Charged ion channel blockers and methods of use thereof

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds, compositions, methods and agents of the present invention may be effectively used to treat pruritus and other skin conditions.

Description

[0001] This application is a divisional application of application number 202180019764.3 filed on March 10, 2021, and the invention name is “Charged ion channel blockers and methods of use thereof”.

[0002] Related Applications

[0003] This application is a continuation-in-part of U.S. application serial number 16 / 815,426 filed on March 11, 2020. The entire contents of the above patent application are hereby incorporated by reference in their entirety. Technical Field

[0004] The present invention generally relates to quaternary ammonium compounds, pharmaceutical compositions and methods useful as selective inhibitors of pain, cough and itch sensing neurons (nociceptors, cough receptors and itch receptors) and for the treatment of neurogenic inflammation. Background Art

[0005] The invention features compounds, compositions and methods for selectively inhibiting sensory neurons (nociceptive neurons, cough receptor neurons and itch receptor neurons), and therapies for treating neurogenic inflammation by targeting nociceptors with small molecule drugs while minimizing effects on non-nociceptive neurons or other types of cells. According to the methods of the invention, small cationic drug molecules enter the intracellular compartment of sensory neurons through macroporous receptors / ion channels that are present in pain-neurons, cough receptor neurons and itch receptor neurons, but to a lesser extent or not at all in other types of neurons or other types of tissues.

[0006] Local anesthetics, such as lidocaine and articaine, work by inhibiting voltage-dependent sodium channels on neurons. These anesthetics can inhibit sodium ion channels, thereby affecting the excitability of all neurons, not just pain neurons (nociceptive neurons). Therefore, although the purpose of local or regional anesthesia is to prevent pain by blocking the signals transmitted by nociceptive neurons, the use of local anesthetics can also produce unwanted or harmful effects, such as general numbness caused by blocking low threshold pressure and touch sensory neurons, movement disorders and / or paralysis caused by blocking motor axes, and other complications caused by blocking autonomic nerve fibers. Local anesthetics are relatively hydrophobic molecules that diffuse through the cell membrane into the blocking points on the sodium channels. Charged derivatives of these compounds are cell membrane impermeable and have no effect on the sodium channels of nerve cells when applied to the outer surface of the nerve membrane, but if introduced into the cell in some way, such as by diffusion from a micropipette used for whole-cell electrophysiological recording of isolated neurons, they can affect the blocking of sodium channels. Pain-, cough-, and itch-receptor neurons differ from other types of neurons (in most cases) in expressing TRPV1 receptors / channels, which are activated by painful heat or capsaicin (the spicy ingredient in chili peppers). Other types of channels are selectively expressed in various types of pain-, cough-, and itch-receptor neurons, including but not limited to TRPV2-4, TRPA1, TRPM8, ASIC, and P2X(2 / 3) channels. It is well known that some cationic small molecules, such as QX-314, are able to enter cells through activated large pore channels, such as TRPV1.

[0007] Neuropathic, inflammatory, and nociceptive pain differ in etiology, pathophysiology, diagnosis, and treatment. Nociceptive pain is produced by the activation of a specific high-threshold subset of peripheral sensory neurons, the nociceptive neurons, by intense or noxious stimuli. It is typically acute, self-limited, and serves to protect biological function by serving as a warning of potential or ongoing tissue damage. It is usually well localized. Examples of nociceptive pain include, but are not limited to, traumatic or surgical pain, labor pain, sprains, fractures, burns, masses, bruises, injections, dental procedures, skin biopsies, and obstructions.

[0008] Inflammatory pain is pain that occurs in the presence of tissue damage or inflammation, including postoperative pain (i.e., pain associated with acute perioperative pain caused by inflammation resulting from tissue trauma (e.g., surgical incision, dissection, burns) or direct nerve injury (e.g., nerve severance, stretching, or compression)), posttraumatic pain, arthritis (rheumatoid; or osteoarthritis (i.e., joint pain and stiffness caused by the gradual deterioration of joint cartilage; risk factors include aging, injury, and obesity; commonly affected joints include the hands, wrists, neck, knees, hips, and spine), pain associated with damage to joints, muscles, and tendons, such as axial low back pain (i.e., a generalized painful condition affecting the lower back; common causes include muscle strain, spinal fracture, bulging or ruptured disc, and arthritis), and severe nociceptive pain that may transform into inflammatory pain if there is associated tissue damage.

[0009] Neuropathic pain is a common, chronic, non-malignant pain condition that is the result of damage or malfunction of the peripheral or central nervous system without protective biological functions. It is estimated to affect more than 1.6 million people in the U.S. population. Neuropathic pain has many different etiologies, for example, due to trauma, surgery, herniated disks, spinal cord injuries, diabetes, herpes zoster infection (shingles), HIV / AIDS, advanced disease / cancer, amputation (including mastectomy), carpal tunnel syndrome, chronic alcohol use, exposure to radiation, and unintended side effects of neurotoxic therapeutic drugs, such as certain anti-HIV and chemotherapy drugs. Peripheral neuropathic pain is damage to the peripheral nerves due to injury, trauma, prolonged pressure, or inflammation that causes numbness and pain in the corresponding area of ​​the body.

[0010] Neuropathic pain is often described as a "burning," "electrical," "tingling," or "throbbing" sensation. It is often characterized by chronic dynamic allodynia (defined as pain evoked by movement stimuli that do not normally evoke a painful response, such as light touch) and hyperalgesia (defined as increased sensitivity to normally painful stimuli) and may persist for months or years until any damaged tissue has significantly healed.

[0011] Patients with cancer also experience pain, which is caused by a variety of reasons: inflammation, compression, invasion, and metastasis to bones or other tissues.

[0012] In some cases, pain occurs in the absence of noxious stimulation, tissue damage, or nervous system injury, known as functional pain, including but not limited to fibromyalgia, tension-type headaches, and irritable bowel disorder.

[0013] Migraine is a type of headache associated with activation of sensory fibers innervating the meninges.

[0014] Pruritus (itch) is a skin disorder that may be localized or systemic and may be associated with skin lesions (rash, atopic eczema, urticaria). Itch accompanies many conditions, including but not limited to stress, anxiety, ultraviolet radiation from the sun, metabolic and endocrine diseases (e.g., liver or kidney disease, hyperthyroidism), cancer (e.g., lymphoma), reactions to medications or foods, parasitic and fungal infections, allergic reactions, blood disorders (e.g., polycythemia vera), and skin diseases. Itch is mediated by a subset of small-diameter primary sensory neurons, the pruritoreceptors, which share many features of nociceptor neurons, including but not limited to the expression of TRPV1 channels, as well as other large-pore channels such as TRPV2-4, TRPA1, TRPM8, ASICs, and P2X(2 / 3). Certain itch mediators—such as eicosanoids, histamine, bradykinin, ATP, and various neurotrophins—function as endogenous anthocyanins. Topical capsaicin can inhibit histamine-induced itch. Therefore, itch receptor neurons, similar to nociceptive receptor neurons, are suitable targets for this approach to deliver ion channel blockers.

[0015] Cough is a defensive reflex designed to protect the airways from foreign bodies and help clear luminal debris. However, this reflex can become abnormal in some diseases, resulting in an ineffective, dry cough with the presence of an excessive cough or ectopic cough state. Excessive cough and ectopic cough states are often chronic, lasting for more than 3 months, and can manifest in many airway disease states, including asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), and lung cancer. In addition, an inappropriate cough reflex can manifest acutely and chronically following viral infections. Furthermore, chronic cough can be idiopathic with unknown etiology.

[0016] Neurogenic inflammation is a mode of inflammation mediated by the efferent (motor) function of sensory neurons. Proinflammatory mediator molecules released peripherally by pain neurons (nociceptive neurons) not only activate multiple inflammatory pathways in immune cells, but also act on the vascular system to change blood flow and capillary permeability.

[0017] Neurogenic inflammation is peripheral inflammation caused by tissue injury, autoimmune disease, infection, allergy, exposure to irritants in various tissues, and is believed to play an important role in the pathogenesis of many diseases (such as allergic inflammation, inflammatory bowel disease, interstitial cystitis, atopic dermatitis, asthma, conjunctivitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine, psoriasis, rhinitis, rosacea, sunburn, pancreatitis, chronic cough, chronic sinusitis, traumatic brain injury, multibacterial sepsis, tendonitis, chronic urticaria, rheumatism, acute lung injury, exposure to irritants, inhaled irritants, pollutants or chemical warfare agents). One way to reduce neurogenic inflammation is to block the excitability of nociceptive neurons, thereby preventing the activation of the peripheral terminals of nociceptive neurons and the release of pro-inflammatory chemicals.

[0018] Despite the diversity of approaches to treat pain, itch, and neurogenic inflammation, additional agents are needed. Summary of the invention

[0019] The present invention provides a compound of formula (I) which can be used to treat or prevent pain, itching, cough and neurogenic inflammation:

[0020]

[0021] in,

[0022] Y - is a pharmaceutically acceptable anion;

[0023] R A , R B , and R C are independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I 、CN、CF3、NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T ;C(O)R U and C(O)NR V R W ;

[0024] R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W Each of R is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; R J and R K or R V and R W or R Q and R R They may also form a substituted or unsubstituted 5-, 6-, 7- or 8-membered ring together with the nitrogen atom to which they are attached;

[0025] R A , R B and / or R C They can form fused bicyclic or tricyclic ring systems together with the benzene ring to which they are attached, such as naphthyl, indanyl, tetrahydronaphthyl, quinolyl, indolyl, etc.;

[0026] R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, cycloalkyl, aryl or heteroaryl, preferably hydrogen, methyl or ethyl;

[0027] n is 0, 1, 2, 3, 4 and 5;

[0028] or R1, R2, R3, R4, R5 and / or R6 together with the carbon atoms to which they are attached form a substituted or unsubstituted cycloalkyl (e.g., C3-C6 cycloalkyl) or a substituted or unsubstituted heterocyclyl (e.g., a 3- to 15-membered heterocyclyl ring);

[0029] R F and R G With N + together to form an optionally substituted heterocyclyl ring, the heterocyclyl ring except N +In addition, it may contain 0, one or more heteroatoms, including but not limited to heteroaryl rings; for example, R E , R F and R G Two of them and N + together to form a heterocyclyl ring, which, except for N + In addition, it has 0, one or more heteroatoms;

[0030] R H is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, for example, -CH2-cycloalkyl, -C2H4-cycloalkyl, substituted or unsubstituted -CH2-C 5- C 10 Aryl, substituted or unsubstituted -C2H4-C 5- C 10 Aryl, substituted or unsubstituted -CH2-C 5- C 10 Heteroaryl, substituted or unsubstituted -C2H4-C 5- C 10 Heteroaryl, -CH2 OC(O)R T 、-CH2CO2R T 、-CH2C(O)NR V R W 、-C2H4OCOR T 、-C2H4OR I or,

[0031] R F ,R G and R H With N + Together they form a substituted or unsubstituted heteroaryl ring (eg, pyridinyl or phenyl-pyridinyl) or a bridged heterocyclyl ring.

[0032] The present invention unexpectedly discovered that these compounds are additionally active in treating pruritus. These compounds have surprisingly high potency and excellent topical localization, making these compounds unexpectedly suitable for skin application. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1A , 1B and 1C show that representative compounds significantly reduced chloroquine-induced pruritus within 8 hours after topical application. DETAILED DESCRIPTION

[0034] The present invention provides a compound represented by the above-mentioned formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or combination thereof. The present invention also provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for example, a composition comprising an effective amount of formula (I), or a pharmaceutically acceptable compound thereof, and a pharmaceutically acceptable excipient. The composition of the present invention may further comprise a compound of the present invention and a bioactive agent. The composition may be formulated for oral, intravenous, intramuscular, rectal, skin, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural or ocular administration. However, a preferred composition may be formulated for topical or dermal administration.

[0035] The present invention also provides a method of treating itching, pruritus, psoriasis or atopic dermatitis in a patient, comprising administering to the patient a composition comprising a compound of formula (I).

[0036] As used herein, the terms "a" and "an" are intended to include one or more than one unless expressly stated otherwise.

[0037] "Biological activity" refers to a molecule, including a biomolecule, such as a nucleic acid, peptide, polypeptide, and protein, that exerts a biological, physical, or chemical effect or activity on a protein, enzyme, receptor, ligand, antigen, itself, or other molecule. For example, a "biologically active" molecule may have, for example, enzymatic activity, protein binding activity, or pharmacological activity.

[0038] Bioactive agents that can be used in the methods and kits described herein include, but are not limited to, TRPA1 receptor agonists, TRPV1-4 receptor agonists, ASIC agonists, TRPM8 agonists, P2X receptor agonists, NSAIDs, glucocorticoids, anesthetics, antiproliferative and immunomodulatory agents, antibodies or antibody fragments, antibiotics, polynucleotides, polypeptides, proteins, anticancer agents, growth factors, and vaccines.

[0039] The term "pruritus" is used here in the broadest sense to refer to all types of itching and tingling sensations, localized and generalized, acute intermittent and persistent. Pruritus may be idiopathic, allergic, metabolic, infectious, drug-induced, due to liver or kidney disease or cancer. "Pruritus" refers to severe itching.

[0040] "Inflammation" refers to any type of inflammation, such as inflammation caused by the immune system (immune-mediated inflammation) and the nervous system (neurogenic inflammation) and any inflammatory symptoms, including redness, heat, swelling, pain and / or loss of function. Skin inflammation is preferred.

[0041] "Neurogenic inflammation" refers to any type of inflammation mediated or contributed to by neurons (such as nociceptive neurons) or any other component of the central or peripheral nervous system. Cutaneous neurogenic inflammation is preferred.

[0042] The term "pain" as used herein is in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, such as somatic pain and visceral pain; inflammatory pain, functional pain, idiopathic pain, neuropathic pain, such as central pain and peripheral pain, migraine, and cancer pain. Skin pain is preferred.

[0043] The term "nociceptive pain" is used to include all pain caused by noxious stimuli that threaten or actually injure body tissue, including but not limited to wounds, abrasions, fractures, crush injuries, burns, etc. Pain receptors for tissue damage (nociceptors) are primarily located in the skin, musculoskeletal system or internal organs, preferably in the skin or epidermis.

[0044] The term "somatic pain" refers to pain arising from bones, joints, muscles, skin or connective tissue, preferably skin and tissues near the skin. This type of pain is usually well localized.

[0045] The term "visceral pain" is used herein to refer to pain arising from visceral organs, such as the respiratory tract, gastrointestinal tract and pancreas, urinary tract and reproductive organs. Visceral pain includes pain caused by tumors invading the capsule of an organ. Another type of visceral pain, usually caused by obstruction of a hollow viscus, is characterized by intermittent cramping and severe localized pain. Visceral pain may be associated with inflammation, such as cystitis or reflux esophagitis.

[0046] The term "inflammatory pain" includes pain associated with activated inflammation, which may be caused by trauma, surgery, infection, and autoimmune disease.

[0047] The term "neuropathic pain" is used herein to refer to pain resulting from abnormal processing of sensory input by the peripheral or central nervous system due to damage to these systems.

[0048] The term "procedural pain" refers to pain experienced during a medical, dental, or surgical procedure, where the procedure is usually planned or associated with an acute trauma.

[0049] "Patient" refers to any animal. In one embodiment, the patient is a human. Other animals that can be treated using the methods, compositions, and kits of the 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, camels), and companion animals (e.g., guinea pigs, mice, rats, lizards, snakes, dogs, cats, fish, hamsters, and birds).

[0050] Compounds useful in the present invention include, but are not limited to, the compounds described herein in any pharmaceutically acceptable form thereof, including isomers of the compounds described herein, such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers.

[0051] As used herein, the term "pharmaceutically acceptable anion" refers to the conjugate base of a pharmaceutically acceptable acid. Such acids are described in Stahl, PH and Wermuth, CG (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-bromobenzenesulfonic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, cyclohexyl acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, sulfuric acid, boric acid, citric acid, formic acid, fumaric acid, galactic acid, gentisic acid, D-glucoheptanoic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxopentanydroxypropanesulfonic acid, 2-hydroxypent ... Diacid, 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, palmitic 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 conjugate bases of any of the above acids.

[0052] The term "pharmaceutically acceptable salts" means salts which 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, and the like, and are commensurate with a reasonable benefit / risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately prepared by reacting a free base function with a suitable organic acid. Representative acid salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor ester, camphor sulfonate, citrate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethane sulfonate, isothiocyanate, lactobionate, lactic acid, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 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.

[0053] "D" is for deuterium.

[0054] As used herein, the term "alkyl" and the prefix "alkyl-" include straight chain groups, branched chain groups and cyclic groups, for example, cycloalkyl. Cyclic groups can be monocyclic or polycyclic, and preferably have 3 to 6 ring carbon atoms or 3 to 7 carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "C 1-* "Alkyl" refers to a branched, unbranched or cyclic hydrocarbon group having 1 to * carbon atoms, where * is an integer, for example, 2, 3, 4, 5, 6, 7, 8, 10, 12 or more. The alkyl group can be substituted or unsubstituted. Exemplary substituents also include alkoxy, aryloxy, mercapto, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoroalkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amino, ester, alkylcarboxyl , alkyloxycarbonyl, alkyloxycarbonyl, aryloxycarbonyl, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphonate, amide (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfoxide, sulfonate, sulfonamide, sulfonamide, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moiety. In certain aspects, the alkyl group is C1-C6 alkyl. C 1-6Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclobutyl, cyclopentyl and cyclohexyl. Other specific examples of substituted alkyl are moieties that can form homodimers or heterodimers, for example:

[0055]

[0056] An example of a substituted alkyl group is a heteroalkyl group. "Heteroalkyl" refers to branched and unbranched alkyl, cycloalkyl, alkenyl, or alkynyl groups having 1 to 7 or more carbon atoms and additional 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S and P. "C 1-7 "Heteroalkyl" refers to branched and unbranched alkyl, alkenyl, or alkynyl groups having 1 to 7 carbon atoms and additionally 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S and P. Heteroalkyl groups include, but are not limited to, tertiary amines, secondary amines, ethers, thioethers, amides, sulfamides, carbamates, thiocarbamates, hydrazones, imides, phosphodiesters, phosphoamides, sulfonamides, and disulfides. Heteroalkyl groups may optionally include monocyclic, bicyclic or tricyclic rings, wherein each ring preferably has three to six ring atoms. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include alkyl, alkoxy, aryloxy, mercapto, alkyl sulfur, arylsulfur, halide (F, Cl, Br or I), hydroxy, fluoroalkyl, perfluoroalkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amino, ester, alkylcarboxyl, alkoxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphonate, amide (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amino, imino, sulfhydryl, alkylsulfide, arylsulfide, sulfocarboxylate, sulfate, alkylsulfoxide, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, aryl, heterocyclyl, alkylaryl, or aromatic or heteroaromatic group. C 1-7 Examples of heteroalkyl groups include, but are not limited to, methoxymethyl and ethoxyethyl.

[0057] Alkenyl refers to a branched or unbranched hydrocarbon group containing one or more double bonds. 2-6"Alkenyl" or "C2-C6 alkenyl" refers to a branched or unbranched hydrocarbon group containing one or more double bonds and having 2 to 6 carbon atoms. The alkenyl group may optionally include a single ring or multiple rings, wherein each ring ideally has three to six ring atoms. The alkenyl group may be substituted or unsubstituted. Exemplary substituents include those described above for alkyl, specifically, including but not limited to alkoxy, aryloxy, mercapto, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, quaternary amine, alkylcarboxyl and carboxyl. C 2-6 Alkenyl groups include, but are not limited to, vinyl, allyl, 2-cyclopropyl-1-ethylene, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl and 2-methyl-2-propenyl.

[0058] Alkynyl refers to a branched or unbranched hydrocarbon group containing one or more triple bonds. 2-6 "Alkynyl" or "C2-C6 alkynyl" refers to a branched or unbranched hydrocarbon group containing one or more triple bonds and having 2 to 6 carbon atoms. The alkynyl group may optionally include a monocyclic, bicyclic or tricyclic ring, wherein each ring ideally has five to six ring atoms. The alkynyl group may be substituted or unsubstituted. Exemplary substituents include those described above for alkyl, specifically, including but not limited to alkyl, as well as alkoxy, aryloxy, thiol, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, quaternary amine, alkylcarboxyl and carboxyl. C 2-6 Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl.

[0059] "Heterocyclyl", "heterocycle" or "heterocycloalkyl" refers to a stable monocyclic or polycyclic (including bicyclic or tricyclic) heterocyclic ring, which may be saturated, partially unsaturated or unsaturated (including heteroaryl or aromatic), and consists of 2 or more carbon atoms and 1, 2, 3, 4 or more heteroatoms independently selected from N, O and S, including any bicyclic or polycyclic group, wherein any of the above-defined heterocycles is fused to a benzene ring, heteroaryl, cycloalkyl or heterocycloalkyl. In certain aspects, the heterocyclyl is a 3-15 membered ring system, a 3-12 membered ring system or a 3-9 membered ring system. "C2-6 heterocyclyl" refers to a stable 5-7 membered monocyclic or 7-14 membered bicyclic heterocyclic ring, which may be saturated, partially unsaturated or unsaturated (including heteroaryl or aromatic), consisting of 2-6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, including any bicyclic group, wherein any of the above heterocyclic rings is fused with a benzene ring, heteroaryl, cycloalkyl or heterocycloalkyl. The heterocyclyl or heteroaryl group may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxyl and carboxyl. The nitrogen and sulfur heteroatoms may be optionally oxidized. The heterocycle can be covalently linked via any heteroatom or carbon atom that results in a stable structure, for example, an imidazoline ring can be linked to a carbon atom position or a nitrogen atom of the ring. The nitrogen atom in the heterocycle can be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other.Heterocyclic rings include, but are not limited to, 1H indole, 2-pyrrolidinyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidinoyl, 4aH carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, oxazolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH carbazolyl, b-carbonyl, chromyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazolyl, dihydrofuran [2,3-b] tetrahydrofuran, furanyl, furazolidinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H indolazolyl, indolinyl, indolazolyl, indolizinyl, indolazolyl, indolizinyl, isobenzylifuranyl, isochromanyl, isoindolinyl, isoindolinyl, isoindolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl oxazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl piperidinyl, phenanthridinyl, phenanthrolinyl, phenanthrosazinyl, phenanthrazinyl, phenothiyl, phenothiazinyl, benzoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidyl, 4-piperidyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinoxazole, pyridinimidazole, pyridinthiazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, pyrrole, quinazolinyl, quinolinyl, 4H-quinazolinyl, quinoxaline 1,2,3-thiazolyl, 1,2,4-thiazolyl, 1,2,5-thiazolyl, 1,3,4-thiazolyl, thienyl, thiazolyl, thienyl, thiazolyl, thienyl, thiazolyl, thienyloxy, thienylimidazolyl, phenylthio, triazine, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, flavonyl, β-lactam, γ-lactam and δ-lactam. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridyl, pyrimidyl, triazine, furanyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, 1H indolazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, octanol, benzoxazolinyl, quinolyl and isoquinolyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridyl, quinolyl, pyrimidyl, triazine, furanyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and tetrazolyl. Preferred substituents include phenyl, methyl, ethyl, propyl, butyl, chlorine, bromine, fluorine and iodine.

[0060] "Aryl" refers to an aromatic group having a ring system consisting of carbon atoms with conjugated π electrons (e.g., phenyl). 12 Aryl" or "C6-C 10 "Aryl" is an aromatic radical having 6 to 12 carbon atoms or 6 to 10 carbon atoms, respectively. Aryl groups may optionally include monocyclic, bicyclic or tricyclic rings, wherein each ring desirably has five or six members. The ring system may be a fused ring (e.g., naphthyl) or a non-fused ring (biphenyl). Aryl groups may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, alkoxy, aryloxy, thiol, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxy, fluoroalkyl, perfluoroalkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amide, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyl, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylformyl, alkylthiocarbonyl, phosphate, phosphoryl, phosphonyl, amido (including alkylcarbonylamino, arylcarbonylamino and ureido), amino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfoxide, sulfonate, sulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, aryl, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.

[0061] "Aralkyl" refers to a substituted or unsubstituted alkyl group substituted with a substituted or unsubstituted aryl group (eg, including benzyl, phenethyl or 3,4-dichlorophenethyl). "Heteroaralkyl" refers to an unsubstituted or substituted alkyl group substituted with a heteroaryl group.

[0062] "Halide" or "halogen" refers to bromine, chlorine, iodine or fluorine.

[0063] "Fluoroalkyl" refers to an alkyl group substituted with one or more fluorine atoms, such as a perfluoroalkyl group. Other examples include trifluoromethyl, difluoromethyl, fluoromethyl, and heptafluoroethyl.

[0064] "Alkoxy" refers to a chemical substituent of the formula -OR, where R is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0065] "Alkylcarboxyl" refers to a chemical moiety of the formula -(R)-COOH, where R is selected from alkyl (e.g., C 1-7 Alkyl, C 2-7 Alkenyl, C 2-7 alkyl), heterocyclyl, aryl, heteroaryl, aralkyl, heterocycloalkyl or heteroalkyl, each of which may be optionally substituted.

[0066] "Charged group" refers to a moiety that acquires a proton and thereby becomes positively charged at physiological pH (eg, ammonium, guanidine, or amide) or a moiety that contains a net formal positive charge without protonation (eg, quaternary ammonium). Charged groups may be permanently or transiently charged.

[0067] "Therapeutically effective amount" or "effective amount" refers to an amount sufficient to produce the desired result, for example, to reduce or eliminate pain, cough, itching or neurogenic inflammation in a patient (e.g., a human) suffering from a certain condition, disease, or a disease caused in whole or in part by neurogenic inflammation (allergic inflammation, inflammatory bowel disease, interstitial cystitis, atopic dermatitis, asthma, conjunctivitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine, psoriasis, rhinitis, rosacea, sunburn, pancreatitis, chronic cough, chronic sinusitis, traumatic brain injury, multibacterial sepsis, tendonitis, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants or pollutants).

[0068] "Solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent.

[0069] Compounds of the present invention, including salts of compounds, can exist in unactivated forms and solvated forms, including hydrated forms and unhydrated forms. Generally speaking, solvated forms are equivalent to unsolvated forms and are included within the scope of the present invention. Non-limiting examples of hydrates include monohydrates, dihydrates, hemihydrates, etc. In some aspects, the compound is a hemihydrate. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0070] The compounds of the present invention may exist in a variety of crystalline or amorphous forms. In general, 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.

[0071] Compounds of formula (I) are preferred:

[0072]

[0073] in,

[0074] Y - is a pharmaceutically acceptable anion;

[0075] R A , R B , and R C are independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORI 、CN、CF3、NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T ;C(O)R U and C(O)NR V R W ;

[0076] R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W Each of R is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; R J and R K or R V and R W or R Q and R R They may also form a substituted or unsubstituted 5-, 6-, 7- or 8-membered ring together with the nitrogen atom to which they are attached;

[0077] R A , R B and / or R C They can form fused bicyclic or tricyclic ring systems together with the benzene ring to which they are attached, such as naphthyl, indanyl, tetrahydronaphthyl, quinolyl, indolyl, etc.;

[0078] Preferably, R A Selected from H, methyl, halogen (e.g., F, Cl or Br), CF3, CN, CO2R T , or OR I, more preferably selected from methyl, F, CF3 or CN, most preferably methyl.

[0079] Preferably, R B It is selected from H and methyl, most preferably methyl.

[0080] Preferably, R C Selected from H, methyl, halogen (e.g., F, Cl or Br), CF3, CN, CO2R T OR I , more preferably H or OR I , most preferably H.

[0081] R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C4 alkyl, cycloalkyl, C1-C4 heteroalkyl, aryl or heteroaryl, preferably hydrogen, methyl or ethyl;

[0082] n is 0, 1, 2, 3, 4 and 5;

[0083] Or R1, R2, R3, R4, R5 and / or R6, together with the carbon atoms to which they are attached, form a substituted or unsubstituted cycloalkyl (e.g., a C3-C6 cycloalkyl) or a substituted or unsubstituted heterocyclyl (e.g., a 3- to 15-membered heterocyclyl ring).

[0084] It will be appreciated by those of ordinary skill in the art that an optionally substituted alkenyl linker of 2 to 7 carbons is formed between ether oxygen and quaternary nitrogen. In preferred compounds, each R1, R2, R3, R4, R5 and / or R6 is hydrogen (e.g., forming a straight chain alkenyl, such as alkenyl, propyl, butenyl or pentenyl). In preferred compounds, R5 and R6 are each hydrogen. In other compounds, R1 and / or R2 are hydrogen. In other compounds, R3 and R4 are hydrogen. Alternatively, R1 is methyl or ethyl, and R2, R3, R4, R5 and R6 are hydrogen. Alternatively, R3 is methyl or ethyl, and R1, R2, R4, R5 and R6 are hydrogen.

[0085] R F and R G With N + together to form an optionally substituted heterocyclyl ring, the heterocyclyl ring except N + In addition, it contains 0, one or more heteroatoms. The ring has 5, 6, 7, 8 or 9 ring atoms, and 7 and 8-membered rings are preferred. Therefore, preferred heterocyclyl rings include:

[0086] It will be understood by those skilled in the art that the formula (I) contains N + -The ring includes: or

[0087] And, most preferably

[0088] The heterocyclyl ring may be optionally substituted, as described above. For example, R7 may be hydrogen or substituted or unsubstituted alkyl. Preferred substituents include alkyl, CF3, halogen, OH and OR I .

[0089] R H is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, for example, -CH2-cycloalkyl, -C2H4-cycloalkyl, substituted or unsubstituted -CH2-C 5- C 10 Aryl, substituted or unsubstituted -C2H4-C 5- C 10 Aryl, substituted or unsubstituted -CH2-C 5- C 10 Heteroaryl, substituted or unsubstituted -C2H4-C 5- C 10 Heteroaryl, -CH2 OC(O)R T 、-CH2CO2R T 、-CH2C(O)NR V R W 、-C2H4OCOR T 、-C2H4OR I or,

[0090] Preferably, R H RH is benzyl or substituted benzyl. Alternatively, RH is unsubstituted alkyl, alkenyl or alkynyl, such as C3, C4, C5, C6, C7 or C8 alkyl. Alkyl can be straight chain or branched chain alkyl. Examples of branched chain alkyl include sec-butyl. Cycloalkyl can be preferably 3 to 6 carbocyclic alkyl, preferably cyclopentyl or cyclohexyl.

[0091] Alternatively, R F ,R G and R H With N + Together they form a heteroaryl ring or a bridged heterocyclyl ring. Examples of heteroaryl rings include substituted or unsubstituted pyridyl (e.g., phenyl-pyridyl). Preferred examples of bridged heterocyclic rings include

[0092]

[0093] Preferred compounds for use in the compositions, kits and methods of the present invention include compounds of formula (II):

[0094]

[0095] in,

[0096] Y- is a pharmaceutically acceptable anion;

[0097] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, methyl, or ethyl

[0098] q is 0, 1, 2, 3, 4, or 5; and

[0099] n is 0, 1, 2, 3, 4 or 5.

[0100] Preferably, Y - is a halogen anion, a carboxylate, or a sulfonate. - It may 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 heterocyclic carboxylate.

[0101] In certain embodiments, Y- is selected from the group consisting of trifluoroacetate, sulfate, phosphate, acetate, fumarate, formate, carbonate, maleate, citrate, pyruvate, succinate, oxalate, sulfonate (e.g., methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, such as p-toluenesulfonate, benzenesulfonate, ethanesulfonate, camphorsulfonate, 2-mesitylenesulfonate, or naphthalenesulfonate, such as 2-naphthalenesulfonate), sodium bisulfate, sodium malonate, sodium octanoate, sodium ascorbate, sodium oleate, sodium nicotinate, sucrose The invention also includes but is not limited to sodium, sodium, sodium adipate, sodium formate, sodium glycolate, sodium L-lactate, sodium D-lactate, sodium aspartate, sodium malate, sodium L-tartrate, sodium D-tartrate, sodium stearate, sodium 2-furoate, sodium 3-furoate, sodium naphthalene dicarboxylate sulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), oxalyl (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isothiocyanate (2-hydroxyethyl sulfonate), D-mandelate, L-mandelate, propionate, tartrate, phthalate, hydrochloride, hydrobromide, and nitrate.

[0102] In one embodiment, Y - is a halogen anion. In a preferred embodiment, Y - The halogen anions are selected from bromide, chloride and iodide.

[0103] It should be understood that when q is 0, 1, 2 or 3, the compound of formula (II) contains N +-The rings are:

[0104]

[0105] or

[0106] Preferably, q is 3. In other preferred embodiments, q is 2. Alternatively, q is 0 or 1.

[0107] In Formula II, each of R1, R2, R3, R4, R5 and / or R6 can be hydrogen (e.g., to form a straight chain alkenyl group, e.g., ethenyl, propenyl, butenyl or pentenyl). In preferred compounds, each of R5 and R6 is hydrogen. In other compounds, R1 and / or R2 are hydrogen. In other compounds, R3 and R4 are hydrogen. Alternatively, R1 is methyl or ethyl, and R2, R3, R4, R5 and R6 are hydrogen. Alternatively, R3 is methyl or ethyl and R1, R2, R4, R5 and R6 are hydrogen.

[0108] For example, q is 0 and R1, R2, R3, R4, R5 and R6 are hydrogen; or

[0109] q is 0, and R1 is methyl, and R2, R3, R4, R5 and R6 are hydrogen; or

[0110] q is 0, and R3 is methyl, and R1, R2, R4, R5 and R6 are hydrogen; or

[0111] q is 1, and R1, R2, R3, R4, R5 and R6 are hydrogen; or

[0112] q is 1, and R1 is methyl, and R2, R3, R4, R5 and R6 are hydrogen; or

[0113] q is 1, and R3 is methyl, and R1, R2, R4, R5 and R6 are hydrogen; or

[0114] q is 2, and R1, R2, R3, R4, R5 and R6 are hydrogen; or

[0115] q is 2, and R1 is methyl, and R2, R3, R4, R5 and R6 are hydrogen; or

[0116] q is 2, and R3 is methyl, and R1, R2, R4, R5 and R6 are hydrogen; or

[0117] q is 3, and R1, R2, R3, R4, R5 and R6 are hydrogen; or

[0118] q is 3, and R1 is methyl, and R2, R3, R4, R5 and R6 are hydrogen; or

[0119] q is 3, and R3 is methyl, and R1, R2, R4, R5 and R6 are hydrogen. For example, n is 0, and R1, R2, R3, R4, R5 and R6 are hydrogen; or

[0120] n is 0, and R1 is methyl, and R2, R3, R4, R5 and R6 are hydrogen; or

[0121] n is 0, and R3 is methyl, and R1, R2, R4, R5 and R6 are hydrogen; or

[0122] n is 1, and R1, R2, R3, R4, R5 and R6 are hydrogen; or

[0123] n is 1, and R1 is methyl, and R2, R3, R4, R5 and R6 are hydrogen; or

[0124] n is 1, and R3 is methyl, and R1, R2, R4, R5 and R6 are hydrogen; or

[0125] n is 2, and R1, R2, R3, R4, R5 and R6 are hydrogen; or

[0126] n is 2, and R1 is methyl, and R2, R3, R4, R5 and R6 are hydrogen; or

[0127] n is 2, and R3 is methyl, and R1, R2, R4, R5 and R6 are hydrogen; or

[0128] n is 3, and R1, R2, R3, R4, R5 and R6 are hydrogen; or

[0129] n is 3, and R1 is methyl, and R2, R3, R4, R5 and R6 are hydrogen; or

[0130] n is 3, and R3 is methyl, and R1, R2, R4, R5 and R6 are hydrogen.

[0131] All the above preferred groups can be combined with any one, more than one or all of the other preferred groups. Preferred compounds are:

[0132]

[0133] Wherein, Y is a pharmaceutically acceptable anion, such as a bromide ion.

[0134] In other embodiments, the compound is not:

[0135]

[0136] Wherein, Y is a pharmaceutically acceptable anion, such as a bromide ion.

[0137] In still other aspects, the compound is selected from the following Table A, or a pharmaceutically acceptable salt thereof, wherein Y - It is a pharmaceutically acceptable anion.

[0138] Table A

[0139]

[0140]

[0141]

[0142] In other preferred aspects, the compound is selected from the following Table B, or a pharmaceutically acceptable salt thereof:

[0143] Table B

[0144]

[0145]

[0146]

[0147]

[0148] Other representative compounds of the present invention:

[0149]

[0150]

[0151] Among them, the representative Z structure is:

[0152]

[0153] The compositions of the invention wherein R is methyl or ethyl may include racemic mixtures, pure enantiomers, or an excess of one enantiomer over the other. For example, the composition may contain a compound having 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%.

[0154] The compounds of the present invention include all enantiomers defined as (R)- or (S)- according to absolute stereochemistry and their racemic and optically pure forms, as well as those described herein in any pharmaceutically acceptable form thereof, including enantiomers, salts, solvates, polymorphs, solvates, hydrates, anhydrous and other crystalline forms and combinations thereof. Likewise, all tautomeric forms are also intended to be included.

[0155] Preferably, the pharmaceutical composition comprises a substantially pure R isomeric form of the compound of the invention; alternatively, a pharmaceutical composition comprises a substantially pure S isomeric form of the compound of the invention; alternatively, a pharmaceutical composition comprises the compound of the invention in the form of an isomeric mixture, which may include an excess of the R enantiomer or an excess of the S enantiomer. It is particularly preferred that the pharmaceutical composition contains a substantially pure optical isomeric form of the compound of the invention. For the avoidance of doubt, the compound of the invention may be used in the form of a solvate if desired.

[0156] The compounds of formula (I) can be prepared using methods analogous to those described in the Examples and the following synthetic schemes:

[0157] Option A:

[0158]

[0159] Option B:

[0160]

[0161] Solution C:

[0162]

[0163] Solution D:

[0164]

[0165] Option E:

[0166]

[0167] Other bioactive agents and exogenous macropore channel agonists

[0168] As described above, the compounds of the invention or the compositions of the invention may be administered with a biologically active agent, for example, one or more other biologically active agents, including agents commonly used to treat neurogenic inflammation, which may be administered in combination with the compounds of the invention or the compositions 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 agents and immunomodulators, antibodies or antibody fragments, antibiotics, polynucleotides, polypeptides, proteins, anticancer agents, growth factors and vaccines.

[0169] TRPV1 agonists that can be used in the methods, kits and compositions of the present invention include, but are not limited to, any drug (e.g., a compound of the present invention) that can activate TRPV1 receptors on nociceptive neurons and allow entry of at least one voltage-gated ion channel inhibitor. Suitable TRPV1 agonists are capsaicin or another capsaicinoid, which are members of the vanillin family of molecules. Naturally occurring capsaicinoids are capsaicinoids themselves, dihydrocapsaicinoids, dedihydrocapsaicinoids, homodihydrocapsaicinoids, homocapsaicinoids, and nonanamide. Other suitable capsaicin and capsaicin analogs and derivatives suitable for use in the compositions and methods of the present invention include naturally occurring and synthetic capsaicin derivatives and analogs, including, for example, vanillins (e.g., N-vanillinyl-alkadienamide, N-vanillinyl-alkadienyl, and N-vanillinyl-cis-monounsaturated alkanamide), capsic acid, dihydrocapsic acid, nordihydrocapsic acid and other capsic acids, capsic esters, dihydrocapsic acid and other arosinic acid esters, capsic acid, resin ester toxins, tintoxins, zucassin, N-phenylmethylalkanamide capsaicin derivatives, avanafil, N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z octadecanoamide, N-oleyl homofragrance, trienols (e.g., cod liver oil), gingerol, pepper, citronella oil, guaiacol, eugenol, zinc ketone, newanil, NE-19550, NE-21610, and NE-28345. Other capsaicinoids, their structures, and methods for making them are described in U.S. Pat. Nos. 7,446,226 and 7,429,673, which are incorporated herein by reference.

[0170] Other suitable TRPV1 agonists include, but are not limited to, eugenol, Avanil (N-arachidonoyl amphetamine), Anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetic acid 13-acetic acid 20-pervanadate (PPAHV), Avanil (NE 19550), Oda (N-oleoyl dopamine), N-arachidonoyl dopamine (NADA), 6′-iodothiocytoxan (6′-IRTX), C18 N-acylethanolamines, lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine ​​knot (ICK) peptides (vanillinotoxins), piperine, MSK195 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide), JYL79 (4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea), hydroxy-α-trihydrate, 2-aminoethoxydiphenylborate, 10-sesame oil, oleyl gingerol, oleyl sesame oil and SU200 (N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea). Other TRPV1 agonists include: isopentocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethoxycaine, dibuvacaine (sinchocaine), dimethocaine (larocaine), eticaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprevacaine (orracaine), metabutocaine, pivacaine, procaine (novacaine), procaine, propoxycaine, lidocaine, ropivacaine, tetracaine (aminocaine), and tamoxifen.

[0171] Suitable TRPV2-4 agonists include, but are not limited to, 2-APB, cannabinol, diphenylboronic anhydride, insulin-like growth factor 1, lysophosphatidylcholine, lysophosphatidylinositol, probenecid, Δ9-tetrahydrocannabinol, vanillin, eugenol, cinnamaldehyde, camphor, carvacrol, thymol, citral, farnesyl diphosphate, tetrahydrocannabinol, sodium acetate, diphenylboronic anhydride, 6-tert-butyl-m-cresol, dihydrocavitin, borneol, (-)-menthol, GSK1016790A, 4α-PDH, 5,6-epoxyeicosatrienoic acid, 4α-PDD, dipyridographolide, citric acid, phorbol 12 tetradecanoate 13 acetate and RN1747.

[0172] Suitable TRPM8 agonists include, but are not limited to, menthol, eucalyptus, linalool, geraniol, hydroxycitronellal, WS-3, WS-23, Frescolat MGA, Frescolat ML, PMD 38, CPS125, Coolact P, M8 Ag, AITC, cryosim-3, and Coolant 10.

[0173] Suitable ASIC agonists include, but are not limited to, clofenac hydrochloride, GMQ hydrochloride, reticulin, the polyamine agmatine, lysophosphatidylcholine, arachidonic acid, and neuropeptide SF.

[0174] Other bioactive agents suitable for use in the methods, compositions and kits of the present invention include bioactive agents that can activate TRP1A receptors on nociceptive neurons or allergic neurons and allow entry of at least one voltage-gated ion channel inhibitor. Suitable TRP1A agonists include, but are not limited to, cinnamaldehyde, allyl isothiocyanate (mustard oil), diallyl disulfide, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy α-trimethoxybenzaldehyde, 2-aminoethoxydiphenyl borate, 4-hydroxynonanal, methyl paraben, and 3′-carbamoylbiphenyl-3-cyclohexylcarbamate (URB597).

[0175] P2X agonists used in the methods, compositions, and kits of the present invention include any agonist that can activate P2X receptors on nociceptors or allergic neurons and allow entry of at least one voltage-gated ion channel inhibitor. 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 ATP5′-O-(3-thiotriphosphate).

[0176] Other biologically active agents that can be used in combination with the compounds of the invention include NSAIDs, glucocorticoids, anesthetics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative and immunomodulatory agents, antibodies or antibody fragments, antibiotics, polynucleotides, polypeptides, a protein, an anticancer agent, a growth factor and vaccines.

[0177] Nonsteroidal anti-inflammatory drugs (NSAIDs) that can be administered to patients (e.g., humans) suffering from neurogenic inflammation in combination with the compositions of the present invention include, but are not limited to, acetylsalicylic acid, amoxicillin, benolide, benolide, choline magnesium salicylate, diflunisal, ethobenzamide, farisin, methyl salicylate, magnesium salicylate, salicylate salicylate, salicylamide, diclofenac, aceclofenac, acetylmethacin, alclofenac, bromfenac, etodolac, indomethacin, nabumetone, oxametacin, promethacin, sulindac, tolmetin, ibuprofen, amorolfen, benoxaprofen, carprofen, dexibuprofen, fenbufen, non- Nurofen, fluniprofen, flurbiprofen, ibuprofen, indolepropylamine, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, supprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, toluene acid, phenbutazone, amprolone, azaprotone, clofetonone, kebuzone, analgin, imidazole, mofebutone, oxyphenbutazone, benazoline, thiopyrazolone, piroxicam, deroxicam, lornoxicam, meloxicam, tenoxicam, and COX-2 inhibitors celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, and pharmaceutically acceptable salts thereof.

[0178] Glucocorticoids that can be administered to patients (e.g., humans) suffering from neurogenic inflammation in combination with the compositions of the present invention include, but are not limited to, hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone acetonide, beclomethasone, fludrocortisone acetate, deoxycortisone acetate, aldosterone, and pharmaceutically acceptable salts thereof.

[0179] Anesthetic agents that can be administered to a patient (eg, a human) suffering from neurogenic inflammation in combination with the compositions of the present invention include, but are not limited to, tramadol, hydrocodone, oxycodone, and pharmaceutically acceptable salts thereof.

[0180] Antiproliferative and immunomodulatory agents that can be administered to patients (e.g., humans) with neurogenic inflammation in combination with the compositions of the present invention include, but are not limited to, alkyl antineoplastic drugs, platinum drugs, antimetabolites, topoisomerase inhibitors, dihydrofolate reductase inhibitors, antitumor antibiotics, antimitotic drugs, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyl transferase 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, hormones, antihormones, photodynamic drugs, and tyrosine kinase inhibitors.

[0181] The above-mentioned biologically active agents may be administered before, simultaneously with, or after administration of the compositions of the present invention, using any formulation, dosage, or administration known in the art to have a therapeutic effect.

[0182] Composition preparation

[0183] The administration of the compounds of the present invention can be carried out by any suitable method that can lead to a reduction in the receptive pain sensation of the target area. The compounds of the present invention can be contained in any suitable carrier material in any appropriate amount, and are generally present in an amount of 1-99% by total weight of the total weight of the composition. The composition can be provided in a dosage form suitable for oral, parenteral administration (e.g., intravenous administration, intramuscular administration), rectal administration, dermal administration, subcutaneous administration, topical administration, transdermal administration, sublingual administration, nasal administration, vaginal administration, intrathecal administration, epidural administration or ocular administration, or administered by injection, inhalation or direct contact with the nasal or oral mucosa.

[0184] Therefore, the composition can be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels, including hydrogels, pastes, ointments, creams, plasters, wet agents, osmotic delivery devices, suppositories, enemas, injections, implants, sprays or aerosols. The composition can be prepared according to conventional pharmaceutical methods (e.g., see Remington: Pharmaceutical Science and Practice, 2013, 22nd edition, LVAllen, Pharmaceutical Publishing House, Philadelphia; and Encyclopedia of Pharmaceutical Technology, 4th edition, J edition. Swarbrick, 2013, China Resources Publishing House, New York).

[0185] Each compound can be formulated in a variety of ways known in the art. For example, the compounds of the invention and the bioactive agents defined herein can be formulated together or separately. Ideally, the compounds of the invention and the bioactive agents are formulated together for simultaneous or near-simultaneous administration. In another embodiment, two or more bioactive agents can be formulated together with the compounds of the invention or separately. Other embodiments include, but are not limited to, formulating two or more compounds of the invention together, wherein the compounds are formulated with or without one or more bioactive agents.

[0186] The reagents, which are formulated separately or separately, can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and powder, a suppository and a liquid in a medicine bottle, two topical creams, and the like. The kit may include optional components that facilitate administration of a unit dose to a patient, such as a medicine bottle for reconstitution of the powder form, a syringe for injection, a customized IV delivery system, an inhaler, and the like. In addition, the unit dose kit may contain instructions for preparation and administration of the composition.

[0187] The kit may be formulated as a unit dosage form for single use by a single patient, or may be formulated for multiple use by a specific patient (at a constant dose or the dose of a single compound may vary as the treatment progresses to vary potency); or, the kit may contain multiple doses suitable for multiple patients ("bulk packaging"). The components of the kit may be assembled in cartons, blister packs, bottles, tubes, and the like.

[0188] Topical preparations

[0189] The compositions of the present invention (alone or in combination with one or more biologically active agents described herein) may also be adapted for topical use, with a topical excipient containing from 0.0001% to 25% (w / w) or more of the active ingredient.

[0190] In preferred combinations, the active ingredients are preferably present at between 0.0001% and 10% (w / w) each, more preferably containing between 0.0005% and 4% (w / w) of the active agent. The topical formulation, including but not limited to a cream, gel or ointment, can be applied one to four times a day, or as needed. To perform the methods described herein, a topical excipient containing a composition of the invention or a combination therapy containing a composition of the invention is preferably applied to the site of inflammation in a patient. For example, a cream can be applied to the fingers of a patient suffering from pruritus, itching, psoriasis or atopic dermatitis.

[0191] 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 to allow the therapeutic agent to enter the skin. Such liposome formulations are described in U.S. Pat. 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 Application WO 96 / 40061. Examples of other suitable carriers are described in U.S. Pat. Nos. 4,877,805, 8,822,537, and EP Patent Publication No. 0586106A1. Suitable carriers of the present invention may also include mineral oil, petrolatum, polydecene, stearic acid, isopropyl myristate, polyoxyethylene stearate 40, stearyl alcohol, or vegetable oils.

[0192] The composition may also include a skin penetration enhancer, such as those described in "Transdermal Permeation Enhancers" (Editors: Smith EW and Maibach H I. CRC Press 1995). Exemplary skin penetration enhancers include alkyl (N, N-disubstituted aminoalkanoate) esters, such as dodecyl 2-(N, N-dimethylamino) propionate (DDAIP), which is described in U.S. Pat. Nos. 6,083,996 and 6,118,020, which are incorporated herein by reference; a water-dispersible acid polymer, such as a polyacrylic acid polymer, a carbomer (e.g., carbomer TM or Carbomer 940P TM , available from BF Goodrich Co., Akron, Ohio, polyacrylic acid copolymers (such as Pemulen TM or Polycarbophil from AHRobbins, Richmond, Virginia TM a polysaccharide gum, such as agar gum, alginate, carrageenan, gati gum, karaya gum, kadaya gum, rhamnose gum, xanthan gum, and galactomannan gums (e.g., guar gum, carob gum, and locust bean gum), as well as other gums known in the art (e.g., see Industrial Gums: Polysaccharides and Their Derivatives, Whistler RL, BeMiller JN (Eds.), 3rd ed. Academic Press (1992) and Davidson RL, Handbook of Water-Soluble Gums and Resins, McGraw Hill, Inc., NY (1980)); or a combination thereof.

[0193] Other suitable polymer skin penetration enhancers are cellulose derivatives, such as ethylcellulose, methylcellulose, hydroxypropylcellulose. In addition, if necessary, known transdermal penetration enhancers can also be added. Exemplary transdermal penetration enhancers are dimethyl sulfoxide (DMSO) and dimethylacetamide (DMA), 2-pyrrolidone, N, N-diethyl-meta-toluidine (DEET), 1-dodecylazacycloheptane-2-one (Azone TM , a registered trademark of Nelson Research Company), N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate and other enhancers such as dioxanalytes, cyclic ketones and their derivatives, etc.

[0194] Also illustrative is a group of biodegradable absorption enhancers which are alkyl N,N-2-(disubstituted amino)alkanoates, as described in U.S. Pat. No. 4,980,378 and U.S. Pat. No. 5,082,866, both of which are incorporated herein by reference, including: tetradecyl (N,N-dimethylamino)ethyl ester, dodecyl (N,N-dimethylamino)ethyl ester, octadecyl (N,N-dimethylamino)ethyl ester, octyl (N,N-dimethylamino)ethyl ester and dodecyl (N,N-diethylamino)ethyl ester.

[0195] Particularly preferred skin penetration enhancers include isopropyl myristate; isopropyl palmitate; dimethyl sulfoxide; decyl methyl sulfoxide; dimethylalanine amides of medium chain fatty acids; dodecyl 2-(N,N-dimethylamino)propionate or its salts, for example, its organic salts (e.g., hydrochloride, hydrobromide, sulfate, phosphate and nitrate addition salts) and inorganic salts (e.g., acetate, benzoate, salicylate, glycolate, succinate, nicotinate, tartrate, maleate, malate, pamoate, methanesulfonate, cyclohexanesulfonate, picrate, and lactic acid addition salts), as described in U.S. Pat. No. 6,118,020; and alkyl 2-(N,N-disubstituted amino)-alkanoic acid esters, as described in U.S. Pat. No. 4,980,378 and U.S. Pat. No. 5,082,866.

[0196] By weight, the content range of the skin penetration enhancer in the composition is 0.5% to 10% (w / w). The optimal range is 1.0% to 5% (w / w). In another embodiment, the skin penetration enhancer accounts for 0.5%-1%, 1%-2%, 2%-3%, 3%-4% or 4%-5% (w / w) of the composition.

[0197] The composition can be provided in any useful form. For example, the composition of the present invention can be formulated into a solution, emulsion (including microemulsion), suspension, cream, ointment, foam, lotion, gel, powder or other typical solid, semisolid or liquid composition (e.g., topical spray) for application to the skin or other tissues to which the composition of the present invention can be used. Such compositions may include other ingredients commonly used in such products, such as colorants, fragrances, thickeners (e.g., xanthan gum, fatty acids, fatty acid salts or esters, fatty alcohols, modified cellulose, modified mineral materials, Krisgel 100) TM, or synthetic polymers), antimicrobial agents, solvents, surfactants, detergents, gelling agents, antioxidants, fillers, dyes, viscosity control agents, preservatives, humectants, emollients (such as natural or synthetic oils, hydrocarbon oils, waxes or silicones), hydrating agents, chelating agents, retarders, solubilizing excipients, adjuvants, dispersants, skin penetration enhancers, plasticizers, preservatives, stabilizers, demulsifiers, wetting agents, sunscreens, emulsifiers, moisturizers, astringents, deodorants, and optionally include anesthetics, antipruritic actives, plant extracts, conditioning agents, darkening or whitening agents, shimmering agents, moisturizers, mica, minerals, polyphenols, silicones or their derivatives, sunscreens, vitamins, and botanicals.

[0198] The composition may also include other similar ingredients to provide additional benefits and improve the feel and / or appearance of the topical formulation. Specific categories of additives commonly used in these formulations include: isopropyl myristate, sorbic acid NF powder, polyethylene glycol, phosphatidylcholine (including mixtures of phosphatidylcholine such as phospholipid G), Krisgel 100 TM Distilled water, sodium hydroxide, decyl methyl sulfoxide (as a skin penetration enhancer), menthol crystals, lavender oil, butylated hydroxytoluene, ethyl diglycol reagent, and 95% ethanol (190 degrees).

[0199] Controlled Release Formulations

[0200] Each compound of the present invention can be prepared separately or can be formulated as controlled release (for example, sustained release or quantitative release) preparation together with one or more bioactive agents described herein, as described in U.S. Patent Application Publication No. 2003 / 0152637 and No. 2005 / 0025765, which are all incorporated herein by reference. For example, the compounds of the present invention can be prepared separately or can be formulated as capsules or tablets together with one or more bioactive agents described herein, and administered to patients.

[0201] Any pharmaceutically acceptable carrier or formulation suitable for topical application and / or for injection into the site to be treated (e.g., painful surgical incisions, wounds or joints) may be used as desired, which is capable of sustained release of the compounds of the invention, which may be used alone or in combination with one or more bioactive agents described herein, to eliminate or alleviate inflammatory responses over a long period of time. Controlled release formulations known in the art include special coated pellets, polymer formulations or matrices for surgical implantation, or as sustained release microparticles for implantation, insertion, infusion or injection, such as microspheres or microcapsules, wherein sustained release of the active drug is achieved by sustained or controlled diffusion from the matrix and / or selective degradation of the formulation coating or selective degradation of the polymer matrix. Other formulations or carriers for controlled, sustained or immediate delivery of the agent to a preferred local site of the patient include, for example, suspensions, emulsions, gels, liposomes and any other suitable known technology delivery carriers or formulations acceptable for topical use, transdermal subcutaneous or intramuscular administration.

[0202] A variety of biocompatible materials can be used as controlled release carriers to control the release of the compounds of the present invention (alone or in combination with one or more bioactive agents described herein). Any pharmaceutically acceptable biocompatible polymer known to those skilled in the art can be used. Preferably, the biocompatible controlled release material degrades in vivo within about one year, preferably within about 3 months, and more preferably within about two months. More preferably, the controlled release material will degrade significantly within one to three months, wherein at least 50% of the material degrades into non-toxic residues that are cleared by the body, and 100% of the compounds of the present invention are released within about two weeks, preferably within a period of about 2 days to about 7 days. Degradable controlled release materials are preferably degraded by hydrolysis, whether by surface erosion or volume erosion, so that not only sustained release can be achieved, but also a desired release rate can be provided. However, the pharmacokinetic release profiles of these preparations can be first order, zero order, biphasic or multiphasic to provide the desired reversible local anti-injury effect within the desired time period.

[0203] Suitable biocompatible polymers can be used as controlled release materials. The polymer material may include biocompatible, biodegradable polymers, and, in certain preferred embodiments, copolymers of lactic acid and glycolic acid are preferred. Preferred controlled release materials useful in the formulations of the present invention include polyanhydrides, polyesters, copolymers of lactic acid and glycolic acid (preferably wherein the weight ratio of lactic acid to glycolic acid does not exceed 4:1, i.e., 80% or less lactic acid to 20% or more glycolic acid (by weight) and polyorthogonal esters containing catalysts or degradation enhancing compounds, for example, containing at least 1% (by weight) of anhydride catalysts, such as maleic anhydride. Examples of polyesters include polylactic acid, polyglycolic acid, and polylactic-polyglycolic acid copolymers. Other useful polymers include protein polymers such as collagen, gelatin, fibrin and fibrinogen, and polysaccharides such as hyaluronic acid.

[0204] The polymer material can be prepared by any method known to those skilled in the art. For example, if the polymer material is composed of a copolymer of lactic acid and glycolic acid, the copolymer can be prepared by the method specified 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 method known to those skilled in the art. Other useful polymers include polylactic acid, polyglycerol ethers, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polyphosphates, polysaccharides, protein polymers, soluble derivatives of polysaccharides, soluble derivatives of protein polymers, polypeptides, polyesters, and polyorthoesters or mixtures or combinations thereof.

[0205] Pharmaceutically acceptable polyanhydrides useful in the present invention have anhydride bonds that are not resistant to water. The drug release rate can be controlled by the specific polyanhydride polymer used and its molecular weight. Polysaccharides can be poly-1,4-glucans, such as starch glycogen, straight-chain starch, amylopectin, and mixtures thereof. Biodegradable hydrophilic or hydrophobic polymers can be water-soluble derivatives of poly-1,4-glucans, including hydrolyzed amylopectin, derivatives of hydrolyzed amylopectin, such as hydroxyethyl starch (HES), hydroxyethyl straight-chain starch, dialdehyde starch, etc. The polyanhydride polymer can be branched or linear.

[0206] Examples of polymers useful in the present invention include (in addition to homopolymers and copolymers of polylactic acid and / or polyglycolic acid), poly[bis(p-carboxyphenoxy)propane anhydride] (PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides of oligounsaturated fatty acids, polyanhydride polymers prepared from amino acids modified to include additional carboxylic acids, aromatic polyanhydride compositions, and copolymers of polyanhydrides with other substances, such as polyanhydrides of terminal fatty acids, such as polyanhydrides polymerized from monomers of unsaturated fatty acids or dimers and / or trimers of unsaturated fatty acids. Polyanhydrides can be prepared according to the methods set forth in U.S. Pat. No. 4,757,128, which is incorporated herein by reference. Polyorthoester polymers can be prepared, for example, as described in U.S. Pat. No. 4,070,347, which is incorporated herein by reference. Polyphosphates can be prepared and used as described in U.S. Patents 6,008,318, 6,153,212, 5,952,451, 6,051,576, 6,103,255, 5,176,907, and 5,194,581, which are incorporated herein by reference in their entireties.

[0207] Protein polymers may also be used. The protein polymers and their soluble derivatives include gelled biodegradable synthetic polypeptides, elastin, alkylated collagen, alkylated elastin, and the like. 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 and other amino acids. Suggested amino acids include L-alanine, L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.

[0208] In other embodiments, the controlled release material, which actually serves as a carrier for the compounds of the invention (used alone or in combination with one or more biologically active agents described herein), may further include a bioadhesive polymer such as pectin (polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) or non-toxic lectins, or the polymer itself may be a bioadhesive, such as a polyanhydride or a polysaccharide, such as chitosan.

[0209] In some embodiments, the biodegradable polymer comprises a gel. One such useful polymer is a thermogelling polymer, such as a polyethylene oxide, polypropylene oxide (PEO-PPO) block copolymer, such as Pluronic® available from BASF Windott Corporation. TMF127. In this case, the local anesthetic can be injected via a syringe as a free-flowing liquid that quickly solidifies above 30°C (e.g., when injected into a patient). The gel system then releases a steady dose of the compound of the invention, alone or in combination with one or more of the bioactive agents described herein, at the site of administration.

[0210] Oral dosage form

[0211] Oral formulations include tablets containing the active ingredient mixed with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch, including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives, including microcrystalline cellulose, starch, including potato starch, cross-linked sodium carboxymethyl cellulose, sodium alginate or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinyl pyrrolidone or polyethylene glycol); and lubricating factors, lubricants, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, humectants, buffers, taste masking agents (eg, hydroxypropyl methylcellulose, hydroxypropyl cellulose), and the like.

[0212] As defined herein, one or more compounds of the present invention and one or more bioactive agents can be mixed together in tablets, capsules or other carriers, or can be separated into individual parts. In one embodiment, the compounds of the present invention are contained inside the tablet, and the bioactive agent is located outside the tablet, so that the bioactive agent part is continuously released before the compounds of the present invention are released.

[0213] Oral preparations can also be made into chewable tablets, hard gelatin capsules (where the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin)), or soft gelatin capsules (where the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil) in the form of provided. Powders, granules, and pills can be prepared in a conventional manner using the ingredients under the above tablets and capsules, for example, using a mixer, a fluidized bed apparatus or a spray drying device.

[0214] Formulations for oral administration in the buccal cavity may also be provided in the form of a mouthwash, mouth spray, mouth rinse, oral ointment or oral gel.

[0215] Dissolving or diffusion control release can be realized by the granular preparation of suitable coating coating tablet, capsule, granule or compound, or by compound being added to suitable matrix.Controlled release coating can comprise above-mentioned one or more coating materials, and / or, for example shellac, beeswax, ethanol wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, palmitostearin, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, pyrrolidone, polyethylene, polymethyl methacrylate, methyl methacrylate, 2-hydroxymethylacrylic acid, methacrylic acid hydrogel, 1,3-butylene glycol, ethylene glycol methacrylate and / or polyethylene glycol.In controlled release matrix formula, matrix material can also comprise for example hydrated methylcellulose, carnauba wax and stearyl alcohol, Carbopol 934, silicone resin, tristearin, methyl acrylate, methyl methacrylate, polyvinyl chloride, polyethylene and / or halogenated fluorocarbon.

[0216] Liquid forms in which the compounds and compositions of the invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions containing edible oils such as cottonseed, sesame, coconut or peanut oil, as well as tinctures and similar pharmaceutical carriers.

[0217] When generally administered to humans, the oral dosage of any compound of the combination of the present invention will depend on the properties of the compound and can be easily determined by those skilled in the art. Generally, the dosage is generally about 0.001 mg to 2000 mg per day, ideally about 1 mg to 1000 mg per day and more ideally about 5 mg to 500 mg per day. If necessary, the daily intake dosage is up to 200 mg.

[0218] As described herein, in combination therapy, each drug may be administered independently one to four times daily for one day to one year and possibly even continuously throughout the patient's life. In many cases, slow, long-term administration is required.

[0219] Parenteral preparations

[0220] Preparations 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 contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, antibacterial agents, suspending agents, thickeners, and solutes that make the preparation isotonic with the blood (or other relevant body fluids) of the intended recipient. Examples of excipients include, for example, water, alcohol, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for such preparations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection. Typically, the concentration of the compound in the liquid is from about 1 ng / ml to about 10 μg / ml, such as from about 10 ng / ml to about 1 μg / ml. The preparation can be present in unit dose or multi-dose sealed containers, for example, in ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, before use. Sterile powders, granules, and tablets can be used to prepare injection solutions or suspensions for immediate use.

[0221] Ophthalmic preparations

[0222] The compounds of the present invention can also be formulated with an ophthalmologically acceptable carrier at a sufficient concentration to deliver an effective amount of the active substance compound to the optic nerve of the eye. Preferably, the ophthalmic treatment solution contains one or more active compounds in a concentration range of about 0.0001% to about 5% (weight per unit volume), more preferably about 0.0005% to about 0.1% (weight per unit volume).

[0223] The ophthalmologically acceptable carrier does not cause significant irritation to the eye and does not abrogate the pharmacological activity and properties of the charged sodium channel blocker.

[0224] Ophthalmologically acceptable carriers are generally sterile, substantially free of foreign particles, and generally have a pH in the range of 5-8. Preferably, the pH is as close as possible to the pH of tear fluid (7.4). Ophthalmologically acceptable carriers include, for example, sterile isotonic solutions, such as isotonic sodium chloride or boric acid solutions. Such carriers are generally aqueous solutions containing sodium chloride or boric acid. Phosphate buffered saline (PBS) solutions are also useful.

[0225] Various preservatives can be used in ophthalmic preparations. Preferred preservatives include, but are not limited to, benzalkonium chloride potassium, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. Similarly, various preferred carriers can also be used in such ophthalmic preparations. These carriers include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, and hydroxyethyl cellulose.

[0226] Tonicity adjusters may be added as needed or convenient and include, but are not limited to, salts, particularly sodium chloride, potassium chloride, and the like, mannitol and glycerin, or any other suitable ophthalmologically acceptable tonicity adjuster.

[0227] Various buffers and methods for adjusting the pH value can be used, as long as the resulting preparation is ophthalmologically acceptable. Therefore, buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases can be used to adjust the pH value of these preparations as needed. Ocularly acceptable antioxidants may also be included. Antioxidants include, but are not limited to, sodium pyrosulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0228] Preparations for nasal administration or inhalation

[0229] The pharmaceutical composition of the present invention can be formulated for nasal or intranasal administration. When the carrier is solid, preparations suitable for nasal administration include coarse powders having a particle diameter, for example, in the range of about 20 to 500 microns, for rapid inhalation through the nasal passages. When the carrier is liquid, for example, as a nasal spray or nasal drops, one or more preparations can be mixed in an aqueous or oily solution and inhaled or sprayed into the nasal cavity through the nasal cavity.

[0230] For administration by inhalation, the active ingredient may conveniently be delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount of capsules and cartridges, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0231] The dry powder composition for local delivery can be delivered to the lungs by inhalation, using an inhaler or an inflator, for example, in the form of capsules and cartridges, for example, gelatin or blisters, for example, laminated aluminum foil. The powder mixture preparation generally comprises a powder mixture of the compound of the present invention for inhalation and a suitable powdered matrix (carrier / diluent / excipient material), such as a monosaccharide, disaccharide or polysaccharide (such as lactose or starch). Lactose is preferably used. In one embodiment, each capsule or cartridge may contain about 2ug to about 100mg of the compound of formula (I), which is optionally combined with another therapeutically active ingredient. In a preferred embodiment, each capsule or cartridge may contain about 10 micrograms to about 50 milligrams of the compound of formula (I), which is optionally combined with another therapeutically active ingredient. In another embodiment, each capsule or cartridge may contain about 20ug to about 10mg of the compound of formula (I), which is optionally combined with another therapeutically active ingredient. Alternatively, the compound of the present invention may be delivered without excipients.

[0232] Suitably, the package / medicament dispenser is selected from the group consisting of a reservoir dry powder inhaler (RDPI), a unit dose dry powder inhaler (eg a capsule or blister pack inhaler), a multi-dose dry powder inhaler (MDPI) and a metered dose inhaler (MDI).

[0233] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers or nebulizers can be formulated to contain an aqueous medium, ethanol, liquid ethanol or other agents suitable for dispersing, dissolving or prolonging the release of the active ingredient; a propellant as a solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid.

[0234] Compositions formulated as nasal or inhaled formulations may include one or more taste masking agents, such as flavoring agents, sweeteners and other solutions, such as sucrose, glucose, and lactose, carboxylic acids, menthol, amino acids or amino acid derivatives, such as arginine, lysine, and sodium glutamate, and / or synthetic flavor oils and flavors and / or natural oils, extracts of plants, leaves, flowers, fruits, etc. and combinations thereof. These may include cinnamon oil, wintergreen oil, peppermint oil, clover oil, bay oil, anise oil, eucalyptus oil, vanilla oil, citrus oils (such as lemon oil, orange oil, grape oil and grapefruit oil), fruit flavors (including apples, peaches, pears, strawberries, raspberries, cherries, plums, pineapples, apricots, etc.). Other sweeteners include sucrose, glucose, aspartame, acesulfame-K, sucralose and saccharin, organic acids (non-limiting examples include citric acid and aspartic acid). Such flavorants are present in an amount of about 0.05% to about 4% by weight, and may be present in lower or higher amounts depending upon factors affecting flavor effect, the solubility of the flavoring, the effect of the flavoring on the solubility or other physicochemical or pharmacokinetic properties of other formulation ingredients, or other factors.

[0235] instruct

[0236] The compounds, compositions, methods and kits of the invention can be used to treat pain, cough or pruritus associated with any of a variety of diseases, including trigeminal neurotrophic 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 and postherpetic neuralgia and other neuropathic pain (including peripheral neuropathy), sickle cell crisis, myalgia, vulvodynia, rectal pain, levator anus syndrome, rectal pain, perianal pain, hemorrhoidal pain, stomach pain, ulcers, inflammatory bowel disease, irritable bowel disease irritable syndrome, irritable bowel syndrome, oral mucositis, esophagitis, interstitial cystitis, urethritis and other urinary tract pain, toothache, burning pain, headache, eye irritation, conjunctivitis (such as allergic conjunctivitis), eye redness, dry eyes, dry eyes (chronic eye pain), complex regional pain syndrome, acute postoperative pain, postoperative pain, postoperative eye pain, and procedural pain (i.e. pain associated with injections, abscess drainage, surgery, dental surgery, ophthalmic surgery, eye irritation, conjunctivitis (such as allergic conjunctivitis)), eye redness, dry eyes, arthroscopy and other medical device use, cosmetic surgery, dermatologic surgery, fixation of fractures, biopsies, etc.).

[0237] Because a subset of nociceptive neurons mediates itch sensations, the compounds, compositions, methods and kits of the invention can also be used to treat itch in patients with conditions such as pruritus (including, but not limited to, brachioradial, chronic idiopathic, genital / anal, paresthesia and scalp itch), allergic dermatitis, atopic dermatitis, contact dermatitis, poison ivy, infections, parasites, insect bites, pregnancy, metabolic disorders, liver or kidney failure, drug reactions, allergic reactions, eczema, hand eczema, genital and anal itch, hemorrhoidal itch, and cancer.

[0238] Since a subset of nociceptive neurons can trigger an abnormal cough reflex, the compounds, compositions, methods and kits of the present invention can also be used to treat asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonary fibrosis, post-viral cough, post-infectious cough, chronic idiopathic cough and cough in patients with lung cancer.

[0239] The compounds, compositions, methods and kits of the present invention can also be used to treat neurogenic inflammation and neurogenic inflammatory diseases. Inflammation is a series of complex responses to noxious stimuli, resulting in local redness, swelling and pain. Inflammation can be innate or adaptive, the latter driven by antigens and mediated by immune cells (immune-mediated inflammation). Neurogenic inflammation originates from the efferent function of pain neurons (nociceptive neurons), in which neuropeptides and other chemicals that serve as proinflammatory 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 proinflammatory neuropeptides include substance P, neurokinin A and B (collectively referred to as tachykinins), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP).

[0240] The release of peripheral chemicals stimulates multiple inflammatory responses. First, the release of substance P can lead to increased capillary permeability, which allows plasma proteins to leak from the intravascular compartment into the extracellular space (plasma extravasation), resulting in edema. This can be detected as a wheal (a firm, raised swelling of the skin), which is one of three inflammatory responses - wheal, erythema, and flare, known as the Lewis triple reaction. Second, the release of calcitonin gene-related peptide causes vasodilation, resulting in increased blood flow. This can be detected as a flare, another component of the Lewis triple reaction.

[0241] Substance P has pro-immune effects on immune cells such as macrophages, T cells, mast cells, and dendritic cells via their neurokinin-1 (NK1) receptors. This effect has been documented in allergic rhinitis, gastritis, and colitis and represents the dividing line between neurogenic and immune-mediated inflammatory components. Substance P released by one nociceptive neuron may also act on NK1 receptors on adjacent nociceptive neurons, sensitizing or activating them, leading to spread of activation and afferent / efferent function. These efferent functions of nociceptive neurons can be triggered by: 1) direct activation of nociceptive neuron terminals by applying sufficient peripheral stimulation (e.g., pressure) to the nociceptive neuron terminals; 2) indirect antidromic activation of non-stimulated nociceptive neuron terminals through axonal reflexes, in which action potential input from one terminal of a nociceptive neuron, upon reaching a converging axon branch point in the periphery, causes the action potential to move downward from the branch point to the peripheral terminal of the non-stimulated terminal; and 3) activation caused by activity of the central terminals of nociceptive neurons in the central nervous system as they move toward the periphery (e.g., GABA-generated primary afferent depolarization of central terminals is sufficient to initiate an action potential that moves the "wrong way").

[0242] Genomic analysis of ILC2 cells in the lung revealed expression of receptors for several neuropeptides released by sensory neurons, including SP, CGRP, and VIP, providing an opportunity for nociceptive neurons to communicate directly with these cells. In particular, VIP was found to be expressed in NaV1.8+ nodose ganglion neurons, including pulmonary afferents in OVA-exposed mice. Stimulation of cultured nodose ganglion neurons with capsaicin or IL5 also released VIP, and VIP levels were elevated in the BALF of mice exposed to OVA compared with vehicle-challenged mice (Talbot et al., Neuron. 2015 July 15;87(2):341–354). These data suggest that VIP is released in the inflamed lung and can be blocked by silencing the neurons using charged sodium channel blockers of the invention. Furthermore, when CD4+ T cells cultured under TH2-biased conditions were exposed to recombinant mouse VIP, transcriptional levels of IL-13 and IL-5 were increased, suggesting that VIP facilitates transcription of these type II regulatory cytokines by TH2 cells.

[0243] Nociceptors, including Nav1.8+ / TRPV1+ nociceptors, have been shown to be integral to the immune response in psoriasis and contact dermatitis models (Riol-Blanco et al., Nature 2014 June 5; 510(7503): 157-161). In studies of imiquimod-induced psoriasis, pharmacological or genetic ablation of nociceptors resulted in dermal dendritic cells (DDCs) no longer producing IL-23. The lack of IL-23 significantly reduced the production of inflammatory cytokines by skin Th17 cells and also significantly reduced the influx of inflammatory cells into the skin. By confocal microscopy, 75% of DDCs were in direct contact with or close to sensory nerves. Pharmacological ablation of Nav1.8+ / TRPV1+ nociceptors also significantly reduced skin inflammation in the IL-12-driven DNFB model of contact dermatitis (Riol-Blanco et al., Nature 2014 June 5; 510(7503): 157-161).

[0244] Immune mediators released by immune cells can also activate nociceptive neurons. Mast cells are in close proximity to primary nociceptive neurons and contribute to the sensitization of nociceptive neurons in many cases. Injection of the secretagogue compound 48 / 80 can promote mast cell degranulation in the dura mater, leading to the excitation of meningeal nociceptors. Mast cell degranulation also contributes to the rapid onset of heat hyperalgesia induced by nerve growth factor. Macrophages promote the sensitization of nociceptive neurons by releasing several soluble mediators. After partial ligation of the sciatic nerve, the expression of the chemokine macrophage inflammatory protein-1α (MIP-1α) and its receptors CCR1 and CCR5 in macrophages and Schwann cells increases and contributes to the occurrence of neuropathic pain. Lymphocytes contribute to the sensitization of peripheral nociceptive neurons. After nerve injury, T cells infiltrate the sciatic nerve and dorsal root ganglia (DRG). In rodents lacking T cells, hyperalgesia and allodynia caused by nerve injury are significantly reduced or eliminated, and the immunosuppressant rapamycin alleviates neuropathic pain in rats, partly due to its effect on T cells. Among T cell subsets, type 1 and type 2 helper T cells (TH1 and TH2 cells) have different roles in neuropathic pain. TH1 cells promote neuropathic pain behavior by releasing proinflammatory cytokines (IL-2 and interferon-γ (IFN-γ)), while TH2 cells inhibit neuropathic pain behavior by releasing anti-inflammatory cytokines (IL-4, IL-10 and IL-13). The complement system also plays a role in inflammatory hyperalgesia and neuropathic pain. C5a is an anaphylatoxin and an important effector of the complement cascade. After binding to the C5aR1 receptor on neutrophils, it becomes an effective neutrophil attractant (Ren & Dubner, Nat. Med. 16: 1267-1276 (2010)).

[0245] Bacterial infection can directly activate nociceptive neurons, and pain caused by Staphylococcus aureus in mice does not require immune responses mediated by TLR2, MyD88, T cells, B cells, and neutrophils and monocytes (Chiu et al., Nature 501: 52-57 (2013)). Mechanical and thermal hyperalgesia in mice is associated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons through different mechanisms, in part through bacterial N-formyl peptides and the pore-forming toxin α-hemolysin. Specific ablation of Nav1.8 lineage neurons, including nociceptive neurons, abolished pain during bacterial infection but simultaneously increased local immune infiltration and lymphadenopathy in draining lymph nodes. Therefore, bacterial pathogens produce pain by directly activating sensory neurons that regulate inflammation, an unexpected role for the nervous system in host-pathogen interactions. Data from Talbot et al. (Neuron. 2015 July 15; 87(2): 341–354) also demonstrated that nociceptive neurons are activated during exposure to allergens in sensitized animals.

[0246] In certain diseases, neurogenic inflammation results in peripheral inflammation caused by tissue injury, autoimmune disease, infection, and exposure to soft tissue, skin, respiratory system, joints, genitourinary and gastrointestinal tracts, liver, and brain. Neurogenic inflammatory diseases 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, rosacea, sunburn, pancreatitis, chronic cough, chronic sinusitis, traumatic brain injury, polymicrobial sepsis, tendinopathy, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhaled irritants or pollutants, as described herein.

[0247] Assessment of pruritus, pain, cough, and neurogenic inflammation

[0248] In order to measure the efficacy of the compounds of the invention, compositions, methods and kits of the invention in treating pain associated with musculoskeletal, immune inflammation and neuropathy, a measurement index table can be used. Useful indexes include visual analog scales (VAS), Likert scales, categorical pain scales, descriptors, Lequesne index, WOMAC index, and AUSCAN index, each of which is well known in the art. These indices can be used to measure pain, pruritus, function, stiffness or other variables.

[0249] Visual analog scale (VAS) provides a one-dimensional quantitative measurement method. VAS is usually expressed using distance, such as a picture of a line with hash marks drawn at regular distance intervals (e.g., ten 1-cm intervals). For example, the patient can be asked to rank the pain or itch sensation by selecting the point on the line that best matches the pain or itch sensation, where one end of the line corresponds to "no pain" (0 cm) or "no itch" and the other end of the line corresponds to "unbearable pain" or "unbearable itch" (10 cm). This method provides a simple and quick way to obtain quantitative information about how the patient experiences pain or itch. VAS scales and their uses are described in U.S. Patents 6,709,406 and 6,432,937.

[0250] The Likert scale also provides a one-dimensional quantitative measurement method. Typically, the Likert scale has discrete integer values ​​ranging from a low value (e.g., 0, indicating no pain) to a high value (e.g., 7, indicating extreme pain). The pain patient is asked to select a number between the low and high values ​​to indicate the degree of pain. The Likert scale and its use are described in U.S. Patents 6,623,040 and 6,766,319.

[0251] The Lequesne Index and the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index assess pain, function, and stiffness of the knee and hip joints using self-administered questionnaires in patients with OA. The knee and hip are both included in the WOMAC, while there is a separate Lequesne questionnaire for the knee and hip. These questionnaires are very useful as they contain more information content compared to the VAS or Likert. The WOMAC Index and the Lequesne Index questionnaires have been extensively validated in osteoarthritis, including in the surgical setting (e.g., knee and hip replacements). There are no significant differences in their measurement characteristics.

[0252] The AUSCAN (Australian-Canadian Hand Arthritis) index uses a valid, reliable and responsive patient self-report questionnaire. In one instance, the questionnaire contains 15 questions in three dimensions (pain, 5 questions; stiffness, 1 question; physical function, 9 questions). The AUSCAN index can utilize Likert or VAS scales, etc.

[0253] Scales for pain measurement used in the methods, compositions and kits of the present invention include the Pain Description Scale (PDS), the Visual Analog Scale (VAS), the Verbal Description Scale (VDS), the Numeric Pain Intensity Scale (NPI), the Neuropathic Pain Scale (NPS), the Neuropathic Pain Symptom Inventory (NPSI), the Current Pain Inventory (PPI), the Geriatric Pain Scale (GPM), the McGill Pain Questionnaire (MPQ), the Average Pain Intensity (Descriptor Difference Scale), the Numeric Pain Scale (NPS) Global Assessment Score (GES), the Short Form McGill Pain Questionnaire, the Minnesota Multiphasic Personality Questionnaire, the Pain Profile and the Multidimensional Pain Questionnaire, the Children's Health Questionnaire, and the Children's Assessment Questionnaire.

[0254] Itch can be measured by subjective measures (VAS, Likert, descriptive scales). Another method is to measure traces, which are objective correlates of itch, using vibration sensors or motion-sensitive meters.

[0255] Cough can be measured using standard questionnaires such as the Leicester Cough Questionnaire as well as validated objective instruments such as the VitaloJAK.

[0256] Example

[0257] The following examples are intended to illustrate the present invention and should not be construed as limiting the present invention.

[0258] Example 1 - Synthesis of Compounds 1A' to 51A'

[0259] Definitions of Common Abbreviations

[0260] ACN Acetonitrile

[0261] AcOH Acetic acid

[0262] aq. Aqueous solution

[0263] BBr3 Boron tribromide

[0264] CDCl3 D3-Chloroform

[0265] δ Chemical shift (ppm)

[0266] DCM Dichloromethane

[0267] DIPEA Diisopropylethylamine

[0268] DMAP 4-dimethylaminopyridine

[0269] DMSO Dimethyl sulfoxide

[0270] ESI Electrospray ionization

[0271] Et2O Diethyl ether

[0272] EtOAc Ethyl acetate

[0273] h hour

[0274] HPLC High Performance Liquid Chromatography

[0275] K2CO3 Potassium carbonate

[0276] LAH Lithium Aluminum Hydride

[0277] MeOH Methanol

[0278] mHz Megahertz

[0279] MS

[0280] m / z mass to charge ratio

[0281] NaCNBH3 Sodium cyanoborohydride

[0282] Na2SO4 Sodium sulfate

[0283] NMR Nuclear Magnetic Resonance

[0284] Pet ether

[0285] RT Room temperature

[0286] TEA Triethylamine

[0287] THF Tetrahydrofuran

[0288] TLC Thin Layer Chromatography

[0289] UV

[0290] Synthesis of 1-Benzyl-1-(2-(2,6-dimethylphenoxy)ethyl)nitrogen-1-bromide

[0291]

[0292] Synthesis of 2-(2-bromoethoxy)-1,3-dimethylbenzene:

[0293] To a stirred solution of 2,6-dimethylphenol (0.50 g, 4.1 mmol) in acetonitrile (8.0 mL) was added potassium carbonate (1.7 g, 12.3 mmol) and 1,2-dibromoethane (3.85 g, 20.5 mmol). The resulting reaction mixture was stirred at 90°C for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 5% ethyl acetate in petroleum ether, observation: UV lamp). The reaction mixture was cooled to room temperature and concentrated under reduced pressure, diluted with water (100 mL) and extracted with dichloromethane (3X 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluted with petroleum ether) to give pure 2-(2-bromoethoxy)-1,3-dimethylbenzene (0.20 g) as a colorless liquid. 1 H NMR (400MHz, CDCl3) δppm 7.00-7.25(m,2H),6.91-6.95(m,1H),4.01-4.10(m,2H),3.65-3.68(m,2H),2.30(s,6H).

[0294] Synthetic intermediate 1-(2-(2,6-dimethylphenoxy)ethyl)hexamethyleneimine:

[0295] To a solution of 2-(2-bromoethoxy)-1,3-dimethylbenzene (200 mg, 0.87 mmol) in acetonitrile (3.0 mL) was added DIPEA (0.45 g, 3.5 mmol) and hexamethyleneimine (0.12 g, 1.2 mmol). The resulting reaction mixture was stirred at 90 °C for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 10% ethyl acetate in petroleum ether, observation: UV lamp). The reaction mixture was cooled to room temperature and concentrated under reduced pressure, diluted with water (20 mL) and extracted with dichloromethane (3X 20 mL). The combined organic phases were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-(2-(2,6-dimethylphenoxy)ethyl)hexamethyleneimine (210 mg). 1 H NMR (400MHz, CDCl3) δppm6.98-7.00(m,2H),6.88-6.92(m,1H),3.85-3.88(m ,2H),2.93-2.96(m,2H),2.75-2.77(m,4H),2.28(s,6H),1.59-1.68(m,8H).

[0296] Synthesis of 1-benzyl-1-(2-(2,6-dimethylphenoxy)ethyl) nitrogen-1-bromide:

[0297] To a solution of 1-(2-(2,6-dimethylphenoxy)ethyl)hexamethyleneimine (0.1 g, 0.4 mmol) in acetonitrile (1.5 mL) was added benzyl bromide (0.072 ml, 0.6 mmol) and the resulting reaction mixture was stirred in a sealed test tube at 90°C for 16 h and the progress of the reaction was monitored by TLC (mobile phase: 50% ethyl acetate in petroleum ether, observation: UV lamp). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude product, which was triturated with ethyl acetate (3X 5 ml) to give 1-benzyl-1-(2-(2,6-dimethylphenoxy)ethyl)azine-1-bromide (80.5 mg) as an off-white solid. MS (ESI): m / z 338.41 [M] + . 1 H NMR(400MHz,DMSO-d6)δppm 7.63-7.65(m,2H),7.49-7.57(m,3H),7.04-7.08(m,2H),6.96-6.98(m,1H),4.72(s,2 H),4.29(t,2H),3.52-3.69(m,6H),2.29(s,6H),1.88-1.92(m,4H),1.59-1.62(m,4H).

[0298] Examples 2-5 were prepared from intermediate 2-(2-bromoethoxy)-1,3-dimethylbenzene, the appropriate azacycloalkane and benzyl bromide in the manner described for the synthesis of compound 1A.

[0299]

[0300] Examples 6-13 were prepared from the intermediate 1-(2-(2,6-dimethylphenoxy)ethyl)hexamethyleneimine and the appropriate alkyl bromide in the manner described for the synthesis of compound 1A. All compounds were isolated by trituration or reverse phase HPLC purification.

[0301]

[0302]

[0303] Examples 14-16 were prepared from 2,6-dimethylphenol and the appropriate dibromoalkylene, heptamethine and benzyl bromide in the manner described for the synthesis of compound 1A.

[0304]

[0305] Examples 17-32 were prepared from appropriately substituted phenols, 1,2-dibromoethane, azacycloalkane and benzyl bromide in the manner described for the synthesis of compound 1A. All compounds were isolated by trituration or reverse phase HPLC purification.

[0306]

[0307]

[0308]

[0309]

[0310] Synthesis of 1-butyl-1-(2-(2-cyano-6-methylphenoxy)ethyl)azo-1-yl:

[0311]

[0312] Synthetic intermediate 2-(2-bromoethoxy)-3-methylbenzonitrile:

[0313] To a solution of 2-hydroxy-3-methylbenzonitrile (0.8 g, 6.0 mmol) and K2CO3 (1.66 g, 12.0 mmol) stirred in acetonitrile (10 mL) was added dibromoethane (2.7 mL, 30.0 mmol), the resulting reaction was heated at 80°C for 16 hours, and the progress of the reaction was monitored by TLC (mobile phase 10% ethyl acetate in petroleum ether, observation: UV lamp), and the crude reaction mixture was concentrated under reduced pressure to produce a residue, which was diluted with water (10 mL) and extracted with ethyl acetate (2X 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to produce a crude product, which was purified by silica gel chromatography (eluted with 10%-15% ethyl acetate in petroleum ether). The combined pure fractions were concentrated under reduced pressure to produce 2-(2-bromoethoxy)-3-methylbenzonitrile (1 g) as a light yellow gum. Mass (ESI): M / z=240.10[M+H]+1H NMR (400MHz, CDCl3) δppm: 7.44-7.40(m,2H),7.09(t,1H),4.43(t,2H),3.71(t,2H),2.36(s,3H).

[0314] Synthetic intermediate 2-(2-(azo-1-yl)ethoxy)-3-methylbenzonitrile:

[0315] A solution of 2-(2-bromoethoxy)-3-methylbenzonitrile (800 mg, 3.3 mmol) and N-DIPEA (1.8 mL, 10.078 mmol, 3 eq) stirred in acetonitrile (10 mL) was treated with azo (0.57 g, 5.0 mmol), and the resulting reaction was heated at 80°C for 16 hours, and the reaction progress was monitored by TLC (mobile phase 50% ethyl acetate in petroleum ether, observation: UV lamp). The resulting mixture was concentrated under reduced pressure to give a crude product, and the residue was diluted with water (40 mL) and extracted with EtOAc (2X50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (eluted with 50%-60% ethyl acetate in petroleum ether). The combined pure fractions were concentrated under reduced pressure to yield pure 2-(2-(azo-1-yl)ethoxy)-3-methylbenzonitrile (0.5 g) as a pale yellow oil. Mass (ESI): M / z = 273.29 [M+H] + 1H NMR (400 MHz, CDCl3) δ ppm: 7.42-7.37 (m, 2H), 7.03 (t, 1H), 4.18 (t, 2H), 2.96 (t, 2H), 2.68 (s, 4H), 2.31 (s, 3H), 1.59-1.54 (m, 10H).

[0316] Synthesis of 1-butyl-1-(2-(2-cyano-6-methylphenoxy)ethyl)azo-1-yl TFA salt:

[0317] To a solution of 2-(2-(azo-1-yl)ethoxy)-3-methylbenzonitrile (0.4 g, 1.5 mmol) stirred in acetonitrile (10 mL) was added 1-bromobutane (0.475 mL, 4.4 mmol) and the resulting reaction was stirred at 80°C for 16 hours and the progress of the reaction was monitored by TLC (mobile phase: 10% methanol in DCM; observation: UV lamp). The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by reverse phase HPLC (column: X-select CSH C18 (150X19) mm, 5μ; mobile phase A / B: 0.1% TFA (aq.) / 1:1 acetonitrile:MeOH; mobile phase: 18 mL / min). The collected pure fractions were freeze dried to give 1-butyl-1-(2-(2-cyano-6-methylphenoxy)ethyl)azo-1-yl trifluoroacetate (220 mg). Mass(ESI):M / z=329.28[M]+.1H NMR(400MHz,DMSO-d6)δppm:7.70-7.67(m,1H),7.64-7.62(m,1H),7.28(t,1H),4.40(t,2H),3.83(t,2H),3.62-3.42(m,6H),2.33(s,3H),1.91(br s,4H),1.71-1.62(m,8H),1.35-1.30(m,2H),0.92(t,3H).

[0318] 1-Benzyl-1-(2-(2,6-dimethylphenoxy)propyl)azo-1-yl bromide:

[0319]

[0320] Synthetic intermediate methyl 2-(2,6-dimethylphenoxy) propionate:

[0321] To a stirred solution of 2,6-dimethylphenol (7 g, 57.3 mmol) in acetonitrile (120 mL) was added K2CO3 (23.7 g, 171.8 mmol) and methyl 2-bromopropionate (9.6 mL, 85.9 mmol) and the resulting reaction was stirred at 80°C for 16 hours while monitoring the progress of the reaction using TLC (mobile phase: 20% ethyl acetate in petroleum ether, observation: UV lamp). The crude reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic extracts were washed with water (200 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to yield methyl 2-(2,6-dimethylphenoxy)propionate (9 g) as a yellow liquid. Mass(ESI):209.17m / z[M+H]+.1H NMR(400MHz,CDCl3)δppm 6.99(d,2H),6.93-6.89(m,1H),4.51(q,1H),3.77(s,3H),2.27(s,6H),1.52(d,3H).

[0322] Synthetic intermediate 2-(2,6-dimethylphenoxy)propan-1-ol:

[0323] To a cooled (0°C) solution of methyl 2-(2,6-dimethylphenoxy)propanoate (5 g, 24.0 mmol) in THF (100 mL) was added 1 M LAH in THF (48.016 mL, 48.0 mml) and the resulting reaction mixture was stirred at room temperature for 16 hours while monitoring the progress of the reaction using TLC (mobile phase: 20% ethyl acetate in petroleum ether, observation: UV lamp). The reaction mixture was cooled to 0°C, quenched with saturated sodium chloride solution (200 ml) and extracted with ethyl acetate (2 x 300 mL). The combined organic extracts were washed with water (300 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (eluted with 5%-10% ethyl acetate in petroleum ether). The combined pure fractions were concentrated under reduced pressure to give 2-(2,6-dimethylphenoxy)propan-1-ol (2.8 g, 64.7%) as a yellow liquid. 1H NMR (400MHz, CDCl3) δppm 7.01(d,2H),6.94-6.90(m,1H),4.26-4.22(m,1H),3.82-3.74(m,2H),2.29(s,6H),2.17-2.14(m,1H),1.17(d,3H).

[0324] Synthetic intermediate 2-(2,6-dimethylphenoxy)propyl methane sulfonate:

[0325] To a cooled (0°C) solution of 2-(2,6-dimethylphenoxy)propan-1-ol (1 g, 5.55 mmol) in DCM (10 mL) was added TEA (2.3 mL, 16.6 mmol) and methanesulfonyl chloride (0.6 mL, 8.3 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours while monitoring the progress of the reaction using TLC (mobile phase: 20% ethyl acetate in petroleum ether, observation: UV lamp). The reaction mixture was diluted with water (50 mL), extracted with DCM (2x100 mL), and the combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-(2,6-dimethylphenoxy)propyl methanesulfonyl ester (1.3 g) as a yellow liquid. 1H NMR (400MHz, CDCl3) δppm 7.01(d,2H),6.94-6.91(m,1H),4.36-4.32(m,3H),3.02(s,3H),2.27(s,6H),1.28(d,3H).

[0326] Synthetic intermediate 1-(2-(2,6-dimethylphenoxy)propyl)azo:

[0327] To a stirred solution of 2-(2,6-dimethylphenoxy)propyl methanesulfonyl ester (1.3 g, 5.0 mmol, 1.0) in ACN (15 mL) was added K2CO3 (2 g, 15.0 mmol) and azo (0.9 mL, 7.5 mmol) at room temperature and the reaction mixture was stirred at 80°C for 16 hours while monitoring the progress of the reaction using TLC (mobile phase: 20% ethyl acetate in petroleum ether, observation: UV lamp). The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2x200 mL). The combined organic extracts (200 mL) were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by flash chromatography on silica gel (eluted with 5%-10% ethyl acetate in petroleum ether). The combined pure fractions were concentrated under reduced pressure to give 1-(2-(2,6-dimethylphenoxy)propyl)azo (560 mg) as a colorless liquid. Mass(ESI):276.37m / z[M+H]+.1H NMR(400MHz, CDCl3)δppm 6.98(d,2H),6.89-6.86(m,1H),4.08-4.05(m,1H),2.87-2.83(m,1H),2.58-2.53(m,5H),2.27(s,6H),1.60-1.50(m,10H),1.27(d,3H).

[0328] Synthesis of 1-benzyl-1-(2-(2,6-dimethylphenoxy)propyl)azo-1-yl bromide:

[0329] To a stirred solution of 1-(2-(2,6-dimethylphenoxy)propyl)azo (500 mg, 1.8 mmol) in acetonitrile (10 mL) was added benzyl bromide (0.43 mL, 3.6 mmol) and the reaction mixture was stirred at 80 °C for 16 hours while monitoring the progress of the reaction using TLC (mobile phase: 10% methanol in DCM, observation: UV lamp). The reaction was concentrated under reduced pressure to give a crude product, which was triturated with ethyl acetate (50 mL) to give 1-benzyl-1-(2-(2,6-dimethylphenoxy)propyl)azo-1-yl bromide (546 mg) as an off-white solid. Mass(ESI):366.3m / z[M]+.1HNMR(400MHz,DMSO-d6)δppm7.67-7.65(m,2H),7.56-7.51(m,3H),7.05(d,2H),6.97-6.93(m,1H),4.97-4.93(m,1 H),4.81-4.70(m,2H),3.78-3.72(m,1H),3.65-3.50(m,4H),3.43-3.39 (m,1H),2.26(s,6H),2.03-1.90(m,4H),1.75-1.50(m,6H),0.98(d,3H).

[0330] Synthesis of 1-(2-(benzoyl)ethyl)-1-(2-(2,6-dimethylphenoxy)ethyl)azepine-1-yl:

[0331]

[0332] Synthetic intermediate 1-(2-(2,6-dimethylphenoxy)ethyl)-1-(2-hydroxyethyl)azepine-1-yl:

[0333] To 1-(2-(2,6-dimethylphenoxy)ethyl)hexamethyleneimine (0.718 g, 2.90 mmol) was added neat 2-bromoethan-1-ol (0.544 g, 4.35 mmol) and the resulting reaction mixture was heated at 90°C in a sealed test tube for 16 hours. The progress of the reaction mixture was monitored using TLC (mobile phase: 10% methanol in DCM, observation: UV lamp). The reaction mixture was diluted with DCM (70 ml) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (diluted with 7% methanol in DCM). The combined fractions were concentrated under reduced pressure to give 1-(2-(2,6-dimethylphenoxy)ethyl)-1-(2-hydroxyethyl)azine-1-bromide (0.450 g) as an off-white solid. MS(ESI):m / z 292.25[M]+.1H NMR(400MHz,DMSO-d6)δppm 7.06-7.04(m,2H),6.97-6.94(m,1H),5.36(t,1H),4.16-4.11(m,2H),3.9 2-3.87(m,4H),3.69-3.65(m,4H),3.62-3.56(m,2H),2.27(s,6H),1.90(br s,4H),1.62(br s,4H).

[0334] Synthesis of 1-(2-(2,6-dimethylphenoxy)ethyl)-1-(2-((4-fluorobenzoyl)oxy)ethyl)azepine-1-yl:

[0335] Benzoyl chloride (377 mg, 2.69 mmol) was added to a solution of 1-(2-(2,6-dimethylphenoxy)ethyl)-1-(2-hydroxyethyl)azepine (200 mg, 0.54 mmol) and DMAP (5.25 mg, 0.04 mmol) in pyridine (2 mL) at 0°C. The resulting reaction mixture was stirred at room temperature for 16 h, and the progress of the reaction mixture was monitored by TLC (mobile phase: 10% methanol in DCM, observation: UV lamp). The precipitated solid was filtered, washed with ethyl acetate (50 mL) and dried under high pressure to give a crude product, which was purified by HPLC (chromatographic column: LUNA C18 (250*21.2) mm, 5u; mobile phase A / B: 0.1% TFA(Aq) / acetonitrile). The pure fractions were freeze dried to yield 1-(2-(2,6-dimethylphenoxy)ethyl)-1-(2-((4-fluorobenzoyl)oxy)ethyl)azepan-1-aspartate TFA salt (91 mg). MS (ESI): M / z=396.37[M]+.1H NMR (400MHz, DMSO-d6)δppm8.00-7.98(m,2H),7.71-7.68(m,1H),7.54(t,2H),7.04(d,2H),6.97-6.94(m,1H),4.79(br s,2H),4.20(t,2H),4.01-4.00(m,4H),3.74-3.72(m,4H),2.25(s,6H),1.95(br s,4H),1.65(br s,4H).

[0336] Examples 36 and 37 were prepared from intermediate 1-(2-(2,6-dimethylphenoxy)ethyl)-1-(2-hydroxyethyl)azepine-1-ol and the appropriate benzoyl chloride following a similar procedure as described for the synthesis of compound 32A.

[0337]

[0338] Synthesis of 1-benzyl-1-(3-(4-butoxyphenoxy)propyl)piperidin-1-yl bromide:

[0339]

[0340] Synthetic intermediate 1-butoxy-4-(3-chloropropoxy)benzene:

[0341] To a stirred solution of 4-butoxyphenol (10 g, 60.2 mmol) in ACN (100.0 mL) was added K2CO3 (24.9 g, 180.5 mmol). After stirring for 10 minutes, 1-bromo-3-chloropropane (14.2 g, 90.2 mmol) was added at room temperature and the reaction mixture was heated at 80°C for 16 h, and the progress of the reaction was monitored by TLC (mobile phase: 10% ethyl acetate in petroleum ether, observed by UV). The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluted with 10%-30% ethyl acetate in petroleum ether). The pure fractions were combined and concentrated under reduced pressure to give 1-butoxy-4-(3-chloropropoxy)benzene (7 g) as a red liquid. Mass (ESI): m / z 243.2 [M+H]+. 1 H NMR (400MHz, CDCl3) δppm 6.82(s,4H),4.05(t,2H),3.90(t,2H),3.73(t,2H),2.23-2.17(m,2H),1.77-1.70(m,2H),1.55-1.49(m,2H),0.95-0.92(m,3H).

[0342] Synthetic intermediate 1-(3-(4-butoxyphenoxy)propyl)piperidine:

[0343] To a stirred solution of 1-butoxy-4-(3-chloropropoxy)benzene (0.5 g, 2.1 mmol) and K2CO3 (0.85 g, 6.2 mmol) in acetonitrile (20 mL) was added piperidine (0.26 g, 3.1 mmol) and the resulting reaction mixture was heated at 80°C for 16 hours, the progress of the reaction was monitored by TLC (mobile phase: 50% ethyl acetate in petroleum ether, UV observation). The reaction mixture was cooled to room temperature, quenched with ice water (10 mL) and extracted with ethyl acetate (3x20 mL). The combined extracts were washed with water (2x20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified using silica gel chromatography (eluted with 20%-30% ethyl acetate in petroleum ether). The pure fractions were combined and concentrated under reduced pressure to give 1-(3-(4-butoxyphenoxy)propyl)piperidine (0.25 g) as an off-white solid. MS (ESI): m / z 292.05 [M+H]+.

[0344] Synthesis of 1-benzyl-1-(3-(4-butoxyphenoxy)propyl)piperidin-1-yl bromide:

[0345] A solution of 1-(3-(4-butoxyphenoxy)propyl)piperidine (0.2 g, 0.69 mmol) in acetonitrile (10 mL) was treated with benzyl bromide (0.25 g, 1.4 mmol) and the resulting reaction mixture was heated at 80° C. in a sealed test tube for 16 hours and the progress of the reaction was monitored by TLC (mobile phase: 10% methanol in DCM, UV observation). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (using 3%-5% methanol in DCM). Pure fractions were combined and concentrated under reduced pressure to give 1-benzyl-1-(3-(4-butoxyphenoxy)propyl)piperidin-1-yl bromide salt (0.70 g) as an off-white solid. Mass(ESI):m / z 382.3[M]+.1H NMR(400MHz,DMSO-d6)δppm7.57-7.51(m,5H),6.87(d,4H),4.61(s,2H),4.03(t,2H),3.89(t,2H) ,3.37-3.28(m,6H),2.28(d,2H),1.86(d,4H),1.68-1.64(m,3H),1.44-1.39(m,3H),0.92(t,3H).

[0346] Examples 39-43 were prepared from the intermediate 1-butoxy-4-(3-chloropropoxy)benzene according to the procedure described for the synthesis of compound 35A using the appropriate substituted piperidine or morpholine and an alkylating agent, benzyl bromide or ethyl iodide.

[0347]

[0348] Synthesis of 1-(3-(4-butoxyphenoxy)propyl)pyridin-1-yl bromide:

[0349]

[0350] To a solution of 1-butoxy-4-(3-chloropropoxy)benzene (0.5 g, 2.1 mmol) stirred in acetonitrile (3 mL) was added pyridine (0.325 g, 4.1 mmol) and the resulting reaction mixture was stirred at 90° C. for 24 hours, and the progress of the reaction was monitored using TLC (mobile phase: 10% methane in DCM, observation: UV lamp). The reaction mixture was concentrated under reduced pressure to give a crude compound, which was triturated with ethyl acetate (15 mL) to give 1-(3-(4-butoxyphenoxy)propyl)pyridin-1-yl chloride (0.145 g). Mass(ESI):m / z 286.2[M]+.1H NMR (400MHz, DMSO-d6) δppm9.14(d,2H),8.63-8.59(m,1H),6.83-6.79(m,2H),6.71-6.69(m,2H),4.79( t,2H),4.00(t,2H),3.87(t,2H),2.43-2.36(m,2H),1.68-1.61(m,2H),1.45-1.38(m,2H),0.93(t,3H).

[0351] Examples 45 and 46 were prepared from the intermediate 1-butoxy-4-(3-chloropropoxy)benzene according to the procedure described for the synthesis of compound 41A using the appropriately substituted pyridine.

[0352]

[0353] Synthesis of 4-benzyl-4-(3-(4-propoxyphenoxy)propyl)morpholin-4-yl bromide:

[0354]

[0355] Synthetic intermediate 4-(3-(4-propoxyphenoxy)propyl)morpholine:

[0356] 4-(3-chloropropyl)morpholine (1.2 g, 7.2 mmol) was added to a solution of 4-propoxyphenol (1 g, 6.6 mmol) and potassium carbonate (1.8 g, 13.1 mmol) in acetonitrile (20 mL) and stirred. The resulting reaction mixture was stirred at 80 °C for 16 hours and the progress of the reaction was monitored by TLC (mobile phase: 50% ethyl acetate in petroleum ether, observation: UV lamp). The reaction mixture was cooled to room temperature, diluted with ice water (10 mL) and extracted with ethyl acetate (40 mL). The organic extract was washed with water (10 mL) and brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified using silica gel chromatography (eluted with 40%-50% ethyl acetate in petroleum ether). The combined pure fractions were concentrated under reduced pressure to produce pure 4-(3-(4-propoxyphenoxy)propyl)morpholine (1.2 g). MS(ESI):m / z280.25[M+H]+.1H NMR(400MHz, CDCl3)δppm 6.82(s,4H),3.96(t,2H),3.86(t,2H),3.72(t,4H),2.53-2.45(m,6H),1.94(t,2H),1.80-1.75(m,2H),1.02(t,3H).

[0357] Synthesis of 4-benzyl-4-(3-(4-propoxyphenoxy)propyl)morpholin-4-yl bromide:

[0358] To a stirred solution of 4-(3-(4-propoxyphenoxy)propyl)morpholine (0.4 g, 1.4 mmol) in acetonitrile (10 mL) was added benzyl bromide (0.98 g, 5.73 mmol) and the resulting reaction mixture was heated in a sealed test tube at 80°C for 16 hours and the progress of the reaction was monitored by TLC (mobile phase: 10% methanol in DCM, observation: UV lamp). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 3%-5% methanol in DCM). The combined pure fractions were concentrated under reduced pressure to give 4-benzyl-4-(3-(4-propoxyphenoxy)propyl)morpholin-4-yl bromide (0.28 g) as an off-white solid. Mass(ESI):m / z 370.2[M]+.1H NMR(400MHz,DMSO-d6)δppm 7.60-7.51(m,5H),6.86(t,4H),4.74(s,2H),4.05-3.99(m,6H),3.85(t,2H),3.53-3.40(m,6H),2.33-2.29(m,2H),0.96(t,3H).

[0359] Examples 48-52 were prepared from 4-(3-chloropropyl)morpholine, an appropriately substituted phenol and benzyl bromide following the procedure described for the synthesis of compound 44A.

[0360]

[0361] Synthesis of 4-benzyl-4-(3-(4-hydroxyphenoxy)propyl)morpholin-4-yl bromide:

[0362]

[0363]

[0364] To a cooled (-78°C) solution of 4-benzyl-4-(3-(4-m-ethoxyphenoxy)propyl)morpholin-4-yl bromide (150 mg) in DCM (3 mL) was added a solution of 1M BBr3 in DCM (1.065 mL, added dropwise). Once the addition was complete, the reaction mixture was stirred at room temperature for 1 hour and the reaction progress was monitored using TLC (mobile phase: 20% methanol in DCM, ninhydrin observation). The reaction mixture was concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (eluted with 20% methanol in DCM). The combined pure fractions were concentrated under reduced pressure to give 4-(3-(4-methoxyphenoxy)propyl)morpholine (30 mg) as an off-white solid. Mass(ESI):m / z 328.2[M]+.UPLC:98.88%.1H NMR(400MHz,DMSO-d6)δppm 8.97(s,1H),7.60-7.51(m,5H),6.78-6.75(m,2H),6.72-6.69(m,2H),4.74( s,2H),4.01-3.98(m,6H),3.53-3.47(m,4H),3.41(d,2H),2.32-3.20(m,2H).

[0365] Synthesis of 4-(3-(4-butoxyphenoxy)propyl)-4-(2-(dimethylamino)-2-oxoethyl)morpholin-4-yl bromide Chemicals:

[0366]

[0367] Synthetic intermediate 4-(3-(4-butoxyphenoxy)propyl)morpholine:

[0368] To a solution of 1-butoxy-4-(3-chloropropoxy)benzene (0.5 g, 2.1 mmol) and K2CO3 (0.57 g, 4.2 mmol) stirred in acetonitrile (15 mL) was added morpholine (0.215 g, 2.5 mmol) and the resulting reaction mixture was heated at 80°C for 16 hours. The progress of the reaction was monitored by TLC (mobile phase: 50% ethyl acetate in petroleum ether, observation: UV lamp). The reaction mixture was diluted with DCM (80 mL) and washed with water (2 x 25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by flash chromatography (eluted with 20%-30% ethyl acetate in petroleum ether). The combined pure fractions were concentrated under reduced pressure to give 4-(3-(4-butoxyphenoxy)propyl)morpholine (560 mg) as a light yellow oil. MS (ESI): m / z 294.18 [M+H]+.

[0369] Synthesis of 4-(3-(4-butoxyphenoxy)propyl)-4-(2-(dimethylamino)-2-oxoethyl)morpholin-4-yl bromide

[0370] 2-Bromo-N,N-dimethylacetamide (0.452 g, 2.73 mmol) was added to a solution of 4-(3-(4-butoxyphenoxy)propyl)morpholine (0.2 g, 0.68 mmol) stirred in ACN (10 mL). The resulting reaction mixture was heated to 80°C for 16 hours, and the progress of the reaction was monitored by TLC (mobile phase: 10% methanol in DCM, observation: UV lamp). The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by reverse phase preparative HPLC (column: X-selected phenylhexyl C18 (19*250) 5um, mobile phase A / B: 0.1% FA (aq) / ACN) to give the product 4-(3-(4-butoxyphenoxy)propyl)-4-(2-(dimethylamino)-2-oxoethyl)morpholin-4-yl bromide (160 mg). MS(ESI):m / z 379.2[M]+.1H NMR(400MHz,DMSO-d6)δppm 6.87-6.82(m,4H),4.60(s,2H),3.99-3.90(m,8H),3.88-3.81(m,4H),3.69-3.64(m,2H),2.9 9(s,3H),2.86(s,3H),2.07-2.03(m,2H),1.67-1.63(m,2H),1.44-1.38(m,2H),0.92(m,3H).

[0371] Examples 55 and 56 were prepared according to the procedure described for the synthesis of compound 38 from 4-butoxyphenol, morpholine, benzyl bromide and the appropriate dihaloalkane.

[0372]

[0373]

[0374] Example 2 - Inhibition of Nav1.7 Current

[0375] Representative compounds of the invention were synthesized according to the methods described above and tested for their ability to inhibit voltage-gated sodium channels.

[0376] Cell culture

[0377] NaV1.7 was induced with tetracycline. Cells were cultured in DMEM containing 10% dialyzed fetal bovine serum (VWR, Radnor, PA), 1% glutamine (VWR, Radnor, PA), 1% penicillin-streptomycin (VWR, Radnor, PA), 100 mg / L hygromycin (ThermoFisher Scientific, Waltham, MA) and 5 mg / L juvenile cytokines (Alfa Aesar, Haverhill, MA). Cells were grown in a humidified environment at 37°C and kept in air containing 10% carbon dioxide. Cells were separated from culture flasks for passage and harvested using 0.05% trypsin EDTA (Thermo Fisher Scientific, Waltham, MA). To induce NaV1.7, cells were induced with tetracycline (0.1-1 μg / mL, IBI Scientific, Peosta, IA) the day before recording and placed on 24-well plates. The cells were washed with DPBS (VWR, Radnor, PA), trypsinized, and then triturated five times in 10 mL of growth medium to separate 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 tetracycline was added. Then 1 mL of mixed medium with cells was added to each well of the 24-well plate, and a 12 mm coverslip was placed in each well. The cells were then cultured overnight at 37°C and 10% CO2.

[0378] Patch clamp solutions and drugs

[0379] The intracellular solution contained the following (in mM): CsCl 135, NaCl 10, EGTA 10, HEPES 10, MgCl2 2, and was adjusted to pH 7.2 with CsOH. The external solution was normal Ringer's solution, containing (in mM) NaCl 155, HEPES 10, glucose 10, KCl 3.5, CaCl2 1.5, MgCl2 1, and was adjusted to pH 7.4 with NaOH. CsCl was from Alpha Essar, Haverhill, MA. All other chemicals were from Sigma-Aldrich, St. Louis, MO. To test the degree of internal blockage of a compound, the compound to be tested was dissolved in the internal solution at the indicated test concentration. In control experiments, the internal solution did not contain any compound. To test the degree of external blockage by a test compound, the compound was dissolved in the external solution at the indicated test concentration.

[0380] Whole-cell patch clamp protocol

[0381] 18-24 hours after induction of cells with tetracycline, coverslips were placed in a chamber filled with normal Ringer's solution at room temperature and the chamber was placed on a microscope. Pipettes were pulled from borosilicate glass on a P97 puller (Sutter Instrument, Novato, CA) and polished with a MF-830 micro glass polisher (Narishige International USA, Inc, Amityville, NY) to a resistance of 1.5-2.5 mΩ when filled with CsCl internal solution at room temperature. Healthy cells (those that were round, translucent and free of visible defects) were selected to form a seal. A seal was formed between the pipette and the cell and a brief pulse of suction was used to "cut in" and establish the entire cell structure. The membrane potential was held at -100 mV before the voltage protocol began. Only cells with a series resistance between 1.5 and 5 MΩ were retained for analysis. The voltage protocol was as follows: the cell was held at -100 mV for 12 ms, followed by a hyperpolarizing step at -105 mV for 12 ms to monitor leakage. The cell was then depolarized to -100 mV for 40 ms. The cell was then depolarized to -20 mV for 10 ms and then back to -100 mV for 26 ms.

[0382] Internal blocking of test compounds

[0383] Once the recording begins, the voltage scheme runs for 5 minutes at 30-second intervals to obtain a stable baseline. Four 30-second 5Hz identical voltage stimulations are subsequently performed, with a 1-minute rest after each voltage stimulation, and then a 0.33Hz stimulation is performed after the last stimulation. Current is recorded using PatchMaster software and Heka EPC10 (Heka Electronics, Lambrecht, Germany). Only cells with inward current amplitudes between -20mV, 400pA and 4nA are accepted. In addition, batteries with leakage currents greater than 10% of their current amplitudes are discarded.

[0384] Data Analysis: Internal Blocking

[0385] Data were plotted using Patchmaster software (HEKA Electronics, Lambrecht, Germany) and analyzed by plotting the minimum current during the voltage step to -20 mV (peak inward current) as a function of time. To determine the extent of depletion during the experiment, the mean peak inward current amplitude before 5 Hz stimulation (2-3 points) was designated as the baseline (I baseline The average peak inward current (I test ). By dividing Itest by I baseline Calculation of the remaining control fraction current. On each recording day, three cells were tested with the control internal solution, and the mean fraction of the remaining current (Ctrl fraction current) was calculated.

[0386] To determine the % block produced by the internally applied test compound, the following procedure was performed. The average peak inward current amplitude (2-3 points) before 5 Hz stimulation was designated as 0% block (I 0％block To correct for current variations under control conditions, I0% block was multiplied by the remaining average Ctrl fractional current to obtain the corrected 0% block current. The average peak inward current during the last 2 seconds of the last 5 Hz stimulation was designated as the unblocked current (I unblocked ). Calculate % blocking using the following equation: (1-I UNBLOCK / (I 0％block *Residual current control fraction) x 100).

[0387] Compounds 1A' to 6A' (Example 1) were tested for intracellular inhibition of NaV 1.7.

[0388] The activity range is percent inhibition: "+++" > 70%, "++" (70-30%) or "+" (<30%). The results are shown below.

[0389]

[0390]

[0391] External blocking of test compounds

[0392] Once recording begins, the voltage scheme runs for 5 minutes at intervals of 30 seconds to obtain a stable baseline. The same voltage scheme is subsequently used to stimulate at 5Hz until the end of the experiment. Test compounds are added during the 5Hz stimulation, and wait until the cell shows a stable consumption rate before ensuring that the compound is added. Test compounds are added for five minutes, followed by conventional Ringer's solution washout. PatchMaster software and Heka EPC10 (Heka Electronics, Lambrecht, Germany) are used to record current. Only cells with inward current amplitudes between -20mV, 400pA and 4nA are accepted. In addition, cells with leakage current greater than 10% of their current amplitude are discarded.

[0393] Data Analysis: External Blocking

[0394] Data were plotted using Patchmaster software (HEKA Electronics, Lambrecht, Germany) and analyzed by plotting the minimum current during the voltage step to -20 mV (peak inward current) as a function of time. To determine the percentage of block produced by externally applied test compounds, the following was performed. Rate (Rate) was calculated by dividing the change in peak current amplitude by time after a stable current decay rate was established during 5 Hz stimulation. rundown The average peak inward current amplitude before compound addition (2-3 seconds) was used to determine the 0% block (I 0％block ). To correct for the loss, I 0％block Subtract(Rate rundown *5 minutes) to obtain the corrected 0% blocking current. The average peak inward current in the last 2-3 seconds of the 5-minute compound addition period before washing was the unblocked current (I unblocked ). The % blockade was then calculated using the following equation: Current blockade fraction = 1 - I UNBLOCK / (I 0％block -Rate rundown *5 minutes).

[0395] Representative compounds of Example 1 were used in the NaV 1.7 extracellular inhibition assay.

[0396] The activity range is the percentage of inhibition: "+++" > 70%, "++" (70-40%) or "+" (< 40%). The results are shown in the table below.

[0397] Compound Experimental concentration <![CDATA[Na V 1.7 Extracellular Inhibition]]> Compound-1 1μM ++ Compound-4 1μM ++ Compound-12 3μM + Compound-38 10μM + Compound-40 10μM + Compound-43 10μM ++

[0398] Example 3 - Antipruritic Activity

[0399] According to similar published methods (Ramachandran et al., JPET 2020), C57BL / 6 mice were used to determine the antipruritic activity of representative compounds of the present invention. In brief, mice were anesthetized with 2.5% isoflurane and the test compound solution (10 mg / mL, 100 μL) was topically applied to the shaved area at the nape of the neck using a solvent pipette (T=0). The test product was injected into the skin until completely absorbed. Chloroquine (100 μg dissolved in 50 μL 0.9% saline) was injected intradermally at the specified time to cause itching. Scratching activity was monitored within 40 minutes using an infrared camera.

[0400] Representative compounds of Example 1 were able to significantly reduce chloroquine-induced pruritus for up to 8 hours after topical application. Figure 1A ,1B and 1C.

[0401] The patents and scientific literature referred to herein build upon the knowledge available to one of ordinary skill in the art to which the invention pertains. All U.S. patents and published or unpublished U.S. patent applications cited herein are hereby incorporated by reference in their entirety. All published foreign patents and foreign patent applications cited herein are hereby incorporated by reference in their entirety. All other published references, documents, manuscripts and scientific articles are hereby incorporated by reference in their entirety.

[0402] Although the present invention has been specifically shown and described in its preferred embodiments, it will be understood by those skilled in the art that various changes may be made in form and detail without departing from the scope of the invention as defined by the appended claims. It should also be understood that none of the embodiments described herein are immutable and may be combined with one another in various ways without departing from the scope of the invention as defined by the claims.

Claims

1. A compound of formula (I): in, Y - is a pharmaceutically acceptable anion; R A , R B , and R C are independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I 、CN、CF3、NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T ;C(O)R U and C(O)NR V R W ; R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W Each of R is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; R J and R K or R V and R W or R Q and R R They may also form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted 5-, 6-, 7- or 8-membered ring; or R A , R B and / or R C They can form fused bicyclic or tricyclic ring systems together with the benzene ring to which they are attached, such as naphthyl, indanyl, tetrahydronaphthyl, quinolyl, indolyl, etc.; R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, cycloalkyl, aryl or heteroaryl, preferably hydrogen, methyl or ethyl; or R1, R2, R3, R4, R5 and / or R6 together with the carbon atoms to which they are attached form a substituted or unsubstituted cycloalkyl (e.g., C3-C6 cycloalkyl) or a substituted or unsubstituted heterocyclyl (e.g., a 3- to 15-membered heterocyclyl ring); n is 0, 1, 2, 3, 4 and 5; R F and R G With N + together to form an optionally substituted heterocyclyl ring, the heterocyclyl ring except N + In addition, it contains 0, one or more heteroatoms, preferably 5, 6, 7, 8 or 9 ring atoms; R H is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, for example, -CH2-cycloalkyl, -C2H4-cycloalkyl, substituted or unsubstituted -CH2-C 5- C 10 Aryl, substituted or unsubstituted -C2H4-C 5- C 10 Aryl, substituted or unsubstituted -CH2-C 5- C 10 Heteroaryl, substituted or unsubstituted -C2H4-C 5- C 10 Heteroaryl, -CH2 OC(O)R T 、-CH2CO2R T 、-CH2C(O)NR V R W 、-C2H4OCOR T 、-C2H4OR I or, R F ,R G and R H With N + Together they form a heteroaryl ring or a bridged heterocyclyl ring.

2. The compound according to claim 1, wherein R A Selected from H, methyl, halogen (such as F, Cl or Br), CF3, CN, CO2R T OR I , more preferably methyl, F, CF3 or CN, most preferably methyl.

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

4. A compound according to any one of the preceding claims, wherein R C Selected from H, methyl, halogen (such as F, Cl or Br), CF3, CN, CO2R T OR I , more preferably H or OR I , most preferably H.

5. A compound according to any preceding claim, wherein Each of R1, R2, R3, R4, R5 and / or R6 is hydrogen.

6. A compound according to any one of claims 1 to 4, wherein R1 is methyl or ethyl and R2, R3, R4, R5 and R6 are all hydrogen.

7. A compound according to any one of claims 1 to 4, wherein R3 is methyl or ethyl and R1, R2, R4, R5 and R6 are all hydrogen.

8. A compound according to any preceding claim, wherein n is 0.

9. A compound according to any preceding claim, wherein n is 1.

10. A compound according to any preceding claim, wherein n is 3.

11. A compound according to any one of the preceding claims, wherein R F and R G With N + Together they form a ring selected from substituted or unsubstituted rings selected from: or And, more preferably in, R7 is hydrogen or substituted or unsubstituted alkyl.

12. The compound according to claim 11, wherein The ring is unsubstituted.

13. A compound according to any preceding claim, wherein R H It is benzyl or substituted benzyl, preferably benzyl.

14. The compound according to any one of claims 1 to 10, wherein R F ,R G and R H With N + Together they form a pyridyl group or 15. A compound according to any preceding claim, provided that the compound is not:

16. A compound represented by formula (II): in, Y- is a pharmaceutically acceptable anion; R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, aryl or heteroaryl, preferably hydrogen, methyl or ethyl; n is 0, 1, 2, 3, 4, and 5; and q is 0, 1, 2, 3, 4 or 5.

17. The compound according to claim 16, wherein q is 3.

18. The compound according to claim 16 or 17, wherein R1, R2, R3, R4, R5 and R6 are hydrogen.

19. The compound according to claim 16, wherein q is 2.

20. The compound according to claim 19, wherein R1, R2, R3, R4, R5 and R6 are hydrogen.

21. The compound according to claim 16, wherein q is 1.

22. The compound according to claim 21, wherein R1, R2, R3, R4, R5 and R6 are hydrogen.

23. The compound according to claim 16, wherein q is 0.

24. The compound according to claim 23, wherein R1, R2, R3, R4, R5 and R6 are hydrogen.

25. The compound according to claim 16, wherein R1 is methyl, and R2, R3, R4, R5 and R6 are hydrogen.

26. The compound according to claim 16, wherein R3 is methyl, and R1, R2, R4, R5 and R6 are hydrogen.

27. The compound according to any one of claims 16 to 26, wherein n is 0.

28. The compound according to any one of claims 16 to 26, wherein n is 1.

29. The compound according to any one of claims 16 to 26, wherein n is 2.

30. The compound according to any one of claims 16 to 26, wherein n is 3.

31. A compound according to any one of claims 16 to 26, wherein n is 4.

32. A compound according to any one of claims 16 to 26, wherein n is 5.

33. A compound according to any preceding claim, wherein Y- is bromide or chloride.

34. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable excipient.

35. The composition according to claim 34, wherein The compositions are formulated for topical or dermal administration.

36. A method for treating pruritus, pain, cough or a neurogenic inflammatory disorder in a patient, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1-33.

37. The method of claim 36, wherein: The itch is selected from the group consisting of pruritus, brachioradial itch, chronic idiopathic itch, genital / anal itch, allodynia, scalp itch, allergic dermatitis, contact dermatitis, atopic dermatitis, hand eczema, poison ivy, infection, parasites, insect bites, pregnancy, metabolic disorders, liver or kidney failure, drug reaction, allergic reaction, eczema, genital and anal itch, hemorrhoidal itch and cancer.

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