no effect on NVC amplitude. NVC amplitude, expressed in mmHg, was not significantly altered after mirabegron or Cpd(IA) treatment compared to vehicle (p>0.05). NVC amplitude, expressed as % change from basal values, was not significantly altered after Cpd(IA) treatment, while mirabegron significantly reduced NVC amplitude (p>0.05 and p<0.05, respectively).

[0405] Results of intravenous (iv) administration

[0406] There were no significant differences in the baseline values ​​of BC, ThP, AM, NVC frequency, NVC amplitude, and bladder weight between the two experimental BOO groups, including the vehicle group (1 mL / kg, iv) and the Cpd(IA) group (3 mg / kg, iv) (p>0.05, Fig.23 ).

[0407] Results for the entire period 0-90 minutes:

[0408] Compared with basal values, vehicle and Cpd(IA) did not significantly alter BC in BOO rats (p>0.05, Fig.24 A and 24B). No significant difference in BC was observed in the Cpd(IA) group compared to vehicle, expressed in mL (p>0.05, Fig.25 Cpd(IA) significantly reduced BC (p<0.01, Fig.25 B).

[0409] No significant effect on ThP was observed after vehicle and Cpd(IA) treatment compared with basal values ​​(p>0.05, Fig.28 A and 28B). ThP, expressed in mmHg, did not change significantly after Cpd(IA) treatment compared to vehicle (p>0.05, Fig.29 A). Expressed as % change relative to basal values, ThP decreased after Cpd(IA) treatment, with a p value approaching significance (p=0.0504, Fig.29 B).

[0410] Compared with basal values, vehicle and Cpd(IA) did not significantly alter AM in BOO rats (p>0.05, Fig.32 Compared with vehicle, AM was not significantly altered after Cpd(IA) treatment (p>0.05, Fig.33 A and 33B).

[0411] Compared with basal values, vehicle and Cpd(IA) did not affect NVC frequency in BOO rats (p>0.05, Fig.36 A and 36B). NVC frequency was not significantly altered after Cpd(IA) treatment compared to vehicle, expressed as number of NVCs / min or as % change from basal values ​​(p>0.05, Fig.37 A and 37B).

[0412] Compared with basal values, vehicle and Cpd(IA) did not change NVC amplitude (p>0.05, Fig.40A and 40B). NVC amplitude was not significantly altered after Cpd(IA) treatment compared to vehicle, expressed in mmHg and as % change from basal values ​​(p>0.05, Fig.41 A and 41B).

[0413] Results for the 60-90 minute interval:

[0414] Compared with basal values, neither vehicle nor Cpd(IA) had a significant effect on BC in BOO rats (p>0.05, Fig.26 A and 26B). No significant differences in BC were observed in the Cpd(IA) group compared to vehicle, expressed as mL and as % change from basal values ​​(p>0.05, Fig. 27 A and 27B).

[0415] In BOO rats, vehicle had no significant effect on ThP compared with basal values ​​(p>0.05, Fig.30 In contrast, Cpd(IA) significantly decreased ThP (p<0.05, Fig.30 B). ThP expressed in mmHg did not change significantly after Cpd(IA) treatment compared to vehicle (p>0.05, Fig.31 A). ThP was significantly decreased after Cpd(IA) treatment (p<0.05, Fig.31 B).

[0416] Compared with basal values, vehicle and Cpd(IA) did not significantly alter AM in BOO rats (p>0.05, Fig.34 A and 34B). No effect on AM was observed after Cpd(IA) treatment compared to vehicle, expressed as mmHg or as % change relative to basal values ​​(p>0.05, Fig.35 A and 35B).

[0417] Compared with basal values, no significant effect on NVC frequency was observed after vehicle and Cpd(IA) in BOO rats (p>0.05, Fig.38 A and 38B). NVC frequency, expressed as number of NVCs / min or as % change from basal values, was not affected after Cpd(IA) treatment compared to vehicle (p>0.05, Fig.39 A and 39B).

[0418] Compared with basal values, vehicle and Cpd(IA) had no effect on NVC amplitude in BOO rats (p>0.05, Fig.42A and 42B). NVC amplitude was not significantly altered after Cpd(IA) treatment compared to vehicle, expressed in mmHg and as % change from basal values ​​(p>0.05, Fig.43 A and 43B).

[0419] in conclusion:

[0420] In sham-operated rats, vehicle (5 mL / kg, ig) increased BC only in the 60-90 minute interval compared to basal values. These effects on BC after administration may be due to time effects. Vehicle also significantly increased AM in the entire period (90 minutes) and the last interval (60-90 minutes) compared to basal values. In BOO rats, vehicle (5 mL / kg, ig) had no effect on all cystometric parameters, allowing for the presence of confounding factors when evaluating the test substances.

[0421] As expected, mirabegron (10 mg / kg, ig) significantly increased BC (compared to basal values) and decreased NVC amplitude and frequency compared to vehicle and basal values ​​(Gillespy et al., 2012).

[0422] As observed in the SCI model study, Cpd(IA)(ig) significantly reduced BC and ThP compared to vehicle. The observed effect on ThP could explain the reduction in bladder capacity, as urination occurs at lower intravesical pressures. The significant decrease in BC after treatment is similar to the results obtained in SCI rats.

[0423] In BOO rats, vehicle (1 mL / kg, iv) had no effect on all cystometric parameters, allowing for the presence of confounding factors when evaluating the test substances. As observed in the SCI study and when administered intragastrically to BOO rats, Cpd(IA)(iv) significantly reduced BC and ThP compared to vehicle and had no effect on all other cystometric parameters.

[0424] These results suggest that the differences in effects observed in SCI and BOO rats compared with normal rats (isovolumetric model) may be due to the different involvement of afferent fibers due to remodeling in pathological models (SCI and BOO rats) ( De Groat, 1995 , De Groat & Yoshimura, 2010 , Aizawa et al., 2017 ).

[0425] Example 5: Phase 1b, blinded, placebo-controlled crossover study to evaluate the effect of oral administration of a compound of formula (IA) in female human subjects with overactive bladder

[0426] The study consisted of a screening / washout period (up to 4 weeks), a single-blind placebo run-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).

[0427] The study design is summarized in Table 8:

[0428] Table 8

[0429]

[0430] A Visit 3, Day -1, is the end of the single-blind run-in period and the beginning of the double-blind treatment period. At Visit 3, subjects who have met all inclusion / exclusion criteria, met all randomization eligibility criteria, and completed all study procedures will be given double-blind study medication and instructed to take the first dose at bedtime that evening.

[0431] B Telephone contact was made during clinic visits to assess tolerability and review diaries / dosing instructions.

[0432] Screening / Washout Period: Informed consent was obtained from each subject prior to performing any study procedures in this study. Evaluation of study eligibility criteria began at the Screening Visit (Visit 1) and included medical history, physical examination, vital signs, clinical laboratory tests, urine culture, pregnancy test, and drug screen. If washout of contraindicated medications was required, such washout was completed during the Screening / Washout Period.

[0433] Subjects discontinued current medications for OAB while continuing any ongoing nonclinical treatments (which may include timed voiding and behavior modification therapies, dietary restrictions, and stress reduction) in a similar and consistent manner throughout the study.

[0434] There is no minimum number of screening days, and subjects can enter the run-in period as long as they meet the eligibility criteria.

[0435] Single-blind run-in period: Eligible subjects will enter the single-blind run-in period (Visit 2). Subjects must still have overactive bladder symptoms after wiping out previous overactive bladder medications. During the run-in period, subjects are instructed to take 1 tablet of study medication every night at bedtime.

[0436] Participants used urination diaries and other assessments to record their personal symptoms related to OAB. Participants completed the Symptom Impact Sleep Questionnaire (SISQ) in the morning.

[0437] During the week prior to the next clinic visit (Visit 3), subjects recorded the time, type, and urgency of urination for each episode for a minimum of 3 days and a maximum of 7 days.

[0438] At visit 3, subjects will be assessed for eligibility for randomization. Prior to randomization, eligibility is confirmed to the clinical center by an algorithm that takes into account the micturition component recorded during the run-in period. In addition, the PI confirms that the subject has not taken any medication for the treatment of OAB symptoms (except study medication) during the run-in period and that all diaries are completed correctly according to the protocol.

[0439] Visit 3, Day -1, marks the end of the single-blind run-in period and the beginning of the double-blind treatment period.

[0440] Double-blind treatment period: At visit 3, subjects who continued to meet eligibility criteria and met all randomization eligibility criteria were randomized into the study and dispensed double-blind study medication with instructions to take the first dose at bedtime that evening. Subjects attended clinic visits every 2 weeks and were required to have telephone contact on days 1 and 15 and at least once per week between clinic visits to assess tolerability and review diaries / dosing instructions.

[0441] During the week prior to each clinic visit (Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8), subjects recorded the time, type, and urgency of urination for each episode for a minimum of 3 days and a maximum of 7 days.

[0442] At clinic visits, subjects completed efficacy / safety and other assessments.

[0443] Single-blind washout period: Subjects follow the assessment. During the week prior to the clinic visit (Visit 8), subjects recorded the time, type, and urgency of urination for each episode for a minimum of 3 days and a maximum of 7 days.

[0444] End of Treatment (EOT) / Early Termination (ET): Subjects underwent EOT procedures at the end of double-blind treatment or when they discontinued the study early. If the assessments required by the EOT were performed on the same day as study completion or the same day as the ET, and study drug was not administered after those assessments, those assessments were not repeated.

[0445] Follow-up Period / End of Study (EOS): A follow-up call was completed approximately one week after the last dose of study drug to monitor AEs and concomitant medications / therapies since the last visit.

[0446] Inclusion criteria:

[0447] 1. Female, aged ≥18 years and able to urinate independently. A woman is eligible to participate if she is not pregnant, not breastfeeding and meets at least one of the following conditions: unless a woman has undergone a hysterectomy, tubal ligation or is at least one year postmenopausal, she is considered to be of childbearing potential; or Female participants of childbearing potential must agree to use reliable contraceptive methods during the trial and for 30 days after the end of the study, which have a failure rate of less than 1% per year when used continuously and correctly, such as implants, injections, combined oral contraceptives, certain intrauterine devices [IUDs], abstinence or vasectomy of the partner.

[0448] 2. Symptoms of overactive bladder, including urinary urgency and frequency, with or without incontinence, for ≥ 3 months.

[0449] 3. Willing to discontinue current medications for overactive bladder (including anticholinergics and beta-3 antagonists) and other contraindicated medications (including antipsychotics, opioids, GABA receptor analogs / modulators / agonists, and renal transport inhibitors), while continuing any ongoing nonclinical treatments (which may include timed voiding and behavior modification therapy, dietary restrictions, and stress reduction) in a similar and consistent manner throughout the study.

[0450] 4. Overall health as determined by the clinical center investigator based on the results of medical history, physical examination, 12-lead ECG, and laboratory test results.

[0451] 5. Ability to understand consent forms and communicate effectively with researchers.

[0452] 6. Voluntarily provide written informed consent and be willing and able to complete all study procedures, including electronic diaries and study-related questionnaires.

[0453] Exclusion criteria:

[0454] 1. UTI, including bacterial cystitis, in the past 30 days, or a history of recurrent UTI, defined as 3 or more documented episodes in the past 6 months.

[0455] 2. Identify hematuria associated with bladder malignancy or other significant pathology.

[0456] 3. Have ever undergone surgery affecting bladder function, surgery for bladder incontinence, urethral surgery, or received botulinum toxin bladder injection in the past 6 months.

[0457] 4. Initiated use of a neuromodulatory device for the sacral and / or pudendal nerves (e.g., Interstim) within the past 9 months. Subjects with a history of cutaneous nerve stimulation for OAB are eligible if the device was initiated >9 months ago and the subject has been stable for the past 6 months with approval by the Medical Monitor.

[0458] 5. Have clinically significant outflow obstruction (determined by the investigator at their discretion).

[0459] 6. Having an indwelling urinary catheter or self-intermittent catheterization.

[0460] 7. Detrusor abnormality due to neurological causes and / or diabetic neuropathy, and / or uncontrolled diabetes. Subjects with early or controlled diabetes are eligible based on A1C records and approval of the medical monitor.

[0461] 8. Chronic inflammation (e.g., interstitial cystitis), bladder stones, previous pelvic radiation therapy, or previous / current pelvic organ malignancy (within the pelvic area). Cyclophosphamide or chemical cystitis, or tuberculosis, or pelvic radiation or active genital herpes or vaginitis.

[0462] 9. Patients with grade III / IV pelvic organ prolapse with or without cystocele or urethral diverticulum.

[0463] 10. Patients with moderate to severe hepatic impairment, defined as Child-Pugh class B or C.

[0464] 11. Any history and / or current evidence of other medical (e.g., cardiac, respiratory, gastrointestinal, renal malignancies, excluding basal cell carcinoma), neurological, or psychiatric disorders that the investigator believes may affect the safety of the subject or interfere with study assessments or may interfere with drug absorption, distribution, metabolism, or excretion (including any surgical intervention for weight loss).

[0465] 12. Positive results on the Columbia-Suicide Severity Rating Scale (C-SSRS), or current or past suicidal ideation / behavior. Positive results on the C-SSRS include, but are not limited to, the following: suicidal ideation related to actual intent and methods or plans in the past year (answered “yes” to item 4 or 5 of the C-SSRS); history of suicidal behavior in the past 5 years (answered “yes” to any suicidal behavior item on the C-SSRS); or any lifetime history of severe or recurrent suicidal behavior.

[0466] 13. Current or recent (within the past 6 months) history of drug abuse or dependence, or diagnosis of substance use disorder.

[0467] 14. Current or past clinically significant renal disease or renal dysfunction, or kidney stones (discovery or symptoms within the past 3 years) or estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m 2 .

[0468] 15. Received medication in a clinical drug study during the 30 days prior to the screening visit.

[0469] Randomization criteria

[0470] At Visit 3, subjects met the following randomization criteria to be eligible for the double-blind treatment period: subjects had to have (i) urinated 8 or more times per day (24 hours) and (ii) urinated 1 or more times per day (24 hours) with an urgency grade of ≥1 on at least 3 days of urination diaries.

[0471] Study Treatment:

[0472] Table 9 provides details of the treatments administered.

[0473] Table 9. Treatments Administered

[0474]

[0475]

[0476] Lifestyle considerations:

[0477] Sleep / Wake Pattern: Subjects were encouraged to continue to maintain a consistent sleep / wake pattern during the study.

[0478] Meals and Dietary Restrictions: During the study, subjects were instructed to maintain a regular daily meal schedule and not to change their usual diet (eg, to begin a weight loss program).

[0479] Caffeine, Alcohol, and Tobacco: Instruct enrolled subjects to limit their intake of caffeine and alcohol. Subjects who smoke will be encouraged not to change the number of cigarettes they smoke per day during their participation in the study.

[0480] Concomitant / Contraindicated Medications:

[0481] During the Screening / Washout Period, subjects discontinued all current medications for OAB while continuing any ongoing behavioral therapy in a similar / consistent manner throughout the study. Any OAB medications were discontinued at least 7 days prior to the start of the single-blind run-in period.

[0482] Any prohibited medications were discontinued at least 7 days prior to the start of the single-blind run-in period. If a medication does not belong to the indicated drug class, the medical monitor was consulted to determine whether its use was permitted.

[0483] Study endpoints:

[0484] A list of study objectives and endpoints is described in Table 10.

[0485] Table 10. Objectives and endpoints

[0486]

[0487]

[0488] Example 6: A Phase 1, Non-Randomized, Open-Label, Parallel-Group Study to Evaluate the Effect of Mild Renal Impairment on Single-Dose Pharmacokinetics and Safety of the Compound of Formula (IA)

[0489] Research design (methodology):

[0490] This was a phase 1, non-randomized, open-label, parallel-group, single-dose study. A total of 20 subjects (10 subjects with mild renal impairment and 10 healthy subjects with normal renal function) were studied.

[0491] At screening, subjects were assigned to study groups based on estimated glomerular filtration rate (eGFR), which was calculated using the Chronic Kidney Disease Epidemiology Initiative 2021 (CKD-EPI 2021) formula as shown in Table 11 below:

[0492] Table 11. Study groups

[0493]

[0494] Abbreviation: eGFR, estimated glomerular filtration rate.

[0495] 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%).

[0496] All subjects were screened within 28 days prior to enrollment, entered the clinical center one day prior to study drug administration (Day -1), and received a single oral dose of the compound of Formula (IA) on Day -1.

[0497] After an overnight fast of at least 10 hours, a single oral dose of the compound of formula (IA) in the form of a 1.0-mg immediate-release tablet was administered in the morning with 240 mL of water. Subjects remained fasting for 4 hours after study drug administration (except for diabetic subjects, who were allowed to eat a light breakfast 2 hours after study drug administration at the discretion of the investigator). Subjects were restricted from drinking water 2 hours before and 2 hours after administration, except as part of study drug administration. At all other times during the study, subjects were able to drink water at will.

[0498] Subjects underwent end-of-study (EOS) procedures and were discharged from the clinical site on Day 5 (or in case of early discontinuation). Subjects received a follow-up call 7 to 10 days after the EOS. Fig.44 Diagram showing the study design.

[0499] Inclusion / Exclusion Criteria:

[0500] Male and female subjects aged 18 to 70 years (inclusive) who are considered by the investigator to be suitable for participation in this clinical study and have no clinically significant medical history, except for a history related to impaired renal function or other stable concomitant medical conditions (only for subjects with impaired renal function).

[0501] Drug concentration measurement:

[0502] For all subjects, blood samples were collected before dosing and up to 96 hours after dosing to analyze the concentration of the compound of formula (IA). Blood samples were collected before dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours after dosing to determine the plasma concentration of the compound of formula (IA).

[0503] Pharmacokinetic results:

[0504] For all subjects, plasma concentrations at 72 and 96 hours were below the limit of quantitation (concentration = 0 pg / mL), therefore, Figures 45-47 depict plasma concentrations from 0 to 48 hours after treatment administration.

[0505] Fig.45A Depicted are the mean plasma concentration versus time curves on a linear scale for subjects with normal renal function (n=10) and subjects with mild renal impairment (n=10). Fig.45B Mean plasma concentration versus time curves on a semi-logarithmic scale are depicted for subjects with normal renal function (n=10) and subjects with mild renal impairment (n=10).

[0506] Fig.46A Plasma concentration versus time curves on a linear scale are depicted for individual subjects (n=10) with impaired renal function. Fig.46BPlasma concentration versus time curves on a semi-logarithmic scale are depicted for individual subjects (n=10) with impaired renal function. Fig.47A Plasma concentration versus time curves on a linear scale are depicted for individual subjects (n=10) with normal renal function. Fig.47B Plasma concentration versus time curves for individual subjects (n=10) with normal renal function are depicted on a semi-logarithmic scale.

[0507] As shown in Figures 45-47, following administration of one 1.0-mg immediate release tablet of the compound of Formula (IA), the plasma concentrations over time in subjects with mild renal impairment were comparable to those in subjects with normal renal function.

[0508] Although the subject matter of the present disclosure has been described with reference to illustrative embodiments and examples, the description is not intended to be interpreted in a limiting sense. Therefore, various modifications of the illustrative embodiments, as well as other embodiments of the present invention, will be apparent to those skilled in the art upon reference to this specification. Therefore, it is contemplated that the appended claims will cover any such modifications or embodiments.

[0509] All publications, patents, and patent applications mentioned herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0510] References:

[0511] ·FDA 2019 Draft Guidance Document.Interstitial Cystitis / Bladder PainSyndrome (IC / BPS): Establishing Effectiveness of Drugs for Treatment Guidance for Industry.

[0512] ·Bosch PC.Examination of the Significant Placebo Effect in theTreatment of Interstitial Cystitis / Bladder Pain Syndrome.Urology 2014;84(2):321-325

[0513] ·Beauval JB et al.,2015.Comparison of the effects ofβ3-adrenoceptoragonism on urinary bladder function in conscious,anesthetized,and spinal cordinjured rats.Neurourol Urodyn.34:578-585.

[0514] ·Cheng C et al.,1995.Effect of capsaicin on micturition andassociated reflexes in chronic spinal rats.Brain Research 678:40-48.

[0515] ·De Groat WC,1995.Mechanism underlying the recovery of lower urinarytract function following spinal cord injury.Paraplegia 33:413-501.

[0516] ·De Groat WC&Yoshimura N.,2010.Changes in afferent activity afterspinal cord injury.Neurourol Urodyn.29:63-76.

[0517] ·Kadekawa K et al.,2017.Effects of an alphal A / D-adrenoceptorantagonist,naftopidil,and a phosphodiesterase type 5 inhibitor,tadalafil,onurinary bladder remodeling in rats with spinal cord injury.NeurourolUrodyn.36:1488-1495.

[0518] ·Wada N et al.,2017.Combination effects of muscarinic receptorinhibition and β3-adrenoceptor stimulation on neurogenic bladder dysfunctionin rats with spinal cord injury.Neurourol Urodyn.36:1039-1045.

[0519] ·Wada N et al.,2018.Urodynamic effects of intravenous andintrathecal administration of E-series prostaglandin 1 receptor antagonist ondetrusor overactivity in rats with spinal cord injury.Neurourol Urodyn.37:132-137.

[0520] ·Yoshiyama M et al.,1999.Changes in micturition after spinal cordinjury in conscious rats.Urology.54:29-933.

[0521] ·Aizawa N et al.,2017.Characteristics of the MechanosensitiveBladder Afferent Activities in Relation With Microcontractions in Male RatsWith Bladder Outlet Obstruction.Sci Rep 7:7646

[0522] ·De Groat WC,1995.Mechanism underlying the recovery of lower urinarytract function following spinal cord injury.Paraplegia 33:413-501.

[0523] ·De Groat WC&Yoshimura N.,2010.Changes in afferent activity afterspinal cord injury.Neurourol Urodyn.29:63-76.

[0524] ·Gillespie J.et al.,2012 Modulation of non-voiding activity by themuscarinergic antagonist tolterodine and theβ(3)-adrenoceptor agonistmirabegron in conscious rats with partial outflow obstruction.BJUInternational 110:132-142

[0525] ·Lluel P.et al.,1998.Experimental bladder instability followingbladder outlet obstruction in the female rat.J Urol.160:2253-2257.

Claims

1. A method of treating or preventing overactive bladder syndrome in a human subject in need of such treatment, the method comprising administering to the human subject a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the compound is a compound of formula (I'): or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or claim 2, wherein the method comprises 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, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

4. The method of any one of claims 1 to 3, wherein the method comprises administering a p-toluenesulfonate, sulfate, phosphate or hydrochloride salt of the compound.

5. The method of any one of claims 1-4, wherein the p-toluenesulfonic acid salt of the compound is administered.

6. The method of any one of claims 1 to 5, wherein the method comprises administering a compound of formula (IA):

7. The method of any one of claims 1-6, wherein the human subject has a reduced frequency of urination.

8. The method of any one of claims 1-6, wherein the human subject has reduced episodes of nocturia.

9. A method of reducing nocturia in a human subject in need of such treatment, the method comprising administering to the human subject a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein the compound is a compound of formula (I'): or a pharmaceutically acceptable salt thereof.

11. The method of claim 9 or claim 10, wherein the method comprises 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, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

12. The method of any one of claims 9 to 11, wherein the method comprises administering a p-toluenesulfonate, sulfate, phosphate or hydrochloride salt of the compound.

13. The method of any one of claims 9 to 12, wherein the p-toluenesulfonic acid salt of the compound is administered.

14. The method of claim 13, wherein the method comprises administering a compound of formula (IA):

15. The method of any one of claims 1-14, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally, parenterally, intravenously, intramuscularly, buccally or transdermally.

16. The method of any one of claims 1-15, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally.

17. The method of any one of claims 1-16, wherein the therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is from about 0.001 mg to about 300 mg.

18. The method of any one of claims 1-17, wherein the therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is from about 0.10 mg to about 10 mg.

19. The method of claim 18, wherein the compound or a pharmaceutically acceptable salt thereof is a compound of formula (IA):

20. The method of any one of claims 1 to 19, wherein the compound or a pharmaceutically acceptable salt thereof is administered once daily.

21. The method of any one of claims 1-20, wherein the compound or a pharmaceutically acceptable salt thereof is administered at night.

22. The method of claim 21, wherein the compound or a pharmaceutically acceptable salt thereof is administered before bedtime.

23. The method of any one of claims 16 to 19, wherein the compound or a pharmaceutically acceptable salt thereof is administered twice daily.

24. The method of claim 23, wherein the compound or a pharmaceutically acceptable salt thereof is administered approximately every 12 hours.

25. The method of claim 23 or 24, wherein the method comprises administering a first therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof during the day and administering a second therapeutically effective amount at night before the human subject's bedtime.

26. The method of claim 25, wherein the first therapeutically effective amount and the second therapeutically effective amount are the same.

27. The method of claim 25, wherein the first therapeutically effective amount and the second therapeutically effective amount are different.

28. The method of claim 27, wherein the second therapeutically effective amount is about 2 times greater than the first therapeutically effective amount.

29. The method of claim 27, wherein the second therapeutically effective amount is about 10 times greater than the first therapeutically effective amount.

30. The method of any one of claims 1-29, wherein administration of the compound or a pharmaceutically acceptable salt thereof increases the urination pressure threshold of the human subject by about 30% to 80%.

31. The method of any one of claims 1-30, further comprising administering to the human subject an effective amount of an antimuscarinic agent.

32. The method of claim 31, wherein the antimuscarinic agent is oxybutynin, tolterodine, trospium chloride, solifenacin, and darifenacin, or a pharmaceutically acceptable salt of any of the foregoing.

33. A method of treating or preventing overactive bladder syndrome in a human subject in need of such treatment, said method comprising administering to said human subject a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein the patient also suffers from a sleep disorder.

34. The method of claim 33, wherein the compound is a compound of formula (I'): or a pharmaceutically acceptable salt thereof.

35. The method of claim 33 or 34, wherein the method comprises 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, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

36. The method of any one of claims 33-35, wherein the pharmaceutically acceptable salt is p-toluenesulfonate, sulfate, phosphate, or hydrochloride.

37. The method of any one of claims 33-36, wherein the pharmaceutically acceptable salt is p-toluenesulfonate.

38. The method of any one of claims 33-37, wherein the method comprises administering the compound of formula (IA):

39. The method of any one of claims 33-38, wherein the human subject is a female 50 years of age or older.

40. A method of treating a sleep disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein the patient also suffers from urinary incontinence.

41. The method of claim 40, wherein the compound is a compound of formula (I'): or a pharmaceutically acceptable salt thereof.

42. The method of claim 40 or 41, wherein the method comprises administering a compound of formula (IA):

43. The method of any one of claims 40-42, wherein the sleep disorder is an insomnia disorder, a hypersomnia disorder, a circadian rhythm sleep-wake disorder, an alcohol-induced sleep disorder, insomnia associated with alcohol withdrawal, or any combination thereof.

44. A method of treating overactive bladder syndrome in a human subject in need thereof, the method comprising administering to the human subject an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein the human subject suffers from mild or mild to moderate renal impairment.

45. The method of claim 44, wherein the human subject with mildly impaired renal function has an estimated glomerular filtration rate (eGFR) of about 60 mL / min to about 89 mL / min.

46. ​​The method of claim 44, wherein the human subject with mild to moderate renal impairment has an eGFR of about 45 mL / min to about 59 mL / min.

47. The method of any one of claims 44 to 46, wherein administration of the compound of formula (I) to the subject results in at least a mean AUC, C max , T max , T 1 / 2 or CL / F and the corresponding mean AUC, C max , T max , T 1 / 2 There was no statistical difference in CL / F.

48. The method of any one of claims 44 to 47, wherein administration of the compound of formula (I) to the human subject results in an average Ae, Fe or CL of at least R The corresponding mean Ae, Fe or CL of similarly situated human subjects without renal impairment R There was no statistical difference.

49. The method of any one of claims 44 to 48, wherein the compound is a compound of formula (I'): or a pharmaceutically acceptable salt thereof.

50. The method of any one of claims 44 to 49, wherein the method comprises administering a pharmaceutically acceptable salt of the compound of formula (I), wherein the salt is selected from the group consisting of sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

51. The method of any one of claims 44 to 50, wherein the method comprises administering a p-toluenesulfonate, sulfate, phosphate or hydrochloride salt of the compound of formula (I).

52. The method of any one of claims 44 to 51, wherein the p-toluenesulfonate salt of the compound of formula (I) is administered.

53. The method of any one of claims 44 to 52, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IA):

54. The method of claim 53, wherein the compound of formula (IA) is administered orally, parenterally, intravenously, intramuscularly, buccally or transdermally.

55. The method of claim 53 or 54, wherein the compound of formula (IA) is administered orally.

56. The method of claim 55, wherein the effective amount of the compound of formula (IA) is from about 0.10 mg to about 10 mg.

57. The method of any one of claims 53 to 56, wherein the compound of formula (IA) is administered once daily.

58. The method of any one of claims 53 to 57, wherein the compound of formula (IA) is administered at night.

59. The method of any one of claims 53 to 58, wherein the compound of formula (IA) is administered before bedtime.

60. The method of any one of claims 53 to 56, wherein the compound of formula (IA) is administered twice daily.

61. The method of claim 60, wherein the compound of formula (IA) is administered approximately every 12 hours.

62. The method of claim 60 or 61, wherein the method comprises administering a first effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof during the day and administering a second effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof during the night before the bedtime of the human subject.

63. The method of claim 62, wherein the first effective amount is a therapeutically effective amount and is the same as the second effective amount.

64. The method of claim 62, wherein the first effective amount and the second effective amount are different.

65. The method of claim 64, wherein the second effective amount is about 2 times the first effective amount.

66. The method of claim 64, wherein the second effective amount is about 10 times greater than the first effective amount.

67. The method of any one of claims 44 to 66, wherein administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof increases the urination pressure threshold of the human subject by about 30% to 80%.

68. The method of any one of claims 44 to 67, further comprising administering to the human subject an effective amount of an antimuscarinic agent.

69. The method of claim 68, wherein the antimuscarinic agent is oxybutynin, tolterodine, trospium chloride, solifenacin, darifenacin, or a pharmaceutically acceptable salt of any of the foregoing.

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