Nitenin analogue compounds and their use in treatment of chronic and acute pain

Abstract

FIELD: pharmaceutical chemistry.SUBSTANCE: compound of formula (I), (III), its pharmaceutically acceptable salts, wherein said compound is not nitin, dihydronitin or their corresponding isomers, enantiomers and stereoisomers, a pharmaceutical composition containing a compound of formula (I) or (III), or their pharmaceutically acceptable salt, use and method for treating acute or chronic pain based on them. In formulas (I), (III) represents a carbon-carbon single bond or a carbon-carbon double bond; X is selected from O, NH; Y is selected from CH, CH2; Z is C; T is OH; for a compound of general formula (I): R1 and R2 each represent H, or one of R1 and R2 is selected from H or C1-C4 alkyl, and the other is selected from -CH2-R3, where R3 is selected from C6 aryl or -R4-R5, where R4 is selected from C1-C4 alkylene, and R5 is selected from C6 aryl or C5-C6 heteroaryl containing at least one heteroatom selected from O and N; Q is selected from C, CH; D is selected from C, CH; one of A and E is H, and the other is R6-R7, where R6 is selected from C1-C4 alkylene, and R7 is selected from C6 aryl or C5-C6 heteroaryl containing at least one heteroatom selected from O and N; J is selected from H and OH. Nitenin and its analog compounds act as analgesics by reducing K+ currents.EFFECT: due to their high efficacy in pain treatment, these compounds are highly selective for slow voltage-activated potassium (K+) currents expressed in small diameter dorsal root ganglion neurons (sDRGn), mainly mediated by the voltage-gated potassium channel (KV), KV1.3, and also result in reduced side effects.11 cl, 12 dwg

Description

[0001] Technical field

[0002] The present invention relates to nitenine analog compounds and their use as analgesic agents for the treatment, prevention or reduction of chronic pain and acute pain.

[0003] Technology Level

[0004] Acute pain typically occurs suddenly, and its cause is specific. It is acute in nature. Acute pain typically lasts no more than three to six months. It resolves when the underlying cause of the pain resolves. The person can then return to normal life. Common causes of acute pain include surgery, bone fractures, dental work, burns and cuts, labor, and childbirth.

[0005] Chronic pain is defined as pain that lasts more than three months or longer than the natural recovery time. Pain signals continue to be triggered in the nervous system, even without physiological stimuli, for weeks, months, or years. It occurs in many pathological conditions, including, for example, diabetes, arthritis, migraine, fibromyalgia, cancer, back pain, herpes zoster, sciatica, trigeminal neuralgia, and previous trauma or injury. Chronic pain can be disabling, significantly impairing a person's quality of life and having a huge negative impact on society. It affects 21% of the world's population (1.5 billion people) and is associated with enormous economic costs. In the United States (US) alone, an estimated $560-635 billion was spent in 2010 on lost wages and low productivity, as well as healthcare.With the aging population, the need for appropriate and better pain management therapies is becoming more pressing.

[0006] While effective and safe analgesics exist for mild pain, treatment options for moderate to severe chronic pain are largely ineffective and cause limiting and harmful side effects. Consequently, the primary concern for patients with most types of chronic pain is the lack of truly adequate pharmaceutical treatment, at least without significant, limiting side effects. For example, in moderate to severe pain, opioid derivatives provide pain relief but also cause significant harmful effects, such as addiction, dependence, and loss of energy or motivation. Opioid use has become an epidemic in several countries, with increasing rates of addiction and a significant burden on society. For example, in the United States, the number of opioid-related deaths far exceeds the number of deaths caused by illicit substances.Other types of medications are used for treatment, including antidepressants, antiepileptic drugs, and nonsteroidal drugs.

[0007] Anti-inflammatory drugs (NSAIDs), but they are either ineffective or also cause relevant side effects.

[0008] Other, such as recently emerging treatment options for moderate to severe pain, more closely related in the pharmacological context of the present invention, include ion channel modulators. Ion channels are key proteins present in neuronal membranes that form the passage

[0009] electrical signals and, consequently, pain signals in the nerves. Neurons involved in pain sensation (nociception), located in the peripheral nervous system, include those whose cell bodies are located in nerve ganglia (dorsal root ganglia - DRG) outside the spinal cord (or trigeminal ganglia - TRG, in the head). Such nociceptive fibers are the first peripheral nerve sensors involved in the physiological pathway that leads to the perception of pain in the brain.

[0010] As for the currently available therapy involving ion channel modulation for pain treatment, there are only two options available on the market.

[0011] However, they are only partially effective or also cause relevant side effects due to the type of ion channel they modulate. Such medications include:

[0012] - Topical capsaicin, transient receptor potential cation channel subfamily V member 1 (TRPV1) agonist;

[0013] - Intrathecal injection of ziconotide (Prialt®), a voltage-gated calcium channel blocker of the N-type obtained from the cone snail; in this case, the action is not peripheral but central.

[0014] New products currently in clinical development (in preparation by several biotech and pharmaceutical companies, but which have not been approved for marketing) include new opioids with some modifications (to make them less addictive) and modulators of other ion channels known to be involved in pain sensation, but more acceptable than TRPV1 and N-type voltage-gated calcium channels (e.g., ion channels such as other TRPs, voltage-gated sodium channels Nav1.7 and Nav1.8). To the best of our knowledge, there are only two agents acting on K + channels that are currently undergoing non-clinical or clinical research for pain treatment.

[0015] a) The anticonvulsant retigabine (Phase II) attenuates nociceptive behavior in rat models of persistent and neuropathic pain. Retigabine acts primarily as a K-opening agent.+ channels, in other words, by activating a specific family of voltage-gated potassium (Kv7 / M) channels in the brain.

[0016] b) Another channel modulator, BL-7050 (preclinical phase), based on the molecular structure of diclofenac (NSAID), binds to and stabilizes the body's potassium channels, controlling their hyperexcitability (by keeping them open) and preventing pain by keeping the channels open for K outflow. + .

[0017] However, despite a significant amount of pharmaceutical research, there is still a need to find improved and specific clinically approved blockers / potentiators for such ion channels, leaving patients with no alternative other than pharmaceutical drugs with severe side effects.

[0018] Brief description of the invention

[0019] In one aspect, the present invention relates to nitenine analog compounds and their use as analgesics for the treatment, prevention or reduction of chronic pain and acute pain.

[0020] Without being limited by theory, in some respects the present invention differs from currently available solutions not only in its chemical nature but also in its mode of action. By "switching off" or reducing the activity of nociceptive fibers, bioactive molecules are expected to block or attenuate the brain's perception of pain, but in a manner that may not affect brain function, as these molecules can act in the "peripheral portion of the pain signaling pathway" to the central nervous system.

[0021] Any aspect or embodiment described herein may be combined with any other aspect or embodiment disclosed herein. Although the present invention has been described in conjunction with its detailed description, the foregoing description is intended to illustrate, but not limit, the scope of the present invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following embodiments / claims.

[0022] Embodiment 1. Compounds of formula I, II, III and IV, their pharmaceutically acceptable salts or prodrug,

[0023]

[0024] where

[0025] represents a carbon-carbon single bond or a carbon-carbon double bond;

[0026] X is selected from O, S, NH, CH2;

[0027] Y is selected from CH, CH2;

[0028] Z is selected from C, N;

[0029] G is selected from O, S;

[0030] T is selected from OH, SH, NH2, halogen;

[0031] R 1 and R 2 independently selected from H, alkyl, alkenyl, cycloalkyl, aryl, or -CH2-R 3 ; where R 3 selected from aryl, cycloalkyl, heteroaryl, -R 4 -R 5 ; where R 4 selected from alkyl, alkenyl; where R 5 selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone;

[0032] Q is selected from C, CH;

[0033] D is selected from C, CH, CH2;

[0034] One of A and E is H, and the other is selected from H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 , where R 6 selected from alkyl, alkenyl and R 7 selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone;

[0035] J is selected from H, OH, SH, NH2, halogen;

[0036] wherein the compound is neither nitin nor dihydronitin nor their corresponding isomers, enantiomers and stereoisomers.

[0037] Embodiment 2. Compounds of formula IV according to embodiment 1, wherein

[0038] X represents O;

[0039] Y represents CH;

[0040] Z represents C;

[0041] R 1 represents H;

[0042] R 2 represents H; and

[0043] J represents OH.

[0044] Embodiment 3. Compounds of formula IV according to embodiment 1, wherein

[0045] X represents O;

[0046] Y represents CH;

[0047] Z represents C;

[0048] R 1 is an alkyl;

[0049] R 2 is -CH2-R 3 ; where R 3 represents -R 4 -R 5 ; Where

[0050] R4 is alkyl and R 5 represents heteroaryl, J represents OH.

[0051] Embodiment 4. Compounds of formula II according to embodiment 1, wherein

[0052] X represents O;

[0053] Y is CH2;

[0054] G represents O;

[0055] R 1 represents H;

[0056] J represents H;

[0057] Q represents C;

[0058] D represents C;

[0059] E represents H;

[0060] A represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl.

[0061] Embodiment 5. Compounds of formula II according to embodiment 1, wherein

[0062] X represents O;

[0063] Y is CH2;

[0064] G represents O;

[0065] R1 represents H;

[0066] J represents H;

[0067] Q represents C;

[0068] D represents C;

[0069] E represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl;

[0070] A represents H.

[0071] Embodiment 6. Compounds of formula I, II, III and IV according to embodiment 1, wherein R 7 does not represent furan-3-yl.

[0072] Embodiment 7. Compounds of formula I, II, III and IV, their pharmaceutically acceptable salts or prodrug,

[0073]

[0074] where

[0075] represents a carbon-carbon single bond or a carbon-carbon double bond;

[0076] X is selected from O, S, NH, CH2; Y is selected from CH, CH2;

[0077] Z is selected from C, N; G is selected from O, S;

[0078] T is selected from OH, SH, NH2, halogen;

[0079] R 1 and R 2 independently selected from H, alkyl, alkenyl, cycloalkyl, aryl, or -CH2-R 3 ; where R 3 selected from aryl, cycloalkyl, heteroaryl, -R 4 -R 5 ; where R 4 selected from alkyl, alkenyl; where R 5 selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone;

[0080] Q is selected from C, CH;

[0081] D is selected from C, CH, CH2;

[0082] One of A and E is H, and the other is selected from H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 , where R 6 selected from alkyl, alkenyl and R 7 selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone;

[0083] J is selected from H, OH, SH, NH2, halogen; for use as a pharmaceutical ingredient.

[0084] Embodiment 8. Compounds of formula I for use as a pharmaceutical ingredient according to embodiment 7, wherein:

[0085] X represents O;

[0086] Y represents CH;

[0087] Z represents C;

[0088] R 1 is an alkyl;

[0089] R 2 is -СН2-R 3 ; where R 3 represents -R 4 -R 5 ; Where

[0090] R 4 is alkyl and R 5 is a heteroaryl;

[0091] Q represents C;

[0092] D represents C;

[0093] A represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is heteroaryl; E is H; and

[0094] J represents H.

[0095] Embodiment 9. Compounds of formula IV for use as a pharmaceutical ingredient according to embodiment 7, wherein:

[0096] X represents O;

[0097] Y represents CH;

[0098] Z represents C;

[0099] R 1 represents H;

[0100] R 2 represents H; and

[0101] J represents OH.

[0102] Embodiment 10. Compounds of formula IV for use as a pharmaceutical ingredient, wherein:

[0103] X represents O;

[0104] Y represents CH;

[0105] Z represents C;

[0106] R 1 is an alkyl;

[0107] R 2 is -CH2-R 3 ; where R 3 represents -R 4 -R 5 ; Where

[0108] R 4 is alkyl and R 5represents heteroaryl, J represents OH.

[0109] Embodiment 11. Compounds of formula II for use as a pharmaceutical ingredient according to embodiment 7, wherein:

[0110] X represents O;

[0111] Y represents CH2;

[0112] G represents O;

[0113] R 1 represents H;

[0114] J represents H;

[0115] Q represents C;

[0116] D represents C;

[0117] E represents H;

[0118] A represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl.

[0119] Embodiment 12. Compounds of formula II for use as a pharmaceutical ingredient according to embodiment 7, wherein:

[0120] X represents O;

[0121] Y represents CH2;

[0122] G represents O;

[0123] R 1 represents H;

[0124] J represents H;

[0125] Q represents C;

[0126] D represents C;

[0127] E represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl;

[0128] A represents H.

[0129] Embodiment 13. For pharmaceutical use, the compounds of formula I, II, III and IV of the present invention are administered to warm-blooded vertebrates, preferably mammals, more preferably humans, at doses in the range of 0.1 μg / ml blood (6 μg / kg body weight) to 30 μg / ml blood (1.8 mg / kg body weight). The above-mentioned effective dose range is for intravenous administration and may differ for other routes of administration.

[0130] Embodiment 14. Compounds of formula I, II, III and IV, their pharmaceutical salts or prodrugs are used in the treatment, prevention or reduction of pain in an individual in need thereof, in particular in the case of acute or chronic pain. Acute and chronic pain is meant to include, but is not limited to, at least one of the following: neuropathic pain, nociceptive pain, psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low back pain, radiculopathic pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, wound-related pain, chemotherapy-induced peripheral neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain,cancer-related pain, fibromyalgia-related pain, hyperalgesia syndrome, infection-related pain, HIV-related pain, sprains and strains, hyperalgesia, somatogenic 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, arthritic pain, somatic visceral pain, phantom pain, radiculopathy, low back pain, visceral pain, bowel pain, and osteoarthritis-related pain.

[0131] Embodiment 15. Compounds of formula I, II, III and IV, their pharmaceutical salts or prodrugs are used in the treatment of autoimmune disorders due to the effects described for Kv1.3, the target in such disorders.

[0132] Embodiment 16. Compounds of formula I, II, III and IV, their pharmaceutical salts or prodrugs are used in the treatment of diabetes, taking into account that their effect on the Kv1.3 channel is considered to be associated with insulin sensitivity, syndromes associated with insulin resistance, and obesity.

[0133] Embodiment 17. Compounds of formula I, II, III and IV, their pharmaceutical salts or prodrugs are used as antiepileptic and anticonvulsant agents.

[0134] Embodiment 18. Compounds of formula I, II, III and IV for use in the treatment or prevention of a disease in which Kv1.3 channels are involved.

[0135] Embodiment 19. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients include at least one compound according to formula I, II, III and IV or a pharmacologically acceptable salt or prodrug thereof.

[0136] Embodiment 20. A method of treating pain in a subject in need thereof, comprising administering to the subject having pain a therapeutically effective amount of a compound of formula I, II, III and IV.

[0137] Embodiment 21. The method according to embodiment 19, characterized in that the pain is an acute and chronic type pain selected from neuropathic pain, nociceptive pain, psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low back pain, radiculopathic pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, pain associated with wounds, chemotherapy-induced peripheral neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain associated with cancer, pain associated with fibromyalgia, hyperalgesia syndrome, pain, infection-related, HIV-related pain, dislocations and sprains, hyperalgesia, somatogenic pain, psychogenic pain,heat-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial pain, vascular pain, migraine, wounds, pain associated with wounds, arthritic pain, somatic visceral pain, phantom pain, radiculopathy, low back pain, visceral pain, bowel pain and pain associated with osteoarthritis.

[0138] Embodiment 22. A method for treating or preventing a disease in which Kv1.3 channels are involved in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula I, II, III and IV to a subject in need of treating or preventing a disease in which Kv1.3 channels are involved.

[0139] Embodiment 23. A method of treating an autoimmune disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula I, II, III and IV to a subject having the autoimmune disease.

[0140] Embodiment 24. A method for treating diabetes or insulin resistance syndromes in a subject in need thereof, comprising administering a therapeutically effective amount of a compound to a subject having diabetes or insulin resistance syndrome.

[0141] Embodiment 25. A method for treating epilepsy or seizures in a subject in need thereof, comprising administering a therapeutically effective amount of a compound to a subject having epilepsy or seizures.

[0142] Embodiment 26. The method according to embodiments 20-23, characterized in that the compound is administered in a therapeutically effective amount of from 0.018 to 1.8 mg / kg.

[0143] Embodiment 27. The compound, composition, use, or method disclosed herein, wherein the compound is a compound of formula I, wherein

[0144] X represents O;

[0145] Y represents CH;

[0146] Z represents C;

[0147] R 1 is an alkyl;

[0148] R 2 is -СН2-R 3 ; where R 3 represents -R 4 -R 5 ; Where

[0149] R 4 is alkyl and R 5 is a heteroaryl;

[0150] Q represents C;

[0151] D represents C;

[0152] A represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl;

[0153] E represents H; and

[0154] J represents H.

[0155] Embodiment 28. Compounds according to embodiments 1-6, characterized in that the compound is isolated or obtained synthetically.

[0156] Embodiment 29. The compounds of embodiments 7-28, wherein the compound is nitinin or dihydronitinin.

[0157] Brief description of graphic materials

[0158] To facilitate understanding of this application, figures are attached to the appendix that represent typical forms of implementation, which, however, do not imply limitations of the technology disclosed in this document.

[0159] Figure 1 illustrates the effect of nitenin (0.1 μg / ml) on voltage-activated currents recorded from small diameter dorsal root ganglia neurons (sdDRGn).

[0160] a) In sdDRGn, voltage-activated potassium (K) outflows + ) currents were excited by a depolarization step to +20 mV (maintaining potential of -70 mV), preceded by a pre-hyperpolarizing pulse of -120 mV. The currents were best approximated by the sum of two exponential functions, identifying two components (referred to herein as I быстрый and I медленный ), whose time constants were τбыстрый ~75 ms and τ медленный ~495 ms.

[0161] b) i. Typical curves of potential-activated current K + , recorded before and in the presence of nitenin (0.1 μg / ml); the lower curve corresponds to the subtraction of the current with the approximation of one exponential function (time constant τ ~150 ms). ii. Typical voltage-activated currents of Na + , recorded before (black line) and in the presence of nitenin (0.1 μg / ml; 0.29 μM) (gray line), demonstrating no effect.

[0162] Figure 2 illustrates the dose-dependent responses to voltage-activated currents K + , recorded for (a) small diameter dorsal root ganglia (sdDRGn) neurons and (b) CHO-K1 cells expressing human Kv1.1, Kv1.2, Kv1.3, Kv1.4, or Kv1.6 cDNAs.

[0163] a) Nitenin effect as a percentage of current blocking on fast (I быстрый , unpainted inverted triangles) and slow (I медленный, filled triangles) components of the current recorded for sdDRGn, as a dose-response relationship. As an indicator of the measurement of I быстрый used the peak current, while I was used as the measurement indicator медленный The current value was obtained at the end of the driving pulse (see Fig. 1). Values ​​are expressed as mean ± SEM. In case I медленный a biphasic relationship could be observed. Therefore, at lower concentrations (up to 1 μM), the relationship was approximated by a Hill function with an IC50 of 120 nM; at concentrations above 1 μM, the dose dependence was consistent with the dose dependence of I быстрый (IC 50 ~ 6 μM).

[0164] b) Effect of nitin on K currents + , recorded for CHO-K1 cells stably transfected and expressing hKv1.1, hKv1.2, hKv1.3, hKv1.4, or hKv1.6. Concentration-% blocking values ​​were approximated by Hill functions, IC values 50The data (in nM) are shown in the figure. The Kv1.3 channel is the most sensitive channel (approximately 6 times more sensitive than the "next most sensitive", Kv1.2). Kv1.2, Kv1.1, and Kv1.6 show similar average sensitivity to nitenin. In contrast, Kv1.4 is the least sensitive (~31 times less sensitive).

[0165] Figure 3 illustrates a typical effect of nitenin on the steady-state voltage dependence of K current inactivation. +, recorded from small-diameter neurons isolated from the dorsal root ganglion isolated from the injured side of a CCI rat model 28 days after surgery, a) Current traces were obtained during a +10 mV drive pulse (600 ms) preceded by a train of 11,040 s prepulses ranging from -140 to +10 mV in 10 mV steps; traces on the left (black) were obtained before and traces on the right (grey) during nitenin (0.1 μg / ml; 0.29 μM) application. b) Current / potential relationships, where peak current amplitudes (obtained in a) are plotted against the potential of the prepulses used in the potential protocol in a (black dots refer to the CCI control; grey dots are obtained during nitenin treatment). A shift towards hyperpolarized values ​​can be seen during nitenin treatment.The relationship was best approximated by the sum of two Boltzmann functions, demonstrating that in both states there are two components: one more hyperpolarized component (component 1) and one more depolarized component (component 2). In fact, the Vh (half-maximal current potential) parameters of the Boltzmann equation showed more hyperpolarized values ​​during nitenin treatment (control: Vh1=-73.3 mV Vh2=-26.3 mV; nitenin: Vh1=-95.3 mV Vh2=-47.0 mV).

[0166] Figure 4 illustrates the behavioral results as indices of pain during nitenin treatment in a rat model of CCI (chronic constriction injury) neuropathic pain. Typical experiments used a group of Wistar rats subjected to four stages of unilateral sciatic nerve compression. The values ​​refer to the mechanical sensitivity to stimulation using calibrated von Frey filaments and therefore reflect hyperalgesia during hypersensitivity (black filled markers represent the operated ipsilateral paw; open markers represent the uninjured contralateral paw).The dotted line represents the mean value for the ipsilateral paw before surgery. a) Induction of the model showing that 3 days after surgery, the mechanical sensitivity of the ipsilateral limb was significantly increased, while the contralateral paw remained unchanged, with values ​​similar to baseline. This trend was maintained for 26 days after surgery, i.e., until the day of nitenin treatment (circle with dotted line). b) The effect of intravenous injection of nitenin (estimated plasma concentration 1 μg / mL) on the mechanical sensitivity of the ipsilateral paw. For the sake of clarity, data for the contralateral limb are not shown, but it remained unchanged. The effect is maximal at approximately ~1 h after injection, reaching values ​​not different from those obtained at baseline before surgery (values ​​for dotted lines).

[0167] Figure 5 illustrates the behavioral results as pain indices during nitenin treatment in a rat orofacial pain model. Representative experiments used a group of Wistar rats that were injected with CFA (CFA was injected directly behind the second row of vibrissae). The values ​​refer to the mechanical sensitivity to stimulation of the snout (whisker area) using calibrated von Frey filaments and therefore reflect hyperalgesia during hypersensitivity (black filled markers represent the ipsilateral lesioned side of the snout; open markers represent the unlesioned contralateral side of the snout). The dotted line refers to the mean value for the ipsilateral side of the snout before CFA injection.a) Induction of the model showing that 3 days after surgery, the mechanical sensitivity of the ipsilateral side of the muzzle increased significantly, while the contralateral side remained relatively unchanged, with values ​​similar to baseline. This trend persisted for 26 days after induction, i.e., until the day of nitenin treatment (circle with a dotted line). b) The effect of intravenous injection of nitenin (estimated plasma concentration 1. (0168 μg / ml) on the mechanical sensitivity of the ipsilateral side of the muzzle. For clarity, data for the contralateral side of the muzzle are not shown, but it remained relatively unchanged. The effect is maximal approximately 1-2 hours after nitenin injection, reaching values ​​similar to those obtained at baseline before induction (values ​​for the dotted lines), but in some cases higher.

[0169] Figure 6 illustrates the formulas of 4 compounds under study, wherein the compound of formula V refers to nitenin (the ion current results are shown in Figures 1, 2 and 3, and in vivo efficacy in Figures 4 and 5). Formulas VIII.A and VIII.B represent the cis-isomer and trans-isomer, respectively, of the compound of formula VIII.

[0170] Figure 7 illustrates the effect of the compound of formula VI (10 μg / mL; 77.9 μM) on the voltage-activated currents recorded for sdDRGn. Typical voltage-activated current curves K + , recorded before and in the presence of the compound of formula VI (10 μg / ml; 77.9 μM); the lower curve corresponds to the subtraction of the current with the approximation of one exponential function (time constant τ -795 ms).

[0171] Figure 8 illustrates the effect of the compound of formula VII (0.1 μg / mL; 399 nM) on the voltage-activated currents recorded for sdDRGn. Typical voltage-activated current curves K +, recorded before and in the presence of the compound of formula VII (0.1 μg / ml; 399 nM); the lower curve corresponds to the current subtraction.

[0172] Figure 9 illustrates the effect of the compound of formula VIII-A (6.5 μg / mL; 29.4 μM) on the voltage-activated currents recorded for sdDRGn. Typical voltage-activated current curves K + , recorded before and in the presence of the compound of formula VIII-A (6.5 μg / ml; 29.4 μM); the lower curve corresponds to the subtraction of the current with approximation by a single-exponential function (time constant τ -450 ms).

[0173] Figure 10 illustrates a typical effect of the compound of formula VI on the steady-state potential dependence of K current inactivation. +, recorded for sdDRGn. a) Current traces were acquired during a +10 mV drive pulse (600 ms) preceded by a series of 11,040 s pre-pulses ranging from -140 to +10 mV in 10 mV steps; the traces on the left (black) were acquired before and the traces on the right (grey) during application of the compound of formula VI (10 μg / mL; 7.9 μM). b) Current / potential relationship, where the peak current amplitudes (obtained in 'a') are plotted against the potential of the pre-pulses used in the potential protocol in 'a' (black dots refer to the CCI control; grey dots are obtained during treatment with the compound of formula VI). A shift towards hyperpolarized values ​​can be seen during treatment with the compound of formula VI.The relationship was best approximated by the sum of two Boltzmann functions, demonstrating that in both states there are two components: one more hyperpolarized component (component 1) and one more depolarized component (component 2). In fact, the Vh (half-maximal current potential) parameters of the Boltzmann equation showed more hyperpolarized values ​​during F2 treatment (control: Vh1=-91.0 mV Vh2=-23.9 mV; F2: Vh1=-102.9 mV Vh2=-40.5 mV).

[0174] Figure 11 illustrates a typical effect of the compound of formula VII on the steady-state potential dependence of K current inactivation. +, recorded for sdDRGn. a) Current curves were obtained during a +10 mV drive pulse (600 ms) preceded by a series of 11,040 s pre-pulses ranging from -140 to +10 mV with a 10 mV step increment; the curves on the left (black) were obtained before, and the curves on the right (gray) during, the application of compound F3 (0.1 μg / mL; 399 nM).

[0175] b) Current / potential relationship, where the peak current amplitudes (obtained in 'a') are plotted against the potential of the pre-pulses used in the potential protocol in 'a' (black dots refer to the CCI control; gray dots are obtained during treatment with compound of formula VII). A shift towards hyperpolarized values ​​can be seen during treatment with compound of formula VII. The relationship was best approximated by the sum of two Boltzmann functions, demonstrating that in both states there are two components: one more hyperpolarized component (component 1) and one more depolarized component (component 2). In fact, the Vh (half-maximal current potential) parameters of the Boltzmann equation showed more hyperpolarized values ​​during treatment with the compound of formula VII (control: Vh1=-64.1 mV Vh2=-13.7 mV; F2: Vh1=-92.6 mV Vh2=-32.4 mV).

[0176] Figure 12 illustrates a typical effect of the compound of formula VIII-A on the steady-state potential dependence of K current inactivation. +, recorded for sdDRGn. a) Current traces were acquired during a +10 mV drive pulse (600 ms) preceded by a series of 11,040 s prepulses ranging from -140 to +10 mV in 10 mV steps; the traces on the left (black) were acquired before and the traces on the right (grey) during application of compound of formula VIII (6.5 μg / mL; 29.4 μM). b) Current / potential relationship, where peak current amplitudes (obtained in 'a') are plotted against the potential of the prepulses used in the potential protocol in 'a' (black dots refer to the CCI control; grey dots are obtained during treatment with compound of formula VIII). A shift towards hyperpolarized values ​​can be seen during treatment with compound of formula VIII.The relationship was best approximated by the sum of two Boltzmann functions, demonstrating that in both states there are two components: one more hyperpolarized component (component 1) and one more depolarized component (component 2). In fact, the Vh (half-maximal current potential) parameters of the Boltzmann equation showed more hyperpolarized values ​​during treatment with compound of formula VIII (control: Vh1=-53.6 mV Vh2=-18.1 mV; F2: Vh1=-88.9 mV Vh2=-35.5 mV).

[0177] Detailed Description

[0178] For the purposes of this application, unless otherwise expressly defined herein, each of the following terms has the meaning given below. Additional definitions are provided in the text of the application.

[0179] References to the compounds of the invention or their pharmaceutically acceptable salts and prodrugs, nitenin, and nitenin analogs are used interchangeably herein. These terms include all stereoisomers of these compounds.

[0180] As used herein, the term "and / or" shall be construed as a separate disclosure of each of the two stated features or components, with or without the other. Thus, the term "and / or" used in an expression such as "A and / or B" is intended to include "A and B," "A or B"; "A" (alone) and "B" (alone). Similarly, the term "and / or" used in an expression such as "A, B and / or C" is intended to cover each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). It should be understood that where aspects are described herein using the phrase "comprising," otherwise similar aspects described in the terms "consisting of" and / or "consisting essentially of" are also provided.

[0181] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0182] Units, prefixes, and symbols are defined in the International System of Units (SI). Numerical ranges include the numbers defining the range. The headings provided herein are not intended to limit the various aspects of the invention, which may be realized with reference to the description as a whole. Accordingly, the terms defined below are defined more fully with reference to this description as a whole.

[0183] The term "administration" refers to the physical introduction of an agent into the body of a subject using any of the various delivery methods and systems known to those skilled in the art. Typical routes of administration for the compounds disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes, such as injection or infusion.As used herein, the term "parenteral administration" means modes of administration other than enteral and local administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. In some embodiments, the compound is administered by a non-parenteral route, such as orally. Other non-parenteral routes include local, epidermal or mucosal administration, such as intranasal, vaginal, rectal, sublingual or topical. The administration may also be carried out, for example, once, multiple times and / or over one or more extended periods.

[0184] The term "isolated" means purified from its natural environment and thus free from natural components that coexist with nitenin in its natural environment and are associated with it in nature. Isolated natural products may have chemical, biochemical, and / or physical properties that differ from those of the same product in its natural state. Synthetic versions of natural products may have chemical, biochemical, and / or physical properties that differ from those of the same product isolated from its natural environment or in its natural state.

[0185] The term "pharmaceutically acceptable" is used in this document to refer to those compounds, materials, compositions, and / or dosage forms that are, from a medical perspective, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, or other problems or complications, in accordance with a reasonable benefit / risk ratio. Registration authorities (e.g., EMA, US-FDA) provide guidance and register pharmaceutically acceptable compounds, materials, compositions, and / or dosage forms. Examples are provided, for example, in the Pharmacopoeias.

[0186] The terms "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" are used herein to refer to a pharmaceutically acceptable material selected from a solvent, dispersant, diluent, dispersion, auxiliary suspension, surface-active agent, isotonic agent, thickener or emulsifier, preservative, polymer, peptide, protein, cell, hyaluronidase, and mixtures thereof. In some embodiments, the solvent is an aqueous solvent.

[0187] A "therapeutically effective amount," "effective dose," or "effective quantity" of a drug or therapeutic agent is any amount of the drug that, when administered alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes disease regression, as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or the prevention of impairment or disability due to the disease. The ability of a therapeutic agent to promote disease regression can be assessed by a variety of methods known to a practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the agent's activity in in vitro assays.

[0188] In one embodiment, a "therapeutically effective dosage" is a dosage that, when administered in a single-dose or multiple-dose regimen, is effective in treating, preventing, and / or reducing pain. This dosage varies depending on the health and physical condition of the individual being treated, age, the degree of analgesia required, and other relevant factors. This amount is expected to fall within a relatively broad range that can be determined through routine testing. As used herein, "prevention" or "warning" does not require absolute success in the sense of completely preventing pain, but rather indicates a reduction in the risk of developing a painful condition or the development of pain of reduced severity. Similarly, "treatment" should not be understood as an absolute cure, but may also refer to the reduction or suppression of pain or pain-related conditions.

[0189] As used interchangeably herein, the terms "alkyl," "alkyl unit," and "alkyl group" refer to a saturated monovalent hydrocarbon radical containing from one to twelve carbon atoms (C1-C12). Alkyl groups may be linear, branched, or cyclic. Alkyl groups may be unsubstituted, or they may be substituted as described elsewhere herein. In some embodiments, an alkyl group contains from one to eight carbon atoms (C1-C8). In some embodiments, an alkyl group contains from one to six carbon atoms (C1-C6). In some embodiments, an alkyl group contains from one to four carbon atoms (C1-C4). In some embodiments, a cyclic alkyl group contains from three to six carbon atoms (C3-C6).

[0190] As used interchangeably herein, the terms "alkenyl," "alkenyl unit," and "alkenyl group" refer to a monovalent hydrocarbon radical containing two to eight carbon atoms (C2-C8) with at least one center of unsaturation (i.e., an sp2 carbon-carbon double bond). Alkenyl groups may be linear, branched, or cyclic. Alkenyl groups may be unsubstituted, or they may be substituted as described elsewhere herein. In some embodiments, an alkenyl group contains two to six carbon atoms (C2-C6). In some embodiments, an alkenyl group contains two to four carbon atoms (C2-C4). Alkenyl groups may have an E or Z orientation. Non-limiting examples of alkenyl groups include ethenyl (also called vinyl), 1-propenyl, isopropenyl, and 2-chloroethenyl.

[0191] As used interchangeably herein, the terms "aryl," "aryl unit," and "aryl group" refer to a monovalent aromatic hydrocarbon radical containing 6-20 carbon atoms (C6-C20) that is derived by the removal of a hydrogen atom from an aromatic ring. Aryl groups may be unsubstituted or substituted with one or more substituents, as described elsewhere herein.

[0192] The terms "heterocycle," "heterocyclyl," "heterocyclic unit," and "heterocyclic group," as used interchangeably herein, refer to a saturated or partially unsaturated ring system containing 3-20 atoms, wherein at least one of the ring atoms is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. The heterocyclic group may be unsubstituted, or it may be substituted with one or more substituents as described elsewhere herein. In some embodiments, the heterocyclic group contains 3-10 atoms. In some embodiments, the heterocyclic group contains 3-7 atoms. In some embodiments, the heterocyclic group is monocyclic. In some embodiments, the heterocyclic group is bicyclic. In some embodiments, the heterocyclic group contains fused rings.

[0193] The terms "heteroaryl," "heteroaryl unit," and "heteroaryl group," as used interchangeably herein, refer to a monovalent aromatic radical containing one or more 5-, 6-, or 7-membered rings and containing one or more heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. The heteroaryl group may be unsubstituted, or it may be substituted with one or more substituents as described elsewhere herein. In some embodiments, the heteroaryl group contains 5-20 atoms. In some embodiments, the heteroaryl group contains 5-9 atoms. In some embodiments, the heteroaryl group contains 5 atoms. In some embodiments, the heteroaryl group contains 6 atoms. In some embodiments, the heteroaryl group contains 7 atoms. In some embodiments, the heteroaryl group is monocyclic.In some embodiments, the heteroaryl group is bicyclic. In some embodiments, the heteroaryl group comprises fused rings.

[0194] As used herein, the term "substituted" refers to the substitution of one or more hydrogen atoms or one or more of a hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group with one or more substituents. In a substituted hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group, any number of hydrogen atoms may be substituted.

[0195] The compounds of the invention may contain one or more chiral centers. The compounds of the invention may exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds described herein, including, but not limited to, diastereomers, enantiomers, and mixtures thereof (including, but not limited to, racemic mixtures), form part of this invention.

[0196] Abbreviations:

[0197] Sa 2+ : Calcium

[0198] CaV: Voltage-gated calcium channel

[0199] CCI: Chronic compression

[0200] CFA: Complete Freund's adjuvant

[0201] SNO: Chinese Hamster Ovary

[0202] CIPN: Chemotherapy-induced peripheral neuropathy of the central nervous system:

[0203] Central nervous system

[0204] SOR: Chronic orofacial pain

[0205] DRG: Dorsal root ganglia

[0206] ECG: Electrocardiogram

[0207] HEK: Human embryonic kidney

[0208] hERG: Human potassium channel alpha subunit gene - Kv11.1

[0209] HFF2: Human Foreskin Fibroblasts 2

[0210] I: current

[0211] I быстрый : Fast current component

[0212] I медленный : Slow component of current

[0213] iv: Intravenous

[0214] K + : Potassium

[0215] Kv: voltage-gated potassium channel

[0216] Kv1.x: subunits of the voltage-gated potassium channel designated x

[0217] L: Lumbar Na + : Sodium

[0218] Nav: Voltage-gated sodium channel

[0219] Nav1.x: subunits of the voltage-gated sodium channel designated x

[0220] NSAID: Non-steroidal anti-inflammatory drug(s) MTS: (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)

[0221] sdDRGN: small diameter dorsal root neurons

[0222] sdTGN: small diameter trigeminal ganglion neurons

[0223] STZ: Streptozotocin

[0224] GTN: Trigeminal ganglion

[0225] TRP: Transient receptor potential cation channel

[0226] TRPV1: Transient receptor potential cation channel subfamily

[0227] USA United States of America

[0228] V, member 1

[0229] V: Potential

[0230] Vh: Half-maximum current potential.

[0231] The compounds of the invention, pharmaceutically acceptable salts of said compounds, and / or pharmaceutical compositions containing said compounds and / or their pharmaceutically acceptable salts, can be administered as a therapeutic treatment. Said compounds, pharmaceutically acceptable salts, and / or pharmaceutical compositions can be administered in unit forms of administration to mammalian subjects, including humans. Suitable unit forms of administration include, but are not limited to, forms administered orally and forms administered parenterally, non-limiting examples of which include inhalation, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, and intravitreal administration.

[0232] In some embodiments, pharmaceutical compositions for oral administration may be in the form of tablets, pills, powders, hard gelatin capsules, soft gelatin capsules, and / or granules. In some embodiments of such pharmaceutical compositions, a compound of the invention and / or a pharmaceutically acceptable salt of a compound of the invention is mixed with one or more inert diluents, non-limiting examples of which include starch, cellulose, sucrose, lactose, and silicon dioxide. In some embodiments, such pharmaceutical compositions may further comprise one or more substances other than diluents, such as (but not limited to) lubricants, dyes, coatings, or varnishes.

[0233] The pharmaceutical compositions of the invention may contain pharmaceutically acceptable carriers, excipients, vehicles, and diluents. Many of these are well known to those skilled in the art and are described, by way of non-limiting example, in Remington: The Science and Practice of Pharmacy, 22 nd Edition, Lippincott Williams & Wilkins, Philadelphia, Pa. (2013) and any other publications incorporated herein by reference.

[0234] In one aspect, this invention relates to nitenine analog compounds and their use as analgesics for the treatment, prevention, or reduction of chronic and acute pain. Using an approach utilizing the physiology and pharmacology of ion currents / channels, this document discloses a novel pharmaceutical application relating to analgesic effect for several types of pain.

[0235] In sharp contrast to existing therapeutic agents, the analgesic compound disclosed herein is positioned as a breakthrough in pain management due to its novel mode of action and predicted efficacy in humans, target specificity, and reduced side effects. The compounds nitenin and dihydronitenin (two of the compounds disclosed herein) are sourced from a sea sponge, but were and can be produced synthetically for the purposes of this invention, and the invention proposes that these compounds specifically act on certain Kv channels, Kv1.x, expressed in pain-sensitive c-fibers of the dorsal root ganglia and trigeminal ganglia. Without being limited by theory, it is proposed that the mode of action involves inhibition of a specific channel (instead of its enhancement, as in the case of retigabine) and has advantageous features such as:

[0236] (a) it is an "open channel blocker", hence an activity-dependent blocker, (b) it involves a change in the potential-dependence of the channel inactivation, and (c) it acts specifically on the K group v -channels, mainly K v 1.3. This specific and novel mode of action explains why and how nitenin and nitenin-analog compounds are effective exclusively in limbs / body parts with damaged / affected nerves. Furthermore, it does not alter nociceptive and sensory assessments in unaffected limbs / body parts.

[0237] In one embodiment, the invention relates to the use of nitenine analog compounds as analgesics for the treatment, prevention, or reduction of chronic and acute pain. Thus, in some aspects of the present invention, compounds referred to as "nitenine analog compounds" are exemplified by compounds of formula I, II, III, and IV, described in the following embodiments:

[0238] Embodiment 1. Compounds of formula I, II, III and IV, their pharmaceutically acceptable salts or prodrug,

[0239]

[0240] where

[0241] represents a carbon-carbon single bond or a carbon-carbon double bond;

[0242] X is selected from O, S, NH, CH2;

[0243] Y is selected from CH, CH2;

[0244] Z is selected from C, N;

[0245] G is selected from O, S;

[0246] T is selected from OH, SH, NH2, halogen;

[0247] R 1 and R 2independently selected from H, alkyl, alkenyl, cycloalkyl, aryl, or -CH2-R 3 ; where R 3 selected from aryl, cycloalkyl, heteroaryl, -R 4 -R 5 ; where R 4 selected from alkyl, alkenyl; where R 5 selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone;

[0248] Q is selected from C, CH;

[0249] D is selected from C, CH, CH2;

[0250] One of A and E is H, and the other is selected from H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 , where R 6 selected from alkyl, alkenyl and R 7 selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone; optionally wherein the compound is neither nitine nor dihydronitine nor their corresponding isomers, enantiomers and stereoisomers; and / or optionally wherein R 7is not furan-3-yl;

[0251] J is selected from H, OH, SH, NH2, halogen.

[0252] Embodiment 2. Compounds of formula IV according to embodiment 1, wherein

[0253] X represents O;

[0254] Y represents CH;

[0255] Z represents C;

[0256] R 1 represents H;

[0257] R 2 represents H; and

[0258] J represents OH.

[0259] Embodiment 3. Compounds of formula IV according to embodiment 1, wherein

[0260] X represents O;

[0261] Y represents CH;

[0262] Z represents C;

[0263] R 1 is an alkyl;

[0264] R 2 is -CH2-R 3 ; where R 3 represents -R 4 -R 5 ; Where

[0265] R 4 is alkyl and R 5represents heteroaryl, J represents OH.

[0266] Embodiment 4. Compounds of formula II according to embodiment 1, wherein

[0267] X represents O;

[0268] Y is CH2;

[0269] G represents O;

[0270] R 1 represents H;

[0271] J represents H;

[0272] Q represents C;

[0273] D represents C;

[0274] E represents H;

[0275] A represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl.

[0276] Embodiment 5. Compounds of formula II according to embodiment 1, wherein

[0277] X represents O;

[0278] Y is CH2;

[0279] G represents O;

[0280] R 1 represents H;

[0281] J represents H;

[0282] Q represents C;

[0283] D represents C;

[0284] E represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl;

[0285] A represents H.

[0286] Embodiment 6. Compounds of formula I, II, III and IV according to embodiment 1, wherein R 7 does not represent furan-3-yl.

[0287] Embodiment 7. Compounds of formula I, II, III and IV, their pharmaceutically acceptable salts or prodrug, wherein

[0288]

[0289] represents a carbon-carbon single bond or a carbon-carbon double bond;

[0290] X is selected from O, S, NH, CH2;

[0291] Y is selected from CH, CH2;

[0292] Z is selected from C, N;

[0293] G is selected from O, S;

[0294] T is selected from OH, SH, NH2, halogen;

[0295] R 1 and R 2 independently selected from H, alkyl, alkenyl, cycloalkyl, aryl, or -CH2-R 3 ; where R 3 selected from aryl, cycloalkyl, heteroaryl, -R 4 -R 5 ; where R 4 selected from alkyl, alkenyl; where R 5 selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone;

[0296] Q is selected from C, CH;

[0297] D is selected from C, CH, CH2;

[0298] One of A and E is H, and the other is selected from H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 , where R 6 selected from alkyl, alkenyl and R 7 selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gamma-lactone;

[0299] J is selected from H, OH, SH, NH2, halogen;

[0300] for use as pharmaceutical ingredient.

[0301] Embodiment 8. Compounds of formula I for use as a pharmaceutical ingredient according to embodiment 7, wherein:

[0302] X represents O;

[0303] Y represents CH;

[0304] Z represents C;

[0305] R 1 is an alkyl;

[0306] R 2 is -CH2-R 3 ; where R 3 represents -R 4 -R 5 ; Where

[0307] R 4 is alkyl and R 5 is a heteroaryl;

[0308] Q represents C;

[0309] D represents C;

[0310] A represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl;

[0311] E represents H; and

[0312] J represents H.

[0313] Embodiment 9. Compounds of formula IV for use as a pharmaceutical ingredient according to embodiment 7, wherein:

[0314] X represents O;

[0315] Y represents CH;

[0316] Z represents C;

[0317] R 1 represents H;

[0318] R 2 represents H; and

[0319] J represents OH.

[0320] Embodiment 10. Compounds of formula IV for use as a pharmaceutical ingredient, wherein:

[0321] X represents O;

[0322] Y represents CH;

[0323] Z represents C;

[0324] R 1 is an alkyl;

[0325] R 2 is -CH2-R 3 ; where R 3 represents -R 4 -R 5 ; Where

[0326] R 4 is alkyl and R 5represents heteroaryl, J represents OH.

[0327] Embodiment 11. Compounds of formula II for use as a pharmaceutical ingredient according to embodiment 7, wherein:

[0328] X represents O;

[0329] Y is CH2;

[0330] G represents O;

[0331] R 1 represents H;

[0332] J represents H;

[0333] Q represents C;

[0334] D represents C;

[0335] E represents H;

[0336] A represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl.

[0337] Embodiment 12. Compounds of formula II for use as a pharmaceutical ingredient according to embodiment 7, wherein:

[0338] X represents O;

[0339] Y is CH2;

[0340] G represents O;

[0341] R 1 represents H;

[0342] J represents H;

[0343] Q represents C;

[0344] D represents C;

[0345] E represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl;

[0346] A represents H.

[0347] Embodiment 13. For pharmaceutical use, the compounds of formula I, II, III and IV of the present invention are administered to warm-blooded vertebrates, preferably mammals, more preferably humans, at doses in the range of 0.1 μg / ml blood (6 μg / kg body weight) to 30 μg / ml blood (1.8 mg / kg body weight). The above-mentioned effective dose range is for intravenous administration and may differ for other routes of administration.

[0348] Embodiment 14. Compounds of formula I, II, III and IV, their pharmaceutical salts or prodrugs are used in the treatment, prevention or reduction of pain in an individual in need thereof, in particular in the case of acute or chronic pain. Acute and chronic pain is meant to include, but is not limited to, at least one of the following: neuropathic pain, nociceptive pain, psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low back pain, radiculopathic pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, wound-related pain, chemotherapy-induced peripheral neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain,cancer-related pain, fibromyalgia-related pain, hyperalgesia syndrome, infection-related pain, HIV-related pain, sprains and strains, hyperalgesia, somatogenic 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, arthritic pain, somatic visceral pain, phantom pain, radiculopathy, low back pain, visceral pain, bowel pain, and osteoarthritis-related pain.

[0349] Embodiment 15. Compounds of formula I, II, III and IV, their pharmaceutical salts or prodrugs are used in the treatment of autoimmune disorders due to the effects described for Kv1.3, the target in such disorders.

[0350] Embodiment 16. Compounds of formula I, II, III and IV, their pharmaceutical salts or prodrugs are used in the treatment of diabetes, taking into account that their effect on the Kv1.3 channel is considered to be associated with insulin sensitivity, syndromes associated with insulin resistance, and obesity.

[0351] Embodiment 17. Compounds of formula I, II, III and IV, their pharmaceutical salts or prodrugs are used as antiepileptic and anticonvulsant agents.

[0352] Embodiment 18. Compounds of formula I, II, III and IV for use in the treatment or prevention of a disease in which Kv1.3 channels are involved.

[0353] Embodiment 19. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients include at least one compound according to formula I, II, III and IV or a pharmacologically acceptable salt or prodrug thereof.

[0354] Embodiment 20. A method of treating pain in a subject in need thereof, comprising administering to the subject having pain a therapeutically effective amount of a compound of formula I, II, III and IV.

[0355] Embodiment 21. The method according to embodiment 19, characterized in that the pain is an acute and chronic type pain selected from neuropathic pain, nociceptive pain, psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low back pain, radiculopathic pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, pain associated with wounds, chemotherapy-induced peripheral neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain associated with cancer, pain associated with fibromyalgia, hyperalgesia syndrome, pain, infection-related, HIV-related pain, dislocations and sprains, hyperalgesia, somatogenic pain, psychogenic pain,heat-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial pain, vascular pain, migraine, wounds, pain associated with wounds, arthritic pain, somatic visceral pain, phantom pain, radiculopathy, low back pain, visceral pain, bowel pain and pain associated with osteoarthritis.

[0356] Embodiment 22. A method for treating or preventing a disease in which Kv1.3 channels are involved in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula I, II, III and IV to a subject in need of treating or preventing a disease in which Kv1.3 channels are involved.

[0357] Embodiment 23. A method of treating an autoimmune disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula I, II, III and IV to a subject having the autoimmune disease.

[0358] Embodiment 24. A method for treating diabetes or insulin resistance syndromes in a subject in need thereof, comprising administering a therapeutically effective amount of a compound to a subject having diabetes or insulin resistance syndrome.

[0359] Embodiment 25. A method for treating epilepsy or seizures in a subject in need thereof, comprising administering a therapeutically effective amount of a compound to a subject having epilepsy or seizures.

[0360] Embodiment 26. The method according to embodiments 20-23, characterized in that the compound is administered in a therapeutically effective amount of from 0.018 to 1.8 mg / kg.

[0361] Embodiment 27. The compound, composition, use, or method disclosed herein, wherein the compound is a compound of formula I, wherein

[0362] X represents O;

[0363] Y represents CH;

[0364] Z represents C;

[0365] R 1 is an alkyl;

[0366] R 2 is -СН2-R 3 ; where R 3 represents -R 4 -R 5 ; where R 4 is alkyl and R 5 is a heteroaryl;

[0367] Q represents C;

[0368] D represents C;

[0369] A represents -R 6 -R 7 ; where R 6 is alkyl and R 7 is a heteroaryl;

[0370] E represents H; and

[0371] J represents H.

[0372] Embodiment 28. Compounds according to embodiments 1-6, characterized in that the compound is isolated or obtained synthetically.

[0373] Embodiment 29. The compounds of embodiments 7-28, wherein the compound is nitinin or dihydronitinin.

[0374] The present invention discloses compelling evidence that nitenin and nitenin analog compounds can be used as analgesics for the treatment, prevention, or reduction of chronic and acute pain. This evidence was obtained using several technical approaches, including ex vivo neuronal preparations, animal pain models, behavioral pain assays, in silico approaches, in vitro toxicity studies, and whole-cell voltage clamp recordings.

[0375] The nitenin analog compounds of the present application were first isolated from the marine sponge Spongia agaracina collected in Sagres, Portugal, but have also been chemically synthesized. As demonstrated in the examples, the nitenin-containing extract exhibited a modulating effect on potassium currents recorded from rat sdDRGN (pain-sensitive neurons), a bioactivity that formed the basis of the biodirected fractionation process. A series of fractions obtained allowed the identification of compounds that not only retained the ability to modulate K currents, but also + , but also demonstrated high levels of efficacy. The results were also confirmed in small-diameter trigeminal ganglion (sdTGN) neurons, which demonstrated identical pharmacological effects with very similar K current profiles. + .

[0376] Toki K +, which were affected by the identified compounds registered for sdDRGN (and sdTGN) using the whole-cell voltage-clamp method, were the subject of intensive research by the author of the application in the field of pain neurophysiology. The use of rat pain models was fundamental for conducting preliminary target validation, i.e., determining the K current component. + , differentially expressed in pain conditions. In one aspect of the invention, it is proposed that the K current component +The component affected by the pain state is predominantly modulated (reduced) by the compounds of interest. The nature of the recorded modulatory effect on currents was investigated by monitoring several biophysical parameters, such as activation and inactivation potential dependence and kinetics. The specificity of bioactivity was determined by comparing the pharmacological effect on currents recorded for sdDRGN with currents in other types of dorsal root ganglia (medium- and large-diameter DRGs).

[0377] Furthermore, drug sensitivity to different voltage-gated channels was assessed by studying the effect of the drug on currents recorded from Chinese hamster ovary (CHO) cells stably transfected with different subunits of human Kv channels (Kv1.1, Kv1.2, Kv1.3, Kv1.4, and Kv1.6). The compound is most active in the case of hKv1.3 (IC 50~190 nM), which represents a 6-30-fold higher sensitivity than other studied Kv1.x.

[0378] One of the competitive advantages of nitenin and nitenin analog compounds over other compounds used in pain therapy, including those acting on ion channels, lies in part in their at least eight properties, which, although interrelated, can be described as follows:

[0379] 1 - Nitenin and nitenin analog compounds are small molecules that can be synthesized using chemical synthetic approaches;

[0380] 2 - Their novel mode of action and the location and nature of their cellular target: Nitenin reduces the activity of Kv channels expressed in snDRG (a Kv1.x subgroup with higher affinity for Kv1.3), which are responsible for the slow delayed rectifier current, which modulates pain signaling and propagation towards the brain. Given this peripheral effect of Nitenin and Nitenin analogs, there is no need to exclude a complementary central effect. There is currently a significant and unmet need for specific blockers of some of these Kv1.x channels (e.g., Kv1.3 and Kv1.6) with clinical potential.

[0381] 3 - Administration of nitenin and nitenin analogue compounds does not result in any loss of sensory and nociceptive ability and nociception of intact limbs / body parts, a feature that is related to their mode of action, such as the fact that it is a channel-opening dependent effect.

[0382] 4 - Nitenin and nitenin analog compounds of the present invention are easy to administer. In animal models used to study nitenin analog compounds, intravenous

[0383] (IV) and intraperitoneal injections have been shown to be successful in their analgesic effect. Importantly, nitenine analog compounds can also be administered orally, thus being a preferred embodiment given that intragastric administration has also been performed in animal models with similar analgesic effects.

[0384] 5 - Based on the toxicology experiments conducted, there are no signs of any toxicity or side effects on the systems examined and described below. Given that nitin acts primarily (but not exclusively) in the peripheral nervous system, no toxicity or side effects related to the brain were observed.

[0385] 6 - Nitenin and its analogs are effective in reducing pain in a range of pain models, including acute and chronic neuropathic pain, chemotherapy-induced peripheral neuropathy, acute and prolonged or chronic inflammatory pain (nociceptive pain), orofacial chronic pain, and diabetic neuropathic chronic pain. These results suggest a wide range of potential clinical applications.

[0386] 7 - Although it is also effective in case of acute / short-term pain, nitin is particularly effective in case of long-term / chronic forms of pain; and

[0387] 8 - Acting specifically on a subgroup of potassium channels (Kv1.x) and having no effect on sodium currents / channels (Na vs), compounds-analogues of nitenin will not compete with Nav-modulating agents, on the contrary, they can be used in combination with them, maximizing the intended analgesic effect or providing a synergistic effect.

[0388] In one embodiment, the compounds of the invention or their pharmaceutically acceptable salts and prodrugs can be used to treat acute pain. Examples of acute pain situations, the type of pain that typically lasts less than 3-6 months, include surgery, bone fractures, dental work, burns and cuts, pain directly associated with soft tissue injury such as an ankle sprain, labor, and childbirth.

[0389] In one embodiment, the compounds of the invention or pharmaceutically acceptable salts and prodrugs thereof can be used to treat chronic pain. Examples of diseases or disorders associated with chronic pain include chronic pain due to peripheral neuropathy, arthritis, especially osteoarthritis, cancer, HIV, diabetes, fibromyalgia, shingles, herpes, headache, migraines, multiple sclerosis, nerve damage (neuropathy), low back pain, injuries and other trauma (e.g., herniated disc, torn ligaments), sciatica, diabetic neuropathy, carpal tunnel syndrome, trigeminal neuralgia, post-surgical pain, chronic fatigue syndrome (or myalgic encephalomyelitis), endometriosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, interstitial cystitis, temporomandibular joint dysfunction (TMJD), vulvodynia, bursitis, celiac disease, lupus,rheumatoid arthritis, complex regional pain syndrome, myofascial pain syndrome, meningitis, Lyme disease and other tick-borne diseases, muscle strains and dislocations.

[0390] In some embodiments, the compounds of the invention or pharmaceutically acceptable salts and prodrugs thereof can be used to treat hyperalgesia, somatogenic pain, psychogenic pain, heat-induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial pain, vascular pain, migraine, wounds, pain associated with wounds, arthritic, somatic, visceral, phantom pain, radiculopathy, low back pain or pain associated with osteoarthritis.

[0391] Both acute and chronic pain involve complex alterations in the processing and transmission of electrical signals from peripheral nerves to the central nervous system (CNS). Electrical excitability and activity levels, whether normal or associated with chronic pain, result from the influx or efflux of charged metal ions such as sodium (Na + ), potassium (K + ) or calcium (Ca 2+) through membrane ion channels (Nav, Kv, or Cav, respectively), leading to the generation, propagation, and transmission of electrical signals across and between cells. Chronic pain involves alterations in the underlying pain-signaling neuronal network, with abnormal ion currents driven by altered expression and biophysics of the underlying channels, leading to long-term neuronal excitability and activity. Therefore, an effective analgesic should be able to suppress the hyperexcitability of the pain-signaling network, restoring the physiological expression and / or biophysical profiles of functioning channels and, in turn, restoring network activity to resting levels.

[0392] Small-diameter c-fiber neurons (c-fibers), also known as pain-sensitive neurons, are located outside the spinal cord, providing nociceptive input to the central nervous system (CNS). Under normal conditions, these neurons typically exhibit no spontaneous firing activity, being silent (e.g., Ly et al., 2018), a situation that changes during painful episodes and in chronic pain. The current standard therapeutic strategy is to target key ion channels located in these neurons, both in c-fiber neurons and in trigeminal ganglion (TG) neurons, to “turn off” this pain-induced hyperexcitability. Consequently, the transmission of the “pain signal” to the CNS is interrupted or reduced, thus preventing the brain from perceiving pain. It is also possible that there is an additional effect in central neurons, contributing to the analgesic effect.

[0393] In some embodiments, the compounds of the invention or their pharmaceutically acceptable salts and prodrugs can be used to inhibit pain-induced hyperexcitability. In some embodiments, they can be used to modulate pain perception in the brain.

[0394] Several ion channels have been identified as key effectors in pain transmission. Some, in particular, are present in these pain-sensitive neurons. Therefore, specific modulation of their activity will block pain without affecting other bodily functions. This paper reveals that nitenin analogs are specific modulators for inhibiting voltage-activated K currents. +, recorded for small-diameter neurons (sdDRGN, as well as sdTGN, are considered to correspond to c-fibers). The cause of this slow current is some Kv1.x channels. This effect is less pronounced in large-diameter neurons in the submicromolar concentration range, i.e., at concentrations below 1 micromolar, and the modulating effect of nitenin is exclusive to sdDRGN and sdTGN.

[0395] In some embodiments, the compounds of the invention or pharmaceutically acceptable salts and prodrugs thereof can be used to modulate slow voltage-activated currents K + In some embodiments, the currents originate from small diameter neurons (sdDRGN, as well as sdTGN).

[0396] Kv1.x, including those mediating slow voltage-gated currents, are ion channels involved in the propagation of pain signals that are initially present in pain-sensitive neurons. Nitenin analog compounds are particularly effective in the case of the slow component of the K current. +, a subcomponent of the current which, given the kinetics and voltage dependence of the nitenin-sensitive current, strongly suggests a role for the Kv1.x subset of channels. Indeed, voltage-clamp studies performed on currents recorded from CHO cells stably transfected and expressing hKv1.1, hKv1.2, hKv1.3, hKv1.4, or hKv1.6 showed that nitenin analog compounds are much more potent for the Kv1.3 channel (approximately 6-fold more sensitive to nitenin than the second most sensitive channel (Kv1.2) and approximately 30-fold more sensitive than the least sensitive channel (Kv1.4)) (see Fig. 2).

[0397] In some embodiments, the compounds of the invention or their pharmaceutically acceptable salts and prodrugs can be used to suppress hyperexcitability in central neurons, specifically neurons associated with seizure episodes. This effect on Kv1.x channels, resulting from the abolition of repetitive neuronal impulse activity, underlies the antiepileptic effect. Therefore, nitenin and nitenin analogs can be used as antiepileptic and anticonvulsant agents.

[0398] In some embodiments, the compounds of the invention or their pharmaceutically acceptable salts and prodrugs can be used as Kv1.3 inhibitors. Kv1.3 has been described as a target for the treatment of immunological pathologies, as well as a target for the treatment of diabetes and other metabolic disorders. The compounds of the invention can be used to treat diabetes and other metabolic disorders.

[0399] In some embodiments, the compounds of the invention or their pharmaceutically acceptable salts and prodrugs can be used to treat autoimmune diseases. In other embodiments, they can be used to improve insulin sensitivity.

[0400] In connection with these therapeutic treatment options, the administration regimen(s), dosage(s), and optimized pharmaceutical form(s) can be determined in accordance with criteria typically considered when prescribing treatment to a patient, such as, but not limited to, the potency of the compound(s) and / or pharmaceutically acceptable salts of the compound(s), the patient's age, the patient's body weight, the severity of the patient's condition(s), the patient's tolerability of the treatment, and secondary effects observed during treatment. Determining dosages effective to provide therapeutic benefit for specific regimens and frequency of administration is within the skill of those skilled in the art.

[0401] EXAMPLES

[0402] In vivo and ex vivo models of pain

[0403] Rat pain models used for both in vivo behavioral work and ex vivo electrophysiological studies were:

[0404] • Naive Wistar rats: control rats; neurons from dorsal root ganglia (DRG), lumbar regions 4, 5 and 6 (L4, L5 and L6).

[0405] • Rat model of acute and chronic neuropathic pain: CCI rats (chronic sciatic nerve compression in Wistar rats), 3 days (in case of acute pain) and 23 to 29 days (in case of chronic pain) after surgery; neurons from the DRG (L4, L5 and L6).

[0406] • Rat model of acute and long-term or chronic inflammatory pain: CFA rats (injection of complete Freund's adjuvant (CFA) into the knee of Wistar rats), 3 days [acute pain], 18 days (subchronic pain) and 23 days (chronic pain) after injection; neurons from the DRG (L4, L5 and L6).

[0407] • Rat model of chronic orofacial (COP) pain: COP rats injected with CFA into the whisker area of ​​Wistar rats, which were analyzed 28-30 days after injection; neurons from the trigeminal ganglion.

[0408] • Rat model of diabetic neuropathic pain: STZ rats, Wistar rats that were given intraperitoneal injections of STZ (streptozotocin) developed pain signs after 30 days, and after another 30 days, they were examined with nitenin (IV) (total 60 days); neurons from the DRG (G4, G5 and G6).

[0409] • Rat model of chronic pain in chemotherapy-induced peripheral neuropathy: CIPN rats, Wistar rats were subjected to 3 sessions (intraperitoneal injections) of paclitaxel (every 2 days), examined 42 days after the induction; neurons from the DRG (L4, L5 and L6).

[0410] For ex vivo electrophysiological studies, voltage-clamp recordings were performed on neurons isolated from rat DRGs (and GTNs). Recordings were made from the soma, which often contained the proximal portion of the axon, 1 hour after completion of the cell isolation process (including enzymatic and mechanical processing).

[0411] Method of action:

[0412] The mode of action of nitenin (represented herein by the compound of formula V) and nitenin analog compounds (represented herein by the compounds of formula I-IV and VI-VIII) as analgesics is disclosed for the first time in this document. It involves reducing K currents + , rather than enhancing them. For this reason, it is important to first study the characteristics of potassium currents present in sdDRGN and sdTGN.

[0413] Potential-activated currents K + Whole-cell currents recorded for sdDRGN after a depolarization step (i.e., to +40 mV with a duration of 1 second, as in Fig. 1) showed rapid activation after two phases of inactivation. The current decay at depolarization potentials is best approximated by the sum of two exponential functions: a relatively fast component (referred to herein as I быстрый , associated with what is known as the A-current), demonstrating time (τ быстрый) on the order of tenths of a millisecond, followed by a much slower inactivating current (referred to in this document as I медленный ), demonstrating time (τ медленный ) on the order of hundredths of milliseconds (see Fig. 1). Different ratios of I were found in different cells. быстрый and I медленный , and some cells showed only one component, I медленный The currents detected in sdDRGn are very similar to those described for sdTGn.

[0414] Nitenin inhibited K currents + from sdDRGN and sdTGN in a dose-dependent manner. At concentrations up to 1 μM (-0.3 μg / ml), it specifically reduces I медленный (see Fig. 1.b), the current component that becomes overexpressed (relative to I медленный) in sdDRGn neurons (and in sdTGn neurons) derived from "injured nerves" of their rat models of chronic pain (CCI, CFA, and orofacial pain). In a typical example, shown in Fig. 1.b, it can be seen that the peak current remains generally unchanged by nitenin treatment, although the slow component does decrease. The nitenin-sensitive current component (subtracting the curve at the bottom of the figure) exhibits a current decay that is best approximated by a single exponential at -150 ms, further suggesting that at moderate concentrations, the effect of nitenin is specific to I медленный In contrast, nitin had little effect on I быстрый at concentrations up to 1 μg / ml; to reduce I быстрый concentrations above 3 μM / ml were required. What is important is the reduction in I медленныйNitenin was more pronounced in neurons obtained from animals with chronic pain, compared with the reduction caused by some concentrations of Nitenin in neurons obtained from control animals.

[0415] The nitenin effect is specific to K currents + , and it is not able to induce relevant changes in voltage-activated currents Na + (Fig. 1.b).

[0416] Different dose-response relationships for I медленный and I быстрый is best seen in the dose-response curves shown in Fig. 2.a. Concentration / blocking relationship for I медленный demonstrates the presence of a double phase. Up to 1 μM (-0.3 μg / mL), the relationship can be approximated by a single Hill function with IC 50 -0.12 μM. At high concentrations, the dependence of I медленный is described by the second phase, when the effect on I медленный added to the effect on I быстрый Indeed, this second phase corresponds to the concentration / blocking relationship for I быстрый, which, in turn, is best approximated by a single Hill function Its IC 50 ~6 μM confirms much lower sensitivity to nitenin.

[0417] Higher sensitivity to nitenin for I медленный (and not I быстрый ) and the nature of the nitenin-sensitive current (see nitenin-sensitive current in Fig. 1.b) allows us to understand which channel K + is the cause of I медленный . Taking into account which Kv channel subunits are expressed in DRGs and the biophysical nature of the nitenin-sensitive current, we investigated the effect of nitenin on whole-cell currents recorded for CHO cells expressing hKv1.1, hKv1.2, hKv1.3, hKv1.4, and hKv1.6. Of this list, only Kv1.4 can be the cause of I быстрый "A-type", and the rest can participate in I медленныйThe results are summarized in Fig. 2.B, which shows the dose-response relationship with relative sensitivity to nitenin. Current inhibition was measured at the end of the 1000 ms pulse. Kv1.3 demonstrated the greatest sensitivity with an IC 50 190 nM, the actual value in the same dose-response range for I медленный for sdDRGN (IC 50 I медленный ~120 nM). In contrast, hKv1.1, hKv1.2, and hKv1.6 demonstrated ~6x lower (or lesser) sensitivity, and hKv1.4 demonstrated ~30x lower sensitivity, being the least sensitive.

[0418] Inhibition of slow K currents by nitenin +involves the pharmacological process of "channel opening block." It also involves a change in the steady-state inactivation potential dependence (and little or no change in the activation potential dependence). In fact, nitinin induces a shift toward more hyperpolarized potentials in the B-A curves related to the inactivation potential dependence (see Fig. 3).

[0419] Compounds inhibit slow voltage-activated currents recorded for sdDRGN by stimulating the inactivation of K channels +, whose inactivation is somewhat impaired in chronic pain conditions. More precisely, the compounds shift the steady-state inactivation potential sensitivity toward less depolarized values ​​(or more hyperpolarized ones), facilitating inactivation. This compound-induced inactivation shift is primarily greater the more depolarized the potential curve profile is (before treatment with nitenin or nitenin analogs). Depolarized inactivation curves are typical for sdDRGNs derived from chronic pain conditions. In other words, in neurons derived from injured nerves (chronic pain), nitenin returns the inactivation potential dependence profile to "control" profiles.Therefore, the compound-induced shift in sensitivity to the inactivation potential is greater in neurons from injured nerves (which exhibit an abnormally depolarized profile) and less so in uninjured neurons, which exhibit hyperpolarized potential profiles. This interesting effect on channel regulation partially explains the compound-induced decrease in neuronal excitability, which is specific / more pronounced in uninjured neurons, i.e., during pain.

[0420] C fibers are typically inactive with little or no spontaneous firing activity, i.e., under control conditions, baseline activity is weak or absent. We began by analyzing the effect of nitenin on intact, inactive neurons. Given the nature of nitenin's mode of action, a weak or absent effect of nitenin on K currents would be expected. +in such "inactive neurons," since it is an open-channel blocker and its effect depends on activity (also, the shift in inactivation curves caused by nitenin should be minimal). Despite this, in this case of intact neurons, there is a moderate decrease in K currents. + , but this effect does not reach the threshold potential for inducing repeated impulses (due to insufficient induced depolarization). This partially explains why nitenin does not change the "perception of pain" in undamaged areas of the body. On the other hand, when chronic pain occurs, damaged neurons are in a hyperexcitable state with repetitive and prolonged impulse activity. In these hyperexcitable neurons, the effect of nitenin is maximal (as explained above). An additional increase in the resting potential (induced by a nitenin-mediated decrease in K currents) +) will lead to suppression of impulse activity due to indirect stimulation of sodium channel inactivation. Consequently, the signal is interrupted, but only in the "damaged" fibers.

[0421] Finally, with regard to specificity, it is important to note that the slow currents obtained for large diameter DRG neurons are about 10 times less sensitive to nitenin.

[0422] The way in which nitenin's effect on Kv currents leads to an analgesic effect is related to a new mode of action, since in the case of traditional approaches to solving this issue, one would expect that an increase in Kv currents, rather than inhibition, would reduce the excitability of hyperexcitable C-fiber neurons. In the present case, it should be emphasized that slowly inactivating potassium currents (I медленный ) Functionally, they are expressed more compared to rapidly inactivating currents (I быстрый) in chronic pain conditions (sdDRGn derived from rat models of CCI, CFA, and STZ, and sdTGn from COP). It is also important to note that in such conditions I медленный exhibits abnormal depolarized inactivation profiles, i.e., less channel inactivation. To maintain impulse activity over long periods, which is a typical situation in chronic pain, an increase in "excitatory force" due to a corresponding increase in Na currents + , must be balanced by an increase in currents K + , which would compensate for the profiles of repetitive long-term spike activity. The effect of the compounds disclosed herein is to return such profiles to control profiles by reducing the slowly inactivating Kv-mediated current. This nitenin-mediated effect on slow Kv currents +would not allow the necessary compensation of sodium conductivity (Nav), which is typical in painful situations. As a result, elevated sodium currents would be inactivated in the presence of nitenin (also due to depolarization caused by the reduction in Kv currents), turning off spiking activity in damaged nerves, but not in normal, undamaged neurons. This means that during pain, particularly chronic pain, Kv blockers, and not just Kv potentiators or substances that stimulate their opening, should be considered as potential analgesics.

[0423] How the reduction of currents K + leads to a significant decrease in neuronal excitability, can be explained in different ways or, most likely, by a combination of phenomena.

[0424] First, as mentioned above, the drug-induced decrease in K currents +may lead to a slow depolarization of damaged neurons in such a way as to maintain the membrane potential at a depolarized level, so that the threshold potential can pass without activating an action potential. This will thus lead to a compensatory process, since depolarization will close the inactivation pathways of Na channels. + , remaining closed, preventing the increase of the action potential (insufficiently “activated” Na channels + ).

[0425] Second, a more direct role for specific blockade of Kv1.3 could be considered because (1) nitinin is particularly effective against Kv1.3 (see Fig. 2.b) and (2) Kv1.3 is expressed in the DRG (Yang et al., 2004) and its expression levels are increased in DRG neurons during chronic pain (unpublished data). The biophysical nature and kinetics of Kv1.3-mediated currents are thought to support stabilized tonic firing (Kupper et al., 2002), a state that corresponds to neurons in a “chronic pain situation.” A reduction in such Kv1.3-mediated currents would result in a decrease in action potential amplitude and a steady-state depolarized state without firing activity, as was found in rat hippocampal neurons (Kupper et al., 2002).

[0426] Efficiency results:

[0427] For efficacy studies, nociception was assessed in all animals across all pain models by regularly observing behavior and quantifying sensitivity to mechanical stimuli using von Frey filaments, thereby reflecting hyperalgesia during hypersensitivity. For the CCI neuropathic pain model, cold allodynia with an acetone challenge was also used, which demonstrated very similar effects to von Frey filaments.

[0428] Efficacy after intravenous administration. The following results are for intravenous (IV) injections of purified nitenin (>98% of the compound of formula V) (1 μg / ml blood, -0.06 mg / kg).

[0429] • Naive control Wistar rats: No change in sensory score was observed in either paw after i.v. injections of nitenine.

[0430] • In CCI rats, a marked decrease in sensitivity to mechanical stimuli was observed after i.v. administration in both acute (3 days after model induction) and chronic (22 or 31 days) situations. A typical experiment is shown in Fig. 4. The nitenin-induced reduction in hypersensitivity was pronounced in both acute and chronic pain conditions, but was clearly greater in the case of chronic pain; in some individuals, nitenin returned scores to control values. The duration of pain relief ranged from 2 to 4 hours. Importantly, in all animals studied, there were no changes in behavioral scores of the contralateral (undamaged) paw.

[0431] • In CFA rats, a significant decrease in sensitivity to mechanical stimuli was observed after intravenous injection of nitenin for all conditions: 3 days (acute pain), 18 days (subchronic pain, intravenous), and 23 days (chronic pain). Again, the effect of nitenin was greater in chronic conditions, even though partial recovery of scores had already occurred by the 23rd day. The duration of pain reduction ranged from 2.5 to 4.5 hours and, as with CCI rats, the effect was limited to the injured paw.

[0432] • In the case of COP rats, intravenous administration of nitenin in a suitable manner resulted in a marked reduction in mechanical sensitivity assessed in the whisker area 23 days after CFA injection (chronic pain). A typical experiment is shown in Fig. 5. The duration of pain relief was 3 to 4 hours, and the effect was limited to the damaged whisker area (damage on only one side of the snout).

[0433] • In the case of STZ rats, the animals achieved diabetic blood glucose levels within a week after STZ injection and hypersensitivity to mechanical stimuli at the end of the 30-day period. Therefore, nitin was administered only intravenously,

[0434] 60 days after STZ treatment, allowing time for chronic diabetic neuropathy to develop. Following administration of nitenin, we observed a decrease in mechanical sensitivity in the hypersensitive paws. The duration of nitenin-induced pain relief ranged from 2 to 3 hours.

[0435] • In CIPN rats, intravenous administration of nitin 42 days after paclitaxel treatment resulted in a correspondingly intense reduction in sensitivity to mechanical stimuli in both paws. However, the pain reduction in this case was less intense and shorter-lived (<2 hours) compared to other pain models, possibly due to the severity of the model.

[0436] - Efficacy after intraperitoneal administration. Intraperitoneal administration was studied in CFA rats (73 days after CFA injection) with a dose of nitenin 10 times higher than that administered by intravenous injection. A clear pain-relieving effect was observed, with scores reaching control levels, and the effect lasted for approximately 4 hours.

[0437] - Efficacy after oral administration. Oral administration of nitenin via a gastric tube (intragastric) at a dose 100 times greater than that administered by intravenous injection was studied in CCI rats (31 days after surgery). All animals showed similar pain reduction, i.e., a decrease in sensitivity values. This effect lasted approximately 2 hours.

[0438] In addition to the studies conducted with nitenin, 3 analogs (compounds of formula VI, VII and VIII) developed based on the core structure of formulas I, II, III and IV were also investigated to demonstrate activity.

[0439] Overall, nitenin compounds have been shown to be effective in the treatment of short-term / acute and long-term / chronic neuropathic pain, short-term / acute and long-term / chronic inflammatory pain, chronic orofacial pain, diabetic neuropathic pain, and chemotherapy-induced peripheral neuropathy. Efficacy has been demonstrated for multiple routes of administration, including intravenous, intraperitoneal, and, most importantly, oral administration.

[0440] The effect of the three nitenin analogs was similar in terms of the effect on the K current component + . In this case, typical effects on I медленный(Figs. 7-9) and the dependence on the steady-state inactivation potential (Figs. 10-12) were observed at other concentrations. This clearly indicates that nitenin analog compounds have a distinct effect on I медленный , albeit with excellent affinity. The strongest effect was observed for compound of formula V, followed by compounds of formula VII, VIIIa, VIIIb, and VI, respectively.

[0441] Based on the dose-response curves when several intravenous concentrations were used and the efficacy levels were then quantitatively evaluated, nitenine analogs can be used for pharmacological use in warm-blooded vertebrates, particularly humans, at doses ranging from 0.1 μg / mL blood (6 μg / kg body weight) to 30 μg / mL blood (1.8 mg / kg body weight).

[0442] Toxicity results:

[0443] The toxicity of nitenin compounds was assessed using various methods. No signs of toxicity were detected.

[0444] 1. In silico toxicity analysis

[0445] Analysis using VEGA® software allowed us to investigate several types of toxicity: mutagenicity, carcinogenicity, developmental toxicity, hepatotoxicity, skin sensitization, estrogen receptor affinity, and several environmental parameters (e.g., aquatic toxicity, bees, bioaccumulation). All tests were negative at various confidence levels.

[0446] 2. In vitro and ex vivo toxicity

[0447] • Cell viability studies (MTS) using HFF2 cell lines did not demonstrate any reduction in cell viability for concentrations up to 200 µM.

[0448] • Cardiotoxicity:

[0449] a) Cell viability studies (MTS) using primary cultures of mouse cardiomyocytes did not demonstrate any reduction in cell viability for concentrations up to 20 μM.

[0450] b) Whole-cell voltage clamp method in hERG: There is no effect of outward currents mediated by hERG expressed in HEK (human embryonic kidney) cells.

[0451] c) Ex vivo rat tissue preparations showed that nitin (up to 10 μM) did not alter sinus heart rate, atrial contractility (in isolated rat atrium), and right ventricular (RV) contractility (in isolated rat ventricles).

[0452] d) In vivo electrocardiogram (ECG) of anesthetized Wistar rats showed that intravenous injection of nitenin (60 μg / kg) did not change sinus rhythm and heart rate and did not induce arrhythmia or any proarrhythmic phenomena.

[0453] 3. In vivo toxicity

[0454] For all in vivo administrations, animal behavior was observed for an additional week, a period after which postmortem examinations were performed. Each group of animals received two intravenous administrations daily (one in the morning and one in the late afternoon) for a full week. No changes in any organ or internal structure were observed.

[0455] Several features are described below, each of which can be used independently or in any combination with other features. However, any single feature may not address all of the issues discussed above, or may address only one of the issues discussed above. Some of the issues discussed above may not be fully addressed by any of the features described in this document. Despite the presence of headings, information relevant to a specific heading but not found in the section with that heading can also be found elsewhere in the description.

[0456] The foregoing description has described embodiments of the invention with reference to numerous specific details, which may vary for different embodiments. Accordingly, the sole and exclusive indicator of the essence of the invention and what is intended by applicants to be the essence of the invention is the claims filed with this application in the specific form in which such claims are filed, including any subsequent amendments. Any definitions expressly provided herein for terms contained in such claims shall be governed by the meaning of such terms used in the claims. Accordingly, no limitation, element, property, characteristic, advantage, or feature that is not expressly stated in a claim shall in any way limit the scope of such claim.Accordingly, the description and graphics should be considered in an illustrative and not limiting sense.

[0457] Various publications, articles, and patents are cited or described throughout the background section and the description; each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles, and the like included in this description is intended to provide context for the invention. Such discussion is not an admission that any or all of these materials form part of the prior art with respect to any disclosed or claimed inventions.

[0458] Bibliographic references:

[0459] Li Y, North RY, Rhines LD, Tatsui CE, Rao G, Edwards DD, Cassidy RM, Harrison DS, Johansson CA, Zhang H, Dougherty PM. (2018). DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain. J Neurosci. 2018 Jan 31;38(5): 1124-1136.

[0460] Kupper J, Prinz AA, Fromherz P (2002).Recombinant Kv1.3 potassium channels stabilize tonic firing of cultured rat hippocampal neurons. Pflugers Arch. Feb;443(4):541-7.

[0461] Yang EK, Takimoto K, Hayashi Y, de Groat WC, Yoshimura N.(2004). Altered expression of potassium channel subunit mRNA and alpha-dendrotoxin sensitivity of potassium currents in rat dorsal root ganglion neurons after axotomy. Neuroscience; 123(4):867-74.

Claims

1. A compound of formula I or III, or a pharmaceutically acceptable salt thereof, Where represents a carbon-carbon single bond or a carbon-carbon double bond; X is selected from O, NH; Y is selected from CH, CH2; Z represents C; T represents OH; for a compound of general formula (I): R 1 and R 2 each represents H, or one of R 1 and R 2 selected from H or C1-C4 alkyl, and the other is selected from -CH2-R 3 , where R 3 selected from C6aryl or -R 4 -R 5 , where R 4 selected from C1-C4 alkylene, and R 5 selected from C6aryl or C5-C6heteroaryl containing at least one heteroatom selected from O and N; Q is selected from C, CH; D is selected from C, CH; one of A and E represents H and the other represents R 6 -R7 , where R 6 selected from C1-C4 alkylene, and R 7 selected from C6aryl or C5-C6heteroaryl containing at least one heteroatom selected from O and N; J is selected from H and OH; wherein the compound does not represent nitin, dihydronitin or their corresponding isomers, enantiomers and stereoisomers.

2. The compound according to claim 1, in which R 7 does not represent furan-3-yl.

3. A compound according to any one of paragraphs 1, 2, characterized in that said compound is isolated or synthetic.

4. A pharmaceutical composition for the treatment of acute or chronic pain, comprising a therapeutically effective amount of one of the compounds of formula I and III, or one of the pharmaceutically acceptable salts of any of the said compounds, and a pharmacologically acceptable diluent or carrier Where represents a carbon-carbon single bond or a carbon-carbon double bond; X is selected from O, NH; Y is selected from CH, CH2; Z represents C; T represents OH; for a compound of general formula (I): R 1 and R 2 each represents H, or one of R 1 and R 2 selected from H or C1-C4 alkyl, and the other is selected from -CH2-R 3 , where R 3 selected from C6aryl or -R 4 -R 5 , where R 4 selected from C1-C4 alkylene, and R 5 selected from C6aryl or C5-C6heteroaryl containing at least one heteroatom selected from O and N; Q is selected from C, CH; D is selected from C, CH; one of A and E represents H and the other represents R 6 -R 7 , where R 6 selected from C1-C4 alkylene, and R 7selected from C6aryl or C5-C6heteroaryl containing at least one heteroatom selected from O and N; J is selected from H and OH.

5. The pharmaceutical composition of claim 4, wherein the compound is a compound of formula I, in which: X represents O; Y represents CH; Z represents C; R 1 is C1-C2 alkyl; R 2 is -CH2-R 3 ; where R 3 represents -R 4 -R 5 , where R 4 is a C1-C4 alkylene and R 5 is a C5-C6 heteroaryl containing at least one heteroatom selected from O and N; Q represents C; D is CH; A represents -R 6 -R 7 , where R 6 represents C1-C4 alkylene and R 7is a C5-C6 heteroaryl containing at least one heteroatom selected from O and N; E is H; and J represents H.

6. A pharmaceutical composition according to claim 4, characterized in that one of the compounds of formula I and III is nitinin or dihydronitinin.

7. Use of a composition according to any one of claims 4-6 for the treatment, prevention or reduction of acute or chronic pain in an individual in need thereof.

8. The use according to claim 7, wherein the pain is selected from one of the following types of acute and chronic pain: neuropathic pain, nociceptive pain, psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low back pain, radiculopathic pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, pain associated with wounds, chemotherapy-induced peripheral neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain associated with cancer, pain associated with fibromyalgia, hyperalgesia syndrome, pain associated with infections, HIV-related pain, dislocations and strains, hyperalgesia, heat-induced pain, physical pain, headache, pelvic pain, bladder pain,vascular pain, wounds, somatic visceral pain, low back pain, visceral pain and intestinal pain., 9. Use according to any of paragraphs 7, 8, characterized in that the compound is administered in a therapeutically effective dose of 0.0018 to 1.8 mg / kg.

10. A method for treating acute or chronic pain in a subject in need thereof, comprising administering to the subject having pain a therapeutically effective amount of a compound according to any one of claims 1-3 or a pharmaceutical composition according to any one of claims 4-6.

11. The method of claim 10, wherein the pain is an acute or chronic pain type selected from neuropathic pain, nociceptive pain, psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low back pain, radiculopathic pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, wound-related pain, chemotherapy-induced peripheral neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain associated with cancer, pain associated with fibromyalgia, hyperalgesia syndrome, pain associated with infections, HIV-related pain, sprains and strains, hyperalgesia, heat-induced pain, physical pain, headache, pelvic pain, bladder pain,vascular pain, wounds, somatic visceral pain, low back pain, visceral pain and intestinal pain.,

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