TW202132291A - Methods of using a phenoxypropylamine compound to treat pain - Google Patents

Abstract

The present disclosure relates to methods of treating pain, fibromyalgia, neuropathy, chemotherapy-induced pain, promoting an antihyperalgesic effect, and reducing sensitivity to pain, in a subject in need of such treatment comprising the administration of a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Description

Methods of using phenoxypropylamine compounds to treat pain [Related Application]

The present invention claims the priority and rights of U.S. Provisional Application No. 62/726,800 filed on September 4, 2018, the content of which is incorporated herein by reference in its entirety.

The present invention relates to methods for treating pain, for example, acute pain, chronic pain, toxic pain, neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, or a combination thereof .

Therapies used to treat pain are usually ineffective due to side effects, tolerability, medical abilities, and quality of life. For example, in the United States, opioid dependence has become a public health emergency. For example, in 2016, 63,632 people died from drug overdose in the United States alone (Scholl, L. et al. "Drug and Opioid-Involved Overdose Deaths-United States, 2013-2017" MMWR Morb Mortal Wkly Rep. 2019 67 (5152): 1419-1427). Therefore, there is a need to develop other non-opioid treatments to treat pain.

In one aspect, the present invention relates to a method for treating or preventing pain in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt or solvate thereof Or prodrugs,

In one aspect, the present invention relates to a method for treating pain in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt, solvate or prophylaxis thereof medicine,

In one aspect, the present invention relates to a method for preventing pain in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof ,

In one aspect, the pain is acute pain, chronic pain, toxic pain, neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, or a combination thereof.

In one aspect, the pain is peripheral neuropathy.

In one aspect, the pain is peripheral neuropathy, and the peripheral neuropathy is peripheral single neuropathy.

In one aspect, the pain is peripheral neuropathy, and the peripheral neuropathy is peripheral polyneuropathy.

In one aspect, the pain is chemotherapy-induced peripheral neuropathy.

In one aspect, the pain is chemotherapy-induced peripheral neuropathy, wherein the chemotherapy is paclitaxel.

In one aspect, the present invention relates to a method for treating or preventing fibromyalgia in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt or solvent thereof Compound or prodrug

In one aspect, the present invention relates to a method for treating or preventing neuropathy in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt or solvent combination thereof Prodrug

In one aspect, the neuropathy is peripheral neuropathy.

In one aspect, the neuropathy is a peripheral single neuropathy.

In one aspect, the neuropathy is peripheral polyneuropathy.

In one aspect, the neuropathy is induced by chemotherapy.

In one aspect, the present invention relates to a method for treating or preventing chemotherapy-induced pain in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt thereof, Solvate or prodrug

In one aspect, the chemotherapy-induced pain is neuropathic pain.

In one aspect, the chemotherapy is paclitaxel.

In one aspect, the present invention relates to a method for reducing the sensitivity of a subject to pain, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof

In one aspect, the present invention relates to a method for reducing the sensitivity of a subject to pain, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof

In one aspect, for any method of the application disclosed herein, the therapeutically effective amount of Compound I is 0.1 mg/kg to 100 mg/kg.

In one aspect, for any of the methods of the application disclosed herein, the therapeutically effective amount of Compound I is about 10 mg/kg.

In one aspect, for any method of the application disclosed herein, the therapeutically effective amount of Compound I is 1 mg to 1,000 mg.

In one aspect, for any method of the application disclosed herein, the therapeutically effective amount of Compound I is once a day, twice a day, 3 times a day, 4 times a day, once every 2 days, and 1 every 3 days. Administer to the subject once, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, or once a month.

In one aspect, for any of the methods of the application disclosed herein, Compound I is formulated as a pharmaceutical composition containing more than one pharmaceutically acceptable excipient. In one aspect, the pharmaceutical composition further contains other therapeutic agents for the treatment of pain.

In one aspect, for any of the methods of the application disclosed herein, Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or comprises Compound I or a pharmaceutically acceptable salt or solvate thereof Or prodrug composition, oral administration, parenteral administration, intravenous administration, intramuscular administration, intrathecal administration, subcutaneous administration, topical administration, systemic administration, intradermal administration, tongue Administering, buccal cavity Administration, rectal administration, vaginal administration, intraocular administration, intra-aural administration, intranasal administration, inhalation administration, atomization administration, or transdermal administration.

In one aspect, for any of the methods of the application disclosed herein, Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or comprises Compound I or a pharmaceutically acceptable salt or solvate thereof Or the drug composition of the prodrug, which is orally administered to the subject, and is formulated into lozenges, capsules, chews, gels, pastes, multiparticulates, nanoparticulates, oral lozenges, and pills Granules, granules, powders, solutions, sprays, emulsions, suspensions, syrups, mouthwashes, or drops.

In one aspect, for any of the methods of the application disclosed herein, Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or comprises Compound I or a pharmaceutically acceptable salt or solvate thereof The pharmaceutical composition of the prodrug is administered locally to the subject and is formulated as a cream, paste, lotion, gel, patch or spray.

In one aspect, it is applicable to any of the methods disclosed herein, and the method further includes the administration of other therapeutic agents for the treatment of pain. In one aspect, the other therapeutic agent and Compound I or a pharmaceutical composition containing Compound I are administered at similar times.

In one aspect, applicable to any method disclosed in this article, the object is a person.

In one aspect, it is applicable to any of the methods disclosed herein when improving the subject’s pain, fibromyalgia, neuropathy or chemotherapy-induced pain, enhancing the subject’s anti-hyperalgesic effect, or reducing the subject’s response to For pain sensitivity, the subject is then administered a maintenance dose of Compound I and/or other therapeutic agents for the treatment of pain. In one aspect, the maintenance dose of Compound I and/or other therapeutic agents is administered at a dose lower than the inducing dose, administered at a frequency lower than the inducing dose, or at a dose lower than the inducing dose and lower than The frequency of the induction dose is administered.

In one aspect, applicable to any of the methods disclosed herein, compound I is hydrochloric acid Salt.

In one aspect, the present invention relates to a pharmaceutical composition comprising the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the pharmaceutical composition being used to treat or prevent pain in a subject in need of treatment,

In one aspect, the present invention relates to a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of pain in a subject in need of treatment,

In one aspect, the present invention relates to a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the prevention of pain in a subject in need of such treatment,

In one aspect, the pain is acute pain, chronic pain, toxic pain, neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, or a combination thereof.

In one aspect, the pain is peripheral neuropathy.

In one aspect, the pain is peripheral neuropathy, and the peripheral neuropathy is peripheral single neuropathy.

In one aspect, the pain is peripheral neuropathy, and the peripheral neuropathy is peripheral polyneuropathy.

In one aspect, the pain is chemotherapy-induced peripheral neuropathy.

In one aspect, the pain is chemotherapy-induced peripheral neuropathy, wherein the chemotherapy is paclitaxel.

In one aspect, the present invention relates to a pharmaceutical composition comprising the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used to treat or prevent fibromyalgia in a subject in need of treatment ,

In one aspect, the present invention relates to a pharmaceutical composition comprising the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the pharmaceutical composition being used to treat or prevent neuropathy in a subject in need of treatment,

In one aspect, the neuropathy is peripheral neuropathy.

In one aspect, the neuropathy is a peripheral single neuropathy.

In one aspect, the neuropathy is peripheral polyneuropathy.

In one aspect, the neuropathy is induced by chemotherapy.

In one aspect, the present invention relates to a pharmaceutical composition comprising the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the pharmaceutical composition being used to treat or prevent chemotherapy induced by a subject in need of treatment pain,

In one aspect, the chemotherapy-induced pain is neuropathic pain.

In one aspect, the chemotherapy is paclitaxel.

In one aspect, the present invention relates to a pharmaceutical composition comprising the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the pharmaceutical composition being used to enhance the anti-hyperalgesia of a subject suffering from hyperalgesia effect

In one aspect, the present invention relates to a pharmaceutical composition comprising the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the pharmaceutical composition being used to reduce the sensitivity of a subject to pain,

In one aspect, applicable to any of the methods disclosed herein, the therapeutically effective amount of the pharmaceutical composition containing Compound I is 0.1 mg/kg to 100 mg/kg.

In one aspect, suitable for any of the methods disclosed herein, the therapeutically effective amount of the pharmaceutical composition containing Compound I is about 10 mg/kg.

In one aspect, suitable for any of the methods disclosed herein, the therapeutically effective amount of the pharmaceutical composition containing Compound I is 1 mg to 1,000 mg.

In one aspect, suitable for any use disclosed herein, the therapeutically effective amount of the pharmaceutical composition containing Compound I is once a day, twice a day, 3 times a day, 4 times a day, once every 2 days, Once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, or once a month Object.

In one aspect, suitable for any of the uses disclosed herein, the pharmaceutical composition containing Compound I is formulated with more than one pharmaceutically acceptable excipient. In one aspect, the pharmaceutical composition further contains other therapeutic agents for the treatment of pain.

In one aspect, suitable for any of the uses disclosed herein, the pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is formulated for oral administration, parenteral administration Administration, intravenous administration, intramuscular administration, intrathecal administration, subcutaneous administration, topical administration, systemic administration, intradermal administration, sublingual administration, buccal administration, rectal administration, vagina Administration, intraocular administration, Intraaural administration, intranasal administration, transdermal administration, inhalation administration or atomization administration.

In one aspect, suitable for any of the uses disclosed herein, a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is formulated as a lozenge for oral administration, Capsules, chews, gels, pastes, multiparticulates, nanoparticulates, lozenges, pills, granules, powders, solutions, sprays, emulsions, suspensions, syrups, Mouthwash, or drops.

In one aspect, suitable for any of the uses disclosed herein, a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is formulated as a cream for topical administration, Paste, lotion, gel, patch or spray.

In one aspect, it is suitable for any use disclosed herein, and the use includes other therapeutic agents for the treatment of pain. In one aspect, the other therapeutic agent and the pharmaceutical composition containing Compound I are administered at similar times.

In one aspect, it is suitable for any purpose disclosed in this article, and the object is a person.

In one aspect, it is suitable for any of the uses disclosed herein, when improving the subject’s pain, fibromyalgia, neuropathy, or chemotherapy-induced pain, enhancing the subject’s anti-hyperalgesic effect, or reducing the subject’s In the case of pain sensitivity, the subject is then administered a maintenance dose of the pharmaceutical composition containing Compound I and/or other therapeutic agents for the treatment of pain. In one aspect, the maintenance dose of the pharmaceutical composition containing Compound I and/or other therapeutic agents is administered at a dose lower than the inducing dose, administered at a frequency lower than the inducing dose, or administered at a lower than the inducing dose The dose and frequency lower than the induced dose.

In one aspect, suitable for any of the uses disclosed herein, Compound I is the hydrochloride salt.

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used to treat or prevent pain in a subject in need of treatment

In one aspect, the present invention relates to the following compound I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of pain in a subject in need of treatment,

In one aspect, the present invention relates to Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the prevention of pain in a subject in need of treatment,

In one aspect, the pain is acute pain, chronic pain, toxic pain, nerve pain Sexual pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, or a combination of these.

In one aspect, the pain is peripheral neuropathy.

In one aspect, the pain is peripheral neuropathy, and the peripheral neuropathy is peripheral single neuropathy.

In one aspect, the pain is peripheral neuropathy, and the peripheral neuropathy is peripheral polyneuropathy.

In one aspect, the pain is chemotherapy-induced peripheral neuropathy.

In one aspect, the pain is chemotherapy-induced peripheral neuropathy, wherein the chemotherapy is paclitaxel.

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used to treat or prevent fibromyalgia in a subject in need of treatment,

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used to treat or prevent neuropathy in a subject in need of treatment,

In one aspect, the neuropathy is peripheral neuropathy.

In one aspect, the neuropathy is a peripheral single neuropathy.

In one aspect, the neuropathy is peripheral polyneuropathy.

In one aspect, the neuropathy is induced by chemotherapy.

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used to treat or prevent chemotherapy-induced pain in a subject in need of treatment,

In one aspect, the chemotherapy-induced pain is neuropathic pain.

In one aspect, the chemotherapy is paclitaxel.

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used to enhance the anti-hyperalgesic effect of a subject suffering from hyperalgesia,

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used to reduce the sensitivity of a subject to pain,

In one aspect, suitable for any use disclosed herein, the therapeutically effective amount of Compound I is 0.1 mg/kg to 100 mg/kg.

In one aspect, suitable for any use disclosed herein, the therapeutically effective amount of Compound I is about 10 mg/kg.

In one aspect, suitable for any use disclosed herein, the therapeutically effective amount of Compound I is 1 mg to 1,000 mg.

In one aspect, suitable for any use disclosed herein, the therapeutically effective amount of Compound I is once a day, twice a day, 3 times a day, 4 times a day, once every 2 days, and once every 3 days , Once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, or once a month to the subject.

In one aspect, suitable for any of the uses disclosed herein, Compound I is formulated with more than one pharmaceutically acceptable excipient. In one aspect, Compound I is formulated with more than one pharmaceutically acceptable excipient and other therapeutic agents for the treatment of pain.

In one aspect, suitable for any of the uses disclosed herein, Compound I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is formulated for oral administration, parenteral administration, and intravenous administration. Medicine, intramuscular administration, intrathecal administration, subcutaneous administration, topical administration, systemic administration, intradermal administration, sublingual administration, buccal administration, rectal administration, vaginal administration, intraocular administration , Intra-aural administration, intranasal administration, transdermal administration, inhalation administration or atomization administration.

In one aspect, suitable for any of the uses disclosed herein, Compound I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is formulated as a lozenge, capsule, or chew for oral administration , Gels, pastes, multiparticulates, nanoparticulates, lozenges, pills, granules, powders, solutions, sprays, emulsions, suspensions, syrups, mouthwashes, or drops Agent.

In one aspect, suitable for any of the uses disclosed herein, Compound I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is formulated as a cream, paste, or lotion for topical administration , Gel, patch or spray.

In one aspect, it is suitable for any use disclosed herein, and the use includes other therapeutic agents for the treatment of pain. In one aspect, the other therapeutic agent and Compound I are administered at similar times.

In one aspect, it is suitable for any purpose disclosed in this article, and the object is a person.

In one aspect, it is suitable for any of the uses disclosed herein, when improving the subject’s pain, fibromyalgia, neuropathy, or chemotherapy-induced pain, enhancing the subject’s anti-hyperalgesic effect, or reducing the subject’s For pain sensitivity, the subject is then administered a maintenance dose of the compound I and/or other therapeutic agents used to treat pain. In one aspect, the maintenance dose of Compound I and/or other therapeutic agents is administered at a dose lower than the inducing dose, administered at a frequency lower than the inducing dose, or at a dose lower than the inducing dose and lower than The frequency of the induction dose is administered.

In one aspect, suitable for any of the uses disclosed herein, Compound I is the hydrochloride salt.

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used in the manufacture of a medicament for the treatment or prevention of pain in a subject in need of treatment,

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used in the manufacture of a medicament for the treatment of pain in a subject in need of treatment,

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used in the manufacture of a medicament for the prevention of pain in a subject in need of treatment,

In one aspect, the pain is acute pain, chronic pain, toxic pain, neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, or a combination thereof.

In one aspect, the pain is peripheral neuropathy.

In one aspect, the pain is peripheral neuropathy, and the peripheral neuropathy is peripheral single neuropathy.

In one aspect, the pain is peripheral neuropathy, and the peripheral neuropathy is peripheral polyneuropathy.

In one aspect, the pain is chemotherapy-induced peripheral neuropathy.

In one aspect, the pain is chemotherapy-induced peripheral neuropathy, wherein the chemotherapy is paclitaxel.

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used in the manufacture of a medicament for the treatment or prevention of fibromyalgia in a subject in need of such treatment,

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used in the manufacture of a medicament for the treatment or prevention of neuropathy in a subject in need of treatment,

In one aspect, the neuropathy is peripheral neuropathy.

In one aspect, the neuropathy is a peripheral single neuropathy.

In one aspect, the neuropathy is peripheral polyneuropathy.

In one aspect, the neuropathy is induced by chemotherapy.

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used in the manufacture of a medicament for the treatment or prevention of chemotherapy-induced pain in a subject in need of treatment,

In one aspect, the chemotherapy-induced pain is neuropathic pain.

In one aspect, the chemotherapy is paclitaxel.

On the one hand, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used in the manufacture of a medicament for enhancing the anti-hyperalgesic effect of a subject suffering from hyperalgesia,

In one aspect, the present invention relates to the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used in the manufacture of a medicament for reducing the sensitivity of a subject to pain,

In one aspect, applicable to any of the methods disclosed herein, the therapeutically effective amount of the agent containing Compound I is 0.1 mg/kg to 100 mg/kg.

In one aspect, suitable for any of the methods disclosed herein, the therapeutically effective amount of the agent containing Compound I is about 10 mg/kg.

In one aspect, applicable to any of the methods disclosed herein, the therapeutically effective amount of the agent containing Compound I is 1 mg to 1,000 mg.

In one aspect, suitable for any use disclosed herein, the medicament containing Compound I is once a day, twice a day, 3 times a day, 4 times a day, once every 2 days, once every 3 days, It is administered to the subject once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, or once a month.

In one aspect, suitable for any of the uses disclosed herein, the medicament is formulated with more than one pharmaceutically acceptable excipient. In one aspect, the medicament contains other therapeutic agents for the treatment of pain.

In one aspect, suitable for any of the uses disclosed herein, the medicament comprising Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is formulated for oral administration, parenteral administration , Intravenous, intramuscular, intrathecal, subcutaneous, topical, systemic, intradermal, sublingual, buccal, rectal, vaginal, Intraocular administration, intra-aural administration, intranasal administration, transdermal administration, inhalation administration or atomization administration.

In one aspect, suitable for any of the uses disclosed herein, the medicament containing Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is formulated as a tablet or capsule for oral administration Agents, chewing agents, gels, pastes, multiparticulates, nanoparticulates, lozenges, pills, granules, powders, solutions, sprays, emulsions, suspensions, syrups, gargles Saliva, or drops.

In one aspect, suitable for any of the uses disclosed herein, a medicament containing Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is formulated as a cream or paste for topical administration , Lotion, gel, patch or spray.

In one aspect, it is suitable for any use disclosed herein, and the use includes other therapeutic agents for the treatment of pain. In one aspect, the other therapeutic agent and the agent containing Compound I are administered at similar times.

In one aspect, it is suitable for any purpose disclosed in this article, and the object is a person.

In one aspect, it is suitable for any of the uses disclosed herein, when improving the subject’s pain, fibromyalgia, neuropathy, or chemotherapy-induced pain, enhancing the subject’s anti-hyperalgesic effect, or reducing the subject’s In the case of pain sensitivity, the subject is then administered a maintenance dose of a compound I-containing agent and/or other therapeutic agents used to treat pain. In one aspect, the maintenance dose of the medicament containing Compound I and/or other therapeutic agents is administered at a dose lower than the inducing dose, administered at a frequency lower than the inducing dose, or at a dose lower than the inducing dose And the frequency of administration is lower than the induced dose.

In one aspect, suitable for any of the uses disclosed herein, Compound I is the hydrochloride salt.

It should be understood that all combinations of the aforementioned concepts and other concepts discussed in more detail below (the prerequisite is that such concepts do not conflict with each other) are expected to be part of the subject matter of the invention disclosed herein. In particular, all combinations of the claimed subject matter appearing at the end of this disclosure are expected to be part of the subject matter of the invention disclosed herein. It should also be understood that the terms explicitly adopted in this article can also appear in any disclosure incorporated by reference, and the term should be based on the most consistent with the specific concept disclosed in this article.

Those with ordinary knowledge in the technical field will understand other methods and features after checking the following figures and embodiments. All such methods and features are included in this specification, in the context of the present invention Within the scope, and protected by the scope of the attached patent application.

Figure 1 summarizes the results of the effects of single intraperitoneal (ip) administration of MIN-117 at 0.1 mg/kg and 1 mg/kg doses ^{in ALGOGram TM.}

Figure 2 is a chart, which shows a single ip administration of MIN-117 (0.01, 0.1 and 1mg/kg ip), morphine (3mg/kg ip, positive control) and vehicle (negative control) in carrageenan Role in induced mechanical hyperalgesia (injured paw) model in rats. The results are expressed as mean ± s.e.m. (###: p<0.05, compared with the control (uninjured) paw of the corresponding group, Mann-Whitney rank sum test) (*: p<0.05, significant compared with the vehicle treatment group Tuckey test after Kruskal-Wallis univariate analysis of variance) ($$$: p<0.001, compared with vehicle treatment group, Mann-Whituey rank sum test)

Figure 3 is a series of bar graphs showing the effects of a single intraperitoneal administration of various doses of MIN-117, morphine and vehicle in a rat peripheral neuropathy model. For vehicle or MIN-117, the injury threshold is measured at 120 minutes after administration, and for morphine injection, the injury threshold is measured at 30 minutes after injection. The results are expressed as mean ± s.e.m. The percentage is expressed as a percentage of activity. (###: p<0.001, compared with the control paw of the corresponding group, Mann-Whitney rank sum test) (*: p<0.05, compared with the vehicle treatment group, significant Kruskal-Wallis one-way analysis of variance Later Tuckey test) ($$: p<0.01, compared with the baseline of the corresponding group, Wilcoxon rank sum test)

Figure 4 is a series of bar graphs showing the effects of a single intraperitoneal administration of various doses of MIN-117, morphine and vehicle in a carrageenan-induced mechanical hyperalgesia rat model. For vehicle or MIN-117, the injury threshold is measured at 120 minutes after administration, while for morphine injection, injury The harm threshold is measured 30 minutes after injection. The results are expressed as mean ± s.e.m. The percentage is expressed as a percentage of activity. ###: p<0.001, compared with the control paw of the corresponding group, Mann-Whitney rank sum test. *: p<0.05, compared with the vehicle treatment group, Kruskal-Wallis single factor analysis of variance. $$: p<0.01, compared with the baseline of the corresponding group, Wilcoxon rank sum test. The results are expressed as mean ± s.e.m. The percentage of dyskinesia is expressed as an increase (+) or decrease (-) compared to the pre-dose threshold, vehicle treatment group, and control paw, or as a percentage of activity. ###: p<0.001, compared with the control paw of the corresponding group, Mann-Whitney rank sum test. *: p<0.05, compared with the vehicle treatment group, Kruskal-Wallis single factor analysis of variance. $$: p<0.01, compared with the baseline of the corresponding group, Wilcoxon rank sum test. NS: Not significant.

Figure 5 is a series of bar graphs showing the baseline body weight before paclitaxel injection in the chemotherapy-induced neuropathic pain study. (Data are presented as mean ± s.e.m.) The analysis of variance of repeated measures showed no significant difference between groups.

Figure 6 is a series of broken line graphs showing the body weight of rats during the chemotherapy-induced neuropathic pain study in Example 5. The arrows on days 1, 3, 5, and 7 indicate the day of paclitaxel injection, and the arrows on day 14 indicate the day of administration of MIN-117 or gabapentin (positive control). (Data are presented as mean ± s.e.m.) The analysis of variance of repeated measures showed no significant difference between groups.

Figure 7 is a series of bar graphs showing the effect of the baseline paw reduction threshold before and after paclitaxel injection with multiple treatment groups (vehicle, gabapentin, and various doses of MIN-117). (Data are presented as mean ± s.e.m.) Before treatment, the analysis of variance showed no significant difference between treatment groups.

Figure 8 is a series of bar graphs showing the 14th from the day of the first paclitaxel treatment The effect of gabapentin, various doses of MIN-117, and vehicle on paw withdrawal threshold. (Data are presented as mean ± s.e.m.) *p<0.05, compared with vehicle.

Figure 9 is a schematic diagram that summarizes experiments to determine the efficacy of MIN-117 in preventing paclitaxel-induced peripheral neuropathic pain.

Figure 10 is a schematic diagram, which summarizes the experiments to determine the efficacy of MIN-117 in reversing the effect of paclitaxel-induced peripheral neuropathic pain.

Figure 11 is a series of broken line graphs showing the effects of paclitaxel and test compounds on the body weight of rats during the study of paclitaxel-induced peripheral neuropathic pain disclosed in Example 6. (The data are presented as mean ± s.e.m.)

Figure 12 is a series of histograms showing that after paclitaxel treatment on days 1, 3, 5, and 7, on days 8, 10, 14 and 21, gabapentin, various doses of MIN-117, and vehicle The effect of objects on the paw withdrawal threshold. (Data are presented as mean ± s.e.m.) *p<0.05, compared with vehicle.

Figure 13 is a series of broken line graphs showing the effects of paclitaxel and test compounds on the body weight of rats during the reversal study of paclitaxel-induced peripheral neuropathic pain disclosed in Example 6. (The data are presented as mean ± s.e.m.)

Figure 14 is a series of bar graphs showing the effect of paclitaxel treatment on the baseline paw withdrawal threshold. (The data are presented as mean ± s.e.m.)

Figure 15 is a series of bar graphs, which show that gabapentin, various doses of MIN-117, and vehicle on days 14, 21, 28, and 35 after paclitaxel treatment on days 1, 3, 5, and 7 The effect of objects on the paw withdrawal threshold. (Data are presented as mean ± s.e.m.) *p<0.05, compared with vehicle.

Figure 16 is a series of bar graphs showing the effect of vehicle and various doses of duloxetine on the paw withdrawal threshold (before treatment and 60 minutes after treatment). (Data are presented as mean ± s.e.m.) *p<0.05, compared with vehicle/vehicle.

Figure 17 is a series of bar graphs showing the effect of vehicle and various doses of amitriptyline on the paw reduction threshold (before treatment and 60 minutes after treatment). (Data are presented as mean ± s.e.m.) *p<0.05, compared with vehicle/vehicle. #p<0.05, compared with paclitaxel/vehicle.

All definitions as specified and used herein should be understood to take precedence over dictionary definitions, definitions in documents incorporated by reference, and/or the general meaning of the defined terms.

Unless clearly indicated otherwise, the term "about" as used herein refers to the listed value +/- 10%, +/- 5%, +/- 2.5%, +/- 1%, +/- 0.5 %, or +/- 0%. For example, "about" can refer to the recited value +/- 5%. Alternatively, in another aspect, "about" can refer to the recited value +/- 0%.

The indefinite articles "一 (a)" and "一 (an)" used in this specification and the scope of the patent application should be understood to mean "at least one" unless clearly indicated to the contrary.

As used in this specification and the scope of the patent application, the phrase "and/or" should be understood to mean "one or both" of the elements so connected , that is, coexist in some cases and coexist in other cases The elements of discontinuous existence below. Multiple elements listed with "and/or" shall be regarded as the same pattern, that is, "more than one" of the elements so connected. There may be other elements other than the elements specially marked by the "and/or" clause as required, regardless of whether the other elements are related to the specially marked elements. Therefore, as a non-limiting example, when used in conjunction with open language such as "including", the description of "A and/or B" can refer to, in one aspect, only A (includes other than B as required In another aspect, only B (including elements other than A as required); in another aspect, both A and B (including other elements as required), etc.

As used herein, phrases containing the term "and/or" such as "A, B, and/or C" refer to any of the following: only A; only B; only C; A and B; A and C; B and C; A, B and C.

As used in this specification and the scope of the patent application, "or" should be understood as having the same meaning as "and/or" as defined above. For example, when terms are separated in a list, "or" or "and/or" should be interpreted as inclusive, that is, it includes at least one of a large number of listed elements, but also includes more than one of the listed elements , And, as needed, other components are not listed. Terms that only expressly indicate the opposite, such as "only one of them" or "exactly one of them" or "consisting of" when used in the scope of the patent application, shall mean the inclusion of one or more The exact one in the component list. Generally, as used herein, the term "or" should only be Interpreted as candidates indicating exclusivity (ie, "one or the other but not both"). When used in the scope of patent application, "essentially composed of" should have the same conventional meaning as the users in the field of patent law.

As used herein, in the specification and the scope of the patent application, the phrase "at least one" referring to more than one element list should be understood to mean at least one element selected from any one or more of the elements in the element list, but It is not necessary to include at least one of each and every element specifically listed in the element list, and any combination of elements in the element list is not excluded. This definition also allows elements other than those specifically identified in the list of elements referred to by the phrase "at least one" to exist as needed, regardless of whether the elements are related to their specifically identified elements. Therefore, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently, "at least one of A and/or B" ) Can refer to one aspect, at least one of which includes more than one A as required, without the existence of B (and In another aspect, at least one includes more than one B as required, and there is no A (and includes elements other than A as required); In one aspect, at least one includes more than one A as required, and at least one includes more than one B as required (and other components as required).

In the scope of patent application and in the above specification, all transitional phrases such as "include", "include", "carry", "have", "contain", "involve", "accommodate", "are by... .. "Constitution" is understood as being open, that is, it means including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" should be closed or semi-closed transitional phrases, respectively, such as the "Patent Examination Procedure of the United States Patent Office" As detailed in Section 2111.03 of the Manual.

As used herein, "prodrug" refers to a compound that can be transformed in vivo by metabolic means (eg, by hydrolysis) to provide the compound described by the formula of the present invention. Various forms of predrugs are known in the field, for example, such as "Design of Prodrugs" (Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985)); "Methods in Enzymology" Volume 4 ( Widder, et al. , (ed.), Methods in Enzymology , vol. 4, Academic Press (1985)); "Design and Application of Prodrugs-Drug Design and Development Tutorial" Chapter 5 (Krogsgaard-Larsen, et al. ,(ed). Design and Application of Prodrugs, Textbook of Drug Design and Development , Chapter 5, 113-191 (1991)); Bundgaard, et al. , Journal of Drug Deliver Reviews , 8: 1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77: 285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and "Hydrolysis in the metabolism of drugs and prodrugs: "Chemistry, Biology and Enzymology" (Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002)).

As used herein, the term "pharmaceutically acceptable prodrugs" refers to their prodrugs of Compound I or their pharmaceutically acceptable salts or solvates, and within the scope of reasonable medical judgment, they are applicable to Abnormal toxicity, irritation, allergic reaction, etc. Contact with human and lower animal tissues has a reasonable benefit/risk ratio and is effective for its intended use.

In one aspect, "pharmaceutically acceptable prodrug" includes "pharmaceutically acceptable ester".

As used herein, the term "pharmaceutically acceptable ester" refers to an ester of Compound I or a pharmaceutically acceptable salt or solvate thereof, which is hydrolyzed in vivo and includes those in the human body. A compound that easily decomposes to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic acid, alkenoic acid, naphthenic acid, and alkanedioic acid, wherein each alkyl or alkenyl moiety It preferably has no more than 6 carbon atoms. Examples of specific esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, and ethyl succinate.

The phrase "pharmaceutically acceptable excipient" refers to any of the following categories of ingredients: fillers, binders, lubricants, disintegrants, slip agents (for example, silica), fragrances And coloring agent. Suitable binder systems include, for example: microcrystalline cellulose (for example, Avicel PH200 LM, PH112, PH101, PH102, PH103, PH113, PH105, PH200, DG), mannitol, dicalcium phosphate, dicalcium phosphate anhydrous, polyethylene Pyrrolidone, lactose, glucose, starch, gelatin, acacia, tragacanth, sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, etc. Lubricants include, for example, glyceryl dibehenate, hydrogenated vegetable oil, sodium oleate, sodium stearate, magnesium stearate, silicon dioxide, sodium benzoate, sodium acetate, sodium chloride, and the like. Other excipients include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked carboxymethyl cellulose, and the like. Other excipients used in capsules include polyethylene glycol or lipids and/or any other excipients known in the art.

As used herein, the term "pharmaceutically acceptable salt" refers to the salt of their compound I, within the scope of reasonable medical judgment, which is suitable for contact with tissues of humans and lower animals without abnormal toxicity, Irritations, allergic reactions, etc., and have a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are those known in the art. For example, SMBerge et al. disclose the pharmaceutically acceptable salts described in detail in J. Pharmaceutical Sciences , 66:1-19 (1977). These salts can be isolated and prepared during the final isolation and purification of Compound I, or can be prepared independently by reaction with a suitable acid.

"Similar time" means that the administration of the other therapeutic agent occurs within a period of time before or after the administration of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, so that the other therapeutic agent or therapy The therapeutic effect is superimposed on the therapeutic effect of Compound I or its pharmaceutically acceptable salt, solvate or prodrug. In some aspects, the therapeutic effect of the other therapeutic agent is completely superimposed with the therapeutic effect of Compound I or its pharmaceutically acceptable salt, solvate or prodrug. In some aspects, "similar time" means that the administration of other therapeutic agents occurs within a period of time before or after administration of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, so that the There is a synergistic effect between other therapeutic agents and Compound I or its pharmaceutically acceptable salts, solvates or prodrugs.

The "similar time" may vary according to a variety of factors, including but not limited to the age, gender, weight, genetic background, physical condition, medical history and treatment history of the subject to be administered the therapeutic agent; the disease to be treated or alleviated Or disease; the therapeutic outcome to be achieved; the dosage, frequency and duration of administration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route of administration of the therapeutic agents. In some aspects, "similar time" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, 24 Within hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or 8 weeks Inside. In some aspects, multiple administrations of one therapeutic agent may occur within a similar time period of a single administration of another therapeutic agent. In some aspects, during the treatment cycle or within the dosing regimen, similar The time can be changed.

The terms "controlled release" or "sustained release" as used interchangeably herein refer to pharmaceutical compositions prepared in a manner designed to release more than one active compound at a predetermined rate. The active compound is prepared with a pharmaceutically acceptable carrier that protects the compound against rapid absorption or rapid elimination from the body, such as a controlled release formulation including grafts and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyalkyd, collagen, polyorthoesters, and polylactic acid. The method of preparing such preparations is obvious to those with ordinary knowledge in the technical field. Liposomal suspensions (including liposomes targeted to infected cells, which have monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those having ordinary knowledge in the art, for example, as disclosed in US Patent No. 4,522,811, which is incorporated herein by reference in its entirety.

As used herein, the phrase "therapeutically effective amount" or "effective amount" refers to the amount necessary for administration to a subject or to cells, tissues, or organs of the subject to achieve a therapeutic effect such as a reduction or healing effect.

In one aspect, the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is the amount necessary to treat pain in the subject.

In one aspect, the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is the amount necessary to prevent pain in the subject.

In one aspect, the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is the amount necessary to relieve pain in the subject.

In one aspect, the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is the amount necessary to eliminate pain in the subject.

In one aspect, the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is the amount necessary to reduce pain symptoms in the subject.

In one aspect, the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is the amount necessary to treat, prevent, eliminate or reduce fibromyalgia or fibromyalgia symptoms in a subject.

In one aspect, the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is the amount necessary to treat, prevent, eliminate, or reduce neuropathy or neuropathic symptoms in a subject.

In one aspect, the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate, or prodrug thereof is the amount necessary to treat, prevent, eliminate, or reduce chemotherapy-induced pain in a subject.

In one aspect, the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is the amount necessary to enhance the anti-hyperalgesic effect of a subject suffering from hyperalgesia.

In one aspect, the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is the amount necessary to reduce the pain sensitivity of the subject.

As used herein, the term "subject" refers to any warm-blooded animal, such as, but not limited to, mice, rats, guinea pigs, dogs, cats, horses, or humans. In one aspect, the subject is a human.

In one aspect, the subject is in a "fasting condition" or a "fasting state". The "fasted condition" or "fasted state" used to describe a subject means that the subject has not eaten food for at least 4 hours at a time point of interest, such as the time of administration of Compound I. In one aspect, a subject in a fasted state has not eaten for at least 6, 8, 10, or 12 hours before administration of Compound I.

In one aspect, the subject is in a "feeding condition" or "feeding state". "Feeding conditions" or "feeding state" used to describe a subject means that the subject is at a point of time of interest, such as administration of a compound For the time of substance I, I had eaten in less than 4 hours before. In one aspect, the subject in the fasted state has not eaten for at least 3, 2, 1 or 0.5 hours before administration of Compound I.

As used herein, the phrase "therapeutic agent for the treatment of pain" refers to any agent other than Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is used to treat and/or Prevent any type of pain disclosed in this article.

In one aspect, Compound I and other therapeutic agents for the treatment of pain are formulated as a single pharmaceutical composition, which further contains more than one pharmaceutically acceptable excipient.

In one aspect, any of the methods disclosed herein further include administering to a subject in need of treatment other therapeutic agents for the treatment of pain. In one aspect, Compound I is administered simultaneously with other therapeutic agents used to treat pain. In one aspect, Compound I is administered before the therapeutic agent used to treat pain. In one aspect, Compound I is administered after the therapeutic agent used to treat pain. In one aspect, Compound I and other therapeutic agents used to treat pain are administered at similar times.

In one aspect, the other therapeutic agents used to treat pain are opioids, such as morphine, codeine, papaverine, thebaine, etc.; semi-synthetic opioids, such as oxycodone, diacetylmorphine, Dihydrocodeine, etc.; synthetic opioids, such as phenylpyridine derivatives, for example, 6-amino-5-(2,3,5-trichlorophenyl)-pyridine-2-carboxylic acid methyl amide Amines, etc.; phenylpiperidine derivatives, for example, fentanil, sulfentanil, alfentanil, etc.; morphinan derivatives, for example, levorphanol, butorphine Butorphanol, etc.; diphenylheptane derivatives, such as methadone, propoxyphene, etc.; benzomorphan derivatives, such as pentazocine, phenazocine ), etc.; drugs that act on opiate receptors and/or monoamine reuptake transporters, that is, tramadol, etc.; NSAIDs, such as aspirin, indomethacin, and Sulindac, etodolac, tolmetin, ketorolac, naphthalene Nabumetone, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, Oxaprozin, piroxicam, meloxicam, tenoxicam, mefenamic acid, meclofenamic acid, Flufenamic acid and pharmaceutically acceptable salts of the foregoing.

Compound I

二唑-2-基)苯并呋喃-4-基)氧基)丙-2-醇，係具有下述結構： Compound I, that is, (2S)-1-(4-(3,4-dichlorophenyl)piperidin-1-yl)-3-((2-(5-methyl-1,3,4 -

Diazol-2-yl)benzofuran-4-yl)oxy)propan-2-ol has the following structure:

二唑-2-基)苯并呋喃-4-基)氧基)丙-2-醇鹽酸鹽，亦指代為MIN-117或MIN117。 The monohydrochloride salt of compound I, that is, (2S)-1-(4-(3,4-dichlorophenyl)piperidin-1-yl)-3-((2-(5-methyl- 1,3,4-

Diazol-2-yl)benzofuran-4-yl)oxy)propan-2-ol hydrochloride, also referred to as MIN-117 or MIN117.

Compound I including MIN-117 and its salts can be prepared according to the methods disclosed in US Patent Nos. 6,720,320 and 7,196,199, both of which are incorporated herein by reference in their entirety. Other publications disclosing the use of Compound I and its salts include US Patent Application Publication No. 2014/0206722 and No. 2019/0183874, both of which are incorporated herein by reference in their entirety.

In one aspect, Compound I may exist in the form of a pharmaceutically acceptable salt. For example, monohydrochloride (MIN-117).

Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic addition salts, which are combined with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphonic acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid , Tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the field such as ion exchange to form the salt of the amine group. Other pharmaceutically acceptable salts include but are not limited to: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyric acid Salt, camphorate, camphor sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, formate, fumarate, Glucoheptonate, glyceryl phosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxyethane sulfonate, lactobionate, lactate, lauric acid Salt, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotine, nitrate, oleate, oxalate, palm Acid salt, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, trimethyl acetate, propionate, stearate, succinate Acid salt, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt and the like. When appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations. The amine cations use counter ions such as halide, carboxylate, sulfate, phosphate, and nitrate. The formation of alkyl sulfonate and aryl sulfonate with three carbon atoms.

In addition, the compound I or the salt of compound I may exist as a solvate, which means a solvent addition form containing a stoichiometric or non-stoichiometric solvent. Some compounds tend to capture solvent molecules with a fixed molar ratio in crystalline solids, thereby forming solvates. If the solvent is water, the formed solvate is a hydrate; if the solvent is alcohol, the formed solvate is an alcoholate. Hydrates are formed by the combination of more than one molecule of water and one molecule of the substance, wherein the water system maintains its _{molecular state as H 2} O, or is in the form of hydrate or non-hydrate (anhydrous) or as a combination of other Solvates of solvent molecules. Non-limiting examples of hydrates include monohydrate, dihydrate, and the like. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

[treatment method]

In one aspect, the present invention relates to a method for treating and preventing pain, which includes administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof to a subject in need of treatment.

In one aspect, the present invention relates to a method of treating and preventing pain, which includes administering a therapeutically effective amount of a pharmaceutically acceptable salt of Compound I to a subject in need of treatment.

In one aspect, the present invention relates to a method for treating and preventing pain, which includes administering to a subject in need of treatment a therapeutically effective amount of compound I hydrochloride, that is, MIN-117.

In one aspect, the pain treated and/or prevented by the method of the present invention is acute pain.

Acute pain includes, but is not limited to, nociceptive or inflammatory pain caused by thermal, mechanical, or chemical stimulation of sensory nerve fibers. The sensory nerve fibers are close to or exceed harmful pain caused by injury and/or visceral pain. Response to stimuli, including but not limited to irritable bowel syndrome (IBS) with or without chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), Crohn's disease, food poisoning , Food allergy, gas-related pain, hernia, pain related to gallstones and/or kidney stones, endometriosis, gastroesophageal reflux disease (GERD), appendicitis, interstitial cystitis, deep body pain (E.g. sprains, fractures), nerve pain caused by injuries or diseases that affect the somatosensory nervous system, and body surface pain (e.g. burns).

In one aspect, the pain treated and/or prevented by the method of the present invention is nociceptive pain.

Nociceptive pain includes, but is not limited to, pain caused by physical damage to the body caused by heat, cold, pressure, pinching, twisting, rubbing, and chemicals. Specific examples of nociceptive pain include sprains, fractures, burns, bruises, contusions, inflammation, obstruction, and myofascial pain.

In one aspect, the pain treated and/or prevented by the method of the present invention is inflammatory pain.

Inflammatory pain includes, but is not limited to, pain caused by inflammation including arthritis.

In one aspect, the pain treated and/or prevented by the method of the present invention is visceral pain.

Visceral pain includes, but is not limited to, pain caused by the expansion, ischemia, and inflammation of the pain receptors in the thoracic, pelvic, or abdominal organs.

In one aspect, the pain treated and/or prevented by the method of the present invention is chronic pain, that is, persistent pain.

Chronic pain includes, but is not limited to, postoperative pain, cancer pain (e.g., pain induced by chemotherapy), degenerative joint disease pain (e.g., osteoarthritis, rheumatoid arthritis, joint adhesive vertebral edge, Reiter’s Syndrome, psoriatic arthritis, gout, pseudogout, infectious arthritis, tendinitis, bursitis, bone injury and inflammation of joint soft tissue), headache (for example, cluster headache, migraine, tension-type headache), Vascular pain (e.g., arteriosclerosis obliterans, thromboangiitis obliterans, acute arterial occlusion, embolism, congenital arteriovenous anoma, vasospasm disease, Raynaud's disease, hand and foot cyanosis, acute meridian occlusion, thrombotic vein Inflammation, varicose veins, and lymphedema), myofascial or muscle pain (e.g., temporomandibular joint (TMJ) diseases/symptoms, chronic musculoskeletal pain, fibromyalgia with or without chronic fatigue syndrome, muscle muscle pain) Membrane pain syndrome or involvement pain), neuralgia (trigeminal neuralgia, postherpetic neuralgia, Glossopharyngeal neuralgia), herpes zoster, neuropathy, central pain syndrome, complex regional pain syndrome, hyperalgesia, hyperalgesia, central sensitization, peripheral sensitization, deinhibition, and augmented facilitation.

In one aspect, the pain treated and/or prevented by the method of the present invention is chemotherapy-induced pain.

In one aspect, the pain treated and/or prevented by the method of the present invention is postoperative pain.

Postoperative pain includes, but is not limited to, tissue damage associated with muscle spasm after surgery.

In one aspect, the pain treated and/or prevented by the method of the present invention is fibromyalgia and/or fibromyalgia syndrome. Fibromyalgia is a lesion characterized by extensive musculoskeletal pain, often accompanied by fatigue and/or sleep disturbance.

In one aspect, the pain treated and/or prevented by the method of the present invention is fibromyalgia with chronic fatigue syndrome and/or fibromyalgia with chronic fatigue syndrome.

In one aspect, the pain treated and/or prevented by the method of the present invention is neuropathic pain, that is, neuropathy. In one aspect, neuropathic pain can be caused by injury or disease in any part of the nervous system or somatosensory system. The types of neuropathic pain include, but are not limited to, diabetic neuropathy and diabetic peripheral neuropathy, that is, diabetic peripheral neuropathic pain.

Neuropathic pain caused by injury or disease in any part of the somatosensory system includes but is not limited to: phantom limb pain, multiple chemical allergy, sick building syndrome, repetitive stress injury, chronic whiplash, Chronic Lyme disease, side effects of silicone breast grafts, candidiasis hypersensitivity, Gulf War syndrome, food allergies, mitral valve prolapse, and hypoglycemia.

In one aspect, the pain treated and/or prevented by the method of the present invention is diabetic neuropathy, that is, nerve damage caused by diabetes.

In one aspect, the pain treated and/or prevented by the method of the present invention is peripheral neuropathy, that is, peripheral neuropathic pain, which is an injury or disease that affects the sensory, motor, and/or autonomic nerves of the peripheral nervous system.

Peripheral neuropathic pain occurs when the peripheral nerves cannot transmit information to or from the brain and spinal cord, resulting in pain, loss of sensation, or inability to control muscles. In some cases, the nerve failure that controls the blood vessels, intestines, and other organs results in abnormal blood pressure, digestive problems, and loss of other basic body processes. Symptoms also depend on whether the symptom affects the system or only one nerve. Risk factors for neuropathy include diabetes, excessive drinking, exposure to certain chemicals and drugs, and prolonged compression of nerves. Some people have a genetic predisposition for peripheral neuropathy.

In one aspect, the subject’s peripheral neuropathy is caused by exposure to toxins, excessive drinking, malnutrition, diabetes, Guillain-Barre syndrome, complications of renal failure, complications of cancer, infections (e.g., AIDS, herpes zoster) , Lyme disease), kidney disease, thyroid disease, parathyroid disease, and/or carpal tunnel syndrome.

The causes of peripheral neuropathic pain include, but are not limited to, neuropathy related to systemic diseases such as diabetic neuropathy, neuropathy related to metabolic status, such as alcoholic neuropathy and lower burning syndrome, and nerves related to viral infection Diseases such as herpes zoster and HIV, neuropathy related to nutritional deficiencies, neuropathy related to toxins, neuropathy related to tumor compression, neuropathy related to remote metastasis of malignant tumors, nerves related to drugs such as chemotherapy Diseases, neuropathy associated with radiation exposure, neuropathy associated with immune-mediated pathology, and neuropathy associated with physical trauma to the nerve trunk.

The four basic patterns of peripheral neuropathic pain are single neuropathy, multiple single neuropathy (monomeuropathic multiplex), multiple neuropathy, and autonomic neuropathy.

In one aspect, the pain treated and/or prevented by the method of the present invention is peripheral neuropathy, and the peripheral neuropathy is peripheral single neuropathy. Single neuropathy is a peripheral neuropathy involving loss of function or pathological changes affecting a single nerve or group of nerves. Single neuropathy is most commonly caused by local damage that leads to injury or trauma, but occasionally systemic disease may cause isolated nerve damage. Common causes are direct trauma, prolonged compression of nerves, and compression of nerves caused by swelling or injury of nearby body structures.

In one aspect, the damage from single neuropathy includes the destruction of the myelin (cover) of a part of the nerve or nerve cell (axon). This damage is to slow down or prevent impulse conduction through the nerve. Single neuropathy can involve any part of the body. Mononeural pain is related to, for example, sciatic nerve dysfunction (a common peroneal nerve dysfunction), radial nerve dysfunction, ulnar nerve dysfunction, single brain neuropathy VI, single brain neuropathy VII, single brain neuropathy Neuropathy III (compression type), single brain neuropathy III (diabetes type), axillary nerve dysfunction, carpal tunnel syndrome, femoral nerve dysfunction, tibial nerve dysfunction, Bell's palsy, thoracic outlet syndrome, carpal tunnel syndrome Or other focal compressive neuropathy and sixth (abduction) nerve palsy. For example, single neuropathy is ulnar nerve dysfunction, radial nerve palsy, or peroneal nerve palsy.

In one aspect, the pain treated and/or prevented by the method of the present invention is a peripheral neuropathy, and the peripheral neuropathy is a multiple single neuropathy. Multiple single neuropathies involve peripheral neuropathy that affects the loss of function or pathological changes of several non-adjacent nerves sequentially or simultaneously in an asymmetrical pattern. Neuropathic pain based on multiple single neuropathies can develop within several days to several years, and is typically manifested as acute or subacute loss of individual nerve sensory or motor functions. Is the mode involved? Symmetrical ones, however, as the disease progresses, the defect system becomes more fused and symmetrical, making it difficult to distinguish it from polyneuropathy. Multiple single neuropathies can also cause pain characterized by deep, severe pain, which worsens at night and frequently occurs in the lower back, buttocks, or legs. Multiple single neuropathies can also cause pain characterized by acute, unilateral, and severe limb pain, followed by forelimb muscle weakness and loss of knee reflexes. Multiple single neuropathic pain is related to, for example, diabetes, infections such as leprosy, Lyme disease, HIV, and toxicity.

In one aspect, the pain treated and/or prevented by the method of the present invention is peripheral neuropathy, which is peripheral polyneuropathy, which involves the loss of function or pathological changes of multiple nerves in the entire body in a symmetrical pattern. Polyneuropathy can appear acute and without warning, or chronic and develop gradually over a longer period of time. Many types of polyneuropathy involve both motor and sensory nerves, and some also involve dysfunction of the autonomic nervous system. These lesions are generally symmetrical and are usually caused by various systemic diseases and disease processes that affect the entire peripheral nervous system. Polyneuropathy frequently affects the feet and hands, causing weakness, loss of sensation, tingling sensation, or burning pain. Polyneuropathy can be classified in different ways, such as according to the cause, according to the rate of progression, or according to the body part involved. The types of polyneuropathy can also be distinguished by the location of the nerve cells that are mainly affected: axon, myelin, or cell body.

The causes of polyneurotic pain include but are not limited to: post-poliomyelitis syndrome, post-mastectomy syndrome, diabetic neuropathy, alcoholic neuropathy, amyloid, toxins, AIDS, hypothyroidism, uremia, Vitamin deficiency, chemotherapy-induced pain, 2',3'-dodeoxycytidine (ddC) treatment, Guillain-Barre syndrome, and Fabry's disease.

In one aspect, the pain treated and/or prevented by the method of the present invention is peripheral neuropathy, and the peripheral neuropathy is autonomic neuropathy. Autonomic neuropathy involves involuntary, involuntary Peripheral neuropathy in which the sensory nervous system (that is, the autonomic nervous system) is lost or pathologically changed. Autonomic neuropathy is a form of polyneuropathy, which mostly affects internal organs such as the bladder, muscles, cardiovascular system, digestive tract, and reproductive organs.

In one aspect, the treatment and/or prevention of pain in a subject with peripheral and/or diabetic neuropathy includes alleviating one or more symptoms of the subject selected from the group consisting of: tingling, Numbness, loss of sensation (e.g., in arms and/or legs), and burning sensation (e.g., feet and/or hands).

In one aspect, the pain treated by the method of the present invention is neuropathy induced by chemotherapy.

In one aspect, the pain prevented by the method of the present invention is neuropathy induced by chemotherapy.

In one aspect, the pain treated and/or prevented by the method of the present invention is neuropathy induced by taxane chemotherapy. For example, paclitaxel, docetaxel, abraxane or taxotere.

In one aspect, the pain treated/prevented by the method of the present invention is neuropathy induced by chemotherapy with alkylating agents. For example, cyclophosphamide, mechlorethanmine, chlorambucil, melphalan, decarbazine, nitrosourea, or temozolomide.

In one aspect, the therapeutic agent/or pain prevented by the method of the present invention is neuropathy induced by chemotherapy with anthracycline. For example, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or valrubicin.

In one aspect, the pain treated and/or prevented by the method of the present invention is neuropathy induced by chemotherapy using antimetabolites or nucleoside analogs. For example, fluorouracil (Adrucil); capecitabine (Xeloda); hydroxyurea (Hydrea); mercaptopurine (Purinethol); pemetrexed (Alimta); fludarabine (Fludara) ); Nelarabine (Arranon); Cladribine (Cladribine Novaplus); Clofarabine (Clolar); Cytarabine (Cytosar-U); Decitabine (decitabine) (Dacogen); Cytarabine liposomal (DepoCyt); Hydroxyurea (Droxia); Pralatrexate (Folotyn); Floxuridine (FUDR); Gemcitabine ( gemcitabine (Gemzar); cladribine (Leustatin); fludarabine (Oforta); methotrexate (MTX; Rheumatrex); methotrexate (Trexall); thioguanine (Tabloid); TS -1 or Tarabine PFS.

In one aspect, the pain treated and/or prevented by the method of the present invention is neuropathy induced by chemotherapy with a CDK inhibitor. For example, pabociclib, dinaciclib, P276-00, roniciclib, ribociclib, P1446A-05, AT7519M, SNS-032, SCH727965, AG -024322, hygrolidin, fascaplysin, abemaciclib, arcyriaflavin A, CINK4, AM-5992, CDK4 inhibitor (CAS # 546102-60-7), CDK4 inhibitor III (CAS # 265312-55-8) , Cdk4/6 inhibitor IV (CAS # 359886-84-3), MM-D37K, NSC 62598 or ON-123300. (See, Law, M.E. et al. "Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics" Mol. Pharmacol. 88:846-852 (2015), which is incorporated herein by reference in its entirety)

In one aspect, the pain treated and/or prevented by the method of the present invention is neuropathy induced by chemotherapy using Catharanthus alkaloids or derivatives thereof. For example, vinblastine, vincristine, vindesine or vinorelbine.

In one aspect, the pain treated/prevented by the method of the present invention is neuropathy induced by chemotherapy with platinum-based agents. For example, cisplatin, carboplatin, or oxaliplatin.

In one aspect, the pain treated and/or prevented by the method of the present invention is neuropathy induced by chemotherapy using nucleotide analogs or nucleotide precursor analogs. For example, azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyl Urea, mercaptopurine, methotrexate, or tioguanine.

In one aspect, the pain treated and/or prevented by the method of the present invention is neuropathy induced by chemotherapy using topoisomerase inhibitors such as topoisomerase I inhibitors or topoisomerase II inhibitors . For example, irinotecan, topotecan, etoposide, teniposide, or tafluposide.

In one aspect, the pain treated and/or prevented by the method of the present invention is neuropathy induced by the use of the following chemotherapy: actinomycin, bleomycin, sorafenib, levatinib (lenvatinib), regorafenib, sunitinib, pabociclib, afatinib, alectinib, axitinib ), bortezomib, bosutinib, cabozantinib, carfilzomib, ceritinib, cobimetinib, gram Crizotinib, dabrafenib, erlotinib, gefitinib, ibrutinib, idelalisib, imatinib Ni (imatinib), ixazomib (ixazomib), lapatinib (lapatinib), nilotinib (nilotinib), nintedanib (nintedanib), niraparib (niraparib), oxitinib ( osimertinib), pazopanib, pegaptanib, ponatinib, rucaparib, ruxolitinib, sonidegib, Entrust Tofacitinib, trametinib, vandetanib, vemurafenib, vismodegibor, necitumumab, cetol Cetuximab, neratinib, panitumumab or dacomitinib.

In one aspect, the pain treated and/or prevented by the method of the present invention is toxic pain.

Toxic pain includes, but is not limited to, pain associated with contact with toxins, poisons, and chemical substances. In one aspect, this can happen through the abuse of drugs or chemicals or through industrial chemicals exposed to the workplace or the environment (or after short-term or long-term exposure). For example, toxins, poisons and/or chemicals can be found in pesticides, solvents, glues or herbicides.

In one aspect, toxic pain is caused by contact with one or more of the following: acrylamide, alcohol, arsenic, dimethionine (via shellfish), sea buckthorn berry toxin, agent orange, Carbon disulfide, coral reef fish toxin (via shellfish), dioxin, ethanol, ethylene glycol (antifreeze), six carbon compounds, tetrodotoxin (via puffer fish), lead, mercury, nitrous oxide, organic phosphorus, saxishell toxin (via shellfish) ), thallium or zinc.

In one aspect, the present invention relates to a method for treating pain, which method comprises administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof to a subject in need of treatment, wherein After less than 8 hours, the subject’s pain was treated, alleviated or eliminated, or the subject’s pain symptoms were reduced. For example, less than 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, after administration of a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes or 5 minutes.

On the one hand, the pain to be treated can be any type of pain disclosed in this article, for example, Acute pain, chronic pain, toxic pain, neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, or a combination thereof.

In one aspect, the present invention relates to prevention of pain, that is, a method of preventive treatment of pain. For example, Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof can be administered to a subject who is about to undergo chemotherapy to prevent the appearance of neuropathy induced by chemotherapy before pain has begun.

In one aspect, for any of the methods for preventing pain disclosed herein, the method comprises administering to a subject in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein , Compound I was administered to the subject before the start of chemotherapy. For example, 8 hours before chemotherapy, 7 hours before chemotherapy, 6 hours before chemotherapy, 5 hours before chemotherapy, 4 hours before chemotherapy, 3 hours before chemotherapy, 2 hours before chemotherapy, 1 hour before chemotherapy, 45 minutes before chemotherapy, 30 minutes before chemotherapy, 20 minutes before chemotherapy, 15 minutes before chemotherapy, 10 minutes before chemotherapy, or 5 minutes before chemotherapy.

On the one hand, the pain to be prevented can be any type of pain disclosed herein, for example, acute pain, chronic pain, toxic pain, neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, Chemo-induced pain, or a combination of these.

On the one hand, the present invention is about simultaneously treating the current pain of the subject and preventing the occurrence of future pain of the subject.

For example, a therapeutically effective amount of Compound I can be administered to a subject undergoing chemotherapy to treat neuropathy induced by chemotherapy. The same subject can be administered Compound I to prevent future chemotherapy-induced neuropathy or any other types of pain disclosed herein, for example, acute pain, chronic pain, toxic pain, nociceptive pain, inflammatory pain, surgery Posterior pain, visceral pain, and chemotherapy-induced pain.

In the presence of peripheral tissue damage, pain receptors can become hyperalgesia (sensitization) through a variety of mechanisms. Individual pain receptors that have been sensitized can be activated by stimuli that were not previously strong enough to cause activation (algesia), as well as by stimuli that were previously harmful but now produce even stronger pain sensations (hyperalgesia). The electrophysiological factors related to the pain response caused by this change include the decrease of the nociceptor activation threshold and the increase of the trigger frequency in response to the over-threshold stimulus. In addition, the clinical symptoms of spontaneous pain can be directly related to the spontaneous peak trigger in the nociceptor. Peripheral sensitization often leads to central sensitization, or an increase in the synaptic function and spontaneous activity of neurons in the dorsal horn of the spinal cord.

As used herein, the term "hyperalgesia" refers to the extreme or increased sensitivity of a subject to pain.

As used herein, "anti-hyperalgesic effect" refers to reducing the sensitivity of a subject to pain.

On the one hand, a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof induces or enhances the anti-hyperalgesic effect, that is, it reduces the sensitivity of the subject to pain. Therefore, in another aspect, the present invention relates to a method for reducing the sensitivity of a subject to pain, the method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof to a subject in need Or prodrug.

On the one hand, a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof induces or enhances the anti-hyperalgesic effect less than 8 hours after administration. For example, less than 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, after administration of a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes or 5 minutes.

In one aspect, the therapeutically effective amount of Compound I or its pharmaceutically acceptable salt, solvent The formulation or prodrug induces or enhances the antihyperalgesic effect, that is, it reduces the subject's sensitivity to pain caused by the subject's opioid treatment of pain.

In one aspect, the anti-hyperalgesic effect of a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof is to reduce or increase the sensitivity of the subject to pain by about 10%, about 20%. %, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

In any of the methods disclosed herein, the treatment or alleviation of pain, fibromyalgia, neuropathy, or chemotherapy-induced pain in the subject, the enhancement of the anti-hyperalgesic effect on the subject, or the reduction of the subject’s sensitivity to pain, It can be determined before or after the evaluation of the subject by the physician using any method known in the art. (Haefeli, M. "Pain Assessment" Eur. Spine J. 2006 Jan; 15(Suppl 1): S17-S24; Stewart, J. "The Challenges of Cancer Pain Assessment" Ulster Med. J. 2014 Jan; 83(1 ): 44-46.)

In the example disclosed in this article, the nociceptive threshold test is to deliberately apply a stimulus to the subject to study the efficacy of pain and analgesic drugs, and to establish the administration level and duration of action. After the baseline level is established, the test drug is administered and the threshold evaluation value is recorded at a specific time point. Once the more than one test drug is exhausted, the threshold should return to the baseline (pre-treatment) value.

For example, carrageenan solution is injected into the hind paws of an animal (for example, a rat) via the sole of the foot to induce mechanical hyperalgesia, as evidenced by a significant and significant decrease in the pain threshold. Morphine used as a positive control completely reversed mechanical hyperalgesia, and reached its maximum effect 30 minutes after administration.

In other examples, sciatic nerve ligation induces mechanical hyperalgesia, as evidenced by a significant and significant decrease in the pain threshold, which is significantly reduced by morphine, which can be used as a positive control .

In other examples, the effect of long-term administration of Compound I on paclitaxel-induced neuropathic pain was evaluated. The effect is to reverse the paclitaxel-induced pain or prevent the pain. In one aspect, compound I at 1, 3, and 10 mg/kg showed a significant increase in pain threshold, suggesting that compound I is effective in preventing chemotherapy-induced peripheral neuropathic pain.

According to the treatment and/or prevention method of the present invention, by administering to a subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the subject’s pain is treated, alleviated, and cured Or prevention, the amount and time of administration are as necessary to achieve the desired effect.

According to the treatment method of the present invention, by administering to a subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the subject’s pain is treated, and the amount and time of administration are As necessary to achieve the desired effect.

According to the treatment method of the present invention, by administering to a subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, one or more symptoms of pain in the subject are reduced, and the administration of The amount and time are as necessary to achieve the desired effect.

According to the treatment method of the present invention, by administering to a subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the subject’s pain is alleviated, and the amount and time of administration are As necessary to achieve the desired effect.

According to the treatment method of the present invention, by administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof to a subject, the pain of the subject is cured, and the amount and time of administration are As necessary to achieve the desired effect.

According to the treatment method of the present invention, by administering to a subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the subject’s pain is prevented, and the amount and time of administration are As necessary to achieve the desired effect.

As is well understood in the medical field, a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof will be at a reasonable action/risk ratio that can be used in any medical treatment.

In one aspect, the present invention relates to the efficacy of Compound I or its pharmaceutically acceptable salts, solvates or prodrugs in various pain fields, including but not limited to acute and toxic pain; neuropathic pain; Inflammatory pain; postoperative pain; visceral pain; and behavioral and acute toxicity, which can be used for high-throughput screening in rats (ie, ALGOGram ^TM ) evaluation and multiple doses of Compound I or its pharmaceutically acceptable The data obtained from the salt, solvate or prodrug of the compound is compared with the known control substance. For example, morphine (for acute pain, toxic pain, neuropathic pain, and postoperative pain); gabapentin (for neuropathic pain); indomethacin (for inflammatory pain) and U- 50488 (for acute pain, toxic pain and visceral pain).

In one aspect, the present invention relates to the anti-hyperalgesic effect of Compound I or its pharmaceutically acceptable salt, solvate or prodrug in a rat model of mechanical hyperalgesia induced by carrageenan. In this model, inflammation is induced by injecting carrageenan into the rat's paw through the sole of the foot. Carrageenan is a polysaccharide obtained from a variety of seaweeds. When injected into the plantar paw or knee joint, carrageenan causes local inflammation, thereby reducing load, changing the protection of the treated limb, and inducing thermal and mechanical hyperalgesia/hyperalgesia. This type of model is widely and reliably used to explore the efficacy of new analgesics. In one aspect, the intraperitoneal administration of Compound I or its pharmaceutically acceptable salts, solvates or prodrugs at various doses induces an increase in pain threshold relative to the control group.

In one aspect, the present invention relates to the anti-hyperalgesic effect of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof in a rat model of peripheral single neuropathy. In this model, the sciatic nerve of the right hind paw of an anesthetized rat is loosely ligated to induce a single operation in the rat. Single neuropathy of lateral peripheral. In one aspect, the intraperitoneal administration of Compound I or its pharmaceutically acceptable salts, solvates or prodrugs at various doses induces an increase in pain threshold relative to the control group.

In one aspect, the present invention relates to the analgesic effect of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof in a rat model of chemotherapy-induced peripheral neuropathic pain. In one aspect, treatment with Compound I or its pharmaceutically acceptable salts, solvates or prodrugs significantly reduced neuropathic pain in rats compared to the control group.

Generally, Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof will be administered in a therapeutically effective amount via any mode known to be available and acceptable in the art, administered alone or in combination with more than one therapeutic agent. Combined administration. Depending on the severity of the pain, the age and relative health of the subject, the clinical condition of the recipient, the experience and judgment of the clinician or practitioner performing the therapy, and other factors that affect the selected dose, the therapeutically effective dose can be large The amplitude changes.

In one aspect, the therapeutically effective amount of Compound I can be daily (for example, 1, 2, or 3 times a day), weekly (for example, 1, 2, 3, 4, or 5 times a week), or monthly (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times) per month) to be administered to the subject. The determination of the appropriate dosing regimen is within the scope of the conventional ability of those with ordinary knowledge in the relevant technical field.

A therapeutically effective amount of Compound I can be administered more than once a day for more than 30 days, after which no Compound I is administered for more than 1 day. This type of treatment regimen, that is, administering Compound I for multiple days and then not administering Compound I for multiple days can be referred to as a treatment cycle. The treatment cycle can be continued as many times as needed to achieve the desired effect.

In one aspect, the therapeutically effective amount of Compound I is 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 , 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1100, 1125, 1150, 1175, 1200, 1225, 1250, 1275, 1300, 1325, 1350, 1375, 1400, 1425, 1450, 1475, 1500, 1525, 1550, 1575, 1600, 1625, 1650, 1675, 1700, 1725, 1750, 1775, 1800, 1825, 1850, 1875, 1900, 1925, 1950, 1975 or 2000mg, continuous administration for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 30 days and once a day, 2 times, 3 times , 4 times or more; or continuous administration for 2 months, 3 months, 4 months, 5 months, 6 months, or longer and once, 2 times, 3 times, 4 times or more per day.

In one aspect, the therapeutically effective amount of Compound I is about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60 to about 90 mg, about 70 to about 100 mg, about 80 to about 110 mg, about 90 to about 120 mg, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 130 to about 160 mg, about 140 to about 170 mg, about 150 to About 180 mg, about 160 to about 190 mg, about 170 to about 200 mg, about 180 to about 210 mg, about 190 to about 220 mg, about 200 to about 230 mg, about 210 to about 240 mg, about 220 to about 250 mg, about 230 to about 260 mg , About 240 to about 270 mg, about 250 to about 280 mg, about 260 to about 290 mg, about 270 to about 300 mg, about 280 to about 310 mg, about 290 to about 320 mg, about 300 to about 330 mg, about 310 to about 340 mg, about 320 to about 350 mg, about 330 to about 360 mg, about 340 to about 370 mg, about 350 to about 380 mg, about 360 to about 390 mg, or about 370 to about 400 mg, administered once, twice, 3 times, 4 times a day The above is administered in a single dose or divided doses (the dose can be ^{adjusted according to the weight of the patient in kg, the body surface area in m 2} and the age in years).

The therapeutically effective amount of Compound I can also be in the range of about 0.001 mg/kg per day to about 1,000 mg/kg per day. In one aspect, the therapeutically effective amount of Compound I can also be in the range of about 0.01 mg/kg per day to about 100 mg/kg per day. In one aspect, the therapeutically effective amount of Compound I can also be in the range of about 0.05 mg/kg per day to about 50 mg/kg per day. In one aspect, the therapeutically effective amount of Compound I can also be in the range of about 0.1 mg/kg per day to about 25 mg/kg per day. In one aspect, the therapeutically effective amount of Compound I can also be in the range of about 0.25 mg/kg per day to about 20 mg/kg per day. In one aspect, the therapeutically effective amount of Compound I can also be in the range of about 0.5 mg/kg per day to about 10 mg/kg per day. In one aspect, the therapeutically effective amount of Compound I can range from about 0.75 mg/kg per day to about 5 mg/kg per day. In one aspect, the therapeutically effective amount of Compound I can also be in the range of about 0.10 mg/kg per day to about 1 mg/kg per day. A therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and administered in a controlled release or sustained release form two, three or four times a day.

In one aspect, the therapeutically effective amount of Compound I is about 0.05 mg/kg per day, About 0.10 mg/kg, about 0.15 mg/kg per day, about 0.20 mg/kg per day, about 0.25 mg/kg per day, about 0.30 mg/kg per day, about 0.35 mg/kg per day, about 0.40 mg/kg per day, about 0.45mg/kg, about 0.50mg/kg per day, about 0.55mg/kg per day, about 0.60mg/kg per day, about 0.65mg/kg per day, about 0.70mg/kg per day, about 0.75mg/kg per day, about 0.80 per day mg/kg, about 0.85 mg/kg per day, about 0.90 mg/kg per day, about 0.95 mg/kg per day, or about 1.00 mg/kg per day. The therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and administered in the form of controlled release or sustained release 2 times, 3 times or 4 times a day.

In one aspect, the therapeutically effective amount of Compound I is about 1.05 mg/kg per day, about 1.10 mg/kg per day, about 1.15 mg/kg per day, about 1.20 mg/kg per day, about 1.25 mg/kg per day, and about 1.25 mg/kg per day. 1.30mg/kg, about 1.35mg/kg per day, about 1.40mg/kg per day, about 1.45mg/kg per day, about 1.50mg/kg per day, about 1.55mg/kg per day, about 1.60mg/kg per day, about 1.65 per day mg/kg, about 1.70 mg/kg per day, about 1.75 mg/kg per day, about 1.80 mg/kg per day, about 1.85 mg/kg per day, about 1.90 mg/kg per day, about 1.95 mg/kg per day, or about 2.00 per day mg/kg. A therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and administered in a controlled release or sustained release form two, three or four times a day.

In one aspect, the therapeutically effective amount of Compound I is about 2.05 mg/kg per day, about 2.10 mg/kg per day, about 2.15 mg/kg per day, about 2.20 mg/kg per day, about 2.25 mg/kg per day, and about 2.30mg/kg, about 2.35mg/kg per day, about 2.40mg/kg per day, about 2.45mg/kg per day, about 2.50mg/kg per day, about 2.55mg/kg per day, about 2.60mg/kg per day, about 2.65 mg/kg per day mg/kg, about 2.70 mg/kg per day, about 2.75 mg/kg per day, about 2.80 mg/kg per day, about 2.85 mg/kg per day, about 2.90 mg/kg per day, about 2.95 mg/kg per day, or about 3.00 per day mg/kg. A therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and in the form of controlled release or sustained release every day Give it 2 times, 3 times or 4 times.

In one aspect, the therapeutically effective amount of Compound I is about 3.05 mg/kg per day, about 3.10 mg/kg per day, about 3.15 mg/kg per day, about 3.20 mg/kg per day, about 3.25 mg/kg per day, and about 3.30mg/kg, about 3.35mg/kg per day, about 3.40mg/kg per day, about 3.45mg/kg per day, about 3.50mg/kg per day, about 3.55mg/kg per day, about 3.60mg/kg per day, about 3.65 mg/kg per day mg/kg, about 3.70 mg/kg per day, about 3.75 mg/kg per day, about 3.80 mg/kg per day, about 3.85 mg/kg per day, about 3.90 mg/kg per day, about 3.95 mg/kg per day, or about 4.00 per day mg/kg. A therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and administered in a controlled release or sustained release form two, three or four times a day.

In one aspect, the therapeutically effective amount of Compound I is about 4.05 mg/kg per day, about 4.10 mg/kg per day, about 4.15 mg/kg per day, about 4.20 mg/kg per day, about 4.25 mg/kg per day, and about 4.30mg/kg, about 4.35mg/kg per day, about 4.40mg/kg per day, about 4.45mg/kg per day, about 4.50mg/kg per day, about 4.55mg/kg per day, about 4.60mg/kg per day, about 4.65 per day mg/kg, about 4.70 mg/kg per day, about 4.75 mg/kg per day, about 4.80 mg/kg per day, about 4.85 mg/kg per day, about 4.90 mg/kg per day, about 4.95 mg/kg per day, or about 5.00 mg/kg per day mg/kg. A therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and administered in a controlled release or sustained release form two, three or four times a day.

In one aspect, the therapeutically effective amount of Compound I is about 5.05 mg/kg per day, about 5.10 mg/kg per day, about 5.15 mg/kg per day, about 5.20 mg/kg per day, about 5.25 mg/kg per day, and about 5.30mg/kg, about 5.35mg/kg per day, about 5.40mg/kg per day, about 5.45mg/kg per day, about 5.50mg/kg per day, about 5.55mg/kg per day, about 5.60mg/kg per day, about 5.65 per day mg/kg, about 5.70mg/kg per day, about 5.75mg/kg per day, about 5.80mg/kg per day, about 5.85mg/kg per day, About 5.90 mg/kg per day, about 5.95 mg/kg per day, or about 6.00 mg/kg per day. A therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and administered in a controlled release or sustained release form two, three or four times a day.

In one aspect, the therapeutically effective amount of Compound I is about 6.05 mg/kg per day, about 6.10 mg/kg per day, about 6.15 mg/kg per day, about 6.20 mg/kg per day, about 6.25 mg/kg per day, and about 6.30mg/kg, about 6.35mg/kg per day, about 6.40mg/kg per day, about 6.45mg/kg per day, about 6.50mg/kg per day, about 6.55mg/kg per day, about 6.60mg/kg per day, about 6.65 per day mg/kg, about 6.70 mg/kg per day, about 6.75 mg/kg per day, about 6.80 mg/kg per day, about 6.85 mg/kg per day, about 6.90 mg/kg per day, about 6.95 mg/kg per day, or about 7.00 per day mg/kg. A therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and administered in a controlled release or sustained release form two, three or four times a day.

In one aspect, the therapeutically effective amount of Compound I is about 7.05 mg/kg per day, about 7.10 mg/kg per day, about 7.15 mg/kg per day, about 7.20 mg/kg per day, about 7.25 mg/kg per day, and about 7.30mg/kg, about 7.35mg/kg per day, about 7.40mg/kg per day, about 7.45mg/kg per day, about 7.50mg/kg per day, about 7.55mg/kg per day, about 7.60mg/kg per day, about 7.65 mg/kg per day mg/kg, about 7.70 mg/kg per day, about 7.75 mg/kg per day, about 7.80 mg/kg per day, about 7.85 mg/kg per day, about 7.90 mg/kg per day, about 7.95 mg/kg per day, or about 8.00 mg/kg per day mg/kg. A therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and administered in a controlled release or sustained release form two, three or four times a day.

In one aspect, the therapeutically effective amount of Compound I is about 8.05 mg/kg per day, about 8.10 mg/kg per day, about 8.15 mg/kg per day, about 8.20 mg/kg per day, about 8.25 mg/kg per day, and about 8.25 mg/kg per day. 8.30mg/kg, about 8.35mg/kg per day, about 8.40mg/kg per day, about 8.45mg/kg per day, About 8.50 mg/kg per day, about 8.55 mg/kg per day, about 8.60 mg/kg per day, about 8.65 mg/kg per day, about 8.70 mg/kg per day, about 8.75 mg/kg per day, about 8.80 mg/kg per day, About 8.85 mg/kg, about 8.90 mg/kg per day, about 8.95 mg/kg per day, or about 9.00 mg/kg per day. A therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and administered in a controlled release or sustained release form two, three or four times a day.

In one aspect, the therapeutically effective amount of Compound I is about 9.05 mg/kg per day, about 9.10 mg/kg per day, about 9.15 mg/kg per day, about 9.20 mg/kg per day, about 9.25 mg/kg per day, and about 9.30mg/kg, about 9.35mg/kg per day, about 9.40mg/kg per day, about 9.45mg/kg per day, about 9.50mg/kg per day, about 9.55mg/kg per day, about 9.60mg/kg per day, about 9.65 mg/kg per day mg/kg, about 9.70 mg/kg per day, about 9.75 mg/kg per day, about 9.80 mg/kg per day, about 9.85 mg/kg per day, about 9.90 mg/kg per day, about 9.95 mg/kg per day, or about 10.00 per day mg/kg. A therapeutically effective amount of Compound I can be conveniently administered, for example, divided into smaller doses and administered in a controlled release or sustained release form two, three or four times a day.

The therapeutically effective dose of Compound I can be initially established in animal models, generally rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine the dosage and route of administration that can be used in humans. The therapeutic/preventive efficacy and toxicity can be determined in laboratory animals by standard pharmaceutical procedures. The dosage can vary within this range depending on the dosage form used, the sensitivity of the patient, and the route of administration used.

After initial treatment with Compound I or its pharmaceutically acceptable salt, solvate or prodrug, the pain of the subject is improved. A maintenance dose of Compound I or its pharmaceutically acceptable salt can be administered as needed. , Solvate or prodrug. Then, the dosage, frequency of administration, or both of Compound I or its pharmaceutically acceptable salt, solvate, or prodrug can be reduced as the symptoms change to improve The condition is maintained at a level, that is, the dose is maintained. Furthermore, if the symptoms have been alleviated to the desired level, the treatment with Compound I or a pharmaceutically acceptable salt, solvate or prodrug should be terminated. However, for any recurrence of disease symptoms or in order to prevent the recurrence of the symptoms, the subject may need to use Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof for long-term intermittent treatment.

After initial treatment with Compound I or its pharmaceutically acceptable salt, solvate or prodrug, the subject’s pain, fibromyalgia, neuropathy, or chemotherapy-induced pain is improved, and the subject’s anti-hyperalgesia effect is obtained To enhance or decrease the subject’s sensitivity to pain, a maintenance dose of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof can be administered as needed. Then, as the symptoms change, the maintenance dose of Compound I or its pharmaceutically acceptable salt, solvate or prodrug can be reduced to the level where the improved condition can be maintained. Furthermore, if the symptoms have been alleviated to the desired level, the treatment with Compound I or a pharmaceutically acceptable salt, solvate or prodrug should be terminated. However, for any recurrence of disease symptoms or in order to prevent the recurrence of the symptoms, the subject may need to use Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof for long-term intermittent treatment.

After initial treatment with Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the subject’s pain, fibromyalgia, neuropathy, or chemotherapy-induced pain is improved, and the subject’s The anti-hyperalgesia effect is enhanced, or the subject's sensitivity to pain is reduced. According to needs, a maintenance dose of Compound I, other therapeutic agents for the treatment of pain, or a combination of these can be administered. The maintenance dose of Compound I and/or other therapeutic agents can be lower than the inducing dose, the administration frequency can be lower than the inducing dose, or both can be lower than the inducing dose.

Then, the maintenance dose of Compound I or its pharmaceutically acceptable salt, solvate or prodrug, the other therapeutic agent, or a combination of these can be reduced as the subject's symptoms change to a level where the improved condition can be maintained . Furthermore, if the symptoms have been reduced to the desired level, the use of the compound should be discontinued Treatment of substance I or a pharmaceutically acceptable salt, solvate or prodrug, the other therapeutic agent, or a combination of these. However, in order to prevent the recurrence of disease symptoms or to treat the disease symptoms when the disease relapses, the subject may need to use Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, the other therapeutic agent, or a combination thereof. Long-term intermittent treatment.

However, it should be understood that the total daily dosage of the compounds and compositions of the present invention should be determined by the attending physician within the scope of reasonable medical judgment. The amount of inhibitor used in any particular patient will depend on many factors, including the disease being treated and the severity of the disease; the activity of the specific compound used; the specific composition used; the age, weight, and general health of the patient Condition, gender, and diet; the administration time, route of administration and excretion rate of the specific compound used; duration of treatment; drugs used in combination or combination with the specific compound used; similar factors commonly known in the medical field.

The method for treating pain of the present invention may further comprise administering more than one other therapeutic agent, and the other therapeutic agent may include but not limited to: anti-epileptic drugs, antidepressant drugs, non-steroidal anti-inflammatory drugs, glucocorticoids, gabapentin ( gabapentin), pregabalin (pregabalin), cannabinoid, botulinum toxin, dietary supplements (e.g., alpha-lipid acid, benfotiamine), neuromodulators and topical agents (e.g., lidoca because).

The method for treating pain of the present invention may include other therapies, including but not limited to: acupuncture, electrical nerve stimulation, minimally invasive spinal surgery, and psychotherapy.

The present invention also provides a pharmaceutical combination, for example, a kit comprising: (a) a first dose, which is the free form or pharmaceutically acceptable salt form of compound I of the present invention as disclosed herein; and, accordingly Required, (b) at least one co-agent. The kit may contain instructions for its administration.

[Drug composition]

According to traditional techniques, such as those disclosed in Remington: The Science and Practice of Pharmacy, 21 ^st Edition, 2000, Lippincott Williams & Wilkins, which is incorporated in this article as a whole Any composition or pharmaceutical composition disclosed herein can be formulated with pharmaceutically acceptable carriers or diluents and any other known adjuvants and excipients. On the one hand, the present disclosure relates to a pharmaceutical composition containing Compound I, which is in the following forms: lozenges, capsules, oral preparations, powders, granules, pills, injections, infusions, solutions, suspensions, emulsions, suppositories , Ointment, cream, lotion, lozenge, chewable, gel, paste, multiparticulate, nanoparticulate, gel, solid solution, liposome, nanoparticle, film, granule Preparations, sprays, injections, and liquid preparations or transdermal delivery devices.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form can also contain inert diluents commonly used in the field, for example: water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil), glycerin , Tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures of these. In addition to the inert diluent, the oral composition may also include adjuvants such as wetting agents, emulsifiers, suspending agents, sweeteners, fragrances and fragrances.

Injectable preparations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, for example, sterile injectable aqueous or oily suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. The acceptable vehicles and solvents that can be used are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are traditionally used as solvents or suspending media. For this purpose, any odorless fixed oil can be used, including synthetic mono- or diglycerin ester. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

In order to prolong the effect of the drug, it is usually desired to slow the absorption of the drug from subcutaneous injection or intramuscular injection. This can be implemented by using a suspension of poorly water-soluble crystalline or amorphous materials. The absorption rate of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of the drug form for parenteral administration is achieved by dissolving or suspending the drug in an oil vehicle.

The composition for rectal or vaginal administration is oleic acid suppository, which can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax The excipient or carrier is solid at ambient temperature but liquid at body temperature, and therefore melts and releases the active compound in the rectum or vaginal cavity.

A similar type of solid composition can also be used as a filler in soft and hard-filled gelatin capsules. The capsules use excipients such as lactose or milk sugar and macromolecule polyethylene glycol.

The active compound may also be in the form of microcapsules with more than one excipient as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings, and other coatings known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. According to conventional practices, such dosage forms may also contain other substances besides inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, these dosage forms may also contain buffering agents.

The dosage form of the compound of the present invention for external or transdermal administration includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active ingredient is mixed with a pharmaceutically acceptable carrier under aseptic conditions, and if necessary, with any preservatives that may be required Or buffer mix. Ophthalmic preparations, ear drops, ophthalmic ointments, powders and solutions can also be considered within the scope of the present invention.

Ointments, pastes, creams and gels, in addition to containing the active compound of the present invention, may also contain excipients such as animal or vegetable fats, oils, waxes, paraffins, starch, tragacanth, and cellulose Derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, zinc oxide, or mixtures of these.

In addition to the compounds of the present invention, powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures of these substances. The spray may additionally contain customary propellants such as chlorofluorocarbons.

Transdermal patches have the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of compounds across the skin. The rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

As a general practice, these compositions are normally accompanied by written or printed instructions for use for treatment.

The composition of the present invention may include more than one therapeutic agent. In one aspect, the therapeutic agent can also be used to treat pain in the subject. The therapeutic agents include but are not limited to antiepileptic drugs, antidepressants, non-steroidal anti-inflammatory drugs, glucocorticoids, gabapentin, pregabalin, cannabinoid, botulinum toxin, dietary supplements ( For example, alpha-lipid acids, benfotiamine), neuromodulators, and external agents (for example, lidocaine).

[Summary of Examples]

Evaluate the effects of a single dose of 0.1 mg/kg MIN-117 and 1.0 mg/kg MIN-117 in a variety of pain areas ^{in ALGOGram TM, including the use of model tests at 0.1 mg/kg MIN-117 and 1.0 mg/kg MIN} -117(ip) Assessment of acute and toxic pain; neuropathic pain; inflammatory pain; postoperative pain; visceral pain; and behavioral and acute toxicity. For each test, an internal reference substance (for example, morphine) was used as a control for comparison. The test is performed 2 hours after treatment.

To evaluate the anti-hyperalgesic effect of a single intraperitoneal administration of MIN-117 in a carrageenan-induced mechanical hyperalgesia rat model (Bennett model). Carrageenan is a polysaccharide obtained from a variety of seaweeds. When carrageenan is injected into the plantar paw or knee joint, it causes local inflammation, thereby reducing weight bearing, changing the protection of the treated limb, and inducing thermal and mechanical hyperalgesia/hyperalgesia.

In this model, inflammation is induced by injecting carrageenan (2%) into the right hind paw of the rat through the sole of the foot. After three hours, the response threshold was measured using a paw pressure test. Pressure was gradually applied to the two hind paws (inflamed paw and control paw) of the rat, and the response threshold was determined as the pressure (g) required to cause paw withdrawal or vocalization. Morphine (3mg/kg, s.c.) was used as a positive control.

This test is widely and reliably used to demonstrate the efficacy of new analgesics in a conscious rat model of inflammatory pain.

Use the paw pressure test or the Randall & Selitto test to assess static mechanical hyperalgesia. This test requires increasing pressure on the hind paw between the flat surface and the blunt pointer. This test is usually used in animals with one hind paw that is inflamed by injection or damaged by ligation and a normal hind paw to evaluate drugs used for analgesia. The device exerts a steady increasing force, and the response threshold is measured as the pressure (g) required to cause paw withdrawal and/or vocalization. In one experiment, static mechanical hyperalgesia was evaluated. Each response threshold was measured on both hind paws.

Five experimental groups were used, with 10 rats in each group. For each group, 100 μL of 2% carrageenan suspension was first injected into the plantar surface of the right hind paw. Three hours after the carrageenan injection, the paw pressure test was used to measure the paw withdrawal threshold (baseline). The following were then administered to 5 groups: vehicle Substance (0.5% HPMC, ip); MIN-117 (0.01 mg/kg, ip); MIN-117 (0.1 mg/kg, ip); MIN-117 (1 mg/kg, ip); and morphine (3 mg/kg , Sc).

After administration of vehicle, MIN-117 or morphine, the paw pressure test was used to evaluate the anti-hyperalgesic effects of these compounds at 0 minutes (T0), 30 minutes, 60 minutes, 120 minutes and 240 minutes.

The vehicle and MIN-117 were administered intraperitoneally at 10 mL/kg. Morphine is administered subcutaneously at 5 mL/kg. Except for the morphine treatment group, the blinded experimenters performed dosing and testing in a random order. The dosage is expressed in the form of free active substance. At the end of the experiment, the _{rats were sacrificed by CO 2} inhalation, and then followed by a certified company for subsequent removal.

All treatment groups showed a significantly lower pain threshold for damaged paws than control paws. During the entire observation period of the study, the injured paws of the rats in the vehicle treatment group showed a decreased and stable pain threshold relative to the control paws. Compared with the vehicle treatment group, subcutaneous administration of morphine at 3 mg/kg induced a significant and significant increase in the paw withdrawal threshold of damaged paws from 30 minutes to 120 minutes after administration, and reached the maximum effect 30 minutes after treatment. During the entire time course of the study, intraperitoneal administration of MIN-117 at 0.01 or 0.1 mg/kg did not induce any significant increase in paw withdrawal threshold. However, relative to the vehicle treatment group, MIN-117 administered intraperitoneally at 1 mg/kg induced a slight increase in pain threshold, and the increase became significant 120 minutes after injection.

To evaluate the anti-hyperalgesic effect of a single intraperitoneal administration of MIN-117 in a single peripheral neuropathy rat model (Bennett model).

The Chronic Compressive Nerve Injury (CCI) model is based on discrete peripheral nerve injury and can be related to the post-traumatic/postoperative neuropathic pain experienced by the patient. In anesthetized rats, unilateral peripheral single neuropathy is induced by loose ligation of the sciatic nerve in the right hind paw of the rat (xylazine) 10mg/kg i.p., ketamine 60mg/kg i.p.). With blunt dissection of the biceps femoris, the total sciatic nerve is exposed to the middle of the thigh. At the proximal end of the sciatic trigeminal nerve, ligate the four ligaments loosely around it at 1mm intervals. Be extra careful when ligating these ligaments, so that the diameter of the nerve is hardly contracted.

After 14 days, static mechanical hyperalgesia was assessed using the paw pressure test. This test requires increasing pressure on the hind paw between the flat surface and the blunt pointer. This test usually uses animals that have one hind paw that is inflamed by injection or damaged by ligation and a normal hind paw to evaluate the analgesic effect of the drug. The device exerts a steady increasing force, and the response threshold is determined as the pressure (g) required to cause paw withdrawal and/or vocalization.

14 days after the operation, the pain response threshold was measured to select animals that met the selection criteria: 20g<paw withdrawal threshold<240g (baseline).

In this experiment, static mechanical hyperalgesia was evaluated. Measure the response threshold of each of the two hind paws.

Five experimental groups were used, with 10 rats in each group. CCI (Chronic Compressive Nerve Injury)/Vehicle (0.5% HPMC, ip); CCI/MIN-117 (1mg/kg, ip); CCI/MIN-117 (3mg/kg, ip); CCI/MIN-117 (10mg/kg, ip); and CCI/morphine (3mg/kg, sc).

The vehicle and MIN-117 were administered intraperitoneally at 10 mL/kg. Morphine is administered subcutaneously at 5 mL/kg. Except for the morphine treatment group, a blinded experimenter performed the administration and testing in a random order.

Thirty minutes after the morphine injection, the paw pressure test was used to evaluate the anti-hyperalgesic effect of morphine. For vehicle and MIN-117 administration, a paw pressure test was used after 120 minutes to evaluate the anti-hyperalgesic effect.

At the end of the experiment, the rats were sacrificed _{by CO 2 inhalation.}

After 14 days, in the 5 experimental groups, the pain threshold induced by sciatic nerve ligation was obvious, Significant and uniform decline.

At 120 minutes after treatment, the 0.5% HPMC treatment group showed a stable pain threshold relative to the damaged paw.

Subcutaneous administration of morphine at 3 mg/kg induced a significant and significant increase in pain threshold 30 minutes after administration.

The intraperitoneal administration of MIN-117 at 1 mg/kg did not induce any significant increase in pain threshold 120 minutes after treatment. However, when MIN-117 was administered at 3 and 10 mg/kg, a significant increase in pain threshold was induced after 120 minutes.

The anti-hyperalgesic effect of a single intraperitoneal administration of MIN-117 in a rat model of mechanical hyperalgesia induced by carrageenan (Bennett model) was also evaluated.

In this model, inflammation is induced by injecting carrageenan (2%) into the right hind paw of the rat through the sole of the foot. After three hours, the response threshold was measured using a paw pressure test. Pressure was gradually applied to the two hind paws (inflamed paw and control paw) of the rat, and the response threshold was determined as the pressure (g) required to cause paw withdrawal or vocalization. Morphine (3mg/kg, s.c.) was used as a positive control.

This test is widely and reliably used to demonstrate the efficacy of new analgesics in a conscious rat model of inflammatory pain.

Five experimental groups were used, with 10 rats in each group. For each group, 100 μL of 2% carrageenan suspension was first injected into the plantar surface of the right hind paw. Three hours after carrageenan injection, the pain response threshold (voice or paw withdrawal) was measured to select animals that met the selection criteria: 20g<paw withdrawal threshold<240g (baseline). The following were then administered to 5 groups: vehicle (0.5% HPMC, ip); MIN-117 (1 mg/kg, ip); MIN-117 (3 mg/kg, ip); MIN-117 (10 mg/kg , Ip); and morphine (3mg/kg, sc).

Thirty minutes after the morphine injection, the paw pressure test was used to evaluate the anti-hyperalgesic effect of morphine. For vehicle and MIN-117 administration, a paw pressure test was used after 120 minutes to evaluate the anti-hyperalgesic effect.

The vehicle and MIN-117 were administered intraperitoneally at 10 mL/kg. Morphine is administered subcutaneously at 5 mL/kg. Except for the morphine treatment group, a blinded experimenter performed the administration and testing in a random order. The dosage is expressed in the form of free active substance.

Before administration, all groups showed a significantly lower pain threshold compared to the control paw after 3 hours of injection of 2% carrageenan suspension. At 120 minutes after treatment, rats from the vehicle treatment group showed a stable pain threshold relative to the injured paw. Subcutaneous administration of morphine at 3 mg/kg induced a significant and significant increase in pain threshold 30 minutes after injection.

The intraperitoneal administration of MIN-117 at 1 mg/kg did not induce any significant increase in pain threshold. However, when MIN-117 was administered at 3 and 10 mg/kg, it induced a significant increase in pain threshold after 120 minutes.

Neuropathic pain assessment using von Frey filament is also performed. The rats were administered paclitaxel (2 mg/kg) every other day for a total of 4 days (days 1, 3, 5, and 7). Von Frey filament was used to assess baseline and paw withdrawal threshold (PWT) after treatment.

Place the animal on a pre-perforated metal platform and allow it to adapt to the surrounding environment for at least 15 minutes before each test. Each filament is perpendicular to the plantar surface, has sufficient force to resist the slight bending of the paw, and then holds it until a positive response (a sharp retraction of the paw) is noted. As disclosed by Chaplan, R. et al., once the threshold is crossed, the 2 responses that cross the threshold are retrospectively designated as the earliest 2 responses. According to the animal's response, another four responses are measured so that the stimulus changes up or down sequentially.

Every other day and a total of 4 days (days 1, 3, 5 and 7) at a dose volume of 1 mL/kg i.p. Paclitaxel (2mg/kg) was injected for a total of 4 injections.

On day 14, the baseline von Frey response was measured to ensure that all rats showed a stable neuropathic pain response. Then, based on the PWT value after paclitaxel treatment, the rats were evaluated and assigned to treatment groups. On the test day, PWT was assessed 2 hours after vehicle or MIN-117 injection and 1 hour after gabapentin administration.

On the 14th day, evaluate the effect of gabapentin or MIN-117 on PWT. Gabapentin was administered orally at a dose volume of 1 mL/kg 60 minutes before the test. MIN-117 (1, 3, and 10 mg/kg) is administered i.p. at a dose volume of 1 mL/kg. MIN-117 was administered 2 hours before the test.

One-way ANOVA showed that there were significant differences between groups. Relative to vehicle, gabapentin showed a significant increase in PWT. Relative to vehicle, animals treated with MIN-117 (3 and 10 mg/kg) also showed significantly increased PWT.

To evaluate the analgesic efficacy of MIN-117 in a rat model of peripheral neuropathic pain induced by chemotherapy after chronic injection. Every other day and for a total of 4 days (days 1, 3, 5 and 7), the reference preparation paclitaxel (2 mg/kg) was injected i.p. with a dose volume of 1 mL/kg, for a total of 4 injections. Gabapentin (100 mg/kg) is dissolved in saline and administered orally at a dose volume of 1 mL/kg. In the prevention study, MIN-117 (10 mg/kg) was administered i.p once a day at a dose volume of 1 mL/kg for 7 or 14 days. On the day of the test, MIN-117 was administered 2 hours before the test.

In the reversal study, MIN-117 (1, 3, and 10 mg/kg) was administered i.p. once a day at a dose volume of 1 mL/kg for 2 weeks. On the day of the test, MIN-117 was administered 2 hours before the test.

For prevention studies, a single dose (10 mg/kg) was tested, and the injection was started for 7 or 14 days the day before the paclitaxel injection. Under this treatment regimen, when compared with the vehicle, after administration A significant increase in PWT was observed on days 10 and 14.

For the reversal study, MIN-117 was tested at 1, 3, and 10 mg/kg after 2 weeks of administration. When tested on days 1, 7 and 14 of MIN-117 treatment (corresponding to days 14, 21 and 28 from the start of the study), all doses showed a significant increase in PWT.

When the rats were tested one week after the treatment was stopped, no analgesic effect was observed at any dose of MIN-117 in any study, suggesting that the effect is not long-lasting.

When gabapentin was administered for a long time or acutely, it showed a significant increase in PWT. The analgesic effect of gabapentin does not last for a long time. After the treatment is stopped, when compared with the vehicle, there is no significant effect on PWT.

Two types of antidepressants were also evaluated in the paw withdrawal threshold (PWT) experiment: duloxetine, a serotonin norepinephrine reuptake inhibitor; and amitriptyline, a three Cyclic antidepressant drugs. The line showed that in rats treated with paclitaxel, duloxetine had no effect on PWT, that is, duloxetine was not found to reverse paclitaxel-induced neuropathy in rats. It was shown that amitriptyline only partially reversed this neuropathy, but only the highest dose tested (30 mg/kg) had this effect.

Other aspects of the invention include:

A. A method for treating pain, which comprises administering to a subject in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof.

B. A method of treating pain, which comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of Compound I to a subject in need of treatment.

C. A method of treating pain, which comprises administering a therapeutically effective amount of compound I hydrochloride to a subject in need of treatment.

D. A method for treating pain, comprising administering to a subject in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof, wherein the pain is acute pain, chronic pain, or toxic pain , Neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, or a combination of these. For example, the pain is peripheral neuropathic pain induced by chemotherapy.

E. A method for treating fibromyalgia, which comprises administering to a subject in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof.

F. A method for treating fibromyalgia, which comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of Compound I to a subject in need of treatment.

G. A method for treating fibromyalgia, which comprises administering a therapeutically effective amount of compound I hydrochloride to a subject in need of treatment.

H. A method of treating neuropathy, which comprises administering to a subject in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof.

I. A method of treating neuropathy, which comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of Compound I to a subject in need of treatment.

J. A method of treating neuropathy, which comprises administering a therapeutically effective amount of compound I hydrochloride to a subject in need of treatment. For example, the neuropathy is peripheral neuropathy. For example, the neuropathy is induced by chemotherapy.

K. A method for treating chemotherapy-induced peripheral neuropathic pain, which comprises administering to a subject in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof.

L. A method for treating chemotherapy-induced peripheral neuropathic pain, which comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of Compound I to a subject in need of treatment.

M. A method for the treatment of peripheral neuropathic pain induced by chemotherapy, which includes administering to a subject in need of treatment A therapeutically effective amount of compound I hydrochloride.

N. Any method disclosed herein, wherein the treatment with a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof is to enhance the anti-hyperalgesic effect in the subject.

O. Any of the methods disclosed herein, including those in aspects A to N, wherein the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof is 0.1 mg/kg to 100 mg/kg. For example, 10mg/kg.

P. Any of the methods disclosed herein, including those in aspects A to N, wherein the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof is 0.5 mg/kg to 50 mg/kg.

Q. Any of the methods disclosed herein, including aspects A to N, wherein the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof is 1 mg/kg to 20 mg/kg.

R. Any method disclosed herein, including those in aspects A to N, wherein the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof administered to the subject is 0.1 mg to 6,000 mg .

S. Any of the methods disclosed herein, including those in aspects A to N, wherein the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof administered to the subject is 1 mg to 1,000 mg.

T. Any of the methods disclosed herein, including aspects A to N, wherein the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof administered to the subject is 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60 , 65, 70, 75, 80, 85, 90, 95 or 100mg.

U. Any of the methods disclosed herein, including those in aspects A to N, wherein the therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof administered to the subject is 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 , 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 mg.

V. Any of the methods disclosed herein, including aspects A to N, wherein the frequency of administration of Compound I or a pharmaceutically acceptable salt or solvate thereof to the subject is once a day , 2 times a day, 3 times a day, 1 time every 2 days, 1 time every 3 days, 1 time every 4 days, 1 time every 5 days, 1 time every 6 days, 1 time a week, 1 time every 2 weeks, Once every 3 weeks, or once a month.

W. Any of the methods disclosed herein, including those in Aspects A to N, wherein Compound I or a pharmaceutically acceptable salt or solvate thereof is formulated to include more than one pharmaceutically acceptable excipient Pharmaceutical composition.

X. Any of the methods disclosed herein, including those in aspects A to N, wherein the pharmaceutical composition further contains other therapeutic agents for the treatment of pain.

Y. Any method disclosed herein, including those in aspects A to N, wherein Compound I or a pharmaceutically acceptable salt or solvate thereof, or comprises Compound I or a pharmaceutically acceptable salt or solvate thereof The pharmaceutical composition of the drug is oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, systemic, intradermal, sublingual Administration, buccal administration, rectal administration, vaginal administration, intraocular administration, intra-aural administration, intranasal administration, inhalation administration, atomization administration or transdermal administration.

Z. Any method disclosed herein, including those of aspects A to N, wherein Compound I or a pharmaceutically acceptable salt or solvate thereof, or comprises Compound I or a pharmaceutically acceptable salt or solvate thereof The pharmaceutical composition of is orally administered to a subject, and is formulated as lozenges, capsules, chews, gels, pastes, multiparticulates, nanoparticulates, lozenges, pills, Granules, powders, solutions, sprays Sprays, emulsions, suspensions, syrups, mouthwashes or drops.

AA. Any method disclosed herein, including those in aspects A to N, wherein Compound I or a pharmaceutically acceptable salt or solvate thereof, or comprises Compound I or a pharmaceutically acceptable salt or solvate thereof The pharmaceutical composition of the drug is administered locally to the subject, and is formulated as a cream, paste, lotion, gel, patch or spray.

BB. Any of the methods disclosed herein, including those in aspects A to N, further include the administration of other therapeutic agents for the treatment of pain.

CC. Any of the methods disclosed herein, including those in aspects A to N, further comprise administering other therapeutic agents for the treatment of pain, wherein the other therapeutic agents for the treatment of pain and Compound I or its pharmaceutically Acceptable salts or solvates, or pharmaceutical compositions containing Compound I or pharmaceutically acceptable salts or solvates thereof, are administered at a similar time.

DD. Any method disclosed in this article, including aspects A to N, where the object is a person.

EE. A pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt or solvate thereof, which is used to treat pain in a subject in need. For example, a pharmaceutical composition containing the hydrochloride salt of Compound I is used to treat pain in a subject in need.

FF. Compound I or a pharmaceutically acceptable salt or solvate thereof is used to treat pain in a subject in need. For example, the hydrochloride salt of Compound I is used to treat pain in subjects in need.

GG. Compound I or a pharmaceutically acceptable salt or solvate thereof is used for the manufacture of a medicament for the treatment of pain in a subject in need. For example, the hydrochloride salt of Compound I is used to manufacture a medicament for treating pain in a subject in need.

[Equivalent]

Those with ordinary knowledge in their technical field should know or be able to use no more than usual Experiments have been conducted to find out a variety of equivalents to the specific aspects and methods disclosed in this article. Such equivalents tend to be covered by the scope of the present invention. All patents, patent applications and other references mentioned in this article are expressly incorporated by reference in their entirety.

The quotation of publications and patent files does not mean that any of them is recognized as related prior art, nor does it constitute recognition of their content or filing date.

Now, the present invention has been disclosed by means of written instructions. Those with ordinary knowledge in their technical field will know that the present invention can be practiced in many ways, but the foregoing specification and the following examples are for illustrative purposes. It is not a restriction on the scope of the attached patent application.

[Example]

Example 1. Evaluation of the efficacy of a single dose of 2 doses of MIN-117 ^{in ALGOGram TM (High-throughput Screening in Rats)}

The effect of a single administration of 2 doses of MIN-117 in ALGOGram ^{TM is summarized in Figure 1.} Use the model test to evaluate various pain areas (acute and toxic pain; neuropathic pain; inflammatory pain; postoperative pain; visceral pain; and behavior) with 0.1mg/kg MIN-117 and 1.0mg/kg MIN-117(ip) And acute toxicity). For each test, an internal reference substance (for example, morphine) was used as a control for comparison. The test is performed 2 hours after treatment. n=4/model/test. The result of each group is expressed as a percentage of activity, calculated by comparing the average value of the vehicle-treated animals with the original animal, control paw, or cut-off value, depending on the test.

Example 2. Evaluation of the anti-hyperalgesic effect of a single intraperitoneal administration of MIN-117 in a rat model of mechanical hyperalgesia induced by carrageenan

In a rat model of mechanical hyperalgesia induced by carrageenan, the anti-hyperalgesic effect of a single intraperitoneal administration of MIN-117 was evaluated.

Carrageenan is a polysaccharide obtained from various seaweeds. When injected into the plantar paw or knee joint, carrageenan causes local inflammation, thereby reducing weight bearing, changing the protection of the treated limb, and inducing thermal and mechanical hyperalgesia/hyperalgesia.

In this model, inflammation is induced by injecting carrageenan (2%) into the right hind paw of the rat. After three hours, the response threshold was measured using a paw pressure test. The pressure was gradually applied to the two hind paws (inflamed paw and control paw) of the rat, and the response threshold was determined as the pressure (g) required to cause paw withdrawal or vocalization. Morphine (3mg/kg, s.c.) was used as a positive control.

This test is widely and reliably used to demonstrate the efficacy of new analgesics in a conscious rat model of inflammatory pain.

The experiments in this study used fifty (50) male Sprague-Dawley rats (SPF status, Janvier, France), each weighing 204 to 260 grams. Rats are caged in a controlled room with temperature (20 to 24°C) and relative humidity (45% to 65%), and are adapted to an artificial day-night cycle of 12 hours of light (6.30 a.m. to 6.30 p.m.)/12 hours of darkness. Rats have free access to sterilized tap water and freely fed food with whole particles (reference material A04, S.A.F.E.). 4 rats were housed in each cage (E-type cage), and they were acclimatized for at least 5 days before any test. Identify each rat by tail markings. According to the SPF status of the animal facility, there is no reason to believe that the presence of contaminants in food, water or bedding can interfere with the level of test results.

MIN-117 is provided by Minerva Neuroscience, Inc. as a white to light yellow powder or crystalline powder, and is stored at room temperature before use.

Morphine was supplied by Francopia (catalog reference number 3695, lot number HR00002) and stored at room temperature before use.

The vehicle (HPMC, water, saline) was stored at 4°C. 0.5% in water for injection (w/v) Hydroxypropyl methylcellulose (HPMC) 80 to 120 centipoise is used as the vehicle of MIN-117. 0.9% NaCl is used as a vehicle for morphine.

Carrageenan was provided by Sigma-Aldrich (catalog reference number C1013, lot number SLBD1934V) and stored in suspension at 4°C. 0.9 NaCl (w/v) is used as a vehicle for 2% carrageenan suspension.

Ugo Basile analgesia instrument (Ugo Basile, Italy) is used for paw pressure test.

SigmaStat software version 3.5 (SPSS Science Software, Erkrath, Germany) and Lab X direct software version 2.4 (Mettler Toledo, France) are used for data processing.

Pain test: Use the paw pressure test or Randall & Selitto test to evaluate static mechanical hyperalgesia (Randall, LOand Selitto, JJ, A method for measurement of analgesic activity on inflamed tissue, Arch Int Pharmacodyn , 1957(111): 409-419) . This test requires increasing pressure on the hind paw between the flat surface and the blunt pointer. This test usually uses animals that have one hind paw that is inflamed by injection or damaged by ligation and a normal hind paw to evaluate the analgesic effect of the drug. The device exerts a steady increasing force, and the response threshold is determined as the pressure (g) required to cause paw withdrawal and/or vocalization. In this experiment, the animals were handled gently by the experimenter and the static mechanical hyperalgesia was evaluated. Each response threshold was measured on both hind paws.

Five (5) experimental groups were used, with 10 rats in each group. For each group, 100 μL of 2% carrageenan suspension was first injected into the plantar surface of the right hind paw. Three hours after the carrageenan injection, the paw pressure test was used to measure the paw withdrawal threshold (baseline). The following were then administered to 5 groups:

Group 1: Vehicle (0.5% HPMC), i.p. (intravenous injection), solution (negative control);

Group 2: MIN-117 (0.01mg/kg, i.p.) in 0.5% HPMC, suspension;

Group 3: MIN-117 (0.1mg/kg, i.p.) in 0.5% HPMC, suspension;

Group 4: MIN-117 (1mg/kg, i.p.) in 0.5% HPMC, suspension; and

Group 5: Morphine (3mg/kg, s.c.) in 0.9% HPMC, solution (positive control).

After administration of vehicle, MIN-117 or morphine, the paw pressure test was used to evaluate the anti-hyperalgesic effects of these compounds at 0 minutes (T0), 30 minutes, 60 minutes, 120 minutes and 240 minutes.

The vehicle and MIN-117 were administered intraperitoneally at 10 mL/kg. Morphine is administered subcutaneously at 5 mL/kg. Except for the morphine treatment group, a blinded experimenter performed the administration and testing in a random order. The dosage is expressed in the form of free active substance. At the end of the experiment, the _{rats were sacrificed by inhalation of CO 2} and then followed up by a certified company for subsequent removal.

Results are evaluated: the paw withdrawal threshold (mean ± sem) of each group in gram contact pressure is calculated from the individual paw withdrawal threshold; the percentage of change in the paw withdrawal threshold is calculated from the average value of the vehicle treatment group; and/ Or the percentage of activity. In order to determine the statistical effect of the test substance and the reference substance, the data is analyzed by non-parametric test. The significance level is p<0.05.

As summarized in Table 1 and Figure 2, the original data in Table 2 shows that before the administration, compared to the control paw, the damaged paws in all treatment groups showed a significantly reduced pain threshold, ranging from 50% to 53% (p<0.001). During the entire observation period of the study, compared to the control paw, the injured paw of the rats in the vehicle (0.5% HPMC) treatment group showed a decreased and stable pain threshold (the range was 178±7.0g(T0+30) Minutes) and 188±6.1g (T0+60 minutes)). Compared with the vehicle treatment group, morphine administered subcutaneously at 3 mg/kg induced a significant and significant increase in the paw withdrawal threshold of damaged paws from 30 minutes to 120 minutes after administration, and reached the maximum effect 30 minutes after treatment (592±31.3 g compared with 178±7.0g, +233%, p<0.05). During the entire time course of the study, MIN-117 administered intraperitoneally at 0.01 or 0.1 mg/kg did not induce any significant increase in paw withdrawal threshold. However, compared with the vehicle treatment group, MIN-117 administered intraperitoneally at 1 mg/kg induced a slight increase in pain threshold, which became Significant (see $$$ in Figure 2) (232±7.4g compared with 186±7.3, +25%, p<0.001, Mann-Whitney rank sum test).

Table 1

Table 1-continued

Table 2

Table 2-continued

Example 3. Evaluation of the anti-hyperalgesic effect of single intraperitoneal administration of MIN-117 in a rat model of peripheral single neuropathy (Bennett model)

To evaluate the anti-hyperalgesic effect of single intraperitoneal administration of MIN-117 in a rat model of peripheral single neuropathy (Bennett model).

Chronic Compressive Nerve Injury (CCI) model is based on discrete peripheral nerve injury and can be related to post-traumatic/postoperative neuropathic pain experienced by patients (Bennett, GJand Xie, YK, A peripheral mononeuropathy in rat that produces disorders of pain sensation). like those seen in man, Pain , 1988(33): 87-107). In anesthetized rats, unilateral peripheral single neuropathy is induced by loose ligation of the sciatic nerve of the right hind paw of the rat (xylazine 10mg/kg ip, ketamine 60mg/kg ip .). With blunt dissection of the biceps femoris, the total sciatic nerve system is exposed to the middle of the thigh. At the proximal end of the sciatic trigeminal nerve, the four ligaments were loosely ligated at its ends at 1 mm intervals. Extra care must be taken when ligating these ligaments, so that the diameter of the nerve is hardly contracted.

After 14 days, a paw pressure test was used to evaluate static mechanical hyperalgesia (Randall, LO and Selitto, JJ, A method for measurement of analgesic activity on inflamed tissue, Arch Int Pharmacodyn , 1957(111): 409-419). This test requires increasing pressure on the hind paw between the flat surface and the blunt pointer. This test usually uses animals that have one hind paw that is inflamed by injection or damaged by ligation and a normal hind paw to evaluate the analgesic effect of the drug. The device exerts a steady increasing force, and the response threshold is determined as the pressure (g) required to cause paw withdrawal and/or vocalization. Ugo Basile analgesia instrument (Ugo Basile, Italy) is used for paw pressure test.

On the 14th day after the operation (D ₀ ), the pain response threshold (voice or paw withdrawal) was measured to select animals that met the selection criteria: 20 g <paw withdrawal threshold <240 g (baseline).

Fifty (50) male Sprague-Dawley rats (SPF status, Janvier, France) were used, weighing 133 to 181 grams on the day of surgery. Rats are kept in a cage in a controlled room with temperature (20 to 24°C) and relative humidity (45% to 65%), and are adapted to 12 hours of light (6.30 a.m. to 6.30 a.m.). 6.30 p.m.)/12 hours of dark artificial day and night cycle. Rats have free access to sterilized tap water and freely fed food with whole particles (reference material A04, S.A.F.E.). There are 4 animals in each cage (E-type cage), and they are acclimatized for at least 5 days before any test. Identify each rat by tail markings. According to the SPF status of the animal facility, there is no reason to believe that the presence of contaminants in food, water or bedding can interfere with the level of test results.

In this experiment, the animals were handled gently by the experimenter and the static mechanical hyperalgesia was evaluated. Measure the response threshold of each of the two hind paws.

Use five (5) experimental groups with 10 rats in each group:

Group 1: CCI (Chronic Compressive Nerve Injury)/Vehicle (0.5% HPMC), i.p., solution (negative control);

Group 2: CCI/MIN-117 (1mg/kg, i.p.) in 0.5% HPMC, suspension;

Group 3: CCI/MIN-117 (3mg/kg, i.p.) in 0.5% HPMC, suspension;

Group 4: CCI/MIN-117 (10mg/kg, i.p.) in 0.5% HPMC, suspension; and

Group 5: CCI/morphine (3mg/kg, s.c.), solution in 0.9% NaCl (positive control).

MIN-117 is provided by Minerva Neuroscience, Inc., is white to light yellow powder or crystalline powder, and is stored at room temperature before use. Morphine was used as a reference material for the positive control. It was provided by Francopia (Catalog Reference No. 3695, Lot No. HR00002) and stored at room temperature before use. The vehicle (HPMC, water, saline) was stored at 4°C. The 0.5% (w/v) hydroxypropyl methylcellulose (HPMC) of 80 to 120 centipoise in water for injection is used as the vehicle of MIN-117. 0.9% NaCl is used as a vehicle for morphine.

The vehicle and MIN-117 were administered intraperitoneally at 10 mL/kg. Morphine is administered subcutaneously at 5 mL/kg. Except for the morphine treatment group, a blinded experimenter performed the administration and testing in a random order.

30 minutes after the morphine injection, use the paw pressure test to evaluate the anti-hyperalgesic effect of morphine effect. For vehicle and MIN-117 administration, a paw pressure test was used after 120 minutes to evaluate the anti-hyperalgesic effect.

At the end of the experiment, the _{rats were sacrificed by inhalation of CO 2} and then followed up by a certified company for subsequent removal.

Result system performance:

The paw withdrawal threshold (average value ± s.e.m.) of each group based on the gram contact pressure gauge is calculated from the individual paw withdrawal threshold;

The percentage change of paw withdrawal threshold is calculated from the average value of the vehicle treatment group;

The percentage of activity of the compound relative to the mechanical hyperalgesia induced by sciatic nerve ligation is calculated as follows:

In order to determine the statistical effect of the test substance and the reference substance, the data is analyzed by non-parametric test. SigmaStat software version 3.5 (SPSS Science Software, Erkrath, Germany) and Lab X direct software version 2.4 (Mettler Toledo, France) are used for data processing. The significance level is p<0.05.

As summarized in Table 3 and Figure 3, the original data in Table 4 show that after 14 days, compared with the control paw, sciatic nerve ligation induced a significant, significant and uniform decrease in pain threshold in the 5 experimental groups. The range is between 49% and 55% (p<0.001).

With respect to the damaged claw, 0.5% HPMC treated group (in the leftmost column of FIG. 3) at 120 minutes after the treatment exhibits stable pain threshold value of (166 ± 6.7g compared with T ₀ of 178 ± 6.3g).

Morphine administered subcutaneously at 3 mg/kg (the rightmost column in Figure 3) was 30 minutes after administration Bell induced a significant and significant increase in pain threshold, and the percentage of activity was +165% (486±42.8g compared with 188±10.4g, p<0.01, compared with baseline before treatment).

Compared with the vehicle treatment group, MIN-117 administered intraperitoneally at 1 mg/kg (the second column from the left in Figure 3) did not induce any significant increase in pain threshold 120 minutes after administration (percentage of activity: + 9%). However, when MIN-117 was administered at 3 and 10 mg/kg (the middle column in Figure 3 and the second column from the right, respectively), compared to the vehicle treatment group, significant pain threshold was induced after 120 minutes Increase (222±9.2g and 280±20.9g, respectively, compared with 166±6.7g), and the percentage of activity is +29% and +59%, respectively.

table 3

Table 4

Table 4-Continued

Example 4. In a rat model of mechanical hyperalgesia induced by carrageenan, assess a single intraperitoneal cavity Anti-hyperalgesic effect of MIN-117 administration

To evaluate the anti-hyperalgesic effect of a single intraperitoneal administration of MIN-117 in a rat model of mechanical hyperalgesia induced by carrageenan (Bennett model).

In this model, inflammation is induced by injecting carrageenan (2%) into the right hind paw of the rat through the sole of the foot. After three hours, the response threshold was measured using a paw pressure test. Pressure was gradually applied to the two hind paws (inflamed paw and control paw) of the rat, and the response threshold was determined as the pressure (g) required to cause paw withdrawal or vocalization. Morphine (3mg/kg, s.c.) was used as a positive control.

This test is widely and reliably used to demonstrate the efficacy of new analgesics in a conscious rat model of inflammatory pain.

The experimental system in this study used fifty (50) male Sprague-Dawley rats (SPF status, Janvier, France), each weighing 183 to 244 g during the experiment. Rats are caged in a controlled room with temperature (20 to 24°C) and relative humidity (45% to 65%), and are adapted to an artificial day-night cycle of 12 hours of light (6.30 a.m. to 6.30 p.m.)/12 hours of darkness. Rats have free access to sterilized tap water and freely fed food with whole particles (reference material A04, S.A.F.E.). There are 4 animals in each cage (E-type cage), and they are acclimatized for at least 5 days before any test. Identify each rat by tail markings. According to the SPF status of the animal facility, there is no reason to believe that the presence of contaminants in food, water or bedding can interfere with the level of test results.

MIN-117 is provided by Minerva Neuroscience, Inc., is white to light yellow powder or crystalline powder, and is stored at room temperature before use.

Morphine is supplied by Francopia (catalog reference number 3695, lot number HR00002) and stored at room temperature before use.

The vehicle (HPMC, water, saline) was stored at 4°C. 80 to 120 in water for injection The 0.5% (w/v) hydroxypropyl methylcellulose (HPMC) of centipoise is used as the vehicle of MIN-117. 0.9% NaCl is used as a vehicle for morphine.

Carrageenan was supplied by Sigma-Aldrich (catalog reference number C1013, lot number SLBD1934V) and stored as a suspension at 4°C. 0.9 NaCl (w/v) is used as a vehicle for 2% carrageenan suspension.

Ugo Basile analgesia instrument (Ugo Basile, Italy) is used for paw pressure test.

SigmaStat software version 3.5 (SPSS Science Software, Erkrath, Germany) and Lab X direct software version 2.4 (Mettler Toledo, France) are used for data processing.

Use the paw pressure test or the Randall & Selitto test to evaluate static mechanical hyperalgesia (Randall, LOand Selitto, JJ, A method for measurement of analgesic activity on inflamed tissue, Arch Int Pharmacodyn , 1957(111):409-419). This test requires increasing pressure on the hind paw between the flat surface and the blunt pointer. This test usually uses animals that have one hind paw that is inflamed by injection or damaged by ligation and a normal hind paw to evaluate the analgesic effect of the drug. The device exerts a steady increasing force, and the response threshold is determined as the pressure (g) required to cause paw withdrawal and/or vocalization. In this experiment, the animals were handled gently by the experimenter and the static mechanical hyperalgesia was evaluated. Each response threshold was measured on both hind paws.

Five (5) experimental groups were used, with 10 rats in each group. For each group, 100 μL of 2% carrageenan suspension was first injected into the plantar surface of the right hind paw. Three hours after carrageenan injection, the pain response threshold (voice or paw withdrawal) was measured to select animals that met the selection criteria: 20g<paw withdrawal threshold<240g (baseline). The following were then administered to 5 groups:

Group 1: Vehicle (0.5% HPMC), intravenous injection, solution (negative control);

Group 2: MIN-117 (1mg/kg, i.p.) in 0.5% HPMC, suspension;

Group 3: MIN-117 (3mg/kg, i.p.) in 0.5% HPMC, suspension;

Group 4: MIN-117 (10mg/kg, i.p.) in 0.5% HPMC, suspension; and

Group 5: Morphine (3mg/kg, s.c.) in 0.9% HPMC, solution (positive control).

Thirty minutes after the morphine injection, the paw pressure test was used to evaluate the anti-hyperalgesic effect of morphine. For vehicle and MIN-117 administration, a paw pressure test was used after 120 minutes to evaluate the anti-hyperalgesic effect.

The vehicle and MIN-117 were administered intraperitoneally at 10 mL/kg. Morphine is administered subcutaneously at 5 mL/kg. Except for the morphine treatment group, a blinded experimenter performed the administration and testing in a random order. The dosage is expressed in the form of free active substance.

At the end of the experiment, the _{rats were sacrificed by inhalation of CO 2} and then followed up by a certified company for subsequent removal.

Result system performance:

‧The paw withdrawal threshold of each group by the gram contact pressure gauge (average ± s.e.m.), calculated from the individual paw withdrawal threshold

‧The percentage change of paw reduction threshold is calculated from the average value of the vehicle treatment group

‧The percentage activity of the compound against mechanical hyperalgesia induced by carrageenan is calculated by the following formula:

In order to determine the statistical effect of the test substance and the reference substance, the data is analyzed by non-parametric test. The significance level is p<0.05.

As summarized in Table 5 and Figure 4, the original data in Table 6 shows that before administration, 3 hours after injection of 2% carrageenan suspension, compared to the control paw, the damaged paws of all treatment groups The pain threshold exhibited a significant decrease, ranging from 46% to 50% (p<0.001). At 120 minutes after treatment, rats in the vehicle treatment group (0.5% HPMC, the leftmost column in Figure 4) showed a stable pain threshold (204±6.5g and T ₀ of 200± 7.3g comparison). Administered subcutaneously at 3 mg/kg (the rightmost column in Figure 4), morphine induces a significant and significant increase in pain threshold 30 minutes after injection, and the percentage of activity is +190% (524±35.6g and 200± 6.7g comparison, p<0.01, compared with baseline before treatment).

Compared with the vehicle treatment group, MIN-117 administered intraperitoneally at 1 mg/kg (the second column from the left in Figure 4) did not induce any significant pain threshold increase 120 minutes after administration (percentage of activity: + 15%). However, when administered at 3 and 10 mg/kg (the middle column in Figure 4 and the second column from the right, respectively), after 120 minutes, MIN-117 induced significant pain sensation relative to the vehicle treatment group The threshold was increased (296±20.8g and 312±22.7g, respectively, compared with 204±6.5g), and the percentage of activity was +55% and +64% (p<0.05). The results are expressed as mean ± s.e.m. The percentage is expressed as a percentage of activity. ###: p<0.001, compared with the control paw of the corresponding group, Mann-Whitney rank sum test. *: p<0.05, compared with the vehicle treatment group, Kruskal-Wallis single factor analysis of variance. $$: p<0.01, compared with the baseline of the corresponding group, Wilcoxon rank sum test.

table 5

Table 6

Table 6-Continued

Example 5. Intraperitoneal administration of MIN-117 to evaluate the analgesic effect of MIN-117 on neuropathic pain in a Sprague Dawley rat model of peripheral neuropathic pain induced by chemotherapy

Neuropathic pain assessment using von Frey filament is also performed. The rats were administered paclitaxel (2 mg/kg) every other day for a total of 4 days (days 1, 3, 5, and 7). Use different tenacity (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, 10, 15, 26g) of von Frey filament (Semmes-Weinstein filament, Stoelting, Wood Dale, IL, USA) to evaluate baseline and treatment Retracted paw threshold (PWT). Place the animal on a pre-perforated metal platform and allow it to adapt to the surrounding environment for at least 15 minutes before each test. Each filament is perpendicular to the surface of the plantar, which has sufficient force to resist the slight bending of the paw, and then holds it until a positive response (a sharp retraction of the paw) is noted. As disclosed by Chaplan, SR et al. "Qualitative Assessment of Tactile Allodynia in the Rat Paw" Journal of Neuroscience Methods, 53 (1994), 55-63 ("Chaplan"), once the threshold is crossed, 2 of the threshold is crossed The two responses are retrospectively designated as the earliest two responses. According to the animal's response, another four responses are measured so that the stimulus changes up or down sequentially. The 6 responses with the closest threshold are used to calculate the 50% g threshold:

50% g threshold=(10 ^[Xf+k*d] )/10000

Xf is the final filament used (in logarithmic units). The parameter k is from Appendix 1 of Chaplan and is determined by the mode of von Frey response (for example, OXOXOX, where "O" indicates no response, and "X" indicates paw withdrawal). The parameter d is the difference between the stimuli used by Chaplan, and is a constant d=0.224. In order to adapt to the use of 10g and 26g filaments, the exact difference between stimuli is used.

Male Sprague Dawley rats from Envigo, Indiana, USA were used in this study. The animals were weighed approximately 250 g at the time of receipt, and 3 animals per cage were tied at the time of arrival. Before the start of the study, all rats were checked, handled and weighed to ensure proper health and suitability. Yu Research During the process, the light/dark cycle of 12h/12h is maintained. The room temperature is maintained between 20°C and 23°C, and the relative humidity is maintained at about 50%. During the research process, food and water are provided without restriction. All tests are performed during the light cycle of animals. Make every effort to minimize harm to animals. Rat lines with a baseline PWT of less than 12 g were not included in this study. The rats were balanced by body weight and PWT value before paclitaxel treatment. Before paclitaxel injection, the baseline body weight (BW) of all rats is shown in Figure 5. The analysis of variance showed no significant difference between the treatment groups.

Paclitaxel was purchased from Biolyse Pharma (Ontario, Canada), and was injected ip (2 mg/kg) at a dose volume of 1 mL/kg every other day for a total of 4 days (days 1, 3, 5, and 7), for a total of 4 injections Second-rate.

On day 14, the baseline VF response was measured to ensure that all rats showed a stable neuropathic pain response. Then, according to the PWT value after paclitaxel treatment, the rats were evaluated and assigned to the treatment group. On the test day, PWT was assessed 2 hours after vehicle or MIN-117 injection and 1 hour after gabapentin administration.

The body weights of all rats during paclitaxel treatment and MIN-117 administration are shown in Figure 6. The analysis of variance of repeated measures showed no significant difference between groups.

The baseline paw withdrawal threshold (PWT) before and after paclitaxel injection is shown in Figure 7. Before treatment, the variance analysis showed no significant difference between the treatment groups.

On the 14th day, the effect of gabapentin or MIN-117 on PWT is shown in Figure 8. Gabapentin was purchased from Toronto Research Chemicals and dissolved in saline, and was administered orally at a dose volume of 1 mL/kg 60 minutes before the test. MIN-117 (1, 3, and 10 mg/kg) formulated in 0.5% (w/v) hydroxypropyl methylcellulose (HPMC, Sigma-Aldrich) was administered i.p. at a dose volume of 1 mL/kg. MIN-117 was administered 2 hours before the test.

One-way ANOVA indicates significant differences between groups. Compared with the vehicle (the leftmost column in Figure 8), gabapentin (the second column from the left in Figure 8) showed a significant increase in PWT. Compared with vehicle, animals treated with MIN-117 at a dose of 3 mg/kg (second column from the right in Figure 8) and animals treated with MIN-117 at a dose of 10 mg/kg (far right in Figure 8) Column) also shows a significant increase in PWT. Compared to vehicle, animals treated with MIN-117 at a dose of 1 mg/kg (middle column in Figure 8) did not show a significant increase in PWT. The original data of these experiments are included in Table 7 below.

Table 7

Relative to the paclitaxel-vehicle group, the significantly increased PWT indicated that treatment with MIN-117 (3 and 10 mg/kg) significantly reduced neuropathic pain.

Example 6. Evaluation of the analgesic effect of MIN-117 on neuropathic pain after long-term administration in a rat model of chemotherapy-induced peripheral neuropathic pain

The goal of this study is to evaluate the analgesic efficacy of MIN-117 after chronic injection in a rat model of chemotherapy-induced peripheral neuropathic pain.

Male Sprague Dawley rats from Envigo were used in this study. The animals were weighed approximately 250 g at the time of receipt, and 3 animals per cage were tied at the time of arrival. Before the start of the study, all rats It is inspected, handled and weighed to ensure proper health and suitability. During the research process, the light/dark cycle of 12h/12h was maintained. The room temperature is maintained between 20°C and 23°C, and the relative humidity is maintained at about 50%. During the research process, food and water are provided without restriction. All tests are performed during the light cycle of animals.

Reference formula:

Paclitaxel (2mg/kg) was purchased from Biolyse Pharma, and was injected ip (2mg/kg) at a dose volume of 1 mL/kg every other day for a total of 4 days (days 1, 3, 5 and 7) for a total of 4 injections .

Gabapentin (100 mg/kg) is dissolved in saline and administered orally at a dose volume of 1 mL/kg. For prevention studies, gabapentin was administered on the 14th day 60 minutes before the test. For the reversal study, gabapentin was administered once a day for 2 weeks. The drug was administered 60 minutes before the test on the day of the test.

[Sponsor test product]

Prevention study: MIN-117 (10mg/kg) is formulated in a 0.5% (w/v) hydroxypropyl methylcellulose (HPMC) aqueous solution of 80 to 120 centipoise, and is ip daily at a dose volume of 1 mL/kg It is administered once for 7 or 14 days. On the day of the test, MIN-117 was administered 2 hours before the test.

Reversal study: MIN-117 (1, 3, and 10 mg/kg) is formulated in a 0.5% (w/v) hydroxypropyl methylcellulose (HPMC) aqueous solution of 80 to 120 centipoise, and is used at 1 mL/kg The dose volume is administered ip once a day for 2 weeks. On the day of the test, MIN-117 was administered 2 hours before the test.

[Behavior Test]

During the treatment, the body weight was measured every day, and twice a week after the administration was terminated.

Use von Frey filament to shrink the claw threshold

The rats were administered paclitaxel (2 mg/kg) every other day for a total of 4 days (days 1, 3, 5, and 7). Use different tenacity (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, 10, 15, 26g) of von Frey filament (Semmes-Weinstein filament, Stoelting, Wood Dale, IL, USA) to evaluate baseline and treatment Retracted paw threshold (PWT). Place the animal on a pre-perforated metal platform and allow it to adapt to the surrounding environment for at least 15 minutes before each test. Each filament is present perpendicularly to the plantar surface, has enough force to resist the slight bending of the paw, and then holds it until a positive response (a sharp retraction of the paw) is noted. As disclosed by Chaplan et al. 1994, once the threshold is crossed, the two responses that cross the threshold are retrospectively designated as the earliest two responses. According to the animal's response, another four responses are measured so that the stimulus changes up or down sequentially. The 6 responses with the closest threshold are used to calculate the 50% g threshold:

50% g threshold = (10 ^[Xf+k*d] )/10000 Xf is the final filament used (in logarithmic units). The parameter k is from Appendix 1 of Chaplan and is determined by the mode of von Frey response (for example, OXOXOX, where "O" indicates no response, and "X" indicates paw withdrawal). The parameter d is the difference between the stimuli used by Chaplan, and is a constant d=0.224. In order to adapt to the use of 10g and 26g filaments, the exact difference between stimuli is used.

Rats with a von Frey score less than 12g before paclitaxel treatment were not included in this study. Measure PWT according to the schematic diagrams in Figure 9 (Prevention) and Figure 10 (Reversal Study).

[Statistical Analysis]

The data was analyzed by analysis of variance (ANOVA) and (if appropriate) subsequent post-hoc comparisons. If p<.05, the effect is considered significant. The data is expressed as the mean value and the standard error (s.e.m) of the mean value. Statistical outliers that were 2 standard deviations above or below the mean were identified, but were not removed from the final analysis.

[result]

weight

Baseline weight-single factor analysis of variance did not find a difference in BW between the groups before treatment.

Body weight during treatment-The effect of paclitaxel and test compounds on BW throughout the study is shown in Figure 11. Repeated measurement ANOVA found that there was a significant interaction between the treatment effect and x days of treatment. Compared with vehicle (line ˙ in Figure 1), rats treated with MIN-11710 mg/kg (line ▲ and line ■ in Figure 11) showed weight loss. The effect was seen from the 2nd day to the 11th day.

Paw withdrawal threshold (PWT)

ANOVA found that there was no difference in baseline PWT between the treatment groups. On the other hand, on the 8, 10, 14 and 21 days, the effect of MIN-117 on PWT is shown in Figure 12. ANOVA found significant therapeutic effects on the 10th and 14th days. Compared with the vehicle (the leftmost column in the figure 12), when tested 2 hours after the administration, treated with MIN-117 at a dose of 10 mg/kg for 1 week (the second column from the right in the figure 12) Or the rat line at 2 weeks (far right column in Figure 12) showed a significantly higher PWT. The gabapentin tested on the 14th day also showed a significantly higher PWT than the vehicle (the second column from the left in the figure 12).

On the 21st day, 1 or 2 weeks after the treatment was terminated, the PWT of the 10 mg/kg MIN-117 treatment group returned to the vehicle level, and there was no significant difference between the different treatment groups.

[Reverse research results]

weight

Baseline weight-single factor analysis of variance did not find a difference in BW between the groups before treatment.

Baseline weight after paclitaxel treatment-univariate analysis of variance was not in the group before treatment BW difference was found between.

Body weight during treatment-throughout the study, the effects of paclitaxel and MIN-117 on BW are shown in Figure 13. Repeated measures ANOVA showed no significant therapeutic effect. Although there is a significant x-day interaction of treatments, none of these treatments have been shown to have a significant effect on BW compared with the vehicle.

Paw withdrawal threshold (PWT)

ANOVA found no difference in baseline PWT between treatment groups (Figure 14).

On the other hand, on the 14, 21, 28 and 35 days, the effect of MIN-117 on PWT is shown in Fig. 15. ANOVA found significant therapeutic effects on the 14, 21 and 28 days. When tested 2 hours after administration, compared with the vehicle (the leftmost column in the figure 15), the dose was 1 mg/kg (the middle column in the figure 15), 3 mg/kg (the right column in the figure 15). Rats treated with MIN-117 at a dose of 10 mg/kg (the rightmost column in the figure 15) or gabapentin at a dose of 100 mg/kg (the second column from the left in the figure 15) showed significantly higher PWT. (Gabapentin is tested 1 hour after administration) On the 35th day, one week after the treatment was terminated, the PWT of the MIN-117 or gabapentin treatment group returned to the vehicle level, and there was no significant difference between the different treatment groups.

Summarize

This study is to evaluate the effect of long-term administration of MIN-117 on paclitaxel-induced neuropathic pain. The effect is to reverse the paclitaxel-induced pain or prevent the pain.

For the prevention study, a single dose (10 mg/kg) was tested. The single dose was injected one day before the paclitaxel injection and lasted for 7 or 14 days. Under this treatment regimen, when compared with vehicle, a significant increase in PWT was seen on the 10th and 14th day after administration.

For reversal studies, MIN-117 was administered continuously at 1, 3, and 10 mg/kg for 2 weeks Test afterwards. When tested on the 1, 7 and 14 days of MIN-117 treatment (corresponding to the 14, 21 and 28 days from the start of the study), all doses showed a significant increase in PWT.

When the rats were tested one week after the treatment was stopped, no analgesic effect was seen at any dose of MIN-117 in any study, suggesting that the effect is not long-lasting.

When long-term administration or acute administration of gabapentin, the PWT showed a significant increase. The analgesic effect of gabapentin does not last for a long time. After the treatment is stopped, when compared with the vehicle, there is no significant effect on PWT.

Example 7. Evaluation of the effect of other antidepressants in the treatment of chemotherapy-induced neuropathy

Two types of antidepressants were also evaluated in the paw reduction threshold (PWT) test: duloxetine, a serotonin norepinephrine reuptake inhibitor; and, amitriptyline, a tricyclic antidepressant. These experiments were performed in a manner similar to the experiments disclosed in Example 6.

On the 22nd day after paclitaxel administration (the leftmost column in Figure 16 corresponds to rats not administered paclitaxel), the vehicle was administered to rats (the second column from the left in Figure 16) or degree Loxetine (oral), and PWT was assessed 60 minutes after injection. The data are expressed as mean ± s.e.m. (*p<0.05, compared with vehicle/vehicle).

It has been shown in rats treated with paclitaxel, 3mg/kg (the middle column in Figure 16), 10mg/kg (the second column from the right in Figure 16) and 30mg/kg (the most in Figure 16 Right column) Duloxetine at the dose is not effective against PWT, that is, duloxetine has not been found to reverse paclitaxel-induced neuropathy in rats.

On the 27th day after the administration of paclitaxel (the leftmost column in Figure 17 corresponds to rats not administered with paclitaxel), the rats were administered vehicle (second column from the left in Figure 17) or Ami Triline (oral), and PWT was assessed 60 minutes after injection. The data are expressed as mean ± s.e.m. (*p<0.05, and medium Compared with paclitaxel/vehicle; #p<0.05, compared with paclitaxel/vehicle).

Amitriptyline has been shown to only partially reverse this neuropathy, but only the highest dose tested, that is, 30 mg/kg has this effect (far right column in Figure 17). At doses of 3 mg/kg (middle column in Figure 17) and 10 mg/kg (second column from right in Figure 17), amitriptyline was not found to reverse paclitaxel-induced neuropathy in rats.

Claims (33)

A method for treating or preventing pain in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof,

The method described in item 1 of the scope of patent application, wherein the pain is acute pain, chronic pain, toxic pain, neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain , Or a combination of these. The method described in item 1 of the scope of patent application, wherein the pain is peripheral neuropathy. The method described in item 3 of the scope of patent application, wherein the peripheral neuropathy is a single peripheral neuropathy. The method described in item 3 of the scope of patent application, wherein the peripheral neuropathy is peripheral polyneuropathy. The method described in item 1 of the scope of patent application, wherein the pain is peripheral neuropathy induced by chemotherapy. The method according to item 6 of the scope of patent application, wherein the chemotherapy is paclitaxel. A method for treating or preventing fibromyalgia for a subject in need of treatment, the method includes Including administering to the subject a therapeutically effective amount of the following Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof,

A method for treating or preventing neuropathy in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof,

The method described in item 9 of the scope of patent application, wherein the neuropathy is peripheral neuropathy. The method described in item 9 of the scope of patent application, wherein the neuropathy is a single peripheral neuropathy. The method described in item 9 of the scope of patent application, wherein the neuropathy is peripheral polyneuropathy. The method described in item 9 of the scope of patent application, wherein the neuropathy is caused by chemotherapy Inducer. A method for treating or preventing chemotherapy-induced pain to a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof,

The method according to item 14 of the scope of patent application, wherein the pain induced by the chemotherapy is peripheral neuropathic pain. The method according to item 14 or 15 of the scope of patent application, wherein the chemotherapy is paclitaxel. A method for enhancing the anti-hyperalgesic effect on a subject suffering from hyperalgesia, the method comprising administering to the subject a therapeutically effective amount of the following compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof,

A method of reducing the sensitivity of a subject to pain, the method includes the subject Administer a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof,

The method according to any one of items 1 to 18 in the scope of the patent application, wherein the therapeutically effective amount of the compound I is 0.1 mg/kg to 100 mg/kg. The method according to any one of items 1 to 19 in the scope of the patent application, wherein the therapeutically effective amount of the compound I is about 10 mg/kg. The method according to any one of items 1 to 18 in the scope of the patent application, wherein the therapeutically effective amount of the compound I is 1 mg/to 1,000 mg. The method according to any one of items 1 to 21 in the scope of patent application, wherein the therapeutically effective amount of Compound I is once a day, twice a day, 3 times a day, 4 times a day, once every 2 days, Once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, or once a month medicine. The method according to any one of items 1 to 22 in the scope of the patent application, wherein Compound I is formulated as a pharmaceutical composition containing more than one pharmaceutically acceptable excipient. The method according to item 23 of the scope of patent application, wherein the pharmaceutical composition further includes other therapeutic agents for treating pain. The method according to any one of items 1 to 24 in the scope of the patent application, wherein Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or comprises Compound I or a pharmaceutically acceptable The pharmaceutical composition of the accepted salt, solvate or prodrug is oral administration, parenteral administration, intravenous administration, intramuscular administration, intrathecal administration, subcutaneous administration, topical administration, system administration Drug, intradermal administration, sublingual administration, buccal administration, rectal administration, vaginal administration, intraocular administration, intra-aural administration, intranasal administration, inhalation administration, atomization administration, or Transdermal administration. The method according to any one of items 1 to 25 in the scope of the patent application, wherein Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or comprises Compound I or a pharmaceutically acceptable salt thereof The pharmaceutical composition of solvate or prodrug is orally administered to the subject, and is formulated as a lozenge, capsule, chew, gel, paste, multiparticulate, nanoparticulate, oral Tablets, pills, granules, powders, solutions, sprays, emulsions, suspensions, syrups, mouthwashes, or drops. The method according to any one of items 1 to 26 in the scope of the patent application, wherein Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or comprises Compound I or a pharmaceutically acceptable salt thereof, The pharmaceutical composition of a solvate or prodrug is topically administered to a subject and formulated as a cream, paste, lotion, gel, patch or spray. The method described in any one of items 1 to 27 in the scope of the patent application further includes the administration of other therapeutic agents for the treatment of pain. The method according to claim 28, wherein the other therapeutic agent for the treatment of pain and Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof, or comprising Compound I or a pharmaceutically acceptable salt, solvate or prodrug thereof Pharmaceutical compositions of acceptable salts, solvates or prodrugs are administered at a similar time. The method according to any one of items 1 to 29 in the scope of patent application, wherein the object is a person. Such as the method described in any one of items 1 to 30 in the scope of the patent application, wherein the When the subject’s pain, fibromyalgia, neuropathy, or chemotherapy-induced pain is improved, when the subject’s anti-hyperalgesic effect is enhanced, or when the subject’s sensitivity to pain is reduced, the subject is then administered a maintenance dose Compound I and/or other therapeutic agents used to treat pain. The method described in item 31 of the patent application, wherein the maintenance dose of Compound I and/or the other therapeutic agent is administered at a dose lower than the induced dose, administered at a frequency lower than the induced dose, or Doses below the induction dose and frequency below the induction dose. The method according to any one of items 1 to 32 in the scope of the patent application, wherein the compound I is hydrochloride.

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