Pruritus treatment with P2X3 antagonists

Abstract

Disclosed is a method for treating pruritus in a mammal using a P2X3 antagonist. The P2X3 antagonist is preferably a compound of formula (I). The pruritus may be associated with an inflammatory skin disorder, an infectious skin disease, an autoimmune skin disease, or a pregnancy-related skin disease. The P2X3 antagonist may be administered by intravenous, subcutaneous, oral, inhaled, nasal, topical, or ocular administration, and may be used in combination with an NK-1 antagonist. The P2X3 antagonist acts by inhibiting pathological ATP release associated with the overexcitability of itch-sensing afferent neurons, thereby inhibiting peripheral hypersensitivity to itch through a wide range of mechanisms unrelated to pathological stimuli acting on itch receptors.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 744,006, filed on October 10, 2018, which is incorporated herein by reference in its entirety. Background Art

[0003] Pruritus is defined as an unpleasant sensation that evokes the desire to scratch. Pruritus may be localized or systemic and may occur as an acute or chronic condition. Certain systemic diseases have long been known to cause pruritus, which ranges in intensity from mildly bothersome to intractable, disabling conditions that can be a diagnostic and therapeutic challenge. Summary of the invention

[0004] The present disclosure provides, for example, a method for treating pruritus in a mammal using a P2X3 modulator. The present disclosure also provides the use of a P2X3 modulator as a medicament and / or in the preparation of a medicament for treating pruritus in a mammal such as a human. In some embodiments, the P2X3 modulator is a P2X3 antagonist.

[0005] In one aspect, a method for treating pruritus in a mammal comprises administering to the mammal a therapeutically effective amount of a P2X3 antagonist. In some embodiments, a method for treating pruritus in a mammal comprises administering to the mammal a therapeutically effective amount of a P2X3 antagonist, wherein the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0006]

[0007]

[0008] in:

[0009] R 1 is selected from cyano, halogen, methyl and ethyl;

[0010] R 2 is selected from hydrogen, halogen, methyl and ethyl;

[0011] R 3 is selected from halogen, methyl and ethyl;

[0012] R 4 is selected from hydrogen, halogen, methyl, ethyl and methoxy;

[0013] R 5 and R 6 independently selected from hydrogen, C1-C6-alkyl and hydroxy-C1-C6-alkyl; or

[0014] R 5 and R 6 together with the nitrogen to which they are both attached, form a 5- or 6-membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4-alkyl;

[0015] R 7 and R 8 independently selected from hydrogen and C1-C4-alkyl;

[0016] R 9 is selected from C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkyl-C3-C6-cycloalkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy and C1-C6-alkoxy-C1-C6-alkyl; and

[0017] X is selected from a bond, CH2 and O.

[0018] In some embodiments, R 1 In some embodiments, R 2 In some embodiments, R 3 In some embodiments, X is O. In some embodiments, the compound of formula (I) corresponds in structure to And R 4 is selected from halogen, methyl and ethyl. 5 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 7 In some embodiments, R 8 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, the compound of formula (I) corresponds in structure to In some embodiments, the compound of formula (I) corresponds structurally to:

[0019]

[0020]

[0021]

[0022]

[0023] In some embodiments, the compound of formula (I) corresponds structurally to

[0024]

[0025] In some embodiments, the compound of formula (I) corresponds structurally to

[0026]

[0027] In some embodiments, the compound of formula (I) corresponds structurally to

[0028]

[0029] In some embodiments, the compound of formula (I) corresponds structurally to

[0030]

[0031] In some embodiments, the P2X3 antagonist corresponds structurally to

[0032]

[0033] In some embodiments, the P2X3 antagonist corresponds structurally to

[0034] In some embodiments, the P2X3 antagonist corresponds structurally to

[0035]

[0036] In some embodiments, the P2X3 antagonist corresponds structurally to

[0037]

[0038] In some embodiments, a method of treating pruritus in a mammal comprises administering to the mammal a therapeutically effective amount of a P2X3 antagonist, wherein the mammal is a human. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with an inflammatory skin disease, an infectious skin disease, an autoimmune skin disease, or a pregnancy-related skin disease. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with an inflammatory skin disease selected from atopic dermatitis, allergic, irritant contact dermatitis, dry dermatitis, nummular and dyshidrotic dermatitis, lichen planus, lichen sclerosus atrophicus, polymorphous light eruption psoriasis, Grover's disease, mucinosis, mastocytosis, and urticaria. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with an infectious skin disease selected from fungal diseases, bacterial and viral infections, scabies, pediculosis, insect bites, and folliculitis. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with an autoimmune skin disease selected from dermatitis herpetiformis (Duhring's disease), bullous pemphigoid, hereditary skin diseases, Darier disease, and Hailey-Hailey disease. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with a pregnancy-related skin disease selected from polymorphic eruption of pregnancy (PEP), atopic eruption of pregnancy, pemphigoid gestationis, neoplasia, and cutaneous T-cell lymphoma. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with kidney disease or a therapeutic procedure used to treat kidney disease. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with chronic kidney disease. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with a therapeutic procedure used to treat kidney disease, wherein the therapeutic procedure used to treat kidney disease is hemodialysis or peritoneal dialysis. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with a medical procedure or treatment. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with medical treatment with a drug selected from opioids, antimalarials, anticancer therapies, and epidermal growth factor receptor inhibitors. In some embodiments, a method of treating pruritus in a mammal, wherein the pruritus is associated with prurigo nodularis. In some embodiments, a method of treating pruritus in a mammal, wherein the P2X3 antagonist is formulated for administration to the mammal by intravenous, subcutaneous, oral, inhaled, nasal, topical, or ocular administration. In some embodiments, a method of treating pruritus in a mammal, wherein the P2X3 antagonist is formulated in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.In some embodiments, a method of treating pruritus in a mammal comprises administering to the mammal a therapeutically effective amount of a P2X3 antagonist, further comprising administering a second therapeutic agent. In some embodiments, a method of treating pruritus in a mammal comprises administering to the mammal a therapeutically effective amount of a P2X3 antagonist, further comprising administering a NK-1 antagonist. In some embodiments, a method of treating pruritus in a mammal comprises administering to the mammal a therapeutically effective amount of a P2X3 antagonist, further comprising administering a NK-1 antagonist, wherein the NK-1 antagonist is selected from serlopitant, oravipitant, rolapitant, aprepitant and fosaprepitant, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating pruritus in a mammal comprises administering to the mammal a therapeutically effective amount of a P2X3 antagonist, further comprising administering a NK-1 antagonist, wherein the NK-1 antagonist is selected from serlopitant, aprepitant, casopitant, dapitant, elopitant, fosaprepitant, lanapitant, maropitant, netupitant, nolpitant, orvipitant, rolapitant, viltipitant, wolflopitant, AV-818, BIIF 1149CL, CP122,721, DNK-333, GSK-424887, L-733060, L-759274, LY-686017, M516102 and TA-5538. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 Depicted are the effects of 10 μM or 50 μM α,β-methylene-adenosine 5'-triphosphate (α,β-Me-ATP) on low-dose chloroquine (CQ)-induced itch behavior.

[0040] Figure 2 Shown are the effects of Compound 1 (three independent doses) and U50,488 on pruritic behavior induced by low-dose chloroquine CQ plus 50 μM α,β-Me-ATP, as measured by the number of scratching episodes elicited within 15 minutes after dosing.

[0041] Figure 3 Shown are the effects of Compound 1 (10 mpk) on pruritic behavior induced by low-dose chloroquine CQ plus 100 μM α,β-Me-ATP, as measured by the number of scratching elicited within 15 minutes after dosing.

[0042] Figure 4 Shown is the effect of Compound 1 (10 mpk) on high-dose chloroquine CQ-induced pruritic behavior as measured by the number of scratching evoked within 30 minutes after dosing.

[0043] Figure 5Shown are the effects of Compound 1 (2, 10 and 50 mg / kg) and U50,488 (3 mg / kg) on ​​chronic itch behavior as measured by the number of spontaneous scratches within 60 minutes on day 10 in the AEW (acetone-ether-water) dry skin model.

[0044] Figure 6 Shown are the effects of Compound 1 (2, 10 and 50 mg / kg) and U50,488 (3 mg / kg) on ​​chronic itch behavior as measured by the number of spontaneous scratching at 10-min intervals on day 10 in the AEW (acetone-ether-water) dry skin model.

[0045] Figure 7 Shown are the effects of Compound 1 (2, 10 and 50 mg / kg) and U50,488 (3 mg / kg) on ​​chronic pruritic behavior as measured by the number of spontaneous scratching within 60 minutes on day 8 in the MC903 atopic dermatitis model.

[0046] Figure 8 Shown are the effects of Compound 1 (2, 10 and 50 mg / kg) and U50,488 (3 mg / kg) on ​​chronic pruritic behavior as measured by the number of spontaneous scratching at 10-min intervals on day 8 in the MC903 atopic dermatitis model.

[0047] Incorporation by reference

[0048] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0049] Itch-causing stimuli can be induced by mechanical, thermal and chemical means, which are sensed by afferent neurons that control the skin and transmitted to the thalamus for processing and reflex initiation. Stimulation and afferent transmission work through a variety of afferent neurons (pruriceptive neurons), which are groups that partially overlap with pain neurons in the skin in terms of molecular phenotype. Itch-sensing neurons can respond to a variety of stimuli, but pathological pruritus is mainly caused by endogenous chemicals (e.g., histamine, substance P, gastrin-releasing peptide, interleukins, nerve growth factor) acting on the ends of skin neurons. These pruritogens are released in the context of conditions with excessive inflammation (e.g., atopic dermatitis, psoriasis), systemic diseases (e.g., chronic liver disease and kidney disease), neurological conditions (e.g., post-herpetic pruritus) or mental disorders (e.g., obsessive-compulsive disorder, substance abuse) (Yosipovitch et al., N. Engl. J. Med., 2013, 1625-1634).

[0050] Itch-sensing afferent neurons are characterized by c-fibers or aδ-fibers of dorsal root ganglia, which innervate skin tissue and form synapses with the spinal cord. The c-fiber or aδ-fiber terminals in the skin express receptors in response to pruritic chemicals, thereby initiating action potentials that are transmitted to the CNS. These neurons also express P2X3 cation channels, which regulate the sensitivity of neurons to excitation caused by pruritic stimuli. It is worth noting that P2X3 channels are co-expressed on the cell membrane of MgprA3+ neurons (the main itch-sensing neuron phenotype that innervates the skin), and the number of these neurons is increased in a mouse chronic itch model (Han et al., Nat. Neurosci., 2013, 174-182; Zhao et al., J. Clin. Invest., 2013, 4769-4780).

[0051] P2X3 channels are neuronal excitability regulators that can be activated by local release of ATP (a neurotransmitter and extracellular messenger with proinflammatory properties). ATP has been recognized as an important chemical messenger, which is excessively released by neuronal cell types and non-neuronal cell types under a variety of pathological conditions (Burnstock, Front. Pharmacol., 2017, 661; Burnstock, Biochem. Pharmacol., 2017, doi: 10.1016 / j.bcp.2017.07.016). Therefore, an increase in ATP release can lead to excessive excitability of itch-sensing afferent neurons, as well as enhanced sensitivity to any pruritogens pathologically released in the skin. In short, P2X3 channels that act through pathological ATP release may be potential relevant targets for regulating the sensitivity of afferent neurons to itch sensation. Their inhibition can provide a method for inhibiting peripheral hypersensitivity to itch in various diseases, and its extensive mechanism is unrelated to pathological stimulation acting on itch receptors.

[0052] definition

[0053] As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or multiple cells) and their equivalents. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments herein are intended to be included. The term "about" used when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within the experimental variability (or within the statistical experimental error range), and thus the number or numerical range varies between 1% and 15% of the number or numerical range. The term "comprising" (and related terms such as "including" or "having" or "containing") is not intended to exclude that, in certain other embodiments, for example, embodiments of any composition of matter, composition, method or process, etc. described herein may be "consisting of" or "essentially consisting of" the features.

[0054] As used in this specification and the appended claims, the following terms have the meanings set forth below unless indicated otherwise.

[0055] As used herein, C1-C x Including C1-C2, C1-C3...C1-C x C1-C x refers to the number of carbon atoms (excluding optional substituents) that make up the moiety to which it refers.

[0056] "Amino" refers to the -NH2 group.

[0057] "Cyano" refers to a -CN group.

[0058] "Nitro" refers to a -NO2 group.

[0059] "Oxa" refers to an -O- group.

[0060] "Oxo" refers to a =0 group.

[0061] "Thio" refers to a =S group.

[0062] "Imino" refers to a =NH group.

[0063] "Oximo" refers to a =N-OH group.

[0064] "Alkyl" or "alkylene" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, the alkyl group contains 1-13 carbon atoms (e.g., C1-C 13 In certain embodiments, the alkyl group contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group contains 1 to 6 carbon atoms (e.g., C1-C6 alkyl). In other embodiments, the alkyl group contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group contains one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group contains 5 to 15 carbon atoms (e.g., C5-C 15In other embodiments, the alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl) and 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specifically stated in this specification, the alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oximo, trimethylsilyl, -OR a 、-SR a 、-OC(O)R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR f 、-OC(O)-NR a R f 、-N(R a )C(O)R f 、-N(R a )S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R f and R is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0065] "Alkoxy" refers to a group of the formula -O-alkyl bonded through an oxygen atom wherein alkyl is an alkyl chain as defined above.

[0066] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon double bond and having 2-12 carbon atoms. In certain embodiments, alkenyl contains 2 to 8 carbon atoms. In other embodiments, alkenyl contains 2 to 4 carbon atoms. The alkenyl is connected to the rest of the molecule by a single bond, for example, vinyl, prop-1-enyl (i.e., allyl), but-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc. Unless otherwise specifically stated in this specification, alkenyl is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime (oximo), trimethylsilyl, -OR a 、-SR a 、-OC(O)R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR f 、-OC(O)-NR a R f 、-N(R a )C(O)R f 、-N(R a )S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R f and R is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0067] "Alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon triple bond, with 2-12 carbon atoms. In certain embodiments, the alkynyl group comprises 2 to 8 carbon atoms. In other embodiments, the alkynyl group has 2 to 4 carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated in this specification, the alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oximo, trimethylsilyl, -OR a 、-SR a 、-OC(O)R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR f 、-OC(O)-NR a R f 、-N(R a )C(O)R f 、-N(R a )S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R f and R is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0068] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from 6 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless otherwise specifically stated in this specification, the term "aryl" or the prefix "ar-" (as in "aralkyl") is intended to include aryl groups optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain.

[0069] "Aryloxy" refers to a group of the formula -O-aryl bonded through an oxygen atom, wherein aryl is as defined above.

[0070] "Arylalkyl" refers to a group of the formula -R c -aryl radical, wherein R c is an alkylene chain as defined above, for example, methylene, ethylene, etc. The alkylene chain part of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl part of the aralkyl group is optionally substituted as described above for the aryl group.

[0071] "Aralkyloxy" refers to a group of the formula -O-aralkyl bonded through an oxygen atom, wherein aralkyl is as defined above.

[0072] "Aralkenyl" refers to a group of the formula -R d -aryl radical, wherein R d is an alkenylene chain as defined above. The aryl part of the aralkenyl group is optionally substituted as described above for aryl. The alkenylene chain part of the aralkenyl group is optionally substituted as described above for alkenylene.

[0073] "Arylalkynyl" refers to a group of the formula -R e -aryl radical, wherein R e is an alkynylene chain as defined above. The aryl part of the aralkynyl group is optionally substituted as described above for aryl. The alkynylene chain part of the aralkynyl group is optionally substituted as described above for alkynylene chains.

[0074] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused rings or bridged ring systems, with 3 to 15 carbon atoms. In certain embodiments, cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, cycloalkyl contains 5 to 7 carbon atoms. Cycloalkyl is connected to the rest of the molecule by a single bond. Cycloalkyl is saturated (i.e., only contains a single C-C bond) or partially unsaturated (i.e., contains one or more double bonds or triple bonds). Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In certain embodiments, cycloalkyl contains 3 to 8 carbon atoms (e.g., C3-C8 cycloalkyl). In other embodiments, cycloalkyl contains 3 to 7 carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, cycloalkyl contains 3 to 6 carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, cycloalkyl contains 3 to 5 carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, cycloalkyl contains 3 to 4 carbon atoms (e.g., C3-C4 cycloalkyl). Partially unsaturated cycloalkyl is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo [2.2.1] heptyl), norbornyl, decahydronaphthyl, 7,7- dimethyl-bicyclo [2.2.1] heptyl, etc. Unless otherwise specifically stated in this specification, the term "cycloalkyl" is intended to include cycloalkyl groups optionally substituted by one or more substituents, the substituents being independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)ORa , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain.

[0075] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0076] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above.

[0077] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluorinated groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl group is optionally substituted as described above for alkyl.

[0078] "Haloalkoxy" means an alkoxy group as defined above substituted with one or more halo groups as defined above.

[0079] "Heterocycloalkyl" refers to a stable 3 to 18-membered non-aromatic ring group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise expressly stated in the specification, the heterocycloalkyl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system including a fused ring, a spirocyclic or a bridged ring system. The heteroatoms in the heterocycloalkyl group are optionally oxidized. If there are one or more nitrogen atoms, it is optionally quaternized. The heterocycloalkyl group is partially or completely saturated. In some embodiments, the heterocycloalkyl is connected to the rest of the molecule by any atom in the ring. Examples of such heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocycloalkyl" is intended to include heterocycloalkyl groups as defined above optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(Ra )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain.

[0080] "Heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring group containing 1 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl group is connected to the rest of the molecule through any atom in the ring. Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(Ra )2. -R b -OR c -C(O)N(R a )2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain.

[0081] "N-heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen, and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. N-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0082] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. A C-heteroaryl group is optionally substituted as described above for a heteroaryl group.

[0083] "Heteroaryloxy" refers to a radical of the formula -O-heteroaryl bonded through an oxygen atom wherein heteroaryl is as defined above.

[0084] "Heteroarylalkyl" refers to a group of the formula -R c -heteroaryl radical, wherein R cis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally connected to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl.

[0085] "Heteroarylalkoxy" refers to a group of the formula -OR c - a heteroaryl group bonded through an oxygen atom, wherein R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally connected to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy group is optionally substituted as defined above for the heteroaryl group.

[0086] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, and thus produce enantiomers, diastereomers, and other stereoisomeric forms defined as (R)- or (S)- according to absolute stereochemistry. Unless otherwise stated, the disclosure is intended to relate to all stereoisomeric forms of compounds disclosed herein. When the compounds described herein contain olefin double bonds, unless otherwise stated, the present invention is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers are also intended to be included, as well as their racemic forms and optically pure forms, and all tautomeric forms. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of olefin double bonds. The term "positional isomer" refers to structural isomers around the central ring, such as ortho, meta, and para isomers around the benzene ring.

[0087] "Tautomers" refer to molecules in which it is possible for a proton to move from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerism is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0088]

[0089] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and means that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and means that the description includes substituted aryl groups and aryl groups that are not substituted.

[0090] "Prodrugs" include compounds that are metabolized into pharmacologically active drugs after administration (RB Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Chapter 8). Prodrugs can be used to improve the absorption, distribution, metabolism, and excretion patterns of a compound.

[0091] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. Any pharmaceutically acceptable salt of a compound described herein is intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0092] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids such as arginates, gluconates, and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). The acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0093] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from organic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0094] The term "mammal" refers to humans, non-human primates, dogs, cats, cows, sheep, pigs, mice or other veterinary or laboratory mammals. Those skilled in the art recognize that a therapy that reduces the severity of pathology in one mammalian species may be predictive of the effect of the therapy in another mammalian species.

[0095] As used herein, "treat" or "treating" or "alleviate" or "ameliorate" are used interchangeably herein. These terms refer to a means of obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or prophylactic benefit. By "therapeutic benefit" is meant the elimination or amelioration of the underlying condition being treated. Additionally, therapeutic benefit may also be achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying condition, such that improvement is observed in the patient, although the patient is still suffering from the underlying condition. For prophylactic benefit, the composition is administered to a patient at risk for developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0096] method

[0097] In some embodiments, a method of treating pruritus in a mammal in need thereof comprises administering to the mammal a therapeutically effective amount of a P2X3 antagonist. In some embodiments, a method of treating pruritus in a mammal in need thereof comprises administering to the mammal a therapeutically effective amount of a P2X3 antagonist, wherein the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, having the following structure:

[0098]

[0099] in:

[0100] R 1 is selected from cyano, halogen, methyl and ethyl;

[0101] R 2 is selected from hydrogen, halogen, methyl and ethyl;

[0102] R 3 is selected from halogen, methyl and ethyl;

[0103] R 4 is selected from hydrogen, halogen, methyl, ethyl and methoxy;

[0104] R 5 and R 6 independently selected from hydrogen, C1-C6-alkyl and hydroxy-C1-C6-alkyl; or

[0105] R 5 and R 6 together with the nitrogen to which they are both attached, form a 5- or 6-membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4-alkyl;

[0106] R 7 and R 8 independently selected from hydrogen and C1-C4-alkyl;

[0107] R 9 is selected from C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkyl-C3-C6-cycloalkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy and C1-C6-alkoxy-C1-C6-alkyl; and

[0108] X is selected from a bond, CH2 and O.

[0109] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is a bond. In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CH2. In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is O.

[0110] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 It is ethyl.

[0111] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 It is ethyl.

[0112] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 It is ethyl.

[0113] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 It is a methoxy group.

[0114] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen and R 6 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen and R 6 It is methyl.

[0115] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen and R 8 It is methyl.

[0116] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 9 It is a methoxy group.

[0117] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) corresponds in structure to And R 4 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) corresponds in structure to

[0118] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is O, R 1 is methyl, R 2 is hydrogen, R 3 is halogen, R 4 is halogen, R 5 is hydrogen, R 6is C1-C6-alkyl, R 7 is hydrogen, R 8 is hydrogen, and R 9 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is O, R 1 is methyl, R 2 is hydrogen, R 3 is fluorinated, R 4 is fluorinated, R 5 is hydrogen, R 6 is methyl, R 7 is hydrogen, R 8 is hydrogen, and R 9 It is methyl.

[0119] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is O, R 1 is methyl, R 2 is hydrogen, R 3 is halogen, R 4 is halogen, R 5 is hydrogen, R 6 is C1-C6-alkyl, R 7 is hydrogen, R 8 is hydrogen, and R 9 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is O, R 1 is methyl, R 2 is hydrogen, R 3 is fluorinated, R 4 is fluorinated, R 5 is hydrogen, R 6 is methyl, R 7 is hydrogen, R 8 is hydrogen, and R 9 It is a methoxy group.

[0120] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is O, R 1 is methyl, R 2 is hydrogen, R 3 is methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 is C1-C6-alkyl, R 7 is hydrogen, R 8 is hydrogen, and R 9In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is O, R 1 is methyl, R 2 is hydrogen, R 3 is methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 is methyl, R 7 is hydrogen, R 8 is hydrogen, and R 9 It is methyl.

[0121] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is O, R 1 is methyl, R 2 is hydrogen, R 3 is methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 is C1-C6-alkyl, R 7 is hydrogen, R 8 is hydrogen, and R 9 In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is O, R 1 is methyl, R 2 is hydrogen, R 3 is methyl, R 4 is hydrogen, R 5 is hydrogen, R 6 is methyl, R 7 is hydrogen, R 8 is hydrogen, and R 9 It is a methoxy group.

[0122] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) corresponds structurally to:

[0123]

[0124]

[0125]

[0126]

[0127] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) corresponds in structure to

[0128]

[0129] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) corresponds in structure to

[0130]

[0131] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) corresponds in structure to

[0132]

[0133] In some embodiments of the methods described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) corresponds in structure to

[0134]

[0135] In some embodiments of the methods described herein, the P2X3 antagonist corresponds structurally to

[0136] In some embodiments of the methods described herein, the P2X3 antagonist corresponds structurally to

[0137] In some embodiments of the methods described herein, the P2X3 antagonist corresponds structurally to

[0138] In some embodiments of the methods described herein is a method of treating renal pruritus. In some embodiments of the methods described herein is a method of treating cholestatic pruritus. In some embodiments of the methods described herein is a method of treating hematological pruritus. In some embodiments of the methods described herein is a method of treating endocrine pruritus. In some embodiments of the methods described herein is a method of treating pruritus associated with malignancy. In some embodiments of the methods described herein is a method of treating idiopathic generalized pruritus.

[0139] In some embodiments of the methods described herein, the pruritus is associated with a primary skin disorder. In some embodiments of the methods described herein, the pruritus is associated with a primary skin disorder selected from xerosis, atopic dermatitis, urticaria, psoriasis, arthropod infestation, mastocytosis, dermatitis herpetiformis, and pemphigoid. In some embodiments of the methods described herein, the pruritus is associated with xerosis. In some embodiments of the methods described herein, the pruritus is associated with atopic dermatitis. In some embodiments of the methods described herein, the pruritus is associated with urticaria. In some embodiments of the methods described herein, the pruritus is associated with psoriasis. In some embodiments of the methods described herein, the pruritus is associated with arthropod infestation. In some embodiments of the methods described herein, the pruritus is associated with mastocytosis. In some embodiments of the methods described herein, the pruritus is associated with dermatitis herpetiformis. In some embodiments of the methods described herein, the pruritus is associated with pemphigoid.

[0140] In some embodiments of the methods described herein, the pruritus is an acute condition. In some embodiments of the methods described herein, the pruritus is a chronic condition.

[0141] In certain embodiments, the disclosed compound used in one or more of the aforementioned methods is one of the generic, subgeneric, or specific compounds described herein, such as a compound of formula (I) described herein.

[0142] Preparation of compounds

[0143] The compounds used in the methods described herein are prepared according to the procedures disclosed in US Patent 9,598,409, which is incorporated herein by reference in its entirety, or are prepared according to known organic synthesis techniques starting from commercially available chemicals and / or from compounds described in the chemical literature.Commercially available chemicals were obtained from standard commercial sources, including Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD) and WuXi (Shanghai, China).

[0144] Suitable reference books and papers detailing the synthesis of reactants useful in the preparation of the compounds described herein, or providing references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd edition, Academic Press, New York, 1983; H O House, "Modern Synthetic Reactions," 2nd edition, WA Benjamin, Inc. Menlo Park, Calif. 1972; T L Gilchrist, "Heterocyclic Chemistry," 2nd edition, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th edition, Wiley-Interscience, New York, 1992. Other suitable reference books and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide references to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4th Edition (1992), John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (Editor), "Modern Carbonyl Chemistry" (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S., "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992), Interscience, ISBN: 0-471-93022-9; Solomons, T.W.G., "Organic Chemistry", 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry", 2nd Edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999), John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942 - 2000), John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups", John Wiley & Sons, 73 volumes.

[0145] Specific and similar reactants are also determined by the known chemical index compiled by the Chemical Abstract Service of the American Chemical Society, which is available from most public and university libraries and through online databases (American Chemical Society can be contacted, Washington, DC for more details). Known but commercially unavailable chemicals in the catalog are optionally prepared by custom chemical synthesis houses, where many standard chemical supply houses (e.g., those listed above) provide custom synthesis services. References for the preparation and selection of pharmaceutical salts of compounds described herein are PHStahl and CGWermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0146] Other forms of the compounds disclosed herein

[0147] Isomers

[0148] In addition, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds proposed herein include all cis, trans, cis, trans, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures. In some cases, the compounds exist as tautomers. The compounds described herein include all possible tautomers within the general formula described herein. In some cases, the compounds described herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimeric forms, and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the enantiomers and / or mixtures of diastereomers produced by a single preparation step, combination or mutual conversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared into their individual stereoisomers by reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, separable complexes are preferred (e.g., crystalline diastereoisomer salts). In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these dissimilarity. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation / resolving techniques based on solubility differences. In some embodiments, optically pure enantiomers are subsequently recovered together with a resolving agent by any practical means that will not result in racemization.

[0149] Labeled compounds

[0150] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as respectively 2 H. 3 H. 13 C. 14 C.l5 N. 16 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds described herein containing the above-mentioned isotopes and / or other isotopes of other atoms and pharmaceutically acceptable salts, esters, solvates, hydrates or derivatives thereof are within the scope of the present invention. Certain isotopically labeled compounds, for example, compounds into which radioactive isotopes such as 3 H and 14 C are useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, heavy isotopes (such as deuterium, i.e. 2 H) substitutions yield certain therapeutic advantages. In some embodiments, isotopically labeled compounds, their pharmaceutically acceptable salts, esters, solvates, hydrates or derivatives are prepared by any suitable method.

[0151] In some embodiments, the compounds described herein are labeled by other means including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0152] Pharmaceutically acceptable salts

[0153] In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

[0154] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with some inorganic or organic bases and any base or acid in inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the purified compound in free form with a suitable acid or base, respectively, and isolating the salt thus formed.

[0155] Prodrug

[0156] In some embodiments, the compounds described herein are formulated into medicaments that are converted into active forms in vivo to change the biodistribution or pharmacokinetics of a particular medicament. For example, a carboxylic acid group can be esterified with, for example, a methyl or ethyl group to produce an ester. When the ester is applied to a subject, the ester is enzymatically or non-enzymatically, reductively, oxidatively or hydrolytically cut to reveal an anionic group. Anionic groups can be esterified with certain parts (e.g., acyloxymethyl esters), which are cut to reveal an intermediate that is subsequently decomposed to produce an active agent. Prodrug moieties can be metabolized to carboxylic acids in vivo by esterases or by other mechanisms. Alternatively, other functional groups can be modified into prodrug forms. For example, an amine group can be converted into a carbamate or amide that can be cleaved in vivo.

[0157] Solvate

[0158] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods for treating diseases by administering such solvates. The present invention also provides methods for treating diseases by administering such solvates in the form of pharmaceutical compositions.

[0159] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, solvates are formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed in the process described herein. By way of example only, hydrates of compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents including but not limited to dioxane, tetrahydrofuran or methanol. In addition, compounds provided herein exist in non-solvated forms as well as solvated forms. Generally, for compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0160] Pharmaceutical composition

[0161] In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also herein a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practices as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005)).

[0162] Therefore, a pharmaceutical composition is provided herein, comprising at least one compound as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. If the carrier is compatible with the other ingredients of the composition and is not harmful to the recipient (i.e., subject) of the composition, the carrier (or excipient) is acceptable or suitable.

[0163] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0164] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0165] In certain embodiments, the compounds described herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as, for example, contaminating intermediates or byproducts produced in one or more steps of the synthetic methods.

[0166] These formulations include those suitable for oral, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal or intravenous) or aerosol administration.

[0167] Exemplary pharmaceutical compositions are used in the form of pharmaceutical preparations, such as solid, semisolid or liquid forms, which contain one or more disclosed compounds as active ingredients mixed with organic or inorganic carriers or excipients suitable for external, enteral or parenteral application. In some embodiments, the active ingredients are compounded with, for example, generally non-toxic, pharmaceutically acceptable carriers for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for application. The pharmaceutical composition contains an amount of the active target compound sufficient to produce the desired effect on the disease process or condition.

[0168] In some embodiments, the compounds of formula (I) described herein are administered to a subject in a biologically compatible form suitable for topical administration to treat or prevent skin diseases, disorders or conditions. "Biologically compatible form suitable for topical administration" refers to a form of the compound of formula (I) to be administered in which the therapeutic effect of the inhibitor outweighs any toxic effects. Administration of the compounds of formula (I) as described herein can be in any pharmacological form, including a therapeutically effective amount of the compound of formula (I) alone or in combination with a pharmaceutically acceptable carrier.

[0169] The topical administration of formula (I) compound can be presented in the form of aerosol, semisolid pharmaceutical composition, powder or solution. The so-called term "semisolid composition" refers to an ointment, cream, salves, jelly or other pharmaceutical compositions with a consistency that is substantially similar and suitable for being applied to the skin. The example of semisolid composition is provided in the 17th chapter of The Theory and Practice of Industrial Pharmacy of Lachman, Lieberman and Kanig published by Lea and Febiger (1970) and the 67th chapter of Remington's Pharmaceutical Sciences published by Mack Publishing Company, the 15th edition (1975).

[0170] Skin patch is another method for transdermal delivery of therapeutic or pharmaceutical compositions described herein. The patch can provide an absorption enhancer, such as DMSO, to increase the absorption of the compound. The patch can include those patches that control the rate at which the drug is delivered to the skin. The patch can provide a variety of drug delivery systems, including a reservoir system or an integral system. For example, the reservoir design can have four layers: an adhesive layer that directly contacts the skin, a control membrane that controls the diffusion of drug molecules, a reservoir of drug molecules, and a waterproof backing. Such a design delivers a uniform amount of drug within a specified time period, and the delivery rate must be less than the saturation limit of different types of skin. For example, an integral design usually has only three layers: an adhesive layer, a polymer matrix containing a compound, and a waterproof backing. This design brings a saturated amount of drug to the skin. Therefore, delivery is controlled by the skin. When the amount of drug in the patch is reduced to below the saturation level, the delivery rate decreases.

[0171] In one embodiment, the topical composition may take the form of, for example, a hydrogel based on polyacrylic acid or polyacrylamide; as an ointment, for example with polyethylene glycol (PEG) as a carrier, such as the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, in particular a microemulsion based on water-in-oil or oil-in-water, optionally with the addition of liposomes. Suitable penetration accelerators (entrainers) include sulfoxide derivatives, such as dimethyl sulfoxide (DMSO) or decyl methyl sulfoxide (decyl-MSO) and dioxydiols (diethylene glycol monoethyl ether) or cyclodextrins; and pyrrolidones, such as 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid or biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and its fatty acid esters; urea derivatives, such as dodecyl urea, 1,3-didodecyl urea and 1,3-diphenyl urea; terpenes, such as D-limonene, menthone, α-terpineol, carvone, limonene oxide or 1,8-cineole.

[0172] Ointments, pastes, creams and gels may also contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycol, polysiloxanes, bentonite, silicic acid and talcum, or mixtures thereof. Powders and sprays may also contain excipients, such as lactose, talcum, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these materials. The solution of nanocrystalline antimicrobial metal may be converted into an aerosol or spray by any known means conventionally used to prepare aerosol medicines. Usually, such methods include pressurizing the container of the solution with an inert carrier gas or providing a pressurizing means, and passing the pressurized gas through an aperture. Sprays may contain conventional propellants in addition, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0173] In some embodiments, to prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier (e.g., conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformulation composition containing a uniform mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as uniform, it is meant that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equivalent unit dosage forms such as tablets, pills, and capsules.

[0174] In a solid dosage form for oral administration (capsule, tablet, pill, lozenge, powder, granule, etc.), the composition of the present invention is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any of the following substances: (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethyl cellulose, hydroxypropyl methyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) moisturizers. In some embodiments, the composition comprises a disintegrant, such as glycerol; (4) disintegrants, such as crospovidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retardants, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, for example, sodium docusate, cetyl alcohol, and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, in some embodiments, the composition comprises a buffer. In some embodiments, a similar type of solid composition is also employed as a filler in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

[0175] In some embodiments, tablets are made by compression or molding optionally with one or more auxiliary ingredients. In some embodiments, compressed tablets are prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant. In some embodiments, molded tablets are prepared by molding a mixture of the present composition moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets and other solid dosage forms, such as lozenges, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[0176] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the composition of the invention, in some embodiments, the liquid dosage form also contains an inert diluent, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0177] In some embodiments, suspensions contain, in addition to the compositions of the present invention, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0178] In some embodiments, in addition to the composition of the present invention, powders and sprays also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. In some embodiments, sprays additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0179] Alternatively, the compositions and compounds disclosed herein are administered by aerosol. This is achieved by preparing an aqueous aerosol, liposome preparation or solid particles containing the compound. In some embodiments, a non-aqueous (e.g., fluorocarbon propellant) suspension is used. In some embodiments, a sonic nebulizer is used because they minimize the exposure of the medicament to shear forces (which cause the degradation of the compound contained in the composition of the present invention). Typically, an aqueous aerosol is prepared by preparing an aqueous solution or suspension of the composition of the present invention with a conventional pharmaceutically acceptable carrier and stabilizer. Carriers and stabilizers vary with the requirements of the specific target composition, but typically include nonionic surfactants (Tween, Pluronics or polyethylene glycol), non-toxic proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffer, salt, sugar or sugar alcohol. Aerosols are typically prepared by isotonic solutions.

[0180] Pharmaceutical compositions suitable for parenteral administration comprise the compositions of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders which are reconstituted into sterile injectable solutions or dispersions immediately prior to use and which, in some embodiments, contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0181] Examples of suitable aqueous and nonaqueous carriers used in pharmaceutical compositions include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrins. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0182] The dosage of the composition comprising at least one compound described herein varies depending on the condition of the patient (eg, human), ie, the disease stage, general health status, age, and other factors.

[0183] The pharmaceutical composition is applied in a manner suitable for the disease to be treated (or prevented). Appropriate dosage and suitable duration and frequency of administration will depend on factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient and the method of administration. Typically, appropriate dosage and treatment regimen provide compositions in an amount sufficient to provide treatment and / or prevention benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or the alleviation of symptom severity). Optimal dose is typically determined using experimental models and / or clinical trials. In some embodiments, optimal dose depends on the patient's body mass, body weight or blood volume.

[0184] Oral dosages are generally in the range of about 1.0 mg to about 1000 mg, one to four times a day or more.

[0185] Itching Conditions:

[0186] In some embodiments of the methods of treating pruritus described herein, the pruritus is associated with an inflammatory skin disease. In some embodiments, the inflammatory skin diseases include but are not limited to atopic dermatitis, allergic, irritant contact dermatitis, dry dermatitis, nummular and dyshidrotic dermatitis, lichen planus, lichen sclerosus atrophicus, polymorphous light eruption psoriasis, Grover's disease, mucinosis, mastocytosis, and urticaria;

[0187] In some embodiments of the methods of treating pruritus described herein, the pruritus is associated with an infectious skin disease. In some embodiments, the infectious skin disease includes, but is not limited to, fungal diseases, bacterial and viral infections, scabies, pediculosis, insect bites and folliculitis.

[0188] In some embodiments of the methods of treating pruritus described herein, the pruritus is associated with an autoimmune skin disease. In some embodiments, the autoimmune skin disease includes, but is not limited to, bullous skin disorders, dermatitis herpetiformis (Duhring disease), bullous pemphigoid, hereditary skin diseases such as Darier disease and Hailey-Hailey disease.

[0189] In some embodiments of the methods of treating pruritus described herein, the pruritus is associated with a pregnancy-related skin disease. In some embodiments, the pregnancy-related skin disease includes but is not limited to polymorphic eruption of pregnancy (PEP, formerly known as PUPPP), atopic eruption of pregnancy, pemphigoid gestationis, and neoplasia such as cutaneous T-cell lymphoma.

[0190] Prurigo nodularis (PN) or nodular pruritus is a particularly severe form of chronic pruritus that can be treated with the methods and compositions of the present invention. PN is characterized by itchy, flaky, lichenified papules and nodules that can occur at any age, but most commonly on the arms and legs of middle-aged and elderly patients (E. Weisshaar and S. Stander, Acta Derm. Venereol., 2012, 92: 532-533). PN can cause permanent changes to the skin, including nodular lichenification, hyperkeratosis, hyperpigmentation, and skin thickening.

[0191] Uremic pruritus is a common and distressing problem affecting chronic kidney disease patients undergoing dialysis and can be treated with the methods and compositions of the present invention. Uremic pruritus has an important clinical impact as it is closely associated with poor quality of life, sleep disturbances and depression.

[0192] In some embodiments, examples of itch-related conditions include, but are not limited to, skin disorders and conditions (including inflammatory and non-inflammatory skin conditions), including, but not limited to, adult Blaschkitis, amyloidosis (e.g., primary cutaneous amyloidosis [including macular amyloidosis, lichen amyloidosis, and nodular amyloidosis]), burns (e.g., chemical burns and sunburn), dermatitis {e.g., atopic dermatitis, contact dermatitis (including allergic contact dermatitis, irritant contact dermatitis, and photodermatitis), eczema (e.g., autosensitivity dermatitis, dermatitis herpetiformis [Duhring's disease], discoid eczema, dyshidrosis [dyshidrosis], wet hands rash, id reactions [generalized eczema], nummular eczema, stasis dermatitis [gravitational eczema], venous eczema, and dry eczema), pustular dermatitis (e.g., eosinophilic pustular folliculitis [Ofuji disease], reactive arthritis [Reiter disease], and subcutaneous pustular dermatosis [Sneddon-Wilkinson disease]) and seborrheic dermatitis (e.g., infantile seborrheic dermatitis, Leiner disease, and pityriasis simplex alopecia [dandruff]), erythroderma (exfoliative dermatitis), folliculitis, pseudofolliculitis barbae (tinea barbae), hidradenitis suppurativa, ichthyosis (e.g., tinea vulgaris, tinea congenita, epidermolytic hyperkeratotic ichthyosis, and lamellar tinea), lichen planus (e.g., cutaneous lichen planus and oral lichen planus), lichen sclerosus and atrophicus (e.g., lichen sclerosus and atrophicus of the vulva), lichen simplex (e.g., lichen simplex chronicus [neurodermatitis]), linear IgA bullous dermatoses (linear IgA dermatoses), lupus erythematosus (e.g., cutaneous lupus erythematosus, discoid lupus erythematosus, and systemic lupus erythematosus), prickly heat (heat rash), palmoplantar keratodermas (e.g., palmoplantar keratodermas punctatus), pityriasis (e.g., pityriasis asbestosis, pityriasis lichenoides [including pityriasis lichenoides chronicus and pityriasis lichenoides acute], pityriasis rosea, pityriasis rubra pilaris [Devergie disease], and pityriasis versicolor), prurigo (e.g., actinic prurigo, Besnier prurigo, prurigo nodularis , prurigo pigmentosa and prurigo simplex), anal pruritus, scrotal pruritus, vulvar pruritus, psoriasis (e.g., erythrodermic psoriasis, guttate psoriasis [eruptive psoriasis], psoriasis vulgaris [chronic quiescent psoriasis], pustular psoriasis, and palmoplantar pustulosis), parapsoriasis (e.g., large plaque parapsoriasis and small plaque parapsoriasis [chronic superficial dermatitis]), pitting pruritus (itchy spots), eruptions (e.g., intertrigo and perioral dermatitis), rosacea, urticaria (e.g., contact urticaria [including hives] and idiopathic urticaria), vitiligo, xerosis (dry skin), cracked skin (e.g., cracked feet), scalp pruritus, healing of crusts, scarring, and the occurrence of moles, acne, and ingrown hairs;Medical disorders and conditions (including peripheral and systemic disorders), including but not limited to atopic diathesis, autoimmune disorders (e.g., celiac disease, dermatomyositis, Graves' disease, pemphigoid [e.g., bullous pemphigoid], scleroderma, and Sjögren's syndrome), blood disorders (e.g., anemia [e.g., iron deficiency anemia and sickle cell anemia], hypercalcemia, myelodysplastic syndrome, and erythrocytosis [e.g., polycythemia vera]), Creutzfeldt-Jakob disease (e.g., prion pruritus), diabetes, genetic diseases (e.g., Alagille syndrome, Darier disease, bullous epidermolysis bullosa, Hailey-Hailey disease, and Sjogren-Larsson syndrome), Grover's disease, HIV / AIDS, renal disorders (e.g., diabetic nephropathy, glomerulonephritis, chronic kidney disease, end-stage renal disease, and chronic renal failure), uremia (e.g., uremic pruritus [renal pruritus]), liver disease (e.g., cirrhosis [e.g., primary biliary cirrhosis], hepatitis [including hepatitis A, B, C, D, and E and chronic conditions thereof], and liver failure), cholestasis (e.g., cholestatic pruritus), jaundice (e.g., biliary pruritus), gonorrhea adenopathy (e.g., lymphadenopathy), mast cell disease (e.g., mast cell activation syndrome and mastocytosis), multiple sclerosis, neuropathy (e.g., peripheral neuropathy [e.g., brachioradialis pruritus, paresthesia, polyneuropathy, and small fiber peripheral neuropathy]), nerve irritation, nerve pinch, parathyroid disorders (e.g., hyperparathyroidism and hypoparathyroidism), thyroid disorders (e.g., hyperthyroidism, hypothyroidism, and myxedema), stroke, cancer {e.g., carcinoid syndrome, leukemia (e.g., leukemia cutis and lymphoid leukemia), lymphoma (e.g., Hodgkin's disease and non-Hodgkin's lymphomas [e.g., cutaneous B-cell lymphomas and cutaneous T-cell lymphomas (including mycosis fungoides and Sézary's disease)]), Kaposi's sarcoma, multiple myeloma, and skin cancers}, tumors (e.g., brain tumors, plasmacytomas, and solid tumors of the cervix, colon, and prostate), paraneoplastic pruritus, psychiatric disorders (e.g., stress, anxiety, delusional parasitosis, depression, obsessive-compulsive disorders [e.g., excoriation neurosis], and tactile hallucinations), aging (e.g., senile pruritus), and changes in hormonal balance associated with aging (e.g., perimenopause and menopause);Infections and infestations, including but not limited to cercarial dermatitis (swimmer's itch), insect bites and stings (e.g., bites and stings from ants, bees, chiggers, fleas, lice (including body lice, head lice and pubic lice), mites, mosquitoes, spiders, ticks and wasps), scabies, bacterial infections (e.g., abscesses, gangrenous dermatitis, acne, erythra, impetigo and Lyme disease), fungal infections (e.g., candidiasis, dermatophytosis, tinea corporis [ringworm of the body], tinea cruris [jock itch]), itch] and tinea pedis [athlete's foot]), viral infections {e.g., herpes (including shingles and post-herpetic pruritus), measles, parvovirus infections (e.g., parvovirus B19), varicella, and yellow fever}, and helminth infections (e.g., helminths (e.g., helminthiasis [enteric worms]), hookworms (e.g., cutaneous larva migrans), Onchocerca worms (e.g., onchocerciasis [river blindness]), pinworms, roundworms (e.g., filariasis and trichinosis), and Schistosoma worms (e.g., schistosomiasis)}; reactions to allergens and irritants, including, but not limited to, allergic rhinitis (e.g., hay fever [including hay fever]), asthma, animal allergens (e.g., cat dander and dog dander), chemical allergens (e.g., acids [e.g., rosin acid and sorbic acid]), cosmetics, detergents, dyes, fabric softeners, fungicides , hydroxyethyl starch, and latex), food allergens (e.g., milk proteins, peanuts, tree nuts, seafood, spices, preservatives [e.g., nitrates], vitamins [e.g., vitamins A and B], alcohols, caffeine, and monosodium glutamate), metal and metal salt allergens (e.g., chromium, cobalt, gold, and nickel and their salts), plant allergens (e.g., balsam of Peru and urushiol [e.g., in poison ivy, poison oak, and poison sumac]), chemical irritants (e.g., acids, bases, metalworking fluids, solvents, surfactants, detergents, soaps, cleaning products, cosmetics, perfumes, deodorants, antiperspirants, food flavorings, fragrances, preservatives [e.g., formaldehyde and parabens], monomers and polymers [e.g., acrylics, epoxies, ethylene oxide, latex, and lacquers], and oils [e.g., kerosene]), fabrics (e.g., wool), plant irritants (e.g., alkylresorcinols [e.g., in Grevillea bankii), Grevillea "Robyn Gordon", and Gingko biloba]) and physical irritants (e.g., water [e.g., aquadynia and aquagenic pruritus], low humidity and cold temperatures caused by air conditioning);Pruritus caused by drugs / medicines, including but not limited to chloroquine, hydroxyethylcellulose, hydroxyethyl starch, angiotensin-converting enzyme inhibitors, xanthine oxidase inhibitors (e.g., allopurinol), antibiotics (e.g., isoniazid, neomycin, penicillin, sulfonamides, and vancomycin), antifungals (e.g., fluconazole, griseofulvin, itraconazole, and ketoconazole), neuroleptics / antipsychotics (e.g., phenothiazines), antiarrhythmics (e.g., amiodarone and quinidine), chemotherapeutic agents, diuretics (e.g., hydrochlorothiazide), statins (e.g., simvastatin), and drugs that activate histamine H1 receptors or trigger histamine release (e.g., opioids); and conditions related to pregnancy, including but not limited to pemphigoid gestationis, impetigo herpetiformis, intrahepatic cholestasis of pregnancy (pruritus gestationis), polymorphic eruption gestationis, prurigo gestationis, pruritic folliculitis gestationis, and pruritic urticarial papules and plaques of pregnancy. ;

[0193] In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with kidney disease or a therapeutic procedure used to treat kidney disease. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with kidney disease. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with chronic kidney disease. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with a therapeutic procedure used to treat kidney disease. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with a therapeutic procedure used to treat kidney disease, wherein the therapeutic procedure used to treat kidney disease is hemodialysis or peritoneal dialysis. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with a therapeutic procedure used to treat kidney disease, wherein the therapeutic procedure used to treat kidney disease is hemodialysis. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with a therapeutic procedure used to treat kidney disease, wherein the therapeutic procedure used to treat kidney disease is peritoneal dialysis. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with a medical procedure or treatment. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with a medical procedure. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with a medical treatment. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with medical treatment with a drug selected from opioids, antimalarials, anticancer therapies, and epidermal growth factor receptor inhibitors. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with medical treatment with opioids. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with medical treatment with antimalarials. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with medical treatment with anticancer therapies. In some embodiments is a method of treating pruritus in a mammal, wherein the pruritus is associated with medical treatment with an epidermal growth factor receptor inhibitor.

[0194] Drug combinations

[0195] This article also relates to combination therapy, for example, co-administering the disclosed compounds and additional active agents as part of a specific treatment regimen intended to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effects of the combination therapy include, but are not limited to, pharmacokinetic or pharmacodynamic co-actions produced by the combination of therapeutic agents. The combined administration of these therapeutic agents is generally carried out over a limited time period (usually weeks, months, or years, depending on the selected combination). Combination therapy is intended to encompass the administration of multiple therapeutic agents in a sequential manner, i.e., wherein the various therapeutic agents are administered at different times, and is intended to encompass the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner.

[0196] For example, substantially simultaneous administration is achieved by administering to the subject each therapeutic agent in the form of a single formulation or composition (e.g., a tablet or capsule with a fixed ratio of various therapeutic agents) or multiple single formulations (e.g., capsules). The sequential administration or substantially simultaneous administration of the various therapeutic agents is achieved by any appropriate route, including but not limited to oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. The therapeutic agents are administered by the same route or by different routes. For example, the first therapeutic agent in the selected combination is administered by intravenous injection, while the other therapeutic agents in the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally, or all therapeutic agents are administered by intravenous injection.

[0197] In some embodiments, a method of treating pruritus in a mammal in need thereof comprises administering a P2X3 antagonist to the mammal, further comprising administering one or more additional pharmaceutical agents to the mammal. In some embodiments, a method of treating pruritus in a mammal in need thereof comprises administering a compound of formula (I) to the mammal, further comprising administering one or more additional pharmaceutical agents to the mammal. In some embodiments, the one or more additional pharmaceutical agents are selected from antihistamines, including but not limited to antihistamines that inhibit the action on histamine H1 receptors (e.g., acrivastine, antazoline, azelastine, bilastine, brompheniramine, buclizine, brompheniramine, carbinoxamine, cetirizine, chlorpromazine, cyclizine, chlorpheniramine, chlorpheniramine, chlorpheniramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, tea Dimenhydrinate, dimethindrine, diphenhydramine, doxepin, doxylamine, ebastine, enbramine, fexofenadine, hydroxyzine, levocetirizine, loratadine, meclizine, mepyramine, mirtazapine, olopatadine, orphenadrine, phenindamide, pheniramine, phenyltoloxamine, promethazine, pyrilamine, quetiapine, rupatadine, tripeliramine, and triprolidine), as well as antihistamines that inhibit the action on histamine H4 receptors (e.g., thioperamide, JNJ 7777120 and VUF-6002), and their analogs and derivatives; serotonin receptor antagonists, including but not limited to 5-HT2 antagonists (e.g., clozapine, cyproheptadine, ketanserin, pizotifen and quetiapine) and 5-HT3 antagonists (e.g., alosetron, cilansetron, dolasetron, granisetron, ondansetron, palonosetron and tropisetron) and their analogs and derivatives; neurokinin-1 (NK-1) receptor antagonists, including but not limited to serlopitant, aprepitant, casopitant (GW679769), dapitant, elopitant, fosaprepitant, lanapitant (LY-303870), maropitant, netupitant, nolpitant, orvipitant, rolapitant, viltipitant, wolflopitant, AV-818, BIIF 1149CL, CP122,721, DNK-333, GSK-424887, L-733060, L-759274, LY-686017, M516102 and TA-5538 and their analogs and derivatives; opioid receptor antagonists, including but not limited to butorphanol, cyprodime, levallorphan (levallorphan tartrate (lorfan) or propylene oxymorphan), nalbuphine, nalorphine (propylene morphine or nalorphine), naloxone, naloxol, nalmefene, naltrexone (e.g., naltrexone 1% cream) and naltrexol and their analogs and derivatives;Opioid receptor agonists, including but not limited to selective kappa opioid receptor agonists (e.g., acipadorin, bumazocin, dynorphin, enadoline, ketazocine, nalfurapine, salvinorin A, 2-methoxymethyl salvinorin B, 2-ethoxymethyl salvinorin B, 2-fluoroethoxymethyl salvinorin B, spirodolin, teflonol, BRL-52537, FE 200665, GR-89696, HZ-2, ICI-199,441, ICI-204,448, LPK-26, U-50488 and U-69,593) and their analogs and derivatives; Janus kinase (JAK) inhibitors, including but not limited to JAK1 inhibitors (e.g., GLPG0634 and GSK2586184), JAK2 inhibitors (e.g., letutinib, pacritinib, CYT387 and TG101348), JAK1 / JAK2 inhibitors (e.g., baricitinib and ruxolitinib) and JAK3 inhibitors (e.g., tofacitinib) and their analogs and derivatives; immunomodulators and immunosuppressants, including but not limited to thalidomide, antimetabolites (e.g., antifolates such as methotrexate), and calcineurin inhibitors (e.g., cyclosporine [Cyclosporin antidepressants, including, but not limited to, tricyclic antidepressants (e.g., amitriptyline, amitriptyline oxy, amoxapine, dosulipin [dothiepin], doxepin, and melitracen), tetracyclic antidepressants (e.g., amoxapine, maprotiline, mazindol, mianserin, mirtazapine, and setiptiline), selective serotonin reuptake inhibitors (SSRIs, e.g., citalopram, dapoxetine), , escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline), and serotonin-norepinephrine reuptake inhibitors (SNRIs, such as bicifadine, duloxetine, milnacipran, levomilnacipran, sibutramine, venlafaxine, desvenlafaxine and SEP-227162) and their analogs and derivatives; anticonvulsants, including but not limited to carbamazepine, gabapentin, pregabalin and valproic acid and its salts (e.g., sodium valproate) and their analogs and derivatives;Corticosteroids, including but not limited to hydrocortisone types (e.g., cortisone and its derivatives [e.g., cortisone acetate], hydrocortisone and its derivatives [e.g., hydrocortisone acetate, hydrocortisone-17-acetate propionate, hydrocortisone-17-butyrate propionate, hydrocortisone-17-butyrate, and hydrocortisone-17-valerate], prednisolone, methylprednisolone and its derivatives [e.g., methylprednisolone acetonide], prednisone and tixocortol and its derivatives [e.g., tixocortol pivalate]), betamethasone types (e.g., betamethasone and its derivatives [e.g., betamethasone dipropionate, betamethasone sodium phosphate, and betamethasone valerate], dexamethasone and its derivatives [e.g., dexamethasone sodium phosphate], and fluocortolone and its derivatives [e.g., fluocortolone caproate] and flucortolone pivalate], halogenated steroids (e.g., alclomethasone and its derivatives [e.g., alclomethasone dipropionate], beclomethasone and its derivatives [e.g., beclomethasone dipropionate], clobetasol and its derivatives [e.g., clobetasol-17-propionate], clobetasone and its derivatives [e.g., clobetasone-17-butyrate], desoximetasone and its derivatives [e.g., desoximetasone acetate], diflorasone and its derivatives [e.g., diflorasone diacetate], diflucortolone and its derivatives [e.g., diflucortolone valerate], flupredniidine and its derivatives [e.g., fluticasone propionate], halobetasol and its derivatives [e.g., halobetasol propionate], halometasone and its derivatives [e.g., halogenated steroids], and mometasone and its derivatives [e.g., mometasone furoate]), acetonides and related substances (e.g., amcinonide, budesonide, ciclesonide, desonide, fluocinolone acetonide, fluocinolone acetonide, flurandrenolide [flurane], halcinonide, triamcinolone acetonide, and triamcinolone alcohol) and carbonates (e.g., prednicarbate) and its analogs and derivatives; local anesthetics, including, but not limited to, amides (e.g., articaine, bupivacaine, cinchocaine [dibucaine], etidocaine, levobupivacaine, lidocaine [e.g., lidocaine 2.5-5% cream], prilocaine [e.g., prilocaine 2.5% cream], EMLA [lidocaine 2.5% / prilocaine 2.5% cream], mepivacaine, ropivacaine, and trimecaine), esters anesthetics (e.g., benzocaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine [larocaine], piperocaine, procaine [novocaine], proparacaine, propoxycaine, stovagine, and tetracaine), ethers (e.g., polidocanol [e.g., polidocanol 3% foam] and pramoxine [pramoxine] [e.g., pramoxine 1% cream]), and naturally derived local anesthetics (e.g., cocaine, eugenol, menthol, saxitoxin, neosaxitoxin, and tetrodotoxin), and their analogs and derivatives; counterirritants and cooling agents, including, but not limited to, capsaicin, camphor, peppermint oil, menthol (e.g., menthol 1-3% cream), and phenol (e.g., in calamine lotion), and their analogs and derivatives;Moisturizers, including but not limited to aqueous moisturizers, low pH moisturizers containing acids (e.g., lactic acid), and moisturizers containing humectants that attract and retain water (e.g., glycerin, sorbitol, lactates, urea, and hyaluronic acid and its salts), occlusive agents that prevent evaporation [e.g., oils (e.g., mineral oil and silicone oils [e.g., dimethicone]) and petrolatum (petrolatum)] and / or emollients that provide partial hydration and occlusion (e.g., oils, waxes [e.g., lanolin and paraffin], lipids [e.g., phospholipids, ceramides, triglycerides, glycol stearate, glyceryl stearate, fatty acids, acid and squalene] and sterols [such as cholesterol and phytosterols]) and their analogs and derivatives; and other types of antipruritic drugs, including but not limited to S-adenosylmethionine, botulinum toxins (such as botulinum toxin types A and B), vitamin D and its analogs and derivatives (such as calcitriol and calcipotriol [calcipotriol]), nonsteroidal anti-inflammatory drugs (NSAIDs, such as aspirin), cannabinoid receptor agonists (such as CB2 agonists such as palmitoylethanolamide), cytokine inhibitors (such as anti-interleukins (such as IL-31) antibodies, antagonists of the prostaglandin D2 receptor (DP1) and / or chemotactic receptor homologous molecule expressed on TH2 cells (CRTH2) (e.g. TS-022), phosphodiesterase (PDE) inhibitors (e.g. PDE4 inhibitors such as apremilast), protease activated receptor 2 (PAR2) antagonists (e.g. GB83), transient receptor potential vanilloid (TRPV) antagonists (e.g. TRPV1 antagonists such as capsazepine and SB-705498 ), inhibitors of neurotrophic tyrosine kinase receptors (e.g., TrkA inhibitors such as CT327), antimicrobial agents (including antibiotics, antifungals, antivirals, and antiparasitics such as crotamiton and rifampicin), agents that reduce bile absorption or sequester bile (e.g., ursodiol), ultraviolet radiation (e.g., ultraviolet A and B), and therapeutic agents that treat the underlying cause of pruritus-related conditions, and their analogs and derivatives. ;

[0198] In some embodiments is a method of treating pruritus in a mammal in need thereof, the method comprising administering to the mammal a P2X3 antagonist, further comprising administering to the mammal a NK-1 antagonist. In some embodiments is a method of treating pruritus in a mammal in need thereof, the method comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt thereof, further comprising administering to the mammal a NK-1 antagonist, wherein the NK-1 antagonist is selected from but not limited to serlopitant, aprepitant, casopitant, dapitant, elopitant, fosaprepitant, lanapitant, maropitant, netupitant, nolpitant, orvipitant, rolapitant, viltipitant, wolflopitant, AV-818, BIIF 1149CL, CP122,721, DNK-333, GSK-424887, L-733060, L-759274, LY-686017, M516102 and TA-5538, and analogs and derivatives thereof. In some embodiments, a method of treating pruritus in a mammal in need thereof, the method comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt thereof, further comprising administering to the mammal a NK-1 antagonist, wherein the NK-1 antagonist is selected from serlopitant, oravipitant, rolapitant, aprepitant and fosaprepitant, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating pruritus in a mammal in need thereof, the method comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt thereof, further comprising administering to the mammal a NK-1 antagonist, wherein the NK-1 antagonist is serlopitant or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating pruritus in a mammal in need thereof, the method comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt thereof, further comprising administering to the mammal a NK-1 antagonist, wherein the NK-1 antagonist is oravipitant or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating pruritus in a mammal in need thereof comprises administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt thereof, and further comprises administering to the mammal a NK-1 antagonist, wherein the NK-1 antagonist is rolapitant or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating pruritus in a mammal in need thereof comprises administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt thereof, and further comprises administering to the mammal a NK-1 antagonist, wherein the NK-1 antagonist is aprepitant or a pharmaceutically acceptable salt thereof.In some embodiments, a method of treating pruritus in a mammal in need thereof comprises administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt thereof, and further comprises administering to the mammal a NK-1 antagonist, wherein the NK-1 antagonist is fosaprepitant or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments of the pharmaceutical combinations described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and the NK-1 antagonist is a compound described in US 2005 / 0176715 (which is incorporated herein by reference).

[0200] In some embodiments of the drug combinations described herein, the P2X3 antagonist is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and the NK-1 antagonist is a compound described in US2017 / 0326141 (which is incorporated herein by reference).

[0201] Combination therapy also includes the therapeutic agent as described above, further administered in combination with other biologically active ingredients and non-drug therapies. In the case where the combination therapy further includes non-drug therapy, the non-drug therapy is performed at any appropriate time, as long as the beneficial effect is achieved by the combined action of the therapeutic agent and the non-drug therapy. For example, in appropriate cases, when the non-drug therapy is temporarily removed from the administration of the therapeutic agent, perhaps for several days or even weeks, a beneficial effect is still achieved.

[0202] The components of the combination are administered to the patient simultaneously or sequentially. It should be understood that these components are present in the same pharmaceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers that are administered simultaneously or sequentially, such as conventional oral dosage forms.

[0203] Example

[0204] This example is provided for illustrative purposes only and is not intended to limit the scope of the claims provided herein.

[0205] Example 1: Chloroquine-induced acute pruritus mouse model

[0206] The effects of the P2X3 receptor antagonist compounds described herein were evaluated in a mouse model of chloroquine-induced acute itch and its enhancement by α,β-methyleneadenosine 5'-triphosphate (α,β-Me-ATP). Compound 1 was evaluated at three doses. The kappa-opioid agonist U50,488 was used as a positive control.

[0207] Low dose chloroquine (CQ, 20 μg, Sigma) and α,β-Me-ATP (10, 50 or 100 μM) were dissolved in saline (0.9% NaCl). High dose CQ (200 μg) was dissolved in saline. Test articles (2, 10 or 50 mg / kg body weight, calculated from 25 g body weight per mouse) were dissolved in vehicle (saline adjusted to pH 5.3 for complete dissolution). U50,488 (3 mg / kg, Sigma) was dissolved in vehicle (saline).

[0208] Mice were shaved at the nape of the neck and placed in a behavior chamber twice for 30 minutes to adapt before injection and itch behavior. 30 minutes before intradermal injection, the mouse was pre-injected with vehicle, compound 1 or U50,488 intraperitoneally (ip) in a volume of 100 μL. Mice were injected with a compound of 50 μL volume intradermally (id) at the nape of the neck skin, placed in a behavior chamber alone, and recorded videos at a side angle for 30 minutes. Scratching is defined as lifting the hind limbs toward the nape of the neck or the head to scratch, and then the hind limbs are put back on the floor, regardless of how many times scratching behavior (Munanairi et al. Cell Rep. 2018, 23, 866-877; Yu et al., Science 2017, 355, 1072-1076) occurred between lifting and putting down the hind limbs. Injection experimenters and scratching behavior observers were not aware of the injection compound and mouse group, respectively.

[0209] All data are presented as mean number of scratches ± standard error of the mean (sem). One-way ANOVA with Tukey multiple comparison post hoc test was performed for total scratching within 15 minutes to compare more than 2 groups. Unpaired t-test was performed for all scratching within 15 or 30 minutes to compare 2 groups. For all data sets, two-way RM ANOVA with Tukey or Sidak multiple comparison post hoc test was performed on the time course with 5-minute scratching intervals.

[0210] Mice co-injected with CQ + 10 μM α, β-Me-ATP showed increased scratching behavior compared to mice injected with CQ alone, while mice injected with 10 μM α, β-Me-ATP alone showed almost no scratching behavior (2.4 ± 0.9 scratches). The increase in scratching caused by the use of CQ + 10 M α, β-Me-ATP was statistically significant (p = 0.0013, CQ vs. CQ + 10 μM α, β-Me-ATP), although it was a relatively modest increase (17.2 ± 2.4 CQ vs. 28.2 ± 2.2 CQ + 10 μM α, β-Me-ATP). To further test the potentiation effect of α, β-Me-ATP on CQ-induced itch, mice were co-injected with CQ + 50 μM α, β-Me-ATP ( Figure 1). Mice co-injected with CQ+50μMα,β-Me-ATP showed further increased scratching behavior compared to CQ alone or CQ+10μMα,β-Me-ATP. Mice injected with 50μMα,β-Me-ATP alone showed almost no scratching behavior (5.6±1.8), which was comparable to 10μMα,β-Me-ATP. The increase in scratching caused by CQ+50μMα,β-Me-ATP was statistically significant (p<0.001, CQ vs. CQ+50μMα,β-Me-ATP).

[0211] Next, the effect of the test substance on acute itch was tested. Compared with mice pre-injected with vehicle, mice pre-injected with 2, 10 or 50 mg / kg of the test substance showed reduced scratching behavior for 20 μg CQ + 50 μM α, β-Me-ATP at a dose of 10 mg / kg, showing a significant difference compared with the vehicle (p = 0.0084, 46.6 ± 2.9 scratches for the vehicle, compared with 28.3 ± 4.6 scratches for the test substance 10 mg / kg) ( Figure 2 ). The effect of reducing scratching behavior was similar to U50,488 (p=0.0016, vehicle 46.6±2.9 scratches compared to U50,488 3mg / kg 25.4±2.5 scratches). Next, higher concentrations of α,β-Me-ATP were tested with CQ itch and the test substance was pre-injected at 10mg / kg. Mice pre-injected with the test substance at 10mg / kg also showed a significant difference in total scratching behavior in response to 20μg CQ+100μM α,β-Me-ATP compared to mice pre-injected with vehicle (p=0.0074, vehicle 67±6.3 scratches compared to test substance 10mg / kg 44.8±3.8 scratches) ( Figure 3 Finally, a high dose of CQ (200 μg) was tested, and the test substance was pre-injected at 10 mg / kg. Mice pre-injected with the test substance at 10 mg / kg showed a significant difference in total scratching behavior in response to 200 μg CQ compared to mice pre-injected with vehicle (p=0.011, 280±16.1 scratches for vehicle compared to 221.8±12.9 scratches for test substance 10 mg / kg) ( Figure 4 ).

[0212] Taken together, the data indicate that ATP can effectively enhance CQ-induced itch. However, ATP itself does not show significant activity as a pruritogen when injected alone at the concentrations tested in this study. The data also indicate that Compound 1 effectively inhibits (40% reduction) the enhancement of CQ-induced itch by ATP, similar to the inhibitory effect of the KOR agonist U50,488 (45% reduction). In addition, Compound 1 also effectively inhibits (33% reduction) the enhancement of CQ-induced itch by higher concentrations of ATP. Finally, the test article is effective in inhibiting itch induced by high doses of CQ (21% reduction).

[0213] Example 2: AEW (acetone-ether-water) dry skin model

[0214] The nape of C57Bl6 / J male mice (6 weeks old) was shaved, and a mixture of acetone and ether (1:1) was applied to the nape skin for 15 seconds with a cotton pad, and then distilled water was applied immediately for 30 seconds. The scheme was applied twice a day for 9 days. On the 10th day, 30 minutes before monitoring pruritus behavior, the mice were pre-injected intraperitoneally with a volume of 4mL / kg body weight with vehicle, compound 1 (2, 10 or 50mg / kg) or U50,488 (3mg / kg). Mice were placed in a behavior chamber alone, and videos were recorded at a side angle for 60-90 minutes. Scratching was defined as lifting the hind limbs toward the nape or head to scratch, and then the hind limbs were put back on the floor, regardless of how many times the scratching behavior occurred between lifting and putting down the hind limbs. The injection experimenter and the scratching behavior observer were unaware of the injection compound and the mouse group, respectively.

[0215] Compared to vehicle-injected mice, mice injected with 2, 10, or 50 mg / kg Compound 1 showed a decrease in spontaneous scratching over 60 minutes, similar to mice injected with U50,488 (positive control) (***p<0.001; ns: not significant) ( Figure 5 ). The reduction in scratching was statistically significant for all Compound 1 doses compared to vehicle. Time course analysis at 10-minute intervals showed that Compound 1 showed significant effects on spontaneous scratching at 20, 40, 50, and 60 minutes (*p<0.05; **p<0.01; ***p<0.001) ( Figure 6 ).

[0216] Example 3: Atopic dermatitis model

[0217] MC903 (calcipotriol, Tocris) was dissolved in 100% ethanol and applied topically to the ears (4 nmol in 40 μl, 10 μl per ear) or nape (4 nmol in 40 μl) of C57Bl6 / J male mice. The regimen was applied twice a day for 7 days. Scratching behavior was recorded 16 hours after the last MC903 treatment. On the 8th day, 30 minutes before monitoring itch behavior, mice were pre-injected intraperitoneally with vehicle, compound 1 (2, 10 or 50 mg / kg) or U50,488 (3 mg / kg) in a volume of 4 mL / kg body weight. Mice were placed in a behavior chamber alone and videos were recorded at a lateral angle for 60-90 minutes. Scratching was defined as lifting the hind limbs toward the nape or head for scratching, and then putting the hind limbs back on the floor, regardless of how many scratching behaviors occurred between lifting and putting down the hind limbs. The injection experimenter and the scratching behavior observer were unaware of the injection compound and the mouse group, respectively.

[0218] Mice injected with 2, 10 or 50 mg / kg of Compound 1 showed a dose-dependent reduction in spontaneous scratching over 60 minutes compared to mice injected with vehicle. The reduction in scratching was statistically significant for all three doses. The two high doses of Compound 1 (10 mg / kg and 50 mg / kg) produced similar effects to the positive control (U50,488) (*p<0.05; ***p<0.001; ns: not significant) ( Figure 7 ). Time course analysis at 10-minute intervals showed that the test substance showed significant effects on spontaneous scratching at 10, 20, 30, 40, 50, and 60 minutes (*p<0.05; **p<0.01; ***p<0.001) ( Figure 8 ).

Claims

1. Use of a compound, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating pruritus in a mammal, wherein the compound is:

2. The use according to claim 1, wherein the mammal is a human.

3. The use according to claim 1, wherein the medicament further comprises a second therapeutic agent.

4. The use according to claim 3, wherein the drug further comprises an opioid receptor agonist, an antihistamine, a JAK inhibitor, a PDE inhibitor or a cytokine inhibitor.

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