Kv1.3 antagonists for use in treatment of chronic and acute pain

Abstract

To provide antagonists of clinically approved ion channels that are superior and specific blockers / enhancers.SOLUTION: Compounds that are antagonists of slow delayed rectifier Kv1.3 channels, or pharmaceutically acceptable salts or prodrugs thereof, for use as analgesics in the treatment, prevention, or reduction of chronic and acute pain are provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure provides compounds useful as pharmaceutical agents in the treatment, prevention, or reduction of both acute and chronic pain. of delayed rectifier potassium (K + ) channel antagonists, more specifically Kv1.3 Regarding the use of blocking agents. [Background technology]

[0002] Acute pain usually occurs suddenly and has a specific cause. It is qualitatively sharp. Acute pain is It usually lasts no longer than 3-6 months, meaning the underlying cause of the pain is no longer present. Sometimes the pain disappears, and the person can then continue with their daily life as usual. Typical causes include surgery, fractures, dental work, burns and amputations, labor and delivery.

[0003] Chronic pain is defined as pain that persists for more than 3 months or beyond the period of natural recovery. Pain signals can persist in the nervous system for weeks, months, or even years without any physiological stimulus. For example, diabetes, arthritis, migraines, fibromyalgia, cancer, back pain, shingles, and sciatica It occurs in many medical conditions, including osteoneuralgia, trigeminal neuralgia, and past trauma or injury. Chronic pain is a disabling condition that significantly interferes with a person's quality of life and has a significant negative impact on society. It affects 21% of the world's population (1.5 billion people) and has huge associated economic costs. In the United States (US) alone, in 2010, It was estimated that $560-635 billion was spent on reproductive and medical expenses. With the growing population comes an increased demand for good and adequate pain management therapies.

[0004] Although there are effective and safe analgesics for mild pain, there are few effective and safe analgesics for moderate and severe chronic pain. Treatment is almost always ineffective and causes limiting and harmful side effects. Therefore, the main problem for patients with most types of chronic pain is at least significant control. The current lack of truly adequate pharmaceutical treatments without limiting side effects. For situations with moderate to severe pain levels, opioid derivatives provide pain relief but can be addictive. Opioids have significant adverse effects, including addiction, loss of energy or motivation, and The use of methicillin has become an epidemic problem in several countries, with increasing incidence and a heavy social burden. For example, in the United States, the number of deaths related to opioid use is 10 times higher than the number of deaths from illicit drugs. The number of deaths is much higher than the number of deaths from antidepressants, antiepileptics, and nonsteroidal anti-inflammatory drugs (NSAIDs). Other types of drugs, including SAIDs, are used in treatment, but these are not fully effective. or cause related side effects.

[0005] Others, such as more recent treatments for moderate to severe pain, are within the pharmacological context of the present invention. Ion channels are closer to the ion channel modulators. Therefore, it is the main protein present in the neuronal membrane that shapes pain signals in the nerve. Neurons involved in pain perception (nociception) located in the peripheral nervous system include those located in ganglia. These include those with their cell bodies located in the dorsal root ganglia (DRG, outside the spinal cord, or These nociceptive fibers are connected to the brain's perception of pain. It is the first peripheral nerve sensor involved in physiological pathways that

[0006] Regarding currently available therapies involving ion channel modulation for the treatment of pain, There are only two examples on the market.

[0007] Nevertheless, they differ in part depending on the type of ion channel that is regulated. These medicines are only effective for a limited period of time or still cause side effects. -Topic Capsaicin, a Transient Receptor Potential Cation Channel Subfamily V Member -1 (TRPV1) channel agonist, - Intrathecal injection of ziconotide (Prialt®), obtained from marine cone snails N-type voltage-dependent calcium channel blockers, which act centrally rather than peripherally do.

[0008] Novel products currently in clinical development (currently underway at several biotechnology and pharmaceutical companies) Among the drugs currently in development but not yet approved for commercialization are novel opioids with specific modifications (usually The use of ion channels known to be involved in pain is reduced by reducing the T Other ion channels are more suitable than RPV1 and N-type voltage-gated calcium channels Modulators (e.g., other TRPs, voltage-gated sodium channels Na v 1.7 and Na v ion channels such as 1.8).

[0009] To date, only two drugs have been shown to + It acts on the acetylcholinesterase (AA) channel and is currently being used in preclinical and clinical trials for the treatment of pain. or in clinical trials.

[0010] a) The anticonvulsant retigabine (Phase II) has been shown to reduce persistent and neuropathic pain in rat models. Retigabine primarily attenuates nociceptive behavior in the K +As a channel opener They act by blocking specific voltage-gated potassium (Kv7 / M) channel families in the brain. It works by activating.

[0011] b) Another channel modulator, BL-7050 (preclinical stage), is a steroid inhibitor of diclofenac (NSAIDS) D) molecular structure that binds to and stabilizes the body's potassium channels, blocking their overactivity. Controlling excitability (by keeping it open) and K + Channel for outflow This keeps the septum open, preventing pain. Summary of the Invention [Problem to be solved by the invention]

[0012] However, despite considerable pharmaceutical research, no better specific blocker / potentiator is available. There remains a need for clinically approved ion channels that are effective against steroids, and patients are experiencing severe side effects. They are left with no alternative but medicines that have the effect. [Means for solving the problem]

[0013] In one aspect, the present disclosure provides a method for treating, preventing, or reducing chronic and acute pain. As an analgesic agent for the treatment of rheumatoid arthritis, we have investigated the use of delayed rectifier channels, especially Kv1.3 channel antagonists. Regarding the use of compounds.

[0014] While not wishing to be bound by theory, in some embodiments, the present invention provides a method for producing a compound comprising: It differs from currently existing solutions not only in its properties but also in its mechanism of action.

[0015] by "switching off" or using bioactive molecules to stimulate nociceptive fibers By reducing the activity of the stimuli, the brain's perception of pain is reduced in a way that cannot affect brain function. These molecules may be involved in pain signaling pathways before they reach the central nervous system. Examples of such molecules are described herein.

[0016] Therefore, in one embodiment, the present disclosure provides a delayed rectifier K + Channel Kv1.3 Anne The present invention relates to the discovery that agonists have analgesic properties and are particularly effective against chronic pain.

[0017] Any aspect or embodiment described herein may be used in conjunction with any other aspect or embodiment disclosed herein. The present invention will be described in conjunction with the detailed description thereof. However, the foregoing description is intended to be illustrative, not limiting, of the scope of the invention. Other aspects, advantages, and modifications are defined by the appended claims. Within the scope of the following embodiments / claims.

[0018] Embodiment 1. As an analgesic in the treatment, prevention, or reduction of chronic and acute pain Compounds which are antagonists of slow delayed rectifier Kv1.3 channels for use in Pharmaceutical salts or prodrugs.

[0019] Embodiment 2. As an analgesic in the treatment, prevention, or reduction of chronic and acute pain Compounds which are antagonists of slow delayed rectifier Kv1.3 channels for use in drugs - Patents.com The compound is a chemical salt or prodrug thereof, and the compound has any of the following properties for the Kv1.3 channel: Other Kv1.x channels, specifically Kv1.1, Kv1.2, Kv1.4, and Kv It has 2.5-fold higher affinity for Kv1.5, Kv1.6, and Kv1.7 than for Kv1.8.

[0020] Embodiment 3. Slow delayed rectifier Kv1 for use in treating, preventing, or reducing pain Compounds that are antagonists of the .3 channel, pharmaceutical salts or prodrugs thereof The compounds are Nitenin, PSORA-4, PAP-1, AM92016 hydrochloride, and or an analogue, salt, or combination thereof.

[0021] Embodiment 4. Compounds that are antagonists of slow delayed rectifier Kv1.3 channels, and drugs thereof The chemical salts or prodrugs are suitable for use in warm-blooded vertebrates, preferably mammals, more preferably humans. Used in the

[0022] Embodiment 5. A method for treating, preventing, or reducing pain, more particularly acute or is a palliative for use in treating, preventing, or reducing pain in individuals with chronic pain. Compounds that are antagonists of the slow delayed rectifier Kv1.3 channel, pharmaceutical salts thereof or prodrugs thereof Acute and chronic pain can be classified as neuropathic, nociceptive, psychogenic or somatic. Neuropathic pain, diabetic neuropathic pain, post-herpetic pain, low back pain, radicular pain, musculoskeletal pain Pain, post-operative and post-traumatic pain, phantom limb pain, surgical pain, wound-related pain, chemotherapy-induced peripheral pain Neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, joint pain, bone pain Arthritis-related pain, myofascial pain, migraine, chronic orofacial pain, trigeminal neuralgia, cancer-related pain, fibromyalgia Muscle-associated pain, hypersensitivity syndrome, infection-associated pain, HIV-associated pain, sprains and strains, hyperalgesia sensitivity, somatic pain, psychogenic pain, heat-induced pain, physical pain, nociceptive pain, rheumatic pain , headache, pelvic pain, myofascial pain, vascular pain, migraine, wound, wound-related pain, arthritis pain, somatic visceral pain Pain, phantom limb pain, nerve root pain, low back pain, visceral pain, intestinal pain, bladder pain, and osteoarthritis-related pain It is intended to include, but not be limited to, at least one of:

[0023] Embodiment 6. A pharmaceutical composition comprising a pharmaceutical composition comprising an active ingredient (e.g., an excipient) and a pharmaceutically acceptable diluent or carrier. and a combination of the active ingredients, wherein the active ingredient is a therapeutically effective dose of nitenin. , PSORA-4, PAP-1, or AM92016 hydrochloride; or A pharmaceutical composition comprising a pharmacologically acceptable salt or prodrug thereof.

[0024] Embodiment 7. A method for treating chronic pain or acute pain in a subject in need of treatment. A method for treating acute pain, comprising administering to a subject a therapeutically effective amount of slow delayed rectifier Kv1.3 channels. The method comprises administering a compound that is an antagonist of the agonist.

[0025] Embodiment 8. The compound binds to Kv1.3 channel by at least one affinity assay. It has a 2.5-fold higher affinity for this channel than for any other Kv1.x channel. The method of embodiment 7,

[0026] Embodiment 9. The compound is selected from the group consisting of nitin, PSORA-4, PAP-1, AM92016 hydrochloride 10. The method of claim 7, wherein the compound is selected from the group consisting of a hydroxybenzoate, ... 8 ways.

[0027] Embodiment 10. The subject is a warm-blooded vertebrate, preferably a mammal, more preferably a human. The method of any one of embodiments 7 to 9.

[0028] Embodiment 11. Acute and chronic pain is neuropathic pain, nociceptive pain, psychogenic pain or Somatic pain, diabetic neuropathic pain, post-herpetic pain, low back pain, radicular pain, muscle pain Skeletal pain, post-operative and post-traumatic pain, phantom limb pain, surgical pain, wound-related pain, chemotherapy-induced Peripheral neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthralgia , osteoarthritis-related pain, myofascial pain, migraine, chronic orofacial pain, trigeminal neuralgia, cancer-related pain, Fibromyalgia-related pain, hypersensitivity syndrome, infection-related pain, HIV-related pain, sprains and strains, pain Hyperesthesia, somatic pain, psychogenic pain, heat-induced pain, physical pain, nociceptive pain, rheumatism Pain, headache, pelvic pain, myofascial pain, vascular pain, migraine, wound, wound-related pain, arthritis pain, somatic pain Visceral pain, phantom limb pain, radicular pain, lower back pain, visceral pain, bowel pain, bladder pain, and osteoarthritis-related pain The method of any one of embodiments 7 to 10, wherein the method is selected from:

[0029] The figures shown below show: (1) the electrical potential recorded from small diameter dorsal root ganglion neurons (sdDRGn); Pressure-activated K + (2) the blocking effects of the four compounds on the current (Figs. 1-4) and (3) the sdDRGn The transient response of three compounds in the voltage sensitivity curves of steady-state inactivation of K+ currents recorded from (3) the sensitivity to mechanical stimuli as a pain score. The purpose of this study is to illustrate the effects of three compounds on the treatment of rheumatoid arthritis and in vivo data.

[0030] Figures 1, 2, and 3 show the relationship between voltage-activated currents recorded from sdDRGn and their Nitenin (0.29 μM), PSORA-4 (3 nM), PAP-1 (2 nM), The effects of AM92016 hydrochloride (40 nM) and AM92016 hydrochloride (40 nM) were shown. Activated outflow potassium (K + ) currents were preceded by a hyperpolarizing prepulse to -120 mV. The evoked response was a depolarization step to +20 mV (holding potential -70 mV) The current is better fitted by the sum of two exponential functions, so the two components minutes (here I slow and I fast ) and their time constants (τ ) is τ fast tens of milliseconds at τ slow It was a few hundred milliseconds. [Brief explanation of the drawings]

[0031] For easier understanding of the present application, figures are attached in the appendix showing exemplary embodiments. However, they are not intended to limit the technology disclosed herein. [Figure 1] Typical voltage-activated K+ current traces recorded before and in the presence of nitenin (0.1 μg / ml, 0.29 μM) are shown, with the bottom trace corresponding to current subtraction fitted with a single exponential function (time constant τ ∼150 ms). [Figure 2] Typical voltage-activated K+ current traces recorded before and in the presence of PSORA-4 (1 ng / mL, 3 nM) are shown, with the bottom trace corresponding to current subtraction fitted with a single exponential function (time constant τ approximately 385 ms). [Figure 3] Typical voltage-activated K+ current traces recorded before and in the presence of PAP-1 (0.7 ng / mL, 2 nM) are shown, with the bottom trace corresponding to current subtraction fitted with a single exponential function (time constant τ approximately 302 ms). [Figure 4] Typical voltage-activated K+ current traces recorded before and in the presence of AM92016 hydrochloride (19.4 ng / mL, 40 nM) are shown, with the bottom trace corresponding to the current subtraction. [Figure 5]Typical effects of nitenin on the steady-state voltage dependence of inactivation of K+ currents recorded from small-diameter neurons isolated from the isolated dorsal root ganglion of the "affected" side of a CCI rat model 28 days after surgery. a) Current traces were evoked during command pulses to +10 mV (600 ms) preceded by consecutive prepulses of 10 s duration, ranging from -140 to +10 mV in 10 mV step increments. The left (black) trace was obtained before application of nitenin (0.1 µg / ml, 0.29 µM), and the right (gray) trace was obtained during application of nitenin. b) Current / voltage relationship in which the current peak amplitude (obtained in "a") is plotted against the prepulse potential used in the voltage protocol in "a" (black symbols are for control-CCI, gray symbols are for nitenin treatment). A shift toward hyperpolarized values ​​can be observed during nitenin treatment. These relationships fit well to the sum of two Boltzmann functions, indicating the presence of two components in both conditions: one more hyperpolarized component (component 1) and the other more depolarized component (component 2). Indeed, the Vh parameter (voltage at half-maximal current) of the Boltzmann equation showed more hyperpolarized values ​​during nitenin treatment (control: Vh1 = -73.3 mV, Vh2 = -26.3 mV; nitenin: Vh1 = -95.3 mV, Vh2 = -47.0 mV). [Figure 6]Typical effects of PSORA-4 (1 ng / mL, 3 nM) on the steady-state voltage dependence of inactivation of K+ currents recorded from small-diameter neurons isolated from the "affected" side of a CCI rat model 28 days after surgery. a) Current traces were evoked during command pulses to +10 mV (600 ms) preceded by consecutive prepulses of 10 s duration, ranging from -140 to +10 mV in 10 mV increments. The left (black) trace was obtained before application of PSORA-4 (1 ng / mL, 3 nM), and the right (gray) trace was obtained during application. b) Current / voltage relationship in which the current peak amplitude (obtained in "a") is plotted against the prepulse potential used in the voltage protocol in "a" (black symbols are for control, gray symbols are for PSORA-4 treatment). A shift in hyperpolarization can be observed during PSORA-4 treatment. This relationship fitted well to a single Boltzmann equation in this example. Indeed, the Vh parameter (voltage at half-maximum current) of the Boltzmann equation showed more hyperpolarized values ​​during PSORA-4 treatment (control: Vh = -78.3 mV, PSORA-4: Vh = -95.5 mV). [Figure 7]Typical effects of PAP-1 (0.7 ng / mL, 2 nM) on the steady-state voltage dependence of inactivation of K+ currents recorded from small-diameter neurons isolated from the "affected" side of a CCI rat model 28 days after surgery. a) Current traces were evoked during command pulses to +10 mV (600 ms) preceded by consecutive prepulses of 10 s duration, ranging from -140 to +10 mV in 10 mV increments. The left (black) trace was obtained before application of PAP-1 (0.7 ng / mL, 2 nM), and the right (gray) trace was obtained during application. b) Current / voltage relationship in which the current peak amplitude (obtained in "a") is plotted against the prepulse potential used in the voltage protocol in "a" (black symbols are for control, gray symbols are for PAP-1 treatment). A shift in hyperpolarization can be observed during PAP-1 treatment. These relationships fit well to the sum of two Boltzmann functions, indicating the presence of two components in both conditions: one more hyperpolarized component (component 1) and one more depolarized component (component 2). Indeed, the Vh parameter (voltage at half-maximal current) of the Boltzmann equation showed more hyperpolarized values ​​during PAP-1 treatment (control: Vh1 = -90.1 mV, Vh2 = -27.8 mV; PAP-1: Vh1 = -101.7 mV, Vh2 = -32.6 mV). [Figure 8]Typical effects of AM92016 hydrochloride (19.4 ng / mL; 40 nM) on the steady-state voltage dependence of inactivation of K+ currents recorded from small-diameter neurons isolated from the "affected" side of a CCI rat model 28 days after surgery. a) Current traces were evoked during command pulses to +10 mV (600 ms) preceded by consecutive prepulses of 10 s duration, ranging from -140 to +10 mV in 10 mV increments. The left (black) trace was obtained before application of AM92016 hydrochloride (19.4 ng / mL; 40 nM), and the right (gray) trace was obtained during application. b) Current / voltage relationship in which the current peak amplitude (obtained in "a") is plotted against the prepulse potential used in the voltage protocol in "a" (black symbols are for control-CCI, gray symbols are for AM92016 hydrochloride treatment). A shift toward hyperpolarized values ​​can be observed during AM92016 hydrochloride treatment. These relationships fit well to the sum of two Boltzmann functions, indicating two components in both conditions: one more hyperpolarized component (component 1) and the other more depolarized component (component 2). Indeed, the Vh parameter (voltage at half-maximum current) of the Boltzmann equation showed more hyperpolarized values ​​during AM92016 hydrochloride treatment (control: Vh1 = -71.3 mV, Vh2 = -28.2 mV; AM92016 hydrochloride: Vh1 = -93.63 mV, Vh2 = -33.6 mV). [Figure 9]Behavioral readouts are shown as a measure of pain during treatment with nitinin in the rat model of neuropathic pain, CCI (chronic constriction injury). A typical experiment was performed using four Wistar rats subjected to unilateral sciatic nerve constriction. Values ​​refer to mechanical sensitivity to stimulation using calibrated von Frey filaments. The black markers relate to scores obtained from the ipsilateral operated paw, while the values ​​observed in the contralateral uninjured paw and, moreover, take into account scores obtained before induction of the model (maximum possible effect %; Altun A, 2015). The graph shows the effect of intravenous injection of nitinin (estimated plasma concentration 1 μg / ml) on mechanical sensitivity of the ipsilateral paw. The effect was maximal approximately 30 seconds to 1 hour after injection, reaching, in some cases, values ​​similar to those obtained during baseline before surgery. The presented experiment resulted in induction of the model, demonstrating a significant increase in mechanical sensitivity of the ipsilateral paw, while that related to the contralateral paw remained unchanged and similar to baseline values. This trend was maintained for 26 days after surgery, the day treatment with nitenin was performed (data not shown). [Figure 10] Behavioral readouts are shown as a measure of pain during treatment with PSORA-4 in the rat model of neuropathic pain, CCI (chronic constriction injury). A typical experiment was performed using a group of Wistar rats subjected to four unilateral sciatic nerve constrictions. Values ​​refer to mechanical sensitivity to stimulation using calibrated von Frey filaments. The black markers relate to scores obtained from the ipsilateral operated paw, but also take into account values ​​observed in the contralateral uninjured paw and scores obtained before induction of the model (maximum possible effect %; Altun A, 2015). The graph shows the effect of intravenous injection of PSORA-4 (estimated plasma concentration 30 μg / ml) on mechanical sensitivity of the ipsilateral paw. The presented experiment resulted in induction of the model, showing a significant increase in mechanical sensitivity in the ipsilateral paw, while that related to the contralateral paw remained relatively unchanged. This trend was maintained for 34 days after surgery, the same day treatment with PSORA-4 was performed (data not shown). [Figure 11]Behavioral readouts are shown as a measure of pain during treatment with PAP-1 in the rat model of neuropathic pain, CCI (chronic constriction injury). A typical experiment was performed using four Wistar rats subjected to unilateral sciatic nerve constriction. Values ​​refer to mechanical sensitivity to stimulation using calibrated von Frey filaments. The black markers relate to scores obtained from the ipsilateral operated paw, but also take into account values ​​observed in the contralateral uninjured paw and scores obtained before induction of the model (maximum possible effect %; Altun A, 2015). The graph shows the effect of intravenous injection of PSORA-4 (estimated plasma concentration 30 μg / ml) on mechanical sensitivity of the ipsilateral paw. The presented experiment resulted in induction of the model, showing a significant increase in mechanical sensitivity of the ipsilateral paw, while that related to the contralateral paw remained relatively unchanged. This trend was maintained for 22 days after surgery, the same day treatment with PAP-1 was performed (data not shown). [Figure 12] Behavioral readouts are shown as a measure of pain during treatment with AM92016 hydrochloride in the rat model of neuropathic pain, CCI (chronic constriction injury). A typical experiment was performed using four Wistar rats subjected to unilateral sciatic nerve constriction. Values ​​refer to mechanical sensitivity to stimulation using a calibrated von Frey filament. The black markers relate to scores obtained from the ipsilateral operated paw, but also take into account values ​​observed in the contralateral uninjured paw and scores obtained before induction of the model (maximum possible effect %; Altun A, 2015). The graph shows the effect of intravenous injection of AM92016 hydrochloride (estimated plasma concentration 2.9 μg / ml) on mechanical sensitivity of the ipsilateral paw. The presented experiment resulted in induction of the model, showing a significant increase in mechanical sensitivity of the ipsilateral paw, while that related to the contralateral paw remained relatively unchanged. This trend was maintained for 28 days postoperatively, the same day treatment with AM92016 hydrochloride was performed (data not shown). DETAILED DESCRIPTION OF THE INVENTION

[0032] As used in this application, except as expressly provided herein, each of the following terms The terms "a," "b," "c," "d," "e," "f," "g," "ma," "math," "maths," "maths," "maths," "maths, ... can be.

[0033] The present disclosure provides a method for the treatment, prevention, or reduction of chronic and acute pain using palliative care. The present disclosure relates to the use of antagonists of the slow delayed rectifier Kv1.3 channel. In the context, a "Kv1.3 antagonist," a "Kv1.3 blocking compound," or a "K Compounds referred to as "v1.3 blockers" are used interchangeably herein and include compounds that Delayed rectification K + channels, preferably the delayed rectifier Kv1.3 channel, and inhibit / antagonize it. Specifically, it should be understood as any compound that inhibits Kv1.3. , any other Kv1.x channels, specifically Kv1.1, Kv1.2, Kv1.4, at least 2.5-fold higher than for Kv.1.5, Kv1.6, and Kv1.7 In some embodiments, the compound is a compound having affinity for human Kv.1. For the three channels, any other Kv1.x, specifically Kv1.1, Kv1.2, 3-fold and 5-fold higher than for Kv1.4, Kv1.5, Kv1.6, and Kv1.7 , 10-fold, 20-fold, or 100-fold higher affinity.

[0034] In the context of the present disclosure, "affinity" relates to the effect on the activity of such channels. Affinity is measured by voltage-clamp recording of currents evoked by cells expressing only a given channel. This can be measured by recording.

[0035] Voltage clamp recordings in the whole-cell configuration allow for the identification of specific signaling pathways in a given channel expressed in a non-excitable cell line. It was / will be used to measure the "amount of inhibition" of whole-cell currents induced by A dose response is obtained by measuring the inhibition per concentration. The K+ currents were analyzed using standard voltage protocols to identify Kv1.1, Kv1.2, and Kv1. 3. Mammalian cell lines expressing Kv1.4, Kv1.5, kv1.6, or kv1.7 induced from ( Schmitz et al., 2005 , Vennekamp et al.).

[0036] As used herein, the term "and / or" refers to the inclusion of other features or elements. It is understood as a specific disclosure of each of the two particular features or components, with or without the other. Therefore, phrases such as "A and / or B" in this specification should be understood as meaning "A and / or B" or "B" in a way that is consistent with the present invention. The term "and / or" as used herein means "A and B" and "A or B." "A" (single) and "B" (single) are intended to include the same. Similarly, "A, B, and The word "and / or" when used in phrases such as "and / or C" means that A, B and and C, A, B, or C, A or C, A or B, B or C, A and The states of C, A and B, B and C, A (single), B (single), and C (single) It is intended to encompass each of the above aspects. When an embodiment is described herein using the language "comprising," Whenever the term "consisting of" and / or "consisting essentially of" is used, It should be understood that other similar aspects are also provided.

[0037] Unless otherwise defined, all technical and scientific terms used herein are have the same meaning as commonly understood by one of ordinary skill in the relevant technical field.

[0038] Units, prefixes, and symbols are shown in the form accepted by the International System of Units (SI). Ranges are inclusive of the numbers defining the range. The headings provided herein provide a general guide to the various aspects of this disclosure. Such limitations may be had by reference to the specification as a whole, without any such limitations. The terms defined immediately below are more fully defined by reference to the specification in its entirety. be defined.

[0039] "Administering" refers to administering a pharmaceutical composition to a subject, using any of a variety of methods and delivery systems known to those skilled in the art. It refers to the physical introduction of a drug into a subject. Possible routes of administration include, for example, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or intravenous administration by injection or infusion. or other parenteral routes. As used herein, the term "parenteral administration" means means modes of administration other than enteral and topical administration, usually by injection, including but not limited to intravenous Intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal intratracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal In some embodiments, the methods include injection and infusion of the antibody, and in vivo electroporation. Alternatively, the compound may be administered by a non-parenteral route, for example orally. Other non-parenteral routes include topical, epidermal, or mucosal routes of administration, e.g., intranasal, intravaginal, rectal, sublingual, or topical Administration can also be, for example, one time, multiple times, and / or over one or more extended periods of time. It can be carried out over a period of time.

[0040] A "therapeutically effective amount," "effective dose," or "effective amount" of a drug or therapeutic agent may refer to a single or multiple When used in combination with another therapeutic agent, it may protect a subject from developing a disease or is characterized by a decrease in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods of the disease, or Promoting regression of the disease as evidenced by prevention of functional impairment or disability resulting from the disease The ability of a therapeutic agent to promote disease regression is evaluated in human trials. in animals, in animal model systems predictive of efficacy in humans, or in vitro by various methods known to those skilled in the art, such as by assaying the activity of the agent in a cytotoxic assay. can be evaluated using

[0041] By "therapeutically effective dose" is meant that the dose may be administered as a single dose or in a multiple dose schedule. This means that the dose is effective in treating, preventing, or reducing pain. The choice of analgesic agent will depend on the health and physical condition of the individual being treated, their age, the degree of pain relief desired, and other relevant factors. The amount will vary depending on the individual. The amount will fall within a relatively wide range that can be determined through routine testing. "Preventing" or "prevention" as used herein means the absolute reduction of pain. Absolute success in the sense of prevention is not required, but the onset or severity of the pain condition Similarly, "treatment" does not imply an absolute cure. The present invention should not be construed as a direct or indirect method of treatment of pain, and may also be associated with the alleviation or suppression of pain or pain-related conditions. .

[0042] Embodiment 1. As an analgesic in the treatment, prevention, or reduction of chronic and acute pain Compounds which are antagonists of slow delayed rectifier Kv1.3 channels for use in Pharmaceutical salts or prodrugs.

[0043] Embodiment 2. As an analgesic in the treatment, prevention, or reduction of chronic and acute pain Compounds which are antagonists of slow delayed rectifier Kv1.3 channels for use in drugs - Patents.com The compound is a chemical salt or prodrug thereof, and the compound has any of the following properties for the Kv1.3 channel: Other Kv1.x channels, specifically Kv1.1, Kv1.2, Kv1.4, and Kv It has 2.5-fold higher affinity for Kv1.5, Kv1.6, and Kv1.7 than for Kv1.8.

[0044] Embodiment 3. Slow delayed rectifier Kv1 for use in treating, preventing, or reducing pain Compounds that are antagonists of the .3 channel, pharmaceutical salts or prodrugs thereof The compounds are Nitenin, PSORA-4, PAP-1, AM92016 hydrochloride, and or an analogue, salt, or combination thereof.

[0045] Embodiment 4. Compounds that are antagonists of slow delayed rectifier Kv1.3 channels, and drugs thereof The chemical salts or prodrugs are suitable for use in warm-blooded vertebrates, preferably mammals, more preferably humans. Used in the

[0046] Embodiment 5. A method for treating, preventing, or reducing pain, more particularly acute or is a palliative for use in treating, preventing, or reducing pain in individuals with chronic pain. Compounds that are antagonists of the slow delayed rectifier Kv1.3 channel, pharmaceutical salts thereof or prodrugs thereof Acute and chronic pain can be classified as neuropathic, nociceptive, psychogenic or somatic. Neuropathic pain, diabetic neuropathic pain, post-herpetic pain, low back pain, radicular pain, musculoskeletal pain Pain, post-operative and post-traumatic pain, phantom limb pain, surgical pain, wound-related pain, chemotherapy-induced peripheral pain Neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, joint pain, bone pain Arthritis-related pain, myofascial pain, migraine, chronic orofacial pain, trigeminal neuralgia, cancer-related pain, fibromyalgia Muscle-associated pain, hypersensitivity syndrome, infection-associated pain, HIV-associated pain, sprains and strains, hyperalgesia sensitivity, somatic pain, psychogenic pain, heat-induced pain, physical pain, nociceptive pain, rheumatic pain , headache, pelvic pain, myofascial pain, vascular pain, migraine, wound, wound-related pain, arthritis pain, somatic visceral pain Pain, phantom limb pain, nerve root pain, low back pain, visceral pain, intestinal pain, bladder pain, and osteoarthritis-related pain It is intended to include, but not be limited to, at least one of:

[0047] Embodiment 6. A pharmaceutical composition comprising a pharmaceutical composition comprising an active ingredient (e.g., an excipient) and a pharmaceutically acceptable diluent or carrier. and a combination of the active ingredients, wherein the active ingredient is a therapeutically effective dose of nitenin. , PSORA-4, PAP-1, or AM92016 hydrochloride; or A pharmaceutical composition comprising a pharmacologically acceptable salt or prodrug thereof.

[0048] Embodiment 7. A method for treating chronic pain or acute pain in a subject in need of treatment. A method for treating acute pain, comprising administering to a subject a therapeutically effective amount of slow delayed rectifier Kv1.3 channels. The method comprises administering a compound that is an antagonist of the agonist.

[0049] Embodiment 8. The compound binds to Kv1.3 channel by at least one affinity assay. It has a 2.5-fold higher affinity for this channel than for any other Kv1.x channel. The method of embodiment 7,

[0050] Embodiment 9. The compound is selected from the group consisting of nitin, PSORA-4, PAP-1, AM92016 hydrochloride 8. The method of claim 7, wherein the compound is selected from the group consisting of a salt, an analog thereof, a salt, or a combination thereof. Any one of eight ways.

[0051] Embodiment 10. The subject is a warm-blooded vertebrate, preferably a mammal, more preferably a human. The method of any one of embodiments 7 to 9.

[0052] Embodiment 11. Acute and chronic pain is neuropathic pain, nociceptive pain, psychogenic pain or Somatic pain, diabetic neuropathic pain, post-herpetic pain, low back pain, radicular pain, muscle pain Skeletal pain, post-operative and post-traumatic pain, phantom limb pain, surgical pain, wound-related pain, chemotherapy-induced Peripheral neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthralgia , osteoarthritis-related pain, myofascial pain, migraine, chronic orofacial pain, trigeminal neuralgia, cancer-related pain, Fibromyalgia-related pain, hypersensitivity syndrome, infection-related pain, HIV-related pain, sprains and strains, pain Hyperesthesia, somatic pain, psychogenic pain, heat-induced pain, physical pain, nociceptive pain, rheumatism Pain, headache, pelvic pain, myofascial pain, vascular pain, migraine, wound, wound-related pain, arthritis pain, somatic pain Visceral pain, phantom limb pain, radicular pain, lower back pain, visceral pain, bowel pain, bladder pain, and osteoarthritis-related pain The method of any one of embodiments 7 to 10, wherein the method is selected from:

[0053] In the foregoing specification, embodiments of the invention have been described with numerous specific details that may vary from implementation to implementation. Therefore, it is clear what the invention is and what has been done by the applicant. The sole and exclusive subject matter contemplated for this invention is the set forth in the claims issuing from this application. and in the particular form in which such claims are issued, any subsequent modifications Any claim expressly set forth in this specification for a term contained in such claim is also included. The meanings of these terms shall govern the meaning of such terms when used in the claims. Accordingly, any limitation, element, property, feature, advantage, or other feature not expressly recited in a claim is hereby excluded. The attribution does not limit the scope of such claims in any way. The figures and drawings are to be regarded in an illustrative rather than a restrictive sense.

[0054] Abbreviation: Ca 2+ :calcium Ca v : Voltage-gated calcium channels CCI: chronic crush injury CFA: Complete Freund's Adjuvant CHO: Chinese hamster ovary CIPN: chemotherapy-induced peripheral neuropathy CNS: central nervous system COP: Chronic orofacial pain DRG: dorsal root ganglion ECG: electrocardiogram HEK: Human Embryonic Kidney hERG: Human Ether-a-go-go related gene-Kv11.1 HFF2: Human foreskin fibroblast 2 I: Current I fast :Rapid current component I slow : slow current component IV: Intravenous K + :potassium K V : Voltage-gated potassium channels K v 1.x: Voltage-gated potassium channel subunit, given by x L: Lumbar vertebrae Na + :sodium Na V : Voltage-gated sodium channels Na v1.x: voltage-gated sodium channel subunit, given by x NSAIDs: Nonsteroidal anti-inflammatory drugs MTS: (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethacrylate) (4-(4-sulfophenyl)-2H-tetrazolium) PAP1: 5-(4-phenoxybutoxy)psoralen PSORA4: 4-(4-phenylbutoxy)-7H-furo[3,2-g][1]benzo Pyran-7-one sdDRGN: small diameter dorsal root neuron sdTGN: small diameter trigeminal ganglion neurons STZ: streptozotocin TG: Trigeminal ganglion TRP: transient receptor potential cation channel TRPV1: Transient receptor potential cation channel subfamily USA: United States of America V Member 1 V: Voltage Vh: Voltage at half the maximum current

[0055] Compounds of the present disclosure, pharmaceutically acceptable salts of said compounds, and / or said compounds and and / or pharmaceutically acceptable salts thereof may be administered as a therapeutic treatment. The compounds, pharmaceutically acceptable salts, and / or pharmaceutical compositions can be used in The compound can be administered in a dosage unit form to a mammalian subject, including a mammalian subject. Non-limiting examples of forms include oral administration forms and forms administered via parenteral routes. Non-limiting examples of which include inhalation, subcutaneous administration, intramuscular administration, intravenous administration, These include intradermal and intravitreal administration.

[0056] In some embodiments, the pharmaceutical composition for oral administration is a tablet, pill, powder, hard It can be in the form of hard gelatin capsules, soft gelatin capsules, and / or granules. In some embodiments of such pharmaceutical compositions, the compounds of the present disclosure and / or The pharmaceutically acceptable salts of the compounds of the present disclosure may be mixed with one or more inert diluents and the non- Non-exclusive examples include starch, cellulose, sucrose, lactose, and silica. In some embodiments, such pharmaceutical compositions contain one or more substances other than a diluent. For example (non-limiting examples), lubricants, colorants, coatings, or varnishes may be added. It may include.

[0057] The pharmaceutical compositions of the present disclosure contain pharmaceutically acceptable carriers, excipients, vehicles, and diluents. Many of these are well known to those skilled in the art and include, by way of non-limiting example, Reming et al. on:The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilki ns, Philadelphia, Pa. (2013) and any other editions and is incorporated herein by reference.

[0058] In one aspect, the present disclosure provides an anti-inflammatory drug for the treatment, prevention, or reduction of chronic and acute pain. Use of Kv1.3 antagonists as pain medications. Physiology of ionic currents / channels. and analgesic effects in some types of pain through pharmacological approaches. Novel pharmaceutical applications for

[0059] In sharp contrast to existing therapeutic agents, the analgesic compounds disclosed herein are Mechanism of action and predicted efficacy, target specificity, and reduced side effects in humans This will position it as a breakthrough in pain management. SORA-4, PAP-1, and AM92016 hydrochloride (Kv1.3 antagonist) 4 cases) showed that slow delayed rectifier Kv expressed in pain-sensing c-fibers of the dorsal root ganglion and trigeminal ganglion Without being bound by theory, the mechanism of action of these drugs is (a) channel inactivation, including channel blockers (rather than openers such as retigabine); (b) especially the series of K V It acts mainly on Kv1.3 channels. This novel mechanism of action explains why and how Kv1.3 antagonists Explain whether the treatment is effective only on the limb / body part with the injured / affected nerve. Additionally, such drugs may reduce nociception and The perceptual score is not changed.

[0060] The present disclosure provides compounds that act as antagonists of delayed rectifier Kv1.3 channels to treat chronic inflammatory bowel disease. It has the potential to be used as an analgesic for the treatment, prevention, or reduction of chronic and acute pain. We disclose solid evidence that includes ex vivo neuronal preparations, animal models of pain, Behavioral readouts of pain, and several technical approaches including whole-cell voltage clamp recordings These experimental results disclosed herein were obtained from four different exemplary Kv1 .3 Blockers Nitenin, PSORA-4, PAP-1, and AM92016 Hydrochloride Regarding. [ka] [ka] [ka] [ka]

[0061] The nitenine compound used as an example in this disclosure was obtained from marine algae caught in Sagres, Portugal. It was isolated and purified from the oceanic sponge Spongia agaracina, but PS ORA-4, PAP-1, and AM92016 hydrochloride were obtained commercially and were slow delayed rectifiers. K + It has been described as an antagonist of the channels PSORA-4 and PAP-1 is mentioned as a specific blocker of Kv1.3. As shown in the Examples, nitinin , PSORA-4, PAP-1, and AM92016 are involved in the sdDRGN (pain-sensing neuron). K recorded from + The results were also very similar. K + Small-diameter trigeminal ganglion neurons ( This was also confirmed in the sdTGN.

[0062] The identified compounds were then subjected to whole-cell voltage clamp techniques to detect the effects of sdDRGN (and K recorded from the sdTGN + The current is a signal that has been developed by the applicant in the field of pain neurophysiology. The use of rat pain models has been the object of intensive research into the use of these drugs to perform previous target validation. Therefore, K that is differentially expressed in pain states +was important for determining the current components In one embodiment of the present disclosure, K affected in pain conditions + The current component is a signal corresponding to the compound of interest. This suggests that the current is primarily regulated (decreased) by The nature of the observed modulatory effect has been investigated in several ways, including the voltage dependence and kinetics of activation and inactivation. The specificity of the bioactivity was tested by monitoring several biophysical parameters. Pharmacological effects on currents recorded from the dDRGN were compared with those from other types of dorsal root ganglia (medium diameter D This was carried out by comparing with those in the GR and large-diameter DGR.

[0063] Furthermore, nitenin is primarily active against hKv1.3 (IC 50 approx. 190nM) This is consistent with other Kv1.x proteins tested (Kv1.1, Kv1.2, Kv1.3, Kv1.4). , and Kv1.6), which are 6 to 30 times more sensitive than PSORA-4 and PAP. At -1, both were primarily active against Kv1.3 (IC 50 Approximately 2-3 nM), This ranges from about 2.5 times (PSORA-4) to about 20 times (PAP) higher than the other Kvs tested. -1) is highly sensitive (Vennekamp et al., 2004, Schmitz et al. , 2005)

[0064] Nitenin, PSORA-4, PAP-1, AM92016 hydrochloride, and other Kv1. 3 Blocking compounds may be used in combination with other compounds used in pain therapy, including those that act on ion channels. One of its competitive advantages over competitors (including the FDA) is due, in part, to at least six key characteristics: , which are interrelated, can be explained as follows. 1- The novel mechanism of action attributed to the Kv1.3 antagonists disclosed herein, and Location and nature of their intracellular targets: Kv1.3 blockers are part of the slow delayed rectifier current K expressed in snDRG (and snTG) is involved in v Reduces channel activity , modulating pain signaling and propagation to the brain. The fact that specific blockers of Kv1.3 channels are sorely needed is particularly relevant given their Concerns about the possibility of euthymopathy will drive the development of related products in the future.

[0065] Administration of a specific Kv1.3 blocker compound improves sensory and nociceptive abilities and does not result in any loss of nociception in the uninjured limb / body part and the mechanism of action is e.g. This is a property related to the fact that it is an activity-dependent effect.

[0066] 3- The Kv1.3 blockers of the present disclosure are easily administered. In animal models used to investigate this, peripheral intravenous (IV) and intraperitoneal injections are the most effective The compound has been used successfully for its analgesic effects.

[0067] 4-Kv1.3 antagonists reduce pain in acute and chronic neuropathic pain Such results predict broad clinical applicability.

[0068] 5-Kv1.3 antagonists are effective for acute / short-term pain, but not for long-term / chronic pain. It is particularly effective for pain.

[0069] 6-specifically acts on a subset of potassium channels (Kv1.x) and inhibits sodium currents / channel(Na v) by having little or no effect on Kv1.3 blocking compounds v It does not compete with the regulators, but rather ultimately combines with them. These compounds may be applied in combination to maximize the potential analgesic effect or act synergistically.

[0070] In one embodiment, the compounds of the present disclosure, or pharmaceutically acceptable salts and prodrugs thereof, Rag can be used to treat acute pain. Examples of acute pain situations include surgery, fractures, dental These include those derived from medical treatment, burns and amputations, labor and childbirth.

[0071] In one embodiment, the compounds of the present disclosure, or pharmaceutically acceptable salts and prodrugs thereof, The rag can be used to treat chronic pain. Examples of diseases or disorders associated with chronic pain include: , chronic peripheral neuropathy, diabetes, arthritis, fibromyalgia, cancer, back pain, shingles, trigeminal neuralgia, and past trauma or injury.

[0072] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and and prodrugs to treat hyperalgesia, somatic pain, psychogenic pain, heat-induced pain, physical pain, and Pain, nociceptive pain, rheumatic pain, headache, pelvic pain, myofascial pain, vascular pain, migraine Wounds, wound-related pain, arthritis-related wounds, somatic visceral pain, phantom pain, radicular pain, low back pain, or Pain associated with osteoarthritis can be treated.

[0073] Both acute and chronic pain involve the processing of electrical signals from peripheral nerves to the central nervous system (CNS). These include complex changes in electrical conduction and excitability, as well as normal electrical excitability and activity levels. Those associated with chronic pain include sodium (Na + ), potassium (K+ ), or Ka Calcium (Ca 2+ ) and other charged metal ions via membrane ion channels (Nav, The result of influx or efflux through the Kv, or Cav) and from the cell throughout the cell. This causes the generation, propagation, and transmission of electrical signals to cells. In chronic pain, pain signals Altered neuronal networks underlying transmission and altered expression of the underlying channels Excessive and persistent neurotransmission, accompanied by abnormal ionic currents caused by biophysics. Therefore, effective analgesics are needed to reduce pain signals. Suppressing the hyperexcitability of the transmission network and enhancing the physiological expression of functional channels and / or Restoring the biophysical profile and then restoring network activity to resting levels It is necessary to be able to do this.

[0074] Small diameter DRG neurons (c-fibers), also called pain-sensing neurons, transmit pain to the CNS. Located outside the spinal cord, which has receptive input (i.e., leads to "pain"). Under normal conditions, these neurons have no spontaneous firing activity—they are silent. (e.g., Ly et al., 2018), a situation that changes during a pain episode and may actually change over time. The therapeutic strategy underlying the present invention is to detect such neuropathic pain in DRG neurons. Targeting the major ion channels located in the thoracic and trigeminal ganglia (TG) This "pain-induced" hyperexcitability is then "switched off." As a result, The transmission of "pain signals" is interrupted or reduced, thereby preventing the brain from perceiving pain. .

[0075] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and Prodrugs and prodrugs may be used to stop pain-induced hyperexcitability. In this context, they can be used to modulate the brain's perception of pain.

[0076] Several ion channels have been identified as key effectors in pain propagation. Some are specifically present in these pain-sensing neurons. Specifically modulating activity can block pain without affecting other bodily functions. Kv1.3 antagonists may be involved in the activation of sdDRGN and sdTGN (corresponding to c-fibers). The slow delayed rectification voltage activation K recorded from + specific regulator of electrical current This effect is observed in large neurons at submicromolar concentrations. range, i.e., at concentrations below 1 micromolar, the modulatory effect of Kv1.3 blockers was lower. is more evident for the sdDRGN and sdTGN.

[0077] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and and prodrugs to detect slow voltage-activated K + The current may be adjusted. In the present study, the current originates from small diameter (sdDRGN, also sdTGN) neurons.

[0078] The Kv1.x and Kv1.3 types, including those mediating slow voltage-activated currents, are the main Ion channels involved in pain signal propagation are present in pain-sensing neurons. The nitenin, PSORA-4, and AM92016 hydrochloride tested herein Salt compounds slowly +This is particularly effective for the current component, resulting in increased activity of Kv1.3 channels. It must be at the root of sexuality.

[0079] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and The prodrugs and prodrugs can be used as blockers of Kv1.3. Kv1.3 is involved in immunological as targets for the treatment of related conditions, as well as for the treatment of diabetes and other metabolic disorders. The compounds of the present disclosure may be used to treat diabetes and other metabolic disorders. .

[0080] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and The compounds and prodrugs may be used as anti-inflammatory agents and to treat autoimmune diseases. They can be used in increasing insulin sensitivity.

[0081] For these therapeutic treatments, the route of administration (or routes of administration), dosage (or Multiple dosages), and an optimized pharmaceutical form(s) may be used to treat patients. The determination can be made according to criteria generally considered in the establishment of the invention, and non-limiting examples include: the potency of the compound and / or a pharmaceutically acceptable salt of the compound, the age of the patient, the weight of the patient, The severity of the patient's condition, the patient's tolerance to treatment, and any secondary effects observed with treatment These include therapeutic effects, etc. Determination of an effective dosage is well within the capability of those skilled in the art. [Example]

[0082] In vivo and ex vivo pain models The rats used for both in vivo behavioral studies and electrophysiological ex vivo tests were The pain model is Naive Wistar: Control rats. Dorsal root ganglia (DRG), lumbar vertebrae 4, 5, and and neurons from L4, L5, and L6. Acute and chronic neuropathic pain rat model: CCI rats (sciatic nerve of Wistar rats) Long-term nerve stenosis) 3 days (acute cases) and 23-29 days (chronic cases) after surgery. et al. neurons (L4, L5, and L6).

[0083] For electrophysiological recordings of ex vivo material, voltage clamp recordings were performed on rat DRG (and Recordings were performed on neurons isolated from the TG (i.e., the saccharin-containing neurons). One hour after the end of the treatment (including mechanical manipulation), neuronal cell bodies, which often contain the proximal fraction of axons, were isolated. This was carried out from

[0084] Mechanism of action: The mechanism of action of Kv1.3 antagonists as analgesics is disclosed herein for the first time. It is K + It involves a reduction of currents rather than an intensification of them. It is important to first characterize the potassium currents present in the dDRGN and sdTGN. do.

[0085] Voltage-activated whole-cell K recorded from the sdDRGN during depolarization steps + Current ( For example, a voltage of +40 mV (lasting for 1 second as shown in Figures 1 to 4) is a rapid activation followed by The current decay at depolarized potentials was therefore It is better fitted to the sum of two exponential functions, i.e., the time course (τ fast ) showing a relatively rapid component (here, I fastIt is called the A current. associated with what is being detected), followed by a time lapse of several hundred milliseconds (τ slow ) showing a much slower The slow inactivation current (here I slow (called). fast and I slo w Different ratios of β- and β-glucan are observed between cells, and some cells contain only one component, I slow of The currents observed in the sdDRGn are similar to those reported for the sdTGn. Very similar.

[0086] Experiments using nitenin, PSORA-4, PAP-1, and AM92016 hydrochloride All of the K from sdDRGN (and sdTGN) + Dose-dependent inhibition of current At moderate concentrations, the effect was slow It is specific for nitin. In the case of I, at concentrations up to 1 μM (approximately 0.3 μg / ml), slow Specifically reduces (See Figure 1) and for PSORA, at concentrations up to 3 nM (1 ng / ml), it is slow (See Figure 2) and, in the case of PAP-1, up to 2 nM (approximately 0.7 ng / ml), which is I slow (See Figure 3, AM920 In the case of 16 hydrochloride, at a concentration of 40 nM (approximately 19.4 ng / ml), I slow Specifically (See Figure 4.) Therefore, all slow The current acts preferentially on The components are derived from "injured nerve" from chronic pain rat models (CCI, CFA, and orofacial). Overexpression of sdDRGn neurons (and sdTGn) from the (I slow In the typical example shown in Figures 1-4, the peak Current was measured by treatment with nitenin, PSORA-4, PAP-1, or AM92016 hydrochloride. Notice that salt does not change much, but the slower components are certainly reduced. Nitenin, PSORA-4, PAP-1, and AM92016 hydrochloride sensitivity The current component (trace subtraction in the lower panels of Figures 1-4) is more fully characterized by a single exponential of several hundred milliseconds. At moderate concentrations, the effect is I slow Specific to In contrast, I fast Kv1.3 amplicon at the maximum concentration mentioned above Importantly, Kv1 was not affected by any of the agonists used. I induced by any of the three antagonists slow The decrease in compared with the reduction induced by the same concentration in neurons obtained from chronic It was greater in neurons obtained from animals with pain.

[0087] Kv1.3 antagonist I slow (I fast Higher sensitivity to The properties of Kv1.3 antagonists that are sensitive to the current and the activity of Kv1.3 antagonists (see current subtraction in Figures 1-4) (Reference) indicates that at the concentrations used, each antagonist induces a single current component and consequently This reinforces the idea that Kv1.3 affects only one channel population (purportedly Kv1.3). .

[0088] Slow K by Kv1.3 antagonist + Inhibition of current is due to the steady-state inactivation including voltage-dependent changes (indeed, all Kv1.3 antagonists inhibit the voltage-dependent inactivation of This induced a shift in the I-V curve associated with the dependence of the ATP concentration towards more hyperpolarized potentials (Figure 5). ~8).

[0089] Therefore, the compound is able to inhibit K + Promoting channel inactivation and inhibit the slow voltage-activated current recorded from the sdDRGN. More precisely, Compounds increase the voltage sensitivity of steady-state inactivation to lower depolarizing values ​​(or higher hyperpolarizing values). Such compound-induced shifts are related to the voltage curve process. The more depolarized the file is than in the initial position, the greater the voltage dependence of inactivation. The depolarized inactivation curves are typical of the sdDRGN obtained from chronic pain states. In other words, in neurons obtained from injured nerves (chronic), Kv1.3 Antagonists restore the voltage-dependent profile of inactivation to a "control" pattern Therefore, compound-induced shifts in the voltage sensitivity of inactivation may be due to the presence of neurons derived from injured nerves. Higher, hyperpolarized voltage profiles were observed in neurons with Files show lower / absent in unaffected neurons. Channel dependence This interesting effect in the affected neurons, i.e., during pain, This may partially explain the compound-induced reduction in neuronal excitability being specific / more pronounced.

[0090] C-fibers are normally silent, with little or no spontaneous firing activity. That is, there is no basal activity in control conditions. We will begin by analyzing the effects of Kv1.3 antagonists on Considering the nature of the mechanism of action of agonists, K + Little or no effect on current is expected because the inactivation curve This is because compounds that induced a shift in the stimuli were minimal in uninjured neurons. Nevertheless, in this example of an unaffected neuron, K + A moderate decrease in current However, such effects may not reach the threshold potential to induce repetitive firing (insufficient This is due to the Kv1.3 antagonist-induced depolarization. This partially explains why pain sensation is not altered in the sciatic region. There is a state of hyperexcitability in injured neurons, with repetitive and sustained firing. "Enhanced channel inactivation" (by the steady-state voltage-dependent depolarization curve of inactivation) In these hyperexcitable neurons, where Kv1.3 antagonists are present, the efficacy of Kv1.3 antagonists is unclear. The effect is maximum. + Kv1.3 antagonist-induced reduction of current Further increases in the level of ATP (emitted by ATP) may also be due to indirect promotion of sodium channel inactivation. Therefore, the signal is interrupted, but the "damaged" fibers Only in.

[0091] How the effects of Kv1.3 antagonists on Kv currents lead to analgesic effects This consists of a novel mechanism of action, which is not the same as the conventional approach to addressing this issue, which is inhibition. Naku K v The increase in current is expected to calm the neural excitability of hyperexcitable C fibers. In this example, the slow inactivating potassium current (I slow ) but (reduced I fas t compared with sdDRGn obtained from chronic pain conditions (CCI, CFA, and STZ) , as well as sdTGn obtained from the COP rat model) and Under these conditions, I slow showed an abnormal depolarized inactivation profile, i.e., It should be emphasized that the channels exhibit low inactivation. To maintain Na + This is the increase in "excitability" brought about by the increased sensitivity of the electric current. The typical situation under chronic pain is a K-like pattern corresponding to a repetitive long-term firing pattern. + In current The effects of the compounds disclosed herein are: It reverts the pattern to the control profile, slowing down the inactivation of Kv-mediated currents. It reduces the flow. + This Kv1.3 antagonist-induced effect of current However, the adjustments required for the increase in sodium conductance (Nav) typical in pain situations are not As a result, the exacerbated sodium currents would be suppressed by the Kv1.3 antagonist. In the presence of Kv currents, the depolarization induced by the decrease in Kv currents is also inactivated. Turns off spike firing in affected nerves but not in normal, undamaged neurons Do not turn off.

[0092] This is because during pain, i.e., chronic pain, Kv enhancers or openers alone are not sufficient to activate Kv This means that blockers should be considered as potential analgesics.

[0093] K + How a reduction in current leads to a significant decrease in neuronal excitability is unclear. To explain something by a combination of phenomena as the most likely or most likely explanation. First, as mentioned above, K + Kv1.3 antagonist-induced reduction in currents It also induces a slow depolarization of the affected neurons in a way that the membrane potential is maintained at a depolarized level. This can cause the normal threshold potential to be passed even though no action potential has been fired. Therefore, depolarization is caused by Na + The inactivation gate of the channel closes and remains closed, preventing activity Prevents the potential from rising (Na + The channel is not sufficiently "activatable" This would result in a containment-like process.

[0094] Second, (1) Kv1.3 antagonists are particularly effective against Kv1.3 channels. (2) Kv1.3 is expressed in DRG (Yang et al., 2004), which may contribute to chronic pain. When K increases its expression level in DRG neurons (unpublished data), A more direct role for specific blockade of Kv1.3 may be considered. The biophysical properties and dynamics of the neuron correspond to the state in "chronic pain situations" This is thought to maintain stable, sustained firing ( Kupper et al., 2002 ). Attenuating such Kv1.3-mediated currents is a promising strategy, as observed in rat hippocampal neurons. This would lead to a reduction in action potential amplitude and a resting depolarized state without firing. (Kupper et al., 2002).

[0095] Efficacy Results: For efficacy testing, receptor nociception is measured in animals by periodic behavioral monitoring. Therefore, we quantified the sensitivity to mechanical stimulation using von Frey filaments. Therefore, as a result, the hyperalgesia evaluated by reflecting the hyperalgesia at the time of hypersensitivity was In the neuropathic pain model CCI, the acetone-induced gastric pain test was also used, as described by von Frey et al. The response was very similar to that of the filament.

[0096] Efficacy of Kv1.3 antagonists after intravenous administration. The following results were obtained using purified nitinin (>98%) (1 μg / mL of blood, approximately 0.06 mg / Kg), PSORA-4 (blood 30 μg / mL, approximately 1.8 mg / Kg), PAP-1 (30 μg / mL of blood, approximately 1.8 mg / Kg), and AM92016 hydrochloride (2.9 μg / mL of blood, approximately 0.17 mg / Kg) for intravenous (IV) injection. Naive Wistar controls: nitenin, PSORA-4, PAP-1, and A After IV injection of M92016 hydrochloride, there was no change in sensitivity scores in either paw. It was. In CCI rats, after IV administration, acute (3 days after model induction) and chronic (22-3 days) In both conditions (day 1 and day 2), sensitivity to mechanical stimuli was significantly reduced. A typical experiment is shown in Figures 5-8. Kv1.3 antagonist-induced reduction in hypersensitivity , was significant in both cases (acute and chronic), but was clearly higher in cases of chronic pain, and several individual In the body, the scores returned to control values. The pain relief period lasted 2-4 hours. Importantly, there was no change in the behavioral scores of the contralateral (uninjured) paw in all animals tested. .

[0097] In summary, nitin, PSORA-4, PAP-1, and AM92016 hydrochloride ( Kv1.3 blockers) are effective for short-term / acute and long-term / chronic neuropathic pain. Efficacy has been demonstrated by intravenous administration, but For some antagonists, such as steroids, intraperitoneal and, importantly, oral administration Treatment via MRI was also successful.

[0098] Based on the dose-response curve, several concentrations are applied IV and efficacy levels are determined as a result. Nitenin and analogs are quantified and available for pharmacological use in warm-blooded vertebrates, particularly humans. 0.1 μg / ml blood (6 μg / kg body weight) to 30 μg / ml blood (1.8 mg / kg body weight) g body weight), and PSORA-4 is effective in warm-blooded vertebrates, especially For pharmacological use in humans, the concentration ranges from 1 μg / ml blood (60 μg / Kg body weight) to 300 It should be used at a dose in the range of μg / ml blood (18 mg / Kg body weight), and PAP- 1 is used for pharmacological use in warm-blooded vertebrates, especially humans, at a concentration of 1 μg / ml blood (60 It is used in doses ranging from 180 μg / kg body weight to 300 μg / ml blood (18 mg / kg body weight). AM92016 hydrochloride should be considered as a potential pharmacological agent for warm-blooded vertebrates, especially humans. For use, 0.1 μg / ml blood (6 μg / kg body weight) to 300 μg / ml blood (18 It should be used in doses ranging from 0.1 mg / kg body weight to 0.2 mg / kg body weight.

[0099] Several features are described below, which may be used independently of one another or in conjunction with other features. However, any individual feature may be used in any combination as discussed above. Some may not address any of the issues discussed above, while others may address only one of the issues discussed above. Some of the problems discussed above may be overcome by the features described herein. Although headings are provided, specific headings may not be fully addressed. Information about this is not in the section with that heading, but is also provided elsewhere in this specification. can be found.

[0100] References: Altun A, Ozdemir E, Yildirim K, Gursoy S, Du rmus N and Bagcivan I(1015)The effects o f endocannabinoid receptor agonist anand amide and antagonist rimonabant on opioi d analgesia and tolerance in rats.Gen.Ph ysiol.Biophys.(2015),34,433-440 433 Li Y, North RY, Rhines LD, Tatsui CE, Rao G, Edwards DD, Cassidy RM, Harrison DS, Johans son CA,Zhang H,Dougherty PM.(2018).DRG V oltage-Gated Sodium Channel 1.7 Is Upreg ulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic P ain.J Neurosci.2018 Jan 31;38(5):1124-11 36. Kupper J,Prinz AA,Fromherz P(2002).Recom Binant Kv1.3 potassium channels stabiliz e tonic firing of cultured rat hippocamp al neurons.Pflugers Arch.Feb;443(4):541- 7. Remington:The Science and Practice of Ph armacy,22nd Edition,Lippincott Williams & Wilkins,Philadelphia,Pa.(2013) and any other edition Schmitz A,Sankaranarayanan A,Azam P,Schm idt-Lassen K,Homerick D,Hansel W and Wul ff H(2005).Design of PAP-1,a Selective S mall Molecule Kv1.3 Blocker,for the Supp ression of Effector Memory T Cells in Au toimmune Diseases.Molecular Pharmacology November,68(5)1254-1270. Vennekamp J,Wulff H,Beeton C,Calabresi P A,Grissmer S,Hansel W,Chandy KG(2004).Kv 1.3-blocking 5-phenylalkoxypsoralens:a n ew class of immunomodulators.Mol Pharmac ol.65(6):1364-74. Yang EK,Takimoto K,Hayashi Y,de Groat WC ,Yoshimura N.(2004).Altered expression o f potassium channel subunit mRNA and alp ha-dendrotoxin sensitivity of potassium currents in rat dorsal root ganglion neu rons after axotomy.Neuroscience;123(4):8 67-74.

Claims

1. For use as an analgesic in the treatment, prevention, or reduction of chronic and acute pain and compounds which are antagonists of the slow delayed rectifier Kv1.3 channel, pharmaceutical salts thereof or or prodrugs.

2. The compound inhibits Kv1.3 channels as compared to any other Kv1.x channel. 2.5-fold higher affinity than the slow delayed rectifier Kv for use according to claim 1.

1. Compounds, pharmaceutical salts or prodrugs thereof which are antagonists of the 3 channel.

3. The compound is nitenin, PSORA-4, PAP-1, AM92016 hydrochloride, or or at least one of the analogs, salts, or combinations thereof. 2 or 3, a compound which is an antagonist of the slow delayed rectifier Kv1.3 channel for the use according to claim 1. compounds, pharmaceutical salts or prodrugs thereof.

4. The compound is for use in warm-blooded vertebrates, preferably mammals, more preferably humans. A slow delayed rectifier Kv1.3 channel for use according to any one of claims 1 to 3. A compound, pharmaceutical salt or prodrug thereof, which is an antagonist of Nel.

5. Acute and chronic pain can be classified as neuropathic pain, nociceptive pain, psychogenic or somatic pain, Diabetic neuropathic pain, post-herpetic pain, low back pain, nerve root pain, musculoskeletal pain, post-operative pain and post-traumatic pain, phantom limb pain, surgical pain, wound-related pain, chemotherapy-induced peripheral neuropathy Pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, joint pain, osteoarthritis-related Pain, myofascial pain, migraine, chronic orofacial pain, trigeminal neuralgia, cancer-related pain, fibromyalgia-related pain Pain, hypersensitivity syndrome, infection-related pain, HIV-related pain, sprains and strains, hyperalgesia, somatic Pain, psychogenic pain, heat-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, bone Pelvic pain, myofascial pain, vascular pain, migraine wound, wound-related pain, arthritis pain, somatic visceral pain, phantom limb pain , nerve root pain, low back pain, visceral pain, bowel pain, bladder pain, and osteoarthritis-related pain The method for treating, preventing, or reducing pain according to any one of claims 1 to 4, including any one of Compounds that are antagonists of the slow delayed rectifier Kv1.3 channel for use in A pharmaceutical salt or prodrug of

6. A combination of an active ingredient (e.g., an excipient) with a pharmaceutically acceptable diluent or carrier. and a pharmaceutical composition comprising the active ingredient in a therapeutically effective dose of nitenin, PSORA -4, PAP-1, AM92016 hydrochloride, or pharmacological A pharmaceutical composition comprising an acceptable salt or prodrug thereof.

7. Treating chronic or acute pain in a subject in need thereof 1. A method of treating a subject with a therapeutically effective amount of an antagonist of a slow delayed rectifier Kv1.3 channel, comprising administering to the subject a therapeutically effective amount of an antagonist of a slow delayed rectifier Kv1.3 channel. The method comprises administering a compound that is an antagonist.

8. The compound binds to the Kv1.3 channel by at least one affinity assay. , which has a 2.5-fold higher affinity than any other Kv1.x channel.

7. The method according to claim 7.

9. The compound is nitenin, PSORA-4, PAP-1, AM92016 hydrochloride, or or an analog thereof, salt thereof, or a combination thereof. method.

10. 10. The method of claim 9, wherein the subject is a warm-blooded vertebrate, preferably a mammal, more preferably a human.

10. The method according to any one of 7 to 9.

11. The acute and chronic pain may be neuropathic pain, nociceptive pain, psychogenic or somatic pain. pain, diabetic neuropathic pain, post-herpetic pain, low back pain, nerve root pain, musculoskeletal pain, Postoperative and post-traumatic pain, phantom limb pain, surgical pain, wound-related pain, chemotherapy-induced peripheral neuropathy Inflammatory pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, joint pain, osteoarthritis Referred pain, myofascial pain, migraine, chronic orofacial pain, trigeminal neuralgia, cancer-related pain, fibromyalgia Pain associated with pain, hypersensitivity syndrome, infection-related pain, HIV-related pain, sprains and strains, hyperalgesia, Pathogenic pain, psychogenic pain, heat-induced pain, physical pain, nociceptive pain, rheumatic pain, headache , pelvic pain, myofascial pain, vascular pain, migraine wound, wound-related pain, arthritis pain, somatic visceral pain, phantom Selected from limb pain, nerve root pain, low back pain, visceral pain, intestinal pain, bladder pain, and osteoarthritis-related pain The method according to any one of claims 7 to 10,

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