Treatment methods for pain or interstitial cystitis using indole compounds

Abstract

To provide an agent for the treatment or prevention of pain or interstitial cystitis. [Solution] The present invention provides an agent for the treatment or prevention of pain or interstitial cystitis, comprising 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 a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to Japanese Patent Application No. 2018-100671, filed on 25 May 2018, Japanese Patent Application No. 2018-246392, filed on 28 December 2018, and U.S. Provisional Application No. 62 / 835,675, filed on 18 April 2019. The contents of the prior applications are incorporated herein by reference in their entirety.

[0002] Technical field The present invention relates to the pharmaceutical use 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 a pharmaceutically acceptable salt thereof as a therapeutic or prophylactic agent for pain or interstitial cystitis. [Background technology]

[0003] background While pain signals play a vital physiological role as a warning system, "pathological" pain has adverse effects on the body and reduces quality of life. Pain is treated with opioids (narcotic analgesics such as morphine), nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and other medications such as duloxetine and pregabalin. However, current pain management with analgesics is insufficient. Furthermore, while opioids are considered the most effective pain relievers, they are linked to widespread abuse, addiction, and overdose in many countries.

[0004] Interstitial cystitis is a disease characterized by nonspecific chronic inflammation of the bladder, presenting with symptoms such as frequent urination, increased urge to urinate, urinary urgency, and / or bladder pain, leading to a significant decline in quality of life. Painful interstitial cystitis or suspected interstitial cystitis may also be included in painful bladder syndrome, bladder pain syndrome, and chronic pelvic pain syndrome. One diagnostic criterion for interstitial cystitis is the presence of lower urinary tract symptoms such as frequent urination, hypersensitivity of the bladder, and / or bladder pain; (2) confirmation of a bladder lesion via endoscopy, such as a Hunner ulcer and / or bleeding after bladder dilation; and (3) exclusion of other diseases such as infection, malignant tumor, or urinary tract stones. Interstitial cystitis is broadly classified into Hunner type, which has a Hunner ulcer, and non-Hunner type, which does not. [Overview of the project]

[0005] summary This invention is based on the inventors' discovery that, at least in part, 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 (referred to hereby as "compound A") reduces hyperalgesia. Based on this discovery, compound A or a pharmaceutically acceptable salt thereof can be used as an effective agent for treating or preventing pain.

[0006] Furthermore, the present invention is based on the inventors' discovery that compound A reduces the severity of interstitial cystitis, at least in part. Based on this discovery, compound A or a pharmaceutically acceptable salt thereof can be used as an effective agent for treating or preventing interstitial cystitis.

[0007] In one embodiment, the present invention relates to a compound represented by the following chemical structural formula:

[0008] [ka]

[0009] A method for treating or preventing pain in a human subject, which comprises administering to the human subject in need of treatment or prevention of pain a therapeutically effective amount of a compound A or a pharmaceutically acceptable salt thereof.

[0010] The present invention also provides a pharmaceutical composition for treating or preventing pain, which comprises compound A or a pharmaceutically acceptable salt thereof.

[0011] The present invention also provides the use of compound A or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for pain.

[0012] The present invention also provides compound A or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of pain.

[0013] The present invention also provides a therapeutic or prophylactic agent for pain, which comprises compound A or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is nociceptive pain. In some embodiments, the pain is mixed pain. In some embodiments, the pain is inflammatory pain, musculoskeletal pain or cancer pain. In some embodiments, the pain is pain associated with osteoarthritis. In some embodiments, the pain is low back pain. In some embodiments, the pain is pain associated with interstitial cystitis. In some embodiments, the pain is pain associated with diabetic peripheral neuropathy. In some embodiments, the pain is pain associated with rheumatoid arthritis. In some embodiments, the pain is not pain associated with rheumatoid arthritis. In some embodiments, the pain is not pain associated with interstitial cystitis. In some embodiments, the pain is not pain associated with rheumatoid arthritis or interstitial cystitis. In some embodiments, the pain is painful bladder syndrome, bladder pain syndrome or chronic pelvic pain syndrome.

[0015] In some embodiments, the pain is inflammation, pancreatitis, kidney stones, headache, dysmenorrhea, musculoskeletal pain, contusion, visceral pain, ovarian cyst, prostatitis, cystitis, inflammatory bowel disease, postoperative pain, migraine, trigeminal neuralgia, burn, wound, trauma, postherpetic neuralgia, musculoskeletal disease, ankylosing spondylitis, periprosthetic joint disease, cancer, bone metastasis, HIV, myocardial infarction, fracture, gout, joint, sciatica, sickle cell crisis, endometriosis, fibromyalgia, incision pain, erythromyalgia, malignant melanoma, Sjögren's syndrome, asthma, chronic nonbacterial prostatitis, uterine fibroids, vulvar pain, phantom limb pain, tooth root exfoliation, painful diabetic neuropathy, painful traumatic mononeuropathy, painful polyneuropathy, central pain, pain of repetitive movement, myofascial pain, perioperative pain, chronic pain, angina, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, osteoporosis, irritable bowel syndrome, pulpitis, skin contusion, tendonitis, sacral pain, appendicitis, peptic ulcer disease, bladder fullness, bruise, peritendinitis, frozen shoulder, spinal compression fracture, spinal stenosis , spinal canal stenosis, intervertebral disc herniation, cervical radiculopathy, spinal burst fracture, pain after tooth extraction, acute arterial occlusion or erythromyalgia.

[0016] 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.

[0017] 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.

[0018] In some embodiments, the pharmaceutically acceptable salt is the monohydrochloride.

[0019] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally, and the pain is moderate. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally, and the pain is moderate to severe. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally, and the pain is severe.

[0020] In some embodiments, a monohydrochloride salt of the compound is administered orally, resulting in moderate pain. In some embodiments, a monohydrochloride salt of the compound is administered orally, and the pain is moderate to severe. In some embodiments, a monohydrochloride salt of the compound is administered orally, and the pain is severe.

[0021] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally in a dose equivalent to 50 mg or more of the compound. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally in a dose equivalent to about 50 to 400 mg of the compound. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally in a dose equivalent to about 50 to 200 mg of the compound. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally in 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 in 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 in doses equivalent to about 75 mg, about 100 mg, about 125 mg, or about 150 mg of the compound.

[0022] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once daily (for example, in doses equivalent to about 50-200 mg of the compound) for at least about 12 weeks to maintain an average trough concentration (C) of the compound ranging from about 100 ng / mL to about 550 ng / mL.trough ) brings about. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once daily (for example, at a dose equivalent to about 50 mg of the compound) for at least about 12 weeks to maintain an average trough concentration (C) of the compound between about 100 ng / mL and about 150 ng / mL. trough ) brings about. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once daily (for example, at a dose equivalent to about 100 mg of the compound) to maintain an average trough concentration (C) of the compound at about 150 ng / mL to about 250 ng / mL for at least about 12 weeks. trough ) brings about. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once daily (for example, at a dose equivalent to about 150 mg of the compound) for at least about 12 weeks to maintain an average trough concentration (C) of the compound at about 250 ng / mL to 350 ng / mL. trough ) brings about. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered once daily (for example, at a dose equivalent to about 200 mg of the compound) for at least about 12 weeks to maintain an average trough concentration (C) of the compound ranging from about 300 ng / mL to about 550 ng / mL. trough ) brings about.

[0023] In another embodiment, the present invention relates to a compound represented by the following chemical structural formula:

[0024] [ka]

[0025] Alternatively, the present invention is characterized by a method of treating or preventing interstitial cystitis in human subjects by administering a therapeutically effective amount of the pharmaceutically acceptable salt thereof to human subjects in need of treatment or prevention of interstitial cystitis. Furthermore, the present invention relates to a compound represented by the following chemical structural formula:

[0026] [ka]

[0027] Alternatively, the present invention is characterized by a method of treating or preventing overactive bladder or cystitis in urinary tract infections in human subjects by administering a therapeutically effective dose of the pharmaceutically acceptable salt thereof to human subjects who require treatment or prevention of overactive bladder or cystitis in urinary tract infections.

[0028] The present invention also includes pharmaceutical compositions for the treatment or prevention of interstitial cystitis (or overactive bladder or cystitis in urinary tract infections) comprising compound A or a pharmaceutically acceptable salt thereof.

[0029] Furthermore, the present invention includes the use of compound A or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for interstitial cystitis (or overactive bladder or cystitis in urinary tract infections).

[0030] The present invention also includes compound A or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of interstitial cystitis (or overactive bladder or cystitis in urinary tract infections).

[0031] Furthermore, the present invention includes a therapeutic or prophylactic agent for interstitial cystitis (or overactive bladder or cystitis in urinary tract infections) comprising compound A or a pharmaceutically acceptable salt thereof.

[0032] 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, irritable bladder, bladder discomfort, bladder pain, and inflammation of the bladder.

[0033] In some embodiments, interstitial cystitis is either Hunner-type interstitial cystitis or non-Hunner-type interstitial cystitis.

[0034] 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 daily. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally once daily.

[0035] In some embodiments, the pharmaceutically acceptable salt is a monohydrochloride salt.

[0036] In some embodiments, the monohydrochloride salt of the compound is administered orally. In some embodiments, the monohydrochloride salt of the compound is administered orally once daily.

[0037] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally in a dose equivalent to 50 mg or more of the compound.

[0038] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally in doses corresponding to about 50 to 400 mg of the compound. For example, in some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally in doses corresponding 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. [Brief explanation of the drawing]

[0039] [Figure 1] Figure 1 shows the pain thresholds of CIA model rats orally administered with a monohydrochloride salt equivalent to 10 mg / kg or 30 mg / kg of the vehicle or compound A, and of normal rats orally administered with the vehicle. [Figure 2] Figures 2A-2C are graphs showing the change from baseline in numerical rating scale (NRS) pain at end of treatment (EOT; Figure 2A), 2 weeks (Figure 2B), and 12 weeks (Figure 2C) after treatment with placebo or compound A monohydrochloride. [Figure 3]Figures 3A-3C are graphs showing the percentage of patients who achieved at least a 30% improvement in pain at EOT (Figure 3A), 2 weeks (Figure 3B), and 12 weeks (Figure 3C) after treatment with placebo or compound A monohydrochloride. [Figure 4] Figures 4A-4C are graphs showing the percentage of patients who achieved at least 50% pain relief at EOT (Figure 4A), 2 weeks (Figure 4B), and 12 weeks (Figure 4C) after treatment with placebo or monohydrochloride of compound A. [Figure 5] Figures 5A-5C are graphs showing the percentage of patients who achieved at least 70% pain relief at EOT (Figure 5A), 2 weeks (Figure 5B), and 12 weeks (Figure 5C) after treatment with placebo or compound A monohydrochloride. [Figure 6] Figures 6A-6C are graphs showing the change from baseline in the Health Assessment Questionnaire's Disability Index (HAQ-DI) score at EOT (Figure 6A), 2 weeks (Figure 6B), and 12 weeks (Figure 6C) after treatment with placebo or compound A monohydrochloride. [Figure 7] Figures 7A-7C are graphs showing the change from baseline in the number of tender joints (TJC) of subjects at EOT (Figure 7A), 2 weeks (Figure 7B), and 12 weeks (Figure 7C) after treatment with placebo or compound A monohydrochloride. [Figure 8] Figures 8A and 8B are graphs showing the change from baseline in pain NRS scores in patients with low baseline pain levels (Figure 8A) or high baseline pain levels (Figure 8B) after treatment with placebo or compound A monohydrochloride. [Figure 9] Figure 9 is a graph showing the measured trough concentrations of compound A in blood samples taken before administration at weeks 2, 4, 8, and 12 from patients who received compound A at doses of 50 mg, 100 mg, 150 mg, or 200 mg once daily. [Figure 10] Figures 10A and 10B are graphs showing the multiples of human exposure to inhibit TrkA in vitro (Figure 10A) and the multiples of human exposure to inhibit NGF-induced hyperalgesia in rats (Figure 10B). [Figure 11] Figure 11 shows the lower abdominal licking time in CYP-induced cystitis model mice administered with vehicle, compound A monohydrochloride, or anti-NGF antibody. [Figure 12] Figure 12A shows the effect of compound A on single-void volume in rats with CYP-induced cystitis. Figure 12B shows the effect of compound A on voiding interval in rats with CYP-induced cystitis. [Modes for carrying out the invention]

[0040] Detailed explanation Compound A and pharmaceutically acceptable salts Compound A is 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, and its chemical structure is as follows:

[0041] [ka]

[0042] It is represented as follows.

[0043] A "pharmaceutically acceptable salt" is any salt known in the art that does not exhibit excessive toxicity. Specifically, this includes salts with inorganic acids, organic acids, inorganic bases, and organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (1977), (b) Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use ” (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007).

[0044] Compound A can be reacted with an inorganic acid, an organic acid, an inorganic base, or an organic base according to a method known to the extent that pharmaceutically acceptable salts thereof can be obtained. The pharmaceutically acceptable salts of compound A may be formed with half the number of acids or bases as compound A, the same number, or at least twice the number.

[0045] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, or sulfuric acid.

[0046] Examples of salts with organic acids include 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, edetate, ethane-1,2-disulfonic acid, dodecyl sulfate, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycolylarsanilic acid, hexylresorcinic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, and malic acid. Examples include salts with maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitrate, 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, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid.

[0047] Examples of salts with inorganic bases include those with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium.

[0048] Examples of salts with organic bases include salts with arecoline, betaine, choline, cremisole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine.

[0049] The preferred embodiments of the "pharmaceutically acceptable salt" are as follows: Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, or hydrobromic acid.

[0050] Examples of salts with organic acids include 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.

[0051] Examples of salts with inorganic bases include salts with sodium, potassium, calcium, magnesium, or zinc.

[0052] Examples of salts with organic bases include salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine.

[0053] Among these, the pharmaceutically acceptable salt of compound A is the monohydrochloride salt of compound A, with the following chemical structure:

[0054] [ka]

[0055] It is represented as follows. Compound A and its pharmaceutically acceptable salts can be prepared by known methods, for example, those described in International Publication No. 2011 / 065402 or International Publication No. 2016 / 002918.

[0056] Compound A or its pharmaceutically acceptable salts may exist as solvates. A "solvate" is a compound in which a solvent molecule is coordinated to compound A or a pharmaceutically acceptable salt thereof, and this includes hydrates. Pharmaceutically acceptable solvates are preferred, and examples include hydrates of compound A or a pharmaceutically acceptable salt thereof, ethanol solvate, and dimethyl sulfoxide solvate. Specifically, examples include the hemihydrate, monohydrate, dihydrate, or monoethanol solvate of compound A, or the 2 / 3 ethanol solvate of the monohydrate or dihydrochloride of the sodium salt of compound A. These solvates can be obtained according to known methods. Compound A or a pharmaceutically acceptable salt thereof is preferably substantially purified. More preferably, Compound A or a pharmaceutically acceptable salt thereof is purified to a purity of 80% or higher.

[0057] The present invention provides a therapeutic or prophylactic agent for pain or interstitial cystitis, which is manufactured by appropriately mixing compound A or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier, etc., in accordance with methods known in the art of pharmaceutical formulations. The content of compound A or a pharmaceutically acceptable salt thereof in the formulation varies depending on the dosage form, dose, etc., but is, for example, 0.1 to 100% by weight of the total formulation.

[0058] The therapeutic or prophylactic agent of the present invention can be administered orally or parenterally. Administration methods include oral administration and parenteral administration such as intravenous, intramuscular, subcutaneous, transdermal, topical, and rectal administration. Suitable dosage forms for oral administration include tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions. Suitable dosage forms for parenteral administration include topical preparations, suppositories, injections, eye drops, eye ointments, patches, gels, inserts, nasal preparations, and pulmonary preparations. These can be prepared according to methods known in the field of pharmaceutical formulation.

[0059] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, disintegrants, binders, fluidizers, lubricants, etc. in solid formulations; solvents, solubilizers, suspending agents, isotonic agents, buffers, analgesics, etc. in liquid formulations; and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solvents, solubilizers, suspending agents, etc. in semi-solid formulations. Furthermore, additives such as preservatives, antioxidants, colorants, and sweeteners may be used as needed.

[0060] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and gum arabic.

[0061] Examples of "disintegrants" include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crystalline cellulose.

[0062] Examples of "binding agents" include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic.

[0063] Examples of "fluidizing agents" include light anhydrous silicic acid and magnesium stearate.

[0064] Examples of "lubricants" include magnesium stearate, calcium stearate, and talc.

[0065] Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.

[0066] Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.

[0067] Examples of "suspending agents" include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, and glyceryl monostearate.

[0068] Examples of "isotonic agents" include glucose, D-sorbitol, sodium chloride, and D-mannitol.

[0069] Examples of "buffering agents" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.

[0070] Examples of "pain-relieving agents" include benzyl alcohol.

[0071] Examples of "bases" include water, animal and 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.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, refined lanolin, absorbent ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, 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 combinations of two or more of these.

[0072] Examples of "preservatives" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.

[0073] Examples of "antioxidants" include sodium sulfite and ascorbic acid.

[0074] Examples of "coloring agents" include food colorings (such as food red No. 2 or 3, food yellow No. 4 or 5), and beta-carotene.

[0075] Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, and aspartame.

[0076] Examples of formulations of the present invention include the following formulations. However, the present invention is not related to these formulations. This is not limited to specific drug examples.

[0077] Formulation Example 1: Capsule Manufacturing 1) Monohydrochloride of compound A, 30 mg 2) Microcrystalline cellulose 10 mg 3) Lactose 19mg 4) Magnesium stearate 1 mg Mix 1), 2), 3), and 4) and fill into gelatin capsules.

[0078] Formulation example 2: Tablet manufacturing 1) Monohydrochloride salt of compound A, 10g 2) Lactose 50g 3) Corn starch 15g 4) Carmellose calcium 44g 5) Magnesium stearate 1g The entire amounts of 1), 2), and 3) and 30 g of 4) are kneaded with water, vacuum-dried, and then granulated. 14 g of 4) and 1 g of 5) are mixed into this granulated powder and compressed into tablets using a tablet press. In this way, 1000 tablets are obtained, each containing 10 mg of compound A monohydrochloride.

[0079] Treatment or prevention of pain Compound A or a pharmaceutically acceptable salt thereof can be used as an active ingredient in pain treatment or prophylactic agents.

[0080] In this specification, “treatment” includes the improvement of pain, prevention or delay of progression, maintenance of remission, prevention of relapse, and prevention of recurrence.

[0081] In this specification, "prevention" means suppressing the onset of pain.

[0082] Compound A or a pharmaceutically acceptable salt thereof may be used in combination with one or more other drugs (hereinafter also referred to as "combination drugs") in a manner common in the pharmaceutical field.

[0083] Examples of concomitant medications include analgesics and adjunct analgesics. Analgesics include opioid receptor agonists, opioid receptor partial agonists, NSAIDs, COX-2 inhibitors, ion channel modulators, central nervous system agents, drugs for neuropathic pain, drugs for cancer pain, and other analgesics. Adjunct analgesics include antidepressants, antiepileptic drugs, antiarrhythmic drugs, N-methyl-D-aspartate antagonists, central muscle relaxants, corticosteroids, anxiolytics, bone modifiers, antihistamines, nerve relaxants, and other adjunct analgesics.

[0084] Examples of opioid receptor agonists include morphine, oxycodone, pethidine, methadone, levorphanol, oxymorphone, fentanyl, pentazocine, tramadol, hydromorphone, fentanyl, remifentanil, tapentadol, hydrocodone, sufentanil, benzhydrocodone, oxycodegolcodeine, and dihydrocodeine.

[0085] Examples of opioid receptor partial agonists include dextromoramide, buprenorphine, butorphanol, nalbufine, meptazinol, eptazocine, and dinalbufine.

[0086] Examples of NSAIDs include acetylsalicylic acid, paracetamol, indomethacin, and melanin. Examples include fenamic acid, ibuprofen, naproxen, diclofenac, fenoprofen, fenbufen, ketoprofen, sulindac, flurbiprofen, diflunisal, piroxicam, acemetacin, meclofename, propasetamol, ketrolac, aceclofenac, zaltoprofen, mofezolac, dexketoprofen, lornoxicam, meloxicam, and perbiprofen.

[0087] Examples of COX-2 inhibitors include rofecoxib, celecoxib, parecoxib, and lumiracoxib.

[0088] Examples of ion channel modulators include diconotide, bupivacaine, and priralfinamide.

[0089] Examples of central nervous system-acting drugs include nefopam and flupirtin.

[0090] Examples of medications for neuropathic pain include carbamazepine, lidocaine, clonidine, gabapentin, duloxetine, pregabalin, capsaicin, and mirogabalin.

[0091] Examples of medications for cancer pain include calcitonin, clodronate, pamidronate, strontium, and lexidronam.

[0092] Other examples of analgesics include eptinezumab, rasmiditan, ubrogepant, atogepant, orycerizine, cebranopadol, facinumab, lucerastat, neridronic acid, relugolix, rimegepant, tanezumab, zoledronic acid, and zucapsaicin.

[0093] Examples of antidepressants include amitriptyline, amoxapine, nortriptyline, duloxetine, paroxetine, fluvoxamine, imipramine, desipramine, trazodone, bupropion, doxepin, and venlafaxine.

[0094] Examples of antiepileptic drugs include pregabalin, gabapentin, valproic acid, phenytoin, clonazepam, and carbamazepine.

[0095] Examples of antiarrhythmic drugs include mexiletine and lidocaine.

[0096] An example of an N-methyl-D-aspartate antagonist is ketamine.

[0097] Examples of central muscle relaxants include baclofen, orphenadrine, carisoprodol, methocarbamol, chlorzoxazone, and cyclobenzaprine.

[0098] Examples of corticosteroids include betamethasone and dexamethasone.

[0099] Examples of anti-anxiety medications include diazepam and lorazepam.

[0100] Examples of bone-modifying agents include zoledronic acid, denosumab, calcitonin, and strontium-89.

[0101] Examples of antihistamines include hydroxyzine and diphenhydramine.

[0102] Examples of nerve relaxants include methotrimeprazine and fluphenazine.

[0103] Other examples of adjunctive analgesics include octreotide, scopolamine, glycopyrrolate, clonidine, and capsaicin.

[0104] The timing of administration of the drug containing compound A or a pharmaceutically acceptable salt thereof and the concomitant drug is not limited. They may be administered to the target patient as a combination preparation, or both preparations may be administered simultaneously or at regular intervals. Furthermore, the present invention may be used as a pharmaceutical product characterized by a kit comprising the therapeutic or prophylactic agent and the concomitant drug. The dosage of the concomitant drug should conform to clinically used dosages and can be appropriately selected depending on the target patient, disease, symptoms, dosage form, route of administration, administration time, combination, etc. The administration form of the concomitant drug is not particularly limited; it is sufficient if the drug containing compound A or a pharmaceutically acceptable salt thereof is combined with the concomitant drug.

[0105] One embodiment of the present invention is a method for treating or preventing pain, comprising administering a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof to a human.

[0106] In this specification, “effective dose” means, for example, the amount of a drug or medicine that elicits a biological or medical response in a tissue, system or human. “Therapeutic dose” means any amount that results in a treatment, cure, prevention or improvement of pain or side effects compared to a corresponding subject that has not received such a dose.

[0107] The dosage of the therapeutic or prophylactic agent of the present invention varies depending on the target patient, disease, symptoms, dosage form, route of administration, etc. However, for example, when administered orally to an adult patient (weighing approximately 60 kg), the dosage is usually 0.1 mg to 1 g, preferably 10 mg to 800 mg, of the active ingredient compound A per day, administered in one to several divided doses per day, regardless of whether it is before, after, or between meals. It may also be taken as needed when pain occurs, for example, once or several times a day. The duration of administration is not particularly limited.

[0108] As the dosage of Compound A or a pharmaceutically acceptable salt thereof, dosages corresponding to 50 mg or more of the compound, for example, dosages corresponding to about 50 to 400 mg of the compound, dosages corresponding to about 50 to 200 mg of the compound, dosages corresponding to about 75 to 200 mg of the compound, or dosages corresponding to about 75 to 150 mg of the compound can be administered orally.

[0109] As the dosage range of the monohydrochloride of Compound A, dosages corresponding to 50 mg or more of the compound, for example, dosages corresponding to about 50 to 400 mg of the compound, dosages corresponding to about 50 to 200 mg of the compound, dosages corresponding to about 75 to 200 mg of the compound, or dosages corresponding to about 75 to 150 mg of the compound can be administered orally. Unless otherwise specified, the compound means the free form of the compound.

[0110] As the dosage of Compound A or a pharmaceutically acceptable salt thereof, oral administration at dosages corresponding to about 75 mg, about 100 mg, about 125 mg, or about 150 mg of the compound can be mentioned.

[0111] Compound A or a pharmaceutically acceptable salt thereof is administered once a day to provide an average trough concentration (C trough ) of the compound from about 100 ng / mL to about 600 ng / mL for at least about 12 weeks. For example, when a dosage corresponding to about 50 to 200 mg of the compound is administered once a day to a human subject, an average trough concentration (C trough ) of the compound from about 100 ng / mL to about 550 ng / mL can be obtained for at least about 12 weeks. The terms "trough concentration" and "C trough " refer to the lowest concentration of Compound A in the plasma of a human subject before the next dosage of Compound A or a pharmaceutically acceptable salt thereof is administered. The average C trough can be from about 120 ng / mL to about 520 ng / mL.

[0112] When a dosage corresponding to about 50 mg of the compound is administered once a day to a human subject, the average trough concentration (C trough ) of the compound can be from about 100 ng / mL to about 150 ng / mL for at least about 12 weeks. For example, the average C troughThis can range from approximately 120 ng / mL to approximately 140 ng / mL.

[0113] When a dose equivalent to approximately 100 mg of the compound is administered once daily to human subjects, the average trough concentration (C) of the compound is maintained for at least approximately 12 weeks. trough ) can range from approximately 150 ng / mL to approximately 250 ng / mL. For example, average C trough This can range from approximately 180 ng / mL to approximately 230 ng / mL.

[0114] When a dose equivalent to approximately 150 mg of the compound is administered once daily to human subjects, the average trough concentration (C) of the compound is maintained for at least approximately 12 weeks. trough ) can range from approximately 250 ng / mL to approximately 350 ng / mL. For example, average C trough This can range from approximately 270 ng / mL to approximately 340 ng / mL.

[0115] When a dose equivalent to approximately 200 mg of the compound is administered once daily to human subjects, the average trough concentration (C) of the compound is maintained for at least approximately 12 weeks. trough ) can range from approximately 300 ng / mL to approximately 550 ng / mL. For example, average C trough This can range from approximately 350 ng / mL to approximately 550 ng / mL. For example, average C trough This can range from approximately 350 ng / mL to approximately 450 ng / mL.

[0116] A numerical rating scale (NRS) can be used to quantify pain and measure the progress of pain management. Using a 0-10 scale, an NRS score of 5 or less is generally considered to correspond to mild pain, a score of 6-7 is generally considered to correspond to moderate pain, and a score of 8 or more is generally considered to correspond to severe pain. As described in the examples, compound A has been found to reduce pain in subjects with an NRS score of 8 or higher, indicating that it can be used to treat subjects with severe pain.

[0117] A Visual Analog Scale (VAS) can also be used to quantify pain and measure progress in pain management. A VAS consists of straight lines with endpoints that define extreme limits, such as "no pain" or "worst pain." Participants are asked to mark their pain level on the line between the two endpoints. The distance between "no pain" and the mark defines the participant's pain level.

[0118] One embodiment of the present invention is a pharmaceutical composition for the treatment or prevention of pain, comprising compound A or a pharmaceutically acceptable salt thereof.

[0119] One embodiment of the present invention involves the use of compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pain treatment or preventive agent.

[0120] One embodiment of the present invention is compound A or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of pain.

[0121] One embodiment of the present invention is a pain treatment or preventive agent comprising compound A or a pharmaceutically acceptable salt thereof.

[0122] Treatment or prevention of interstitial cystitis Compound A or its pharmaceutically acceptable salts can be used as active ingredients in therapeutic or prophylactic agents for interstitial cystitis. Compound A or its pharmaceutically acceptable salts can also be used for frequent urination and nocturia. It can be used to treat or prevent symptoms of interstitial cystitis, such as urination, urinary urgency, increased urge to urinate, irritable bladder, bladder discomfort, bladder pain, and bladder inflammation.

[0123] Interstitial cystitis is broadly classified into the Hunner type, which has Hunner ulcers, and the non-Hunner type, which does not. Compound A or its pharmaceutically acceptable salts can be used as active ingredients in therapeutic or prophylactic agents for either type of interstitial cystitis.

[0124] Compound A or its pharmaceutically acceptable salts can also be used as active ingredients in therapeutic or prophylactic drugs for overactive bladder or cystitis in urinary tract infections. Overactive bladder and cystitis in urinary tract infections are conditions that present with frequent urination (i.e., polyuria), a symptom common to interstitial cystitis. In some cases, overactive bladder is diagnosed as a different condition from interstitial cystitis because there are no microscopic findings in the bladder. However, in some cases, the population of patients with overactive bladder may include patients with interstitial cystitis who do not have such microscopic findings.

[0125] In this specification, “treatment” includes improvement of interstitial cystitis (or overactive bladder or cystitis in urinary tract infections), prevention or delay of progression, maintenance of remission, prevention of relapse, and prevention of recurrence. In this specification, “prevention” means suppressing the development of interstitial cystitis (or overactive bladder or cystitis in urinary tract infections).

[0126] The therapeutic or preventive agent of the present invention can be used in combination with one or more other agents (hereinafter also referred to as "combination agents") in a manner common in the pharmaceutical field.

[0127] The timing of administration of the drug containing compound A or a pharmaceutically acceptable salt thereof and the concomitant drug is not limited. They may be administered to the target patient as a combination drug, or both preparations may be administered simultaneously or at regular intervals. They may also be used as a pharmaceutical product characterized by being a kit consisting of the drug and the concomitant drug. The dosage of the concomitant drug should be in accordance with clinically used dosages and can be appropriately selected depending on the target patient, disease, symptoms, dosage form, route of administration, time of administration, combination, etc. The form of administration of the concomitant drug is not particularly limited, as long as the drug containing compound A or a pharmaceutically acceptable salt thereof and the concomitant drug are combined. Examples of concomitant drugs include hydroxyzine, amitriptyline, suplatast tosylate, cimetidine, corticosteroids, cyclosporine, antibiotics, and oxybutynin.

[0128] One embodiment of the present invention is a method for treating or preventing interstitial cystitis (or overactive bladder or cystitis in urinary tract infections) comprising administering a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof to a human.

[0129] In this specification, “effective dose” means, for example, the amount of a drug or medicine that elicits a biological or medical response in a tissue, system or human. “Therapeutic dose” means any amount that results in improved treatment, cure, prevention or improvement of interstitial cystitis or side effects compared to a corresponding subject that has not received such a dose.

[0130] The dosage of the therapeutic or prophylactic agent of the present invention varies depending on the target patient, disease, symptoms, dosage form, route of administration, etc. However, for example, when administered orally to an adult patient (weighing approximately 60 kg), the dosage is usually 0.1 mg to 1 g, preferably 10 mg to 800 mg, of the active ingredient compound A per day, administered in one to several divided doses per day, regardless of whether it is before, after, or between meals. It may also be taken as needed when pain occurs, for example, once or several times a day. The duration of administration is not particularly limited.

[0131] The range of pharmaceutically acceptable doses of compound A or its pharmaceutically acceptable salts includes doses equivalent to 50 mg or more of the compound, for example, doses equivalent to approximately 50-400 mg of the compound, doses equivalent to approximately 50-200 mg of the compound, doses equivalent to approximately 75-200 mg of the compound, or doses equivalent to approximately 75-150 mg of the compound, administered orally.

[0132] Examples of pharmaceutically acceptable doses of compound A or its pharmaceutically acceptable salts include orally administering doses equivalent to approximately 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, or 400 mg of the compound.

[0133] One embodiment of the present invention is a pharmaceutical composition for the treatment or prevention of interstitial cystitis (or overactive bladder or cystitis in urinary tract infections), comprising compound A or a pharmaceutically acceptable salt thereof.

[0134] One embodiment of the present invention involves the use of compound A or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for interstitial cystitis (or overactive bladder or cystitis in urinary tract infections).

[0135] One embodiment of the present invention is compound A or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of interstitial cystitis (or overactive bladder or cystitis in urinary tract infections).

[0136] One embodiment of the present invention is a therapeutic or prophylactic agent for interstitial cystitis (or overactive bladder or cystitis in urinary tract infections) comprising compound A or a pharmaceutically acceptable salt thereof.

[0137] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0138] The following examples are provided to better illustrate the claimed invention and should not be construed as limiting the scope of the invention. Where specific materials are mentioned, they are for illustrative purposes only and not intended to limit the invention. Those skilled in the art can develop equivalent means or reactants without exercising their inventive capacity and without departing from the scope of the invention. [Examples]

[0139] Example 1: Analgesic effect of oral administration of compound A monohydrochloride in a rat collagen-induced arthritis (CIA) model. The analgesic effect of compound A on hyperalgesia in rat CIA models was evaluated. Hyperalgesia was assessed using the Randall-Seritt method to measure the pain threshold (Paw Withdrawal Threshold, PWT) to mechanical stimuli.

[0140] Female LEW / CrlCrlj rats (Charles River Japan Co., Ltd.) were used as experimental animals. Compound A monohydrochloride was dissolved in 0.5% methylcellulose (MC) to prepare 6 mg / mL and 2 mg / mL solutions of Compound A. Bovine articular cartilage-derived type II collagen (Collagen Research Center) was dissolved in acetic acid to prepare a 2 mg / mL type II collagen solution. An equal volume of 2 mg / mL type II collagen solution was mixed with Freund's incomplete adjuvant to prepare a 1 mg / mL type II collagen emulsion.

[0141] On day 1, type II collagen emulsion was intradermally injected into the vehicle group, compound A 10 mg / kg dose group, and compound A 30 mg / kg dose group. On day 8, the vehicle group and compound A 10 Type II collagen emulsion was administered intradermally to the mg / kg dose group and the compound A 30 mg / kg dose group. From day 22 to day 28, the vehicle group was orally administered 0.5% MC solution at a dose of 5 mL / kg once daily. During the same period, the compound A 10 mg / kg dose group and the compound A 30 mg / kg dose group were orally administered 2 mg / mL or 6 mg / mL of compound A solution at a dose of 5 mL / kg once daily. On day 28, the analgesic effect was measured using a Randall-Selitt analgesic effect meter (TK-201, UNICOM). The mean and standard deviation of the PWT value were calculated for each group. The results are shown in Figure 1. Compound A reduced hyperalgesia in CIA-treated rats.

[0142] Example 2: Effect of compound A on nerve growth factor (NGF)-induced hyperalgesia in rats Compound A has an inhibitory effect on TrkA, a receptor for NGF. The purpose of this study is to investigate the effect of compound A on NGF-induced hyperalgesia in rats.

[0143] To induce pain-related behaviors (avoidance behaviors), NGF was injected into the sole of the left hind leg of rats, and the thermal latency / mechanical threshold was measured. The effect of compound A on these avoidance behaviors was investigated.

[0144] Two days before NGF injection, the thermal latency or mechanical threshold was measured to assess acclimatization to the experimental environment. On the day before NGF injection, body weight and the thermal latency or mechanical threshold values ​​were obtained.

[0145] 50 μL of NGF solution was injected intrapectomy into the left hind foot of rats. 0.5 μg / site of NGF was selected to evaluate thermal stimulation, and 1 μg / site was selected to evaluate mechanical stimulation. Compound A monohydrochloride (1, 3, or 10 mg / kg) was administered orally simultaneously with the NGF injection.

[0146] The response latency to thermal stimulation was measured at 3 and 6 hours after injection of NGF solution, and the threshold for mechanical stimulation was measured at 1, 3, and 6 hours after injection of NGF solution. Evaluation was conducted as a blind test for each group.

[0147] Thermal latency was measured using a planter test apparatus. Infrared thermal stimulation was transmitted to the soles of the hind feet, and the time it took to withdraw the feet from the heat source was automatically recorded as thermal latency. Measurements were performed five times for both hind feet of each animal, and the average of the last three values ​​for each hind foot was considered as the thermal latency for each animal. Only three measurements were performed for habituation.

[0148] The mechanical threshold is measured using a pressure analgesic meter. A mechanical stimulus (pressure) was applied to the hind limbs at a constant rate, and the pressure under load until the animal retracted its hind limb or vocalized was recorded as the mechanical threshold (mmHg).

[0149] Compound A, compared to the vehicle, suppressed the NGF-induced decrease in thermal latency in a dose-dependent manner. See Table 1. A significant effect of Compound A was observed at a dose of 3 mg / kg at 6 hours after NGF injection.

[0150] [Table 1]

[0151] Compound A, compared to the vehicle, suppressed the NGF-induced mechanical threshold reduction in a dose-dependent manner. See Table 2. A significant effect of Compound A was observed at a dose of 3 mg / kg at 6 hours after NGF injection.

[0152] [Table 2]

[0153] Example 3: Pain assessment in a clinical trial for human rheumatoid arthritis Compound A was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in subjects with active rheumatoid arthritis. Subjects received either placebo or free compound A (50 mg, 100 mg, 150 mg, or 200 mg) orally once daily for 12 weeks. Participants were randomized to ingest a sufficient amount of compound A monohydrochloride to provide the desired result.

[0154] Pain was assessed by subjects using a numerical rating scale (NRS). The pain NRS is an 11-point scale ranging from 0 (no pain) to 10 (maximum pain) and represents the severity of arthritis pain over the past three days. The reduction in NRS from baseline after drug administration was evaluated.

[0155] Data was collected at EOT (End of Treatment), 2 weeks, and 12 weeks. EOT is a commonly used measurement point in clinical research. In a 12-week study, it refers to all analyses at the 12-week mark. However, since some subjects discontinued the study, the data at the time of discontinuation is treated as the EOT for these subjects (for example, the data from week 8 is used as the EOT for subjects who discontinued at week 8). 2-week (for subjects who fully completed 2 weeks) and 12-week (for subjects who fully completed 12 weeks) data are also shown.

[0156] Figures 2A (EOT), 2B (2 weeks), and 2C (12 weeks) show the change from baseline pain on the NRS after treatment with either placebo or compound A.

[0157] The achievement rate (the percentage of subjects showing pain improvement) was also used to measure clinical improvement. The percentage of patients whose pain improved by at least 30% after treatment with either placebo or one of the dosages of compound A is shown in Figures 3A (EOT), 3B (2 weeks), and 3C (12 weeks). The percentage of patients whose pain improved by at least 50% after treatment with either placebo or one of the dosages of compound A is shown in Figures 4A (EOT), 4B (2 weeks), and 4C (12 weeks). The percentage of patients whose pain improved by at least 70% after treatment with either placebo or one of the dosages of compound A is shown in Figures 5A (EOT), 5B (2 weeks), and 5C (12 weeks).

[0158] The HAQ-DI (Health Assessment Questionnaire Disability Index) questionnaire was used to assess the improvement in the quality of life of treated patients. The HAQ-DI assesses the degree of functional ability of subjects by evaluating the difficulty they experienced in eight categories of daily living activities: dressing and grooming, standing, eating, walking, hygiene, movement, grip strength, and general daily activities over the past week. A higher HAQ-DI score indicates a worsening of the subject's function. The change from baseline in HAQ-DI scores after treatment with either placebo or compound A is shown in Figures 6A (EOT), 6B (2 weeks), and 6C (12 weeks).

[0159] The number of tender joints (TJC; the number of joints that were painful to press out of 68 joints) was evaluated to determine the number of joints that were considered tender or painful. The change in TJC from baseline after treatment with either placebo or compound A is shown in Figures 7A (EOT), 7B (2 weeks), and 7C (12 weeks).

[0160] Changes in pain NRS were assessed in two subgroups of patients: those with high baseline pain levels (mean baseline pain NRS ≥ 8.0) and those with low baseline pain levels (mean baseline pain NRS < 8.0). A greater decrease in pain NRS was observed in subjects who started treatment with higher baseline pain levels. See Figures 8A and 8B. While the magnitude of the pain NRS decrease differed between the low and high baseline pain NRS subgroups, both subgroups ultimately achieved a pain NRS score of approximately 4.

[0161] Clinical studies have shown that rapid (within 2 weeks) and long-lasting (12 weeks) analgesic effects were observed after treatment with compound A. Since improvement resulting solely from anti-inflammatory effects would likely take longer to show beneficial effects, 2 weeks after treatment with compound A An improvement in pain scores within a certain timeframe indicates that the compound has an analgesic effect.

[0162] The incidence of serious adverse events (SAEs) and severe treatment-related adverse events (TEAEs) in clinical studies was low in subjects treated with either dose of compound A (3.4% and 2.9%, respectively). Compound A was safe and tolerable at doses up to 200 mg over a 12-week treatment period.

[0163] Example 4: Pharmacokinetic evaluation In the human clinical study described in Example 3, blood samples were collected from subjects before administration at weeks 2, 4, 8, and 12 to quantify the plasma level of compound A. The trough concentration (C) of compound A was measured. trough The results are shown in Figure 9. The mean trough concentration increased as the dose increased from 50 mg to 200 mg, and the trough concentration was maintained throughout the study. See Table 3.

[0164] [Table 3]

[0165] Human C to preclinical pharmacology resultstrough Multiples of the value were determined. The multiples are based on human exposure (average C over 12 weeks). trough ) Preclinical IC 50 or IC 90 The values ​​were calculated by division. Figure 10A shows the multiple of human exposure to inhibit TrkA in vitro. Figure 10B shows the multiple of human exposure to inhibit NGF-induced hyperalgesia in rats.

[0166] Example 5: Effect of oral administration of compound A in a mouse cyclophosphamide (CYP)-induced cystitis model The inhibitory effect of compound A on lower abdominal licking time was evaluated in a mouse CYP-induced cystitis model. The evaluation was conducted using the Eur J Pain Report by M. Fujita et al. This study was conducted based on 20(2016)79-91. Male C57BL / 6J mice (Charles River Co., Ltd.) were used as experimental animals.

[0167] For four days (Days 1-4), the vehicle group, compound A administration group, and anti-NGF antibody group received intraperitoneal administration of 20 mg / mL of CYP (Sigma-Ace) dissolved in physiological saline at a volume of 10 mL / kg, while the sham group received intraperitoneal administration of physiological saline at a volume of 10 mL / kg. The monohydrochloride salt of compound A was dissolved in 0.5% methylcellulose (MC) to prepare solutions of compound A at concentrations of 3 mg / mL, 6 mg / mL, and 10 mg / mL.

[0168] For three days (Days 7-9), 0.5% (w / v) (MC) was orally administered once daily to the sham group, vehicle group, and anti-NGF antibody administration group at a dose of 10 mL / kg. Compound A monohydrochloride dissolved in 0.5% (w / v) MC at a dose of 3 mg / mL, 6 mg / mL, or 10 mg / mL was administered to the compound A administration group. In addition, on Day 7, isotype control BE0083 (Bio X Cell) was administered intraperitoneally as a single dose to the sham group, vehicle group, and compound A administration group, and monoclonal anti-nerve growth factor-β (NGF) antibody (Sigma-A) was administered intraperitoneally at a dose of 150 μg / head to the anti-NGF antibody administration group.

[0169] Before the first CYP administration (Pre), on Day 7, Day 8, and Day 10, the behavior of mice was videotaped for 90 minutes, and the lower abdominal licking time (sec) was measured. On Day 7 and Day 8, after filming the mice's behavior, 0.5% (w / v) MC was orally administered to the sham group, vehicle group, and anti-NGF antibody administration group, and compound A monohydrochloride was orally administered to the compound A administration group. Also on Day 7, after filming the mice's behavior, isotype control BE0083 was intraperitoneally administered to the sham group, vehicle group, and compound A administration group, and anti-NGF antibody was administered to the anti-NGF antibody administration group. The average licking time for each individual was calculated for each group, and the results are shown in Figure 11. Compound A reduced the lower abdominal licking time in this cystitis animal model.

[0170] Example 6: Effect of oral administration of compound A on frequent urination in a rat CYP-induced cystitis model The effect of compound A on frequent urination, calculated from single-void volume and urination interval, was evaluated using a rat CYP-induced cystitis model. The evaluation was conducted as described in GM. Herrera et al., PLoS ONE 5(8): The procedure was carried out in accordance with e12298. Female CD(SD) rats (Charles River Co., Ltd. Japan) The company used the following animal as an experimental animal. The monohydrochloride salt of compound A was dissolved in 0.5% MC to prepare 2 mg / mL and 6 mg / mL solutions of compound A.

[0171] CYP (Sigma-A) at a dose of 30 mg / mL dissolved in physiological saline was administered intraperitoneally to the vehicle group and compound A group at a dose of 5 mL / kg, while physiological saline was administered to the sham group at a dose of 5 mL / kg (Day 1).

[0172] 0.5% (w / v) MC was orally administered to the sham group and vehicle group at a dose of 5 mL / kg once daily for 2 days (Day 1-2), and a 2 mg / mL or 6 mg / mL solution of compound A was orally administered to the compound A group at a dose of 5 mL / kg twice daily (Day 1-2).

[0173] On Day 3, bladder pressure and urination volume were measured using the cystomometry method, and single-void urination volume and urination interval were calculated. The average values ​​for each group were calculated from the individual single-void urination volume and urination interval, and the results are shown in Figures 12A and 12B, respectively. Compound A suppressed frequent urination in this animal model of cystitis.

[0174] Other embodiments Although the present invention has been described in conjunction with its detailed description, the foregoing description is illustrative of, and not limited to, the scope of the present invention as defined by the appended claims. Other embodiments, The advantages and modifications are within the scope of the attached claims.

Claims

1. A therapeutic agent for NGF-induced pain, with the following chemical structure: 【Chemistry 1】 A therapeutic agent comprising the compound indicated by or a pharmaceutically acceptable salt thereof.

2. The therapeutic agent according to claim 1, wherein the NGF-induced pain is neuropathic pain, nociceptive pain, or mixed pain.

3. The therapeutic agent according to claim 1, wherein the NGF-induced pain is musculoskeletal pain or cancer pain.

4. The therapeutic agent according to claim 1, wherein the NGF-induced pain is pain from osteoarthritis, lower back pain, or pain from diabetic peripheral neuropathy.

5. NGF-induced pain can be associated with pancreatitis, kidney stones, headaches, dysmenorrhea, musculoskeletal pain, sprains, visceral pain, ovarian cysts, prostatitis, cystitis, postoperative pain, migraines, trigeminal neuralgia, burns, wounds, trauma, postherpetic neuralgia, musculoskeletal disorders, ankylosing spondylitis, periarticular lesions, cancer, bone metastases, HIV, myocardial infarction, fractures, gout, joint problems, sciatica, sickle cell crisis, endometriosis, fibromyalgia, incision pain, erythromelitis, malignant melanoma, Sjögren's syndrome, chronic nonbacterial prostatitis, uterine fibroids, vulvar pain, phantom limb pain, root detachment, and diabetic neuropathy. The therapeutic agent according to claim 1 for pain, painful traumatic mononeuropathy, painful polyneuropathy, central pain, pain from repetitive movements, myofascial pain, perioperative pain, chronic pain, angina pectoris, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, osteoporosis, irritable bowel syndrome, pulpitis, skin contusion, tendinitis, colic, appendicitis, peptic ulcer disease, bladder distension, contusions, peritendinitis, frozen shoulder, vertebral compression fracture, spinal stenosis, spinal canal stenosis, herniated disc, cervicobrachial syndrome, vertebral burst fracture, post-extraction pain, acute arterial occlusion, or erythromelitis.

6. The therapeutic agent according to any one of claims 1 to 5, wherein the NGF-induced pain is moderate, moderate to severe, or severe.

7. The therapeutic agent according to any one of claims 1 to 6, wherein the pharmaceutically acceptable salt is a monohydrochloride salt.

8. A therapeutic agent according to any one of claims 1 to 7, comprising administering a compound or a pharmaceutically acceptable salt thereof orally.

9. A therapeutic agent according to any one of claims 1 to 8, comprising administering the compound or a pharmaceutically acceptable salt thereof once daily.

10. A therapeutic agent according to any one of claims 1 to 9, comprising orally administering a compound or a pharmaceutically acceptable salt thereof in a dose equivalent to 50 mg or more of the compound.

11. The therapeutic agent according to claim 10, comprising orally administering a compound or a pharmaceutically acceptable salt thereof in a dose equivalent to 50 to 400 mg of the compound.

12. The therapeutic agent according to claim 10, comprising orally administering a compound or a pharmaceutically acceptable salt thereof in a dose equivalent to 50 to 200 mg of the compound.

13. The therapeutic agent according to claim 10, comprising orally administering a compound or a pharmaceutically acceptable salt thereof in a dose equivalent to 75 to 200 mg of the compound.

14. The therapeutic agent according to claim 10, comprising orally administering a compound or a pharmaceutically acceptable salt thereof in a dose equivalent to 75 to 150 mg of the compound.

15. The therapeutic agent according to claim 10, comprising orally administering a compound or a pharmaceutically acceptable salt thereof in a dose equivalent to 75 mg, 100 mg, 125 mg, or 150 mg of the compound.

16. The compound or a pharmaceutically acceptable salt thereof is administered once daily, and the average trough concentration of the compound is maintained at 100 ng / mL to 550 ng / mL for at least 12 weeks. Ｃｔｒｏｕｇｈ A therapeutic agent according to any one of claims 1 to 15, which brings about ).

17. The compound or a pharmaceutically acceptable salt thereof is administered once daily, and the average trough concentration of the compound is maintained at 100 ng / mL to 150 ng / mL for at least 12 weeks. Ｃｔｒｏｕｇｈ The therapeutic agent according to claim 16, which brings about ).

18. The compound or a pharmaceutically acceptable salt thereof is administered once daily, and the average trough concentration of the compound is maintained at 150 ng / mL to 250 ng / mL for at least 12 weeks. Ｃｔｒｏｕｇｈ The therapeutic agent according to claim 16, which brings about ).

19. The compound or a pharmaceutically acceptable salt thereof is administered once daily, and the average trough concentration of the compound is maintained at 250 ng / mL to 350 ng / mL for at least 12 weeks. Ｃｔｒｏｕｇｈ The therapeutic agent according to claim 16, which brings about ).

20. The compound or a pharmaceutically acceptable salt thereof is administered once daily, and the average trough concentration of the compound is maintained at 300 ng / mL to 550 ng / mL for at least 12 weeks. Ｃｔｒｏｕｇｈ The therapeutic agent according to claim 16, which brings about ).

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