Nitenine analog compounds and their use in the treatment of chronic and acute pain

Abstract

The present disclosure relates to nitenin analog compounds (of Formulas I, II, III, and IV) and their use as pharmaceuticals in the treatment, prevention, or reduction of both acute and chronic pain. The mechanism of action disclosed herein is that nitenin and nitenin analog compounds act by inhibiting the K + This allows these compounds to act as analgesics by reducing, rather than enhancing, the slow voltage-activated potassium (K) currents present in small diameter dorsal root neurons (sDRGn), which contributes to their high efficacy in treating pain. + ) currents, and are primarily voltage-gated potassium channels (K V )K V 1.3. These results, combined with the results showing that nitenin and nitenin analog compounds act as activity-dependent blockers, result in greatly reduced side effects. The results disclosed herein indicate that nitenin and nitenin analog compounds described herein are viable alternatives to existing pharmaceutical compounds used to treat pain.

Description

[Technical Field]

[0001] This disclosure relates to nitenine analog compounds and their use as analgesics for the treatment, prevention, or reduction of chronic and acute pain. [Background technology]

[0002] Acute pain usually comes on suddenly, and its cause is specific. It is qualitatively sharp. Acute pain usually does not last longer than 3 to 6 months. It disappears when the underlying cause of the pain is no longer present. After that, the person can continue living as usual. Illustrative causes of acute pain include surgery, fractures, dental work, burns and amputations, childbirth and delivery.

[0003] Chronic pain is defined as pain that persists for more than three months or beyond the natural recovery period. Pain signals continue to fire in the nervous system for weeks, months, or even years, even without physiological stimulation. It can occur in many medical conditions, including diabetes, arthritis, migraines, fibromyalgia, cancer, back pain, shingles, sciatica, trigeminal neuralgia, and past trauma or injury. Chronic pain can cause incapacitation, significantly impairing a person's quality of life and having a major negative impact on society. It affects 21% of the world's population (1.5 billion people) and has enormous associated economic costs. In the United States alone, it was estimated in 2010 that wage losses and lower productivity, as well as healthcare costs, amounted to $560-635 billion. With the increasing elderly population, the demand for appropriate and effective pain management is growing.

[0004] While there are effective and safe analgesics for mild pain, treatments for moderate and severe chronic pain are, in most cases, ineffective and cause limiting and harmful side effects. Therefore, the primary problem for patients with most types of chronic pain is the existence of truly appropriate pharmaceutical treatments that are at least without significant limiting side effects. For example, for situations with moderate to severe pain levels, opioid derivatives relieve pain but are conjunct with significant adverse effects such as addiction, habituation, and loss of energy or motivation. Opioid use has become an epidemic problem in several countries, accompanied by increased habituation and a heavy burden on society. For example, in the United States, the number of deaths associated with opioid use is far greater than the number of deaths from illegal drugs. Other types of drugs, including antidepressants, anticonvulsants, and nonsteroidal anti-inflammatory drugs (NSAIDs), are used for treatment, but these are either ineffective or cause associated side effects.

[0005] Other, more recent treatments for moderate to severe pain, are closer to the pharmacological context of the present invention and include ion channel modulators. Ion channels are major proteins present in the nerve cell membrane that shape electrical signaling, and therefore pain signals in nerves. Neurons involved in pain sensing (nociception) located in the peripheral nervous system include those whose cell bodies are located in ganglia (dorsal root ganglia - DRG) on the lateral side of the spinal cord (or trigeminal ganglion - TG in the head). Such nociceptive fibers are the primary peripheral nerve sensors involved in the physiological pathways that lead to the brain's recognition of pain.

[0006] Regarding currently available therapies for pain treatment that involve ion channel modulation, there are only two already on the market.

[0007] Nevertheless, depending on the type of ion channel being regulated, they may be only partially effective or still cause associated side effects. Such drugs, -Topic: Capsaicin, a transient receptor potential cation channel subfamily V member 1 (TRPV1) channelagonist. - Diconotide (Prialt®) is administered intrathecally; it is an N-type voltage-dependent calcium channel blocker derived from marine cone snails, and in this case, it acts centrally rather than peripherally.

[0008] Novel products currently in clinical development (in progress at several biotechnology and pharmaceutical companies, but not yet approved for commercialization) include novel opioids with specific modifications (to reduce addiction potential) and other ion channel modulators that capture ion channels known to be involved in pain, but are more suitable than TRPV1 and N-type voltage-gated calcium channels (e.g., other TRP, voltage-gated sodium channels Na). v 1.7 and Na v It includes ion channels such as 1.8.

[0009] Based on conventional technology, as far as is currently known, only two drugs are known to produce K + It acts on channels and is currently undergoing preclinical or clinical trials for pain treatment. a) The anticonvulsant retigabine (Phase II) attenuates nociceptive behavior in rat models of persistent and neuropathic pain. Retigabin is primarily K + It acts as a channel opener, that is, it works by activating a specific voltage-dependent potassium (Kv7 / M) channel family in the brain. b) Another channel modulator, BL-7050 (preclinical stage), is based on the molecular structure of diclofenac (NSAID) and binds to and stabilizes potassium channels in the body, controlling their hyperexcitability (by keeping them open), K + Pain is prevented by keeping the channel open to allow fluid to drain. [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] However, despite considerable medical research, there is still a need for clinically approved, superior, and more specific blockers / enhancers for these ion channels, leaving patients with no alternatives to medications that have severe side effects. [Means for solving the problem]

[0011] In one embodiment, the disclosure relates to nitenine analog compounds and their use as analgesics for the treatment, prevention, or reduction of chronic and acute pain.

[0012] While we do not wish to be constrained by theory, in some aspects the present invention differs from current existing solutions not only in its chemical properties but also in its mechanism of action. By "switching off" or by reducing the activity of nociceptive fibers using bioactive molecules, it is predicted that the brain's perception of pain will be blocked or attenuated in a manner that does not affect brain function, because these molecules can act in the "peripheral portion of the pain signaling pathway" in front of the central nervous system.

[0013] Any aspect or embodiment described herein may be combined with any other aspect or embodiment disclosed herein. While the present invention is described in conjunction with its detailed description, the foregoing description is intended to illustrate, not limit, the scope of the invention and is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following embodiments / claims.

[0014] Embodiment 1. Compounds of formulas I, II, III, and IV, pharmaceutically acceptable salts or prodrugs thereof, [ka] During the ceremony, [ka] represents a carbon-carbon single bond or a carbon-carbon double bond, X is selected from O, S, NH, CH2, Y is selected from CH, CH2, Z is selected from C, N, G is selected from O, S, T is selected from OH, SH, NH2, halogen, R 1 and R 2 are independently selected from H, alkyl, alkenyl, cycloalkyl, aryl, or -CH2-R 3 where R 3 is selected from aryl, cycloalkyl, heteroaryl, -R 4 -R 5 where R 4 is selected from alkyl, alkenyl, and R 5 is selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone, Q is selected from C, CH, D is selected from C, CH, CH2, One of A and E is H, and the other is selected from H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 where R 6 is selected from alkyl, alkenyl, and R 7 is selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone, J is selected from H, OH, SH, NH2, halogen, The compound is not nitenin, dihydronitenin, or their respective isomers, enantiomers, and stereoisomers, and is a compound of formula I, II, III, and IV, its pharmaceutically acceptable salt or prodrug.

[0015] Embodiment 2. X is O, Y is CH, Z is C, R 1 However, H is, R 2 However, H is, A compound of formula IV according to Embodiment 1, wherein J is OH.

[0016] Embodiment 3. X is O, Y is CH, Z is C, R 1 However, it is alkyl, R 2 However, it is -CH2-R3, and R 3 is, -R 4 -R 5 And R 4 is alkyl, and R 5 A compound of formula IV according to Embodiment 1, wherein is a heteroaryl compound and J is OH.

[0017] Embodiment 4. X is O, Y is CH2, G is O, R 1 However, H is, J is H, Q is C, D is C, E is H, A, -R 6 -R 7 And R 6 is alkyl, and R 7 The compound of formula II according to Embodiment 1 is a heteroaryl compound.

[0018] Embodiment 5. X is O, Y is CH2, G is O, R 1 However, H is, J is H, Q is C, D is C, E, -R 6 -R 7And R 6 is alkyl, and R 7 It is a heteroaryl, A compound of formula II according to Embodiment 1, wherein A is H.

[0019] Embodiment 6.R 7 However, the compounds of formulas I, II, III, and IV according to Embodiment 1 are not furan-3-yl.

[0020] Embodiment 7. Compounds of formulas I, II, III, and IV, pharmaceutically acceptable salts thereof, or prodrugs for use as pharmaceutical ingredients, [ka] During the ceremony, [ka] This represents a carbon-carbon single bond or a carbon-carbon double bond. X is selected from O, S, NH, CH2. Y is selected from CH and CH2. Z is selected from C and N. G is selected from O and S. T is selected from OH, SH, NH2, and halogens. R 1 and R 2 These are independently H, alkyl, alkenyl, cycloalkyl, aryl, or -CH2-R 3 Selected from, R 3 However, aryl, cycloalkyl, heteroaryl, -R 4 -R 5 Selected from, R 4 However, selected from alkyl and alkenyl, R 5 However, they are selected from aryls, substituted or unsubstituted heteroaryls, and substituted or unsubstituted gammaractones. Q is selected from C and CH. D is selected from C, CH, and CH2. One of A and E is H, and the other is H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 Selected from, R 6 However, selected from alkyl and alkenyl, R 7 However, selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted gamaractone, J is selected from H, OH, SH, NH2, and halogens. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs.

[0021] Embodiment 8. X is O, Y is CH, Z is C, R 1 However, it is alkyl, R 2 However, -CH2-R 3 And R 3 is, -R 4 -R 5 And R 4 R5 is an alkyl group, and R5 is a heteroaryl group. Q is C, D is C, A, -R 6 -R 7 And R 6 is alkyl, and R 7 It is a heteroaryl, E is H, A compound of formula I for use as a pharmaceutical ingredient according to Embodiment 7, wherein J is H.

[0022] Embodiment 9. X is O, Y is CH, Z is C, R 1 However, H is, R 2 However, H is, A compound of formula IV for use as a pharmaceutical ingredient according to Embodiment 7, wherein J is OH.

[0023] Embodiment 10. X is O, Y is CH, Z is C, R 1 However, it is alkyl, R 2 However, it is -CH2-R3, and R 3 is, -R 4 -R 5 And R 4 is alkyl, and R 5 This is a heteroaryl compound of formula IV for use as a pharmaceutical ingredient, where J is OH.

[0024] Embodiment 11. X is O, Y is CH2, G is O, R 1 However, H is, J is H, Q is C, D is C, E is H, A, -R 6 -R 7 And R 6 is alkyl, and R 7 The compound of formula II for use as a pharmaceutical ingredient according to Embodiment 7 is a heteroaryl compound.

[0025] Embodiment 12. X is O, Y is CH2, G is O, R 1 However, H is, J is H, Q is C, D is C, E, -R 6 -R 7 And R 6 is alkyl, and R7 It is a heteroaryl, A compound of formula II for use as a pharmaceutical ingredient according to Embodiment 7, wherein A is H.

[0026] Embodiment 13. For pharmaceutical use, the compounds of Formulas I, II, III, and IV of this patent application are used in warm-blooded vertebrates, preferably mammals, more preferably humans, in doses ranging from 0.1 μg / ml blood (6 μg / kg body weight) to 30 μg / ml blood (1.8 mg / kg body weight). The above effective dose range is for intravenous administration and may differ for other routes of administration.

[0027] Embodiment 14. Compounds of Formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs are used to treat, prevent, or reduce pain in individuals having acute or chronic pain, more specifically those requiring treatment, prevention, or reduction of pain. Acute and chronic pain includes neuropathic pain, nociceptive pain, psychogenic or somatic pain, diabetic neuropathic pain, postherpetic pain, low back pain, radicular pain, musculoskeletal pain, postoperative 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, orofacial chronic pain, trigeminal neuralgia, cancer-related pain, and It is intended to include, but is not limited to, at least one of the following: visceral pain-related pain, hypersensitivity syndrome, infection-related pain, HIV-related pain, sprains and strains, hyperalgesia, somatic pain, psychogenic pain, fever-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial pain, vascular pain, migraine wound, wound-related pain, arthralgia, somatic visceral pain, phantom limb pain, radicular pain, lower back pain, visceral pain, bowel pain, and osteoarthritis-related pain.

[0028] Embodiment 15. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs are used in the treatment of autoimmune disorders due to the effects described for Kv1.3, which is a target of such diseases.

[0029] Embodiment 16. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs are used in the treatment of diabetes, taking into account their effects on the Kv1.3 channel, which is thought to be associated with insulin sensitivity, insulin resistance-related syndromes, and obesity.

[0030] Embodiment 17. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs are used as antiepileptic and antiseizure agents.

[0031] Embodiment 18. Compounds of formulas I, II, III, and IV for use in the treatment or prevention of diseases involving the Kv1.3 channel.

[0032] Embodiment 19. A pharmaceutical composition comprising a combination of a pharmacologically acceptable diluent or carrier and an active ingredient, wherein the active ingredient comprises at least one compound according to formulas I, II, III, and IV, or a pharmacologically acceptable salt or prodrug thereof.

[0033] Embodiment 20. A method for treating pain in a person requiring pain treatment, comprising administering a therapeutically effective amount of compounds of formulas I, II, III, and IV.

[0034] Embodiment 21. Pain is neuropathic pain, nociceptive pain, psychogenic or somatic pain, diabetic neuropathic pain, postherpetic pain, low back pain, radicular pain, musculoskeletal pain, postoperative 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, orofacial chronic pain, trigeminal neuralgia, cancer-related pain, fibrous pain A method according to Embodiment 19 for acute and chronic pain types selected from myalgia-related 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, pelvic pain, bladder pain, myofascial pain, vascular pain, migraine wound, wound-related pain, arthralgia, somatic visceral pain, phantom limb pain, radicular pain, lower back pain, visceral pain, enteritis pain, and osteoarthritis-related pain.

[0035] Embodiment 22. A method for treating or preventing a Kv1.3 channel-related disease in a subject requiring treatment or prevention of the disease, comprising administering a therapeutically effective amount of compounds of formulas I, II, III, and IV to a subject requiring treatment or prevention of the disease.

[0036] Embodiment 23. A method for treating an autoimmune disease in a subject requiring treatment for an autoimmune disease, comprising administering a therapeutically effective amount of compounds of formulas I, II, III, and IV to a subject having an autoimmune disease.

[0037] Embodiment 24. A method for treating diabetes or insulin resistance syndrome in a subject requiring treatment for diabetes or insulin resistance syndrome, comprising administering a therapeutically effective amount of a compound to a subject having diabetes or insulin resistance syndrome.

[0038] Embodiment 25. A method for treating epilepsy or seizure in a subject requiring treatment of epilepsy or seizure, the method comprising administering to a subject having epilepsy or seizure a therapeutically effective amount of a compound.

[0039] Embodiment 26. The method according to Embodiments 20 - 23, wherein the compound is administered at a therapeutically effective amount of 0.018 - 1.8 mg / kg.

[0040] Embodiment 27. The compound, composition, use, or method disclosed herein, wherein the compound is a compound of Formula I, in which X is O, Y is CH, Z is C, R 1 is alkyl, R 2 is -CH2-R 3 where R 3 is -R 4 -R 5 where R 4 is alkyl, R 5 is heteroaryl, Q is C, D is C, A is -R 6 -R 7 where R 6 is alkyl, R 7 is heteroaryl, E is H, J is H, the compound, composition, use, or method.

[0041] Embodiment 28. The compound according to Embodiments 1 - 6, wherein the compound is isolated or synthetically produced.

[0042] Embodiment 29. The compound according to Embodiments 7 - 28, wherein the compound is nitenin or dihydronitenin.

[0043] For a more readily understandable purpose of this application, figures illustrating exemplary embodiments are attached to an annex, but they are not intended to limit the art disclosed herein. [Brief explanation of the drawing]

[0044] [Figure 1] This paper demonstrates the effect of nitenine (0.1 μg / ml) on voltage-activated currents recorded from small-diameter dorsal root ganglion neurons (sdDRGn). a) In sdDRGn, the voltage-activated outward potassium (K+) current was induced by a depolarization step up to +20 mV (holding potential -70 mV) led by a hyperpolarization prepulse up to -120 mV. The current was better fitted by the sum of two exponential functions, thus revealing two components (referred to here as Islow and Ifast), with time constants of τfast approximately 75 ms and τslow approximately 495 ms. b) Typical voltage-activated K+ current traces recorded before and in the presence of nitenine (0.1 μg / ml): The traces in the figure below, corresponding to the current subtraction, fit with a single exponential function (time constant τ approximately 150 ms). ii. Typical voltage-activated Na+ currents recorded before (black line) and in the presence of nitenine (0.1 μg / ml, 0.29 μM) (gray line) show no effect. [Figure 2]This shows the dose-dependent response of nytenine to voltage-activated K+ current recorded from (a) small-diameter dorsal root ganglion neurons (sdDRGn) and (b) CHO-K1 cells expressing human Kv1.1, Kv1.2, Kv1.3, Kv1.4, or Kv1.6 cDNA. a) The effect of nytenine was recorded as a dose-response relationship to rapid (Ifast, white inverted triangle) and slow (Islow, black triangle) current components recorded from sdDRGn, expressed as the percentage of current interruption. Peak current was used as the measure of Ifast, while current values ​​were obtained at the end of the command pulse as the measure of Islow (see Figure 1). Values ​​are expressed as mean ± SEM. A dual-phase relationship can be observed in Islow. Therefore, at lower concentration values ​​(maximum 1 μM), the relationship fits to the Hill function and shows an IC50 of 120 nM, and at concentrations above 1 μM, the dose-dependency appears in agreement with the dose-dependency of Ifast (IC50 of approximately 6 μM). b) Effect of nytenine on K+ current recorded from CHO-K1 cells stably transfected and expressing hKv1.1, hKv1.2, hKv1.3, hKv1.4, or hKv1.6. Concentration-% blockade values ​​are fitted to the Hill function, and IC50 values ​​(nM) are shown in the figure. The Kv1.3 channel is the most sensitive channel (approximately 6 times more sensitive than Kv1.2, which is the "next most sensitive channel"), while Kv1.2, Kv1.1, and Kv1.6 show similar intermediate sensitivity to nytenine. Conversely, Kv1.4 is less sensitive (approximately 31 times less sensitive). [Figure 3]This study demonstrates the typical effect of nitenin on the steady-state voltage dependence of K+ current inactivation recorded from small-diameter neurons isolated from isolated dorsal root ganglia on the injured side of a CCI rat model 28 days postoperatively. a) Current traces were induced up to +10mV (600ms) during a command pulse led by a continuous prepulse duration of 11040 seconds, in 10mV stepwise increments, ranging from -140 to +10mV. The left (black) trace was obtained before the application of nitenin (0.1μg / ml, 0.29μM), and the right (gray) trace was obtained during the application of nitenin. b) Current / voltage relationships are plotted (black marks are for control-CCI, gray marks are during nitenin treatment) with current peak amplitude (obtained in "a") against the potential of the prepulse used in the voltage protocol in "a". A shift to hyperpolarization can be observed during nitenin treatment. These relationships fit well to the sum of two Boltzmann functions, showing that both conditions have two components, one being a more hyperpolarized component (component 1) and the other a more depolarized component (component 2). Indeed, the Vh parameter of the Boltzmann equation (voltage at half the maximum current) showed a more hyperpolarized value during the nitenine treatment (control: Vh1=-73.3mV Vh2=-26.3mV, nitenine: Vh1=-95.3mV Vh2=-47.0mV). [Figure 4]Behavioral readout is shown as a measure of pain during nitenin treatment in a rat model of neuropathic pain, CCI (chronic sciatic nerve injury). A typical experiment was conducted using a group of Wistar rats subjected to four unilateral sciatic nerve stenoses. The values ​​refer to mechanical sensitivity to stimulation using calibrated von Frey filaments, and consequently reflect hyperalgesia during hypersensitivity (black marker - ipsilateral, operated paw; white marker - contralateral, uninjured paw). The dotted line indicates the mean value for the ipsilateral paw before surgery. a) Model induction showed a significant increase in ipsilateral paw mechanical sensitivity at 3 days postoperatively, while those related to the contralateral paw remained unchanged and similar to baseline values. This trend was maintained over 26 days postoperatively, with nitenin treatment on day 26 (dotted circle). b) Effect of intravenous injection of nitenin (estimated plasma concentration 1 μg / ml) on ipsilateral paw mechanical sensitivity. For clarity, data for the contralateral paw are not shown, but they remained unchanged. The effect is maximized approximately one hour after injection, reaching a level before surgery that is no different from the baseline value (dotted line). [Figure 5]Behavioral readout was used as a measure of pain during treatment with nitenin in an orofacial pain rat model, in a typical experiment using a group of Wistar rats subjected to CFA injection (CFA was injected immediately behind the second row of villous cilia). The values ​​refer to mechanosensitivity to facial stimulation (villous cilia region) using calibrated von Frey filaments, and consequently reflect hyperalgesia during hypersensitivity (black marker - ipsilateral, injured facial side; white marker - contralateral, uninjured facial side). The dotted line indicates the mean value of the ipsilateral face before CFA injection. a) Induction in the model showed a significant increase in ipsilateral facial mechanosensitivity 3 days postoperatively, while those related to the contralateral foot remained relatively unchanged and similar to baseline values. This trend was maintained for 26 days after induction, with nitenin treatment performed on day 26 (dotted circle). b) Effect of intravenous injection of nitenin (estimated plasma concentration 1 μg / ml) on ipsilateral facial mechanosensitivity. For clarity, data for the contralateral face are not shown, but they remained relatively unchanged. The effect was maximum approximately 1-2 hours after nitenin injection, reaching values ​​before induction that were no different from the baseline values ​​(dotted line values), but in some cases were higher. [Figure 6] The formulas of four of the tested compounds are shown, with compound V representing nytenine (results in ionic current are shown in Figures 1, 2, and 3, and in vivo efficacy is shown in Figures 4 and 5). Formulas VIII.A and VIII.B represent the cis and trans isomers of compound VIII, respectively. [Figure 7] The effect of compound VI (10 μg / ml, 77.9 μM) on the recorded voltage activation current of sdDRGn is shown. Typical voltage activation K+ current traces recorded before and in the presence of compound VI (10 μg / ml, 77.9 μM): The traces in the figure below, corresponding to current subtraction, are fitted to a single exponential function (time constant τ approximately 795 ms). [Figure 8]The effect of compound VII (0.1 μg / mL, 399 nM) on the recorded voltage activation current of sdDRGn is shown. Typical voltage activation K+ current traces recorded before and in the presence of compound VII (0.1 μg / mL, 399 nM) are shown below; the traces correspond to current subtraction. [Figure 9] The effect of compound VIII-A (6.5 μg / mL, 29.4 μM) on the voltage activation current of recorded sdDRGn is shown. Typical voltage activation K+ current traces recorded before and in the presence of compound VIII-A (6.5 μg / mL, 29.4 μM): The traces in the figure below, corresponding to current subtraction, are fitted to a single exponential function (time constant τ approximately 450 ms). [Figure 10] The typical effect of the compound of formula VI on the steady-state voltage dependence of K+ current deactivation recorded from sdDRGn is shown. a) Current traces were induced up to +10mV (600ms) during a command pulse preceded by a continuous prepulse duration of 11040 seconds, in stepwise increments of 10mV, ranging from -140 to +10mV. The left (black) trace was obtained before application of the compound of formula VI (10μg / ml, 77.9μM), and the right (gray) trace was obtained during application of nitenine. b) Current / voltage relationships are plotted against the potential of the prepulse used in the voltage protocol in "a" (black marks are for control-CCI, and gray marks are during treatment with the compound of formula VI). A shift to hyperpolarized values ​​can be observed during treatment with the compound of formula VI. These relationships fit well to the sum of two Boltzmann functions, showing that both conditions have two components, one being a more hyperpolarized component (component 1) and the other a more depolarized component (component 2). Indeed, the Vh parameter of the Boltzmann equation (voltage at half the maximum current) showed a more hyperpolarized value during the F2 treatment (control: Vh1=-91.0mV Vh2=-23.9mV, F2: Vh1=-102.9mV Vh2=-40.5mV). [Figure 11]This shows the typical effect of the compound of formula VII on the steady-state voltage dependence of K+ current deactivation recorded from sdDRGn. a) Current traces were induced up to +10mV (600ms) during a command pulse preceded by a continuous prepulse duration of 11040 seconds, in stepwise increments of 10mV, ranging from -140 to +10mV. The left (black) trace was obtained before the application of F3 (0.1μg / ml, 399nM), and the right (gray) trace was obtained during the application of nytenine. b) Current / voltage relationships are plotted against the potential of the prepulse used in the voltage protocol in "a" (black marks are for control-CCI, and gray marks are during treatment with the compound of formula VII). A shift to hyperpolarized values ​​can be observed during treatment with the compound of formula VII. These relationships fit well to the sum of two Boltzmann functions, showing that both conditions have two components, one being a more hyperpolarized component (component 1) and the other a more depolarized component (component 2). Indeed, the Vh parameter of the Boltzmann equation (voltage at half the maximum current) showed a more hyperpolarized value during treatment with the compound of equation VII (control: Vh1=-64.1mV Vh2=-13.7mV, F2: Vh1=-92.6mV Vh2=-32.4mV). [Figure 12]This shows the typical effect of the compound of formula VIII-A on the steady-state voltage dependence of K+ current deactivation recorded from sdDRGn. a) Current traces were induced up to +10mV (600ms) during a command pulse preceded by a continuous pre-pulse duration of 11040 seconds, in 10mV stepwise increments, ranging from -140 to +10mV. The left (black) trace was obtained before application of the compound of formula VIII (6.5μg / ml, 29.4μM), and the right (gray) trace was obtained during application of nytenine. b) Current / voltage relationships are plotted against the potential of the pre-pulse used in the voltage protocol in "a" (black marks are for control-CCI, and gray marks are during treatment with the compound of formula VIII). A shift to hyperpolarized values ​​can be observed during treatment with the compound of formula VIII. These relationships fit well to the sum of two Boltzmann functions, showing that both conditions have two components, one being a more hyperpolarized component (component 1) and the other a more depolarized component (component 2). Indeed, the Vh parameter of the Boltzmann equation (voltage at half the maximum current) showed a more hyperpolarized value during treatment with the compound of equation VIII (control: Vh1=-53.6mV Vh2=-18.1mV, F2: Vh1=-88.9mV Vh2=-35.5mV). [Modes for carrying out the invention]

[0045] When used in this application, unless expressly provided herein, each of the following terms shall have the meanings set forth below. Additional definitions are provided throughout this application.

[0046] References to the compounds disclosed herein, their pharmaceutically acceptable salts and prodrugs, ninetine, and ninetine analogs are used interchangeably herein. These terms include all stereoisomers of these compounds.

[0047] Where used herein, the term “and / or” should be understood as a specific disclosure of each of two particular characteristics or components, with or without other characteristics or components. Thus, the term “and / or” as used in phrases such as “A and / or B” is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to include each of the embodiments of A, B, and C, A, B, or C, A or C, A or B, B or C, A and C, A and B, B and C, A (alone), B (alone), and C (alone). Whenever an embodiment is described herein in the language of “includes,” it should be understood that other similar embodiments described in the terms “consist of” and / or “essentially consist of.”

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art in which this disclosure relates.

[0049] Units, prefixes, and symbols are given in the form approved by the International System of Units (SI). Numerical ranges include the numerical values ​​that define the range. The headings provided herein may be used by referring to this specification as a whole, rather than being limitations on the various aspects of this disclosure. Thus, terms defined immediately thereafter are more fully defined by referring to this specification as a whole.

[0050] "Administering" means physically introducing a drug into a subject using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration for the compounds disclosed herein include, for example, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes by injection or infusion. As used herein, the term "parenteral administration" generally means, but is not limited to, methods of administration other than enteral and topical administration by injection, and includes, intravenous, intramuscular, intra-arterial, intrathecal, intralymphatic, intrafocal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, as well as in vivo electroporation. In some embodiments, the compounds are administered via routes other than parenteral, for example, orally. Other non-parenteral routes of administration include topical, epidermal, or mucosal routes of administration, for example, intranasal, intravaginal, rectal, sublingual, or topical. The administration may also be carried out, for example, once, multiple times, and / or over one or more extension periods.

[0051] The term "isolated" means that it is purified from nature and therefore does not contain the naturally occurring compounds that exist with nytenine in its natural environment, and is associated with its natural state. Isolated natural products may have different chemical, biochemical, and / or physical properties than the same natural product. Synthetic versions of natural products may have different chemical, biochemical, and / or physical properties than the same natural product isolated from nature or that exists in nature.

[0052] The term "pharmaceutically acceptable" is used herein to refer to these compounds, materials, compositions, and / or drug formulations that, within the bounds of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio. Drug approval agencies (e.g., EMA, US-FDA) provide guidance and approve pharmacopoeias for pharmacopoeias. Examples are listed, for example, in pharmacopoeias.

[0053] The terms “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” are used herein to refer to pharmaceutically acceptable materials selected from solvents, dispersions, diluents, dispersants, suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, polymers, peptides, proteins, cells, hyaluronidases, and mixtures thereof. In some embodiments, the solvent is an aqueous solvent.

[0054] The “therapeutic effective dose,” “effective dose,” or “effective amount” of a drug or therapeutic agent is any amount of the drug, when used alone or in combination with another therapeutic agent, that protects a subject from the onset of the disease or promotes disease regression, as demonstrated by a reduction in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic periods of the disease, or the prevention of functional or physical impairment resulting from the onset of the disease. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to those skilled in the art, such as by assaying the activity of the drug in human subjects during clinical trials, in animal model systems to predict efficacy in humans, or in in vitro assays.

[0055] In one embodiment, the “therapeutic effective dose” is the dose that, whether administered as a single dose or in a multi-dose schedule, is effective in treating, preventing, and / or reducing pain. This dose will vary depending on the health and physical condition of the individual being treated, age, the desired degree of analgesia, and other relevant factors. The dose is expected to fall within a relatively wide range that can be determined through standardized testing. “Preventing” or “preventing” as used herein does not require absolute success in the sense of absolute prevention of pain, but indicates a reduction in the risk of developing a painful condition or pain with reduced severity. Similarly, “treatment” should not be interpreted as an absolute cure and may also relate to the alleviation or suppression of pain or a pain-related condition.

[0056] As used interchangeably herein, the terms “alkyl,” “alkyl unit,” and “alkyl group” refer to saturated monovalent hydrocarbon radicals containing 1 to 12 carbon atoms (C1 to C12). Alkyl groups may be linear, branched, or cyclic. Alkyl groups may be unsubstituted or substituted as described elsewhere herein. In some embodiments, alkyl groups contain 1 to 8 carbon atoms (C1 to C8). In some embodiments, alkyl groups contain 1 to 6 carbon atoms (C1 to C6). In some embodiments, alkyl groups contain 1 to 4 carbon atoms (C1 to C4). In some embodiments, cyclic alkyl groups contain 3 to 6 carbon atoms (C3 to C6).

[0057] The terms “alkenyl,” “alkenyl unit,” and “alkenyl group,” as used interchangeably herein, refer to a monovalent hydrocarbon radical comprising 2 to 8 carbon atoms (C2 to C8) having at least one unsaturated site (i.e., an sp2 carbon-carbon double bond). Alkenyl groups can be linear, branched, or cyclic. Alkenyl groups can be unsubstituted or substituted as described elsewhere herein. In some embodiments, alkenyl groups comprise 2 to 6 carbon atoms (C2 to C6). In some embodiments, alkenyl groups comprise 2 to 4 carbon atoms (C2 to C4). Alkenyl groups can have an E or Z orientation. Non-limiting examples of alkenyl groups include ethenyl (also called vinyl), 1-propenyl, iso-propenyl, and 2-chloroethenyl.

[0058] The terms “aryl,” “aryl unit,” and “aryl group,” as used interchangeably herein, refer to monovalent aromatic hydrocarbon radicals containing 6 to 20 carbon atoms (C6 to C20) derived by removing a hydrogen atom from an aromatic ring. The aryl group may be unsubstituted or substituted with one or more substituents, as described elsewhere herein.

[0059] The terms “heterocyclic,” “heterocyclyl,” “heterocyclic unit,” and “heterocyclic group,” as used interchangeably herein, refer to a saturated or partially unsaturated cyclic system containing 3 to 20 atoms, wherein at least one of the ring atoms is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. A heterocyclic group may be unsubstituted or may be substituted with one or more substituents, as described elsewhere herein. In some embodiments, a heterocyclic group contains 3 to 10 atoms. In some embodiments, a heterocyclic group contains 3 to 7 atoms. In some embodiments, a heterocyclic group is monocyclic. In some embodiments, a heterocyclic group is bicyclic. In some embodiments, a heterocyclic group contains a fused ring.

[0060] The terms “heteroaryl,” “heteroaryl unit,” and “heteroaryl group,” as used interchangeably herein, refer to a monovalent aromatic radical comprising one or more five-membered, six-membered, or seven-membered rings and independently comprising one or more heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. Heteroaryl groups may be unsubstituted or may be substituted with one or more substituents, as described elsewhere herein. In some embodiments, a heteroaryl group contains 5 to 20 atoms. In some embodiments, a heteroaryl group contains 5 to 9 atoms. In some embodiments, a heteroaryl group contains 5 atoms. In some embodiments, a heteroaryl group contains 6 atoms. In some embodiments, a heteroaryl group contains 7 atoms. In some embodiments, a heteroaryl group is monocyclic. In some embodiments, a heteroaryl group is bicyclic. In some embodiments, a heteroaryl group contains a fused ring.

[0061] As used herein, the term “substituted” means replacing one or more hydrogen atoms, or one or more of a hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group, with one or more substituents. In a substituted hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group, any number of hydrogen atoms may be replaced by substituents.

[0062] The compounds of this disclosure may contain one or more chiral centers. Therefore, the compounds of this disclosure may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds described herein, including, but not limited to, diastereomers, enantiomers, and mixtures thereof (including, but not limited to, racemic mixtures), are intended to form part of this disclosure.

[0063] Abbreviation: Ca 2+ :calcium Ca v Voltage-dependent calcium channels CCI: Chronic Compression Injury CFA: Fully Freund Adjuvant CHO: Chinese hamster ovaries 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 prepectinate fibroblast 2 I: Current I fast :Rapid current component I slow : Slow current component IV: Intravenous K+ : Potassium K V : Voltage-dependent potassium channel K v 1.x: Voltage-dependent potassium channel subunit, given by x L: Lumbar Na +: Sodium Na V : Voltage-dependent sodium channel Na v 1.x: Voltage-dependent sodium channel subunit, given by x NSAID: Non-steroidal anti-inflammatory drug MTS: (3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) sdDRGN: Small-diameter dorsal root neuron sdTGN: Small-diameter trigeminal ganglion neuron 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-maximal current

[0064] The compounds of the present disclosure, pharmaceutically acceptable salts of such compounds, and / or pharmaceutical compositions containing such compounds and / or their pharmaceutically acceptable salts can be administered as a therapeutic treatment. The compounds, pharmaceutically acceptable salts, and / or pharmaceutical compositions can be administered in unit dosage forms for administration to mammalian subjects, including humans. Suitable unit dosage forms include, by way of non-limiting examples, forms for oral administration and forms for administration via non-oral routes, and these non-limiting examples include inhalation, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, and intravitreal administration.

[0065] In some embodiments, the pharmaceutical composition for oral administration may be in the form of tablets, pills, powders, rigid gelatin capsules, soft gelatin capsules, and / or granules. In some embodiments of such pharmaceutical composition, the compounds of the Disclosure and / or pharmaceutically acceptable salts of the compounds of the Disclosure are mixed with one or more inert diluents, non-limiting examples of which include starch, cellulose, sucrose, lactose, and silica. In some embodiments, such pharmaceutical composition may further include one or more substances other than diluents, for example (non-limiting examples), lubricants, colorants, coatings, or varnishes.

[0066] The pharmaceutical compositions of this disclosure may include pharmaceutically acceptable carriers, excipients, vehicles, and diluents. Many of these are well known to those skilled in the art and are described, in non-limiting examples, in Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins, Philadelphia, Pa. (2013) and any other editions, which are incorporated herein by reference.

[0067] In one embodiment, this disclosure relates to nytenine analog compounds and their use as analgesics for the treatment, prevention, or reduction of chronic and acute pain. Novel pharmaceutical applications relating to analgesic effects in several types of pain are disclosed herein through approaches using the physiology and pharmacology of ion currents / channels.

[0068] In stark contrast to existing therapeutic agents, the analgesic compounds disclosed herein are poised to be groundbreaking in pain management due to their novel mechanisms of action, as well as their predicted efficacy, target specificity, and reduced side effects in humans. Nitenine and dihydronitenine compounds (two of the compounds disclosed herein) originate from marine sponges, but are synthetically prepared and can be synthetically prepared in this disclosure. This disclosure also reveals that these compounds are expressed in pain-sensing c fibers of the dorsal root ganglia and trigeminal ganglia, and that these compounds are specifically K123- V Channel K v 1. Provides specific action on x. Without being constrained by theory, the mechanism of action involves specific channel inhibition (rather than enhancement like retigabine), (a) it is an "open channel blocker", and therefore activity-dependent blockade, (b) it involves voltage-dependent changes in channel inactivation, and (c) a series of K in particular V It possesses advantageous properties, such as specifically acting on channels, primarily Kv1.3. This specific and novel mechanism of action explains why and how nytenine and nytenine analog compounds are effective only in limbs / body parts with injured / affected nerves. Furthermore, it does not alter nociceptivity and sensory scores in unaffected limbs / body parts.

[0069] In one embodiment, the disclosure relates to the use of nitene analog compounds as analgesics for the treatment, prevention, or reduction of chronic and acute pain. Accordingly, in some embodiments of the disclosure, the compounds referred to as “nitene analog compounds” are represented by the compounds of formulas I, II, III, and IV described in the following embodiments.

[0070] Embodiment 1. Compounds of formulas I, II, III, and IV, pharmaceutically acceptable salts or prodrugs thereof, [ka] During the ceremony, [ka] This represents a carbon-carbon single bond or a carbon-carbon double bond. X is selected from O, S, NH, CH2. Y is selected from CH and CH2. Z is selected from C and N. G is selected from O and S. T is selected from OH, SH, NH2, and halogens. R 1 and R 2 These are independently H, alkyl, alkenyl, cycloalkyl, aryl, or -CH2-R 3 Selected from, R 3 However, aryl, cycloalkyl, heteroaryl, -R 4 -R 5 Selected from, R 4 However, selected from alkyl and alkenyl, R 5 However, they are selected from aryls, substituted or unsubstituted heteroaryls, and substituted or unsubstituted gammaractones. Q is selected from C and CH. D is selected from C, CH, and CH2. One of A and E is H, and the other is H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 Selected from, R 6 However, selected from alkyl and alkenyl, R 7 However, selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone, the compound is neither nytenine nor dihydronytenine, nor their respective isomers, enantiomers, and stereoisomers, and / or optionally, R7 is not furan-3-yl, J is a compound of formulas I, II, III, and IV, selected from H, OH, SH, NH2, and halogens, its pharmaceutically acceptable salt, or prodrug.

[0071] Embodiment 2. X is O, Y is CH, Z is C, R 1 However, H is, R 2 However, H is, A compound of formula IV according to Embodiment 1, wherein J is OH.

[0072] Embodiment 3. X is O, Y is CH, Z is C, R 1 However, it is alkyl, R 2 However, it is -CH2-R3, and R 3 is, -R 4 -R 5 And R 4 is alkyl, and R 5 A compound of formula IV according to Embodiment 1, wherein is a heteroaryl compound and J is OH.

[0073] Embodiment 4. X is O, Y is CH2, G is O, R 1 However, H is, J is H, Q is C, D is C, E is H, A, -R 6 -R 7 And R 6 is alkyl, and R 7 The compound of formula II according to Embodiment 1 is a heteroaryl compound.

[0074] Embodiment 5. X is O, Y is CH2, G is O, R 1 However, H is, J is H, Q is C, D is C, E, -R 6 -R 7 And R 6 is alkyl, and R 7 It is a heteroaryl, A compound of formula II according to Embodiment 1, wherein A is H.

[0075] Embodiment 6.R 7 However, the compounds of formulas I, II, III, and IV according to Embodiment 1 are not furan-3-yl.

[0076] Embodiment 7. Compounds of formulas I, II, III, and IV, pharmaceutically acceptable salts thereof, or prodrugs for use as pharmaceutical ingredients, [ka] During the ceremony, [ka] This represents a carbon-carbon single bond or a carbon-carbon double bond. X is selected from O, S, NH, CH2. Y is selected from CH and CH2. Z is selected from C and N. G is selected from O and S. T is selected from OH, SH, NH2, and halogens. R 1 and R 2 These are independently H, alkyl, alkenyl, cycloalkyl, aryl, or -CH2-R 3 Selected from, R 3 However, aryl, cycloalkyl, heteroaryl, -R 4 -R 5 Selected from, R 4 However, selected from alkyl and alkenyl, R 5However, they are selected from aryls, substituted or unsubstituted heteroaryls, and substituted or unsubstituted gammaractones. Q is selected from C and CH. D is selected from C, CH, and CH2. One of A and E is H, and the other is H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 Selected from, R 6 However, selected from alkyl and alkenyl, R 7 However, selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted gamaractone, J is selected from H, OH, SH, NH2, and halogens. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs.

[0077] Embodiment 8. X is O, Y is CH, Z is C, R 1 However, it is alkyl, R 2 However, -CH2-R 3 And R 3 is, -R 4 -R 5 And R 4 R5 is an alkyl group, and R5 is a heteroaryl group. Q is C, D is C, A, -R 6 -R 7 And R 6 is alkyl, and R 7 It is a heteroaryl, E is H, A compound of formula I for use as a pharmaceutical ingredient according to Embodiment 7, wherein J is H.

[0078] Embodiment 9. X is O, Y is CH, Z is C, R 1 However, H is, R 2 However, H is, A compound of formula IV for use as a pharmaceutical ingredient according to Embodiment 7, wherein J is OH.

[0079] Embodiment 10. A compound of formula IV for use as a pharmaceutical ingredient, wherein the formula comprises X is O, Y is CH, Z is C, R 1 It is an alkyl, R 2 It is -CH2-R3, and R 3 However, -R 4 -R 5 And R 4 However, it is alkyl, R 5 However, it is a heteroaryl compound, and J is OH, a compound of formula IV.

[0080] Embodiment 11. X is O, Y is CH2, G is O, R 1 However, H is, J is H, Q is C, D is C, E is H, A, -R 6 -R 7 And R 6 is alkyl, and R 7 The compound of formula II for use as a pharmaceutical ingredient according to Embodiment 7 is a heteroaryl compound.

[0081] Embodiment 12. X is O, Y is CH2, G is O, R 1 However, H is, J is H, Q is C, D is C, E, -R 6 -R 7 And R 6 is alkyl, and R 7 It is a heteroaryl, A compound of formula II for use as a pharmaceutical ingredient according to Embodiment 7, wherein A is H.

[0082] Embodiment 13. For pharmaceutical use, the compounds of Formulas I, II, III, and IV of this patent application are used in warm-blooded vertebrates, preferably mammals, more preferably humans, in doses ranging from 0.1 μg / ml blood (6 μg / kg body weight) to 30 μg / ml blood (1.8 mg / kg body weight). The above effective dose range is for intravenous administration and may differ for other routes of administration.

[0083] Embodiment 14. Compounds of Formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs are used to treat, prevent, or reduce pain in individuals having acute or chronic pain, more specifically those requiring treatment, prevention, or reduction of pain. Acute and chronic pain includes neuropathic pain, nociceptive pain, psychogenic or somatic pain, diabetic neuropathic pain, postherpetic pain, low back pain, radicular pain, musculoskeletal pain, postoperative 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, orofacial chronic pain, trigeminal neuralgia, cancer-related pain, and It is intended to include, but is not limited to, at least one of the following: visceral pain-related pain, hypersensitivity syndrome, infection-related pain, HIV-related pain, sprains and strains, hyperalgesia, somatic pain, psychogenic pain, fever-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial pain, vascular pain, migraine wound, wound-related pain, arthralgia, somatic visceral pain, phantom limb pain, radicular pain, lower back pain, visceral pain, bowel pain, and osteoarthritis-related pain.

[0084] Embodiment 15. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs are used in the treatment of autoimmune disorders due to the effects described in Kv1.3, which target such diseases.

[0085] Embodiment 16. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs are used in the treatment of diabetes, considering their effects on Kv1.3 channels, which are thought to be associated with insulin sensitivity, insulin resistance-related syndromes, and obesity.

[0086] Embodiment 17. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs are used as antiepileptic and antiseizure agents.

[0087] Embodiment 18. Compounds of formulas I, II, III, and IV for use in the treatment or prevention of diseases involving the Kv1.3 channel.

[0088] Embodiment 19. A pharmaceutical composition comprising a combination of a pharmacologically acceptable diluent or carrier and an active ingredient, wherein the active ingredient comprises at least one compound according to formulas I, II, III, and IV, or a pharmacologically acceptable salt or prodrug thereof.

[0089] Embodiment 20. A method for treating pain in a subject requiring pain treatment, comprising administering a therapeutically effective amount of compounds of formulas I, II, III, and IV to the subject having pain.

[0090] Embodiment 21. Pain is neuropathic pain, nociceptive pain, psychogenic or somatic pain, diabetic neuropathic pain, postherpetic pain, low back pain, radicular pain, musculoskeletal pain, postoperative 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, orofacial chronic pain, trigeminal neuralgia, cancer-related pain, and A method according to Embodiment 19 for acute and chronic pain selected from visceral pain-related 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, pelvic pain, bladder pain, myofascial pain, vascular pain, migraine wound, wound-related pain, arthralgia, somatic visceral pain, phantom limb pain, radicular pain, lower back pain, visceral pain, enteritis pain, and osteoarthritis-related pain.

[0091] Embodiment 22. A method for treating or preventing a Kv1.3 channel-related disease in a subject requiring treatment or prevention of the disease, comprising administering a therapeutically effective amount of compounds of formulas I, II, III, and IV to a subject requiring treatment or prevention of the disease.

[0092] Embodiment 23. A method for treating an autoimmune disease in a subject requiring treatment for an autoimmune disease, comprising administering a therapeutically effective amount of compounds of formulas I, II, III, and IV to a subject having an autoimmune disease.

[0093] Embodiment 24. A method for treating diabetes or insulin resistance syndrome in a subject requiring treatment for diabetes or insulin resistance syndrome, comprising administering a therapeutically effective amount of a compound to a subject having diabetes or insulin resistance syndrome.

[0094] Embodiment 25. A method for treating epilepsy or seizures in a subject requiring treatment for epilepsy or seizures, comprising administering a therapeutically effective amount of a compound to a subject having epilepsy or seizures.

[0095] Embodiment 26. The method according to Embodiments 20-23, wherein the compound is administered in a therapeutically effective dose of 0.018-1.8 mg / kg.

[0096] Embodiment 27. A compound, composition, use, or method disclosed herein, wherein the compound is a compound of formula I, where, X is O, Y is CH, Z is C, R 1 It is an alkyl, R 2 -CH2-R 3 And R 3 However, -R 4 -R 5 And R 4 However, it is alkyl, R 5 However, it is a heteroaryl compound, Q is C, D is C, A is -R 6 -R 7 And R 6 However, it is alkyl, R 7 However, it is a heteroaryl compound, E is H, J is a compound, composition, use, or method of which is H.

[0097] Embodiment 28. Compounds according to Embodiments 1-6, wherein the compound is isolated or produced synthetically.

[0098] Embodiment 29. Compounds according to Embodiments 7-28, wherein the compound is nitenine or dihydronitenine.

[0099] This disclosure presents robust evidence that nitenine and nitenine analog compounds may be used as analgesics for the treatment, prevention, or reduction of chronic and acute pain. This evidence was obtained from several technical approaches, including ex vivo neuronal preparations, animal models of pain, behavioral readouts of pain, computer approaches, in vitro toxicity studies, and whole-cell voltage clamp recordings.

[0100] The nitenine analog compound of this application was initially obtained from the marine sponge Spongia agaracina, captured in Sagres, Portugal, but has also been chemically synthesized. As shown in the examples, the nitenine-containing extract showed a modulating effect on potassium current recorded from rat sdDRGN (pain-sensing neurons), which was a bioactivity underlying the bio-induced fraction differentiation process. The resulting series of fractions were K + This not only allowed for the identification of compounds that not only maintain the ability to regulate electric current but also exhibit high levels of efficacy. The results also showed very similar K + This was also confirmed in small trigeminal ganglion neurons (sdTGNs), which showed the same pharmacological effect in the current profile.

[0101] The K2 cells, affected by the identified compounds, are recorded from sdDRGN (and sdTGN) by whole-cell voltage clamping technique. + The application's focused research in the field of pain neurophysiology was aimed at identifying currents. The use of a rat pain model was to perform previous target validation, namely, K, which is differentially expressed in pain states. + This was important for determining the current component. In one aspect of this disclosure, K is affected by the pain state. +The current component is suggested to be mainly regulated (decreased) by the compound of interest. The nature of the recorded regulatory effect on the current was tested by monitoring several biophysical parameters such as the voltage-dependence and kinetics of activation and inactivation. The specificity of the biological activity was performed by comparing the pharmacological effects on the currents recorded from sdDRGNs with those in other types of dorsal root ganglia (medium-diameter DGRs and large-diameter DGRs).

[0102] Furthermore, the drug sensitivities to different voltage-activated channels were evaluated by testing the drug effects on the currents recorded from Chinese hamster ovary (CHO) cells stably transfected with different human Kv channel subunits (Kv1.1, Kv1.2, Kv1.3, Kv1.4, and Kv1.6). Most of the compounds are active against hKv1.3 (IC 50 ~ 190 nM), which is 6 - 30-fold more sensitive than the other Kv1.x tested.

[0103] One of the competitive advantages of nitenin and nitenin analog compounds used in pain therapy over other compounds (including those acting on ion channels) lies, in part, in at least eight of their properties, which are interrelated and can be explained as follows. 1 - Nitenin and nitenin analog compounds are low-molecular-weight compounds that can be synthesized using chemical synthesis approaches. 2 - Their novel mechanisms of action and the location and nature of their intracellular targets. Nitenin reduces the activity of K V channels expressed in snDRGs (a subset of Kv1.x with high affinity for Kv1.3), is involved in the slow delayed rectifier current, and regulates pain signal transmission and propagation to the brain. Along with this peripheral effect of nitenin and nitenin analogs, complementary central effects are not excluded. Currently, important requirements have not been met for specific blockers of some such Kv1.x channels (e.g., Kv1.3 and Kv1.6) with clinical potential. Administration of 3-nitenin or nitenin analog compounds causes no loss of sensation and nociceptive ability and no loss of nociception in non-injured limbs / body parts, and its mechanism of action is a property related to the fact that it is, for example, an open-channel dependent effect. 4-The nitenin and nitenin analog compounds of the present disclosure are easily administered. In animal models used to test nitenin analog compounds, intravenous (IV) and intraperitoneal injections have been successfully used with respect to their analgesic effects. Importantly, nitenin analog compounds can be administered orally, so that in a preferred embodiment, it is obtained that intragastric administration is also carried out in an animal model with a similar analgesic effect. 5-Based on the toxicological experiments performed, there are no signs of any toxicity or side effects in the systems tested and described below. It is obtained that nitenin acts mainly (but not exclusively) on the peripheral nervous system, and no brain-derived toxicity / side effects have been shown to occur. 6-Nitenin and its analogs are effective in reducing pain in many pain models, including acute and neuropathic chronic pain, chemotherapy-induced peripheral neuropathy, acute and long-term or chronic inflammatory pain (nociceptive pain), orofacial chronic pain, and diabetic neuropathic chronic pain. Such results predict wide clinical application possibilities. 7-Although effective for acute / short-term pain, nitenin is particularly effective for long-term / chronic pain. 8-Specifically acting on a subset of potassium channels (Kv1.x) and having no effect on sodium current / channels (Na v ), nitenin analog compounds do not compete with Na v modulators, but rather can be applied in combination with them and may maximize the expected analgesic effect or act synergistically.

[0104] In one embodiment, the compounds of the present disclosure, or their pharmaceutically acceptable salts and prodrugs, may be used to treat acute pain. Examples of acute pain conditions, typically the type of pain lasting between three and six months, include pain directly related to surgery, fractures, dental work, burns and cuts, soft tissue injuries such as ankle sprains, childbirth, and delivery.

[0105] In one embodiment, chronic pain may be treated using the compounds of the present disclosure, or their pharmaceutically acceptable salts and prodrugs. Examples of diseases or disorders associated with chronic pain include peripheral neuropathy, chronic pain, arthritis, especially osteoarthritis, cancer, HIV, diabetes, fibromyalgia, herpes zoster, herpes, headache, migraine, multiple sclerosis, nerve injury (neuropathy), lower back pain, trauma and other injuries (e.g., herniated disc, torn ligament), sciatica, diabetic neuropathy, carpal tunnel syndrome, trigeminal neuralgia, postoperative conditions, chronic fatigue syndrome (or myalgic encephalomyelitis), endometriosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, interstitial cystitis, temporomandibular joint dysfunction (TMJ), vulvovaginal pain, bursitis, celiac disease, lupus, rheumatoid arthritis, complex regional pain syndrome, myofascial pain syndrome, meningitis, Lyme disease and other tick-borne diseases, muscle strains, and sprains.

[0106] In some embodiments, the compounds of the present disclosure, or their pharmaceutically acceptable salts and prodrugs, may be used to treat hyperalgesia, somatic pain, psychogenic pain, fever-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial pain, vascular pain, migraine wounds, arthritis-related wounds, somatic visceral pain, phantom pain, curative pain, low back pain, or osteoarthritis-related pain.

[0107] Both acute and chronic pain involve complex changes in the processing and conduction of electrical signals from the peripheral nerves to the central nervous system (CNS). Electrical excitability and activity levels in a normal state, or those associated with chronic pain, are related to sodium (Na) + ), potassium (K + ), or calcium (Ca 2+Pain is the result of the influx or efflux of charged metal ions, such as ions, through membrane ion channels (Nav, Kv, or Cav, respectively), which cause the generation, propagation, and transmission of electrical signals from cell to cell throughout the cell. In chronic pain, the underlying neuronal network of pain signaling is altered, resulting in abnormal ionic currents brought about by altered expression and biophysics of the underlying channels, leading to excessive and persistent neuronal excitability and activity. Therefore, effective analgesics need to be able to suppress the hyperexcitability of the pain signaling network, restore the physiological expression and / or biophysical profile of functional channels, and then restore network activity to restorative levels.

[0108] Small-diameter DRG neurons (c fibers), also known as pain-sensing neurons, are located lateral to the spinal cord and have nociceptive input to the CNS (i.e., leading to "pain"). Normally, under normal conditions, these neurons do not have spontaneous firing activity—they are silent (e.g., Ly et al., 2018), a situation that changes during pain episodes, and is actually associated with chronic pain. The therapeutic strategy underlying this invention targets such neurons in the DRG and the major ion channels located in them in the trigeminal ganglion (TG) to "switch off" such "pain-inducing" hyperexcitability. As a result, the transmission of "pain signals" to the CNS is interrupted or reduced, thereby preventing the brain from recognizing pain. However, complementaryly, there may be effects on central neurons that contribute to the analgesic effect.

[0109] In some embodiments, the compounds of this disclosure, or their pharmaceutically acceptable salts and prodrugs, can be used to denounce pain-induced hyperexcitability. In some embodiments, they can be used to modulate the brain's perception of pain.

[0110] Several ion channels have been identified as major effectors in pain transmission. Some are particularly present in these pain-sensing neurons. Therefore, specifically regulating their activity would block pain without affecting other bodily functions. Nitenin analogs are recorded from small-diameter (sdDRGN, and also sdTGN, which are thought to correspond to c fibers) slow voltage activation K + It is disclosed herein that it is a specific modulator of electric current. Underlying such slow currents are specific Kv1.x channels. This effect is less pronounced in large-diameter neurons in the submicromolar concentration range, i.e., below 1 micromolar, and the modulatory effect of nytenin is exclusive to sdDRGN and sdTGN.

[0111] In some embodiments, the compounds of the present disclosure, or their pharmaceutically acceptable salts and prodrugs, are used to slowly activate K + The current can be regulated. In some embodiments, the current originates from small-diameter (sdDRGN, and even sdTGN) neurons.

[0112] Kv1.x is an ion channel involved in pain signal propagation, primarily found in pain-sensing neurons, including those that mediate slow voltage activation currents. Nitenine analog compounds are slow K + Particularly effective in the current component, and considering the dynamics and voltage dependence of nytenine-sensitive current, the subcurrent component strongly suggests the involvement of a subset of Kv1.x channels. Indeed, voltage-clamp tests on currents recorded from stably transfected CHO cells expressing hKv1.1, hKv1.2, hKv1.3, hKv1.4, or hKv1.6 showed that nytenine analog compounds were far more effective in the Kv1.3 channel (approximately 6 times more sensitive to nytenine compared to the second most sensitive channel (Kv1.2), and approximately 30 times more sensitive compared to the least sensitive channel) (Kv1.4) (see Figure 2).

[0113] In some embodiments, the compounds of this disclosure, or their pharmaceutically acceptable salts and prodrugs, can be used to suspend hyperexcitability in central neurons, i.e., neurons under a seizure episode. The above effect on Kv1.x channels, resulting in the cessation of recurrent neuronal firing, is the basis for the antiepileptic effect. Therefore, nytenine and nytenine analogs can be used as antiepileptic and antiseizure agents.

[0114] In some embodiments, the compounds of the present disclosure, or their pharmaceutically acceptable salts and prodrugs, may be used as Kv1.3 inhibitors. Kv1.3 has been reported as a target for the treatment of immunologically related conditions, as well as for the treatment of diabetes and other metabolic disorders. The compounds of the present disclosure may be used for the treatment of diabetes and other metabolic disorders.

[0115] In some embodiments, the compounds of this disclosure, or their pharmaceutically acceptable salts and prodrugs, may be used to treat autoimmune diseases. In other embodiments, they may be used to increase insulin sensitivity.

[0116] With respect to these therapeutic treatments, the mode of administration (or multiple modes of administration), the dosage (or multiple dosages), and the optimized pharmaceutical form (or multiple forms) can be determined according to criteria generally considered when establishing a patient's treatment, including, but not limited to, the potency of the compound and / or pharmaceutically acceptable salts of the compound, the patient's age, the patient's weight, the severity of the patient's condition, the patient's tolerance to the treatment, and any secondary effects observed in the treatment. Determining an effective dosage that provides therapeutic benefit in a particular mode and frequency of administration is within the scope of the skills of those skilled in the art. [Examples]

[0117] In vivo and ex vivo pain models The rat pain model used for both in vivo behavioral studies and electrophysiological ex vivo testing was: ●Naive Wistar: Control rat. Neurons from the dorsal root ganglion (DRG), lumbar vertebrae 4, 5, and 6 (L4, L5, and L6). ● Acute and chronic neuropathic pain rat models: CCI rats (long-term sciatic nerve stenosis in Wistar rats) 3 days post-surgery (acute) and 23-29 days post-surgery (chronic). Neurons from the DRG (L4, L5, and L6). ● Acute and long-lasting or chronic inflammatory pain rat models: CFA rats (knee administration of total Freund's adjuvant (CFA) in Wistar rats) 3 days (acute), 18 days (subchronic), and 23 days (chronic) after injection. Neurons from DRG (L3, L4 e L5). ●Chronic Orofacial Pain (COP) Rat Model: COP rats were analyzed 28-30 days after injection of CFA into the villous cilia pads of Wistar rats. Neurons from the trigeminal ganglion. ●Diabetic neuropathic pain rat model: STZ rats and Wistar rats were given intraperitoneal injections of STZ (streptozotocin), and pain symptoms were induced after 30 days. At the end of the 30th day, they were further tested with nitenin (IV) (total 60 days). Neurons from the DRG (L4, L5, e, L6). ● Chemotherapy-induced peripheral neuropathy chronic pain rat model: CIPN rats and Wistar rats were administered paclitaxel three times (intraperitoneal injection) every two days, and tested 42 days after induction. Neurons from DRG (L4, L5, e, L6).

[0118] For electrophysiological recording of ex vivo materials, voltage clamp recordings were performed on neurons isolated from rat DRG (and TG). Recordings were taken from neuronal cell bodies, often containing the proximal axonal fraction, one hour after the completion of the cell isolation process (including enzymatic and mechanical processing).

[0119] Mechanism of action Nitenin (represented herein as a compound of Formula V) and the analgesic mechanism of action of nitenin analog compounds (exemplified herein as compounds of Formulas I-IV and VI-VIII) are disclosed herein for the first time. It is K + associated with a decrease rather than an enhancement of current. For this reason, it is important to first characterize the potassium currents present in sdDRGN and sdTGN.

[0120] The voltage-activated whole-cell K + currents recorded from sdDRGN during depolarization steps (e.g., up to +40 mV for 1 second as shown in Figure 1) showed rapid activation followed by two inactivation phases. Thus, the current decay at depolarized potentials fit better to the sum of two exponential functions, namely, a relatively rapid component showing a time course of tens of milliseconds (τ fast ) (associated here with what is known as the I fast -A current), followed by a much slower inactivating current showing a time course of hundreds of milliseconds (τ slow ) (here called I slow ) (see Figure 1). Different ratios of I fast and I slow were observed between cells, and some cells showed only one component I slow . The currents observed in sdDRGn are very similar to the currents reported for sdTGn.

[0121] Nitenin inhibited the K + currents from sdDRGN and sdTGN in a dose-dependent manner. At a concentration of up to 1 μM (about 0.3 μg / ml), it specifically decreased I slow (see Figure 1.b), and this current component was overexpressed in sdDRGn neurons (and sdTGn) obtained from "injured nerves" in chronic pain rat models (CCI, CFA, and orofacial) (I slow(In relation to ). In a typical example shown in Figure 1.b, it can be noticed that the peak current is hardly changed by nitenine treatment, but the slower component is certainly reduced. The nitenine-sensitive current component (trace subtraction in the figure below) shows current decay that fits better with a single exponent of about 150 ms, and at moderate concentrations, the nitenine effect is I slow This further suggests that it is specific to I. fast It is hardly affected by nytenine at concentrations up to 1 μg / ml, and at concentrations exceeding 3 μM / ml, I fast It was necessary to reduce it. Importantly, slow The decrease in nytenine was greater in neurons obtained from chronic pain animals compared to the decrease induced by several concentrations of nytenine in neurons obtained from "control" animals.

[0122] The effect of nitenin is K + It is specific to electric current and voltage-activated Na + It is not possible to induce changes related to electric current (Figure 1.b).

[0123] I slow and I fast The differential dose-response in this case is better identified in the dose-response curve shown in Figure 2.a. slow The concentration / blocking relationship in this case shows a biphase relationship. From the beginning up to 1 μM (approximately 0.3 μg / ml), the relationship is approximately 0.12 μM IC 50 It can be fitted to a single Hill function having . At higher concentrations, I slow The relationship is, slow The effect on I fast It follows a second phase in addition to the effects on I fast It matches the concentration / cutoff relationship in and similarly fits well to a single Hill function. Its approximately 6 μM IC 50 This confirms a considerably low sensitivity to nytenine.

[0124] Nitenin's (I fast Rather than) Islow Due to its high sensitivity to and the nature of its nitenine-sensitive current (see nitenine-sensitive current in Figure 1.b), which K + Channel is I slow Emphasis or understanding was encouraged. By considering which Kv channel subunits are expressed in DRGs and the biophysical properties of nytenin-sensitive currents, nytenin was tested for whole cell currents recorded from CHO cells expressing hKv1.1, hKv1.2, hKv1.3, hKv1.4, and hKv1.6. From this list, only Kv1.4 was identified as "Type A" I. fast It forms the basis, and the rest is I slow This may be related. The results are summarized in Figure 2.B, showing the dose-response due to relative sensitivity to nytenine. Current inhibition was measured at the end of the 1000 ms pulse. Kv1.3 is 190 nM IC 50 It shows higher sensitivity and the actual value is from sdDRGN I slow Dose-response in (IC50 I slow These values ​​were observed within the same range (approximately 120 nM). In contrast, hKv1.1, hKv1.2, and hKv1.6 showed approximately 6 times lower (or less) sensitivity, and hKv1.4 showed approximately 30 times lower sensitivity, clearly the lowest sensitivity.

[0125] Slow K + Current inhibition of nytenine involves a pharmacological process of "open channel blockade." It also involves changes in the steady-state voltage dependence of inactivation (and little to no change in the voltage dependence of activation). In fact, nytenine shifts the IV curve related to the voltage dependence of inactivation to more hyperpolarized potentials (see Figure 3).

[0126] The compound is K +The slow voltage activation current recorded from sdDRGN is inhibited by promoting channel inactivation, and this inactivation is somewhat impaired in chronic pain states. More precisely, the compound promotes inactivation by shifting the voltage sensitivity of steady-state inactivation to lower depolarization values ​​(or higher hyperpolarization). Such compound-induced shifts in inactivation become larger when the voltage curve profile is more depolarized than its *initial position* (before treatment with nitenine or a nitenine analog). Depolarized inactivation curves are typical of sdDRGN obtained from chronic pain states. In other words, in neurons obtained from damaged nerves (chronic), nitenine returns the voltage-dependent profile of inactivation to a "control" pattern. Therefore, the compound-induced shift in the voltage sensitivity of inactivation is higher in neurons derived from damaged nerves (showing abnormally depolarized profiles) and lower in unaffected neurons showing hyperpolarized voltage profiles. This intriguing effect in channel dependence partially explains the compound-induced decrease in neuronal excitability, which is specific / more pronounced in affected neurons, i.e., during pain.

[0127] C fibers are typically silent, exhibiting little to no spontaneous firing activity; that is, they have little to no basal activity under control conditions. We begin by analyzing the effects of nytenine on undamaged, silent neurons. Given the nature of nytenine's mechanism of action, we anticipate that K fibers in such "silent neurons" will exhibit K + The effect of nytenine on current is expected to be little or no, because, as an open-channel blocker, its effect is activity-dependent (and the nytenine shift in the inactivation curve will be minimal). Nevertheless, in this example of an unaffected neuron, K +There is a moderate decrease in current, but this effect will not reach the threshold potential that induces repetitive firing (due to insufficient induced depolarization). This partially explains why nytenin does not alter "pain sensation" in areas of the body that are not affected. On the other hand, in the development of chronic pain, there is a state of hyperexcitability in the damaged neurons, accompanied by repetitive and sustained firing. In these hyperexcitable neurons, the nytenin effect is maximal (as explained above). Resting potential (K) + A further increase in current (induced by a nytenin-induced decrease) requires firing impairment, which is brought about by the indirect promotion of sodium channel inactivation. Thus, the signal is interrupted, but only in "damaged" fibers.

[0128] Finally, regarding specificity, it is important to note that the slow currents obtained from large-diameter DRG neurons are approximately 10 times less sensitive to nytenine.

[0129] The mechanism by which the nytenin effect in Kv currents produces analgesic effects is novel, and it addresses this problem through conventional methods that do not involve inhibition of Kv current. V This is because an increase in current is expected to calm the neuronal excitability of hyperexcitable C fibers. In this example, in chronic pain states (sdDRGn obtained from CCI, CFA, and STZ, and sdTGn obtained from the COP rat model), potassium current (I) slowly inactivates the nerves. slow ) is a current (I) that deactivates quickly. fast It must be emphasized that it is expressed more functionally compared to ). Also, under such conditions, I slow It is important to note that it exhibits an abnormally depolarized inactivation profile, i.e., a channel with less inactivation. To maintain repetitive firing over a long period, Na + An increase in "excitability" brought about by increased electrical resonance is a typical situation in chronic pain, corresponding to a recurrent long-term firing pattern. +This must be maintained by an increase in the cancellation in the current. The effect of the compounds disclosed herein is that they return such a pattern to a control profile and reduce the Kv-mediated current that slowly deactivates. + This nitenine-induced effect on the current would not allow for the adjustment necessary for the typical increase in sodium conductance (Nav) in pain situations. As a result, the intensified sodium current is inactivated in the presence of nitenine (partly due to depolarization induced by the decrease in Kv current), turning off spike firing in affected nerves but not in normal, undamaged neurons. This means that during pain, i.e., in chronic pain, Kv blockers, as well as Kv enhancers or openers alone, should be considered as potential analgesics.

[0130] K + How a decrease in electrical current leads to a significant decrease in neuronal excitability can be explained in different ways, or most likely, by a combination of phenomena.

[0131] Firstly, as mentioned above, K + Drug-induced reduction in current can lead to slow depolarization of affected neurons in a way that maintains the membrane potential at the depolarization level, so that the normal threshold potential can pass even without an action potential firing. Therefore, depolarization occurs in Na + The channel inactivation gate is closed and remains closed, preventing the increase of the action potential (Na + This would lead to a process like containment, where the channel is not sufficiently "activatable."

[0132] Secondly, (1) nytenine is particularly effective with Kv1.3 (see Figure 2.b), and (2) Kv1.3 is expressed in DRG (Yang et al., 2004), increasing its expression level in DRG neurons with chronic pain (unpublished data), so a more direct role of specific blockade in Kv1.3 may be considered. The biophysical properties and dynamics of Kv1.3-mediated currents are thought to maintain stable, sustained firing, a state corresponding to neurons in a "chronic pain situation" (Kupper et al., 2002). Reducing such Kv1.3-mediated currents would lead to a decrease in action potential amplitude and a state of resting depolarization without firing, as observed in rat hippocampal neurons (Kupper et al., 2002).

[0133] Efficacy results: For efficacy testing, nociception was assessed in all animals from all pain models by quantifying sensitivity to mechanical stimulation using von Frey filaments through periodic behavioral monitoring, thereby reflecting hyperalgesia during hypersensitivity. In the neuropathic pain model CCI, a cold allodynia test with acetone was also used, showing a response very similar to that of von Frey filaments.

[0134] Efficacy after intravenous administration. The following results pertain to intravenous (IV) injection of purified nitenine (>98% - compound of formula V) (1 μg / mL in blood, approximately 0.06 mg / Kg). ● Naive Wistar Control: After intravenous injection of Nitenine, there was absolutely no change in sensitivity scores in either foot. ●In CCI rats, sensitivity to mechanical stimuli was significantly reduced after IV administration in both acute (3 days after model induction) and chronic (22 or 31 days) conditions. A typical experiment is shown in Figure 4. The nitenin-induced reduction in hypersensitivity was robust in both cases (acute and chronic), but significantly higher in cases of chronic pain, and in some individuals, nitenin returned the score to the control level. The pain relief period lasted 2–4 hours. Importantly, there was no change in the behavioral score of the contralateral (uninjured) foot in all animals tested. ●In CFA rats, a significant decrease in sensitivity to mechanical irritation was observed after Nitenin IV injection in all conditions: 3 days (acute), 18 days (subchronic, intravenous), and 23 days (chronic). Again, the Nitenin effect was greater in the chronic condition, even though some score recovery had already occurred by 23 days. The duration of pain relief was limited to the injured paw and lasted 2.5–4.5 hours, similar to CCI rats. ●In COP rats, administration of nitenin IV consistently resulted in a significant decrease in mechanical sensitivity assessed in the cilia pad area 23 days (chronic) after CFA injection. A typical experiment is shown in Figure 5. The duration of pain relief lasted 3–4 hours and was limited to the damaged cilia pad (damaged surface only). ●In STZ rats, the animals reached diabetic glucose blood levels within one week of STZ injection and exhibited hypersensitivity to mechanical stimuli at the end of day 30. Therefore, nitenin was administered IV only at day 60 after STZ treatment, allowing time for the establishment of chronic diabetic neuropathy. A decrease in mechanical sensitivity was observed in the hypersensitive paws after nitenin administration. The duration of nitenin-induced pain relief lasted 2-3 hours. ●In CIPN rats, nitenine was administered intravenously. 42 days after treatment with paclitaxel, this consistently resulted in an extreme decrease in sensitivity to mechanical stimulation in both paws. Nevertheless, in this case, pain relief was not as strong or long-lasting (<2 hours) compared to other pain models, likely due to the severity of the model.

[0135] - Efficacy after intraperitoneal administration. Intraperitoneal administration was tested in CFA rats (23 days after CFA injection) at 10 times the amount of nytenine administered by IV injection. In this example, there was a clear pain relief effect, as indicated by score values ​​reaching the control level, and the effect lasted for approximately 4 hours.

[0136] - Efficacy after oral administration. Oral administration of nitenine via a gastric tube (intra-stomach) was tested in CCI rats (31 days post-surgery) at 100 times the amount administered by IV injection. All animals tested showed similar pain relief, i.e., a decrease in sensitivity. This effect lasted for approximately 2 hours.

[0137] In addition to the tests conducted using nitenine, three analogues (compounds of formulas VI, VII, and VIII) designed around the core structures of formulas I, II, III, and IV were also tested to demonstrate their activity.

[0138] In summary, nitenine compounds have been shown to be effective for short-term / acute and long-term / chronic neuropathic pain, short-term / acute and long-term / chronic inflammatory pain, chronic orofacial pain, diabetic neuropathic pain, and chemotherapy-induced peripheral neuropathy. Their efficacy has been demonstrated for several routes of administration, including intravenous, intraperitoneal, and, importantly, oral administration.

[0139] The effect of the three nytenine analogs is that the affected K + They were similar in that they involved the electric current component. However, I slow Typical effects in (Figures 7-9) and the voltage dependence of steady-state inactivation (Figures 10-12) were obtained at different concentrations. This is because the nytenine analog compound, slow While they exhibit a clear effect, they strongly suggest different affinities. The strongest effect was observed with compound V, followed by compounds VII, VIIIa, VIIIb, and VI, respectively.

[0140] Based on dose-dependent curves, several concentrations and efficacy levels applied under IV administration were quantified as a result, and nytenine analogs are used for pharmacological purposes in warm-blooded vertebrates, particularly humans, at doses ranging from 0.1 μg / ml blood (6 μg / kg body weight) to 30 μg / ml blood (1.8 mg / kg body weight).

[0141] Toxicity results: The toxicity of nitenine compounds was evaluated using different techniques. No signs of toxicity were detected.

[0142] 1. Computer-aided toxicity assay Assays using VEGA® software allowed testing for mutagenicity, carcinogenicity, developmental toxicity, hepatotoxicity, skin sensitization, affinity for estrogen receptors, and several environmental parameters (e.g., aquatic toxicity, bee population, bioaccumulation). All tests were negative with varying levels of confidence.

[0143] 2. In vitro and ex vivo toxicity ● Cell viability studies (MTS) using the HFF2 cell line showed no decrease in cell viability at concentrations up to 200 μM. ● Cardiotoxicity: a) Cell viability tests (MTS) using primary mouse cardiomyocyte cultures did not show a decrease in cell viability at concentrations up to 20 μM. b) Whole-cell voltage clamp in hERG: There is no effect on the outward current mediated by hERG expressed in HEK (human embryonic kidney) cells. c) Ex vivo rat preparations demonstrated that nitenine (up to 10 μM) did not alter sinus rate, atrioventricular anisotropy (isolated rat atria), and right ventricular (RV) anisotropy (isolated rat ventricles). d) In vivo electrocardiogram (ECG) recordings of anesthetized Wistar rats showed that intravenous injection of nitenin (60 μg / Kg) did not alter sinus rhythm or heart rate, nor did it induce arrhythmias or any proarrhythmic events.

[0144] 3. In vivo toxicity For all in vivo administrations, the animals' behavior was tracked for an additional week, followed by post-mortem examination. Each pair of individuals received two IV doses per day (one in the morning and one at the end of the afternoon) for a full week. No external changes in any organs or internal structures were detected.

[0145] Several features are described below, which can be used independently of each other or in any combination of other features. However, any individual feature may not address any of the problems discussed above, or it may address only one of the problems discussed above. Some of the problems discussed above may not be fully addressed by any of the features described herein. Headings are provided, but information regarding a particular heading may not be found in the section containing that heading, but may be found elsewhere in this specification.

[0146] In the aforementioned specification, embodiments of the present invention have been described with reference to numerous specific details that may vary between executions. Therefore, the sole and exclusive indicator of what the present invention is and what the applicant intends to express in the present invention is the set of claims issued in this application, including any subsequent modifications in the particular form in which such claims are issued. Any definitions expressly provided herein for terms contained in such claims shall govern the meaning of such terms as used in the claims. Accordingly, no limitations, elements, characteristics, features, advantages, or attributes not expressly enumerated in the claims shall limit such claims in any way. Therefore, this specification and the drawings should be considered illustrative, not restrictive.

[0147] Various publications, articles, and patents are cited or referenced throughout the background and this specification, and each of these references is incorporated herein in its entirety by reference. The consideration of documents, acts, materials, devices, articles, etc., included herein is for the purpose of providing context for the invention. Such consideration does not constitute an admission that any or all of these matters form part of the prior art with respect to any invention disclosed or claimed.

[0148] References: Li Y,North RY,Rhines LD,Tatsui CE,Rao G,Edwards DD,Cassidy RM,Harrison DS,Johansson CA,Zhang H,Dougherty PM.(2018).DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain.J Neurosci.2018 Jan 31;38(5):1124-1136. Kupper J,Prinz AA,Fromherz P(2002).Recombinant Kv1.3 potassium channels stabilize tonic firing of cultured rat hippocampal neurons.Pflugers Arch.Feb;443(4):541-7. Yang EK, Takimoto K, Hayashi Y, de Groat WC, Yoshimura N. (2004).Altered expression of potassium channel subunit mRNA and alpha-dendrotoxin sensitivity of potassium currents in rat dorsal root ganglion neurons after axotomy.Neuroscience;123(4):867-74.

Claims

1. Compounds of formula I or III, or pharmaceutically acceptable salts thereof, 【Chemistry 1】 During the ceremony, 【Chemistry 2】 This represents a carbon-carbon single bond or a carbon-carbon double bond. X is selected from O and NH. Y is CH, CH ２ Selected from, Z is selected from C and CH. T is selected from OH and SH. R １ is selected from -CH ２ -R ３ where R ３ is selected from -R ４ -R ５ where R ４ is selected from alkylene and alkenylene, and R ５ is selected from unsubstituted aryl, unsubstituted heteroaryl, and unsubstituted gamma-lactone. R ２ It is selected from H and alkyl, Q is selected from C and CH. D is selected from C and CH. One of A and E is H, and the other is -R ６ -R ７ Selected from, R ６ However, R is selected from alkylene and alkenylene. ７ However, they are selected from unsubstituted aryls, unsubstituted heteroaryls, and unsubstituted gamma lactones. J is selected from H and OH. The aforementioned compound is neither nytenine nor dihydronytenine, nor their respective enantiomers or stereoisomers, The aforementioned aryl refers to a monovalent aromatic hydrocarbon radical containing 6 to 20 carbon atoms (C6 to C20) that is derived by removing a hydrogen atom from an aromatic ring; The alkyl group refers to a saturated monovalent hydrocarbon radical containing 1 to 4 carbon atoms (C1 to C4), which may be linear or branched; The aforementioned heteroaryl refers to a monovalent aromatic radical comprising 5 to 20 atoms, comprising one or more 5-membered, 6-membered, or 7-membered rings, and independently comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur; The aforementioned alkenyl refers to a monovalent hydrocarbon radical containing 2 to 8 carbon atoms (C2 to C8) having at least one unsaturated site.

2. R ７ However, the compound of formula I or III described in claim 1, or a pharmaceutically acceptable salt thereof, is not furan-3-yl.

3. Pharmaceutical compositions comprising a compound of formula I or III, or a pharmaceutically acceptable salt thereof: 【Transformation 3】 During the ceremony, 【Chemistry 4】 This represents a carbon-carbon single bond or a carbon-carbon double bond. X is selected from O and NH. Y is CH, CH ２ Selected from, Z is selected from C and CH. T is selected from OH and SH. R １ is, -CH ２ -R ３ Selected from, R ３ However, -R ４ -R ５ Selected from, R ４ However, R is selected from alkylene and alkenylene. ５ However, they are selected from unsubstituted aryls, unsubstituted heteroaryls, and unsubstituted gamma lactones. R ２ It is selected from H and alkyl, Q is selected from C and CH. D is selected from C and CH. One of A and E is H, and the other is -R ６ -R ７ Selected from, R ６ However, R is selected from alkylene and alkenylene. ７ However, they are selected from unsubstituted aryls, unsubstituted heteroaryls, and unsubstituted gamma lactones. J is selected from H and OH. The aforementioned aryl refers to a monovalent aromatic hydrocarbon radical containing 6 to 20 carbon atoms (C6 to C20) that is derived by removing a hydrogen atom from an aromatic ring; The alkyl group refers to a saturated monovalent hydrocarbon radical containing 1 to 4 carbon atoms (C1 to C4) and which may be linear or branched; The aforementioned heteroaryl refers to a monovalent aromatic radical comprising 5 to 20 atoms, comprising one or more 5-membered, 6-membered, or 7-membered rings, and independently comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur; The aforementioned alkenyl refers to a monovalent hydrocarbon radical containing 2 to 8 carbon atoms (C2 to C8) having at least one unsaturated site.

4. X is O, Y is CH, Z is C, R2 is an alkyl group, R1 is -CH ２ -R ３ And R ３ is, -R ４ -R ５ And R ４ It is an alkylene, and R ５ It is an unsubstituted heteroaryl, Q is C, D is C, A is -R ６ -R ７ And R ６ It is an alkylene, and R ７ It is an unsubstituted heteroaryl, E is H, and The pharmaceutical composition according to claim 3, wherein J is H.

5. A pharmaceutical composition according to claim 3 or 4 for treating or suppressing pain in a person requiring pain treatment.

6. The aforementioned pain includes neuropathic pain, nociceptive pain, psychogenic or somatic pain, diabetic neuropathic pain, postherpetic pain, low back pain, radicular pain, musculoskeletal pain, postoperative 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, orofacial chronic pain, trigeminal neuralgia, cancer-related pain, and fibromyalgia. The pharmaceutical composition according to claim 5, which is for acute and chronic pain selected from referred pain, hypersensitivity syndrome, infection-related pain, HIV-related pain, sprains and strains, hyperalgesia, somatic pain, psychogenic pain, fever-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial pain, vascular pain, migraine wound, wound-related pain, arthralgia, somatic visceral pain, phantom limb pain, radicular pain, lower back pain, visceral pain, enteritis pain, and osteoarthritis-related pain.

7. A pharmaceutical composition according to claim 3 or 4 for the treatment of diabetes or insulin resistance syndrome or epilepsy or seizures.

8. The pharmaceutical composition according to any one of claims 3 to 4, wherein the compound is administered in a therapeutically effective dose of 0.018 to 1.8 mg / kg.

9. The pharmaceutical composition according to any one of claims 3 to 4, wherein the compound is nitenine or dihydronitenine, or an enantiomer, stereoisomer, or salt thereof.

10. The pharmaceutical composition according to any one of claims 3 to 4, wherein the compound is administered in a dose in the range of 0.1 μg / ml blood to 30 μg / ml blood.

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