Methods for treating irritable cough or itch using ion channel blocking compounds

Abstract

To provide new chemical entities which primarily inhibit the human T-type calcium channels and differentially modulate other key ion channels to control cell excitability, and abnormal neuronal activity, particularly involved in hypersensitive cough or itching.SOLUTION: The present invention provides compositions for use in methods for treating itches, where the compositions include therapeutically effective amounts of compounds or pharmaceutically acceptable salts thereof, where the methods include the step for administering the compositions, where an example of the compounds is the compound illustrated below.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and is incorporated by reference in its entirety from U.S. Patent Application No. 16 / 115,549, filed August 28, 2018. U.S. Patent Application No. 16 / 115,549 is related to Patent Cooperation Treaty Application No. US2016 / 061918, which is incorporated by reference in its entirety. Government Rights Statement

[0003] This invention was made with government support under Grant I R44NS086343-01 awarded by the National Institute of Neurological Disorders and Stroke, National Institute of Health. The government has certain rights in this invention. Technical Field

[0004] The field of the invention relates to novel ion channel modulator compounds (inhibitors or antagonists of one type of ion channel and / or combinations of inhibition of multiple ion channels), compositions comprising ion channel modulators, and methods of treating conditions and disorders using the compounds and compositions. A more particular field relates to selective T-type Ca modulators for the relief of irritable / chronic cough or itching. v3 Compounds having channel-blocking effects, pharmaceutical formulations containing such compounds, and methods for the selective treatment of irritable cough or itch are included. [Background technology]

[0005] Voltage-dependent calcium (Ca 2+) channels (VGCCs) play essential roles in regulating membrane ion conductance, cell excitability, and neurotransmitter release. VGCCs are composed of a pore-forming α1 subunit and auxiliary α2δppm and β subunits that regulate channel expression and function. Some low-voltage-activated channels are Ca v3 There is a channel subtype, which mediates T-type calcium currents that may be targeted to treat epilepsy, particularly childhood absence epilepsy, and chronic pain ( Huguenard, 1998 ; Cribbs et al., 2000 ; Perez-Reyes et al., 2009 ; Perez-Reyes, 2010 ).

[0006] T-type or "low-voltage-activated" calcium channels are so named because they open for a shorter duration (T = transient) than L-type (L = long-lasting) calcium channels. T-type channels are activated at relatively negative membrane potentials (approximately -60 mV). In many types of neurons, Ca transport through T channels is 2+ The influx of low-threshold Ca 2+ This causes a spike, which in turn induces voltage-dependent sodium (Na + T channels induce bursts of action potentials mediated by T channels. Brief burst firing is thought to play an important role in synchronous activity of the thalamus and neural pacemakers under physiological conditions, but also contributes to a wide range of thalamocortical arrhythmias under pathological conditions, such as neuropathic pain or seizures. T channels can be activated by mild depolarization of the cell membrane (Talley et al., 1999; Perez-Reyes, 2003; Perez-Reyes, 2010; Pexton et al., 2011; Todorovic and Jevtovic-Todorovic, 2011).

[0007] Molecular cloning has revealed that Ca v3.1 , Ca v3.2 , and Ca v3.3 Three distinct T-channel proteins have been identified, called Ca v3.1 channels and Ca v3.3Ca channels are expressed primarily, but not exclusively, in the CNS. v3.2 Ca channels are not only present in the CNS but are also expressed in peripheral neuronal cell bodies and nerve endings of afferent fibers (Hegueuard, 1998; Cribbs et al., 2000; Perez-Reyes et al., 2009; Perez-Reyes, 2010). v3.2 The channel is highly expressed in dorsal root ganglion (DRG) neurons, but is not expressed in small-diameter DRG neurons. v3.1 is hardly expressed, and Ca v3.3 is not expressed at all (Nelson et al., 1992). v3.2 The channel is also expressed at low levels in several non-neuronal tissues, such as the heart, liver, kidney, and pituitary gland. Both diabetic neuropathy and chronic constriction injury models in rats express Ca channels. v3.2 This pathological adaptation increases the excitability of sensory neurons, leading to hyperalgesia and allodynia (Jagodic et al., 2007; Jagodic et al., 2008; Latham et al., 2009; Messinger et al., 2009; Yue et al., 2013). Conversely, Ca v3.2 Knockout or antisense knockdown of the isoforms results in analgesic effects ( Messinger et al., 2009 ).

[0008] T-type channel inhibitors have two known clinical uses. The anti-absence seizure effects of ethosuximide and lamotrigine are thought to be mediated by the inhibition of T channel activity in the thalamus (Gomora et al., 2001; Huguenard, 2002). However, both drugs are weak and not specific for T channels (Xie et al., 1995; Zhang et al., 1996). The antihypertensive effect of mibefradil is traditionally produced by the inhibition of T channels. However, mibefradil has low selectivity and inhibits L-type Ca channels. 2+ Current or voltage-dependent Na +Inhibition of T-channel activity is approximately 3-10 times more potent than inhibition of current (Avdonin et al., 2000). In the absence of selective T-channel blockers, it is unclear whether and to what extent inhibition of T-channel activity at therapeutically relevant concentrations contributes to the therapeutic utility of a wide range of drugs.

[0009] T channels, especially Ca v3.2 Targeting T-type Ca isoforms is highly useful for alleviating thermal and mechanical hyperalgesia in pathological conditions such as diabetic neuropathy. As exemplified below, potent and selective T-type Ca isoforms are 2+ Several efforts to discover channels have been described in the literature.

[0010] 1,4-Substituted piperidines, such as "Compound 30" (3,5-dichloro-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide) and "TTA-P2" (3,5-dichloro-N-((1-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-4-fluoropiperidin-4-yl)methyl)benzamide) were synthesized by Merck and used in the preparation of T-type Ca2+. v3.2 It was found to potently block the channel [J.Med.Chem.51,3692,(2008); J.Med.Chem.51,6471,(2008); U.S. Patent Application Publication Nos. 2010 / 0222387; 2013 / 8501773]. TTA-A2 suppresses active wakefulness, promotes slow-wave sleep (Kraus et al., 2010), and prevents weight gain in mice fed a high-fat diet (Uebele et al., 2009).

[0011] By a scaffold-hopping approach, ML218 (3,5-dichloro-N-[[(1α,5α,6-exo,6α)-3-(3,3-dimethylbutyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl]benzamide, CID 45115620) selectively binds T-type Ca 2+ML218 possessed acceptable in vivo rat PK and was effective in preclinical Parkinson's disease models. Thus, ML218 is a potent inhibitor of T-type Ca2+ receptors in vitro and in vivo. 2+ It is a useful new biological probe for investigating function ( Xie et al., 2010 ; Xiang et al., 2011 ).

[0012] Certain lactam acetamides have been synthesized by Abbott et al. v2.2 and Ca v3.2 Described as a calcium channel blocker, ABT-639 is not expected to cross the blood-brain barrier and is therefore a potential calcium channel blocker for treating diabetic neuropathic pain through peripheral action. v3.2 It has been reported as a calcium channel blocker ( Jarvis et al., 2014 ).

[0013] N-piperidinylacetamide derivatives as calcium channel blockers have been described by Zalicus Pharmaceuticals, Ltd. (U.S. Pat. No. 8,569,344 (2013); U.S. Pat. No. 8,377,968 (2013)). Z944, a piperidine-based compound, blocks Ca in a voltage-dependent manner. v3 It inhibits the channel, reducing thalamic burst seizures and suppressing absence seizures in rats ( Tringham et al., 2012 ). Z944 has shown promising results in a Phase I clinical trial for pain in humans ( Lee, 2014 ).

[0014] Many T-type Ca 2+ Despite the fact that channel inhibitors have been discovered and are in various stages of development, no FDA-approved selective T-type channel blocking compounds are available for clinical application.

[0015] Coughing is a physiological defense mechanism for the removal of foreign bodies and excess bronchial secretions from the airways, but it is also a common symptom of various respiratory diseases. The cough reflex is triggered by activation of rapidly adapting receptors (or irritant receptors) in the larynx, trachea, and proximal bronchi, as well as activation of C-fiber endings found in the bronchial airway walls. Afferent signals are transmitted via sensory vagus nerve fibers to the cough center, which has been experimentally identified as located in the region of the nucleus tractus solitarius in the medulla oblongata (Kase, Wakita, et al., 1970). From the cough center, impulses are transmitted via efferent pathways to the respiratory muscles (diaphragm, intercostal muscles, and abdominal muscles) and the airways (Irwin, Rosen, et al., 1977).

[0016] Experimental research has shown that peripheral neurons may be involved in "hypersensitive cough." This type of cough is an acute cough or a chronic / persistent cough that can result from diseases such as cough syndrome or COPD, asthma, gastroesophageal reflux disease, postnasal drip syndrome, and exposure to pollutants such as smog and wildfire smoke (see, for example, Chung and Widdicombe, The Pharmacology and Therapeutics of Cough, In Handbook of Experimental Pharmacology ISSN 0171-2004, Library of Congress Control Number: 200892959, Springer-Verlag Berlin Heidelberg, 2009).

[0017] Similar to coughing, which is a defense mechanism to eliminate irritants or pathogens in the airways under physiological conditions, itch is a defense mechanism to protect the body from insects, harmful chemicals, and poisonous plants by triggering a scratching response. However, persistent or chronic itchy skin (pruritus) under pathological conditions is a significant unmet clinical problem. More than 30 million people in the United States suffer from eczema, such as atopic dermatitis, and approximately 7 million suffer from psoriasis. Furthermore, pruritus can be a symptom of underlying diseases, such as liver disease, renal failure, iron deficiency anemia, thyroid problems, or cancers, such as leukemia and lymphoma. In hemodialysis patients, the prevalence of chronic kidney disease-associated pruritus is high in both men and women, at 55% (Prevalence of chronic kidney disease-associated pruritus among adult dialysis patients: A meta-analysis of cross-sectional studies, Hu et al.).

[0018] Currently, there are no effective treatments for various chronic disease-related pruritus or the uncontrollable itch symptoms. Recent studies have implicated activation of Cav3.2 channels in NaHS-induced itch in experimental animals (Wang et al., Scientific Reports 5:16768 (2015)), suggesting that Cav3.2 channels may be a target for anti-itch compounds.

[0019] Indeed, the present inventors have demonstrated that the T-type Ca2+ receptors disclosed herein, such as EX-17, EX-128, EX-130, and EX-132, 2+ The present inventors have also discovered that the T-type Ca channel inhibitors disclosed herein are useful for the treatment and prevention of irritable cough. 2+ We have discovered that channel inhibitors, such as EX-31, EX-55, EX-130, EX-132, and AFA-258 (i.e., Z944), AFA-309, and AFA-358, are useful for treatment and prevention. 2+The channel inhibitors EX-128 and AFA-258 did not produce anti-itch effects in both chloroquine- and histamine-induced itch models. However, unexpectedly, compounds that are mixed modulators of major ion channels, such as voltage-gated Na channels, as exemplified by EX-31, EX-130, and AFA-358, were effective in both chloroquine- and histamine-induced itch models. Summary of the Invention

[0020] The present invention relates to a method for detecting major ion channels, particularly T-type Ca channels. 2+ The present invention provides compounds, formulations, and methods of use for the treatment and prevention of irritable cough and / or itch, in which the channel is involved. The compounds and methods can be used in both human and veterinary medicine.

[0021] In one aspect, the invention provides a method of treating chronic cough, the method comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] or [ka] where R 1 is phenyl-substituted with 1 to 3 substituents, each of which is a member selected from the group consisting of F, Cl, and CF3, thereby treating chronic cough.

[0022] In one embodiment, the compound is [ka] [ka] [ka] [ka] where R 1a and R 1b are each independently selected members from the group consisting of F, Cl, and CF3.

[0023] In another embodiment, the compound is [ka] [ka] [ka] or

[0024] [ka] is.

[0025] In another embodiment, the irritable cough or chronic cough is caused by a disease or syndrome selected from the group consisting of COPD, asthma, gastroesophageal reflux disease, postnasal drip syndrome, and chronic exposure to pollutants.

[0026] In another embodiment, the compound is administered orally or intranasally.

[0027] In one aspect, the method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] or [ka] is selected from the group consisting of:

[0028] In one embodiment, the itch is caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, poisonous plant exposure, chemical exposure, smog exposure, insect bites, or an allergic reaction to a food allergen.

[0029] In another embodiment, the compound is administered orally or intranasally.

[0030] In another aspect, the invention provides a method of treating itch, the method comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is

[0031] [ka]

[0032] [ka] or

[0033] [ka] is selected from the group consisting of:

[0034] In one embodiment, the itch is caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, poisonous plant exposure, chemical exposure, smog exposure, insect bites, or an allergic reaction to a food allergen.

[0035] In another embodiment, the compound is administered orally or intranasally. [Brief explanation of the drawings]

[0036] [Figure 1A] Figure 1 shows the effect of three doses of representative compound EX-17 (3 mg / kg, 10 mg / kg, and 30 mg / kg) and baseline dextromethorphan (60 mg / kg) on ​​cough frequency, as determined in naive, conscious guinea pigs using the citric acid-induced cough model. All test compounds were formulated with 0.5% hydroxypropyl cellulose and administered orally (po). Data are presented as mean ± SEM for n = 8 animals per group. P values ​​(<0.05, indicated by *) represent significant differences compared to the vehicle-treated control group using one-way analysis of variance followed by Fisher's LSD post-hoc test. [Figure 1B] Figure 1 shows the effect of three doses of EX-17 (3 mg / kg, 10 mg / kg, and 30 mg / kg) and dextromethorphan (60 mg / kg) on ​​latency to first cough, as determined by citric acid-induced cough in guinea pigs. EX-17 (30 mg / kg) and dextromethorphan (60 mg / kg) significantly increased latency compared with the vehicle-treated control group (double-checked) using one-way ANOVA followed by Fisher's LSD post-hoc test. [Figure 2A]Figure 1 shows the effect of three compounds, EX-128, EX-130, and EX-132 (each at 30 mg / kg) and baseline dextromethorphan (60 mg / kg / kg), on the number of cough events determined in naive, conscious guinea pigs using the citric acid-induced cough model. All test compounds were formulated with 0.5% hydroxypropyl cellulose and administered orally. Data are presented as mean ± SEM for n = 8 animals per group. P values ​​(<0.05, indicated by *) represent significant differences compared to the vehicle-treated control group using one-way analysis of variance followed by Fisher's LSD post-hoc test. [Figure 2B] Figure 1 shows the effect of three compounds, EX-128, EX-130, EX-132, and dextromethorphan, on the latency to first cough, as determined in citric acid-induced cough in guinea pigs. There is a tendency for the latency to increase, but the difference does not reach significance when compared to the vehicle-treated control group using one-way ANOVA followed by Fisher's LSD post-hoc test. [Figure 3A] FIG. 1 shows the effect of AFA compounds on inhibiting itch scratching behavior in two established itch models in mice. [Figure 3B] FIG. 1 shows the effect of AFA compounds on inhibiting itch scratching behavior in two established itch models in mice. DETAILED DESCRIPTION OF THE INVENTION

[0037] As described herein, the present invention provides novel methods for treating irritable or chronic cough using inhibitors of selective T-type channel blocking compounds.

[0038] Symptomatic chronic cough caused by various respiratory diseases impacts quality of life and further exacerbates respiratory morbidity. Pharmacological interventions are currently limited to treating the cause of the cough, and symptomatic treatment options for controlling the cough with an acceptable therapeutic index are also limited. Centrally acting cough therapies, such as dextromethorphan and codeine (both sedatives used clinically as cough suppressants), suppress the cough center and are considered the most clinically effective; however, sedative and addictive effects may limit their use. Local anesthetics, which interfere with the conduction of afferent nerve impulses, have been shown to be peripherally active antitussive compounds, but their considerable side effects make their use inappropriate. Extracellular adenosine 5'-triphosphate (ATP) activates P2X receptors on the cell surface and within primary afferent nerves. The development of various selective P2X receptor blockers has led to clinical trials evaluating their efficacy in managing cough, pain, inflammation, and certain neurodegenerative diseases (North, 2016).

[0039] In contrast, T-type Ca in the cough reflex and persistent cough under pathological conditions 2+ Little is known about the role of T-type Ca channels. 2+ Channels, primarily the Cav3.2 subtype, are expressed in the nodose ganglion (Pachuau and Martin-Caraballo, 2007) and play a role in regulating its axonal vagus nerve excitability, but apparently not conventional T-type Ca channels. 2+ Channel Rocker Ni 2+ (300 μM) did not alter the responses of guinea pig tracheobronchial cough receptor fibers or nociceptors to citric acid (Canning and Chou, 2004). Therefore, the role of T-type Ca2+ in the antitussive properties of the citric acid-induced cough model in guinea pigs is unclear. 2+ The possible effectiveness of T-type Ca channel modulators was investigated. 2+Novel compounds (e.g., EX-17, EX-128, EX-130, and EX-132) that potently and selectively inhibit the channel were investigated (see, e.g., PCT / US2016 / 061918, incorporated herein by reference in its entirety), and the results were compared to clinically used treatment with dextromethorphan.

[0040] Many chronic itch disorders do not respond to commonly used antihistamines, suggesting that histamine-independent itch models may be more relevant for identifying new targets and discovering novel compounds for chronic itch treatment. The recent identification of the first spinal itch receptor, the gastrin-releasing peptide receptor (GRPR), has led to extensive molecular studies of itch transduction pathways in the nervous system. GRP-GRPR signaling mediates a histamine-independent pathway in both acute and chronic itch. Although it is currently unclear which ion channels mediate specific itch signaling pathways, various ion channels, such as voltage-gated sodium (Na) channels, N-type Cav2.2, T-type Cav3.2 channels, and transient receptor potential vanilloid 1 (TRPV1) channels, have been suggested to be involved in the itch transmission pathway (J Neurol Set. 1999, January 15;162(2):162-8. Positive symptoms in multiple sclerosis: their treatment with sodium channel blockers, lidocaine, and mexiletine. Sakurai M1, Kanazawa I.). Therefore, we investigated the anti-itch properties of T-type Ca channels in two different models of itch in mice. 2+ The possible effectiveness of T-type Ca channel modulators was investigated. 2+ Novel compounds (e.g., EX-31, EX-55, EX-130, EX-132, AEA-258, AFA-309, and AFA-358) that potently and selectively inhibit the channel were investigated (see, e.g., PCT / US2016 / 061918, which is incorporated herein by reference in its entirety).

[0041] The following are definitions of representative types of irritable cough and itch that the compounds, pharmaceutical formulations, and methods are used to treat.

[0042] The term "method of treating irritable or chronic cough" refers to the partial or complete relief of cough symptoms or the prevention of irritable cough, which includes the description of irritable cough provided herein, often defined as a chronic cough of greater than 8 weeks in duration. Irritable or chronic cough can be caused by a disease or syndrome selected from the group consisting of COPD, asthma, gastroesophageal reflux disease, postnasal drip syndrome, and chronic exposure to pollutants such as smog and wildfire smoke.

[0043] The term "method of treating itch" refers to partial or complete relief from the symptoms of itch or prevention of itch, which may be caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, exposure to poisonous plants, exposure to chemicals, exposure to smog, insect bites, or an allergic reaction to a food allergen.

[0044] As used herein, "compounds of the invention" refers to the compounds discussed herein and salts of these compounds (eg, pharmaceutically acceptable salts).

[0045] "Alkyl" is intended to embrace monovalent saturated straight or branched hydrocarbon chains having the specified number of carbon atoms, or, if no number is specified, 1 to 8 carbon atoms. "Alkylene" refers to a similar group which is divalent. "Optionally substituted" alkyl refers to an unsubstituted alkyl group or -OH, -(C1-C4 alkyl)-OH, halo, fluoro, chloro, bromo, iodo, -(C1-C4 alkyl), -(C1-C4)haloalkyl, -(C1-C4)perhaloalkyl, -O-(C1-C4 alkyl), -O-(C1-C4 haloalkyl), -O-(C1-C4 perhaloalkyl), -(C1-C4)perfluoroalkyl, -(C=O)-(C1-C4)alkyl, -(C=O)-(C1-C4)haloalkyl, -(C=O)-(C1-C4)perhaloalkyl, -NH, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4) (each C1-C4 alkyl is selected independently of the other), -NO, - refers to any of the alkyl groups substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) selected from the group consisting of CN, isocyano (NC-), oxo (=O), -C(=O)H, -C(=O)-(C1-C4 alkyl), -COOH, -C(=O)-O-(C1-C4 alkyl), -C(=O)NH2, -C(=)ONH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl) (each C1-C4 alkyl is selected independently of the other), -SH, -(C1-C4 alkyl)-SH, -S-(C1-C4 alkyl), -S(=O)-(C1-C4 alkyl), -SO2-(C1-C4 alkyl), and -SO2-(C1-C4 perfluoroalkyl). Examples of such substituents are -CH3, -CH2CH3, -CF3, -CH2CF3, -CF2CF3, -OCH3, -NH(CH3), -N(CH3)2, -SCH3, and SO2CH3. An "optionally substituted alkylene" group can be unsubstituted or substituted in the same manner as a substituted alkyl group.

[0046] "Cycloalkyl" is intended to encompass a monovalent saturated cyclic hydrocarbon chain having the specified number of carbon atoms, or if no number is specified, having 3 to 10 carbon atoms, or 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. "Cycloalkylene" refers to the same group that is a divalent cycloalkyl; cycloalkyl and cycloalkylene groups can be unsubstituted or substituted in the same ways as substituted alkyl groups.

[0047] "Alkenyl" is intended to encompass a monovalent straight or branched hydrocarbon chain having at least one carbon-carbon double bond and having the specified number of carbon atoms, or 2 to 8 carbon atoms if no number is specified. "Alkenylene" refers to a similar group that is divalent. Alkenyl and alkenylene groups can be unsubstituted or, where chemically possible, substituted in the same manner as substituted alkyl groups.

[0048] "Cycloalkenyl" is intended to encompass a monovalent cyclic hydrocarbon chain having at least one carbon-carbon double bond and having the specified number of carbon atoms, or if no number is specified, 4 to 10 carbon atoms, or 4 to 8 carbon atoms, or 4 to 6 carbon atoms. "Cycloalkenylene" refers to a similar group that is divalent. Cycloalkenyl and cycloalkenylene groups can be unsubstituted or, where chemically possible, substituted in the same manner as substituted alkyl groups.

[0049] "Alkynyl" is intended to include monovalent straight or branched hydrocarbon chains having at least one carbon-carbon triple bond and having the specified number of carbon atoms, or 2 to 8 carbon atoms if no number is specified. "Alkynylene" refers to a similar group that is divalent. Alkynyl and alkynylene groups can be unsubstituted or, where chemically possible, substituted in the same manner as substituted alkyl groups.

[0050] "Aryl" is defined as a monovalent aromatic ring system. Aryl groups include monocyclic and polycyclic aromatic ring systems containing the specified number of carbon atoms, or, if no number is specified, 6 to 20 carbon atoms. In other embodiments, aryl groups may contain 6 to 10 carbon atoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxaxolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, and the like. Examples of quinolyl include thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.

[0051] In some embodiments, the aryl group can be unsubstituted. In other embodiments, the aryl group can be any of a variety of groups, such as, for example, —OH, —(C1-C4 alkyl)-OH, halo, fluoro, chloro, bromo, iodo, —(C1-C4 alkyl), —(C1-C4)haloalkyl, —(C1-C4)perhaloalkyl, —O—(C1-C4)alkyl), —O—(C1-C4)haloalkyl), —O—(C1-C4)perhaloalkyl), —(C1-C4)perfluoroalkyl, —(C═O)—(C1-C4)alkyl, —(C═O)—(C1-C4)haloalkyl, —(C═O)—(C1-C4)perhaloalkyl, —NH, —NH(C1-C4 alkyl), —N(C1-C4 alkyl).

[0023] The aryl and heteroaryl groups may be optionally substituted with one, two, three, or more substituents independently selected from the group consisting of -C(C-C alkyl)(C1-C4 alkyl) (each C1-C4 alkyl is selected independently of the other), -NO2, -CN, (NC-), -C(=O)H, -C(=O)-(C1-C4 alkyl), -COOH, -C(=O)-O-(C1-C4 alkyl), -C(=O)NH2, -C(=)ONH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl) (each C1-C4 alkyl is selected independently of the other), -SH, -(C1-C4 alkyl)-SH, and -S-C1-C4 alkyl. In some embodiments, any of the aryl and heteroaryl groups are optionally substituted, for example, with one or more groups referred to herein as "aryl group substituents." "Arylene" refers to a similar group that is divalent.

[0052] The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.

[0053] "Hydrocarbyl" is defined as a monovalent hydrocarbon group, i.e., a group composed of hydrogen and carbon, whether aliphatic or aromatic, acyclic or cyclic, or any combination of aliphatic, aromatic, acyclic, and cyclic, or all combinations thereof. Hydrocarbyl groups have a specified number of carbon atoms, or, if no number is specified, 1 to 10 carbon atoms. "Hydrocarbylene" refers to a similar group that is divalent. Hydrocarbyl and hydrocarbylene groups can be unsubstituted or, where chemically possible, substituted in the same manner as substituted alkyl groups.

[0054] A "heterocycle" or "heterocyclic group" is defined as a ring system containing a specified number of carbon atoms and one or more heteroatoms (e.g., 1-6 heteroatoms, 1-3 heteroatoms, or 1 heteroatom), including, but not limited to, oxygen, nitrogen, sulfur, and phosphorus. A "heteroaryl" is defined as an aromatic ring system containing a specified number of carbon atoms and one or more heteroatoms (e.g., 1-6 heteroatoms, 1-3 heteroatoms, or 1 heteroatom), including, but not limited to, oxygen, nitrogen, sulfur, and phosphorus; heteroaryl groups are a subset of heterocyclic groups. In some embodiments, the heteroatoms of heterocyclyl and heteroaryl groups are selected from the group consisting of oxygen and nitrogen. In various embodiments, heterocyclic groups can contain 2 to 20 carbon atoms and 1 to 6 heteroatoms, 2 to 12 carbon atoms and 1 to 4 heteroatoms, 2 to 12 carbon atoms and 1 to 3 heteroatoms, 2 to 10 carbon atoms and 1 to 3 heteroatoms, 2 to 6 carbon atoms and 1 to 3 heteroatoms, or 2 to 6 carbon atoms and 2 to 4 heteroatoms. In other embodiments, heterocyclic groups can be unsubstituted.In other embodiments, heterocyclic groups may be selected from the group consisting of -OH, (C1-C4 alkyl)-OH, halo, fluoro, chloro, bromo, iodo, -(C1-C4 alkyl), -(C1-C4)haloalkyl, -(C1-C4)perhaloalkyl, -O-(C1-C4 alkyl), -O-(C1-C4 haloalkyl), -O-(C1-C4 perhaloalkyl), -(C1-C4)perfluoroalkyl, -(C=O)-(C1-C4)alkyl, -(C=O)-(C1-C4)haloalkyl, -(C=O)-(C1-C4)perhaloalkyl, -NH, -NH(C1-C4 alkyl), -N(C1 -C4 alkyl)(C1-C4 alkyl) (each C1-C4 alkyl is selected independently of the others), -NO2, -CN, (NC-), -C(=O)H, -C(O)-(C1-C4 alkyl), -COOH, -C(-O)-O-(C1-C4 alkyl), -C(=O)NH2, -C(=)ONH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl) (each C1-C4 alkyl is selected independently of the others), -SH, -(C1-C4 alkyl)-SH and -S-C1-C4 alkyl. Examples of heterocycles include aziridine, oxirane, oxetane, azetidine, pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene, imidazolidine, imidazole, pyrazolidine, pyrazole, 1,2,3-triazole, 1,2,4-triazole, piperidine, pyridine, pyran, piperazine, and morpholine.

[0055] A "heteroalkyl" group is defined as a monovalent hydrocarbyl group in which one or more of the carbon atoms are independently replaced, wherever chemically possible, with a heteroatom, including, but not limited to, oxygen, nitrogen, sulfur, and phosphorus. Heteroalkyl groups have the specified number of carbon atoms, or, if no number is specified, 1 to 10 carbon atoms, and at least one heteroatom, e.g., 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, 1 heteroatom, etc. "Heteroalkylene" refers to the same group that is divalent. Heteroalkyl and heteroalkylene groups can be unsubstituted or, where chemically possible, substituted in the same manner as substituted alkyl groups. Examples of heteroalkyl and heteroalkylene groups include, but are not limited to, (-CHCH-O). n -H (monovalent heteroalkyl group) and (-CH2CH2-O-) n Ethylene glycol and polyethylene glycol moieties such as (divalent heteroalkylene group), where n is an integer from 1 to 12, and (—CHCH(CH)—O—) n -H (monovalent heteroalkyl group) and (-CHCH(CH)-O-) nExamples include propylene glycol and polypropylene glycol moieties such as -(divalent heteroalkylene group), where n is an integer from 1 to 12. The heteroatom(s) O, N, and S and Si can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CHCH-O-CH3, -Si(CH3)3, -CH2-CH-N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH-NH-OCH and -CH-O-Si(CH). Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from a heteroalkyl, as exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -COR'- represents both -C(O)OR' and -OC(O)R'.

[0056] The various groups described above can be attached to the remainder of the molecule at any chemically feasible location on the fragment, including attachment via a substituent when the group is substituted. For structural depiction purposes, groups are typically attached by replacing a hydrogen, hydroxyl, methyl, or methoxy group on the "intact" molecule to generate the appropriate fragment, with a bond being made through an open valence on the fragment to the remainder of the molecule. For example, attachment of the heteroalkyl group -CH2-O-CH3 proceeds by removing a hydrogen from one of the methyl groups of CH3-O-CH3, generating the heteroalkyl fragment -CH2-O-CH3, from which a bond can be made through an open valence to the remainder of the molecule.

[0057] Reference herein to "about" a value or parameter includes (and describes) a variation on that value or parameter itself. For example, a description referring to "about X" includes a description of "X."

[0058] As used herein, the terms "a" or "an" mean one or more, unless the context clearly indicates otherwise.

[0059] By "subject," "individual," or "patient" is meant an individual organism, preferably a vertebrate, more preferably a mammal, and most preferably a human.

[0060] This description is intended to encompass all salts of the compounds described herein, as well as methods of using such compound salts. In one embodiment, the salts of the compounds include pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts that can be administered to humans and / or animals as drugs or pharmaceuticals and that, upon administration, retain at least some of the biological activity of the free compound (neutral or non-salt compound). The desired salt of a basic compound can be prepared by treating the compound with an acid by methods known to those skilled in the art. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic 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, sulfonic acid, and salicylic acid. Salts of basic compounds containing amino acids, such as aspartate and glutamate, can also be prepared. The desired salt of an acidic compound can be prepared by treating the compound with a base using methods known to those skilled in the art. Examples of inorganic salts of acidic compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium, potassium, magnesium, and calcium salts, ammonium salts, and aluminum salts. Examples of organic salts of acidic compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamine, and triethylamine salts. Salts of acidic compounds containing amino acids, such as lysine salts, can also be prepared. For a list of pharmaceutically acceptable salts, see, for example, P. H. Stahl and C. G. Wermuth (eds.), "Handbook of Pharmaceutical Salts, Properties, Selection and Use," Wiley-VCH, 2011 (ISBN: 978-3-90639-051-2). Some pharmaceutically acceptable salts are also disclosed in Berge, J. Pharm. Sci. 66:1 (1977).

[0061] As used herein, the phrase "therapeutically effective amount" means an amount of a compound, material, or formulation, including a compound of the invention, effective to produce some desired therapeutic effect by inhibiting T channels in at least a subpopulation of cells in an animal, thereby blocking or mitigating the biological consequences of that pathway in the treated cells, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0062] In an exemplary embodiment, the invention provides a method for treating a condition described herein in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound described herein, or a compound according to a formula described herein, or a pharmaceutically acceptable salt thereof, sufficient to treat the condition, thereby treating the condition. In an exemplary embodiment of any method described herein, the mammal is in need of treatment with the compound. In an exemplary embodiment of any method described herein, the mammal is a dog, cat, horse, pig, cow, sheep, mouse, guinea pig, or rat. In an exemplary embodiment of any method described herein, the mammal is a human.

[0063] In an exemplary embodiment, the invention provides a method for treating a condition described herein in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a pharmaceutical formulation described herein sufficient to treat the condition, thereby treating the condition. In an exemplary embodiment of any method described herein, the mammal is in need of treatment with the pharmaceutical formulation. In an exemplary embodiment of any method described herein, the mammal is not otherwise in need of treatment with the pharmaceutical formulation. In an exemplary embodiment of any method described herein, the mammal is a mouse or rat. In an exemplary embodiment of any method described herein, the mammal is a human.

[0064] The term “IC 50 " refers to the concentration that causes 50% inhibition of specific binding of the control substance.

[0065] The following abbreviations may be used herein: JPEG0007824349000023.jpg124124JPEG0007824349000024.jpg191118JPEG0007824349000025.jpg135124

[0066] In one aspect, the invention provides a compound of the invention. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. In an exemplary embodiment, the salt of a compound described herein is a pharmaceutically acceptable salt. In an exemplary embodiment, the invention provides a compound described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the invention provides a compound described by a formula provided herein. In an exemplary embodiment, the invention provides a compound described herein.

[0067] One object of the present invention is to provide compounds of the general structure or pharmaceutically acceptable salts thereof that can be used to treat chronic cough or itching. [ka] In the formula, R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X is —N(R 14 )-C(=O)-, or -N(R 14 )-S(=O)k-, or -CH2-N(R 14 )-C(=O)-, or -CH2-N(R 14 )-S(-O) k -, or C(=O)-N(R 14 ), and -CH2-C(=O)-N(R 14 ), or CH2-N(R 14 ) is selected from; k is selected from 1 and 2; R 14 is H or substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroalkyl; R 2is selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; R 3 , R 4 , R 3 , R 6 are each independently hydrogen, substituted or unsubstituted -C 1~6 Alkyl, substituted or unsubstituted -C 1~6 haloalkyl, 3-, 4-, 5-, or 6-membered substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl group; R 3 and R 4 together with the carbon to which they are attached, optionally form a 3- to 6-membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl group, the heterocycloalkyl group optionally containing 1 or 2 heteroatoms independently selected from O, N, or S, and the substituted cycloalkyl or substituted heterocycloalkyl group optionally contains F, -C 1~6 R is substituted with 1, 2, or 3 substituents independently selected from alkyl, and -CF. 5 and R 6 together with the carbon to which they are attached, optionally form a 3-, 4-, 5-, or 6-membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl group, the heterocycloalkyl group optionally containing one or two heteroatoms independently selected from O, N, or S, and the cycloalkyl or heterocycloalkyl group optionally contains one or more heteroatoms selected from F, -C 1~6 R is substituted with 1, 2, or 3 substituents independently selected from alkyl, and -CF3. 7 , R 8 , R 9 , and R 10 are each independently hydrogen, fluorine, or a substituted or unsubstituted —C 1~6 Alkyl, substituted or unsubstituted -C 1~6 haloalkyl, 3-, 4-, 5-, or 6-membered substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl group; R 7 and R 8together with the carbon to which they are attached, optionally form a 3-, 4-, 5-, or 6-membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl group, where the heterocycloalkyl group optionally contains one or two heteroatoms independently selected from O, N, or S, and the substituted cycloalkyl or substituted heterocycloalkyl group optionally contains one or more heteroatoms selected from F, -C 1~6 substituted with 1, 2, or 3 substituents independently selected from alkyl, or -CF; R 9 and R 10 together with the carbon to which they are attached, optionally form a 3-, 4-, 5-, or 6-membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl group, wherein the heterocycloalkyl group contains one or two heteroatoms independently selected from O, N, or S, and the substituted cycloalkyl or substituted heterocycloalkyl group optionally contains one or more heteroatoms selected from F, -C 1~6 substituted with 1, 2, or 3 substituents independently selected from alkyl, or -CF; R 11 , R 12 and R 13 are each independently hydrogen, fluorine, or a substituted or unsubstituted —C 1~6 Alkyl, substituted or unsubstituted -C 1~6 haloalkyl, 3-, 4-, 5-, or 6-membered substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl group; R 11 and R 12 or R 13 together with the carbon to which they are attached optionally form a 3-, 4-, 5-, 6-, or 7-membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl group.

[0068] In an exemplary embodiment, 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R12 , R 13 and X is as described herein, R 1 is selected from substituted or unsubstituted benzyl or a substituted or unsubstituted polycyclic cycloalkyl ring, e.g., adamantyl. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X is as described herein; R 1 is a substituted adamantyl. In an exemplary embodiment, 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X is as described herein; R 3 is a substituted adamant-1-yl. In an exemplary embodiment, 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X is as described herein; R 1 is unsubstituted adamantyl. In an exemplary embodiment, 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9, R 10 , R 11 , R 12 , R 13 and X is as described herein; R 1 is unsubstituted adamant-1-yl.

[0069] In an exemplary embodiment, 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X is as described herein; R 1 is substituted with 1, 2, 3, or 4 non-hydrogen substituents selected from halo, haloalkyl, substituted or unsubstituted alkoxy, and cyano.

[0070] In an exemplary embodiment, the compound of the invention used to treat chronic cough or itch has a structure according to Formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X is as described herein; R 1 But the expression: [ka] wherein A, B, C and D are independently selected from "aryl group substituents" and the indices a, b, c and d are independently selected from 0 and 1.

[0071] In an exemplary embodiment, the compound of the invention used to treat chronic cough or itch has a structure according to Formula 1, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X are as described herein. A, B, C, and D are independently selected from CN, Cl, Br, F, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C1-C6 haloalkyl, and substituted or unsubstituted C1-C6 alkoxy.

[0072] In an exemplary embodiment, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X is as described herein; R 2 is C1~C 10 Straight-chain or branched substituted or unsubstituted C1-C6 alkyl, and C1-C 10 In an exemplary embodiment, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X is as described herein; R 2includes substituted alkyl or heteroalkyl groups, which are substituted with amido, oxo, substituted or unsubstituted aryl, or substituted or unsubstituted heterocycloalkyl. Exemplary substituted aryl groups include substituted or unsubstituted phenyl, and exemplary heterocycloalkyl moieties are oxygen-containing heterocycles.

[0073] In an exemplary embodiment, the compound of the invention used to treat chronic cough or itch has the formula: [ka] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and X are as described herein, and q is an integer selected from 1, 2, 3, 4, and 5. In an exemplary embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X is as described herein; R 11a and R 11b are each a member independently selected from H, methyl, and fluorine. In an exemplary embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, q is 1, and R 11ais H and R 11b is F. In an exemplary embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, q is 1, and R 11a is F and R 11b is F.

[0074] In an exemplary embodiment, the compound of the invention used to treat chronic cough or itch has the formula: [ka] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, and q is an integer selected from 1, 2, 3, 4, and 5.

[0075] In an exemplary embodiment, the compound of the invention used to treat chronic cough or itch has the formula: [ka] X, R 1 and R 2 is as described herein and q is 1 or 2.

[0076] In an exemplary embodiment, the compound of the invention used to treat chronic cough or itch has the formula: [ka] X, R 1 and R 2 is as described herein and q is 1 or 2.

[0077] In an exemplary embodiment, the compound of the invention used to treat chronic cough or itch has the formula: [ka] X, R 1 and R 2 is as described herein and q is 1 or 2.

[0078] In an exemplary embodiment, the compound of the invention used to treat chronic cough or itch has the formula: [ka] X, R 1 and R 2 is as described herein and q is 1 or 2.

[0079] In an exemplary embodiment, the compound of the invention used to treat chronic cough or itch has the formula: [ka] X, R 1 and R 2 is as described herein and q is 1 or 2.

[0080] In an exemplary embodiment, q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X is as described herein; R 1is substituted or unsubstituted benzyl or substituted or unsubstituted adamantyl. In an exemplary embodiment, q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X is as described herein; R 1 is substituted phenyl. In an exemplary embodiment, q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X is as described herein; R 1 is unsubstituted phenyl. In an exemplary embodiment, q, R 2 , R 4 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X is as described herein; R 1 is a substituted or unsubstituted adamantyl. In an exemplary embodiment, q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X is as described herein;

[0081] R 1 teeth, [ka] or [ka] or [ka] and [ka] is R 1 represents the covalent linkage between X and R 1a and R 1b Each of q, R is a member independently selected from halo, haloalkyl, substituted or unsubstituted alkoxy, and cyano. In an exemplary embodiment, q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X is as described herein;

[0082] R 1 teeth, [ka] or [ka] or [ka] and [ka] is R 1 represents a covalent link between X and R 1a and R 1b are each a member independently selected from F, Cl, Br, CF, methoxy, methyl, and CN. In an exemplary embodiment, q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7, R 8 , R 9 , R 10 and X is as described herein;

[0083] R 1 teeth [ka] or [ka] or [ka] and [ka] is R 1 represents a covalent link between X and R 1a and R 1b are each independently selected members from F, Cl, and CF3.

[0084] In an exemplary embodiment, q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X is as described herein; R 2 is substituted or unsubstituted alkyl. In an exemplary embodiment, q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X is as described herein; R 2 is substituted or unsubstituted heteroalkyl. In an exemplary embodiment, q, R 2 , R 3 , R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X is as described herein;

[0085] R 2 teeth, [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] or [ka] and [ka] is R 2 and the piperidine nitrogen.

[0086] In an exemplary embodiment, the compound used to treat chronic cough or itch has the formula: [ka] In the formula, X, R 2 , and R 1 is as described herein.

[0087] In an exemplary embodiment, the compound used to treat chronic cough or itch has the formula: [ka] wherein X, R 2 , and R 1is as described herein. In an exemplary embodiment, the compound is according to the formula described herein, R 1 is phenyl substituted with 1 to 3 substituents, each of which is a member selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is a compound according to the formula described herein, 1 is phenyl substituted with one substituent that is a member selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is 1 is phenyl substituted with two substituents, each independently a member selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is 1 is phenyl substituted with three substituents, each independently a member selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound has the formula: [ka] wherein X, R 2 and R 1 is as described herein. In an exemplary embodiment, the compound has the formula: [ka] wherein X, R 2 , and R 1 is as described herein.

[0088] In an exemplary embodiment, the compound used to treat chronic cough or itch is: [ka] and X and R 1 as described herein. In an exemplary embodiment, the compound is [ka] and X and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and X and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and X and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and X and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and X and R 1 is as described herein.

[0089] In an exemplary embodiment, the compound is: [ka] and R 1 and R 2 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 and R 2 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 and R 2is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 and R 2 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 and R 2 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 and R 2 is as described herein.

[0090] In an exemplary embodiment, the compound is: [ka] and X and R 2 is as described herein, and R 1a and R 1b are each independently selected members from the group consisting of F, Cl, and CF3.

[0091] In an exemplary embodiment, the compound is: [ka] and X and R 2 is as described herein, and R 1a and R 1b are each independently selected members from the group consisting of F, Cl, and CF3.

[0092] In an exemplary embodiment, the compound is: [ka] and X and R 2 is as described herein, and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and X and R 2 is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and X and R 2 is as described herein, and R 1 is unsubstituted adamant-1-yl.

[0093] In an exemplary embodiment, the compound is: [ka] and R 2 , R 1a and R 1b is as described herein. In an exemplary embodiment, the compound is 1a and R 1b and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is 1a and R 1b and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is 1a and R 1b and R 1ais as described herein, and R 1b is F. In an exemplary embodiment, the compound is 1a and R 1b and R 1a is as described herein, and R 1b is Cl. In an exemplary embodiment, the compound has R 1a and R 1b and R 1a is as described herein, and R 1b is CF. In an exemplary embodiment, the compound is 1a and R 1b and R 1b is as described herein, and R 1a is F. In an exemplary embodiment, the compound is 1a and R 1b and R 1b is as described herein, and R 1a is Cl. In an exemplary embodiment, the compound has R 1a and R 1b and R 1b is as described herein, and R 1a is CF. In an exemplary embodiment, the compound is [ka] and R 2 , R 1a and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and R 2 , R 1a and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and R 2 , R 1a and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and R 2 , R 1a and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and R 2 , R 1a and R 1b is as described herein.

[0094] In an exemplary embodiment, the compound is: [ka] and R 2 , R 1a and R 1b is as described herein. In an exemplary embodiment, the compound is 1a and R 1b and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is 1a and R 1b and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is 1a and R 1b and R 1ais as described herein, and R 1b is F. In an exemplary embodiment, the compound is 1a and R 1b and R 1a is as described herein, and R 1b is Cl. In an exemplary embodiment, the compound has R 1a and R 1b and R 1a is as described herein, and R 1b is CF. In an exemplary embodiment, the compound is 1a and R 1b and R 1b is as described herein, and R 1a is F. In an exemplary embodiment, the compound is 1a and R 1a and R 1b is as described herein, and R 1a is Cl. In an exemplary embodiment, the compound has R 1a and R 1b and R 1b is as described herein, and R 1a is CF. In an exemplary embodiment, the compound is [ka] and R 2 , R 1a and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and R 2 , R 1a and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and R 2 , R 1a and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and R 2 , R 1a and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and R 2 , R 1a and R 1b is as described herein.

[0095] In an exemplary embodiment, the compound is: [ka] and R 2 is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 2 is as described herein, and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 2 is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 2 is as described herein, and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 2 is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 2 is as described herein, and R 1 is unsubstituted adamant-1-yl.

[0096] In an exemplary embodiment, the compound is: [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein. In an exemplary embodiment, the compound is [ka] and R 1 is as described herein.

[0097] In an exemplary embodiment, the compound is: [ka] and X, R 1a , and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and X, R 1a , and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and X, R 1a , and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and X, R 1a , and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and X, R 1a , and R 1b is as described herein. In an exemplary embodiment, the compound is [ka] and X, R 1a , and R 1b is as described herein.

[0098] In an exemplary embodiment, the compound is: [ka] and X is as described herein, and R 1is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and X is as described herein, and R 1 is unsubstituted adamant-1-yl.

[0099] In an exemplary embodiment, the compound is: [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound [ka] and R1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected members from the group consisting of F, Cl, and CF3.

[0100] In an exemplary embodiment, the compound is: [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1bare each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected from the group consisting of F, Cl, and CF. In an exemplary embodiment, the compound is [ka] and R 1a and R 1b are each independently selected members from the group consisting of F, Cl, and CF3.

[0101] In an exemplary embodiment, the compound is: [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is [ka] and R 1 is unsubstituted adamant-1-yl.

[0102] In an exemplary embodiment, the compound is: [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0103] In an exemplary embodiment, the compound is: [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0104] In an exemplary embodiment, the compound is: [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0105] In an exemplary embodiment, the compound is: [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0106] In an exemplary embodiment, the compound is: [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0107] In an exemplary embodiment, the compound is: [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0108] In an exemplary embodiment, the compound is: [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0109] In an exemplary embodiment, the compound is: [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0110] In an exemplary embodiment, the compound is: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted adamant-1-yl. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted adamant-1-yl.

[0111] In an exemplary embodiment, the compound is: [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0112] In an exemplary embodiment, the structure of AFA-358 is: [ka] is.

[0113] In an exemplary embodiment, the structure of AFA-309 is: [ka] is.

[0114] In an exemplary embodiment, the structure of AFA-258 is: [ka] is.

[0115] In an exemplary embodiment, the structure of AFA-353 is: [ka] is.

[0116] AFA-309, AFA-353, and AFA-358 are novel T-type Cav3 channel modulators used to treat pathological conditions such as pain, irritable cough, and itch.

[0117] The present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound according to Formula I or as individually disclosed herein. The formulation further comprises a pharmaceutically acceptable carrier.

[0118] The present invention also provides a method for treating Cav1, which comprises administering to a mammal a therapeutically effective amount of a compound according to Formula I or individually disclosed herein. 3.2 The present invention provides a method for treating irritable cough or itching that responds to the selective inhibition of T channels, known as T channels.

[0119] The present invention provides compounds that are selective T channel blocking compounds useful in the relief of irritable cough or itching.

[0120] The present invention also includes all stereoisomers and geometric isomers of the compounds, including diastereomers, enantiomers, and cis / trans (E / Z) isomers, where chemically possible. The present invention also includes mixtures of stereoisomers and / or geometric isomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly shown in a structure, the structure is intended to encompass all possible stereoisomers of the compound depicted. When stereochemistry is explicitly shown for one or more portions of a molecule but not for another portion or portions of the molecule, the structure is intended to encompass all possible stereoisomers of the portion or portions where stereochemistry is not explicitly shown.

[0121] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention. Unless a specific isotope is indicated, the present invention includes all isotopologues of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds (H is 2 H, i.e., D).

[0122] In the context of the present invention, compounds that are believed to possess activity as T channel inhibitors are those that inhibit Ca at concentrations of about 100 μM or less, preferably about 10 μM or less, more preferably about 1 μM or less, and most preferably about 100 nM or less. ++ Potential (IC 50 ) shows 50% inhibition. chemical synthesis

[0123] Terms related to "protecting," "deprotecting," and "protected" functions are used throughout this specification. Such terms are well understood by those skilled in the art and are used in the context of processes involving sequential treatment with a series of reagents. In that context, a protecting group refers to a group used to mask a function during a process step where reaction would otherwise be undesirable. The protecting group prevents reaction at that step but can be subsequently removed to expose the original functionality. Removal or "deprotection" occurs after completion of one or more reactions in which the function interferes. Thus, when a sequence of reagents is specified, as in the processes of the present invention, one of skill in the art can readily envision those groups that would be suitable as "protecting groups." Groups suitable for this purpose are described in standard textbooks in the field of chemistry, such as "Greene's Protective Groups in Organic Synthesis; 5th Edition" (Peter G, M. Wuts, [John Wiley & Sons, New York, 2014], DOI: 10.1002 / 9781118905074), which is incorporated herein by reference.

[0124] A comprehensive list of abbreviations used by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry, typically presented in a table entitled "List of Standard Abbreviations," which is incorporated herein by reference.

[0125] In general, the compounds of the present invention can be prepared by the methods shown in the general reaction schemes, for example as described below, or by modifying them using readily available starting materials, reagents, and conventional synthetic procedures. These reactions can also utilize variants that are known per se but are not mentioned herein. For example, the starting materials for suitably substituted benzimidazole ring compounds can be commercially available, synthesized as described in the examples, or obtained by methods well known to those skilled in the art. Pharmaceutical preparations

[0126] The present invention further provides pharmaceutical formulations comprising, as an active agent, a compound described herein.

[0127] In an exemplary embodiment, the invention is a pharmaceutical formulation comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the invention is a pharmaceutical formulation comprising a therapeutically effective amount of a compound of the formula described herein, or a pharmaceutically acceptable salt thereof.

[0128] In an exemplary embodiment, the invention is a pharmaceutical formulation comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In an exemplary embodiment, the invention is a pharmaceutical formulation comprising a therapeutically effective amount of a compound of a formula described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0129] In an exemplary embodiment, the invention is a pharmaceutical formulation, as described herein, wherein the formulation is in a unit dosage form.

[0130] As used herein, a "pharmaceutical formulation" refers to a preparation of one or more of the compounds described herein or their physiologically acceptable salts or solvates (such as hydrates) together with other chemical components, such as physiologically suitable carriers and excipients.

[0131] Pharmaceutical formulations containing the compound of Formula 1 and any of the compounds described herein may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. Preferred unit dosage formulations are those containing an effective amount of the active ingredient, or an appropriate fraction thereof, or a pharmaceutically acceptable salt thereof. The magnitude of a prophylactic or therapeutic dose typically varies depending on the nature and severity of the condition being treated and the route of administration. The dose, and perhaps the frequency of administration, will also vary according to the age, weight, and response of the individual patient. Generally, dosages range from about 0.1 mg to about 7000 mg, preferably from about 1 mg to about 100 mg, and more preferably from about 25 mg to about 50 mg, in single or divided doses. In some embodiments, dosages may range from about 50 mg to about 500 mg, preferably from about 100 mg to about 500 mg. Such doses may be administered 1, 2, 3, 4, 5, 6, or more times daily. Children, patients over 65 years old, and patients with impaired renal or hepatic function may be recommended to initially receive a low dose, and then titrate the dosage based on individual response and / or blood level.As will be clear to those skilled in the art, in some cases, it may be necessary to use dosages outside these ranges.In addition, it should be noted that clinicians or treating physicians know how and when to interrupt, adjust, or terminate treatment in relation to the response of individual patients.

[0132] Therefore, the pharmaceutical preparation for use according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of active compound into pharmaceutically usable preparations.Carrier must be acceptable in the sense that it is compatible with other components of the preparation and is not harmful to its recipient.Suitable formulation depends on the selected route of administration.

[0133] Compounds that inhibit T channels can be formulated as pharmaceutical preparations and administered to mammalian subjects, such as human patients, in a variety of forms adapted to the selected route of administration, i.e., by intravenous, intramuscular, topical, transdermal, intradermal, intraarticular, or subcutaneous routes, orally, rectally, topically (such as cutaneous, buccal, sublingual, and intraocular), or parenterally.

[0134] For oral administration, compounds can be easily formulated by combining the active compound with pharmaceutically acceptable carriers known in the art. Such carriers allow the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by patients. Pharmacological preparations for oral use can be made using solid excipients, optionally milling the resulting mixture, and processing the granular mixture into tablets or dragee cores, after adding suitable excipients if desired. Suitable excipients are, in particular, fillers such as sugars, such as lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carbomethylcellulose, and / or physiologically acceptable polymers, such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0135] Additionally, enteric coatings may be useful as it may be desirable to prevent exposure of the compounds of the invention to the gastric environment.

[0136] Orally usable pharmaceutical preparations include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol).Push-fit capsules may contain active ingredients mixed with fillers such as lactose, binders such as starch, lubricants such as talc or magnesium stearate, and optionally stabilizers.In soft capsules, active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol.Furthermore, stabilizers may be added.

[0137] Formulations for topical administration in the mouth, e.g., buccal or sublingual, include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia. All formulations for oral administration should be in dosages appropriate for the chosen route of administration.

[0138] For injection, the compound of the present invention can be formulated in aqueous solution, preferably in physiologically compatible buffer such as Hanks' or Ringer's solution or physiological saline buffer.For transmucosal and transdermal administration, penetrants suitable for the barrier to be permeated can be used in the formulation.Such penetrants, for example, DMSO or polyethylene glycol, are known in the art.

[0139] For administration by inhalation, the compound for use according to the present invention can be conveniently delivered in the form of aerosol spray from pressurized pack or nebulizer, using suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide.For pressurized aerosol, dosage unit can be determined by providing a valve to deliver a metered amount.For example, gelatin capsules and cartridges for use in inhaler or insufflator can be formulated to contain the powder mixture of compound and suitable powder base such as lactose or starch.

[0140] Pharmaceutical preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient. Preparations also include aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Pharmaceutical preparations for parenteral administration in aqueous solution contain the active ingredient in water-soluble form. Furthermore, suspensions of the active compound may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0141] The formulations may be presented in unit-dose, multi-dose containers, for example, sealed ampoules and vials and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, phosphate-buffered saline (PBS), etc. immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0142] The compounds of the present invention may also be formulated in rectal preparations such as suppositories or retention enemas, using, for example, conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0143] Depending on the severity and responsiveness of the condition being treated, dosing may also be a single dose of a sustained-release formulation, with the course of treatment lasting from several days to several weeks, or until a cure is effected or a diminution of the disease state is achieved. Naturally, the amount of formulation administered will depend on many factors, including the subject being treated, the severity of the affliction, the method of administration, and the judgment of the prescribing physician. The compounds of the present invention may be administered orally or by injection at a dose of 0.001 to 250 mg / kg per day. The dose range for adults is generally 0.5 mg to 10 g per day. Tablets or other forms of presentation provided in individual units may conveniently contain an effective amount of the compounds of the present invention in such a dosage amount or in a multiple thereof, e.g., as a unit containing 5 mg to 500 mg (usually about 10 mg to 200 mg). The precise amount of compound administered to a patient is the responsibility of the attending physician. However, the dosage used will vary depending on several factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.

[0144] As used herein, and as understood by those skilled in the art, a recitation of a "compound" is intended to include salts, solvates, and inclusion complexes of that compound. The term "solvate" refers to a compound described herein and / or a compound from Formula I in the solid state, in which molecules of a suitable solvent are incorporated into the crystal lattice. A solvent suitable for therapeutic administration is physiologically acceptable at the administered dosage. Examples of solvents suitable for therapeutic administration are ethanol and water. When water is the solvent, the solvent is called a hydrate. Solvates are generally formed by dissolving the compound in an appropriate solvent and isolating the solvate by cooling or using an antisolvent. Solvates are typically dried under ambient conditions or azeotropically dried. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy, 19th Edition (1995), Vol. 1, pp. 176-177, which is incorporated herein by reference. The most commonly used inclusion complexes are those involving cyclodextrins, and all cyclodextrin complexes, both natural and synthetic, are specifically claimed.

[0145] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, such as inorganic acids and bases and organic acids and bases. When the compound of the present invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, such as inorganic acids and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Suitable pharmaceutically acceptable base addition salts for compounds of the invention, when the compound contains an acidic side chain, include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0146] The term "prevent" as used herein refers to administering a pharmaceutical agent in advance to forestall or blunt an attack. Those skilled in the medical arts (which refer to the method claims) recognize that the term "prevent" is not an absolute term. It is understood in the medical arts to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition, and this is the meaning intended herein.

[0147] It will be understood that in addition to the ingredients particularly mentioned above, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question, e.g., those suitable for oral administration may include flavoring agents.

[0148] The preparation can be presented in a packaging device or dispenser, which can contain one or more unit dosage forms containing active ingredients.Examples of packaging device include metal or plastic foil, such as blister pack and inhalation nebulizer.Packaging device or dispenser can also be provided with instructions for administration.The preparation that comprises the compound of the present invention formulated in compatible pharmaceutical carrier can also be placed in a suitable container and labeled for the treatment of indicated conditions.

[0149] Some embodiments described herein are described as "comprising" or "comprise" with respect to their various elements. In alternative embodiments, these elements can be recited with the transitional phrase "consisting essentially of" or "consists essentially of," when applied to those elements. In further alternative embodiments, these elements can be recited with the transitional phrase "consisting of" or "consist of," when applied to those elements. Thus, for example, if a compound, formulation, or method is disclosed herein as comprising A and B, alternative embodiments of that compound, formulation, or method that "consist essentially of A and B," and alternative embodiments of that compound, formulation, or method that "consist A and B," are also considered to be disclosed herein. Similarly, embodiments described as "consisting essentially of" or "consisting of" with respect to their various elements can also be described as "comprising," when applied to those elements. Finally, embodiments described as "consisting essentially of" with respect to their various elements can also be described as "consisting of" when applied to those elements, and vice versa.

[0150] When a compound or formulation is described as "consisting essentially of the recited components," the compound or formulation includes the explicitly recited components and may include other components that do not substantially affect the condition being treated. That is, either the compound or formulation does not include any other components other than the explicitly recited components that substantially affect the condition being treated, or the compound or formulation includes additional components other than those recited that substantially affect the condition being treated, but the compound or formulation does not include those extra components in concentrations or amounts sufficient to substantially affect the condition being treated. When a method is described as "consisting essentially of the recited steps," the method includes the recited steps and may also include other steps that do not substantially affect the condition being treated, but the method does not include any other steps other than the explicitly recited steps that substantially affect the condition being treated.

[0151] The following examples are provided to illustrate, but not limit, the present invention. Compounds disclosed herein are numbered and preceded by the prefix EX- or AFA-. Example Example A In vivo effects of EX / AFA compounds in a representative hypersensitive cough model in guinea pigs

[0152] Guinea pigs (male, weighing 280 g, Hanley Crl:HA, Charles River) were maintained at 21 ± 2°C, 55 ± 10% humidity, and a 12-hour light / 12-hour dark light cycle. Food and water were available ad libitum for at least 1 week prior to testing. Coughing was induced by inhalation of citric acid aerosol, and coughing was assessed by manual recording (Gallico, Borghi, et al., 1994). Individual animals were placed in a 4-liter Plexiglas observation chamber continuously filled with 17.5% citric acid aerosol. The number of coughs per animal was recorded for 5 minutes. Coughing was recognized based on the sound associated with rapid inspiration followed by rapid expiration. Only animals with 10 or more coughs per 5 minutes were selected for the study. The selected animals were then randomly divided into five groups, with n = 8 per group. Five days after the screening study, based on the PK profile, EX-17, a representative AFA compound, was administered at 0, 3, 10, and 30 mg / kg doses 30 minutes before citric acid inhalation. The benchmark, dextromethorphan hydrobromide (60 mg / kg, po), was administered 60 minutes before citric acid inhalation. EX-17 produced a dose-dependent inhibition of cough frequency, with reductions of 7.2%, 23.3%, and 36.8% at doses of 3, 10, and 30 mg / kg, respectively (Figure 1A). 30 mg / kg of EX-17 produced a comparable inhibition to dextromethorphan (40.0% at 60 mg / kg, po). The latency to first cough was used as an additional parameter to evaluate antitussive properties. EX-17 also dose-dependently increased the latency to first cough. Only 30 mg / kg EX-17 and dextromethorphan hydrobromide (60 mg / kg, po) reached significance under the experimental conditions (Fig. 1B).

[0153] Using the same study protocol, three additional representative EX compounds, EX-128, EX-130, and EX-132 (each at 30 mg / kg, po) or vehicle were tested based on their pharmacokinetic profiles by oral administration 30 min before citric acid inhalation, while dextromethorphan hydrobromide (60 mg / kg, po) was administered orally 60 min before citric acid inhalation. Compared with the vehicle control compound, EX-128 and dextromethorphan significantly reduced the number of coughs, with reductions of 39.1% and 42.6%, respectively (Figure 2A). EX-130 and EX-132 showed a trend toward a reduction in the number of coughs, with reductions of 33% and 15.7%, respectively, but did not reach significance. The latency to first cough was increased for all three compounds and evaluation criteria, but none of these achieved significance under the experimental conditions (Figure 2B). References Canning, BJ and Chou, YL (2004). "Cough Sensors. I. Physiological and Pharmacological Properties of the . Afferent Nerves Regulating Cough" in “Pharmacology and Therapeutics of Cough" ed, Chung and Widdicomb, pp 23-47, Handbook of Experimental Pharmacology ISSN 0171-2004 Gallico, Lic., A. Borghi, C. Dalla Rosa, R. Ceserani and S. Tognella (1994), "Moguistrine: a novel peripheral non-narcotic antitussive drug." Br J Pharmacol 112(3): 795-800. Irwin, RS, MJ Rosen and SS Braman (1977). "Cough. A comprehensive review." Arch Intern Med 137(9): 1186-1191. Kase, Y., Y. Wakita, G. Kito, T. Miyata, T. Yuizono and M. Kataoka (1970). "Centrally-induced coughs in the cat." Life Sci 9(1): 49-59. North, RA (2016). "P2X receptors." Philos Trans R Soc Load B Biol Sci 371(1700). Pachuau, J, Martin- Caraballo, M. (2007). Expression pattern of T-type Ca(2+) channels in embryonic chick nodose ganglion neurons, Dev Neurobiol. 67(14);1901-14. Example B: In vivo effects of AFA / EX compounds in two representative itch models in mice

[0154] A representative panel of AFA / EX compounds was investigated with various recombinant human ion channels expressed in mammalian cells and native ion channels in dissociated rat dorsal root ganglion (DRG) neurons. As shown in Table 1, the selected 10 AFA compounds produced differential modulation of various ionic currents mediated by the selected ion channels. Therefore, this panel of compounds was next investigated for their effects on itch-scratching behavior in two well-established itch models in mice.

[0155] We used the neck itch model. Mice (C57BL / 6, male, 3-4 months old) were shaved at the nape of the neck 2-3 days before the experiment. On the day of behavioral testing, mice were individually placed in small plastic chambers (12cm L x 9.5cm W x 12cm H) and inserted into their normal home cages for at least 30 minutes for habituation. Baseline behavior was recorded using a video camera and piezoelectric floor sensors operated by SmartCage, a validated home cage behavior monitoring system capable of simultaneously monitoring the scratching behavior of multiple mice.

[0156] Treatment with individual test articles (30 representative AFA compounds at 30 mg / kg each) or vehicle (0.5% aqueous hydroxypropyl cellulose solution containing 2% DMSO) was administered intraperitoneally (ip) 30 minutes before itch induction. Mice were intradermally injected with 50 μl of pruritogen, chloroquine, or histamine in the nape of the neck. Immediately after injection, mice were returned to the chamber and continuously recorded for 30 minutes by a piezoelectric floor sensor. Itchy scratching behavior was scored manually in real time by a human and confirmed offline by video and / or piezoelectric recordings. Itch behavior was quantified by counting the number of scratches in a blinded environment. Scratches were counted when the mouse lifted its hind paw to scratch the shaved area, then returned its paw to the floor or its mouth and licked. Scratching episodes and duration were objectively quantified offline by analyzing the larger, more regular waveform of the piezoelectric signal, which is distinct from normal home cage activity.

[0157] These studies revealed the unexpected finding that, despite compounds with similar potency against T-type Cav3.2 channels, the compounds differentially modulated itch-scratching behavior in these two different itch models (Figure 3A). AFA-221 (EX-31), AFA-281 (EX-130), and AFA-358 produced potent and comparable efficacy against chloroquine- and histamine-induced inhibition, whereas AFA-309, AFA-258 (Z944), AFA-322 (EX-132), and AFA-206 (EX-55) preferentially suppressed histamine-induced itch (Figure 3B).

[0158] In conclusion, itch scratching behavior phenotyping can be used to discover novel compounds for the potential treatment of chronic itch disorders. [Table 1] Effects of representative AFA compounds on recombinant and native ion channels

[0159] h = human isoform; Use Dep = use dependent; DRG = dorsal root ganglion; hERG = human ether-a-go-go related gene (hERG) potassium (K + )channel Additional References Avdonin PV, Buhler FR, Tkachuk VA (2000) Ca2+-agonistic effect of a T-type Ca-channel blocker mibefradil (Ro 40-5967). Membr Cell Biol 13:645-655. Caviedes BE, Herranz JL (2001) [Use of antiepileptic drugs in non epileptic disorders]. Rev Neurol 33:241-249. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. Journal of neuroscience methods 53:55-63. Chaudhry V, Rowinsky EK, Sartorius SE, Donehower RC, Cornblath DR (1994) Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Annals of neurology 35:304-311. Choi S, Na HS, Kim J, et al. (2007) Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels. Genes Brain Behav 6:425-431. Cribbs LL, Gomora JC, Daud AN, Lee JH, Perez-Reyes E (2000) Molecular cloning and functional expression of Ca(v)3.1c, a T-type calcium channel from human brain. FEBS Lett 466:54-58. Decosterd I, Woolf CJ (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87:149-158. Gomora JC, Daud AN, Weiergraber M, Perez-Reyes E (2001) Block of cloned human. T-type calcium channels by succinimide antiepileptic drugs. Mol Pharmacol 60: 1121-1132. Han HA, Cortez MA, Snead OC III, (2012) GABA B Receptor and Absence Epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US) Huguenard JR (1998) Low-voltage-activated (T-type) calcium-channel genes identified. Trends Neurosci 21:451-452. Huguenard JR (2002) Block of T-Type Ca(2+) Channels Is an Important Action of Succinimide Antiabsence Drugs. Epilepsy Curr 2:49-52. Jagodic MM, Pathirathna S, Joksovic PM, Lee W, Nelson MT, Naik AK, Su P, Jevtovic- Todorovic V, Todorovic SM (2008) Upregulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. J Neurophysiol 99:3151-3156. Jagodic MM Pathirathna S, Nelson MT, Mancuso S, Joksovic PM, Rosenberg ER, Bayliss DA, Jevtovic-Todorovic V, Todorovic SM (2007) Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. J Neurosci 27:3305-3316. Jarvis MF, Scott VE, McGaraughty S, Chu KL, Xu J, Niforatos W, Milicic I, Joshi S, Zhang Q, Xia Z (2014) A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats. Biochemical pharmacology 89:536-544. Jenkins ID, Lacrampe F, Ripper J, Alcaraz L, Le PV, Nikolakopoulos G, de Almeida Leone P, White RH, Quinn RJ (2009) Synthesis of four novel natural product inspired scaffolds for drug discovery. The Journal of organic chemistry 74:1304-1313. Kim SH, Chung JM (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain. 50(3):355-63. Kraus RL, Li Y, Gregan Y, Gotter AL, Uebele VN, Fox SV, Doran SM, Barrow JC, Yang ZQ, Reger TS, Koblan KS, Renger JJ (2010) In vitro characterization of T-type calcium channel antagonist TTA-A2 and in vivo effects on arousal in mice. J Pharmacol Exp Ther 335:409-417. Latham JR, Pathirathna S, Jagodic MM, Choe WJ, Levin ME, Nelson MT, Lee WY, Krishnan K, Covey DF, Todorovic SM, Jevtovic-Todorovic V (2009) Selective T-type calcium channel blockade alleviates hyperalgesia in ob / ob mice. Diabetes 58:2656-2665. Lee M (2014) Z944: a first in class T-type calcium channel modulator for the treatment of pain, Journal of the peripheral nervous system : JPNS 19 Suppl 2:S11-12. Messinger RB, Naik AK, Jagodic MM, Nelson MT, Lee WY, Choe WJ, Orestes P, Latham JR, Todorovic SM, Jevtovic-Todorovic V (2009) In vivo silencing of the Ca(V)3.2 T-type calcium channels in sensory neurons alleviates hyperalgesia in rats with streptozocin- induced diabetic neuropathy. Pain 145:184-195. Nahab FB, Handforth A, Brown T, et al., (2012) Octanoic acid suppresses harmaline-induced tremor in mouse model of essential tremor. Neurotherapeutics, 9:635-638 Nelson SC, Friedman HS, Oakes WJ, Halperin EC, Tien R, Fuller GN, Hockenberger B, Scroggs MW, Moncino M, Kurtzberg J, et al. (1992) Successful therapy for trilateral retinoblastoma. Am J Ophthalmol 114:23-29. Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83:117-161. Perez-Reyes E (2010) G protein-mediated inhibition of Cav3.2 T-type channels revisited. Molecular pharmacology 77:136-138. Perez-Reyes E, Van Deusen AL, Vitko I (2009) Molecular Pharmacology of Human Cav3.2 T- Type Ca2+ Channels: Block by Antihypertensives, Antiarrhythmics, and Their Analogs. Journal of Pharmacology and Experimental Therapeutics 328:621-627. Pexton T, Moeller-Bertram T, Schilling JM, Wallace MS (2011) Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development. Expert opinion on investigational drugs 20:1277-1284. Pogatzki-Zahn EM, Wagner C, Meinhardt-Renner A (2003) Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision. Pain 105(1-2):97-107. Sanguinetti, MC, Jiang C, Curran ME, Keating MT (1995) A mechanistic link between an inherited and an acquired cardiac arrhythmia: hERG encodes the IKr potassium channel Cell, 81:299-307. Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss DA (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 19:1895-1911. Todorovic SM, Jevtovic-Todorovic V (2011) T-type voltage-gated calcium channels as targets for the development of novel pain therapies. British journal of pharmacology 163:484- 495. Tringham E, Powell KL, Cain SM, Kuplast K, Mezeyova J, Weerapura M, Eduljee C, Jiang X, Smith P, Morrison JL, Jones NC, Braine E, Rind G, Fee-Maki M, Parker D, Pajouhesh H, Parmar M, O’Brien TJ, Snutch TP (2012) T-type calcium channel blockers that, attenuate thalamic burst firing and suppress absence seizures. Science translational medicine 4:121ra119. Uebele VN, Gotter AL, Nuss CE, Kraus RL, Doran SM, Garson SL, Reiss DR, Li Y, Barrow JC, Reger TS, Yang ZQ, Ballard JE, Tang C, Metzger JM, Wang SP, Koblan KS, Renger JJ (2009) Antagonism of T-type calcium channels inhibits high-fat diet-induced weight gain in mice. J Clin Invest 119:1659-1667. Wang Y, Liu JJ, Dransfield PJ, Zhu L, Wang Z, Du X, Jiao X, Su Y, Li AR, Brown SP, Kasparian A, Vimolratana M, Yu M, Pattaropong V, Houze JB, Swaminath G, Tran T, Nguyen K, Guo Q, Zhang J, Zhuang R, Li F, Miao L, Bartberger MD, Correll TL, Chow D, Wong S, Luo J, Lin DC, Medina JC (2013) Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles. ACS medicinal chemistry letters 4:551-555. Xiang Z, Thompson AD, Brogan JT, Schulte ML, Melancon BJ, Mi D, Lewis LM, Zou B, Yang L, Morrison R, Santomango T, Byers F, Brewer K, Aldrich JS, Yu H, Dawson ES, Li M, McManus O, Jones CK, Daniels JS, Hopkins CR, Xie XS, Conn PJ, Weaver CD, Lindsley CW (2011) The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson's Disease. ACS chemical neuroscience 2:730-742. Xie X, Brogan JT, Schulte ML, Mi D, Yu H, Dawson ES, Li M, McManus O, Engers J, Lewis LM, Thompson A, Jones CK, Weaver CD, Lindsley CW (2010) Scaffold Hopping Affords a Highly Selective in vitro and in vivo T-Type Calcium Inhibitor Probe Free From IP Issues. In: Probe Reports from the NIH Molecular Libraries Program Bethesda (MD). Xie X, Lancaster B, Peakman T, Garthwaite J (1995) Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type IIA Na+ channels and with native Na+ channels in rat hippocampal neurones. Pflugers Archiv : European journal of physiology 430:437-446. Xie X, Van Deusen AL, Vitko I, Babu DA, Davies LA, Huynh N, Cheng H, Yang N, Barrett PQ, Perez-Reyes E (2007) Validation of high throughput screening assays against three subtypes of Ca(v)3 T-type channels using molecular and pharmacologic approaches. Assay and drug development technologies 5:191-203. Yang ZQ, Barrow JC, Shipe WD, Schlegel KA, Shu Y, Yang FV, Lindsley CW, Rittle KE, Bock MG, Hartman GD, Uebele VN, Nuss CE, Fox SV, Kraus RL, Doran SM, Connolly TM, Tang C, Ballard JE, Kuo Y. Adarayan ED, Prueksaritanont T, Zrada MM, Marino MJ, Graufelds VK, DiLella AG, Reynolds IJ, Vargas HM, Bunting PB, Woltmann RF, Magee MM, Koblan KS, Renger JJ (2008) Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels. J Med Chem 51:6471-6477. Yue J, Liu L, Liu Z, Shu B, Zhang Y (2013) Upregulation of T-type Ca2+ channels in primary sensory neurons in spinal nerve injury. Spine 38:463-470. Zhang YF, Gibbs JW, 3rd, Coulter DA (1996) Anticonvulsant drug effects on spontaneous thalamocortical rhythms in vitro: ethosuximide, trimethadione, and dimethadione. Epilepsy Res 23:15-36.

Claims

1. 1. A composition for use in a method for treating itch, said composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, said method comprising the step of administering said composition, said compound comprising: 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 or 【Transformation 6】 A composition selected from the group consisting of:

2. The composition described in claim 1, wherein the compound is EX-31, EX-130, or AFA-358.

3. 3. The composition of claim 1 or 2, wherein the itching is caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, or thyroid disease.

4. The composition described in claim 1 or 2, wherein the itching is caused by exposure to a poisonous plant, exposure to a chemical, exposure to smog, an insect bite, or an allergic reaction to a food allergen.

5. The composition of claim 1 or 2, wherein the compound is administered orally or nasally.

Images