Methods for Treating Interstitial Cystitis / Bladder Pain Syndrome - Patent application

Abstract

The present disclosure provides a method for treating interstitial cystitis / bladder pain syndrome in a human subject in need of such treatment, comprising administering a therapeutically effective amount of a compound of formula (I) or its pharma- ceutical acceptable salt to the human subject.In certain embodiments, the method comprises administering a compound of formula (IA).

Description

[Background technology]

[0001] Interstitial cystitis / bladder pain syndrome is a debilitating chronic disease characterized by suprapubic pain associated with bladder filling, with additional symptoms such as increased daytime and nocturnal frequency, urgency, nocturia, and pelvic discomfort. See Yoshimura et al. (2014), Int J Urol. 2014, Apr;21 Suppl 1(01):18-25. Patients with interstitial cystitis / bladder pain syndrome experience a breakdown of the glycosaminoglycan layer that protects the bladder epithelium, which causes irritation of the bladder wall. Patients with interstitial cystitis / bladder pain syndrome may experience moderate or severe pain.

[0002] Medications such as antihistamines, antidepressants, and antispasmodics have been used to treat interstitial cystitis / bladder pain syndrome, but with limited success. A drug called pentosan polysulfate sodium, which restores damaged or leaky bladder surface, has been approved for the treatment of interstitial cystitis / bladder pain syndrome. However, most patients do not respond effectively to this medication.

[0003] Although the exact mechanism that produces interstitial cystitis / bladder pain syndrome has not been fully elucidated, sensitization of bladder afferents and subsequent increased sensory processing in the spinal cord have been proposed as important mechanisms inducing interstitial cystitis / bladder pain syndrome. Yoshimura et al.(2014),Int J Urol.21(0 1):18-25. Therefore, pharmacological targets that may suppress bladder afferent activity have been investigated for the treatment of interstitial cystitis / bladder pain syndrome. Such treatments include opioids, adenosine receptor agonists, and GlyT inhibitors.

[0004] The present disclosure provides certain ORL-1 receptor modulators useful for the treatment of interstitial cystitis / bladder pain syndrome. Summary of the Invention

[0005] The present disclosure provides a method of treating interstitial cystitis / bladder pain syndrome in a human subject identified as in need of such treatment, comprising administering to a subject a compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof. The compounds of formula (I) include all stereoisomers (e.g., enantiomers) and polymorphs thereof.

[0006] In some embodiments, the present disclosure provides a method of treating interstitial cystitis / bladder pain syndrome in a human subject identified as in need of such treatment, comprising administering to a subject a compound of formula (I'): [ka] or a pharma- ceutical acceptable salt thereof. As will be appreciated by those skilled in the art, the compound of formula (I') is a stereoisomer of the compound of formula (I).

[0007] In certain embodiments, the compound of formula (I) or formula (I') is administered as a tosylate salt. For example, in certain embodiments, the present disclosure provides a method of treating interstitial cystitis / bladder pain syndrome in a human subject in need of such treatment, comprising administering a compound of formula (IA): [ka] The method includes administering to a subject a therapeutically effective amount of a compound having the formula:

[0008] In one aspect, the disclosure provides a method for treating or alleviating symptoms associated with interstitial cystitis / bladder pain syndrome in a human subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof. In one such embodiment, the symptom is visceral pain. In another such embodiment, the symptom is urgency. In another such embodiment, administration of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, reduces the occurrence of nocturnal polyuria.

[0009] In certain embodiments, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is administered orally. Oral administration of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, results in high concentrations of the compound in the bladder.

[0010] In certain embodiments, the present disclosure provides a method for treating a patient suffering from sleep disorder and interstitial cystitis / bladder pain syndrome at the same time.Thus, in one aspect, the present disclosure provides a method for treating a human subject suffering from sleep disorder with interstitial cystitis / bladder pain syndrome, comprising administering a therapeutically effective amount of a compound having formula (I) or (I') or a pharmaceutically acceptable salt thereof to the subject.In some embodiments, the human subject suffers from insomnia.In some embodiments, the compound having formula (I) or (I') or a pharmaceutically acceptable salt thereof is administered at night. [Brief description of the drawings]

[0011] [Figure 1]Figure 1 shows that the basal responses to vehicle (saline), vehicle (CYP), ibuprofen / CYP, and compound of formula (IA) groups were similar. A: Nociceptive threshold. B: Nociceptive score. AUC 1-6. C: AUC 1-6g. D: AUC 6-26g. Results are expressed as ± sem. NSp>0.05, Kruskal-Wallis test, one-way ANOVA or two-way RM ANOVA with Sidak's post-hoc test. [Diagram 2] Time course of nociceptive threshold (g) after injection of CYP or saline in both vehicle groups is shown. Results are expressed as ± sem. ****p>0.0001, two-way RM ANOVA with Sidak's post-hoc test. [Diagram 3] Nociceptive scores (%) are shown 2 (A), 3 (B), 4 (C) and 24 (D) hours after injection of CYP in both vehicle groups. Results are expressed as ± sem. ****p<0.0001, 2-way RM ANOVA. [Figure 4] Time courses of AUC 1-6 g (A) and 6-26 g (B) following injection of CYP or saline in both vehicle groups are shown. Results are expressed as ± sem. *p<0.05 and ****p<0.0001, two-way RM ANOVA with Sidak's post-hoc test. [Diagram 5] Figure 1 shows the time course of nociceptive threshold (g) after CYP injection in the vehicle and ibuprofen groups. Results are expressed as ± sem. ****p<0.0001, two-way RM ANOVA with Sidak's post-hoc test. [Figure 6] Nociceptive scores (%) are shown 2 (A), 3 (B), 4 (C), and 24 (D) hours after injection of CYP in the vehicle and ibuprofen groups. Results are expressed as ± sem. ****p<0.0001, two-way RM ANOVA. [Figure 7]Time courses of AUC 1-6 g (A) and 6-26 g (B) after injection of CYP or saline in both vehicle and ibuprofen groups are shown. Results are expressed as ± sem. *p<0.05 and ****p<0.0001, two-way RM ANOVA with Sidak's post-hoc test. [Figure 8] Figure 1 shows the time course of nociceptive threshold (g) after CYP injection in the vehicle and compound of formula (IA) groups. Results are expressed as ± sem. NSp>0.05, **p<0.01, two-way RM ANOVA with Sidak's post-hoc test. [Figure 9] Nociceptive scores (%) are shown 2 hours (A), 3 hours (B), 4 hours (C) and 24 hours (D) after injection of CYP in the vehicle group and the compound of formula (1A) group. Results are expressed as ± sem. **p<0.01, ***p<0.001 **** and p<0.0001, two-way RM ANOVA. [Figure 10] Figure 1 shows the time course of AUC 1-6g (A) and 6-26g (B) following injection of CYP or saline in both vehicle and compound of formula (IA) groups. Results are expressed as ±sem. NSp>0.05, *p<0.05, **p<0.01, **p<0.001, and ****p<0.0001, two-way RM ANOVA with Sidak's post-hoc test. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present disclosure provides a method of treating interstitial cystitis / bladder pain syndrome in a human subject identified as in need of such treatment, comprising administering to the subject an agonist of the nociceptin opioid peptide receptor, also referred to as the ORL-1 receptor.

[0013] The identification of the ORL-1 receptor, which is distinct from the three major opioid receptor classes long known in the central nervous system (mu, kappa, and delta), came from experiments with these opioid receptor classes. The ORL-1 receptor showed no overlapping pharmacological properties with the classical mu opioid receptor, and thus the ORL-1 receptor was identified and classified as an opioid receptor based solely on amino acid sequence homology. Initially, it was demonstrated that nonselective ligands with high affinity for the mu, kappa, and delta opioid receptors have low affinity for the ORL-1 receptor. This feature, combined with the fact that an endogenous ligand has yet to be discovered, gave rise to the term "orphan receptor." See, e.g., Henderson et al., "The orphan opioid receptor and its endogenous ligand - nociceptin / orphanin FQ," Trends Pharmacol.Sci.18(8):293-300(1997). Subsequent investigations led to the isolation and structure of the endogenous ligand for the ORL-1 receptor (i.e., nociceptin; also known as orphanin FQ or OFQ), a 17 amino acid peptide structurally similar to members of the opioid peptide family. 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).

[0014] Nociceptin exerts inhibitory activity on the micturition reflex through interaction with ORL-1 in various animal models. Direct administration of nociceptin and peptide analogues of nociceptin to the bladder has been investigated as a means of alleviating urinary incontinence, presumably due to reduced afferent signaling. However, there remains a need for an effective treatment of lower urinary tract disorders, such as interstitial cystitis / bladder pain, based on orally available non-peptide small molecule modulators of the ORL-1 receptor.

[0015] The inventors have surprisingly discovered that a therapeutically effective amount of a compound of formula (I): [ka] It has been found that interstitial cystitis / bladder pain can be alleviated through administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0016] One particular embodiment has the structure shown below: [ka] or a pharma-ceutically acceptable salt thereof. In one embodiment, the pharma-ceutically acceptable salt of the compound of formula (I) is the para-toluenesulfonic acid salt (i.e., the tosylate salt) of the compound of formula (I) (referred to as the compound of formula (IA)), the structure of which is shown below: [ka]

[0017] Compounds of formula (I), (I'), and (IA) are prepared as described in U.S. Patent No. 8,476,221, which is incorporated herein by reference. As mentioned below, the compounds of the present disclosure include compounds of formula (I) and (I'), or their stereoisomers, pharma- ceutically acceptable salts (e.g., compounds of formula (IA)), polymorphs, solvates, or hydrates.

[0018] In certain embodiments, administration of a compound of Formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, also improves symptoms associated with interstitial cystitis / bladder pain, including, but not limited to, visceral pain and urinary urgency.

[0019] As used herein, the terms "treatment of," "treating," and related terms include alleviating, reducing, slowing, or cessation of a condition or its symptoms by administration of an effective amount of a compound of Formula (I) or (I'), or a pharma- ceutically acceptable salt thereof. In some embodiments, treating includes inhibiting, e.g., reducing 1) the overall frequency of episodes of a condition (e.g., interstitial cystitis / bladder pain); and / or 2) a symptom of the condition (e.g., visceral pain) or the severity of the condition or its symptoms; and / or 3) the duration of the condition or its symptoms.

[0020] In December 2019, the U.S. Food and Drug Administration (FDA) issued guidance for industry on the treatment of interstitial cystitis / bladder pain syndrome. According to the FDA guidance, a diagnosis of interstitial cystitis / bladder pain syndrome requires chronic bladder pain or discomfort accompanied by lower urinary tract symptom(s) such as urinary frequency, urgency, or nocturia, and other disorders such as malignancy, endometriosis, chronic prostatitis, and bladder outlet obstruction must be excluded. The FDA guidance further indicates that some patients suffering from interstitial cystitis / bladder pain syndrome may experience persistent bladder pain / discomfort. Other patients experience interstitial cystitis / bladder pain syndrome when urinating or as a burning sensation between urination as the bladder fills with urine.

[0021] As used herein, the terms "prevention of," "preventing," and related terms include avoiding the onset of a condition or a symptom thereof, or reducing the incidence or frequency of a condition or a symptom thereof, by administration of an effective amount of a compound of Formula (I) or (I'), or a pharma- ceutically acceptable salt thereof.

[0022] The term "effective amount," when used in connection with a method for treating or preventing interstitial cystitis / bladder pain by administering a compound of Formula (I) or (I'), or a pharma- ceutically acceptable salt thereof (e.g., a compound of Formula (IA)), refers to the amount of the compound administered to an animal that results in a therapeutic effect.

[0023] The compounds of formula (I) or (I'), or pharmaceutically acceptable salts thereof, exert beneficial effects through modulation of the ORL-1 receptor expressed on the afferent nerve / fiber terminals of the lower urinary tract. The terms "modulate", "modulating" and related terms as used herein with respect to the ORL-1 receptor mean to mediate a pharmacodynamic response (e.g., interstitial cystitis / bladder pain) in animals by (i) inhibiting or activating the receptor, or (ii) directly or indirectly affecting the normal regulation of receptor activity. Compounds that modulate receptor activity include agonists, partial agonists, biased agonists, antagonists, mixed agonists / antagonists, mixed partial agonists / antagonists, and compounds that directly or indirectly affect the regulation of receptor activity. The compounds of formula (I) or (I'), and pharmaceutically acceptable salts thereof, are partial agonists. As used herein, a compound that binds to a receptor and is only partially effective as an agonist is defined as a "partial agonist". The partial agonists of the present disclosure can achieve the desired therapeutic effect (e.g., treatment of interstitial cystitis / bladder pain) without the side effects that often accompany the administration of full agonists.

[0024] The compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, may be administered as a component of a composition comprising a pharma- ceutically 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. In yet another embodiment, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is delivered in a controlled or sustained release system. Controlled or sustained release pharmaceutical compositions may have a common goal of improving drug therapy over that achieved by their non-controlled or non-sustained release counterparts. For example, controlled or sustained release pharmaceutical compositions may provide the following benefits compared to their non-controlled or non-sustained release counterparts: reduced frequency of administration; increased duration of effect; increased magnitude of effect, e.g., C at the site(s) of action; max Decrease in or C average improved safety / tolerability; and improved patient compliance (less frequent dosing, better tolerability).

[0025] In one embodiment, the controlled or sustained release composition comprises a pharma- ceutically acceptable amount of the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, for long-term treatment or prevention of interstitial cystitis or its symptoms.The advantages of the controlled or sustained release composition include extended drug activity, reduced dosing frequency, and increased compliance.The administration of the compound of formula (I) or (I'), or a pharma-ceutically acceptable salt thereof, can be by controlled or sustained release means, or delivery devices known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Many other controlled or sustained release delivery devices are known to those skilled 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 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, polymeric materials may be used (Goodson; Smolen et al., "Drug Product Design and Performance," Controlled Drug Bioavailability Vol. 1, John Wiley and Sons, New York (1984); Langer et al., "Chemical and Physical Structure of Polymers as Carriers for Controlled Release of Bioactive Agents: A Review," J. Macromol. Sci. Rev. Macromol. Chem. C23(1):61-126 (1983); Levy et al., "Inhibition of Calcification of Bioprosthetic Heart Valves by Local Controlled-Release Diphosphonate," Science 228:190-192 (1985); During et al., "Controlled Release of Dopamine from a Polymeric Brain Implant: In Vivo Characterization," Ann. Neurol. 25:351-356 (1989); and Howard et al., "Intracerebral drug delivery in rats with (see, "lesion-induced memory deficits," J. Neurosurg. 71:105-112 (1989)).

[0026] Suitable dosage forms can be used to provide controlled or sustained release of one or more active ingredients, for example, hydropropylmethylcellulose, ethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, multiparticulates, liposomes, microspheres, or combinations thereof, to provide 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 easily selected for use with the active ingredients of the present disclosure.Therefore, the present disclosure encompasses single unit dosage forms suitable for oral administration that are adapted for controlled or sustained release, such as, but not limited to, tablets, capsules, gel caps, and caplets.

[0027] The composition may optionally (but preferably) further comprise a suitable amount of a pharma- ceutically acceptable excipient to provide a form for proper administration to an animal (e.g., a human). Such pharmaceutical excipients may be diluents, suspending agents, solubilizers, binders, disintegrants, preservatives, coloring agents, lubricants, and the like. The pharmaceutical excipients may be liquids such as water or oils (including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like). The pharmaceutical excipients may be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants, and coloring agents may be used. In one embodiment, the pharma-ceutically acceptable excipients are sterile when administered to an animal. Water is a particularly useful excipient when the compound of formula (I) or (I'), or a pharma-ceutically acceptable salt thereof, is administered intravenously. Physiological saline solution and aqueous solutions of dextrose and glycerol can also be used as liquid excipients, particularly for injection solutions.Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, 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 contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if necessary.Specific examples of pharma-ceutically 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 in Radebough et al., “Preformulation,” pp. 1447-1676 in Remington's Pharmaceutical Sciences Vol. 2 (Gennaro, ed., 1999), incorporated herein by reference. th Ed., Mack Publishing, Easton, PA, 1995).

[0028] In one embodiment, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is formulated according to routine procedures as a composition adapted for oral administration to humans. The compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, delivered orally, may be in the form of, for example, a tablet, capsule, gelcap, caplet, lozenge, aqueous or oily solution, suspension, granule, microparticle, multiparticulate, powder, emulsion, syrup, or elixir. When the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is incorporated into an oral tablet, such tablet may be compressed, powdered, enteric coated, sugar coated, film coated, multiple compressed, or multi-layered. Techniques and compositions for making solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman et al., eds., 2001). nd Ed., Marcel Dekker, Inc., 1989 and 1990. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin), and pills are also described in King, “Tablets, Capsules, and Pills,” pp. 1553-1593 in Remington's Pharmaceutical Sciences (Osol, ed., 16 th Ed., Mack Publishing, Easton, PA, 1980).

[0029] Liquid oral dosage forms include aqueous and non-aqueous solutions, emulsions, suspensions, and solutions and / or suspensions reconstituted from non-effervescent granules, optionally containing one or more suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, colorants, flavoring agents, etc. Techniques and compositions for making liquid oral dosage forms are described in Pharmaceutical Dosage Forms: Disperse Systems (Lieberman et al., eds., 2003). ndEd., Marcel Dekker, Inc., 1996 and 1998).

[0030] Orally administered compounds of formula (I) or (I'), or pharma- ceutically acceptable salts thereof, can include one or more excipients, such as sweeteners, such as fructose, aspartame, or saccharin; flavorings, such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives, to provide a pharma- cetically palatable preparation. Furthermore, when in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these latter platforms, fluid from the capsule's surrounding environment is imbibed by the driving compound, which expands and forces the drug or drug composition through an opening. These delivery platforms can provide an essentially zero order delivery profile, as opposed to the spiked profiles of immediate release formulations. Time-delay materials, such as glycerol monostearate or glycerol stearate, can also be used. Oral compositions 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.

[0031] The composition may 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, multiparticulate, fast dissolving film, or other form for oral or mucosal administration, or any other form suitable for use. In one embodiment, the composition is in the form of an ODT (see, e.g., U.S. Pat. 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. Pat. 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. Pat. No. 5,698,155). In another embodiment, the composition is in a form suitable for buccal administration, for example, as a tablet, lozenge, gel, patch, or film formulated in a conventional manner (see, 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, for example, as a polymeric film comprising 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.

[0032] In one embodiment, the compound of formula (I) or (I') or its pharmaceutically acceptable salt is formulated for parenteral administration. When the compound of formula (I) or (I') or its pharmaceutically acceptable salt is parenterally injected, it can be in the form of, for example, an isotonic sterile solution. In one embodiment, parenteral administration includes the compound of formula (IA).

[0033] When the compound of formula (I) or (I') or a pharma- ceutically acceptable salt thereof (e.g., the compound of formula (IA)) is administered parenterally, the formulation for parenteral administration may be in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle. Such formulations may further contain one or more pharma- ceutical necessary additives, such as stabilizers, suspending agents, dispersing agents, buffers, etc. The compound of formula (I) or (I') or a pharma- ceutical acceptable salt thereof (e.g., the compound of formula (IA)) may also be in the form of a powder for reconstitution as an injectable formulation.

[0034] In another embodiment, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof (e.g., the compound of formula (IA)) may be formulated for intravenous administration. In certain embodiments, the composition for intravenous administration comprises a sterile isotonic aqueous buffer. If necessary, the composition may also comprise a solubilizing agent. The compound of formula (I) or (I'), or a pharma-ceutically acceptable salt thereof (e.g., the compound of formula (IA)) for intravenous administration may optionally comprise a local anesthetic, such as benzocaine or prilocaine, to ease pain at the injection site. Generally, the ingredients are supplied in unit dosage form, either separately or mixed together, as a dry lyophilized powder or water-free concentrate, for example, in a hermetically sealed container, such as an ampoule or sachet indicating the quantity of active agent. The compound of formula (I) or (I'), or a pharma-ceutically acceptable salt thereof (e.g., the compound of formula (IA)), when administered by infusion, may be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where a compound of Formula (I) or (I'), or a pharma- ceutically acceptable salt thereof (e.g., a compound of Formula (IA)), is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0035] The compound of formula (I) or (I') is excreted largely unchanged, primarily via urine. See Example 2. Thus, the compound of formula (I) or (I') exhibits high concentrations in the bladder after administration. For example, when administered orally, the compound of formula (I) or (I') excreted in urine ranges from about 30% to about 95%, depending on the dose administered. Furthermore, the concentration of the compound of formula (I) or (I') in urine is maintained up to 24 hours after oral administration at a particular dose. In certain embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration is greater than 100 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration is greater than 500 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration is greater than 1,000 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration is greater than 5,000 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration is greater than 10,000 nM. In certain embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration can range from about 100 nM to about 30,000 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration can range from about 500 nM to about 15,000 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration can range from about 1,000 nM to about 10,000 nM.

[0036] In some embodiments, the compound of formula (I) or (I') is administered in the form of a pharma- ceutically acceptable salt. As used herein, the term "pharma-ceutically acceptable salt" refers to any pharma- ceutically acceptable salt that can be prepared from a compound 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, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts). In one embodiment, the pharma- ceutically acceptable salt is a hydrochloride, sulfate, sodium salt, potassium salt, benzenesulfonate, para-toluenesulfonate, or fumarate salt. In another embodiment, the pharma- ceutically acceptable salt is a hydrochloride or sulfate salt. In another embodiment, the pharma- ceutically acceptable salt is a hydrochloride salt. In another embodiment, the pharma- ceutically acceptable salt is a sulfate salt. In another embodiment, the pharma- ceutically acceptable salt is a sodium salt. In another embodiment, the pharma- ceutically acceptable salt is a potassium salt. In another embodiment, the pharma- ceutically acceptable salt is a fumarate salt. In another embodiment, the pharma- ceutically acceptable salt is a para-toluenesulfonate salt (also known as a "tosylate salt"). In another embodiment, the pharma- ceutically acceptable salt is a choline salt.

[0037] In another embodiment, the pharma- ceutically acceptable para-toluenesulfonic acid salt contains 1 equivalent of the compound of formula (I) or (I') and about 1.0 equivalent of 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 equivalents to about 1.01 equivalents of para-toluenesulfonic acid. In another embodiment, the pharma- ceutically acceptable para-toluenesulfonic acid salt contains about 1 equivalent of the compound of formula (I) or (I') and about 1 equivalent of para-toluenesulfonic acid (i.e., it is a monotosylate salt). In another embodiment, the pharma-ceutically acceptable para-toluenesulfonate salt contains one equivalent of a compound of formula (I) or (I'). In another embodiment, the pharma-ceutically acceptable para-toluenesulfonate salt contains one equivalent of a compound of formula (I'), i.e., the monotosylate salt of the compound of formula (I') (i.e., the following formula (IA): [ka] It contains the compound

[0038] The disclosed method provided herein also encompasses the use of any solvate of the compound of formula (I), (I') or a pharmaceutically acceptable salt thereof. A "solvate" is generally known in the art and is herein considered to be a combination, physical association, and / or solvation of the compound of formula (I), (I') or a pharmaceutically acceptable salt thereof. This physical association may include varying 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), (I') or a pharmaceutically acceptable salt thereof is constant. The compound of formula (I), (I') or a pharmaceutically acceptable salt thereof may exist as a solvate form with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, etc.

[0039] The methods of the disclosure provided herein also encompass the use of any crystalline form (or polymorph) of the compound of formula (I), (I') or a pharma- ceutically acceptable salt thereof. As used herein, the term "crystalline" and related terms, when used to describe a substance, component, or product, means that the substance, component, or product is substantially crystalline as determined by X-ray diffraction, microscopy, polarized light microscopy, or other known analytical procedures known to those 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 resulting from diverse molecular conformations and molecular packing. Polymorphs of a single compound may 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 flow, water absorption, compaction, and particle morphology. Differences in stability can be due to changes in chemical reactivity (e.g., differential oxidation such that a dosage form discolors more quickly when composed of one polymorph than when composed of another), or mechanical changes (e.g., crystals change on storage as a kinetically favored polymorph converts to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another).

[0040] 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 by reference. In some embodiments, the compound of formula (IA) is of crystalline form A. In other embodiments, the compound of formula (IA) is of crystalline form B. In other embodiments, the compound of formula (IA) is of crystalline form C. In other embodiments, the compound of formula (IA) is of crystalline form D. In other embodiments, the compound of formula (IA) is of crystalline form E.

[0041] As used herein, the amount by weight of "dose", "dosage amount" and related terms to be administered refers to the free acid and free base form, i.e., non-salt form, of the compound of formula (I) or (I'). For example, a dose of 10.0 mg of the compound of formula (I) or (I') in non-salt form means that 10.0 mg is actually administered. However, as an example, a dose of 10.0 mg of, for example, the monohydrochloride or 1:1 molar hydrochloride salt of the compound of formula (1) means that 10.84 mg of the compound is actually administered, which 10.84 mg results in 10.00 mg of the compound of formula (I) or (I') in non-salt form (0.0229 mmol) and 0.84 mg of hydrochloric acid (0.0229 mmol). Similarly, a dose of 10.00 mg of, for example, the monotosylate salt (1:1 molar para-toluenesulfonic acid salt) of a compound of formula (IA) means that 13.93 mg of said compound is actually administered, which 13.93 mg results in 10.00 mg of the non-salt form of compound of formula (I') (0.0229 mmol) and 3.93 mg of para-toluenesulfonic acid (0.0229 mmol).

[0042] With respect to methods for treating or preventing a condition or symptom in a human subject, a suitable effective dosage of a compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is, in one embodiment, from about 0.00002 mg / kg to about 10 mg / kg of the human subject's body weight 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 10 mg / kg / day. In certain embodiments, a suitable effective dosage of a compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof (e.g., a compound of formula (IA)) is about 0.00002 mg / kg / day to about 10 mg / kg / day, about 0.001 mg / kg / day to about 10 mg / kg / day. In another embodiment, the effective dosage is about 1.0 mg / kg / day or less. With respect to these dosages, the term "day" should be understood to mean a 24-hour cycle beginning at the time of administration of a compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof. It is generally understood that suitable doses can be extrapolated between animals and humans (Nair et al., J. Basic Clin. Pharm., March-May 2016;7(2):27-31).

[0043] In embodiments where a compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof (e.g., a compound of formula (IA)) is orally administered, a suitable effective dosage of the compound as a single dose is about 0.001 mg to about 300 mg, about 0.005 mg to about 250 mg, about 0.01 mg to about 200 mg, about 0.05 mg to about 150 mg, about 0.075 mg to about 50 mg, or about 0.10 mg to about 10 mg. In one embodiment, the compound of the present disclosure is administered as a single dose of a non-controlled or non-sustained release formulation. In another embodiment, the effective dosage of the compound of the present disclosure is administered as multiple doses of a non-controlled or non-sustained release formulation.

[0044] In certain embodiments, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.100 mg, about 0.120 mg, about 0.125 mg, about 0.150 mg, about 0.175 mg, about 0.200 mg, about 0.225 mg, about 0.250 mg, about 0.275 mg, about 0.30 mg, about 0.35 mg, about 0.40 mg, about 0.45 mg, about 0.50 mg, about 0.55 mg, about 0.60 mg, about 0.65 mg, about 0.70 mg, about 0.75 mg, about 0.80 mg, about 0.85 mg, about 0.90 mg, about 0.95 mg, About 1.00mg, about 1.25mg, about 1.50mg, about 1.75mg, about 2.00mg, about 2.25mg, about 2.50mg, about 2.75mg, about 3.00mg, about 3.25mg, about 3.50mg, about 3.75mg, about 4.0mg, about 4.5mg, about 5.0mg, about 5.5mg, about 6.0mg, about 6.5mg, about 7.0mg, about 7.5mg, about 8.0mg, about 9.0mg or about 10mg of the compound of formula (I) or (I'), or its pharma- ceutically acceptable salt (e.g., the compound of formula (IA)) is orally administered to a human subject in need thereof.As known to those skilled in the art, for human animals, the daily dose (mg) can be converted to mg / kg / day dosage by dividing the mg dose by 60kg, which is the average mass of a human animal recognized in the art. For example, a single daily dose of 12 mg in humans thus translates to a dosage of approximately 0.20 mg / kg / day.

[0045] In certain embodiments, the controlled release composition comprising a therapeutically effective amount of the disclosed compound is administered as a single dose or multiple doses.The controlled release composition may contain up to 100 times the dose of the compound of formula (I) or (I') or its pharma- ceutically acceptable salt (e.g., the compound of formula (IA)) used in a non-controlled or non-sustained release formulation.

[0046] In some embodiments, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, may be administered once a day. In some such embodiments, the compound of formula (I) is administered every night. As shown in Example 2, daily administration of the compound of formula (I), (I'), or (IA) results in urinary concentrations that are well above the in vitro activity of the compound.

[0047] In addition to the beneficial effect of treating conditions associated with interstitial cystitis, compounds of formula (I), (I'), or (IA) can also induce sleepiness and treat sleep disorders when administered at sufficient dosage levels. See U.S. Patent Publication No. 2020 / 0345726, incorporated herein by reference. Patients suffering from symptoms associated with interstitial cystitis often suffer from poor sleep quality, insomnia, and / or nocturia. In some embodiments, the patient suffering from sleep disorders is a woman aged 50 years or older. In other embodiments, the patient suffering from sleep disorders is a man aged 50 years or older. Nightly administration of a compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, improves both sleep quality and symptoms associated with interstitial cystitis. In certain embodiments, a compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is administered by the patient every night before sleep. For example, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, may be administered about 1 minute to about 3 hours before sleep. In some embodiments, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, may be administered about 5 minutes to about 60 minutes before sleep. In other embodiments, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, may be administered about 10 minutes to about 30 minutes before sleep.

[0048] In one embodiment, an effective dose or dosage of a compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is administered about 60 minutes before the median habitual bedtime of a human. In another embodiment, an effective dose or dosage is administered about 45 minutes before the median habitual bedtime of a human. In another embodiment, an effective dose or dosage is administered about 30 minutes before the median habitual bedtime of a human. In another embodiment, an effective dose or dosage is administered about 20 minutes before the median habitual bedtime of a human. In another embodiment, an effective dose or dosage is administered about 20 minutes or less before the median habitual bedtime of a human. In another embodiment, an effective dose or dosage is administered about 15 minutes before the median habitual bedtime of a human. In another embodiment, an effective dose or dosage is administered about 15 minutes or less before the median habitual bedtime of a human. In another embodiment, an effective dose or dosage is administered about 10 minutes before the median habitual bedtime of a human. In another embodiment, the effective dose or dosage is administered about 10 minutes or less before the median habitual bedtime of a human. In another embodiment, the effective dose or dosage is administered about 5 minutes before the median habitual bedtime of a human.

[0049] In other embodiments, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, may be administered multiple times per day. For example, the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered twice a day or three times a day. In embodiments in which the compound is administered multiple times per day, each dose may be administered in the same or different amounts. In some embodiments, a dose of the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is administered in a higher dose than other doses provided earlier in the day. In some embodiments, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is administered twice a day, about every 12 hours. In other embodiments, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is administered three times a day, about every 8 hours.

[0050] In certain embodiments, the compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, is administered twice daily, with the second dose (i.e., the second therapeutically effective amount) being administered before bedtime as described above. In some such embodiments, the second dose is administered in an amount greater than the first dose (i.e., the first therapeutically effective amount). For example, the second dose may 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 may be administered in an amount about 1.5-fold to about 10-fold greater than the first dose. In other embodiments, the second dose may be administered in an amount about 1.5-fold to about 100-fold greater than the first dose. In other embodiments, the second dose may be administered in an amount about 1.5-fold to about 1000-fold greater than the first dose. In other embodiments, the second dose may be administered in an amount that is about 3 to about 100 times greater than the first dose. In other embodiments, the second dose may be administered in an amount that is about 3 to about 1000 times greater than the first dose. In other embodiments, the second dose may be administered in an amount that is about 5 to about 100 times greater than the first dose. In other embodiments, the second dose may be administered in an amount that is about 5 to about 1000 times greater than the first dose. Such an administration schedule ensures that in a human subject, the first dose is effective to treat interstitial cystitis and symptoms associated with interstitial cystitis without leaving drowsiness, while the second dose is effective to treat interstitial cystitis and symptoms associated with interstitial cystitis and to produce drowsiness or induce sleep. In certain embodiments, both the first and second doses are administered via (the same or different) non-controlled or non-sustained release formulations. In other embodiments, the first dose is administered via a controlled or non-sustained release formulation and the second dose is administered via a non-controlled or non-sustained release formulation.

[0051] In another embodiment, the composition comprising the disclosed compound is useful as a medicament in the treatment of human subjects suffering from both interstitial cystitis / bladder pain and certain sleep disorders.Such sleep disorders include, but are not limited to, insomnia, hypersomnia, circadian rhythm sleep-wake disorder, alcohol-induced sleep disorder, or any combination thereof.Other sleep disorders include alcohol-induced sleep disorder (e.g., insomnia-type alcohol-induced sleep disorder, daytime sleepiness-type alcohol-induced sleep disorder, parasomnia-type alcohol-induced sleep disorder, and mixed alcohol-induced sleep disorder); insomnia in alcohol use disorder, sleep disturbance associated with alcohol withdrawal (e.g., insomnia associated with alcohol withdrawal), or any combination thereof.

[0052] The method for treating or preventing interstitial cystitis / bladder pain in a patient in need thereof may further comprise co-administering a compound of formula (I) or (I'), or a pharma- ceutically acceptable salt thereof, and a second therapeutic agent to the patient. In one embodiment, the second therapeutic agent is also administered in an amount effective to achieve its desired therapeutic effect. In one embodiment, the second therapeutic agent is an antimuscarinic agent. In some such embodiments, the antimuscarinic agent is oxybutynin. In other such embodiments, the antimuscarinic agent is tolterodine. In other such embodiments, the antimuscarinic agent is trospium. In other such embodiments, the antimuscarinic agent is solifenacin. In other such embodiments, the antimuscarinic agent is darifenacin. In other such embodiments, the antimuscarinic agent is flavoxate. EXAMPLES

[0053] Example 1: Cyclophosphamide-induced visceral pain mode 1 in interstitial cystitis / bladder pain syndrome Cyclophosphamide (CYP)-induced inflammatory visceral pain is a well-established experimental model of interstitial cystitis / bladder pain syndrome. Intraperitoneal (ip) injection of CYP was able to reproduce most of the characteristics of interstitial cystitis / bladder pain syndrome in humans, such as increased micturition frequency, decreased urine volume per micturition, and visceral pain (Takagi-Matsumoto et al., 2004; Boucher et al., 2000; Smaldone et al., 2009). Therefore, the CYP-induced cystitis model is widely used in rats for the evaluation of candidate compounds (Juszczak et al., 2007). CYP is an antitumor agent that is widely used to treat malignant tumors such as lymphoma and leukemia. CYP administered into the peritoneum is converted in the kidney to the toxic metabolite acrolein, which accumulates in the bladder and damages the urinary tract (Cox, 1979).

[0054] In female Sprague-Dawley rats, a single ip injection of CYP was shown to induce bladder inflammation and visceral pain-associated behaviors that peaked immediately after CYP injection and persisted for up to 24 hours (Lluel et al., 2010 and Auge et al., 2011 and 2013). CYP-induced visceral pain is characterized by both mechanically-associated hyperalgesia (increased sensitivity to pain) and allodynia (a nociceptive response elicited by normally innocuous stimuli) (Auge et al., 2013).

[0055] The purpose of this study was to evaluate the effect of a single oral dose of 30 mg / kg of the compound of formula (IA) on visceral pain in a CYP-induced acute cystitis model in female Sprague-Dawley rats. Ibuprofen (300 mg / kg, po) was used as the active substance. Visceral pain was assessed in a blinded manner by the von Frey test.

[0056] 1.1 Study design 1.1.1 Protocol Design On day 1 ("D1"), the day before cystitis induction, rats were acclimated to individual Plexiglas boxes (minimum 30 min) and to the application of von Frey filaments in order to reduce the level of stress due to the novel environment. Acclimation was performed under exactly the same experimental conditions as pain assessment (see §2.4.1 for details). On day 0 ("D0"), the von Frey test was first performed to obtain baseline nociceptive behavior. · Immediately prior to induction of cystitis on D0, pharmacological treatments were performed as described in §2.4.2. On D0, acute cystitis was induced by CYP injection. Control rats received saline (see §2.4.3 for details) (D0, T=0).

[0057] On D0 and D1, von Frey tests were performed 2, 3, 4, and 24 hours after induction of cystitis to analyze the effects of test substances and positive substances on CYP-induced visceral pain (D0, T=+2 hours, T=+3 hours, T=+4 hours, and D1, T=+24 hours). Rats were euthanized immediately after the last von Frey test.

number

[0058] 1.1.2 Experimental group Four experimental groups were included as described in the table below. [Table 1]

[0059] 1.2 Animals All experiments were performed in accordance with the European Community Council Directive 2010 / 63 / UE and the French Ministry for Agriculture, Agrifood and Forestry Decree 2013-118. The experimental protocol was reviewed by the Ethics Committee for the Protection of Animals Used for Scientific Purposes (CEEA-122) and approved by the French Ministry of Education, Higher Education and Research under number APAFIS#21140-2019062010159601 v2.

[0060] Female Sprague-Dawley rats were acclimated to laboratory conditions for at least 3 days before the start of the experiment. Animals were housed in groups of 3 in polysulfone Sealsafe Plus 1291H cages (Tecniplast, Lyon, France) with wood chip (Souralit, Girona, Spain) bedding and had free access to food (Rodent Maintenance Diet A04 / 10 from Safe) and water (0.2 μm filtered water). Species-appropriate environmental enrichment (Aspen bricks, Plexx, Uden, Netherlands) was added to the cages. The animal room was maintained under artificial lighting (12 h) from 7:00 am to 7:00 pm with a controlled ambient temperature of 22 ± 2 °C and relative humidity maintained at 55 ± 10%.

[0061] 1.3 Substance 1.3.1 Test substances and vehicles 1.3.1.1 Preparation of the formulation A formulation of compound of formula (IA) was prepared at room temperature at a final concentration of 6 mg / mL (based on the free base form). The appropriate mass of compound of formula (IA) was weighed and the vehicle was slowly added to a porcelain mortar. The powder was ground with a pestle until a suspension was obtained. Aliquots of the suspension were made (1 aliquot / dose) and kept at +4° C. for up to 3 days. On each experimental day, the suspension was equilibrated to room temperature for at least 30 minutes before administration.

[0062] 1.3.1.2 Vehicle The vehicle was 0.5% methylcellulose (MC) with a viscosity of 400 cP. It was prepared in water for injection (WFI) and kept at 4° C. for 1 week. MC (batch number SLBR8963V) was purchased from Sigma-Aldrich (Saint-Quentin Fallavier, France).

[0063] 1.3.2 Positive substances Ibuprofen was freshly prepared at a final concentration of 60 mg / mL (free base form) on each day of administration. An appropriate mass of ibuprofen was weighed and dissolved in the vehicle at room temperature. The solution was vortexed for 15-30 seconds, then sonicated for 1 minute, then vortexed for an additional 15-30 seconds. Ibuprofen was purchased from Sigma-Aldrich (Batch No. BCBR4459V).

[0064] 1.3.3 Anaesthetic / euthanasia substances Dolethal® was purchased from Vetoquinol via Centravet (Lapalisse, France, batch number 9C2800C).

[0065] 1.3.4 Further substances CYP was purchased from Sigma-Aldrich (batch number MKCG5464). Saline was purchased from B-Braun via Centravet (batch number 18465450). WFI was obtained from Cooper (Melun, France; batch number 19MD16GA).

[0066] 1.4 Test Protocol 1.4.1 Assessment of visceral pain using von Frey filaments To minimize variability in behavior-based pain testing, standardized conditions were applied, including single-experimenter testing of all animals.

[0067] Visceral pain was assessed blindly by applying a set of eight calibrated von Frey filaments of increasing force (1, 2, 4, 6, 8, 10, 15, and 26 g) with a 5-second interstimulus interval to the lower abdomen near the bladder. Prior to testing, the abdominal area designated for mechanical stimulation was shaved for each animal. Animals were placed on an elevated wire mesh floor under individual transparent Plexiglas boxes and allowed to acclimate for at least 30 minutes before starting the von Frey test. The filament was then applied for 1-2 seconds through the mesh floor with enough force to cause a slight bending of the filament. Each filament was tested three times. Care was taken to stimulate different areas of the lower abdominal region near the bladder to avoid desensitization.

[0068] For each animal and each filament, nociceptive behavior was scored as follows: [Table 2]

[0069] 1.4.2 Pharmacological treatment Prior to the experiment, animals were randomly assigned to treatment groups using a blocking method, which consisted of distributing at least one animal per treatment or control within the same block.

[0070] The compound of formula (IA) (30 mg / kg), ibuprofen (300 mg / kg), and vehicle were administered orally (po) once immediately prior to injection of CYP or saline. On the morning of each experimental day, rats were weighed and dosed in a volume of 5 mL / kg.

[0071] 1.4.3 Induction of acute cystitis To induce acute cystitis, CYP was injected ip once at a dose of 150 mg / kg in a final volume of 5 mL / kg (in saline). Control rats received saline under the same experimental conditions as CYP.

[0072] 1.5 Laboratory Equipment Mechanical stimulation was performed using von Frey filaments of different strengths (reference: Bio-VF-M; BioSeb ID Tech, Vitrolles, France). Filaments were purchased and pre-calibrated. Animals were weighed using a LS620C balance (PRECISA, Dietikon, Switzerland).

[0073] 1.6 Presentation and analysis of results All raw data were compared by two individuals prior to data analysis. Results are expressed as mean ± standard error of the mean (sem). 1.6.1 Visceral pain [Table 3]

[0074] 1.7 Statistical analysis Statistical analysis and graphing were performed using GraphPad Prism® (GraphPad Software Inc., La Jolla, Calif., USA). A p-value <0.05 was accepted as statistically significant.

[0075] Except when two-way analysis was applied, data were tested for normal distribution (Shapiro-Wilk normality test) and their variance was assessed (F test or Bartlett test for two or more groups, respectively) before any statistical tests were performed. Consequently, the appropriate statistical test was applied.

[0076] 1.7.1 Comparison of basal nociceptive responses Group comparisons were performed between all groups to demonstrate that all groups had similar baseline values, followed by post-hoc tests. Post-hoc tests were performed to analyze where potential differences between groups occurred. For ease of viewing the graphs, results of post-hoc tests were not shown when p>0.05. - The Kruskal-Wallis test was used as a non-parametric analysis of variance (ANOVA) with Dunn's multiple comparisons. - One-way ANOVA test was used as parametric ANOVA with Holm-Sidak multiple comparisons. - Repeated measures (RM) two-way ANOVA followed by Holm Sidak's multiple comparisons was used for nociceptive scores.

[0077] 1.7.2 Time course analysis of CYP effects To analyze the effects of CYP, individual pairwise comparisons were performed between the vehicle / saline and vehicle / CYP groups.

[0078] A two-way RM ANOVA with Sidak's post-hoc test was applied, which indicates whether there was an overall difference between the groups, whereas Sidak's post-hoc test compares the means at each time point (+2, 3, 4, and 24 h).

[0079] 1.7.3 Time Course Analysis of the Effects of Ibuprofen or Compounds of Formula (IA) To analyze the effect of the substances on CYP-induced acute cystitis, individual pairwise comparisons were performed between the ibuprofen / CYP or compound of formula (IA) / CYP groups and the vehicle / CYP group.

[0080] A two-way RM ANOVA with Sidak's post-hoc test was used, which indicates whether there was an overall difference between the groups, whereas Sidak's post-hoc test compares the means at each time point (+2, 3, 4, and 24 hours).

[0081] When individual pairwise comparisons were performed, statistical significance was indicated by the symbol “ * " and non-significance is indicated by " ns Please note that for group comparisons, statistical non-significance was indicated with the symbol "NS."

[0082] 1.8 Results 1.8.1 Baseline responses were similar within the various experimental groups The basal (before CYP or saline injection) nociceptive responses were similar among all experimental groups. In fact, no significant differences in nociceptive parameters were observed among all experimental groups before CYP or saline injection (p>0.05, Figure 1A-D).

[0083] 1.8.2 CYP (150 mg / kg ip) induced visceral pain for up to 24 hours after injection. To confirm CYP-induced visceral pain, a comparison of nociceptive responses between saline- or CYP-injected rats within the vehicle group was performed.

[0084] At all time points evaluated (i.e., 2 h to 24 h), CYP was found to induce a significant decrease in the nociceptive threshold compared to saline (p<0.0001, Figure 2). The shape of the time course curves showed that the magnitude of the effect of CYP was relatively low at 2 h, but remained comparable from +3 to +24 h.

[0085] Furthermore, CYP was found to induce a significant increase in nociceptive scores compared to saline at all time points evaluated (p<0.0001, Figures 3A-D).

[0086] In parallel with the effect of CYP on nociceptive scores, there was an overall significant increase in AUC 1-6g (p<0.0001, Fig. 4A). Consistent with the results above, the effect of CYP was relatively less pronounced at +2 h compared to saline-injected rats and remained comparable at +3-24 h (p<0.05 and p<0.0001 for +2 h and +3-24 h, respectively, Fig. 4A). Finally, within the vehicle group, CYP-injected rats showed a significant increase in AUC 6-26g at all time points (p<0.0001, Fig. 4B).

[0087] 1.8.3 Ibuprofen (300 mg / kg, po) reduced CYP-induced visceral pain After CYP injection, ibuprofen-treated rats showed a significant overall increase in nociceptive threshold compared to vehicle (p<0.0001, Figure 5). Post-hoc statistical analysis of the means at each time point showed that there was a small and gradual decrease in the ibuprofen effect over time, but the level of significance was greatest at all time points evaluated (p<0.0001, Figure 5).

[0088] In addition, ibuprofen significantly reduced nociceptive scores over the entire observation period (p<0.0001, Figures 6A-D).

[0089] Ibuprofen treatment resulted in an overall decrease in the corresponding AUC 1-6g (p<0.0001, FIG. 7A). When the means were statistically compared at each time point (i.e., post-hoc test), it was noted that the level of significance at +2 h was lower compared to the other time points (p<0.05 vs. p<0.0001 at +2 h and +3-+24 h, respectively, FIG. 7A), although the values ​​themselves were in the same range (5.5±5.5 and 6.6±4.4 at +2 h and +3 h, respectively). This can be explained by the relatively low degree of CYP influence at +2 h within the vehicle group (FIG. 4A).

[0090] Figure 7B shows that ibuprofen caused a significant overall decrease in AUC 6-26 g compared to vehicle (p<0.0001, Figure 7B). The ibuprofen effect was slightly and progressively reduced over time, but significance reached the highest level at all time points (p<0.0001, Figure 7B).

[0091] 1.8.4 Compound of formula (IA) (30 mg / kg, po) reduced and reversed CYP-induced visceral pain In CYP-injected rats, an overall inhibitory effect of the compound of formula (IA) on the nociceptive threshold was observed when compared to vehicle (p>0.01, FIG. 8). Comparison at specific time points (i.e., post-hoc analysis) showed that the statistical significance level was reached only at +3 h (p>0.01, FIG. 8). However, it is noteworthy that at +2 h and +3 h the values ​​of the compound of formula (IA) were in a similar range (6.6±0.8 vs. 6.3±1.2 at +2 h and +3 h, respectively). Thus, the lack of significance at +2 h could be explained by the lowest extent of the influence of CYP at +2 h (see §4.2). From +3 h onwards, the effect of the compound of formula (IA) tapered over time (4.8±0.8 and 3.7±0.8 at +4 h and +24 h, respectively).

[0092] Compared to vehicle, a significant reduction in nociceptive scores was observed in the compound of formula (IA) group starting from 2 hours to 24 hours after CYP injection (p<0.01, FIG. 9). The highest level of significance was obtained at +3 hours (p<0.001, FIG. 9B).

[0093] The reduction in nociceptive scores by treatment with the compound of formula (IA) was accompanied by an overall decrease in AUC 1-6g (p<0.001, FIG. 10A). In agreement with the results of the nociceptive threshold, the highest level of significance was reached at +3 h (p<0.01, FIG. 10A), although the values ​​themselves were in a similar range at +2 and +3 h (19.8±6.9 and 19.3±6.3 at +2 and +3 h, respectively). After 3 h, the efficacy of the compound of formula (IA) was slightly and progressively reduced over time (34.1±7.9 and 61.8±15.7 at +4 and +24 h, respectively).

[0094] Finally, the compound of formula (IA) caused a significant overall inhibitory effect on the CYP-induced increase in AUC 6-26g (p<0.0001, FIG. 10B). Statistical significance was achieved at all time points, with levels being higher at earlier time points (p<0.001 at +2 and +3 h, p,0.01 at +4 and +24 h, FIG. 10B).

[0095] Example 2: Pharmacokinetic studies on the compound of formula (IA) Urinary concentrations were assessed in humans (total of 9 subjects) up to 48 hours after a single oral dose of the compound of formula (IA) in the form of a methylcellulose suspension. Urine samples (continuous pooled samples of total voided urine) for determination of the compound of formula (IA) concentration were collected for each subject at the following time intervals: 0-8 hours, 8-16 hours, 16-24 hours, 24-32 hours, and 40-48 hours after dosing. A summary of the urinary concentrations of the compound of formula (IA) by individual subject and treatment and time interval is shown in Table 4 below. [Table 4]

[0096] The data in Table 4 show the mean urinary concentration levels and standard deviations of the compound of formula (IA) at specific time intervals following administration of specific doses of the compound of formula (IA) (0.2 mg, 0.6 mg, 2 mg, and 10 mg). Table 4 shows that even the lowest dose (0.2 mg) of the compound of formula (IA) had a Ki and EC 50 These results demonstrate that urinary concentrations are several orders of magnitude greater than the in vitro activity of compounds of formula (IA) as determined by .

[0097] Example 3: A Phase 1b, blinded, placebo-controlled, crossover study to investigate the effects of the compound of formula (IA) in female human subjects with interstitial cystitis / bladder pain syndrome. Primary evaluation: To evaluate the effect of the compound of formula (IA) compared to placebo on change in mean daily bladder pain / discomfort symptom score in subjects diagnosed with IC / BPS. Each subject must identify their most bothersome bladder pain / discomfort symptom at screening. To be eligible for randomization, subjects must report experiencing this specific symptom with sufficient severity (protocol-defined intensity or frequency) during the 2-week single-blind placebo run-in period.

[0098] The average daily bladder pain / discomfort score will be assessed twice daily (morning and evening) using an electronic diary based on an 11-point Numeric Rating Scale (NRS), ranging from 0 = "no bladder pain / discomfort" to 10 = "worst pain / discomfort imaginable." The symptom that the subject considers to be most bothersome will be based on a consensus determination between the subject and the primary investigator made during screening (and in the electronic diary) during protocol-specified IC / BPS-related symptom assessment procedures.

[0099] Secondary Evaluation: To evaluate the effect of the compound of formula (IA) compared to placebo on the change in the mean number of urinations per 24 hours in subjects diagnosed with IC / BPS. Subjects will be asked to record all voiding episodes in an electronic diary for 7 days prior to each scheduled clinic visit to the investigational site. Subjects will be required to record the time, type, and urgency of each voiding episode for all 7 days, as well as record urine volume over 2 weekend days. · The type of episode is classified as micturition (urinating in the toilet) or incontinence (involuntary release of urine). Urgency of the episode (a sudden, compelling feeling of the need to urinate that is difficult to postpone) is rated for each episode on an 11-point NRS ranging from 0 = "no urgency" to 10 = "the worst urgency imaginable." Episode volume is the total urine volume per void during a single recorded episode.

[0100] Other Ratings: To evaluate the effect of compounds of formula (IA) on changes in other bladder pain / discomfort components and further lower urinary tract components.

[0101] The following measurements are taken by the subject at home using an electronic diary: - Daily average and daily maximum (worst) bladder pain / discomfort scores obtained twice daily (morning and evening). - All voiding episodes occurring during the 1 week (7 day period) prior to each scheduled clinic visit to the investigational site. The time, type, intensity, and volume of each episode will be collected over a 24-hour period on each day.

[0102] The following measurements will be taken at each clinic visit: - Bladder Pain / Interstitial Cystitis Symptom Score (BPIC-SS). The BPIC-SS includes 8 questions about bladder pain over the past 7 days. Questions 1-5 assess how often the subject had to urinate due to pain, had to urinate immediately after the previous urination, urinate to avoid pain, had pressure on the bladder, and had pain in the bladder, rated on a 5-point scale from 0 = "not at all" to 4 = "very much". Questions 6 and 7 assess how much the subject was bothered by frequent urination during the day and at night, rated on a 5-point scale from 0 = "not at all" to 4 = "very much". Question 8 assesses the subject's worst bladder pain over the past 7 days, rated on an 11-point NRS ranging from 0 = "no bladder pain" to 10 = "the worst bladder pain possible". The BPIC-SS total score is the sum of the individual question scores and ranges from 0 to 38, with higher scores indicating a worse situation and a score of 19 or higher may represent moderate / severe disease activity. The total score and the worst bladder pain (Q8) should be assessed. - O'Leary-Sant Interstitial Cystitis Symptom Score (ICSI). The ICSI includes four questions measuring urinary urgency and frequency, nocturnal urination, and pain or burning. Each question is rated using a 6-point scale ranging from 0 = no symptoms / problems to 5 = worst symptoms / problems. Total scores range from 0 to 20. A 1-week recall period is used. - O'Leary-Sant Interstitial Cystitis Problem Score (ICPI). The ICPI includes four questions that assess the severity of symptoms (frequency, nocturia, urgency, discomfort) and how much of a problem the symptoms cause the patient. Each question is rated using a 5-point scale ranging from 0 = "no problem" to 4 = "big problem". Total scores range from 0 to 16. A 1-week recall period is used. - Subject Global Response Assessment (SGRA). The SGRA is a self-rated, balanced measure of the subject's clinical status compared to baseline. It has one question: a) "How would you rate your overall interstitial cystitis / bladder pain symptoms now compared to when you started the study?" using a 7-point rating scale: 1 = "much worse", 2 = "moderately worse", 3 = "slightly worse", 4 = "no change", 5 = "slightly improved", 6 = "moderately improved", or 7 = "much improved". - Subject's Self-Assessment of Treatment Efficacy (SGRA)-Bothersome Symptoms. The SGRA is used to assess the subject's clinical status compared to baseline regarding the most bothersome symptom and includes two questions: a) "Compared to when you started the study, how would you rate your most bothersome bladder pain / discomfort symptom now?" and b) "Compared to when you started the study, how would you rate your most bothersome lower urinary tract symptom now?". For both questions, use a 7-point rating scale: 1 = "markedly worse", 2 = "moderately worse", 3 = "slightly worse", 4 = "no change", 5 = "slightly improved", 6 = "moderately improved", or 7 = "markedly improved". - Nocturia Sleep Quality Scale (NSQS). The NSQS consists of six items assessing hypothesized domains of nocturnal awakenings, amount of sleep, and quality of sleep. The NSQS uses a short recall period from the time the patient goes to bed to wake up to start the day, allowing patients to assess the impact of nocturnal polyuria on their sleep over time.

[0103] Safety rating: To evaluate the safety and tolerability of the compound of formula (IA) as measured by adverse events (AEs), chemistry results, hematology results, urinalysis (including microscopy) results, electrocardiogram (ECG), physical examination, vital signs, Columbia-Suicide Severity Scale (C-SSRS), Hospital Anxiety and Depression Scale (HADS), Karolinska Sleepiness Scale (KSS), and Digit Symbol Substitution Test (DSST).

[0104] Diagnosis and main inclusion criteria: The following inclusion / exclusion criteria will be used at Screening Visit 1 to determine eligibility to participate in the Lead-in Phase. Enrollment criteria for the double-blind, randomized treatment period are also provided below. Inclusion: 1. Non-pregnant (confirmed by urine pregnancy test), non-lactating female, 18-64 years old, able to urinate independently. 2. Have a diagnosis of interstitial cystitis / bladder pain syndrome (IC / BPS) according to the American Urological Association (AUA) guidelines, documented in the subject's medical record at least 6 months prior to screening. 3. Have bladder pain / discomfort with lower urinary tract symptoms at screening as assessed by a healthcare provider that meet the following criteria: a. Subjects have had complaints of bladder pain / bladder pressure / bladder discomfort for 6 months or more accompanied by other lower urinary tract symptoms for 6 months or more b. Subject has a Bladder Pain / Interstitial Cystitis Symptom Scale (BPIC-SS) total score of 19 or greater c. The subject's average daily most bothersome bladder pain during the past week is 4 or greater and 8 or less, as rated by the subject using an 11-point numeric rating scale ranging from 0 (no pain) to 10 (worst pain). d. Subject's urinary frequency is estimated to be ≥11 and ≤30 urinations per 24 hours during the last week. 4. Have cystoscopy findings at screening or obtained within 6 months of screening that exclude other conditions causing bladder pain and discomfort (e.g., transitional cell carcinoma of the bladder, endometriosis of the bladder). 5. Have not received any pharmacologic treatment for IC / BPS in the past 30 days OR have received oral pharmacologic treatment for interstitial cystitis / bladder pain syndrome at a stable dose / regimen in the past 30 days and are expected to remain at the same stable dose / regimen throughout the study, as determined by the investigator. 6. Meet study inclusion criteria despite a history of previous or ongoing treatment, including conservative measures which may include one or more of the following: a) scheduled voiding and behavioral modification therapy; b) dietary restriction; c) stress reduction; and despite oral therapy with any of the following medications: antidepressants, antihistamines, antimuscarinics, and anticholinergics, alpha-adrenergic blockers, analgesics, and pentosan polysulfate. 7. Deemed to be in generally good health, in the opinion of the clinical site investigator, based on the results of medical history, physical examination, 12-lead ECG, and clinical laboratory profile 8. Able to speak, read, write, and understand English, understand the consent form, and communicate effectively with study staff. 9. Willing and able to voluntarily provide written informed consent and complete all study procedures, including daily bladder diaries (pain and voiding assessments) Exclude: 1. Having pelvic floor pain (score of more than 5 out of 10 on the 11-point NRS pain scale) 2. Receiving any opioid therapy for any indication within the past 30 days 3. Have used opioids >70 milligrams of oral morphine equivalents per week to manage pain for IC / BPS within the past 30 days or anticipate needing this level of opioid pain control during the study. 4. Have had a urinary tract infection (UTI), including bacterial cystitis, within the past 30 days or have a history of recurrent UTI defined as 3 or more episodes in the past 6 months. Note: Infected subjects may be rescreened in 30 days. 5. Hematuria by microscopy. Note: Subjects with microhematuria may be accepted for enrollment after review and approval by the Study Medical Monitor. 6. Has undergone a surgical procedure affecting bladder function at any time (e.g., cystoaugmentation, cystectomy, cystolysis, neurectomy, hypogastric plexus ablation) or has received bladder injections of botulinum toxin within the past 9 months. 7. Received intravesical therapy or bladder hydrodistention (infusions including fluid or drug delivery devices, pentosan polysulfate sodium, lidocaine, steroids, heparin, chondroitin, and any combination or additional preparations) within the past 30 days. 8. Use of a sacral and / or pudendal neuromodulation device (e.g., Interstim) within the past 6 months (subjects were not excluded if device was initiated >6 months prior and had been in stable condition for the past 3 months). 9. Have had a percutaneous tibial nerve stimulation (PTNS) procedure within the past 90 days 10. History of concomitant malignancy or cancer, except noninvasive skin cancer, within the past 5 years (Note: Patients with a history of cancer are eligible if they have been treated and considered disease-free for at least 5 years). 11. Had a bladder tumor (benign or malignant) at any time. 12. Active genital herpes or vaginitis 13. Having a urethral diverticulum 14.Have had cyclophosphamide or chemical cystitis, or tuberculosis, or have received pelvic irradiation 15.Having poorly controlled diabetes 16.Currently pregnant or breastfeeding, or planning to become pregnant during the course of the study 17.Has moderate to severe hepatic impairment defined as Child-Pugh classification B or C. 18. Has any history and / or current evidence of any other medical condition (e.g., cardiac, respiratory, gastrointestinal, renal, malignancy other than basal cell carcinoma), neurological, or psychiatric condition that, in the opinion of the investigator, may affect the subject's safety or interfere with the study evaluations. 19. Clinically significant depression based on a score of 11 or greater on the Hospital Anxiety and Depression Scale (HADS), suicidal ideation with actual attempt and method or plan in the past year (answering "yes" to items 4 or 5 on the Columbia Suicide Severity Rating Scale [C-SSRS]), any history of suicidal behavior in the past 5 years (answering "yes" to any suicidal behavior item on the C-SSRS), or any lifetime history of severe or recurrent suicidal behavior. Non-suicidal self-harm behavior is not a trigger for risk assessment unless indicated by the clinical site investigator's judgment. 20. Have any history or any current condition (including any surgical intervention for weight loss) that may interfere with drug absorption, distribution, metabolism, or excretion. 21. At the time of screening, have a substance use disorder or have a positive UDT for illicit drugs (including tetrahydrocannabinol [THC]), non-prescription controlled substances (opioid or non-opioid), or alcohol, or have ever overdosed on opioids for any reason. 22.20kg / m 2 Less than or equal to 35kg / m 2 Have a body mass index of over 23. Abnormal blood urea nitrogen and creatinine levels and a blood urea nitrogen level of 60 mL / min / 1.73 m 2 Have abnormal renal function as evidenced at screening by an estimated glomerular filtration rate (eGFR) less than 24. Have clinically significant abnormalities in clinical chemistry, hematology, or urinalysis at screening, including serum glutamic-oxaloacetic transaminase / aspartate aminotransferase or serum glutamic-pyruvic transaminase / alanine aminotransferase ≥3x the upper limit of the reference range, or serum creatinine >2mg / dL. 25. Have an abnormal cardiac condition, including poorly controlled hypertension (systolic > 140mmHg / diastolic > 90mmHg) or QTcF > 450msec (males) and > 470msec (females) confirmed by repeat ECG, or clinically significant ECG abnormalities. 26. Having excessive caffeine intake of 300 mg / day or more (e.g., approximately three 6-ounce cups of caffeinated coffee, or three 12-ounce cups of caffeinated soda water, or three 8-ounce cups of caffeinated tea). 27. Received in a clinical drug study within 30 days (or 5 half-lives of investigational drug treatment, whichever is longer) prior to the first dose of investigational drug dispensed in this study. 28. Had previously been exposed to a compound of formula (IA). 29. Patients scheduled to undergo surgery during the study.

[0105] Randomization Criteria (double-blind phase): Subjects must meet the following criteria for randomization into the double-blind randomized treatment phase after completing a daily bladder diary: a) Average daily bladder pain score of 5 or greater for at least 9 days during the induction phase b) The average number of voiding episodes is ≥10 and <30 in each 24-hour period for at least 3 days c) Bladder Pain / Interstitial Cystitis Symptom Scale (BPIC-SS) score ≥ 19 d) The new IC / BPS therapy was at a stable dose / regime and was expected to be maintained for the duration of the study. e) The subject completed the diary appropriately as instructed by the investigator.

[0106] Study design: A Phase 1b, blinded, placebo-controlled, crossover study evaluating the effects of oral administration of 1 mg / day of the compound of formula (IA) compared to placebo in female subjects with IC / BPS.

[0107] The study consisted of two phases: a pre-randomized phase consisting of a screening period (up to 4 weeks) and a single-blind placebo run-in period (2 weeks), and a randomized treatment phase consisting of a double-blind treatment period (9 weeks) and a follow-up period (up to 1 week). [Table 5]

[0108] Screening / Washout Period (Days -42 to -15): After informed consent is obtained from each subject, subjects will be subjected to all study procedures performed in the study. Assessment of study eligibility criteria will begin at the screening visit and will include medical history, physical examination, vital signs, laboratory test results, urine culture, pregnancy test, and drug screen. If washout of prohibited medications (Appendix A) is required, this should be completed during screening (Days -42 to -15). Subjects must have a diagnosis of interstitial cystitis / bladder pain syndrome (IC / BPS) according to American Urological Association (AUA) guidelines documented in the subject's medical record at least 6 months prior to screening. If not available within the past 6 months, subjects must undergo cystoscopy at screening to rule out other conditions and document the presence or absence of Hannah lesions. Subjects should either have not received pharmacologic treatment for IC / BPS in the past 30 days or have received oral pharmacologic treatment for IC / BPS at a stable dose / regimen in the past 30 days and are expected, in the investigator's judgment, to remain at the same stable dose / regimen throughout the study. Subjects who have used opioids for any reason in the past 30 days or who are expected to require opioid therapy for bladder pain or any indication will be excluded from enrollment in the study. Subjects will identify their most bothersome bladder pain / discomfort symptom and their most bothersome lower urinary tract symptom related to IC / BPS.

[0109] Single-Blind Placebo Run-In Period (Days -14 to -1): Once subjects have successfully completed the Screening Visit, they will enter the placebo run-in period and will take one tablet of study medication orally each night 30 minutes before bedtime. Medication intake will be recorded in an electronic diary each night. Subjects will record their daily average and daily worst bladder pain / discomfort scores twice daily, in the morning and evening. Subjects will record all voiding episodes over a 24-hour period during the week prior to Visit 2 (including time, type, intensity, and volume of each). To be eligible for enrollment into the double-blind treatment period, subjects must meet the following criteria: a) Average daily bladder pain / discomfort score of 5 or greater for at least 9 days during the run-in phase b) The average number of voiding episodes is ≥10 and <30 in each 24-hour period for at least 3 days c) Bladder Pain / Interstitial Cystitis Symptom Scale (BPIC-SS) score ≥ 19 d) The new IC / BPS therapy was at a stable dose / regime and was expected to be maintained for the duration of the study. e) The subject completed the diary appropriately as instructed by the investigator.

[0110] If a subject meets the enrollment criteria and completes all evaluations, the subject is randomized.

[0111] Treatment period (days 1-63) All subjects will be assigned to the same crossover treatment regimen of the compound of formula (IA) and placebo. Subjects will visit the clinic every 2 weeks with virtual calls / phone calls during weeks when no clinic visits are scheduled.

[0112] Subjects will continue to record their bladder pain scores twice daily. Subjects will also record all voiding episodes over a 24-hour period during the 7 days prior to each scheduled clinic visit to the investigational site. At clinic visits, subjects will complete efficacy assessments (BPIC-SS, ICSI, ICPI, NSQS, GRA, and SGRAB) and safety / other assessments.

[0113] End of Study (EOS) (Day 63 / Early Termination [ET]): Subjects will undergo EOS procedures either at the end of double-blind treatment or upon early discontinuation from the study. If the assessments required at EOS are performed on the same day of study completion or the same day as the ED, and no study drug is administered after these assessments, these assessments do not need to be repeated.

[0114] Follow-up period (days 64-70) A follow-up phone call will be completed 7-10 days after the last dose of study medication to monitor for adverse events and use of concomitant medications / therapies since the previous visit.

[0115] While 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. Thus, various modifications of the exemplary embodiments, as well as other embodiments of the invention, will become apparent to those skilled in the art upon reference to this description. Thus, it is intended that the appended claims cover any such modifications or embodiments.

[0116] 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.

[0117] References Auge C.et al.,2011.Pharmacological modulation of urinary bladder inflammation in a rat model of cyclophosphamide-induced acute bladder pain.Inflamm.Res.60(Suppl 1):S248. Auge C.et al.,2013.Relevance of the cyclophosphamide-induced cystitis model for pharmacological studies targeting inflammation and pain of the bladder.Eur.J.Pharmacol.707(1-3):32-40. Boucher M.et al.,2000.Cyclophospham ide-induced cystitis in freely-moving conscious rats:behavioral approach to a new model of visceral pain.J.Urol.164(1):203-8. Cox PJ.,1979.Cyclophosphamide cystitis-identification of acrolein as the causative agent.Biochem.Pharmacol.28(13):2045-9. Juszczak K.et al.,2007.Animal models of overactive bladder:cyclophosphamide(CYP)-induced cystitis in rats.Folia Med.Cracov.48(1-4):113-23. Lluel P.et al.,2010.Cyclophosphamide-induced cystitis in conscious female rats:development and pharmacological validation of an experimental model of referred visceral pain.Annual meeting of the International Continence Society(ICS),Toronto,Canada. Payne CK.et al.,2007.Interstitial cystitis and painful bladder syndrome.J.Urol.177(6):2042-9. Smaldone MC.et al.,2009.Multiplex analysis of urinary cytokine levels in rat model of cyclophosphamide-induced cystitis.Urology.73(2):421-6. Takagi-Matsumoto H.et al.,2004.Effects of NSAIDs on bladder function in normal and cystitis rats:a comparison study of aspirin,indomethacin,and ketoprofen.J.Pharmacol.Sci.,95,458-465. Bosch PC.Examination of the Significant Placebo Effect in the Treatment of Interstitial Cystitis / Bladder Pain Syndrome.Urology 2014;84(2):321-325. Garzon S,Lagana AS,Casarin J et al.An update on treatment options for interstitial cystitis.Menopause Rev 2020;19(1):35-43. Hanno MP,Burks DA,Clemens JQ,et al.American Urological Association(AUA)Guideline:Diagnosis and treatment of interstitial cystitis / bladder pain syndrome 2014. FDA 2019 Draft Guidance Document.Interstitial Cystitis / Bladder Pain Syndrome(IC / BPS):Establishing Effectiveness of Drugs for Treatment Guidance for Industry.

Claims

1. 1. A pharmaceutical composition for treating interstitial cystitis / bladder pain syndrome in a human subject in need thereof, comprising a compound of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. 1. A pharmaceutical composition for treating or alleviating symptoms associated with interstitial cystitis / bladder pain syndrome in a human subject in need of such treatment, comprising a compound represented by formula (I): 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 2, wherein the symptom is visceral pain or urgency.

4. The compound of formula (I) or a pharma- ceutically acceptable salt thereof may be represented by the formula (I'): 【Chemistry 3】 3. The pharmaceutical composition according to claim 1 or 2, wherein the compound is:

5. The method of claim 1, wherein the treatment comprises administering to the human subject a therapeutically effective amount of a pharma- ceutically acceptable salt of the compound, wherein the pharma- ceutically acceptable salt is a p-toluenesulfonate, sulfate, phosphate or hydrochloride salt, or the compound has formula (IA): 【Chemistry 4】 3. The pharmaceutical composition according to claim 1 or 2, wherein the compound is

6. 3. The pharmaceutical composition of claim 1 or 2, wherein the compound or a pharma- ceutically acceptable salt thereof is administered orally, parenterally, intravenously, intramuscularly, bucally, or transdermally.

7. 6. The pharmaceutical composition of claim 5, wherein the therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof is from 0.001 mg to 30 mg, or from 0.005 mg to 25 mg, or from 0.075 mg to 12 mg, or from 0.1 mg to 10 mg, or 1 mg.

8. 3. The pharmaceutical composition of claim 1 or 2, wherein the compound or a pharma- ceutically acceptable salt thereof is administered once daily.

9. 3. The pharmaceutical composition of claim 1 or 2, wherein the compound or a pharma- ceutically acceptable salt thereof is administered to the human subject at night or at night prior to bedtime.

10. The compound or a pharma- ceutically acceptable salt thereof is administered twice daily or every 12 hours; and / or and / or, wherein the treatment comprises administering a first therapeutically effective amount of the compound, or a pharma- ceutically acceptable salt thereof, during the day and a second therapeutically effective amount during the night prior to bedtime of the human subject. wherein the treatment comprises administering the same therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof each time. The pharmaceutical composition according to claim 1 or 2.

11. 3. The pharmaceutical composition of claim 1 or 2, wherein administration of said compound or a pharma- ceutically acceptable salt thereof increases the micturition pressure threshold in said human subject by 30% to 80%.

12. A pharmaceutical composition for treating interstitial cystitis / bladder pain syndrome in a human subject in need of such treatment, comprising a therapeutically effective dose of a compound of formula (I'): 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof, wherein the human subject further suffers from a sleep disorder.

13. The pharmaceutical composition of claim 12, wherein the sleep disorder is insomnia associated with alcohol withdrawal.

14. 14. The pharmaceutical composition of claim 12 or 13, wherein the human subject is a woman aged 50 years or older.

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