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EP-3938345-B1 - CHARGED ION CHANNEL BLOCKERS AND METHODS FOR USE

EP3938345B1EP 3938345 B1EP3938345 B1EP 3938345B1EP-3938345-B1

Inventors

  • COLE, Bridget, M.
  • ELLIS, James, Lamond

Dates

Publication Date
20260506
Application Date
20200311

Claims (15)

  1. A compound represented by Formula (I) wherein: Y - is a pharmaceutically acceptable anion; R A , R B , and R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I , CN, NR J R K , NR L C(O)R M , S(O)R N , S(O) 2 R N , SO 2 R O R P , SO 2 NR O R R , SO 3 R S , CO 2 R T ; C(O)R U , and C(O)NR V R W ; each of R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R Y , and R W is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or R J and R K or R V and R W or R Q and R R can be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5, 6, 7, or 8 membered ring; R A , R B , and/or R C can be taken together with the phenyl ring to which they are attached can form a fused bicyclic or tricyclic ring system; X 1 is -NR Z C(O)-; R Z is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; each of R D and R E is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl; or R D and R E together with the carbon to which they are attached form a substituted or unsubstituted C 3- C 6 cycloalkyl, substituted or unsubstituted heterocyclic; or R D and R Z together with the carbon and the -N-C(O)- to which they are attached form an optionally substituted 5-8-membered lactam; R F and R G together with the N + to which they are attached form an optionally substituted heterocyclic ring having zero, one or more nitrogen atoms in addition to the N+; R H is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl; each optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl group is optionally substituted with substituents independently selected from alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety; each optionally substituted heterocyclyl or heteroaryl group is optionally substituted with substituents independently selected from substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, oxo, and carboxyl groups; and each optionally substituted aryl group is optionally substituted with substituents independently selected from substituted or unsubstituted alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, alkylcarboxy, amino, alkylamino, monosubstituted amino, disubstituted amino, and quaternary amino groups.
  2. The compound of claim 1, wherein Y - is bromide, chloride, or iodide.
  3. The compound of claim 1, wherein X 1 is -NHC(O)-.
  4. The compound of claim 1, wherein: (a) R Y is selected from a C 6-10 aryl or a C 5-10 heteroaryl, each optionally substituted with C 1-6 alkane, C 3 -C 6 cycloalkyl, heterocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, hydroxyl, amide, ester, sulfonamide, urea, nitrile, or halogen; or (b) R H is a C 6-10 aryl or a 5- to 10-membered heteroaryl, each optionally substituted with a substituted or unsubstituted C 1 -C 6 alkyl, halo, nitrile, hydroxyl, and alkoxy.
  5. The compound of claim 1, wherein each of R A and R B is independently selected from H, halogen, C 1-4 alkyl, and NR J R K ; each of R J and R K is independently selected from H or C 1-4 alkyl; and wherein R C is H, halogen, C 1-4 alkyl, or NR J R K .
  6. The compound of claim 1, wherein R A , R B , and R C are each independently selected from H, D, halogen, OR I , substituted or unsubstituted C 1- C 4 alkyl, and NR J R K ; wherein each of R I , R J and R K is independently selected from H and substituted or unsubstituted C 1- C 4 alkyl.
  7. The compound of claim 1, wherein each of R A and R B is CH 3 , and R C is selected from the group consisting of H, CH 3 , halogen, nitrile, methoxy, and ethoxy.
  8. The compound of claim 1, wherein R D is C 1-4 alkyl optionally substituted with halogen, oxygen, C 3-8 cyclic alkyl, aryl, or heteroaryl, and wherein R E is H, D, or C 1-4 alkyl.
  9. The compound of claim 1, wherein: (a) R D and R E are both hydrogen; or (b) R D is hydrogen and R E is an alkyl; or (c) R D and R E are taken together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl.
  10. The compound of claim 1, wherein R F and R G together with the N + to which they are attached form a substituted or unsubstituted five, six, seven-, or eight-membered heterocyclic ring.
  11. The compound of claim 1, wherein the compound is represented by Formula (II): wherein: Y - is a pharmaceutically acceptable anion; q is 0, 1, 2, or 3; R D is hydrogen, methyl, or ethyl; and R 1B is hydrogen.
  12. The compound of claim 1, wherein: Y - is a pharmaceutically acceptable anion; R A and R B are each independently selected from substituted or unsubstituted alkyl; or R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I , CN, NR J R K , NR L C(O)R M , S(O)R N , S(O) 2 R N , SO 2 R O R P , SO 2 NR Q R R , SO 3 R S , CO 2 R T ; C(O)R Y , and C(O)NR V R W ; X 1 is -NR Z C(O)-; R F and R G together with the N + to which they are attached form an optionally substituted heterocyclic ring having zero, one or more nitrogen atoms in addition to the N+.
  13. The compound of claim 1, wherein the compound is selected from: (a) the Table below: Compound # Structure Compound # Structure 16A 17A 3A 18A 4A 19A 5A 20A 6A 21A 7A 22A 8A 23A 9A 24A 10A 25A 11A 26A 12A 27A 13A 28 14A 29 15A 30A 16A 31A ; or (b) the Table below: Compound # Structure Compound # Structure 16B 17B 3B 18B 4B 19B 5B 20B 6B 21B 7B 22B 8B 23B 9B 24B 10B 25B 11B 26B 12B 27B 13B 30B 14B 31B 15B
  14. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, optionally wherein said composition is formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural, or ocular administration.
  15. The compound of claim 1, for use in a method for treating pain, cough, itch, or a neurogenic inflammatory disorder in a patient, comprising administering to said patient, optionally wherein: (a) said pain is selected from the group consisting of pain due to back and neck pain, lower back pain, cancer pain, gynecological and labor pain, fibromyalgia, arthritis, rheumatoid arthritis, osteoarthritis, rheumatological pains, orthopedic pains, acute and post herpetic neuralgia and other neuropathic pains (including peripheral neuropathy), sickle cell crises, vulvodynia, peri-anal pain, irritable bowel disease, irritable bowel syndrome, inflammatory bowel disease, oral mucositis, esophagitis, interstitial cystitis, urethritis and other urological pains, dental pain, headaches, trigeminal trophic syndrome, erythromelalgia, abdominal wall pain, chronic abdominal wall pain, allergic rhinitis, muscle pain, rectal pain, Levator ani syndrome, proctalgia fugax, hemorrhoid pain, stomach pain, skin ulcers, stomach ulcers, burn pain, ophthalmic irritation, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, dry eye syndrome (chronic ocular pain), complex regional pain syndrome, post-surgical ocular pain, postoperative pain, acute postoperative pain, and procedural pain (i.e., pain associated with injections, draining an abscess, surgery, dental procedures, ophthalmic procedures, ophthalmic irritation, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, arthroscopies and use of other medical instrumentation, cosmetic surgical procedures, dermatological procedures, setting fractures, and biopsies); or (b) said cough is selected from the group consisting of cough in patients with asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonary fibrosis, post viral cough, post-infection cough, chronic idiopathic cough and lung cancer; or (c) said itch is selected from the group consisting of itch due to pruritus, brachioradial pruritus, chronic idiopathic pruritus, genital/anal pruritus, notalgia paresthetica, scalp pruritus, allergic dermatitis, contact dermatitis, atopic dermatitis, hand eczema, poison ivy, infections, parasites, insect bites, pregnancy, metabolic disorders, liver or renal failure, drug reactions, allergic reactions, eczema, genital and anal itch, hemorrhoid itch, and cancer; or (d) said neurogenic inflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine headache, rosacea, sunburn, pancreatitis, chronic rhinosinusitis, traumatic brain injury, polymicrobial sepsis, tendinopathies, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, pollutants, chemical warfare agents, and atopic dermatitis; or (e) the use is in combination with one or more exogenous large pore receptor agonists.

Description

TECHNICAL FIELD The present invention relates generally to quaternary ammonium compounds, pharmaceutical compositions, and their use as selective inhibitors of pain, cough, and itch sensing neurons (nociceptors, cough receptors and pruriceptors) and their use in the treatment of neurogenic inflammation. BACKGROUND OF THE INVENTION The invention features compounds, compositions and compounds for use in methods for the selective inhibition of sensory neurons (nociceptors, cough receptors and pruriceptors) and the treatment of neurogenic inflammation by targeting nociceptors with a small molecule drug, while minimizing effects on non-nociceptive neurons or other types of cells. According to the invention, small, cationic drug molecules gain access to the intracellular compartment of sensory neurons via entry through large pore receptor/ion channels that are present in pain- cough- and itch-sensing neurons but to a lesser extent or not at all in other types of neurons or in other types of tissue. Local anesthetics such as lidocaine and articaine act by inhibiting voltage-dependent sodium channels in neurons. These anesthetics block sodium channels and thereby the excitability of all neurons, not just pain-sensing neurons (nociceptors). Thus, while the goal of topical or regional anesthesia is to block transmission of signals in nociceptors to prevent pain, administration of local anesthetics also produces unwanted or deleterious effects such as general numbness from block of low threshold pressure and touch receptors, motor deficits and/or paralysis from block of motor axons and other complications from block of autonomic fibers. Local anesthetics are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing through the cell membrane. Charged derivatives of these compounds, which are not membrane-permeable, have no effect on neuronal sodium channels when applied to the external surface of the nerve membrane but can block sodium channels if somehow introduced inside the cell, for example by diffusion from a micropipette used for whole-cell electrophysiological recording from isolated neurons. Pain-, cough-, and itch-sensing neurons differ from other types of neurons in expressing (in most cases) the TRPV1 receptor/channel, which is activated by painful heat or by capsaicin, the pungent ingredient in chili pepper. Other types of channels selectively expressed in various types of pain-sensing, cough-sensing and itch-sensing (pruriceptor) neurons include but are not limited to TRPV2-4, TRPA1, TRPM8, ASIC and P2X(2/3) channels. It is well established that some cationic small molecules such as QX-314 are able to enter a cell via passage through activated large pore channels such as TRPV1. Neuropathic, inflammatory, and nociceptive pain differ in their etiology, pathophysiology, diagnosis, and treatment. Nociceptive pain occurs in response to the activation of a specific subset of high threshold peripheral sensory neurons, the nociceptors, by intense or noxious stimuli. It is generally acute, self-limiting and serves a protective biological function by acting as a warning of potential or on-going tissue damage. It is typically well-localized. Examples of nociceptive pain include, but are not limited to, traumatic or surgical pain, labor pain, sprains, bone fractures, burns, bumps, bruises, injections, dental procedures, skin biopsies, and obstructions. Inflammatory pain is pain that occurs in the presence of tissue damage or inflammation including postoperative (i.e. pain associated with acute perioperative pain resulting from inflammation caused by tissue trauma (e.g., surgical incision, dissection, burns) or direct nerve injury (e.g., nerve transection, stretching, or compression)), posttraumatic pain, arthritic pain (rheumatoid; or osteoarthritis (i.e. joint pain and stiffness due to gradual deterioration of the joint cartilage; risk factors include aging, injury, and obesity; commonly affected joints are the hand, wrist, neck, knee, hip, and spine), pain and pain associated with damage to joints, muscle, and tendons as in axial low back pain (i.e. a prevalent, painful condition affecting the lower portion of the back; common causes include muscle strain, spine fracture, bulging or ruptured disc, and arthritis), severe nociceptive pain may transition to inflammatory pain if there is associated tissue injury. Neuropathic pain is a common type of chronic, non-malignant pain, which is the result of an injury or malfunction in the peripheral or central nervous system and serves no protective biological function. It is estimated to affect more than 1.6 million people in the U.S. population. Neuropathic pain has many different etiologies, and may occur, for example, due to trauma, surgery, herniation of an intervertebral disk, spinal cord injury, diabetes, infection with herpes zoster (shingles), HIV/AIDS, late-stage cancer, amputation (including mastectomy), carpal tunne