Compositions and methods for treating pruritus

Abstract

Provided are methods for treating pruritus, reducing pruritus, and / or suppressing pruritus in a patient, the method comprising administering to the patient a therapeutically effective amount of an alpha-2B adrenergic receptor antagonist, where the alpha-2B adrenergic receptor antagonist comprises a 2,3-dihydrobenzothiazole core or is a compound of Formula (I).

Description

Atty. Dkt. No.: 142581-0102COMPOSITIONS AND METHODS FOR TREATING PRURITUS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 739,358, filed on December 27, 2024, the contents of which are incorporated herein by reference in their entirety.BACKGROUND

[0002] Pruritus is the medical term for an itchy skin sensation that causes the urge to scratch, and this condition can negatively impact psychological and physical aspects of life. Pruritus can be localized to one area of the body, or it can affect the entire body.[0003 [ Pruritus can be categorized into four classifications: dermatological conditions; systemic diseases, where pruritus is triggered by disorders affecting organs other than the skin, such as hepatobiliary, and renal disorders; neurological diseases; and psychiatric disorders. For dermatological conditions, pruritus is a common symptom of multiple skin diseases, including highly prevalent diseases such as allergic contact dermatitis, atopic dermatitis, psoriasis, chronic urticaria, and xerosis cutis, as well as rare skin diseases such as prurigo nodularis, epidermolysis bullosa, lichen planus, actinic prurigo, morgellons disease, and aquagenic pruritus.

[0004] When pruritus lasts for longer than six weeks, it is considered chronic pruritus (CP). A recurrent cycle is often developed in patients experiencing CP due to skin damage resultant from scratching, leading to stimulation and sensitization of sensory fibers, which is a trigger for further scratching, thus exacerbating skin damage. This positive feedback cycle prolongs itch, contributes to skin injury, reducing skin healing, and may lead to infection and / or scarring.

[0005] It is generally considered that the cause of itching is complicated and many factors are involved in itching including internal and external factors. The intrinsic factors may be related to chronic infection, block of blood circulation, change of endocrine and metabolism, hereditary tendency to allergies, and so on, while the extrinsic ones are more complex and -1- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102changeable, consisting of food, inhaled substances, chemical materials, animal hair and fur skin, etc.

[0006] There is a need in the art for pharmaceutical compositions and treatment methods for pruritus, and the present disclosure satisfies this need.SUMMARY

[0007] In an aspect, provided is a method for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt thereof,wherein:X is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, a hydroxy group, a cycloalkyl group, and a heterocyclic group;Y is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a cycloalkyl group; andZ represents one to four substituents, wherein each Z is independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, a heterocyclic group, a halogen, and a hydroxy group.

[0008] In another aspect, provided is a method for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the method comprising administering to the patient a therapeutically effective amount of an alpha-2B adrenergic receptor antagonist, wherein the alpha-2B adrenergic receptor antagonist comprises a 2,3 -dihydrobenzothiazole core.-2- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102[00091 In yet another aspect, provided is method of inducing noradrenaline release in a patient, the method comprising administering to the patient a therapeutically effective amount of an alpha-2B adrenergic receptor antagonist, wherein the alpha-2B adrenergic receptor antagonist comprises a 2,3-dihydrobenzothiazole core.

[0010] In another aspect, provided is a pharmaceutical composition for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a subject diagnosed with pruritis, the pharmaceutical composition comprising a physiologically effective amount of a compound that induces noradrenaline release and which is an alpha-2B adrenergic receptor antagonist, wherein the alpha-2B adrenergic receptor antagonist comprises a 2,3-dihydrobenzothiazole core.

[0011] In some embodiments, the alpha-2B adrenergic receptor antagonist having a 2,3-dihydrobenzothiazole core is a compound of Formula (I), as defined above.[00121 In another aspect, provided is a method for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound that induces noradrenaline release, wherein the compound that induces noradrenaline release is a compound of Formula (I), as defined above.

[0013] In yet another aspect, provided is a pharmaceutical composition for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), as defined above.

[0014] In some embodiments, for the compound of Formula (I):X is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, and a hydroxy group;Y is selected from the group consisting of a hydrogen atom and an alkyl group; and Z is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, and a hydroxy group.

[0015] In some embodiments, for the compound of Formula (I):-3- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102X is selected from the group consisting of an alkyl group and an alkoxy group;Y is selected from the group consisting of a hydrogen atom and an alkyl group; and Z is selected from the group consisting of an alkoxy group and a halogen.

[0016] In some embodiments, for the compound of Formula (I):X is an alkyl group;Y is an alkyl group; andZ is selected from the group consisting of an alkoxy group and a halogen.

[0017] In some embodiments, for the compound of Formula (I):X is a methyl group;Y is an ethyl group; andZ is selected from the group consisting of a methoxy group, a fluorine atom, a chlorine atom, and a bromine atom.]0018[ In some embodiments, the compound of Formula (I) is selected from the group consisting of:

[0019] In some embodiments, the patient suffers from acute pruritus.

[0020] In some embodiments, the patient suffers from chronic pruritus.

[0021] In some embodiments, the therapeutically effective amount of the compound is from about 0.1 mg / kg to about 50 mg / kg.

[0022] In some embodiments, the pharmaceutical composition is formulated for oral, topical, transdermal, intravenous, intramuscular, or intrathecal administration.-4- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102[00231 In some embodiments, the pharmaceutical composition is formulated for topical administration and is a gel, an ointment, a paste, or a cream.

[0024] In some embodiments, the pharmaceutical composition is administered to the patient once a day, twice a day, or three times a day.

[0025] Both the foregoing summary and the following brief description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the invention, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 is a schematic drawing of the neuronal interactions between dorsal root ganglia (DRG) neurons and spinal neurons in the itch (top) and pain (bottom) pathways. The bold or thicker lines indicate the activated pathways. In the itch pathway, when pruriceptive DRG neurons are selectively activated by either pruriceptive or nociceptive stimuli, the itch sensation is produced. In the pain pathway, when nociceptive stimuli activate both pruriceptive and nociceptive DRG neurons, the itch sensation is suppressed by the inhibitory spinal interneurons, and only the pain sensation is produced. For the purposes of this figure, the sensory fibers of all DRG neurons are bundled into one single line to represent the peripheral and central terminals. Each different population of spinal neurons is represented by a single neuron. Minus signs indicate the inhibitory synapse between the interneuron and the pruriceptive spinal neuron.

[0027] FIG. 2 is a schematic drawing of the neural itch pathway (5-HT = 5-Hydroxytryptamine (serotonin); CGRP = calcitonin gene-related peptide; ETA = endothelin-A receptor; Glu = glutamate; IL = interleukin; LTB4 = leukotriene B4 ; Mrgpr = Mas-related G protein-coupled receptor; NE = norepinephrine; OSMR = oncostatin M receptor; Oxid. stress = oxidative stress; PAF = platelet-activating factor; PAR = protease-activated receptor; PAFR = platelet-activating factor receptor; SP = substance P; TGR5 = G protein-coupled bile acid receptor; TLR = Toll-like receptor).-5- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102[0028| FIG. 3 is a schematic drawing depicting the relationships between the pain pathway, noradrenaline, and alpha-2B adrenergic receptor antagonists. The compounds as described herein are alpha-2B adrenergic receptor antagonists, which induce noradrenaline release in the spinal dorsal horn (a descending pathway). The alpha-2B adrenergic receptor antagonists demonstrate analgesic effects in pain model animals and demonstrate pain-killer effects in non-human primates.

[0029] FIG. 4A shows the treatment method and dosing timeline used in the chloroquine-induced itch model for assessing whether the compounds as described herein can ameliorate itch. C57BL / 6J mice were administered vehicle (5% dimethylsulfoxide (DMSO), 5% HS15 (Kolliphor® HS15) in saline), a compound as described herein (ADR), and nalfurafine hydrochloride, then were administered chloroquine to induce itching. Scratching behavior time was monitored over a period of 30 minutes after chloroquine injection.

[0030] FIG. 4B shows the results of the scratching behavior in mice using the methods shown in FIG. 4A. A decrease in the time spent scratching was observed in the mice treated with a compound as described herein (* P < 0.05, Bonferroni’s multiple comparisons test, compared with vehicle; ns = not significant).

[0031] FIG. 5 shows the results of treatment with the compounds as described herein in an atopic dermatitis model. Atopic dermatitis was induced in mice using MC903 (calcipotriene), then mice were orally administered a compound as described herein (ENDOPIN). Mice treated with a compound as described herein (3, 6, or 10 mg / kg) exhibited a decreased number of scratching bouts compared with mice that were not treated with a compound as described herein (0 mg / kg; *P < 0.05, **P < 0.01, Tukey's multiple comparisons test, compared with vehicle).DETAILED DESCRIPTIONOverview

[0032] Pruritus, commonly known as itching, is a sensation that leads to the urge to scratch. It is a complex and subjective experience that can range from mild irritation to intense, chronic discomfort. The sensation of itch is typically mediated by the activation of sensory -6- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102nerve fibers in the skin, which are responsible for transmitting the itch signal to the brain. While itching is a normal response to certain stimuli, such as insect bites or mild skin irritation, it can also be a symptom of underlying health conditions.

[0033] Dorsal root ganglia (DRG) neurons play a crucial role in the sensation of pruritus (FIG. 1). DRG neurons are primary sensory neurons located just outside the spinal cord and act as the initial relay points for sensory information from the periphery (such as the skin) to the central nervous system. They are involved in detecting various stimuli, including mechanical, thermal, and chemical changes, and they transmit this information to the spinal cord, which processes and relays it to the brain.

[0034] Alpha-adrenoceptors are a class of G protein-coupled receptors (GPCRs) that respond to noradrenaline (norepinephrine), a neurotransmitter primarily released by sympathetic nerve fibers. Alpha-2 adrenoceptors play a direct role in modulating sensory signaling, including itch, and are found on both DRG neurons and spinal cord neurons. In the spinal cord, noradrenaline acts on alpha-2 adrenoceptors to modulate the transmission of itch signals from the periphery to the brain (FIG. 2). Activation of these receptors reduces the activity of second-order neurons in the dorsal horn, which relay itch information to higher centers in the brain. This descending inhibition reduces the intensity of itch sensations and can help in controlling chronic or severe itching.

[0035] Understanding the role of these receptors in pruritus is important for developing new therapeutic approaches, particularly in the treatment of pruritus.Methods

[0036] Provided herein are methods for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (I):-7- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102or a pharmaceutically acceptable salt thereof,wherein:X is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, a hydroxy group, a cycloalkyl group, and a heterocyclic group;Y is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a cycloalkyl group; andZ represents one to four substituents, wherein each Z is independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, a heterocyclic group, a halogen, and a hydroxy group.

[0037] Provided are methods for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the methods comprising administering to the patient a therapeutically effective amount of a compound that induces noradrenaline release, wherein the compound that induces noradrenaline release is a compound of Formula (I), as defined above.

[0038] Provided herein are methods for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the methods comprising administering to the patient a physiologically effective amount of a compound of Formula (I), as defined above.

[0039] Provided are methods for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the methods comprising administering to the patient a therapeutically effective amount of an alpha-2B adrenergic receptor antagonist, wherein the alpha-2B adrenergic receptor antagonist comprises a 2,3 -dihydrobenzothiazole core.

[0040] Provided are methods of inducing noradrenaline release in a patient, the methods comprising administering to the patient a therapeutically effective amount of an alpha-2B -8- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102adrenergic receptor antagonist, wherein the alpha-2B adrenergic receptor antagonist comprises a 2,3-dihydrobenzothiazole core.

[0041] As used herein, a receptor antagonist can also be referred to as a compound or composition that inhibits or blocks a receptor. In one or more embodiments, inhibition and blockage includes suppression of the activity of a receptor on which a compound or composition acts, compared to when it does not act on the receptor.[00421 In one or more embodiments, the alpha-2 adrenergic receptor antagonist is preferably a compound or composition that inhibits the alpha-2B adrenergic receptor, and more preferably a compound or composition that selectively inhibits the a2B adrenergic receptor. It was surprisingly found that the compounds described herein, which are alpha-2 adrenergic receptor antagonists, induce noradrenaline release, which results in the treatment, reduction, and / or suppression of pruritus.[00431 In some embodiments, the alpha-2B adrenergic receptor antagonist having a 2,3-dihydrobenzothiazole core is a compound of Formula (I), as defined above.

[0044] In some embodiments, for the compound of Formula (I):X is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, and a hydroxy group;Y is selected from the group consisting of a hydrogen atom and an alkyl group; and Z is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, and a hydroxy group.

[0045] In some embodiments, for the compound of Formula (I):X is selected from the group consisting of an alkyl group and an alkoxy group;Y is selected from the group consisting of a hydrogen atom and an alkyl group; and Z is selected from the group consisting of an alkoxy group and a halogen.[0046J In some embodiments, for the compound of Formula (I):X is an alkyl group;Y is an alkyl group; andZ is selected from the group consisting of an alkoxy group and a halogen.-9- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102[0O47| In some embodiments, for the compound of Formula (I):X is a methyl group;Y is an ethyl group; andZ is selected from the group consisting of a methoxy group, a fluorine atom, a chlorine atom, and a bromine atom.[0048J In some embodiments, for the compound of Formula (I), X is a heterocyclic group that is selected from the group consisting of an imidazoyl group, an imidazoylmethyl group, an N-alkyl imidazoyl group, an N-alkyl imidazoylmethyl group, a 4,5-dihydroimidazoyl group, a 4,5-dihydroimidazoylmethyl group, an N-alkyl-4,5-dihydroimidazoyl group, anN-alkyl-4,5-dihydroimidazoylmethyl group, a pyridyl group, a pyridylmethyl group, a pyrazyl group, a pyrazylmethyl group, a pyrimidyl group, a pyrimidylmethyl group, a triazinyl group, a triazinylmethyl group, a thiazolyl group, a thiazolylmethyl group, a thiadiazolyl group, and a thiadiazolylmethyl group

[0049] In some embodiments, the compound of Formula (I) is selected from the group consisting of:

[0050] In some embodiments, the patient suffers from acute pruritus. In some embodiments, the patient suffers from chronic pruritus.[00511 In some embodiments, the therapeutically effective amount is from about 0.1 mg / kg to about 50 mg / kg. In some embodiments, the therapeutically effective amount is from about 0.5 mg / kg to about 50 mg / kg, about 1 mg / kg to about 50 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 50 mg / kg, about 15 mg / kg to about 50 mg / kg, about 204898-5097-2032.1Atty. Dkt. No.: 142581-0102mg / kg to about 50 mg / kg, about 25 mg / kg to about 50 mg / kg, about 30 mg / kg to about 50 mg / kg, about 35 mg / kg to about 50 mg / kg, about 40 mg / kg to about 50 mg / kg, or about 45 mg / kg to about 50 mg / kg.

[0052] In some embodiments, the therapeutically effective amount is from about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 45 mg / kg, about 1 mg / kg to about 40 mg / kg, about 1 mg / kg to about 35 mg / kg, about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 5 mg / kg.

[0053] In some embodiments, the therapeutically effective amount is from about 0.1 mg / kg to about 1 mg / kg, about 1 mg / kg to about 10 mg / kg, about 10 mg / kg to about 20 mg / kg, about 20 mg / kg to about 30 mg / kg, about 30 mg / kg to about 40 mg / kg, or about 40 mg / kg to about 50 mg / kg.]0054[ In some embodiments, the therapeutically effective amount is about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, or about 50 mg / kg.

[0055] In some embodiments, the patient is administered a physiologically effective amount of any one of the compounds as described herein.

[0056] In some embodiments, after administration of the alpha-2B adrenergic receptor antagonist, the patient experiences a decrease or reduction in symptoms related to pruritus.-11- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102Such symptoms may include, but are not limited to, itching sensation, localized or generalized itching, dry skin, skin redness, skin irritation, rashes, lesions, excoriations, pain or burning sensation, sleep disruption, and / or secondary infections. Such symptoms may be monitored by a medical professional and can be measured using assessments such as a visual analog scale, a numeric rating scale, a severity scale that measures the intensity of itching, frequency, an impact of pruritus on daily activities, questionnaires, scratching behavior observation, dermatologic examination, or by any other clinically acceptable method.

[0057] In some embodiments, administration of the alpha-2B adrenergic receptor antagonist results in a decrease in one or more symptoms of pruritus in the patient by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, as determined by a clinically acceptable method (e.g., comparing the symptoms pre-administration and post-administration).Pharmaceutical compositions

[0058] The alpha-2 adrenergic receptor antagonists as described herein may be in the form of compositions suitable for administration to a patient for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus. Such compositions are pharmaceutical compositions comprising any one of the alpha-2 adrenergic receptor antagonists described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0059] Provided herein is a pharmaceutical composition for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a subject diagnosed with pruritis, the pharmaceutical composition comprising a physiologically effective amount of a compound that induces noradrenaline release and which is an alpha-2B adrenergic receptor antagonist, wherein the alpha-2B adrenergic receptor antagonist comprises a 2,3 -dihydrobenzothiazole core.

[0060] Effective dosage forms, modes of administration and dosage amounts of the pharmaceutical composition may be determined empirically, and making such determinations is within the skill of the art. It is understood by those skilled in the art that the dosage amount -12- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102will vary with the particular composition employed, the condition being treated, the severity of the condition, the route of administration, the rate of excretion, the duration of the treatment, the identity of any other drugs being administered to the mammal, the age, size and species of the mammal, and like factors well known in the medical and veterinary arts.

[0061] In general, a suitable daily dose of an alpha-2 adrenergic receptor antagonist described herein will be that amount which is the lowest dose effective to produce a therapeutic effect. However, the total daily dose will be determined by an attending physician or veterinarian within the scope of sound medical judgment. If desired, the daily dose may be administered in multiple sub-doses, administered separately at appropriate intervals throughout the day. As an example, the pharmaceutical composition may be administered to the patient once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day.

[0062] The pharmaceutical compositions as described herein can be formulated to be compatible with the intended method or route of administration. Routes of administration may include those known in the art. For example, the pharmaceutical composition may be formulated for oral, topical, transdermal, intravenous, intramuscular, or intrathecal administration. In some embodiments, the pharmaceutical composition is formulated for topical administration and is a gel, an ointment, a paste, or a cream.

[0063] The pharmaceutical compositions of the invention comprise a composition of the technology as an active ingredient in admixture with one or more pharmaceutically-acceptable vehicles and, optionally, with one or more other compounds, drugs, or other materials. Such vehicles are well known in the art, as are methods of preparing pharmaceutical compositions.

[0064] Pharmaceutical compositions of the present technology suitable for administrations comprise one or more compositions described herein in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient, or -13- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102suspending or thickening agents. Pharmaceutically acceptable cations include metallic ions and organic ions. Metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiologically acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Organic ions include, but are not limited to, protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.

[0065] Examples of suitable aqueous and nonaqueous vehicles which may be employed include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of surfactants.

[0066] These compositions may also contain adjuvants such as wetting agents, emulsifying agents and dispersing agents. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin, or by dissolving or suspending the composition(s) in an oil vehicle.

[0067] The formulations may be presented in unit-dose or multi-dose sealed containers (for example, ampoules and vials). The formulations may be stored in a lyophilized condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.-14- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102[0O68| The pharmaceutical compositions described herein may be stored in an appropriate sterile container or containers. In some embodiments, the container is designed to maintain stability for the pharmaceutical composition over a given period of time.Definitions

[0069] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

[0070] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0071] As used herein, comparative terms as used herein, such as higher, lower, increase, decrease, reduce, or any grammatical variation thereof, can refer to certain variation from the reference. In some embodiments, such variation can refer to about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 1 fold, or about 2 folds, or about 3 folds, or about 4 folds, or about 5 folds, or about 6 folds, or about 7 folds, or about 8 folds, or about 9 folds, or about 10 folds, or about 20 folds, or about 30 folds, or about 40 folds, or about 50 folds, or about 60 folds, or about 70 folds, or about 80 folds, or about 90 folds, or about 100 folds or more lower than the reference. In some embodiments, such variation can refer to about 1%, or about 2%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 8%, or 0%, or about 10%, or about 20%,-15- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102or 30%, or 40%, or 50%, or 60%, or 70%, or 75%, or 80%, or 85%, or 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the reference.10072] “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

[0073] As used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0074] As used herein, the “administration” of an agent or drug to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including but not limited to, orally, topically, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), or intrathecally. Administration includes self-administration and the administration by another.

[0075] As used herein, a "control" is an alternative sample used in an experiment for comparison purpose. A control can be "positive" or "negative." For example, where the purpose of the experiment is to determine a correlation of the efficacy of a therapeutic agent for the treatment for a particular type of disease, a positive control (a compound or composition known to exhibit the desired therapeutic effect) and a negative control (a subject or a sample that does not receive the therapy or receives a placebo) are typically employed.

[0076] As used herein, the term “effective amount” refers to a quantity sufficient to achieve a desired therapeutic, e.g., an amount which results in a decrease in a disease or condition described herein or one or more signs or symptoms associated with a disease or condition described herein. In the context of therapeutic applications, the amount of a composition administered to the subject will vary depending on the composition, the degree, type, and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compositions can also be administered in combination with one or more additional therapeutic compounds. In the methods described herein, the therapeutic compositions can be administered to a subject having one or more signs or symptoms of a disease or condition described herein.-16- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102[0O77| As used herein, a “therapeutically effective amount” of a composition refers to composition levels in which the physiological effects of a disease or condition are ameliorated or eliminated. A therapeutically effective amount can be given in one or more administrations. In some embodiments, an “effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the therapeutic agents disclosed herein for any particular subject depends upon a variety of factors including the activity of the specific compound employed, bioavailability of the compound, the route of administration, the age of the animal and its body weight, general health, sex, the diet of the animal, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.

[0078] The terms “pharmaceutically-acceptable,” “physiologically-tolerable,” and grammatical variations thereof, as they refer to compositions, carriers, diluents, and reagents, are used interchangeably and represent that the materials are capable of administration to or upon a subject without the production of undesirable physiological effects to a degree that would prohibit administration of the composition. For example, “pharmaceutically-acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous. “Pharmaceutically-acceptable salts and esters” means salts and esters that are pharmaceutically-acceptable and have the desired pharmacological properties. Such salts include salts that can be formed where acidic protons present in the composition are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, e.g., sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as the amine bases, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Such salts also include acid -17- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102addition salts formed with inorganic acids e.g., hydrochloric and hydrobromic acids) and organic acids (e.g., acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid). Pharmaceutically acceptable esters include esters formed from carboxy, sulfonyloxy, and phosphonoxy groups present in the compound, e.g., Ci-6 alkyl esters. When there are two acidic groups present, a pharmaceutically acceptable salt or ester can be a mono-acid-mono-salt or ester or a di-salt or ester; and similarly where there are more than two acidic groups present, some or all of such groups can be salified or esterified. A person of ordinary skill in the art, would have no difficulty determining the appropriate timing, sequence, and dosages of administration for particular drugs and compositions of the present disclosure.

[0079] The term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal compounds, isotonic and absorption delaying compounds, and the like, compatible with pharmaceutical administration. Pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Pharmaceutically acceptable carriers and their formulations are known to one skilled in the art and are described, for example, in Remington's Pharmaceutical Sciences (20thedition, ed. A. Gennaro, 2000, Lippincott, Williams & Wilkins, Philadelphia, Pa.).

[0080] As used herein, the terms “subject”, “patient”, or “individual” can be an individual organism, a vertebrate, a mammal, or a human. In some embodiments, the subject, patient, or individual is a human. In some aspects, the subject is a mammal selected from a canine, a feline, an equine, a simian, or other. The methods can be used to treat non-human animals or to test for new or combination therapies when in an acceptable animal model.-18- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102[00811 The term “in need thereof’ would be a subject known or suspected of having or being at risk of having pruritus.

[0082] As used herein, the term “therapeutic agent” is intended to mean a compound that, when present in an effective amount, produces a desired therapeutic effect on a subject in need thereof.

[0083] “Treating” or “treatment” as used herein covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, z.e., arresting its development; (ii) relieving a disease or disorder, z.e., causing regression of the disorder; (iii) slowing progression of the disorder; and / or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder. In some embodiments, treatment means that the symptoms associated with the disease are, e.g., alleviated, reduced, cured, or placed in a state of remission. In a further aspect, the term “treatment” excludes prevention or prophylactic use.

[0084] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., Ci-io alkyl). Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; e.g., "1 to 10 carbon atoms" means that the alkyl group can consist of 1, 2, 3, ,45, 6, 7, 8, 9, or 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups; while saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3 -methylbutyl, 2-methylpentyl, 3 -methylpentyl, 4-m ethylpentyl, 2methylhexyl, 3 -methylhexyl, 4-m ethylhexyl, 5-methylhexyl, 2,3 -dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group may be optionally substituted by one or more of substituents disclosed herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2-hydroxy ethyl, 3hydroxypropyl, benzyl, and phenethyl.-19- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102[0085| "Alkoxy" refers to the group -O-alkyl, including from 1 to 10 carbon atoms of a straight, branched, saturated cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tbutoxy, pentoxy, cyclopropyloxy, cyclohexyloxy and the like. "Lower alkoxy" refers to alkoxy groups containing one to six carbons. In some embodiments, Ci-4alkoxy is an alkoxy group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms. Unless stated otherwise in the specification, an alkoxy group may be optionally substituted by one or more of substituents disclosed herein. The terms "alkenoxy" and "alkynoxy" mirror the above description of "alkoxy" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein.|0086] " Aromatic" or "aryl" refers to a radical with 6 to 14 ring atoms (e.g., Ce-14 aromatic or Ce-i4 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). In some embodiments, the aryl is a Ce-io aryl group. For example, bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. In other embodiments, bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in"-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as "6 to 14 aryl “refers to each integer in the given range; e.g., "6 to 14 ring atoms" means that the aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 14 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In a multi-ring group, only one ring is required to be aromatic, so groups such as indanyl are encompassed by the aryl definition. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like. Unless stated otherwise in the specification, an aryl group may be optionally substituted by one or more of substituents disclosed herein.-20- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102[0087| "Cycloalkyl" and "carbocyclyl" each refer to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond.Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C3-13 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In some embodiments, “cycloalkyl” can be a C3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C3-5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce) and the like. Examples of C3-7 carbocyclyl groups include norbornyl (C7). Examples of C3-8 carbocyclyl groups include the aforementioned C3-7 carbocyclyl groups as well as cycloheptyl(C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples of C3-13 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro-lH indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and the like. Unless stated otherwise in the specification, a cycloalkyl group may be optionally substituted by one or more of substituents disclosed herein. The terms “cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.[0()88| "Halo", "halide", or, alternatively, "halogen" means fluoro, chloro, bromo or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with -21- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102combinations thereof, preferably substituted with one, two, or three halo groups. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2trifluoroethyl, l-fluoromethyl-2 -fluoroethyl, -O-CHF2, and the like. Each of the alkyl, alkenyl, alkynyl and alkoxy groups are as defined herein and can be optionally further substituted as defined herein.

[0089] "Heteroaryl" or, alternatively, "heteroaromatic" refers to a refers to a radical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic and the like) aromatic ring system (e.g., having 6, 10 or 147t electrons shared in a cyclic array) having one or more ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-18 membered heteroaryl"). Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; e.g., "5 to 18 ring atoms" means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some instances, a heteroaryl can have 5 to 14 ring atoms. In some embodiments, the heteroaryl has, for example, bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-ene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylene.

[0090] For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. One or more heteroatom(s) in the heteroaryl radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxides. The heteroaryl is attached to the parent molecular structure through any atom of the ring(s).

[0091] "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment to the parent molecular-22- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102structure is either on the aryl or on the heteroaryl ring, or wherein the heteroaryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment to the parent molecular structure is on the heteroaryl ring. For polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl and the like), the point of attachment to the parent molecular structure can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur.

[0092] Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4] oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzopyranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[ l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-23- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102benzo[6,7]cyclohepta[ l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo [3,2 -c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctafd] pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl -IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5, 6,7,8-tetrahydrobenzo [4,5 ] thieno [2,3 -d]pyrimdinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno [2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno [2,3-c]pridinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted by one or more of substituents disclosed herein.

[0093] "Heterocyclyl", "heterocycloalkyl" or “heterocarbocyclyl" each refer to any 3 to 18-membered non-aromatic radical monocyclic or polycyclic moiety comprising at least one carbon atom and at least one heteroatom selected from nitrogen, oxygen, phosphorous and sulfur. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the polycyclic ring systems can be a fused, bridged or spiro ring system. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. A heterocyclyl group can be saturated or partially unsaturated. Partially unsaturated heterocycloalkyl groups can be termed "heterocycloalkenyl" if the heterocyclyl contains at least one double bond, or "heterocycloalkynyl" if the heterocyclyl contains at least one triple bond. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; e.g., "5 to 18 ring atoms" means that the heterocyclyl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. For example, bivalent radicals derived from univalent heterocyclyl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-ene" to the -24- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102name of the corresponding univalent radical, e.g., a piperidine group with two points of attachment is a piperidylene.

[0094] An N-containing heterocyclyl moiety refers to a non-aromatic group in which at least one of the ring atoms is a nitrogen atom. The heteroatom(s) in the heterocyclyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can be optionally quatemized. Heterocyclyl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as piperidinyl N-oxides. The heterocyclyl is attached to the parent molecular structure through any atom of any of the ring(s).

[0095] "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment to the parent molecular structure is on the heterocyclyl ring. In some embodiments, a heterocyclyl group is a 5-14 membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-14 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 3-10 membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("3-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen phosphorous and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorous and sulfur. In-25- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous and sulfur.

[0096] "Heterocyclyl" may include one or more ketone group (-C(=O)-) as part of the ring. Examples of a ketone-contianing heterocycle include, without limitation, pyridin-2(lH)-one, pyrazin-2(lH)-one, pyrimidin-2(lH)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, pyridin-4(lH)-one, imidazolidin-2-one, l,3-dihydro-2H-imidazol-2-one, 2,4-dihydro-3H-l,2,4-triazol-3-one, oxazol-2(3H)-one, and oxazolidin-2-one. A ketone-containing heterocyclyl is obtainable by removing a hydrogen atom from its corepsonding ketone-contianing heterocycle at any available N-H or C-H position.

[0097] Exemplary 3-membered heterocyclyls containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyls containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclyls containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyls containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, thiazolidinyl, and dithiolanyl. Exemplary 5-membered heterocyclyls containing 3 heteroatoms include, without limitation, triazolinyl, diazolonyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6 membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, and triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiol any 1, benzothianyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, 3-lH-benzimidazol-2-one, (l-substituted)-2-oxo-benzimidazol-3-yl,-26- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8-naphthyridinyl, octahydropyrrolo[3,2 -b]pyrrole, phenanthridinyl, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e] [l,4]diazepinyl, 1, 4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo [3,2-b]pyranyl, 5,7-dihydro-4H-thieno [2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, hydrofuro[2,3-b]pyridinyl, 4, 5, 6, 7 tetrahydro- lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1, 2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0098] As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution can be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

[0099] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds provided herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Any appropriate method can be used to prepare optically active forms from, for example, optically inactive starting materials. For example, techniques such as resolution of racemic mixtures or stereoselective synthesis can be used to prepare optically active forms of a compound provided herein. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like also can be present in a compound described herein, and all such stable isomers are contemplated herein. Cis and trans geometric isomers of the compounds provided herein are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0100] Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include, without limitation, ketone - enol pairs, amide - imidic acid-27- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-l,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. For example, in aqueous solution, pyrazoles can exhibit the following isomeric forms, which are referred to as tautomers of each other:I0101] As readily understood by one skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of compounds as described herein are within the scope provided herein.[01021 Unless stated otherwise in the specification, a heterocyclyl group may be optionally substituted by one or more of substituents disclosed herein.

[0103] Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment s).

[0104] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.EXAMPLES

[0105] Example 1. Use of the alpha-2B adrenergic receptor antagonists in treating pruritus.[0106| The chloroquine-induced itch model was used to determine whether the alpha-2B adrenergic receptor antagonists as described herein can be used in the treatment of pruritus.-28- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102

[0107] The alpha-2B adrenergic receptor antagonist (ADRIANA, ADR) was orally administered to C57BL / 6J mice (male, 8-12 weeks) at concentrations of 3 mg / kg and 10 mg / kg. Mice were also administered vehicle (5% DMSO, 5% HS15 in saline) and TRK-820 HC1 (nalfurafine hydrochloride, at 0.01 mg / kg) as controls. TRK-820 HC1 is a K-opioid receptor agonist that has been used for the treatment of refractory pruritus in patients with chronic liver disease or who are undergoing hemodialysis or peritoneal dialysis.

[0108] Two hours after administration, chloroquine (CQ, 20 pL at 20 mg / mL) was injected intradermally to the nape for itch induction, and scratching behavior was measured for 30 minutes after CQ injection (FIG. 4A). The alpha-2B adrenergic receptor antagonist attenuated itch in the chloroquine model at both doses (FIG. 4B): compared to the vehicle, treatment with the non-opioid analgesic compound resulted in a decrease in time spent scratching.

[0109] Example 2. A Mouse Model of MC903-Induced Atopic Dermatitis.[01.10] MC903 (calcipotriene, CAS#112965-21-6) was applied to the auricles (ear pinnae) of mice. On days 0-11: MC903 was continuously applied to the auricles of the mice for 12 consecutive days. On days 13-15, mice were observed for scratching behavior. Scratching behavior was observed for 30 min, from 2.0 to 2.5 hours after oral administration of a compound described herein (mice were administered 0, 3, 6, or 10 mg / kg ENDOPIN).[01.11] To measure scratching behavior, mice were individually video recorded, and scratching bouts were manually counted over a 30-min observation period. A single “bout” was defined as a continuous scratching behavior directed at the same site and was counted as one event. The number of individual scratching times within a single bout was not taken into account.

[0112] Compared to mice treated with vehicle (i.e., 0 mg / kg), mice administered a compound as described herein (3, 6, or 10 mg / kg) exhibited reduced scratching behavior (FIG. 5).

[0113] Accordingly, these results demonstrate that the alpha-2B adrenergic receptor antagonists as described herein are useful in the treatment of pruritus.***

[0114] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.-29- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102[0115J The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0116] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0117] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0118] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range-30- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.[0119| All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.[0120J Other embodiments are set forth in the following claims.-31- 4898-5097-2032.1

Claims

Atty. Dkt. No.: 142581-0102WHAT IS CLAIMED IS:

1. A method for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt thereof,wherein:X is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, a hydroxy group, a cycloalkyl group, and a heterocyclic group;Y is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a cycloalkyl group; andZ represents one to four substituents, wherein each Z is independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, a heterocyclic group, a halogen, and a hydroxy group.

2. The method of claim 1, wherein:X is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, and a hydroxy group;Y is selected from the group consisting of a hydrogen atom and an alkyl group; andZ is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, and a hydroxy group.

3. The method of claim 1 or 2, wherein:X is selected from the group consisting of an alkyl group and an alkoxy group; Y is selected from the group consisting of a hydrogen atom and an alkyl group; and-32- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102Z is selected from the group consisting of an alkoxy group and a halogen.

4. The method of any one of claims 1-3, wherein:X is an alkyl group;Y is an alkyl group; andZ is selected from the group consisting of an alkoxy group and a halogen.

5. The method of any one of claims 1-4, wherein:X is a methyl group;Y is an ethyl group; andZ is selected from the group consisting of a methoxy group, a fluorine atom, a chlorine atom, and a bromine atom.

6. The method of any one of claims 1-5, wherein the compound of Formula (I) is selected from the group consisting of:

7. The method of any one of claims 1-6, wherein the patient suffers from acute pruritus.

8. The method of any one of claims 1-6, wherein the patient suffers from chronic pruritus.

9. A method for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the method comprising administering to the patient a therapeutically effective amount of an alpha-2B adrenergic receptor antagonist, wherein the alpha-2B adrenergic receptor antagonist comprises a 2,3-dihydrobenzothiazole core.

10. A method for inducing noradrenaline release in a patient, the method comprising administering to the patient a therapeutically effective amount of an alpha-2B adrenergic-33- 4898-5097-2032.1Atty. Dkt. No.: 142581-0102receptor antagonist, wherein the alpha-2B adrenergic receptor antagonist comprises a 2,3-dihydrobenzothiazole core.

11. The method of claim 9 or claim 10, wherein the alpha-2B adrenergic receptor antagonist having a 2,3 -dihydrobenzothiazole core is a compound of Formula (I):or a pharmaceutically acceptable salt thereof,wherein:X is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, a hydroxy group, a cycloalkyl group, and a heterocyclic group;Y is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a cycloalkyl group; andZ represents one to four substituents, wherein each Z is independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, a heterocyclic group, a halogen, and a hydroxy group.

12. A method for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound that induces noradrenaline release, wherein the compound that induces noradrenaline release is a compound of Formula (I):or a pharmaceutically acceptable salt thereof,wherein:4898-5097-2032.1Atty. Dkt. No.: 142581-0102X is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, a hydroxy group, a cycloalkyl group, and a heterocyclic group;Y is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a cycloalkyl group; andZ represents one to four substituents, wherein each Z is independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, a heterocyclic group, a halogen, and a hydroxy group.

13. A pharmaceutical composition for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a patient, the pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt thereof,wherein:X is selected from the group consisting of an alkyl group, an alkoxy group, a halogen, a hydroxy group, a cycloalkyl group, and a heterocyclic group;Y is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a cycloalkyl group; andZ represents one to four substituents, wherein each Z is independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, a heterocyclic group, a halogen, and a hydroxy group.

14. The pharmaceutical composition of claim 13, wherein the therapeutically effective amount of the compound is from about 0.1 mg / kg to about 50 mg / kg.

15. The method of claim 13 or 14, wherein the pharmaceutical composition is formulated for oral, topical, transdermal, intravenous, intramuscular, or intrathecal administration.-35- 4898-5097-2032.1Atty. Dkt. No.: 142581-010216. The method of claim 15, wherein the pharmaceutical composition is formulated for topical administration and is a gel, an ointment, a paste, or a cream.

17. The method of any one of claims 13-16, wherein the pharmaceutical composition is administered to the patient once a day, twice a day, or three times a day.

18. A pharmaceutical composition for treating pruritus, reducing pruritus, suppressing and / or inhibiting pruritus in a subject diagnosed with pruritis, the pharmaceutical composition comprising a physiologically effective amount of a compound that induces noradrenaline release and which is an alpha-2B adrenergic receptor antagonist, wherein the alpha-2B adrenergic receptor antagonist comprises a 2,3-dihydrobenzothiazole core.4898-5097-2032.1

Images