Nitenine analogs and their use in the treatment of chronic and acute pain

Abstract

The present invention provides compounds useful as analgesics for the treatment, prevention, or reduction of chronic and acute pain. [Solution] A nitenine analog compound of formulas I, II, III, and IV, a pharmaceutically acceptable salt or prodrug thereof, which is neither nitenine nor dihydronitenine nor their respective isomers, enantiomers, and stereoisomers, a five-membered ring compound containing an oxo group, a pharmaceutically acceptable salt or prodrug thereof. TIFF2026090288000014.tif89170

Description

[Technical Field]

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

[0002] Acute pain usually comes on suddenly, and its cause is specific. It is qualitatively sharp. Acute pain is, Typically, it doesn't last longer than 3-6 months. This is because the underlying cause of the pain has disappeared. Sometimes it disappears. Afterwards, the person can continue living their life as usual. Example of acute pain. Typical causes 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 can persist for weeks, months, or even years without physiological stimulation. The system continues to fire. For example, diabetes, arthritis, migraines, fibromyalgia, cancer, back pain, shingles. It can occur in many medical conditions, including sciatica, trigeminal neuralgia, and past trauma or injury. Chronic pain significantly impairs a person's quality of life and has a major negative impact on society, leaving people helpless. It could happen. It would affect 21% of the world's population (1.5 billion people) and have enormous related economic consequences. It incurs costs. In the United States (USA) alone, in 2010, there were wage losses and low It was estimated that $560 to $635 billion was spent on productivity and healthcare. With the increase in the elderly population, the demand for appropriate and effective pain management therapy is growing.

[0004] There are effective and safe analgesics for mild pain, but for moderate and severe chronic pain... The treatment is, in most cases, ineffective and causes limiting and harmful side effects. For most patients with chronic pain, the main problem is at least significant control The goal is for truly appropriate pharmaceutical treatments to exist without limited side effects. For example, moderate While opioid derivatives relieve pain in situations with severe pain levels, they can become habit-forming. Regular use can lead to serious adverse effects such as loss of energy or motivation. Its use has become a problem in some countries due to outbreaks, leading to increased regular use and a heavy burden on society. This was accompanied by, for example, in the United States, the number of deaths related to opioid use was higher than the number of deaths from illegal drugs. The number is far greater than the number. Antidepressants, antiepileptic drugs, and nonsteroidal anti-inflammatory drugs (NSAIDs) Other types of drugs, including AIDs, are used for treatment, but they are not efficient, or This can cause related side effects.

[0005] Others, such as more recent treatments for moderate to severe pain, are within the pharmacological context of this invention. It is closer to and contains ion channel modulators. Ion channels are involved in electrical signaling. Therefore, the major proteins present in the nerve cell membrane that form pain signals in nerves Neurons involved in pain perception (nociception) located in the peripheral nervous system include those in the spinal cord. Located in the lateral ganglia (or trigeminal ganglion - TG in the head) (dorsal root ganglion - DRG) These include those that have cell bodies. Such nociceptive fibers are involved in the brain's perception of pain. It is the primary peripheral nerve sensor involved in interconnected physiological pathways.

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

[0007] Nevertheless, they are partially controlled by the type of ion channel being regulated. It is effective only for, or still causes related side effects. Such drugs - Topic: Capsaicin, a member of the transient receptor potential cation channel subfamily V. -1 (TRPV1) channel agonist, - Intrathecal injection of diconotide (Prialt®), obtained from marine cone snails. It is an N-type voltage-dependent calcium channel blocker, and in this case, it acts centrally, not peripherally. do.

[0008] New products currently in clinical development (progressing at several biotechnology and pharmaceutical companies) (Although not yet approved for commercialization) Novel opioids with specific modifications (conventional) (By reducing its effectiveness), it captures ion channels known to be involved in pain, Other ion channels that are more suitable than RPV1 and N-type voltage-dependent calcium channels Regulators (e.g., other TRPs, voltage-dependent 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 the channel, and currently, It is currently undergoing non-clinical or clinical trials for pain treatment. a) The anticonvulsant retigabine (Phase II) is used in rats to treat persistent and neuropathic pain. It reduces nociceptive behavior in Dell. Retigabin is primarily K + Channel opener It functions as a specific voltage-dependent potassium (Kv7 / M) channel family in the brain. It works by activating -. b) Other channel modulators include BL-7050 (preclinical stage) and diclofenac (NSAID). Based on the molecular structure of D), it binds to and stabilizes potassium channels in the body, and their excess Controlling excitability (by keeping it open), K + Channel for leakage Keeping it open prevents the onset of pain. [Overview of the project] [Problems that the invention aims to solve]

[0010] However, despite considerable medical research, such ion channels remain There is a need for more clinically approved, superior, specific blockers / enhancers, and patients are severely affected. There are no alternatives to the medications that have side effects. [Means for solving the problem]

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

[0012] While we do not wish to be bound by theory, in some embodiments, the present invention relates to its chemical It differs from current existing solutions not only in its properties but also in its mechanism of action. "Turn off the switch" By doing so, or by using bioactive molecules to reduce the activity of nociceptive fibers. As a result, the brain's perception of pain is blocked or attenuated in a way that does not affect brain function. It is predicted that these molecules will be in front of the central nervous system, in the "pain signaling pathway". This is because it can act on the peripheral parts of the brain.

[0013] Any aspect or embodiment described herein can be combined with any other aspect or embodiment disclosed herein. The invention has been described in connection with its detailed description, which is intended to illustrate, and not limit, the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following

[0014] Embodiment 1. A compound of formula I, II, III, and IV, a pharmaceutically acceptable salt or prodrug thereof,

Chemical formula

Chemical formula

[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 R4 is alkyl R 5 The compound of formula IV according to Embodiment 1 is a heteroaryl compound where J is OH. thing.

[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 It is a heteroaryl compound. , the compound of formula II according to embodiment 1.

[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 7 And R 6 is alkyl, and R 7 It is a heteroaryl compound. , A compound of formula II according to Embodiment 1, wherein A is H.

[0019] Embodiment 6.R 7 However, it is not Fran-3-yl, but formulas I, II, II according to Embodiment 1 Compounds I and IV.

[0020] Embodiment 7. Compounds of Formulas I, II, III, and IV for use as pharmaceutical ingredients , a pharmaceutically acceptable salt or prodrug 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, and aryl. , or -CH2-R 3 Selected from, R 3 However, aryl, cycloalkyl, heteroaryl R, -R 4 -R 5 Selected from, R 4 However, selected from alkyl and alkenyl, R 5 but aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gammalactone They were selected, 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, or alkyl. , Alkenil, R 6 -R 7 Selected from, R 6 However, selected from alkyl and alkenyl, R 7However, alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetyl Selected from loaryl, substituted or unsubstituted gammalactones, J is selected from H, OH, SH, NH2, and halogens. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts or prodromal Bag.

[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 is alkyl R5 is a heteroaryl compound. Q is C, D is C, A, -R 6 -R 7 And R 6 is alkyl, and R 7 It is a heteroaryl compound. , 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 R 5 It is a heteroaryl compound, where J is OH, and is intended for use as a pharmaceutical ingredient. Compound of formula IV.

[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 It is a heteroaryl compound. , a compound of formula II for use as a pharmaceutical ingredient according to Embodiment 7.

[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 R 7 It is a heteroaryl compound. , 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 chemical formulations of Formulas I, II, III, and IV of this patent application The combined solution contains 0.1 μg / ml blood (6 μg / kg body weight) to 30 μg / ml blood (1.8 mg In doses ranging from ( / kg body weight), warm-blooded vertebrates, preferably mammals, more preferably humans. It is used in the following. The above effective dose range is for intravenous administration, and it is for other It may vary depending on the route of administration.

[0027] Embodiment 14. Compounds of Formulas I, II, III, and IV, their pharmaceutically acceptable salts or compounds Drugs are used to treat, prevent, or reduce pain, more specifically acute or It is used to treat, prevent, or reduce pain in individuals with chronic pain. Diffuse pain includes neuropathic pain, nociceptive pain, psychogenic or somatic pain, and diabetic pain. Transpathogenic pain, post-herpetic pain, low back pain, nerve root pain, musculoskeletal pain, postoperative and traumatic pain. Post-operative 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, fascia Pain, migraines, orofacial chronic pain, trigeminal neuralgia, cancer-related pain, fibromyalgia-related pain, hyper Sensitivity syndrome, infection-related pain, HIV-related pain, sprains and contusions, hyperalgesia, somatic pain, Psychogenic pain, heat-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvis Pain, bladder pain, myofascial pain, vascular pain, migraine wound, wound-related pain, joint pain, somatic visceral pain, hallucinations At least one of the following: limb pain, nerve root pain, lower back pain, visceral pain, bowel pain, and osteoarthritis-related pain It is intended to include one, but is not limited to these.

[0028] Embodiment 15. Compounds of Formulas I, II, III, and IV, their pharmaceutically acceptable salts or compounds The drug is used in the treatment of autoimmune disorders, specifically targeting Kv1.3, which is a target of these diseases. It is used due to the effects described.

[0029] Embodiment 16. Compounds of Formulas I, II, III, and IV, their pharmaceutically acceptable salts or compounds The drug is associated with insulin sensitivity, insulin resistance-related syndromes, and obesity. Considering their effects on the possible Kv1.3 channels, in the treatment of diabetes It will be used.

[0030] Embodiment 17. Compounds of Formulas I, II, III, and IV, their pharmaceutically acceptable salts or compounds The drug is used as an antiepileptic and antiseizure agent.

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

[0032] Embodiment 19. A combination of a pharmacologically acceptable diluent or carrier and an active ingredient. A pharmaceutical composition containing the active ingredient, wherein the active ingredient is a small amount of the active ingredient of formulas I, II, III, and IV Contains at least one compound, or a pharmacologically acceptable salt or prodrug thereof. Pharmaceutical composition.

[0033] Embodiment 20. A method for treating pain in a person requiring pain treatment, wherein A method comprising administering therapeutically effective doses 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, post-herpetic pain, low back pain, nerve root pain, musculoskeletal pain, postoperative pain and post-traumatic pain, phantom limb pain, surgical pain, wound-related pain, chemotherapy-induced peripheral neuropathy Pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, joint pain, osteoarthritis-related pain Pain, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, cancer-related pain, fibromyalgia-related pain Pain, hypersensitivity syndrome, infection-related pain, HIV-related pain, sprains and contusions, hyperalgesia, body Pathogenic 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, joint pain, somatic pain Select from visceral pain, phantom limb pain, nerve root pain, lower back pain, visceral pain, bowel pain, and osteoarthritis-related pain. A method according to Embodiment 19 for acute and chronic pain types.

[0035] Embodiment 22. Subjects requiring treatment or prevention of diseases involving Kv1.3 channels A method for treating or preventing a disease involving the Kv1.3 channel, wherein Kv1 For subjects requiring treatment or prevention of diseases involving channel 3, a therapeutically effective dose of formula I, A method comprising administering compounds II, III, and IV.

[0036] Embodiment 23. Treatment of autoimmune diseases in subjects requiring treatment for autoimmune diseases. A law that provides a therapeutically effective dose of formulas I, II, III, and I to subjects with autoimmune diseases. A method comprising administering compound V.

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

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

[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. Embodiment 20 - 23. 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, wherein X is O; 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 and R 5 is heteroaryl; Q is C; D is C; A is -R 6 -R 7 where R 6 is alkyl and R 7 is heteroaryl and E is H; J is H.

[0041] Embodiment 28. The compound is isolated or produced synthetically, as in Embodiments 1-6. Compounds produced by [unspecified source].

[0042] Embodiment 29. Embodiments 7-28, wherein the compound is nitenine or dihydronitenine. Compounds produced by [unspecified source].

[0043] For a more easily understood understanding of this application, figures illustrating exemplary embodiments are attached to the annex. However, these are not intended to limit the technologies 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 If ast (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 The terms are to have the meanings set forth below. Additional definitions are provided throughout this application. It can be done.

[0046] The compounds disclosed herein, or their pharmaceutically acceptable salts and prodrugs, ninetin, References to ninetin analogs are used interchangeably in this specification. This includes all stereoisomers of these compounds.

[0047] As used herein, the term "and / or" means other characteristics or components Regardless of whether they are elements or not, they are considered as specific disclosures of each of two particular characteristics or components. It should be understood that the phrases such as "A and / or B" in this specification The terms "and / or" as used are "A and B" and "A or B". It is intended to include "A" (alone) and "B" (alone). Similarly, "A, B, The term "and / or" as used in phrases such as "and / or C" refers to A, B, or and C, A, B, or C, A or C, A or B, B or C, A and The states of C, A and B, B and C, A (alone), B (alone), and C (alone) Each of the manners is intended to be included. The manners described herein in the language "includes" are included. Whenever this occurs, it will be described using the terms "consisting of" and / or "essentially becoming from". Please understand that other similar embodiments are also provided.

[0048] Unless otherwise defined, all technical and scientific terms used herein are defined as follows: The disclosure has the same meaning as is generally understood by those skilled in the art in the relevant field.

[0049] Units, prefixes, and symbols are shown in the format approved by the International System of Units (SI). Numerical values The range includes a numerical value that defines the range. The headings provided herein refer to various aspects of this disclosure. This may be done by referring to this specification as a whole, rather than by any specific limitations. Terms that will be defined immediately below are more fully referred to in this specification by their entirety. It is defined.

[0050] "Administering" means using any of the various methods and delivery systems known to those skilled in the art. This refers to the physical introduction of a drug into a target. Exemplary examples of compounds disclosed herein include... Other routes of administration include, for example, intravenous, intramuscular, subcutaneous, intraperitoneal, and spinal injection or infusion. Or other parenteral routes may be included. The term “parenteral administration” as used herein means This usually refers to, but is not limited to, methods of administration other than enteral and local administration by injection, including intravenous administration. Internal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, abdominal cavity Internal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal. This includes injection and infusion, as well as in vivo electroporation. In some embodiments, The compound is administered via a route other than parenteral administration, for example, orally. Other routes other than parenteral administration are also available. , local administration, epidermal or mucosal route, for example, intranasal cavity, vaginal, rectal, sublingual, or local This includes administration in, for example, one, multiple, and / or one or more extended periods. It can be implemented over a period of time.

[0051] The term "isolated" means that something is purified from nature and therefore in its natural environment. It does not contain any naturally occurring compounds that are present with nitenine, and it is not related to its natural state. This means that isolated naturally occurring products have different chemical properties than the same naturally occurring products. , may have biochemical and / or physical properties. Synthetic versions of naturally occurring products are , different chemical and biochemical from the same product isolated from nature or existing in nature. It may have targets and / or physical properties.

[0052] The phrase "pharmaceutically acceptable" in this specification means, within the bounds of sound medical judgment. Excessive toxicity, irritation, allergic reactions, or other issues commensurate with a reasonable benefit / risk ratio. These are suitable for use in contact with human and animal tissues without problems or complications. Used to refer to compounds, materials, compositions, and / or drug formulations. Officials (e.g., EMA, US-FDA) provide guidance on pharmaceutically acceptable compounds Approve of substances, materials, compositions, and / or drug formulations. Examples include, for example, those listed in the pharmacopoeia. It is being done.

[0053] The terms "pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" are, In the detailed description, solvents, dispersion media, diluents, dispersants, suspension aids, surfactants, isotonic agents, and thickeners are used. Agents or emulsifiers, preservatives, polymers, peptides, proteins, cells, hyaluronidase, It is used to refer to pharmaceutically acceptable materials selected from 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 may not be used alone or in any other way. When used in combination with other therapeutic agents, it may protect the subject from the onset of the disease, or This may involve a decrease in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic periods, or a decrease in the disease. Promoting disease regression demonstrated by the prevention of functional impairment or physical disability resulting from the disease. The amount of the drug is any amount. The ability of a therapeutic agent to promote disease regression is measured in human trials. In elephants, in animal model systems predicting effectiveness in humans, or in vitro Various methods known to those skilled in the art, such as assaying the activity of a drug in a assay. It can be evaluated using

[0055] In one embodiment, the "therapeutic effective dose" is the amount administered as a single dose or multiple doses. Any dose in joules that is effective in treating, preventing, and / or reducing pain. The dosage will be determined based on the health and physical condition of the individual being treated, their age, the desired degree of analgesia, and It varies depending on other related factors. The amount can be determined through a relatively broad range of standardized tests. It is expected to fall within the scope. In this specification, “prevention” or “prevention” means Absolute success in the sense of absolute pain prevention is not required, but if a painful condition develops, Alternatively, it indicates a reduction in the risk of developing pain of reduced severity. Similarly, "treatment" is absolute. It should not be interpreted as a cure, but rather as relief or suppression of pain or pain-related conditions. This may also be related.

[0056] The terms "alkyl," "alkyl unit," and "alkyl group" are used interchangeably in this specification. The term "saturated monovalent hydrocarbons containing 1 to 12 carbon atoms (C1 to C12)" refers to radicans. This refers to alkyl groups. Alkyl groups can be linear, branched, or cyclic. Alkyl groups are non-linear. It may be replaced or substituted as described elsewhere in this specification. In the application form, alkyl groups contain 1 to 8 carbon atoms (C1 to C8). In some embodiments, the alkyl group contains 1 to 6 carbon atoms (C1 to C6). In this embodiment, the alkyl group contains 1 to 4 carbon atoms (C1 to C4). In that embodiment, the cyclic alkyl group contains 3 to 6 carbon atoms (C3 to C6).

[0057] The terms "alkenyl," "alkenyl unit," and "alkenyl unit" as used interchangeably in this specification refer to the same terms used interchangeably. The term "nyl group" refers to a group with at least one unsaturated site (i.e., sp2 carbon-carbon double). This refers to a monovalent hydrocarbon radical containing 2 to 8 carbon atoms (C2 to C8) that have a bond. Alkenyl groups can be linear, branched, or cyclic. Alkenyl groups are unsubstituted. Some embodiments may be replaced as described elsewhere in this specification. In this context, the alkenyl group contains 2 to 6 carbon atoms (C2 to C6). Several implementations Morphologically, an alkenyl group contains 2 to 4 carbon atoms (C2 to C4). The group may have an E or Z orientation. Non-restrictive examples of alkenyl groups include ethenyl (vinyl) groups. It also contains 1-propenyl, iso-propenyl, and 2-chloroethenyl. It can be done.

[0058] The terms "aryl," "aryl unit," and "aryl group" are used interchangeably in this specification. The term "aromatic ring" refers to a ring induced by removing hydrogen atoms from an aromatic ring, with 6 to 20 atoms. It refers to a monovalent aromatic hydrocarbon radical containing carbon atoms (C6-C20). The aryl group is It may be unsubstituted, or one or more substituents as described elsewhere in this specification. It can be replaced with.

[0059] The terms "heterocyclic ring," "heterocycline," and "heterocyclic unit" are used interchangeably in this specification. The term "heterocyclic group" refers to a saturated or partially unsaturated ring containing 3 to 20 atoms. This refers to a system in which at least one of the ring atoms is selected from nitrogen, oxygen, phosphorus, and sulfur. It is a heteroatom. The heterocyclic group may be unsubstituted or otherwise described elsewhere in this specification. As such, it can be substituted with one or more substituents. In some embodiments, heterocycle The group contains 3 to 10 atoms. In some embodiments, the heterocyclic group contains 3 to 7 atoms. Contains atoms. In some embodiments, the heterocyclic group is monocyclic. In terms of form, the heterocyclic group is bicyclic. In some embodiments, the heterocyclic group is It contains a fused ring.

[0060] The terms "heteroaryl," "heteroaryl unit," and, as used interchangeably in this specification, The term "heteroaryl group" includes one or more 5-membered, 6-membered, or 7-membered rings, independently and containing one or more heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, monovalent Refers to aromatic radicals. Heteroaryl groups may be unsubstituted or otherwise specified in this specification. As described in [reference], it can be substituted with one or more substituents. In some embodiments The heteroaryl group contains 5 to 20 atoms. In some embodiments, hetero The aryl group contains 5 to 9 atoms. In some embodiments, a heteroaryl group It contains 5 atoms. In some embodiments, the heteroaryl group contains 6 atoms. It includes. In some embodiments, the heteroaryl group contains seven atoms. How many In that embodiment, the heteroaryl group is monocyclic. In some embodiments Furthermore, the heteroaryl group is bicyclic. In some embodiments, heteroaryl The group includes a fused ring.

[0061] As used herein, the term "substituted" means one or more hydrogen atoms, These are hydrocarbon radicals, alkyl groups, alkylene groups, alkenyl groups, alkenylene groups, and Among quinyl groups, alkynylene groups, aryl groups, heterocyclic groups, or heteroaryl groups This refers to replacing one or more substituents with one or more substituents. A substituted hydrocarbon radical, Alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene For aryl, heterocyclic, or heteroaryl groups, any number of hydrogen atoms This can be replaced by a substituent.

[0062] The compounds of this disclosure may contain one or more chiral centers. Therefore, the compounds of this disclosure They may exist in different stereoisomer forms. All stereoisomers of the compounds described herein Body forms include, as non-limiting examples, diastereomers, enantiomers, and mixtures thereof. (Including, in non-limiting examples, racemic mixtures) and which are intended to form part of this disclosure It is illustrated.

[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 KV : Voltage-dependent potassium channel K v 1.x: Voltage-dependent potassium channel subunit, given by x L: Lumbar spine 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-carboxymeth oxyphenyl)-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 thereof, and / or pharmaceutical compositions containing the 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 example, forms This includes intradermal and intravitreal administration.

[0065] In some embodiments, the pharmaceutical composition for oral administration is a tablet, pill, powder, or hard tablet. It can be in the form of firm gelatin capsules, soft gelatin capsules, and / or granules. In some embodiments of such pharmaceutical compositions, the compounds of the present disclosure and / or A pharmaceutically acceptable salt of the compound of this disclosure is mixed with one or more inert diluents, and its non Limited examples include starch, cellulose, sucrose, lactose, and silica. In some embodiments, such pharmaceutical compositions include one or more substances other than diluents. For example (as a non-limiting example), lubricants, colorants, coatings, or varnishes It may include.

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

[0067] In one embodiment, the present disclosure relates to nitenine analog compounds and the treatment of chronic and acute pain. Regarding their use as analgesics for treatment, prevention, or reduction. Ion current / charging Through an approach using Nell's physiology and pharmacology, several types of pain can be treated. Novel pharmaceutical applications relating to analgesic effects are disclosed herein.

[0068] In stark contrast to existing therapeutic agents, the analgesic compounds disclosed herein are novel in their formulation. Mechanism of use, as well as expected efficacy, target specificity, and reduced side effects in humans. Therefore, it will be positioned as a groundbreaking development in pain management. Dihydronytenine compounds (two of the compounds disclosed herein) are marine sponges Although it originates from animals, it is synthetically prepared in this disclosure, and is synthetically prepared This disclosure shows that these compounds can affect pain perception in the dorsal root ganglia and trigeminal ganglia. Specific K expressed in fibers V Channel K v It provides a mechanism that acts specifically on 1.x. Without being constrained by theory, the mechanism of action is (not enhancement like retigabine) a specific channel (a) It is an "open channel blocker", and therefore, activity-dependent blockade. (b) includes voltage-dependent changes in channel deactivation, and (c) in particular a series of K V Cha Nell has advantageous properties, such as those that are particularly effective in Kv1.3. The novel mechanism of action explains why and how nitene and nitene analogs cause injury / shadow It explains whether it is effective only in the limbs / body parts that have nerves that are affected. Furthermore, it explains whether it is effective only in the limbs / body parts that have nerves that are affected. , altering nociceptivity and perceptual scores in unaffected limbs / body parts. I won't let them.

[0069] In one embodiment, the present disclosure relates to the treatment, prevention, or reduction of chronic and acute pain. This relates to the use of nitene analog compounds as analgesics. Accordingly, some of the disclosures In this embodiment, the compound referred to as a "nytenine analog compound" is as follows: It is represented by the compounds of formulas I, II, III, and IV described in

[0070] Embodiment 1. A compound of formula I, II, III, or IV, a pharmaceutically acceptable salt or prodrug thereof,

Chemical formula

Chemical formula

[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 R 5 The compound of formula IV according to Embodiment 1 is a heteroaryl compound where J is OH. thing.

[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 It is a heteroaryl compound. , the compound of formula II according to embodiment 1.

[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 compound. , A compound of formula II according to Embodiment 1, wherein A is H.

[0075] Embodiment 6.R 7 However, it is not Fran-3-yl, but formulas I, II, II according to Embodiment 1 Compounds I and IV.

[0076] Embodiment 7. Compounds of Formulas I, II, III, and IV for use as pharmaceutical ingredients , a pharmaceutically acceptable salt or prodrug 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, and aryl. , or -CH2-R 3 Selected from, R 3 However, aryl, cycloalkyl, heteroaryl R, -R 4 -R 5 Selected from, R 4 However, selected from alkyl and alkenyl, R 5 but aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gammalactone They were selected, 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, or alkyl. , Alkenil, R 6 -R 7 Selected from, R 6 However, selected from alkyl and alkenyl, R 7 However, alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetyl Selected from loaryl, substituted or unsubstituted gammalactones, J is selected from H, OH, SH, NH2, and halogens. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts or prodromal Bag.

[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 is alkyl R5 is a heteroaryl compound. Q is C, D is C, A, -R 6 -R 7 And R 6 is alkyl, and R 7 It is a heteroaryl compound. , 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 R4 However, it is alkyl R 5 However, it is a heteroaryl compound, and J is an OH group, 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 It is a heteroaryl compound. , a compound of formula II for use as a pharmaceutical ingredient according to Embodiment 7.

[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 compound. , 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 chemical formulations of Formulas I, II, III, and IV of this patent application The combined solution contains 0.1 μg / ml blood (6 μg / kg body weight) to 30 μg / ml blood (1.8 mg In doses ranging from ( / kg body weight), warm-blooded vertebrates, preferably mammals, more preferably humans. It is used in the following. The above effective dose range is for intravenous administration, and it is for other The route of administration may differ.

[0083] Embodiment 14. Compounds of Formulas I, II, III, and IV, their pharmaceutically acceptable salts or compounds Drugs are used to treat, prevent, or reduce pain, more specifically acute or It is used to treat, prevent, or reduce pain in individuals with chronic pain. Diffuse pain includes neuropathic pain, nociceptive pain, psychogenic or somatic pain, and diabetic pain. Transpathogenic pain, post-herpetic pain, low back pain, nerve root pain, musculoskeletal pain, postoperative and traumatic pain. Post-operative 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, fascia Pain, migraines, orofacial chronic pain, trigeminal neuralgia, cancer-related pain, fibromyalgia-related pain, hyper Sensitivity syndrome, infection-related pain, HIV-related pain, sprains and contusions, hyperalgesia, somatic pain, Psychogenic pain, heat-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvis Pain, bladder pain, myofascial pain, vascular pain, migraine wound, wound-related pain, joint pain, somatic visceral pain, hallucinations At least one of the following: limb pain, nerve root pain, lower back pain, visceral pain, bowel pain, and osteoarthritis-related pain It is intended to include one, but is not limited to these.

[0084] Embodiment 15. Compounds of Formulas I, II, III, and IV, their pharmaceutically acceptable salts or compounds The drug is used in the treatment of autoimmune disorders, and is a target of the disease as described in Kv1.3. It is used due to the effects it has.

[0085] Embodiment 16. Compounds of Formulas I, II, III, and IV, their pharmaceutically acceptable salts or compounds The drug is associated with insulin sensitivity, insulin resistance-related syndromes, and obesity. Considering their effects on possible Kv1.3 channels, in the treatment of diabetes It will be used.

[0086] Embodiment 17. Compounds of Formulas I, II, III, and IV, their pharmaceutically acceptable salts or compounds The drug is used as an antiepileptic and antiseizure agent.

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

[0088] Embodiment 19. A combination of a pharmacologically acceptable diluent or carrier and an active ingredient. A pharmaceutical composition containing the active ingredient, wherein the active ingredient is a small amount of the active ingredient of formulas I, II, III, and IV Contains at least one compound, or a pharmacologically acceptable salt or prodrug thereof. Pharmaceutical composition.

[0089] Embodiment 20. A method for treating pain in a person requiring pain treatment, To administer therapeutically effective doses of compounds I, II, III, and IV to subjects experiencing pain. A method that includes [this].

[0090] Embodiment 21. Pain is neuropathic pain, nociceptive pain, psychogenic or somatic pain, Diabetic neuropathic pain, post-herpetic pain, low back pain, nerve root pain, musculoskeletal pain, postoperative pain and post-traumatic pain, phantom limb pain, surgical pain, wound-related pain, chemotherapy-induced peripheral neuropathy Pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, joint pain, osteoarthritis-related pain Pain, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, cancer-related pain, fibromyalgia-related pain Pain, hypersensitivity syndrome, infection-related pain, HIV-related pain, sprains and contusions, hyperalgesia, body Pathogenic 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, joint pain, somatic pain Select from visceral pain, phantom limb pain, nerve root pain, lower back pain, visceral pain, bowel pain, and osteoarthritis-related pain. A method according to Embodiment 19 for acute and chronic pain.

[0091] Embodiment 22. Subjects requiring treatment or prevention of diseases involving Kv1.3 channels A method for treating or preventing a disease involving the Kv1.3 channel, wherein Kv1 For subjects requiring treatment or prevention of diseases involving channel 3, a therapeutically effective dose of formula I, A method comprising administering compounds II, III, and IV.

[0092] Embodiment 23. Treatment of autoimmune diseases in subjects requiring treatment for autoimmune diseases. A law that provides a therapeutically effective dose of formulas I, II, III, and I to subjects with autoimmune diseases. A method comprising administering compound V.

[0093] Embodiment 24. In subjects requiring treatment for diabetes or insulin resistance syndrome A method for treating diabetes or insulin resistance syndrome, which is a method for treating diabetes or insulin resistance syndrome. A method comprising administering a therapeutically effective amount of a compound to a subject having an anti-inflammatory syndrome.

[0094] Embodiment 25. Epilepsy or seizures in subjects requiring treatment for epilepsy or seizures A method of treating the condition, comprising administering a therapeutically effective amount of a compound to a subject with epilepsy or seizures. A method that includes giving in to something.

[0095] Embodiment 26. The compound is administered in a therapeutically effective dose of 0.018 to 1.8 mg / kg. Method according to embodiments 20 to 23.

[0096] Embodiment 27. Compounds, compositions, uses, or methods disclosed herein, which are chemical The compound is the compound of formula I, in which, X is O, Y is CH, Z is C, R 1 It is an alkyl, R 2 is -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. The compound is isolated or produced synthetically, as in Embodiments 1-6. Compounds produced by [the company / organization].

[0098] Embodiment 29. Embodiments 7-28, wherein the compound is nitenine or dihydronitenine. Compounds produced by [the company / organization].

[0099] This disclosure relates to the treatment and prevention of chronic and acute pain. We disclose strong evidence that it can be used as an analgesic for reducing or reducing this evidence. This involves ex vivo neuronal preparation, animal models of pain, behavioral re-reading of pain, and computation. Several approaches, including in vitro toxicity testing and whole-cell voltage clamp recordings. It was obtained from that technical approach.

[0100] The nitenine analog compound of this application is from marine sponges captured in Sagres, Portugal. It was first obtained from Spongia agaracina, but it has also been chemically synthesized. As shown in the examples, the nitenin-containing extract was used in rat sdDRGN (pain sensation). This shows the regulatory effect on potassium current recorded from intelligent neurons, which is a bio-induced image. It was the biological activity that underlies the differentiation process. The series of fractions obtained were K + Adjust the current This not only allowed for the identification of compounds that maintain their capabilities but also exhibit high levels of efficacy. Also, very similar K + The small diameter three showed the same pharmacological effect in the current profile. This was also observed in sdTGN neurons.

[0101] Influenced by the identified compounds, sdDRGN (and more) is detected by whole-cell voltage clamping technology. K recorded from (sdTGN) + The electric current, in the field of pain neurophysiology, according to the applicant The purpose of this intensive research was to conduct previous target validations using a rat pain model. In other words, K is expressed differently depending on the pain state. + It was important for determining the current components. In one aspect of this disclosure, K affected by pain state+ The current component is the compound of interest. It is suggested that it is mainly regulated (reduced) by the current. The properties of the modulating effect include several aspects such as the voltage dependence of activation and deactivation, as well as dynamics. The biophysical parameters were tested by monitoring them. The specificity of the biological activity was determined by s The pharmacological effects on currents recorded from dDRGN are compared to other types of dorsal root ganglia (medium diameter D This was done by comparing it with that of GR and large-diameter DGR.

[0102] Furthermore, drug sensitivity to different voltage-activated channels was investigated using different human KV channel services. In the Kv1.1, Kv1.2, Kv1.3, Kv1.4, and Kv1.6 units Recorded from stably transfected Chinese hamster ovary (CHO) cells. The drug's effect on the applied electric current was evaluated by testing. The compounds were mostly hK v1.3(IC 50 It is active at approximately 190 nM, which is more active than other Kv1.x compounds tested. Their sensitivity is 6 to 30 times higher.

[0103] Nitenine and nitenine analog compounds used in pain therapy may be affected by other compounds (iontophoresis). One of the competitive advantages that surpasses (including those that act on channels) is, in part, its characteristics. It is found in at least eight of these, and they are interrelated, but can be explained as follows: Cut. 1-nytenine and nytenine analog compounds can be synthesized using a chemical synthesis approach. It is a small molecule. 2. Their novel mechanisms of action, as well as the location and properties of their intracellular targets, Nin is expressed in snDRG (a subset of Kv1.x with high affinity for Kv1.3). K V It reduces channel activity, is involved in slow delayed rectification current, and is a pain signal to the brain. It regulates transmission and propagation. Along with this peripheral effect of nitenine and nitenine analogs, Complementary central effects are not excluded. Currently, such Kv1 has clinical potential. Regarding specific blockers for some .x channels (e.g., Kv1.3 and Kv1.6): Therefore, important requirements are not being met. Administering 3-nytenine or nytenine analog compounds improves sensory and nociceptive abilities. Furthermore, no loss of nociception occurs in the undamaged limbs / body parts, and its mechanism of action is, For example, this is a characteristic related to the fact that it is an open channel-dependent effect. 4. The nitene and nitene analog compounds of this disclosure are readily administered. In animal models used to test the analogues, intravenous (IV) and intraperitoneal injections are administered. Injection has been successfully used for its analgesic effect. Importantly, nitenine analog compounds It can be administered orally, and therefore, in a preferred embodiment, intragastric administration is also possible in animal models. It can be concluded that this is performed with a similar analgesic effect. 5. Based on the toxicological experiments conducted, in the systems tested and described below: There are no signs of toxicity or side effects. Nitenine primarily acts on the peripheral nervous system (but (and non-exclusive) results were obtained, and no brain-derived toxicity / side effects have been shown. stomach. 6-nytenine and its analogues are effective in reducing pain in many pain models. This includes acute and neuropathic chronic pain, chemotherapy-induced peripheral neuropathy, and acute and long-term Or chronic inflammatory pain (nociceptive pain), chronic orofacial pain, and diabetic neuropathy. This includes harmful chronic pain. These results suggest potential for a wide range of clinical applications. 7. While effective for acute / short-term pain, nitenine is particularly effective for long-term / chronic pain. ru. It specifically acts on a subset of 8-potassium channels (Kv1.x) and sodium current / channel(Na) v By having no effect on ), the nitenine analog compound, Na v It does not compete with modifiers, but rather can be applied in combination with them, and its expected analgesic effect It can either maximize the effect or have a synergistic effect.

[0104] In one embodiment, the compounds of the present disclosure, or their pharmaceutically acceptable salts and prod Rag can be used to treat acute pain. It typically lasts between 3 and 6 months. Examples of acute pain conditions, which are a type of pain, include those resulting from surgery, fractures, dental work, burns, and cuts. This includes pain directly related to soft tissue injuries such as ankle sprains, as well as childbirth and delivery.

[0105] In one embodiment, the compounds of the present disclosure, or their pharmaceutically acceptable salts and prod LUG can be used to treat chronic pain. Examples of diseases or disorders associated with chronic pain include: For example, peripheral neuropathy, chronic pain, arthritis, especially osteoarthritis, cancer, HIV, diabetes, and fibromyalgia. Shingles, herpes, headache, migraine, multiple sclerosis, nerve damage (neuropathy), lower back pain, Wounds and other injuries (e.g., herniated discs, torn ligaments), sciatica, diabetic Nerve disorders, carpal tunnel syndrome, trigeminal neuralgia, post-surgery conditions, chronic fatigue syndrome (or myalgic encephalomyelitis) ), endometriosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, interstitial bladder Cervitis, temporomandibular joint dysfunction (TMJ), vulvovaginal pain, bursitis, celiac disease, lupus, Rheumatoid arthritis, complex regional pain syndrome, myofascial pain syndrome, meningitis, Lyme disease and other diseases Examples include diabetic diseases, muscle contusions, and sprains.

[0106] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, Prodrugs are used for hyperalgesia, somatic pain, psychogenic pain, heat-induced pain, physical pain, and invasive pain. Nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial pain, vascular pain, unilateral pain Painful wounds, arthritis-related wounds, somatic visceral pain, phantom pain, curative pain, lower back pain, or osteoarthritis-related conditions. It can be used to treat pain.

[0107] Both acute and chronic pain involve the processing of electrical signals from the peripheral nerves to the central nervous system (CNS). This involves complex changes in principle and conduction. It includes normal electrical excitability and activity levels, as well as Those related to chronic pain include sodium (Na + ), potassium (K + ), or Ka Calcium (Ca 2+ ) and other charged metal ions, membrane ion channels (Nav, respectively) This is the result of inflow or outflow through Kv (or Cav), throughout the cell, from the cell. It causes the generation, propagation, and transmission of electrical signals to cells. In chronic pain, pain signals The underlying neuronal network for transmission changes, and the underlying channels undergo altered expression. And accompanied by abnormal ionic currents caused by biophysics, excessive and persistent nucleation This leads to steroid excitability and activity. Therefore, effective analgesics stimulate pain signals. Suppresses the excessive excitability of the signaling network, and promotes the physiological expression of functional channels and / or Restore the biophysical profile, and then restore network activity to a dormant level. It requires the ability to do so.

[0108] Small-diameter DRG neurons (c fibers), also known as pain-sensing neurons, cause damage to the CNS. It is located lateral to the spinal cord, which has receptive input (i.e., leads to "pain"). Usually, correct Under normal conditions, these neurons do not possess spontaneous firing activity—they are silent. (For example, Ly et al., 2018) the situation changes during a painful episode, and is actually chronic. It is accompanied by sexual pain. The therapeutic strategy that forms the basis of this invention is such neurons in DRG neurons Targeting the major ion channels located in the Ron and trigeminal ganglia (TG) This "pain-inducing" hyperexcitability is "switched off." As a result, the CNS The transmission of "pain signals" is interrupted or reduced, thereby preventing the brain from recognizing pain. However, complementaryly, it has an effect on central neurons and contributes to the analgesic effect. There is a possibility that this will happen.

[0109] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, By using prodrugs, pain-induced hyperexcitability can be terminated. In some embodiments, By using these, the brain's perception of pain can be modified.

[0110] Several ion channels have been identified as major effectors in pain transmission. They exist. Some are particularly present in these pain-sensing neurons. Therefore, their Specifically regulating activity blocks pain without affecting other bodily functions. It is likely. Nitenine analogs are small in diameter (sdDRGN, which is thought to correspond to c fibers, and further Slow voltage activation K recorded from sdTGN) + It is primarily a substance that specifically regulates electric current. This will be disclosed in the details. The source of this slow current is a specific Kv1.x channel. This effect is observed in large-diameter neurons at concentrations below micromolar, i.e., 1 micromolar. At concentrations below chromol, the regulatory effect of nitenine is even lower, and it is found in sdDRGN and sdTG. It is mutually exclusive with respect to N.

[0111] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, Using prodrugs, slow voltage activation K + The current can be adjusted. Several embodiments In this case, the current originates from small-diameter (sdDRGN, and further sdTGN) neurons.

[0112] Kv1.x primarily affects pain-sensing neurons, including those that mediate slow voltage activation currents. One example that exists is an ion channel involved in pain signal propagation. It is similar to nitenine. The compound is slowly K + It is particularly effective for the current component, and for the dynamics and voltage of nitenin-sensitive currents. Considering the dependencies, the subcurrent components strongly indicate the involvement of a subset of the Kv1.x channels. It is inviting. In fact, it is stably transfected, hKv1.1, hKv1.2, hKv Currents recorded from CHO cells expressing 1.3, hKv1.4, or hKv1.6 The voltage clamp test in the case of the nitene analog compound is in the Kv1.3 channel This demonstrated its effectiveness (compared to the second most sensitive channel (Kv1.2)). In this case, sensitivity to nitenine is approximately 6 times higher, and compared to the least sensitive substance, sensitivity is approximately 30 times higher. Sex) (Kv1.4) (See Figure 2).

[0113] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, By using prodrugs, central neurons, i.e., the neurons under seizure episodes It can stop hyperexcitability in the Kv1.x channel, leading to the cessation of recurrent neuronal firing. The above effects on are the basis for the antiepileptic effect. Therefore, nitenine and Nitenine analogs can be used as antiepileptic and anticonvulsant agents.

[0114] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, The prodrug can be used as a Kv1.3 inhibitor. Kv1.3 is immunologically involved Targets for the treatment of related conditions, as well as targets for the treatment of diabetes and other metabolic disorders. It has been reported that the compounds of this disclosure may be used in the treatment of diabetes and other metabolic disorders. .

[0115] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, Biprodrugs can be used to treat autoimmune diseases. In other embodiments These can be used to increase insulin sensitivity.

[0116] Regarding these therapeutic treatments, the method of administration (or multiple methods of administration are possible), the dosage (or Multiple dosages and optimized pharmaceutical forms (or multiple forms) are used to treat patients. It can be determined according to the criteria generally considered when establishing, and as a non-limiting example, The potency of the compound and / or the pharmaceutically acceptable salt of the compound, the patient's age, the patient's weight, The severity of the patient's condition, the patient's tolerance to treatment, and secondary effects observed during treatment. Examples include therapeutic effects. It provides therapeutic benefits in a specific manner and frequency of administration. Determining the effective dosage is within the scope of the skills of those skilled in the art. [Examples]

[0117] In vivo and ex vivo pain models The LA5 was used in both in vivo behavioral studies and electrophysiological ex vivo trials. The pain model, ●Naive Wister: Control rat. Dorsal root ganglion (DRG), lumbar vertebrae 4, 5, Neurons from L4, L5, and L6. ● Acute and chronic neuropathic pain rat model: CCI rat (Wister rat stool) Long-term stenosis of the bone nerve) 3 days post-surgery (acute cases) and 23-29 days post-surgery (chronic cases). DRG Neurons from (L4, L5, and L6). ● Acute and long-lasting or chronic inflammatory pain rat model: CFA rat (Wista) - Three days after knee injection of complete Freund's adjuvant (CFA) in rats (acute) 18 days (subchronic), and 23 days (chronic). From DRG (L3, L4 e L5) Yuron. ● Chronic Orofacial Pain (COP) Rat Model: CFA in the villous cilia pads of Wistar rats COP rats were injected with [substance name] and analyzed 28-30 days after injection. Neurons from the trigeminal ganglion. ● Diabetic neuropathic pain rat model: STZ rats, Wistar rats with STZ ( Intraperitoneal injection of streptozotocin was added, and signs of pain developed 30 days later, and further 3 At the end of day 0, tested with Nitenine (IV) (total 60 days). New from DRG -ron (L4, L5 e L6). ● Chemotherapy-induced peripheral neuropathy chronic pain rat model: CIPN rat, paclitaxel Wistar rats were given the drug three times (intraperitoneal injection) every two days, and tested 42 days after induction. Neurons from the DRG (L4, L5, e, L6).

[0118] Regarding electrophysiological recordings of ex vivo materials, voltage clamp recordings were used in rat DRG (o The procedure was performed on neurons isolated from TG. The recording was made during the cell isolation process (enzymatic and One hour after the completion of (including mechanical processing), the nerve cell body often contains the proximal fraction of the axon. It was implemented from there.

[0119] Mechanism of action Nitenine (represented herein as a compound of formula V) and nitenine analogues Compounds (exemplified herein as compounds of formulas I-IV and VI-VIII) The mechanism of action of this analgesic is disclosed herein for the first time. + Current This involves a decrease in those values, not an increase. For this reason, sdDRGN and sdTGN It is important to first characterize the potassium current present in [the sample].

[0120] Voltage-activated whole cell K recorded from sdDRGN during the depolarization step + Current ( For example, as shown in Figure 1, up to +40mV lasting for 1 second, rapid activation followed by two It showed an inactivation phase. Therefore, the current decay at the depolarized potential is two It fits better to the sum of exponential functions, i.e., the time elapsed over several tens of milliseconds (τ fas t ) a relatively rapid component (here I fast Although it is known as a -A current, (related to this), followed by a time interval of several hundred milliseconds (τ slow ) shows a much slower inactivation. Transformation current (here I slow It is called (see Figure 1). fast and I slow Different ratios were observed between cells, and some cells even had one component I sl ow Only this is shown. The current observed in SdDRGn is reported for sdTGn. It is very similar to electric current.

[0121] Nitenine is derived from K from sdDRGN and sdTGN. + The current was inhibited in a dose-dependent manner. At a maximum concentration of 1 μM (approximately 0.3 μg / ml), it is I slow It specifically reduces ( (See Figure 1.b), its current component is found in chronic pain rat models (CCI, CFA, and oral sdDRGn neurons (and sdTG) obtained from "damaged nerves" from the cavofacial region. n) is overexpressed (I slow (In relation to) A typical example shown in Figure 1.b In one example, the peak current hardly changes with nitenine treatment, but the slower component does not. You can notice that it decreases significantly. Nitenine-sensitive current component (trace reduction in the figure below) The calculation shows current decay that is better fitted by a single exponential of approximately 150 ms, moderate At this concentration, the nitene effect is I slow This further suggests that it is specific to [the subject]. In contrast, , I fast It is hardly affected by nitenine at a maximum concentration of 1 μg / ml, and 3 μ Concentrations exceeding M / ml fast It was necessary to reduce it. Importantly, s lowHow many neurons obtained from "control" animals showed a decrease in nytenin? Compared to the reduction induced by that concentration of nitenin, the results obtained from animals with chronic pain showed a significant decrease. It was huge.

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

[0123] I slow and I fast The differential dose-response in this case is shown in Figure 2.a. It is better distinguished by the curve. slow The concentration / blockage relationship in this case shows a biphase relationship. From the initial concentration up to 1 μM (approximately 0.3 μg / ml), the relationship is approximately 0.12 μM IC 50 has It can be fitted to a single Hill function. At higher concentrations, I slow and The relationship is, slow The effect on I fast The second effect added to the effect against It follows the rules. In fact, this second phase is I fast This matches the concentration / blockage relationship in [location]. Similarly, it fits well to a single Hill function. Its IC is approximately 6 μM. 50 by This confirms a considerably low sensitivity to nytenine.

[0124] Nitenin's (I fast Rather than) I slow High sensitivity to and nytenin Depending on the properties of the sensitivity current (see the nytenine sensitivity current in Figure 1.b), which K + channel I slow It was emphasized or encouraged to understand which Kv channel subunit is D By considering whether it is expressed in RG and the biophysical properties of the nytenine-sensitive current, So, nitenine is used in hKv1.1, hKv1.2, hKv1.3, hKv1.4, and The whole-cell current recorded from CHO cells expressing hKv1.6 was examined. From the list, only Kv1.4 is "Type A" I fast It forms the basis, and the rest is I slow Regarding The results were obtained and are shown in Figure 2.B, which illustrates the dose-response relationship based on relative sensitivity to nitenine. In summary, current inhibition was measured at the end of a 1000ms pulse. Kv1.3 was 190nM IC 50 It shows higher sensitivity and the actual value is from sdDRGN I slow in Dose-response (IC50 I slow This was shown in the same range as approximately 120 nM. In contrast, hK v1.1, hKv1.2, and hKv1.6 are approximately 6 times (or less) less susceptible. This indicates that hKv1.4 has approximately 30 times lower susceptibility, clearly representing the lowest level of susceptibility.

[0125] Slow K + The inhibition of nytenine by electric current involves a pharmacological process of "open channel blockade." Furthermore, the change in the steady-state voltage dependence of deactivation (and the change in the voltage dependence of activation) The transformation is accompanied by little or no change. In fact, nitenine has voltage dependence of inactivation. The IV curve associated with this is shifted to a more hyperpolarized potential (see Figure 3).

[0126] The compound is K + Recorded from sdDRGN by promoting channel inactivation It inhibits slow voltage activation current, and its inactivation is somewhat impaired in chronic pain states. For compounds, the voltage sensitivity of steady-state inactivation is lower (or higher) the depolarization value. It shifts to hyperpolarity and promotes inactivation. Compound-induced properties in such inactivation. The shift is when the voltage curve profile is in its *first position* (nitenine or nitenine-like). The more depolarized it becomes compared to before processing by the body, the larger it becomes. Depolarized inactivation The curve is typical of sdDRGN obtained from a chronic pain state. In other words, the injury In neurons obtained from chronically affected nerves, nytenin showed a voltage-dependent profile of inactivation. The il is returned to the "control" pattern. Therefore, the deactivation in voltage sensitivity Compound-induced shifts are caused by neurons derived from damaged nerves (which exhibit abnormally depolarized profiles). Unaffected neurons show higher, hyperpolarized voltage profiles (as shown). Lower. This interesting effect in channel dependence is due to the affected neurons Therefore, in other words, during pain, neuronal excitatory compounds that are specific / more pronounced are induced This partially explains the decline.

[0127] C fibers are usually silent, with little to no spontaneous firing activity. In other words, under control conditions, the basal activity is little or no. We will begin by analyzing the effects of nytenin on silent neurons. Considering the nature of the mechanism of action of tenin, K in such "silent neurons" + electric The effect of nitenine on flow is expected to be little or no, because open Because it is a channel blocker, its effect is activity-dependent (and also inactivates The nitenin shift in the curve will be minimal. Nevertheless, it will be affected. In this example of a neuron that is not K + There is a moderate decrease in current, but this effect is repetitive. The threshold potential required to induce sexual firing will likely not be reached (due to insufficient induced depolarization). This explains why nytenin does not alter "pain sensation" in areas of the body that are not affected. Let's explain it step by step. On the other hand, in the development of chronic pain, the hyperexcitatory state in damaged neurons It is present and involves repetitive and sustained firing. In these hyperexcitable neurons, the nytenin effect is most It is large (as explained above). Resting potential (K + The decrease in the nytenine-induced properties of electric current induces Further increases in (emissions) are also due to the indirect promotion of sodium channel inactivation. It requires a fire failure to occur. Therefore, the signal is interrupted, but the "damaged" fibers are not affected. It is only in [location / platform].

[0128] Finally, regarding specificity, the slow current obtained from large-diameter DRG neurons is nytenine. It is important to note that their sensitivity to it is approximately 10 times lower.

[0129] How the nytenine effect in kv currents produces analgesic effects is a novel mechanism of action. It is constructed, and the conventional way of dealing with this problem is not inhibition but K V The increase in current is excessive The aim is to reduce the excitability of excitatory C fibers. In this case, chronic Pain status (sdDRGn obtained from CCI, CFA, and STZ, and COPL In the sdTGn obtained from the net model, a potassium current (I) slowly deactivates the potassium current. s low ) is a current (I) that deactivates quickly. fastCompared to ), it is expressed more functionally. It must be emphasized that, I slow This is abnormal depolarization Note that this indicates an inactivation profile, i.e., a channel with less inactivation. This is important. To maintain repetitive firing over a long period of time, Na + Due to the increase in the sensitivity of the electric current A typical situation in chronic pain is an increase in "excitability" resulting from recurrent long-term firing. K corresponding to the pattern + This must be maintained by an increase in the cancellation in the current. The effects of the compounds disclosed in the specification are such that they control the pattern of the control profile This reduces the Kv-mediated current, which slowly deactivates the current. + This current The nitenin-induced effect is the typical increase in sodium conductance (Nav) in pain situations. The necessary adjustments would not be possible. As a result, the intensified sodium current will be In the presence of (and also due to depolarization induced by the decrease in kv current), it becomes inactive, shadow It turns off spike firing in affected nerves, but normal, undamaged nerves Do not turn it off. This is during pain, i.e., chronic pain, with Kv enhancers or openers. This means that not only that, but Kv blockers should also be considered as potential analgesics. ru.

[0130] K + How a decrease in electrical current leads to a significant decrease in neuronal excitability is different. To explain by law, or most likely by a combination of phenomena. It is possible.

[0131] Firstly, as mentioned above, K +Drug-induced decrease in current is maintained at the depolarization level. This method can lead to slow depolarization of affected neurons, and therefore, the normal threshold The value potential can pass even if no action potential is fired. Therefore, depolarization occurs in Na + blood The channel's inactivation gate is closed and remains closed, preventing the increase of action potentials. (Na + Processes like containment may also occur if the channel is not sufficiently "activatable". It will spill.

[0132] Secondly, (1) Nitenine is particularly effective in Kv1.3 (see Figure 2.b), (2 )Kv1.3 is expressed in DRG (Yang et al., 2004), and DRG with chronic pain It increases the expression level in neurons (unpublished data), so in Kv1.3 A more direct role of specific blockage can be considered. The biophysical role of Kv1.3-mediated current The properties and dynamics correspond to the neuronal state in a "chronic pain situation," It is thought to maintain a standardized, persistent firing pattern (Kupper et al., 2002). 1.3 Reducing mediated currents is observed in rat hippocampal neurons, and activity This would lead to a decrease in potential amplitude and a state of stationary depolarization without ignition (Kupp er et al., 2002).

[0133] Efficacy results: For efficacy testing, nociception was determined in all animals from all pain models. By periodically monitoring behavior, mechanical processes using von Frey filaments can be achieved. By quantifying sensitivity to stimuli, the resulting pain perception in hypersensitivity can be determined. It was evaluated by reflecting hypersensitivity. In the neuropathic pain model CCI, acetone was used. We also used the cold-induced allergic pain test, which showed a response very similar to that of von Frey filaments.

[0134] Efficacy after intravenous administration. The following results are for purified nitenine (>98% - compound of formula V). This concerns intravenous (IV) injection of blood at a concentration of 1 μg / mL, approximately 0.06 mg / kg. ● Naive Wister Control: After IV injection of Nitenine, sensitive skin is applied to both feet. There were absolutely no changes to the core. ●In CCI rats, acute (3 days after model induction) and chronic (22 In both situations (days or 31 days later), sensitivity to mechanical stimuli was significantly reduced. Typical A typical experiment is shown in Figure 4. The hypersensitive nytenin-induced decrease was observed in both cases (acute and chronic). It was robust, but clearly higher in cases of chronic pain, and in some individuals, nitenin scored The value was returned to the control value. The pain relief period lasted for 2-4 hours. Importantly, the test There was no change in the behavioral score of the contralateral (uninjured) leg in any of the animals. ●In CFA rats, the incubation periods were 3 days (acute), 18 days (subchronic, intravenous), and 23 days (chronic). In all situations, after Nitenin IV injection, the sensitivity to mechanical irritation is exacerbated. There was a significant decline. To reiterate, the nitene effect was already part of the score after 23 days. Even if recovery occurred, it was more pronounced in chronic situations. The duration of pain relief was higher in CCI (Chronic Infection Controlled) It lasted for 2.5 to 4.5 hours, like a bout of blood, and was limited to the injured foot. ●In COP rats, nitenin IV administration was consistently given 23 days after CFA injection. This resulted in a significant decrease in mechanical sensitivity, as assessed in the sinus cilia pad area (chronic). The experiment is shown in Figure 5. The duration of pain relief lasted for 3-4 hours, and the damaged sinus cilia pad (damage) (Only the surface that was treated) was limited. ●Regarding STZ rats, the animals had diabetic glucose levels in their blood within one week of STZ injection. It reaches a certain level and, at the end of day 30, exhibits hypersensitivity to mechanical stimuli. Therefore, Nin allows for a period of time to establish chronic diabetic neuropathy after treatment with STZ 60 It was administered IV only on days. After nitenin administration, mechanical sensitivity in the hypersensitive foot A decrease was observed. The duration of nitenin-induced pain relief lasted for 2-3 hours. ●In CIPN rats, nitenine was administered intravenously. After 42 days, it consistently resulted in an extreme decrease in sensitivity to mechanical stimuli in both feet. Nevertheless, in this example, pain relief is likely due to the severity of the model. Compared to other pain models, the pain was not severe and did not last long (<2 hours).

[0135] -Efficacy after intraperitoneal administration. In intraperitoneal administration was observed in CFA rats (23 days after CFA injection). The test was conducted with 10 times the amount of nitene administered by IV injection. In this example, control A score that reaches the roll level indicates a clear pain relief effect, and the effect lasts for approximately 4 hours. It continued.

[0136] - Efficacy after oral administration. Oral administration of nitenine via gastric tube (into the stomach) is performed by IV injection. The drug was administered at 100 times the normal dose and tested in CCI rats (31 days post-surgery). In all the animals, a similar reduction in pain relief, i.e., a decrease in sensitivity, was observed. The effect lasted for about two hours.

[0137] In addition to the tests conducted using nitenine, the core structures of formulas I, II, III, and IV were also examined. Three analogues (compounds of formulas VI, VII, and VIII) designed around the same core were also tested. The activity was demonstrated.

[0138] In summary, nitenine compounds are used 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 It has been shown to be effective for chemotherapy-induced peripheral neuropathy. Its indications include intravenous and intraperitoneal administration. And, importantly, several routes of administration via oral administration have been demonstrated.

[0139] The effect of the three nytenine analogs is that the affected K + Similar to those involving electric current components However, I slow (Figures 7-9), and voltage dependence of steady-state deactivation (Figure 1 Typical effects in 0-12) were obtained at different concentrations. This is due to nytenine analogization. The combination is I slow It has a clear effect, but strongly indicates that it has different affinities. The strong effect was observed with compound V, and then with compounds of formulas VII, VIIIa, VIIIb, and Compounds Y and VI followed, respectively.

[0140] Based on the dose-dependent curve, several concentrations and efficacy levels applied under IV treatment showed the following results. The effect was quantified, and the nytenine analog was found at 0.1 μg / ml blood (6 μg / kg body weight) ~ In doses ranging from 30 μg / ml blood (1.8 mg / kg body weight), warm-blooded vertebrates, especially humans, are being treated. It is used for pharmacological purposes in [unspecified field].

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

[0142] 1. Computer-aided toxicity assay Assays using VEGA® software can detect mutagenicity, carcinogenicity, Developmental toxicity, hepatotoxicity, skin sensitization, affinity for estrogen receptors, and several It was possible to test environmental parameters (e.g., aquatic toxicity, honeybees, bioaccumulation). All tests were negative, with varying levels of reliability.

[0143] 2. In vitro and ex vivo toxicity ● The cell viability test (MTS) using the HFF2 cell line can be performed at a maximum concentration of 200 μM. It did not show any decrease in cell viability. ● Cardiotoxicity: a) Cell viability tests (MTS) using primary mouse cardiomyocyte cultures were performed with a maximum of 20 μM. The concentration of did not show a decrease in cell viability. b) Whole-cell voltage clamp in hERG: Expressed in HEK (human embryonic kidney) cells There is no effect on the outward current mediated by the hERG. c) Exvivorat preparations contain nitenine (maximum 10 μM), which affects sinus heart rate and atrioventricular anisotropy. Sexual (isolated rat atria), and right ventricular (RV) anisotropy (isolated rat ventricles) They made it clear that they would not make any changes. d) In vivo electrocardiogram (ECG) recordings of anesthetized Wistar rats were obtained by intravenous injection of nitenin. The injection (60 μg / kg) did not alter sinus rhythm or heart rate, and did not cause arrhythmia or any adverse reaction. It was also shown that no pulsational phenomena were induced.

[0144] 3. In vivo toxicity For all in vivo administrations, the animals' behavior was tracked for an additional week, followed by a post-mortem examination. The procedure was performed. Each pair of individuals received IV administration twice a day (once in the morning and once in the afternoon). (Later, at the end) it was used for a full week. Any external changes in any organ or internal structure were detected. It wasn't released.

[0145] Several features are listed below, each independently of the others, or depending on the circumstances of the other features. It can be used in any combination of meanings. However, any individual feature is considered above. In some cases, none of the problems discussed may be addressed, or only one of the problems considered above may be addressed. In some cases, this may be the case. Some of the issues discussed above are related to the features described herein. Neither method may fully address the issue. Headlines are provided, but specific headlines Information regarding this is not found in the section with that heading, but elsewhere in this specification. It can be found.

[0146] In the aforementioned specification, embodiments of the present invention are described in detail, which may vary between executions. This has been explained by referring to the present invention. Therefore, the present applicant will explain what the present invention is and by The sole and exclusive indicator intended in this invention is the claims of the patent issued from this application. This is a set, and in the particular form in which such claims are issued, any subsequent modifications Including positive. For terms included in such claims, the terms expressly shown herein are negative. The definition of "int" shall govern the meaning of such terms as used in the claims. Therefore, limitations, elements, characteristics, features, advantages, or limitations not expressly enumerated in the claims The attributes do not limit the scope of such claims in any way. Therefore, this specification The term "drawing" should be considered in an illustrative sense, not in a restrictive sense.

[0147] Various publications, articles, and patents are cited or mentioned throughout this specification and in the background. Each of these references is incorporated herein by reference in its entirety. The considerations of documents, actions, materials, devices, articles, etc., included in this book provide the context of the present invention. This is for the purpose of this discussion. Such considerations apply to any invention disclosed or claimed. , acknowledging that any or all of these matters constitute part of the prior art It's not that.

[0148] References: Li Y, North RY, Rhines LD, Tatsui CE, Rao G ,Edwards DD,Cassidy RM,Harrison DS,Johan sson CA, Zhang H, Dougherty PM. (2018).DRG Voltage-Gated Sodium Channel 1.7 Is Upre gulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain.J Neurosci.2018 Jan 31;38(5):1124-1 136. Kupper J, Prinz AA, Fromherz P (2002). Reco. mbinant Kv1.3 potassium channels stabili ze tonic firing of cultured rat hippocam pal neurons.Pflugers Arch.Feb;443(4):541 -7. Yang EK,Takimoto K,Hayashi Y,de Groat W C,Yoshimura N.(2004).Altered expression of potassium channel subunit mRNA and al pha-dendrotoxin sensitivity of potassium currents in rat dorsal root ganglion ne urons after axotomy.Neuroscience;123(4): 867-74.

Claims

1. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts or prodromal It is a bag, 【Chemistry 1】 During the ceremony, 【Chemistry 2】 This represents a carbon-carbon single bond or a carbon-carbon double bond. X is O, S, NH, CH ２ Selected from, Y is CH, CH ２ Selected from, Z is selected from C and N. G is selected from O and S. T stands for OH, SH, NH ２ , selected from halogens, R １ and R ２ These are independently H, alkyl, alkenyl, cycloalkyl, and aryl. , or -CH ２ -R ３ Selected from, R ３ However, aryl, cycloalkyl, heteroaryl -R, -R ４ -R ５ selected from, R ４ is selected from alkyl, alkenyl, R ５ is aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamaractone They were selected, Q is selected from C and CH. D is C, CH, CH ２ Selected from, One of A and E is H, and the other is H, OH, SH, aryl, alkyl Alkenil, R ６ -R ７ Selected from, R ６ However, selected from alkyl and alkenyl, R ７ However, alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetyl Selected from loaryl, substituted or unsubstituted gamaractones, J is H, OH, SH, NH ２ , selected from halogens, The aforementioned compound may be nitenine, dihydronitenine, or their respective isomers, mirrors. Compounds of formulas I, II, III, and IV that are neither stereoisomers nor image isomers, and A pharmaceutically acceptable salt or prodrug.

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

3. X is O, Y is CH, Z is C, R １ However, it is alkyl, R ２ However, -CH ２ -R ３ And R ３ is, -R ４ -R ５ And R ４ is alkyl R ５ The compound of formula IV according to claim 1, wherein is a heteroaryl compound and J is OH thing.

4. X is O, Y is CH ２ And, G is O, R １ However, it is H, J is H, Q is C, D is C, E is H, A is -R ６ -R ７ And R ６ is alkyl, R ７ It is a heteroaryl compound. , the compound of formula II as described in claim 1.

5. X is O, Y is CH ２ And, G is O, R １ However, it is H, J is H, Q is C, D is C, E is -R ６ -R ７ And R ６ is alkyl, R ７ It is a heteroaryl compound. 、 A compound of formula II according to claim 1, wherein A is H.

6. R ７ However, formulas I, II, III, and I described in claim 1 are not Fran-3-yl. A compound of V.

7. Compounds of formulas I, II, III, and IV for use as pharmaceutical ingredients, and their pharmaceutical A salt or prodrug that is acceptable to the following: 【Transformation 3】 During the ceremony, 【Chemistry 4】 This represents a carbon-carbon single bond or a carbon-carbon double bond. X is O, S, NH, CH ２ Selected from, Y is CH, CH ２ Selected from, Z is selected from C and N. G is selected from O and S. T stands for OH, SH, NH ２ , selected from halogens, R １ and R ２ These are independently H, alkyl, alkenyl, cycloalkyl, and aryl. , or -CH ２ -R ３ Selected from, R ３ However, aryl, cycloalkyl, heteroaryl R, -R ４ -R ５ Selected from, R ４ However, selected from alkyl and alkenyl, R ５ but aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamaractone They were selected, Q is selected from C and CH. D is C, CH, CH ２ Selected from, One of A and E is H, and the other is H, OH, SH, aryl, alkyl Alkenil, R ６ -R ７ Selected from, R ６ However, selected from alkyl and alkenyl, R ７ However, alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetyl Selected from loaryl, substituted or unsubstituted gamaractones, J is H, OH, SH, NH ２ Selected from halogens, Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts or prodromal Bag.

8. X is O, Y is CH, Z is C, R1 is an alkyl group, R2 is -CH ２ -R ３ And R ３ is, -R ４ -R ５ And R ４ is alkyl Furthermore, R5 is a heteroaryl compound. Q is C, D is C, A is -R ６ -R ７ And R ６ is alkyl, R ７ It is a heteroaryl compound. 、 E is H, A compound of formula I for use as a pharmaceutical ingredient according to claim 7, wherein J is H.

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

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 R ５ It is a heteroaryl compound, where J is OH. A compound of formula IV for use as a pharmaceutical ingredient as described in claim 7.

11. X is O, Y is CH ２ And, G is O, R １ However, it is H, J is H, Q is C, D is C, E is H, A is -R ６ -R ７ And R ６ is alkyl, R ７ It is a heteroaryl compound. 、 A compound of formula II for use as a pharmaceutical ingredient as described in claim 7.

12. X is O, Y is CH ２ And, G is O, R １ However, it is H, J is H, Q is C, D is C, E is -R ６ -R ７ and R ６ is alkyl, and R ７ is heteroaryl 、 A is H. A compound of formula II for use as a pharmaceutical ingredient as described in claim 7.

13. In individuals requiring treatment, prevention, or reduction of pain, Formulas I, II, III, and O according to any one of claims 7 to 12 for use in reduction Compounds of type IV.

14. Neuropathic pain, nociceptive pain, psychogenic or somatic pain, diabetic neuropathy Post-herpetic pain, low back pain, nerve root pain, musculoskeletal pain, postoperative and post-traumatic pain, phantom limb Pain, surgical pain, wound-related pain, chemotherapy-induced peripheral neuropathic pain, short-term / acute or Long-term / chronic inflammatory pain, rheumatic pain, joint pain, osteoarthritis-related pain, myofascial pain, hemiplegia Pain, chronic orofacial pain, trigeminal neuralgia, cancer-related pain, fibromyalgia-related pain, hypersensitivity syndrome, sensation Infection-related pain, HIV-related pain, sprains and contusions, hyperalgesia, somatic pain, psychogenic pain, Heat-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, Myofascial pain, vascular pain, migraine wounds, wound-related pain, arthralgia, somatic visceral pain, phantom limb pain, nerve root pain Acute and chronic pain, including pain, back pain, visceral pain, bowel pain, and osteoarthritis-related pain. For use in the treatment of at least one of the following, as described in any one of claims 7 to 12 Compounds of formulas I, II, III, and IV shown above.

15. Claims 7-1 for use in the treatment or prevention of diseases involving the Kv1.3 channel Compounds of formulas I, II, III, and IV as described in any one of item 2.

16. Formula I according to any one of claims 7 to 12, for use in the treatment of autoimmune disorders Compounds of types II, III, and IV.

17. Any of claims 7 to 12 for use in the treatment of diabetes and insulin resistance syndrome A compound of formulas I, II, III, and IV as described in any one of the items.

18. Compounds of formulas I, II, III, and IV, their pharmaceutically acceptable salts, or prodrugs are anti- It is used as an epileptic and antiseizure agent.

19. Claim that the compound is administered at a therapeutically effective dose of 0.0018 to 1.8 mg / kg. Compounds of formulas I, II, III, and IV as described in any one of items 7 to 12.

20. A pharmaceutical composition comprising a combination of a pharmacologically acceptable diluent or carrier and an active ingredient. The active ingredient is formula I, II, or III as described in any one of claims 7 to 12. , and at least one compound described in IV, or a pharmaceutically acceptable salt thereof Alternatively, a pharmaceutical composition containing a prodrug.

21. A method for treating pain in a person who has pain The target is a therapeutically effective amount of formulas I, II, III, and A method comprising administering a compound IV.

22. The pain may be neuropathic pain, nociceptive pain, psychogenic or somatic pain, or diabetic pain. Transpathogenic pain, post-herpetic pain, low back pain, nerve root pain, musculoskeletal pain, postoperative and traumatic pain. Post-operative 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, fascia Pain, migraines, orofacial chronic pain, trigeminal neuralgia, cancer-related pain, fibromyalgia-related pain, hyper Sensitivity syndrome, infection-related pain, HIV-related pain, sprains and contusions, hyperalgesia, somatic pain, Psychogenic pain, heat-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvis Pain, bladder pain, myofascial pain, vascular pain, migraine wound, wound-related pain, joint pain, somatic visceral pain, hallucinations Acute pain selected from limb pain, nerve root pain, lower back pain, visceral pain, bowel pain, and osteoarthritis-related pain. The method according to claim 21, and for chronic pain.

23. In subjects requiring treatment or prevention of diseases involving the Kv1.3 channel, 1. A method for treating or preventing a disease involving the Kv1.3 channel, wherein the Kv1.3 channel For a subject requiring treatment or prevention of the disease involved, any of claims 7 to 12 in a therapeutically effective amount A method comprising administering any one of the compounds of formulas I, II, III, and IV described in any one of the items. 。

24. A method for treating autoimmune diseases in subjects requiring treatment for autoimmune diseases, A therapeutically effective amount of the compound described in any one of claims 7 to 12 for a subject with an autoimmune disease. A method including administering [a substance].

25. In patients requiring treatment for diabetes or insulin resistance syndrome, A method for treating insulin resistance syndrome, which involves having diabetes or insulin resistance syndrome. To administer a therapeutically effective amount of the compound described in any one of claims 7 to 12 to the target subject. Methods that include...

26. Methods of treating epilepsy or seizures in patients requiring treatment for epilepsy or seizures and any of claims 7 to 12, in a therapeutically effective amount for a subject having epilepsy or seizures. A method comprising administering the compound described in paragraph one.

27. Claim 21, wherein the compound is administered in a therapeutically effective dose of 0.018 to 1.8 mg / kg. The method described in any one of the following 25 items.

28. The aforementioned compound is the compound of formula I, in which, X is O, Y is CH, Z is C, R １ However, it is alkyl, R ２ is -CH ２ -R ３ and R ３ is -R ４ -R ５ and R ４ is alkyl R ５ It is a heteroaryl, Q is C, D is C, A is -R ６ -R ７ And R ６ is alkyl, R ７ It is a heteroaryl compound. 、 E is H, J is H. The compound, composition, use, or method according to any one of claims 1 to 27.

29. The compound is isolated or produced synthetically, as described in any one of claims 1 to 6. The compounds listed in the section.

30. The compound is nitenine or dihydronitenine, any one of claims 7 to 28. The compounds listed in the section.

Images