How to treat interstitial cystitis / bladder pain syndrome

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 condition characterized by suprapubic pain associated with bladder distension, accompanied by additional symptoms such as increased daytime and nocturia, urinary urgency, nocturia, and pelvic discomfort. See Yoshimura et al. (2014), Int J Urol. 2014, Apr;21 Suppl 1(01):18-25. In patients with interstitial cystitis / bladder pain syndrome, the glycosaminoglycan layer protecting the bladder epithelium is disrupted, leading to irritation of the bladder wall. Patients with interstitial cystitis / bladder pain syndrome may experience moderate to severe pain.

[0002] Drug therapies such as antihistamines, antidepressants, and anticonvulsants have been used to treat interstitial cystitis / bladder pain syndrome, but with limited success. Pentosan polysulfate sodium, a drug that restores damaged or leaky bladder surfaces, is approved for the treatment of interstitial cystitis / bladder pain syndrome. However, most patients do not respond effectively to this drug therapy.

[0003] Although the precise mechanism by which interstitial cystitis / bladder pain syndrome develops is not fully understood, sensitization of the bladder afferent pathway and subsequent increased sensory processing in the spinal cord have been proposed as important mechanisms in 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 studied for the treatment of interstitial cystitis / bladder pain syndrome. Such treatments include opioids, adenosine receptor agonists, and GlyT inhibitors.

[0004] This disclosure provides a specific ORL-1 receptor modulator useful for the treatment of interstitial cystitis / bladder pain syndrome. [Overview of the project]

[0005] This disclosure relates to a method for treating interstitial cystitis / bladder pain syndrome in human subjects identified as requiring treatment for the syndrome, comprising formula (I): [ka] The present invention provides a method for administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to a target. The compound of formula (I) includes all of its stereoisomers (e.g., enantiomers) and polymorphs.

[0006] In some embodiments, the present disclosure relates to a method for treating interstitial cystitis / bladder pain syndrome in a human subject identified as requiring treatment for interstitial cystitis / bladder pain syndrome, wherein formula (I'): [ka] The present invention provides a method for administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to a target. As will be readily apparent to 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 relates to a method for treating interstitial cystitis / bladder pain syndrome in a human subject requiring treatment for interstitial cystitis / bladder pain syndrome, wherein the compound of formula (IA): [ka] The present invention provides a method comprising administering a therapeutically effective amount of a compound having the specified properties to a target.

[0008] In one embodiment, the present disclosure provides a method for treating or alleviating symptoms associated with interstitial cystitis / bladder pain syndrome in a human subject requiring treatment of symptoms associated with interstitial cystitis / bladder pain syndrome, comprising administering a therapeutically effective amount of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, to the subject. In one such embodiment, the symptom is visceral pain. In another such embodiment, the symptom is urinary 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 pharmaceutically acceptable salt thereof, is administered orally. Oral administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof increases the concentration of the compound in the bladder.

[0010] In certain embodiments, the Disclosure provides a method for simultaneously treating patients suffering from sleep disorders and interstitial cystitis / bladder pain syndrome. Thus, in one embodiment, the Disclosure provides a method for treating interstitial cystitis / bladder pain syndrome in a human subject suffering from a sleep disorder, 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 explanation of the drawing]

[0011] [Figure 1]This shows that the baseline responses to the vehicle (saline) group, vehicle (CYP) group, ibuprofen / CYP group, and the compound group of formula (IA) were similar. A represents the nociceptive threshold. B represents the nociceptive score. AUC 1-6. C represents AUC 1-6g. D represents AUC 6-26g. Results are expressed as ±sem. One-way ANOVA or two-way RM ANOVA with NSp > 0.05, Kruskal-Wallis test, and Sidak's post-hoc test. [Figure 2] The time course of the nociceptive threshold (g) after injection of CYP or saline into both vehicle groups is shown. Results are expressed as ±sem. ****p>0.0001, two-way RM ANOVA with Sidak's post-hoc test. [Figure 3] The nociceptivity scores (%) at 2 hours (A), 3 hours (B), 4 hours (C), and 24 hours (D) after CYP injection in both vehicle groups are shown. Results are expressed as ±sem. ****p<0.0001, two-way RM ANOVA. [Figure 4] The time course of AUC 1–6g (A) and 6–26g (B) after injection of CYP or physiological saline into both vehicle groups is shown. Results are expressed as ±sem. *p<0.05 and ****p<0.0001, two-way RM ANOVA with Sidak's post-hoc test. [Figure 5] The time course of nociceptive threshold (g) after CYP injection in the vehicle group and the ibuprofen group is shown. Results are expressed as ±sem. ****p<0.0001, two-way RM ANOVA with Sidak's post-hoc test. [Figure 6] The nociceptivity scores (%) at 2 hours (A), 3 hours (B), 4 hours (C), and 24 hours (D) after CYP injection in the vehicle and ibuprofen groups are shown. Results are expressed as ±sem. ****p<0.0001, two-way RM ANOVA. [Figure 7]Shows the time courses of AUC 1 - 6 g (A) and 6 - 26 g (B) after injection of CYP or saline into both the vehicle group and the ibuprofen group. Results are expressed as ±s.e.m. *p < 0.05 and ****p < 0.0001, two-way repeated measures ANOVA with Sidak's post hoc test. [Figure 8] Shows the time course of the nociceptive threshold (g) after CYP injection in the vehicle group and the group of compounds of formula (IA). Results are expressed as ±s.e.m. NSp > 0.05, **p < 0.01, two-way repeated measures ANOVA with Sidak's post hoc test. [Figure 9] Shows the nociceptive scores (%) at 2 hours (A), 3 hours (B), 4 hours (C), and 24 hours (D) after injection of CYP into both the vehicle group and the group of compounds of formula (1A). Results are expressed as ±s.e.m. **p < 0.01, ***p < 0.001, ****p < 0.0001, two-way repeated measures ANOVA. [Figure 10] Shows the time courses of AUC 1 - 6 g (A) and 6 - 26 g (B) after injection of CYP or saline into both the vehicle group and the group of compounds of formula (IA). Results are expressed as ±s.e.m. NSp > 0.05, *p < 0.05, **p < 0.01, **p < 0.001, and ****p < 0.0001, two-way repeated measures ANOVA with Sidak's post hoc test.

Mode for Carrying Out the Invention

[0012] The present disclosure provides a method for treating interstitial cystitis / bladder pain syndrome in a human subject identified as needing treatment for interstitial cystitis / bladder pain syndrome, the method comprising administering to the subject through administration of 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 long-known major classes of opioid receptors in the central nervous system (mu, kappa, and delta), was brought about by experiments on these classes of opioid receptors. Since the ORL-1 receptor did not exhibit pharmacological properties overlapping with those of the classical mu opioid receptor, the ORL-1 receptor was identified and classified as an opioid receptor based solely on amino acid sequence homology. Initially, it was demonstrated that non-selective ligands with high affinity for mu, kappa, and delta opioid receptors had low affinity for the ORL-1 receptor. This feature, combined with the fact that an endogenous ligand had not yet been discovered, gave rise to the term "orphan receptor." See, for example, Henderson et al., “The orphan opioid receptor and its endogenous ligand - nociceptin / orphanin FQ,” Trends Pharmacol. Sci. 18(8):293-300 (1997). Subsequent investigations led to the isolation and structure of an endogenous ligand for the ORL-1 receptor, a 17-amino acid peptide structurally similar to members of the opioid peptide family (i.e., nociceptin; also known as orphanin FQ or OFQ). For a general review of the ORL-1 receptor, see Calo’ et al., “Pharmacology of nociceptin and its receptor: a novel therapeutic target,” Br. J. Pharmacol. 129:1261-1283 (2000).

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

[0015] The inventors have surprisingly found that the formula for the therapeutically effective dose is (I): [ka] We found that interstitial cystitis / bladder pain can be alleviated through the administration of the compound or a pharmaceutically acceptable salt thereof.

[0016] A particular embodiment has the following structure: [ka] The present invention provides the compound of formula (I) or a pharmaceutically acceptable salt thereof as a single enantiomer (i.e., the compound of formula (I')). In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I') is the p-toluenesulfonate (i.e., tosylate salt) (referred to as the compound of formula (IA)) of the compound of formula (I'), whose structure is shown below: [ka]

[0017] The compounds of formulas (I), (I'), and (IA) are prepared as described in U.S. Patent No. 8,476,221, which is incorporated herein by reference. The compounds of this disclosure include the compounds of formulas (I) and (I'), or their stereoisomers, pharmaceutically acceptable salts (e.g., the compounds of formula (IA)), polymorphs, solvates, or hydrates, as referred to below.

[0018] In certain embodiments, administration of a compound of formula (I) or (I'), or a pharmaceutically 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,” “treatment,” and related terms include the alleviation, reduction, 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 pharmaceutically acceptable salt thereof. In some embodiments, treatment includes suppressing, for example, 1) the overall frequency of episodes of a condition (e.g., interstitial cystitis / bladder pain); and / or 2) reducing the symptoms of that condition (e.g., visceral pain), or the severity of the condition or its symptoms; and / or 3) reducing the duration of the condition or its symptoms.

[0020] In December 2019, the U.S. Food and Drug Administration (FDA) issued industry guidance on the management 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 symptoms such as frequent urination, urinary urgency, or nocturia, and other disorders such as malignancies, endometriosis, chronic prostatitis, and bladder outlet obstruction must be ruled out. The FDA guidance further indicates that some patients with interstitial cystitis / bladder pain syndrome may experience persistent bladder pain / discomfort. Others may experience interstitial cystitis / bladder pain syndrome during urination or as a burning sensation between urinations as the bladder fills with urine.

[0021] As used herein, the terms “prevention of,” “prevention,” and related terms include avoidance of the development of a condition or its symptoms, or a reduction in the incidence or frequency of a condition or its symptoms, by administration of an effective amount of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof.

[0022] The term "effective dose" refers to the amount of compound administered to an animal that produces a therapeutic effect when used in relation to methods for treating or preventing interstitial cystitis / bladder pain by administering a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (IA)).

[0023] Compounds of formula (I) or (I'), or their pharmaceutically acceptable salts, exert beneficial effects through the modulation of ORL-1 receptors expressed at afferent nerve / fiber terminals of the lower urinary tract. As used herein with respect to the ORL-1 receptor, the terms “modulate,” “to modulate,” and related terms mean mediating 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 agonist / antagonists, mixed partial agonist / antagonists, and compounds that directly or indirectly affect the regulation of receptor activity. Compounds of formula (I) or (I'), and their pharmaceutically acceptable salts, 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.” Partial agonists of this disclosure can achieve desired therapeutic effects (e.g., treatment of interstitial cystitis / bladder pain) without the side effects often associated with the administration of full agonists.

[0024] Compounds of formula (I) or (I'), or pharmaceutically acceptable salts thereof, may be administered as components of a composition comprising a pharmaceutically acceptable carrier or excipient. Routes of administration include, but are not limited to, oral, intravesical, intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, epidural, transmucosal, buccal, gingival, sublingual, intraocular, intracerebral, intravaginal, transdermal (e.g., via a patch), rectal, inhalation, or topical. In other embodiments, routes of administration include, but are not limited to, intravenous, intravesical, oral, or inhalation. In another embodiment, the route of administration is oral. In another embodiment, the route of administration is intravesical. In another embodiment, the route of administration is intravenous. In yet another embodiment, the route of administration is inhalation. In yet another embodiment, compounds of formula (I) or (I'), or pharmaceutically acceptable salts thereof, are delivered via controlled-release or sustained-release systems. Controlled-release or sustained-release pharmaceutical compositions may share the common objective of improving pharmacotherapy beyond what is achieved by their uncontrolled-release or non-sustained-release counterparts. For example, controlled-release or sustained-release pharmaceutical compositions offer the following benefits compared to their uncontrolled-release or non-sustained-release counterparts: reduced administration frequency; increased duration of effect; increased degree of effect, e.g., C at the site of action. max A decrease or C average This may result in one or more of the following: an increase in [specific factor]; improved safety / tolerability; and improved patient compliance (reduced dosing frequency, improved tolerability).

[0025] In one embodiment, a controlled-release or sustained-release composition comprises a pharmaceutically acceptable amount of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, for the treatment or prevention of interstitial cystitis or its symptoms over a long period. Advantages of controlled-release or sustained-release compositions include extended drug activity, reduced administration frequency, and increased compliance. Administration of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be by controlled-release means, sustained-release means, or delivery devices known to those skilled in the art. Examples include, but are not limited to, U.S. Patents No. 3,845,770, No. 3,916,899, No. 3,536,809, No. 3,598,123, No. 4,008,719, No. 5,674,533, No. 5,059,595, No. 5,591,767, No. 5,120,548, No. 5,073,543, No. 5,639,476, No. 5,354,556, and No. 5,733,566 (each of which is incorporated herein by reference). Many other controlled-release or sustained-release devices known to those skilled in the art can be used (see, for example, Goodson, “Dental Applications,” in Medical Applications of Controlled Release, Vol. 2, Applications and Evaluation, Langer and Wise, eds., CRC Press, Chapter 6, pp. 115-138 (1984) (hereinafter referred to as “Goodson”)). Other controlled-release or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) may also be used.In one embodiment, a pump may be used (Langer, Science 249:1527-1533 (1990); Sefton, “Implantable Pumps,” in CRC Crit. Rev. Biomed. Eng. 14(3):201-240 (1987); Buchwald et al., “Long-term, Continuous Intravenous Heparin Administration by an Implantable Infusion Pump in Ambulatory Patients with Recurrent Venous Thrombosis,” Surgery 88:507-516 (1980); and Saudek et al., “A Preliminary Trial of the Programmable Implantable Medication System for Insulin Delivery,” New Engl. J. Med. 321:574-579 (1989)).In another embodiment, polymer materials may be used (Goodson; Smolen et al., “Drug Product Design and Performance,” Controlled Drug Bioavailability Vol.1, John Wiley and Sons, New York (1984); Langer et al., “Chemical and Physical Structure of Polymers as Carriers for Controlled Release of Bioactive Agents: A Review,” J.Macromol.Sci.Rev.Macromol.Chem.C23(1):61-126 (1983); Levy et al., “Inhibition of Calcification of Bioprosthetic Heart Valves by Local Controlled-Release Diphosphonate,” Science 228:190-192 (1985); During et al., “Controlled Release of Dopamine from a Polymeric Brain Implant: In Vivo Characterization,” Ann.Neurol.25:351-356 (1989); and Howard et al., “Intracerebral drug delivery in rats with See "leaf-induced memory deficits," J. Neurosurg. 71:105-112 (1989).

[0026] Using suitable dosage forms, for example, hydroxypropylmethylcellulose, ethylcellulose, other polymer matrices, gels, permeable membranes, permeable systems, multilayer coatings, microparticles, multiplicities, liposomes, microspheres, or combinations thereof, controlled release or sustained release of one or more active ingredients can be achieved, providing desired release profiles in various proportions. Suitable controlled-release or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of this disclosure. Accordingly, this disclosure encompasses single-unit dosage forms suitable for oral administration adapted for controlled release or sustained release (including, but not limited to, tablets, capsules, gel caps, and caplets).

[0027] The composition may optionally (but preferably) further contain suitable amounts of pharmaceutically acceptable excipients to provide a form suitable for administration to animals (e.g., humans). Such pharmaceutically acceptable excipients may be diluents, suspending agents, solvents, binders, disintegrants, preservatives, colorants, lubricants, etc. The pharmaceutically acceptable excipients may be liquids such as water or oil (of petroleum, animal, plant, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). The pharmaceutically acceptable excipients may be physiological saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliary agents, stabilizers, thickeners, lubricants, and colorants may be used. In one embodiment, the pharmaceutically acceptable excipient is sterile when administered to animals. Water is a particularly useful excipient when the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof is administered intravenously. Physiological saline solutions and aqueous solutions of dextrose and glycerol can also be used as liquid excipients (especially for injectable solutions). Suitable pharmaceutically acceptable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol. The composition may optionally contain small amounts of wetting agents or emulsifiers or pH buffers. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients (Amer. Pharmaceutical Ass'n, Washington, DC, 1986), which is incorporated herein by reference. Other examples of suitable pharmaceutically acceptable excipients are incorporated herein by reference in Radebough et al., “Preformulation,” pp. 1447–1676 in Remington's Pharmaceutical Sciences Vol. 2 (Gennaro, ed., 19 th This is described in Ed., Mack Publishing, Easton, PA, 1995.

[0028] In one embodiment, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is formulated as a composition suitable for oral administration to humans according to routine procedures. The orally delivered compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be in the form of, for example, tablets, capsules, gel caps, caplets, lozenges, aqueous or oily solutions, suspensions, granules, microparticles, multiplicities, powders, emulsions, syrups, or elixirs. When the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is incorporated into an oral tablet, such tablet may be compressed, powdered, enteric-coated, sugar-coated, film-coated, multi-compressed, or multi-layered. Techniques and compositions for producing solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman et al., eds., 2 nd This is described in (Ed., Marcel Dekker, Inc., 1989 and 1990). Techniques and compositions for preparing tablets (compressed and molded), capsules (rigid and soft gelatin), and pills are also described in King, “Tablets, Capsules, and Pills,” pp. 1553-1593 in Remington's Pharmaceutical Sciences (Osol, ed., 16 th This is described in Ed., Mack Publishing, Easton, PA, 1980.

[0029] Liquid oral dosage forms include aqueous and non-aqueous solutions, emulsions, suspensions, and solutions and / or suspensions reconstituted from non-foaming granules, and optionally contain one or more suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, colorants, flavoring agents, etc. Techniques and compositions for preparing liquid oral dosage forms are described in Pharmaceutical Dosage Forms: Disperse Systems (Lieberman et al., eds., 2) ndThis is described in (Ed., Marcel Dekker, Inc., 1996 and 1998).

[0030] A pharmaceutically acceptable preparation can be provided by including one or more excipients, such as sweeteners like fructose, aspartame, or saccharin; flavoring agents like peppermint, wintergreen oil, or cherry; colorants; and preservatives, with a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof administered orally. Furthermore, in the form of tablets or pills, the composition may be coated to slow down breakdown and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. A selectively permeable membrane surrounding an osmotically active driving compound is also suitable for orally administered compositions. In these latter platforms, fluids from the surrounding environment of the capsule are absorbed by the driving compound, which expands and pushes the drug or drug composition through the opening. These delivery platforms can provide an essentially zero-order delivery profile, in contrast to the spiked profile of immediate-release formulations. Time-delaying materials such as glycerol monostearate or glycerol stearate may also be used. The oral composition may contain standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

[0031] The composition may take the form of a solution, suspension, emulsion, tablet (e.g., orally disintegrating tablet (ODT) or sublingual tablet), pill, pellet, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, suspension, fine particles, multiply particles, rapid-dissolving film, or other form for oral or mucosal administration, or any other form suitable for use. In one embodiment, the composition is in the form of an ODT (see, for example, U.S. Patents 7,749,533 and 9,241,910). In another embodiment, the composition is in the form of a sublingual tablet (see, for example, U.S. Patents 6,572,891 and 9,308,175). In yet another embodiment, the composition is in the form of a capsule (see, for example, U.S. Patent 5,698,155). In another embodiment, the composition is in a form suitable for buccal administration, for example, as a tablet, lozenge, gel, patch, or film formulated in a conventional manner (see, for example, Pater et al., “Current status and the future of buccal drug delivery systems,” Expert Opin. Drug Deliv. 5(5):531-542 (2008)). In another embodiment, the composition is in a form suitable for gingival administration, for example, as a polymer film containing polyvinyl alcohol, chitosan, polycarbophil, hydroxypropyl cellulose, or Eudragit S-100, as disclosed by Padula et al., “In Vitro Evaluation of Mucoadhesive Films for Gingival Administration of Lidocaine,” AAPS PharmSciTech 14(4):1279-1283 (2013). In another embodiment, the composition is in a form suitable for intraocular administration.

[0032] In one embodiment, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is formulated for parenteral administration. When administered parenterally by injection, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be, for example, in the form of an isotonic sterile solution. In one embodiment, parenteral administration includes a compound of formula (IA).

[0033] When a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (IA)), is administered parenterally, the parenteral formulation may be in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle. Such a formulation may further contain one or more pharmaceutically necessary additives, such as stabilizers, suspenders, dispersants, or buffers. The compound of formula (I) or (I'), or a pharmaceutically acceptable one thereof (e.g., a 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 pharmaceutically acceptable 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 contain a solubilizer. The compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (IA)), for intravenous administration may optionally contain a local anesthetic such as benzocaine or prilocaine to relieve pain at the injection site. Generally, the components are supplied in unit dosage forms, either separately or mixed together, as dry lyophilized powder or water-free concentrate, in airtight containers such as ampoules or sachets indicating the amount of the activator. When administered by infusion, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (IA)), may be dispensed, for example, in an infusion bottle containing sterile pharmaceutical-grade water or saline. When a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (IA)), is administered by injection, an ampoule of sterile water for injection or saline solution may be provided so that the components can be mixed before administration.

[0035] Compounds of formula (I) or (I') are mostly excreted unchanged, primarily through urine. See Example 2. Therefore, compounds of formula (I) or (I') exhibit high concentrations in the bladder after administration. For example, when administered orally, the amount of compound of formula (I) or (I') excreted in urine ranges from approximately 30% to approximately 95%, depending on the dose administered. Furthermore, the concentration of compound of formula (I) or (I') in urine is maintained up to 24 hours after oral administration at a certain dose. In certain embodiments, the concentration of compound of formula (I) or (I') 12 hours after oral administration is greater than 100 nM. In other embodiments, the concentration of compound of formula (I) or (I') 12 hours after oral administration is greater than 500 nM. In other embodiments, the concentration of 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 may be in the range of about 100 nM to about 30,000 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration may be in the range of about 500 nM to about 15,000 nM. In other embodiments, the concentration of the compound of formula (I) or (I') 12 hours after oral administration may be in the range of about 1,000 nM to about 10,000 nM.

[0036] In some embodiments, the compound of formula (I) or (I') is administered in the form of a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt that can be prepared from the compound of formula (I). Examples of salts include, but are not limited to, sulfates, citrates, acetates, trifluoroacetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucoronates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts). In one embodiment, pharmaceutically acceptable salts are hydrochloride, sulfate, sodium salt, potassium salt, benzenesulfonate, p-toluenesulfonate, or fumarate. In another embodiment, pharmaceutically acceptable salts are hydrochloride or sulfate. In another embodiment, pharmaceutically acceptable salts are hydrochloride. In another embodiment, pharmaceutically acceptable salts are sulfate. In another embodiment, pharmaceutically acceptable salts are sodium salt. In another embodiment, pharmaceutically acceptable salts are potassium salt. In another embodiment, pharmaceutically acceptable salts are fumarate. In another embodiment, pharmaceutically acceptable salts are p-toluenesulfonate (also known as "tosylate salt"). In another embodiment, pharmaceutically acceptable salts are choline salt.

[0037] In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains 1 equivalent of the compound of formula (I) or (I') and about 1.0 equivalent of toluenesulfonic acid, for example, about 0.8 to about 1.2 equivalents of p-toluenesulfonic acid in one embodiment, about 0.9 to about 1.1 equivalents of p-toluenesulfonic acid in another embodiment, about 0.93 to about 1.07 equivalents of p-toluenesulfonic acid in another embodiment, about 0.95 to about 1.05 equivalents of p-toluenesulfonic acid in another embodiment, about 0.98 to about 1.02 equivalents of p-toluenesulfonic acid in another embodiment, or about 0.99 to about 1.01 equivalents of p-toluenesulfonic acid in another embodiment. In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains about 1 equivalent of the compound of formula (I) or (I') and about 1 equivalent of p-toluenesulfonic acid (i.e., a monotosylate salt). In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains one equivalent of the compound of formula (I) or (I'). In another embodiment, the pharmaceutically acceptable p-toluenesulfonate contains one equivalent of the compound of formula (I'), i.e., the monotosylate salt of the compound of formula (I') (i.e., formula (IA) below): [ka] It contains (a compound).

[0038] The methods of the disclosure provided herein also encompass the use of any solvates of the compounds of formula (I), (I') or their pharmaceutically acceptable salts. “Solvate” is a term commonly known in the art and is hereby considered to be a combination, physical association, and / or solvation of the compounds of formula (I), (I') or their pharmaceutically acceptable salts. This physical association may include varying degrees of ionic and covalent bonding, including hydrogen bonding. If the solvate is stoichiometric, the ratio of solvent molecules to the compounds of formula (I), (I') or their pharmaceutically acceptable salts is constant. The compounds of formula (I), (I') or their pharmaceutically acceptable salts may exist in solvated forms with pharmaceutically acceptable solvents, such as water, methanol, ethanol, etc.

[0039] The methods of this disclosure provided herein also encompass the use of any crystalline form (or polymorph) of the compounds of formula (I), (I') or any pharmaceutically acceptable salts thereof. As used herein, the term “crystalline” and related terms, when used to describe a substance, component, or product, mean that the substance, component, or product is substantially crystalline as determined by X-ray diffraction, microscopy, polarized light microscopy, or other known analytical procedures known to those skilled in the art. As used herein, the term “polymorph” refers to the crystalline structure of a compound having different unit cell structures in the crystal, resulting from diverse molecular stereochemistry and molecular packing. Polymorphs of a single compound may have one or more different chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties from one another. Differences in physical properties exhibited by polymorphisms can affect pharmaceutical parameters such as storage stability, compressibility, density (important in the manufacture of compositions and products), dissolution rate (a key factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water absorption, compaction, and particle morphology. Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, where the dosage form discolors more rapidly when composed of one polymorph than when composed of another), mechanical changes (e.g., changes in crystals during storage as a kinetically favorable polymorph is converted 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 crystalline forms 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, “dose,” “amount,” and related terms refer to the weight of the compound of formula (I) or (I') in its free acid and free base forms, i.e., non-salt forms. For example, a dose of 10.0 mg of the non-salt form of the compound of formula (I) or (I') means that 10.0 mg is actually administered. However, for example, a dose of 10.0 mg of, for example, the monohydrochloride or 1:1 molar hydrochloride of the compound of formula (1) means that 10.84 mg of the compound is actually administered, which results in 10.00 mg of the non-salt form of the compound of formula (I) or (I') (0.0229 mmol) and 0.84 mg of hydrochloride (0.0229 mmol). Similarly, a dose of 10.00 mg of, for example, the monotosylate salt of the compound of formula (IA) (1:1 mole of p-toluenesulfonate) means that 13.93 mg of the compound is actually administered, which 13.93 mg results in 10.00 mg of the unsalted form of the compound of formula (I') (0.0229 mmol) and 3.93 mg of p-toluenesulfonic acid (0.0229 mmol).

[0042] With respect to methods for treating or preventing conditions or symptoms in human subjects, preferred effective doses of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, are, in one embodiment, about 0.00002 mg / kg to about 10 mg / kg of body weight of the human subject per day; in another embodiment, about 0.00025 mg / kg / day to about 5 mg / kg / day; in another embodiment, about 1.5 mg / kg / day to about 3 mg / kg / day; in another embodiment, about 0.2 mg / kg / day to about 2 mg / kg / day; in another embodiment, about 2.5 mg / kg / day to about 10.0 mg / kg / day; and in another embodiment, about 3.0 mg / kg / day to about 10 mg / kg / day. In certain embodiments, preferred effective doses of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (IA)), are approximately 0.00002 mg / kg / day to approximately 10 mg / kg / day, and approximately 0.001 mg / kg / day to approximately 10 mg / kg / day. In other embodiments, the effective dose is approximately 1.0 mg / kg / day or less. It should be understood that, with respect to these doses, the term "day" refers to a 24-hour cycle starting from the time of administration of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof. Generally, it is understood that preferred 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 in which a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (IA)), is administered orally, suitable effective doses of the compound as a single dose are approximately 0.001 mg to approximately 300 mg, approximately 0.005 mg to approximately 250 mg, approximately 0.01 mg to approximately 200 mg, approximately 0.05 mg to approximately 150 mg, approximately 0.075 mg to approximately 50 mg, and approximately 0.10 mg to approximately 10 mg. In one embodiment, the compound of the Disclosure is administered as a single dose of an uncontrolled-release formulation or a non-sustained-release formulation. In another embodiment, the effective dose of the compound of the Disclosure is administered as multiple doses of an uncontrolled-release formulation or a non-sustained-release formulation.

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

[0045] In certain embodiments, a controlled-release composition containing a therapeutically effective amount of the compound of this disclosure is administered as a single dose or multiple doses. The controlled-release composition may contain up to 100 times the dose of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (IA)), used in an uncontrolled-release or unsustained-release formulation.

[0046] In some embodiments, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered once daily. In some such embodiments, the compound of formula (I) is administered nightly. As shown in Example 2, daily administration of the compound of formula (I), (I'), or (IA) results in urinary concentrations 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 drowsiness and treat sleep disturbances when administered at sufficient dose levels. See U.S. Patent Publication 2020 / 0345726, incorporated herein by reference. Patients suffering from symptoms associated with interstitial cystitis often experience poor sleep quality, insomnia, and / or nocturia. In some embodiments, the patient suffering from sleep disturbances is a woman aged 50 years or older. In other embodiments, the patient suffering from sleep disturbances is a man aged 50 years or older. Nightly administration of a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, improves both sleep quality and symptoms associated with interstitial cystitis. In certain embodiments, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered by the patient nightly before sleep. For example, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered approximately 1 minute to 3 hours before sleep. In some embodiments, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered approximately 5 minutes to 60 minutes before sleep. In other embodiments, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered approximately 10 minutes to 30 minutes before sleep.

[0048] In one embodiment, the effective dose or dosage of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered about 60 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 45 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 30 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 20 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 20 minutes before or earlier than the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 15 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 15 minutes before or earlier than the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered about 10 minutes before the median of a person's habitual bedtime. In another embodiment, the effective dose or dosage is administered approximately 10 minutes or earlier than the median of the human's habitual bedtime. In yet another embodiment, the effective dose or dosage is administered approximately 5 minutes before the median of the human's habitual bedtime.

[0049] In other embodiments, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, may be administered multiple times a day. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered twice or three times a day. In embodiments in which the compound is administered multiple times a day, each dose may be the same or different. In some embodiments, the dose of the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered at a higher dose than any other dose provided at an earlier point in the day. In some embodiments, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered twice a day, approximately every 12 hours. In other embodiments, the compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered three times a day, approximately every 8 hours.

[0050] In certain embodiments, a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, is administered twice daily, with the second dose (i.e., the second therapeutically effective dose) being administered before bedtime as described above. In some such embodiments, the second dose is administered in a larger amount than the first dose (i.e., the first therapeutically effective dose). For example, the second dose may be administered in an amount approximately 1.5 times, 2 times, 3 times, 5 times, 10 times, 20 times, 50 times, 100 times, or 1000 times greater than the first dose. In some embodiments, the second dose may be administered in an amount approximately 1.5 times to approximately 10 times greater than the first dose. In other embodiments, the second dose may be administered in an amount approximately 1.5 times to approximately 100 times greater than the first dose. In other embodiments, the second dose may be administered in an amount approximately 1.5 times to approximately 1000 times greater than the first dose. In other embodiments, the second dose may be administered in amounts approximately 3 to 100 times greater than the first dose. In other embodiments, the second dose may be administered in amounts approximately 3 to 1000 times greater than the first dose. In other embodiments, the second dose may be administered in amounts approximately 5 to 100 times greater than the first dose. In other embodiments, the second dose may be administered in amounts approximately 5 to 1000 times greater than the first dose. Such a dosing schedule ensures that in human subjects, the first dose is effective in treating interstitial cystitis and its associated symptoms without causing drowsiness, while the second dose is effective in treating interstitial cystitis and its associated symptoms and inducing drowsiness or sleep. In certain embodiments, both the first and second doses are administered through (the same or different) uncontrolled-release or unsustained-release formulations. In other embodiments, the first dose is administered via a controlled-release formulation or a non-sustained-release formulation, and the second dose is administered via a non-controlled-release formulation or a non-sustained-release formulation.

[0051] In another embodiment, compositions comprising the compounds of the present disclosure are useful as pharmaceuticals 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 disorders, alcohol-induced sleep disorders, or any combination thereof. Other sleep disorders include alcohol-induced sleep disorders (e.g., insomnia-type alcohol-induced sleep disorder, daytime sleepiness-type alcohol-induced sleep disorder, parasomnia-type alcohol-induced sleep disorder, and mixed-type alcohol-induced sleep disorder); insomnia in alcohol use disorder, sleep disturbances associated with alcohol cessation (e.g., insomnia associated with alcohol cessation), or any combination thereof.

[0052] A method for treating or preventing interstitial cystitis / bladder pain in a patient requiring treatment or prevention may further include co-administering to the patient a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof, and a second therapeutic agent. In one embodiment, the second therapeutic agent is 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 throspium. In other such embodiments, the antimuscarinic agent is solifenacin. In other such embodiments, the antimuscarinic agent is dalifenacin. 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 has been able to reproduce most of the characteristics of interstitial cystitis / bladder pain syndrome in humans, including increased urination frequency, decreased urine volume per void, 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 evaluating candidate compounds (Juszczak et al., 2007). CYP is an antitumor agent widely used to treat malignancies such as lymphoma and leukemia. When administered peritoneally, CYP is converted in the kidneys 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 intravenous injection of CYP induced bladder inflammation and visceral pain-associated behaviors, which peaked immediately after CYP injection and lasted 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 (nociceptive responses triggered by normally harmless stimuli) (Auge et al., 2013).

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

[0056] 1.1 Study Design 1.1.1 Protocol Design On day 1 ("D1"), the day before cystitis induction, rats were adapted to individual Plexiglas boxes (minimum 30 minutes) and von Frey filament application to reduce the level of stress from the new environment. Adaptation was carried out under the exact same experimental conditions as the pain assessment (see §2.4.1 for details). On day 0 ("D0"), the von Frey test was first conducted to obtain baseline values ​​for nociceptive behavior. Immediately before the induction of cystitis in D0, pharmacological treatment was performed as described in §2.4.2. Acute cystitis was induced in D0 rats by CYP injection. Control rats were administered physiological saline (see §2.4.3 for details) (D0, T=0).

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

number

[0058] 1.1.2 Experimental Group The four experimental groups were included as shown in the table below. [Table 1]

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

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

[0061] 1.3 Substance 1.3.1 Test substance and vehicle 1.3.1.1 Preparation of the formulation A formulation of the compound of formula (IA) was prepared at room temperature to a final concentration of 6 mg / mL (based on the free base form). An appropriate mass of the 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 prepared (1 aliquot / dose) and maintained at +4°C for up to 3 days. On each experimental day, the suspension was allowed to equilibrate at 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. This was prepared in water for injection (WFI) and maintained at 4°C for one week. The MC (batch number SLBR8963V) was purchased from Sigma-Aldrich (Saint-Quentin Fallavier, France).

[0063] 1.3.2 Positive substances Ibuprofen was freshly prepared at a final concentration of 60 mg / mL (free base form) on each administration day. The appropriate mass of ibuprofen was weighed and dissolved in a vehicle at room temperature. This solution was vortexed for 15-30 seconds, then sonicated for 1 minute, and then vortexed for another 15-30 seconds. Ibuprofen was purchased from Sigma-Aldrich (batch number BCBR4459V).

[0064] 1.3.3 Anesthetics / 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 solution was purchased from B-Braun via Centralet (batch number 18465450). WFI was obtained from Cooper (Melun, France; batch number 19MD16GA).

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

[0067] Visceral pain was blinded and assessed by applying a set of eight calibrated von Frey filaments (1, 2, 4, 6, 8, 10, 15, and 26 g) with progressively increasing force at 5-second intervals to the lower abdomen near the bladder. Prior to the test, the abdominal region designed for mechanical stimulation was shaved in each animal. Animals were placed on a raised wire mesh bed under individual clear Plexiglas boxes and allowed to adapt for at least 30 minutes before the von Frey test was initiated. The filaments were then applied through the mesh bed for 1–2 seconds with sufficient force to slightly bend the filaments. 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] The nociceptive behavior of each animal and each filament was scored as follows: [Table 2]

[0069] 1.4.2 Pharmacological treatment Before the experiment, animals were randomly assigned to treatment groups using a block method. The block method consists of distributing at least one animal per treatment or control group 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 before injection of CYP or physiological saline. On the morning of each experimental day, rats were weighed and administered in a volume of 5 mL / kg.

[0071] 1.4.3 Induction of acute cystitis To induce acute cystitis, CYP was administered as a single intravenous injection at a dose of 150 mg / kg in a final volume of 5 mL / kg (in physiological saline). Control rats were administered physiological saline under the same experimental conditions as CYP.

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

[0073] 1.6 Presentation and Analysis of Results All raw data was compared with the raw data by two individuals before data analysis. The results are expressed as the 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, CA, USA). A p-value < 0.05 was considered statistically significant.

[0075] Unless two-way ANOVA was applied, the data were tested for normality (Shapiro-Wilk normality test) and their variances were assessed (F-test or Bartlett test for two or more groups, respectively) before performing any statistical tests. As a result, appropriate statistical tests were applied.

[0076] 1.7.1 Comparison of Basic Nociceptive Responses To demonstrate that all groups had similar baseline values, group comparisons were performed among all groups, followed by post-hoc tests. Post-hoc tests were also conducted to analyze areas where potential differences occurred between groups. For clarity of the graphs, the results of post-hoc tests were not shown when p > 0.05. - The Kruskal-Wallis test was used as a nonparametric analysis of variance (ANOVA) with Dunn's multiple comparisons. - A one-way ANOVA test was used as a parametric ANOVA with Holm-Sidak multiple comparisons. - Repeated measures (RM) two-way ANOVA, followed by Holm Sidak's multiple comparisons, was used to score nociceptivity.

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

[0078] We applied a two-way RM ANOVA with Sidak's post-hoc test. The two-way RM ANOVA shows whether there was an overall difference between the two groups, while Sidak's post-hoc test compares the means at each time point (+2, 3, 4, and 24 hours).

[0079] 1.7.3 Time-course analysis of the effects of ibuprofen or compounds of formula (IA) To analyze the effects of substances on CYP-induced acute cystitis, individual pairwise comparisons were performed between the ibuprofen / CYP group or the compound of formula (IA) / CYP group and the vehicle / CYP group.

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

[0081] When individual pairwise comparisons are performed, statistical significance is indicated by the symbol " * This indicates " and non-significance is " ns Please note the points indicated by "[ ]". In the case of group comparisons, statistically insignificantness is indicated by the symbol "NS".

[0082] 1.8 Results 1.8.1 The basic reaction was similar across different experimental groups. The baseline nociceptive response (before CYP or saline injection) was similar across all experimental groups. In fact, no significant differences in nociceptive parameters were observed among the experimental groups before CYP or saline injection (p>0.05, Figures 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, we compared nociceptive responses between saline-injected rats and CYP-injected rats within the vehicle group.

[0084] At all time points evaluated (i.e., 2 to 24 hours), CYP was found to induce a significant decrease in the nociceptive threshold compared to physiological saline (p<0.0001, Figure 2). The shape of the time curves indicated that the degree of CYP's effect was relatively low at 2 hours, but remained at a similar level from +3 to +24 hours.

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

[0086] In parallel with the effect of CYP on nociceptivity scores, AUC 1–6g was significantly increased overall (p<0.0001, Figure 4A). Consistent with the above results, the effect of CYP was relatively low at +2 hours compared to saline-injected rats, and was maintained at a similar level from +3 hours to +24 hours (p<0.05 and p<0.0001 at +2 hours and +3 hours to +24 hours, respectively, Figure 4A). Finally, within the vehicle group, CYP-injected rats showed a significant increase in AUC 6–26g at all time points (p<0.0001, Figure 4B).

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

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

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

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

[0091] 1.8.4 The compound of formula (IA) (30 mg / kg, po) reduced and reversed CYP-induced visceral pain. In CYP-injected rats, the compound of formula (IA) exhibited an overall inhibitory effect on the nociceptive threshold compared to the vehicle (p>0.01, Figure 8). Comparison at specific time points (i.e., post-hoc analysis) showed that statistical significance was reached only at +3 hours (p>0.01, Figure 8). However, it should be noted that the values ​​of the compound of formula (IA) were within a similar range at +2 and +3 hours (6.6±0.8 vs. 6.3±1.2 at +2 and +3 hours, respectively). Therefore, the lack of significance at +2 hours could be explained by the fact that the effect of CYP was lowest at +2 hours (see §4.2). After +3 hours, the effect of the compound of formula (IA) gradually decreased over time (4.8±0.8 and 3.7±0.8 at +4 and +24 hours, respectively).

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

[0093] Treatment with the compound of formula (IA) resulted in a reduction in nociceptivity score accompanied by an overall decrease in AUC from 1 to 6 g (p<0.001, Figure 10A). Consistent with the nociceptivity threshold results, the highest level of significance was reached at +3 hours (p<0.01, Figure 10A), although the values ​​themselves were within a similar range at +2 and +3 hours (19.8±6.9 and 19.3±6.3 at +2 and +3 hours, respectively). After 3 hours, the efficiency of the compound of formula (IA) decreased slightly and progressively over time (34.1±7.9 and 61.8±15.7 at +4 and +24 hours, respectively).

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

[0095] Example 2: Pharmacokinetic study on the compound of formula (IA) The urine concentration was evaluated in humans (total 9 subjects) up to 48 hours after single oral administration of the compound of formula (IA) in the form of a methylcellulose suspension. Urine samples (serial samples pooling all voided urine) for determination of the concentration of the compound of formula (IA) 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 administration. An overview of the urine concentrations of the compound of formula (IA) for each subject as well as by treatment and time interval is shown in Table 4 below. [Table 4]

[0096] The data in Table 4 show the mean urine concentration levels and standard deviations of the compound of formula (IA) at specific time intervals after administration of specific doses (0.2 mg, 0.6 mg, 2 mg, and 10 mg) of the compound of formula (IA). Table 4 shows that even for the lowest dose (0.2 mg) of the compound of formula (IA), the urine concentration is several orders of magnitude higher than the in vitro activity of the compound of formula (IA) measured by Ki and EC 50 [[ID=1st]]which indicates that the urine concentration is several orders of magnitude higher than the in vitro activity of the compound of formula (IA) measured by Ki and EC [[ID=xx]]

[0097] [[ID=xx]] Example 3: A Phase 1b, double-blind, placebo-controlled, crossover study to investigate the effect 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) on the change in the mean daily bladder pain / discomfort symptom score in subjects diagnosed with IC / BPS, compared to placebo. Each subject needs to identify their most bothersome bladder pain / discomfort symptom at the time of screening. To be eligible for randomization, the subject must report experiencing this specific symptom at a sufficient severity (intensity or frequency as defined in the protocol) during a 2-week single-blind placebo lead-in period.

[0098] It should be noted that there was an error in the original text where "Ki及びEC" was not fully explained. I have made a reasonable guess in the translation of item

[13] to make the text more understandable. If there are specific requirements for this part, please let me know and I will adjust accordingly.The average daily bladder pain / discomfort score is assessed twice daily (morning and evening) using an electronic diary based on an 11-point numerical rating scale (NRS). The 11-point NRS ranges from 0 = "no bladder pain / discomfort" to 10 = "worst pain / discomfort imaginable." The symptoms considered most bothersome by the subject are determined by agreement between the subject and the primary investigator during screening (and in the electronic diary) using the IC / BPS-related symptom assessment procedure specified in the protocol.

[0099] Secondary evaluation: To evaluate the effect of the compound of formula (IA) on the change in mean voiding rate per 24 hours compared to placebo in subjects diagnosed with IC / BPS. Subjects will be asked to record all voiding episodes (acts of urination) in an electronic diary for 7 days prior to their scheduled visit to each clinic at the clinical trial site. Subjects will need to record the time, type, and urgency of each voiding episode for 7 days, and also record urine volume for 2 days over the weekend. The types of episodes are classified as urination (urination in the toilet) or incontinence (involuntary release of urine). • The level of urinary urgency (a sudden, irresistible urge to urinate that is difficult to postpone) for each episode is rated on an 11-point NRS scale. The NRS ranges from 0 = "no urinary urgency" to 10 = "worst possible level of urinary urgency." • Episode volume is the total urine volume per urination during a single recorded episode.

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

[0101] The following measurements will be performed by the subjects at home using an electronic diary. - The average and worst-case bladder pain / discomfort score obtained twice a day (morning and evening). - All urination episodes (acts of urination) that occurred during the week (7 days) prior to each scheduled clinic visit to the clinical trial site. The time, type, intensity, and volume of each episode will be collected over a 24-hour period each day.

[0102] The following measurements will be taken when you visit the clinic. - Bladder Pain / Interstitial Cystitis Symptom Score (BPIC-SS). The BPIC-SS consists of eight questions about bladder pain over the past seven days. Questions 1-5 assess how often subjects urinated due to pain, how often they needed to urinate immediately after the previous urination, how often they urinated to avoid pain, how often their bladder was pressured, and how often they experienced bladder pain, rated on a 5-point scale from 0 = "never" to 4 = "very often". Questions 6 and 7 assess how much daytime and nighttime frequent urination bothered subjects, rated on a 5-point scale from 0 = "never" to 4 = "very often". Question 8 assesses the subject's worst bladder pain over the past seven days, rated on an 11-point NRS ranging from 0 = "no bladder pain" to 10 = "worst possible bladder pain". The BPIC-SS total score is the sum of the individual question scores, ranging from 0 to 38. A higher score indicates a worse condition, and a score of 19 or higher may indicate moderate / severe disease activity. The total score and the worst bladder pain (Q8) should be evaluated. - O'Leary-Sant Interstitial Cystitis Symptom Score (ICSI). The ICSI consists of four questions that measure urinary urgency and frequent urination, nocturia, and pain or burning. Each question is rated using a 6-point scale ranging from 0 = no symptoms / problems to 5 = worst symptoms / problems. The total score ranges from 0 to 20. A one-week recall period is used. - O'Leary-Sant Interstitial Cystitis Problem Score (ICPI). The ICPI consists of four questions that assess the severity of symptoms (frequency, nocturia, urinary urgency, discomfort) and the magnitude of the problem the symptoms cause the patient. Each question is rated using a 5-point scale ranging from 0 = "no problem" to 4 = "major problem". The total score ranges from 0 to 16. A one-week recall period is used. - Subject Global Response Assessment (SGRA). The SGRA is a balanced, self-assessed measure of a subject's clinical condition compared to baseline. It includes one question: a) How would you rate the overall symptoms of interstitial cystitis / bladder pain now compared to baseline? Use a 7-point rating scale: 1 = significantly worse, 2 = moderately worse, 3 = slightly worse, 4 = no change, 5 = slightly improved, 6 = moderately improved, or 7 = significantly improved. - Subject Self-Assessment of Treatment Effectiveness (SGRA) - Discomfort Symptoms. The SGRA is used to assess the subject's clinical condition compared to baseline regarding the most discomfort symptom and includes two questions: a) How do you rate your most discomfortating bladder pain / discomfort symptom now compared to baseline? and b) How do you rate your most discomfortating lower urinary tract symptom now compared to baseline? For both questions, use a 7-point rating scale: 1 = significantly worse, 2 = moderately worse, 3 = slightly worse, 4 = no change, 5 = slightly improved, 6 = moderately improved, or 7 = significantly improved. - Nocturia Sleep Quality Scale (NSQS). The NSQS consists of six items that assess hypothetical domains related to the number of nighttime awakenings, sleep volume, and sleep quality. The NSQS uses a short recall period, "from the time of going to bed with the intention of falling asleep until the start of the day after waking up," so that patients can assess the impact of nocturia on their sleep over time.

[0103] Safety evaluation: Evaluate the safety and tolerability of the compound of formula (IA) as measured by adverse events (AEs), chemical results, hematological results, urinalysis (including microscopic examination), electrocardiogram (ECG), physical examination, vital signs, Columbia Suicide Severity Scale (C-SSRS), Hospital Anxiety and Depression Scale (HADS), Karolinska Sleepiness Scale (KSS), and the Digital Sign Substitution Test (DSST).

[0104] Diagnostic and primary inclusion criteria: The following inclusion / exclusion criteria will be used at screening visit 1 to determine eligibility for participation in the induction phase. The criteria for enrollment in the double-blind, randomized treatment period are also shown below. Incorporation: 1. Non-pregnant (confirmed by urine pregnancy test) and non-breastfeeding women, aged 18-64, able to urinate independently. 2. The subject has a diagnosis of interstitial cystitis / bladder pain syndrome (IC / BPS) in accordance with American Urological Association (AUA) guidelines, recorded in the subject's medical record at least six months prior to screening. 3. The patient presents with bladder pain / discomfort accompanied by lower urinary tract symptoms meeting the following criteria, as assessed by a healthcare provider, at the time of screening. a. The subject has had complaints of bladder pain / bladder compression / bladder discomfort for at least 6 months, accompanied by other lower urinary tract symptoms for at least 6 months. b. The subject's total score on the Bladder Pain / Interstitial Cystitis Symptom Scale (BPIC-SS) is 19 or higher. c. The subject's average daily pain level over the past week, as rated by the subject using an 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain), is between 4 and 8. d. The subject's urination frequency is estimated to be between 11 and 30 times per 24 hours during the past week. 4. Cystoscopy findings are present at the time of screening or obtained within six months of screening, and these findings rule out other conditions that cause bladder pain or discomfort (e.g., transitional cell carcinoma of the bladder, endometriosis of the bladder). 5. Patients who have not received pharmacological treatment for IC / BPS in the past 30 days, or who have received oral pharmacological treatment for interstitial cystitis / bladder pain syndrome with a stable dose / regimen in the past 30 days and who, in the judgment of the principal investigator, are expected to maintain the same stable dose / regimen throughout the study. 6. Despite a history of past or ongoing treatments, including conservative measures that may include one or more of the following: a) scheduled urination and behavioral modification therapy, b) dietary restrictions, and c) stress reduction, and despite oral therapy with any of the following drugs: antidepressants, antihistamines, antimuscarinic agents, and anticholinergic agents, alpha-adrenergic blockers, analgesics, and pentosan polysulfate, the patient meets the criteria for study inclusion. 7. The patient is considered generally healthy based on the opinion of the principal investigator at the clinical site, taking into account the medical history, physical examination, 12-lead electrocardiogram, and laboratory profile. 8. You can speak, read, write, and understand English, understand consent forms, and communicate effectively with examination staff. 9. The patient voluntarily provides written informed consent and is willing and able to complete all examination procedures, including daily bladder diaries (assessment of pain and urination). Exclude: 1. Having pelvic floor pain (score of 5 or higher out of 10 on the 11-point NRS pain scale) 2. You have received any opioid therapy for any indication in the past 30 days. 3. Within the past 30 days, you have used more than 70 milligrams of oral morphine equivalent per week of opioids to manage pain in IC / BPS, or you anticipate needing this level of opioid pain management during the trial. 4. Have you had a urinary tract infection (UTI), including bacterial cystitis, within the past 30 days, or have a history of recurrent UTIs defined as three or more episodes in the past six months? Note: Infected subjects may be rescreened within 30 days. 5. Hematuria detected by microscopic examination. Note: Subjects with minute hematuria may be approved for enrollment after review and approval by the investigational medical monitor. 6. You have undergone any surgical procedure affecting bladder function (e.g., bladder augmentation, cystectomy, cystolysis, nerve resection, or lower abdominal plexus ablation) at any time, or have received botulinum toxin injection into the bladder within the past nine months. 7. You have received intravesical therapy or hydrodistension (infusion including liquid or drug delivery devices, pentosan polysulfate sodium, lidocaine, steroids, heparin, chondroitin, and any combination or additional formulations) within the past 30 days. 8. Use of a sacral and / or pudendal nerve neuromodulation device (e.g., Interstim) within the past six months (not excluded if device use was initiated more than six months prior to the past six months and the subject has been in a stable condition for the past three months). 9. You have received percutaneous tibial nerve stimulation (PTNS) treatment within the past 90 days. 10. A history of concomitant malignancies or cancer, excluding non-invasive skin cancer, within the past five years (Note: Patients with a history of cancer who have received treatment and have been considered disease-free for at least five years are eligible). 11. At any point in time, the patient had a bladder tumor (benign or malignant). 12. Having active genital herpes or vaginitis 13. Having a urethral diverticulum. 14. Had cyclophosphamide cystitis or chemical cystitis, or had tuberculosis, or had received pelvic irradiation. 15. Having poorly controlled diabetes. 16. Are you currently pregnant or breastfeeding, or do you plan to become pregnant during the course of the trial? 17. Having moderate to severe liver impairment as defined by Child-Pugh classification B or C. 18. Any history and / or current evidence of other medical conditions (e.g., cardiac, respiratory, gastrointestinal, renal, or malignant tumors other than basal cell carcinoma), neurological conditions, or psychiatric conditions that, in the opinion of the principal investigator, could affect the safety of the subject or interfere with the evaluation of the study. 19. Clinically significant depression based on a Hospital Anxiety and Depression Scale (HADS) score of 11 or higher; suicidal ideation with actual attempts, methods, or plans in the past year (answering "yes" to item 4 or 5 of the Columbia Suicide Severity Rating Scale [C-SSRS]); a history of suicidal behavior in the past five years (answering "yes" to any item of suicidal behavior on the C-SSRS); or any lifetime history of serious or recurrent suicidal behavior. Non-suicidal self-injury behavior is not an incentive for risk assessment unless indicated by the principal investigator of the clinical site. 20. Having a history or current condition that may interfere with the absorption, distribution, metabolism, or excretion of the drug (including any surgical intervention for weight loss). 21. At the time of screening, the individual has a substance use disorder, or has tested positive for UDTs for illegal drugs (including tetrahydrocannabinol [THC]), unregulated substances (opioids or non-opioids), or alcohol, or has a history of opioid overdose for any reason. 22.20 kg / m 2 Less than 35 kg / m 2 Having a super body mass index 23. Abnormal blood urea nitrogen and creatinine levels, and 60 mL / min / 1.73 m 2 The patient has renal dysfunction, as evidenced by an estimated glomerular filtration rate (eGFR) of less than a certain level during screening. 24. At screening, the patient has clinically significant abnormalities in clinical chemistry, hematology, or urinalysis, including serum glutamate-oxaloacetate transaminase / aspartate aminotransferase or serum glutamate pyruvate transaminase / alanine aminotransferase at three times or more the upper limit of the reference range, or serum creatinine greater than 2 mg / dL. 25. Poorly controlled hypertension (systolic >140 mmHg / diastolic >90 mmHg) or QTcF >450 msec (male) and QTcF >470 msec (female), as confirmed by repeated ECGs, or other abnormal cardiac conditions including clinically significant ECG abnormalities. Having an excessive caffeine intake of 26,300 mg / day or more (for example, roughly equivalent to three 6-ounce cups of caffeinated coffee, or three 12-ounce caffeinated sodas, or three 8-ounce caffeinated teas). 27. The investigational drug was administered in a clinical trial within 30 days prior to the first dose of the investigational drug allocated in this study (or within 5 half-lives of the investigational drug treatment, whichever is longer). 28. The person had already been exposed to the compound of formula (IA). 29. I have surgery scheduled during the exam.

[0105] Randomization criteria (double-blind phase): After completing a daily bladder diary, participants must meet the following criteria for randomization to a double-blind, randomized treatment phase. a) The average daily bladder pain score is 5 or higher for at least 9 days during the induction phase. b) The mean number of urination episodes is 10 or more but less than 30 for each 24-hour period over at least 3 days. c) The score on the Bladder Pain / Interstitial Cystitis Symptom Scale (BPIC-SS) is 19 or higher. d) The newly administered IC / BPS therapy was a stable dose / regime and was expected to be maintained during the trial. e) The subject properly completed the diary in accordance with the instructions of the principal investigator.

[0106] Experimental design: A phase 1b blinded, placebo-controlled crossover trial evaluating the effect of oral administration of compound (IA) at a dose of 1 mg / day compared to placebo in female subjects with IC / BPS.

[0107] This study consists of two phases: a pre-randomized phase consisting of a screening period (up to 4 weeks) and a single-blind placebo induction 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 obtaining informed consent from each subject, subjects will be subjected to all study procedures performed in this study. Assessment of study eligibility criteria will begin at the screening visit, and this will include medical history, physical examination, vital signs, laboratory results, urine culture, pregnancy test, and drug screening. If a washout for prohibited drugs (Appendix A) is required, this washout should be completed during the screening period (Days -42 to -15). Subjects must have a diagnosis of interstitial cystitis / bladder pain syndrome (IC / BPS) in accordance with American Urological Association (AUA) guidelines, recorded in the subject's medical record at least six months prior to screening. If this has not been obtained within the past six months, subjects must undergo cystoscopy at screening to rule out other conditions and to record the presence or absence of Hunner's lesions. Participants should either have not received any pharmacological treatment for IC / BPS in the past 30 days, or have received oral pharmacological treatment for IC / BPS at a stable dose / regimen in the past 30 days and, in the investigator's judgment, expect to maintain the same stable dose / regimen throughout the study. Participants 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. Participants will identify their most bothersome bladder pain / discomfort symptoms and their most bothersome lower urinary tract symptoms associated with IC / BPS.

[0109] Single-blind placebo induction period (-14 to -1 day): Once a subject successfully completes their screening visit, they enter the placebo induction period, taking one tablet of the study drug orally 30 minutes before bedtime each night. Medication is recorded in an electronic diary each night. Subjects record their average and worst bladder pain / discomfort scores twice a day, in the morning and evening. Subjects record all urination episodes over a 24-hour period in the week prior to visit 2 (including time, type, intensity, and volume of each). To be eligible for enrollment in the double-blind treatment period, subjects must meet the following criteria: a) The average daily bladder pain / discomfort score is 5 or higher for at least 9 days during the induction phase. b) The mean number of urination episodes is 10 or more but less than 30 for each 24-hour period over at least 3 days. c) The score on the Bladder Pain / Interstitial Cystitis Symptom Scale (BPIC-SS) is 19 or higher. d) The newly administered IC / BPS therapy was a stable dose / regime and was expected to be maintained during the trial. e) The subject properly completed the diary in accordance with the instructions of the principal investigator.

[0110] If a participant meets the enrollment criteria and completes all assessments, they will be randomized.

[0111] Treatment period (days 1-63) All subjects will be assigned to the same crossover treatment regimen of compound (IA) and placebo. Subjects will visit the clinic every two weeks and will receive virtual calls / telephone calls during weeks when they are not scheduled to visit the clinic.

[0112] Participants will continue to record bladder pain scores twice a day. In addition, participants will record all 24-hour voiding episodes for seven days prior to each scheduled clinic visit to the clinical trial site. Upon clinic visit, participants will complete efficacy assessments (BPIC-SS, ICSI, ICPI, NSQS, GRA, and SGRAB) as well as safety / other assessments.

[0113] End of Study (EOS) (Day 63 / Early Termination [ET]): The End-of-Study (EOS) procedure will be performed on subjects either at the end of the double-blind treatment or if the study is terminated early. The evaluations required at the time of EOS should be performed on the same day as the completion of the study or on the same day as the End-of-Study (ED), and if the study drug is not administered after these evaluations, these evaluations do not need to be repeated.

[0114] Follow-up period (days 64-70) To monitor adverse events and concomitant medication / therapy use since the last visit, follow-up phone calls will be completed 7-10 days after the final dose of the study drug.

[0115] While the subject matter of this disclosure has been described with reference to exemplary embodiments and examples, this description is not intended to be constrained. Various modifications of the exemplary embodiments and other embodiments of the invention will be apparent to those skilled in the art by reference to this description. Accordingly, the appended claims are intended to cover any such modifications or embodiments.

[0116] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference in whole.

[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. A pharmaceutical composition for treating interstitial cystitis / bladder pain syndrome in human subjects requiring treatment for the said interstitial cystitis / bladder pain syndrome, comprising formula (I): 【Chemistry 1】 The pharmaceutical composition comprising a compound having or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition for treating or alleviating symptoms associated with interstitial cystitis / bladder pain syndrome in human subjects requiring treatment of symptoms associated with the said interstitial cystitis / bladder pain syndrome, comprising formula (I): 【Chemistry 2】 The pharmaceutical composition comprising a compound having or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, wherein the aforementioned symptom is visceral pain or urinary urgency.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof is of formula (I'): 【Transformation 3】 The pharmaceutical composition according to claim 1 or 2, wherein the compound is or a pharmaceutically acceptable salt thereof.

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

6. The pharmaceutical composition according to claim 1 or 2, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally, parenterally, intravenously, intramuscularly, buccally, or transdermally.

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

8. The pharmaceutical composition according to claim 1 or 2, wherein the compound or a pharmaceutically acceptable salt thereof is administered once daily.

9. The pharmaceutical composition according to claim 1 or 2, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the human subject at night or at night before bedtime.

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

11. The pharmaceutical composition according to claim 1 or 2, wherein administration of the compound or a pharmaceutically acceptable salt thereof increases the urination pressure threshold in the human subject by 30% to 80%.

12. A pharmaceutical composition for treating interstitial cystitis / bladder pain syndrome in human subjects requiring treatment for the said interstitial cystitis / bladder pain syndrome, wherein the formula for the therapeutically effective dose is (I'): 【Transformation 5】 The pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, wherein the human subject further suffers from a sleep disorder.

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

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

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