4-Thiocarbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate for the treatment of pain associated with urological chronic 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 methods of treating or preventing pain associated with urological chronic pelvic pain syndromes (UCPPS), including interstitial cystitis / bladder pain syndrome (IC / BPS) and chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS), using 4-thiocarbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof. [Background technology]

[0002] NSAIDs are routinely used to treat acute and chronic pain, together with opioids, anticonvulsants and antimigraine drugs such as 5-HT receptor agonists and ergot derivatives. The introduction of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ketoprofen, is known in clinical pharmacology to be accompanied by various gastrointestinal (GI) side effects, including mild or severe dyspepsia symptoms, the development of gastric or duodenal ulcers, bleeding, perforation, and other events (Rusell RI, 2001). In particular, NSAIDs are used in the treatment of chronic inflammation in patients with rheumatoid arthritis, but very often induce gastritis (Bindu S et al., 2020). One of the most important mechanisms underlying NSAID-induced GI damage involves, but is not limited to, the inhibition of cyclooxygenase (COX)-1 or COX-2-produced gastroprotective prostaglandins (PGs), such as PGE2 (Bindu S et al., 2020; Glowacka et al., 2020). These drugs are also generally short-acting and thus require repeated administration. Therefore, there is a need for more effective analgesics for pain treatment. For example, urological chronic pelvic pain syndrome (UCPPS) is a challenging 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 disability.

[0003] Hydrogen sulfide (H2S) is produced by any cell type, including the GI tract, where it has been shown to contribute to gastrointestinal mucosal defense and ulcer healing. It is an endogenous antioxidant gas mediator that has been shown to play a role in gastrointestinal physiology, promote gastric ulcer healing, and protect the GI tract against injury 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] US Patent No. 8,541,398 discloses NSAID derivatives covalently linked to H2S-releasing moieties, and it has been found that the anti-inflammatory effect of various NSAIDs is significantly enhanced when covalently linked to H2S-releasing moieties or when NSAID salts are formed with H2S-releasing moieties. Furthermore, US Patent No. 8,541,398 discloses that these NSAID derivatives covalently linked to H2S-releasing moieties provide strong anti-inflammatory properties without causing gastrointestinal toxicity. Among the many NSAID derivatives covalently linked to H2S-releasing moieties, US Patent No. 8,541,398 discloses a hydrogen sulfide-releasing derivative of ketoprofen, chemically known as 4-thiocarbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate, sometimes known as ATB-352 (Antibe Therapeutics Inc., Toronto, Canada). ATB-352 is more potent and efficacious than its parent drug in the inflammatory condition periodontitis (Gugliadola et al., 2018) and has been shown to have increased GI safety compared to ketoprofen (Glowacka et al., 2022). ATB-352 has also been shown to have greater efficacy than ketoprofen in a murine surgical incision pain model (Costa et al., 2020). Summary of the Invention [Problem to be solved by the invention]

[0005] Applicants have shown that a compound of formula I, i.e., an NSAID derivative covalently linked to an H2S releasing moiety, wherein the NSAID is ketoprofen and the H2S releasing moiety is 4-hydroxythiobenzamide (TBZ), sometimes known as ATB-352, can reduce bladder inflammation and pain associated with urologic chronic pelvic pain syndrome. [Means for solving the problem]

[0006] Accordingly, the present application provides a method of treating pain associated with urologic chronic pelvic pain syndrome (UCPPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0007] [ka]

[0008] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0009] In some embodiments, the pain associated with UCPPS is selected from one or more of visceral pain, neuropathic pain, neuralgia, allodynia, causalgia, hyperalgesia, hyperesthesia, dysalgia, and neuropathy secondary to surgical procedures.

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

[0011] The present application also provides a method of treating urologic chronic pelvic pain syndrome (UCPPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I

[0012] [ka]

[0013] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0014] The present application provides a method for treating one or more symptoms associated with urologic chronic pelvic pain syndrome (UCPPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I

[0015] [ka]

[0016] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0017] The present application also provides a method of treating bladder inflammation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0018] [ka]

[0019] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0020] The present application also provides a method for increasing bladder contraction and relaxation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0021] [ka]

[0022] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0023] The present application provides a method of treating acute pain in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0024] [ka]

[0025] or a pharma- ceutically 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, the compound of formula I, or a pharma- ceutically acceptable salt, prodrug, and / or solvate thereof, is formulated into a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt, prodrug, and / or solvate thereof, and one or more pharmaceutical carriers.

[0028] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating embodiments of the present application, are given by way of illustration only. 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] Embodiments of the present application will now be described in more detail with reference to the accompanying drawings. [Brief description of the drawings]

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

[0031] [Diagram 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 of ​​hemorrhagic gastric lesion (mm2) 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 compared with the compound of formula I group (one-way ANOVA followed by Turkey's test).

[0032] [Diagram 3]Figure 3 shows the comparative effects of the compound of formula I (ATB-352) and ketoprofen on reversing CYP-induced bladder contractility reduction in response to KCl and CCh. (A) Contractile response to KCl (80 mM) and (B) carbachol maximum contractile response in bladders from vehicle, CYP, compound of formula I (4.6, 15, 46 and 77 mg kg-1) and ketoprofen (3, 10, 30 or 50 mg kg-1) groups are shown. Data are presented as mean ± SEM (n = 4-7). *P < 0.05 vs. vehicle. #P < 0.05 vs. CYP. ##P < 0.001 vs. vehicle (A and B: one-way ANOVA followed by Turkey's test). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] I. Definition Unless otherwise indicated, the definitions and embodiments described in this section and other sections are intended to be applicable to all embodiments and aspects of the application described herein where they are appropriate, as would be understood by one of skill in the art.

[0034] For purposes of understanding the scope of this application, the term "comprising" and its derivatives, as used herein, are intended to be open-ended terms that specify the presence of stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers, and / or steps. The above also applies to words of similar meaning, such as the terms "including," "having," and their derivatives.

[0035] The term "consisting of" and its derivatives, as used herein, is intended to be a closed term that specifies the presence of stated features, elements, components, groups, integers, and / or steps, but excludes the presence of other unrecited features, elements, components, groups, integers, and / or steps.

[0036] The term "consisting essentially of," as used herein, is intended to specify the presence of recited features, elements, components, groups, integers, and / or steps, as well as things that do not materially affect the basic and novel characteristics of the features, elements, components, groups, integers, and / or steps.

[0037] Terms of degree, such as "substantially," "about," and "approximately," as used herein, refer to a reasonable amount of deviation from the modified term so that the end result is not materially altered. These terms of degree should be construed to include a deviation of at least ±5% of the modified term if this deviation does not negate the meaning of the word it modifies.

[0038] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0039] In embodiments that include an "additional" or "second" component, the second component, as that term is used herein, is chemically distinct from the other component or the first component. A "third" component is distinct from the other component, the first component, and the second component, and further recited or "additional" components are similarly distinct.

[0040] The term "and / or" as used herein means that the listed items may be present or used either individually or in any combination. In effect, the term means that "at least one" or "one or more" of the listed items are used or present.

[0041] The term "compound of formula I" or "ATB-352" as used herein has the chemical name: 4-thiocarbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate and the chemical formula

[0042] [ka]

[0043] It refers to a compound having the formula:

[0044] The term "ketoprofen" as used herein has the chemical name m-benzoylhydratropic acid or 2-(4-benzoylphenyl)propanoic acid and the chemical formula:

[0045] [ka]

[0046] It refers to a compound having the formula:

[0047] The term "pharmaceutically acceptable salt" means either an acid addition salt or a base addition salt that is suitable or compatible with the treatment of a subject.

[0048] Acid addition salts suitable or compatible with the treatment of a subject are any non-toxic organic or inorganic acid addition salts of any basic compound.

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

[0050] The term "solvate" as used herein means a compound or a salt of a compound wherein molecules of a suitable solvent are incorporated into the crystal lattice, said suitable solvent being physiologically tolerated at the dosage administered.

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

[0052] The term "administered" as used herein means administration of a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt, prodrug, and / or solvate thereof, or a composition comprising a compound or a pharma- ceutically acceptable salt, prodrug, and / or solvate thereof, to a cell in cell culture or in a subject.

[0053] As used herein, the terms "effective amount," "therapeutically effective amount" mean an amount of a compound of Formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, or a composition comprising a compound of Formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, effective, at dosages and for periods of time necessary, to achieve a desired result, including therapeutic and prophylactic results.

[0054] The term "subject" as used herein includes all members of the animal kingdom, including mammals, and suitably refers to humans. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0055] The term "pharmaceutical composition," as used herein, refers to a composition of matter for pharmaceutical use.

[0056] The term "pharmaceutical acceptable" means compatible with the treatment of a subject.

[0057] The term "parenteral," as used herein, means ingested into the body or administered in any way other than through the gastrointestinal tract.

[0058] The terms "to treat", "treating" and "treatment" as used herein and as well understood in the art refer to an approach for obtaining beneficial or desired results, including clinical results. Examples of beneficial or desired clinical results include, but are not limited to, a reduction in the extent of disease, a stable (i.e., not worsening) state of disease, prevention of disease spread, slowing or delaying disease progression, improvement or palliation of the disease state, and remission (whether partial or total), which is a reduction in the recurrence of disease, whether detectable or undetectable. "To treat", "treating" and "treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. "To treat", "treating" and "treatment" also include prophylactic treatment.

[0059] By "alleviating" a disease, disorder, or condition, it is meant that the severity and / or undesirable clinical symptoms of the disease, disorder, or condition are reduced and / or the time course of progression is slowed or prolonged compared to if the disorder is not treated.

[0060] The terms "prevention" or "prophylaxis," or their equivalents, as used herein, refer to a reduction in the risk or probability that a patient will suffer from a disease, disorder, or condition, or will exhibit symptoms associated with a disease, disorder, or condition.

[0061] The term "treating pain associated with urologic chronic pelvic pain syndrome," as used herein, means any detectable reduction in the sensation or duration of pain associated with urologic chronic pelvic pain syndrome, e.g., following administration or use of a compound, as compared to otherwise the same conditions except that the compound is not administered or used.

[0062] The term "treating pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS)," as used herein, means any detectable reduction in the sensation or duration of pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS) following, for example, administration or use of a compound, as compared to otherwise the same conditions except that the compound is not administered or used.

[0063] The term "treating pain associated with chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS)," as used herein, means any detectable reduction in the sensation or duration of pain associated with chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS), e.g., following administration or use of a compound, as compared to otherwise the same conditions except that the compound is not administered or used.

[0064] The term "urological chronic pelvic pain syndrome" or "UCPPS" as used herein refers to a chronic pain condition of the pelvis, prostate, bladder, and / or genitals accompanied by urination frequency and urgency. UCPPS encompasses interstitial cystitis / bladder pain syndrome and chronic prostatitis / chronic pelvic pain syndrome.

[0065] The term "interstitial cystitis / bladder pain syndrome" or "IC / BPS" as used herein refers to a 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 term "chronic prostatitis / chronic pelvic pain syndrome" or "CP / CPPS" as used herein refers 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 conditions involving the bladder, urethral sphincter, urethra, and, in men, the prostate.

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

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

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

[0071] The term "acute pain" as used herein means pain that is of sudden onset and in response to a stimulus associated with, for example, surgery, trauma, and / or acute illness that lasts or is expected to last for a short period of time (e.g., weeks, days, hours). 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] The term "chronic pain" as used herein means pain associated with a chronic disorder such as UCPPS.

[0073] The term "visceral pain", as used herein, refers to any pain felt by a subject that is associated with a disease, disorder, or condition of the internal organs.

[0074] The term "allodynia," as used herein, refers to pain resulting from a stimulus that does not normally elicit pain.

[0075] The term "burning pain" as used herein refers to a syndrome of persistent burning pain, allodynia and dysodynia following a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and subsequent trophic changes.

[0076] The term "hyperalgesia," as used herein, refers to an increased response to a stimulus that is normally painful.

[0077] The term "hyperdynia" as used herein refers to a pain syndrome characterized by an abnormally painful response to a stimulus, particularly a repetitive stimulus, and an elevated pain threshold.

[0078] The term "increasing bladder contraction and relaxation," as used herein, refers to any detectable increase in bladder contractile function following administration or use of a compound compared to otherwise identical conditions except that the compound is not administered or used.

[0079] The term "treating acute pain," as used herein, means any detectable reduction in the sensation or duration of acute pain, e.g., following administration or use of a compound, as compared to otherwise the same conditions except that the compound is not administered or used.

[0080] The terms "exacerbation" or "flare-up" as used herein in reference to chronic pain conditions refer to an increase in pain intensity.

[0081] For example, as used in relation to the treatment methods, uses, compositions and kits of the present application, a subject, e.g., a subject "in need thereof", is one who has been diagnosed with, suspected of having, and / or previously been treated for, e.g., urological chronic pelvic pain syndrome or pain or bladder inflammation associated with urological chronic pelvic pain syndrome.

[0082] II. Methods and Uses of the Present Application The applicant has shown that the compound of formula I, a NSAID derivative covalently linked to a H2S-releasing moiety, where the NSAID is ketoprofen and the H2S-releasing moiety is 4-hydroxythiobenzamide (TBZ), also known as ATB-352, can reduce bladder inflammation and pain associated with urological chronic pelvic pain syndrome. For example, the applicant has studied the acute effect of the compound of formula I on inflammatory bladder pain and bladder function, and has shown that the compound of formula I can reduce 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 contractile function in the IC / BPS model. Surprisingly, the efficacy of the compound of formula I for reducing visceral bladder pain and / or pelvic pain and bladder inflammation and improving bladder contractile function in the IC / BPS model has been found to be higher than that of the parent ketoprofen compound.

[0083] Accordingly, the present application provides a method of treating pain associated with urologic chronic pelvic pain syndrome (UCPPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0084] [ka]

[0085] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0086] The application also includes the use of a compound of formula I, or a pharma- ceutically 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 pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for the preparation of a medicament for treating pain associated with UCPPS in a subject, and a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for use in treating pain associated with UCPPS in a subject.

[0087] One of skill in the art will recognize that a syndrome characterizes or is indicative of one or more diseases, disorders, or conditions. Thus, one of skill 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] Accordingly, the present application provides a method of treating pain associated with interstitial cystitis / bladder pain syndrome (IC / BPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0089] [ka]

[0090] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

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

[0092] In some embodiments, the pain is associated with interstitial cystitis. Thus, in some embodiments, a compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is used or administered to treat pain associated with interstitial cystitis.

[0093] In some embodiments, the pain is associated with bladder pain syndrome. Thus, in some embodiments, a compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is used or administered to treat pain associated with bladder pain syndrome.

[0094] The present application also provides a method of treating pain associated with chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0095] [ka]

[0096] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0097] The application also includes the use of a compound of formula I, or a pharma- ceutically 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 pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for the preparation of a medicament for treating pain associated with CP / CPPS in a subject, and a compound of formula I, or a pharma- ceutically 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, causalgia, hyperalgesia, hyperesthesia, dysalgia, and neuropathy associated with surgical procedures. In some embodiments, UCPPS includes IC / BPS and / or CP / CPPS. Thus, in some embodiments, the pain associated with IC / BPS is selected from one or more of visceral pain, neuropathic pain, neuralgia, allodynia, causalgia, hyperalgesia, hyperesthesia, dysalgia, 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, causalgia, hyperalgesia, hyperesthesia, dysalgia, 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, the 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 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 lower abdominal (pelvic) pain, bladder pain, suprapubic 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, the visceral pain is visceral abdominal pain.

[0103] In some embodiments, the 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, the 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, the pain associated with interstitial cystitis is acute and / or chronic pain associated with interstitial cystitis. In some embodiments, the pain associated with bladder pain syndrome is acute and / or chronic pain associated with bladder pain syndrome. In some embodiments, the pain associated with CP / CPPS is acute and / or chronic pain associated with CP / CPPS.

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

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

[0106] In some embodiments, the acute pain associated with UCPPS is a transient exacerbation or relapse of pain associated with UCPPS. In some embodiments, the 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, the acute pain associated with interstitial cystitis is a transient exacerbation or relapse of pain associated with interstitial cystitis. In some embodiments, the acute pain associated with bladder pain syndrome is a transient exacerbation or relapse of pain associated with bladder pain syndrome. In some embodiments, the 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 in a short period of time, e.g., 14 days or less. In some embodiments, chronic pain is pain that is expected to persist for a long period of time, e.g., 15 days or more. Acute pain is distinguishable from chronic pain.

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

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

[0110] The present application also provides a method of treating urologic chronic pelvic pain syndrome (UCPPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I

[0111] [ka]

[0112] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0113] The application also includes the use of a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for treating UCPPS in a subject, the use of a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for the preparation of a medicament for treating UCPPS in a subject, and a compound of formula I, or a pharma- ceutically 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] Accordingly, the present application provides a method of treating interstitial cystitis / bladder pain syndrome (IC / BPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0116] [ka]

[0117] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0118] The application also includes the use of a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for treating IC / BPS in a subject, the use of a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for the preparation of a medicament for treating IC / BPS in a subject, and a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for use in treating IC / BPS in a subject.

[0119] In some embodiments, a compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is used or administered to treat interstitial cystitis. In some embodiments, a compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is used or administered to treat bladder pain syndrome.

[0120] The present application also provides a method of treating chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0121] [ka]

[0122] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0123] The application also includes the use of a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for treating CP / CPPS in a subject, the use of a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for the preparation of a medicament for treating CP / CPPS in a subject, and a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for use in treating CP / CPPS in a subject.

[0124] The present application also provides a method of treating one or more symptoms associated with urologic chronic pelvic pain syndrome (UCPPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I

[0125] [ka]

[0126] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0127] The application also includes the use of a compound of formula I, or a pharma- ceutically 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 pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for the preparation of a medicament for treating one or more symptoms associated with UCPPS in a subject, and a compound of formula I, or a pharma- ceutically 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. Thus, in some embodiments, the present application also includes methods or uses of compounds of formula I or pharma- ceutically acceptable salts, prodrugs and / or solvates thereof for treating one or more symptoms associated with IC / BPS. In some embodiments, the present application also includes methods or uses of compounds of formula I or pharma- ceutically acceptable salts, prodrugs and / or solvates thereof for treating one or more symptoms associated with CP / CPPS.

[0129] In some embodiments, the one or more symptoms are selected from irritative voiding symptoms, urination frequency, urgency, nocturia, incontinence, and suprapubic or pelvic pain associated with and relieved by urination.

[0130] Applicants have demonstrated that compounds of formula I can be used to reduce bladder inflammation. Accordingly, the present application also provides a method of treating bladder inflammation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0131] [ka]

[0132] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0133] The application also includes the use of a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for treating bladder inflammation in a subject, the use of a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for the preparation of a medicament for treating bladder inflammation in a subject, and a compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for use in treating bladder inflammation in a subject.

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

[0135] The present application provides a method for increasing bladder contraction and relaxation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0136] [ka]

[0137] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0138] The application also includes the use of a compound of formula I, or a pharma- ceutically 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 pharma-ceutically acceptable salt, prodrug and / or solvate thereof, for the preparation of a medicament for increasing bladder contraction and relaxation in a subject; and the use of a compound of formula I, or a pharma-ceutically 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 has UCPPS, hi some embodiments, the UCPPS is IC / BPS and / or CP / CPPS.

[0140] The present application provides a method of treating acute pain in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0141] [ka]

[0142] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

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

[0144] In some embodiments, the acute pain is a transient exacerbation or flare-up.

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

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

[0147] In some embodiments, the acute pain is post-operative pain resulting from abdominal and / or pelvic surgery. The present application provides a method for treating acute pain resulting from abdominal and / or pelvic surgery in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I.

[0148] [ka]

[0149] or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0150] The application also includes the use of a compound of formula I, or a pharma- ceutically 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 pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for the preparation of a medicament for treating acute pain resulting from abdominal and / or pelvic surgery in a subject, and a compound of formula I, or a pharma- ceutically 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, the abdominal and / or pelvic surgery is selected from, but is not limited to, inguinal hernia repair, e.g., open inguinal herniectomy, abdominal hysterectomy, open surgery, cholecystectomy, vaginal hysterectomy, abdominal hernia repair, myectomy, salpingo-oophorectomy, bariatric surgery, partial colectomy surgery, and gynecological or genitourinary surgery.

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

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

[0154] In some embodiments, the acute pain is not post-operative pain.

[0155] In some embodiments, the subject in need thereof is a subject with urological chronic pelvic pain syndrome (UCPPS), pain and / or bladder inflammation associated with UCPPS. In some embodiments, the subject in need thereof is a subject with interstitial cystitis / bladder pain syndrome (IC / BPS), pain and / or bladder inflammation associated with IC / BPS. In some embodiments, the subject in need thereof is a subject with interstitial cystitis, pain and / or bladder inflammation associated with interstitial cystitis. In some embodiments, the subject in need thereof is a subject with bladder pain syndrome, pain and / or bladder inflammation associated with bladder pain syndrome. In some embodiments, the subject in need thereof is a subject with chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS), pain and / or bladder inflammation associated with CP / CPPS.

[0156] In one embodiment, the compound of formula I is in the form of a pharma- ceutically acceptable solvate. In one embodiment, the compound of formula I is in 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 a prodrug of the compound of formula I.

[0157] The present application also includes the use of a compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof for treating urological chronic pelvic pain syndrome (UCPPS), pain associated with UCPPS, bladder inflammation and / or acute pain in a subject in need thereof 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. The present application also includes the use of a compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof for preparing a medicament for treating urological chronic pelvic pain syndrome (UCPPS), pain associated with UCPPS, bladder inflammation and / or acute pain in a subject in need thereof 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. The present application further includes a compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof for use in treating urological chronic pelvic pain syndrome (UCPPS), pain associated with UCPPS, bladder inflammation and / or acute pain in a subject in need thereof in combination with another known agent useful for treating 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 drugs useful for treating or preventing pain, UCPPS, or bladder inflammation associated with UCPPS, the methods and uses of the present application reduce the amount of other known drugs used or administered. In some embodiments, when used in conjunction with other known drugs useful for treating or preventing pain, UCPPS, or bladder inflammation associated with UCPPS, the methods and uses of the present application reduce the amount of other known drugs 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, another known drug for treating UCPPS or pain associated with UCPPS is selected from antihistamines including H1 blockers such as hydroxyzine hydrochloride and H2 blockers such as cimetidine, dimethyl sulfoxide, pain regulators including tricyclic antidepressants such as amitriptyline, anticonvulsants such as gabapentin and dimethyl sulfoxide, opiate antagonists, corticosteroids, antirheumatic drugs, immunomodulators, immunosuppressants such as prednisone and triamcinolone, interleukin production inhibitors, bladder mucosal protectants such as pentosan polysulfate and hyaluronic acid, hormone modulators such as chondroitin sulfate leukotriene-D4 receptor antagonist montelukast, L-arginine, oxybutynin, tolterodine, leuprolide acetate, anti-inflammatory drugs such as anti-TNF, 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, and combinations thereof.

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

[0162] Those skilled in the art will recognize that pain assessment scales are well known and are used in routine clinical practice to measure pain intensity. For example, commonly used measurement scales include 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). Especially in acute pain, Total Pain Relief (TOTPAR) and / or Sum of Pain Intensity Difference (SPID) are commonly used metrics in the art to evaluate pain. Numerical Rating Scale (NRS) similar to VAS in acute pain testing is also available. In some embodiments, the visual analog scale (VAS) is a vertical or horizontal line measuring 10 cm with word anchors at each end, such as "no pain" at one end and "pain as bad as it can be" at the other end. The patient is asked to make a mark along the line to indicate pain intensity. On the visual analog scale (VAS), moderate or severe pain is defined as a pain intensity greater than about 50 mm on a 0-100 mm visual analog scale (VAS). In some embodiments, moderate pain is characterized as a pain intensity greater than about 50 mm and less than about 70 mm on a 1-100 mm VAS. Severe pain is characterized as a pain intensity greater than about 70 mm on a 1-100 mm VAS. Graphic rating scales (GRS) are a variation of visual scales that add words such as "no pain", "mild", "severe", or include numbers between the two ends. The descriptor scale (SDS) is a list of adjectives such as "no pain," "mild," "moderate," or "severe," which describe different levels of pain intensity.Numeric Pain Rating Scales (NPRS) refer to either a numerical rating of 0–10 or 0–5, or a visual scale using both words and numbers. A visual analogue scale (VAS) version of the WOMAC is also commonly used.

[0163] In some embodiments, subject treatment is assessed using one or more biomarkers known to indicate 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 indicative of a pain response are known in the art, as are methods for detecting their levels in a subject.

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

[0165] In some embodiments, the methods and uses of the present application provide pain relief within about 30 minutes to about 4 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours, or about 2 hours to about 3 hours after administration of the compound of formula I. In some embodiments, the methods of the present application provide pain relief within about 1 hour to about 3 hours, about 1 hour to about 2 hours, or about 2 hours to about 3 hours after administration of the compound of formula I.

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

[0167] The dosage of the compound of formula I or its pharma- ceutically acceptable salt, prodrug and / or solvate may vary depending on many factors, such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of treatment, and the type of co-treatment, if any, and the clearance rate of the compound in the subject being treated. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound of formula I or its pharma- ceutically acceptable salt, prodrug and / or solvate may be initially administered at an appropriate dosage, which may be adjusted as necessary depending on the clinical response. The dosage is generally selected to maintain a serum level of the compound at about 0.01 μg / cc to about 1000 μg / cc, or about 0.1 μg / cc to about 100 μg / cc. As a representative example, the oral dosage of the compound of formula I or its pharma- ceutically acceptable salt, prodrug and / or solvate is in the range of about 1 mg / day to about 1000 mg / day for an adult, suitably 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 per day. For parenteral administration or use, a representative amount is about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg, administered or used. For oral administration or use, a representative amount is about 0.001 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 10 mg / kg. For administration or use in suppository form, a typical amount is from about 0.1 mg / kg to about 10 mg / kg.

[0168] In some embodiments, the oral dosage of the compound of formula I, or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, for an adult is in the range of 50 mg per day to about 500 mg per day, suitably 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 dosage of the compound of formula I or a pharma- ceutically acceptable salt, prodrug, and / or solvate thereof is in the range of about 50 mg per day to about 500 mg per day, about 100 mg per day to about 400 mg per day, about 200 mg per day to about 400 mg per day, about 250 mg per day to about 350 mg per day, or about 250 mg per day to about 325 mg per day. In some embodiments, the oral dosage of the compound of formula I or a pharma- ceutically acceptable salt, prodrug, and / or solvate thereof is in the range of about 200 mg per day to about 400 mg per day, or about 250 mg per day to about 325 mg per day. In some embodiments, the oral dosage of the compound of formula I or a pharma- ceutically acceptable salt, prodrug, and / or solvate thereof is about 325 mg per day.

[0169] In some embodiments, the compound of formula I is formulated for oral administration or use, suitably in the form of a tablet or other solid form oral dosage form 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 active ingredient per tablet.

[0170] In some embodiments, the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates may be administered or used in a single daily dose, or the total daily dose may be divided into 2, 3, 4, 5 or 6 doses per day, hi some embodiments, the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates are administered 2, 3, 4, 5 or 6 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 a pharma- ceutically acceptable salt, prodrug 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. In some embodiments, the acute pain is a transient exacerbation or flare. In some embodiments, the compound of formula I is used or administered as described intermittently for more than 3 months, or for more than 6 months.

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

[0173] In some embodiments, the oral dosage of the compound of formula I, or a pharma- ceutically acceptable salt, prodrug, and / or solvate thereof, is from about 200 mg per day to about 400 mg per day, from about 250 mg per day to about 350 mg per day, or from about 250 mg per day to about 325 mg per day, and the compound of formula I, or a pharma- ceutically acceptable salt, prodrug, 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. In some embodiments, the oral dosage of the compound of formula I, or a pharma- ceutically acceptable salt, prodrug, and / or solvate thereof, is about 250 mg per day to about 350 mg per day, or about 250 mg per day to about 325 mg per day, or about 250 mg per day, about 275 mg per day, about 300 mg per day, about 325 mg per day, or about 350 mg per day, and the compound of formula I, or a pharma- ceutically acceptable salt, prodrug, and / or solvate thereof, 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 length of the treatment period depends on various factors, such as the severity of acute pain, the age of the subject, the concentration and / or activity of the compound of formula I or its pharma- ceutically acceptable salt, prodrug and / or solvate, and / or combinations thereof. It will also be recognized that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment regimen. Changes in dosage may occur and be evident by standard diagnostic assays known in the art. For example, the compound of formula I or its pharma-ceutically acceptable salt, prodrug and / or solvate is administered to the subject in an amount and for a period 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] The compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates may be used or administered alone or in combination with other known drugs useful for treating pain associated with urological chronic pelvic pain syndrome (UCPPS), UCPPS, acute pain and / or bladder inflammation. When used or administered in combination with other drugs or therapies, it is an embodiment that the compound of formula I or its pharma-ceutically acceptable salts, prodrugs and / or solvates are used or administered simultaneously with those drugs or therapies. As used herein, "co-administration" or "co-use" of two substances or therapies to a subject means providing each of the two substances or therapies so that they are biologically active in the individual at the same time. The exact details of administration or use will depend on the pharmacokinetics of the two substances or therapies in the presence of each other, and may even include administering or using the two substances or therapies within a few hours of each other, or administering or using one substance or therapy within 24 hours of administering or using the other, if the pharmacokinetics are appropriate. Designing an appropriate administration regimen is routine 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. It is a further embodiment of the present application that a combination of agents or therapies is administered to a subject or used asynchronously.

[0177] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt and / or solvate thereof or a composition of the present application is used or administered in combination with other known agents useful for treating or preventing pain associated with urologic chronic pelvic pain syndrome (UCPPS), UCPPS, acute pain, and / or bladder inflammation.

[0178] In one embodiment of the methods and uses of the present application, the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates are administered or used orally. In one embodiment, the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates are administered or used by parenteral administration. In one embodiment, the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates are administered or used by intramuscular, transepithelial, topical administration, including transdermal administration.

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

[0180] The acid addition salt suitable for or compatible with the treatment of a subject is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form acid addition salts include, for example, compounds that contain 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 acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids. Examples of such organic acids are, 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-acid salts are formed, and such salts exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts are soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points compared to their free base forms. The criteria for selecting the appropriate salt are known to those skilled in the art. For example, in isolating the compounds of the present application for laboratory use or for subsequent conversion to a pharma-ceutically acceptable acid addition salt, other pharma-ceutically unacceptable salts may be used, such as, but not limited to, oxalates.

[0181] The base addition salt suitable for or compatible with the treatment of a subject is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form base addition salts include, for example, compounds that contain 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 aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. The selection of an appropriate salt may be useful, for example, to prevent hydrolysis of an ester function present elsewhere in the compound. The criteria for the selection of an appropriate salt are known to those skilled in the art.

[0182] Solvates of the compounds of formula I include, for example, those prepared with pharma- ceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are called hydrates), ethanol, etc. Suitable solvents are physiologically tolerated at the dosage administered.

[0183] The compounds of formula I or pharma- ceutically acceptable salts, prodrugs and / or solvates thereof may further exist in amorphous or various polymorphic forms, and any amorphous form, any polymorph or mixture thereof, which forms are contemplated within the scope of this application.

[0184] The compounds of formula I or their pharma- ceutically acceptable salts, prodrugs and / or solvates may further be radiolabeled, and therefore all radiolabeled versions of the compounds of the present application are included within the scope of the present application, including those that have one or more radioactive atoms incorporated into their structure.

[0185] III. Compositions of the Present Application In one embodiment, the compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is

[0186] [ka]

[0187] The compositions are suitably formulated in a conventional manner using one or more carriers.

[0188] The compounds of formula I or pharma- ceutically acceptable salts and / or solvates thereof are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. Thus, the compounds of formula I or pharma- ceutically acceptable salts and / or solvates thereof are each referred to as compounds of formula I or pharma- ceutically acceptable salts, prodrugs and / or solvates thereof.

[0189] [ka]

[0190] and suitably formulated into a pharmaceutical composition comprising a pharma- ceutically acceptable carrier.

[0191] Thus, the present application further includes a method or use for treating pain associated with urologic chronic pelvic pain syndrome (UCPPS), pain associated with UCPPS, acute pain and / or pain associated with bladder inflammation as described above, by administering or using a composition comprising a compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

[0192] Although the compounds of formula I or pharma- ceutically acceptable salts, prodrugs and / or solvates thereof may be suitably used per se, they will generally be administered in the form of a composition together with an acceptable carrier.Depending on the mode of administration, the composition will contain from about 0.05% to about 99% by weight, or from about 0.10% to about 70% by weight, of one or more forms, and from about 1% to about 99.95% by weight, or from about 30% to about 99.90% by weight of the acceptable carrier, all weight percentages being based on the total composition.

[0193] As will be appreciated by those skilled in the art, the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates may also be administered to a subject or used in various forms depending on the selected route of administration. In one embodiment, the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates are administered to a subject or used by oral (including sublingual and buccal) or parenteral (including intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, topical, patch, pump and transdermal) administration, and are formulated accordingly. Again, conventional procedures and ingredients 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 includes intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form is sterile and fluid to the extent that it is easily syringable.

[0195] The compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates may be orally administered, for example, with an inert diluent or an assimilable edible carrier, or may be enclosed in a hard or soft shell gelatin capsule, or may be compressed into tablets, or may be directly incorporated into dietary foods. For oral therapeutic administration, the compound may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets, the carriers used include lactose, corn starch, sodium citrate, and salts of phosphoric acid. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), 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 can 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™, which are designed to control the release of active ingredients, are optionally used. Oral dosage forms also include modified release formulations, such as immediate release formulations and sustained release formulations. Examples of modified release formulations include, for example, sustained release (SR), extended release (ER, XR or XL), timed or sustained release, controlled release (CR), or continuous release (CR or Contin) used in the form of, for example, coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles such as, for example, molecular sieve type particles, or fine hollow permeable fiber bundles or chopped hollow permeable fibers agglomerated or held in fibrous packets.Sustained release compositions can be formulated, for example, in liposomes, or those in which the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, useful carriers or diluents include lactose and dried cornstarch.

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

[0197] It is also possible to lyophilize the compounds of formula I or their pharma- ceutically acceptable salts, prodrugs and / or solvates and use the resulting lyophilizates, for example, in the preparation of injectable products.

[0198] The compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates may also be administered parenterally. Solutions of the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates may be prepared in water, suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Those skilled in the art will know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates are usually prepared, and the pH of the solution is suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ophthalmic administration, ointments or droppable liquids may be delivered by ophthalmic delivery systems known in the art, such as applicators or eyedroppers. Such compositions may contain mucosal mimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and a conventional amount of diluent or carrier. For pulmonary administration, the diluent or carrier is selected to be appropriate to allow the formation of an aerosol.

[0199] The compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates can be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. The formulation for injection can be provided in unit dosage form, for example in ampoules or multi-dose containers, with the addition of a preservative. The composition can take the form of a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulatory agents, such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and fluid to the extent that it is easily injectable. Alternatively, the compound of formula I or its pharma-ceutically acceptable salts, prodrugs and / or solvates is suitably in sterile powder form for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

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

[0201] For intranasal administration or administration by inhalation, the compound of formula I or its pharma- ceutically acceptable salt, prodrug and / or solvate is conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray presentation from a pressurized container or nebulizer. Aerosol formulations typically contain a solution or fine suspension of active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided in single or multiple doses in a sterile form in a sealed container that can be in the form of a cartridge or refill for use with a nebulizer device. 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. When the dosage form includes an aerosol dispenser, it contains a propellant that can be a compressed gas, such as compressed air, or an organic propellant, such as fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (e.g., made from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the compound of formula I or its pharma- ceutically acceptable salt, 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-atomizer.

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

[0203] Suppository forms of the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates are useful for vaginal, urethral and rectal administration.Such suppositories are generally constructed from a mixture of materials that are solid at room temperature but melt at body temperature.Materials commonly used to create such vehicles include, but are not limited to, theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycols.For further discussion of suppository dosage forms, see, for example, Remington's Pharmaceutical Sciences, 16th ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0204] The compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates may also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compound of formula I or its pharma- ceutically acceptable salts, prodrugs and / or solvates may be linked to crosslinked or amphiphilic block copolymers of biodegradable polymer classes useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.

[0205] In one embodiment, the compound of formula I or its pharma- ceutically acceptable salt, prodrug and / or solvate may be linked to a viral, non-viral or other vector. Viral vectors may include retroviruses, lentiviruses, adenoviruses, herpes viruses, poxviruses, alphaviruses, vaccinia viruses or adeno-associated viruses. Non-viral vectors may include nanoparticles, cationic lipids, cationic polymers, metal nanoparticles, nanorods, liposomes, micelles, microbubbles, cell penetrating peptides or liposomes. Nanoparticles may include silica, lipids, carbohydrates or other pharma- ceutically acceptable polymers.

[0206] In one embodiment, depending on the mode of administration, the pharmaceutical composition comprises from about 0.05% to about 99% by weight, or from about 0.10% to about 70% by weight of the active ingredient (compound of formula I) and from about 1% to about 99.95% by weight, or from about 30% to about 99.90% by weight of one or more pharma- ceutically acceptable carriers, all weight percentages being based on the total 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 pharma- ceutically acceptable salt, prodrug, and / or solvate thereof.

[0208] In one embodiment, the compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is administered with another therapeutic agent either simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.Thus, the present application provides a single unit dosage form comprising the compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof, an additional therapeutic agent, and a pharma- ceutically acceptable carrier.

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

[0210] The compounds of formula I or pharma- ceutically acceptable salts, prodrugs and / or solvates thereof may be used alone to treat acute pain, urologic chronic pelvic pain syndrome (UCPPS) or bladder inflammation, or in combination with another known agent useful for treating acute pain, urologic chronic pelvic pain syndrome (UCPPS) or bladder inflammation.

[0211] This is an embodiment in which another known drug useful for treating acute pain, urologic chronic pelvic pain syndrome (UCPPS), or bladder inflammation is administered or used according to known treatment protocols.

[0212] In one embodiment, the compound of formula I is in the form of a pharma- ceutically acceptable solvate. In one embodiment, the compound of formula I is in 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 a prodrug of the compound of formula I.

[0213] IV. Preparation method The compound 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 commercial chemical sources.Other starting materials, such as those described below, are easily 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 schemes. Those skilled in the art will recognize that many of the reactions shown in the following schemes are sensitive to oxygen and water, and will know to carry out the reactions under anhydrous, inert atmospheres as necessary. Reaction temperatures and times are provided for illustrative purposes only, and may be altered to optimize yields, as will be understood by those skilled in the art.

[0215] Thus, the compound of formula I is prepared as shown in Scheme 1. Thus, a compound of formula A (ketoprofen) is coupled with a 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 a compound of formula C. The compound of formula C is then thionate using a suitable thionation agent such as Lawesson's reagent in a suitable solvent such as anhydrous benzene to obtain a compound of formula I.

[0216] [ka]

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

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

[0219] Example 1: Synthesis of Compounds of Formula 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 h. The reaction mixture was added with 4-hydroxybenzamide (2, 2.43 g, 17.7 mmol) and stirred at 0° C. for 1 h and at room temperature for 2 h. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate and the organic layer was washed with 5% NaHCO3, 10% citric acid in brine, then dried over anhydrous MgSO4, filtered and the solvent was evaporated. The crude product 3 was loaded onto a silica gel open column and eluted with CH2Cl2 / MeOH (9.5 / 0.5) to give 4-carbamoylphenyl 2-(4-oxophenyl)-phenylpropanoate (3) (1.84 g, 42% yield).

[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 Lawesson's reagent (2 g, 4.93 mmol) were dissolved in 100 ml of anhydrous benzene. The reaction was warmed to 60° C. and stirred for 4 h. The solvent was removed under reduced pressure. The resulting compound was purified on a silica gel open column and eluted with CHCl / MeOH (9.5 / 0.5) to give pure compound 4 (0.45 g, 23% yield).

[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 the compound of formula I in a mouse model of interstitial cystitis / visceral pain syndrome Materials and Methods Test substances and reagents Compound of formula I (ATB-352) was provided by Antibe Therapeutics, Inc. and ketoprofen was purchased from Sigma-Aldrich (Oakville, Ontario, Canada). Suspensions of compound of formula I (4.6, 15, 46 or 77 mg kg-1) and molar equivalent doses of ketoprofen (3, 10, 30 or 50 mg kg-1) 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, MO). Isoflurane was obtained from Cristalia Prod Quimicos Farm Ltda (Itapira / São Paulo, Brazil). animal Experiments were performed with male C57BL / 6 SPF mice (6–10 weeks old) obtained from the Animal Care Facility of the University of São Paulo, School of Medicine, Brazil. Mice were randomly divided into different treatment groups (n = 5–7 per group). Groups of 5 or less mice were kept in Perspex cages under standard controlled conditions (22 °C; 12 / 12 h light / dark cycle) and provided with food (Nuvilab CR-1, Quimtia S / A, Brazil) and filtered tap water ad libitum. The study was carried out in accordance with the guidelines of the Brazilian Committee for the Control of Animal Experiments (CONCEA), in line with the Animal Welfare Law. All experimental protocols were approved by the local ethical committee (CEUA-ICB; protocol n° 2055050819). Euthanasia was performed in case of severe distress related to the test drug during the experiment, in accordance with internal laboratory regulations.

[0225] Cystitis induction and experimental design Cystitis was treated with cyclophosphamide CYP (300 mg kg -1 ; Oliveira et al., 2018 ), whereas the control group received saline (10 ml kg ). -1 ) ip injection. 21 hours after CYP injection, mice were orally treated with vehicle, ketoprofen or a compound of formula I, including a fixed dose of ketoprofen (3, 10, 30 or 50 mg kg -1 ), the compound of formula I (4.6, 15, 46 or 77 mg kg -1 ) or vehicle (0.5% carboxymethylcellulose; 0.5% CMC). -1 The treatment groups were listed in Table 1.

[0226] [Table 1]

[0227] Measurement of mechanical allodynia by electronic von Frey testing Mice were placed individually into transparent Perspex testing chambers (11 cm × 9.5 cm × 18 cm) on an elevated wire grid platform (0.5 cm grid) for proper acclimation (approximately 1 h). Mechanical sensitivity assessment was performed in groups of 5–7 mice each using an electronic von Frey apparatus (Insight Inc., Ribeirao Preto, São Paulo, Brazil) as previously described (Costa et al., 2020). Force-generating pressure was applied to the lower abdomen near the bladder (pelvic region between the urethra and anus) using a pressure transducer connected to a digital force detector (Insight Ltd, Repeirao Preto / São Paulo, Brazil). Abdominal contractions from the probe (mechanical allodynia) were considered a positive response to the stimulus and were recorded in grams (g). Stimuli were applied twice with an interstimulus interval of at least 5–10 s, and the mean (g) of these positive responses was registered as abdominal withdrawal threshold (mechanical allodynia) and expressed as area under the curve (AUC) over several time points (21–24 h 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 Turkey's post-hoc test. All mice were euthanized with an overdose of isoflurane followed by cervical dislocation.

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

[0229] In vitro bladder function assay After 24 h, mice with CYP-induced cystitis were euthanized and the bladders were immediately transferred to a Petri dish. Adipose tissue was carefully removed as described in Calmasini et al., 2021. The bladders were divided into two longitudinal strips and mounted in an isolated organ bath system (Panlab Harvard, MA, USA) with Krebs-Henseleit solution at 37 °C (pH 7.4, O2 / CO2 9 / 5 v / v) under a resting tension of 5 mN. The tissue was allowed to stabilize for 1 h, and the bath solution was changed every 15 min during this period. Isometric forces were recorded using a PowerLab 8 / 30 Data Acquisition System (Software Chart, version 6.0, ADlnstrument, Milford, MA, USA).

[0230] All groups, including vehicle (normal animals), a CYP control group (untreated animals with interstitial cysts (IC)), and two CYP groups (IC) treated with test agents (ketoprofen and the compound of formula I), received either a single concentration of KCl (80 mM) or cumulatively increasing concentrations of carbachol (10 -9 ~10 -5 ) was examined in the bladder contraction response.

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

[0232] result A ketoprofen-based H2S donor (ATB-352) exhibited potent antihyperalgesic effects in a mouse model of interstitial cystitis / visceral (bladder) pain syndrome Figure 1 shows that injection of CYP significantly reduced the nociceptive threshold, expressed as AUC, in the pelvic region of mice orally treated with 0.5% CMC compared to the saline-injected control group. The lowest equimolar dose of the compound of formula I or ketoprofen had no antihyperalgesic effect on lowering the withdrawal threshold in this mouse model of IC / BPS. At higher doses, the compound of formula I dose-dependently reduced cyclophosphamide-induced abdominal mechanical allodynia. Ketoprofen reduced abdominal mechanical allodynia in CPY-induced IC / BPS at 10 and 30 mg kg -1 The effect was significantly reversed at a dose of 50 mg kg -1 The intermediate and high equimolar doses of the compound of formula I (15, 46 and 77 mg kg -1 ) 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 -1 ) enhanced analgesic effects were observed compared with ketoprofen (P<0.001; Fig. 1).

[0233] Inhibition of ketoprofen-induced gastric mucosal injury by ATB-352 As shown in Figure 2, a high dose of ketoprofen (50 mg kg -1 Systemic treatment of mice with 100 mg / kg of 10 ...

[0234] Panels A-D of Figure 2 (first, second, third, and fourth pictures 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 the compound of formula I, and IC / BPS mice treated with a high dose of ketoprofen. Panels A, B, and C (first, second, and third pictures from the left) show normal gastric mucosa, while panel D (fourth picture from the left) shows extensive hemorrhagic gastric ulceration.

[0235] The compound of formula I is superior to ketoprofen in improving CYP-induced bladder dysfunction in a mouse model of IC / BPS In control CYP bladder strips, the reduction in contractility to KCl (80 mM) was significantly different from the vehicle-treated group (Fig. 3A). However, the contractile response to KCl (Fig. 3A), which was reduced in CYP bladder strips, was significantly greater at 15 and 46 mg kg−1 compared to the control group. -1 There was a significant dose-dependent increase in schizophrenia in mice treated with the compound of formula I (77 mg kg 2 ), but not with an equimolar dose of ketoprofen (p<0.05). -1 ) and ketoprofen (50 mg kg -1 ) at high doses also did not significantly improve the decreased bladder contractility in response to KCl in IC / BPS mice.

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

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

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

[0239] Additionally, the compound of formula I was found to reduce the GI toxicity of ketoprofen while enhancing the efficacy of the analgesic / anesthetic. Collectively, these data demonstrate that the compound of formula I, an H2S donating drug, may have significant potential for improving or treating urothelial health and symptoms, including visceral pain (bladder inflammation), in patients with IC / BPS.

[0240] Although the present 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, but should be accorded the broadest interpretation consistent with the description as a whole.

[0241] All publications, patents, and patent applications are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In the event that terms in this application are found to have different definitions in the documents incorporated herein by reference, the definitions provided herein shall serve as the definitions of the terms.

[0242] Full citations for documents referred to in the specification Several publications are cited herein. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0243] Bindu S, Mazumder S, and Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective. Biochem Pharmacol 180:114147, 2020.

[0244] Calmasini FB, Alexandre EC, Oliveira MG, Silva FH, Soares AG, Costa SKP, Antunes E. Lipopolysaccharide reduces urethral smooth muscle contractility via cyclooxygenase activation. J Physiol Biochem. May 21, 2021 doi:10.1007 / s13105-021-00819-8

[0245] Clemens JQ, Mullins C, Acherman et al. 2019. Urologic chronic pelvic pain syndrome: insights from the MAPP Research Network. Nature Reviews Urology 16, 187-200.2

[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. 2020 Feb 16 doi:10.1089 / ars. 2019.7884

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Claims

1. 1. A method of treating pain associated with urological chronic pelvic pain syndrome (UCPPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I 【Chemistry 1】 or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

2. 2. The method of claim 1, wherein the pain associated with UCPPS is selected from one or more of visceral pain, neuropathic pain, neuralgia, allodynia, causal pain, hyperalgesia, hyperesthesia, dysalgia, and neuropathy secondary to surgical procedures.

3. 3. The method of claim 2, wherein the pain associated with UCPPS is allodynia associated with UCPPS.

4. 3. The method of claim 2, wherein the pain associated with UCPPS is UCPPS-associated hyperalgesia.

5. 3. The method of claim 2, wherein the pain associated with UCPPS is visceral pain associated with UCPPS.

6. The method 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. 7. The method of claim 6, wherein the pain associated with UCPPS is chronic pain associated with UCPPS.

8. 7. The method of claim 6, wherein the pain associated with UCPPS is acute pain associated with UCPPS.

9. 9. The method of claim 8, wherein the acute pain associated with UCPPS is a transient exacerbation or exacerbation of pain associated with UCPPS.

10. 10. The method of claim 8 or claim 9, wherein the acute pain lasts for less than about 14 days, less than about 12 days, less than about 10 days, less than about 7 days, less than about 5 days, or less than 3 days from onset of the acute pain.

11. 10. The method of claim 8 or claim 9, wherein the acute pain lasts for about 1 day to about 14 days, about 1 day to about 12 days, about 1 day to about 10 days, about 1 day to about 7 days, about 1 day to about 5 days, about 1 day to about 3 days, or about 3 days to 14 days, about 3 days to about 10 days, about 3 days to about 7 days, or about 5 days to about 10 days.

12. 12. The method of any one of claims 8 to 11, wherein the acute pain occurs intermittently for more than 3 months, or for more than 6 months.

13. 13. The method of any one of claims 1 to 12, wherein the pain associated with UCPPS is selected from one or more of lower abdominal (pelvic) pain, bladder pain, suprapubic pain, vaginal pain, penile pain, testicular pain, scrotal pain, perineal pain, urethral pain, dyspareunia, or increasing pain, pressure or discomfort as the bladder fills.

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

15. 15. The method of claim 14, wherein the UCPPS is interstitial cystitis (IC).

16. 15. The method of claim 14, wherein the UCPPS is Bladder Pain Syndrome (BPS).

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

18. 1. A method of treating urological chronic pelvic pain syndrome (UCPPS) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I 【Chemistry 2】 or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

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

20. 20. The method of claim 19, wherein the UCPPS is interstitial cystitis (IC).

21. 20. The method of claim 19, wherein the UCPPS is bladder pain syndrome (BPS).

22. 19. The method of claim 18, wherein the UCPPS is chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

23. 1. A method of treating one or more symptoms associated with urological chronic pelvic pain syndrome (UCPPS) in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound of formula I 【Chemistry 3】 or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

24. 24. The method of claim 23, wherein the UCPPS is interstitial cystitis / bladder pain syndrome (IC / BPS).

25. 25. The method of claim 24, wherein the UCPPS is interstitial cystitis (IC).

26. 25. The method of claim 24, wherein the UCPPS is bladder pain syndrome (BPS).

27. 24. The method of claim 23, wherein the UCPPS is chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

28. 28. The method of any one of claims 23 to 27, wherein the one or more symptoms are selected from irritative voiding symptoms, frequency, urgency, nocturia, incontinence, and suprapubic or pelvic pain associated with and relieved by urination.

29. A method of treating bladder inflammation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I. 【Chemistry 4】 or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

30. 30. The method of claim 29, wherein the bladder inflammation is associated with urologic chronic pelvic pain syndrome (UCPPS).

31. 31. The method of claim 30, wherein the UCPPS is interstitial cystitis / bladder pain syndrome (IC / BPS).

32. 32. The method of claim 31 , wherein the UCPPS is interstitial cystitis (IC).

33. 32. The method of claim 31, wherein the UCPPS is bladder pain syndrome (BPS).

34. 31. The method of claim 30, wherein the UCPPS is chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

35. A method for increasing bladder contraction and relaxation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I. 【Chemistry 5】 or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

36. 36. The method of claim 35, wherein the subject has urologic chronic pelvic pain syndrome (UCPPS).

37. 36. The method of claim 35, wherein the subject has interstitial cystitis / bladder pain syndrome (IC / BPS).

38. 36. The method of claim 35, wherein the subject has chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS).

39. A method of treating acute pain in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I. 【Chemistry 6】 or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof.

40. 40. The method of claim 39, wherein the acute pain is a transient exacerbation or flare-up.

41. 41. The method of claim 39 or claim 40, wherein the acute pain is pain expected to resolve in 14 days or less.

42. 42. The method of any one of claims 39 to 41, wherein the acute pain occurs intermittently for more than 3 months, or for more than 6 months.

43. 40. The method of claim 39, wherein the acute pain is post-operative pain resulting from abdominal and / or pelvic surgery.

44. 44. The method of any one of claims 1 to 43, wherein the compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is administered at an oral dosage of from 50 mg per day to about 500 mg per day for an adult human.

45. 45. The method of claim 44, wherein the compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is administered at 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.

46. 45. The method of claim 44, wherein the compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is administered at an oral dosage ranging from about 200 mg per day to about 400 mg per day or from about 250 mg per day to about 325 mg per day.

47. 47. The method of any one of claims 1 to 46, wherein the compound of formula I, or a pharma- ceutically acceptable salt, prodrug 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.

48. 45. The method of any one of claims 1 to 44, wherein the compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is administered at an oral dosage ranging from about 400 mg to about 500 mg per day, and the compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is administered for one day.

49. 45. The method of any one of claims 1 to 44, wherein the compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is administered at an oral dosage ranging from about 200 mg per day to about 400 mg per day, from about 250 mg per day to about 350 mg per day, or from about 250 mg per day to about 325 mg per day, and wherein the compound of formula I or a pharma- ceutically acceptable salt, prodrug 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.

50. 50. The method of any one of claims 1 to 49, wherein said compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof is formulated into a pharmaceutical composition comprising said compound of formula I or a pharma- ceutically acceptable salt, prodrug and / or solvate thereof and one or more pharmaceutical carriers.

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