Pain treatment compounds

Abstract

This invention relates to compounds for treating neuropathic pain. The invention also relates to the pharmaceutical composition thereof and to methods for treating neuropathic pain.

Description

[Technical Field]

[0001] This invention relates to compounds for treating neuropathic pain. The invention also relates to the pharmaceutical composition thereof and to methods for treating neuropathic pain. [Background technology]

[0002] Neuropathic pain develops after lesions or injuries to the somatosensory system and significantly impacts quality of life. Examples include trigeminal neuralgia, painful polyneuropathy, postherpetic neuralgia, and central post-stroke pain. The induced pain can spread to adjacent areas and may be accompanied by peripheral and central sensitization. The prevalence of neuropathic pain is 6.9–10%, and it often affects people with diabetes. Currently, 200 million people worldwide suffer from neuropathic pain, also known as diabetic polyneuropathy.

[0003] Anticonvulsants that affect sodium channels, such as carbamazepine, oxycarbazepine, and topiramates, are generally not recommended. The same applies to other anticonvulsants, such as lamotrigine, lacosamide, phenytoin, and levetiracetam. Tricyclic and tetracyclic antidepressants are recommended as first-line treatments for neuropathic pain. Nevertheless, risk-benefit assessments must consider the side effects, drug interactions, and cardiotoxicity of these medications.

[0004] Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, is recommended as the first-line treatment. It has shown comparable efficacy to amitriptyline and pregabalin in patients with diabetic neuropathy. Serious side effects are rare. However, side effects such as nausea, fatigue, dizziness, increased sweating, dry mouth, constipation, loss of appetite, insomnia, diarrhea, impaired consciousness and tremors, as well as elevated intraocular pressure and hypertension (BP) may occur. Furthermore, duloxetine is converted by cytochrome P450 (CYP) 1A2 and interacts with ciprofloxazine and metoprolol; therefore, it cannot be used in combination with serotonergic drugs.

[0005] Topical treatments including lidocaine, capsaicin, and botulinum toxin are considered treatments for neuropathic pain. However, there is a substantial unmet need in patients with neuropathic pain due to insufficient response to drug therapy, and currently, less than one-third of patients with painful diabetic neuropathy receive adequate pain relief from existing drug therapies.

[0006] Inadequate response to drug therapy represents a substantial unmet need for patients with neuropathic pain. Therefore, there is a significant unmet need for novel treatments for neuropathic pain. [Overview of the Initiative]

[0007] As outlined above, there is a strong demand for compounds that can treat neuropathic pain. This disclosure provides compounds useful for treating pain, including neuropathic pain.

[0008] Therefore, in one primary embodiment, the present disclosure relates to a compound of formula (I) for use in the treatment, prevention, or relief of pain in a subject. [ka] Alternatively, a pharmaceutically acceptable salt thereof may be provided, in which case the compound may be administered at a dose of approximately 0.001 mg / kg to approximately 1 mg / kg.

[0009] The inventors have surprisingly demonstrated that the use of the compound of Formula I described herein has antinociceptive effects in various models of pain, including neuropathic pain. The inventors have also surprisingly found that the use of the compound has antinociceptive effects in various models of neuropathic injury in mammals, including humans, and that the compound for use described herein effectively treats spontaneous, ongoing pain symptoms following neuropathic injury.

[0010] In humans, the inventors have surprisingly shown that the use of the compound of formula I improves the evaluation of various parameters, including subjective assessments of pain, allodynia, and hyperalgesia following neuropathic injury induced by intradermal injection of capsaicin.

[0011] Surprisingly, the inventors demonstrated in a study of healthy volunteers that when the compound dose was 10 mg or less, the incidence of therapeutic adverse events (TEAEs) was lower compared to higher doses.

[0012] These findings represent a completely new way of treating neuropathic pain using the compounds of this disclosure, and the administration regimen is effective, carries a low risk of adverse events, and has the potential to significantly improve the quality of life for patients suffering from various forms of neuropathic pain.

[0013] One embodiment is a compound of formula I for use in the manufacture of a pharmaceutical product for the treatment, prevention, or relief of pain in subjects requiring the treatment, prevention, or relief of pain. [ka] The following is provided, in which case the compound is administered in a dose of approximately 0.001 mg / kg to approximately 1 mg / kg.

[0014] One embodiment provides a method for treating, preventing, or relieving pain in a subject requiring treatment, prevention, or relief of pain, the method comprising administering a compound of formula I in an amount of about 0.001 mg / kg to about 1 mg / kg to the subject requiring treatment, prevention, or relief of pain. [ka] or administering a pharmaceutically acceptable salt thereof.

[0015] One aspect of this disclosure provides a method for inducing pain relief in a subject requiring pain relief, wherein the subject is given a compound of formula I in an amount of about 0.001 mg / kg to about 1 mg / kg. [Chemical formula] including administering a compound of formula I or a pharmaceutically acceptable salt thereof.

[0016] One embodiment of the present disclosure provides a method for improving the function of a subject having pain, the method comprising administering to the subject a compound of formula I in an amount of about 0.001 mg / kg to about 1 mg / kg, [Chemical formula] including administering a compound of formula I or a pharmaceutically acceptable salt thereof.

[0017] In a final aspect, the present disclosure provides a solid dosage form comprising a compound of formula I, [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the compound is present in an amount of about 1 mg to about 10 mg. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] [Figure 1] In mice, microdialysis tests in the (A) cortex and (B) striatum performed after an IP injection of 2015 at 10 mg / kg. The increase in dopamine (DA) is most prominent in the cortex, while the increase in DA in the striatum is slight. NA = norepinephrine; NM = NE metabolite (normetanephrine); 3MT = DA metabolite (3-methoxytyramine); 5-HT, 5-hydroxytryptamine. The number of animals (n) was 1 - 2. Note that the scales on the y-axis are different for (A) and (B). [Figure 2]IP2015 reduces nociceptive behavior in CCI rats. Adult male rats were injected with either vehicle or IP2015 (3.10 mg / kg, subcutaneously) 60 minutes before evaluating hind paw nociceptive behavior. (a) Hind paw retraction reflex threshold (g) to low-threshold von Frey stimulation; baseline (pre-CCI vs. post-CCI) = 17.3 vs. 1.4 g (b) Hind paw retraction reflex time (seconds) to high-threshold pin-piercing stimulation; baseline (pre-CCI vs. post-CCI) = 0 vs. 14.9 seconds (c) Load difference (g) as a surrogate indicator of spontaneous, ongoing pain; -9.6 vs. 42.1 g. All groups n=8 rats. Data are presented as mean ± SEM. (a) F(2,21)=5.302 P=0.0137, (b) F(2,21)=2.588, P=0.0989, (c) F(2,21)=5.118, P=0.0155. *P<0.05, **P<0.01 for the corresponding vehicles; Dunnett's test was performed after one-way ANOVA. [Figure 3] IP2015 reduces nociceptive behavior in the formalin test. Adult male rats were injected with either vehicle or IP2015 (1, 3, 10, 30 mg / kg, subcutaneously) 60 minutes before injecting 5% formalin into the dorsal surface of the hind leg. (a) Changes in atrophy behavior over time after formalin injection. (b) Total atrophy behavior in phase 1 (P1=0-5 min), intermediate phase (Int=6-15 min), and phase 2 (P2=16-40 min) of the test after formalin administration. All groups consisted of n=8 rats, except for IP2015 1 mg / kg, which consisted of n=4 rats. Data are shown as mean ± SEM. P1F(4,31)=7.944, P=0.0022; IntF(4,31)=10.23, P<0.0001; P2F(4,31)=23.07; P<0.0001 *P<0.05,***P<0.001,****P<0.0001 for corresponding vehicles. Dunnett's test was performed after conducting one-way ANOVA. [Figure 4A] Adjusted mean area (mm) of subjective pain assessments using MMRM analysis. Abbreviation: MMRM - Mixed Model Repeated Measures. Error bars represent the 95% confidence interval of the adjusted mean from the MMRM model. [Figure 4B]Adjusted mean area (cm²) of hyperalgesia by MMRM analysis. Abbreviation: MMRM - Mixed Model Repeated Measures. Error bars represent the 95% confidence interval of the adjusted mean from the MMRM model. [Figure 4C] Adjusted mean area of ​​pain scores for hyperalgesia using NRS from MMRM analysis. Abbreviation: MMRM - Mixed Model Repeated Measures. Error bars represent the 95% confidence interval of the adjusted mean from the MMRM model. [Figure 4D] Adjusted mean area (cm²) of brush-induced allodynia by MMRM analysis. Abbreviation: MMRM - Mixed Model Repeated Measures. Error bars represent the 95% confidence interval of the adjusted mean from the MMRM model. [Figure 4E] Adjusted mean area of ​​pain score for brush-induced allodynia using NRS by MMRM analysis. Abbreviation: MMRM - Mixed Model Repeated Measures. Error bars represent the 95% confidence interval of the adjusted mean from the MMRM model.

[0019] definition "Pharmacologically acceptable" means that a pharmaceutical composition is generally safe, non-toxic, and useful in preparing a pharmaceutical composition that is biologically and otherwise desirable (this includes pharmaceutical compositions that are acceptable for veterinary and human pharmaceutical use).

[0020] The term “pharmaceutically acceptable salt” of a compound refers to a salt that is pharmaceutically acceptable, as defined herein, and preferably has the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include acid addition salts formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or from organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, and trimethylacetic acid; or salts formed by the replacement of acidic protons present in the parent compound with metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions, or by coordination bonding with organic or inorganic bases. Examples of acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, morpholine, and tromethamine. Examples of acceptable inorganic bases include ammonia, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0021] As used herein, the term “treatment” or “to treat” means an approach to obtain a beneficial or desired outcome, including a clinical outcome. Beneficial or desired clinical outcomes may include, but are not limited to, reduction or improvement of one or more symptoms or conditions, whether detectable or undetectable; attenuation of the severity of a disease or disability; stabilization (i.e., no worsening) of a disease or disability; prevention of a disease or disability; delay or slowing of the progression of a disease or disability; improvement or mitigation of a disease condition; and remission (partial or complete), whether detectable or undetectable.

[0022] If a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon are included in that structure unless otherwise specified. Using the Cahn-Ingold-Prelog RS notation system, a chiral carbon atom can exist in either the (R) or (S) configuration, and the compound can exist as a mixture of stereoisomers, e.g., a racemic mixture, or as a single stereoisomer.

[0023] The compounds of the present invention may exist in tautomeristic forms. Any such tautomers are considered to fall within the scope of the present invention.

[0024] Furthermore, in the compounds of formula I as defined herein, any hydrogen atom is deuterium ( 2 Such deuterated compounds of formula I, which may be replaced by H and contain one or more deuterium atoms instead of the corresponding number of hydrogen atoms, are considered to be within the scope of the present invention.

[0025] It is known in the art that prodrugs can be produced. Those skilled in the art will know what types of molecular moieties can be introduced into a drug to produce a prodrug. Prodrugs relating to the compound of formula I are considered to be within the scope of the present invention.

[0026] As used herein, “neuropathic pain” includes references to the neuropathic component of nociceptive pain.

[0027] As used herein, “nociceptivity” means relating to the perception or sensation of pain.

[0028] "IP2015" or "Compound I" refers to the compound of formula I. The compound of formula I is also known as pudafensin. The compound of formula I is [ka] That is the case.

[0029] As used herein, “formulation” refers to the result of combining different substances, including an active ingredient, to produce a final product.

[0030] The term “about” as used herein to refer to a quantity or percentage shall be interpreted as a variation of ±10%, such as ±5%, with respect to the value of the quantity or percentage it refers to. [Modes for carrying out the invention]

[0031] Compounds for use One embodiment of the present disclosure relates to a compound of formula (I) for use in treating, preventing, or alleviating pain in a subject. [ka] or a pharmaceutically acceptable salt thereof is provided. The compounds of this disclosure are monoamine reuptake inhibitors. The compounds may be tested for their ability to inhibit the reuptake of the monoamines dopamine, norepinephrine, and serotonin in synaptosomes, as described, for example, in WO97 / 30997 or WO97 / 16451. The hydrochloride salt of the compound of formula (I) is IC 50 The reported values ​​are 0.0029 μM (serotonin), 0.07 μM (dopamine), and 0.0038 μM (norepinephrine) (US9,133,184B1).

[0032] In one embodiment, the compound of formula (I) is the following compound of formula (Ia) [ka] or having the structure of a pharmaceutically acceptable salt thereof.

[0033] In one embodiment, the compound is 7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxychromen-2-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxychromen-2-one or a pharmaceutically acceptable salt thereof. In one embodiment, the name "IP2015" means the compound of formula I. In one embodiment, the name "IP2015" means the compound of formula Ia. In specific embodiments of the present disclosure, "IP2015" means the hydrochloride salt of the compound of formula I.

[0034] In one embodiment, the pharmaceutically acceptable salt is a salt of an organic or inorganic counterion. In one embodiment, the pharmaceutically acceptable salt is selected from the list consisting of hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, nitrate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, and toluene-p-sulfonate. Other pharmaceutically acceptable salts are known to those skilled in the art. Such salts can be formed by well-known procedures and may be described in the art.

[0035] In one embodiment of the present disclosure, the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxychromen-2-one hydrochloride.

[0036] The compounds of this disclosure are monoamine reuptake inhibitors. The compounds may be tested for their ability to inhibit the reuptake of the monoamines dopamine, norepinephrine, and serotonin in synaptosomes, as described, for example, in WO97 / 30997 or WO97 / 16451. The hydrochloride salt of the compound of formula (I) is IC50 The reported values ​​are 0.0029 μM (serotonin), 0.07 μM (dopamine), and 0.0038 μM (norepinephrine) (US9,133,184B1).

[0037] One embodiment of the present disclosure relates to a compound of formula I for use in treating, preventing, or alleviating pain in a subject. [ka] or a pharmaceutically acceptable salt thereof is provided. The examples disclosed herein demonstrate that the compounds of formula I are useful in treating pain such as nociceptive pain and / or neuropathic pain.

[0038] One embodiment of the present disclosure relates to a compound of formula I for use in treating, preventing, or alleviating pain in a subject. [ka] Alternatively, a pharmaceutically acceptable salt thereof may be provided, in which case the compound may be administered at a dose of approximately 0.001 mg / kg to approximately 1 mg / kg.

[0039] In one embodiment, the compound of formula I is administered at a dose of approximately 0.001 mg / kg to approximately 1 mg / kg per individual dose, for example, 0.005 mg / kg, for example, 0.01 mg / kg, for example, 0.015 mg / kg, for example, 0.02 mg / kg, for example, 0.025 mg / kg, for example, 0.03 mg / kg, for example, 0.035 mg / kg, for example, 0.04 mg / kg, for example, 0.045 mg / kg, for example, 0.05 mg / kg, for example, 0.055 mg / kg, for example, 0.06 mg / kg, for example, 0.065 mg / kg, for example, 0.07 mg / kg, 0.075 mg / kg, for example, 0.08 mg / kg, for example, 0.08 Administer in doses of 5 mg / kg, 0.09 mg / kg, for example, 0.095 mg / kg, for example, 0.1 mg / kg, for example, 0.15 mg / kg, for example, 0.2 mg / kg, for example, 0.25 mg / kg, for example, 0.3 mg / kg, 0.35 mg / kg, for example, 0.4 mg / kg, for example, 0.45 mg / kg, for example, 0.5 mg / kg, for example, 0.55 mg / kg, for example, 0.6 mg / kg, for example, 0.65 mg / kg, for example, 0.7 mg / kg, for example, 0.75 mg / kg, for example, 0.8 mg / kg, for example, 0.85 mg / kg, for example, 0.9 mg / kg, for example, 0.95 mg / kg, for example, 1 mg / kg.

[0040] In one embodiment, the compound is orally administered in amounts ranging from approximately 0.01 mg / kg to approximately 1 mg / kg per individual dose, for example, 0.01 mg / kg, for example, 0.05 mg / kg, for example, 0.1 mg / kg, 0.15 mg / kg, for example, 0.2 mg / kg, for example, 0.25 mg / kg, for example, 0.3 mg / kg, for example, 0.35 mg / kg, for example, 0.4 mg / kg, for example, 0.45 mg / kg, 0.5 mg / kg, for example, 0.55 mg / kg, for example, 0.6 mg / kg, for example, 0.65 mg / kg, for example, 0.7 mg / kg, for example, 0.75 mg / kg, for example, 0.8 mg / kg, for example, 0.85 mg / kg, for example, 0.9 mg / kg, for example, 0.95 mg / kg, for example, 1 mg / kg.

[0041] In one embodiment, the compound is administered at approximately 0.01 to approximately 1 mg / kg per individual dose, for example, 0.001 mg / kg, for example, 0.005 mg / kg, for example, 0.01 mg / kg, 0.015 mg / kg, for example, 0.02 mg / kg, for example, 0.025 mg / kg, for example, 0.03 mg / kg, for example, 0.035 mg / kg, for example, 0.04 mg / kg, for example, It is administered intravenously in amounts of 0.045 mg / kg, 0.05 mg / kg, for example, 0.055 mg / kg, for example, 0.06 mg / kg, for example, 0.065 mg / kg, for example, 0.07 mg / kg, for example, 0.075 mg / kg, for example, 0.08 mg / kg, for example, 0.085 mg / kg, for example, 0.09 mg / kg, for example, 0.095 mg / kg, for example, 0.1 mg / kg.

[0042] One embodiment of the present disclosure relates to a compound of formula I for use in treating, preventing, or alleviating pain in a subject. [ka] Alternatively, a pharmaceutically acceptable salt thereof may be provided, in which case the compound may be administered in a dose of approximately 0.5 mg to approximately 100 mg.

[0043] In one embodiment, the compound is administered in amounts of 0.5 mg to 100 mg per individual dose.

[0044] In one embodiment, the compound is administered in amounts of approximately 0.5 mg to 400 mg per individual dose, for example, approximately 0.5 mg to 100 mg, for example, approximately 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, Administer in doses of 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, or 99mg.

[0045] In one embodiment, the compound is administered in an amount of 10-20 mg per dose. In another embodiment, the compound is administered in an amount of 20-30 mg per dose. In yet another embodiment, the compound is administered in an amount of 30-40 mg per dose.

[0046] Surprisingly, the inventors have shown that in healthy volunteers, a single dose of 0.01–10 mg of the compound of formula I resulted in a lower incidence of therapeutic adverse events compared to a single dose of 16.2 mg. Therefore, in one embodiment, the compound is administered in amounts of 0.5–10 mg per individual dose, for example, 1–10 mg per individual dose, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg per individual dose. In another embodiment, the compound is administered in amounts of 5–10 mg per individual dose. These dosing regimens are advantageous because they are associated with a reduced incidence of therapeutic adverse events.

[0047] In one embodiment, the compound is administered multiple times a day, for example, twice a day, three times a day, four times a day, five, six, seven, or eight times a day.

[0048] In one embodiment, the compound is administered once a day. In another embodiment, the compound is administered orally.

[0049] In one embodiment, the total daily dose of the compound of formula I is, for example, about 0.5 mg to 100 mg, for example, 0.6 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg The total daily dose is 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, or 99mg.

[0050] In one embodiment, the compound is administered for at least one day. In one embodiment, the compound is administered for at least three days. In one embodiment, the compound is administered for at least five days. In one embodiment, the compound is administered for at least one week. In one embodiment, the compound is administered for at least two weeks. In one embodiment, the compound is administered for at least three weeks. In one embodiment, the compound is administered for at least one month. In one embodiment, the compound is administered for at least three months.

[0051] One embodiment of the present disclosure relates to a compound of formula I for use in treating, preventing, or alleviating pain in a subject. [ka] or provide a pharmaceutically acceptable salt thereof for the treatment, prevention, or relief of, for example, acute pain, chronic pain, mild pain, moderate or severe pain, postoperative pain, neuropathic pain, central nervous system pain, diabetic neuropathy, postherpetic neuralgia, peripheral neuropathy, phantom limb pain, restless limb syndrome, neurogenic inflammation, fibromyalgia, pain associated with chronic regional pain syndrome, somatic pain, visceral or cutaneous pain, pain caused by inflammation or infection, arthritis, osteoarthritis, rheumatoid arthritis, and neuronal hyperexcitability disorders. The treatment, prevention, or relief of pain associated with peripheral nerve excitability, back pain, cancer pain, toothache, irritable bowel pain, irritable bowel syndrome, postoperative pain, postmastectomy pain syndrome (PMPS), poststroke pain, drug-induced neuropathy, complex regional pain syndrome (CRPS), sympathetic nerve-dependent pain (SMP), trigeminal neuralgia, myofascial pain, chronic headache, migraine, migraine-related disorder, or tension-type headache, in which case the compound is administered at doses of 0.001 and 1 mg / kg or 0.5 to 10 mg per individual dose.

[0052] "Pain" is an unpleasant sensory and emotional experience associated with, or similar to, actual or potential tissue damage. "Chronic pain" is pain that persists or recurs for more than three months. "Acute pain" refers to pain that persists or recurs for less than three months. "Primary pain" is used to describe pain that is not caused by a different medical condition. "Secondary pain" is used to describe pain that is a result of another condition.

[0053] In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is primary pain. In one embodiment, the pain is secondary pain.

[0054] In one embodiment, pain is selected from the following group: (i) Chronic or acute primary pain, (ii) Chronic or acute cancer-related pain, (iii) Chronic or acute postoperative pain, (iv) Chronic or acute post-traumatic pain, (v) Chronic or acute secondary musculoskeletal pain, (vi) Chronic or acute secondary visceral pain, (vii) Chronic or acute neuropathic pain, and (viii) Chronic or acute secondary headache or orofacial pain.

[0055] In one embodiment, the pain is chronic or acute primary pain. In one embodiment, chronic or acute primary pain is chronic or acute widespread pain, fibromyalgia syndrome, chronic or acute primary musculoskeletal pain, chronic or acute primary headache or orofacial pain, such as migraine, burning mouth syndrome, tension headache, cluster headache, or persistent hemigraine, complex regional pain syndrome (CRPS), or painful contusion syndrome.

[0056] In one embodiment, the pain is chronic or acute cancer-related pain. In one embodiment, the chronic or acute cancer-related pain is associated with visceral cancer pain, bone cancer pain, or neuropathic cancer pain. In one embodiment, the chronic or acute cancer-related pain is post-cancer treatment pain, e.g., chemotherapy-induced polyneuropathic pain, e.g., post-radiation therapy pain, e.g., radiation-induced neuropathic pain.

[0057] In one embodiment, the pain is chronic or acute postoperative pain. In one embodiment, the chronic or acute postoperative pain is postoperative pain after spinal surgery, hernia incision, hysterectomy, amputation, thoracotomy, breast surgery, or arthroplasty.

[0058] In one embodiment, the pain is chronic or acute post-traumatic pain. In one embodiment, the chronic or acute post-traumatic pain is post-burn injury pain, whiplash-related pain, or post-musculoskeletal injury pain.

[0059] In one embodiment, the pain is chronic or acute secondary musculoskeletal pain. In one embodiment, chronic or acute secondary musculoskeletal pain is pain resulting from persistent inflammation such as inflammation due to infection, inflammation due to crystal deposition, or inflammation due to autoimmune and autoinflammatory disorders; pain related to structural changes, e.g., osteoarthritis-related pain or spondylosis-related pain; pain resulting from disorders of the nervous system, e.g., Parkinson's disease-related pain, e.g., multiple sclerosis-related pain or peripheral nerve disease-related pain.

[0060] In one embodiment, the pain is chronic or acute secondary visceral pain. In one embodiment, the chronic or acute secondary visceral pain is pain resulting from mechanical factors, vascular mechanisms, or persistent inflammation, for example, in the head, neck, chest, abdomen, or pelvic region.

[0061] In one embodiment, the pain is chronic or acute neuropathic pain. In one embodiment, chronic or acute neuropathic pain is central nervous system pain such as spinal cord injury, brain injury, post-stroke pain, or multiple sclerosis-related central nervous system pain; peripheral nervous system pain, peripheral nervous system pain after nerve injury, polyneuropathic pain, or radicular pain; or neuropathic orofacial pain.

[0062] In one embodiment, the pain is peripheral neuropathic pain.

[0063] In one embodiment, the pain is a chronic or acute secondary headache or orofacial pain. In one embodiment, the chronic or acute secondary headache or orofacial pain is a chronic toothache, chronic neuropathic orofacial pain, headache, or orofacial pain associated with temporomandibular joint disorder, homeostasis or its non-pharmacological treatment, cranial or cervical vascular disorder, nonvascular intracranial disorder, substance or its removal, or traumatic injury to the head.

[0064] In one embodiment, the pain is neuropathic pain. “Neuropathic pain” is caused by a lesion or disease of the somatosensory nervous system. It can be described as something like an electric shock, burning, or jolt. Pain may occur spontaneously without provocation, or it may be induced by harmful or non-harmful stimuli. Pain may be constant or intermittent and may be described as a burning, stinging, or icy sensation. Neuropathic pain can arise from several different causes.

[0065] In one embodiment, the pain is chronic neuropathic pain. In another embodiment, the pain is acute neuropathic pain.

[0066] Neuropathic pain can result from several different causes. In one embodiment, neuropathic pain may be caused by alcoholism, diabetes, multiple sclerosis, multiple myeloma, stroke, cancer, cytomegalovirus, trigeminal neuralgia, spinal cord injury, or amputation. In another embodiment, neuropathic pain may be caused by a chronic or progressive neurological disease.

[0067] In one embodiment, neuropathic pain is caused by an infection. In one embodiment, neuropathic pain is caused by an injury. In one embodiment, neuropathic pain is ongoing pain following a neuropathic injury. In one embodiment, neuropathic pain is caused by a side effect of drug therapy. In one embodiment, neuropathic pain is caused by a medical procedure such as surgery.

[0068] In one embodiment, neuropathic pain is idiopathic. In one embodiment, neuropathic pain is the neuropathic component of nociceptive pain.

[0069] In one embodiment, neuropathic pain is caused by diabetic neuropathy. In one embodiment, diabetes is chronic diabetes.

[0070] In one embodiment, neuropathic pain is neuropathic cancer pain.

[0071] In one embodiment, neuropathic pain is caused by neurological damage that develops under treatment. In one embodiment, the neurological damage that develops under treatment is caused by surgery.

[0072] In one embodiment, the pain is orofacial pain.

[0073] In one embodiment, the pain is trigeminal neuralgia. Trigeminal neuralgia is a symptom of orofacial neuropathic pain localized to one or more compartments of the trigeminal nerve. The pain is recurrent, sudden onset and sudden termination, triggered by harmless stimuli, and usually described as an electric shock or as a shooting or stabbing pain. Some patients experience persistent pain between these painful episodes.

[0074] In one embodiment, the pain is typical trigeminal neuralgia. In another embodiment, the pain is secondary trigeminal neuralgia, such as that caused by multiple sclerosis or a spatial occupancy lesion. In another embodiment, the trigeminal neuralgia is idiopathic trigeminal neuralgia.

[0075] In one embodiment, the pain is postherpetic neuralgia. In another embodiment, the pain is Parkinson's disease pain.

[0076] In one embodiment, the pain is allodynia. Allodynia refers to pain resulting from stimuli that would not normally cause pain, such as a light touch on the skin.

[0077] In one embodiment, pain is hyperalgesia. "Hyperalgesia" refers to excessive sensitivity to painful stimuli.

[0078] In one embodiment, pain is dyspareunia. Dyspareunia refers to a significant, persistent, or recurrent distress in adults associated with pain during sexual activity that is not entirely attributable to an underlying condition, insufficient lubrication in women, age-related changes, or menopausal changes in women, and which is clinically significant.

[0079] In one embodiment, dyspareunia is dyspareunia and dyspareunia. Dyspareunia and dyspareunia is characterized by at least one of the following: 1) marked, persistent, or recurrent difficulty in insertion, including due to involuntary hardening or rigidity of the pelvic floor muscles at the time of insertion; 2) marked, persistent, or recurrent vulvovaginal or pelvic pain during insertion; or 3) marked, persistent, or recurrent fear or anxiety regarding vulvovaginal or pelvic pain, either in anticipation of, during, or as a result of insertion. The symptoms recur during sexual intercourse involving or potentially involving insertion, despite sufficient sexual desire and sexual stimulation, and adversely affect the pelvic region, and are clinically significant distress, not solely attributable to conditions leading to genital pain and / or dyspareunia, mental disorders, or insufficient vaginal lubrication or postmenopausal / age-related changes.

[0080] In one embodiment, the dyspareunia / insertive dysfunction is either congenital or acquired. In one embodiment, the dyspareunia / insertive dysfunction is either generalized or situational. In one embodiment, the dyspareunia / insertive dysfunction is unspecified. Congenital generalized dyspareunia / insertive dysfunction is characterized by a subject who has consistently experienced genital pain, pelvic pain, or insertion difficulties since the initiation of the relevant sexual activity, and currently experiences a lack or reduction of the desired response in all environments, including masturbation. Congenital situational dyspareunia / insertive dysfunction is characterized by a subject who has consistently experienced genital pain, pelvic pain, or insertion difficulties since the initiation of the relevant sexual activity, and currently experiences a lack or reduction of the desired response depending on the environment, by a partner, or in response to certain stimuli, but not in other situations. Acquired generalized dyspareunia / insertive dysfunction is characterized by the onset of genital pain, pelvic pain, or insertion dysfunction after a period in which the person had not experienced genital pain, pelvic pain, or insertion dysfunction, and currently, the desired response is absent or reduced in all environments, including masturbation. Acquired situational dyspareunia / insertive dysfunction is characterized by the onset of genital pain, pelvic pain, or insertion dysfunction after a period in which the person had not experienced genital pain, pelvic pain, or insertion dysfunction, and currently, the desired response is absent or reduced depending on the environment, by a partner, or in response to certain stimuli, but not absent or reduced in other situations. In one embodiment, the dyspareunia / insertive dysfunction is congenital generalized dyspareunia / insertive dysfunction. In one embodiment, the dyspareunia / insertive dysfunction is congenital situational dyspareunia / insertive dysfunction. In one embodiment, the dyspareunia / insertive dysfunction is acquired generalized dyspareunia / insertive dysfunction. In one embodiment, the dyspareunia and difficulty with penetration are acquired, situational dyspareunia and difficulty with penetration.

[0081] In one embodiment, the painful intercourse and difficulty with insertion are (i) Significant, persistent, or recurrent difficulty in insertion, including in cases of involuntary hardening or rigidity of the pelvic floor muscles during insertion attempts. (ii) Significant, persistent, or recurrent vulvovaginal pain or pelvic pain during insertion, and / or (iii) Marked, persistent, or recurrent fear or anxiety relating to vulvovaginal pain or pelvic pain, whether in anticipation of, during, or as a result of insertion; It is characterized by the following.

[0082] In one embodiment, the painful intercourse and difficulty with insertion are addressed by: (i) Symptoms that recur during sexual intercourse involving or potentially involving penetration, despite sufficient sexual desire and sexual stimulation (ii) Conditions that adversely affect the pelvic region and lead to genital pain and / or pain during intercourse, or symptoms that are not entirely attributable to a mental disorder, (iii) Symptoms not entirely attributable to insufficient vaginal lubrication or postmenopausal / age-related changes, (iv) Clinically significant distressing symptoms, There is.

[0083] In one embodiment, the pain is vulvar pain. Vulvar pain can be caused by infectious factors, inflammatory factors, neoplastic factors, neurological factors, traumatic or iatrogenic factors, or certain disorders such as hormone deficiencies. In one embodiment, vulvar pain has a neurological component, for example, vulvar pain is caused by postherpetic neuralgia, nerve compression, nerve injury, or neuroma.

[0084] In one embodiment, the pain is vulvodinia, i.e., persistent vulvar pain. Vulvodinia is persistent, unexplained pain in the vulva, the female genital area, including the skin surrounding the vaginal opening. In one embodiment, vulvodinia is localized vulvodinia, such as vaginal vestibular pain or clitoral pain, or systemic vulvodinia. In one embodiment, vulvodinia is a mixed type of vulvodinia having both localized and systemic vulvodinia components. Vulvodinia may be associated with or coexist with other medical conditions.

[0085] In one embodiment, the pain is pain associated with menopausal genitourinary syndrome (GSM). GSM is a set of symptoms and signs caused by changes in the labia majora / minora, clitoris, vaginal vestibule / vaginal orifice, vagina, urethra, and bladder that occur in menopausal women. The term menopausal genitourinary syndrome is used instead of the terms vaginal atrophy or vulvovaginal atrophy, genitourinary atrophy, or atrophic vaginitis. Symptoms of GSM include, but are not limited to, genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and dysfunction; and urinary tract symptoms of urinary urgency, dysuria, and recurrent urinary tract infections. In one embodiment, the pain is pain associated with menopausal genitourinary syndrome or associated with vaginal atrophy, vulvovaginal atrophy, genitourinary atrophy, or atrophic vaginitis. In one embodiment, GSM or vaginal atrophy is caused by low-estrogen factors.

[0086] In one embodiment, the compound can reduce painful intercourse.

[0087] One embodiment provides a compound of formula (I) described herein for use in the treatment, prevention, or relief of pain, for example, of the type of pain described herein, in which case the compound is administered in an amount of 0.5 to 10 mg per individual dose, for example, 1 to 10 mg per individual dose, preferably 5 to 10 mg.

[0088] One embodiment provides a compound of formula (I) described herein for use in the treatment, prevention, or relief of neuropathic pain, for example, neuropathic pain of the type described herein, in which case the compound is administered in an amount of 0.5 to 10 mg per individual dose, for example, 1 to 10 mg per individual dose, preferably 5 to 10 mg.

[0089] One embodiment provides a compound of formula (I) described herein for use in the treatment, prevention, or relief of dyspareunia, of the type of dyspareunia described herein, in which case the compound is administered in an amount of 0.5 to 10 mg per individual dose, for example, 1 to 10 mg per individual dose, preferably 5 to 10 mg.

[0090] One embodiment provides a compound of formula (I) described herein for use in the treatment, prevention, or relief of trigeminal neuralgia, in which the compound is administered in an amount of 0.5 to 10 mg per individual dose, for example, 1 to 10 mg per individual dose, preferably 5 to 10 mg.

[0091] One embodiment provides a compound of formula (I) as described herein for use in the treatment, prevention, or relief of vulvodinia or progressive vulvodinia or vulvar pain as described herein, in which case the compound is administered in an amount of 0.5 to 10 mg per individual dose, for example, 1 to 10 mg per individual dose, preferably 5 to 10 mg.

[0092] In one embodiment, the pain occurs for at least one minute, for example, at least five minutes, for example, at least ten minutes, for example, at least thirty minutes.

[0093] In one embodiment, the pain occurs for at least one minute, for example, at least five minutes, for example, at least ten minutes, for example, at least thirty minutes, for example, at least one hour, for example, at least two hours, for example, for more than two hours.

[0094] In one embodiment, the pain occurs or recurs for at least one day, for example, at least three days, for example, at least one week.

[0095] In one embodiment, the compounds for use described herein can induce a pain reduction of at least 5% in a subject, for example, at least 10%, for example at least 15%, for example 20%, for example 30%, for example 40%, for example 50%, for example 60%, for example 70%, or more in a subject.

[0096] In one embodiment, the compounds for use described herein can reduce pain sensitivity.

[0097] Pain response or reduction can be assessed by subjective pain measures, such as subjective measurements performed on a visual analog scale (VAS). For example, if there is a 100mm line, 0 represents "no pain" and 100 represents "worst pain imaginable." Participants are asked to mark the VAS using a single vertical line at a point they believe best reflects their pain level.

[0098] Pain response or pain reduction can also be assessed using a numerical rating scale (NRS). For example, an 11-point scale from 0 ("no pain") to 10 ("worst pain") can be used to ask participants to rate their pain.

[0099] Pain response or reduction may also be measured by other subjective measures, such as evaluating responses to questionnaires on a numerical scale. For example, dyspareunia may be assessed using a patient-reported outcomes (PRO) questionnaire that includes questions related to various aspects of dyspareunia and assesses responses before, after, and / or during treatment. The same approach can be used for other types of pain. For example, in women, dyspareunia can be measured using questions in the pain area of ​​the Female Sexual Function Scale (FSFI).

[0100] In one embodiment, the pain response or reduction during the treatment described herein is measured by subjective measurements such as visual analog scales, numerical rating scales, or patient-reported outcomes.

[0101] In one embodiment, the compounds for use described herein can improve sensory parameters such as detection and pain thresholds. For example, the compounds for use described herein can improve mechanical pain thresholds and / or detection, or thermal detection and / or thermal pain thresholds, such as cold pain thresholds or thermal pain thresholds, mechanical pain sensitivity, wind-up rate, and pressure pain thresholds.

[0102] In one embodiment, the compound administered as described herein can improve the mechanical pain threshold. In one embodiment, the compound administered as described herein can improve the detection of tenderness. In one embodiment, the compound administered as described herein can improve mechanical pain sensitivity. In one embodiment, the compound administered as described herein can improve the thermal pain threshold. In one embodiment, the compound administered as described herein can improve the thermal pain threshold. In one embodiment, the compound administered as described herein can improve the cold pain threshold. In one embodiment, the compound administered as described herein can improve thermal pain sensitivity, such as thermal or cold pain sensitivity. In one embodiment, the compound administered as described herein can improve the tenderness threshold. In one embodiment, the compound administered as described herein can improve tenderness sensitivity.

[0103] In one embodiment, the compounds for use described herein can improve function in a person experiencing pain, for example, by improving sleep quality, for example, by improving quality of life, for example, by improving social activities and maintaining social relationships, or for example, by maintaining or restoring the ability to work or perform activities.

[0104] In one embodiment, functional improvement is an improvement in sleep quality. In one embodiment, functional improvement is an improvement in quality of life. In one embodiment, functional improvement is the maintenance or restoration of the ability to work or perform activities.

[0105] As shown in the examples, the compounds at doses of 5 and 10 mg produced efficacy in a model of neuropathic pain while exhibiting fewer side effects compared to higher doses. These results highlight the advantages of establishing a chronic dosing plan with individual doses of 10 mg or less, for example, individual doses of 0.5–10 mg, for example, individual doses of 0.5–5 mg, for example, 0.5–1 mg, 1–2 mg, 2–3 mg, 3–4 mg, 4–5 mg per individual dose, so that steady-state plasma levels of IP2015 can yield positive therapeutic outcomes without adverse side effects.

[0106] Therefore, in one embodiment, the compound of formula I is administered once, twice, three, or four times a day in individual doses of 0.5 to 10 mg over a period of one, two, three, or four weeks, as described herein. In another embodiment, the compound is administered once, twice, three, or four times a day over a period of one month or longer, for example, two months, three months, six months, or one year.

[0107] Therefore, in one embodiment, the compound of formula I is administered once, twice, three, or four times per week in individual doses of 0.5 to 10 mg over a period of one, two, three, or four weeks, as described herein. In another embodiment, the compound is administered once, twice, three, or four times per week over a period of one month or longer, for example, two months, three months, six months, or one year.

[0108] In one embodiment, the subject is a mammal. In one embodiment, the mammal is a human.

[0109] The compounds for use according to this disclosure may be used in combination with one or more further therapeutic agents. In one embodiment, one or more further therapeutic agents effective in treating or preventing pain are administered to the target. In one embodiment, one or more further therapeutic agents are selected from the group consisting of opioid receptor agonists such as tramadol or tapentadol, methadone, nalbufine, butorphanol, buprenorphine, oxycodone, or morphine, and nonsteroidal anti-inflammatory drugs such as COX-2 inhibitors, diclofenac, naproxen, ibuprofen, celecoxib, mefenamic acid, etoricoxib, or indomethacin.

[0110] In one embodiment, one or more further therapeutic agents are effective in treating neuropathic pain. In one embodiment, one or more further therapeutic agents are selected from the group consisting of gamma-aminobutyric acid analogs such as gabapentin or pregabalin; capsaicinoids such as capsaicin; dual serotonin-norephrine reuptake inhibitors such as duloxetine; anticonvulsants such as carbamazepine or oxacarbazepine; tricyclic antidepressants such as amitriptyline or nortriptyline; TRPV1 receptor modulators such as TRPV1 receptor agonists or TRPV1 receptor antagonists; and neurokinin receptor modulators such as neurokinin receptor antagonists or neurokinin receptor agonists.

[0111] In one embodiment, the compound of formula I is administered orally. In another embodiment, the compound of formula I is administered parenterally, for example, by skin, mucous membrane, subcutaneous, intramuscular, intraperitoneal, intravenous, or intra-arterial injection.

[0112] In one embodiment, the compounds for use described herein are formulated into a pharmaceutical composition further comprising a pharmaceutically acceptable diluent, carrier, and / or excipient. In one embodiment, the compounds are formulated as solid dosage forms such as tablets, capsules, pills, granules, or powders.

[0113] In one embodiment, a compound according to formula (I) and one or more further therapeutic agents described herein are administered in the same formulation.

[0114] One aspect of this disclosure is a compound of formula I, [ka] Alternatively, a solid dosage form containing a pharmaceutically acceptable salt thereof is provided, in which case the compound is present in an amount of about 1 mg to about 10 mg.

[0115] Pharmaceutical use The inventors have shown that the administration of compounds of formula I described herein is useful for the treatment of neuropathic pain. Accordingly, this disclosure provides the use of compounds of formula I as described in the section “Compounds for Use”.

[0116] One embodiment of the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for the treatment, prevention, or relief of pain, wherein the compound is administered in a dose of about 0.001 mg / kg to 1 mg / kg. One embodiment of the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for the treatment of pain.

[0117] One embodiment of the present disclosure provides a method for treating, preventing, or alleviating pain in a subject of interest, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.001 mg / kg to about 1 mg / kg.

[0118] One embodiment of the present disclosure provides a method for inducing pain relief in a subject of need, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.001 mg / kg to about 1 mg / kg.

[0119] One embodiment of the present disclosure provides a method for improving function in a subject experiencing pain, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.001 mg / kg to about 1 mg / kg.

[0120] item 1. Compounds of formula I for use in the treatment, prevention, or relief of pain in the subject. [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.5 to 100 mg.

[0121] 2. The compound for use as described in item 1, wherein the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxychromen-2-one or a pharmaceutically acceptable salt thereof.

[0122] 3. The compound for use as described in any one of the preceding items, administered in an amount of approximately 0.5 mg to approximately 30 mg per individual dose, for example, approximately 1 mg to approximately 10 mg per individual dose.

[0123] 4. The compound for use as described in any one of the preceding items, administered once daily.

[0124] 5. The compound for use as described in any one of items 1 to 3, administered multiple times a day, for example, twice a day, three times a day, or four times a day.

[0125] 6. The pain described above, (i) Chronic or acute primary pain, (ii) Chronic or acute cancer-related pain, (iii) Chronic or acute postoperative pain, (iv) Chronic or acute post-traumatic pain, (v) Chronic or acute secondary musculoskeletal pain, (vi) Chronic or acute secondary visceral pain, (vii) Chronic or acute neuropathic pain, and (viii) A compound for use as described in any one of the preceding items selected from the group consisting of chronic or acute secondary headache or orofacial pain.

[0126] 7. A compound for use as described in any one of the preceding items, wherein the pain is neuropathic pain.

[0127] 8. A compound for use as described in any one of the preceding items, wherein the neuropathic pain is peripheral neuropathic pain.

[0128] 9. The compound described in any one of the preceding items, wherein the neuropathic pain is the neuropathic component of nociceptive pain.

[0129] 10. A compound for use as described in any one of the preceding items, wherein the pain is trigeminal neuralgia.

[0130] 11. A compound for use as described in any one of the preceding items, wherein the subject is further administered an additional therapeutic agent for the treatment of pain, such as pregabalin.

[0131] 12. A compound for use according to any one of the preceding items, wherein the compound can induce a pain reduction of at least 5%, for example, at least 10%, for example, at least 15%, for example, 20%, in the subject.

[0132] 13. A compound for use as described in any one of the preceding items, wherein the administration of the compound is by oral administration.

[0133] 14. A compound for use as described in any one of the preceding items, wherein the compound is formulated as a solid dosage form such as a tablet.

[0134] 15. Compounds of formula I, [ka] A solid dosage form comprising a pharmaceutically acceptable salt thereof, wherein the compound is present in an amount of about 1 mg to about 10 mg. [Examples]

[0135] Example 1: Efficacy in vitro Materials and methods As described in WO97 / 16451 (NeuroSearch A / S), the compounds were tested for their ability to inhibit the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NA), and serotonin (5-HT) in synaptosomes. Furthermore, the compounds were tested for 5-HT (SERT), dopamine (DAT), and norepinephrine (NET) in human epithelial cells expressing human transporters.

[0136] result The test value is IC 50 (The test substance is 3 H-DA, 3 H-NA or 3 The concentration (μM) is shown as the concentration that inhibits the specific binding of H-5-HT by 50%. See Table A.

[0137] [Table 1] Table B shows the concentrations that cause 50% inhibition of the 5-hydroxytryptamine transporter (5-HTT or SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) in human epithelial cells.

[0138] [Table 2] a The maximum inhibition of IP2015 in 5-HTT was 80%.

[0139] Example 2: Microdialysis test in mouse brain Materials and methods In a small subset of mice, microdialysis was performed by placing a probe in either the striatum or cortex using stereotactic methods. After subcutaneous injection of IP2015 10 mg / kg, the perfusion fluid was sampled, and amines were measured by high-pressure liquid chromatography and standardized to the internal sample.

[0140] result The results shown in Figure 1 indicate that dopamine levels increased in the cortex and decreased in the striatum compared to NA and 5-HT.

[0141] conclusion These findings support the idea that IP2015 is a DAT-preferring monoamine reuptake inhibitor. The distinct increases in amines at the two sites are consistent with the in vivo binding properties of IP2015, as well as the known expression of DAT, NAT, and SERT.

[0142] Example 3: Effect of IP2015 in a rat model of chronic constriction injury for neuropathic pain. Chronic pain, particularly neuropathic pain, is characterized by spontaneous pain and paresthesia. Underlying these signs and symptoms after injury are multiple mechanisms, including primary afferent ectopic activity, induction of central sensitization in response to increased primary afferent drive, and spinal cord disinhibition.

[0143] The chronic constriction injury (CCI) model of neuropathic pain is a well-characterized preclinical model typically used as a primary behavioral screening tool for assaying the antinociceptive activity of compounds in laboratory rodents. Following CCI, the injured hind paw becomes more sensitive to mechanical, thermal, and cold stimuli, usually lasting for 6–8 weeks.

[0144] The objective of this study was to evaluate the antinociceptive effect of the triple monoamine reuptake inhibitor IP2015 in this rodent model of neuropathic pain.

[0145] Materials and methods IP2015 was dissolved in 15% hydroxypropyl β-cyclodextrin (Sigma) in 50 mM phosphate buffer. All treatments were administered subcutaneously at a dose volume of 2 ml / kg 60 minutes prior to behavioral assessment.

[0146] Mature male Sprague-Dawley rats (Harlan Scandinavia, Alleroed, Denmark) were used. They were housed in Macrolon III cages (20×14×18cm or 20×40×18cm; 2-5 rats per cage depending on weight) with wood chip bedding (3×1×4mm). The environment was controlled by temperature (20±2℃) and humidity (55±15%) and consisted of a 13:11 light-dark cycle (lights on at 06:00, off at 19:00). Food (Altromin®) and water were freely available. The rats were acclimated to the containment facility for at least one week before being randomly assigned to behavioral experiments. All experiments were conducted in accordance with the ethical guidelines of the International Association for the Study of Pain (Zimmermann, 1983) and the Danish Committee for Experiments on Animals.

[0147] Test design All drug studies in CCI rats were blinded by observers. A 2-3 day drug recovery period was observed, and the studies were conducted 4-5 weeks post-surgery. The CCI rats used in this study had previously been enrolled in similar experiments evaluating the efficacy of other compounds(s). Only animals exhibiting clear neurological impairment (von Frey response <4g, pin-prick response >10 seconds) were included in the study. The experimental groups are shown in Table C.

[0148] [Table 3]

[0149] procedure Treatment of chronic compression injury. Chronic compression injury (CCI) was performed in rats (body weight 180-220g at the time of surgery) under isoflurane anesthesia, as previously described (Bennett and Xie, 1988). The sciatic nerve was exposed at the mid-thigh level proximal to the ischial trifunction. Four chromium ligatures (4 / 0) (Ethicon, New Brunswick, NJ) were loosely tied around the nerve at intervals of 1-2 mm to avoid impairing vascular supply. The upper layers of muscle were sutured in layers with 4 / 0 synthetic absorbable surgical sutures. The skin was closed and sutured with 4 / 0 silk sutures.

[0150] Behavioral testing of nerve-injured rats. Nerve-injured rats were tested for the presence of pain-like behaviors for up to 5 weeks post-surgery according to a previously described method (Munro et al., 2008). For mechanical hypersensitivity testing, individual rats were removed from their home cages and acclimatized for 15 minutes in a 15 × 20 cm white plexiglass test cage placed on a metal grid elevated to allow access to the plantar surface of the injured hind paw. A series of calibrated von Frey hairs (lower limit = 0.065 g, upper limit = 19.3 g, Stoelting Co, Wood Dale IL) were used to assess the presence of mechanical allodynia by applying them to the plantar surface of the hind paw, increasing the force until each filament began to bend. The filament was applied for 1-2 seconds, and this was repeated 5 times at 1-2 second intervals. Filaments that induced a foot withdrawal reflex in 3 out of 5 applications were considered to represent the threshold level at which the response occurred. The presence of mechanical hyperalgesia was assessed by applying pressure to the plantar surface of the hind leg with the tip of a safety pin, using a force strong enough to elicit a withdrawal reflex response in healthy, unsurgery-free animals, but not strong enough to penetrate the skin. A 15-second cutoff time was applied to the prolonged withdrawal often seen in feet with nerve damage.

[0151] Changes in hind leg weight-bearing were assessed using a weight-bearing instrument (Linton Instrumentation, UK) incorporating a dual-channel scale used to individually assess the weight distributed to each hind leg of a rat. Normally, uninjured rats distribute their weight evenly between the two hind legs (50:50). However, after tissue injury, rats preferentially favor the uninjured hind leg, and consequently, the difference in weight-bearing can be used as an indicator of spontaneous pain. Rats were placed in an attached Perspex chamber designed so that each hind leg was placed on a separate transducer pad. The test duration was set to 5 seconds, and digital readings for each hind leg were taken as the weight distributed to each leg (g). Three readings were taken to ensure that a consistent response was measured. These were averaged for each hind leg, and the difference in weight-bearing was calculated as the difference between the two hind legs.

[0152] Statistical values Data analysis was initially performed using Sigmastat 2.03 (SPSS Inc., Chicago, ILL.) and then re-verified using GraphPadPrism v8.0.3. All data are presented as mean ± SEM. One-way analysis of variance (ANOVA) was used to analyze the overall effect of the treatment. If the F-value was significant, this was followed up with Dunnett's test. P<0.05 was considered statistically significant.

[0153] Exam deviation Rats injected with 10 mg / kg, and especially 30 mg / kg, of IP2015 appeared extremely aroused and may have exhibited signs of anxiety-inducing behavior. Due to the nature of the behavioral testing procedure employed, the rats were optimally required to be calm and relatively still; therefore, only two rats were injected with 30 mg / kg of IP2015. Consequently, due to the small group size (n), this treatment was not included in the overall data analysis.

[0154] result Figure 2 shows the results of this test.

[0155] IP2015 slightly but significantly increased the hind paw retraction reflex threshold to mechanical von Frey stimulation in CCI rats. Following IP2015 administration, CCI-induced weight-bearing impairment recovered more robustly and in a dose-dependent manner, suggesting that IP2015 may be particularly effective in treating spontaneous and persistent pain symptoms following neuropathic injury.

[0156] Animals in the vehicle group showed a low threshold (approximately 1.1 g) for von Frey stimulation. In contrast, animals treated with IP2015 were far less sensitive to the stimulation; the group administered 3 mg of IP2015 per kg of body weight had a foot-withdrawal reflex threshold of approximately 5.7 g, while the group administered 10 mg of IP2015 per kg of body weight had a foot-withdrawal reflex threshold of approximately 3.6 g.

[0157] Animals in the vehicle group showed a duration of approximately 14.9 seconds for the leg withdrawal reflex. In comparison, animals treated with IP2015 showed a reduction in leg withdrawal reflex duration, specifically approximately 12.3 seconds in the group treated with 3 mg of IP2015 per kg of body weight and approximately 11.1 seconds in the group treated with 10 mg of IP2015 per kg of body weight.

[0158] Regarding load loading, a clear difference was observed between the vehicle group and the IP2015 group. In the vehicle group, the animals showed a load loading difference of approximately 51%. In contrast, the IP2015 group, which received 3 mg per kg of body weight, showed a lower difference of approximately 17%, while the IP2015 group, which received 10 mg per kg of body weight, showed an even lower difference of approximately 11%.

[0159] conclusion IP2015 slightly but significantly increased the hind paw retraction reflex threshold to mechanical von Frey stimulation in CCI rats. Following IP2015 administration, CCI-induced weight-bearing impairment recovered more robustly and in a dose-dependent manner, suggesting that IP2015 may be particularly effective in treating spontaneous and persistent pain symptoms following neuropathic injury.

[0160] Example 4: Effect of IP2015 in automated rat formalin testing for persistent nociceptive pain Chronic pain, particularly neuropathic pain, is characterized by spontaneous pain and paresthesia. Underlying these signs and symptoms after injury are multiple mechanisms, including primary afferent ectopic activity, induction of central sensitization in response to increased primary afferent drive, and spinal cord disinhibition.

[0161] The formalin test is used as a primary behavioral screening tool to assay the antinociceptive activity of compounds in laboratory rodents. Following formalin injection of the hind leg, nociceptive behavior is represented in a biphasic pattern separated by a quiescent phase called the intermediate phase. From a purely constructive standpoint, the phases of the constituent elements show reasonable overlap with various mechanisms of clinical neuropathic pain, thereby supporting its routine use as a primary behavioral screening tool to assay the antinociceptive activity of novel compounds.

[0162] The objective of this study was to evaluate the antinociceptive effect of the triple monoamine reuptake inhibitor IP2015 in this animal model.

[0163] Materials and methods IP2015 was dissolved in 15% hydroxypropyl β-cyclodextrin (Sigma) in 50 mM phosphate buffer. All preparations were administered subcutaneously at a dose volume of 2 ml / kg 60 minutes prior to formalin injection.

[0164] Mature male Sprague-Dawley rats (Harlan Scandinavia, Alleroed, Denmark) were used. They were housed in Macrolon III cages (20×14×18cm or 20×40×18cm; 2-5 rats per cage depending on weight) with wood chip bedding (3×1×4mm). The environment was controlled by temperature (20±2℃) and humidity (55±15%) and consisted of a 13:11 light-dark cycle (lights on at 06:00, lights off at 19:00). Food (Altromin®) and water were freely available. The rats were acclimated to the housing for at least one week before being randomly assigned to behavioral experiments. At the end of each experiment, the rats were euthanized by cervical dislocation. All experiments were conducted in accordance with the ethical guidelines of the International Association for the Study of Pain (Zimmermann, 1983) and the Danish Committee for Experiments on Animals.

[0165] Test design As highlighted in the section on the following steps, four rats were included in each automated test session. Four separate treatments were evaluated during the session, and the treatments were rotated to minimize bias associated with specific test chambers. The experimental groups are shown in Table D.

[0166] [Table 4]

[0167] procedure The formalin-induced atrophy behavior in normal, undamaged rats (body weight 180–220 g) was evaluated using an automated nociceptive analyzer (University of California, San Diego, CA; Yaksh et al., 2001). Briefly, this involved placing a small C-shaped metal band (10 mm wide × 27 mm long) around the hind leg of the rat being tested. Each rat (four rats were included in each test session) was administered a drug or vehicle according to the experimental paradigm followed and then placed in a cylindrical acrylic observation chamber (30.5 cm in diameter, 15 cm high). The individual rats were then gently restrained and formalin (5% saline, 50 ml, subcutaneously) was injected into the dorsal surface of the hind leg using a 27 G needle. They were then returned to their respective separate observation chambers, each of which was placed on a sealed detection device consisting of two electromagnetic coils designed to generate an electromagnetic field in which the movement of the metal band could be detected. Next, the analog signals were digitized, and a software algorithm was applied to distinguish between atrophy behavior and other foot movements before binning at a 1-minute sampling interval. In the initial formalin concentration response test, five phases of nociceptive behavior were identified and scored according to Yaksh et al., (2001): Phase 1 (P1=0-5 mins), Intermediate Phase (Int=6-15 mins), Early Phase 2 (P2A=16-40 mins), Late Phase 2 (P2B=41-60 mins), and the entire Phase 2 (P2A+P2B=16-60 mins). Subsequently, three of these phases were selected for drug administration experiments: Phase 1 (P1=0-5 mins), Intermediate Phase (Int=6-15 mins), and Early Phase 2 (hereinafter referred to as Phase 2 (P2=16-40 mins)) (Munro et al., 2007). The raw data from the 1-minute sampling interval was summed for each phase to obtain the total number of atrophy behaviors that occurred during that period.

[0168] Statistical values Data analysis was initially performed using Sigmastat 2.03 (SPSS Inc., Chicago, ILL.) and then re-verified using GraphPadPrism v8.0.3. All data are presented as mean ± SEM. One-way analysis of variance (ANOVA) was used to analyze the overall effect of the treatment. If the F-value was significant, this was followed up with Dunnett's test. P<0.05 was considered statistically significant.

[0169] Exam deviation All rats injected with 10 or 30 mg / kg of IP2015 exhibited spontaneous erection and / or ejaculation. This did not preclude registering those rats for formalin testing.

[0170] The automated test procedures used herein allow for offline analysis of data after each single test session. Importantly, this makes it possible to administer higher or lower doses of the compound before the test is completed. Typically, other treatments are tested alongside additional treatment groups to minimize bias within a single test session. Therefore, when it became clear that the minimum effective dose of IP2015 was likely less than 3 mg / kg, particularly in the intermediate and second phases, four additional rats were injected with a 1 mg / kg dose of IP2015.

[0171] result Figure 3 shows the results of this study. Figure 3(a) shows the atrophy behavior per minute in animals treated with the vehicle group and with IP2015 at doses of 1, 3, 10, or 30 mg per kg of body weight. IP2015 dose-dependently reduced the prevalence of atrophy behavior in both P1, the intermediate phase, and P2. Figure 3(b) shows the dose-dependent total atrophy behavior in P1, the intermediate phase, and P2.

[0172] conclusion IP2015 resulted in robust, dose-dependent inhibition of spontaneous nociceptive behavior throughout the rat formalin study. This inhibition was particularly pronounced during the intermediate phase, a period associated with the adoption of descending and spinal cord inhibitory control mechanisms.

[0173] Example 5: A randomized, double-blind, placebo-controlled trial to investigate the pharmacodynamic effects of IP2015 in healthy men using an intradermal capsaicin model. The primary objective of this study was to determine the pharmacodynamic (PD) effects of IP2015 in an intradermal (ID) capsaicin model in healthy men.

[0174] Materials and methods Study Design: This was a Phase I, randomized, double-blind, placebo-controlled, four-direction crossover study investigating the pharmacodynamic efficacy, safety, tolerability, and pharmacokinetic / pharmacodynamic correlation of two single-dose levels of IP2015 compared to pregabalin 300 mg and placebo in a healthy male population using an intradermal capsaicin model.

[0175] Participant volunteers were men aged 18–55 years with a Body Mass Index (BMI) of 18–30 kg / m2. These volunteers were determined to be healthy by their physicians based on a medical assessment including medical history, physical examination, concomitant medications, vital signs, 12-lead ECG, and laboratory evaluation. Participants were required to be in good overall health, have a skin type that met the measurement criteria, and be free from significant skin allergies, pigmentation abnormalities, or any skin conditions. Furthermore, these volunteers were able to tolerate capsaicin injections during screening and exhibited positive hyperalgesia, defined as an area of ​​hyperalgesia ≥ 15 cm2, 15 minutes after an ID dose of 100 μg of capsaicin administered at an additional screening visit at least 7 days prior to the initial dose. Only non-smokers or those who did not smoke more than 5 cigarettes per day (or used an equivalent amount of e-cigarettes) were accepted. Participants submitted written informed consent agreeing to abide by the requirements and limitations outlined in the consent form, which included the use of condoms during the study period and for three months after the final dose of the study drug if their partner was of childbearing potential.

[0176] Randomization. The randomization scheme was developed by MAC Clinical Research. After obtaining informed consent, each participant was assigned a unique screening number. Only participants who adhered to all inclusion criteria and did not meet any exclusion criteria were randomized to the trial. Participants were assigned randomization numbers in the order of inclusion. All screened participants were identifiable throughout the trial.

[0177] Block sorting randomization schedules were created by open-label MAC statisticians using SAS PROC PLAN. Participants were randomly assigned to one of four treatment sequences in a 1:1:1:1 ratio. Treatment sequences were assigned using a Latin square grid. Each of the four treatments was administered over four treatment periods according to the assigned treatment sequence. Treatment sequences were blinded until the database was locked.

[0178] Intervention. This study was designed to investigate the PD efficacy, safety, tolerability, and PK / PD correlation of two single-dose levels of IP2015 compared to 300 mg of pregabalin and placebo in healthy men using the ID capsaicin model.

[0179] A crossover design was used to enable within-subject comparative evaluation of disease progression (PD), safety, and pharmacokinetics (PK) at two single-dose levels of IP2015 compared to 300 mg pregabalin and placebo in healthy male subjects. A minimum dosing rest period of 5 days was selected based on the half-lives (t1 / 2) of IP2015 and pregabalin, which was sufficient to ensure drug clearance.

[0180] To enable a comparative evaluation of the safety and tolerability of IP2015 (5 mg or 10 mg) and pregabalin, and to assess the balance of benefits and risks of IP2015, a placebo was included in the study.

[0181] In this study, a double-dummy approach was used. A double-dummy approach is a technique used to maintain blinding when administering materials in a clinical trial where two treatments cannot be identical. Materials were prepared for IP2015 (active drug and its corresponding placebo solution) and pregabalin (active drug and placebo capsule). Participants received two sets of treatment (IP2015 or placebo solution and pregabalin or placebo capsule) during each treatment period, and during that period, they received the appropriate randomized treatment.

[0182] Clinical and examination data. Pain, hyperalgesia, allodynia, and AF were measured before and 15 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes after the administration of capsaicin. Two hours after the capsaicin injection, the subjects completed a quantitative sensory testing (QST) battery at two locations on the palmar surface of each forearm. One site was the most recent capsaicin injection site, and the other site was an equivalent location on the opposite forearm. After the collection of safety evaluations, PK blood samples, and pain measurements at multiple time points, if the principal investigator of the clinical trial determined that it was safe, all subjects were to be discharged from the CRU 8 hours after the administration of IP at 2015 / placebo solution. The minimum dosing interval between treatment periods was set at 5 days.

[0183] Test drug, dosage, and administration method: IP2015 was provided as a powder in a bottle for oral solution. IP2015 was dissolved using a 5% HPβCD solution. Reconstitution was performed by a pharmacist at the clinical facility prior to dosing.

[0184] To maintain blinding, a double-dummy approach was used. During each treatment period, the subjects were administered a solution (containing either 5 mg of IP2015, 10 mg of IP2015, or placebo) and a capsule (either 300 mg of pregabalin or placebo). The treatment combinations were as follows: · 5 mg of IP2015 solution and placebo capsule · 10 mg of IP2015 solution and placebo capsule · placebo solution and 300 mg pregabalin capsule · placebo solution and placebo capsule The subjects were randomized and received a single administration of the treatment combination during each treatment period. All subjects received each treatment combination only once. For IP2015 and pregabalin, since the capsaicin injection was scheduled to be administered at approximately t max IP2015 or placebo solution was administered 3 hours before the capsaicin injection, and pregabalin or placebo capsule was administered 1 hour before the capsaicin injection.

[0185] Evaluation methods: Pain was measured (response to ID capsaicin injection, pain measurement using a visual analog scale, area and pain score of hyperalgesia, area and pain score of allodynia, and AF), and pharmacodynamics were evaluated using the ID capsaicin model. Participants also completed a QST battery at two sites on the palmar surface of either forearm. The QST battery included the following tests: thermal detection and pain threshold, mechanical detection and pain threshold, stimulus / response function, wind-up rate, and pressure pain threshold.

[0186] Safety was assessed through AE reporting, 12-lead ECG, vital signs, physical examination, and clinical laboratory evaluation. Pharmacokinetics were evaluated by blood sampling.

[0187] Pain was measured using a Visual Analog Scale (VAS). The VAS consisted of a 100mm line, with 0 representing "no pain" and 100 representing "worst imaginable pain." Participants were asked to mark their VAS using a single vertical line at a location they considered to adequately reflect the level of pain (not systemic pain) caused by capsaicin injection. A new VAS was provided at each time point, and participants were not allowed to see previous VAS responses. The VAS was scored by measuring from the left side of the scale to the point where the participant marked the line, and the distance was recorded in millimeters.

[0188] The response to pain was also evaluated using a numerical rating scale (NRS). For example, participants were asked to rate their pain using an 11-point scale ranging from 0 ("no pain") to 10 ("worst pain"). In some evaluations, an NRS scale ranging from 0 to 100 was also used.

[0189] Thermal testing was performed using a thermal electrode probe (Medoc). Cold and warm sensation detection thresholds were measured first, followed by the determination of cold and heat pain sensation thresholds. The average threshold temperature was calculated from three consecutive measurements. All thresholds were obtained using a ramp stimulation (1°C / second) that ended when the subject pressed a button. For the thermal detection threshold, the ramp returning to baseline was 1°C / second, while for the thermal pain sensation threshold, this ramp was selected at the device's maximum capacity, approximately 5°C / second nominally.

[0190] The mechanical detection threshold was measured using a standardized, modified von Frey nylon set that applied forces ranging from 0.25 to 512 mN, stepped in multiples of 2 during bending (contact time 1-2 seconds). The skin contact surface of the von Frey nylon was made uniform in size and shape (rounded tip, 0.5 mm in diameter) to avoid sharp edges that might have promoted nociceptor activation. Using the method of limits, five thresholds were determined, each representing a series of increasing and decreasing stimulus intensities. The final threshold was the geometric mean of these five series.

[0191] The mechanical pain threshold was measured using custom-made weighted pinprick stimuli as a set of seven pinprick mechanical stimulators with fixed stimulus intensities (flat contact area with a diameter of 0.2 mm) and applying forces of 8, 16, 32, 64, 128, 256, and 512 mN. The stimulators were applied in ascending order at speeds of 2 seconds on, 2 seconds off until the first degree of sharpness was perceived. The final threshold was the geometric mean of the five ascending and descending stimuli. This study was designed to detect pinprick hypoesthesia.

[0192] Wind-up rate: In this study, the perceived intensity of a single pinprick stimulus (256 mN pinprick, tested on the arm) was compared to the perceived intensity of a series of 10 repeated pinprick stimuli of the same physical intensity (applied once per second within an area of ​​1 cm²). Participants were asked to rate the pain representing a single stimulus and to provide an estimated mean value across the entire series of 10 stimuli using a numerical rating scale from 0 to 100. The entire procedure was repeated 5 times. The wind-up rate was calculated by dividing the average rating of the 5 series by the average rating of the 5 single stimuli. Wind-up is a frequency-dependent increase in spinal neuronal excitability that reaches a plateau after approximately 5 stimuli, and its perceptual correlation was explained by this ratio.

[0193] A pressure meter device with a probe area of ​​1 cm² (probe diameter 1.1 cm) that exerts a maximum force of 20 kg / cm², equivalent to approximately 2000 kPa, was used to conduct a pressure pain threshold test. The pressure pain threshold was set at 50 kPa / second (approximately 0.5 kg / cm²). 2 The intensity was determined using three series of gradually increasing stimulus intensities applied as a slowly increasing ramp over a period of seconds.

[0194] Statistical method: Area (cm²) of brush-induced hyperalgesia, the primary PD evaluation item. 2 The results were derived from the ID capsaicin model recorded in the electronic case report form (eCRF) at each point in time and during each treatment period / visit.

[0195] The following secondary PD assessment items were also derived from the eCRF ID capsaicin model: • Subjective pain assessment (mm) • Pain score for hyperalgesia using a numerical rating scale (NRS) • Area (cm²) of brush-induced allodynia • Pain score for brush-induced allodynia using NRS • AF (cm2) from ID capsaicin A summary of whether or not the ID capsaicin response was measured is provided for each treatment, time point, and treatment duration / visit. Summary statistics including the arithmetic mean, standard deviation (SD), minimum, maximum, and median values ​​for each treatment, time point, and treatment duration / visit are presented. The effect of IP2015 on the evaluation item values ​​of the ID capsaicin model was analyzed using mixed-model repeated measures (MMRM).

[0196] Other secondary pharmacodynamic (PD) endpoints were associated with changes in QST battery assessments compared to placebo. Summary statistics for both the study and control areas, including arithmetic mean, standard deviation (SD), minimum, maximum, and median, as well as the overall coefficient of variation (CV) for each treatment and visit, and changes between the two, are shown. Additional exploratory statistical analyses were performed on QST battery assessments. The effect of IP2015 on QST endpoint values ​​was analyzed using MMRM.

[0197] result Subjective pain assessment: Administration of IP2015 had a positive effect on subjective pain assessment. The adjusted mean subjective pain assessment (mm) was lower at all time points after capsaicin injection compared to placebo with 5 mg IP2015, 10 mg IP2015, and 300 mg pregabalin (Table 1, Figure 4A). Therefore, IP2015 reduced the mean assessment in a dose-dependent manner, with the difference being most pronounced with 10 mg IP2015 treatment at 15, 30, and 60 minutes after capsaicin treatment, where IP2015 reduced the assessment by 7.2 mm, 8.3 mm, and 7.5 mm compared to placebo. Pregabalin reduced the assessment by 1.5 mm, 3.8 mm, and 4.4 mm at 15, 30, and 60 minutes after capsaicin injection, respectively, compared to placebo.

[0198] [Table 5] Abbreviations: CI - Confidence interval; MMRM - Repeated measures of a mixed model; N - Number of subjects who received the described treatment. [a] The whole includes all points in time. [b] The adjusted mean represents the observed value.

[0199] Area of ​​hyperalgesia: Administration of IP2015 had a positive effect on the area of ​​hyperalgesia compared to placebo (Figure 4B). Hyperalgesia increased after intradermal injection of capsaicin. The area of ​​hyperalgesia was smaller than placebo at all time points after capsaicin injection with 10 mg IP2015 and 300 mg pregabalin, and was observed to decrease from 60 minutes after capsaicin injection with 5 mg IP2015. The mean reduction in the area of ​​hyperalgesia compared to placebo at all time points with pregabalin and 10 mg IP2015 was 7.8 cm, respectively. 2 and 4cm 2 The effect of 5 mg IP2015 was more pronounced 60 minutes after capsaicin injection and reached its peak 120 minutes after capsaicin injection. 120 minutes after injection, similar effects of reducing the area of ​​hyperalgesia were observed with both doses of IP2015 and pregabalin.

[0200] Pain score after hyperalgesia: Administration of IP2105 had a positive effect on the pain score after hyperalgesia (Figure 4C). The adjusted mean pain score for hyperalgesia was lower than placebo at all time points after capsaicin injection for 5 mg IP2015, 10 mg IP2015, and 300 mg pregabalin. The pain score for hyperalgesia 120 minutes after capsaicin injection was similar for 300 mg pregabalin, 5 mg IP2015, and 10 mg IP2015. With pregabalin, the pain score was lower at all time points after capsaicin. In the group treated with 10 mg IP2015, the adjusted mean curve overlapped with the pain score for pregabalin (Figure 4C).

[0201] Area of ​​brush-induced allodynia: Administration of IP2015 showed a positive effect on the area of ​​brush-induced allodynia (Figure 4D). Both doses of IP2015 reduced the mean area of ​​brush-induced allodynia at all time points. The adjusted mean area of ​​brush-induced allodynia was lower with 300 mg of pregabalin compared to placebo at all time points after capsaicin injection (Figure 4D). Allodynia area with 5 mg IP2015 was lower compared to placebo at 30–120 minutes after capsaicin injection, and significantly lower at 120 minutes after capsaicin injection (P=0.049).

[0202] Pain score for allodynia: Administration of IP2015 showed a positive effect on pain scores for brush-induced allodynia. The adjusted mean pain score for allodynia across all time points (Table 2) was lower with 5 mg IP2015, 10 mg IP2015, and 300 mg pregabalin compared to placebo. For both doses of IP2015 and 300 mg pregabalin, the adjusted mean pain score for allodynia was lower than placebo at all time points after capsaicin injection (Figure 4E).

[0203] [Table 6] Abbreviations: CI - Confidence interval; MMRM - Repeated measures of a mixed model; N - Number of subjects who received the described treatment. [a] The whole includes all points in time. [b] The adjusted mean represents the observed value.

[0204] A post-hoc analysis was performed on quantitative sensory tests (QST) evaluations. Treatment with 10 mg IP2015 showed comparable results to pregabalin in terms of mechanical pain threshold and wind-up rate. For tenderness threshold, 10 mg IP2015 showed the best efficacy.

[0205] The overall increase in the thermal sensation threshold between the test and control areas was significant with 10 mg IP2015 (p=0.013) and nearly significant with 300 mg pregabalin (p=0.063). Treatment with IP2015 showed an improved effect on thermal sensation threshold in the thermal sensation test compared to pregabalin.

[0206] Safety evaluation: No deaths, serious adverse events (SAEs), or therapeutically adverse events (TEAEs) leading to withdrawal occurred during the study. Overall, 20 participants (80.0%) experienced 67 TEAEs across all treatment groups. Of the 67 TEAEs reported during the study, 63 events reported by 19 participants (76.0%) were of mild severity, and 4 events reported by 3 participants (12.0%) were of moderate severity. All four moderate events were thought to be related to the study drug and were reported after administration of 300 mg pregabalin or placebo. The four moderate events consisted of dizziness (2 participants; 1 participant received 300 mg pregabalin and 1 participant received placebo), mood swings (1 participant received 300 mg pregabalin), and syncope (1 participant received placebo). All TEAEs reported after administration of 5 mg IP2015 and 10 mg IP2015 were of mild severity.

[0207] TEAEs were most frequently reported in subjects treated with 300 mg pregabalin (19 subjects [79.2%] reported 28 events), followed by 10 mg IP2015 (13 subjects [54.2%] reported 19 events). The incidence of TEAEs in subjects treated with 5 mg IP2015 (7 subjects [29.2%] reported 10 events) was similar to that in subjects treated with placebo (8 subjects [32.0%] reported 10 events).

[0208] conclusion Single doses of 5 and 10 mg of IP2015 were positive in various measures related to the experience of neuropathic pain and were well-tolerated after transdermal injection of capsaicin in healthy male volunteers.

[0209] Example 6. Measurement of the safety and tolerability of an escalating single dose of IP2015 in healthy male subjects. The objectives of this study were to measure the safety and tolerability of an escalating single dose of IP2015 in healthy male subjects, and to measure the pharmacokinetics (PK) of a single oral dose of IP2015 in healthy male subjects.

[0210] Materials and methods Study Design: This study was a Phase I, randomized, double-blind, placebo-controlled, escalating single-dose safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) study of IP2015 in healthy male subjects.

[0211] Each participant received a single oral dose of either IP2015 or the corresponding placebo. The starting dose of IP2015 was 0.01 mg in Cohort 1. The dose level was gradually increased to a maximum of 0.05 mg in Cohort 2 and a maximum of 0.2 mg in Cohort 3. The doses for the remaining five cohorts were determined based on dose escalation criteria. In all cohorts, no more than two participants (one receiving the active drug and one receiving the placebo) were administered on the first day of administration, so that no more than one participant at each dose level received the active IP2015 for the first time.

[0212] Participants were required to join a Clinical Research Unit (CRU) for a screening visit within 28 days prior to administration. To collect baseline safety and pharmacodynamic (PD) assessments, participants were admitted to the CRU on day 1 and administered either IP2015 or placebo to a fasted state on the morning of day 1. All participants remained in the CRU until day 3 (48 hours after administration) to collect safety assessments, PK blood and urine samples, and CNS assessments.

[0213] Participants attended follow-up appointments 5-7 days after discharge from the CRU. The participation period for each participant was approximately 5 weeks.

[0214] Healthy participants were males of any racial origin, aged 18-59 years (inclusive), and with a BMI of 18-32 kg / m². 2 The participants were (including both ends) and weighed 50 kg or more. These participants were determined to be healthy by their physician based on their medical history, physical examination, concomitant medications, vital signs, 12-lead ECG, and clinical laboratory evaluation. All participants submitted written informed consent, including compliance with the requirements and restrictions outlined in the consent form.

[0215] Randomization and blinding were used. In cohorts 1 and 2, a total of 5 subjects were randomly assigned to receive either IP2015 (3 subjects) or placebo (2 subjects). Of the first two subjects, one received placebo and the other received IP2015. In all other cohorts 3–8, a total of 8 subjects were randomly assigned to receive either IP2015 (6 subjects) or placebo (2 subjects). Of the first two subjects, one received placebo and the other received IP2015. The randomization scheme was generated by a statistician using a SAS PROC plan.

[0216] The trial was conducted in a double-blind format (blinded for both the principal investigator and the subjects / patients). The randomization list was kept in a secure location until the end of the trial.

[0217] Either IP2015 or a placebo was poured into a blinded medication container and provided to the CRU's medication staff.

[0218] Investigational drug, dosage, and mode of administration. IP2015 and the corresponding placebo were provided as powders in bottles for oral solution. A 5% hydroxypropyl β-cyclodextrin solution was reconstituted to form the placebo, which was then used to dissolve IP2015. Reconstitution was performed by a pharmacist at the clinical facility prior to administration. This was stored at a controlled room temperature of 15–25°C until IP2015 was distributed to subjects / participants.

[0219] IP2015 or the corresponding placebo was administered once orally as a solution in the morning on day 1 in a fasting state. The dose was taken with 240 mL of water at room temperature. The subjects / participants were fasted overnight from before administration until 4 hours after administration. Water was given freely except for 1 hour before and 1 hour after administration.

[0220] The doses used in each cohort were as follows: · Cohort 1 - 0.01 mg · Cohort 2 - 0.05 mg · Cohort 3 - 0.2 mg · Cohort 4 - 0.6 mg · Cohort 5 - 1.8 mg · Cohort 6 - 5.4 mg · Cohort 7 - 16.2 mg · Cohort 8 - 10 mg

[0221] Evaluation. In this study, clinical safety data from adverse event (AE) reports, 12-lead electrocardiogram (ECG), cardiac remote monitoring, vital signs (standing and supine blood pressure (BP), heart rate (HR), oral temperature), and clinical laboratory evaluations (chemistry, hematology, urine tests) and physical examinations in healthy male subjects were evaluated.

[0222] In this study, parameters including, but not limited to, plasma PK concentrations, and area under the plasma concentration-time curve (AUC), time from zero to the last quantifiable concentration (AUC0-t), AUC from zero to infinity (AUC0-∞), observed maximum plasma concentration (Cmax), time to reach maximum plasma concentration (tmax), and elimination half-life (T1 / 2) in healthy male subjects were also evaluated. Blood samples for measuring the plasma concentration of IP2015 were taken before administration and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours after administration.

[0223] CNS evaluations (impulsive eye movement and Visual Analog Scale [VAS] evaluations) were performed before dosing and at 1, 2, 4, and 8 hours after dosing on day 1, and prolactin measurements were performed 24 and 48 hours after dosing.

[0224] To determine the potential CNS effects of IP2015, CNS evaluations were performed, which included the following: · Impulsive eye movement (sedation test, only for cohorts 3 - 8 in part A): Impulsive eye movement was measured using a saccade meter, a small portable device for recording the impulsive response to visual stimuli. Eye movement was measured non-invasively using infrared reflection, and a small laser mounted on the transducer projected a small stimulus in front of the subject's eyes. A hundred impulsive movements were performed at each time point. · Visual Analog Scale: Using the VAS, a series of symptoms (drowsiness, hunger, dizziness, nausea, anxiety, hypersensitivity) were evaluated on a scale from "none" to "extreme". · Prolactin level: Serum prolactin levels were obtained via blood samples and analyzed.

[0225] The parameters shown in Table E were derived to evaluate the effect of IP2015.

[0226]

Table 7

[0227] Statistical methods. Safety parameters were enumerated and summarized using descriptive statistics. Pharmacokinetic parameter estimates were calculated using a non-compartmental method. Pharmacokinetic data were enumerated for each subject / patient and summarized by descriptive statistics.

[0228] The dose proportionality in part A was analyzed using a linear regression model that used the logarithm of the PK parameters as the response variable and the logarithm of the dose as the independent variable. The linear regression model was Log(y i )=α+β * log dosei +ε i It can be expressed as follows, where α is the intercept and the dose i is the actual dose of IP2015 for the i-th subject, and ε i is, y i This is the random error (within the target) when observing the data.

[0229] The above model was applied to the following PK parameters: AUC0-t, AUC0-∞, and Cmax. Based on the linear regression model, the dose-proportionality coefficient (slope) and its two-sided 90% confidence interval (CI) were estimated. Dose-proportionality was declared if the 90% CI of the slope was entirely contained within the following ranges: 1+log(0.5) / log(r), 1+log(2) / log(r) (where r is the high dose / low dose).

[0230] Pharmacodynamic data are presented for each subject, along with summary statistics including arithmetic mean, standard deviation, minimum, maximum, and median, broken down by time period and dose cohort.

[0231] result Pharmacokinetics of IP2015 single dose Plasma concentrations of IP2015 were below LLOQ in all subjects administered 0.01 mg and 0.05 mg of IP2015, as well as in 3 / 7 of subjects administered 0.2 mg of IP2015. The plasma concentration-time characteristics of IP2015 at doses of 0.6 mg and above were characterized by a relatively rapid absorption phase. The median tmax was generally similar across all doses, ranging from 2.25 to 5.00 hours post-administration, and across all dose levels, tmax ranged from 1.00 to 6.00 hours post-administration. After reaching Cmax, plasma concentrations of IP2015 appeared to decrease biphasically. The mean T1 / 2 of IP2015 was generally similar across doses from 5.4 mg to 16.2 mg, with a mean range of 23.11 to 26.30 hours. At the lower dose levels of 0.6 mg and 1.8 mg, the mean t1 / 2 was shorter (14.49 hours and 16.09 hours, respectively), which is likely due to the fact that the elimination phase was not fully defined at these doses, as T1 / 2 could only be calculated for 1 / 6 of the subjects who received 0.6 mg of IP2015 and 3 / 6 of the subjects who received 1.8 mg of IP2015. At the 0.2 mg dose level, the half-life could not be calculated for any of the subjects.

[0232] The dose-proportional analysis is shown in Table F. The slope estimate (90% CI) from the regression analysis of Cmax was 1.1389 (1.1005~1.1773) for IP2015. The lower limit of the 90% CI was above 1, which indicates that it was slightly greater than the dose-proportional increase in Cmax over the range of 0.2 to 16.2 mg. The slope estimates (90% CI) for AUC0-∞ and AUC0-t for IP2015 were 1.1884 (1.0721~1.3048) and 1.5579 (1.4007~1.7151), respectively. The lower limit of the 90% CI was above 1 for both parameters, which indicates that over the dose range of 0.2 to 16.2 mg, it was slightly greater than the dose-proportional increase in systemic exposure based on AUC0-∞ and greater than the dose-proportional increase in systemic exposure based on AUC0-t.

[0233] [Table 8] Abbreviations: AUC0-∞ - Area under the time curve of plasma concentration from zero to infinity; AUC0-t - Area under the time curve of plasma concentration from zero to the last quantifiable concentration; CI - Confidence interval; Cmax - Maximum plasma concentration.

[0234] Adverse events: Overall, 24 subjects (42.1%) experienced 44 therapeutic adverse events (TEAEs). The incidence of TEAEs was relatively low across the dose range of 0.01 mg to 10 mg. In the 16.2 mg dose group, all four subjects reported at least one TEAE. The majority of events were mild in severity, and no subjects discontinued treatment due to TEAEs. Of the 40 subjects who received IP2015, 16 experienced a total of 32 TEAEs during the study. Therapeutic AEs were reported in all dose groups except the 0.05 mg and 0.6 mg dose groups. Eight subjects in the placebo group experienced a total of 12 TEAEs.

[0235] There were no significant treatment-related or dose-related trends in mean or individual subject hematological, serum biochemical, or urinalysis data during the study, and no clinically significant findings were observed on the physical examinations performed. There were no significant treatment-related or dose-related trends in mean or individual subject vital signs across the dose range of 0.01 mg to 10 mg. At the 16.2 mg dose level, increases from baseline in standing heart rate were observed at 2, 3, 4, 6, 8, 10, and 12 hours after administration, while increases from baseline in supine heart rate were observed at 6, 8, and 10 hours after administration, respectively. These increases from baseline were the result of two subjects who exhibited sustained tachycardia for several hours.

[0236] No significant treatment-related or dose-related trends were observed in mean ECG parameters across the dose range of 0.01 mg to 10 mg. At the 16.2 mg dose level, increases in heart rate from baseline were observed 8 and 12 hours after administration, respectively.

[0237] conclusion The incidence of TEAEs was relatively low across the dose range of 0.01 mg to 10 mg. The incidence of adverse events increased at 16.2 mg compared to the 0.01 mg to 10 mg dose range. The majority of events were mild in severity, and no patients discontinued treatment due to TEAEs.

Claims

1. Compounds of formula (I) for use in the treatment, prevention, or relief of pain in the subject, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a dose of 0.5 to 10 mg per individual dose.

2. The aforementioned compound is of formula (Ia), 【Chemistry 2】 A compound for use according to claim 1, having the structure of a pharmaceutically acceptable salt thereof.

3. The compound for use according to any one of claims 1 and 2, wherein the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxychromen-2-one or a pharmaceutically acceptable salt thereof.

4. The compound for use according to any one of the prior claims, wherein the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxychromen-2-one hydrochloride.

5. The compound for use according to any one of the prior claims, wherein the compound of formula I is administered in an amount of about 1 mg to about 10 mg per individual dose, for example, about 1 mg to about 10 mg per individual dose, for example, about 3 to about 10 mg per individual dose, for example, about 5 mg per individual dose, for example, about 10 mg per individual dose.

6. The compound for use as described in any one of the preceding items, wherein the compound is administered orally in an amount of about 0.01 to about 0.25 mg / kg per individual dose, for example 0.01 mg / kg, for example 0.05 mg / kg, for example 0.1 mg / kg, for example 0.15 mg / kg, for example 0.2 mg / kg, for example 0.25 mg / kg.

7. The compound for use according to any one of the prior claims, wherein the compound is administered once daily.

8. The compound for use according to any one of claims 1 to 6, wherein the compound is administered multiple times a day, for example, twice a day, three times a day, or four times a day.

9. The compound for use as described in any one of the preceding items, wherein the total daily dose of the compound is approximately 1 to 10 mg, for example 3 to 10 mg, for example 5 mg, or for example 10 mg.

10. The compound for use according to any one of the prior claims, wherein the pain is selected from the group consisting of acute pain, chronic pain, mild pain, moderate or severe pain, postoperative pain, neuropathic pain, central nervous system pain, diabetic neuropathy, postherpetic neuralgia, peripheral neuropathy, phantom limb pain, neurogenic inflammation, fibromyalgia, pain associated with chronic regional pain syndrome, somatic pain, visceral or cutaneous pain, pain caused by inflammation or infection, arthritis, osteoarthritis, rheumatoid arthritis, neuronal hyperexcitability disorder, peripheral nerve hyperexcitability, back pain, cancer pain, toothache, irritable bowel pain, irritable bowel syndrome, postoperative pain, postmastectomy pain syndrome (PMPS), poststroke pain, drug-induced neuropathy, complex regional pain syndrome (CRPS), sympathetic nerve-dependent pain (SMP), trigeminal neuralgia, myofascial pain, chronic headache, migraine, migraine-related disorder, or tension-type headache.

11. The compound for use according to any one of claims 1 to 10, wherein the pain is chronic pain.

12. The compound for use according to any one of claims 1 to 10, wherein the pain is acute pain.

13. The compound for use according to any one of claims 1 to 12, wherein the pain is primary pain.

14. The compound for use according to any one of claims 1 to 12, wherein the pain is secondary pain.

15. The aforementioned pain, (i) Chronic or acute primary pain, (ii) Chronic or acute cancer-related pain, (iii) Chronic or acute postoperative pain, (iv) Chronic or acute post-traumatic pain, (v) Chronic or acute secondary musculoskeletal pain, (vi) Chronic or acute secondary visceral pain, (vii) Chronic or acute neuropathic pain, and (viiii) A compound for use according to any one of claims 1 to 14, selected from the group consisting of chronic or acute secondary headache or orofacial pain.

16. The compound for use according to claim 15, wherein the chronic or acute primary pain is chronic or acute primary visceral pain, chronic or acute widespread pain, fibromyalgia syndrome, chronic or acute primary musculoskeletal pain, chronic or acute primary headache or orofacial pain, such as migraine, burning mouth syndrome, tension headache, cluster headache, or persistent hemigraine, complex regional pain syndrome (CRPS), or painful contusion syndrome.

17. The compound for use according to claim 15, wherein the chronic or acute cancer-related pain is associated with visceral cancer pain, bone cancer pain, or neuropathic cancer pain.

18. The compound for use according to claim 15, wherein the chronic or acute cancer-related pain is post-cancer treatment pain, e.g., post-cancer medical treatment pain, e.g., chemotherapy-induced polyneuropathic pain, e.g., post-radiation therapy pain, e.g., radiation-induced neuropathic pain.

19. The compound for use according to claim 15, wherein the chronic or acute postoperative pain is postoperative pain after spinal surgery, hernia incision, hysterectomy, amputation, thoracotomy, breast surgery, or artificial joint replacement surgery.

20. The compound for use according to claim 15, wherein the chronic or acute post-traumatic pain is post-burn injury pain, whiplash-related pain, or post-musculoskeletal injury pain.

21. The compound for use according to claim 15, wherein the chronic or acute secondary musculoskeletal pain is pain resulting from persistent inflammation such as inflammation due to infection, inflammation due to crystal deposition, or inflammation due to autoimmune disorders and autoinflammatory disorders; pain related to structural changes, such as osteoarthritis-related pain or spondylosis-related pain; pain resulting from a disorder of the nervous system, such as Parkinson's disease-related pain, such as multiple sclerosis-related pain or peripheral nerve disease-related pain.

22. The compound for use according to claim 15, wherein the chronic or acute secondary visceral pain is pain resulting from mechanical factors, vascular mechanisms, or persistent inflammation, for example, in the head, neck, chest, abdomen, or pelvic region.

23. The compound for use according to claim 15, wherein the chronic or acute neuropathic pain is central nervous system pain such as spinal cord injury, brain injury, post-stroke pain, or multiple sclerosis-related central nervous system pain, peripheral nervous system pain, peripheral nervous system pain after nerve injury, polyneuropathic pain, or radicular pain, or neuropathic orofacial pain.

24. The compound for use according to claim 15, wherein the chronic or acute secondary headache or orofacial pain is chronic toothache, chronic neuropathic orofacial pain, headache, or orofacial pain associated with temporomandibular joint disorder, homeostasis or its non-pharmacological treatment, cranial or cervical vascular disorder, nonvascular intracranial disorder, substance or its removal, or traumatic injury to the head.

25. The compound for use according to any one of claims 1 to 15 or 23, wherein the pain is neuropathic pain.

26. The compound for use according to any one of claims 1 to 15 or any one of claims 23 or 25, wherein the neuropathic pain is acute neuropathic pain.

27. The compound for use according to any one of claims 1 to 15 or any one of claims 23 or 25, wherein the neuropathic pain is chronic neuropathic pain.

28. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is caused by alcoholism, diabetes, multiple sclerosis, multiple myeloma, stroke, cancer, cytomegalovirus, trigeminal neuralgia, spinal cord injury, or amputation.

29. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is caused by a chronic progressive neurological disease.

30. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is caused by an infection.

31. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is caused by injury.

32. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is progressive pain following a neuropathic injury.

33. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is caused by a side effect of drug therapy.

34. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is caused by a medical procedure such as surgery.

35. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is idiopathic.

36. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is the neuropathic component of nociceptive pain.

37. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is caused by diabetic neuropathy.

38. The compound for use according to claim 37, wherein the diabetes is chronic diabetes.

39. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is neuropathic cancer pain.

40. The compound for use according to any one of claims 25 to 27, wherein the neuropathic pain is caused by a neuropathy that develops under treatment.

41. The compound for use according to claim 40, wherein the neuropathy that develops under the aforementioned treatment is caused by chemotherapy.

42. The compound for use according to claim 40, wherein the neurological impairment occurring under the aforementioned treatment is attributable to radiotherapy.

43. The compound for use according to claim 40, wherein the neurological disorder that develops under the aforementioned treatment is caused by surgery.

44. The compound for use according to any one of the prior claims, wherein the pain is trigeminal neuralgia, allodynia, or hyperalgesia.

45. The compound for use according to any one of the prior claims, wherein the pain is trigeminal neuralgia.

46. The compound for use according to claim 45, wherein the pain is selected from classical trigeminal neuralgia, secondary trigeminal neuralgia, for example, secondary trigeminal neuralgia resulting from multiple sclerosis, secondary trigeminal neuralgia resulting from space-occupying lesions, and idiopathic trigeminal neuralgia.

47. The compound for use according to any one of claims 45 to 46, wherein the pain is painful trigeminal nerve disorder, for example, painful trigeminal nerve disorder caused by herpes zoster, for example, postherpetic neuralgia, for example, posttraumatic trigeminal nerve disorder, for example, idiopathic painful trigeminal nerve disorder.

48. The compound for use according to any one of the prior claims, wherein the pain is postherpetic neuralgia.

49. The compound for use according to any one of the prior claims, wherein the pain is pain in Parkinson's disease.

50. The compound for use according to any one of the prior claims, wherein the pain is dyspareunia (pain during intercourse).

51. The compound for use according to any one of the prior claims, wherein the pain is vulvar pain.

52. The compound for use according to any one of the prior claims, wherein the pain is vvorodynia or progressive vvorodynia.

53. The compound for use according to any one of the prior claims, wherein the pain is pain associated with menopausal genitourinary syndrome (GSM), or pain associated with vaginal atrophy, vulvar atrophy, genitourinary atrophy, or atrophic vaginitis.

54. A compound for use according to any one of the prior claims, comprising administering to the subject a further therapeutic agent effective in treating pain.

55. The compound for use according to any one of the prior claims, wherein the further therapeutic agent is selected from the group consisting of opioid receptor agonists such as tramadol or tapentadol, methadone, nalbufine, butorphanol, oxycodone, or morphine, and nonsteroidal anti-inflammatory drugs such as COX-2 inhibitors, diclofenac, naproxen, ibuprofen, celecoxib, mefenamic acid, or etoricoxib or indomethacin.

56. A compound for use according to any one of the prior claims, wherein the subject is administered another therapeutic agent effective in treating neuropathic pain.

57. The compound for use according to claim 56, wherein the therapeutic agent is selected from the group consisting of gabapentin, gamma-aminobutyric acid analogs such as pregabalin, capsaicinoids such as capsaicin, dual serotonin-norephrine reuptake inhibitors such as duloxetine, anticonvulsants such as carbamazepine or oxacarbazepine, tricyclic antidepressants such as amitriptyline or nortriptyline, TRPV1 receptor modulators such as transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor agonists or TRPV1 receptor antagonists, and neurokinin receptor modulators such as neurokinin receptor antagonists or neurokinin receptor agonists.

58. The compound for use according to any one of the prior claims, wherein the pain occurs for at least one minute, for example, at least five minutes, for example, at least ten minutes, for example, at least thirty minutes, for example, at least one hour, for example, at least two hours, for example, for more than two hours.

59. The compound for use according to any one of the prior claims, wherein the pain occurs for at least one day, for example, for at least three days, for example, for at least one week.

60. The compound for use according to any one of the prior claims, wherein the pain occurs for at least 20%, for example, at least 30%, for example, at least 40%, or at least 50% of the days over a period of more than one week, for example, more than two weeks, for example, more than three weeks, for example, more than one month, for example, more than two months, for example, more than three months.

61. The compound for use according to any one of the prior claims, wherein the compound can induce a pain reduction of at least 5%, for example, at least 10%, for example, at least 15%, for example, 20% in the subject.

62. The compound for use according to claim 61, wherein the reduction of the aforementioned pain is a subjective pain scale.

63. The compound for use according to claim 61, wherein the reduction of pain is the measurement of the pain threshold.

64. The compound for use according to any one of claims 61 to 63, wherein the measurement of the pain is performed using a visual analog scale (VAS), a numerical rating scale (NRS), or a patient-reported outcome (PRO).

65. The compound for use according to any one of the prior claims, administered once, twice, three, or four times a day over a period of one, two, three, or four weeks.

66. The compound for use according to any one of the prior claims, administered once, twice, three, or four times a day for a period of more than one month, for example, two months, three months, six months, or one year.

67. The compound for use according to any one of the prior claims, administered once, twice, three, four, or five times per week over a period of one, two, three, or four weeks.

68. The compound for use according to any one of the prior claims, administered once, twice, three, four, or five times a week for a period of more than one month, for example, two months, three months, six months, or one year.

69. The compound for use according to any one of the prior claims, wherein the compound can improve function in a person experiencing pain, such as improving sleep quality, improving quality of life, improving the maintenance of social activities and social relationships, or maintaining the ability to work.

70. The compound for use according to any one of the prior claims, wherein the subject is a mammal.

71. The compound for use according to any one of the prior claims, wherein the subject is a human.

72. The compound for use according to any one of the prior claims, wherein the administration of the compound is by oral administration.

73. The compound for use according to any one of claims 1 to 71, wherein the administration of the compound is parenteral administration such as by skin, mucous membrane, subcutaneous, intramuscular, intraperitoneal, intravenous, or intra-arterial injection.

74. A compound for use according to any one of the prior claims, comprising formulating the compound into a pharmaceutical composition further comprising a pharmaceutically acceptable diluent, carrier, and / or excipient.

75. The compound for use according to claim 74, wherein the compound is formulated as a solid dosage form such as a tablet, capsule, pill, granule, or powder.

76. Use of compounds of formula (I) to treat, prevent, or alleviate pain in the target population. 【Transformation 3】 Alternatively, the manufacture of a pharmaceutical product, wherein the compound is administered in an amount of 0.5 mg to 10 mg per individual dose, or the use of the compound or manufacture of a pharmaceutical product.

77. A method for treating, preventing, or alleviating pain in a subject requiring treatment, prevention, or relief of pain, wherein the method involves applying a compound of formula (I) to the subject requiring treatment, prevention, or relief of pain. 【Chemistry 4】 The treatment, prevention, or relief method comprising administering a pharmaceutically acceptable salt thereof in an amount of 0.5 mg to 10 mg per individual dose.

78. A method for inducing pain relief in a subject requiring pain relief, wherein the method involves administering to the subject a compound of formula I in an amount of 0.5 mg to 10 mg per individual dose. 【Transformation 5】 The induction method, comprising administering a pharmaceutically acceptable salt thereof.

79. A method for improving function in a subject experiencing pain, wherein the method involves administering to the subject a compound of formula I in an amount of 0.5 mg to 10 mg per individual dose. 【Transformation 6】 The improvement method, comprising administering a pharmaceutically acceptable salt thereof.

80. Compound of formula I, 【Transformation 7】 A solid dosage form comprising a pharmaceutically acceptable salt thereof, wherein the compound is present in an amount of about 1 mg to about 10 mg.

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