Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/36—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the present disclosure relates to nitenin analogue compounds and their use as analgesic agents for the treatment, prevention or reduction of chronic pain and acute pain.
• Acute pain usually arises on suddenly and the cause is specific. It is sharp in quality. Acute pain commonly does not last longer than tree- six months. It goes away when there is no longer an underlying cause for the pain. A person can then go on with life as usual. Exemplary causes of acute pain include surgery, broken bones, dental work, burns and cuts, labor and childbirth.
• Chronic pain is defined as pain persisting for more than three months or beyond the natural recovery time. Pain signals keep firing in the nervous system, even without physiological stimuli, for weeks, months or years. It arises in many medical conditions, including for example diabetes, arthritis, migraine, fibromyalgia, cancer, back pain, shingles, sciatica, trigeminal neuralgia and previous trauma or injury. Chronic pain can cause disability significantly interfering with a person's quality of life and causing a huge negative impact on society. It affects 21% of the world's population (1.5 billion people) and has enormous economic costs associated. In the United States of America (USA) alone, in 2010, it was estimated that there were $560- 635 billion spent in salary losses and low productivity, and health care costs. With increasing aged population, the demand for adequate and better pain management therapies is on the rise.
• opioid derivatives do alleviate pain but co-inflict important noxious effects like habituation, addiction and loss of drive or motivation.
• the use of opioids became an epidemical problem in several countries, with increasing addiction situations and a heavy burden for the society. For example, in USA, the number of deaths related to opioids use is much greater than the number of deaths caused by illicit drugs.
• Other kinds of drugs are used for treatments, including antidepressants, antiepileptic drugs, and non-steroidal anti-inflammatory drugs (NSAIDs), but these are either not efficient or also cause relevant side-effects.
• Ion channel modulators include ion channel modulators.
• Ion channels are key proteins present in neuronal membranes that shape electrical signaling, and thus, pain signals in nerves.
• Neurons involved in pain sensing (nociception) located in the peripheral nervous system include those that have their cell bodies located in the nervous ganglia (dorsal root ganglia-DRG) outside the spinal cord (or trigeminal ganglia- TG, in the head) .
• Such nociceptive fibers are the first peripheral nerve sensors involved in the physiological pathway that leads to the brain perception of pain.
• Such medications are:
• TRPV1 Transient Receptor Potential Cation channel subfamily V member 1
• New products currently under clinical development include new opioids with certain modifications (making them less addictive) and other ion channel modulators tackling ion channels known to be involved in pain, but more adequate than TRPV1 and N-type voltage gated calcium channels (e.g. ion channels such as other TRPs, voltage-gated sodium channels Na v l .7 and Na v 1.8) .
• ion channels such as other TRPs, voltage-gated sodium channels Na v l .7 and Na v 1.8
• Retigabine works primarily as a K + channel opener - that is, by activating a certain family of voltage gated potassium (Kv7/M) channels in the brain.
• the present disclosure relates to nitenin analogue compounds and their use as analgesics for the treatment, prevention or reduction of chronic pain and acute pain .
• the present invention differentiates from the presently existing solutions not only by its chemical nature but also by its mode of action.
• brain perception of pain is predicted to be blocked or attenuated, but in a manner that may not affect brain functioning, because these molecules may act in the "peripheral portion of pain signaling pathway", prior to the central nervous system.
• Any aspect or embodiment described herein may be combined with any other aspect or embodiment as disclosed herein. While the present invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and 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 .
• Embodiment 1 Compounds of formula I, II, III and IV, pharmaceutically acceptable salts or prodrug thereof,
• X is selected from 0, S, NH, 03 ⁇ 4;
• Y is selected from CH, 03 ⁇ 4; Z is selected from C, N;
• G is selected from 0, S;
• T is selected from OH, SH, N3 ⁇ 4, halogen
• R 1 and R 2 are independently selected from H, alkyl, alkenyl, cycloalkyl, aryl or -CH2-R 3 ; wherein R 3 is selected from aryl, cycloalkyl, heteroaryl, -R 4 -R 5 ; wherein R 4 is selected from alkyl, alkenyl; wherein R 5 is selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama-lactone ;
• Q is selected from C, CH;
• D is selected from C, CH, CH ;
• a and E is H and the other is selected from H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 , wherein R 6 is selected from alkyl, alkenyl, and R 7 is selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama- lactone ;
• J is selected from H, OH, SH, N3 ⁇ 4, halogen
• the compound is not nitenin, dihydronitenin nor their respective isomers, enantiomers and stereoisomers.
• Embodiment 2 The compounds of formula IV according to embodiment 1, wherein
• X is 0;
• Y is CH
• R 1 is H
• R 2 is H
• Embodiment 3 The compounds of formula IV according to embodiment 1, wherein
• R 1 is alkyl
• R 2 is -CH 2 -R 3 ; wherein R 3 is -R 4 -R 5 ; wherein R 4 is alkyl and R 5 is heteroaryl J is OH.
• Embodiment 4 The compounds of formula II according to embodiment 1, wherein
• X is 0;
• Y is CH 2 ;
• G is 0;
• R 1 is H
• A is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl.
• Embodiment 5 The compounds of formula II according to embodiment 1, wherein
• X is 0;
• Y is CH 2 ;
• G is 0;
• R 1 is H
• E is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl;
• A is H.
• Embodiment 6 The compounds of formula I, II, III and IV, according to embodiment 1, wherein R 7 is not furan-3-yl.
• Embodiment 7. Compounds of formula I, II, III and IV, pharmaceutically acceptable salts or prodrug thereof,
• X is selected from 0, S, NH, C3 ⁇ 4;
• Y is selected from CH, C3 ⁇ 4;
• Z is selected from C, N;
• G is selected from 0, S;
• T is selected from OH, SH, N3 ⁇ 4, halogen
• R 1 and R 2 are independently selected from H, alkyl, alkenyl, cycloalkyl, aryl or -CH2-R 3 ; wherein R 3 is selected from aryl, cycloalkyl, heteroaryl, -R 4 -R 5 ; wherein R 4 is selected from alkyl, alkenyl; wherein R 5 is selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama-lactone ;
• Q is selected from C, CH;
• D is selected from C, CH, CH ;
• a and E is H and the other is selected from H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 , wherein R 6 is selected from alkyl, alkenyl, and R 7 is selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama- lactone ;
• J is selected from H, OH, SH, N3 ⁇ 4, halogen
• Embodiment 8 The compounds of formula I for use as pharmaceutical ingredient according to embodiment 7, wherein;
• X is 0;
• Y is CH
• R 1 is alkyl
• R 2 is -CH2-R 3 ; wherein R 3 is -R 4 -R 5 ; wherein R 4 is alkyl and R5 is heteroaryl;
• A is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl;
• Embodiment 9 The compounds of formula IV for use as pharmaceutical ingredient according to embodiment 7, wherein;
• X is 0;
• Y is CH
• R 1 is H
• R 2 is H; and J is OH.
• Embodiment 10 The compounds of formula IV for use as pharmaceutical ingredient, wherein;
• X is 0;
• Y is CH
• R 1 is alkyl
• R 2 is -CH2-R3 ; wherein R 3 is -R 4 -R 5 ; wherein R 4 is alkyl and R 5 is heteroaryl J is OH.
• Embodiment 11 The compounds of formula II for use as pharmaceutical ingredient according to embodiment 7, wherein;
• X is 0;
• Y is CH 2 ;
• G is 0;
• R 1 is H
• A is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl.
• Embodiment 12 The compounds of formula II for use as pharmaceutical ingredient according to embodiment 7, wherein;
• X is 0;
• Y is CH 2 ;
• G is 0;
• R 1 is H
• E is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl;
• A is H.
• Embodiment 13 For pharmaceutical use, the compounds of formula I, II, III and IV, of the present patent application is used in warm-blooded vertebrates, preferably mammals, more preferably humans, in doses ranging from 0. lpg /ml blood (6 pg/Kg body weight) to 30pg /ml blood (1.8 mg/Kg body weight) .
• the previously-mentioned effective dose range is for intravenous administration and it may differ in other routes of administration.
• Embodiment 14 The compounds of formula I, II, III and IV pharmaceutical salts or prodrug thereof are used in the treatment, prevention or reduction of pain in an individual in need thereof, more specifically with acute or chronic pain.
• Acute and chronic pain is intended 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, radiculopathy pain, musculoskeletal pain, post operative and post-traumatic pain, phantom pain, surgical pain, wound associated 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 syndromes, pain associated with infections, HIV
• Embodiment 15 The compounds of formula I, II, III and IV, pharmaceutical salts or prodrug thereof are used in the treatment of autoimmune disorders, due to effects described upon Kvl.3, a target for such disorders.
• Embodiment 16 The compounds of formula I, II, III and IV, pharmaceutical salts or prodrug thereof are used in the treatment of diabetes, considering their effect on Kvl.3 channel believed to be related to insulin-sensitivity, insulin-resistance related syndromes and obesity.
• Embodiment 17 The compounds of formula I, II, III and IV, pharmaceutical salts or prodrug thereof are used as antiepileptic and antiseizures agents.
• Embodiment 18 The compounds of formula I, II, III and IV, for use in the treatment or prophylaxis of a disease in which Kvl.3 channels are involved.
• a pharmaceutical composition comprises a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to formula I, II, III and IV or a pharmacologically acceptable salt or prodrug thereof.
• 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.
• Embodiment 21 The method according to embodiment 19, wherein the pain is of an acute and chronic pain types selected from neuropathic pain, nociceptive pain , psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low-back pain, radiculopathy pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, wound associated 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 syndromes, pain associated with infections, HIV related pain, sprains and strains, hyperalgesia, somatogenic pain, psychogenic pain, heat induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvi
• Embodiment 22 A method of treatment or prophylaxis of a disease in which Kvl .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 treatment or prophylaxis of a disease in which Kvl .3 channels are involved.
• Embodiment 23 A method of treatment of 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 an autoimmune disease.
• Embodiment 24 A method of treatment of 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 an insulin resistance syndrome.
• Embodiment 25 A method of treatment of 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.
• Embodiment 26 The method according to embodiments 20 through 23, wherein the compound is administered in a therapeutically effective amount between 0.018 and 1.8 mg/kg.
• Embodiment 27 The compound, composition, use, or method disclosed here, wherein the compound is a compound of formula I, wherein
• X is 0;
• Y is CH
• R 1 is alkyl
• R 2 is -CH2-R 3 ; wherein R 3 is -R 4 -R 5 ; wherein R 4 is alkyl and R 5 is heteroaryl;
• A is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl;
• Embodiment 28 The compounds according to embodiments 1 through 6, wherein the compound is isolated or synthetically produced .
• Embodiment 29 The compounds according to embodiments 7 through 28, wherein the compound is nitenin or dihydronitenin .
• Figure 1 illustrates the effect of nitenin (0.1 pg/ml) on voltage activated currents recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns)
• Figure 2 shows dose dependent responses of nitenin on voltage activated K + currents recorded from (a) small diameter Dorsal Root Ganglia neurons (sdDRGns) and from (b) CHO-K1 cells expressing human Kvl.l, Kvl.2, Kvl.3, Kvl .4 or Kvl .6 cDNA.
• sdDRGns small diameter Dorsal Root Ganglia neurons
• Kvl.3 channel is the most sensitive channel (around 6-fold more sensitive in comparison to the "next most sensitive one", the Kvl.2) Kvl.2, Kvl.l and Kvl .6 show similar, intermediate sensitivities to nitenin. In opposition, Kvl .4 is the less sensitive ( ⁇ 31 times less sensitive) .
• Figure 3 shows a typical effect of nitenin on the voltage dependence of steady state of inactivation of the K + currents recorded from a small diameter neuron isolated from a dorsal- root ganglion isolated of the injured side of a CCI rat model 28 days after surgery, a) Current traces were elicited during a command pulse to +10 mV (600 ms) preceded by a series pre pulses of 11040 s duration, ranging from -140 to +10 mV in a 10 mv step increments; traces in the left (black) were obtained before and those on the right (in grey), during the application of nitenin (0.1 pg/ml; 0.29 mM) .
• Vh parameters voltage of half maximum current
• Vh2 -26.3 mV
• Figure 4 illustrates behavioral readouts as measures of pain during treatment with nitenin on a Neuropatic pain rat model CCI (Chronic constriction injury) .
• CCI Chronic constriction injury
• Values refer to the mechanical sensitivity to stimulation using calibrated von Frey Filaments, and consequently reflecting hyperalgesia when hypersensitive (black filled markers - ipsilateral, operated leg; Open markers - contralateral, uninjured leg) .
• Dotted line refers to the average value of the ipsilateral paw prior to surgery.
• Figure 5 shows behavioral readouts as measures of pain during treatment with nitenin on an Orofacial pain rat model; Typical experiment using a group of Wistar rats subjected to injection of CFA (CFA was injected just posterior to the second row of vibrissae) .
• Values refer to the mechanical sensitivity to face stimulation (whiskers region) using calibrated von Frey Filaments, and consequently reflecting hyperalgesia when hypersensitive (black filled markers- ipsilateral, injured face-side; Open markers- contralateral, uninjured face-side) .
• Dotted line refers to the average value of the ipsilateral face prior to the CFA injection.
• Figure 6 illustrates the formulas of 4 of the compounds tested where the compound of formula V refers to nitenin (results on ionic currents are presented in Figures 1, 2 and 3, and, the in vivo efficacy, in Figures 4 and 5) .
• Formulas is VIII.A and VIII. B represent the Cis-isomer and Trans isomer, respectively, of the compound of formula VIII.
• Figure 7 illustrates the effect of the compound of formula VI (10 pg/ml; 77.9 mM) on voltage activated currents recorded sdDRGns .
• Figure 8 illustrates the effect of the compound of formula VII (0.1 pg/ml; 399 nM) on voltage activated currents recorded sdDRGns.
• Figure 9 illustrates the effect of the compound of formula VIII-A (6.5pg/ml; 29.4 mM) on voltage activated currents recorded sdDRGns .
• Figure 10 shows a typical effect of the compound of formula VI on the voltage dependence of steady state of inactivation of the K + currents recorded from a sdDRGn.
• Figure 12 shows a typical effect of the compound of formula VIII-A on the voltage dependence of steady state of inactivation of the K + currents recorded from a sdDRGn.
• references to compounds of the disclosure, or pharmaceutically acceptable salts and prodrugs thereof, ninetin, and ninetin analogues, are used herein interchangeably.
• the terms include all stereoisomers of these compounds.
• administering refers to the physical introduction of an agent to a subject, using any of the various methods and delivery systems known to those skilled in the art.
• exemplary routes of administration for the compounds disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal , spinal or other parenteral routes of administration, for example by injection or infusion.
• parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional , intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal , transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation.
• the compound is administered via a non-parenteral route, e.g., orally.
• non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically.
• Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
• isolated means purified from nature and thus free from the natural compounds that exist with nitenin in its natural environment and it associates with in nature. Isolated products of nature may have different chemical, biochemical, and/or physical properties than the same product as it exists in nature. Synthetic versions of products of nature may have different chemical, biochemical, and/or physical properties than the same product isolated from nature or as it exists in nature.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• Drug-approval agencies e.g., EM ⁇ , US-FDA
• Examples are listed in, for example, Pharmacopeias.
• phrases "pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” are employed herein to refer to a pharmaceutically acceptable material chosen from a solvent, dispersion media, diluent, dispersion, suspension aid, surface active agent, isotonic agent, thickening or emulsifying agent, preservative, polymer, peptide, protein, cell, hyaluronidase, and mixtures thereof.
• the solvent is an aqueous solvent.
• a “therapeutically effective amount, " "effective dose, “ or “effective amount, “ of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
• the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
• the "therapeutically effective dosage” is the dosage whose administration, either in a single dose or multiple dose schedule, is effective for treatment, prevention and/or reduction of pain.
• This dosage varies depending upon the health and physical condition of the individual to be treated, age, degree of analgesia desired, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.
• Preventing or “prevention” herein does not require absolute success in the sense of an absolute prevention of pain but indicates a reduced risk of developing a painful condition or developing pain with reduced severity.
• treatment shall not be construed as an absolute cure, but may also relate to amelioration or suppression of pain or pain associated conditions.
• alkyl refers to a saturated monovalent hydrocarbon radical comprising 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.
• an alkyl group comprises one to eight carbon atoms (C1-C8) .
• an alkyl group comprises one to six carbon atoms (C1-C6) .
• an alkyl group comprises one to four carbon atoms (C1-C4) .
• a cyclic alkyl group comprises three to six carbon atoms (C3-C6) .
• alkenyl refers to a monovalent hydrocarbon radical comprising two to eight carbon atoms (C2-C8) with at least one site 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 comprises two to six carbon atoms (C2-C6) . In some embodiments, an alkenyl group comprises two to four carbon atoms (C2-C4) . Alkenyl groups may have E or Z orientations. Non-limiting examples of alkenyl groups include ethenyl (also called vinyl), 1- propenyl, iso-propenyl , and 2-chloroethenyl .
• aryl refers to a monovalent aromatic hydrocarbon radical comprising 6-20 carbon atoms (C6-C20) that is derived by removing a hydrogen atom from an aromatic ring.
• Aryl groups can be unsubstituted, or they can substituted with one or more substituents as described elsewhere herein.
• heterocycle refers to a saturated or partially unsaturated ring system comprising 3 to 20 atoms, wherein at least one of the ring atoms is a heteroatom chosen from nitrogen, oxygen, phosphorous, and sulfur.
• a heterocyclic group may be unsubstituted or may be substituted with one or more substituents as described elsewhere herein.
• a heterocyclic group comprises 3 to 10 atoms.
• a heterocyclic group comprises 3 to 7 atoms.
• a heterocyclic group is monocyclic.
• a heterocyclic group is bicyclic.
• a heterocyclic group comprises fused rings.
• heteroaryl refers to a monovalent aromatic radical comprising one or more 5-, 6-, or 7-membered rings and comprising one or more heteroatoms independently chosen from nitrogen, oxygen, phosphorous, and sulfur.
• a heteroaryl group may be unsubstituted or may be substituted with one or more substituents as described elsewhere herein.
• a heteroaryl group comprises 5 to 20 atoms.
• a heteroaryl group comprises 5 to 9 atoms.
• a heteroaryl group comprises
• a heteroaryl group comprises
• a heteroaryl group comprises
• a heteroaryl group is monocyclic. In some embodiments, a heteroaryl group is bicyclic. In some embodiments, a heteroaryl group comprises fused rings.
• substituted refers to the replacement 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.
• a substituted hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group any number of hydrogen atoms may be replaced by substituents.
• Compounds of the disclosure may contain one or more chiral centers. Compounds of the disclosure thus may exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds described herein, including, as non-limiting examples, diastereomers , enantiomers, and mixtures thereof (including, as a non limiting example, racemic mixtures) form parts of the disclosure .
• CIPN Chemotherapy-induced Peripheral Neuropathy
• CNS Central nervous system
• DRG Dorsal root ganglion
• HER Human embryonic kidney
• hERG Human Ether-a-go-go-Related Gene - Kvll.l
• HFF2 Human foreskin fibroblasts 2
• K v l.x voltage-dependent potassium channel subunits, given by x
• Na v l.x voltage-dependent sodium channel subunits, given by x
• NSAID(s) non-steroidal anti-inflammatory drug(s)
• MTS ( 3- ( 4 , 5-dimethylthiazol-2-yl ) -5- ( 3- carboxymethoxyphenyl ) -2- ( 4-sulfophenyl ) -2H-tetrazolium) sdDRGN: small diameter dorsal root neurons
• sdTGN small diameter trigeminal ganglion neurons
• STZ Streptozotocin
• TRP Transient Receptor Potential Cation channel
• TRPV1 Transient Receptor Potential Cation channel subfamily
• Vh Voltage of half maximum current
• compositions comprising said compounds and/or pharmaceutically acceptable salts thereof can be administered as therapeutic treatments.
• Said compounds, pharmaceutically acceptable salts, and/or pharmaceutical compositions can be administered in unit forms of administration to mammalian subjects, including human beings. Suitable unit forms of administration include, as non-limiting examples, forms administered orally and forms administered via a parenteral route, non-limiting examples of which including inhalation, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, and intravitreal administration .
• compositions for oral administration can be in the form of tablets, pills, powders, hard gelatine capsules, soft gelatine capsules, and/or granules.
• a compound of the disclosure and/or a pharmaceutically acceptable salt of a compound of the disclosure is (or are) mixed with one or more inert diluents, non-limiting examples of which including starch, cellulose, sucrose, lactose, and silica.
• such pharmaceutical compositions may further comprise one or more substances other than diluents, such as (as non-limiting examples), lubricants, coloring agents, coatings, or varnishes .
• compositions of the disclosure may comprise pharmaceutically acceptable carriers, excipients, vehicles, and diluents. Many of these are well-known to persons having ordinary skill in the art and are described in, as a non-limiting example, Remington : The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins , Philadelphia , Pa. (2013) and any other editions, which are hereby incorporated by reference.
• this disclosure relates to nitenin analogue compounds and their use as analgesics for the treatment, prevention or reduction of chronic and acute pain.
• analgesic effect for several types of pain is disclosed herein.
• Nitenin and dihydronitenin compounds (two of the compounds disclosed herein) have their origin in a marine sponge, but have been, and can be, synthetically prepared for this disclosure and the disclosure provides that these compounds act specifically on certain K v channels K v l.x, expressed in the pain-sensing c-fibers of the dorsal root ganglia and of the trigeminal ganglia.
• the mode of action involves a particular channel inhibition (rather than potentiation, like Retigabine) and has advantageous particularities, such as: (a) it is an "open channel blocker", thus an activity dependent blockage, (b) involves a change of the voltage- dependence of inactivation of the channel, and, (c) acts specifically on a set of K v channels, mainly Kvl .3.
• This specific and novel mode of action explains why and how nitenin and and nitenin analogue compounds are solely effective in body limbs/body parts with injured/affected nerves. Additionally, it does not alter nociceptive and sensorial scores, in unaffected body limbs/body parts.
• the disclosure relates to the use of nitenin analogue compounds as analgesics for the treatment, prevention or reduction of chronic and acute pain.
• nitenin analogue compounds are illustrated by the compounds of formula I, II, III and IV as described in the following embodiments:
• Embodiment 1 Compounds of formula I, II, III and IV, pharmaceutically acceptable salts or prodrug thereof,
• X is selected from 0, S, NH, C3 ⁇ 4;
• Y is selected from CH, C3 ⁇ 4;
• Z is selected from C, N;
• G is selected from 0, S;
• T is selected from OH, SH, N3 ⁇ 4, halogen
• R 1 and R 2 are independently selected from H, alkyl, alkenyl, cycloalkyl, aryl or -CH2-R 3 ; wherein R 3 is selected from aryl, cycloalkyl, heteroaryl, -R 4 -R 5 ; wherein R 4 is selected from alkyl, alkenyl; wherein R 5 is selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama-lactone ;
• Q is selected from C, CH;
• D is selected from C, CH, CH ;
• a and E is H and the other is selected from H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 , wherein R 6 is selected from alkyl, alkenyl, and R 7 is selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama- lactone; optionally, wherein the compound is not nitenin, dihydronitenin nor their respective isomers, enantiomers and stereoisomers; and/or, optionally, wherein R7 is not furan- 3-yl; J is selected from H, OH, SH, N3 ⁇ 4, halogen.
• Embodiment 2 The compounds of formula IV according to embodiment 1, wherein
• X is 0;
• Y is CH
• R 1 is H
• R 2 is H
• Embodiment 3 The compounds of formula IV according to embodiment 1, wherein
• X is 0;
• Y is CH
• R 1 is alkyl
• R 2 is -CH 2 -R 3 ; wherein R 3 is -R 4 -R 5 ; wherein R 4 is alkyl and R 5 is heteroaryl J is OH.
• Embodiment 4 The compounds of formula II according to embodiment 1, wherein
• X is 0;
• Y is CH 2 ;
• G is 0;
• R 1 is H
• A is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl.
• Embodiment 5 The compounds of formula II according to embodiment 1, wherein
• X is 0;
• Y is CH 2 ;
• G is 0;
• R 1 is H
• E is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl;
• A is H.
• Embodiment 6 The compounds of formula I, II, III and IV, according to embodiment 1, wherein R 7 is not furan-3-yl.
• Embodiment 7 Compounds of formula I, II, III and IV, pharmaceutically acceptable salts or prodrug thereof,
• X is selected from 0, S, NH, C3 ⁇ 4;
• Y is selected from CH, C3 ⁇ 4;
• Z is selected from C, N;
• G is selected from 0, S;
• T is selected from OH, SH, N3 ⁇ 4, halogen
• R 1 and R 2 are independently selected from H, alkyl, alkenyl, cycloalkyl, aryl or -CH2-R 3 ; wherein R 3 is selected from aryl, cycloalkyl, heteroaryl, -R 4 -R 5 ; wherein R 4 is selected from alkyl, alkenyl; wherein R 5 is selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama-lactone ;
• Q is selected from C, CH;
• D is selected from C, CH, CH ;
• a and E is H and the other is selected from H, OH, SH, aryl, alkyl, alkenyl, R 6 -R 7 , wherein R 6 is selected from alkyl, alkenyl, and R 7 is selected from alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted gama- lactone ;
• J is selected from H, OH, SH, N3 ⁇ 4, halogen
• Embodiment 8 The compounds of formula I for use as pharmaceutical ingredient according to embodiment 7, wherein;
• X is 0;
• Y is CH
• R 1 is alkyl
• R 2 is -C3 ⁇ 4-R 3 ; wherein R 3 is -R 4 -R 5 ; wherein R 4 is alkyl and R5 is heteroaryl;
• A is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl;
• Embodiment 9 The compounds of formula IV for use as pharmaceutical ingredient according to embodiment 7, wherein;
• X is 0;
• Y is CH
• R 1 is H
• R 2 is H
• Embodiment 10 The compounds of formula IV for use as pharmaceutical ingredient, wherein;
• X is 0;
• Y is CH
• R 1 is alkyl
• R 2 is -CH2-R3 ; wherein R 3 is -R 4 -R 5 ; wherein R 4 is alkyl and R 5 is heteroaryl J is OH.
• Embodiment 11 The compounds of formula II for use as pharmaceutical ingredient according to embodiment 7, wherein;
• X is 0;
• Y is CH 2 ;
• G is 0; R 1 is H;
• A is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl.
• Embodiment 12 The compounds of formula II for use as pharmaceutical ingredient according to embodiment 7, wherein;
• X is 0;
• Y is CH 2 ;
• G is 0;
• R 1 is H
• E is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl;
• A is H.
• Embodiment 13 For pharmaceutical use, the compounds of formula I, II, III and IV, of the present patent application is used in warm-blooded vertebrates, preferably mammals, more preferably humans, in doses ranging from 0. lpg /ml blood (6 pg/Kg body weight) to 30pg /ml blood (1.8 mg/Kg body weight) .
• the previously-mentioned effective dose range is for intravenous administration and it may differ in other routes of administration.
• Embodiment 14 The compounds of formula I, II, III and IV pharmaceutical salts or prodrug thereof are used in the treatment, prevention or reduction of pain in an individual in need thereof, more specifically with acute or chronic pain.
• Acute and chronic pain is intended 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, radiculopathy pain, musculoskeletal pain, post operative and post-traumatic pain, phantom pain, surgical pain, wound associated 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 syndromes, pain associated with infections, HIV
• Embodiment 15 The compounds of formula I, II, III and IV, pharmaceutical salts or prodrug thereof are used in the treatment of autoimmune disorders, due to effects described upon Kvl.3, a target for such disorders.
• Embodiment 16 The compounds of formula I, II, III and IV, pharmaceutical salts or prodrug thereof are used in the treatment of diabetes, considering their effect on Kvl.3 channel believed to be related to insulin-sensitivity, insulin-resistance related syndromes and obesity.
• Embodiment 17 The compounds of formula I, II, III and IV, pharmaceutical salts or prodrug thereof are used as antiepileptic and antiseizures agents.
• Embodiment 18 The compounds of formula I, II, III and IV, for use in the treatment or prophylaxis of a disease in which Kvl .3 channels are involved.
• a pharmaceutical composition comprises a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to formula I, II, III and IV or a pharmacologically acceptable salt or prodrug thereof.
• 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.
• Embodiment 21 The method according to embodiment 19, wherein the pain is of an acute and chronic pain types selected from neuropathic pain, nociceptive pain , psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low-back pain, radiculopathy pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, wound associated 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 syndromes, pain associated with infections, HIV related pain, sprains and strains, hyperalgesia, somatogenic pain, psychogenic pain, heat induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvi
• Embodiment 22 A method of treatment or prophylaxis of a disease in which Kvl .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 treatment or prophylaxis of a disease in which Kvl .3 channels are involved.
• Embodiment 23 A method of treatment of 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 an autoimmune disease.
• Embodiment 24 A method of treatment of 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 an insulin resistance syndrome.
• Embodiment 25 A method of treatment of 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.
• Embodiment 26 The method according to embodiments 20 through 23, wherein the compound is administered in a therapeutically effective amount between 0.018 and 1.8 mg/kg.
• Embodiment 27 The compound, composition, use, or method disclosed here, wherein the compound is a compound of formula I, wherein
• X is 0;
• Y is CH
• R 1 is alkyl
• R 2 is -CH2-R 3 ; wherein R 3 is -R 4 -R 5 ; wherein R 4 is alkyl and R 5 is heteroaryl;
• A is -R 6 -R 7 ; wherein R 6 is alkyl and R 7 is heteroaryl;
• Embodiment 28 The compounds according to embodiments 1 through 6, wherein the compound is isolated or synthetically produced .
• Embodiment 29 The compounds according to embodiments 7 through 28, wherein the compound is nitenin or dihydronitenin .
• the present disclosure discloses robust evidence that nitenin and nitenin analogue compounds may be used as analgesics for the treatment, prevention or reduction of chronic and acute pain.
• This evidence was obtained from several technical approaches, including ex vivo neuronal preparations, animal models of pain, behavioural readouts of pain, in silico approaches, in vitro toxicity tests and, whole-cell voltage-clamp recordings.
• the nitenin analogue compounds of the present application were first obtained from the marine sponge Spongia agaracina captured in Sagres, Portugal, but have also been chemically synthesized. As shown in the EXAMPLES, the nitenin- containing extract showed a modulatory effect on potassium currents recorded from rat sdDRGNs (pain-sensing neurons), a bioactivity that was the base of a bio-guided fractionation process. The series of obtained fractions allowed the identification of compounds that not only kept the capacity of modulating the K + currents, but also showed high levels of potency. Results were also confirmed in small diameter trigeminal ganglion neurons (sdTGNs)that showed identical pharmacological effects in very similar K + current profiles.
• sdTGNs small diameter trigeminal ganglion neurons
• the K + current component affected with pain condition is the one principally modulated (diminished) by the compound (s) of interest.
• the nature of the recorded modulatory effect on the currents was studied by monitoring several biophysical parameters, such as voltage dependencies of activation and inactivation and kinetics.
• the specificity of the bioactivity was carried out by comparing the pharmacological effect on currents recorded from the sdDRGNs with those in other types of dorsal root ganglia (medium and large diameter DGRs) .
• Nitenin and nitenin analogue compounds are small molecules that are synthesizable using chemistry synthesis approaches;
• nitenin reduces the activity of K v channels expressed in snDRGs (a subset of Kvl.x with higher affinity to Kvl.3), responsible for the slow delayed rectifying current, which modulate pain signalling and propagation towards the brain. Together with this peripheral effect of nitenin and nitenin analogues, a complementary central effect is not to be ruled out.
• Kvl.x channels e.g. Kvl.3 and Kvl.6
• nitenin and nitenin analogue compounds of the present disclosure are easily administrated.
• IV intravenous
• intraperitoneal injections were used with success regarding its analgesic effect.
• the nitenin analogue compounds can be also administered orally, thus in a preferable embodiment, given the fact that endogastric administration was also performed in the animal models with similar analgesic effects.
• 6-Nitenin and its analogues are effective on mitigating pain in a number of pain models, including acute and neuropathic chronic pain, chemotherapy-induced peripheral neuropathy, acute and long-term or chronic inflammatory pain (nociceptive pain) , orofacial chronic pain and diabetic neuropathic chronic pain.
• pain models including acute and neuropathic chronic pain, chemotherapy-induced peripheral neuropathy, acute and long-term or chronic inflammatory pain (nociceptive pain) , orofacial chronic pain and diabetic neuropathic chronic pain.
• the nitenin analogue compounds By acting specifically in a subset of potassium channels (Kvl.x), and not having any effect on sodium currents/channels (Na v s), the nitenin analogue compounds will not compete with Nav modulatory agents but rather, they may eventually be applied in combination with those, maximising the envisaged analgesic effect or acting in a synergistically manner.
• the compounds of the disclosure, or pharmaceutically acceptable salts and prodrugs thereof may be used to treat acute pain.
• situations of acute pain a type of pain that typically lasts less than 3 to 6 months, include surgery, broken bones, dental work, burns and cuts, pain that is directly related to soft tissue damage such as a sprained ankle, labor and childbirth
• the compounds of the disclosure, or pharmaceutically acceptable salts and prodrugs thereof may be used to treat chronic pain.
• diseases or disorders associated with chronic pain include peripheral neuropathy chronic pain Arthritis, especially osteoarthritis, Cancer, HIV, Diabetes, Fibromyalgia, Shingles, Herpes, Headache, Migraines, , Multiple sclerosis, Nerve damage (neuropathy) , Low back pain, Trauma and other injuries (eg, herniated disk, torn ligament) , Sciatica, Diabetic neuropathy, Carpal tunnel syndrome, Trigeminal neuralgia , post-surgical, Chronic Fatigue Syndrome (or Myalgic Encephalomyelitis), Endometriosis, Inflammatory Bowel Disease, irritable bowel Syndrome, Crohn's disease, Ulcerative colitis, Interstitial Cystitis, Temporomandibular Joint Dysfunction (TMJ) , Vulvodynia, Bursitis, Celiac disease, Lupus, Reuma
• the compounds of the disclosure can be used to treat hyperalgesia, somatogenic pain, psychogenic pain, heat induced pain, physical pain, nociceptive pain, rheumatic, headache, pelvic pain, bladder pain, myofascial, vascular pain, migraine wound, wound associated, arthritic, somatic visceral, phantom pain, radiculopathy, lumbar pain, or pain associated with osteoarthritis.
• Both acute and chronic pain involves the complex alteration of the processing and conduction of electrical signals from peripheral nerves to the central nervous system (CNS) .
• the electrical excitability and activity levels of a normal condition, or those related to chronic pain are result of the inflow or outflow of charged metal ions such as sodium (Na + ) , potassium (K + ) or calcium (Ca 2+ ) through membrane ion channels (Nav, Kv or Cav, respectively) , causing the generation, propagation and transmission of electric signals throughout the cell and from cell to cell.
• the neuronal network underlying pain signalling is altered, with abnormal ionic currents brought by altered expression and biophysics of the underlying channels, resulting in excessive and sustained neuronal excitability and activity. Therefore, an effective analgesic would need to be able to suppress the hyperexcitability of the pain signalling network, restoring the physiologic expression and/or biophysical profiles of the functioning channels, and, in turn, restoring the network activity to resting levels.
• Small-diameter DRG neurons also called pain sensing neurons, are located outside of the spinal cord that carry the nociceptive input to the CNS (i.e, leading to 'pain' ) .
• these neurons do not have spontaneous firing activity - they are silent (e.g Ly et al . , 2018)-, situation that changes during pain episodes and, indeed with chronic pain.
• the present underlying therapeutics strategy is to target key ion channels localized in such neurons in the DRG neurons and those in trigeminal ganglia (TG) , to "switch-off" such 'pain-induced' hyperexcitability. Consequently, the transmission of the "pain signal" to the CNS is interrupted or diminished, preventing, this way, brain perception of pain. It is possible however that, complementary, there is an effect in central neurons, cooperating into the analgesic effect.
• the compounds of the disclosure, or pharmaceutically acceptable salts and prodrugs thereof may be used to halt pain-induced hyperexcitability. In some embodiments, they can be used to modulate the brain's perception of pain.
• nitenin analogues are specific modulators of slow voltage-activated K + currents recorded from the small diameter (sdDRGNs also sdTGNs, thought to correspond with c-fibers) . Underlying such slow current are certain Kvl.x channels. This effect is lower in large diameter neurons at a sub micromolar concentration range, i.e. at concentrations below 1 micromolar, the modulatory effect of nitenin is exclusive for sdDRGNs and sdTGNs .
• the compounds of the disclosure, or pharmaceutically acceptable salts and prodrugs thereof may be used to modulate slow-voltage activated K + currents.
• the currents are from the small diameter (sdDRGNs also sdTGNs) neurons.
• Kvl.x including those mediating slow voltage-activated currents, are ion channels involved in pain signal propagation as principally present in pain-sensing neurons.
• the nitenin analogue compounds are particularly effective on the slow K + current-component, sub current-component that, considering the kinetics and voltage dependence of the nitenin-sensitive current, strongly suggests the involvement of a subset of Kvl.x channels.
• the compounds of the disclosure, or pharmaceutically acceptable salts and prodrugs thereof may be used to stop hyperexcitability in central neurons, namely neurons under episodes of seizures.
• the mentioned effect on Kvl.x channels resulting in abolishing repetitive neural firing is the basis for an anti-epileptic effect.
• the nitenin and nitenin analogues may be used as antiepileptic and antiseizures agents.
• the compounds of the disclosure, or pharmaceutically acceptable salts and prodrugs thereof may be used as blockers of Kvl .3.
• Kvl .3 has been described as a target for treatment of immunological related pathologies as well as a target for treatment of diabetes and other metabolic disorders.
• the compounds of the disclosure may be used in the treatment of diabetes and other metabolic disorders .
• the compounds of the disclosure, or pharmaceutically acceptable salts and prodrugs thereof may be used to treat autoimmune diseases. In other embodiments, they may be used to increase insulin sensitivity.
• the mode (or modes) of administration, dosage (or dosages), and optimized pharmaceutical form (or forms) can be determined according to criteria generally considered during the establishment of a treatment of a patient, such as, by way of non-limiting examples, the potency of the compound (s) and/or pharmaceutically acceptable salts of the compound(s), the age of the patient, the body weight of the patient, the severity of the patient's condition (or conditions), the patient's tolerance to the treatment, and secondary effects observed in treatment. Determination of dosages effective to provide therapeutic benefit for specific modes and frequency of administration is within the capabilities of those skilled in the art .
• Naive Wistar control rats; neurons from the dorsal root ganglia (DRG) , lumbar 4, 5 and 6 (L4, L5 and L6) .
• Acute and chronic neuropathic pain rat model CCI rats ( chronic constriction of the sciatic nerve of Wistar rats) 3 days (for acute) and 23 to 29 days (for chronic) after surgery; neurons from DRGs (L4, L5 and L6) .
• Acute and long-lasting or chronic inflammatory pain rat model CFA rats (knee administrations of Complete Freund's Adjuvant (CFA) on Wistar rats) with 3 days (acute), 18 days (sub-chronic) and 23 days (chronic) after injection; neurons from DRGs ( L3 , L4 e L5 ) .
• CFA Complete Freund's Adjuvant
• COP Chronic orofacial pain
• Diabetic Neuropathic pain rat model STZ rats, Wistar rats were submitted to intraperitoneal injections of STZ ( streptozotocin) , developed signs of pain 30 days after, and at the end of further 30 days, were tested with nitenin (IV) (60 days total) ; neurons from DRGs (L4, L5 e L6) .
• Chemotherapy-induced peripheral neuropathy chronic pain rat model CIPN rats, Wistar rats submitted to 3 sessions ( intra-peritoneal injections) of paclitaxel (every 2 days), tested 42 days after induction; neurons from DRGs (L4, L5 e L6 ) .
• nitenin represented herein as the compound of formula V
• nitenin analogue compounds exemplified herein as the compounds of formula I-IV and VI- VIII
• analgesic is disclosed herein for the first time. It involves reduction of K + currents rather than their potentiation. For such reason, it is important to characterise first the potassium currents present in the sdDRGNs and in sdTGNs .
• the voltage activated whole-cell K + currents recorded from sdDRGNs upon a depolarizing step showed a fast activation followed by two phases of inactivation.
• the current decay at depolarised potentials are thus better fit by a sum of two exponential functions: a relatively fast component (here termed I fast - associated to what is known as A-current) , showing a time course (i fast ) of tens of milliseconds, followed by a much slower inactivating current (here termed Isiow) t showing a time course (i s iow) of hundreds of milliseconds (see Figure 1) .
• I fast and I siow are found from cell to cell and even some cells show only one component, I s iow ⁇
• the currents found in sdDRGns are very similar to those described for sdTGns .
• concentrations up to ImM ⁇ 0.3 g/ml
• it specifically reduces I s iow see Figure l.b
• CCI, CFA and Orofacial chronic pain rat models
• the nitenin sensitive current-component shows a current decay that is better fit by a single exponential of ⁇ 150 ms, further suggesting that, at moderate concentrations, nitenin effect is specific on I s iow In contrast, If as t, was little affected by nitenin at concentrations up to 1 pg/ml; concentrations above 3 mM/ml were needed to reduce I fast . Importantly, nitenin reductions of I s iow were larger in neurons obtained from chronic pain animals when compared from the reductions evoked by some concentrations of nitenin in neurons obtained from 'control' animals.
• Nitenin effect is specific to K + currents, not being able to induce relevant changes on voltage-activated Na + currents ( Figure l.b)
• the differential dose responses on I s iow and If as t are better discerned in the dose-response curves presented in Figure 2.
• a. The concentration/blockage relationship for I s iow shows a dual phase. Up to one to 1 mM ( ⁇ 0.3 pg/ml), the relationship can be fit by a single Hill function with a IC50 of ⁇ 0.12 mM. For larger concentrations, the relationship for Isiow follows a second phase where the effect on the I s iow is added to the effect on I fast . Indeed, this second phase coincides with the concentration/blockage relationship for I fast , that in turn, is better fit by a single Hill function. Its IC50 of ⁇ 6 mM confirms a much lower sensitivity to Nitenin .
• Nitenin inhibition of slow K + currents involves a pharmacological process of 'open-channel blockage' . Also, it involves a change in the voltage dependence of steady state of inactivation (and little or no change for the voltage dependence of activation) . In fact, nitenin shifts to more hyperpolarised potentials the I-V curves related to the voltage dependence of inactivation (see Figure 3) .
• the compounds inhibit slow voltage-activated currents recorded from sdDRGNs by promoting K + channel inactivation, inactivation of which, is somewhat impaired in chronic pain conditions. More precisely, the compounds shift the voltage sensitivity of the steady-state inactivation to less depolarised values (or more hyperpolarised) , facilitating inactivation. Such compound-evoked shift in inactivation is as greater as more depolarised the voltage curve profile is in the first place (before treatment with nitenin or nitenin analogues) .
• Depolarised Inactivation curves are typical from sdDRGNs obtained from chronic pain conditions. In other words, in neurons obtained from injured nerves (chronic) , nitenin reverts the voltage dependence profile of inactivation to 'control' patterns.
• the compound-evoked shift in the voltage sensitivity of inactivation is higher in neurons from injured nerves (that exhibit an abnormally depolarized profile) and lower in unaffected neurons that show hyperpolarised voltage profiles.
• This interesting effect on channel gating explains in part the compound-evoked decrease of neuronal excitability that is specific/more pronounced in affected neurons, i.e. during pain.
• C-fibers are usually silent, with little or no spontaneous firing activity, i.e., there is little or no basal activity in control conditions.
• I s iow shows abnormal depolarised inactivation profiles, i.e. channels inactivating less.
• the increase of the "excitatory force" brought by the consensual increase in Na + currents has to be sustained by a counter-balancing increase in K + currents that would accommodate repetitive -long-term firing patterns.
• the effect of the compounds disclosed herein is such that it reverts such patterns to control profiles, decreasing the slowly-inactivating Kv-mediated current. This nitenin-evoked effect of the slow K + currents would not allow the required accommodation of the increase of sodium conductance (Nav) , typical in pain situations.
• Nav sodium conductance
• the drug-induced decrease of K + currents may result in a slow depolarization of the affected neurons in a way that membrane potential is kept at a depolarized level, so the usual threshold potential may pass without an action potential having been fired. It would thus result in an accommodation-like process as depolarization would close inactivation gates of the Na + channels, remaining closed, preventing the upstroke of action potential to occur (not enough Na + channels 'activatable' ) .
• Kvl.3 nitenin is particularly effective on Kvl.3 (see Figure 2.b) and (2) Kvl.3 expressed in DRG (Yang et al . , 2004) and increases it expression levels in DRG neurons with chronic pain (unpublished data) .
• the biophysical nature and the kinetics of Kvl.3 mediated currents are thought to sustain stabilised tonic firing (Kupper et al . , 2002), a state that correspond to neurons in a 'chronic pain situation'.
• nociception was assessed in all animals from all pain models by regular behavioural monitoring, by quantifying the sensitivity to mechanical stimuli with Von Frey filaments, and consequently reflecting hyperalgesia when hypersensitive.
• the cold allodynia with acetone test was also used and showed very similar responses as those with Von Frey Filaments.
• IV intravenous injections of purified nitenin ( >98 % - compound of formula V) (1 pg/mL of blood ⁇ 0.06 mg/Kg.
• Intraperitoneal administration was tested in CFA rats (23 days after CFA injection), with 10 times the nitenin quantity administered by I.V. injections. In this case, there was a clear mitigation effect of pain with score values reaching control levels, effect that lasted for about 4 hours .
• nitenin compounds have shown to be effective for short-term/acute and long-term/chronic neuropathic pain, short-term/acute and long-term/chronic inflammatory pain, chronic orofacial pain, diabetic neuropathic pain, and chemotherapy-induced peripheral neuropathy. Efficacy has been demonstrated for several administration routes, such as intravenously, intraperitoneally and, importantly, via oral administration .
• the effects of the three nitenin analogues were similar in what the affected K + current component is concerned. However, the typical effects on I s iow ( Figure 7-9), and on the voltage dependence of steady-state inactivation ( Figures 10-12) were obtained at different concentrations. This strongly indicates that nitenin analogue compounds have a clear effect on I slow/ although with different affinities. The strongest effect was observed for the compound of formula V, followed by the compounds of formula VII, Villa, Vlllb and VI, respectively .
• Nitenin analogs should be used for pharmacological use in warm-blooded vertebrates, particularly humans, in doses ranging from 0. lpg /ml blood (6 pg/Kg body weight) to 30pg /ml blood (1.8 mg/Kg body weight) .
• Assays with the VEGA® software allowed to test several types of toxicity: mutagenicity, carcinogenicity, developmental toxicity, hepatotoxicity, dermal sensitisation, affinity to oestrogen receptor and several environmental parameters (e.g. aquatic toxicity, bees, bioaccumulations) . At various levels of confidence, all tests were negative.

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