RU2791025C2 - Method for treatment of pain or interstitial cystitis, using indole compound - Google Patents

Abstract

FIELD: medicine; therapy; urology.

SUBSTANCE: invention relates to the field of medicine, namely to therapy and urology; it is intended for the treatment or prevention of interstitial cystitis in a human subject who needs it. A method for the treatment or prevention of interstitial cystitis includes administration to a human subject of therapeutically effective amount of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-yl)-1H-indole-6-yl]-N-methyl-(2S)-2-(morpholine-4-yl)propanamide or its pharmaceutically acceptable salt.

EFFECT: use of the invention provides effective treatment or prevention of interstitial cystitis in a human subject who needs it.

6 cl, 12 dwg, 3 tbl, 6 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the priority of Japanese Patent Application No. 2018-100671, filed May 25, 2018, Japanese Patent Application No. 2018-246392, filed December 28, 2018, and U.S. Provisional Application No. 62/835675, filed on April 18, 2019. The entire contents of the previous applications are given in the present description by reference.

FIELD OF TECHNOLOGY

The present invention relates to the medical use of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl- (2S)-2-(morpholin-4-yl)propanamide or a pharmaceutically acceptable salt thereof as a therapeutic or prophylactic agent for pain or interstitial cystitis.

BACKGROUND OF THE INVENTION

From a physiological point of view, pain signals play a key role as a warning system for the body, however, "pathological" pain adversely affects the body and reduces the quality of life. Opioids (narcotic analgesics such as morphine), non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and other drugs such as duloxetine and pregabalin are used to treat pain. However, managing the course of pain with modern painkillers is not enough. In addition, opioids, while considered the most effective of pain relievers, are associated with a growing epidemic of abuse, dependence and overdose in many countries.

Interstitial cystitis is a disease that is associated with non-specific chronic inflammation of the bladder and manifests itself with symptoms such as frequent urination, increased urge to urinate, urinary urgency, and/or pain in the bladder, and leads to a marked deterioration in quality of life. Interstitial cystitis associated with pain, or a condition where interstitial cystitis is suspected, sometimes includes irritable bladder syndrome, painful bladder syndrome, or chronic pelvic pain syndrome. Three conditions (1) presence of lower urinary tract symptoms such as frequent urination, hypersensitive bladder and/or bladder pain, (2) possibility of endoscopic confirmation of lesions in the bladder resulting from Hanner's ulcers and/or bleeding after dilatation bladder, and (3) the fact that other disorders such as infection, malignancy, or urinary calculus can be ruled out is one example of a diagnostic standard for interstitial cystitis. Interstitial cystitis is broadly classified as either Hanner type presenting with Hanner ulcers or non-Hanner type presenting without Hanner ulcers.

SUMMARY OF THE INVENTION

The present invention is based at least in part on the discovery of the inventors that N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol- 6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide (designated "compound A") reduces pain sensitivity. Based on this discovery, Compound A, or a pharmaceutically acceptable salt thereof, can be used as an effective drug for the treatment or prevention of pain.

The present invention is also based, at least in part, on the discovery of the inventors that compound A reduces the severity of interstitial cystitis. Based on this discovery, Compound A or a pharmaceutically acceptable salt thereof can be used as an effective drug for the treatment or prevention of interstitial cystitis.

In one aspect, the present invention relates to a method of treating or preventing pain in a human subject in need thereof by administering to the human subject a therapeutically effective amount of a compound represented by the following chemical structural formula:

,

,

or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition for the treatment or prevention of pain, containing Compound A or a pharmaceutically acceptable salt thereof.

The present invention also relates to the use of Compound A or a pharmaceutically acceptable salt thereof for the preparation of a therapeutic or prophylactic agent against pain.

The present invention also relates to Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of pain.

The present invention also relates to a therapeutic or prophylactic agent for pain, containing Compound A or a pharmaceutically acceptable salt thereof.

In some embodiments, the pain is neuropathic pain.

In some embodiments, the pain is nociceptive pain.

In some embodiments, the pain is a mixed pain.

In some embodiments, the pain is inflammatory pain, musculoskeletal pain, or cancer pain.

In some embodiments, the pain is osteoarthritis pain.

In some embodiments, the pain is low back pain.

In some embodiments, the pain is interstitial cystitis pain.

In some embodiments, the pain is diabetic peripheral neuropathy pain.

In some embodiments, the pain is rheumatoid arthritis pain.

In some embodiments, the pain is not rheumatoid arthritis pain.

In some embodiments, the pain is not interstitial cystitis pain.

In some embodiments, the pain is not rheumatoid arthritis or interstitial cystitis pain.

In some embodiments, the pain is irritable bladder syndrome, painful bladder syndrome, or chronic pelvic pain syndrome.

In some embodiments, the pain is associated with inflammation, pancreatitis, kidney stones, headache, dysmenorrhea, musculoskeletal pain, dislocation, visceral pain, ovarian cyst, prostatitis, cystitis, inflammatory bowel disease, postoperative pain, migraine, trigeminal neuralgia , burns, wounds, trauma, postherpetic neuralgia, musculoskeletal disease, ankylosing spondylitis, periarticular pathology, malignancy, bone metastases, HIV, myocardial infarction, fracture, gout, joints, sciatica, sickle cell crisis, endometriosis, fibromyalgia, incisional pain, erythromelalgia, malignant melanoma, Sjögren's syndrome, asthma, chronic abacterial prostatitis, uterine fibroids, vulvodynia, phantom limb pain, traumatic root avulsion, diabetic neuropathic pain, painful traumatic mononeuropathy, painful polyneuropathy, central pain syndrome, pain from repetitive movements, myofascial pain syndrome, perioperative pain, chronic pain, angina pectoris, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, osteoporosis, irritable bowel syndrome, pulpitis, skin trauma, tendinitis, colic, appendicitis, peptic ulcer, bladder distension, hematoma, peritendinitis, frozen shoulder, spinal compression fracture, spinal stricture, spinal stenosis, herniated disc, cervicobrachial syndrome, burst fracture of the spine, pain after tooth extraction, acute arterial occlusion, or erythromelalgia .

In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once a day.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally once a day.

In some embodiments, the pain is moderate pain.

In some embodiments, the pain is moderate to severe pain.

In some embodiments, the pain is severe pain.

In some embodiments, the pharmaceutically acceptable salt is a monohydrochloride.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally and the pain is moderate pain.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally and the pain is moderate to severe pain.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally and the pain is severe pain.

In some embodiments, the compound monohydrochloride is administered orally and the pain is moderate pain.

In some embodiments, the compound monohydrochloride is administered orally and the pain is moderate to severe pain.

In some embodiments, the compound monohydrochloride is administered orally and the pain is severe pain.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered orally at a dose equivalent to at least 50 mg of the compound.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered orally at a dose equivalent to about 50-400 mg of the compound.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered orally at a dose equivalent to about 50-200 mg of the compound.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered orally at a dose equivalent to about 75-200 mg of the compound.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered orally at a dose equivalent to about 75-150 mg of the compound.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered orally at a dose equivalent to about 75 mg, about 100 mg, about 125 mg, or about 150 mg of the compound.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered once daily (e.g., at a dose equivalent to about 50-200 mg of the compound) and this results in an average residual concentration (C _residual ) of the compound from about 100 ng/mL to about 550 ng/ml for at least about 12 weeks.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered once per day (e.g., at a dose equivalent to about 50 mg of the compound) and this results in an average residual concentration (C _residual ) of the compound from about 100 ng/mL to about 150 ng/ml for at least about 12 weeks.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered once per day (e.g., at a dose equivalent to about 100 mg of the compound) and this results in an average residual concentration (C _residual ) of the compound from about 150 ng/mL to about 250 ng/ml for at least about 12 weeks.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered once per day (e.g., at a dose equivalent to about 150 mg of the compound) and this results in an average residual concentration (C _residual ) of the compound from about 250 ng/mL to about 350 ng/ml for at least about 12 weeks.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered once daily (e.g., at a dose equivalent to about 200 mg of the compound) and this results in an average residual concentration (C _residual ) of the compound from about 300 ng/mL to about 550 ng/ml for at least about 12 weeks.

In another aspect, the present invention relates to a method of treating or preventing interstitial cystitis in a human subject in need thereof by administering to the human subject a therapeutically effective amount of a compound represented by the following chemical structural formula:

,

,

or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating or preventing an overactive bladder or cystitis associated with a urinary tract infection in a human subject in need thereof by administering to the human subject a therapeutically effective amount of a compound represented by the following chemical structural formula:

,

,

or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition for the treatment or prevention of interstitial cystitis (or overactive bladder or urinary tract infection cystitis) comprising Compound A or a pharmaceutically acceptable salt thereof.

The present invention also relates to the use of Compound A or a pharmaceutically acceptable salt thereof for the preparation of a therapeutic or prophylactic agent for interstitial cystitis (or overactive bladder or urinary tract infection cystitis).

The present invention also provides Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of interstitial cystitis (or overactive bladder or urinary tract infection cystitis).

The present invention also relates to a therapeutic or prophylactic agent for interstitial cystitis (or overactive bladder or urinary tract infection cystitis) comprising Compound A or a pharmaceutically acceptable salt thereof.

In some embodiments, interstitial cystitis is characterized by at least one symptom selected from the group consisting of frequent urination, nocturia, urinary urgency, increased urge to urinate, hypersensitivity bladder, bladder discomfort, bladder pain, and bladder inflammation. bubble.

In some embodiments, the interstitial cystitis is Hanner type interstitial cystitis or non-Hanner type interstitial cystitis.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once a day.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally once a day.

In some embodiments, the pharmaceutically acceptable salt is a monohydrochloride.

In some embodiments, the compound monohydrochloride is administered orally.

In some embodiments, the compound monohydrochloride is administered orally once a day.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered orally at a dose equivalent to at least 50 mg of the compound.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is administered orally at a dose equivalent to about 50-400 mg of the compound. For example, the compound or a pharmaceutically acceptable salt thereof, in some embodiments, is administered orally at a dose equivalent to about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg. mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of the compound.

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 shows pain thresholds in a CIA model in rats given oral vehicle or compound A monohydrochloride equivalent to 10 mg/kg or 30 mg/kg compound A and normal rats given oral vehicle.

Fig. 2A-2C are graphs depicting the level of change from baseline pain on the Numeric Rating Scale (NRS), after treatment with placebo or Compound A monohydrochloride, at the end of treatment (EOT; FIG. 2A), 2 weeks later (FIG. 2B) and 12 weeks later (Fig. 2C).

Fig. 3A-3C are graphs depicting the percentage of patients achieving at least 30% pain relief after treatment with placebo or Compound A monohydrochloride, at EOT (Figure 3A), at 2 weeks (Figure 3B), and at 12 weeks (Figure 3B). .3C).

Fig. 4A-4C are graphs depicting the percentage of patients achieving at least 50% pain relief after treatment with placebo or Compound A monohydrochloride, at EOT (Figure 4A), at 2 weeks (Figure 4B), and at 12 weeks (Figure 4B). .4C).

Fig. 5A-5C are graphs depicting the percentage of patients achieving at least 70% pain relief after treatment with placebo or Compound A monohydrochloride, at EOT (Figure 5A), at 2 weeks (Figure 5B), and at 12 weeks (Figure 5B). .5C).

Fig. 6A-6C are graphs depicting the level of change from baseline in the Health Assessment Invalidation Index (HAQ-DI), after treatment with placebo or Compound A monohydrochloride, at EOT (FIG. 6A), after 2 weeks (FIG. 6B ) and 12 weeks later (Fig. 6C).

Fig. 7A-7C are graphs depicting the rate of change from baseline in number of tender joints (TJC) in subjects, after treatment with placebo or Compound A monohydrochloride, at EOT (Figure 7A), at 2 weeks (Figure 7B), and at 12 weeks (Fig. 7C).

Fig. 8A-8B are graphs depicting the change from baseline NRS pain following placebo or Compound A monohydrochloride treatment in patients with lower baseline pain levels (FIG. 8A) or higher baseline pain levels (FIG. 8B).

Fig. 9 is a graph depicting the residual concentrations ( _Cresidual ) of Compound A in blood samples collected from patients administered Compound A 50 mg, 100 mg, 150 mg, or 200 mg once daily measured before dosing at weeks 2, 4 , 8 and 12.

Fig. 10A-10B are graphs depicting estimated human exposure ratios for in vitro TrkA inhibition (FIG. 10A) and estimated human exposure ratios for inhibition of NGF-induced hyperalgesia in rats (FIG. 10B).

In FIG. 11 shows lower abdomen lick time periods for a mouse model of CYP-induced cystitis treated with vehicle, Compound A monohydrochloride, or anti-NGF antibody.

In FIG. 12A shows the effect of compound A on single micturition volume in rats with CYP-induced cystitis.

In FIG. 12B shows the effect of Compound A on micturition interval in rats with CYP-induced cystitis.

DETAILED DESCRIPTION

Compound A and pharmaceutically acceptable salts

"Compound A" is N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl- (2S)-2-(morpholin-4-yl)propanamide, and is represented by the following chemical structural formula:

.

.

Any salt known in the art is acceptable as a "pharmaceutically acceptable salt" provided it is not accompanied by excessive toxicity. Specifically, salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases can be exemplified. Various pharmaceutically acceptable salt forms are well known in the art and are described in the references below, for example:

(a) Berge et al, J. Pharm. Sci., 66, p 1-19 (1977),

(b) Stahl et al, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002), and

(c) Paulekuhn et al, J. Med. Chem., 50, p 6665-6672 (2007).

It is possible to obtain the corresponding pharmaceutically acceptable salts of Compound A by reacting Compound A with an inorganic acid, an organic acid, an inorganic base, or an organic base according to a method known per se. It is also acceptable for a pharmaceutically acceptable salt of Compound A to form, from an acid or base that is half the number of molecules of Compound A, the same number of molecules as Compound A, or at least two times the number of Compound A molecules.

Salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid are given as examples of salts with inorganic acids.

Salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, 1.2 -ethanedisulfonic acid, dodecyl sulfate, ethanesulfonic acid, fumaric acid, glucoheptonate, gluconic acid, glucuronic acid, glycolylarsanilate, hexylresorcinate, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid , methanesulfonic acid, methylsulfuric acid, methyl nitrate, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theoclate, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid or glutamic acid are given as examples of salts with organic acids.

Salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth or ammonium are given as examples of salts with inorganic bases.

Salts with arecoline, betaine, choline, clemisole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine or lysine are given as examples of salts with organic bases.

Preferred embodiments of the "pharmaceutically acceptable salt" are as follows.

Salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or hydrobromic acid are given as examples of salts with inorganic acids.

Salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 2-hydroxy-1-ethanesulfonic acid are given as examples of salts with organic acids.

Salts with sodium, potassium, calcium, magnesium or zinc are given as examples of salts with inorganic bases.

Salts with tris(hydroxymethyl)methylamine, N-methylglucamine or lysine are given as examples of salts with organic bases.

The preferred pharmaceutically acceptable salt of Compound A among them is Compound A monohydrochloride represented by the following chemical structural formula:

.

.

Compound A and its pharmaceutically acceptable salts can be prepared using a known method, the method described for example in WO 2011/065402 or WO 2016/002918.

Compound A, or pharmaceutically acceptable salts thereof, may exist in solvate form.

A "solvate" has a solvent molecule coordinated to Compound A or a pharmaceutically acceptable salt thereof, and this includes a hydrate. A pharmaceutically acceptable solvate is preferred as the solvate, and examples include a hydrate, an ethanol solvate, or a dimethyl sulfoxide solvate of Compound A or a pharmaceutically acceptable salt thereof.

Specifically, the hemihydrate, monohydrate, dihydrate or mono(ethanol)solvate of compound A, or the sodium salt monohydrate or 2/3(ethanol)dihydrochloride solvate of compound A can be exemplified. These solvates can be obtained in accordance with known methods.

Compound A or a pharmaceutically acceptable salt thereof, each of which is substantially purified, is preferred as Compound A or a pharmaceutically acceptable salt thereof. More preferably, compound A or a pharmaceutically acceptable salt thereof is purified to at least 80% purity.

The therapeutic agent or prophylactic agent for pain or interstitial cystitis of the present invention is prepared, for example, according to a method known in the field of medical preparations, by mixing compound A or a pharmaceutically acceptable salt thereof with a suitable amount of at least one kind of pharmaceutically acceptable carrier or t .p., if necessary. The amount of Compound A or a pharmaceutically acceptable salt thereof in said preparation differs according to dosage form, dose, etc., but is, for example, 0.1-100 wt%. from the entire drug.

The therapeutic agent or prophylactic agent of the present invention may be administered orally or parenterally. Oral administration or parenteral administration such as intravenous, intramuscular, subcutaneous, transdermal, topical, or rectal administration may be exemplified by dosage forms. Tablets, capsules, granules, powders, lozenges, syrups, emulsions, suspensions, and the like. may be cited as examples of dosage forms suitable for oral administration, and topical preparations, suppositories, injections, eye drops, eye ointments, patches, gels, implants, nasal preparations or pulmonary preparations may be cited as examples of dosage forms suitable for parenteral administration . They can be obtained in accordance with methods known in the field of medical drugs.

Examples of a "pharmaceutically acceptable carrier" include various organic or inorganic carrier materials commonly used as formulation materials, and examples include fillers, disintegrants, binders, flow agents, lubricants, and the like. for solid preparations; solvents, solubilizing agents, suspending agents, isotonic agents, buffering agents, emollients, and the like. for liquid preparations; and bases, emulsifiers, wetting agents, stabilizers, activators, dispersants, plasticizers, pH adjusters, absorption promoters, gelling agents, antiseptics, fillers, solvents, solubilizers, suspending agents, and the like. for semi-solid preparations. It is also acceptable to use additives such as preservatives, antioxidants, coloring agents, sweeteners, and the like, as needed.

Examples of "filler" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, calcium carmellose, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, gum arabic, and the like.

Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, and the like.

Examples of the "binder" include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like.

Examples of the "fluidizer" include light anhydrous silicic acid, magnesium stearate, and the like.

Examples of the "lubricant" include magnesium stearate, calcium stearate, talc, and the like.

Examples of the "solvent" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

Examples of the "solubilizer" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like.

Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerol monostearate, and the like.

Examples of the "isotonic agent" include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like.

Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, and the like.

Examples of the "emollient" include benzyl alcohol and the like.

Examples of "base" include water, vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.). etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, paraffin oil, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointments, aqueous lanolin, hydrophilic ointments, starches, pullulan, gum arabic, gum tragacanth, gelatins, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.). ), propylene glycol, macrogol (macrogol 200-600, etc.), and a combination of two or more of these.

Examples of the "preservative" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like.

Examples of the "antioxidant" include sodium sulfite, ascorbic acid, and the like.

Examples of the "coloring agent" include food coloring (such as Food Red No. 2 or No. 3, or Food Yellow No. 4 or No. 5), β-carotene, and the like.

Examples of the "sweetener" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.

Examples of the composition of the present invention include the following compositions. The present invention, however, is not limited to these formulation examples.

Formulation Example 1: Capsule Preparation

1) Compound A monohydrochloride 30 mg 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg 4) Magnesium Stearate 1 mg

1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

Formulation Example 2: Tablet Preparation

1) Compound A monohydrochloride 2) Lactose 3) Cornstarch 4) Carmellose calcium 5) Magnesium Stearate

The total amounts of 1), 2) and 3) and 30 g of 4) are mixed with water, dried in vacuo and sieved. The sifted powder is mixed with 14 g of 4) and 1 g of 5) and the mixture is stamped with a tableting machine. Thus, 1000 tablets are obtained, each containing 10 mg of Compound A monohydrochloride per tablet.

Treatment or prevention of pain

Compound A, or a pharmaceutically acceptable salt thereof, can be used as an active ingredient in a therapeutic or prophylactic agent for pain.

As used herein, "therapy" includes alleviating pain, preventing or delaying an increase in severity, maintaining remission, preventing flare-ups, and furthermore, preventing relapse.

As used herein, "prevention" refers to the suppression of the onset of pain.

Compound A, or a pharmaceutically acceptable salt thereof, may be used in combination (hereinafter also referred to as "simultaneously") with one or more other drugs (hereinafter also referred to as "comorbid drug") using common practice in the art. medicine.

Examples of concomitant drug include analgesics and auxiliary analgesics. Analgesics include opioid receptor agonists, partial opioid receptor agonists, NSAIDs, COX-2 inhibitors, ion channel modulators, centrally acting agents, neuropathic pain agents, cancer pain agents, and other analgesics. Adjuvant analgesics include antidepressants, antiepileptics, antiarrhythmics, N-methyl-D-aspartate antagonists, centrally acting muscle relaxants, corticosteroids, anti-anxiety agents, bone-improving agents, antihistamines, neuroleptics, and other auxiliary analgesics.

Examples of opioid receptor agonists include morphine, oxycodone, pethidine, methadone, levorphanol, oxymorphone, fentanyl, pentazocine, tramadol, hydromorphone, fentanyl, remifentanil, tapentadol, hydrocodone, sufentanil, benzhydrocodone, oxycodegol, codeine, and dihydrocodeine.

Examples of opioid receptor partial agonists include dextromoramide, buprenorphine, butorphanol, nalbuphine, meptazinol, eptazocine and dinalbuphine.

Examples of NSAIDs include acetylsalicylic acid, paracetamol, indomethacin, mefenamic acid, ibuprofen, naproxen, diclofenac, fenoprofen, fenbufen, ketoprofen, sulindac, flubiprofen, diflunisal, piroxicam, acemethacin, meclofenamate, propacetamol, ketorolac, aceclozol-ketocamprofen, , meloxicam and pelubiprofen.

Examples of COX-2 inhibitors include rofecoxib, celecoxib, parecoxib, and lumiracoxib.

Examples of ion channel modulators include ziconotide, bupivacaine, and priralfinamide.

Examples of centrally acting agents include nefopam and flupirtine.

Examples of neuropathic pain agents include carbamazepine, lidocaine, clonidine, gabapentin, duloxetine, pregabalin, capsaicin, and myrogabaline.

Examples of anticancer pain agents include calcitonin, clodronate, pamidronate, strontium and lexidronam.

Examples of other analgesics include eptinezumab, lasmiditan, ubrogepant, atogepant, oliceridin, cebranopadol, fazinumab, lucerastat, neridronic acid, relugolix, rimegepant, tanezumab, zoledronic acid, and zucapsaicin.

Examples of antidepressants include amitriptyline, amoxapine, nortriptyline, duloxetine, paroxetine, fluvoxamine, imipramine, desipramine, trazodone, bupropion, doxepin, and venlafaxine.

Examples of antiepileptic agents include pregabalin, gabapentin, valproic acid, phenytoin, clonezepam and carbamazepine.

Examples of antiarrhythmic agents include mexiletine and lidocaine.

Examples of N-methyl-D-aspartate antagonists include ketamine.

Examples of centrally acting muscle relaxants include baclofen, orphenadrine, carisoprodol, methocarbamol, chlorzoxazone, and cyclobenzaprine.

Examples of corticosteroids include betamethasone and dexamethasone.

Examples of anti-anxiety agents include diazepam and lorazepam.

Examples of bone-improving agents include zoledronic acid, denosumab, calcitonin, and strontium 89.

Examples of antihistamines include hydroxyzine and diphenhydramine.

Examples of neuroleptics include methotrimeprazine and fluphenazine.

Examples of other auxiliary analgesics include octreotide, scopolamine, glycopyrrolate, clonidine and capsaicin.

The administration schedule of the drug containing Compound A or a pharmaceutically acceptable salt thereof and the concomitant drug is not limited, it is acceptable for their administration to the subject of administration, as a combination drug, and it is also acceptable for the administration of two formulations, either simultaneously or at a fixed interval. In addition, it is also acceptable to use the therapeutic agent or prophylactic agent of the present invention and the concomitant drug as a medicine, characterized in that the medicine is a kit containing said agent and a concomitant drug. The dose of the concomitant drug is acceptable as long as it is based on the dose used in clinical practice, and the dose can be appropriately selected according to the subject of administration, disease, symptoms, dosage form, route of administration, administration time, combination, etc. d. The dosage form of the concomitant drug is not particularly limited, and is acceptable as long as the drug containing Compound A or a pharmaceutically acceptable salt thereof is combined with the concomitant drug.

Examples of one embodiment of the present invention include a method for treating or preventing pain, comprising administering to a human a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

As used herein, an "effective amount" means, for example, an amount of a drug or drug that elicits a biological or medical response in a tissue, system, or human. In addition, "therapeutically effective amount" means an arbitrary amount that provides either treatment, cure, prevention, or relief, where the pain or side effect is alleviated, compared with the corresponding subject who was not administered such an amount.

The dose of the therapeutic agent or prophylactic agent of the present invention differs according to the administration subject, disease, symptoms, dosage form, administration method, and so on. For example, a daily oral dose for an adult patient (body weight: about 60 kg) is typically in the range of 0.1 mg to 1 g, and preferably 10 mg to 800 mg, when calculated using Compound A in as the active ingredient, and this amount can be administered in one to several servings per day before meals, after meals, or during meals. It is also acceptable to administer the agent once or multiple times a day, for example as needed if pain develops. The duration of administration is not particularly limited.

Examples of dosage ranges for Compound A or a pharmaceutically acceptable salt thereof include oral administration of a dose equivalent to at least 50 mg of the compound, e.g., a dose equivalent to about 50-400 mg of the compound, a dose equivalent to about 50-200 mg of the compound, a dose equivalent to about -200 mg of the compound, or a dose equivalent to approximately 75-150 mg of the compound.

Examples of compound A monohydrochloride dosage ranges include oral administration of a dose equivalent to at least 50 mg of the compound, e.g., a dose equivalent to about 50-400 mg of the compound, a dose equivalent to about 50-200 mg of the compound, a dose equivalent to about 75-200 mg of the compound , or a dose equivalent to about 75-150 mg of the compound. Unless otherwise indicated, compound refers to the free form of the compound.

Exemplary dosages of Compound A, or a pharmaceutically acceptable salt thereof, include oral administration at a dose equivalent to about 75 mg, about 100 mg, about 125 mg, or about 150 mg of the compound.

Compound A, or a pharmaceutically acceptable salt thereof, may be administered once daily to a subject to provide a mean residual concentration (C _residual ) of the compound from about 100 ng/mL to about 600 ng/mL for at least about 12 weeks. For example, administering a dose equivalent to about 50-200 mg of a compound to a human subject once daily can result in a mean residual concentration (C _residual ) of the compound from about 100 ng/mL to about 550 ng/mL for at least about 12 weeks. The terms "residual concentration" and " _Cresidual " refer to the lowest plasma concentration of Compound A in a human subject prior to administration of the next dose of Compound A or a pharmaceutically acceptable salt thereof. The average C _residual can be from about 120 ng/ml to about 520 ng/ml.

Administration of a dose equivalent to about 50 mg of the compound once daily to a human subject can result in a mean residual concentration (C _residual ) of the compound from about 100 ng/ml to about 150 ng/ml for at least about 12 weeks. For example, the mean C _residual may be from about 120 ng/mL to about 140 ng/mL.

Administration of a dose equivalent to about 100 mg of a compound once daily to a human subject can result in a mean residual concentration (C _residual ) of the compound from about 150 ng/ml to about 250 ng/ml for at least about 12 weeks. For example, the mean C _residual may be from about 180 ng/mL to about 230 ng/mL.

Administration of a dose equivalent to about 150 mg of the compound once daily to a human subject can result in a mean residual concentration (C _residual ) of the compound from about 250 ng/ml to about 350 ng/ml for at least about 12 weeks. For example, the mean C _residual may be from about 270 ng/mL to about 340 ng/mL.

Administration of a dose equivalent to about 200 mg of the compound once daily to a human subject can result in a mean residual concentration (C _residual ) of the compound from about 300 ng/ml to about 550 ng/ml for at least about 12 weeks. For example, the mean C _residual may be from about 350 ng/mL to about 550 ng/mL. For example, the mean C _residual may be from about 350 ng/mL to about 450 ng/mL.

The Numeric Rating Scale (NRS) can be used to quantify pain and measure progress in pain management. Using a scale of 0-10, NRS scores less than or equal to 5 are generally considered to correspond to mild pain, scores of 6-7 are generally considered to correspond to moderate pain, and scores greater than or equal to 8 are generally considered to correspond to severe pain. pain. As described in the examples, compound A was found to reduce pain in subjects having pain greater than or equal to 8 on the NRS scale, indicating that it can be used to treat subjects having severe pain.

The Visual Analogue Scale (VAS) can also be used to quantify pain and measure progress in pain management. The VAS consists of a straight line with endpoints defining limits such as "no pain" and "worst possible pain". The subject is asked to note his/her level of pain on the line between the two endpoints. The distance between "no pain" and the mark defines the subject's pain.

Examples of one embodiment of the present invention include a pharmaceutical composition for the treatment or prevention of pain comprising Compound A or a pharmaceutically acceptable salt thereof.

Examples of one embodiment of the present invention include the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament or prophylactic against pain.

Examples of one embodiment of the present invention include Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of pain.

Examples of one embodiment of the present invention include a therapeutic agent or a prophylactic agent against pain, containing Compound A or a pharmaceutically acceptable salt thereof.

Treating or preventing interstitial cystitis

Compound A, or a pharmaceutically acceptable salt thereof, can be used as an active ingredient in a therapeutic agent or prophylactic agent for interstitial cystitis. In addition, Compound A or a pharmaceutically acceptable salt thereof can be used to treat or prevent symptoms of interstitial cystitis such as frequent urination, nocturia, urinary urgency, increased urge to urinate, hypersensitivity bladder, bladder discomfort, bladder pain, and cystitis.

Interstitial cystitis is broadly classified as either Hanner type presenting with Hanner ulcers or non-Hanner type presenting without Hanner ulcers. Compound A, or a pharmaceutically acceptable salt thereof, can be used as an active ingredient in a therapeutic or prophylactic agent for any type of interstitial cystitis.

Compound A, or a pharmaceutically acceptable salt thereof, can also be used as an active ingredient in a therapeutic or prophylactic agent for overactive bladder or cystitis in urinary tract infection. Overactive bladder and cystitis in urinary tract infection are disorders characterized by frequent urination (ie, pollakiuria), a symptom shared with interstitial cystitis. In some cases, an overactive bladder is diagnosed as a disease other than interstitial cystitis due to the absence of microscopic findings in the bladder. In some cases, however, the overactive bladder population may include subjects with interstitial cystitis without such a microscopic diagnosis.

As used herein, "treatment" includes alleviating interstitial cystitis (or overactive bladder or urinary tract infection cystitis), preventing or delaying progression in severity, maintaining remission, preventing flare-ups, and furthermore, preventing relapse.

As used herein, "prevention" means suppression of the onset of interstitial cystitis (or overactive bladder or cystitis in urinary tract infection).

The therapeutic agent or prophylactic agent of the present invention can be used in combination (hereinafter also referred to as "simultaneously" in the present description) with one or more other drugs (hereinafter also referred to as "concomitant drug") using common practice in the field of medicine.

The administration schedule of the drug containing Compound A or a pharmaceutically acceptable salt thereof and the concomitant drug is not limited, it is acceptable for their administration to the subject of administration, as a combination drug, and it is also acceptable for the administration of two formulations, either simultaneously or at a fixed interval. In addition, it is also acceptable to use the therapeutic agent or prophylactic agent of the present invention and the concomitant drug as a medicine, characterized in that the medicine is a kit containing said agent and a concomitant drug. The dose of the concomitant drug is acceptable as long as it is based on the dose used in clinical practice, and the dose can be appropriately selected according to the subject of administration, disease, symptoms, dosage form, route of administration, administration time, combination, etc. d. The dosage form of the concomitant drug is not particularly limited, and is acceptable as long as the drug containing Compound A or a pharmaceutically acceptable salt thereof is combined with the concomitant drug. Examples of a concomitant drug include hydroxyzine, amitriptyline, suplatast tosylate, cimetidine, corticosteroids, cyclosporine, antibiotics, and oxybutynin.

Examples of one embodiment of the present invention include a method of treating or preventing interstitial cystitis (or overactive bladder or urinary tract infection cystitis) comprising administering to a human a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

As used herein, an "effective amount" means, for example, an amount of a drug or drug that elicits a biological or medical response in a tissue, system, or human. In addition, "therapeutically effective amount" means an arbitrary amount that provides either treatment, cure, prevention, or relief, where the interstitial cystitis or side effect is alleviated, compared with the corresponding subject who was not administered such an amount.

The dose of the therapeutic agent or prophylactic agent of the present invention differs according to the administration subject, disease, symptoms, dosage form, administration method, and so on. For example, a daily oral dose for an adult patient (body weight: about 60 kg) is typically in the range of 0.1 mg to 1 g, and preferably 10 mg to 800 mg, when calculated using Compound A in as the active ingredient, and this amount can be administered in one to several servings per day before meals, after meals, or during meals. It is also acceptable to administer the agent once or multiple times a day, for example as needed if pain develops. The duration of administration is not particularly limited.

Examples of dosage ranges for Compound A or a pharmaceutically acceptable salt thereof include oral administration of a dose equivalent to at least 50 mg of the compound, e.g., a dose equivalent to about 50-400 mg of the compound, a dose equivalent to about 50-200 mg of the compound, a dose equivalent to about -200 mg of the compound, or a dose equivalent to approximately 75-150 mg of the compound.

Exemplary dosages of Compound A or a pharmaceutically acceptable salt thereof include oral administration of a dose equivalent to about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg , about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of the compound.

Examples of one embodiment of the present invention include a pharmaceutical composition for the treatment or prevention of interstitial cystitis (or overactive bladder or urinary tract infection cystitis) comprising Compound A or a pharmaceutically acceptable salt thereof.

Examples of one embodiment of the present invention include the use of Compound A or a pharmaceutically acceptable salt thereof for the preparation of a medicament or prophylactic for interstitial cystitis (or overactive bladder or urinary tract infection cystitis).

Examples of one embodiment of the present invention include Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of interstitial cystitis (or overactive bladder or urinary tract infection cystitis).

Examples of one embodiment of the present invention include a therapeutic or prophylactic agent for interstitial cystitis (or overactive bladder or urinary tract infection cystitis) comprising Compound A or a pharmaceutically acceptable salt thereof.

The present invention is explained in detail below using exemplary embodiments, however, the present invention is not limited to these exemplary embodiments.

The following examples are presented to better illustrate the claimed invention and should not be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, this is for the purpose of illustration only and is not intended to limit the invention. A person skilled in the art can develop equivalent methods or reagents without demonstrating inventive ability and without deviating from the scope of the invention.

EXAMPLES

Example 1 Analgesic Effect Resulting from Oral Administration of Compound A Monohydrochloride in a Collagen-Induced Arthritis (CIA) Rat Model

The analgesic effect of Compound A on pain hypersensitivity during the onset of arthritis was evaluated in the CIA rat model. Hypersensitivity to pain was assessed using the paw withdrawal threshold (PWT) in association with mechanical stimulus using the Randall-Selitto method.

Female LEW/CrlCrlj rats (Charles River Laboratories Japan, Inc.) were used for the experiment. Compound A monohydrochloride was dissolved in 0.5% methylcellulose (MC) to prepare 2 mg/mL and 6 mg/mL solutions of Compound A. Type II collagen obtained from bovine cartilage (Collagen Research Center) was dissolved in acetic acid to prepare a solution 2 mg/ml collagen type II. Equal volumes of 2 mg/ml collagen type II solution and incomplete Freund's adjuvant were mixed to form a 1 mg/ml collagen type II emulsion.

On day 1, type II collagen emulsion was intradermally injected into the animals in the vehicle group, in the 10 mg/kg compound A group, and in the 30 mg/kg compound A group. On day 8, the type II collagen emulsion was intradermally injected into the animals in the vehicle group, in the 10 mg/kg administration group of Compound A and in the 30 mg/kg administration group of Compound A. On days 22-28, a 0.5% MC solution was administered orally once a day in the vehicle group at a volume of 5 ml/kg. During the same period, a 2 mg/mL or 6 mg/mL solution of Compound A was administered orally once a day in the 10 mg/kg Compound A and 30 mg/kg Compound A administration groups, respectively, in a volume of 5 ml. /kg. On day 28, the analgesic effect was measured using a Randall-Selitto analgesimeter (TK-201, UNICOM). Means and standard deviations of PWT values were calculated for each group. The results are shown in FIG. 1. Compound A attenuated hyperalgesia in CIA rats.

Example 2 Effect of Compound A on Nerve Growth Factor (NGF) Induced Hyperalgesia in Rats

Compound A has an inhibitory effect on TrkA, the receptor for NGF. The aim of this study was to investigate the effects of Compound A on NGF-induced hyperalgesia in rats.

To induce pain-related behavior (withdrawal behavior), NGF was injected into the plantar region of the left hind paw of rats, and response delays to thermal stimuli/mechanical stimulus thresholds were measured. The effects of Compound A on these withdrawal behaviors were investigated.

Two days prior to NGF injection, thermal stimulus response delays or mechanical stimulus thresholds were measured for acclimatization to the experimental environment. On the day prior to NGF injection, body weights and response delays to thermal stimuli or thresholds of mechanical stimuli were obtained.

50 μl of NGF solution was injected intraplantarly into the left hind paw of rats. 0.5 μg/site of NGF was selected for thermal stimulus evaluation and 1 μg/site was selected for mechanical stimulus evaluation. Compound A monohydrochloride (1, 3 or 10 mg/kg) was administered orally at the same time as the NGF injection.

Thermal stimulus response delays were measured 3 and 6 hours after NGF solution injection, and mechanical stimulus thresholds were measured 1, 3 and 6 hours after NGF solution injection. Evaluation was performed as a blind test of each group.

The delay in response to thermal stimuli was measured using a plantar test device. Infrared heat stimuli were applied to the plantar region of the hind paw, and the time to withdrawal of the paw from the heat source was automatically recorded as a delay in response to thermal stimuli. The measurement was carried out 5 times for both hind legs of each animal, the average of the last 3 values for each hind leg was taken into account as delays in response to thermal stimuli for each animal. Measurement for acclimatization was carried out only 3 times.

The threshold of mechanical stimuli was measured using a pressure analgesimeter. A mechanical stimulus (pressure) increasing at a constant rate was applied to the hind leg, and the pressure under load until the animals jerked their hind legs or made sounds was recorded as the mechanical threshold (mm Hg).

Compound A prevented NGF-induced reduction in thermal stimulus response delays compared to vehicle in a dose-dependent manner. See Table 1. Significant effects of Compound A were observed starting at a dose of 3 mg/kg 6 hours after NGF injection.

Table 1: Effect of compound A on NGF-induced thermal hyperalgesia in female rats

Paw withdrawal delay(s) Group Right hind leg (non-injected side) Left hind leg (injection side) before 3 hour 6 hour before 3 hour 6 hour False processing 11.4±2.0 10.7±2.0 10.4±1.8 10.8±1.8 10.5±2.0 9.7±1.8 Carrier (0 mg/kg) 10.5±0.9 10.0±1.1 11.4±1.8 10.9±1.9 5.7±1.5** 5.4±1.5** Compound A HCl, 1 mg/kg 11.6±1.1 10.9±1.4 10.8±2.4 11.4±1.2 10.0±2.6# 8.7±2.0 Compound A HCl, 3 mg/kg 11.6±1.5 12.3±2.2 11.9±1.9 11.2±1.9 10.3±1.6# 9.9±1.5# Compound A HCl, 10 mg/kg 11.9±1.2 11.9±2.7 11.5±1.2 12.0±1.1 11.6±2.4# 11.3±1.4#

Each value represents the mean ± standard deviation, n=6.

NGF at a concentration of 0.5 μg/site was injected intraplantarly in the left hind paw.

**, p<0.01 compared to sham treatment (Wilcoxon test)

#, p<0.05 vs vehicle (0 mg/kg) (Steele test)

Compound A prevented NGF-induced reduction in mechanical stimulus thresholds compared to vehicle in a dose dependent manner. See Table 2. Significant effects of Compound A were observed starting at a dose of 3 mg/kg 6 hours after NGF injection.

Table 2: Effect of Compound A on NGF-Induced Mechanical Hyperalgesia in Female Rats

Paw withdrawal threshold (mmHg) Group Right hind leg (non-injected side) Left hind leg (injection side) before 1 hour 3 hour 6 hour before 1 hour 3 hour 6 hour False processing 137±20 128±19 128±14 138±29 135±20 136±20 131±10 134±23 Carrier (0 mg/kg) 131±18 133±15 126±10 139±23 131±15 94±18** 72±22** 75±15** Compound A HCl, 1 mg/kg 132±15 134±16 135±21 133±9 126±21 107±17 104±20 90±11 Compound A HCl, 3 mg/kg 148±25 133±19 141±10 144±23 152±26 118±17 121±21# 106±11# Compound A HCl, 10 mg/kg 139±17 144±14 139±17 139±13 136±17 130±20# 134±22# 130±18#

Each value represents the mean ± standard deviation, n=6.

NGF at a concentration of 1 μg/site was injected intraplantarly in the left hind paw.

**, p<0.01 compared to sham treatment (Wilcoxon test)

#, p<0.05 vs vehicle (0 mg/kg) (Steele test)

Table 2: Effects of Compound A on NGF-induced mechanical hyperalgesia in female rats

Example 3 Pain Evaluation in a Human Rheumatoid Arthritis Clinical Study

Compound A was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel group study in subjects with acute rheumatoid arthritis. Subjects were randomized to receive oral placebo or an amount of Compound A monohydrochloride sufficient to provide 50 mg, 100 mg, 150 mg, or 200 mg free form once daily for 12 weeks.

Pain was rated by subjects using a numerical rating scale (NRS). The pain NRS represents the severity of their arthritis-induced pain over the past 3 days using an 11-point scale from 0 (no pain) to 10 (maximum pain). An assessment was made of how much NRS had decreased from baseline NRS after drug administration.

Received data EOT (at the end of treatment), after 2 weeks and after 12 weeks. EOT is a measurement point commonly used in clinical research. In a 12 week study, it refers to all analyzes at the 12 week time point. However, because some subjects may be forced to terminate the study in the middle, data at the time of termination of the study is treated as the EOT for these subjects (eg, data for week 8 is used as the EOT for subjects who discontinued the study at week 8). Data are also shown for 2 weeks (for subjects who have completed 2 weeks) and 12 weeks (for subjects who have completed 12 weeks).

Levels of change from baseline NRS pain following treatment with placebo or one dose of Compound A are shown in FIG. 2A (in EOT), FIG. 2B (after 2 weeks) and FIG. 2C (after 12 weeks).

The success rate (percentage of subjects showing pain relief) was also used to measure clinical improvement. The percentages of patients achieving at least 30% pain relief after treatment with placebo or one of the doses of Compound A are shown in FIG. 3A (in EOT), FIG. 3B (after 2 weeks) and FIG. 3C (after 12 weeks). The percentages of patients who achieved at least 50% pain relief after treatment with either placebo or one dose of Compound A are shown in FIG. 4A (at EOT), FIG. 4B (after 2 weeks) and FIG. 4C (after 12 weeks). The percentages of patients achieving at least 70% pain relief after treatment with placebo or one of the doses of Compound A are shown in FIG. 5A (at EOT), FIG. 5B (after 2 weeks) and FIG. 5C (after 12 weeks).

The HAQ-DI (Health Assessment Disability Index) questionnaire was used to assess the improvement in quality of life in treated patients. HAQ-DI assesses the degree of the subject's functional status by assessing the degree of difficulty the subject experienced during the last week in eight categories of self-care: dressing and grooming, standing upright, eating, walking, hygiene procedures, reaching, grasping, and normal daily activities. Higher HAQ-DI scores indicate deterioration in the subject's functional status. Levels of change from baseline in HAQ-DI after placebo or single dose Compound A treatment are shown in FIG. 6A (in EOT), FIG. 6B (after 2 weeks) and FIG. 6C (after 12 weeks).

The number of painful joints (TJC; the number of joints of 68 joints painful when pressed) was evaluated to determine the number of joints considered sensitive or painful. The rate of change from baseline TJC after treatment with placebo or one of the doses of Compound A is shown in FIG. 7A (in EOT), FIG. 7B (after 2 weeks) and FIG. 7C (after 12 weeks).

Change in NRS pain was assessed in two subgroups of patients, patients with higher baseline pain levels (median baseline pain NRS ≥8.0) and patients with lower baseline pain levels (median baseline pain NRS <8.0). A stronger NRS pain reduction was observed in subjects who started treatment with higher baseline pain levels. See fig. 8A and 8B. Although the amplitude of NRS pain reduction was different between subgroups with lower and higher NRS pain, both subgroups ultimately achieved an NRS pain score of approximately 4.

A clinical study showed that rapid (within 2 weeks) and sustained (12 weeks) analgesic effects were observed after treatment with Compound A. Pain relief rates within two weeks of treatment with Compound A indicate that the compound has an analgesic effect, since any improvement that occurs only as a result of the anti-inflammatory effect, requires a longer period of time before the manifestation of a beneficial effect.

The incidence of serious adverse events (SAE) and serious adverse events occurring during treatment (TEAE) in the clinical study was low (3.4% and 2.9%, respectively) in subjects treated with one of the doses of Compound A in the clinical study. research. Compound A was safe and tolerated at doses up to 200 mg for 12 weeks of treatment.

Example 4 Pharmacokinetic Evaluations

In the human clinical study described in Example 3, blood samples were collected from subjects prior to dosing at weeks 2, 4, 8 and 12 to quantify Compound A plasma levels. Residual concentrations (C _residual ) of Compound A are shown in FIG. 9. Mean residual concentrations increased as the dose was increased from 50 mg to 200 mg, and residual concentrations were maintained throughout the study. See table 3.

Table 3: Plasma Residual Concentrations of Compound A (ng/mL) at Treatment and Evaluation

Connection A Connection A Connection A Connection A 50 mg QD 100 mg QD 150 mg QD 200 mg QD Statistics (N=46) (N=47) (N=44) (N=46) 2 weeks N 46 46 41 46 Average (SD) 134(87.0) 204(168) 335(242) 521(381) Ratio (1) 1.00 1.52 2.51 3.89 Median 118 191 300 436 Min - Max. 0.00-387 0.00-825 1.47-1110 5.01-2210 CV% 65.1 82.6 72.1 73.1 4 weeks N 46 44 41 40 Average (SD) 135(88.4) 216(144) 309(217) 450(300) Ratio (1) 1.00 1.60 2.28 3.33 Median 119 215 277 402 Min - Max. 0.00-356 0.00-650 0.00-748 0.00-1570 CV% 65.3 66.5 70.2 66.6 8 weeks N 45 42 41 36 Average (SD) 129(102) 228(167) 272(185) 402(336) Ratio (1) 1.00 1.77 2.10 3.11 Median 108 194 277 392 Min - Max. 0.00-436 0.00-785 0.00-743 0.00-1660 CV% 79.1 73.1 68.2 83.5 12 weeks N 40 42 40 35 Average (SD) 119(96.9) 178(156) 312(252) 354(281) Ratio (1) 1.00 1.50 2.63 2.98 Median 100 175 246 323 Min - Max. 0.00-531 0.00-728 0.00-992 0.00-1170 CV% 81.7 88.0 80.7 79.4

Individual concentrations of BLQ (<2.00 ng/mL) were taken as plasma concentration 0.

[1] Average ratio, relative to 50 mg QD of Compound A at the same examination.

Estimates of human exposure to _residual C were determined for preclinical pharmacology results. Estimated coefficients were calculated by dividing the estimated human exposure coefficients (average C _residual at week 12) by the preclinical IC ₅₀ or IC ₉₀ values. In FIG. 10A shows estimated human exposure ratios for in vitro TrkA inhibition. In FIG. 10B shows estimated human exposure ratios for inhibition of NGF-induced hyperalgesia in rats.

Example 5 Effect of Oral Administration of Compound A in a Mouse Model of Cyclophosphamide (CYP) Induced Cystitis

The inhibitory effect of Compound A on lower abdominal lick time was evaluated in a mouse model of CYP-induced cystitis. The evaluation was carried out in accordance with M. Fujita et al., Eur J Pain. 20 (2016) 79-91. Male C57BL/6J mice (Charles River Laboratories Japan, Inc.) were used as experimental animals.

Once a day for four days (days 1-4), 20 mg/ml CYP (Sigma) dissolved in saline was administered intraperitoneally in the vehicle group, in the compound A group and in the anti-NGF antibody group in a volume of 10 ml / kg, and saline solution was injected intraperitoneally in the sham treatment group, in a volume of 10 ml/kg. Compound A monohydrochloride was dissolved in 0.5% methylcellulose (MC) to prepare 3 mg/ml, 6 mg/ml and 10 mg/ml solutions of compound A.

Once a day for three days (days 7-9), 0.5% (w/v) MC was administered orally in the sham treatment group, in the vehicle group and in the anti-NGF antibody group, and solutions of 3 mg/ml , 6 mg/ml or 10 mg/ml Compound A solutions were administered orally in the Compound A administration group in a volume of 10 ml/kg. In addition, once (day 7) isotype control BE 0083 (Bio X Cell) was administered intraperitoneally in the sham treatment group, in the vehicle group and in the compound A administration group, and anti-nerve growth factor-β (NGF) monoclonal antibody (Sigma) was administered intraperitoneally in the anti-NGF antibody group, in a volume of 150 μg per animal.

The behavior of mice was recorded for 90 minutes using a video camera prior to the initial administration of CYP (before) and on day 7, day 8 and day 10, and the time (in seconds) of licking the lower abdomen was measured. On day 7 and day 8, after recording the behavior of mice, 0.5% (w/v) MC was administered orally in the sham treatment group, in the vehicle group and in the anti-NGF antibody group, and a solution of Compound A was administered orally in the administration group compound A. In addition, on day 7, after recording the behavior of mice, isotype control BE0083 was injected intraperitoneally in the sham treatment group, in the vehicle group and in the compound A administration group, and anti-NGF antibody was administered intraperitoneally in the anti-NGF antibody administration group. The average values of the time periods of licking the lower abdomen in individual animals were calculated for each group, and the results are shown in Fig. 11. Compound A reduced lower abdominal lick time in this animal model of cystitis.

Example 6 Effect of Oral Administration of Compound A on Urinary Frequency in a Rat Model of CYP-Induced Cystitis

The effect of Compound A on urinary frequency, calculated from single voiding volume and voiding interval, was evaluated using a CYP induced cystitis model in rats. The evaluation was carried out in accordance with GM. Herrera et al., PLoS ONE 5 (8): e12298. Female CD (SD) rats (Charles River Laboratories Japan, Inc.) were used as experimental animals. Compound A monohydrochloride was dissolved in 0.5% MC to prepare 2 mg/ml and 6 mg/ml solutions of compound A.

30 mg/ml CYP (Sigma) dissolved in saline was administered ip in the vehicle group and compound A group, and saline was administered ip in the sham treatment group at 5 ml/kg (day 1).

0.5% (w/v) MC was administered orally once a day for 2 days (days 1-2) in the sham treatment group and in the vehicle group at 5 ml/kg, and solutions of 2 mg/ml or 6 mg/ml Compound A was administered orally twice a day (Days 1-2) in the Compound A administration group at 5 ml/kg.

Intravesical pressure and micturition volume were measured by cystometry on day 3, and single urination volumes and intervals between urination were calculated. Mean values were calculated for each group for individual single micturition volumes and micturition intervals, and the results are shown in FIG. 12A and FIG. 12B, respectively. Compound A suppressed frequent urination in this animal model of cystitis.

Other embodiments

While the invention has been described in conjunction with its detailed description, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are included within the scope of the following claims.

Claims (8)

1. A method of treating or preventing interstitial cystitis in a human subject in need, comprising administering to the human subject a therapeutically effective amount of a compound represented by the following chemical structural formula:

, or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein the interstitial cystitis is characterized by at least one symptom selected from the group consisting of frequent urination, nocturia, urinary urgency, increased urge to urinate, hypersensitivity bladder, bladder discomfort, bladder pain. bladder and inflammation of the bladder. 3. The method of claim 1 wherein the interstitial cystitis is Hanner type interstitial cystitis or non-Hanner type interstitial cystitis. 4. The method according to any one of paragraphs. 1-3, where the pharmaceutically acceptable salt is the monohydrochloride. 5. The method according to any one of paragraphs. 1-4, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally. 6. The method according to any one of paragraphs. 1-5 wherein the compound or a pharmaceutically acceptable salt thereof is administered once a day.

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