Charged Ion Channel Blocking Agents 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 useful for treating pain, cough, itch and neurogenic inflammation.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 816,441, filed Mar. 11, 2019, and U.S. Provisional Application No. 62 / 931,599, filed Nov. 6, 2019. The entire contents of the above applications are incorporated by reference.

Background Art

[0002] Background of the Invention The present invention features compounds, compositions, and methods for the treatment of neuroinflammation by targeting nociceptors with small molecule drugs while minimizing the selective inhibition of sensory neurons (nociceptors, cough receptors, and pruriceptors) 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 pain-, cough-, and itch-sensing neurons but are present to a lesser extent or not at all in other types of neurons or other types of tissues.

[0003] Local anesthetics such as lidocaine and articaine act by inhibiting voltage-dependent sodium channels within neurons. These anesthetics block sodium channels and thereby the excitability of all neurons except precisely the pain-sensing neurons (nociceptors). Thus, 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 the cell membrane. 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 (in most cases) express the TRPV1 receptor / channel, which is activated by painful 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 pruriceptors) 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.

[0004] Neuropathic, inflammatory, and nociceptive pain differ in their etiology, pathophysiology, diagnosis, and treatment. Nociceptive pain occurs in response to the activation of a specific subset of 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.

[0005] Inflammatory pain occurs in the presence of tissue damage or inflammation, including post-operative pain (i.e., pain associated with acute surgical 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., the dominant 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.

[0006] 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 etiologies and can occur, for example, due to trauma, surgery, herniated discs, spinal cord injury, diabetes, infection by herpes zoster (shingles), HIV / AIDS, advanced cancer, amputation (including mastectomy), carpal tunnel syndrome, chronic alcohol use, radiation exposure, 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.

[0007] Neuropathic pain is naturally often described as "burning," "electric," "tingling," or "shooting." It is often characterized by chronic dynamic allodynia (defined as pain caused by a stimulus of movement that normally does not elicit a painful response such as light touch) and hyperalgesia (defined as increased sensitivity to a normal painful stimulus) and can persist for months or years beyond the visible healing of any damaged tissue.

[0008] Pain can occur in patients with cancer and can be due to multiple causes; inflammation, compression, invasion, metastatic spread to bone or other tissues.

[0009] 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.

[0010] Migraine headache is a headache associated with activation of sensory fibers that innervate the meninges of the brain.

[0011] Itch is a dermatological condition that can be localized and generalized and can be associated with skin lesions (rashes, atopic eczema, hives). Itch is associated with many conditions including, but not limited to, stress, anxiety, UV irradiation from the sun, metabolic and endocrine disorders (such as liver or kidney disease, hyperthyroidism), cancer (such as lymphoma), reactions to drugs or foods, infestations and fungal infections, allergic reactions, blood disorders (such as polycythemia vera), and dermatological conditions. Itch is mediated by a subset of small diameter primary sensory neurons called itch receptors that share many features of nociceptive neurons including, but not limited to, the expression of TRPV1 channels and other large pore channels (such as 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 itch. Thus, itch receptors such as nociceptors are suitable targets for this method of delivering ion channel blockers.

[0012] Cough is a defensive reflex designed to protect the airways from foreign substances and assist in the removal of luminal debris. However, this reflex can become abnormal in several diseases, resulting in a non-productive dry cough with excessive or abnormal coughing (hyper- or allo-tussive) states. Excessive and abnormal coughing states are often chronic in nature, lasting longer than 3 months, and can be manifested in many airway diseases 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.

[0013] 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) act on the vasculature to activate various inflammatory pathways in immune cells and alter blood flow and capillary permeability.

[0014] Neurogenic inflammation contributes to peripheral inflammation induced by tissue damage, autoimmune diseases, infections, allergies, and radiation exposure in various tissues and is thought to play an important role in the etiology of many disorders (such as migraine, arthritis, rhinitis, gastritis, colitis, cystitis, and sunburn). One way to reduce neurogenic inflammation is to block excitability in nociceptors, thereby preventing activation of nociceptor nerve endings and release of pro-inflammatory chemicals.

[0015] Despite the development of various treatments for pain, itching, and neurogenic inflammation, there is a need for additional agents. SUMMARY OF THE INVENTION

[0016] Summary of the Invention The present invention relates to a compound of formula (I) that can be used to treat or prevent pain, itching, and neurogenic inflammation:

Chemical formula

[0017] In a preferred embodiment, X 1 is -NHC(O)- or -C(O)NH-. In a further preferred embodiment, X 1 is -NHC(O)-.

[0018] In some embodiments, each of R A and R B is independently selected from H, D, halogen, substituted or unsubstituted C 1-4 (C1-C4) alkyl, and NR J R K ; each of R J and R K is independently selected from H and substituted or unsubstituted C 1-4selected from alkyl; and / or where R C is not H, for example halogen, C 1-4 alkyl and NR J R K is.

[0019] In a preferred embodiment, each of R A and R B is -CH3.

[0020] In certain other embodiments, R D is C optionally substituted with a substituent selected from the group consisting of halogen, oxygen (oxo), C 3-8 (C3-C8) cycloalkyl, aryl and heteroaryl, and / or R 1-4 is H, or C optionally substituted with a substituent selected from the group consisting of halogen, oxygen, C E cycloalkyl, aryl and heteroaryl. 3-8 alkyl. 1-4 is.

[0021] In a preferred embodiment, each of R D and R E is independently selected from -H, -CH3, -CH2CH3 and -(CH2)2CH3. In a more preferred embodiment, R E is hydrogen and R D is -H, -CH3, -CH2CH3 or -(CH2)2CH3.

[0022] In certain preferred embodiments, both R D and R E are hydrogen. In yet a further preferred embodiment, R D is hydrogen and R E is alkyl, for example C1-C6 alkyl or C1-C4 alkyl including but not limited to methyl, ethyl, propyl and butyl. In certain further preferred embodiments, each of R D and R ETogether with the carbon to which they are attached, they form a C3-C6 cycloalkyl which includes, but is not limited to, cyclopropyl or cyclobutyl.

[0023] In some embodiments, Y - includes, but is not limited to, halide ions, substituted or unsubstituted alkyl sulfonates, substituted or unsubstituted aryl sulfonates, aliphatic carboxylates, substituted aliphatic carboxylates, aryl carboxylates, substituted aryl carboxylates, heterocyclyl carboxylates or substituted heterocyclyl carboxylates.

[0024] In a further aspect, Y - is a halide ion. In one embodiment, Y - is a halide ion selected from bromide, chloride and iodide.

[0025] Each embodiment described herein may be employed in combination with one, any or all of the other embodiments.

Mode for Carrying Out the Invention

[0026] 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 described herein may be formulated for oral, intravenous, intramuscular, rectal, dermal, subcutaneous, topical, transdermal, sublingual, nasal, inhaled, vaginal, intrathecal, intradural or intraocular administration.

[0027] The present invention further provides a method for treating pain, cough, itching or a neuroinflammatory disorder in a patient, comprising administering to the patient a composition comprising a compound having formula (I), wherein the compound inhibits one or more voltage-dependent ion channels when exposed or applied to the inner surface of one or more voltage-dependent ion channels present in nociceptors and / or cough receptors and / or pruriceptors, and does not substantially inhibit the channels when applied to the outer surface of the channels, and the compound can enter nociceptors, cough receptors or pruriceptors through the channels when the large pore channels are activated, and can inhibit one or more voltage-dependent ion channels present in nociceptors, cough receptors or pruriceptors.

[0028] In certain embodiments, the large pore channels are transient receptor potential ion channels (TRP channels). In other embodiments, the TRP channels are activated by exogenous or endogenous agonists. In still other embodiments, the large pore channels are TRPA1, TRPV1-4, TRPM8, ASIC or P2X. In certain embodiments, the compound can enter nociceptors, cough receptors or pruriceptors through the receptor / channel when the TRPA1, TRPV1-4, TRPM8, ASIC or P2X receptor / channel is activated. In yet another embodiment, the compound inhibits voltage-dependent sodium channels. In yet another embodiment, the type of pain treated by the methods, compositions and kits of the present invention is selected from the group consisting of neuropathic pain, inflammatory pain, nociceptive pain, pain due to infection, and procedural pain, or wherein the neuroinflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis and atopic dermatitis.

[0029] The inventors have found that formula (I) can pass through open large pore channels expressed on nociceptors and / or cough receptors and / or pruriceptors, rather than motor neurons:

Chemical formula

[0030] Voltage-dependent ion channels in pain-sensing neurons are currently of great interest in the development of drugs for treating pain. By blocking voltage-dependent sodium channels in pain-sensing neurons, pain signals can be blocked by blocking the initiation and transmission of action potentials. Furthermore, by blocking voltage-dependent sodium channels in nociceptors, neurogenic inflammation can be reduced or eliminated by preventing the activation of the nociceptor peripheral terminals and the release of pro-inflammatory chemicals therefrom.

[0031] So far, the limitation in the treatment using molecules that block sodium channels or calcium channels is that most of such externally applied molecules are hydrophobic and can pass through the membrane. For this reason, they penetrate all cells and thus do not have selectivity for affecting only nociceptors.

[0032] The inhibitor of the present invention is membrane-impermeable and is effective only when inside the nociceptive receptor cell. Therefore, in order to produce an effect, it must pass through the cell membrane via channels or receptors such as large-pore channels (e.g., TRPAV1-4, TRPA1, TRPM8, ASIC, and P2X(2 / 3)). Under normal circumstances, most large-pore channels in nociceptors are inactive and require noxious thermal, mechanical, or chemical stimuli to activate them. For example, TRP channels in nociceptors can be activated by exogenous TRP ligands (i.e., TRP agonists) such as capsaicin, which opens the TRPV1 channel. Thus, one approach to selectively targeting nociceptors is to co-administer a membrane-impermeable ion channel inhibitor with an exogenous TRP ligand that enables the inhibitor to pass intracellularly through the TRP channel. In addition to capsaicin, the exogenous TRP ligand can also be another capsaicinoid, mustard oil, or lidocaine. In another example, TRP channels can become active in response to exogenous irritant activators such as acrolein inhaled from chemical warfare agents such as smoking or tear gas.

[0033] Under certain circumstances, macroporous channels can be activated by endogenous inflammatory activators resulting from tissue injury, infection, autoimmunity, atopy, ischemia, hypoxia, cellular stress, immune cell activation, immune mediator production, and oxidative stress, in the absence of exogenous macroporous channel agonists / ligands. Under such conditions, endogenous molecules (e.g., protons, lipids, and reactive oxygen species) can activate macroporous channels expressed on nociceptors, and membrane-impermeable voltage-dependent ion channel blockers can gain access to the interior of nociceptors through endogenously activated macroporous channels. Examples of endogenous inflammatory activators of macroporous channels include prostaglandins, nitric oxide (NO), peroxide (H2O2), cysteine-reactive immune mediators such as 4-hydroxynonenal, protons, ATP, endogenous alkenyl aldehydes, endocannabinoids, and immune mediators (e.g., interleukin 1 (IL-1), nerve growth factor (NGF), and bradykinin, whose receptors are linked to macroporous channels).

[0034] Definitions As used herein, the terms "a" and "an" mean one or more, unless specified otherwise.

[0035] "Biologically active" means that a molecule, including a biological molecule such as a nucleic acid, peptide, polypeptide, and protein, exerts a biological, physical, or chemical effect or activity on a protein, enzyme, receptor, ligand, antigen, itself, or another molecule. For example, a "biologically active" molecule can have, for example, enzyme activity, protein-binding activity, or pharmacological activity.

[0036] 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 anti-inflammatory agents, antibodies or antibody fragments, antibiotics, polynucleotides, polypeptides, proteins, anti-cancer agents, growth factors, and vaccines.

[0037] "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.

[0038] "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.

[0039] 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., stomach pain and visceral pain; inflammatory pain, dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrally arising pain and peripherally arising pain, migraine pain, and cancer pain.

[0040] The term "nociceptive pain" is used to include all pain caused by noxious stimuli that threaten or actually damage body tissues, such as cuts, bruises, fractures, crushed injuries, burns, etc., without limitation. Pain receptors (nociceptors) for tissue damage are mostly located in the skin, musculoskeletal system, or internal organs.

[0041] The term "physical pain" is used to refer to pain arising from bone, joint, muscle, skin, or connective tissue. This type of pain is typically well-localized.

[0042] 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.

[0043] The term "inflammatory pain" includes pain associated with active inflammation that can be caused by trauma, surgery, infection and autoimmune diseases.

[0044] 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.

[0045] The term "procedural pain" refers to pain resulting from a medical, dental or surgical procedure, where the procedure is usually planned or related to an acute injury.

[0046] The term "pruritus" is used herein in the broadest sense and refers to all types of acute intermittent and persistent localized and generalized itchy and stabbing sensations. Pruritus can be idiopathic, allergic, metabolic, infectious, drug-induced due to liver, kidney disease or cancer. "So itchy" is severe pruritus.

[0047] As used herein, the term "cough" refers to an abnormal cough reflex that results in a chronic non-productive dry cough manifested by a hyper- or allo-tussive state. This cough can be seen in many 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 infection. Furthermore, chronic cough can be idiopathic by nature, with an unknown etiology.

[0048] "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).

[0049] Useful compounds in the present invention include, but are not limited to, isomers such as their diastereomers and enantiomers, salts, esters, amides, thioesters, solvates and polymorphs, and racemic mixtures and pure isomers of the compounds described herein, in any of their pharmaceutically acceptable forms as described herein. The term "pharmaceutically acceptable anion" as used herein 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, salicylic acid, 4-aminosalicylic 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 above acids.

[0050] The term "pharmaceutically acceptable salt" refers to salts that are within the scope of sound medical judgment, 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 functional group with a suitable organic acid. Representative acid 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, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, 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.

[0051] In the general description of the compounds of the invention, the number of certain types of atoms in a substituent is generally given as a range, for example an alkyl group containing 1 to 4 carbon atoms or C 1-4 alkyl or C1-C4 alkyl. References to such ranges are intended to include specific references to groups having each of the integer atoms within the specific range. For example, an alkyl group of 1 to 4 carbon atoms includes C1, C2, C3, and C4 alkyl, respectively. Other numbers of atoms and other types of atoms can be shown in a similar manner.

[0052] "D" is deuterium.

[0053] 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 can preferably have from 3 to 6 or from 3 to 7 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

[0054] "C 1-4 alkyl" or "C1-C4 alkyl" means a branched or unbranched hydrocarbon group having from 1 to 4 carbon atoms. Similarly, "C 1-6 alkyl" or "C1-C6" is a branched or unbranched hydrocarbon group having from 1 to 6 carbon atoms. For example, C 1-4Alkyl, including an alkyl or C1-6 alkyl group, may be substituted or unsubstituted. Exemplary substituents include, but are not limited to, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy and carboxyl groups. Exemplary substituents also 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 or heteroaromatic moiety. C 1-4 Examples of alkyl include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and cyclobutyl. C 1-6 Examples of alkyl include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0055] Examples of alkyl to be replaced are 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. "C 1-7 heteroalkyl" means a branched or unbranched alkyl, alkenyl or alkynyl group having 1 to 7 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, quaternary 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 substitutions 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.

[0056] An 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 desirably 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.

[0057] An 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 desirably 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 2-6Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0058] "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), consists of two or more carbon atoms and one, two, three, four, or more heteroatoms independently selected from N, O, and S, and includes 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. "C" 2-6"Heterocyclyl" is saturated, partially unsaturated or unsaturated (including heteroaryl or aromatic), and is a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring consisting of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. For example, any bicyclic group in which any of the heterocyclic rings defined above is condensed with a benzene ring, heteroaryl, cycloalkyl or heterocycloalkyl is meant. The heterocyclyl or heteroaryl group can be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, oxo and carboxyl groups. Nitrogen and sulfur heteroatoms can be optionally oxidized. The heterocyclic ring can be covalently bonded via any 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. The nitrogen atom in the heterocyclic ring can be quaternized. Preferably, when the total number of S and O atoms in the heterocyclic ring exceeds 1, these heteroatoms are not adjacent to each other. Examples of 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, benzothiophenyl, 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] Tetrahydrofuranyl, 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, oxazolidinylperimidinyl, 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]isoxazolyl, thieno[2,3-b]imidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,Examples include 4-triazolyl, xanthenyl, β-lactam, γ-lactam and δ-lactam. 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, benzisoxazolyl, 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, chloro, bromo, fluoro and iodo.,

[0059] "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" is an aryl group having 6 to 12 carbon atoms or 6 to 10 carbon atoms, respectively. The aryl group may optionally include monocyclic, bicyclic or tricyclic rings each preferably having 5 or 6 members. The aryl group may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, alkylcarboxy, amino, alkylamino, mono-substituted amino, di-substituted amino and quaternary amino groups. A preferred aryl group is phenyl.

[0060] "Aralkyl" means a substituted or unsubstituted alkyl or an alkyl substituted by a substituted or unsubstituted aryl (e.g., including benzyl, phenethyl or 3,4-dichlorophenethyl).

[0061] "Heteroaralkyl" means a substituted or unsubstituted alkyl substituted by a heteroaryl or a heteroaryl group.

[0062] "C 7-14 aralkyl" means an alkyl having 7 to 14 carbon atoms and substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl).

[0063] "C 3-10 heterocycloalkyl" means an alkyl-substituted heterocyclic group having 3 to 10 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl or 2-tetrahydrofuranylmethyl).

[0064] "Halide" or "halogen" means bromine, chlorine, iodine or fluorine.

[0065] "Fluoroalkyl" means an alkyl group substituted by a fluorine atom.

[0066] "Alkylcarboxy" has the formula -(R)-COOH, where R is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 aralkyl, C 3-10 heterocycloalkyl or C 1-7 heteroalkyl).

[0067] "Alkoxy" means a chemical substituent of the formula -OR (wherein R is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, or R is C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 aralkyl, C 3-10 heterocycloalkyl or C 1-7 heteroalkyl).

[0068] "Aryloxy" means a chemical substituent of the formula -OR (wherein R is a C 6-12 aryl group). "Alkylthio" means a chemical substituent of the formula -SR (wherein R is C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 aralkyl, C 3-10 heterocycloalkyl or C 1-7 heteroalkyl).

[0069] "Arylthio" means a chemical substituent of the formula -SR (wherein R is a C 6-12 aryl group).

[0070] "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.

[0071] "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 neurogenic inflammation, in a patient (e.g., a human) suffering from a condition, disorder or disease caused wholly or in part by neurogenic inflammation (e.g., asthma, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, chronic intractable cough, post-viral cough, gastritis, migraine, psoriasis, rhinitis, hives or sunburn).

[0072] "Solvate" means a solvate addition form containing any amount of solvent, either stereochemical or non-stereochemical.

[0073] The compounds of the present invention, including salts of the compounds, may exist in unsolvated and solvated forms, e.g., hydrated and non-hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be encompassed 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.

[0074] 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.

[0075] The compounds that may be used in the compositions, kits and methods of the present invention have the formula (I):

Chemical formula

[0076] In some embodiments, the heteroaryl ring or bicyclic heteroaryl ring formed by R F and R G together with the N + to which they are attached is a substituted or unsubstituted C 1-6 alkane, C 1-6It may be optionally substituted with heteroalkane, carbocyclic ring, substituted carbocyclic ring, heterocarbocyclic ring, substituted heterocarbocyclic ring, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carboxamide, hydroxy, ether, amide, ester, sulfonamide, sulfone, amino, aminoalkyl, urea, nitrile or halogen. In certain aspects, N + together with R F and R G The heteroaryl ring or bicyclic heteroaryl ring formed by may be unsubstituted. In a further aspect, N + together with R F and R G The heteroaryl ring or bicyclic heteroaryl ring formed by may be substituted with substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted and unsubstituted 3- to 15-membered heterocyclyl, alkoxy or CO2R 2A where R 2A is selected from H, D, substituted or unsubstituted alkyl, such as substituted or unsubstituted C1-C6 alkyl) and substituted or unsubstituted alkenyl (such as C2-C6 alkenyl). In still further preferred aspects, N + together with R F and R G The heteroaryl ring or bicyclic heteroaryl ring formed by may be substituted with substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted and unsubstituted 3- to 8-membered heterocyclyl, OR 2B or CO2R 2A where R 2A is selected from H or substituted or unsubstituted C1-C6 alkyl, and R 2B is substituted or unsubstituted C1-C6 alkyl. In a further aspect, N + together with R F and R GThe heteroaryl ring or bicyclic heteroaryl ring formed thereby may be substituted with a substituted or unsubstituted 3- to 8-membered heterocyclyl, where the 3- to 8-membered heterocyclyl contains at least one nitrogen ring atom.

[0077] In a preferred embodiment, N + together with R F and R G The heteroaryl ring or bicyclic heteroaryl ring formed thereby is substituted with a C 1-6 alkane or C1-C6 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl. In a preferred embodiment, N + together with R F and R G The heteroaryl ring or bicyclic heteroaryl ring formed thereby is substituted with a group selected from -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclohexyl, -O-cyclopentyl and -ethyl-O-methyl. In a preferred embodiment, N + together with R F and R G The heteroaryl ring or bicyclic heteroaryl ring formed thereby is substituted with a C3-C6 cycloalkyl selected from a carbocyclic ring or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a preferred embodiment, N + together with R F and R G The heteroaryl ring or bicyclic heteroaryl ring formed thereby is substituted with a heterocarbocyclic or heterocyclic selected from aziridine, azetidine, furan, pyrrolidine, pyran, piperidine, piperazine, azepine and diazepine. In yet a further aspect, N + together with R F and R GThe heteroaryl ring or bicyclic heteroaryl ring formed thereby is substituted with a heterocyclic or heterocyclic carbon ring selected from those shown in Tables 2 to 6.

[0078] In a preferred embodiment, N + together with R F and R G The heteroaryl ring or bicyclic heteroaryl ring formed thereby may be optionally substituted with methylphenyl, pyridinyl, methylpyridinyl, -C(O)NH2, -C(O)N(CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -S(O)2NH2, -S(O)2N(CH3)2, -S(O)2CH3, -NHS(O)2CH3, -NHC(O)CH3, -C(O)N(CH3)2, -O(CH2)2OCH3, fluorine, chlorine, tetrazolyl, methylpyrrolidinyl, methylamino, pyrrolidine and dimethylamino.

[0079] In a preferred embodiment, X 1 is -NHC(O)- or -C(O)NH-. In another preferred embodiment, X 1 is -NHC(O)-.

[0080] In some embodiments, each of R A and R B is independently selected from H, D, halogen, substituted or unsubstituted C 1-4 alkyl and NR J R K ; each of R J and R K is independently selected from H and substituted or unsubstituted C 1-4 alkyl; and / or R C is not H and is, for example, halogen, substituted or unsubstituted C 1-4 alkyl and NR J R K is.

[0081] In an even more preferred aspect, R A , R B and R Cindependently, is H, D, halogen, OR I , substituted or unsubstituted C 1- C4 alkyl and NR J R K selected from; where R I , R J and R K each of which is independently selected from H and substituted or unsubstituted C 1- C4 alkyl. In a preferred embodiment, R A and R B each is CH3, and R C is selected from the group consisting of H, CH3, halogen, nitrile (cyano), methoxy and ethoxy. In a further preferred embodiment, R A and R B each is CH3, and R C is selected from the group consisting of H, CH3, fluoro, chloro, nitrile, methoxy and ethoxy. In a further preferred embodiment, R A and R B each is CH3, and R C is hydrogen.

[0082] In a preferred embodiment, R A and R B each is -CH3.

[0083] In certain aspects, or R B and vicinal R C together with the carbon atom to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl (C3-C7 cycloalkyl) or a substituted or unsubstituted aryl (e.g., phenyl).

[0084] In certain other aspects, R D is optionally substituted C 3-8 alkyl substituted with a substituent selected from the group consisting of halogen, oxygen, C 1-4 cycloalkyl, aryl and heteroaryl, and / or R E is H, or halogen, oxygen, C 3-8C optionally substituted with a substituent selected from the group consisting of cyclic alkyl, aryl or heteroaryl 1-4 is alkyl.

[0085] In a preferred embodiment, each of R D and R E is independently selected from -H, -CH3, -CH2CH3 and -(CH2)2CH3. In a more preferred embodiment, R E is hydrogen and R D is -H, -CH3, -CH2CH3 or -(CH2)2CH3.

[0086] In certain preferred embodiments, both R D and R E are hydrogen. In yet a further preferred embodiment, R D is hydrogen and R E is alkyl, such as C1-C6 alkyl or C1-C4 alkyl including but not limited to methyl, ethyl, propyl and butyl. In certain further preferred embodiments, R D and R E together with the carbon to which they are attached form a C3-C6 cycloalkyl including but not limited to cyclopropyl or cyclobutyl.

[0087] In some embodiments, 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.

[0088] In some 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, phthalate, 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. In one embodiment, Y - is a halide anion.

[0089] In one embodiment, Y - is a halide ion selected from bromide, chloride, and iodide.

[0090] Each embodiment described herein can be employed in combination with one, any, or all of the other embodiments.

[0091] In certain preferred aspects, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R F and R G are N +Together, they form an optionally substituted pyridinium ring. In a further aspect, N + together with R F and R G form an unsubstituted pyridinium ring. In yet a further aspect, N + together with R F and R G formed pyridinium may be substituted with a substituent selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted and unsubstituted 3- to 15-membered heterocyclyl, alkoxy and CO2R 2A wherein R 2A is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl. In yet a further preferred aspect, N + together with R F and R G formed pyridinium ring may be substituted with a substituent selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted and unsubstituted 3- to 8-membered heterocyclyl, OR2 B or CO2R 2A wherein R 2A is selected from H or substituted or unsubstituted C1-C6 alkyl, R 2B is substituted or unsubstituted C1-C6 alkyl. In a further aspect, N + together with R F and R G formed pyridinium ring may be substituted with a substituted or unsubstituted 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl contains a nitrogen ring atom.

[0092] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R F and R G together with N + are as follows:

Chemical formula

[0093] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R F and R G together with N + form:

Chemical formula

[0094] In an even more preferred aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R F and R G together with N + form a heteroaryl ring selected from those shown in Tables 1 - 6 below.

[0095] In a further embodiment, the present invention relates to formula (II):

Chemical formula

[0096] In certain aspects, the compound has formula (II), wherein Y -is a halide ion, a sulfonate (including substituted or unsubstituted alkyl sulfonates and substituted or unsubstituted aryl sulfonates), or a carboxylate (including substituted or unsubstituted alkyl or aliphatic carboxylates, substituted or unsubstituted aryl carboxylates, or substituted or unsubstituted heterocyclyl carboxylates). In a further aspect, the compound has formula (II), where Y- is selected from the group consisting of trifluoroacetate, sulfate, phosphate, acetate, fumarate, formate, carbonate, maleate, citrate, pyruvate, succinate, oxalate, sulfonate (such as methanesulfonate, trifluoromethanesulfonate, toluenesulfonate such as p-toluenesulfonate, benzenesulfonate, ethanesulfonate, camphorsulfonate, 2-mesitylenesulfonate, or naphthalenesulfonate such as 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. In one aspect, Y - is a halide anion.

[0097] In a further aspect, the compound has formula (II), where Y - is a halide ion. In one aspect, Y - is a halide ion selected from bromide, chloride, and iodide.

[0098] In certain embodiments, the compound has formula (II), where R 2 is hydrogen, R 1 is selected from the group consisting of methyl, ethyl, unsubstituted phenyl, and C(O)OR 3 , and R 3 is selected from hydrogen, methyl, and ethyl. In a preferred aspect, R 1 is unsubstituted phenyl and R 2 is hydrogen. In an even more preferred aspect, R 1 is methyl and R 2 is hydrogen. In a further preferred aspect, R 1 is ethyl and R 2 is hydrogen. In a further preferred aspect, R 1 is C(O)OR 3 , where R 3 is methyl or ethyl and R 2 is hydrogen. In a further preferred aspect, R 1 is C(O)OR 3 , where R 3 is ethyl and R 2 is hydrogen.

[0099] In a further embodiment, the compound has formula (II), where R 1 is hydrogen, R 2 is selected from the group consisting of methyl, ethyl, unsubstituted phenyl, and C(O)OR 3 , and R 3 is hydrogen, methyl, or ethyl. In a preferred aspect, R 1 is hydrogen and R 2 is unsubstituted phenyl. In an even more preferred aspect, R 1 is hydrogen and R 2 is methyl. In a further preferred aspect, R 1 is hydrogen and R is ethyl. In a further preferred aspect, R 1 is hydrogen and R 2 is C(O)OR 3 , where R 3is methyl or ethyl. In a further preferred aspect, R 1 is hydrogen, and R 2 is C(O)OR 3 wherein R 3 is ethyl.

[0100] In still further embodiments, the invention provides a compound of formula (III):

Chemical formula

[0101] In certain aspects, the compound has formula (III), wherein Y -is a halide ion, a sulfonate (including substituted or unsubstituted alkyl sulfonates and substituted or unsubstituted aryl sulfonates), or a carboxylate (including substituted or unsubstituted alkyl or aliphatic carboxylates, substituted or unsubstituted aryl carboxylates, or substituted or unsubstituted heterocyclyl carboxylates). In a further aspect, the compound has the formula (III), where Y− is trifluoroacetate, sulfate, phosphate, acetate, fumarate, formate, carbonate, maleate, citrate, pyruvate, succinate, oxalate, sulfonate (such as methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, such as p-toluenesulfonate, benzenesulfonate, ethanesulfonate, camphorsulfonate, 2,4,6-trimethylbenzenesulfonate, or naphthalenesulfonate, such as 2-naphthalenesulfonate), bisulfate, malonate, xylenesulfonate, 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, tartrate, phthalate, hydrochloride, hydrobromide, and nitrate, and is selected from the group consisting of. In one aspect, Y - is a halide anion.

[0102] In a further aspect, the compound has the formula (III), where Y - is a halide ion. In one aspect, Y - is a halide ion selected from bromide, chloride, and iodide.

[0103] In a further aspect, the compound has formula (III), where R1 is methyl and R2 is hydrogen. In yet a further aspect, the compound has formula (III), where both R1 and R2 are methyl.

[0104] In yet a further embodiment, the compound has formula (III), where R1 is ethyl and R2 is hydrogen. In another aspect, the compound has formula (III), where R1 is ethyl and R2 is methyl.

[0105] In a further embodiment, the compound has formula (III), where R1 is n-propyl or iso-propyl and R2 is hydrogen. In yet a further embodiment, the compound has formula (III), where R1 is n-propyl or iso-propyl and R2 is methyl.

[0106] In a further aspect, the compound has formula (III), where R1 is n-butyl, iso-butyl, tert-butyl or sec-butyl and R2 is hydrogen. In a further aspect, the compound has formula (III), where R1 is n-butyl, iso-butyl, tert-butyl or sec-butyl and R2 is methyl. In yet a further aspect, the compound has formula (III), where R1 is iso-butyl and R2 is hydrogen. In a further embodiment, the compound has formula (III), where R1 is iso-butyl and R2 is methyl.

[0107] In a further embodiment, the compound has formula (III), where R1 is cyclohexyl and R2 is hydrogen. In yet a further aspect, the compound has formula (III), where R1 is cyclohexyl and R2 is methyl.

[0108] In another embodiment, the compound has formula (III), where R1 is phenyl and R2 is hydrogen. In yet a further aspect, the compound has formula (III), where R1 is phenyl and R2 is methyl.

[0109] In other aspects, the compound has the formula (III), where R1 is CH2C(O)NHR3 and R2 is hydrogen. In a further aspect, the compound has the formula (III), where R1 is CH2C(O)NHR3 and R2 is methyl. In a further aspect, R1 is CH2C(O)NHR3, R2 is hydrogen, and R3 is methyl or ethyl. In yet a further aspect, R1 is CH2C(O)NHR3, R2 is methyl, and R3 is methyl or ethyl. In a particular further aspect, R1 is CH2C(O)NHR3, R2 is hydrogen, and R3 is ethyl. In a further aspect, R1 is CH2C(O)NHR3, R2 is methyl, and R3 is ethyl.

[0110] In a particular aspect, the compound or a pharmaceutically acceptable salt thereof is selected from Table A below, where Y− is a pharmaceutically acceptable anion: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0111] In a further preferred aspect, the compound or a pharmaceutically acceptable salt thereof is selected from Table B below: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

Table 2-5

Table 2-6

Table 2-7

Table 2-8

[0112] In a specific situation, the compound or its pharmaceutically acceptable salt is selected from Table C below, where Y- is a pharmaceutically acceptable anion:

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

[0113] In a further preferred aspect, the compound or a pharmaceutically acceptable salt thereof is selected from Table D below: [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7]

[0114] In a further preferred aspect, the compound or a pharmaceutically acceptable salt thereof is selected from Table E below: [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0115] Each of the preferred embodiments described herein can be employed in combination with one, any, or all of the other preferred embodiments, as shown herein in all permutations.

[0116] The compositions of the present invention can include a racemic mixture, a pure enantiomer, or an excess of one enantiomer over the other. For example, the α atom of compound 3 is chiral. Thus, the compound can have the structures (3a) and (3b): [Chemical formula] and can have the stereochemistry shown therein.

[0117] The compositions of the present invention can include a racemic mixture of structures 3a and 3b, a pure enantiomer of either structure 3a or structure 3b, or an excess of one enantiomer over the other. For example, the composition can include a compound with 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%.

[0118] The compounds of the present invention include all enantiomers that can be defined as (R)- or (S)- with respect to the 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, solvato-polymorphs, hydrates, anhydrates, and other crystalline forms, and combinations thereof. Similarly, all tautomeric forms are intended to be included.

[0119] Preferably, the pharmaceutical composition includes the compound of the present invention as the R enantiomer in a substantially pure form; or the pharmaceutical composition includes the compound of the present invention as the S enantiomer in a substantially pure form; or the pharmaceutical composition includes 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 includes the compound of the present invention that is a substantially pure optical isomer. To avoid uncertainty, the compound of the present invention can be used in the form of a solvate if desired.

[0120] Synthesis The compound having formula (I) can be synthesized according to the following general synthetic scheme: [Chemistry] and [Chemistry] can be prepared using a method similar thereto.

[0121] For example [Chemistry] and [Chemistry]

[0122] The compounds of formula (II) are those described in the examples and the following general synthetic scheme: [Chemistry] can be prepared using a method similar thereto.

[0123] The compounds having formula (III) are those described in the examples and the following synthetic scheme: [Chemistry] can be prepared using a method similar thereto.

[0124] Representative heterocycles that can couple with halide ions such as bromide or chloride are not limited to, [Chemistry] include.

[0125] Additional biological agents and exogenous macropore channel agonists As described above, the compounds or compositions of the present invention can be administered together with a biologically active agent. For example, one or more additional biologically active agents, including those typically used to treat neuroinflammation, can be used in combination with the compounds or compositions of the present invention described herein. Biologically active agents include, but are not limited to, TRP1A 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, anticancer agents, growth factors, and vaccines.

[0126] 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 an afferent receptor to permit entry of at least one inhibitor of a voltage-dependent ion channel (e.g., a compound of the present invention). Suitable TRPV1 agonists are capsaicin or another capsinoid that is a member of the vanilloid family of molecules. Naturally occurring capsinoids are capsaicin itself, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, and nonivamide. Other suitable capsinoids, capsinoid 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-alkanedienamide, N-vanillyl-alkanedienyl, and N-vanillyl-cis-monounsaturated alkeneamide), capsiate, dihydrocapsiate, nordihydrocapsiate, and other capsinoids, capsiconiate, dihydrocapsiconiate, and other coniferyl esters, capsiconinoid, resiniferatoxin, tinyatoxin, civamide, N-phenylmethylalkeneamide capsaicin derivatives, olvanil, N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octadecanamide, N-oleyl-homovanillylamide, triprenylphenol (e.g., scutigeral), gingerol, piperine, shogaol, guaiacol, eugenol, gingerone, nuvanil, NE-19550, NE-21610, and NE-28345. Further capsinoids, 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.

[0127] 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 - arachidonyldopamine (NADA), 6'-iodoresiniferatoxin (6'-IRTX), lipoxygenase derivatives such as C18 N - acyl ethanolamine, 12 - hydroxyeicosatetraenoic 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), propalacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and trimecaine.

[0128] Suitable TRPV2-4 agonists include, but are not limited to, 2-APB, cannabinol, diphenylboric anhydride, insulin-like growth factor 1, lysophosphatidylcholine, lysophosphatidylinositol, probenecid, Δ9-tetrahydrocannabinol, vanillin, eugenol, cinnamaldehyde, camphor, carbachol, thymol, citral, farnesyl diphosphate, tetrahydrocannabivarin, incensole acetate, diphenylboric 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.

[0129] 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 and Cooling Agent 10.

[0130] Suitable ASIC agonists include, but are not limited to, chlorophenylguanidine hydrochloride, GMQ hydrochloride, tetrahydropapaveroline (THP), reticuline, polyamine agmatine, lysophosphatidylcholine, arachidonic acid and neuropeptide SF.

[0131] Other biological active agents that can be used in the methods, compositions and kits of the present invention include anything that activates the TRP1A receptor on nociceptors or pruriceptors and allows entry of at least one inhibitor of voltage-dependent ion channels. Suitable TRP1A 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).

[0132] 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-dependent 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).

[0133] 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.

[0134] 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, proglumetacin, 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.

[0135] Examples of glucocorticoids that can be administered in combination with the composition of the present invention to patients (such as humans) suffering from neuroinflammation 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.

[0136] Examples of anesthetics that can be administered in combination with the composition of the present invention to patients (such as humans) suffering from neuroinflammation include, but are not limited to, tramadol, hydrocodone, oxycodone, morphine, and pharmaceutically acceptable salts thereof.

[0137] Examples of anti-proliferative and immunomodulatory agents that can be administered in combination with the composition of the present invention to patients (such as humans) suffering from neuroinflammation 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.

[0138] 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.

[0139] 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 sensation in the target area. The compounds of the present invention can be included in any suitable carrier substance in any suitable amount and generally are 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.

[0140] Accordingly, the composition can be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels such as hydrogels, pastes, ointments, creams, plasters, soaks, osmotic delivery devices, suppositories, enemas, injections, implants, sprays or aerosols. 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).

[0141] 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 nearly 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.

[0142] Agents formulated individually or separately can be packaged together as a kit. Non-limiting examples include kits containing, but not limited to, 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, an injection syringe, a customized IV delivery system, an inhaler, etc. Further, the unit dose kit can include instructions for the preparation and administration of the composition.

[0143] The kit can be manufactured as a single-use unit dose for one patient, as a multiple-use for a specific patient (at a fixed dose or where the individual compounds vary in efficacy as the treatment progresses); or the kit can include multiple doses ( "bulk packaging") suitable for administration to multiple patients. The kit components can be assembled in a carton, blister pack, bottle, tube, etc.

[0144] Controlled release formulations 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 quantitative) 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 capsules or tablets for administration to a patient.

[0145] 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 the compounds of the present invention can be used alone or in combination with one or more biologically active agents, as described herein, to provide, if desired, an extended elimination or amelioration of inflammation. Controlled release formulations known in the art include pellets specially coated for surgical insertion, polymeric formulations or matrices, or sustained release microparticles, such as microspheres or microcapsules, for implantation, insertion, injection or infusion, 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 formulation 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 that can be acceptable for subcutaneous or intramuscular administration.

[0146] A wide range of biocompatible materials can be used as controlled release carriers for the controlled delivery 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 about 2 weeks, preferably within a time period of about 2 days to about 7 days. The degradable controlled release material preferably degrades 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 the desired time.

[0147] 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 where the weight ratio of lactic acid to glycolic acid is 4:1 or less, i.e., 80% or less lactic acid 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, and polysaccharides such as hyaluronic acid.

[0148] The polymeric material can be prepared by any method known to those skilled in the art. For example, when 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 mixtures or blends thereof.

[0149] 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. The polysaccharides can be poly-1,4-glucans, such as starch, glycogen, amylose, amylopectin, and mixtures thereof. The 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, and the like. The polyanhydride polymer can be branched or linear.

[0150] 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 include 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 hereby incorporated by reference. The polyorthoester polymers can be prepared as described, for example, in U.S. Patent No. 4,070,347, which is hereby incorporated 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 hereby incorporated by reference.

[0151] 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, etc. 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, etc.

[0152] In a further aspect, a controlled release material that actually serves 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, for example a polysaccharide such as a polyanhydride or chitosan.

[0153] In embodiments where the biodegradable polymer comprises a gel, one such useful polymer is a thermogelating 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 freely 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.

[0154] Dosage forms for oral use Examples of formulations for oral use include tablets containing the active ingredient(s) in a mixture with a non-toxic pharmaceutically acceptable excipient. 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, hydroxypropylmethyl cellulose, ethyl cellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricants, glidants and anti-adhesion agents (such as magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, wetting agents, buffering agents, taste masking agents (such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose), etc.

[0155] One or more compounds of the invention and one or more biologically active agents 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.

[0156] 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 abovementioned ingredients, under tablets and capsules.

[0157] Formulations for oral administration to the mouth can also be provided as oral rinses, oral sprays, oral rinse solutions, oral ointments or oral gels.

[0158] 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 one or more of the abovementioned coating substances and / or, for example, shellac, beeswax, glyceryl wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylic acid, 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 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 fluorocarbons.

[0159] 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.

[0160] 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.

[0161] 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, and even for the lifetime of the patient. In many cases, chronic long-term administration is indicated.

[0162] 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 solution. Typically, the concentration of the compound in the liquid is from about 1 ng / ml to about 10 μg / ml, such as 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.

[0163] Topical formulations The compositions of the present invention may 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, as described herein.

[0164] In preferred combinations, the active ingredients are preferably each from 0.0001% to 10% (w / w), more preferably from 0.0005% to 4% (w / w) of the active agent. Topical formulations including, but not limited to, creams, gels or ointments may be applied 1 to 4 times daily or as needed. When practicing the methods described herein, the topical vehicle comprising the composition of the present invention or the combination therapy comprising the composition of the present invention is preferably applied to the site of inflammation of the patient. For example, a cream may be applied to the hand of a patient suffering from arthritic fingers.

[0165] 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.

[0166] 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 available from B. F. Goodrich Company (Akron, Ohio)) TM or Carbopol 940P TM) copolymers of polyacrylic acid (e.g., Pemulen from B. F. Goodrich Company TM or Polycarbophil from A. H. Robbins, Richmond, Va. TM ; polysaccharide gums such as agar gum, alginates, carrageenan gum, 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.

[0167] Other suitable polymeric skin permeation enhancers are cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose. Further, known transdermal penetration enhancers may also be added if desired. Exemplifications 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 promoters such as dioxolane, cyclic ketones and their derivatives, etc.

[0168] 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.

[0169] Particularly preferred skin penetration enhancers include isopropyl myristate, a medium-chain fatty acid; isopropyl palmitate; dimethyl sulfoxide; decyl methyl sulfoxide; dimethylalanine amide; dodecyl 2-(N,N-dimethylamino) propionate or a salt thereof described in U.S. Patent No. 6,118,020, for example, 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.

[0170] The skin penetration enhancer in this composition by weight ranges from 0.5% to 10% (w / w). The most preferred range is 1.0% to 5% (w / w). In another embodiment, the skin penetration enhancer comprises 0.5% to 1%, 1% to 2%, 2% to 3%, 3% to 4%, or 4% to 5% (w / w) of the composition.

[0171] 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 can include anesthetics, anti-itch actives, plant extracts, conditioning agents, darkening or lightening agents, glitter, wetting agents, mica, minerals, polyphenols, silicones or their derivatives, sunscreens, vitamins and phytomedicinals.

[0172] The composition can also include other similar ingredients 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 diluted 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.

[0173] Formulations for ophthalmic administration The compounds of the present invention can 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 about 0.0001% to about 5% (weight per volume) and more preferably in the range of about 0.0005% to about 0.1% (weight per volume).

[0174] 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.

[0175] An ophthalmically acceptable carrier is generally sterile, essentially free of foreign particles, and generally has a pH in the range of 5 - 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) solutions are also useful.

[0176] 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, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, and hydroxyethylcellulose.

[0177] 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.

[0178] As long as the resulting formulation is ophthalmologically 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. Ophthalmologically acceptable antioxidants may also be included. Antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0179] Formulations for nasal and inhalation administration The pharmaceutical compositions of the present invention can be formulated for nasal or intranasal administration. When the carrier is solid, formulations suitable for nasal administration include, for example, coarse powders having a particle size in the range of about 20 to 500 microns that are administered by rapid inhalation through the nasal route. When the carrier is 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.

[0180] 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 fixed amount, and capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated, which contain a compound and a suitable powder mixture based on a powder such as lactose or starch.

[0181] Dry powder compositions for topical delivery to the lungs by inhalation can be provided, for example, in gelatin capsules and cartridges for use in inhalers or insufflators or in blisters of, for example, thin sheet aluminum foil. The powder blend formulations generally comprise a powder mixture for inhalation of a compound of the invention and a suitable powder base (carrier / diluent / excipient substance), such as a monosaccharide, disaccharide or polysaccharide (e.g., lactose or starch). The use of lactose is preferred. In one embodiment, each capsule or cartridge can contain from about 2 μg to about 100 mg of a 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 a 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 a compound of formula (I), optionally in combination with another therapeutically active ingredient. Alternatively, the compounds of the invention can be delivered without excipients.

[0182] Suitably, the encapsulating / pharmaceutical dispenser is of a type selected from the group consisting of a reservoir dry powder inhaler (RDPI), a unit dose dry powder inhaler (e.g., a capsule or blister pack inhaler), a multi-dose powder inhaler (MDPI) and a metered dose inhaler (MDI).

[0183] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers or nebulizers can be formulated to contain an aqueous medium, ethanol, aqueous ethanol or suitable alternative agents 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.

[0184] Compositions formulated for nasal or inhalation administration may include 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, methanol, arginine, lysine and sodium glutamate, and / or amino acids or amino derivatives such as these, 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, fruit essences including apples, peaches, pears, strawberries, raspberries, cherries, plums, pineapples, apricots, etc. Further sweeteners include sucrose, dextrose, aspartame, acesulfame-K, sucralose and saccharin, organic acids (non-limiting examples being citric acid and aspartic acid). Such fragrances may be present at about 0.05 to about 4% by weight and may be present in lower or higher amounts as one or more of the potential for effect on the fragrance, 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.

[0185] Index The compounds, compositions, methods, and kits of the invention are useful for treating pain, cough, or itch associated with any of several conditions including trigeminal trophic syndrome, erythromelalgia, back and neck pain, lower back pain, cancer pain, gynecological and labor 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, pain of hemorrhoids, 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 irritation, 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 of procedures (i.e., injection, drainage of abscess, surgery, dental procedure, eye procedure, eye irritation, conjunctivitis (e.g., allergic conjunctivitis), eye redness, dry eye, arthroscopy and use of other medical devices, cosmetic surgical procedure, dermatological procedure, setting fractures, biopsy, etc.).

[0186] Because subclasses of nociceptors mediate itch sensation, the compounds, compositions, methods, and kits of the invention can also be used to treat itch in patients having conditions such as pruritus (including, but not limited to, brachioradialis, chronic idiopathic, genital / anal, back dysesthesia, and scalp), allergic dermatitis, atopic dermatitis, contact dermatitis, poison ivy, infection, infestation, insect bite, pregnancy, metabolic disorder, liver or kidney insufficiency, drug reaction, allergic reaction, eczema, hand eczema, genital and anal itch, itch of hemorrhoids, and conditions such as cancer.

[0187] Subclasses of nociceptors can initiate an abnormal cough reflex, so 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.

[0188] The compounds, compositions, methods, and kits of the present invention can also be used to treat neuroinflammation and neuroinflammatory disorders. Inflammation is a complex set of responses to harmful stimuli that result 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). Neuroinflammation 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).

[0189] The release of peripheral terminal chemicals stimulates various inflammatory responses. First, the release of substance P can result in an increase in 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 inflammatory response known as Lewis's triple response - the triad of wheal, flare, and erythema. Second, the release of CGRP causes vasodilation and an increase in blood flow. This can be detected as flare, another component of Lewis's triple response.

[0190] Substance P also has pro-inflammatory effects on immune cells (e.g., 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 an appropriate peripheral stimulus (e.g., pinch) 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 convergence axon branch point in the periphery gives rise to an action potential that moves downstream 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 (e.g., primary centripetal depolarization of the central terminal caused by GABA can be sufficient to initiate an action potential moving along the "wrong path").

[0191] Genetic analysis of ILC2 cells intrinsic to the lung has revealed the expression of receptors for several neuropeptides released by sensory neurons, such as SP, CGRP, and VIP, providing the opportunity for nociceptors to communicate directly with these cells. In particular, VIP has been 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 release 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 of 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 transcriptional 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.

[0192] Release of immunomodulators 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. 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 (DRGs) after nerve injury. Allodynia and hyperalgesia induced by nerve injury are significantly attenuated or abolished in rodents lacking T cells, and the immunosuppressant rapamycin attenuates neuropathic pain in rats, in part because of 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 HTwo 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, when binding to the C5aR1 receptor on neutrophils, it becomes a potential neutrophil chemoattractant (Ren & Dubner, Nat. Med. 16:1267-1276 (2010)).

[0193] Bacterial infection has been shown to directly activate nociceptors, and the immune responses mediated by TLR2, MyD88, T cells, B cells, as well as neutrophils and monocytes are not required for Staphylococcus aureus-induced pain in mice (Chiu et al., Nature 501:52-57 (2013)). Mechanical and thermal hyperalgesia in mice is related to the load of live bacteria rather than tissue swelling or immune activation. Bacteria induce calcium influx 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 of lymph node efflux. Thus, bacterial pathogens cause pain as an unexpected role for the nervous system in host-pathogen interactions by directly activating the sensory neurons that regulate inflammation. Data from Talbot et al., (Neuron. 2015 July 15; 87(2): 341-354.) also suggest that nociceptors are activated during exposure to allergens in sensitized animals.

[0194] In certain disorders, neuroinflammation contributes to peripheral inflammation induced by tissue damage, autoimmune diseases, infections, and exposure to irritants in soft tissues, skin, respiratory system, joints, urogenital and GI tracts, liver, and brain. Neuroinflammatory 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, polymicrobial sepsis, tendinopathy, chronic fatigue, rheumatic diseases, acute lung injury, exposure to irritants, inhalation of irritants, contaminants, or chemical warfare agents, as described herein.

[0195] Assessment of pain, cough, itch, and neuroinflammation Measurement indicators can be used to measure the effectiveness of any of the compounds, compositions, methods, and kits of the present invention in the treatment of pain associated with musculoskeletal, immune-inflammatory, and neuropathic disorders. Useful indicators include the Visual Analog 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, itch, function, stiffness, or other variables.

[0196] 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 itch by selecting the spot on the line that best corresponds to the sensation of pain or itch where one end of the line corresponds to "no pain" (a score of 0 cm) or "no itch", and the other end of the line corresponds to "unbearable pain" or "unbearable itch" (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 itch. The VAS scales and their use are described, for example, in U.S. Patent Nos. 6,709,406 and 6,432,937.

[0197] The Likert scale similarly provides a reference for a one-dimensional quantity. Generally, the Likert scale has discrete integer values in a range 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 and high values 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.

[0198] 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 the WOMAC, while there is one Lequesne questionnaire for the knees and another for the hips. These questionnaires are useful because they contain more information content compared to 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 significantly.

[0199] The AUSCAN (Australian-Canadian Hand Arthritis) index uses questions reported by patients themselves that are reliable, highly reliable, and responsive. In one example, this question includes 15 questions within three ranges (pain, 5 questions; stiffness, 1 question; and physical function, 9 questions). The AUSCAN index can use, for example, the Likert or VAS scale.

[0200] Useful indicators in the methods, compositions and kits of the present invention for pain measurement include Pain Descriptor Scale (PDS), Visual Analogue Scale (VAS), Verbal Descriptor Scales (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.

[0201] 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.

[0202] Cough can be measured by standard questions such as the Leicester Cough Questionnaire and a reliable objective device (e.g., VitaloJAK) for measuring cough frequency.

Example

[0203] Example The following examples are intended to illustrate the present invention and are not intended to limit the present invention.

[0204] Example 1 - Compound Synthesis General Abbreviation Definitions ACN Acetonitrile aq. Aqueous ℃ Degree Celsius δ Chemical Shift (ppm) DCM Dichloromethane DMSO Dimethyl Sulfoxide ESI Electrospray Ionization Et2O Diethyl Ether EtOAc Ethyl Acetate h Hour MeOH Methanol mHz Megahertz min min ml Milliliter MS Mass Spectrometry m / z Mass to Charge Ratio NMR Nuclear Magnetic Resonance Pet Ether Petroleum Ether RT Room Temperature TLC Thin Layer Chromatography UV Ultraviolet

[0205] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide:

Chem.

[0206] ·Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide. To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl)acetamide (0.25 g, 1.03 mmol, 1.0 equiv) in EtOAc (10 mL) was added pyridine (0.166 mL, 2.06 mmol, 2.0 equiv), and the resulting mixture was stirred at 80 °C in a sealed tube, monitoring the consumption of the starting material by TLC (mobile phase: 10% MeOH in DCM, visualization by UV). After 16 h, the crude solution was cooled to room temperature, and the resulting precipitate was collected by filtration, washed with EtOAc (2 x 10 mL), and dried under vacuum to give N-(2,6-dimethylphenyl)-2-(pyridin-1-yl)acetamide bromide (0.1 g) as a white solid. MS (ESI): m / z 241.1 [M]+. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.08 (d, J = 5.5 Hz, 2H), 8.69 (t, J = 7.8 Hz, 1H), 8.22 (dd, J = 6.8, 7.5 Hz, 2H), 7.16 - 6.99 (m, 3H), 5.75 (s, 2H), 2.20 (s, 6H).

[0207] Synthesis of 3-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-methyl-1H-imidazol-3-ium bromide:

Chemical Structure

[0208] Synthesis of 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)pyridin-1-ium bromide:

Chemical Structure

[0209] ·Synthesis of intermediate 2-bromo-N-(2,6-dimethylphenyl)butanamide. A solution of 2,6-dimethylaniline (15 g, 121.18 mmol, 1.0 equiv) and pyridine (15 mL, 189.6 mmol, 1.5 equiv) in DCM (400 mL) was cooled to 0 °C in an ice bath. To this solution, a solution of 2-bromobutanoyl chloride (27.5 g, 148.6 mmol, 1.2 equiv) in DCM (50 mL) was slowly added, and the resulting mixture was warmed to room temperature with stirring for 2 h. The reaction mixture was adjusted to pH about 5 - 6 using 2N HCl and extracted with DCM (2 x 200 mL). The combined organic extracts were washed with water (250 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was triturated with n-pentane (150 mL) to give 2-bromo-N-(2,6-dimethylphenyl)butanamide (30 g). MS (ESI): m / z 272.13 [M + 2] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.15 - 7.02 (m, 3H), 4.51 (t, J = 7.3 Hz, 1H), 2.22 - 2.04 (m, 7H), 2.03 - 1.91 (m, 1H), 0.98 (t, J = 7.3 Hz, 3H).

[0210] ·Synthesis of 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)pyridin-1-ium bromide. To a stirred solution of 2-bromo-N-(2,6-dimethylphenyl)butanamide (0.2 g, 0.7 mmol, 1.0 equiv) in acetonitrile (3 mL) was added pyridine (0.12 mg, 1.4 mmol, 2.0 equiv), and the resulting mixture was heated at 90 °C for 36 h in a sealed tube. After cooling to rt, the solution was concentrated under reduced pressure, and the resulting crude product was triturated with EtOAc (5 mL) to afford 1-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)pyridin-1-ium bromide (0.17 g). MS (ESI): m / z 269.2 [M] + . 1HNMR (400 MHz, DMSO-d6) δ 0.92 (t, J = 7.23 Hz, 3H), 2.10 (br s, 6H), 2.28 - 2.45 (m, 1H), 2.59 (dt, J = 13.98, 6.93 Hz, 1H), 5.75 (dd, J = 9.43, 5.92 Hz, 1H), 7.00 - 7.20 (m, 3H), 8.25 (t, J = 7.13 Hz, 2H), 8.73 (t, J = 7.78 Hz, 1H), 9.23 (d, J = 5.70 Hz, 2H), 10.12 (s, 1H).

[0211] Synthesis of 3-(1-((2,6-dimethylphenyl)amino)-1-oxobutan-2-yl)-1-methyl-1H-imidazol-3-ium bromide:

Chemical formula

[0212] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-2-methylpyridin-1-ium bromide:

Chemical Structure

[0213] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-2,6-dimethylpyridin-1-ium bromide:

Chemical Structure

[0214] Synthesis of 1-(2-((4-fluoro-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide:

Chemical Structure

[0215] · Synthesis of 1-(2-((4-fluoro-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide. A stirred solution of 2-bromo-N-(4-fluoro-2,6-dimethylphenyl)acetamide (0.2 g, 0.8 mmol, 1.0 equiv) in EtOAc (5 mL) was treated with pyridine (0.126 g, 1.6 mmol, 2.0 equiv) and the reaction mixture was stirred at 80 °C for 16 h in a sealed tube, monitoring the consumption of the starting material by TLC (mobile phase: 10% MeOH in DCM, visualized by UV). The solution was concentrated under reduced pressure and the crude product was triturated with EtOAc (15 mL) to afford 1-(2-((4-fluoro-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide (0.15 g). MS (ESI): m / z 259.2 [M] +. 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.07 (d, J = 5.48 Hz, 2H), 8.68 (t, J = 7.89 Hz, 1H), 8.22 (dd, J = 7.67, 6.80 Hz, 2H), 6.95 (d, J = 9.43 Hz, 2H), 5.75 (s, 2H), 2.20 (s, 6H).

[0216] Synthesis of 1-(2-(mesitylamino)-2-oxoethyl)pyridin-1-ium bromide:

Chemical Structure

[0217] · Synthesis of 1-(2-(mesitylamino)-2-oxoethyl)pyridin-1-ium bromide. To a stirred solution of 2-bromo-N-mesitylacetamide (0.2 g, 0.8 mmol, 1.0 equiv) in ethyl acetate (5 mL) was added pyridine (0.126 g, 1.6 mmol, 2.0 equiv), and the reaction mixture was stirred in a sealed tube at 80 °C for 16 h while monitoring the progress of the reaction by TLC (mobile phase: 10% MeOH in DCM, visualized by UV). The reaction mixture was concentrated under reduced pressure, and the crude product was triturated with EtOAc (15 mL) to give 1-(2-(mesitylamino)-2-oxoethyl)pyridin-1-ium bromide (0.13 g). MS (ESI): m / z 255.2 [M] +. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.07 (d, J = 5.48 Hz, 2H), 8.68 (t, J = 7.78 Hz, 1H), 8.22 (t, J = 7.13 Hz, 2H), 6.89 (s, 2H), 5.73 (s, 2H), 2.22 (s, 3H), 2.15 (s, 6H).

[0218] Synthesis of 1-(2-((4-chloro-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide: [Chemical formula] ·Synthesis of the intermediate 2-bromo-N-(4-chloro-2,6-dimethylphenyl)acetamide. To a stirred solution of 4-chloro-2,6-dimethylaniline (0.5 g, 3.592 mmol, 1 equiv) in water (5 mL) was added 2-bromoacetyl bromide (0.797 g, 3.952 mmol, 1.1 equiv) at 0 °C, and the resulting mixture was stirred for 1 h while monitoring the progress of the reaction by TLC (mobile phase: 50% EtOAc in petroleum ether, visualized by UV). The pH of the reaction mixture was adjusted with 15% Na2CO3(aq.) solution and extracted with EtOAc (2 X 25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-bromo-N-(4-chloro-2,6-dimethylphenyl)acetamide (0.45 g). MS (ESI): m / z 276.05 [M+H]. 1H NMR (400 MHz, CDCl3) δ 7.66 (br s, 0.5 H), 7.09 (s, 1H), 6.89 - 6.96 (m, 2H), 4.07 (s, 1H), 2.22 (s, 3H), 2.12 - 2.19 (m, 6H).

[0219] ·Synthesis of 1-(2-((4-chloro-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide. To a stirred solution of 2-bromo-N-(4-chloro-2,6-dimethylphenyl)acetamide (0.15 g, 0.5 mmol, 1.0 equiv) in EtOAc (5 mL) was added pyridine (0.085 g, 1.1 mmol, 2.0 equiv), and the reaction mixture was stirred at 80 °C for 16 h in a sealed tube, monitoring the consumption of the starting material by TLC (mobile phase: 10% MeOH in DCM, visualized by UV). The solution was concentrated under reduced pressure, and the crude product was triturated with EtOAc (15 mL) to afford 1-(2-((4-chloro-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide (0.1 g). MS (ESI): m / z 275.1 [M]+. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.07 (d, J = 5.48 Hz, 2H), 8.68 (t, J = 7.89 Hz, 1H), 8.22 (t, J = 7.23 Hz, 2H), 7.19 (s, 2H), 5.75 (s, 2H), 2.20 (s, 6H).

[0220] Synthesis of 1-(2-((4-methoxy-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide:

Chemical Structure

[0221] · Synthesis of 1-(2-((4-methoxy-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide. To a stirred solution of 2-bromo-N-(4-methoxy-2,6-dimethylphenyl)acetamide (60 mg, 0.2 mmol, 1.0 equiv) in EtOAc (1 mL), pyridine (34 mg, 0.4 mmol, 2.0 equiv) was added, and the reaction mixture was stirred in a sealed tube at 80 °C for 16 h, and the consumption of the starting material was monitored by TLC (mobile phase: 10% MeOH in DCM, visualized by UV). The solution was concentrated under reduced pressure, and the crude product was triturated with EtOAc (2 X 5 mL) to give 1-(2-((4-methoxy-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide (0.07 g). MS (ESI): m / z 271.1 [M] + . 11H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.07 (d, J=5.70 Hz, 2H), 8.68 (t, J=7.89 Hz, 1H), 8.22 (t, J=7.13 Hz, 2H), 6.66 (s, 2H), 5.72 (s, 2H), 3.71 (s, 3H), 2.16 (s, 6H).

[0222] Synthesis of 1-(2-((4-cyano-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide: [Chemical Structure] · Synthesis of the intermediate 2-bromo-N-(4-cyano-2,6-dimethylphenyl)acetamide. To a stirred solution of 4-amino-3,5-dimethylbenzonitrile (0.5 g, 3.4 mmol, 1.0 equiv) in DCM (20 mL) was added K2CO3 (0.563 g, 4.08 mmol, 1.2 equiv), and the resulting mixture was cooled to 0 °C. Then, 2-bromoacetyl bromide (0.823 g, 4.08 mmol, 1.2 equiv) was added dropwise, and the reaction was warmed to RT and stirred at RT for 16 h. The progress of the reaction was monitored by TLC (mobile phase: 50% ethyl acetate in pet ether, Rf: 0.41, visualized by UV). The reaction mixture was basified with 15% Na2CO3 solution at 0 °C to obtain a precipitate, which was filtered and dried under vacuum to give 2-bromo-N-(4-cyano-2,6-dimethylphenyl)acetamide (0.35 g). MS (ESI): m / z 267.36 [M+H]. 1H NMR (400 MHz, CDCl3) δ 7.80 (br s, 1H), 7.41 (s, 2H), 4.09 (s, 2H), 2.29 (s, 6H).

[0223] · Synthesis of 1-(2-((4-cyano-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide. To a stirred solution of 2-bromo-N-(4-cyano-2,6-dimethylphenyl)acetamide (0.2 g, 0.7 mmol, 1.0 equiv) in EtOAc (5 mL) was added pyridine (0.1106 g, 1.6 mmol, 2.0 equiv), and the reaction mixture was stirred at 80 °C for 16 h in a sealed tube, monitoring the consumption of the starting material by TLC (mobile phase: 10% MeOH in DCM, visualized by UV). The solution was concentrated under reduced pressure, and the crude product was triturated with EtOAc (15 mL) to afford 1-(2-((4-cyano-2,6-dimethylphenyl)amino)-2-oxoethyl)pyridin-1-ium bromide (0.14 g). MS (ESI): m / z 266.1 [M]+. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.08 (d, J = 5.70 Hz, 2H), 8.69 (t, J = 7.78 Hz, 1H), 8.23 (t, J = 7.23 Hz, 2H), 7.60 (s, 2H), 5.79 (s, 2H), 2.25 (s, 6H).

[0224] Synthesis of 1-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-3-phenylpyridin-1-ium bromide:

Chemical Structure

[0225] Synthesis of Compounds 13 - 28: Table F. Table F provides further representative examples of the present invention synthesized from 2-bromo-N-(2,6-dimethylphenyl)acetamide and appropriate heterocycles as shown above or according to the method described for the synthesis of compound 12.

Table 6-1

Table 6-2

Table 6-3

[0226] Synthesis of 2-(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1-(2-(ethylamino)-2-oxoethyl)-1H-pyrazol-2-ium bromide:

Chem.

[0227] Synthesis of Compounds 31 - 105: Table G. The following Table G provides further representative examples of the present invention synthesized from either 2-bromo-N-(2,6-dimethylphenyl)acetamide or 2-chloro-N-(2,6-dimethylphenyl)acetamide and an appropriate heterocycle as shown above. The compounds were purified by grinding or reverse phase prep HPLC.

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

Table 7-6

Table 7-7

[0228] Synthesis of 1-(1-((2,6-dimethylphenyl)amino)-1-oxo-3-phenylpropan-2-yl)pyridin-1-ium chloride

Chemical formula

[0229] ·Synthesis of 1-1-(1-((2,6-dimethylphenyl)amino)-1-oxo-3-phenylpropan-2-yl)pyridin-1-ium chloride A stirred solution of 2-chloro-N-(2,6-dimethylphenyl)-3-phenylpropanamide (0.05 g, 0.174 mmol) in EtOAc (5 ml) was added pyridine (0.059 g, 0.745 mmol) at room temperature, and the resulting reaction was stirred in a sealed tube at 120 °C for 16 h, and the progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction mixture was concentrated under reduced pressure to give the crude product, which was triturated with ethyl acetate (20 ml X 3) to give 1-1-(1-((2,6-dimethylphenyl)amino)-1-oxo-3-phenylpropan-2-yl)pyridin-1-ium chloride (42.3 mg) as an off-white solid. MS (ESI): m / z 331.25 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (s, 1 H), 9.28 (d, 2 H), 8.64-8.60 (m, 1 H), 8.18-8.14 (m,2 H), 7.34-7.19 (m, 5 H), 7.13-7.05 (m, 3 H), 6.33-6.29 (m, 1 H), 4.03-3.98 (m, 1 H), 3.73-3.67 (m, 1H), 2.03 (s, 6 H).

[0230] Synthesis of Compounds 107 - 108: Table H. The following Table H provides further representative examples of the present invention synthesized from appropriately substituted 2-bromo-propanoic acid, 2,6-dimethylaniline and pyridine.

Table 8

[0231] Synthesis of 1,2-bis(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1H-pyrazol-2-ium bromide

Chemical Structure

[0232] Synthesis of 1,3-bis(2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-1H-imidazol-3-ium bromide

Chemical Structure

[0233] Synthesis of 1-cyclohexyl-2-(2-(2,6-dimethylphenoxy)-2-oxoethyl)-1H-pyrazol-2-ium bromide

Chemical Structure

[0234] ·Synthesis of 1-cyclohexyl-2-(2-(2,6-dimethylphenoxy)-2-oxoethyl)-1H-pyrazol-2-ium bromide To a stirred solution of 2,6-dimethylphenyl 2-bromoacetate (0.5 g, 2.056 mmol) in ACN (5 ml), 1-cyclohexyl-1H-pyrazole (0.617 g, 4.112 mmol) was added at room temperature and the resulting reaction mixture was heated to 90 °C for 16 h. The progress of the reaction was monitored by TLC (10% MeOH in DCM, visualization: UV). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified by normal phase flash chromatography (10% - 50% MeOH in DCM) to afford 1-cyclohexyl-2-(2-(2,6-dimethylphenoxy)-2-oxoethyl)-1H-pyrazol-2-ium bromide (20 mg) as an off-white solid. Mass (ESI): m / z 313.2 [M]+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (d, 1 H), 8.68 (d, 1 H), 7.17 - 7.11 (m, 4 H), 6.32 (s, 2 H), 4.66 - 4.61 (m, 1 H), 2.16 ( s, 6 H ), 2.05 - 2.02 ( m, 2 H ), 1.87 - 1.78 (m, 4 H ), 1.71 - 1.67 (m, 1 H ), 1.44 - 1.41 (m, 2 H ), 1.25 - 1.22 (m, 1 H).

[0235] Synthesis of Compounds 112 - 130: Table I. The following Table I provides further representative examples of the present invention synthesized from 2-bromoacetyl bromide and appropriately substituted anilines and heterocycles according to the methods described. Compounds were purified by trituration or reverse phase prep HPLC.

Table 9-1

Table 9-2

Table 9-3

Table 9-4

Table 12-6

Table 12-7

Table 12-8

Table 12-9

Table 12-10

Table 12-11

Table 12-12

Table 13-1

Table 13-2

Table 13-3

Table 13-4

Table 13-5

Table 13-6

Table 13-7

Table 14-1

Table 14-2

Table 14-3

Table 15-1

Table 15-2

Table 15-3

Table 16-1

Table 16-2

Table 16-3

Table 16-4

Table 16-5

Table 16-6

Table 16-7

Table 16-8

[0236] Preferred compounds according to the present invention, as well as their enantiomers and their pharmaceutically acceptable salts, are of formula (IV)

Chemical formula

Table 17-1

Table 17-2

Table 17-3

Table 17-4

Table 17-5

Table 17-6

Table 17-7

Table 17-8

Table 17-9

Table 17-10

Table 17-11

Table 17-12

Table 17-13

Table 17-14

Table 17-15

Table 17-16

Table 17-17

Table 17-18

Table 17-19

Table 17-20

Table 17-21

Table 17-22

Table 17-23

Table 17-24

Table 17-25

Table 17-26

Table 17-27

Table 17-28

Table 17-29

[0237] Example 3 - Inhibition of Nav1.7 Current Representative compounds of the present invention were synthesized according to the described methods and tested for their ability to inhibit voltage - dependent sodium channels.

[0238] Cell Culture NaV1.7 was expressed during 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. For subculture, cells were detached from the culture flask using 0.05% trypsin-EDTA (Thermo Fisher Scientific, Waltham, MA) and harvested. 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 5 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 medium mixed 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.

[0239] Patch-Clamp Solutions and Drugs The intracellular solution contained (in mM) CsCl 135, NaCl 10, EGTA 10, HEPES 10, and 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, and 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 degree of internal blockade by the test compound, the compound was dissolved in the internal solution at the indicated test concentrations. In the control experiment, the internal solution contained no compound. To test the degree of external blockade by the test compound, the compound was dissolved in the external solution at the indicated test concentrations.

[0240] Whole - cell patch - clamp protocol Eighteen to twenty - four hours after the 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 a 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 cells were held at - 100 mV for 12 ms, and the hyperpolarization step was continued at - 105 mV for 12 ms while monitoring for leakage. Then the cells were stepped back to - 100 mV for 40 ms. Then the cells were depolarized to - 20 mV for 10 ms and then returned to - 100 mV for 26 ms.

[0241] 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, a 5 - Hz stimulus for 30 seconds was repeated 4 times with the same voltage protocol separated by a 1 - minute rest, and a 0.33 - Hz stimulus 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.

[0242] 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 the 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 stimulus was designated as the baseline (I\(_\text{baseline}\)). The average peak inward current was measured during the last 2 seconds of the last 5 - Hz procedure (I\(_\text{test}\)). The remaining control fractional current was calculated by dividing I\(_\text{test}\) by I\(_\text{baseline}\). On each recording day, 3 cells were tested with the control internal solution to calculate the average fraction of the remaining current (Ctrl fractional current).

[0243] 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 stimulus was designated as 0% blockade (I 0% blockade). To correct for current changes under control conditions, I 0% blockade was multiplied by the remaining average Ctrl fractional current to obtain a 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 (I\(_\text{unblocked}\)). % blockade was calculated using the following equation: (1 - I\(_\text{unblocked}\) / (I 0%Calculated using (blocking remaining Ctrl fraction current) x 100).

[0244] Representative examples of the present invention were tested for intracellular inhibition of NaV 1.7. The activity range is the % inhibition at a test concentration of 32 μM: "++++" (>95%), "+++" 95 - 70%, "++" (70 - 40%) or "+" (<40%). The results are shown below. [Table 18]

[0245] Representative examples of the present invention were tested for intracellular inhibition of NaV 1.7. The activity range is the % inhibition at 10 μM: "++++" (>95%), "+++" 95 - 70%, "++" (70 - 40%) or "+" (<40%). The results are shown below. [Table 19]

[0246] External block by test compound Once recording was started, the voltage protocol was run for 5 minutes at 30 - second intervals to obtain a stable baseline. To this, the same voltage protocol of 5 Hz stimulation was continued until the end of the experiment. The test compound was added during the 5 Hz stimulation procedure, ensuring a wait until the cells showed a stable rate of current decrease before the addition of the test 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 those current amplitudes were discarded.

[0247] Data analysis: External block Data was plotted using Patchmaster software (HEKA Electronics, Lambrecht, Germany), and the minimum current (peak inward current) during voltage steps up to -20 mV was plotted and analyzed as a function of time. To determine the % block caused by the externally applied test compound, the following was done. After the steady-state current decay rate was established during the 5 Hz stimulation protocol, the rate of decay was calculated by dividing the change in peak current amplitude by time. Using the average peak inward current amplitude (2 - 3 s) before addition of the compound, 0% block (I 0% block) was determined. To correct for the decay, subtract (rate of decay * 5 min) from I 0% block to obtain the corrected 0% block current. The average peak inward current during the last 2 - 3 s of the 5 min compound application time before washout is the non-blocked current (I non-blocked). Then, the following equation: fractional current block = 1 - I non-blocked / (I 0% block - rate of decay * 5 min) was used to calculate the % block.

[0248] Representative examples of the present invention were tested for extracellular inhibition of NaV 1.7. The activity range is % inhibition: "++++" (>95%), "+++" 95 - 70%, "++" (70 - 40%) or "+" (<40%). The results are shown below:

Table 20

[0249] Automated patch clamp: Cell culture During induction with tetracycline, NaV1.7 was expressed in HEK293 cells. The 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). The cells were grown and maintained at 37 °C in a humidified environment containing 10% CO2 in air. For subculture, the cells were detached from the culture flask using 0.05% trypsin-EDTA (Thermo Fisher Scientific, Waltham, MA) and harvested. To induce NaV1.7, the cells were induced with tetracycline (0.1 - 1 μg / mL, IBI Scientific, Peosta, IA) on the day before recording.

[0250] Before the experiment, the cells were washed with DPBS (VWR, Radnor, PA), digested with Detachin (VWR Radnor, PA), and then disrupted 10 times in CHO serum-free medium (VWR Radnor, PA) to resuspend the cells and break up cell aggregates. The cells were counted and the final concentration was set to 2 - 5,000,000 per mL.

[0251] Patch-clamp solutions and drugs The intracellular solution contained the following: 140 mM CsF, 1 mM / 5 mM EGTA / CsOH, 10 mM HEPES, 10 mM NaCl, adjusted to pH 7.3 with CsOH and to a weight osmolarity of 320 with sucrose. The external solution contained the following: 145 mM NaCl, 4 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10 mM HEPES, 10 mM glucose, adjusted to pH 7.4 with CsOH and to a weight osmolarity of 305 with sucrose. All 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 concentrations. 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 concentrations.

[0252] Automated patch - clamp protocol Automated patch - clamp was performed on a Qube 384 (Sophion Bioscience, Woburn MA) with a multi - hole Qchip at a temperature setting of 22 degrees. Whole - cell configurations were formed with default Qube seal and push - in parameters. Before starting the voltage protocol, the membrane potential was held at - 100 mV. The two voltage protocols were as follows. Step 1: Cells were held at - 100 mV with a depolarizing pulse to - 20 mV for 10 ms, with an interval set at 5 s. Currents were corrected by default leak subtraction from all pulses. The duration was set at 5 min. Step 2: Cells were held at - 100 mV with a depolarizing pulse to - 20 mV for 10 ms. The frequency was 5 Hz. Currents were corrected by leak subtraction calculated prior to Step 2. The duration was set at 4 min.

[0253] Internal blockade by test compound After step 2, the Qchip was removed from the recording chamber. The internal solution was exchanged with a solution containing the test compound. After the replacement in the recording chamber, the Qchip was held at -100 mV without pulses. The total solution exchange time was 8 minutes. After the internal solution exchange, the cells were recorded and step 2 was repeated for 10 minutes.

[0254] Data analysis was performed using a Sophion Analyzer. Cells were filtered with a minimum seal resistance of 50 MΩ and a minimum starting current of 5 nA. The decrease in current was corrected with control cells (without drug). The rest was calculated by averaging the last 3 points at the end of the experiment. The baseline was calculated as the average of the last 3 points of step 2. The IC 50 curve was plotted using a DR-plot / Hill function (dose-response plot with Hill fit). Data analysis was performed using a Sophion Analyzer.

[0255] A representative example of the present invention was tested for intracellular inhibition of NaV 1.7 in an automated patch-clamp assay. The activity range was recorded as IC 50 : “++++” (<1 μM), “+++” (1 - 3 μM), “++” (3 - 10 μM) or “+” (10 - 30 μM). The results are shown in Table M.

Table 21

[0256] External blockade by the test compound After step 2, the external solution was changed to a solution containing the test compound. The Qchip was held at -100 mV without pulses. The total solution exchange time was 8 minutes. After the external solution exchange, the cells were recorded for 10 minutes using the same procedure as in step 2.

[0257] Data analysis was performed using a Sophion Analyzer. The data was corrected with control cells (without drug). The IC 50 data was plotted using a DR-plot / Hill function (dose-response plot with Hill fit).

[0258] A representative example of the present invention was tested for extracellular inhibition of NaV 1.7 in an automated patch-clamp assay. The activity range is reported as IC 50 : "++++" (<10 μM), "+++" (10 - 30 μM), "++" (30 - 100 μM) or "+" (>100 μM). The results are shown in Table N. [Table 22]

[0259] Example 4 - Membrane Permeability The PAMPA assay (pION, Inc., Woburn MA) was used to determine the ability of the compounds of the present invention to pass through an artificial lipid membrane by passive diffusion. The test compound was dissolved in DMSO (10 mM) and diluted 200-fold in buffer (pION Inc., pH 7.4) to obtain a 50 μM stock solution. Buffer (150 μL) was added to a UV blank plate, and the stock solution (150 μL) was transferred to a UV reference plate. The blank and reference spectra were read using a spectrophotometer. The stock solution (200 μL) was added to the donor plate of a PAMPA sandwich plate, and a receptor plate coated with GIT lipid (pION Inc, 5 μL) was placed on top. Buffer (200 μL) was added to the receptor plate, and the PAMPA sandwich plate was incubated for 4 hours. An aliquot (150 μL) from the receptor plate was added to a UV plate and read as the receptor spectrum. An aliquot (150 μL) of the donor solution was added to a UV analysis plate and read as the donor spectrum. The permeability coefficient of the test compound was calculated using PAMPA Explorer TM software (version 3.5.0.4) based on the AUC of the reference plate, donor plate, and receptor plate.

[0260] PAMPA permeability results of representative compounds (10 -6 cm / s) are "+" (<0.1 10 -6 cm / s). "++" (0.1 - 2.0 10 -6cm / s), "+++" (2.0 to 10.0 10 -6 cm / s) or "++++" (> 10.0 10 -6 cm / s) and reported as (Table O).

Table 23

[0261] The patents and scientific documents referred to in this specification establish the knowledge available to those skilled 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, papers and scientific documents cited herein are incorporated herein by reference

[0262] The present invention has been particularly shown and described with respect 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 included in the appended claims. It is also understood that none of the embodiments described herein are mutually exclusive and that they may be combined in various ways without departing from the scope of the invention as included in the appended claims Examples of aspects of the present invention include the following. Item 1 Formula (I)

Chemical formula

Chem.

Chem.

Table A-1-1

Table A-1-2

Table A-1-3

Table A-1-4

Table A-1-5

Table A-1-6

Table A-1-7

Table A-1-8

Table A-1-9

Table A-1-10

Table A-1-11

Table A-1-12

Table A-1-13

Table A-1-14

Table A-1-15

Claims

1. Formula (I) 【Chemical 1】 (wherein: Y - is a pharmaceutically acceptable anion; R F and R G together with the N to which they are attached form a pyridinium ring substituted with one or more substituents, at least one of which substituents is a substituted or unsubstituted C + -C 3 -cycloalkyl, a substituted or unsubstituted 3- to 15-membered heterocyclyl, a substituted or unsubstituted phenyl, an alkoxy or CO 6 selected from the group consisting of R 2 R 2A where R 2A is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl; R A and R B are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, nitrile, OR I , NR J R K , NR L C(O)R M , CO 2 R T , C(O)R U and C(O)NR V R W selected from; R C is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, nitrile, OR I , NR J R K , NR L C(O)R M , CO 2 R T , C(O)R U and C(O)NR V R W selected from; or R Band vicinal R C together with the carbon atoms to which they are attached form a substituted or unsubstituted 3- to 7-membered cycloalkyl or a substituted or unsubstituted aryl; R I R J R K R L R M R T R U R V and R W each independently is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; X 1 is -NR Z C(O)-; R Z is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R D and R E together with the carbon to which they are attached form C 3 -C6 cycloalkyl) A compound represented by.

2. Y - is iodide, bromide or chloride, The compound according to claim 1.

3. X 1 is -NHC(O)-, The compound according to claim 1 or 2.

4. R A and R B each is C 1-4 alkyl, The compound according to any one of claims 1 to 3.

5. R A and R B each is CH 3 and R C is H, CH 3, a compound according to any one of claims 1 to 3, selected from the group consisting of halogen, nitrile, methoxy and ethoxy.

6. together to form R F and R G the pyridinium ring formed by is substituted or unsubstituted C 3 -C 6 cycloalkyl or CO 2 R 2A substituted, where R 2A is selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, a compound according to any one of claims 1 to 5.

7. as follows: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 (wherein: Y- is a pharmaceutically acceptable anion) a compound selected from those of.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. Formulated for oral, intravenous, intramuscular, rectal, dermal, subcutaneous, topical, transdermal, sublingual, nasal, inhaled, vaginal, intrathecal, epidural or intraocular administration, the composition according to claim 8.

10. A pharmaceutical composition according to claim 8 or 9 for use in a method of treating pain, cough, itching or a neuroinflammatory disorder in a patient, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 7 or a composition according to any one of claims 8 to 9.

11. The pharmaceutical composition according to claim 10, wherein the pain is selected from the group consisting of neck and back pain, low back pain, cancer pain, gynecological and childbirth pain, fibromyalgia, arthritis, rheumatoid arthritis, osteoarthritis, rheumatic pain, orthopedic pain, acute postherpetic neuralgia and other neuropathic pain (such as peripheral neuropathy), sickle cell disease, vulvodynia, perianal pain, irritable bowel disease, irritable bowel syndrome, inflammatory bowel disease, oral mucositis, esophagitis, interstitial cystitis, urethritis and other urological pain, toothache, headache, trigeminal trophic disorder syndrome, erythromelalgia, abdominal wall pain, chronic abdominal wall pain, allergic rhinitis, myalgia, rectal pain, levator ani syndrome, transient rectal pain, hemorrhoid pain, stomach pain, skin ulcer, gastric ulcer, burn pain, eye allergy, conjunctivitis (such as allergic conjunctivitis), eye redness, dry eye, dry eye syndrome (chronic eye pain), complex regional pain syndrome, postoperative eye pain, postoperative pain, acute postoperative pain, and pain due to treatment (i.e., injection, abscess drainage, surgery, dental treatment, eye treatment, eye allergy, conjunctivitis (such as allergic conjunctivitis), eye redness, dry eye, arthroscopy and use of other medical devices, cosmetic surgery, dermatological treatment, fracture sclerosis, biopsy, etc.).

12. The pharmaceutical composition according to claim 10, wherein the cough is selected from the group consisting of asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonary fibrosis, post-viral cough, post-infection cough, chronic idiopathic cough, and cough in patients with lung cancer.

13. The pharmaceutical composition according to claim 10, wherein the itching is selected from the group consisting of 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 itching, hemorrhoid itching, and itching due to cancer.

14. The pharmaceutical composition according to claim 10, wherein the neurological inflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine, hives, sunburn, pancreatitis, chronic rhinosinusitis, traumatic brain injury, polymicrobial sepsis, tendon disorder, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, irritants, contaminants, inhalation of chemical warfare agents, and atopic dermatitis.

15. The pharmaceutical composition according to claim 10, wherein the compound represented by formula (I) is used in combination with one or more exogenous macroporous receptor agonists.

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