Methods for treating or preventing overactive bladder syndrome

Abstract

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

Description

Background Art

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

[0002] OBS results from abnormal and involuntary contractions of the detrusor muscle of the bladder that are mediated by muscarinic receptors. When the bladder fills with urine, the bladder begins to stretch. Such stretching sensed by afferent neurons results in the urge to urinate. Nerves in the muscle wall of the bladder release the neurotransmitter acetylcholine, which binds to muscarinic receptors in the muscle wall of the bladder and causes the cells to contract, further increasing the urge to urinate. When these muscarinic receptors are stimulated by acetylcholine, bladder contractions are induced, leading to urination. Normally, when the bladder fills with urine, the detrusor muscle remains at rest. However, in the case of OBS patients, the bladder contracts during the filling phase.

[0003] The common pharmacological treatment for OBS is an antimuscarinic agent (i.e., a muscarinic receptor antagonist) that inhibits the stimulation of muscles by the neurotransmitter acetylcholine. Several antimuscarinic agents, including oxybutynin, tolterodine, trospium, solifenacin, and darifenacin, are approved for use in the treatment of OBS. Antimuscarinic agents delay the increase in pressure within the bladder, reduce the urge to urinate, and prevent uncontrollable urination by blocking the effect of acetylcholine on muscle cells.

[0004] Administration of antimuscarinic agents affects the efferent pathways associated with the muscle contractions that result in urination. Treatments that affect the sensory (afferent) pathways associated with urination have not had great success. Afferent nerve fibers conduct from the lower urinary tract to the spinal cord through the pelvic, hypogastric, and pudendal nerves. The afferent nerves in the lower urinary tract are composed of two fibers (A-δ and C-fibers) associated with the sensation of pressure and that respond to bladder distension when the bladder is filled with urine. Afferent neurons express different types of receptors and ion channels, including transient receptor potential channels, purinergic, muscarinic, endothelin, neurotrophic factor, and estrogen receptors. These receptors have various functions, many of which are involved in enhancing or reducing neuronal excitability. One role of these afferent fibers is to transmit information regarding bladder pressure to the central nervous system, thereby initiating the efferent pathways.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0005] There is a need for effective treatment of lower urinary tract disorders using small molecule therapeutic agents that are orally administrable.

MEANS FOR SOLVING THE PROBLEMS

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

[0007] In one aspect, the present disclosure provides a method of administering such treatment to a human subject identified as in need of treatment or prevention of OBS, the method comprising administering to the human subject a therapeutically effective amount of a compound of formula (I):

CHEMICAL

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

Chemical formula

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

Chemical formula

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

[0011] In certain embodiments, 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 the compounds of formula (I) and (I’) (including all stereoisomers), pharmaceutically acceptable salts thereof (e.g., the compound of formula (IA)), polymorphs, solvates, or hydrates. Suitable effective dosages of the compounds of the present disclosure as a single oral dose range 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 administered is the compound of formula (IA).

[0012] In certain embodiments, the compounds of the present disclosure are administered orally. In certain embodiments, the compound administered is the compound of formula (IA). It is understood that oral administration of the compounds of the present disclosure (e.g., compounds of formula (I), (I’), or (IA)) results in increased concentrations of the compound in the bladder.

[0013] A particular advantage of the methods of the present disclosure is that they are capable of simultaneously treating patients suffering from both sleep disorders and lower urinary tract complications (e.g., OBS). Thus, in one aspect, the present disclosure provides a method of treating or preventing OBS in a human subject suffering from a sleep disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the compound is the 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

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Mode for Carrying Out the Invention

[0015] The present disclosure provides a method for treating or preventing a condition associated with overstimulation of the afferent nerves associated with the lower urinary tract. Such conditions include overactive bladder syndrome (OBS), urinary urge, increased micturition frequency, nocturia, and urinary incontinence. Specifically, the present disclosure provides a method for treating or preventing a condition associated with overstimulation of the afferent nerves via administration of an agonist of the nociceptin opioid peptide receptor, also referred to as the ORL-1 receptor.

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

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

[0018] The inventors have unexpectedly found that conditions associated with overstimulation of the afferent nerves related to the lower urinary tract can be improved or treated through the administration of a therapeutically effective amount of a compound of formula (I)

Chemical formula

[0019] In certain embodiments, the compound of formula (I) is a single stereoisomer, namely, a compound of formula (I’) having the structure illustrated below.

Chemical formula

[0020] Accordingly, in one aspect, the present disclosure provides a method of treating a human subject in need of treatment or prevention of overactive bladder syndrome (OBS), the method comprising administering to the subject a therapeutically 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 certain embodiments, administration of a compound of the present disclosure also improves (e.g., alleviates the severity of) symptoms associated with OBS, including but not limited to urinary urge, increased urinary frequency, nocturia, and urinary incontinence.

[0021] In one embodiment, administration of a compound of the present disclosure increases the pressure threshold for urination by about 10% to about 99.5%. In another embodiment, administration of a compound of the present disclosure increases the pressure threshold for urination by about 20% to about 90%. In another embodiment, administration of a compound of the present disclosure increases the pressure threshold for urination by about 30% to about 80%.

[0022] In another aspect, the present disclosure provides a method of treating a human subject in need of reducing the occurrence of nocturia, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. In some embodiments, nocturnal administration refers to administering the compound before bedtime. In some embodiments, a compound of the present disclosure can be administered at any time from about 3 hours before to immediately before bedtime of the human subject. In one embodiment, after nightly administration of a compound of the present disclosure, the instances of nocturnal urination decrease from more than twice per night to less than twice per night. For example, the number of times the subject urinates at night can decrease from more than twice to 0 or 1 time after nightly administration of a compound of the present disclosure.

[0023] In certain embodiments, the methods of the present disclosure include administering to a human subject a therapeutically effective amount of a compound of the present disclosure once every two nights. In other embodiments, the method includes administering to a human subject a therapeutically effective amount of a compound of the present disclosure once every three nights. In another embodiment, the method includes administering to a human subject a therapeutically effective amount of a compound of the present disclosure once a week. In other embodiments, the method includes administering to a human subject a therapeutically effective amount of a compound of the present disclosure once every three nights. In yet another embodiment, the method includes administering to a human subject a therapeutically effective amount of a compound of the present disclosure twice a week.

[0024] In another aspect, the present disclosure provides a method of treating a human subject identified as in need of treatment or prevention of urinary incontinence, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

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

[0026] In another aspect, the present disclosure provides a method of 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), which acts by reducing the frequency of contractions of the detrusor muscle in the bladder of the subject. In some embodiments, the frequency of contractions of the detrusor muscle in the bladder is reduced by at least 20% after administration of the compound of the present disclosure. In other embodiments, the frequency of contractions of the detrusor muscle in the bladder is reduced by at least 30% after administration of the compound of the present disclosure. In other embodiments, the frequency of contractions of the detrusor muscle in the bladder is reduced by at least 50% after administration of the compound of the present disclosure. In other embodiments, the frequency of contractions of the detrusor muscle in the bladder is reduced by at least 70% after administration of the compound of the present disclosure. In other embodiments, the frequency of contractions of the detrusor muscle in the bladder is reduced by at least 80% after administration of the compound of the present disclosure. In other embodiments, the frequency of contractions of the detrusor muscle in the bladder is reduced by at least 90% after administration of the compound of the present disclosure. In certain embodiments, the frequency of contractions of the detrusor muscle in the bladder is reduced by about 20% to about 90%, about 30% to about 85%, about 40% to about 80%, or about 50% to about 70% after administration of the compound of the present disclosure.

[0027] As used herein, the terms "treatment of", "treating", and related terms include amelioration, alleviation, reduction, deceleration, or arrest of a condition or its symptoms by administration of an 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 some embodiments, treating includes inhibiting an episode of a condition (e.g., OBS) or its symptoms (e.g., urinary incontinence or nocturia) (e.g., reducing its overall frequency), or reducing the severity of a condition or its symptoms.

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

[0029] When used in connection 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), produces a partial or complete therapeutic effect desired by one of ordinary skill in the art (e.g., a physician) as a result of such administration.

[0030] When used in connection with the methods of the present disclosure, the term "therapeutically effective amount" refers to the amount of a compound that, when administered to an animal (e.g., a human subject), produces a desired therapeutic effect.

[0031] While not wishing to be bound by any theory, it is believed that the compounds of the present disclosure exert beneficial effects through modulation of the ORL-1 receptor expressed on afferent nerve fibers / terminals in the lower urinary tract. As used herein, the terms "modulate", "modulating" with respect to the ORL-1 receptor, and related terms mean to mediate 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 agonist / antagonists, mixed partial agonist / antagonists, and compounds that directly or indirectly affect the regulation of receptor activity. The compounds of formulas (I) and (I') and their pharmaceutically acceptable salts (e.g., the 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 the native ligand, is defined as a "partial agonist". It is believed that the partial agonists of the present disclosure can achieve the desired therapeutic effect (e.g., treatment of OBS) without, or with substantially reduced, the concomitant side effects often associated with the administration of full agonists.

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

[0033] As used herein, a human subject with "no renal insufficiency" or "normal renal function" means that the human subject has an eGFR of 90 mL / min or greater.

[0034] As used herein, a human subject having "mild renal impairment" means that the human subject has an eGFR of about 60 mL / min to about 89 mL / min.

[0035] As used herein, a human subject having "mild to moderate renal impairment" means that the human subject has an eGFR of about 45 mL / min to about 59 mL / min.

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

[0037] In yet another embodiment, the compounds of the present disclosure can be delivered in a controlled release or sustained release system. As is well understood in the art (e.g., the pharmaceutical industry), controlled release or sustained release pharmaceutical compositions can improve drug therapy over that achieved by their non-controlled release or non-sustained release counterparts (e.g., immediate release formulations). In one embodiment, the controlled release or sustained release composition comprises a therapeutically effective amount of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, for treating or preventing OBS or its symptoms over a long period of time. Advantages of the controlled release or sustained release composition include extended drug activity, reduced dosing frequency, and increased compliance.

[0038] Administration of the compounds of the present disclosure can be by controlled release means or sustained release means, or by delivery devices known to those of skill in the art. Examples include, but are not limited to, those described in U.S. Patent 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 known to those of skill in the art (see, e.g., Goodson, “Dental Applications,” in Medical Applications of Controlled Release, Vol. 2, Applications and Evaluation, Langer and Wise, eds., CRC Press, Chapter 6, pp. 115-138 (1984) (hereinafter “Goodson”)). Other controlled release or sustained release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used.In one embodiment, a pump may be used (Langer, Science 249:1527-1533 (1990); Sefton, “Implantable Pumps,” in CRC Crit. Rev. Biomed. Eng. 14(3):201-240 (1987); Buchwald et al., “Long-term, Continuous Intravenous Heparin Administration by an Implantable Infusion Pump in Ambulatory Patients with Recurrent Venous Thrombosis,” Surgery 88:507-516 (1980); and Saudek et al., “A Preliminary Trial of the Programmable Implantable Medication System for Insulin Delivery,” New Engl. J. Med. 321:574-579 (1989)).In another embodiment, a polymeric material 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)).

[0039] Using suitable dosage forms, for example, hydroxypropyl methylcellulose, ethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, multiparticulates, liposomes, microspheres, or combinations thereof, can provide controlled or sustained release of one or more active ingredients and can provide the desired release profiles at various rates. 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. Accordingly, the present disclosure encompasses single unit dosage forms suitable for oral administration that are adapted for controlled or sustained release (including, but not limited to, tablets, capsules, gelcaps, and caplets, etc.).

[0040] The composition may optionally but preferably further comprise a pharmaceutically acceptable excipient in an amount suitable for providing a form suitable for proper administration to an animal. Such pharmaceutical excipients can be diluents, suspending agents, solubilizing agents, binders, disintegrants, preservatives, colorants, lubricants, and the like. The pharmaceutical excipient can be a liquid such as water or an oil (including those derived from petroleum, animals, plants, or synthetic sources, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc.). The pharmaceutical excipient can be physiological saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, adjuvants, stabilizers, thickeners, lubricants, and colorants can be used. In one embodiment, the pharmaceutically acceptable excipient is sterile when administered to an animal. Water is a particularly useful excipient when the compound of formula (I) or its pharmaceutically acceptable salt is administered intravenously. Aqueous physiological saline solutions as well as aqueous solutions of dextrose and glycerol can also be used as liquid excipients (especially for injection solutions). Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The composition may optionally contain a small amount of wetting agent or emulsifying agent, or a pH buffering agent. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, (Amer. Pharmaceutical Ass’n, Washington, DC, 1986), which is incorporated herein by reference. Other examples of suitable pharmaceutical excipients are described by Radebough et al., “Preformulation,” pp.1447-1676 in Remington’s Pharmaceutical Sciences Vol.2 (Gennaro, ed., 19 th Ed., Mack Publishing, Easton, PA, 1995), which is incorporated herein by reference.

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

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

[0043] An oral pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof) can include one or more excipients, such as sweeteners like fructose, aspartame, or saccharin; flavoring agents like peppermint, wintergreen oil, or cherry; coloring agents; and preservatives, in order to provide a pharmaceutically palatable preparation. Further, in the case of tablet or pill form, the composition can be coated to delay degradation and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period. A selectively permeable membrane surrounding an osmotically active driving compound is also suitable for an orally administered composition. In these latter platforms, fluid from the surrounding environment of the capsule is absorbed by the driving compound, which swells and extrudes the drug or pharmaceutical composition through an opening. These delivery platforms can provide an essentially zero-order delivery profile, in contrast to the spiked profile of an immediate-release formulation. Time-delay materials such as glyceryl monostearate or glyceryl stearate can also be used. The oral composition can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

[0044] The composition can be in the form of a solution, suspension, emulsion, tablet (e.g., orally disintegrating tablet (ODT) or sublingual tablet), pill, pellet, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, suspension, microparticle, multiparticle, rapidly dissolving film, or other form suitable 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, such as a tablet, troche, gel, patch, or film formulated by conventional methods (see, e.g., Pather et al., “Current status and the future of buccal drug delivery systems,” Expert Opin. Drug Deliv. 5(5):531-542 (2008)). In another embodiment, the composition is in a form suitable for gingival administration, such as a polymeric film containing polyvinyl alcohol, chitosan, polycarbophil, hydroxypropylcellulose, or Eudragit S-100, as disclosed by Padula et al., “In Vitro Evaluation of Mucoadhesive Films for Gingival Administration of Lidocaine,” AAPS PharmSciTech 14(4):1279-1283 (2013). In another embodiment, the composition is in a form suitable for intraocular administration.

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

[0046] When the compounds of the present disclosure are administered parenterally, the formulations for parenteral administration can be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles. Such formulations may further contain pharmaceutically necessary additives such as one or more stabilizers, suspending agents, dispersing agents, buffers, etc. The compounds of the present disclosure can also be in the form of powders for reconstitution as injectable formulations.

[0047] In another embodiment, the compounds of the present disclosure can 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 contain a solubilizing agent. The intravenous composition containing the compounds of the present disclosure may optionally contain a local anesthetic such as benzocaine or prilocaine to relieve the pain at the injection site. Generally, the components are supplied in unit dosage form separately or mixed, as a lyophilized powder or anhydrous concentrate in a sealed container such as an ampoule or sachet indicating the amount of the active agent, for example. When the compounds of the present disclosure are administered by infusion, they can be dispensed in an infusion bottle containing, for example, sterile pharmaceutical grade water or physiological saline. When the compounds of the present disclosure are administered by injection, an ampoule of sterile water or physiological saline for injection may be provided so that the components can be mixed prior to administration.

[0048] The compounds of the present disclosure, such as the compounds of formula (I) or (I'), are mainly excreted from urine with most of them remaining unchanged (see Example 2 below). Therefore, the compounds of formula (I) or (I') are concentrated mainly in the bladder after administration. For example, when administered orally, 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. Further, the concentration of the compounds of formula (I) or (I') in urine remains high until at least 24 hours after oral administration. In certain embodiments, the concentration of the compounds of formula (I) or (I') 12 hours after oral administration is greater than 100 nM. In other embodiments, the concentration of the compounds of formula (I) or (I') 12 hours after oral administration is greater than 500 nM. In other embodiments, the concentration of the compounds of formula (I) or (I') 12 hours after oral administration is greater than 1,000 nM. In other embodiments, the concentration of the compounds of formula (I) or (I') 12 hours after oral administration is greater than 5,000 nM. In other embodiments, the concentration of the compounds of formula (I) or (I') 12 hours after oral administration is greater than 10,000 nM. In certain embodiments, the concentration of the compounds of formula (I) or (I') 12 hours after oral administration can be in the range of about 100 nM to about 30,000 nM. In other embodiments, the concentration of the compounds of formula (I) or (I') 12 hours after oral administration can be in the range of about 500 nM to about 15,000 nM. In other embodiments, the concentration of the compounds of formula (I) or (I') 12 hours after oral administration can be in the range of about 1,000 nM to about 10,000 nM.

[0049] In some embodiments, the compounds of formula (I) or (I’) are administered in the form of a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (including both inorganic and organic salts) that can be prepared from the compounds of formula (I). Exemplary salts include, but are not limited to, 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, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate) salt). In one embodiment, the pharmaceutically acceptable salt is hydrochloride, sulfate, sodium salt, potassium salt, benzenesulfonate, para-toluenesulfonate, or fumarate. In another embodiment, the pharmaceutically acceptable salt is hydrochloride or sulfate. In another embodiment, the pharmaceutically acceptable salt is hydrochloride. In another embodiment, the pharmaceutically acceptable salt is sulfate. In another embodiment, the pharmaceutically acceptable salt is sodium salt. In another embodiment, the pharmaceutically acceptable salt is potassium salt. In another embodiment, the pharmaceutically acceptable salt is fumarate. In another embodiment, the pharmaceutically acceptable salt is p-toluenesulfonate, i.e., para-toluenesulfonate (also known as “tosylate salt”). In another embodiment, the pharmaceutically acceptable salt is choline salt.

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

Chemical formula

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

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

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

[0054] As used herein, the amounts on a weight basis of the “dosage,” “dose,” and related terms being administered refer to the free acid and free base forms, i.e., the non-salt forms, of the compounds of formula (I) or (I’). For example, a dosage of 10.0 mg means that 10.0 mg of the non-salt form of the compound of formula (I) or (I’) is actually administered. However, by way of example, a dosage of 10.0 mg of, for example, the monohydrochloride or 1:1 molar hydrochloride salt of a compound of formula (I) or (I’) means that 10.84 mg of the above compound is actually administered, and this 10.84 mg results in 10.00 mg of the non-salt form of the compound of formula (I) or (I’) (0.0229 millimoles) and 0.84 mg of hydrochloric acid (0.0229 millimoles). Similarly, a dosage of 10.00 mg of, for example, the monotosylate salt (1:1 molar para-toluenesulfonate) of a compound of formula (IA) means that 13.93 mg of the above compound is actually administered, and this 13.93 mg results in 10.00 mg of the non-salt form of the compound of formula (I) or (I’) (0.0229 millimoles) and 3.93 mg of para-toluenesulfonic acid (0.0229 millimoles).

[0055] Regarding a method for treating or preventing a condition or symptom in a human subject, a suitable effective dosage of a compound of the present disclosure is, in one embodiment, from about 0.0002 mg / kg to about 10 mg / kg of the body weight of the human subject per day, in another 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, and in another embodiment from about 3.0 mg / kg / day to about 5.0 mg / kg / day. In another embodiment, the effective dosage is about 10 mg / kg / day or less. In certain embodiments, a suitable effective dosage of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is from about 0.0002 mg / kg / day to about 10 mg / kg / day, from about 0.001 to about 10 mg / kg / day, from about 0.002 mg / kg / day to about 10 mg / kg / day, from about 0.003 mg / kg / day to about 10 mg / kg / day, from about 0.0005 mg / kg / day to about 5.0 mg / kg / day, from about 0.001 mg / kg / day to about 2.5 mg / kg / day, from about 0.002 mg / kg / day to about 2.0 mg / kg / day, or from about 0.002 mg / kg / day to about 1.0 mg / kg / day. In another embodiment, the effective dosage is about 1.0 mg / kg / day or less. In certain other embodiments, a suitable effective dosage 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. With respect to these dosages, it should be understood that the term "day" means a 24-hour cycle starting from the time of administration of a compound of the present disclosure, such as a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof.

[0056] 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 dosage 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 as a single dose of a non-controlled release formulation or a non-sustained release formulation (e.g., an immediate release formulation). In another embodiment, the effective dosage of the compounds of the present disclosure is administered as multiple doses of a non-controlled release formulation or a non-sustained release formulation.

[0057] In certain embodiments, a compound of formula (I) or (I’), or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (IA)), at 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 mg, about 0.95 mg, about 1.00 mg, about 1.25 mg, about 1.50 mg, about 1.75 mg, about 2.00 mg, about 2.25 mg, about 2.50 mg, about 2.75 mg, about 3.00 mg, about 3.25 mg, about 3.50 mg, about 3.75 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 9.0 mg, or about 10 mg, is orally administered to a human subject in need thereof. In some embodiments, a compound of formula (I) or (I’), or an equivalent amount of a pharmaceutically acceptable salt thereof, at about 1 mg is orally administered to a human subject in need thereof. In some embodiments, a compound of formula (I) or (I’), or an equivalent amount of a pharmaceutically acceptable salt thereof, at about 1.5 mg is orally administered to a human subject in need thereof. As is known to those skilled in the art, in the case of human animals, a once-daily dose (in mg) can be converted to a dose in mg / kg / day by dividing the mg dose by the average mass of 60 kg of human animals recognized in the art. For example, a once-daily human dose of 12 mg is thus converted to a dose of about 0.20 mg / kg / day.

[0058] In certain embodiments, a controlled-release composition comprising a therapeutically effective amount of a compound of the present disclosure is administered as a single dose or multiple doses. The controlled-release composition can 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 an uncontrolled-release or non-sustained-release formulation.

[0059] In some embodiments, the compound of formula (I) or (I’), or a pharmaceutically acceptable salt thereof, 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, as a result of daily administration of the compound of formula (I) or (I’), the urinary concentration is several orders of magnitude greater than the in vitro activity of the compound of formula (IA) as measured by Ki and EC 50 and is several orders of magnitude greater than the in vitro activity of the compound of formula (IA).

[0060] In addition to the beneficial effect of treating or preventing conditions associated with overactive bladder, the compounds of the present disclosure can also induce drowsiness and treat sleep disorders when administered at a sufficient dosage level. See U.S. Patent Publication No. 2020 / 0345726, which is incorporated herein by reference. Patients suffering from symptoms associated with overactive bladder often suffer from poor sleep quality, insomnia, and / or nocturia. In some embodiments, the patient suffering from a sleep disorder is a female over 50 years old. In other embodiments, the patient suffering from a sleep disorder is a male over 50 years old. By administering the compound of formula (I) or (I’), or a pharmaceutically acceptable salt thereof, every night, both the sleep quality and the symptoms associated with overactive bladder are improved. In certain embodiments, the compound of formula (I) or (I’), or a pharmaceutically acceptable salt thereof, is administered by the patient before sleep every night. For example, the compound of formula (I) or (I’), or a pharmaceutically acceptable salt thereof, can be administered from about 1 minute to about 3 hours before sleep. In some embodiments, the compound of formula (I) or (I’), or a pharmaceutically acceptable salt thereof, can be administered from about 5 minutes to about 60 minutes before sleep. In other embodiments, the compound of formula (I) or (I’), or a pharmaceutically acceptable salt thereof, can be administered from about 10 minutes to about 30 minutes before sleep.

[0061] In one embodiment, an effective amount or dosage 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 of a human's habitual bedtime. In another embodiment, the effective amount or dosage is administered about 45 minutes before the median of a human's habitual bedtime. In another embodiment, the effective amount or dosage is administered about 30 minutes before the median of a human's habitual bedtime. In another embodiment, the effective amount or dosage is administered about 20 minutes before the median of a human's habitual bedtime. In another embodiment, the effective amount or dosage is administered within about 20 minutes before the median of a human's habitual bedtime. In another embodiment, the effective amount or dosage is administered about 15 minutes before the median of a human's habitual bedtime. In another embodiment, the effective amount or dosage is administered within about 15 minutes before the median of a human's habitual bedtime. In another embodiment, the effective amount or dosage is administered about 10 minutes before the median of a human's habitual bedtime. In another embodiment, the effective amount or dosage is administered within about 10 minutes before the median of a human's habitual bedtime. In another embodiment, the effective amount or dosage is administered about 5 minutes before the median of a human's habitual bedtime.

[0062] In certain embodiments, a compound of formula (I) or (I'), or a pharmaceutical salt thereof, may be administered multiple times a day. For example, a compound of formula (I) or (I') or a pharmaceutical salt thereof may be administered twice or three times a day. In embodiments where the compound is administered multiple times a day, each dosage may be administered in the same amount or a different amount. In some embodiments, the dosage of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered in a higher amount than other dosages provided earlier in the day. In some embodiments, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered twice a day, about every 12 hours. In other embodiments, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered three times a day, about every 8 hours.

[0063] In certain embodiments, the compounds of the present disclosure are administered twice daily, 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 greater than the first dose. For example, the second dose can be administered in an amount about 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or 1000-fold greater than the first dose. In some embodiments, the second dose can be administered in an amount about 1.5-fold to about 10-fold greater than the first dose. In other embodiments, the second dose can be administered in an amount about 1.5-fold to about 100-fold greater than the first dose. In other embodiments, the second dose can be administered in an amount about 1.5-fold to about 1000-fold greater than the first dose. In other embodiments, the second dose can be administered in an amount about 3-fold to about 100-fold greater than the first dose. In other embodiments, the second dose can be administered in an amount about 3-fold to about 1000-fold greater than the first dose. In other embodiments, the second dose can be administered in an amount about 5-fold to about 100-fold greater than the first dose. In other embodiments, the second dose can be administered in an amount about 5-fold to about 1000-fold greater than the first dose. Such a dosing schedule ensures that in a human subject, the first dose is effective to treat or prevent OBS and the symptoms associated therewith without leaving drowsiness, while the second dose is effective to treat or prevent OBS inflammation and the symptoms associated with OBS and to cause drowsiness or induce sleep. In certain embodiments, both the first dose and the second dose are administered through (the same or different) non-controlled release formulations or non-sustained release formulations. In other embodiments, the first dose is administered through a controlled release formulation or a non-sustained release formulation, and the second dose is administered through a non-controlled release formulation or a non-sustained release formulation.

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

[0065] A method for treating or preventing it in a human subject (e.g., a patient) in need of treatment or prevention of lower urinary tract disorders (such as OBS) may further comprise co-administering to the human subject 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. In one embodiment, the second therapeutic agent is administered in an effective amount to achieve the desired therapeutic effect by the method of the present disclosure. In one embodiment, the second therapeutic agent is an antimuscarinic agent. In some such embodiments, the antimuscarinic agent is oxybutynin. In other such embodiments, the antimuscarinic agent is tolterodine. In other such embodiments, the antimuscarinic agent is trospium. In a separate embodiment, the antimuscarinic agent is solifenacin. In a particular embodiment, the antimuscarinic agent is darifenacin. In other such embodiments, the antimuscarinic agent is flavoxate. A method of treating this in a human subject in need of treatment for overactive bladder syndrome, the compound of formula (I) in a therapeutically effective amount:

Chemical formula

[0066] In some embodiments, administering the compound of formula (I) to the subject results in an average AUC, C max , T max , T 1 / 2 , or CL / F that is not statistically different from that in a human subject under similar circumstances who does not have renal insufficiency (or has normal renal function). In some embodiments, an average AUC, C max , T max , T 1 / 2 , or CL / F that is at least achievable can be obtained. As used herein, a human subject is considered to be "under similar circumstances" if the human subject meets the same selection / exclusion criteria as other human subjects being treated by the methods of the present disclosure and also conforms to other relevant characteristics in a clinical trial, such as gender, age, weight, and body mass index.

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

[0068] In some embodiments, administering a compound of formula (I) to a subject can result in at least obtaining an average AUC that has no statistical difference from the corresponding average AUC in a human subject without renal insufficiency (or with normal renal function) under similar circumstances. In some embodiments, administering a compound of formula (I) to a subject can result in at least obtaining an average C max with no statistical difference from the corresponding average C max in a human subject without renal insufficiency under similar circumstances. In some embodiments, administering a compound of formula (I) to a subject can result in at least obtaining an average T max with no statistical difference from the corresponding average T max in a human subject without renal insufficiency under similar circumstances. In some embodiments, administering a compound of formula (I) to a subject can result in at least obtaining an average T 1 / 2 with no statistical difference from the corresponding average T 1 / 2 in a human subject without renal insufficiency under similar circumstances. In some embodiments, administering a compound of formula (I) to a subject can result in at least obtaining an average CL / F that has no statistical difference from the corresponding average CL / F in a human subject without renal insufficiency under similar circumstances.

[0069] In some embodiments, administering a compound of formula (I) to a human subject can result in at least obtaining an average Ae, Fe, or CL R with no statistical difference from the corresponding average Ae, Fe, or CL R in a human subject without renal insufficiency under similar circumstances. As used herein, "Ae" refers to the amount of drug excreted unchanged in the urine after dosing with the test drug. As used herein, "Fe" refers to, for example, the fraction of the test drug excreted in the urine, calculated as (Ae 0~96 / dose). As used herein, "CL R " refers to, for example, the estimated renal clearance of the test drug for the total collection interval (e.g., 0 to 96 hours), calculated as (Ae 0~96 / AUC inf ).

[0070] In some embodiments, administering a compound of formula (I) to a human subject can result in at least obtaining an average Ae that has no statistical difference from the corresponding average Ae in a human subject in a similar situation without renal insufficiency. In some embodiments, administering a compound of formula (I) to a human subject can result in at least obtaining an average Fe that has no statistical difference from the corresponding average Fe in a human subject in a similar situation without renal insufficiency. In some embodiments, administering a compound of formula (I) to a human subject can result in at least obtaining an average CL R that has no statistical difference from the corresponding average CL R in a human subject in a similar situation without renal insufficiency.

[0071] In some embodiments, the compound of formula (I) is a compound of formula (I’):

Chemical formula

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

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

Chemical formula

[0074] 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.

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

[0076] In some embodiments, the first effective amount and the second effective amount may be different. In some embodiments, the second effective amount may be about two times more than the first effective amount. In some embodiments, the second effective amount may be about ten times more than the first effective amount.

[0077] In some embodiments, administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof can increase the micturition pressure threshold in 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 can be oxybutynin, tolterodine, trospium, solifenacin, darifenacin, or a pharmaceutically acceptable salt of any of the foregoing.

[0078] The present disclosure provides additional embodiments. A) A method of treating such a human subject in need of treatment or prevention of overactive bladder syndrome, the method comprising administering to the human subject a therapeutically effective amount of a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical Formula

Example

[0079] Example 1: Isovolumetric model for measuring the effect of a compound of formula (IA) on OBS In rats, under isovolumetric conditions, bladder distension induced 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. Neurourology & Urodynamics 34:368 - 374). This isovolumetric model allows for the evaluation of compounds on RBC. It is a closed system in which saline is slowly injected into the bladder via a urethral catheter until spontaneous rhythmic bladder contractions occur.

[0080] The objective of this study was to evaluate the effect of intravenous administration of the compound of formula (IA) on bladder measurement parameters in an isovolumetric model of anesthetized female rats. The effect of the test substance was compared with that of the reference substance, tolterodine (an antimuscarinic receptor commercially available for overactive bladder in humans).

[0081] Test Design Protocol · Animals were anesthetized with urethane (i.p.). · The ureters were ligated and excised near the kidneys. · An intravesical catheter was inserted into the bladder through the urethral orifice. · The urethral orifice was closed. · For compound administration, a catheter was inserted into the jugular vein. · The bladder was filled with saline until RBC occurred. · After a 30 - minute baseline period, the compound was administered as described below. · The effect of the test substance was followed up for 1 hour after administration.

[0082] Experimental Groups: Three experimental groups were included as described in Table 1 below.

Table 1

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

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

[0085] Female Sprague-Dawley rats were acclimatized to laboratory conditions for at least 3 days before the start of the experiment. The animals were housed in groups of three in polysulfone-type Sealsafe Plus 1291H cages (Tecniplast, Lyon, France) with a wood chip (Souralit, Girona, Spain) bedding, and were allowed free access to food (Rodent Maintenance Diet A04 / 10 from Safe) and water (0.2 μm filtered water). Appropriate environmental enrichment for the species (Aspen brick, Plexx, Uden, Netherlands) was added to the cages. The animal breeding room was maintained at a controlled ambient temperature of 22 ± 2 °C and a relative humidity of 55 ± 10% under artificial lighting (12 hours) from 7:00 am to 7:00 pm.

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

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

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

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

[0090] Test protocol Rats were anesthetized by intraperitoneal administration of urethane (1 g / kg). The ureters were ligated and excised near the kidneys. After inserting catheters (inner diameter 0.30 mm and outer diameter 0.70 mm each) into the bladder via the urethral orifice, urethral ligation was performed. Another catheter (inner diameter 0.58 mm and outer diameter 0.96 mm each) was inserted into the jugular vein for intravenous (i.v.) administration.

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

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

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

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

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

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

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

[0098] Statistical analysis: Statistical analysis and graphing were performed using GraphPad Prism® (GraphPad Software Inc., La Jolla, CA, USA). A p-value < 0.05 was accepted as statistically significant. One-way analysis of variance and subsequent Turkey’s test were used to compare the baseline values of RBC frequency and amplitude among all groups. The baseline and treatment periods of RBC frequency and amplitude in each group were compared using the paired Student’s t-test or Wilcoxon test. The percentage change from the baseline value of RBC frequency, inhibition time, or inhibition amplitude of tortelodine and the compounds of formula (IA) were compared with the vehicle group using the Kruskal–Wallis or one-way analysis of variance, and subsequent Dunnett’s test or Dunnett’s test.

[0099] Results There was no significant difference in the baseline value of RBC frequency among all experimental groups (p > 0.05, Figure 1A). The baseline values of RBC frequency were 25.90 ± 1.91, 25.90 ± 1.36, and 23.00 ± 0.87 within 30 minutes in the vehicle, compound of formula (IA), and tortelodine groups, respectively (Tables 2–4).

[0100] There was no significant difference in the baseline value of RBC amplitude among all experimental groups (p > 0.05, Figure 1B). The baseline values of RBC amplitude were 29.13 ± 3.02, 29.49 ± 2.46, and 27.22 ± 2.03 mmHg in the vehicle, compound of formula (IA), and tortelodine groups, respectively (Tables 2–4). [Table 2] [Table 3] Note: In the Cpd(IA) group, since there were no RBCs after administration, only 8 rats were averaged for RBC amplitude. [Table 4]

[0101] Vehicle (1 mL / kg, i.v.), the compound of formula (IA) (3 mg / kg, i.v.), and tortelodine (1 mg / kg, i.v.) significantly decreased the RBC frequency (p < 0.05 and p < 0.0001, Figures 2A - B - C, Tables 2 - 4).

[0102] The values of RBC frequency during the late treatment period of 0 / 60 minutes were 18.50 ± 2.42, 3.05 ± 1.02, and 15.30 ± 2.72 RBCs at 30 minutes after treatment with vehicle, the compound of formula (IA), and tortelodine, respectively (Figures 2A - B - C, Tables 2 - 4).

[0103] After treatment with the compound of formula (IA) (3 mg / kg, i.v.), the RBC frequency significantly decreased (p < 0.0001, Figure 3, Table 3), while tortelodine (1 mg / kg, i.v.) did not significantly change the RBC frequency (p > 0.05, Figure 3, Table 4). The decrease in RBC frequency after treatment with the compound of formula (IA) reached - 88.57 ± 3.68%, while the decreases after treatment with vehicle and tortelodine were - 28.18 ± 7.30 and - 33.93 ± 10.93%, respectively (Figure 3, Tables 2 - 4).

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

[0105] Compared to vehicle, tortelodine (1 mg / kg, i.v.) significantly decreased the RBC amplitude (p < 0.001, Figure 5 and Tables 2 - 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 in RBC amplitude from the basal value after tortelodine was - 30.83 ± 5.24% compared to - 5.18 ± 2.12% in the vehicle group.

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

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

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

[0109] Example 2: Pharmacokinetic Study of the Compound of Formula (IA) The urinary concentrations in humans (9 in total) were evaluated up to 48 hours after administration of a single oral dose of the compound of formula (IA) (alias Cpd(IA)) in the form of a methylcellulose suspension. Urine samples (pooled consecutive samples of all voided urine) for determination of the concentration of the compound of formula (IA) for each individual subject were collected at the following time intervals: 0 - 8 hours, 8 - 16 hours, 16 - 24 hours, 24 - 32 hours, and 40 - 48 hours after administration. An overview of the urinary concentrations of the compound of formula (IA) for each individual subject and by treatment and time interval is shown in Table 5 below.

Table 5

[0110] Table 5 shows the mean urinary concentration levels and standard deviations of the compound of formula (IA) at specific time intervals after administration of specific dosages (0.2 mg, 0.6 mg, 2 mg, and 10 mg) of the compound of formula (IA). Table 5 shows that even for the lowest dosage (0.2 mg) of the compound of formula (IA), the urinary concentration is several orders of magnitude higher than the in vitro activity of the compound of formula (IA) as measured by Ki and EC 50 indicating that the urinary concentration is several orders of magnitude greater than the in vitro activity of the compound of formula (IA) as measured by Ki and EC

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

[0112] Combined with problems of coordination between the bladder and sphincter, abnormal reflex pathways result in bladder hypertrophy, inefficient micturition, and overactivity of the detrusor muscle (de Groat & Yoshimura., 2010). SCI in rats has been shown to increase the frequency of non-voiding contractions (NVC) and bladder volume and decrease micturition efficiency at the thoracic level (Yoshiyama et al., 1999, Kadekawa et al., 2017, Wada et al., 2017, Wada et al., 2018). SCI in rats is also characterized by bladder hypertrophy. As a result, this model is widely used for the evaluation of substances dedicated to neurogenic bladder dysfunction. Furthermore, the β3-adrenergic receptor agonist CL-316,243 has been shown to significantly increase bladder volume and decrease the frequency of NVC (Beauval et al., 2015).

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

[0114] Study Design Protocol Design · In W-5, spinal cord injury was performed at the T8 level as described below. · During W-5, rats were treated daily with gentamicin. · Between W-5 and W-4, the bladder was emptied manually once a day. · From W-5 to W0, the body weight of the animals was measured once a week. · On D-2 (W0), catheter implantation was performed under isoflurane anesthesia as described below. · On D0 (W0), measurement of intravesical pressure was performed.

[0115] The scheme of the protocol design is shown in Figure 9. Experimental Groups:

[0116] Four experimental groups were included as described in the following table.

Table 6

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

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

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

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

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

[0122] Test protocol SCI surgery: Rats were anesthetized with isoflurane (3%). During the surgery, the body temperature was maintained at 37 °C by placing the animals on a thermoregulated hot plate. Laminectomy was performed, and the spinal cord was transected at the T8 level using microsurgical scissors. Care was taken to ensure that the transection was complete by confirming that the two segments had slightly retracted. The muscles were then sutured, and the skin was stapled. The wound was disinfected with Vetedine. For the sham group, the same surgery was performed without transecting the spinal cord.

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

[0124] Surgery for cystomanometry: Rats were anesthetized with isoflurane (3%). During the surgery, the body temperature was maintained at 37 °C by placing the animals on a thermoregulated hot plate. Polyethylene catheters (inner diameter 0.58 mm and outer diameter 0.96 mm each) were inserted into the bladder through the dome for recording bladder pressure. Another catheter (inner diameter 0.58 mm and outer diameter 0.96 mm each) was inserted into the stomach for intragastric administration. The catheters were led outside the body at the level of the scapula. After the surgery, each rat was housed individually until the end of the protocol and allowed free access to food and water.

[0125] The animals were maintained partially restrained in a restraint device. Physiological saline was infused into the bladder at a constant flow rate of 2 mL / h or 6 mL / h for sham or SCI rats, respectively. After at least 45 minutes (three complete micturition cycles corresponding to the baseline value), the test substance was administered via the intragastric route. Next, the bladder pressure was recorded for 90 minutes.

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

[0127] Results and Analysis All raw data were entered into an Excel® spreadsheet. All entered data were compared with the raw data by two people before data analysis. Results are presented as mean ± standard error of the mean (s.e.m.).

[0128] The following bladder measurement parameters were analyzed (see Figure 10): · Micturition amplitude (AM, mmHg) · Threshold pressure (ThP, mmHg) · Intercontraction interval (ICI, seconds): the time between the basal pressure and ThP. ICI was not shown because the infusion rates were different between sham rats and SCI rats. ICI was analyzed only for calculating bladder volume. · Bladder capacity (BC, mL) BC = ICI × infusion rate · Amplitude of non-voiding contractions (NVC, mmHg) · Frequency of NVC (number per minute).

[0129] NVC was defined as an increase in intravesical pressure with an amplitude exceeding 1.5 mmHg without urine leakage.

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

[0131] For each bladder measurement parameter and each period, comparisons were made as follows. The baseline values of each bladder measurement parameter in the sham / vehicle group and the SCI / vehicle group were compared using an unpaired Student's t-test. One-way analysis of variance or the Kruskal–Wallis test was used to compare the baseline values of each bladder measurement parameter in the entire SCI group. For each bladder measurement parameter within the same group, the three 30-minute intervals after treatment were compared with the corresponding baseline values using one-way analysis of variance or the Friedman test with repeated measures, followed by Dunnett's or Dunn's post hoc test. For the three 30-minute intervals after treatment of each bladder measurement parameter, one-way analysis of variance or the Kruskal–Wallis test, followed by Holm–Sidak's or Dunn's post hoc test against the vehicle, was used to compare between all SCI groups.

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

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

[0134] In sham rats, the vehicle (5 mL / kg, i.g.) significantly decreased BC during the 0–30-minute interval after administration and significantly increased BC during the last interval (60–90 minutes) (p < 0.01 and p < 0.001, respectively, Figure 13A).

[0135] In SCI rats, the vehicle (5 mL / kg, i.g.) and mirabegron (10 mg / kg, i.g.) did not significantly change BC (p > 0.05, Figures 13B and C). In SCI rats, Cpd(IA) (30 mg / kg, i.g.) significantly decreased BC during the 0–30-minute and 30–60-minute intervals after administration (p < 0.001, Figure 13D).

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

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

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

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

[0140] In sham rats, vehicle (5 mL / kg, i.g.) did not significantly change the NVC frequency (p > 0.05, Figure 19A). In SCI rats, vehicle (5 mL / kg, i.g.) significantly decreased the NVC frequency during the 30 - 60 min and 60 - 90 min intervals (p < 0.05, Figure 19B). In SCI rats, mirabegron (10 mg / kg, i.g.) significantly decreased the NVC frequency during the 30 - 60 min and 60 - 90 min intervals (p < 0.01 and p < 0.05, Figure 19C). In SCI rats, Cpd(IA) (30 mg / kg, i.g.) significantly decreased the NVC frequency during the 0 - 30 min and 60 - 90 min intervals (p < 0.05 and p < 0.01, Figure 19D).

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

[0142] In sham rats, vehicle (5 mL / kg, i.g.) did not significantly change the NVC amplitude (p > 0.05, Figure 21A). In SCI rats, vehicle (5 mL / kg, i.g.) significantly decreased the NVC amplitude during the 60 - 90 min interval after administration (p < 0.05, Figure 21B). In SCI rats, mirabegron (10 mg / kg, i.g.) did not significantly change the NVC amplitude (p > 0.05, Figure 21C). In SCI rats, Cpd(IA) (30 mg / kg, i.g.) significantly decreased the NVC amplitude during the 30 - 60 min and 60 - 90 min intervals after administration (p < 0.05 and p < 0.001, Figure 21D).

[0143] Figures 22A - B show that the NVC amplitude did not significantly change after treatment with mirabegron or Cpd(IA) (p > 0.05, expressed as mmHg or % change from the basal value).

[0144] In sham rats, compared with the basal level, the vehicle (5 mL / kg, i.g.) decreased BC immediately after administration and increased BC during the 60 - 90 - minute interval period. The effect on BC after administration was probably due to the effect of the vehicle itself, while the increase in BC during the 60 - 90 - minute interval period after administration was due to the time effect. In SCI rats, the vehicle (5 mL / kg, i.g.) affected the NVC frequency and NVC amplitude during the last post - administration interval period, supporting the effect of the vehicle itself or the time effect.

[0145] As expected, mirabegron (10 mg / kg, i.g.) significantly decreased the NVC frequency, although slightly, compared with the basal level (Beauval et al., 2015).

[0146] The compound of formula (IA) (30 mg / kg, i.g.) significantly decreased the NVC frequency compared with the basal value during the 0 - 30 - minute and 60 - 90 - minute interval periods after administration. This is the effect expected for substances dedicated to overactive bladder (OAB). Cpd(IA) also significantly decreased BC compared with the vehicle during the 0 - 30 - minute interval period after administration, which is not a desirable effect for the treatment of OAB.

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

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

[0149] Design of the test protocol · At W-6, partial ligation of the urethra was performed. · From W-6 for 3 consecutive days, rats were treated daily with gentamicin and Ketofen®. The bladder was emptied manually once a day. · From W-6 to W-1, animals were monitored and weighed once a week. · At W0 (D-2), a catheter was implanted under isoflurane anesthesia. · At D0, measurement of intravesical pressure was performed.

[0150] Animals and test substances: Female Sprague-Dawley rats were acclimatized to laboratory conditions for at least 3 days before the start of the experiment. The animals were housed in groups of 2 or 3 and individually up to cytometry in polysulfone-type Sealsafe Plus 1291H cages (Tecniplast, Lyon, France) with a wood chip (Souralit, Girona, Spain) bedding, and were allowed free access to food (Rodent Maintenance Diet A04 / 10 from Safe) and water (0.2 μm filtered water). Appropriate environmental enrichment for the species (Aspen brick, Plexx, Uden, Netherlands) was added to the cages. The animal breeding room was maintained at a controlled ambient temperature of 22 ± 2 °C and a relative humidity of 55 ± 10% under artificial lighting (12 hours) from 7:00 am to 7:00 pm.

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

[0152] The vehicle was 0.5% methylcellulose (MC). This was prepared in water for injection (WFI) and maintained at 4 °C for 1 week. MC (batch number SLBR8963V) was purchased from Sigma-Aldrich (Saint-Quentin Fallavier, France).

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

[0154] Six experimental groups are shown in the following table.

Table 7

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

[0156] The basal values of BC, ThP, AM, NVC frequency, NVC amplitude, and bladder weight were not significantly different in all experimental BOO groups including vehicle (5 mL / kg, i.g.), mirabegron (10 mg / kg, i.g.), and Cpd(IA) (30 mg / kg, i.g.).

[0157] For the entire period from 0 to 90 minutes: In sham and BOO rats, when compared to the basal values, the vehicle was found to have no significant effect on BC. In BOO rats, mirabegron did not significantly change BC, while Cpd(IA) significantly decreased BC. When compared to the vehicle, no significant difference in BC was observed in the mirabegron group and the Cpd(IA) group, expressed in mL. Expressed as the percentage change from the basal value, Cpd(IA) significantly decreased BC. The percentage changes in BC from the basal values were -13±6% and 11±6% in the BOO / Cpd(IA) group and the BOO / vehicle group, respectively. After mirabegron treatment, BC did not change significantly.

[0158] When compared to the basal values, in sham and BOO rats, the vehicle had no significant effect on ThP (p>0.05), and mirabegron and Cpd(IA) did not change ThP (p>0.05). When compared to the vehicle, expressed in mmHg, ThP did not change significantly after treatment with mirabegron or Cpd(IA) (p>0.05). Expressed as the percentage change from the basal value, ThP significantly decreased after treatment with Cpd(IA) (p<0.05), but no significant effect was observed after mirabegron treatment (p>0.05).

[0159] When compared to the basal values, in sham rats, the vehicle significantly increased AM (p<0.01). In BOO rats, the vehicle had no significant effect on AM (p>0.05), while mirabegron and Cpd(IA) did not significantly change AM (p>0.05). When compared to the vehicle, expressed in mmHg or as the percentage change from the basal value, AM did not change significantly after treatment with mirabegron or Cpd(IA) (p>0.05).

[0160] Compared with the baseline value, in sham and BOO rats, the vehicle did not significantly change the NVC frequency (p > 0.05). In BOO rats, mirabegron significantly decreased the NVC frequency (p < 0.01). In BOO rats, Cpd(IA) did not affect the NVC frequency (p > 0.05). Compared with the vehicle, the NVC frequency did not significantly change after treatment with mirabegron or Cpd(IA), as represented by the number of NVCs per minute or the percentage change from the baseline value (p > 0.05).

[0161] Compared with the baseline value, in all experimental groups, the vehicle, mirabegron, and Cpd(IA) did not change the NVC amplitude (p > 0.05). When compared with the vehicle, the NVC amplitude did not significantly change after treatment with mirabegron or Cpd(IA), as represented by the number of mmHg (p > 0.05). As represented by the percentage change from the baseline value, the NVC amplitude significantly decreased only after treatment with mirabegron and was not affected by Cpd(IA) (p < 0.05 and p > 0.05).

[0162] For the 60 - 90 minute interval period: Compared with the baseline value, in sham rats, the vehicle significantly increased the BC (p < 0.001). In BOO rats, the vehicle did not have a significant effect on the BC (p > 0.05). In BOO rats, mirabegron significantly increased the BC (p < 0.05), while Cpd(IA) significantly decreased the BC (p < 0.05, Figure 5D). When compared with the vehicle, no significant difference in BC was observed in the mirabegron group and the Cpd(IA) group, as represented by mL (p > 0.05). As represented by the percentage change from the baseline value, Cpd(IA) significantly decreased the BC (p < 0.05), while no significant difference was observed after treatment with mirabegron (p > 0.05).

[0163] When compared with the baseline value, in sham and BOO rats, the vehicle did not have a significant effect on ThP (p > 0.05). In BOO rats, mirabegron had no effect on ThP (p > 0.05), while Cpd(IA) significantly decreased ThP (p < 0.01). When compared with the vehicle, expressed in mmHg, ThP did not change significantly after treatment with mirabegron or Cpd(IA) (p > 0.05). Expressed as the percentage change from the baseline value, ThP significantly decreased after treatment with mirabegron or Cpd(IA) (p < 0.05).

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

[0165] In sham and BOO rats, no significant effect on the NVC frequency was observed after the vehicle compared with the baseline value (p > 0.05). In BOO rats, mirabegron significantly decreased the NVC frequency (p < 0.01), while Cpd(IA) had no effect on the NVC frequency (p > 0.05). When expressed relative to the vehicle, the NVC frequency was not affected after treatment with mirabegron or Cpd(IA), expressed as the number of NVCs per minute or as the percentage change from the baseline value (p > 0.05).

[0166] The vehicle did not significantly change the NVC amplitude in sham and BOO rats compared to the basal value (p > 0.05). In BOO rats, mirabegron significantly decreased the NVC amplitude (p < 0.05), but Cpd(IA) had no effect on the NVC amplitude. When compared to the vehicle, expressed in mmHg, the NVC amplitude did not significantly change after treatment with mirabegron or Cpd(IA) (p > 0.05). Expressed as the percentage of change from the basal value, the NVC amplitude did not significantly change after treatment with Cpd(IA), but mirabegron significantly decreased the NVC amplitude (p > 0.05 and p < 0.05).

[0167] Results of intravenous (i.v.) administration The basal values of BC, ThP, AM, NVC frequency, NVC amplitude, and bladder weight were not significantly different in both experimental BOO groups including vehicle (1 mL / kg, i.v.) and Cpd(IA) (3 mg / kg, i.v.) (p > 0.05, Figure 23). Results from the entire period of 0 - 90 minutes:

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

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

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

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

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

[0173] Results from the 60 - 90 minute interval period: When compared to the baseline values, in BOO rats, neither vehicle nor Cpd(IA) had a significant effect on BC (p>0.05, Figures 26A and 26B). When compared to vehicle, expressed as mL and % change from baseline values, no significant difference in BC was observed in the Cpd(IA) group (p>0.05, Figures 27A and 27B).

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

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

[0176] When compared to the baseline value, in BOO rats, no significant effect on NVC frequency was observed after vehicle and Cpd(IA) (p>0.05, Figures 38A and 38B). When compared to vehicle, NVC frequency was not affected after Cpd(IA) treatment, expressed as number of NVCs per minute or % change from the baseline value (p>0.05, Figures 39A and 39B).

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

[0178] Conclusion: In sham rats, compared to the baseline, vehicle (5 mL / kg, i.g.) increased BC only during the 60 - 90 minute interval period. These effects on BC after administration are thought to be due to a time effect. Vehicle also significantly increased AM during the entire period (90 minutes) and the last interval period (60 - 90 minutes) compared to the baseline value. In BOO rats, vehicle (5 mL / kg, i.g.) has no effect on all bladder measurement parameters, thus providing a confounding factor for the evaluation of test substances.

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

[0180] As observed in the SCI model test, Cpd(IA) (i.g.) significantly decreased BC and ThP compared to the vehicle. Since urination occurs at a lower bladder pressure, the effect observed with ThP can be interpreted as a decrease in bladder volume. The significant decrease in BC after treatment was similar to the results obtained in SCI rats.

[0181] In BOO rats, the vehicle (1 mL / kg, i.v.) has no effect on all bladder measurement parameters, thus providing a confounding factor for the evaluation of test substances. As observed in the SCI test and intragastrically administered BOO rats, Cpd(IA) (i.v.) significantly decreased BC and ThP compared to the vehicle and had no effect on all other bladder measurement parameters.

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

[0183] Example 5: A Phase 1b, blinded, placebo-controlled, crossover trial to evaluate the effect of oral administration of a compound of formula (IA) in female human subjects with overactive bladder This trial includes 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). The trial design is summarized in Table 8:

Table 8

[0184] Screening / Washout Period: Prior to any test procedure conducted in this trial, informed consent is obtained from each subject. The assessment of eligibility criteria begins at the screening visit (Visit 1), which includes medical history, physical examination, vital signs, clinical laboratory tests, urine culture, pregnancy test, and drug screening. If a washout of prohibited medications is required, this washout is completed during the screening / washout period.

[0185] Subjects discontinue current medical treatment for OAB, but ongoing non-clinical treatments (which may include timed voiding and behavioral modification therapy, dietary restrictions, and stress reduction) continue in a similar and consistent manner throughout the trial.

[0186] There is no minimum number of days for screening, and subjects can enter the run-in period as soon as they meet the eligibility criteria.

[0187] Single-Blind Run-In Period: Eligible subjects enter the single-blind run-in period (Visit 2). Subjects must have overactive bladder symptoms after washing out previous overactive bladder medications. During the run-in period, subjects are instructed to take one tablet of the test drug at bedtime every night.

[0188] Subjects record their individual overall symptoms related to OAB using a voiding diary and other evaluations. Subjects complete the Symptom Impact Sleep Questionnaire (SISQ) in the morning regarding the impact of symptoms on sleep.

[0189] During the week prior to the next clinic visit (Visit 3), subjects record the voiding time, type, and urgency of each episode for a minimum of 3 days and a maximum of 7 days.

[0190] At Visit 3, eligibility for randomization of the subjects is evaluated. Eligibility is confirmed for the facility prior to randomization by an algorithm that takes into account the urination components recorded during the run-in period. Further, the PI confirms that the subjects have not used any medications (other than the investigational drug) for the treatment of OAB symptoms during the run-in, and that all diaries are appropriately completed according to the protocol.

[0191] Visit 3 on Day 1 is at the end of the single-blind run-in period and the start of the double-blind treatment period.

[0192] Double-blind treatment period: At Visit 3, subjects who continue to meet the eligibility criteria and satisfy all randomization eligibility criteria are randomized to the study, given the double-blind investigational drug, and instructed to take the first dose at bedtime that night. Subjects are required to visit the clinic every two weeks, and to have at least one phone call on Day 1, Day 15, and each week between clinic visits to assess tolerability and confirm diaries / dosing instructions.

[0193] During the week prior to each clinic visit (Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8), the subject records the urination time, type, and urgency of each episode for a minimum of 3 days to a maximum of 7 days.

[0194] At the clinic visit, the subject completes the efficacy / safety and other evaluations.

[0195] Single-blind washout period: The subject follows the evaluations. During the week prior to the clinic visit (Visit 8), the subject records the urination time, type, and urgency of each episode for a minimum of 3 days to a maximum of 7 days.

[0196] End of treatment (EOT) / Early termination (ET): The subject undergoes the EOT procedure either at the end of the double-blind treatment or when the study is prematurely interrupted. The assessments call at EOT is conducted on the same day as study completion or the same day as ET, and if the investigational drug is not administered after these evaluations, these evaluations are not repeated.

[0197] Follow-up period / End of study (EOS): To monitor AEs and concomitant medications / treatments since the previous hospital visit, a follow-up phone call is completed approximately 1 week after the last dose of the investigational drug.

[0198] Inclusion criteria: 1. Female, 18 years of age or older, and able to void spontaneously. Females are eligible to participate if they are not pregnant, not lactating, and meet at least one of the following. Females are considered to have childbearing potential unless they have had a hysterectomy, a tubal ligation, or at least 1 year has elapsed since menopause. Alternatively, female participants with childbearing potential must agree to use a highly reliable contraceptive method (e.g., implant, injection, oral contraceptive, some intrauterine devices (IUDs), sexual abstinence, or a partner who has had a vasectomy) with a failure rate of less than 1% per year if used continuously and appropriately during the study and for 30 days after the end of the study. 2. Have symptoms of overactive bladder, including urinary urgency and frequency, regardless of the presence or absence of urinary incontinence for more than 3 months. 3. Any ongoing non-clinical treatments (which may include timed voiding and behavioral modification therapy, dietary restrictions, and stress reduction) are to be continued in a similar and consistent manner throughout the study, while having the intention to discontinue any ongoing drug treatments for overactive bladder (including anticholinergic agents and beta-3 antagonists), and other prohibited drugs (including antipsychotics, opioids, GABA receptor analogs / modulators / agonists, and renal transport inhibitors). 4. Considered generally healthy based on the results of the medical history, physical examination, 12-lead electrocardiogram, and clinical laboratory profile, as determined by the opinion of the clinical trial responsible physician at the clinical facility. 5. Able to understand the consent form and communicate effectively with the study staff. 6. Voluntarily provide written informed consent and have the intention and ability to complete all study procedures, including an electronic diary and study-related questionnaires.

[0199] Exclusion criteria: 1. Have had a UTI including bacterial cystitis within the past 30 days or have a history of recurrent UTI defined as culture documented episodes demonstrated by cultures three or more times in the past six months. 2. Hematuria judged to be associated with bladder malignancy or other serious lesions. 3. Have undergone any surgical treatment, bladder incontinence surgery, urethral surgery that affects bladder function at any time, or have received botulinum toxin bladder injection within the past six months. 4. Have initiated the use of a neuromodulation device (e.g., Interstim) for sacral nerves and / or pudendal nerves within the past nine months. Subjects with a history of transcutaneous nerve stimulation for OAB who initiated device use more than nine months ago are eligible if the subject has been in a stable environment for the past six months and has permission from the medical monitor. 5. Have a clinically significant outflow obstruction (as determined by the treating investigator). 6. Have an indwelling catheter or are performing intermittent self-catheterization. 7. Have abnormal detrusor muscle activity and / or a neurological cause of diabetic neuropathy and / or have uncontrolled diabetes. Subjects with newly diagnosed or controlled diabetes are eligible based on A1C records and permission from the medical monitor. 8. Have had chronic inflammation (e.g., interstitial cystitis), bladder stones, past pelvic radiotherapy, or past / current malignant disease of pelvic organs (within the pelvis). Have had cyclophosphamide cystitis or chemical cystitis or tuberculosis, have received pelvic irradiation, have active vulvar herpes or vaginitis. 9. Have had grade III / IV pelvic organ prolapse with or without a bladder tumor or urethral diverticulum. 10. Have moderate to severe liver impairment defined as Child-Pugh class B or C. 11. Have any past and / or current evidence (including any surgical intervention for weight loss) of other medical conditions (e.g., heart, respiratory, gastrointestinal, kidney, malignancies other than basal cell carcinoma), neurological conditions, or psychiatric conditions that, according to the opinion of the principal investigator of the clinical trial, may affect the safety of the subject, interfere with the trial evaluation, or interfere with the absorption, distribution, metabolism, or excretion of the drug. 12. Have a positive finding on the Columbia Suicide Severity Rating Scale (C-SSRS) or have a current history of suicidal ideation / behavior. Positive findings on the C-SSRS include suicidal ideation with actual intent and method or plan in the past year (answering "yes" to item 4 or 5 of the C-SSRS), a history of past suicidal behavior in the past 5 years (answering "yes" to any item of suicidal behavior on the C-SSRS), or any past history of severe or recurrent suicidal behavior throughout life, but are not limited to these. 13. Have a current drug abuse or dependence or a recent (within the past 6 months) history thereof, or have a diagnosis of substance use disorder. 14. Have a current or past clinically significant kidney disease or renal dysfunction, or nephrolithiasis (findings or symptoms in the past 3 years), or an estimated glomerular filtration rate (eGFR) of less than 60 mL / min / 1.73m 2 ². 15. Have received medication in a clinical drug trial within 30 days prior to screening admission.

[0200] Randomization Criteria At Visit 3, subjects who meet the following randomization criteria are eligible to participate in the double-blind treatment period. In at least 3 days of the voiding diary, the subject must have (i) more than 8 voids per day (24 hours), and (ii) at least 1 void per day (24 hours) with an urge grade of ≥ 1.

[0201] Trial Treatment: The details of the treatment administered are shown in Table 9.

Table 9

[0202] Considerations on lifestyle: Sleep / wake pattern: The subject is recommended to maintain a consistent sleep / wake pattern during the test period.

[0203] Diet and dietary restrictions: During the test, the subject is instructed to maintain a regular daily meal schedule and not to make any changes to the normal diet (e.g., start a weight loss program).

[0204] Caffeine, alcohol, and tobacco: The participating subjects are instructed to limit their intake of caffeine and alcohol. Smoking subjects are encouraged not to change the number of cigarettes smoked per day during the test.

[0205] Concomitant drugs / prohibited drugs: During the screening / washout period, the subject discontinued all current drug treatments for OAB. On the other hand, any ongoing behavioral therapy was continued in the same / consistent manner throughout the test. Any OAB drugs were discontinued at least 7 days before starting the single-blind run-in period.

[0206] Any prohibited drugs were discontinued at least 7 days before starting the single-blind run-in period. If a drug does not fall within the class of drugs described, consult the medical monitor to determine whether it is permitted.

[0207] Test endpoints: The objectives and list of endpoints of the test are described in Table 10.

Table 10

[0208] Example 6: A Phase 1, non-randomized, non-blinded, parallel-group trial to evaluate the effect of mild renal dysfunction on the pharmacokinetics and safety of a single-dose of a compound of formula (IA) Study Design (Methodology): This was a Phase 1, non-randomized, non-blinded, 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 tested.

[0209] At screening, as shown in Table 11 below, subjects were assigned to study groups according to the estimated glomerular filtration rate (eGFR) calculated using the 2021 Chronic Kidney Disease Collaboration (CKD-EPI 2021) formula. [Table 11]

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

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

[0212] A single oral dose of the compound of formula (IA) in 1.0 mg immediate-release tablets was administered with 240 mL of water to subjects after an overnight fast of at least 10 hours on the morning following the fast. Subjects maintained a fasting state for 4 hours after dosing with the test drug (however, diabetic subjects were allowed a light breakfast 2 hours after dosing with the test drug at the discretion of the treating physician). Except when part of the test drug administration, subjects restricted water intake 2 hours before and 2 hours after dosing. At all other times during the study, subjects were allowed free access to water.

[0213] Subjects underwent the end-of-study (EOS) procedure and were discharged from the clinical facility on Day 5 (or at early termination). Subjects received a follow-up phone call 7 - 10 days after EOS. Figure 44 shows a diagram of the study design.

[0214] Selection / Exclusion Criteria: Subjects aged 18 to 70 years (including 18 and 70 years old), male and female, who are considered by the principal investigator of the clinical trial to be suitable for participation in this clinical trial and who have no clinically significant medical history except for those related to renal impairment or other stable comorbidities (in the case of subjects only with renal dysfunction).

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

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

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

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

[0219] As shown in FIGS. 45 to 47, after a single 1.0 mg immediate-release tablet of the compound of formula (IA), the plasma concentration over time in subjects with mild renal impairment was equivalent to that in subjects with normal renal function.

[0220] Although the subject matter of the present disclosure has been described with reference to exemplary embodiments and examples, this description is not intended to be construed in a limiting sense. Accordingly, various modifications of the exemplary embodiments and other embodiments of the invention will become apparent to those skilled in the art by reference to this description. Accordingly, the appended claims are intended to cover any such modifications or embodiments.

[0221] All publications, patents, and patent applications mentioned in this specification 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.

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

Claims

1. A method of treating a human subject in need of treatment or prevention of overactive bladder syndrome, said method comprising administering to said human subject a therapeutically effective amount of a compound of formula (I): 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof, said method.

2. Said compound is a compound of formula (I'): [Chemical 2] or a pharmaceutically acceptable salt thereof, the method according to claim 1.

3. Said method comprises administering a pharmaceutically acceptable salt of said compound, said salt being 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, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate, the method according to claim 1 or 2.

4. Said method comprises administering the p-toluenesulfonate, sulfate, phosphate, or hydrochloride salt of said compound, the method according to any one of the preceding claims.

5. The method according to any one of the preceding claims, wherein the p-toluenesulfonate salt of said compound is administered.

6. The method according to any one of the preceding claims, comprising administering a compound of formula (IA). 【Chemical Formula 3】

7. The method according to any one of the preceding claims, wherein the urinary frequency of said human subject is reduced.

8. The method according to any one of the preceding claims, wherein the episodes of nocturia of said human subject are reduced.

9. A method of treating a human subject in need of reducing nocturia, said method comprising administering to said human subject a therapeutically effective amount of a compound of formula (I): 【Chemical Formula 4】 or a pharmaceutically acceptable salt thereof, said method.

10. Said compound is a compound of formula (I'): 【Chemical Formula 5】 or a pharmaceutically acceptable salt thereof, the method according to claim 9.

11. The method includes 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, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate, the method according to claim 9 or 10.

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

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

14. The method according to claim 13, which includes administering a compound of formula (IA). 【Chemical Formula 6】

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

16. The method according to any one of the preceding claims, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally.

17. The method according to any one of the preceding claims, 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 according to any one of the preceding claims, 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 according to claim 18, wherein the compound or a pharmaceutically acceptable salt thereof is a compound of formula (IA). 【Chemical Formula 7】

20. The method according to any one of the preceding claims, wherein the compound or a pharmaceutically acceptable salt thereof is administered once a day.

21. The method according to any one of the preceding claims, wherein the compound or a pharmaceutically acceptable salt thereof is administered at night.

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

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

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

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

26. The method according to claim 25, wherein the first therapeutically effective amount is the same as the second therapeutically effective amount.

27. The method according to claim 25, wherein the first therapeutically effective amount is different from the second therapeutically effective amount.

28. The method according to claim 27, wherein the second therapeutically effective amount is approximately more than twice the first therapeutically effective amount.

29. The method according to claim 27, wherein the second therapeutically effective amount is approximately more than ten times the first therapeutically effective amount.

30. The method according to any one of the preceding claims, wherein administration of the compound or a pharmaceutically acceptable salt thereof increases the micturition pressure threshold in the human subject by about 30% to 80%.

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

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

33. A method of treating a human subject in need of treatment or prevention of overactive bladder syndrome, the method comprising administering to the human subject a therapeutically effective amount of a compound of formula (I): 【Chemical Formula 8】 or a pharmaceutically acceptable salt thereof, wherein the patient also suffers from a sleep disorder.

34. The method according to claim 33, wherein the compound is a compound of formula (I'): 【Chemical Formula 9】 or a pharmaceutically acceptable salt thereof.

35. The method includes 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, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate, the method according to claim 33 or 34.

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

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

38. The method according to any one of claims 33 to 37, including administering a compound of formula (IA). 【Chemical Formula 10】

39. The method according to any one of claims 33 to 38, wherein the human subject is a female over 50 years old.

40. A method for treating sleep disorders in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I): 【Chemical 11】 or a pharmaceutically acceptable salt thereof, wherein the patient also suffers from urinary incontinence, the method.

41. The compound is a compound of formula (I'): 【Chemical 12】 or a pharmaceutically acceptable salt thereof, the method according to claim 40.

42. The method according to claim 40 or 41, including administering a compound of formula (IA). 【Chemical 13】

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

44. A method for treating overactive bladder syndrome in a human subject in need of treatment for overactive bladder syndrome, comprising administering to the human subject an effective amount of a compound of formula (I): 【Chemical 14】 or a pharmaceutically acceptable salt thereof, wherein the human subject has mild or mild to moderate renal impairment, the method.

45. The method according to claim 44, wherein the human subject having mild renal dysfunction has an estimated glomerular filtration rate (eGFR) of about 60 mL / min to about 89 mL / min.

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

47. By administering the compound of formula (I) to the subject, an average AUC, C in a human subject under similar circumstances without renal insufficiency ｍａｘ , T ｍａｘ , T １／２ , or an average AUC, C with no statistical difference from CL / F ｍａｘ , T ｍａｘ , T １／２ , or CL / F is obtained at least, the method according to any one of claims 44 to 46.

48. By administering the compound of formula (I) to the human subject, the corresponding average Ae, Fe, or CL in a human subject under similar circumstances without renal insufficiency Ｒ Average Ae, Fe, or CL with no statistical difference from Ｒ is at least obtained, the method according to any one of claims 44 to 47.

49. The compound is a compound of formula (I’): 【Chemical 15】 Or a pharmaceutically acceptable salt thereof, the method according to any one of claims 44 to 48.

50. The method includes administering a pharmaceutically acceptable salt of the compound of formula (I), and 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, hydrogen tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate, the method according to any one of claims 44 to 49.

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

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

53. The compound of formula (I) or its pharmaceutically acceptable salt is a compound of formula (IA), the method according to any one of claims 44 to 52. 【Chemical Formula 16】

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

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

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

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

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

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

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

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

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

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

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

65. The method according to claim 64, wherein the second effective amount is approximately more than twice the first effective amount.

66. The method according to claim 64, wherein the second effective amount is approximately more than ten times the first effective amount.

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

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

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

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