Charged Ion Channel Blockers and Methods of Use

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds, compositions, methods and kits of the present invention are particularly useful for treating itch and other skin conditions.

Description

Technical Field

[0001] Related Applications This application is a continuation-in-part of U.S. Application No. 16 / 815,426, filed on March 11, 2020. The entire content of the above application is incorporated herein by reference.

[0002] Technical Field The present invention generally relates to quaternary ammonium compounds, pharmaceutical compositions, and methods useful as selective inhibitors of pain, cough, and itch sensory neurons (nociceptors, cough receptors, and pruriceptors) and for the treatment of neuroinflammation.

Background Art

[0003] Background of the Invention The present invention features compounds, compositions, and methods for the treatment of itch and / or neuroinflammation by targeting nociceptors using small molecule drugs while minimizing the selective inhibition of sensory neurons and effects on non-nociceptive neurons or other types of cells. According to the method of the present invention, small cationic drug molecules gain access to the intracellular compartment of sensory neurons via entry through large pore receptors / ion channels that are present in itch sensory neurons but are present to a lesser extent or not at all in other types of neurons or other types of tissues.

[0004] Local anesthetics such as lidocaine, articaine, and pramocaine work by inhibiting voltage-dependent sodium channels within neurons. These anesthetics block the excitability of sodium channels and thus all neurons, not just pain-sensing neurons (nociceptors). Therefore, the aim of local or regional anesthesia is to block the transmission of signals within nociceptors to prevent pain, but the administration of local anesthetics also produces unwanted or harmful effects such as general numbness due to the blockade of low-threshold pressure and touch receptors, motor deficits and / or paralysis due to the blockade of motor axons, and other complications due to the blockade of autonomic fibers. Local anesthetics are relatively hydrophobic molecules that gain access to their blocking sites on sodium channels by diffusing through cell membranes. Charged derivatives of these compounds that are not membrane-permeable have no effect on neuronal sodium channels when applied to the outer surface of the nerve membrane, but can block sodium channels if somehow introduced into the cell interior, for example, by diffusion from a micropipette used for whole-cell electrophysiological recordings from isolated neurons. Neurons that sense pain, cough, and itch differ from other types of neurons in that they (mostly) express the TRPV1 receptor / channel, which is activated by noxious heat or by capsaicin, the pungent component in chili peppers. Other types of channels that are selectively expressed in neurons that sense various types of pain, cough, and itch (so-called itch receptors) 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 can enter cells by passing through activated large-pore channels such as TRPV1.

[0005] Neuropathic, inflammatory, and nociceptive pain differ in their etiology, pathophysiology, diagnosis, and treatment. Nociceptive pain occurs in response to activation of a specific subset of nociceptors, which are high-threshold peripheral sensory neurons, by intense or noxious stimuli. This is generally acute, self-limiting, and serves a protective biological function by acting as a warning of potential or progressive tissue damage. It is typically well localized. Examples of nociceptive pain include, but are not limited to, traumatic or surgical pain, labor pain, sprains, fractures, burns, collisions, contusions, injections, dental procedures, skin biopsies, and obstructions.

[0006] Inflammatory pain occurs in the presence of tissue damage or inflammation, including postoperatively (i.e., pain associated with acute intraoperative pain caused by inflammation resulting from tissue trauma (e.g., surgical incision, dissection, burn) or direct nerve injury (e.g., nerve transection, stretch, or compression)), post-traumatic pain, arthritic pain (rheumatoid; or osteoarthritis (i.e., pain and stiffness of joints due to progressive deterioration of articular cartilage; risk factors include aging, injury, and obesity; commonly affected joints are the hands, wrists, neck, knees, hips, and spine)), pain associated with injury to joints, muscles, and tendons as in the case of pain and axial low back pain (i.e., a prevalent painful condition affecting the lower back; common causes include muscle tension, vertebral fractures, swollen or ruptured discs, and arthritis), and severe nociceptive pain can transition to inflammatory pain if there is associated tissue damage.

[0007] Neuropathic pain is a common type of chronic, non-malignant pain that results from damage or dysfunction of 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 United States population. Neuropathic pain has many different causes, such as trauma, surgery, herniated discs, spinal cord injury, diabetes, infection by herpes zoster (shingles), HIV / AIDS, late-stage cancer, amputation (including mastectomy), carpal tunnel syndrome, chronic alcohol use, exposure to radiation, and as an unintended side effect of neurotoxic therapeutic agents such as certain anti-HIV and chemotherapy drugs. Peripheral neuropathy is caused by damage to the peripheral nerves from injury, trauma, prolonged pressure or inflammation that causes numbness and pain in the corresponding areas of the body.

[0008] Neuropathic pain is naturally often described as "burning," "electric," "tingling," or "shooting." This is often characterized by chronic dynamic allodynia (defined as pain caused by stimuli of movement that usually do not elicit a painful response such as light touch) and hyperalgesia (defined as increased sensitivity to normal painful stimuli), and can persist for months or years beyond the visible healing of any damaged tissue.

[0009] Pain can occur in patients with cancer, due to multiple causes; it can be due to inflammation, compression, invasion, metastatic spread to bone or other tissues.

[0010] There are several conditions in which pain, termed functional pain, occurs in the absence of a noxious stimulus, tissue damage, or lesion to the nervous system, including, but not limited to, fibromyalgia, tension-type headache, and irritable bowel syndrome.

[0011] Migraine headache is a headache associated with activation of sensory fibers that innervate the meninges of the brain.

[0012] Itching is a dermatological condition that can be localized or generalized and can be associated with skin lesions (rashes, atopic eczema, hives). Itching is associated with many conditions including, but not limited to, stress, anxiety, UV irradiation from the sun, metabolic and endocrine disorders (e.g., liver or kidney disease, hyperthyroidism), cancer (e.g., lymphoma), reactions to drugs or food, infestations and fungal infections, allergic reactions, blood disorders (e.g., polycythemia vera), and dermatological conditions. Itching is mediated by itch receptors, a subset of small-diameter primary sensory neurons that share many features of nociceptive neurons including, but not limited to, the expression of TRPV1 channels and other large pore channels (e.g., TRPV2-4, TRPA1, TRPM8, ASIC, and P2X(2 / 3)). Certain itch mediators such as eicosanoids, histamine, bradykinin, ATP, and various neurotrophins have endovanilloid functions. Topical capsaicin suppresses histamine-induced itching. Thus, itch receptors such as nociceptors are suitable targets for this method of delivering ion channel blockers.

[0013] Cough is a defensive reflex designed to protect the airways from foreign bodies and assist in the removal of luminal debris. However, this reflex can be abnormal in several diseases, resulting in a non-productive dry cough with hyper- or allo-tussive states. Hyper- and allo-tussive states are often chronic in nature, lasting longer than three months, and can be manifested in many airway disease states including asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), and lung cancer. In addition, inappropriate cough reflexes can be manifested acutely and chronically after viral infections. Furthermore, chronic cough can be idiopathic in nature, with an unknown etiology.

[0014] Neurogenic inflammation is a form of inflammation mediated by the efferent (motor) function of sensory neurons, where pro-inflammatory mediator molecules released peripherally by pain-sensing neurons (nociceptors) activate various inflammatory pathways in immune cells and act on the vasculature to alter blood flow and capillary permeability.

[0015] Neurogenic inflammation contributes to peripheral inflammation induced by tissue damage, autoimmune diseases, infections, allergies, exposure to irritants in various tissues, and is thought to play an important role in the etiology of many disorders (such as allergic inflammation, inflammatory bowel disease, interstitial cystitis, atopic dermatitis, asthma, conjunctivitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine, psoriasis, rhinitis, hives, sunburn, pancreatitis, chronic cough, chronic rhinosinusitis, traumatic brain injury, polymicrobial sepsis, tendinopathy, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, contaminants or chemical warfare agents). One way to reduce neurogenic inflammation is to block excitability in nociceptors, thereby preventing activation of nociceptor nerve endings and release of pro-inflammatory mediators.

[0016] Despite the development of various treatments for pain, itching and neurogenic inflammation, there is a need for additional agents. SUMMARY OF THE INVENTION

[0017] Summary of the Invention The present invention provides a compound of formula (I) which can be used for treating or preventing itching, pain, cough and neurogenic inflammation:

Chemical formula

[0018] The present invention includes the surprising discovery that the compound is particularly active in the treatment of itching. The compound has surprisingly high potency and excellent topical localization, making it surprisingly suitable for topical application to the skin. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Brief Description of the Drawings

Figure 1

[0020] Detailed Description of the Invention The present invention provides a compound represented by the above formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or combination thereof. The present invention also provides a composition comprising a compound having the formula (I) or a pharmaceutically acceptable salt thereof, for example, a composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The compositions of the present invention may further comprise a compound of the present invention and a biologically active agent. The compositions may be formulated for oral, intravenous, intramuscular, rectal, dermal, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural or intraocular administration. However, preferred compositions may be formulated for topical or dermal administration.

[0021] The present invention further provides a method for treating itching, pruritis, psoriasis or atopic dermatitis in a patient, comprising the step of administering to the patient a composition comprising a compound having formula (I).

[0022] As used herein, the terms "a" and "an" mean one or more, unless specified otherwise.

[0023] "Biologically active" means that a molecule, including biological molecules such as nucleic acids, peptides, polypeptides and proteins, exerts a biological, physical or chemical effect on a protein, enzyme, receptor, ligand, antigen, itself or other molecules. For example, a "biologically active" molecule can have, for example, enzyme activity, protein binding activity or pharmacological activity.

[0024] Biologically active agents that can be used in the methods and kits described herein include, without limitation, TRPA1 receptor agonists, TRPV1-4 receptor agonists, ASIC agonists, TRPM8 agonists, P2X receptor agonists, NSAIDs, glucocorticoids, anesthetics, anti-proliferative and immunomodulatory agents, antibodies or antibody fragments, antibiotics, polynucleotides, polypeptides, proteins, anti-cancer agents, growth factors and vaccines.

[0025] The term "itching" is used herein in the broadest sense and refers to acute intermittent and persistent localized, generalized itching and prickling sensations. Itching can be idiopathic, allergic, metabolic, infectious, drug-induced due to liver, kidney diseases or cancer. "Pruritis" is severe itching.

[0026] "Inflammation" means any type of inflammation, such as that caused by the immune system (immune-mediated inflammation) and by the nervous system (neurogenic inflammation), and any symptoms of inflammation such as redness, heat, swelling, pain and / or loss of function. Inflammation of the skin is preferred.

[0027] "Neurogenic inflammation" means any type of inflammation mediated or contributed to by neurons (e.g., nociceptors) or any other component of the central or peripheral nervous system. Neurogenic inflammation of the skin is preferred.

[0028] The term "pain" is used herein in its broadest sense and refers to all types of pain, acute and chronic, such as nociceptive pain, e.g., somatic pain and visceral pain; inflammatory pain, dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrally arising pain and peripherally arising pain, migraine and cancer pain. Pain of the skin is preferred.

[0029] The term "nociceptive pain" is used to include, without limitation, all pain caused by noxious stimuli that threaten or actually damage body tissues, e.g., by cuts, bruises, fractures, crushed injuries, burns, etc. Pain receptors (nociceptors) for tissue damage are mostly located in the skin, the musculoskeletal system or internal organs, preferably the skin or dermis.

[0030] The term "somatic pain" is used to refer to pain arising from bone, joint, muscle, skin or connective tissue, preferably the skin and the tissues adjacent to the skin. This type of pain is typically well localized.

[0031] The term "visceral pain" is used herein to refer to pain arising from visceral organs such as the respiratory, gastrointestinal and pancreatic, urinary and reproductive organs. Visceral pain includes pain caused by tumor involvement of the organ capsule. Another type of visceral pain typically caused by obstruction of a hollow viscus is characterized by intermittent spasms and poorly localized pain. Visceral pain can be associated with inflammation such as that in cystitis or reflux esophagitis.

[0032] The term "inflammatory pain" includes pain associated with active inflammation that can be caused by trauma, surgery, infection and autoimmune diseases.

[0033] The term "neuropathic pain" is used herein to refer to pain that results from abnormal processing of sensory input by these systems as a result of lesions to the peripheral or central nervous system.

[0034] The term "procedural pain" refers to pain resulting from a medical, dental, or surgical procedure, where the procedure is typically planned or associated with acute trauma.

[0035] "Patient" means any animal. In one aspect, the patient is a human. Other animals that can be treated using the methods, compositions, and kits of the present invention include, but are not limited to, non-human primates (e.g., monkeys, gorillas, chimpanzees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas), and companion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds).

[0036] Compounds useful in the present invention include, but are not limited to, isomers such as their diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs, as well as racemic mixtures and pure isomers of the compounds described herein, in any of their pharmaceutically acceptable forms described herein.

[0037] As used herein, the term "pharmaceutically acceptable anion" refers to the conjugate base of a pharmaceutically acceptable acid. Such acids are described in Stahl, P.H. and Wermuth, C.G. (eds.), Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley VCH (2008). Pharmaceutically acceptable acids include, but are not limited to, acetic acid, dichloroacetic acid, adipic acid, alginic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, 4-acetamidobenzoic acid, benzoic acid, p-bromophenylsulfonic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, sulfuric acid, boric acid, citric acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicyclic acid, 4-aminosalicyclic acid, sebacic acid, stearic acid, succinic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid. Pharmaceutically acceptable anions include the conjugate bases of any of the foregoing acids.

[0038] The term "pharmaceutically acceptable salt" refers to salts that are within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that exhibit a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, isethionate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like.

[0039] "D" is deuterium.

[0040] As used herein, the terms "alkyl" and the prefix "alk-" include both straight and branched chain groups as well as cyclic groups, i.e., cycloalkyl. The cyclic groups can be monocyclic or polycyclic and preferably can have from 3 to 6 ring carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. "C" 1-*"Alkyl" means a branched, unbranched or cyclic hydrocarbon group having 1 to * carbon atoms, where * is an integer such as 2, 3, 4, 5, 6, 7, 8, 10, 12 or more. The alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoroalkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amide, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, aryl, heterocyclyl, alkylaryl, or an aromatic moiety or heteroaromatic moiety. In certain aspects, alkyl is C1-C6 alkyl. C 1-6 Examples of alkyl include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl and cyclohexyl. Another specific example of a substituted alkyl is: [Chemical formula] a moiety that forms homodimers or heterodimers such as etc.

[0041] Another example of an alkyl to be replaced is heteroalkyl. "Heteroalkyl" means a branched or unbranched alkyl, cycloalkyl, alkenyl or alkynyl group having 1 to 7 or more carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S and P. Examples of heteroalkyl include, but are not limited to, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides and disulfides. Optionally, heteroalkyl may include monocyclic, bicyclic or tricyclic rings each of which preferably has 3 to 6 members. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoroalkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amide, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, aryl, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. C 1-7 Examples of heteroalkyl include, but are not limited to, methoxymethyl and ethoxyethyl.

[0042] Alkenyl is a branched or unbranched hydrocarbon group containing one or more double bonds. For example, "C 2-6"Alkenyl" or "C2-C6 alkenyl" means a branched or unbranched hydrocarbon group containing one or more double bonds and having 2 to 6 carbon atoms. Optionally, the alkenyl may include monocyclic or polycyclic rings, each ring preferably having 3 to 6 members. The alkenyl group may be substituted or unsubstituted. Exemplary substituents include those described above for alkyl, specifically, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy and carboxyl groups. C 2-6 Examples of alkenyl include, but are not limited to, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl and 2-methyl-2-propenyl.

[0043] Alkynyl is a branched or unbranched hydrocarbon group containing one or more triple bonds. For example, "C 2-6 "Alkynyl" or "C2-C6 alkynyl" means a branched or unbranched hydrocarbon group containing one or more triple bonds and having 2 to 6 carbon atoms. Optionally, the alkynyl may include monocyclic, bicyclic or tricyclic rings, each ring preferably having 5 or 6 members. The alkynyl group may be substituted or unsubstituted. Exemplary substituents are those described above for alkyl, specifically, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy and carboxyl groups. C 2-6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl.

[0044] "Heterocyclyl", "heterocyclic", or "heterocycloalkyl" means a stable monocyclic or polycyclic (including bicyclic or tricyclic) heterocyclic ring that is saturated, partially unsaturated, or unsaturated (including heteroaryl or aromatic), consisting of two or more carbon atoms and one, two, three, four, or more heteroatoms independently selected from P, N, O, and S, and including any bicyclic or polycyclic group in which any of the previously defined heterocyclic rings is fused to a benzene ring, heteroaryl, cycloalkyl, or heterocycloalkyl. In certain aspects, heterocyclyl is a 3- to 15-membered ring system, a 3- to 12-membered ring system, or a 3- to 9-membered ring system. Heterocyclyl (e.g., a heteroaryl group) can be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br, or I), hydroxyl, fluoroalkyl, perfluoroalkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amide, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, acylamino (e.g., alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Nitrogen and sulfur heteroatoms can be optionally oxidized. The heterocyclic ring can be covalently bonded through a heteroatom or carbon atom that results in a stable structure; for example, an imidazolinyl ring can be bonded at either a ring carbon atom position or a nitrogen atom. Nitrogen or phosphorus atoms in the heterocycle can be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1,These heteroatoms are not adjacent to each other. The heterocyclic rings include, but are not limited to, 1H-indazole, 2-pyrrolidinyl, 2H,6H-1,5,2-dithiadinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiadinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thieno[2,3-b]thiazolyl, thieno[2,3-b]oxazolyl, thieno[2,3-b]imidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, β-lactam, γ-lactam and δ-lactam are included. Preferred 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl and isoquinolinyl. Preferred 5- to 6-membered heterocycles include, without limitation, pyridinyl, quinolinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and tetrazolyl. Preferred substituents include phenyl, methyl, ethyl, propyl, butyl, oxo, chloro, bromo, fluoro and iodo.,

[0045] "Aryl" means an aromatic group (e.g., phenyl) having a ring system composed of carbon atoms with conjugated π electrons. "C 6- C 12 aryl" or "C6-C 10"Aryl" means an aryl group having 6 to 12 carbon atoms or 6 to 10 carbon atoms respectively. Optionally, the aryl group may include monocyclic, bicyclic or tricyclic rings each preferably having 5 or 6 members. The ring system may be fused (e.g., naphthyl) or unfused (biphenyl). The aryl group may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoroalkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amide, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, acylamino (e.g., alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, aryl, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0046] "Aralkyl" means a substituted alkyl or unsubstituted alkyl substituted by a substituted or unsubstituted aryl (e.g., including (e.g., benzyl, phenethyl or 3,4-dichlorophenethyl)). "Heteroaralkyl" means a substituted or unsubstituted alkyl substituted by a heteroaryl group or a heteroaryl group.

[0047] "Halide" or "halogen" means bromine, chlorine, iodine or fluorine.

[0048] "Fluoroalkyl" means an alkyl group substituted by one or more fluorine atoms such as a perfluoroalkyl group. Examples are trifluoromethyl, difluoromethyl, fluoromethyl and heptafluoroethyl.

[0049] "Alkoxy" means a chemical moiety having the formula -O-R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.

[0050] "Alkylcarboxy" means a chemical moiety having the formula -(R)-COOH, where R is selected from alkyl (e.g., C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl), heterocyclyl, aryl, heteroaryl, aralkyl, heterocycloalkyl or heteroalkyl, each optionally substituted.

[0051] "Charged moiety" means a moiety that acquires a proton at physiological pH and thereby becomes positively charged (e.g., ammonium, guanidinium or amidinium) or a moiety that contains a net formal positive charge without being protonated (e.g., quaternary ammonium). The charged moiety can be either permanently charged or temporarily charged.

[0052] "Therapeutically effective amount" or "effective amount" means an amount sufficient to produce a desired result, e.g., reduction or elimination of pain, cough, itching or neuroinflammation, in a patient (e.g., a human) suffering from a condition, disorder or disease (e.g., allergic inflammation, inflammatory bowel disease, interstitial cystitis, atopic dermatitis, asthma, conjunctivitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine, psoriasis, rhinitis, sunburn, pancreatitis, chronic cough, chronic rhinosinusitis, traumatic brain injury, polymicrobial sepsis, tendon disorder, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, irritants, contaminants or chemical warfare agents) caused wholly or in part by neuroinflammation.

[0053] "Solvate" means a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent.

[0054] The compounds of the present invention including salts of the compounds may exist in unsolvated and solvated forms, such as hydrated and non-hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present invention. Non-limiting examples of hydrates include monohydrate, dihydrate, hemihydrate, etc. In certain aspects, the compound is a hemihydrate. Non-limiting examples of solvates include ethanol solvate, acetone solvate, etc.

[0055] The compounds of the present invention may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0056] Formula (I):

Chemical formula

[0057] Preferred R A is selected from H, methyl, halo (e.g., F, Cl or Br), CF3, CN, CO2R T or OR I 、more preferably methyl, F, CF3 or CN, most preferably methyl.

[0058] Preferred R B is selected from H and methyl, most preferably methyl.

[0059] Preferred R C is H, methyl, halo (e.g., F, Cl or Br), CF3, CN, CO2R T or OR I , more preferably H or OR I , most preferably selected from H.

[0060] R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C4 alkyl, cycloalkyl, C1-C4 heteroalkyl, aryl or heteroaryl, preferably hydrogen, methyl or ethyl; n is 0, 1, 2, 3, 4 and 5; alternatively, R1, R2, R3, R4, R5 and / or R6, together with the carbon(s) to which they are attached, form a substituted or unsubstituted cycloalkyl (e.g., C3-C6 cycloalkyl) or a substituted or unsubstituted heterocyclic (e.g., 3- to 15-membered heterocyclic ring).

[0061] It is understood that the optionally substituted alkenylenyl linker of 2 to 7 carbons is formed between the ether oxygen and the fourth nitrogen. In preferred compounds, each of R1, R2, R3, R4, R5 and / or R6 is hydrogen (e.g., forming a linear alkenylenyl, e.g., ethenyl, propenyl, butenyl or pentenyl). In preferred compounds, each of R5 and R6 is hydrogen. In other compounds, both of R1 and / or R2 are hydrogen. In other compounds, both of R3 and R4 are hydrogen. Alternatively, R1 is methyl or ethyl and R2, R3, R4, R5 and R6 are hydrogen. Alternatively, R3 is methyl or ethyl and R1, R2, R4, R5 and R6 are hydrogen.

[0062] R F and R G are, together with N + form N +In addition, it forms an optionally substituted heterocyclic ring having 0, 1 or more heteroatoms. The ring may have 5, 6, 7, 8 or 9 ring members. 7- and 8-membered rings are preferred. Thus, examples of preferred heterocyclic rings include:

[0063] As is understood, the N of formula (I) + Examples of the containing ring include:

Chemical formula

Chemical formula

[0064] The heterocyclic ring may optionally be substituted as described above. For example, R7 may be hydrogen or substituted or unsubstituted alkyl. Preferred substituents include alkyl, CF3, halogen, OH and OR I are included.

[0065] R H is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, for example -CH2-cycloalkyl, -C2H4-cycloalkyl, substituted or unsubstituted -CH2-C 5- C 10 aryl, substituted or unsubstituted -C2H4-C 5- C 10 aryl, substituted or unsubstituted -CH2-C 5- C 10 heteroaryl, substituted or unsubstituted -C2H4-C 5- C 10 heteroaryl, -CH2OC(O)R T 、-CH2CO2R T 、-CH2C(O)NR V R W 、-C2H4OCOR T 、-C2H4OR I is selected from, or Preferably, R H is benzyl or substituted benzyl. Alternatively, RH is unsubstituted alkyl, alkenyl or alkynyl, such as C3, C4, C5, C6, C7 or C8 alkyl. The alkyl can be straight-chain or branched-chain alkyl. An example of branched-chain alkyl is sec-butyl. The cycloalkyl can preferably be 3- to 6-carbon cycloalkyl, preferably cyclopentyl or cyclohexyl.

[0066] Alternatively, R F , R G and R H together with N + form a heteroaryl ring or a bridged heterocyclic ring. Examples of heteroaryl groups include substituted or unsubstituted pyridinyl (such as phenyl-pyridinyl). Preferred examples of bridged heterocycles include

Chemical formula

[0067] Preferred compounds that can be used in the compositions, kits and methods of the present invention are of formula (II):

Chemical formula

[0068] Preferably, Y - is a halide anion, carboxylate or sulfonate. Y -can be, for example, a halide ion, a substituted or unsubstituted alkyl sulfonate, a substituted or unsubstituted aryl sulfonate, a substituted or unsubstituted alkyl or aliphatic carboxylate, a substituted or unsubstituted aryl carboxylate or a substituted or unsubstituted heterocyclyl carboxylate.

[0069] In certain embodiments, Y - is selected from the group consisting of trifluoroacetate, sulfate, phosphate, acetate, fumarate, formate, carbonate, maleate, citrate, pyruvate, succinate, oxalate, sulfonate (e.g., methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, e.g., p-toluenesulfonate, benzenesulfonate, ethanesulfonate, camphorsulfonate, 2,4,6-trimethylbenzenesulfonate, or naphthalenesulfonate, e.g., 2-naphthalenesulfonate), bisulfate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, 2-furoate, 3-furoate, napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isethionate (2-hydroxyethylsulfonate), D-mandelate, L-mandelate, propionate, tartarate, phthalate, hydrochloride, hydrobromide and nitrate.

[0070] In one embodiment, Y - is a halogenated anion. In a preferred embodiment, Y - is selected from bromide, chloride or iodide which are halogenated ions.

[0071] As will be appreciated, when q is 0, 1, 2 or 3, the N of formula (II)+ The one containing a ring is: [Chemical formula] Each of them. Preferably, q is 3. In another preferred embodiment, q is 2. Alternatively, q is 0 or 1.

[0072] In Formula II, each of R1, R2, R3, R4, R5 and / or R6 can be hydrogen (for example, forming a linear alkenylenyl, such as ethenylenyl, propenylenyl, butenylenyl or pentenylenyl). In a preferred compound, each of R5 and R6 is hydrogen. In other compounds, both R1 and / or R2 are hydrogen. In other compounds, both R3 and R4 are hydrogen. Alternatively, R1 is methyl or ethyl, and R2, R3, R4, R5 and R6 are hydrogen. Alternatively, R3 is methyl or ethyl, and R1, R2, R4, R5 and R6 are hydrogen.

[0073] For example, q is 0 and R1, R2, R3, R4, R5 and R6 are hydrogen; or q is 0 and R1 is methyl and R2, R3, R4, R5 and R6 are hydrogen; or q is 0 and R3 is methyl and R1, R2, R4, R5 and R6 are hydrogen; or q is 1 and R1, R2, R3, R4, R5 and R6 are hydrogen; or q is 1 and R1 is methyl and R2, R3, R4, R5 and R6 are hydrogen; or q is 1 and R3 is methyl and R1, R2, R4, R5 and R6 are hydrogen; or q is 2 and R1, R2, R3, R4, R5 and R6 are hydrogen; or q is 2 and R1 is methyl and R2, R3, R4, R5 and R6 are hydrogen; or q is 2 and R3 is methyl and R1, R2, R4, R5 and R6 are hydrogen; or q is 3, and R1, R2, R3, R4, R5, and R6 are hydrogen; or q is 3, R1 is methyl, and R2, R3, R4, R5, and R6 are hydrogen; or q is 3, R3 is methyl, and R1, R2, R4, R5, and R6 are hydrogen.

[0074] For example, n is 0, and R1, R2, R3, R4, R5, and R6 are hydrogen; or n is 0, R1 is methyl, and R2, R3, R4, R5, and R6 are hydrogen; or n is 0, R3 is methyl, and R1, R2, R4, R5, and R6 are hydrogen; or n is 1, and R1, R2, R3, R4, R5, and R6 are hydrogen; or n is 1, R1 is methyl, and R2, R3, R4, R5, and R6 are hydrogen; or n is 1, R3 is methyl, and R1, R2, R4, R5, and R6 are hydrogen; or n is 2, and R1, R2, R3, R4, R5, and R6 are hydrogen; or n is 2, R1 is methyl, and R2, R3, R4, R5, and R6 are hydrogen; or n is 2, R3 is methyl, and R1, R2, R4, R5, and R6 are hydrogen; or n is 3, and R1, R2, R3, R4, R5, and R6 are hydrogen; or n is 3, R1 is methyl, and R2, R3, R4, R5, and R6 are hydrogen; or n is 3, R3 is methyl, and R1, R2, R4, R5, and R6 are hydrogen.

[0075] Each of the above preferred groups can be employed in combination with one, any, or all of the other preferred groups.

[0076] Preferred compounds are:

Chemical formula

[0077] In another aspect, the compound is: [Chemical formula] not, and in the formula, Y is a pharmaceutically acceptable anion, for example bromide.

[0078] In yet a further aspect, the compound is selected from Table A below or a pharmaceutically acceptable salt thereof, wherein Y - is a pharmaceutically acceptable anion. [Table 1-1] [Table 1-2] [Table 1-3]

[0079] In a further preferred aspect, the compound is selected from Table B below or a pharmaceutically acceptable salt thereof: [Table 2-1] [Table 2-2] [Table 2-3]

[0080] Further representative compounds of the present invention: [Table 3-1] [Table 3-2]

[0081] Here, a representative Z structure is:

Chemical formula

[0082] The compositions of the present invention wherein R is methyl or ethyl may contain a racemic mixture, a pure enantiomer, or an excess of one enantiomer over the other. For example, the composition may contain an enantiomeric excess of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90%. In one embodiment, the enantiomeric excess is at least 95%.

[0083] The compounds of the present invention include all enantiomers that can be defined as (R)- or (S)- with respect to absolute stereochemistry, as well as their racemic and optically pure forms, and are not limited to those described herein in any of their pharmaceutically acceptable forms including enantiomers, salts, solvates, polymorphs, solvatomorphs, hydrates, anhydrates, and other crystalline forms and combinations thereof.

[0084] Preferably, the pharmaceutical composition contains the compound of the present invention as the R enantiomer in substantially pure form; or the pharmaceutical composition contains the compound of the present invention as the S enantiomer in substantially pure form; or the pharmaceutical composition contains the compound of the present invention as an enantiomeric mixture containing an excess of the R enantiomer or an excess of the S enantiomer. It is particularly preferred that the pharmaceutical composition contains the compound of the present invention which is a substantially pure optical isomer. To avoid ambiguity, the compounds of the present invention may, if desired, be used in the form of solvates.

[0085] The compounds having formula (I) can be prepared using methods similar to those described in the Examples and the following synthetic schemes:

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

[0086] Additional biological agents and exogenous large pore channel agonists As described above, the compounds or compositions of the present invention can be administered together with a biological agent. For example, one or more additional biological agents, including those typically used to treat neuroinflammation, can be used in combination with the compounds or compositions of the present invention described herein. Biological agents include, but are not limited to, TRPA1 receptor agonists, TRPV1-4 receptor agonists, TRPM8 agonists, ASIC agonists, P2X receptor agonists, acetaminophen, NSAIDs, glucocorticoids, anesthetics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative and immunomodulatory agents, antibodies or antibody fragments, antibiotics, polynucleotides, polypeptides, proteins, anti-cancer agents, growth factors, and vaccines.

[0087] TRPV1 agonists that can be used in the methods, kits and compositions of the present invention include, but are not limited to, any agent that activates the TRPV1 receptor on the nociceptor and allows entry of at least one inhibitor of a voltage-gated ion channel (e.g., a compound of the present invention). Suitable TRPV1 agonists are capsaicin, a member of the vanilloid family of molecules, or another capsaicinoid. Naturally occurring capsaicinoids are capsaicin itself, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin and nonivamide. Other suitable capsaicinoids and capsaicinoid analogs and derivatives for use in the compositions and methods of the present invention include naturally occurring and synthetic capsaicin derivatives and analogs, such as vanilloids (e.g., N-vanillyl-alkanedienamides, N-vanillyl-alkandienyls and N-vanillyl-cis-monounsaturated alkenamides), capsiate, dihydrocapsiate, nordihydrocapsiate and other capsinoids, capsiconiate, dihydrocapsiconiate and other coniferyl esters, capsiconinoid, resiniferatoxin, tinyatoxin, civamide, N-phenylmethylalkenamide capsaicin derivatives, olvanil, N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octadecanamide, N-oleoyl-homovanillylamide, triprenylphenol (e.g., scutigeral), gingerol, piperine, shogaol, guaiacol, eugenol, gingerone, nuvanil, NE-19550, NE-21610 and NE-28345. Further capsaicinoids, their structures and methods for their production are described in U.S. Patent Nos. 7,446,226 and 7,429,673, which are incorporated herein by reference.

[0088] Additional suitable TRPV1 agonists include, but are not limited to, eugenol, arvanil (N - arachidonoyl vanillylamine), anandamide, 2 - aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol 12 - phenylacetate 13 - acetate 20 - homovanillate (PPAHV), olvanil (NE 19550), OLDA (N - oleoyl dopamine), N - arachidonyl dopamine (NADA), 6'-iodoresiniferatoxin (6'-IRTX), C18 N - acyl ethanolamine, lipoxygenase derivatives such as 12 - hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (ICK) peptides (vanillotoxin), piperine, MSK195 (N - [2 - (3,4 - dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2 - aminoethoxy)-3 - methoxyphenyl]acetamide), JYL79 (N - [2 - (3,4 - dimethylbenzyl)-3-(pivaloyloxy)propyl]-N'-(4 - hydroxy - 3 - methoxybenzyl)thiourea), hydroxy - alpha - sanshool, 2 - aminoethoxydiphenyl borate, 10 - gingerol, oleyl gingerol, oleyl shogaol and SU200 (N-(4 - tert - butylbenzyl)-N'-(4 - hydroxy - 3 - methoxybenzyl)thiourea).Still other TRPV1 agonists include amylocaine, articaine, benzocaine, bupivacaine, carbocaine, articaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novocaine), propanocaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and trimecaine.

[0089] Suitable TRPV2-4 agonists include, but are not limited to, 2-APB, cannabinol, diphenylboronic anhydride, insulin-like growth factor 1, lysophosphatidylcholine, lysophosphatidylinositol, probenecid, Δ9-tetrahydrocannabinol, vanillin, eugenol, cinnamaldehyde, camphor, carbachol, thymol, citral, farnesyl diphosphate, tetrahydrocannabivarin, incensole acetate, diphenylboronic anhydride, 6-tert-butyl-m-cresol, dihydrocarveocarveol, borneol, (-)-menthol, GSK1016790A, 4α-PDH, 5,6-epoxyeicosatrienoic acid, 4α-PDD, bisandrographolide, citric acid, phorbol 12-myristate 13-acetate, and RN1747.

[0090] Suitable TRPM8 agonists include, but are not limited to, menthol, icilin, eucalyptus, linalool, geraniol, hydroxy-citronellal, WS-3, WS-23, Frescolat MGA, Frescolat ML, PMD 38, CPS125, Coolact P, M8-Ag, AITC, cryosim-3, AX-8 and Cooling Agent 10.

[0091] Suitable ASIC agonists include, but are not limited to, chlorophenylguanidine hydrochloride, GMQ hydrochloride, tetrahydropapaveroline (THP), reticuline, polyamine agmatine, lysophosphatidylcholine, arachidonic acid and neuropeptide SF.

[0092] Other biologically active agents that can be used in the methods, compositions and kits of the present invention include anything that activates the TRPA1 receptor on nociceptors or pruriceptors and allows entry of at least one inhibitor of a voltage-gated ion channel. Suitable TRPA1 agonists include, but are not limited to, cinnamaldehyde, allyl-isothiocyanate (mustard oil), diallyl disulfide, icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl p-hydroxybenzoate and 3'-carbamoyl-biphenyl-3-yl cyclohexylcarbamate (URB597).

[0093] Examples of P2X agonists that can be used in the methods, compositions and kits of the present invention include anything that activates P2X receptors on nociceptive or pruriceptive receptors and allows entry of at least one inhibitor of voltage-gated ion channels. Suitable P2X agonists include, but are not limited to, ATP, α,β-methylene ATP, 2-methylthio-ATP, 2' and 3'-O-(4-benzoylbenzoyl)-ATP and ATP 5'-O-(3-thiotriphosphate).

[0094] Other biologically active agents that can be used in combination with the compounds of the present invention include NSAIDs, glucocorticoids, anesthetics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative and immunomodulatory agents, antibodies or antibody fragments, antibiotics, polynucleotides, polypeptides, proteins, anti-cancer agents, growth factors and vaccines.

[0095] Examples of non-steroidal anti-inflammatory drugs (NSAIDs) that can be administered in combination with the composition of the present invention to patients (e.g., humans) suffering from neurological inflammation include, but are not limited to, acetylsalicylic acid, amoxaprine, benorylate, choline magnesium salicylate, diflunisal, ethenzamide, faislamine, methyl salicylate, magnesium salicylate, salicylsalicylate, salicylamide, diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indomethacin, nabumetone, oxametacin, progulmetacin, sulindac, tolmetin, ibuprofen, alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, phenylbutazone, aminopyrine, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam, droxicam, lornoxicam, meloxicam, tenoxicam, and the COX-2 inhibitors celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, and pharmaceutically acceptable salts thereof.

[0096] Examples of glucocorticoids that can be administered to patients (e.g., humans) suffering from neuroinflammation in combination with the composition of the present invention include, but are not limited to, hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, and pharmaceutically acceptable salts thereof.

[0097] Examples of anesthetics that can be administered to patients (e.g., humans) suffering from neuroinflammation in combination with the composition of the present invention include, but are not limited to, tramadol, hydrocodone, oxycodone, morphine, and pharmaceutically acceptable salts thereof.

[0098] Examples of anti-proliferative and immunomodulatory agents that can be administered to patients (e.g., humans) suffering from neuroinflammation in combination with the composition of the present invention include, but are not limited to, alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, dihydrofolate reductase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF-α agonists, TNF-α antagonists or scavengers, interleukin 1 (IL-1) antagonists or scavengers, endothelin A receptor antagonists, retinoic acid receptor agonists, hormonal agents, antihormonal agents, photodynamic agents, and tyrosine kinase inhibitors.

[0099] The bioactive agent can be administered before, simultaneously with, or after administration of the composition of the present invention using any formulation, dosage, or administration known in the art that is therapeutically effective.

[0100] Formulation of the composition Administration of the compounds of the present invention can be by any suitable means that results in a reduction in the perceived pain or itching sensation in the target area. The compounds of the present invention can be included in any suitable amount in any suitable carrier substance and are generally present in an amount that occupies 1 to 99% by weight of the total weight of the composition. The composition is in a dosage form suitable for oral, parenteral (e.g., intravenous, intramuscular), rectal, dermal, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intrathecal, epidural or intraocular administration, or can be provided by injection, inhalation or direct contact with the nasal or oral mucosa. Topical or dermal administration is preferred.

[0101] Thus, the composition can be in the form of, for example, suspensions, emulsions, solutions, gels such as hydrogels, pastes, ointments, creams, plasters, sprays, aerosols, soaks, permeation delivery devices, suppositories, enemas, injections, implants, tablets, capsules, pills, powders, granules. The composition can be formulated according to conventional pharmaceutical practice (see, for example, Remington: The Science and Practice of Pharmacy, 22nd edition, 2013, ed. L.V. Allen, Pharmaceutical Press, Philadelphia and Encyclopedia of Pharmaceutical Technology, 4 th Edition, ed. J. Swarbrick, 2013, CRC Press, New York).

[0102] Each compound can be formulated by various methods known in the art. For example, the compounds of the present invention and biologically active agents, as defined herein, can be formulated together or separately. Desirably, the compounds of the present invention and biologically active agents are formulated together for their simultaneous or substantially simultaneous administration. In another aspect, two or more biologically active agents can be formulated together or separately with the compounds of the present invention. Other examples include, but are not limited to, two or more compounds of the present invention formulated together, where the compounds are formulated with or without one or more biologically active agents.

[0103] Agents formulated individually or separately can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include any component that aids in the administration of a unit dose to a patient, such as a vial for reconstituting a powder form, a syringe for injection, a customized IV delivery system, an inhaler, etc. Further, a unit dose kit can include instructions for the preparation and administration of the composition.

[0104] The kit can be manufactured as a single-use unit dose for one patient, or as multiple uses for a specific patient (at a fixed dose, or where the individual compounds can vary in potency as the treatment progresses); or the kit can include multiple doses suitable for administration to multiple patients (“bulk packaging”). The kit components can be assembled in a carton, blister pack, bottle, tube, etc.

[0105] Topical formulations The compositions of the present invention can also be adapted for topical use by a topical vehicle containing from 0.0001% to 25% (w / w) or more of the active ingredient(s), alone or in combination with one or more biologically active agents described herein.

[0106] In a preferred combination, the active ingredients are preferably each an active agent of from 0.0001% to 10% (w / w), more preferably from 0.0005% to 4% (w / w). Topical formulations including, but not limited to, creams, gels or ointments can be applied 1 to 4 times daily or as needed. When practicing the methods described herein, the topical vehicle containing the composition of the present invention or the combination therapy containing the composition of the present invention is preferably applied to the site of inflammation of the patient. For example, a cream can be applied to the hands of a patient suffering from itching, pruritis, psoriasis or atopic dermatitis.

[0107] The composition can be formulated using any dermatologically acceptable carrier. Exemplary carriers include solid carriers such as alumina, clay, microcrystalline cellulose, silica or talc; and / or liquid carriers such as alcohol, glycol or water-alcohol / glycol mixtures. The therapeutic agent can also be administered in a liposomal formulation that allows the therapeutic agent to penetrate the skin. Such liposomal formulations are described in U.S. Patent Nos. 5,169,637; 5,000,958; 5,049,388; 4,975,282; 5,194,266; 5,023,087; 5,688,525; 5,874,104; 5,409,704; 5,552,155; 5,356,633; 5,032,582; 4,994,213; 8,822,537 and PCT Publication No. WO 96 / 40061. Examples of other suitable vehicles are described in U.S. Patent Nos. 4,877,805, 8,822,537 and European Publication No. 0586106A1. Suitable vehicles for the present invention can also include mineral oil, petrolatum, polydecene, stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol or vegetable oil.

[0108] The composition can further include a percutaneous penetration enhancer such as those described in "Percutaneous Penetration enhancers" (eds. Smith E W and Maibach H I. CRC Press 1995). Exemplary percutaneous penetration enhancers include alkyl (N,N-disubstituted aminoalkanoic acid) esters described in U.S. Patent Nos. 6,083,996 and 6,118,020, both of which are incorporated herein by reference, such as dodecyl 2-(N,N-dimethylamino)propionate (DDAIP); water-dispersible acid polymers such as polyacrylic acid polymers, carbomers (e.g., Carbopol TM or Carbopol 940P TM ) available from B. F. Goodrich Company (Akron, Ohio), copolymers of polyacrylic acid (e.g., Pemulen from B. F. Goodrich CompanyTM or Polycarbophil of A. H. Robbins, Richmond, Va. TM ; polysaccharide gums such as agar gum, alginates, carrageenan gums, ghatti gum, karaya gum, kadaya gum, rhamsan gum, xanthan gum and galactomannan gums (e.g., guar gum, carob gum and locust bean gum) and other gums known in the art (see, e.g., Industrial Gums: Polysaccharides & Their Derivatives, Whistler R. L., BeMiller J. N. (eds.), 3rd Ed. Academic Press (1992) and Davidson, R. L., Handbook of Water-Soluble Gums & Resins, McGraw-Hill, Inc., N.Y. (1980)); or combinations thereof.

[0109] Other suitable polymeric skin penetration enhancers are cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose. Further, if desired, known transdermal penetration enhancers may also be added. Exemplary are dimethyl sulfoxide (DMSO) and dimethylacetamide (DMA), 2-pyrrolidone, N,N-diethyl-m-toluamide (DEET), 1-dodecylazacycloheptan-2-one (Azone TM , a registered trademark of Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate and other enhancers such as dioxolane, cyclic ketones and their derivatives, etc.

[0110] Also, the examples include the group of biodegradable absorption promoters that are alkyl N,N-2-(disubstituted amino) alkanoates described in U.S. Patent No. 4,980,378 and U.S. Patent No. 5,082,866, both of which are incorporated herein by reference, for example: tetradecyl (N,N-dimethylamino) acetate, dodecyl (N,N-dimethylamino) acetate, decyl (N,N-dimethylamino) acetate, octyl (N,N-dimethylamino) acetate, and dodecyl (N,N-diethylamino) acetate.

[0111] Particularly preferred skin penetration enhancers include isopropyl myristate; isopropyl palmitate; dimethyl sulfoxide; decyl methyl sulfoxide; dimethylalanine amide of medium-chain fatty acids; dodecyl 2-(N,N-dimethylamino) propionate or its salts described in U.S. Patent No. 6,118,020, such as its organic (e.g., addition salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid) and inorganic salts (e.g., addition salts of acetic acid, benzoic acid, salicylic acid, glycolic acid, succinic acid, nicotinic acid, tartaric acid, maleic acid, malic acid, pamoic acid, methanesulfonic acid, cyclohexanesulfamic acid, picric acid, and lactic acid); and alkyl 2-(N,N-disubstituted amino)-alkanoic acids described in U.S. Patent No. 4,980,378 and U.S. Patent No. 5,082,866.

[0112] The skin penetration enhancer in this composition by weight is in the range of 0.5% - 10% (w / w). The most preferred range is 1.0% - 5% (w / w). In another embodiment, the skin penetration enhancer comprises 0.5% - 1%, 1% - 2%, 2% - 3%, 3% - 4%, or 4% - 5% (w / w) of the composition.

[0113] The composition can be provided in any useful form. For example, the compositions of the present invention can be formulated as solutions, emulsions (including microemulsions), suspensions, creams, ointments, foams, lotions, gels, powders, or other typical solid, semi-solid, or liquid compositions (such as topical sprays) for application to the skin or other tissues to which the composition can be used. Such compositions can include other ingredients typically used in such products, such as colorants, fragrances, thickeners (such as xanthan gum, fatty acids, fatty acid salts or esters, fatty alcohols, modified celluloses, modified mineral materials, Krisgel 100 TM , or synthetic polymers), antibacterial agents, solvents, surfactants, detergents, gelling agents, antioxidants, fillers, dyes, viscosity modifiers, preservatives, wetting agents, emollients (such as natural or synthetic oils, hydrocarbon oils, waxes or silicones), hydrating agents, chelating agents, lubricants, solubilizing excipients, adjuvants, dispersants, skin penetration enhancers, plasticizers, preservatives, stabilizers, demulsifiers, wetting agents, sunscreens, emulsifiers, humectants, astringents, deodorants, and optionally anesthetics, anti-itch active, plant extracts, conditioning agents, darkening or lightening agents, glitter, wetting agents, mica, minerals, polyphenols, silicones or their derivatives, sunscreens, vitamins, and phytomedicinals.

[0114] The composition can also include other similar ingredients in order to provide additional benefits and to improve the feel and / or appearance of the topical formulation. Specific classes of additives commonly used in these formulations include: isopropyl myristate, sorbic acid NF powder, polyethylene glycol, phosphatidylcholine (including mixtures of phosphatidylcholine such as Phospholipon G), Krisgel 100 TM distilled water, sodium hydroxide, decyl methyl sulfoxide (as a skin penetration enhancer), menthol crystals, lavender oil, butylated hydroxytoluene, ethyl diglycol reagent, and 95% percent (190 proof) ethanol.

[0115] Controlled release formulation Each compound of the present invention, alone or in combination with one or more biologically active agents, as described herein, can be formulated for controlled release (e.g., sustained or metered) administration as described in U.S. Patent Application Publication Nos. 2003 / 0152637 and 2005 / 0025765, each of which is incorporated herein by reference. For example, the compounds of the present invention, alone or in combination with one or more biologically active agents, as described herein, can be incorporated into patches, capsules or tablets administered to a patient.

[0116] Any pharmaceutically acceptable vehicle or formulation suitable for topical application and / or injection to a site to be treated (e.g., a painful surgical incision, wound or joint) that can provide sustained release of a compound of the present invention, alone or in combination with one or more biologically active agents, can be used as needed to provide extended elimination or alleviation of inflammation. Controlled release formulations known in the art include pellets specially coated for surgical insertion, polymeric formulations or matrices, or sustained release microparticles for implantation, insertion, injection or injection, such as microspheres or microcapsules, where the delayed release of the active pharmaceutical is caused by sustained or controlled diffusion from the matrix and / or selective disruption of the coating of the preparation or selective disruption of the polymeric matrix. Other formulations or vehicles for the controlled, sustained or immediate delivery of a drug to a preferred localized site in a patient include, for example, suspensions, emulsions, gels, liposomes and any other suitable delivery vehicle or formulation known in the art acceptable for topical, transdermal, subcutaneous or intramuscular administration.

[0117] A wide range of biocompatible materials can be utilized as controlled release carriers for providing controlled release of the compounds of the present invention, either alone or in combination with one or more biologically active agents, as described herein. Any pharmaceutically acceptable biocompatible polymer known to those skilled in the art can be used. The biocompatible controlled release material is preferably degraded in vivo within about 1 year, preferably within about 3 months, more preferably within about 2 months. More preferably, the controlled release material significantly degrades within 1 to 3 months, at least 50% of the material degrades into non-toxic residues removed by the body, and 100% of the compounds of the present invention are released within a time period of about 2 weeks, preferably within about 2 days to about 7 days. The degradable controlled release material should preferably degrade by hydrolysis, either by surface erosion or bulk erosion, so that the release not only persists but also provides the desired release rate. However, the pharmacokinetic release profiles of these formulations can be mono-, zero-, bi- or multi-phasic in order to provide a desirable reversible local anti-nociceptive effect over a desired time period.

[0118] Suitable biocompatible polymers can be used as controlled release materials. The polymeric material can include biocompatible and biodegradable polymers, and in certain preferred embodiments, is preferably a copolymer of lactic acid and glycolic acid. Preferred controlled release materials useful in the formulations of the present invention include polyanhydrides, polyesters, copolymers of lactic acid and glycolic acid (preferably here, the weight ratio of lactic acid to glycolic acid is 4:1 or less, i.e., 80% or less lactic acid relative to 20% or more glycolic acid) and polyorthoesters containing a catalyst or degradation accelerating compound, such as an anhydride catalyst including at least 1% by weight maleic anhydride. Examples of polyesters include polylactic acid, polyglycolic acid, and polylactic acid-polyglycolic acid copolymers. Other useful polymers include protein polymers such as collagen, gelatin, fibrin, and fibrinogen, as well as polysaccharides such as hyaluronic acid.

[0119] The polymeric material can be prepared by any method known to those skilled in the art. For example, if the polymeric material is composed of a copolymer of lactic acid and glycolic acid, this copolymer can be prepared by the procedure described in U.S. Patent No. 4,293,539, which is incorporated herein by reference. Alternatively, the copolymer of lactic acid and glycolic acid can be prepared by any other procedure known to those skilled in the art. Other useful polymers include polylactide, polyglycolide, polyanhydrides, polyorthoesters, polycaprolactone, polyphosphazene, polyphosphoesters, polysaccharides, protein-like polymers, soluble derivatives of polysaccharides, soluble derivatives of protein-like polymers, polypeptides, polyesters, and polyorthoesters, or any mixture or blend thereof.

[0120] The pharmaceutically acceptable polyanhydrides useful in the present invention have a water-labile anhydride bond. The rate of drug release can be controlled by the particular polyanhydride polymer used and its molecular weight. Polysaccharides can be poly-1,4-glucans, such as starch, glycogen, amylose, amylopectin, and mixtures thereof. Biodegradable hydrophilic or hydrophobic polymers can be water-soluble derivatives of poly-1,4-glucans such as hydrolyzed amylopectin, derivatives of hydrolyzed amylopectin such as hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, etc. The polyanhydride polymer can be branched or linear.

[0121] Examples of polymers useful in the present invention include (in addition to homopolymers and copolymers of poly(lactic acid) and / or poly(glycolic acid)), poly[bis(p-carboxyphenoxy)propane anhydride] (PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides of oligomerized unsaturated fatty acids, polyanhydride polymers prepared from amino acids modified to contain additional carboxylic acids, aromatic polyanhydride compositions, and fatty acid-terminated polyanhydrides, such as copolymers of polyanhydrides with other substances such as polyanhydrides polymerized from monomers of dimers and / or trimers of unsaturated fatty acids or unsaturated aliphatic acids. The polyanhydrides can be prepared according to the method described in U.S. Patent No. 4,757,128, which is incorporated herein by reference. The polyorthoester polymers can be prepared as described, for example, in U.S. Patent No. 4,070,347, which is incorporated herein by reference. The polyphosphoesters can be prepared and used as described in U.S. Patent Nos. 6,008,318, 6,153,212, 5,952,451, 6,051,576, 6,103,255, 5,176,907, and 5,194,581, each of which is incorporated herein by reference.

[0122] Protein-like polymers can also be used. Examples of protein-like polymers and their soluble derivatives include gel-forming biodegradable synthetic polypeptides, elastin, alkylated collagen, alkylated elastin, and the like. Examples of biodegradable synthetic polypeptides include poly-(N-hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalkyl)-L-glutamine, copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutamine with other amino acids. Suggested amino acids include L-alanine, L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.

[0123] In a further aspect, a controlled release material that substantially acts as a carrier for the compounds of the present invention, alone or in combination with one or more biologically active agents as described herein, may further comprise a bioadhesive polymer such as pectin (polygalacturonic acid), mucopolysaccharide (hyaluronic acid, mucin) or non-toxic lectin, or the polymer itself may be bioadhesive, such as a polysaccharide such as a polyanhydride or chitosan.

[0124] In embodiments where the biodegradable polymer comprises a gel, one such useful polymer is a thermogel-forming polymer, such as polyethylene oxide, polypropylene oxide (PEO-PPO) block copolymer, such as Pluronic of BASF Wyandotte TM F127. In such cases, the topical anesthetic formulation can be injected via a syringe as a free-flowing liquid that rapidly gels at temperatures higher than 30°C (e.g., when injected into a patient). The gel system then releases a stable dose of the compounds of the present invention, alone or in combination with one or more biologically active agents, as described herein, at the site of administration.

[0125] Dosage forms for oral use Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. For example, these excipients may be inert diluents or fillers (such as starches like sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate); granulating and disintegrating agents (such as cellulose derivatives like microcrystalline cellulose, starches like potato starch, croscarmellose sodium, alginates or alginic acid); binders (such as sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pre-gelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, polyvinyl pyrrolidone or polyethylene glycol); and lubricants, glidants and antiadhesives (such as magnesium stearate, zinc stearate, stearic acid, silica, hardened vegetable oil or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, wetting agents, buffering agents, taste masking agents (such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose), etc.

[0126] One or more compounds and one or more biologically active agents of the invention as defined herein may be mixed together or separated in tablets, capsules or other vehicles. In one example, the compound of the invention is contained within the tablet and the biologically active agent is outside the tablet, and a substantial portion of the biologically active agent is released prior to the release of the compound of the invention.

[0127] Formulations for oral use can be provided as chewable tablets, or as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium such as peanut oil, liquid paraffin or olive oil. Powders, granules and pellets can be prepared in a conventional manner using, for example, a mixer, a fluidized bed apparatus or a spray drying facility, using the above-mentioned ingredients, under tablets and capsules.

[0128] Formulations for oral administration to the mouth can also be provided as mouthwashes, oral sprays, oral rinse solutions, or oral ointments or gels.

[0129] Controlled release of dissolution or diffusion can be achieved by appropriate coating of tablets, capsules, pellets or granule formulations of the compound, or by incorporating the compound into an appropriate matrix. Controlled release coatings can include the above-mentioned coating substances and / or one or more of, for example, shellac, beeswax, glyceryl wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxy methacrylate, methacrylic acid hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate and / or polyethylene glycol. In controlled release matrix formulations, the matrix material can also include, for example, hydrated methyl cellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene and / or halogenated fluorocarbon.

[0130] Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral administration include aqueous solutions, properly flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0131] Generally, when administered to humans, the oral dosage of any of the compounds of the combination of the present invention can be readily determined by one of ordinary skill in the art depending on the nature of the compound. Typically, such dosages are usually about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day. Dosages up to 200 mg per day may be required.

[0132] The administration of each drug in combination therapy can, as described herein, independently be from 1 to 4 times per day for between 1 day and 1 year, or even throughout a patient's lifetime. In many cases, chronic long-term administration is indicated.

[0133] Parenteral formulations Formulations suitable for parenteral administration (e.g., by injection) include aqueous or non-aqueous, isotonic, pyrogen-free sterile liquids (e.g., solutions, suspensions) in which the compound is dissolved, suspended or otherwise provided (e.g., in liposomes or other microparticles). Such liquids may further contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, bacteriostatic agents, suspending agents, thickening agents, and solutes that render the formulation isotonic with the blood (or other relevant body fluid) of the intended recipient. Examples of excipients include, for example, water, alcohol, polyols, glycerol, vegetable oils, etc. Examples of suitable isotonic carriers for use in such formulations include sodium chloride injection, Ringer's solution or lactated Ringer's injection. Typically, the concentration of the compound in the liquid is from about 1 ng / ml to about 10 μg / ml, for example from about 10 ng / ml to about 1 μg / ml. The formulation may be presented in unit dose or multi-dose sealed containers, such as ampoules and vials, and may be stored in a freeze-dried (lyophilised) state that requires only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0134] Formulations for ophthalmic administration The compounds of the present invention may also be formulated with an ophthalmically acceptable carrier at a concentration sufficient to deliver an effective amount of the active compound(s) to the optic nerve site of the eye. Preferably, the ophthalmic, therapeutic solution contains one or more of the active compounds at a concentration in the range of from about 0.0001% to about 5% (weight per volume) and more preferably from about 0.0005% to about 0.1% (weight per volume).

[0135] An ophthalmically acceptable carrier does not cause significant irritation to the eye and does not eliminate the pharmacological activity and properties of the charged sodium channel blocker.

[0136] An ophthalmically acceptable carrier is generally sterile, essentially free of foreign particles, and generally has a pH in the range of 5 to 8. Preferably, the pH is as close as possible to the pH of the lacrimal fluid (7.4). An ophthalmically acceptable carrier is, for example, a sterile isotonic solution, such as an isotonic sodium chloride or boric acid solution. Such carriers are typically aqueous solutions containing sodium chloride or boric acid. Phosphate buffered saline (PBS) solution is also useful.

[0137] Various preservatives can be used in ophthalmic formulations. Preferred preservatives include, but are not limited to, potassium benzalkonium, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. Similarly, various preferred vehicles can be used in such ophthalmic formulations. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, and hydroxyethyl cellulose.

[0138] If necessary or convenient, tonicity adjusters can be added. These include, but are not limited to, salts, especially sodium chloride, potassium chloride, etc., mannitol, and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

[0139] As long as the resulting preparation is ophthalmically acceptable, various buffers and means for adjusting the pH can be used. Thus, buffers include, but are not limited to, acetate buffer, citrate buffer, phosphate buffer, and borate buffer. Acids or bases can be used to adjust the pH of these formulations as needed. Ophthalmically acceptable antioxidants can also be included. Antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0140] Formulations for nasal and inhalation administration The pharmaceutical composition of the present invention can be formulated for nasal or intranasal administration. When the carrier is solid, a formulation suitable for nasal administration includes, for example, a coarse powder having a particle size in the range of about 20 to 500 microns, which is administered by rapid inhalation through the nasal route. When the carrier is a liquid, such as a nasal spray or nasal drops, one or more formulations can be mixed in an aqueous or oily solution and inhaled or sprayed via the nasal route.

[0141] For administration by inhalation, the active ingredient can conveniently be delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer using a suitable high-pressure gas such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount, and gelatin capsules and cartridges for use in an inhaler or insufflator, for example, containing a powder mixture of the compound and a suitable powder base such as lactose or starch can be formulated.

[0142] A dry powder composition for topical delivery to the lungs by inhalation can be provided, for example, in gelatin capsules and cartridges for use in an inhaler or insufflator or in blisters of, for example, thin sheet aluminum foil. The powder blend formulations generally include a powder mixture of the compound of the present invention and a suitable powder base (carrier / diluent / excipient substance), such as a monosaccharide, disaccharide or poly (poly) saccharide (e.g., lactose or starch) for inhalation. The use of lactose is preferred. In one embodiment, each capsule or cartridge can contain from about 2 μg to about 100 mg of the compound of formula (I), optionally in combination with another therapeutically active ingredient. In a preferred embodiment, each capsule or cartridge can contain from about 10 μg to about 50 mg of the compound of formula (I), optionally in combination with another therapeutically active ingredient. In another embodiment, each capsule or cartridge can contain from about 20 μg to about 10 mg of the compound of formula (I), optionally in combination with another therapeutically active ingredient. Alternatively, the compounds of the present invention can be delivered without an excipient.

[0143] Suitably, the packaging / medical dispenser is of a type selected from the group consisting of a reservoir dry powder inhaler (RDPI), a multi-dose dry powder inhaler (MDPI), and a metered dose inhaler (MDI).

[0144] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer or nebulizer may be formulated to contain an aqueous medium, ethanol, aqueous ethanol or a suitable alternative agent for dispersing, solubilizing or extending the release of the active ingredient(s); a high-pressure gas as a solvent; and / or a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

[0145] Compositions formulated for nasal or inhalation administration may contain one or more taste masking agents, such as flavoring and odor masking agents, sweeteners and other strategies, such as sucrose, dextrose and lactose, carboxylic acids, menthol, arginine, lysine and amino acids or amino acid derivatives such as monosodium glutamate, and / or synthetic flavor oils and flavoring and odor masking fragrances and / or extracts derived from natural oils, plants, leaves, flowers, fruits, etc., and combinations thereof. These may include cinnamon oil, wintergreen oil, peppermint oil, clover oil, bay oil, anise oil, eucalyptus, vanilla, lemon oil, orange oil, citrus oils such as grape and grapefruit oil, and fruit essences including apples, peaches, pears, strawberries, raspberries, cherries, plums, pineapples, apricots, etc. Further sweeteners include sucrose, dextrose, aspartame, acesulfame-K, sucralose and saccharin, and organic acids (non-limiting examples being citric acid and aspartic acid). Such flavors may be present at from about 0.05 to about 4% by weight and may be present in lower or higher amounts depending on one or more factors such as the potency of the effect on the flavor, the solubility of the flavorant, the effect of the flavorant on the solubility or other physicochemical or pharmacokinetic properties of the solubility or other formulation components, or other factors.

[0146] Application The compounds, compositions, methods and kits of the invention can be used to treat itching, pain or cough. Conditions include trigeminal trophic syndrome, acral erythema, back and neck pain, lower back pain, cancer pain, gynecological and childbirth pain, abdominal wall pain, chronic abdominal wall pain, fibromyalgia, allergic rhinitis, arthritis, rheumatoid arthritis, osteoarthritis, rheumatic pain, orthopedic pain, acute post-herpetic neuralgia and other neuropathic pain (including peripheral neuropathy), sickle cell disease, myalgia, vulvodynia, rectal pain, levator ani syndrome, transient rectal pain, perianal pain, hemorrhoid pain, stomach pain, ulcers, inflammatory bowel disease, irritable bowel disease, irritable bowel syndrome, oral mucositis, esophagitis, interstitial cystitis, urethritis and other urological pain, toothache, burn pain, headache, eye allergy, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, dry eye syndrome (chronic eye pain), complex regional pain syndrome, acute postoperative pain, postoperative pain, postoperative eye pain, and pain due to procedures (i.e., injection, abscess drainage, surgery, dental procedures, eye procedures, eye irritation, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, arthroscopy and use of other medical devices, cosmetic surgery procedures, dermatological procedures, pain associated with setting fractures, biopsies, etc.).

[0147] Since subclasses of nociceptors mediate the itch sensation, the compounds, compositions, methods and kits of the invention are particularly suitable for treating itching in patients with conditions such as pruritus (including but not limited to brachioradialis, chronic idiopathic, genital / anal, dorsal dysesthesia, and scalp), allergic dermatitis, atopic dermatitis, contact dermatitis, poison ivy, infection, parasites, insect bite, pregnancy, metabolic disorders, liver or kidney failure, drug reactions, allergic reactions, eczema, hand eczema, genital and anal itching, hemorrhoid itching, and conditions such as cancer.

[0148] Subclasses of nociceptors can initiate an abnormal cough reflex, and thus the compounds, compositions, methods and kits of the present invention can also be used to treat cough in patients having conditions such as asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonary fibrosis, post-viral cough, post-infectious cough, chronic idiopathic cough and lung cancer.

[0149] The compounds, compositions, methods and kits of the present invention can also be used to treat neurogenic inflammation and neurogenic inflammatory disorders. Inflammation is a complex set of responses to harmful stimuli that results in local redness, swelling and pain. Inflammation can be innate or adaptive, the latter being antigen-driven and mediated by immune cells (immune-mediated inflammation). Neurogenic inflammation results from the efferent function of pain-sensing neurons (nociceptors), where neuropeptides and other chemicals that are pro-inflammatory mediators are released from the peripheral terminals of nociceptors when activated. This release process is mediated by calcium influx and exocytosis of peptide-containing vesicles, and pro-inflammatory neuropeptides include substance P, neurokinin A and B (collectively known as tachykinins), calcitonin gene-related peptide (CGRP), and vasoactive intestinal polypeptide (VIP).

[0150] Release of peripheral terminal chemicals stimulates various inflammatory responses. First, release of substance P can result in increased capillary permeability such that plasma proteins leak from the intravascular compartment into the extracellular space (plasma extravasation), causing edema. This can be detected as wheal (a firm, raised swelling of the skin), which is one of the components of the triple response of inflammation known as Lewis's triple response - wheal, flare and erythema. Second, release of CGRP causes vasodilation and an increase in blood flow. This can be detected as erythema, another component of Lewis's triple response.

[0151] Substance P also has pro-inflammatory effects on immune cells (such as macrophages, T cells, mast cells and dendritic cells) via their neurokinin-1 (NK1) receptors. This effect has been documented in allergic rhinitis, gastritis and colitis, presenting an interface between the neural and immune-mediated components of inflammation. Substance P released from one nociceptor can also act on NK1 receptors on adjacent nociceptors, sensitizing or activating them and causing activation and spread of centripetal / centrifugal functions. These centrifugal functions of nociceptors are: 1) direct activation of the nociceptor terminal by appropriate peripheral stimuli (such as pinching) applied to the terminal; 2) indirect retrograde activation of non-stimulated nociceptor terminals by axon reflex, where an action potential input from one terminal of a nociceptor at the convergent axon branch point in the periphery gives rise to an action potential moving from the branch point to the peripheral end of the non-stimulated terminal; and 3) activation as a result of activity in the central terminals of nociceptors in the CNS moving peripherally (for example, a primary centripetal depolarization of the central terminal caused by GABA may be sufficient to initiate an action potential moving in the "wrong path").

[0152] Genomic analysis of ILC2 cells intrinsic to the lung revealed the expression of receptors for several neuropeptides released by sensory neurons, such as SP, CGRP and VIP, providing an opportunity for nociceptors to communicate directly with these cells. In particular, VIP was found to be expressed in NaV1.8+ nodose ganglion neurons, including the centripetal portion of the lung, in OVA-exposed mice. Cultured nodose ganglion neurons stimulated with capsaicin or IL5 also released VIP, while BALF from OVA-exposed mice contained increased VIP compared to vehicle-loaded control mice (Talbot et al., Neuron. 2015 July 15; 87(2): 341-354). These data indicate that VIP is released in the inflamed lung and can be blocked by silencing neurons with the charged sodium channel blockers of the present invention. Also, T HWhen CD4+ T cells cultured under asymmetric (skewing) conditions are exposed to recombinant murine VIP, the transcript levels of IL-13 and IL-5 increase, suggesting that VIP contributes to the ability of these type II regulatory cytokine-transcribing T H cells.

[0153] Nav1.8 + / TRPV1 + nociceptors, including those that are Nav1.8 + / TRPV1 + have been shown to be essential for the immune response in models of psoriasis and contact dermatitis (Riol-Blanco et al., Nature 2014 June 5; 510(7503): 157-161). In a test for imiquimod-induced psoriasis, pharmacological or genetic ablation of nociceptors caused skin dendritic cells (DDCs) to no longer produce IL-23. This deletion of IL-23 significantly reduced the production of inflammatory cytokines by skin Th17 cells and also significantly reduced the influx of inflammatory cells into the skin. By confocal microscopy, 75% of DDCs were either in direct contact with or in close proximity to sensory nerves. Nav1.8

[0154] The release of immune mediators from immune cells can also activate nociceptors. Mast cells are close to primary nociceptive neurons and have been found to contribute to nociceptor sensitization in some contexts. Injection of the secretagogue compound 48 / 80 promotes mast cell degranulation in the dura mater and causes excitation of meningeal nociceptors. Mast cell degranulation also contributes to the rapid onset of nerve growth factor-induced thermal hyperalgesia. Macrophages contribute to nociceptor sensitization by releasing several soluble mediators. The expression of the chemokine macrophage inflammatory protein-1α (MIP-1α) and its receptors CCR1 and CCR5 increases in macrophages and Schwann cells after partial ligation of the sciatic nerve and contributes to the development of neuropathic pain. Lymphocytes contribute to the sensitization of peripheral nociceptors. T cells infiltrate the sciatic nerve and dorsal root ganglia (DRG) after nerve injury. The hyperalgesia and allodynia induced by nerve injury are significantly attenuated or eliminated in rodents lacking T cells, and the immunosuppressant rapamycin attenuates neuropathic pain in rats, in part due to its effect on T cells. Among subsets of T cells, type 1 and type 2 helper T cells (T H 1 and T H 2 cells) have been shown to have different roles in neuropathic pain. T H 1 cells promote neuropathic pain behavior by releasing pro-inflammatory cytokines (IL-2 and interferon-γ (IFNγ)), while T H 2 cells inhibit it by releasing anti-inflammatory cytokines (IL-4, IL-10, and IL-13). The complement system also has a role in inflammatory hyperalgesia and neuropathic pain. Anaphylatoxin C5a is an important effector of the complement cascade and becomes a potent neutrophil chemoattractant when binding to the C5aR1 receptor on neutrophils (Ren & Dubner, Nat. Med. 16:1267-1276 (2010)).

[0155] Bacterial infection has been shown to directly activate nociceptors, and the immune responses mediated by TLR2, MyD88, T cells, B cells, and neutrophils and monocytes are not necessary for Staphylococcus aureus-induced pain in mice (Chiu et al., Nature 501:52-57 (2013)). Mechanical and thermal hyperalgesia in mice correlates with the burden of live bacteria rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons through different mechanisms, partially via bacterial N-formylated peptides and the pore-forming toxin α-hemolysin. Specific ablation of Nav1.8-lineage neurons, including nociceptors, eliminated pain during bacterial infection but simultaneously increased local immune infiltration and lymphadenopathy in the draining lymph node. Thus, bacterial pathogens cause pain as an unexpected role of the nervous system in host-pathogen interactions by directly activating sensory neurons that regulate inflammation. Data from Talbot et al., (Neuron. 2015 July 15; 87(2): 341-354.) also suggested that nociceptors are activated during exposure to allergens in sensitized animals.

[0156] In certain disorders, neurogenic inflammation contributes to peripheral inflammation induced by tissue damage in soft tissues, skin, respiratory system, joints, urogenital and GI tracts, liver and brain, autoimmune diseases, infections and exposure to irritants. Neurogenic inflammatory disorders include, but are not limited to, allergic inflammation, inflammatory bowel disease, interstitial cystitis, atopic dermatitis, asthma, conjunctivitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine, psoriasis, rhinitis, hives, sunburn, pancreatitis, chronic cough, chronic rhinosinusitis, traumatic brain injury, multiple bacterial sepsis, tendon disorders, chronic hives, rheumatic diseases, acute lung injury, exposure to irritants, inhalation of irritants, contaminants or chemical warfare agents as described herein.

[0157] Evaluation of Itch, Pain, Cough and Neurogenic Inflammation To measure the efficacy of any of the compounds, compositions, methods, and kits of the present invention in the treatment of pain associated with skeletal, immune-inflammatory, and neuropathic disorders, measurement indicators can be used. Useful indicators include the Visual Analogue Scale (VAS), Likert scale, categorical pain scale, descriptor, Lequesne index, WOMAC index, and AUSCAN index, each of which is well known in the art. Such indicators can be used to measure pain, itching, function, stiffness, or other variables.

[0158] The Visual Analogue Scale (VAS) provides a reference for a one-dimensional quantity. The VAS generally uses a display of distance, such as a photograph of a line with hash marks drawn at regular distance intervals, for example, 10 1-cm intervals. For example, a patient may be asked to rate the sensation of pain or itching by selecting the spot on the line that best corresponds to the sensation of pain or itching where one end of the line corresponds to "no pain" (a score of 0 cm) or "no itching" and the other end of the line corresponds to "unbearable pain" or "unbearable itching" (a score of 10 cm). This procedure provides a simple and rapid approach for obtaining quantitative information about how a patient is experiencing pain or itching. The VAS scales and their use are described, for example, in U.S. Patent Nos. 6,709,406 and 6,432,937.

[0159] The Likert scale likewise provides a reference for a one-dimensional quantity. Generally, the Likert scale has discrete integer values ranging from a low value (e.g., 0, meaning no pain) to a high value (e.g., 7, meaning extreme pain). A patient experiencing pain is asked to select a number between the low value and the high value to indicate the degree of pain experienced. The Likert scale and its use are described, for example, in U.S. Patent Nos. 6,623,040 and 6,766,319.

[0160] The Lequesne index and the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index use self-administered questionnaires to evaluate pain, function, and stiffness in the knees and hips of OA patients. Both the knees and hips are included in WOMAC, while there is one Lequesne questionnaire for the knees and another for the hips. These questionnaires are useful because they contain more information than the VAS or Likert. Both the WOMAC index and the Lequesne index questionnaires have been extensively validated in OA, including surgical settings (e.g., knee and hip arthroplasty). Their measurement criteria characteristics do not differ greatly.

[0161] The AUSCAN (Australian-Canadian hand arthritis) index uses valid, reliable, and responsive patient-reported questionnaires. In one example, the questionnaire contains 15 questions within three dimensions (pain, 5 questions; stiffness, 1 question; and physical function, 9 questions). The AUSCAN index can use, for example, the Likert or VAS scale.

[0162] Useful indicators for the methods, compositions and kits of the present invention for pain measurement include Pain Descriptor Scale (PDS), Visual Analogue Scale (VAS), Verbal Descriptor Scale (VDS), Numeric Pain Intensity Scale (NPIS), Neuropathic Pain Scale (NPS), Neuropathic Pain Symptom Inventory (NPSI), Present Pain Inventory (PPI), Geriatric Pain Measure (GPM), McGill Pain Questionnaire (MPQ), Mean Pain Intensity (Descriptor Differential Scale), numeric pain scale (NPS) global evaluation score (GES) Short-Form McGill Pain Questionnaire, Minnesota Multiphasic Personality Inventory, Pain Profile and Multidimensional Pain Inventory, Child Heath Questionnaire and Child Assessment Questionnaire.

[0163] Itching can be measured by subjective criteria (VAS, Likert, descriptors). Another approach is to measure scratching, an objective correlate of itching, using a vibration transducer or a kinethesis meter.

[0164] Cough can be measured by standard questions such as the Leicester Cough Questionnaire and a validated objective device (e.g., VitaloJAK) for measuring cough frequency.

Example

[0165] Example The following examples are intended to illustrate the present invention and are not intended to limit the present invention.

[0166] Example 1 - Synthesis of Compounds 1A' to 51A' Definition of General Abbreviations ACN Acetonitrile AcOH Acetic Acid aq. Aqueous BBr3 Boron Tribromide CDCl3 D3 - Chloroform δ Chemical Shift (ppm) DCM Dichloromethane DIPEA Diisopropylethylamine DMAP 4 - Dimethylaminopyridine DMSO Dimethyl Sulfoxide ESI Electrospray Ionization Et2O Diethyl Ether EtOAc Ethyl Acetate h Hour HPLC High - Performance Liquid Chromatography K2CO3 Potassium Carbonate LAH Lithium Aluminum Hydride MeOH Methanol mHz Megahertz MS Mass Spectrometry m / z Mass to Charge Ratio NaCNBH3 Sodium Cyanoborohydride Na2SO4 Sodium Sulfate NMR Nuclear Magnetic Resonance Pet Ether Petroleum Ether RT Room Temperature TEA Triethylamine THF Tetrahydrofuran TLC Thin Layer Chromatography UV Ultraviolet

[0167] Synthesis of 1-Benzyl-1-(2-(2,6-dimethylphenoxy)ethyl)azepan-1-ium bromide

Chem.

[0168] ·Synthesis of Intermediate 1-(2-(2,6-dimethylphenoxy)ethyl)azepane: To a solution of 2-(2-bromoethoxy)-1,3-dimethylbenzene (200 mg, 0.87 mmol) in acetonitrile (3.0 mL) were added DIPEA (0.45 g, 3.5 mmol) and azepane (0.12 g, 1.2 mmol). The resulting reaction mixture was stirred at 90 °C for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 10% EtOAc in pet ether, visualization: UV). The reaction mixture was cooled to RT and concentrated under reduced pressure, diluted with water (20 mL), and extracted with dichloromethane (3 × 20 mL). The combined organic extracts were washed with brine solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-(2-(2,6-dimethylphenoxy)ethyl)azepane (210 mg). 1 H NMR (400 MHz, CDCl3) δ ppm 6.98 - 7.00 (m, 2 H), 6.88 - 6.92 (m, 1 H), 3.85 - 3.88 (m, 2 H), 2.93 - 2.96 (m, 2 H), 2.75 - 2.77 (m, 4 H), 2.28 (s, 6 H), 1.59 - 1.68 (m, 8 H).

[0169] ·Synthesis of 1-benzyl-1-(2-(2,6-dimethylphenoxy)ethyl)azepanium bromide: To a solution of 1-(2-(2,6-dimethylphenoxy)ethyl)azepane (0.1 g, 0.4 mmol) in acetonitrile (1.5 mL) was added benzyl bromide (0.072 ml, 0.6 mmol), and the resulting reaction mixture was stirred in a sealed tube at 90 °C for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 50% EtOAc in pet ether, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was triturated with ethyl acetate (3 × 5 ml) to give 1-benzyl-1-(2-(2,6-dimethylphenoxy)ethyl)azepanium bromide (80.5 mg) as an off-white solid. MS (ESI): m / z 338.41 [M] + . 11H NMR (400 MHz, DMSO-d6) δ ppm 7.63 - 7.65 (m, 2 H), 7.49 - 7.57 (m, 3 H), 7.04 - 7.08 (m, 2 H), 6.96 - 6.98 (m, 1 H), 4.72 (s, 2 H), 4.29 (t, 2 H), 3.52 - 3.69 (m, 6 H), 2.29 (s, 6 H), 1.88 - 1.92 (m, 4 H), 1.59 - 1.62 (m, 4 H).

[0170] Examples 2 to 5 were prepared from the intermediate 2-(2-bromoethoxy)-1,3-dimethylbenzene, the appropriate azacycloalkane, and benzyl bromide according to the procedure described for the synthesis of compound 1A. [Table 4]

[0171] Examples 6 to 13 were prepared from the intermediate 1-(2-(2,6-dimethylphenoxy)ethyl)azepane and the appropriate alkyl bromide according to the procedure described for the synthesis of compound 1A. All compounds were isolated by titration or purified by reverse-phase HPLC. [Table 5-1] [Table 5-2]

[0172] Examples 14 to 16 were prepared from 2,6-dimethylphenol, the appropriate dibromoalkane, azocane, and benzyl bromide according to the procedure described for the synthesis of compound 1A. [Table 6]

[0173] Examples 17 to 32 were prepared from appropriately substituted phenols, 1,2-dibromoethane, azacyclolkane, and benzyl bromide according to the procedures described for the synthesis of Compound 1A. All compounds were isolated by titration or purified by reverse-phase HPLC.

Table 7-1

Table 7-2

Table 7-3

[0174] Synthesis of 1-butyl-1-(2-(2-cyano-6-methylphenoxy)ethyl)azocan-1-ium:

Chemical formula

[0175] · Synthesis of intermediate 2-(2-(azocan-1-yl)ethoxy)-3-methylbenzonitrile: A stirred solution of 2-(2-bromoethoxy)-3-methylbenzonitrile (800 mg, 3.3 mmol) and N-DIPEA (1.8 mL, 10.078 mmol, 3 eq) in acetonitrile (10 mL) was treated with azocane (0.57 g, 5.0 mmol), and the resulting reaction mixture was heated at 80 °C for 16 h while monitoring the progress of the reaction by TLC (mobile phase 50% ethyl acetate in pet ether, visualization: UV). The reaction mixture was concentrated under reduced pressure to give a crude residue, which was diluted with water (40 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluting with 50% - 60% EtOAc in pet ether). The combined pure fractions were concentrated under reduced pressure to give pure 2-(2-(azocan-1-yl)ethoxy)-3-methylbenzonitrile as a pale yellow oil (0.5 g). Mass (ESI): M / z = 273.29 [M+H] + 1H NMR (400 MHz, CDCl3) δ ppm: 7.42 - 7.37 (m, 2 H), 7.03 (t, 1 H), 4.18 (t, 2 H), 2.96 (t, 2 H), 2.68 (s, 4 H), 2.31 (s, 3 H), 1.59 - 1.54 (m, 10 H).

[0176] · Synthesis of 1-butyl-1-(2-(2-cyano-6-methylphenoxy)ethyl)azocan-1-ium TFA salt: To a stirred solution of 2-(2-(azocan-1-yl)ethoxy)-3-methylbenzonitrile (0.4 g, 1.5 mmol) in acetonitrile (10 mL), 1-bromobutane (0.475 mL, 4.4 mmol) was added and the resulting reaction mixture was stirred at 80 °C for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 10% MeOH in DCM; visualization: UV). The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by reverse-phase HPLC (column: X-Select CSH C18 (150X19) mm, 5 μ; mobile phase A / B: 0.1% TFA (aq.) / 1:1 acetonitrile:MeOH; flow: 18 mL / min). The collected pure fractions were lyophilized to give 1-butyl-1-(2-(2-cyano-6-methylphenoxy)ethyl)azocan-1-ium trifluoroacetate (220 mg). Mass (ESI): M / z = 329.28 [M]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.70 - 7.67 (m, 1 H), 7.64 - 7.62 (m, 1 H), 7.28 (t, 1 H), 4.40 (t, 2 H), 3.83 (t, 2 H), 3.62 - 3.42 (m, 6 H), 2.33 (s, 3 H), 1.91 (br s, 4 H), 1.71 - 1.62 (m, 8 H), 1.35 - 1.30 (m, 2 H), 0.92 (t, 3 H).

[0177] 1-Benzyl-1-(2-(2,6-dimethylphenoxy)propyl)azocan-1-ium bromide: [Chemical formula] ·Synthesis of intermediate methyl 2-(2,6-dimethylphenoxy)propanoate: To a stirred solution of 2,6-dimethylphenol (7 g, 57.3 mmol) in acetonitrile (120 mL) were added K2CO3 (23.7 g, 171.8 mmol) and methyl 2-bromopropanoate (9.6 mL, 85.9 mmol), and the resulting reaction mixture was stirred at 80 °C for 16 h while monitoring the progress of the reaction mixture by TLC (mobile phase: 20% EtOAc in pet ether, visualization: UV). The crude reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 250 mL). The combined organic extracts were washed with water (200 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give methyl 2-(2,6-dimethylphenoxy)propanoate (9 g) as a yellow liquid. Mass (ESI): 209.17 m / z [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 6.99 (d, 2 H), 6.93 - 6.89 (m, 1 H), 4.51 (q, 1 H), 3.77 (s, 3 H), 2.27 (s, 6 H), 1.52 (d, 3 H).

[0178] · Synthesis of intermediate 2-(2,6-dimethylphenoxy)propan-1-ol: To a cooled (0 °C) solution of methyl 2-(2,6-dimethylphenoxy)propanoate (5 g, 24.0 mmol) in THF (100 mL) was added a 1 M solution of LAH in THF (48.016 mL, 48.0 mmol), and the resulting reaction mixture was stirred at room temperature for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 20% EtOAc in pet ether, visualization: UV). The reaction mixture was cooled to 0 °C, quenched with saturated NaCl solution (200 mL), and extracted with EtOAc (2 x 300 mL). The combined organic extracts were washed with water (300 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (eluting with 5% - 10% EtOAc in pet ether). The combined pure fractions were concentrated under reduced pressure to obtain 2-(2,6-dimethylphenoxy)propan-1-ol (2.8 g, 64.7%) as a yellow liquid. 1H NMR (400 MHz, CDCl3) δ ppm 7.01 (d, 2 H), 6.94 - 6.90 (m, 1 H), 4.26 - 4.22 (m, 1 H), 3.82 - 3.74 (m, 2 H), 2.29 (s, 6 H), 2.17 - 2.14 (m, 1 H), 1.17 (d, 3 H).

[0179] · Synthesis of Intermediate 2-(2,6-Dimethylphenoxy)propyl Methanesulfonate: To a cooled (0 °C) solution of 2-(2,6-dimethylphenoxy)propan-1-ol (1 g, 5.55 mmol) in DCM (10 mL), TEA (2.3 mL, 16.6 mmol) and methanesulfonyl chloride (0.6 mL, 8.3 mmol) were added and the resulting reaction mixture was stirred at room temperature for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 20% EtOAC in pet ether, visualization: UV). The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-(2,6-dimethylphenoxy)propyl methanesulfonate (1.3 g) as a yellow liquid. 1H NMR (400 MHz, CDCl3) δ ppm 7.01 (d, 2 H), 6.94 - 6.91 (m, 1 H), 4.36 - 4.32 (m, 3 H), 3.02 (s, 3 H), 2.27 (s, 6 H), 1.28 (d, 3 H).

[0180] · Synthesis of Intermediate 1-(2-(2,6-dimethylphenoxy)propyl)azocane: To a stirred solution of 2-(2,6-dimethylphenoxy)propyl methanesulfonate (1.3 g, 5.0 mmol, 1.0) in ACN (15 mL) were added K2CO3 (2 g, 15.0 mmol) and azocane (0.9 mL, 7.5 mmol) at room temperature, and the resulting reaction mixture was stirred at 80 °C for 16 h while monitoring the progress of the reaction mixture by TLC (mobile phase: 20% EtOAc in pet ether, visualization: UV). The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (eluting with 5% - 10% EtOAc in pet ether). The combined pure fractions were concentrated under reduced pressure to obtain 1-(2-(2,6-dimethylphenoxy)propyl)azocane (560 mg) as a colorless liquid. Mass (ESI): 276.37 m / z [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 6.98 (d, 2 H), 6.89 - 6.86 (m, 1 H), 4.08 - 4.05 (m, 1 H), 2.87 - 2.83 (m, 1 H), 2.58 - 2.53 (m, 5 H), 2.27 (s, 6 H), 1.60 - 1.50 (m, 10 H), 1.27 (d, 3 H).

[0181] ·Synthesis of 1-benzyl-1-(2-(2,6-dimethylphenoxy)propyl)azocanium bromide: To a stirred solution of 1-(2-(2,6-dimethylphenoxy)propyl)azanium (500 mg, 1.8 mmol) in acetonitrile (10 mL) was added benzyl bromide (0.43 mL, 3.6 mmol), and the resulting reaction mixture was stirred at 80 °C for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 10% MeOH in DCM, visualization: UV). The reaction was concentrated under reduced pressure to afford the crude product, which was triturated with EtOAc (50 mL) to give 1-benzyl-1-(2-(2,6-dimethylphenoxy)propyl)azanium-1-ium bromide (546 mg) as an off-white solid. Mass (ESI): 366.3 m / z [M]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.67 - 7.65 (m, 2 H), 7.56 - 7.51 (m, 3 H), 7.05 (d, 2 H), 6.97 - 6.93 (m, 1 H), 4.97 - 4.93 (m, 1 H), 4.81 - 4.70 (m, 2 H), 3.78 - 3.72 (m, 1 H), 3.65 - 3.50 (m, 4 H), 3.43 - 3.39 (m, 1 H), 2.26 (s, 6 H), 2.03 - 1.90 (m, 4 H), 1.75 - 1.50 (m, 6 H), 0.98 (d, 3 H).

[0182] Synthesis of 1-(2-(benzoyloxy)ethyl)-1-(2-(2,6-dimethylphenoxy)ethyl)azepan-1-ium:

Chemical Structure

[0183] · Synthesis of 1-(2-(2,6-dimethylphenoxy)ethyl)-1-(2-((4-fluorobenzoyl)oxy)ethyl)azepan-1-ium: To a stirred solution of 1-(2-(2,6-dimethylphenoxy)ethyl)-1-(2-hydroxyethyl)azepan-1-ium (200 mg, 0.54 mmol) and DMAP (5.25 mg, 0.04 mmol) in pyridine (2 mL), benzoyl chloride (377 mg, 2.69 mmol) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 10% MeOH in DCM, visualization: UV). The precipitated solid was filtered, washed with ethyl acetate (50 mL), and dried under high vacuum to obtain the crude product, which was purified by HPLC (column: LUNA C18 (250*21.2) mm, 5u; mobile phase A / B: 0.1% TFA (Aq) / acetonitrile). The combined pure fractions were lyophilized to obtain 1-(2-(2,6-dimethylphenoxy)ethyl)-1-(2-((4-fluorobenzoyl)oxy)ethyl)azepan-1-ium as the TFA salt (91 mg). MS (ESI): M / z = 396.37 [M]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00-7.98 (m, 2 H), 7.71-7.68 (m, 1 H), 7.54 (t, 2 H), 7.04 (d, 2 H), 6.97-6.94 (m, 1 H), 4.79 (br s, 2 H), 4.20 (t, 2 H), 4.01-4.00 (m, 4 H), 3.74-3.72 (m, 4 H), 2.25 (s, 6 H), 1.95 (br s, 4 H), 1.65 (br s, 4 H).

[0184] Examples 36 and 37 were prepared from the intermediate 1-(2-(2,6-dimethylphenoxy)ethyl)-1-(2-hydroxyethyl)azepan-1-ium and the appropriate benzoyl chloride according to the procedure described for the synthesis of Compound 32A.

Table 8

[0185] Synthesis of 1-benzyl-1-(3-(4-butoxyphenoxy)propyl)piperidin-1-ium bromide: [Chemical formula] ·Synthesis of intermediate 1-butoxy-4-(3-chloropropoxy)benzene: K2CO3 (24.9 g, 180.5 mmol) was added to a stirred solution of 4-butoxyphenol (10 g, 60.2 mmol) in ACN (100.0 mL). After stirring for 10 minutes, 1-bromo-3-chloropropane (14.2 g, 90.2 mmol) was added at room temperature, and the resulting reaction mixture was heated at 80 °C for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 10% ethyl acetate in pet ether, visualization by UV). The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 × 150 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (eluted with 10% - 30% EtOAc in pet ether). The pure fractions were combined and concentrated under reduced pressure to obtain 1-butoxy-4-(3-chloropropoxy)benzene (7 g) as a red liquid. Mass (ESI): m / z 243.2 [M+H]+. 1 H NMR (400 MHz, CDCl3) δ ppm 6.82 (s, 4 H), 4.05 (t, 2 H), 3.90 (t, 2 H), 3.73 (t, 2 H), 2.23 - 2.17 (m, 2 H), 1.77 - 1.70 (m, 2 H), 1.55 - 1.49 (m, 2 H), 0.95 - 0.92 (m, 3 H).

[0186] ·Synthesis of intermediate 1-(3-(4-butoxyphenoxy)propyl)piperidine: A stirred solution of 1-butoxy-4-(3-chloropropoxy)benzene (0.5 g, 2.1 mmol) and K2CO3 (0.85 g, 6.2 mmol) in acetonitrile (20 mL) was added with piperidine (0.26 g, 3.1 mmol), and the resulting reaction mixture was heated at 80 °C for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 50% EtOAc in pet ether, visualization by UV). The reaction mixture was cooled to room temperature, quenched with ice-cold water (10 mL), and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 20% - 30% EtOAc in pet ether). The pure fractions were combined and concentrated under reduced pressure to obtain 1-(3-(4-butoxyphenoxy)propyl)piperidine (0.25 g) as an off-white solid. MS (ESI): m / z 292.05 [M+H]+.

[0187] · Synthesis of 1-benzyl-1-(3-(4-butoxyphenoxy)propyl)piperidin-1-ium bromide: A solution of 1-(3-(4-butoxyphenoxy)propyl)piperidine (0.2 g, 0.69 mmol) in acetonitrile (10 mL) was treated with benzyl bromide (0.25 g, 1.4 mmol), and the resulting reaction mixture was heated at 80 °C for 16 h in a sealed tube while monitoring the progress of the reaction by TLC (mobile phase: 10% MeOH in DCM, visualization by UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 3% - 5% MeOH in DCM). The pure fractions were combined and concentrated under reduced pressure to give 1-benzyl-1-(3-(4-butoxyphenoxy)propyl)piperidin-1-ium bromide salt (0.70 g) as an off-white solid. Mass (ESI): m / z 382.3 [M]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.57 - 7.51 (m, 5 H), 6.87 (d, 4 H), 4.61 (s, 2 H), 4.03 (t, 2 H), 3.89 (t, 2 H), 3.37 - 3.28 (m, 6 H), 2.28 (d, 2 H), 1.86 (d, 4 H), 1.68 - 1.64 (m, 3 H), 1.44 - 1.39 (m, 3 H), 0.92 (t, 3 H).

[0188] Examples 39 - 43 were prepared from intermediate 1-butoxy-4-(3-chloropropoxy)benzene according to the procedure described for Compound 35A using appropriately substituted piperidine or morpholine and an alkylating agent, benzyl bromide or ethyl iodide. [Table 9]

[0189] Synthesis of 1-(3-(4-butoxyphenoxy)propyl)pyridin-1-ium bromide: [Chemical formula] To a stirred solution of 1-butoxy-4-(3-chloropropoxy)benzene (0.5 g, 2.1 mmol) in acetonitrile (3 mL), pyridine (0.325 g, 4.1 mmol) was added and the resulting reaction mixture was stirred at 90 °C for 24 h while monitoring the progress of the reaction by TLC (mobile phase: 10% methanol in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to afford the crude compound, which was triturated with ethyl acetate (15 mL) to give 1-(3-(4-butoxyphenoxy)propyl)pyridin-1-ium chloride (0.145 g). Mass (ESI): m / z 286.2 [M]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (d, 2 H), 8.63 - 8.59 (m, 1 H), 6.83 - 6.79 (m, 2 H), 6.71 - 6.69 (m, 2 H), 4.79 (t, 2 H), 4.00 (t, 2 H), 3.87 (t, 2 H), 2.43 - 2.36 (m, 2 H), 1.68 - 1.61 (m, 2 H), 1.45 - 1.38 (m, 2 H), 0.93 (t, 3 H).

[0190] Examples 45 and 46 were prepared from the intermediate 1-butoxy-4-(3-chloropropoxy)benzene and appropriately substituted pyridines according to the procedure described for Compound 41A. [Table 10]

[0191] Synthesis of 4-benzyl-4-(3-(4-propoxyphenoxy)propyl)morpholin-4-ium bromide: [Chemical formula] ·Synthesis of the intermediate 4-(3-(4-propoxyphenoxy)propyl)morpholine: To a stirred solution of 4-propoxyphenol (1 g, 6.6 mmol) and potassium carbonate (1.8 g, 13.1 mmol) in acetonitrile (20 mL) was added 4-(3-chloropropyl)morpholine (1.2 g, 7.2 mmol), and the resulting reaction mixture was heated at 80 °C for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 50% EtOAc in pet ether, visualization: UV). The reaction mixture was cooled to room temperature, diluted with ice-cold water (10 mL), and then extracted with EtOAc (40 mL). The organic extract was washed with water (10 mL) and brine solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 40% - 50% EtOAc in pet ether). The combined pure fractions were concentrated under reduced pressure to give pure 4-(3-(4-propoxyphenoxy)propyl)morpholine (1.2 g). MS (ESI): m / z 280.25 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 6.82 (s, 4 H), 3.96 (t, 2 H), 3.86 (t, 2 H), 3.72 (t, 4 H), 2.53 - 2.45 (m, 6 H), 1.94 (t, 2 H), 1.80 - 1.75 (m, 2 H), 1.02 (t, 3 H).

[0192] ·Synthesis of 4-benzyl-4-(3-(4-propoxyphenoxy)propyl)morpholin-4-ium bromide: To a stirred solution of 4-(3-(4-propoxyphenoxy)propyl)morpholine (0.4 g, 1.4 mmol) in acetonitrile (10 mL) was added benzyl bromide (0.98 g, 5.73 mmol), and the resulting reaction mixture was heated at 80 °C for 16 h in a sealed tube while monitoring the progress of the reaction by TLC (mobile phase: 10% methanol in DCM, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 3% - 5% MeOH in DCM). The combined pure fractions were concentrated under reduced pressure to afford 4-benzyl-4-(3-(4-propoxyphenoxy)propyl)morpholin-4-ium bromide (0.28 g) as an off-white solid. Mass (ESI): m / z 370.2 [M]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.60 - 7.51 (m, 5 H), 6.86 (t, 4 H), 4.74 (s, 2 H), 4.05 - 3.99 (m, 6 H), 3.85 (t, 2 H), 3.53 - 3.40 (m, 6 H), 2.33 - 2.29 (m, 2 H), 0.96 (t, 3 H).

[0193] Examples 48 - 52 were prepared from 4-(3-chloropropyl)morpholine, appropriately substituted phenol, and benzyl bromide according to the procedure described for compound 44A.

Table 11

[0194] Synthesis of 4-benzyl-4-(3-(4-hydroxyphenoxy)propyl)morpholin-4-ium bromide:

Chem.

[0195] Synthesis of 4-(3-(4-butoxyphenoxy)propyl)-4-(2-(dimethylamino)-2-oxoethyl)morpholin-4-ium bromide:

Chemical Structure

[0196] · Synthesis of 4-(3-(4-butoxyphenoxy)propyl)-4-(2-(dimethylamino)-2-oxoethyl)morpholin-4-ium bromide To a stirred suspension of 4-(3-(4-butoxyphenoxy)propyl)morpholine (0.2 g, 0.68 mmol) in ACN (10 mL) was added 2-bromo-N,N-dimethylacetamide (0.452 g, 2.73 mmol). The resulting reaction mixture was heated to 80 °C for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 10% MeOH in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by reverse phase prep HPLC (column: X select phenylhexyl C18 (19*250) 5um, mobile phase A / B: 0.1% FA (aq) / ACN) to afford the product 4-(3-(4-butoxyphenoxy)propyl)-4-(2-(dimethylamino)-2-oxoethyl)morpholin-4-ium bromide (160 mg). MS (ESI): m / z 379.2 [M] +. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.87-6.82 (m, 4 H), 4.60 (s, 2 H), 3.99-3.90 (m, 8 H), 3.88-3.81 (m, 4 H), 3.69-3.64 (m, 2 H), 2.99 (s, 3 H), 2.86 (s, 3 H), 2.07-2.03 (m, 2 H), 1.67-1.63 (m, 2 H), 1.44-1.38 (m, 2 H), 0.92 (m, 3 H).

[0197] Examples 55 and 56 were prepared from 4-butoxyphenol, morpholine, benzyl bromide and the appropriate dihaloalkane according to the procedure described for the synthesis of Compound 38. [Table 12]

[0198] Example 2 - Inhibition of Nav1.7 Current Compounds were synthesized according to the described methods and tested for their ability to inhibit voltage-gated sodium channels.

[0199] Cell Culture NaV1.7 was expressed upon induction with tetracycline. Cells were cultured in DMEM containing 10% dialyzed fetal bovine serum (VWR, Radnor, PA), 1% Glutamax (VWR, Radnor, PA), 1% penicillin-streptomycin (VWR, Radnor, PA), 100 mg / L hygromycin (Thermo Fisher Scientific, Waltham, MA and 5 mg / L blasticidin (Alfa Aesar, Haverhill, MA). Cells were grown and maintained at 37 °C in a humidified environment containing 10% CO2 in air. Cells were detached from the culture flask for passage and harvested using 0.05% trypsin-EDTA (Thermo Fisher Scientific, Waltham, MA). To induce NaV1.7, cells were induced with tetracycline (0.1 - 1 μg / mL, IBI Scientific, Peosta, IA) on the day prior to recording and plated on 24-well plates. Cells were washed with DPBS (VWR, Radnor, PA), trypsinized, and then disrupted five times in 10 mL of growth medium to break up cell aggregates. For one 24-well plate, 2 mL of cell suspension was mixed with 23 mL of fresh growth medium and 0.1 - 1 μg / mL of tetracycline was added. Then 1 mL of the mixed medium with cells was added to each well of a 24-well plate that already had a 12 mm coverslip placed at the bottom of the well. Cells were then incubated overnight at 37 °C and 10% CO2.

[0200] Patch clamp solutions and drugs The intracellular solution contained, in mM: CsCl 135, NaCl 10, EGTA 10, HEPES 10, MgCl2 2, and was adjusted to pH 7.2 with CsOH. The external solution was a standard Ringer's solution containing, in mM: NaCl 155, HEPES 10, glucose 10, KCl 3.5, CaCl2 1.5, MgCl2 1, and was adjusted to pH 7.4 with NaOH. CsCl was from Alfa Aesar, Haverhill, MA. All other chemicals were from Sigma-Aldrich, St. Louis, MO. To test the extent of internal blockade by the test compound, the compound was dissolved in the internal solution at the indicated test concentration. In control experiments, the internal solution contained no compound. To test the extent of external blockade by the test compound, the compound was dissolved in the external solution at the indicated test concentration.

[0201] Whole-cell patch-clamp protocol 18 - 24 hours after cells were induced with tetracycline, the cover glass was placed at room temperature in a chamber filled with standard Ringer's solution, and the chamber was placed on the microscope. The pipette was pulled from borosilicate glass with a P97 puller (Sutter Instrument, Novato, CA) and polished with an MF-830 microforge (Narishige International USA, Inc, Amityville, NY) to have a resistance of 1.5 - 2.5 MΩ when filled with the CsCl internal solution at room temperature. Healthy cells (round, not translucent and not visible) were selected for seal formation. A seal was formed between the pipette and the cell, and "push-in" was performed using short pulses of suction to establish the whole-cell configuration. Before starting the voltage protocol, the membrane potential was held at -100 mV. Only cells with a continuous resistance of 1.5 - 5 MΩ were retained for analysis. The voltage protocol was as follows: The cell was held at -100 mV for 12 ms, and the hyperpolarization step was continued for 12 ms until -105 mV, and the leak was monitored. Then the cell was stepped back to -100 mV for 40 ms. Then the cell was depolarized to -20 mV for 10 ms and then back to -100 mV for 26.

[0202] Internal blockade by the test compound Once recording was initiated, the voltage protocol was run for 5 minutes at 30 - second intervals to obtain a stable baseline. To this, four 30 - second 5 - Hz stimulations of the same voltage protocol were continued with a 1 - minute rest in between, and then a 0.33 - Hz stimulation was continued after the last procedure. Currents were recorded using PatchMaster software with a Heka EPC10 (HEKA Electronics, Lambrecht, Germany). Only cells with an inward current amplitude between 400 pA and 4 nA at - 20 mV were accepted. Also, cells with a leakage current higher than 10% of those current amplitudes were discarded.

[0203] Data analysis: Internal blockade Data were plotted using Patchmaster software (HEKA Electronics, Lambrecht, Germany) and analyzed by plotting the minimum current (peak inward current) during voltage steps up to - 20 mV as a function of time. To determine the degree of decrease over the course of the experiment, the average peak inward current amplitude (2 - 3 points) before the 5 - Hz stimulation was designated as the baseline (I₀ - baseline). The average peak inward current was measured during the last 2 seconds of the last 5 - Hz procedure (Iₜₑₛₜ). The remaining control fraction current was calculated by dividing Iₜₑₛₜ by I₀ - baseline. On each recording day, three cells were tested using the control internal solution to calculate the average fraction of the remaining current (Ctrl fraction current).

[0204] To determine the % blockade caused by the test compound applied internally, the following was done. The average peak inward current amplitude (2 - 3 points) before the 5 - Hz stimulation was designated as 0% blockade (I₀ - blockade). To correct for current changes under control conditions, I₀ - blockade was multiplied by the remaining average Ctrl fraction current to obtain the corrected 0% blockade current. The average peak inward current during the last 2 seconds of the last 5 - Hz procedure was designated as the unblocked current (Iᵤₙₙₗₒₓ). % blockade was calculated using the following equation: (1 - Iᵤₙₙₗₒₓ / (I₀ - blockade)) 0% blockade) 0% blockade and the remaining average Ctrl fraction current was multiplied to obtain the corrected 0% blockade current. The average peak inward current during the last 2 seconds of the last 5 - Hz procedure was designated as the unblocked current (Iᵤₙₙₗₒₓ). % blockade was calculated using the following equation: (1 - Iᵤₙₙₗₒₓ / (I₀ - blockade)) 0%Calculated using (blocked remaining Ctrl fraction current) x 100).

[0205] For the intracellular inhibition of NaV 1.7, compounds 1A' - 6A' (Example 1) were tested. The activity range is % inhibition: "+++" > 70%, "++" (70 - 30%) or "+" (< 30%). The results are shown below.

Table 13

[0206] External block by test compound Once recording was initiated, the voltage protocol was run for 5 minutes at 30 - second intervals to obtain a stable baseline. To this, the same voltage protocol run of 5 Hz stimulation was continued until the end of the experiment. The test compound was added during the 5 Hz stimulation procedure and allowed to wait until the cells showed a stable rate of current decrease before the addition of the compound. The test compound was added for 5 minutes before washing with standard Ringer's solution. Currents were recorded using PatchMaster software with a Heka EPC10 (HEKA Electronics, Lambrecht, Germany). Only cells with an inward current amplitude between 400 pA and 4 nA at - 20 mV were accepted. Also, cells with a leak current greater than 10% of their current amplitude were discarded.

[0207] Data analysis: External block Data was plotted using Patchmaster software (HEKA Electronics, Lambrecht, Germany) and analyzed by plotting the minimum current (peak inward current) during the voltage step to - 20 mV as a function of time. To determine the % block caused by the externally applied test compound, the following was done. After a stable current decrease rate was established during the 5 Hz stimulation procedure, the rate decrease was calculated by dividing the change in peak current amplitude by time. Using the average peak inward current amplitude (2 - 3 seconds) before the addition of the compound, 0% block (I 0% block) was determined. To correct for the decrease, I 0%Subtract (speed reduction * 5 min) from the block to obtain the corrected 0% block current. The average peak inward current during the last 2 - 3 seconds of the 5-minute compound application time before washing is the non-blocking current (I_non-blocking). Then, use the following equation: Fractional current block = 1 - I_non-blocking / (I 0% block - speed reduction * 5 min) to calculate the % block.

[0208] For the extracellular inhibition of NaV 1.7, representative compounds of Example 1 were tested. The activity range is % inhibition: "+++" > 70%, "++" (70 - 40%) or "+" (< 40%). The results are shown below.

Table 14

[0209] Example 3 - Anti-itch activity The anti-itch activity of representative compounds of the present invention was determined in C57BL / 6 mice according to a similar published procedure (Ramachandran et al, JPET 2020). Briefly, mice were anesthetized with 2.5% isoflurane and a solution of the test compound (10 mg / mL, 100 μL) was topically applied to the shaved area of the neck muscle using a solvent pipette (T = 0). The test substance messaged the skin until complete absorption occurred. To induce itching, chloroquine (50 μL of 100 μg in 0.9% saline) was injected intradermally at the indicated time. Scratching behavior was monitored for 40 minutes using an infrared camera.

[0210] Representative compounds of Example 1 significantly reduce chloroquine-induced itching up to 8 hours after topical administration. See Figures 1A, 1B and 1C.

[0211] The patents and scientific literature referenced herein establish knowledge available to those of ordinary skill in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are incorporated herein by reference. All other published references, documents, manuscripts, and scientific literature cited herein are incorporated herein by reference.

[0212] The invention has been particularly shown and described with reference to its preferred embodiments, but it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined in the appended claims. It is also understood that none of the embodiments described herein are mutually exclusive and can be combined in various ways without departing from the scope of the invention as defined in the appended claims. Examples of aspects of the present invention include the following. Item 1 Formula (I):

Chemical formula

Chem.

Chem.

Chem.

Chem.

Claims

1. Formula (I): 【Chemical 1】 (wherein Y - is a pharmaceutically acceptable anion; R A 、R B and R C are each independently 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, CF 3 、NR J R K 、NR L C(O)R M 、S(O)R N 、S(O) 2 R N 、SO 2 NR Q R R 、SO 3 R S 、CO 2 R T ; C(O)R U and C(O)NR V R W selected from; R I 、R J 、R K 、R L 、R M 、R N 、R Q 、R R 、R S 、R T 、R U 、R V and R W each of which 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; R J and R K or R V and R W or R Q and R R may also together with the nitrogen to which they are attached form a substituted or unsubstituted 5-, 6-, 7- or 8-membered ring; or R A 、R B and / or R C may, together with the phenyl ring to which they are attached, form a fused bicyclic or tricyclic ring system; R 1 、 R 2 、 R 3 、 R 4 、 R 5 and R 6 are each independently selected from hydrogen, C 1 -C 4 -alkyl, cycloalkyl, C 1 -C 4 -heteroalkyl, aryl or heteroaryl; Alternatively, R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 together with one or more carbons to which they are attached form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycle; n is 0, 1, 2, 3, 4 or 5; R F and R G are, together with N + to form: 【Chemical 2】 (wherein R7 is hydrogen or substituted or unsubstituted alkyl) forms a ring selected from substituted or unsubstituted rings selected from R H is benzyl or substituted benzyl) a compound represented by

2. R A is H, methyl, halo, CF 3 , CN, CO 2 R T or ORI, the compound according to claim 1

3. R B The compound according to claim 1 or 2, wherein R is selected from H and methyl.

4. R C is H, methyl, halo, CF 3 , CN, CO 2 R T or ORI, and is a compound according to any one of claims 1 to 3.

5. Each R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 is hydrogen, the compound according to any one of claims 1 to 4.

6. R 1 is methyl or ethyl, and R 2 , R 3 , R 4 , R 5 and R 6 is hydrogen, the compound according to any one of claims 1 to 4.

7. R 3 is methyl or ethyl, and R 1 , R 2 , R 4 , R 5 and R 6 is hydrogen, the compound according to any one of claims 1 to 4.

8. The compound according to any one of Claims 1 to 7, wherein n is 0.

9. The compound according to any one of Claims 1 to 7, wherein n is 1.

10. The compound according to any one of Claims 1 to 7, wherein n is 3.

11. The compound according to Claim 1, wherein the ring formed by RF and RG is unsubstituted.

12. Formula (II): 【Chemical Formula 3】 (wherein: Y - is a pharmaceutically acceptable anion; R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are each independently selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -heteroalkyl, aryl or heteroaryl; n is 0, 1, 2, 3, 4 or 5; q is 3) a compound represented by

13. R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are hydrogen, the compound according to claim 12.

14. R 1 is methyl and R 2 , R 3 , R 4 , R 5 and R 6 is hydrogen, the compound according to claim 12.

15. R 3 is methyl, and R 1 , R 2 , R 4 , R 5 and R 6 is hydrogen, the compound according to claim 12.

16. The compound according to any one of Claims 12 to 15, wherein n is 0.

17. The compound according to any one of Claims 12 to 15, wherein n is 1.

18. The compound according to any one of Claims 12 to 15, wherein n is 2.

19. The compound according to any one of Claims 12 to 15, wherein n is 3.

20. The compound according to any one of Claims 12 to 15, wherein n is 4.

21. The compound according to any one of Claims 12 to 15, wherein n is 5.

22. The compound according to any one of Claims 1 to 21, wherein Y− is bromide or chloride.

23. A pharmaceutical composition comprising the compound according to any one of Claims 1 to 22 and a pharmaceutically acceptable excipient.

24. The composition according to Claim 23, wherein the composition is formulated for topical or dermal administration.

25. The pharmaceutical composition according to Claim 23 or 24 for treating pruritus, pain, cough or a neuroinflammatory disorder in a patient.

26. The pruritus according to Claim 25, wherein the pruritus is selected from the group consisting of uremic pruritus, brachioradial pruritus, chronic idiopathic pruritus, genital / anal pruritus, back dysesthesia, scalp pruritus, allergic dermatitis, contact dermatitis, atopic dermatitis, hand eczema, poison ivy, infection, parasite, insect bite, pregnancy, metabolic disorder, liver or kidney failure, drug reaction, allergic reaction, eczema, genital and anal pruritus, pruritus due to hemorrhoids and pruritus due to cancer.

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