4-thiocarbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate for the treatment of pain associated with chronic urological pelvic pain syndrome

Abstract

This application relates to methods of treating urological chronic pelvic pain syndrome (UCPPS) or pain associated with UCPPS using a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof. UCPPS includes interstitial cystitis / bladder pain syndrome (IC / BPS) and chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS). JPEG2025507826000032.jpg35110

Description

[Technical Field]

[0001] This application relates to a method for treating or preventing pain associated with chronic urinary pelvic pain syndrome (UCPPS) using 4-thiocarbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof. UCPPS includes interstitial cystitis / bladder pain syndrome (IC / BPS) and chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS). [Background technology]

[0002] NSAIDs, along with opioids, anticonvulsants, and anti-migraine medications such as 5-HT receptor agonists and ergot derivatives, are routinely used to treat acute and chronic pain. In clinical pharmacology, the introduction of non-steroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen is known to be associated with a variety of gastrointestinal (GI) side effects, including mild to severe dyspepsia, the development of gastric or duodenal ulcers, bleeding, perforation, and other events (Rusell RI, 2001). In particular, NSAIDs are used to treat chronic inflammation in patients with rheumatoid arthritis, but very often they induce gastritis (Bindu S et al., 2020). One of the most important mechanisms underlying NSAID-induced gastric damage involves, but is not limited to, the inhibition of cyclooxygenase (COX)-1 or COX-2-producing gastric protective prostaglandins (PGs), such as PGE2 (Bindu S et al., 2020; Glowacka et al., 2020). These drugs are also generally short-acting and therefore require repeated administration. Consequently, there is a need for more effective analgesics for pain management. For example, urological chronic pelvic pain syndrome (UCPPS) is a difficult painful condition that encompasses interstitial cystitis / bladder pain syndrome (IC / BPS) and chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS). People suffering from UCPPS often experience pain in the pelvic region, which can cause significant discomfort and impairment.

[0003] Hydrogen sulfide (H2S) is produced by any cell type, including GI tubules, and is known to contribute to the defense of the gastrointestinal mucosa and the healing of ulcers. It is an endogenous antioxidant gas mediator involved in gastrointestinal physiology and has been shown to promote gastric ulcer healing and protect GI tubules against damage induced by stress, ischemia / reperfusion, and drugs, including NSAIDs (Lasheen NN et al., 2019; Sun H. et al., 2020; Wallace JL et al., 2017).

[0004] U.S. Patent No. 8,541,398 discloses NSAID derivatives covalently linked to the H2S-releasing moiety, and it was found that the anti-inflammatory effects of various NSAIDs were significantly enhanced when covalently linked to the H2S-releasing moiety, or when an NSAID salt was formed together with the H2S-releasing moiety. Furthermore, U.S. Patent No. 8,541,398 discloses that these NSAID derivatives covalently linked to the H2S-releasing moiety provide potent anti-inflammatory properties without causing gastrointestinal toxicity. Among the many NSAID derivatives covalently linked to the H2S-releasing moiety, U.S. Patent No. 8,541,398 discloses a hydrogen sulfide-releasing derivative of ketoprofen, chemically known as 4-thiocarbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate and sometimes known as ATB-352 (Antibe Therapeutics Inc., Toronto, Canada). ATB-352 has been shown to be more potent and effective than its parent drug in periodontitis, an inflammatory condition (Gugliadola et al., 2018), and to have increased GI safety compared to ketoprofen (Glowacka et al., 2022). ATB-352 has also been shown to have higher efficacy than ketoprofen in a mouse model of surgical incision pain (Costa et al., 2020). [Overview of the project] [Problems that the invention aims to solve]

[0005] The applicant has shown that a compound of formula I, namely an NSAID derivative covalently linked to the H2S-releasing portion, which is ketoprofen and whose H2S-releasing portion is 4-hydroxythiobenzamide (TBZ), and which is sometimes known as ATB-352, can alleviate bladder inflammation and pain associated with chronic pelvic pain syndrome. [Means for solving the problem]

[0006] Therefore, this application relates to a method for treating pain associated with urological chronic pelvic pain syndrome (UCPPS) in a subject requiring the treatment, wherein the subject is given an effective amount of a compound of formula I.

[0007] [ka]

[0008] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0009] In some embodiments, the pain associated with UCPPS is selected from one or more of the following: visceral pain, neuropathic pain, neuralgia, allodynia, burning pain, hyperalgesia, hyperesthesia, parodynia, and neuropathy associated with surgical procedures.

[0010] In some embodiments, the pain associated with UCPPS is acute pain associated with UCPPS.

[0011] This application also relates to a method for treating urological chronic pelvic pain syndrome (UCPPS) in a subject requiring the treatment, wherein the subject is given an effective amount of a compound of formula I.

[0012] [ka]

[0013] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0014] This application is a method for treating one or more symptoms associated with urological chronic pelvic pain syndrome (UCPPS) in a subject that requires it, comprising administering to the subject an effective amount of a compound of formula I

[0015]

Chemical formula

[0016] or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0017] This application is also a method for treating bladder inflammation in a subject that requires it, comprising administering to the subject an effective amount of a compound of formula I

[0018]

Chemical formula

[0019] or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0020] This application is also a method for increasing bladder contraction and relaxation in a subject that requires it, comprising administering to the subject an effective amount of a compound of formula I<000011(0>][[ID=]37]

[0021]

Chemical formula

[0022] or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

[0023] This application is a method for treating acute pain in a subject that requires it, comprising administering to the subject an effective amount of a compound of formula I [[ID=5`3]]

[0024]

Chemical formula

[0025] Or a method further comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0026] In some embodiments, UCPPS includes interstitial cystitis / bladder pain syndrome (IC / BPS) and chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

[0027] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is formulated into a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof and one or more pharmaceutical carriers.

[0028] Other features and advantages of this application will become apparent from the detailed description below. However, it should be understood that the detailed description and specific examples illustrate embodiments of this application, but are given only as examples. The claims should not be limited by these embodiments, but rather they should be given the broadest interpretation consistent with the description as a whole.

[0029] Herein, embodiments of this application will be described in more detail with reference to the attached drawings. [Brief explanation of the drawing]

[0030] [Figure 1]Figure 1 is a graph showing the comparative analgesic effects of compound I (ATB-352) and ketoprofen in a mouse model of visceral pain (cyclophosphamide (CYP)-induced interstitial cystitis). Mice were orally treated 21 hours after induction of cystitis with compound I (4.6, 15, 46, or 77 mg / kg), equimolar doses of ketoprofen (3, 10, or 50 mg / kg), or vehicle (5% CMC). Data are expressed as the area under the curve at 21–24 hour intervals after treatment with the test compound. Data are expressed as mean ± SEM (n=5–7). * indicates P<0.05 compared to vehicle. # indicates P<0.05 compared to the CYP group and expP<0.001 compared to equimolar doses of ketoprofen. One-way ANOVA and subsequent Turkey test.

[0031] [Figure 2] Figure 2 shows that gastric mucosal hemorrhagic injury was induced by ketoprofen but not by the compound of formula I (ATB-352). The area (mm2) of hemorrhagic gastric lesions was evaluated using computerized flattening software (ImageJ®) 3 hours after oral administration of vehicle (0.5% carboxymethylcellulose, 10 ml kg-1), compound of formula I (77 mg kg-1), or ketoprofen (50 mg kg-1). (1) P<0.05 Comparison with the group of compounds of formula I (one-way ANOVA and subsequent Turkey test).

[0032] [Figure 3]Figure 3 shows the comparative effects of compound I (ATB-352) and ketoprofen on reversing CYP-induced bladder contractility reduction in response to KCl and CCh. (A) shows the contractile response to KCl (80 mM), and (B) shows the maximal carbachol contractile response in the bladder from the vehicle, CYP, compound I (4.6, 15, 46, and 77 mg kg-1), and ketoprofen (3, 10, 30, or 50 mg kg-1) groups. Data are expressed as mean ± SEM (n=4~7). *P<0.05 for vehicle. #P<0.05 for CYP. ##P<0.001 for vehicle (A and B: one-way ANOVA followed by Turkey test). [Modes for carrying out the invention]

[0033] I. Definition Unless otherwise indicated, the definitions and embodiments set forth in this section and other sections are intended to be applicable to all embodiments and aspects of this application described herein, as they are relevant to those skilled in the art, as can be understood.

[0034] In understanding the scope of this application, the term “comprising” and its derivatives, as used herein, are intended to be open-ended terms that identify the presence of described features, elements, components, groups, integers, and / or processes, but do not exclude the presence of other undescribed features, elements, components, groups, integers, and / or processes. The same applies to similarly meaning words such as “including,” “having,” and their derivatives.

[0035] When used herein, the term "consisting" and its derivatives are intended to be closed terms that identify the presence of the described features, elements, components, groups, integers, and / or processes, but exclude the presence of other undescribed features, elements, components, groups, integers, and / or processes.

[0036] When used herein, the term "consisting essentially of" is intended to identify the presence of features, elements, components, groups, integers, and / or processes described, as well as those that do not substantially affect the fundamental and novel characteristics of the features, elements, components, groups, integers, and / or processes.

[0037] Terms of degree such as "substantially," "about," and "approximately," when used herein, mean a reasonable deviation from the modified term so as not to significantly alter the final result. These terms of degree should be interpreted as including a deviation of at least ±5% of the modified term, provided that the deviation does not negate the meaning of the word it modifies.

[0038] As used herein, the singular forms "a," "an," and "the" refer to multiple objects unless the context clearly indicates otherwise.

[0039] In embodiments including an “additional” or “second” component, the second component, when used herein, is chemically different from the other components or the first component. The “third” component is different from the other components, the first component, and the second component, as are any further listed or “additional” components.

[0040] When used herein, the term "and / or" means that the listed items exist or are used individually or in combination. In practice, the term means that "at least one" or "one or more" of the listed items are used or are present.

[0041] When used herein, the terms “compound of formula I” or “ATB-352” have the chemical name: 4-thiocarbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate and chemical formula

[0042] [ka]

[0043] This refers to compounds that possess [a certain characteristic].

[0044] When used herein, the term "ketoprofen" refers to a compound having the chemical name: m-benzoylhydratropic acid or 2-(4-benzoylphenyl)propanoic acid, and the chemical formula:

[0045] [ka]

[0046] This refers to compounds that possess [a certain characteristic].

[0047] The term "medically acceptable salt" means either an acid addition salt or a base addition salt that is suitable for or compatible with the treatment in question.

[0048] An acid addition salt suitable for or compatible with the treatment in question is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0049] A base addition salt suitable for or compatible with the treatment in question is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0050] As used herein, the term "solvate" means a compound or salt of a compound in which molecules of a suitable solvent are incorporated into the crystal lattice. The suitable solvent is physiologically tolerable at the administered dose.

[0051] As used herein, the term "prodrug" means a compound or salt of a compound that is converted to an active drug after administration.

[0052] As used herein, the term "administered" means the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, or a composition comprising the compound or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, to cells in a cell culture or to cells in a subject.

[0053] As used herein, the terms “effective dose” and “therapeutic effective dose” mean an amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, prodrug and / or solvate, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, prodrug and / or solvate, that is effective in the dose and duration required to achieve the desired outcome, including therapeutic and prophylactic outcomes.

[0054] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and appropriately refers to humans. Thus, the methods and uses of this application are applicable to both human therapeutic and veterinary applications.

[0055] As used herein, the term "pharmaceutical composition" refers to a composition of a substance for pharmaceutical use.

[0056] The term "medically acceptable" means that it is suitable for the treatment in question.

[0057] As used herein, the term "parenteral" means administered by means other than by ingestion or through the gastrointestinal tract.

[0058] The terms “to treat,” “treating,” and “treatment,” as used herein and as is well understood in the art, mean an approach to obtain beneficial or desired outcomes, including clinical outcomes. Examples of beneficial or desired clinical outcomes include, but are not limited to, a reduction in the severity of the disease, a stable (i.e., non-exacerbating) state of the disease, prevention of disease spread, delay or stagnation of disease progression, improvement or mitigation of the disease state, and remission (whether partial or total), which is a reduction in disease recurrence, whether detectable or undetectable. “To treat,” “treating,” and “treatment” may also mean extending survival compared to the survival expected without treatment. “To treat,” “treating,” and “treatment” may also include prophylactic treatment.

[0059] To “alleviate” a disease, disability, or condition means that the severity and / or undesirable clinical symptoms of the disease, disability, or condition are reduced and / or the time course of its progression is delayed or prolonged compared to when the disability is left untreated.

[0060] The terms “prevention” or “prophylaxis,” as used herein, refer to a reduction in the risk or probability that a patient will contract a disease, disability or condition, or exhibit symptoms associated with such a disease, disability or condition.

[0061] When used herein, the term "to treat pain associated with urological chronic pelvic pain syndrome" means any detectable reduction in the sensation or duration of pain associated with urological chronic pelvic pain syndrome, for example, after administration or use of the compound, compared to conditions that are otherwise identical except for the absence of administration or use of the compound.

[0062] When used herein, the term "to treat pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS)" means any detectable reduction in the sensation or duration of pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS) compared to other conditions that are otherwise identical except for the absence of administration or use of the compound.

[0063] When used herein, the term "to treat pain associated with chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS)" means any detectable reduction in the sensation or duration of pain associated with chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS) after administration or use of the compound, compared to other conditions that are otherwise identical except for the absence of administration or use of the compound.

[0064] The term “Uro-Pelvic Pain Syndrome” or “UCPPS,” as used herein, refers to a chronic pain condition of the pelvis, prostate, bladder, and / or genitals accompanied by frequent urination and urinary urgency. UCPPS encompasses interstitial cystitis / bladder pain syndrome and chronic prostatitis / chronic pelvic pain syndrome.

[0065] The terms “interstitial cystitis / bladder pain syndrome” or “IC / BPS,” as used herein, refer to perceived pressure or discomfort associated with the bladder, accompanied by at least one other voiding symptom, such as persistent or recurrent chronic pelvic pain, urgency, or frequency.

[0066] The terms “chronic prostatitis / chronic pelvic pain syndrome” or “CP / CPPS” are, as used herein, used to refer to long-term pelvic pain and lower urinary tract symptoms (LUTS) without evidence of bacterial infection.

[0067] The term “lower urinary tract symptoms” or “LUTS,” as used herein, refers to a group of clinical symptoms including the bladder, urethral sphincter, urethra, and, in men, the prostate.

[0068] The term "pain associated with urological chronic pelvic pain syndrome" refers to pain that is directly or indirectly caused by or associated with urological chronic pelvic pain syndrome.

[0069] The term "pain associated with interstitial cystitis / bladder pain syndrome" refers to pain directly or indirectly caused by interstitial cystitis / bladder pain syndrome.

[0070] The term "pain associated with chronic prostatitis / chronic pelvic pain syndrome" refers to pain directly or indirectly caused by chronic prostatitis / chronic pelvic pain syndrome.

[0071] As used herein, the term “acute pain” means pain in response to a stimulus associated with an acute illness that has a sudden onset and lasts or is expected to last for a short period of time (e.g., weeks, days, hours), such as surgery, trauma, and / or an acute illness. The term “acute pain” includes, but is not limited to, mild to moderate, moderate, moderate to moderately severe, or moderate to severe acute pain.

[0072] As used herein, the term "chronic pain" means pain associated with a chronic disorder such as UCPPS.

[0073] As used herein, the term "visceral pain" refers to any pain experienced by an subject in conjunction with a disease, disorder, or condition of an internal organ.

[0074] As used herein, the term "allodynia" refers to pain caused by stimuli that do not normally induce pain.

[0075] As used herein, the term "burning pain" refers to the syndromes of persistent burning pain, allodynia, and parodynia following traumatic neurological lesions, often in combination with vasomotor and diaphoretic dysfunction and subsequent nutritional changes.

[0076] As used herein, the term "hyperalgesia" refers to an increased response to stimuli that are normally painful.

[0077] As used herein, the term "abnormal pain syndrome" refers to a painful syndrome characterized by an abnormally painful response to stimuli, particularly repetitive stimuli, and an elevated pain threshold.

[0078] When used herein, the term "increases bladder contraction and relaxation" refers to any detectable increase in bladder contraction function after administration or use of the compound, compared to conditions that are otherwise identical except for the absence of administration or use of the compound.

[0079] When used herein, the term "treating acute pain" means any detectable reduction in the sensation or duration of acute pain, for example, after administration or use of the compound, compared to conditions that are otherwise identical except for the absence of administration or use of the compound.

[0080] When used herein in relation to a chronic pain condition, the terms “transient exacerbation” or “relapse” refer to an increase in pain intensity.

[0081] For example, when used with respect to the treatment methods, uses, compositions and kits of this application, the subject, for example, the subject "requiring it," is, for example, a subject diagnosed with, suspected of having, and / or previously treated with, urinary tract chronic pelvic pain syndrome or pain or cystitis associated with urinary tract chronic pelvic pain syndrome.

[0082] II. Method and Use of the Application The applicant has shown that a compound of formula I, sometimes known as ATB-352, is an NSAID derivative covalently linked to the H2S-releasing portion of 4-hydroxythiobenzamide (TBZ), where the NSAID is ketoprofen, can alleviate bladder inflammation and pain associated with urological chronic pelvic pain syndrome. For example, the applicant has studied the acute effects of the compound of formula I on inflammatory bladder pain and bladder function, showing that the compound of formula I can alleviate visceral bladder pain and / or pelvic pain and bladder inflammation in an established mouse model of interstitial cystitis / bladder pain syndrome (IC / BPS). The compound of formula I has also been shown to improve bladder contraction function in the IC / BPS model. Surprisingly, the efficacy of the compound of formula I in alleviating visceral bladder pain and / or pelvic pain and bladder inflammation, and improving bladder contraction function in the IC / BPS model, was found to be higher than that of the parent ketoprofen compound.

[0083] Therefore, this application relates to a method for treating pain associated with urological chronic pelvic pain syndrome (UCPPS) in a subject requiring the treatment, wherein the subject is given an effective amount of a compound of formula I.

[0084] [ka]

[0085] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0086] The application also includes the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for treating pain associated with UCPPS in a subject; the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for preparing a pharmaceutical for treating pain associated with UCPPS in a subject; and a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for use in treating pain associated with UCPPS in a subject.

[0087] A person skilled in the art will recognize that a syndrome characterizes or suggests one or more diseases, disorders, or conditions. Therefore, a person skilled in the art will recognize that UCPPS is a syndrome that includes interstitial cystitis / bladder pain syndrome (IC / BPS) and chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

[0088] Therefore, this application relates to a method for treating pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS) in a subject requiring the treatment, wherein the subject is given an effective amount of a compound of formula I.

[0089] [ka]

[0090] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0091] The application also includes the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for treating pain associated with IC / BPS in a subject; the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for the preparation of a pharmaceutical for treating pain associated with IC / BPS in a subject; and a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for use in treating pain associated with IC / BPS in a subject.

[0092] In some embodiments, pain is associated with interstitial cystitis. Therefore, in some embodiments, compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates are used or administered to treat pain associated with interstitial cystitis.

[0093] In some embodiments, pain is associated with bladder pain syndrome. Therefore, in some embodiments, compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates are used or administered to treat pain associated with bladder pain syndrome.

[0094] This application also relates to a method for treating pain associated with chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS) in a subject requiring the treatment, wherein the subject is given an effective amount of a compound of formula I.

[0095] [ka]

[0096] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0097] The application also includes the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for treating pain associated with CP / CPPS in a subject; the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for the preparation of a pharmaceutical for treating pain associated with CP / CPPS in a subject; and a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for use in treating pain associated with CP / CPPS in a subject.

[0098] In some embodiments, the pain associated with urological chronic pelvic pain syndrome (UCPPS) is selected from one or more of visceral pain, neuropathic pain, neuralgia, allodynia, burning pain, hyperalgesia, hyperesthesia, parodynia, and neuropathy associated with surgical procedures. In some embodiments, UCPPS includes IC / BPS and / or CP / CPPS. Therefore, in some embodiments, the pain associated with IC / BPS is selected from one or more of visceral pain, neuropathic pain, neuralgia, allodynia, burning pain, hyperalgesia, hyperesthesia, parodynia, and neuropathy associated with surgical procedures. In some embodiments, the pain associated with CP / CPPS is selected from one or more of visceral pain, neuropathic pain, neuralgia, allodynia, burning pain, hyperalgesia, hyperesthesia, parodynia, and neuropathy associated with surgical procedures.

[0099] In some embodiments, the pain associated with UCPPS is allodynia associated with UCPPS. In some embodiments, the pain associated with IC / BPS is IC / BPS associated with allodynia. In some embodiments, the pain associated with interstitial cystitis is interstitial cystitis associated with allodynia. In some embodiments, the pain associated with bladder pain syndrome is bladder pain syndrome associated with allodynia. In some embodiments, the pain associated with CP / CPPS is CP / CPPS associated with allodynia. In some embodiments, the allodynia associated with UCPPS is abdominal or pelvic allodynia associated with UCPPS. In some embodiments, the allodynia associated with IC / BPS is abdominal or pelvic allodynia associated with IC / BPS. In some embodiments, allodynia is abdominal or pelvic allodynia associated with IC / BPS. In some embodiments, the allodynia associated with CP / CPPS is abdominal or pelvic allodynia associated with CP / CPPS.

[0100] In some embodiments, the pain associated with UCPPS is hyperalgesia associated with UCPPS. In some embodiments, the pain associated with IC / BPS is hyperalgesia associated with IC / BPS. In some embodiments, the pain associated with interstitial cystitis is hyperalgesia associated with interstitial cystitis. In some embodiments, the hyperalgesia associated with pain associated with CP / CPPS is hyperalgesia associated with bladder pain syndrome. In some embodiments, the pain associated with CP / CPPS is hyperalgesia associated with CP / CPPS.

[0101] In some embodiments, the pain associated with UCPPS is selected from one or more of the following: lower abdominal (pelvic) pain, bladder pain, suprapubine pain, vaginal pain, penile pain, testicular pain, scrotal pain, perineal pain, urethral pain, dyspareunia, or pain, pressure, or discomfort that may increase as the bladder fills. In some embodiments, UCPPS includes IC / BPS and / or CP / CPPS.

[0102] In some embodiments, the pain associated with UCPPS is visceral pain associated with UCPPS. In some embodiments, the pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS) is visceral pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS). In some embodiments, the pain associated with interstitial cystitis is visceral pain associated with interstitial cystitis. In some embodiments, the pain associated with bladder pain syndrome is visceral pain associated with bladder pain syndrome. In some embodiments, the pain associated with CP / CPPS is visceral pain associated with CP / CPPS. In some embodiments, visceral pain is visceral abdominal pain.

[0103] In some embodiments, pain associated with urological chronic pelvic pain syndrome (UCPPS) is acute and / or chronic pain associated with urological chronic pelvic pain syndrome (UCPPS). In some embodiments, pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS) is acute and / or chronic pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS). In some embodiments, pain associated with interstitial cystitis is acute and / or chronic pain associated with interstitial cystitis. In some embodiments, pain associated with bladder pain syndrome is acute and / or chronic pain associated with bladder pain syndrome. In some embodiments, pain associated with CP / CPPS is acute and / or chronic pain associated with CP / CPPS.

[0104] In some embodiments, pain associated with urological chronic pelvic pain syndrome (UCPPS) is chronic pain associated with urological chronic pelvic pain syndrome (UCPPS). In some embodiments, pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS) is chronic pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS). In some embodiments, pain associated with interstitial cystitis is chronic pain associated with interstitial cystitis. In some embodiments, pain associated with bladder pain syndrome is chronic pain associated with bladder pain syndrome. In some embodiments, pain associated with CP / CPPS is chronic pain associated with CP / CPPS.

[0105] In some embodiments, pain associated with urological chronic pelvic pain syndrome (UCPPS) is acute pain associated with urological chronic pelvic pain syndrome (UCPPS). In some embodiments, pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS) is acute pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS). In some embodiments, pain associated with interstitial cystitis is acute pain associated with interstitial cystitis. In some embodiments, pain associated with bladder pain syndrome is acute pain associated with bladder pain syndrome. In some embodiments, pain associated with CP / CPPS is acute pain associated with CP / CPPS.

[0106] In some embodiments, acute pain associated with UCPPS is a transient exacerbation or relapse of pain associated with UCPPS. In some embodiments, acute pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS) is a transient exacerbation or relapse of pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS). In some embodiments, acute pain associated with interstitial cystitis is a transient exacerbation or relapse of pain associated with interstitial cystitis. In some embodiments, acute pain associated with bladder pain syndrome is a transient exacerbation or relapse of pain associated with bladder pain syndrome. In some embodiments, acute pain associated with CP / CPPS is a transient exacerbation or relapse of pain associated with CP / CPPS.

[0107] In some embodiments, acute pain is pain that is expected to resolve within a short period, e.g., 14 days or less. In some embodiments, chronic pain is pain that is expected to persist for a long period, e.g., 15 days or more. Acute pain is distinguishable from chronic pain.

[0108] In some embodiments, the acute pain lasts for less than approximately 14 days, less than approximately 12 days, less than approximately 10 days, less than approximately 7 days, less than approximately 5 days, or less than 3 days from the onset of the acute pain. In some embodiments, the acute pain lasts for approximately 1 to 14 days, approximately 1 to 12 days, approximately 1 to 10 days, approximately 1 to 7 days, approximately 1 to 5 days, approximately 1 to 3 days, or approximately 3 to 14 days, approximately 3 to 10 days, approximately 3 to 7 days, or approximately 5 to 10 days.

[0109] In some embodiments, acute pain occurs intermittently for more than three months or more than six months.

[0110] This application also relates to a method for treating urological chronic pelvic pain syndrome (UCPPS) in a subject requiring the treatment, wherein the subject is given an effective amount of a compound of formula I.

[0111] [ka]

[0112] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0113] The application also includes the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for treating UCPPS in a subject; the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for preparing a pharmaceutical for treating UCPPS in a subject; and a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for use in treating UCPPS in a subject.

[0114] In some embodiments, UCPPS includes interstitial cystitis / bladder pain syndrome (IC / BPS) and chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

[0115] Therefore, this application relates to a method for treating interstitial cystitis / bladder pain syndrome (IC / BPS) in a subject requiring the treatment, wherein the subject is given an effective amount of a compound of formula I.

[0116] [ka]

[0117] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0118] The application also includes the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for treating IC / BPS in a subject; the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for preparing a pharmaceutical for treating IC / BPS in a subject; and a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for use in treating IC / BPS in a subject.

[0119] In some embodiments, the compound of formula I or its pharmaceutically acceptable salts, prodrugs, and / or solvates are used or administered to treat interstitial cystitis. In some embodiments, the compound of formula I or its pharmaceutically acceptable salts, prodrugs, and / or solvates are used or administered to treat bladder pain syndrome.

[0120] This application also relates to a method for treating chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS) in a subject requiring the treatment, wherein the subject is given an effective amount of a compound of formula I.

[0121] [ka]

[0122] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0123] The application also includes the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for treating CP / CPPS in a subject; the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for preparing a pharmaceutical for treating CP / CPPS in a subject; and a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for use in treating CP / CPPS in a subject.

[0124] This application also relates to a method for treating one or more symptoms associated with urological chronic pelvic pain syndrome (UCPPS) in a subject requiring the treatment, wherein the subject is given an effective amount of a compound of formula I.

[0125] [ka]

[0126] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0127] The application also includes the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for treating one or more symptoms associated with UCPPS in a subject; the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for the preparation of a pharmaceutical for treating one or more symptoms associated with UCPPS in a subject; and a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for use in treating one or more symptoms associated with UCPPS in a subject.

[0128] In some embodiments, UCPPS includes IC / BPS and / or CP / CPPS. Accordingly, in some embodiments, the application also includes methods or uses of compounds of formula I or pharmaceutically acceptable salts, prodrugs and / or solvates thereof for treating one or more symptoms associated with IC / BPS. In some embodiments, the application also includes methods or uses of compounds of formula I or pharmaceutically acceptable salts, prodrugs and / or solvates thereof for treating one or more symptoms associated with CP / CPPS.

[0129] In some embodiments, one or more symptoms are selected from irritant urination symptoms, frequent urination, urinary urgency, nocturia, incontinence, and suprapubic or pelvic pain associated with and relieved by urination.

[0130] The applicants have shown that cystitis can be alleviated using a compound of formula I. Accordingly, the application also relates to a method for treating cystitis in a subject in need, wherein the subject is given an effective amount of a compound of formula I.

[0131] [ka]

[0132] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0133] The application also includes the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for treating cystitis in a subject; the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for the preparation of a pharmaceutical for treating cystitis in a subject; and a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for use in treating cystitis in a subject.

[0134] In some embodiments, cystitis is associated with urological chronic pelvic pain syndrome (UCPPS). In some embodiments, cystitis is associated with interstitial cystitis / bladder pain syndrome (IC / BPS). In some embodiments, cystitis is associated with interstitial cystitis. In some embodiments, cystitis is associated with bladder pain syndrome. In some embodiments, cystitis is associated with chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

[0135] This application relates to a method for increasing bladder contraction and relaxation in a subject requiring it, wherein the subject is given an effective amount of a compound of formula I.

[0136] [ka]

[0137] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0138] The application also includes the use of a compound of formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for increasing bladder contraction and relaxation in a subject; the use of a compound of formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for the preparation of a pharmaceutical for increasing bladder contraction and relaxation in a subject; and the use of a compound of formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for use in treating increased bladder contraction and relaxation in a subject.

[0139] In some embodiments, the subject is an subject having a UCPPS. In some embodiments, the UCPPS is an IC / BPS and / or a CP / CPPS.

[0140] This application relates to a method for treating acute pain in a subject requiring the treatment, wherein the subject is given an effective amount of a compound of formula I.

[0141] [ka]

[0142] Or a method comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0143] The application also includes the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for treating acute pain in a subject; the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for the preparation of a pharmaceutical for treating acute pain in a subject; and a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for use in treating acute pain in a subject.

[0144] In some embodiments, acute pain is a transient exacerbation or relapse.

[0145] In some embodiments, acute pain is pain that is expected to resolve within a short period, for example, 14 days or less. In some embodiments, acute pain lasts for less than approximately 14 days, less than approximately 12 days, less than approximately 10 days, less than approximately 7 days, less than approximately 5 days, or less than 3 days from the onset of acute pain. In some embodiments, acute pain lasts for approximately 1 to 14 days, approximately 1 to 12 days, approximately 1 to 10 days, approximately 1 to 7 days, approximately 1 to 5 days, approximately 1 to 3 days, or approximately 3 to 14 days, approximately 3 to 10 days, approximately 3 to 7 days, or approximately 5 to 10 days.

[0146] In some embodiments, acute pain occurs intermittently for more than three months or more than six months.

[0147] In some embodiments, acute pain is postoperative pain resulting from abdominal and / or pelvic surgery. This application relates to a method for treating acute pain resulting from abdominal and / or pelvic surgery in a subject requiring such treatment, wherein the subject is given an effective amount of a compound of formula I.

[0148] [ka]

[0149] Or a method further comprising administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0150] The application also includes the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for treating acute pain resulting from abdominal and / or pelvic surgery in a subject; the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for the preparation of a pharmaceutical for treating acute pain resulting from abdominal and / or pelvic surgery in a subject; and a compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, for use in treating acute pain resulting from abdominal and / or pelvic surgery in a subject.

[0151] In some embodiments, abdominal and / or pelvic surgery is selected from, but is not limited to, inguinal hernia repair, e.g., open inguinal hernia removal, abdominal hysterectomy, open surgery, cholecystectomy, vaginal hysterectomy, abdominal hernia repair, myectomy, salpingooophorectomy, bariatric surgery, partial colectomy, and gynecological or genitourinary surgery.

[0152] In some embodiments, abdominal and / or pelvic surgery is selected from inguinal hernia repair, such as open inguinal hernia resection, abdominal hysterectomy, abdominal surgery, or bariatric surgery, but is not limited to the following. In some embodiments, abdominal and / or pelvic surgery is inguinal hernia repair. In some embodiments, inguinal hernia repair is open inguinal hernia resection.

[0153] In some embodiments, abdominal surgery and / or pelvic surgery is abdominal laparotomy or bariatric surgery. In some embodiments, abdominal surgery and / or pelvic surgery is bariatric surgery.

[0154] In some embodiments, acute pain is not postoperative pain.

[0155] In some embodiments, the subjects requiring it are those with urological chronic pelvic pain syndrome (UCPPS), pain associated with UCPPS and / or cystitis. In some embodiments, the subjects requiring it are those with interstitial cystitis / bladder pain syndrome (IC / BPS), pain associated with IC / BPS and / or cystitis. In some embodiments, the subjects requiring it are those with interstitial cystitis, pain associated with interstitial cystitis and / or cystitis. In some embodiments, the subjects requiring it are those with bladder pain syndrome, pain associated with bladder pain syndrome and / or cystitis. In some embodiments, the subjects requiring it are those with chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS), pain associated with CP / CPPS and / or cystitis.

[0156] In one embodiment, the compound of formula I is in the form of a pharmaceutically acceptable solvate. In one embodiment, the compound of formula I is in a neutral form (i.e., not a salt). In one embodiment, the compound of formula I is a prodrug of the compound of formula I. In one embodiment, the compound of formula I is a solvate of the prodrug of the compound of formula I.

[0157] This application also includes the use of a compound of formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for the treatment of urological chronic pelvic pain syndrome (UCPPS), pain associated with UCPPS, cystitis and / or acute pain in subjects requiring such treatment, in combination with another known agent useful for treating UCPPS, pain associated with UCPPS, cystitis and / or acute pain. This application also includes the use of a compound of formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof for the preparation of a pharmaceutical for the treatment of urological chronic pelvic pain syndrome (UCPPS), pain associated with UCPPS, cystitis and / or acute pain in subjects requiring such treatment, in combination with another known agent useful for treating UCPPS, pain associated with UCPPS, cystitis and / or acute pain. This application further comprises a compound of formula I or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof for use in subjects requiring such treatment, in combination with another known agent useful for treating urological chronic pelvic pain syndrome (UCPPS), pain associated with UCPPS, bladder inflammation, and / or acute pain. In some embodiments, the method or use is for treating pain associated with UCPPS. In some embodiments, the method or use is for treating pain associated with IC / BPS. In some embodiments, the method or use is for treating pain associated with interstitial cystitis. In some embodiments, the method or use is for treating pain associated with bladder pain syndrome. In some embodiments, the method or use is for treating pain associated with CP / CPPS. In some embodiments, the pain is acute pain. In some embodiments, the method or use is for treating IC / BPS. In some embodiments, the method or use is for treating interstitial cystitis. In some embodiments, the method or use is for treating bladder pain syndrome.In some embodiments, the method or use is for treating CP / CPPS.

[0158] In some embodiments, when used in conjunction with other known agents useful for treating or preventing pain associated with UCPPS, UCPPS, or cystitis, the method and use of the present application reduces the amount of other known agents used or administered. In some embodiments, when used in conjunction with other known agents useful for treating or preventing pain associated with UCPPS, UCPPS, or cystitis, the method and use of the present application reduces the amount of other known agents by about 40% to 60% within about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration.

[0159] In some embodiments, other known agents for treating UCPPS or pain associated with UCPPS are selected from antihistamines including H1 blockers such as hydroxyzine hydrochloride and H2 blockers such as cimetidine and dimethyl sulfoxide; pain modifiers including tricyclic antidepressants such as amitriptyline; anticonvulsants such as gabapentin and dimethyl sulfoxide; narcotic antagonists; corticosteroids; antirheumatic drugs; immunomodulators; immunosuppressants such as prednisone and triamcinolone; interleukin production inhibitors; bladder mucosal protectants such as pentosan polysulfate and hyaluronic acid; hormonal modifiers such as chondroitin sulfate leukotriene-D4 receptor antagonist montelukast, L-arginine, oxybutynin, tolterodine, and leuprolide acetate; anti-inflammatory agents such as anti-TNF; and narcotics and analgesics such as opioids and tramadol.

[0160] In one embodiment, the corticosteroid is selected from cortisone, hydrocortisone, prednisone, methylprednisolone, deflazacort, prednisolone, triamcinolone, dexamethasone, betamethasone, halopredone, beclomethasone, and fludrocortisone, as well as combinations thereof.

[0161] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is used or administered alone without other known agents useful for treating or preventing pain associated with chronic urinary pelvic pain syndrome (UCPPS).

[0162] Pain assessment scales are well-known and, as those skilled in the art will recognize, are used in routine clinical practice to measure pain intensity. For example, commonly used scales include the Visual Analog Scale (VAS), Graphic Rating Scale (GRS), Simple Descriptor Scale (SDS), Numerical Rating Scale (NRS), Faces Rating Scale (FRS), and Total Pain Relief (TOTPAR) and / or Sum of Pain Intensity Difference (SPID). In particular, in acute pain, Total Pain Relief (TOTPAR) and / or Sum of Pain Intensity Difference (SPID) are commonly used metrics for pain assessment in the art. Numerical Rating Scales (NRS) similar to VAS in acute pain testing are also available. In some embodiments, the Visual Analog Scale (VAS) is a vertical or horizontal line that is 10 cm long and has word anchors at both ends, such as “No pain” at one end and “Pain as severe as possible” at the other end. The patient is asked to mark along the line to represent the pain intensity. In the Visual Analog Scale (VAS), moderate or severe pain is defined as a pain intensity greater than approximately 50 mm on a Visual Analog Scale (VAS) of 0–100 mm. In some embodiments, moderate pain is characterized as a pain intensity greater than approximately 50 mm and less than approximately 70 mm on a VAS of 1–100 mm. Severe pain is characterized as a pain intensity greater than approximately 70 mm on a VAS of 1–100 mm. The Graphic Rating Scale (GRS) is a variation of the Visual Analog Scale that adds words such as “No pain,” “Mild,” “Severe,” or numbers between the two ends. A Descriptor Scale (SDS) is a list of adjectives, such as "no pain," "mild," "moderate," or "severe," that represent different levels of pain intensity.Numerical Pain Rating Scales (NPRS) refer to numerical ratings ranging from 0 to 10 or 0 to 5, or visual scales using both words and numbers. The WOMAC Visual Analog Scale (VAS) version is also commonly used.

[0163] In some embodiments, the treatment of a subject is evaluated using one or more biomarkers known to represent the activation of pathways that result in pain relief (including, but not limited to, plasma levels of thromboxane B2 (TXB2), prostaglandin E2 (PGE2), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and / or C-reactive protein (CRP). The levels of these markers indicating a pain response, as well as methods for detecting their levels in a subject, are known in the art.

[0164] In some embodiments, the pain is mild to moderate, moderate to moderately severe, or moderately severe to severe.

[0165] In some embodiments, the method and use of the present invention provide pain relief within approximately 30 minutes to 4 hours, 1 hour to 4 hours, 1 hour to 3 hours, 1 hour to 3 hours, 1 hour to 2 hours, and 2 hours to 3 hours after administration of the compound of formula I. In some embodiments, the method of the present invention provides pain relief within approximately 1 hour to 3 hours, 1 hour to 2 hours, and 2 hours to 3 hours after administration of the compound of formula I.

[0166] The effective dose may vary depending on factors such as the disease state, age, sex, and / or weight of the subject. The amount of a given compound corresponding to such a dose varies depending on various factors such as the given drug or compound, pharmaceutical formulation, route of administration, and type of viral infection in the subject being treated, but nevertheless, it can be routinely determined by those skilled in the art. The effective dose is the amount that, after treatment with the drug, results in improvement or reduction of any disease symptoms.

[0167] The dosage of the compound of formula I or its pharmaceutically acceptable salts, prodrugs, and / or solvates may vary depending on many factors, including the pharmacodynamic properties of the compound, the method of administration, the recipient's age, health status, and weight, the nature and severity of symptoms, the frequency of treatment, and, if any, the type of concurrent treatment, as well as the clearance rate of the compound in the treated area. Those skilled in the art can determine an appropriate dosage based on the above factors. The compound of formula I or its pharmaceutically acceptable salts, prodrugs, and / or solvates may be initially administered in an appropriate dosage that can be adjusted as needed depending on the clinical response. The dosage is generally selected to maintain serum levels of the compound at approximately 0.01 μg / cc to approximately 1000 μg / cc, or approximately 0.1 μg / cc to approximately 100 μg / cc. Typical oral doses of compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates are approximately 1 mg / day to 1000 mg / day for adults, and appropriately in the range of approximately 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg per day. For parenteral administration or use, typical doses are approximately 0.001 mg / kg to 10 mg / kg, approximately 0.01 mg / kg to 10 mg / kg, approximately 0.01 mg / kg to 1 mg / kg, or approximately 0.1 mg / kg to 1 mg / kg. For oral administration or use, typical doses are approximately 0.001 mg / kg to 10 mg / kg or approximately 0.1 mg / kg to 10 mg / kg. When administered or used in suppository form, typical doses range from approximately 0.1 mg / kg to approximately 10 mg / kg.

[0168] In some embodiments, the oral dose of the compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate is in the range of 50 mg to about 500 mg per day for adults, preferably in the range of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg or about 500 mg per day. In some embodiments, the oral dose of the compound of formula I or its pharmaceutically acceptable salt, prodrug, and / or solvate is in the range of about 50 mg to about 500 mg per day, about 100 mg to about 400 mg per day, about 200 mg to about 400 mg per day, about 250 mg to about 350 mg per day, or about 250 mg to about 325 mg per day. In some embodiments, the oral dose of the compound of formula I or its pharmaceutically acceptable salt, prodrug, and / or solvate is in the range of about 200 mg to about 400 mg per day, or about 250 mg to about 325 mg per day. In some embodiments, the oral dose of the compound of formula I or its pharmaceutically acceptable salt, prodrug, and / or solvate is about 325 mg per day.

[0169] In some embodiments, the compound of formula I is formulated for oral administration or use, and the compound of formula I is preferably in the form of tablets or other solid oral dosage forms containing 0.25, 0.5, 0.75, 1, 5, 10, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 400, 450, or 500 mg of the active ingredient per tablet.

[0170] In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, prodrug, and / or solvate may be administered or used in a once-daily dose, or the total daily dose may be divided into two, three, four, five, or six doses per day. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, prodrug, and / or solvate may be administered two, three, four, five, or six times per day.

[0171] In some embodiments, for example, when a compound of formula I is used or administered to treat acute pain, including acute pain associated with UCPPS, the compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate is administered for 1 to 14 days, 2 to 10 days, 2 to 9 days, 2 to 8 days, 2 to 7 days, 2 to 6 days, or 3 to 5 days. In some embodiments, the acute pain is a transient exacerbation or relapse. In some embodiments, the compound of formula I is used or administered intermittently for more than 3 months or more than 6 months, as described.

[0172] In some embodiments, the oral dose of the compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate is about 400 mg to about 500 mg per day, and the compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate is administered for 1 day. In some embodiments, the oral dose of the compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate is about 400 mg to about 500 mg per day, about 400 mg to about 450 mg per day, or about 450 mg to about 500 mg per day, or about 400 mg per day, about 450 mg per day, or about 500 mg per day, and the compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate is administered for 1 day.

[0173] In some embodiments, the oral dose of the compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate is about 200 mg to about 400 mg per day, about 250 mg to about 350 mg per day, or about 250 mg to about 325 mg per day, and the compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate is administered for 1 to 10 days, 1 to 8 days, 1 to 7 days, 1 to 5 days, 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, 2 to 5 days, 3 to 5 days, 4 to 5 days, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some embodiments, the oral dose of the compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate is about 250 mg to about 350 mg per day or about 250 mg to about 325 mg per day, or about 250 mg, about 275 mg, about 300 mg, about 325 mg per day or about 350 mg per day, and the compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate is administered for 1 to 8 days, 1 to 7 days, 1 to 5 days, 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, 2 to 5 days, 3 to 5 days, 4 to 5 days, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.

[0174] The duration of treatment depends on various factors, including the severity of acute pain, the age of the subject, the concentration and / or activity of the compound of formula I or its pharmaceutically acceptable salt, prodrug, and / or solvate, and / or combinations thereof. It will also be recognized that the effective dose of the compound used in treatment may increase or decrease over the course of a particular treatment plan. Changes in dosage can be produced and revealed by standard diagnostic assays known in the art. For example, the compound of formula I or its pharmaceutically acceptable salt, prodrug, and / or solvate is administered to the subject in an amount and duration sufficient to treat the subject.

[0175] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. In one embodiment, the subject is a non-human animal.

[0176] Compounds of Formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates are used or administered alone or in combination with other known agents useful for treating pain associated with urological chronic pelvic pain syndrome (UCPPS), UCPPS, acute pain, and / or cystitis. When used or administered in combination with other agents or therapies, embodiments of compounds of Formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates are used or administered simultaneously with those agents or therapies. As used herein, “simultaneous administration” or “simultaneous use” of two substances or therapies to a target means providing each of the two substances or therapies so that they are simultaneously biologically active in the individual. The exact details of administration or use depend on the pharmacokinetics of the two substances or therapies in the presence of each other and may include administering or using the two substances or therapies within a few hours of each other, or even administering or using one substance or therapy within 24 hours of the other administration or use, provided the pharmacokinetics are appropriate. Designing appropriate administration regimens is commonplace for those skilled in the art. In certain embodiments, the substances or therapies are administered or used substantially simultaneously, i.e., within minutes of each other, or, in the case of administration or use of two or more substances, in a single composition. Further embodiments of this application involve combinations of agents or therapies being administered to or used non-concurrently.

[0177] In some embodiments, the compound of formula I or its pharmaceutically acceptable salts and / or solvates or compositions of the present application are used or administered in combination with other known agents useful for treating or preventing pain associated with chronic urinary pelvic pain syndrome (UCPPS), UCPPS, acute pain and / or cystitis.

[0178] In one embodiment of the method and use of this application, the compound of formula I or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is administered or used orally. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is administered or used parenterally. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is administered or used intramuscular, transepithelial, or topical, including transdermal administration.

[0179] In one embodiment, pharmaceutically acceptable salts are acid addition salts or base addition salts. The selection of an appropriate salt can be made by those skilled in the art (see, for example, SMBerge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, pp. 1-19).

[0180] Suitable or compatible acid addition salts for the treatment in question are any non-toxic organic or inorganic acid addition salts of any basic compound. Examples of basic compounds that form acid addition salts include compounds containing an amine group. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium bisulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids. Examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In one embodiment, mono- or di-salts are formed, and such salts exist in either hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts are soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. Criteria for selecting a suitable salt are known to those skilled in the art. For example, in the isolation of the compounds of this application for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts, other pharmaceutically acceptable salts such as, but not limited to, oxalates may be used.

[0181] Suitable or compatible base addition salts for the treatment in question are any non-toxic organic or inorganic base addition salts of any acidic compound. Examples of acidic compounds that form base addition salts include compounds containing a carboxylic acid group. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide and ammonia. Exemplary organic bases that form suitable salts include isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and aliphatic, alicyclic, or aromatic organic amines such as polyamine resins. Exemplary organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of a suitable salt can be useful, for example, to prevent hydrolysis if an ester functional group is present elsewhere in the compound. Criteria for selecting a suitable salt are known to those skilled in the art.

[0182] Examples of solvates of the compound of formula I include those prepared using pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvate is called a hydrate), ethanol, and the like. A suitable solvent is physiologically tolerable at the administered dose.

[0183] Compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates may further exist in amorphous or various polymorphic forms, any amorphous form, any polymorph, or mixture thereof whose form falls within the scope of this application.

[0184] Compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates may be further radiolabeled, and therefore all radiolabeled versions of the compounds of this application are included within the scope of this application. Compounds of this application also include those in which one or more radioactive atoms are incorporated into their structure.

[0185] III. Compositions of this Application In one embodiment, a compound of formula I or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is

[0186] [ka]

[0187] It is appropriately incorporated into the composition in a conventional manner using one or more carriers.

[0188] Compounds of formula I or their pharmaceutically acceptable salts and / or solvates are appropriately formulated into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. Therefore, compounds of formula I or their pharmaceutically acceptable salts and / or solvates are each formulated as a compound of formula I or its pharmaceutically acceptable salt, prodrug and / or solvate.

[0189] [ka]

[0190] Furthermore, it is appropriately incorporated into pharmaceutical compositions containing pharmaceutically acceptable carriers.

[0191] Accordingly, this application further includes methods or uses for treating pain associated with chronic urinary pelvic pain syndrome (UCPPS), UCPPS, acute pain, and / or pain associated with cystitis by administering or using a composition comprising a compound of formula I or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0192] Compounds of Formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates are appropriately used on their own, but are generally administered in the form of compositions with acceptable carriers. Depending on the method of administration, the compositions contain one or more forms in amounts of about 0.05% to about 99% by weight or about 0.10% to about 70% by weight, and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of acceptable carriers, all weight percentages based on the total composition.

[0193] As will be understood by those skilled in the art, compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates are also administered to or used in various forms depending on the selected route of administration. In one embodiment, compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates are administered to or used in a subject by oral (including sublingual and buccal) or parenteral (including intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, transnasal, intrapulmonary, intrathecal, rectal, topical, patch, pump, and transdermal) administration, and are formulated accordingly. Here again, conventional procedures and components for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000-20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.

[0194] Parenteral administration methods include intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, transnasal, intrapulmonary (e.g., by aerosol), intrathecal, rectal, and topical (including the use of patches or other transdermal delivery devices). Parenteral administration may also be by continuous infusion over a selected period. Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. In all cases, the form is sterile and fluid enough to be readily injectable.

[0195] Compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates may be administered orally, for example, with an inert diluent or an assimilated food carrier, or encapsulated in hard or soft shell gelatin capsules, or compressed into tablets, or directly incorporated into food. For oral therapeutic administration, the compounds may be used in the form of tablets, buccal tablets, lozenges, capsules, caplets, pellets, granules, lozenges, chewing gums, powders, syrups, elixirs, wafers, aqueous solutions, and suspensions that can be incorporated with an excipient and ingested. In the case of tablets, carriers that can be used include salts of lactose, corn starch, sodium citrate, and phosphoric acid. pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, pH-sensitive enteric coatings such as Eudragits®, designed to control the release of the active ingredient, are optionally used. Oral dosage forms also include modified release formulations, such as immediate-release and sustained-release formulations. Examples of modified release formulations include, for example, coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, aggregated particles such as molecular sieve-type particles, or fine hollow permeable fiber bundles or shredded hollow permeable fibers aggregated or held in fibrous packets, such as sustained release (SR), extended release (ER, XR, or XL), time-based release or sustained release, controlled release (CR), or continuous release (CR or Contin).Sustained-release compositions can be formulated, for example, by protecting liposomes or active compounds with differentially degradable coatings, such as microencapsulation or multiple coatings. Liposome delivery systems include, for example, small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, useful carriers or diluents include lactose and dried corn starch.

[0196] Liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or may be appropriately provided as dry products to be combined with water or other suitable vehicles before use. When aqueous suspensions and / or emulsions are administered orally, the compound of formula I or its pharmaceutically acceptable salts, prodrugs, and / or solvates are appropriately suspended or dissolved in an oily phase in combination with emulsifiers and / or suspending agents. Certain sweeteners and / or flavoring agents and / or coloring agents may be added if desired. Such liquid preparations for oral administration may be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fat), emulsifiers (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol), and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycol.

[0197] The compound of formula I or its pharmaceutically acceptable salts, prodrugs, and / or solvates can be freeze-dried, and the resulting freeze-dried product can be used, for example, in the preparation of injectable products.

[0198] Compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates may also be administered parenterally. Solutions of compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates can be prepared in water by being appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, and in oil. Under normal conditions of storage and use, these preparations contain preservatives to prevent microbial growth. Those skilled in the art will know how to prepare suitable formulations. For parenteral administration, sterile solutions of compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates are usually prepared, with the pH of the solution appropriately adjusted and buffered. For intravenous use, the total concentration of the solute should be controlled to make the preparation isotonic. For ocular administration, ointments or droppable liquids may be delivered by ocular delivery systems known in the art, such as applicators or eyedroppers. Such compositions may include mucosal mimics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose, or polyvinyl alcohol, preservatives such as sorbic acid, EDTA, or benzyl chromium chloride, and a typical amount of diluent or carrier. For pulmonary administration, the diluent or carrier is selected to be appropriate for enabling aerosol formation.

[0199] Compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates may be formulated for parenteral administration by injection, including using conventional catheter placement techniques or infusions. Injectable formulations may be provided in preservative-containing unit dosage forms, such as ampoules or multi-dose containers. Compositions may take the form of sterile suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. In all cases, the form must be sterile and fluid enough to be readily injectable. Alternatively, compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates may be in sterile powder form for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0200] Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels, and powders.

[0201] For intranasal or inhalation administration, the compound of formula I or its pharmaceutically acceptable salts, prodrugs, and / or solvates are preferably delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually supplied in a sterile form in a sealed container, which can take the form of a cartridge or refill for use with a spray device, in single or multiple doses. Alternatively, the sealed container may be an integrated dispensing device such as a single-dose nasal inhaler or aerosol dispenser with a metering valve for disposal after use. If the dosage form includes an aerosol dispenser, it contains a propellant which may be a compressed gas such as compressed air or an organic propellant such as a fluorochloro hydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide, or another suitable gas. In the case of pressurized aerosols, the dosage unit is appropriately determined by providing a valve for delivering the measured amount. The pressurized container or sprayer may contain a solution or suspension of the active compound. Capsules and cartridges (e.g., made from gelatin) for use in inhalers or injectors may be formulated containing a powder mixture of the compound of formula I or a pharmaceutically acceptable salt thereof, a prodrug and / or solvate, and a suitable powder base such as lactose or starch. The aerosol dosage form may also take the form of a pump sprayer.

[0202] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and troches in which the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are preferably in the form of suppositories containing conventional suppository bases such as cocoa butter.

[0203] Suppository forms of compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates are useful for vaginal, urethral, ​​and rectal administration. Such suppositories are generally constructed from mixtures of substances that are solid at room temperature but melt at body temperature. Substances commonly used to create such vehicles include, but are not limited to, theobroma oil (also known as cocoa butter), glycerin-gelatinized, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. For further consideration of suppository dosage forms, see, for example, Remington's Pharmaceutical Sciences, 16th edition, Mack Publishing, Easton, PA, 1980, 1530–1533.

[0204] Compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates may also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamidophenol, polyhydroxy-ethyl aspartamidophenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates may be coupled to a class of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked block copolymers or amphiphilic block copolymers of hydrogels.

[0205] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate may be linked to a virus, nonviral, or other vector. Viral vectors may include retroviruses, lentiviruses, adenoviruses, herpesviruses, poxviruses, alphaviruses, vaccinia viruses, or adeno-associated viruses. Nonviral vectors may include nanoparticles, cationic lipids, cationic polymers, metal nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-permeable peptides, or liposomes. Nanoparticles may include silica, lipids, carbohydrates, or other pharmaceutically acceptable polymers.

[0206] In one embodiment, depending on the administration method, the pharmaceutical composition comprises about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of an active ingredient (compound of formula I) and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of one or more pharmaceutically acceptable carriers, where all weight percentages are based on the total amount of the composition.

[0207] In one embodiment, the pharmaceutical composition is formulated for oral administration. In one embodiment, the pharmaceutical composition is formulated for oral administration and comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate.

[0208] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof, a prodrug, and / or solvate thereof is administered simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form, together with another therapeutic agent. Accordingly, this application provides a single unit dosage form comprising the compound of formula I or a pharmaceutically acceptable salt thereof, a prodrug, and / or solvate thereof, a further therapeutic agent, and a pharmaceutically acceptable carrier.

[0209] In one embodiment, the composition is formulated for parenteral administration. In another embodiment, the composition is formulated for transdermal administration.

[0210] Compounds of formula I or their pharmaceutically acceptable salts, prodrugs, and / or solvates may be used alone or in combination with other known agents useful for treating acute pain, urological chronic pelvic pain syndrome (UCPPS), or cystitis.

[0211] This is an embodiment in which another known agent useful for treating acute pain, urinary tract chronic pelvic pain syndrome (UCPPS), or cystitis is administered or used in accordance with a known treatment protocol.

[0212] In one embodiment, the compound of formula I is in the form of a pharmaceutically acceptable solvate. In one embodiment, the compound of formula I is in a neutral form (i.e., not a salt). In one embodiment, the compound of formula I is a prodrug of the compound of formula I. In one embodiment, the compound of formula I is a solvate of the prodrug of the compound of formula I.

[0213] IV. Preparation method Compounds of formula I can be prepared by various synthetic processes. The selection of a particular process is within the understanding of those skilled in the art. Some starting materials are available from commercially available chemical sources. Other starting materials, such as those described below, can be readily prepared from available precursors using direct conversions well known in the art.

[0214] Compounds of formula I can generally be prepared according to the processes illustrated in the following scheme. Those skilled in the art will recognize that many of the reactions shown in the following scheme are sensitive to oxygen and water, and that the reactions may be carried out under an anhydrous, inert atmosphere as needed. The reaction temperatures and times are presented for illustrative purposes only and may be modified to optimize the yield, as will be understood by those skilled in the art.

[0215] Therefore, the compound of formula I is prepared as shown in Scheme 1. Thus, the compound of formula A (ketoprofen) is coupled with the compound of formula B (hydroxybenzamide) using a suitable coupling agent such as dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBt) in a suitable solvent such as dimethylformamide under suitable coupling conditions to obtain the compound of formula C. Then, the compound of formula C is thionated in a suitable solvent such as anhydrous benzene using a suitable thionate agent such as Lawson's reagent to obtain the compound of formula I.

[0216] [ka]

[0217] Compounds of formula I can also be prepared by methods known in the art, for example, by the methods disclosed in U.S. Patent No. 8,541,398 and / or U.S. Patent No. 7,910,568. [Examples]

[0218] The following non-limiting examples are illustrative of this application.

[0219] Example 1: Synthesis of compound I

[0220] [ka]

[0221] Step 1: Synthesis of 4-carbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate To a solution of 1 (ketoprofen, 3 g, 11.8 mmol) in 80 mL of dimethylformamide, hydroxybenzotriazole (1.76 g, 13 mmol) and DCC (2.68 g, 13 mmol) were added with stirring at 0°C for 1 hour. 4-hydroxybenzamide (2, 2.43 g, 17.7 mmol) was added to the reaction mixture and stirred at 0°C for 1 hour and at room temperature for 2 hours. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The resulting oily residue was dissolved in ethyl acetate, the organic layer was washed with brine containing 5% NaHCO3 and 10% citric acid, then dried over anhydrous MgSO4, filtered, and the solvent was evaporated. Crude product 3 was loaded onto a silica gel open column and eluted with CH2Cl2 / MeOH (9.5 / 0.5) to obtain 4-carbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate (3) (1.84 g, yield 42%).

[0222] Step 2: Synthesis of 4-thiocarbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate 4-Carbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate (3) (1.84 g, 4.93 mmol) and Lawson's reagent (2 g, 4.93 mmol) were dissolved in 100 ml of anhydrous benzene. The reaction mixture was heated to 60°C and stirred for 4 hours. The solvent was removed under reduced pressure. The resulting compound was purified by silica gel open column elution and eluted with CH2Cl2 / MeOH (9.5 / 0.5) to obtain pure compound 4 (0.45 g, yield 23%).

[0223] 1 H NMR(DMSO-d6):8 1.53(d,3H),4.25(dd,1H),7.08(d,2H),7.54-7.73(m,9H),7.90(d,2H),9.51 and 9.88(s,2H,NH2). 13 C NMR(DMSO-d6):8 19.2,44.9,121.6,129.3,129.5,129.8,130.3,132.6,133.5,137.6,137.9,138.1,141.2,153.3,154.5,156.1,163.8,172.9,199.6. MS(EI),m / e 390(M + ) mp: 114~116℃

[0224] Biological data Example 2: Comparative evaluation of ketoprofen and compound I in a mouse model of interstitial cystitis / visceral pain syndrome. Materials and methods Test substances and reagents The compound of formula I (ATB-352) was supplied by Antibe Therapeutics, Inc., and ketoprofen was purchased from Sigma-Aldrich (Oakville, Ontario, Canada). Suspensions of the compound of formula I (4.6, 15, 46, or 77 mg / kg) and molar equivalent doses of ketoprofen (3, 10, 30, or 50 mg / kg) were freshly prepared in 0.5% CMC (Cromoline Quimica Fina Ltd., Diadema, São Paulo, Brazil). Cyclophosphamide, carbachol, KC1, and CMC were purchased from Sigma Chemical Co. (St. Louis, Missouri). Isoflurane was obtained from Cristalia Prod Quimicos Farm Ltda (Itapira / São Paulo, Brazil). animal The experiment was conducted using male C57BL / 6 SPF mice (6-10 weeks old) obtained from the animal care facility of the Faculty of Medicine, University of São Paulo, Brazil. Mice were randomly divided into different treatment groups (n=5-7 per group). Groups of 5 or fewer mice were kept in Perspex cages under standard control conditions (22°C; 12 / 12 hour light / dark cycle) and were given free access to food (Nuvilab CR-1, Quimtia S / A, Brazil) and filtered tap water. The study was conducted in accordance with the guidelines of the Brazilian Animal Experiment Management Committee (CONCEA) and in accordance with animal welfare laws. All experimental protocols were approved by the regional ethics committee (CEUA-ICB; protocol n°2055050819). In accordance with laboratory rules, euthanasia was performed if severe suffering related to the test drug occurred during the experiment.

[0225] Cystitis induction and experimental design Cystitis treated with cyclophosphamide CYP (300 mg kg) -1 The induction was achieved by a single IP injection (Oliveira et al., 2018), while the control group received physiological saline (10 ml / kg). -1 The mice received an IP injection of ) 21 hours after the CYP injection, they were orally treated with a vehicle, ketoprofen, or a compound of formula I. This included a certain dose of ketoprofen (3, 10, 30, or 50 mg / kg). -1 ), compound of formula I (4.6, 15, 46 or 77 mg kg) -1 ) or vehicle (0.5% carboxymethylcellulose; 0.5% CMC) was included. The drug was administered at 10 ml / kg -1 It was dissolved in 0.5% CMC at the specified concentration. Table 1 lists the treatment groups.

[0226] [Table 1]

[0227] Measurement of mechanical dysalgia using the electronic von Frey test. Mice were individually placed in transparent Perspex test chambers (11 cm × 9.5 cm × 18 cm) on an elevated wire grid platform (0.5 cm2 grid) for appropriate adaptation (about 1 hour). Mechanical sensitivity evaluation was performed in groups of 5 - 7 mice each, as previously described (Costa et al., 2020), using an electronic von Frey apparatus (Insight Inc., Ribeirao Preto, Sao Paulo, Brazil). A pressure transducer connected to a digital force detector (Insight Ltd, Ribeirao Preto / Sao Paulo, Brazil) was used to apply a pressure that generated a force in the lower abdomen near the bladder (pelvic region between the urethra and anus). Abdominal contractions (mechanical allodynia) from the probe were considered a positive response to the stimulus and were recorded in grams (g). The stimulus was applied twice at a stimulus interval of at least 5 - 10 seconds, and the average (g) of these positive responses was registered as the abdominal withdrawal threshold (mechanical allodynia) and represented as the area under the curve (AUC) over several time points (21 - 24 hours after CYP injection). All mechanical sensitivity tests were performed in a blinded fashion. Response threshold data were analyzed by analysis of variance (ANOVA) followed by Tukey's post - hoc test. After all mice were euthanized by overdose of isoflurane, cervical dislocation was performed.

[0228] Evaluation of gastric lesions in IC / BPS mice treated with ketoprofen vs. ATB - 352 Compound of formula I (77 mg kg -1 , oral) and the ability of systemic treatment with an equimolar dose of ketoprofen at a high dose (50 mg kg -1 , oral) to induce gastric mucosal bleeding injury were tested as observed in previous studies (Costa et al., 2020). Briefly, mice in different experimental groups were euthanized by cervical dislocation under isoflurane anesthesia, the stomach was excised, opened along the lesser curvature, gently rinsed with saline, and then photographed with a digital camera (Samsung Galaxy S20, Campinas / Sao Paulo, Brazil). The hemorrhagic gastric lesion area was blindly measured (mm 2 ) using computerized flattening software (ImageJ, Maryland, USA).

[0229] In vitro bladder function assay After 24 hours, mice with CYP-induced cystitis were euthanized, and their bladders were immediately transferred to petri dishes. Adipose tissue was carefully removed, as described by Calmasini et al., 2021. The bladders were divided into two longitudinal strips and mounted in an isolated organ bath system (Panlab Harvard, Massachusetts, USA) containing Krebs-Henselite solution at 37°C (pH 7.4, O2 / CO29 / 5 v / v) under a resting tension of 5 mN. The tissue was stabilized for 1 hour, during which the bath solution was changed every 15 minutes. Isometric forces were recorded using a PowerLab 8 / 30 Data Acquisition System (Software Chart, version 6.0, AD Institute, Milford, Massachusetts, USA).

[0230] In all groups—vehicle (normal animals), CYP control group (untreated animals with interstitial cysts (ICs)), and two CYP groups (ICs) treated with the test drugs (ketoprofen and compounds of formula I)—a single concentration of KCl (80 mM) or a cumulatively increasing concentration of carbachol (10 mM) was used. -9 ~10 -5 The bladder's contraction response to ) was investigated.

[0231] statistical analysis This analysis was performed using GraphPad Prism® version 6.0 (GraphPad Software, San Diego, USA). Data were analyzed using one-way analysis of variance (ANOVA) followed by a Turkey post-hoc test. All results were expressed as mean ± standard error of the mean (SEM), with a significance level of *P<0.05.

[0232] result A ketoprofen-based H2S donor (ATB-352) showed excellent anti-algesic effects in a mouse model of interstitial cystitis / visceral (bladder) pain syndrome. Figure 1 shows that in the pelvic region of mice orally treated with 0.5% CMC, CYP injection significantly reduced the nociceptive threshold, expressed as AUC, compared to a control group injected with physiological saline. At the lowest equimolar doses of the compound of formula I or ketoprofen, there was no anti-algesic hyperalgesic effect on reducing the withdrawal threshold in this mouse model of IC / BPS. At higher doses, the compound of formula I reduced cyclophosphamide-induced abdominal mechanical allodynia in a dose-dependent manner. Ketoprofen reduced abdominal mechanical allodynia in CPY-induced IC / BPS at 10 and 30 mg / kg -1 The dosage significantly reversed the effect, but 50 mg kg -1 So, the reverse was not performed. The intermediate and high doses were equimolar doses of the compound of formula I (15, 46, and 77 mg kg). -1 Using this method, a significant dose-dependent difference in the response to (mechanical allodynia) was detected compared to control IC / BPS mice treated with the vehicle, 0.5% CMC. Furthermore, the highest equimolar dose of the compound of formula I (77 mg kg) was detected. -1 In this study, an enhanced analgesic effect was observed compared to ketoprofen (P<0.001; Figure 1).

[0233] Inhibition of ketoprofen-induced gastric mucosal injury by ATB-352 As shown in Figure 2, high doses of ketoprofen (50 mg kg) -1 Systemic treatment of mice (oral) resulted in extensive gastric lesions over a 3-hour period (Figure 2, Panel D, fourth screen from the left), but this was not the case with treatment of mice with equimolar doses of the compound of formula I (77 mg kg-1) or the vehicle (Panels B and C, second and third pictures from the left, respectively).

[0234] Panels A-D in Figure 2 (first, second, third, and fourth photographs from the left) show photographs of the gastric mucosa of vehicle-treated mice, IC / BPS mice treated with 0.5% CMC, IC / BPS mice treated with a high dose of formula I, and IC / BPS mice treated with a high dose of ketoprofen. Panels A, B, and C (first, second, and third photographs from the left) show normal gastric mucosa, while panel D (fourth photograph from the left) shows extensive hemorrhagic gastric ulcer formation.

[0235] The compound of formula I is superior to ketoprofen in improving CYP-induced bladder dysfunction in a mouse model of IC / BPS. In the control CYP bladder strip, the decrease in contractility to KCl (80 mM) was significantly different from that in the vehicle-treated group (Figure 3A). However, the contractile response to KCl that was reduced in the CYP bladder strip (Figure 3A) was 15 and 46 mg / kg, respectively, compared to the control group. -1 Mice treated with the compound of formula I showed a significant dose-dependent increase, but mice treated with equimolar doses of ketoprofen did not show an increase (p<0.05). -1 ) also ketoprofen (50mg kg -1 However, at high doses, it did not significantly improve the decrease in bladder contractility in IC / BPS mice in response to KCl.

[0236] Similarly, in bladder strips of IC / BPS mice, the maximum (E) decrease induced by CCh was observed. max The contractile response was significantly increased in mice treated with high doses of the compound of formula I and ketoprofen, but not at low doses of each compound (Figure 3B). -1 ) is the maximal contraction response (E) induced by CCh. max The decrease in ) was significantly reversed, but this was not the case for the compound of formula I (Figure 3B).

[0237] conclusion The data generated in this study demonstrate that injection of CYP into C57B1 / 6 mice induces cystitis and associated visceral / pelvic pain, in addition to decreased functional contractility in the isolated bladder phenotype. These functional and kinetic changes in the CYP-induced IC / BPS-like model were significantly reduced by treatment with medium and high doses of the compound of formula I, with the reduction being less pronounced with the parent molecule (ketoprofen).

[0238] Based on the increased beneficial effect of compound I compared to ketoprofen on abdominal hyperalgesia and the reduced bladder contraction response in the CYP-induced IC / BPS model, it can be concluded that compound I is more potent than ketoprofen when administered orally as a single dose.

[0239] Furthermore, the compound of formula I was found to reduce the GI toxicity of ketoprofen while enhancing the efficacy of analgesics / anesthetics. In summary, these data demonstrate that the compound of formula I, an H2S donating agent, may have significant potential for improving or treating urothelial health and symptoms, including visceral pain (cystitis), in patients with IC / BPS.

[0240] Although this application has been described with reference to examples, it should be understood that the claims should not be limited by the embodiments described in the examples, and that the broadest interpretation consistent with the description as a whole should be given.

[0241] All publications, patents, and patent applications are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference in whole. If any term in this application is found to have a different definition in any document incorporated herein by reference, the definition provided herein shall function as the definition of the term.

[0242] Complete citation of the literature mentioned in the specification Several publications are cited in this specification. The complete citations for these references are provided below. Each of these references is hereby incorporated by reference in its entirety as if each individual reference was specifically and individually indicated to be incorporated by reference.

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[0246] Costa SK, Muscara M, Allain T, Dallazen J, Santos LG, Buret AG, Vaughan D, Fowler CJ, De Nucci GN, Wallace JL. Enhanced analgesic effects and GI safety of a novel hydrogen sulfide-releasing anti-inflammatory drug(ATB-352): A role for endogenous cannabinoids. Antioxid Redox Signal. February 16, 2020 doi:10.1089 / ars.2019.7884

[0247] de Oliveira MG, Calmasini FB, Alexandre EC, De Nucci G, Monica FZ, Antunes E (2016). Activation of soluble guanylyl cyclase by BAY 58-2667 improves bladder function in cyclophosphamide-induced cystitis in mice. Am J Physiol Renal Physiol. 311:F85-F93

[0248] Glowacka et al., Microbiome Profile and Molecular Pathway Alterations in Gastrointestinal Tract by Hydrogen Sulfide-Releasing Nonsteroid Anti-inflammatory Drug (ATB-352): Considerations on Possible Safer Polypharmacy, ANTIOXIDANTS & REDOX SIGNALING, Vol. 36, (4-6), 2022.

[0249] Gugliandolo E, Fusco R, D'Amico R, Militi A, Oteri G, Wallace JL, Di Paola R, and Cuzzocrea S. Antiinflammatory effect of ATB-352, an H2S-releasing ketoprofen derivative, on lipopolysaccharide-induced periodontitis in rats. Pharmacol Res 132:220-231, 2018.

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[0257] Winfield RD, Reese S, Bochicchio K, Mazuski JE, Bochicchio GV. Obesity and the risk for surgical site infection in abdominal surgery. Am Surg . 2016;82:331 - 336 Exemplary embodiments of the present invention are described below. <1> A method for treating pain associated with urological chronic pelvic pain syndrome (UCPPS) in a subject requiring treatment for pain associated with UCPPS, wherein the subject is given an effective amount of a compound of formula I.

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Claims

1. An agent for use in a method of treating pain associated with urological chronic pelvic pain syndrome (UCPPS), comprising the compound of formula I. 【Chemistry 1】 A preparation comprising a pharmaceutically acceptable salt and / or solvate thereof.

2. The agent according to claim 1, wherein the pain associated with UCPPS is selected from one or more of visceral pain, neuropathic pain, neuralgia, allodynia, burning pain, hyperalgesia, hyperesthesia, parodynia, and neuropathy associated with surgical procedures.

3. The agent according to claim 2, wherein the pain associated with UCPPS is allodynia associated with UCPPS.

4. The agent according to claim 2, wherein the pain associated with UCPPS is hyperalgesia associated with UCPPS.

5. The agent according to claim 2, wherein the pain associated with UCPPS is visceral pain associated with UCPPS.

6. The agent according to any one of claims 1 to 5, wherein the pain associated with UCPPS is acute pain and / or chronic pain associated with UCPPS.

7. The agent according to claim 6, wherein the pain associated with UCPPS is chronic pain associated with UCPPS.

8. The agent according to claim 6, wherein the pain associated with UCPPS is acute pain associated with UCPPS.

9. The agent according to claim 8, wherein the acute pain associated with UCPPS is a transient exacerbation or relapse of pain associated with UCPPS.

10. The agent according to claim 8 or 9, wherein the acute pain persists for less than approximately 14 days, less than approximately 12 days, less than approximately 10 days, less than approximately 7 days, less than approximately 5 days, or less than 3 days from the onset of the acute pain.

11. The agent according to claim 8 or claim 9, wherein the acute pain persists for approximately 1 to 14 days, approximately 1 to 12 days, approximately 1 to 10 days, approximately 1 to 7 days, approximately 1 to 5 days, approximately 1 to 3 days, or approximately 3 to 14 days, approximately 3 to 10 days, approximately 3 to 7 days, or approximately 5 to 10 days.

12. The agent according to any one of claims 8 to 11, wherein the acute pain occurs intermittently for a period of more than three months or more than six months.

13. The agent according to any one of claims 1 to 12, wherein the pain associated with UCPPS is selected from one or more of the following: lower abdominal (pelvic) pain, bladder pain, suprapitic pain, vaginal pain, penile pain, testicular pain, scrotal pain, perineal pain, urethral pain, dyspareunia, or pain, pressure, or discomfort that increases as the bladder fills.

14. The agent according to any one of claims 1 to 12, wherein the UCPPS is interstitial cystitis / bladder pain syndrome (IC / BPS).

15. The agent according to claim 14, wherein the UCPPS is interstitial cystitis (IC).

16. The agent according to claim 14, wherein the UCPPS is bladder pain syndrome (BPS).

17. The agent according to any one of claims 1 to 12, wherein the UCPPS is chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

18. An agent for use in a method for treating urological chronic pelvic pain syndrome (UCPPS), comprising the compound of formula I. 【Chemistry 2】 A preparation comprising a pharmaceutically acceptable salt and / or solvate thereof.

19. The agent according to claim 18, wherein the UCPPS is interstitial cystitis / bladder pain syndrome (IC / BPS).

20. The agent according to claim 19, wherein the UCPPS is interstitial cystitis (IC).

21. The agent according to claim 19, wherein the UCPPS is bladder pain syndrome (BPS).

22. The agent according to claim 18, wherein the UCPPS is chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

23. An agent for use in a method for treating cystitis, comprising a compound of formula I. 【Chemistry 4】 A preparation comprising a pharmaceutically acceptable salt and / or solvate thereof.

24. The agent according to claim 23, wherein the bladder inflammation is associated with urological chronic pelvic pain syndrome (UCPPS).

25. The agent according to claim 24, wherein the UCPPS is interstitial cystitis / bladder pain syndrome (IC / BPS).

26. The agent according to claim 25, wherein the UCPPS is interstitial cystitis (IC).

27. The agent according to claim 25, wherein the UCPPS is bladder pain syndrome (BPS).

28. The agent according to claim 24, wherein the UCPPS is chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

29. The agent according to any one of claims 1 to 28, wherein the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is administered to an adult in an oral dose of 50 mg to about 500 mg per day.

30. The agent according to claim 29, wherein the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is administered in an oral dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg per day.

31. The agent according to claim 29, wherein the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is administered in an oral dose ranging from about 200 mg to about 400 mg per day or from about 250 mg to about 325 mg per day.

32. The agent according to any one of claims 1 to 31, wherein the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is administered for 1 to 14 days, 2 to 10 days, 2 to 9 days, 2 to 8 days, 2 to 7 days, 2 to 6 days, or 3 to 5 days.

33. The agent according to any one of claims 1 to 29, wherein the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is administered orally in a dose ranging from about 400 mg to about 500 mg per day, and the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is administered for one day.

34. The agent according to any one of claims 1 to 29, wherein the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is administered orally in a dose ranging from about 200 mg to about 400 mg per day, from about 250 mg to about 350 mg per day, or from about 250 mg to about 325 mg per day, and the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is administered for 1 to 10 days, 1 to 8 days, 1 to 7 days, 1 to 5 days, 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, 2 to 5 days, 3 to 5 days, 4 to 5 days, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.

35. The agent according to any one of claims 1 to 34, wherein the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is formulated into a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof and one or more pharmaceutical carriers.

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