Methods of treating allergic cough or pruritus using ion channel inhibiting compounds

Abstract

The present application relates to methods of treating allergic cough or pruritus using ion channel inhibiting compounds. The present invention relates to novel chemical entities that predominantly inhibit human T-type calcium channels and differentially modulate other critical ion channels to control cellular excitability and abnormal neuronal activity specifically involved in allergic cough or pruritus.

Description

[0001] This application is a divisional application of an application with an application date of August 28, 2019, application number 201980071612.0, and invention name “Method for treating allergic cough or itching using ion channel inhibitory compounds”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to and incorporates by reference U.S. Patent Application No. 16 / 115,549, filed on August 28, 2018, which is incorporated by reference in its entirety. U.S. Patent Application No. 16 / 115,549 is related to Patent Cooperation Treaty Application No. PCT / US2016 / 061918, which is incorporated by reference in its entirety herein. Field of the Invention

[0004] The field of the invention relates to novel ion channel modulator compounds (inhibitors or antagonists of one type of ion channel and / or a combination of inhibition of multiple ion channels), compositions comprising ion channel modulators, and methods of using the compounds and compositions to treat conditions and disorders. A more specific field relates to selective T-type Ca2+ inhibitors for alleviating allergic / chronic cough or pruritus. v3 Compounds with channel inhibitory effects, pharmaceutical preparations containing such compounds, and methods for selectively treating allergic cough or pruritus. Background of the Invention

[0006] Voltage-gated calcium (Ca 2+ ) channels (VGCCs) play an integral role in the regulation of membrane ion conductance, cellular excitability, and neurotransmitter release. VGCCs contain a pore-forming α1 subunit and auxiliary α2δppm and β subunits that regulate channel expression and function. Among the low voltage-activated channels, there is Ca v3 Channel subtypes that mediate T-type calcium currents that can be targeted for the treatment of epilepsy, particularly childhood absence epilepsy, and chronic pain (Huguenard, 1998, Cribbs et al., 2000, Perez-Reyes et al., 2009, Perez-Reyes, 2010).

[0007] T-type or "low voltage activated" calcium channels are so named because they are open for a shorter duration (T = transient) than L-type (L = long duration) calcium channels. T-type channels are activated at relatively low negative membrane potentials (~-60 mV). In many types of neurons, Ca2+ through T channels is activated by the membrane potential of the T channel. 2+ Influx triggers low threshold Ca 2+ discharge, which in turn triggers voltage-gated sodium (Na +) channel-mediated burst discharge of action potentials. Brief burst firing is believed to play an important role in the synchronization of thalamic neuronal pacemaker activity under physiological conditions, but it is also the basis of widespread thalamocortical rhythm disorders in pathological conditions such as neuropathic pain or epileptic 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).

[0008] Molecular cloning has revealed three different T channel proteins, named Ca v3.1 , Ca v3.2 and Ca v3.3 .Ca v3.1 and Ca v3.3 The channel is expressed primarily (but not exclusively) in the CNS. v3.2 The channel is not only present in the CNS, but is also expressed in peripheral nerve cell bodies and nerve terminals of afferent fibers (Huguenard, 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, whereas very little Ca v3.1 And there is almost no Ca v3.3 Expressed in small diameter DRG neurons (Nelson et al., 1992). v3.2 The channel is also expressed at lower levels in several non-neuronal tissues, including the heart, liver, kidney, and pituitary. Both diabetic neuropathy and chronic constrictive injury models in rats result in Ca v3.2 DRG neuron-specific upregulation of Ca channels and T current density. This pathological adaptation leads to enhanced excitability of sensory neurons and causes hyperalgesia and allodynia (Jagodic et al., 2007, Jagodic et al., 2008, Latham et al., 2009, Messinger et al., 2009, Yue et al., 2013). In contrast, Ca v3.2 Gene knockout or antisense knockout of the isoform produces analgesia (Messinger et al., 2009).

[0009] T-type channel inhibitors have two known uses clinically. The anti-absence seizure effect of ethosuximide and lamotrigine is believed 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 have no specificity for T channels (Xie et al., 1995, Zhang et al., 1996). The antihypertensive effect of mibefradil is generally attributed to its inhibition of T channels. However, mibefradil has poor selectivity, wherein the inhibition of T-type is stronger than that of L-type Ca channels. 2+ Current or voltage gated Na + Inhibition of the current is approximately 3-10 times more potent (Avdonin et al., 2000). Because there are no 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 effectiveness of a wide range of drugs.

[0010] Targeting T channels, particularly Ca v3.2 Isotypes are very useful, for example, in reducing thermal hyperalgesia and mechanical allodynia in pathological conditions such as diabetic neuropathy. The discovery of potent and selective T-type Ca 2+ Several efforts at channeling are exemplified below.

[0011] 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 found to effectively block T-type Ca v3.2 Channel [J.Med.Chem.51,3692,(2008); J.Med.Chem.51,6471,(2008); US2010 / 0222387; US2013 / 8501773]. TTA-A2 inhibits active wake, promotes slow-wave sleep (Kraus et al., 2010), and prevents weight gain in mice fed a high-fat diet (Uebele et al., 2009).

[0012] The scaffold hopping approach provided ML218 (3,5-dichloro-N-[[(1α,5α,6-exo,6α)-3-(3,3-dimethylbutyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl]benzamide, CID45115620), a selective T-type Ca 2+ ML218 has an acceptable PK in rats and is effective in preclinical Parkinson's models. Therefore, ML218 is a promising candidate for studying T-type Ca2+ in vitro and in vivo. 2+ Useful new biological probes of function (Xie et al., 2010, Xiang et al., 2011).

[0013] Abbott and others described certain lactam acetamides as Ca v2.2 and Ca v3.2 Calcium channel blockers, and ABT-639 has been reported as a Ca v3.2 Calcium channel blockers are used to treat diabetic neuropathic pain through peripheral action, as ABT-639 is presumed to be unable to penetrate the blood-brain barrier (Jarvis et al., 2014).

[0014] Zalicus Pharmaceuticals, Ltd has described N-piperidinyl acetamide derivatives as calcium channel blockers (US8569344 (2013); US8377968 (2013)). The piperidine-based compound Z944 inhibits Ca in a voltage-dependent manner. v3 channels, and was able to attenuate thalamic burst discharges and inhibit absence seizures in rats (Tringham et al., 2012). Z944 showed promising results in a Phase I clinical study of human pain (Lee, 2014).

[0015] Although there are many T-type Ca 2+ The fact that channel inhibitors have been discovered and have entered various stages of development, but no FDA-approved selective T-type channel inhibitory compounds are available for clinical use.

[0016] Cough is a physiological defense mechanism for clearing foreign bodies and excessive bronchial secretions in the airway, but it is also a common symptom of multiple respiratory diseases. The cough reflex is triggered by the activation of the C fiber endings present in the airway wall of the larynx, trachea and proximal bronchi by the activation of rapidly adapting receptors (or irritant receptors) and bronchial airway walls. The incoming signal is transmitted to the cough center by sensory vagal fibers, and the cough center has been experimentally determined to be in the solitary tract nucleus region in the medulla of the brain (Kase, Wakita et al. 1970). From the cough center, the impulse is propagated to the respiratory muscles (diaphragm, intercostal muscles and abdominal muscles) and airway by the efferent pathway (Irwin, Rosen et al. 1977).

[0017] Experimental studies have shown that peripheral neurons may be involved in "allergic cough." This type of cough is a chronic / persistent cough that may be caused by an acute cough, or by a cough syndrome or disease such as COPD, asthma, GI reflux, postnasal drip syndrome, and exposure to pollutants including smog and wildfire smoke (see, e.g., Chung and Widdicombe, The Pharmacology and Therapeutics of Cough, In Handbook of Experimental Pharmacology ISSN 0171-2004, Library of Congress Control Number: 200892959, 2009 Springer-Verlag Berlin Heidelberg).

[0018] Similar to coughing (which is a defense mechanism to eliminate irritants or pathogens in the airways under physiological conditions), pruritus is also a defense mechanism that protects our body from bugs, harmful chemicals and poisonous plants by causing a scratching response. However, persistent or chronic itchy skin (pruritus) under pathological conditions is an important, unresolved clinical problem. More than 30 million people in the United States suffer from eczema, including atopic dermatitis, and about 7 million people suffer from psoriasis. In addition, pruritus may be a symptom of underlying internal diseases, including liver disease, renal failure, iron deficiency anemia, thyroid problems or cancers such as leukemia and lymphoma. In hemodialysis patients, the prevalence of pruritus associated with chronic kidney disease is as high as 55% in both men and women (Prevalence of chronic kidney disease-associated pruritus among adult dialysis patients: Ameta-analysis of cross-sectional studies, Hu et al.).

[0019] Currently, there are no effective therapies for pruritus, or the irresistible itching symptom associated with a variety of chronic diseases. Recent studies have implicated Ca in NaHS-induced itch in experimental animals. v3.2 Activation of the channel (Wang et al., Scientific Reports 5:16768 (2015)), indicating that Ca v3.2 The channel may be a target for antipruritic compounds.

[0020] In fact, the inventors have found that the T-type Ca 2+ Channel inhibitors can be used to treat and prevent allergic cough; for example, EX-17, EX-128, EX-130 and EX-132. The inventors have also found that the T-type Ca 2+ Channel inhibitors can be used for treatment and prevention, for example, EX-31, EX-55, EX-130, EX-132 and AFA-258 (ie, Z944), AFA-309 and AFA-358. In both itch models, chloroquine-induced itch and histamine-induced itch, highly potent and highly selective T-type Ca 2+ Neither the channel inhibitors EX-128 nor AFA-258 produced an antipruritic effect. However, unexpectedly, compounds that are mixed modulators of key ion channels including voltage-gated Na channels, exemplified by EX-31, EX-130, and AFA-358, were effective in both the chloroquine-induced and histamine-induced itch models. SUMMARY OF THE INVENTION

[0022] The present invention provides a method for treating and preventing diseases involving key ion channels, particularly T-type Ca 2+ Compounds, formulations and methods for treating allergic cough and / or pruritus. These compounds and methods can be used in both human and veterinary medicine.

[0023] In one aspect, the present invention provides a method for treating chronic cough, the method comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0024]

[0025] Where R 1 is a phenyl group 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.

[0026] In one embodiment, the compound is:

[0027]

[0028]

[0029] Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3.

[0030] In another embodiment, the compound is:

[0031] EX-17

[0032] EX-128

[0033] EX-130 or

[0034] EX-132

[0035] In another embodiment, the allergic cough or chronic cough is caused by a disease or syndrome selected from the group consisting of COPD, asthma, GI reflux, postnasal drip syndrome, and chronic exposure to pollutants.

[0036] In another embodiment, the compound is administered orally or nasally.

[0037] In one aspect, the method comprises the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0038] EX-31

[0039] EX-55

[0040] EX-130

[0041] EX-132

[0042] AFA-258

[0043] AFA-309 or

[0044] AFA-358

[0045] In one embodiment, the pruritus is caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, exposure to toxic plants, exposure to chemicals, exposure to smoke, insect bites, or an allergic reaction to a food allergen.

[0046] In another embodiment, the compound is administered orally or nasally.

[0047] In another aspect, the present invention provides a method for treating pruritus, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0048] EX-31

[0049] EX-130 or

[0050] AFA-358

[0051] In one embodiment, the pruritus is caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, exposure to toxic plants, exposure to chemicals, exposure to smoke, insect bites, or an allergic reaction to a food allergen.

[0052] In another embodiment, the compound is administered orally or nasally.

[0053] The present invention relates to the following items:

[0054] 1) A method for treating allergic cough, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0055]

[0056] Where R 1 is a phenyl group substituted with 1 to 3 substituents, each of which is a member selected from the group consisting of F, Cl and CF3, thereby treating allergic cough.

[0057] 2) The method according to item 1), wherein the compound is:

[0058]

[0059] Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3.

[0060] 3) The method according to item 1), wherein the compound is:

[0061] EX-17

[0062] EX-128

[0063] EX-130 or

[0064] EX-132

[0065] 4) The method according to item 1), wherein the allergic cough is caused by a disease or syndrome selected from the group consisting of COPD, asthma, GI reflux, postnasal drip syndrome and long-term exposure to pollutants.

[0066] 5) The method according to item 1), wherein the compound is administered orally or nasally.

[0067] 6) A method for treating pruritus, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0068] EX-31

[0069] EX-55

[0070] EX-130

[0071] EX-132

[0072] AFA-258

[0073] AFA-309 or

[0074] AFA-358 Thereby treating itching.

[0075] 7) The method according to item 6), wherein the itching is caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, exposure to toxic plants, exposure to chemicals, exposure to smoke, insect bites, or allergic reactions to food allergens.

[0076] 8) The method according to item 6), wherein the compound is administered orally or nasally.

[0077] 9) A method for treating pruritus, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0078] EX-31

[0079] EX-130 or

[0080] AFA-358 Thereby treating itching.

[0081] 10) The method according to item 9), wherein the itching is caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, exposure to toxic plants, exposure to chemicals, exposure to smoke, insect bites, or allergic reactions to food allergens.

[0082] 11) The method according to item 9), wherein the compound is administered orally or nasally. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] Figure 1A . Figure 1A The effects of three doses (3 mg / kg, 10 mg / kg and 30 mg / kg) of the representative compound EX-17 and the benchmark dextromethorphan (60 mg / kg) on ​​the number of cough events were determined in a citric acid-induced cough model in naive conscious guinea pigs. All test compounds were formulated with 0.5% hydroxypropylcellulose and given orally (po) by gavage. Data are presented as mean ± SEM for n = 8 animals per group. p values ​​(<0.05, indicated by *) represent significant differences compared to vehicle-treated controls using one-way ANOVA followed by Fisher's LSD post hoc test.

[0085] Figure 1B The effects of three doses (3 mg / kg, 10 mg / kg and 30 mg / kg) of EX-17 and dextromethorphan (60 mg / kg) on ​​the latency to the first coughing event were determined in citric acid-induced cough in guinea pigs. Using one-way ANOVA followed by Fisher's LSD post hoc test (bicheeks), EX-17 (30 mg / kg) and dextromethorphan (60 mg / kg) resulted in a significant increase in latency compared to vehicle-treated controls.

[0086] Figure 2A The effects of three compounds, EX-128, EX-130 and EX-132 (each 30 mg / kg) and the benchmark dextromethorphan (60 mg / kg) on ​​the number of cough events were determined in a citric acid-induced cough model in naive conscious guinea pigs. All test compounds were formulated with 0.5% hydroxypropylcellulose and administered po. Data are presented as mean ± SEM for n = 8 animals per group. p values ​​(<0.05, indicated by *) represent significant differences compared to vehicle-treated controls using one-way ANOVA followed by Fisher's LSD post hoc test.

[0087] Figure 2B The effects of three compounds, EX-128, EX-130 and EX-132, and dextromethorphan on the latency to the first cough event were determined in citric acid-induced cough in guinea pigs. There was a trend toward an increase in latency, but no significant differences were achieved compared to vehicle-treated controls using a one-way ANOVA followed by Fisher's LSD post hoc test.

[0088] Figure 3A and Figure 3B : Effects of AFA compounds on the inhibition of itch-scratch behavior in two well-established itch models in mice. DETAILED DESCRIPTION OF THE INVENTION

[0090] As described herein, the present invention provides novel methods for treating allergic cough or chronic cough using inhibitors of selective T-type channel inhibitory compounds.

[0091] Chronic cough, a symptom caused by a variety of airway disorders, affects quality of life and further exacerbates airway pathology. Currently, pharmacological interventions are limited to treating the cause of cough, and symptomatic treatment options to control cough itself with an acceptable therapeutic index are also limited. Centrally acting cough therapies, such as dextromethorphan and codeine, both opioids used clinically as cough suppressants, depress the cough center and are considered the most clinically effective, although sedation and addiction may limit their use. Local anesthetics that interfere with the conduction of afferent nerve impulses have been shown to be peripherally active antitussive compounds, but their considerable side effects make them unsuitable for use. Extracellular adenosine 5'-triphosphate (ATP) activates P2X receptors on the cell surface and in primary afferent nerves. The development of selective blockers of different P2X receptors has led to clinical trials of their effectiveness in managing cough, pain, inflammation, and certain neurodegenerative diseases (North 2016).

[0092] In contrast, for T-type Ca 2+ The role of T-type Ca channels in the cough reflex and in persistent cough under pathological conditions is poorly understood. 2+ channels, mainly Ca v3.2 The T-type Ca isoform is expressed in the nodose ganglion (Pachuau and Martin-Caraballo, 2007) and plays a role in the regulation of axonal and vagal excitability in the nodose ganglion, but the conventional T-type Ca 2+ Channel blocker Ni 2+ (300 μM) did not significantly alter the response of tracheobronchial cough receptor fibers or nociceptors to citric acid in guinea pigs (Canning and Chou, 2004). Therefore, the role of T-type Ca2+ in the citric acid-induced cough model in guinea pigs was investigated using novel compounds (e.g., EX-17, EX-128, EX-130, and EX-132). 2+ Potential efficacy of channel modulators in terms of antitussive properties, the novel compounds potently and selectively inhibit T-type Ca 2+ The study was conducted in a controlled setting (see, e.g., PCT / US2016 / 061918, which is incorporated herein by reference in its entirety), and the results were compared to clinically used treatment with dextromethorphan.

[0093] Many chronic itch disorders are unresponsive to commonly used antihistamines, suggesting that non-histamine-dependent itch models may be more relevant for identifying new targets and discovering new compounds for the treatment of chronic itch. The recent identification of the first spinal itch receptor, the gastrin-releasing peptide receptor (GRPR), has triggered extensive molecular studies of itch transmission pathways in the nervous system. GRP-GRPR signaling mediates non-histamine-dependent pathways in both acute and chronic itch. Which ion channel mediates the specific itch signaling pathway is currently unknown, although multiple ion channels, such as voltage-gated sodium (Na) channels, N-type Ca channels, and mitochondria have been identified. v2.2 , T-type Ca v3.2 Channels and transient receptor potential vanilloid type 1 (TRPV1) channels have been proposed to be involved in the itch transmission pathway (J Neurol Sci. 1999 Jan 15; 162(2):162-8. Positive symptoms in multiple sclerosis: their treatment with sodium channel blockers, lidocaine and mexiletine. Sakurai M1, Kanazawa I.). Therefore, the T-type Ca channel was investigated in two different itch models in mice using novel compounds (e.g., EX-31, EX-55, EX-130, EX-132, AEA-258, AFA-309, and AFA-358). 2+ Potential efficacy of channel modulators in terms of antipruritic properties, the novel compounds potently and selectively inhibit T-type Ca 2+ Channel (see, e.g., PCT / US2016 / 061918, which is incorporated herein by reference in its entirety).

[0094] Below are definitions of representative types of allergic cough and pruritus for which compounds, pharmaceutical formulations and methods are useful in treatment.

[0095] The term "method for treating allergic cough or chronic cough" means partially or completely relieving the symptoms of cough or preventing allergic cough, which is generally defined as a chronic cough lasting more than 8 weeks, including the description of allergic cough provided herein. Allergic cough or chronic cough can be caused by a disease or syndrome selected from the group consisting of COPD, asthma, GI reflux, postnasal drip syndrome, and long-term exposure to pollutants such as smoke and wildfire smoke.

[0096] The term "method of treating pruritus" means partial or complete relief of the symptoms of pruritus or prevention of pruritus. Pruritus may be caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, exposure to toxic plants, exposure to chemicals, exposure to smoke, insect bites, or allergic reactions to food allergens.

[0097] As used herein, "compounds of the invention" refer to the compounds discussed herein and salts (eg, pharmaceutically acceptable salts) of these compounds.

[0098] "Alkyl" is intended to encompass a monovalent saturated straight or branched hydrocarbon chain having the specified number of carbon atoms, or if no number is specified, 1 to 8 carbon atoms. "Alkylene" refers to a similar group that is divalent. "Optionally substituted" alkyl refers to an unsubstituted alkyl group or an alkyl group substituted with one or more substituents (such as 1, 2, 3, 4 or 5 substituents) selected from the group consisting of: -OH, -(C1-C4 alkyl)-OH, halogen, fluorine, chlorine, bromine, iodine, -(C1-C4 alkyl), -(C1-C4)haloalkyl, -(C1-C4)perhaloalkyl, -O-(C1-C4 alkyl), -O-(C1-C4haloalkyl), -O-(C1-C4perhaloalkyl), -(C1-C4)perfluoroalkyl, -(C=O)-(C1-C4)alkyl, -(C=O)-(C1-C4)haloalkyl, -(C=O)-(C1-C4)perhaloalkyl, -NH2, -NH(C1-C4 alkyl), - N(C1-C4 alkyl)(C1-C4 alkyl)(wherein each C1-C4 alkyl is selected independently of one another), -NO2, -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)(wherein each C1-C4 alkyl is selected independently of one another), -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 may be unsubstituted or substituted in the same manner as a substituted alkyl group.

[0099] "Cycloalkyl" is intended to encompass a monovalent saturated cyclic hydrocarbon chain having the specified number of carbon atoms or, if no number is specified, 3 to 10 carbon atoms or 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. "Cycloalkylene" refers to a similar group, which is divalent. Cycloalkyl and cycloalkylene groups may be unsubstituted or substituted in the same manner as substituted alkyl groups.

[0100] "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, if no number is specified, 2 to 8 carbon atoms. "Alkenylene" refers to a similar group that is divalent. Alkenyl and alkenylene groups may be unsubstituted or substituted in the same manner as substituted alkyl groups (where chemically possible).

[0101] "Cycloalkenyl" is intended to encompass monovalent cyclic hydrocarbon chains 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, which is divalent. Cycloalkenyl and cycloalkenylene groups may be unsubstituted or substituted in the same manner as substituted alkyl groups (where chemically possible).

[0102] "Alkynyl" is intended to encompass a monovalent straight or branched hydrocarbon chain having at least one carbon-carbon triple bond and having the number of carbon atoms specified, or, if no number is specified, 2 to 8 carbon atoms. "Alkynylene" refers to a similar group, which is divalent. Alkynyl and alkynylene groups can be unsubstituted or substituted in the same manner as substituted alkyl groups (where chemically possible).

[0103] "Aryl" is defined as a monovalent aromatic ring system. Aryl groups include monocyclic aromatic ring systems 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-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.

[0104] In some embodiments, the aryl group can be unsubstituted. In other embodiments, the aryl group can be substituted by, for example, 1, 2, 3 or more substituents independently selected from the group consisting of: -OH, -(C1-C4 alkyl)-OH, halogen, fluorine, chlorine, bromine, iodine, -(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, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl) (wherein each C1-C4 alkyl is selected independently of one another), -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) (wherein each C1-C4 alkyl is selected independently of one another), -SH, -(C1-C4 alkyl)-SH and -S-C1-C4 alkyl. In some embodiments, any aryl group and heteroaryl group are optionally substituted by, for example, one or more groups referred to herein as "aryl group substituents". "Arylene" refers to a similar group that is divalent.

[0105] The term "heteroaryl" refers to an aryl group (or ring) containing from 1 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroaryl group can be attached to the rest of the molecule through a heteroatom.

[0106] "Hydrocarbyl" is defined as a monovalent hydrocarbon radical, i.e., a radical comprising hydrogen and carbon, whether aliphatic or aromatic, acyclic or cyclic, or any combination or all of aliphatic, aromatic, acyclic, and cyclic. Hydrocarbyl groups have the number of carbon atoms specified, or, if no number is specified, have from 1 to 10 carbon atoms. "Hydrocarbylene" refers to a similar group, which is divalent. Hydrocarbyl and hydrocarbylene groups may be unsubstituted or substituted in the same manner as substituted alkyl groups (when chemically possible).

[0107] "Heterocycle" or "heterocyclic group" is defined as a ring system containing a specified number of carbon atoms and one or more heteroatoms (such as 1 to 6 heteroatoms or 1 to 3 heteroatoms or 1 heteroatom), wherein heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur and phosphorus. "Heteroaryl" is defined as an aromatic ring system containing a specified number of carbon atoms and one or more heteroatoms (such as 1 to 6 heteroatoms or 1 to 3 heteroatoms or 1 heteroatom), wherein heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur and phosphorus; heteroaryl groups are a subset of heterocyclic groups. In some embodiments, the heteroatoms for heterocyclic groups and heteroaryl groups are selected from the group consisting of oxygen and nitrogen. In various embodiments, the heterocyclic group 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 some embodiments, the heterocyclic group can be unsubstituted. In other embodiments, the heterocyclic group can be substituted with any chemically possible valence by, for example, 1, 2 or 3 substituents independently selected from the group consisting of: -OH, -(C1-C4 alkyl)-OH, halogen, fluorine, chlorine, bromine, iodine, -(C1-C4 alkyl), -(C1-C4)haloalkyl, -(C1-C4)perhaloalkyl, -O-(C1-C4 alkyl), -O-(C1-C4haloalkyl), -O-(C1-C4perhaloalkyl), -(C1-C4)perfluoroalkyl, -(C=O)-(C1-C4)alkyl, -(C=O)-(C1-C4)haloalkyl, -(C=O)-(C1-C4)perhaloalkyl -C1-C4 alkyl), -C(=O)NH2, -C(=)ONH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl) (wherein each C1-C4 alkyl group is independently selected), -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.

[0108] "Heteroalkyl" groups are defined as monovalent hydrocarbon groups in which one or more carbon atoms have been independently replaced by heteroatoms at any chemically possible position, wherein heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, and phosphorus. Heteroalkyl groups have a specified number of carbon atoms, or if no number is specified, have 1 to 10 carbon atoms, and also have at least one heteroatom, such as 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or one heteroatom. "Heteroalkylene" refers to a similar group, which is divalent. Heteroalkyl groups and heteroalkylene groups can be unsubstituted or substituted in the same manner as substituted alkyl groups (when chemically possible). Examples of heteroalkyl groups and heteroalkylene groups include, but are not limited to, ethylene glycol and polyethylene glycol moieties, such as (-CH2CH2-O) n -H (monovalent heteroalkyl group) and (-CH2CH2-O-) n (divalent heteroalkylene group), wherein n is an integer from 1 to 12 (inclusive), and propylene glycol and polypropylene glycol moieties, such as (-CH2CH(CH3)-O-) n -H (monovalent heteroalkyl group) and (-CH2CH(CH3)-O-) n -(divalent heteroalkylene group), wherein n is an integer from 1 to 12 (including end values). Heteroatoms O, N and S and Si can be located at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest 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, -CH=CH-O-CH3, -Si (CH3)3, -CH2-CH=N-OCH3 and -CH=CH-N (CH3)-CH3. Up to two heteroatoms can be continuous, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si (CH3)3. Similarly, the term "heteroalkylene" itself or as a part of another substituent means a divalent group derived from a heteroalkyl group, such as -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2- exemplified but not limited thereto. For heteroalkylene groups, heteroatoms may also occupy any one or two of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further still, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the formula of the linking group is written. For example, the formula -CO2R' represents both -C(O)OR' and -OC(O)R'.

[0109] The various groups described above can be attached to the rest of the molecule at any chemically possible position on the fragment, including attachment via a substituent when the group is substituted. For the purpose of drawing the structure, the group is typically attached by replacing a hydrogen, hydroxyl, methyl or methoxy group on the "complete" molecule to produce an appropriate fragment, and the bonds from the open valences on the fragment to the rest of the molecule are drawn. For example, the attachment of a heteroalkyl group -CH2-O-CH3 is carried out by removing a hydrogen from one of the methyl groups of CH3-O-CH3 to produce a heteroalkyl fragment -CH2-O-CH3, from which bonds from the open valences to the rest of the molecule are drawn.

[0110] Reference to "about" a value or parameter herein includes (and describes) variations to that value or parameter itself. For example, description referring to "about X" includes description of "X".

[0111] As used herein, the terms "a" or "an" mean one or more than one, unless the context clearly indicates otherwise.

[0112] "Subject," "individual," or "patient" means an individual organism, preferably a vertebrate, more preferably a mammal, most preferably a human.

[0113] This description is intended to cover all salts of the compounds described herein, as well as methods of using the salts of such compounds. In one embodiment, the salt of the compound includes a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are those salts that can be administered to humans and / or animals as a drug or medicament, and retain at least some biological activity of the free compound (neutral compound or non-salt compound) after administration. The salt of the desired 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 and amino acids, such as aspartate and glutamate, can also be prepared. The salt of the desired acidic compound can be prepared by treating the compound with an alkali by methods known to those skilled in the art. Examples of inorganic salts of acidic compounds include, but are not limited to, alkali metal salts and alkaline earth metal salts, such as sodium salts, potassium salts, magnesium salts and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acidic compounds include, but are not limited to, salts of procaine, dibenzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamine and triethylamine. Salts of acidic compounds and 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). Several pharmaceutically acceptable salts are also disclosed in Berge, J. Pharm. Sci. 66: 1 (1977).

[0114] As used herein, the phrase "therapeutically effective amount" means an amount of a compound, material, or formulation comprising a compound of the invention that is effective to produce some desired therapeutic effect by inhibiting T channels in at least a subset of cells in an animal, thereby blocking or reducing the biological consequences of the pathway in the treated cells at a reasonable benefit / risk ratio applicable to any medical treatment.

[0115] 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, according to any of the methods described herein, the mammal is in need of treatment with the compound. In an exemplary embodiment, according to any of the methods described herein, the mammal is a dog, cat, horse, pig, cow, sheep, mouse, guinea pig, or rat. In an exemplary embodiment, according to any of the methods described herein, the mammal is a human.

[0116] 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, according to any of the methods described herein, the mammal is in need of treatment with the pharmaceutical formulation. In an exemplary embodiment, according to any of the methods described herein, the mammal is not otherwise in need of treatment with the pharmaceutical formulation. In an exemplary embodiment, according to any of the methods described herein, the mammal is a mouse or a rat. In an exemplary embodiment, according to any of the methods described herein, the mammal is a human.

[0117] The term "IC 50 ” refers to the concentration that causes 50% inhibition of specific binding of the control substance.

[0118] The following abbreviations may be used in this article:

[0119]

[0120]

[0121]

[0122]

[0123]

[0124] In one aspect, the present invention provides compounds of the present invention. In an exemplary embodiment, the present invention provides compounds described herein or salts thereof. In an exemplary embodiment, the salts of compounds described herein are pharmaceutically acceptable salts. In an exemplary embodiment, the present invention provides compounds described herein or pharmaceutically acceptable salts thereof. In an exemplary embodiment, the present invention provides compounds described in the formula provided herein. In an exemplary embodiment, the present invention provides compounds described herein.

[0125] An object of the present invention is to provide a compound having the following general structure or a pharmaceutically acceptable salt thereof which can be used to treat chronic cough or pruritus:

[0126]

[0127] Where R 1 is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; X is selected from -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 ); k is selected from 1 and 2; and R 14 is H or substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted heteroalkyl; R 2 is selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; R 3 , R 4 , R 5 , R 6 are each independently hydrogen, substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 1-6 A haloalkyl, a 3-membered, 4-membered, 5-membered or 6-membered substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl group, wherein R 3 and R 4 The substituted cycloalkyl or substituted heterocycloalkyl groups optionally form, together with the carbon to which they are attached, 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 is optionally substituted by 1, 2 or 3 independently selected from F, -C 1-6 Alkyl and -CF3 substituents. 5 and R 6The cycloalkyl or heterocycloalkyl groups optionally contain 1 or 2 heteroatoms independently selected from O, N or S, and the cycloalkyl or heterocycloalkyl groups optionally contain 1, 2 or 3 heteroatoms independently selected from F, -C 1-6 Alkyl and -CF3 substituents. 7 , R 8 , R 9 and R 10 are each independently hydrogen, fluorine, substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 1-6 A haloalkyl, a 3-membered, 4-membered, 5-membered or 6-membered substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl group, wherein R 7 and R 8 The substituted cycloalkyl or substituted heterocycloalkyl groups optionally contain 1 or 2 heteroatoms independently selected from O, N or S, and the substituted cycloalkyl or substituted heterocycloalkyl groups are optionally substituted by 1, 2 or 3 independently selected from F, -C 1-6 Alkyl or -CF3 substituent; R 9 and R 10 The substituted cycloalkyl or substituted heterocycloalkyl groups optionally form, together with the carbon to which they are attached, a 3-, 4-, 5- or 6-membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from O, N or S, and the substituted cycloalkyl or substituted heterocycloalkyl groups are optionally substituted by 1, 2 or 3 independently selected from F, -C 1-6 Alkyl or -CF3 substituent; R 11 , R 12 and R 13 are each independently hydrogen, fluorine, substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 1-6 A haloalkyl, a 3-membered, 4-membered, 5-membered or 6-membered substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl group, wherein R 11 and R 12 or R 13 Together with the carbon to which they are attached they optionally form a 3-, 4-, 5-, 6- or 7-membered substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl group.

[0128] In an exemplary embodiment, wherein R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X as described herein, R 1 is selected from substituted or unsubstituted benzyl or substituted or unsubstituted polycyclic cycloalkyl ring, such as adamantyl. In an exemplary embodiment, 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 as described herein, R 1 is a substituted adamantyl group. In an exemplary embodiment, 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 as described herein, R 1 is a substituted adamantane-1-yl. In an exemplary embodiment, 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 as described herein, R 1 is an unsubstituted adamantyl group. In an exemplary embodiment, 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 as described herein, R 1 is unsubstituted adamantane-1-yl.

[0129] In an exemplary embodiment, 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 as described herein, R 1 Substituted with 1, 2, 3 or 4 non-hydrogen substituents selected from halogen, haloalkyl, substituted or unsubstituted alkoxy and cyano.

[0130] In an exemplary embodiment, the compound of the invention for treating chronic cough or pruritus 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 as described herein, R 1 Has the following formula:

[0131]

[0132] 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.

[0133] In an exemplary embodiment, the compound of the invention for treating chronic cough or pruritus has a structure according to Formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R9 , R 10 , R 11 , R 12 , R 13 and X are as described herein, and 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.

[0134] In an exemplary embodiment, wherein 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 as described herein, R 2 Selected from C1-C 10 Straight or branched chain substituted or unsubstituted C1-C6 alkyl and C1-C 10 Substituted or unsubstituted C1-C6 alkylheteroalkyl. In an exemplary embodiment, wherein 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 as described herein, R 2 Including substituted alkyl or substituted heteroalkyl groups, it is replaced by amide, oxo, substituted or unsubstituted aryl or substituted or unsubstituted heterocycloalkyl. Exemplary substituted aryl groups include substituted or unsubstituted phenyl, and exemplary heterocycloalkyl parts are oxygen-containing heterocycles.

[0135] In an exemplary embodiment, the compound of the invention for use in treating chronic cough or pruritus has the following formula:

[0136]

[0137] Where 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, wherein q is an integer selected from 1, 2, 3, 4, and 5. In an exemplary embodiment, wherein 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, wherein R 11a and R 11b are members each independently selected from H, methyl and fluoro. In an exemplary embodiment, wherein 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, q is 1, R 11a is H and R 11b is F. In an exemplary embodiment, wherein 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, q is 1, R 11a is F and R 11b It's F.

[0138] In an exemplary embodiment, the compound of the invention for use in treating chronic cough or pruritus has the following formula:

[0139]

[0140] Where 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, and q is an integer selected from 1, 2, 3, 4 and 5.

[0141] In an exemplary embodiment, the compound of the invention for use in treating chronic cough or pruritus has the following formula:

[0142]

[0143] Among them, X, R 1 and R 2 As described herein, and q is 1 or 2.

[0144] In an exemplary embodiment, the compound of the invention for use in treating chronic cough or pruritus has the following formula:

[0145]

[0146] Among them, X, R 1 and R 2 As described herein, and q is 1 or 2.

[0147] In an exemplary embodiment, the compound of the invention for use in treating chronic cough or pruritus has the following formula:

[0148]

[0149] Among them, X, R 1 and R 2 As described herein, and q is 1 or 2.

[0150] In an exemplary embodiment, the compound of the invention for use in treating chronic cough or pruritus has the following formula:

[0151]

[0152] Among them, X, R 1 and R 2 As described herein, and q is 1 or 2.

[0153] In an exemplary embodiment, the compound of the invention for use in treating chronic cough or pruritus has the following formula:

[0154]

[0155] Among them, X, R 1 and R 2 As described herein, and q is 1 or 2.

[0156] In an exemplary embodiment, wherein q, R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, wherein R 1 is a substituted or unsubstituted benzyl or a substituted or unsubstituted adamantyl. In an exemplary embodiment, wherein q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, wherein R 1 is a substituted phenyl. In an exemplary embodiment, wherein q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, wherein R 1 is unsubstituted phenyl. In an exemplary embodiment, wherein q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, wherein R 1 is a substituted or unsubstituted adamantyl group. In an exemplary embodiment, wherein q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, wherein R 1 yes: in Represents R 1 and X; and R 1a and R1b are members independently selected from halogen, haloalkyl, substituted or unsubstituted alkoxy, and cyano. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, wherein R 1 yes in Represents R 1 and X; and R 1a and R 1b are members independently selected from F, Cl, Br, CF3, methoxy, methyl and CN. In an exemplary embodiment, wherein q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, wherein R 1 yes in Represents R 1 and X; and R 1a and R 1b are members each independently selected from F, Cl and CF3.

[0157] In an exemplary embodiment, wherein q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, wherein R 2 is a substituted or unsubstituted alkyl group. In an exemplary embodiment, wherein q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10and X are as described herein, wherein R 2 is a substituted or unsubstituted heteroalkyl. In an exemplary embodiment, wherein q, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and X are as described herein, wherein R 2 yes

[0158]

[0159] in Represents R 2 and a covalent bond between the piperidine nitrogen.

[0160] In an exemplary embodiment, the compound for treating chronic cough or pruritus has the formula:

[0161]

[0162] Among them, X, R 2 and R 1 As described herein.

[0163] In an exemplary embodiment, the compound for treating chronic cough or pruritus has the formula:

[0164] Among them, X, R 2 and R 1 As described herein. In an exemplary embodiment, the compound is according to a formula described herein, and 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. In an exemplary embodiment, the compound is according to the formula described herein, and R 1 is phenyl substituted with a substituent selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is according to the formula described herein, and R 1 is phenyl substituted with two substituents, each of which is independently selected from a member of the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is according to the formula described herein, and R 1is a phenyl group substituted with three substituents, each of which is independently selected from a member of the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound has the formula: Among them, X, R 2 and R 1 As described herein. In an exemplary embodiment, the compound has the formula: Among them, X, R 2 and R 1 As described herein.

[0165] In an exemplary embodiment, the compound for treating chronic cough or pruritus is Where X and R 1 As described herein. In an exemplary embodiment, the compound is Where X and R 1 As described herein. In an exemplary embodiment, the compound is Where X and R 1 As described herein. In an exemplary embodiment, the compound is Where X and R 1 As described herein. In an exemplary embodiment, the compound is Where X and R 1 As described herein. In an exemplary embodiment, the compound is Where X and R 1 As described herein.

[0166] In an exemplary embodiment, the compound is Where R 1 and R 2 As described herein. In an exemplary embodiment, the compound is Where R 1 and R 2 As described herein. In an exemplary embodiment, the compound is Where R 1 and R 2 As described herein. In an exemplary embodiment, the compound is Where R 1 and R 2 As described herein. In an exemplary embodiment, the compound is Where R 1 and R 2 As described herein. In an exemplary embodiment, the compound is Where R 1 and R 2 As described herein.

[0167] In an exemplary embodiment, the compound is Where X and R 2 As described in this article, R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3.

[0168] In an exemplary embodiment, the compound is Where X and R 2 As described in this article, R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3.

[0169] In an exemplary embodiment, the compound is Where X and R 2 As described in this article, R 1 As described herein. In an exemplary embodiment, the compound is Where X and R 2 As described in this article, R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where X and R 2 As described in this article, R 1 is unsubstituted adamantane-1-yl.

[0170] In an exemplary embodiment, the compound is

[0171] Where R 2 , R 1a and R 1b As described herein. In an exemplary embodiment, the compound is according to the invention comprising R 1a and R 1b of the formula described herein, wherein R 1a and R 1b are members independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is according to the invention comprising R 1a and R 1b of the formula described herein, wherein R 1a and R 1b are members independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is according to the invention comprising R 1a and R 1b of the formula described herein, wherein R 1a As described herein, and R 1b is F. In an exemplary embodiment, the compound is according to 1a and R 1b of the formula described herein, wherein R 1aAs described herein, and R 1b is Cl. In an exemplary embodiment, the compound is according to 1a and R 1b of the formula described herein, wherein R 1a As described herein, and R 1b In an exemplary embodiment, the compound is according to the invention comprising R 1a and R 1b of the formula described herein, wherein R 1b As described herein, and R 1a is F. In an exemplary embodiment, the compound is according to 1a and R 1b of the formula described herein, wherein R 1b As described herein, and R 1a is Cl. In an exemplary embodiment, the compound is according to 1a and R 1b of the formula described herein, wherein R 1b As described herein, and R 1a is CF3. In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein.

[0172] In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein. In an exemplary embodiment, the compound is according to the invention comprising R 1a and R 1b of the formula described herein, wherein R 1a and R1b are members independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is according to the invention comprising R 1a and R 1b of the formula described herein, wherein R 1a and R 1b are members independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is according to the invention comprising R 1a and R 1b of the formula described herein, wherein R 1a As described herein, and R 1b is F. In an exemplary embodiment, the compound is according to 1a and R 1b of the formula described herein, wherein R 1a As described herein, and R 1b is Cl. In an exemplary embodiment, the compound is according to 1a and R 1b of the formula described herein, wherein R 1a As described herein, and R 1b In an exemplary embodiment, the compound is according to the invention comprising R 1a and R 1b of the formula described herein, wherein R 1b As described herein, and R 1a is F. In an exemplary embodiment, the compound is according to 1a and R 1b of the formula described herein, wherein R 1b As described herein, and R 1a is Cl. In an exemplary embodiment, the compound is according to 1a and R 1b of the formula described herein, wherein R 1b As described herein, and R 1a is CF3. In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Where R 2 , R 1a and R 1b As described herein.

[0173] In an exemplary embodiment, the compound is Where R 2 As described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 2 As described herein, and R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 2 As described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 2 As described herein, and R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 2 As described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 2 As described herein, and R 1 is unsubstituted adamantane-1-yl.

[0174] In an exemplary embodiment, the compound is Where R 1 As described herein. In an exemplary embodiment, the compound is Where R 1 As described herein. In an exemplary embodiment, the compound is Where R 1 As described herein. In an exemplary embodiment, the compound is Where R 1 As described herein. In an exemplary embodiment, the compound is Where R 1 As described herein. In an exemplary embodiment, the compound is Where R 1 As described herein. In an exemplary embodiment, the compound is Where R1 As described herein. In an exemplary embodiment, the compound is Where R 1 As described herein. In an exemplary embodiment, the compound is Where R 1 As described herein. In an exemplary embodiment, the compound is Where R 1 As described herein. In an exemplary embodiment, the compound is Where R 1 As described herein. In an exemplary embodiment, the compound is Where R 1 As described herein.

[0175] In an exemplary embodiment, the compound is Among them, X, R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Among them, X, R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Among them, X, R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Among them, X, R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Among them, X, R 1a and R 1b As described herein. In an exemplary embodiment, the compound is Among them, X, R 1a and R 1b As described herein.

[0176] In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is wherein X is as described herein, and R 1 is unsubstituted adamantane-1-yl.

[0177] In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3.

[0178] In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3. In an exemplary embodiment, the compound is Where R 1a and R 1b are members each independently selected from the group consisting of F, Cl and CF3.

[0179] In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantyl. In an exemplary embodiment, the compound is Where R 1 is unsubstituted adamantane-1-yl.

[0180] In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof.

[0181] In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof.

[0182] In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof.

[0183] In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof.

[0184] In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof.

[0185] In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof.

[0186] In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof.

[0187] In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof.

[0188] In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted adamantane-1-yl. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted adamantane-1-yl.

[0189] In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof.

[0190] In an exemplary embodiment, the structure of AFA-358 is

[0191]

[0192] In an exemplary embodiment, the structure of AFA-309 is

[0193]

[0194] In an exemplary embodiment, the structure of AFA-258 is

[0195]

[0196] In an exemplary embodiment, the structure of AFA-353 is

[0197]

[0198] AFA-309, AFA-353, and AFA-358 are novel T-type Ca 2+ inhibitors for the treatment of pathological conditions. v3 Channel modulators, pathological conditions including pain, allergic cough and pruritus.

[0199] The present invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound according to Formula I or a compound disclosed herein alone. The formulation further comprises a pharmaceutically acceptable carrier.

[0200] The present invention also provides for treating a condition responsive to a substance called Ca v3.2 A method for allergic cough or pruritus caused by selective inhibition of the T channel of the T channel of the T channel, the method comprising administering to a mammal a therapeutically effective amount of a compound according to Formula I or a compound disclosed herein alone.

[0201] The present invention provides compounds that are selective T channel inhibitory compounds useful for relieving allergic cough or pruritus.

[0202] When chemically possible, the present invention also includes all stereoisomers and geometric isomers of the compound, including diastereomers, enantiomers and cis / trans (E / Z) isomers. The present invention also includes mixtures of stereoisomers and / or geometric isomers in any proportion, including but not limited to racemic mixtures. Unless stereochemistry is clearly indicated in the structure, the structure is intended to cover all possible stereoisomers of the compound depicted. If stereochemistry is clearly indicated for one or more parts of the molecule, and stereochemistry is not clearly indicated for another part or more parts of the molecule, the structure is intended to cover all possible stereoisomers of the part or parts where stereochemistry is not clearly indicated.

[0203] The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be substituted with radioactive isotopes such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) is radiolabeled. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be included within the scope of the invention. Unless a specific isotope is specified, the invention includes all isotopologues of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds (where H may be 2 H, that is, D).

[0204] In the context of the present invention, compounds that are considered to have activity as T channel inhibitors are those that show an inhibitory effect on Ca at a concentration of no greater than about 100 μM, preferably no greater than about 10 μM, more preferably no greater than about 1 μM, and most preferably no greater than about 100 nM. ++ 50% suppression of voltage (IC 50 ) of those compounds.

[0205] Chemical synthesis

[0206] Terms related to "protection", "deprotection" and "protected" functional groups appear throughout this application. Such terms are well understood by those skilled in the art and are used in the context of processes involving continuous treatment with a series of reagents. In this case, a blocking group refers to a group used to mask a functional group during a process step in which the functional group would react if not protected but in which the reaction is undesirable. The blocking group prevents the reaction at this step, but can be removed subsequently to expose the original functional group. Removal or "deprotection" occurs after the completion of one or more reactions in which the functional group will interfere. Therefore, when specifying a reagent sequence, as in the process of the present invention, a person of ordinary skill can easily envision those groups that will be suitable as "blocking groups". Suitable groups for this purpose are discussed in standard textbooks in the field of chemistry, such as "Greene's Protective Groups in Organic Synthesis: Fifth Edition" by Peter GM Wuts, [John Wiley & Sons, New York, 2014], DOI: 10.1002 / 9781118905074, which is incorporated herein by reference.

[0207] A comprehensive list of abbreviations used by organic chemists appears in Journal of Organic Chemistry The list generally set out in a table entitled "Standard List of Abbreviations" is incorporated herein by reference.

[0208] Usually, the compound of the present invention can be prepared by the method shown in the general reaction scheme as described below or by its modification, using the starting material, reagent and conventional synthesis procedure that are easily available.In these reactions, it is also possible to utilize variants known per se, but not mentioned here.Starting material, for example in the case of a suitably substituted benzimidazole ring compound, is commercially available, synthesized as described in the embodiment, or can be obtained by methods well known to those skilled in the art.

[0209] Pharmaceutical preparations

[0210] The present invention also provides pharmaceutical formulations comprising as active agents a compound described herein.

[0211] 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.

[0212] 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 the formula described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0213] In an exemplary embodiment, the invention is a pharmaceutical formulation described herein, wherein the formulation is in unit dosage form.

[0214] As used herein, "pharmaceutical preparation" refers to a preparation of one or more compounds described herein, or a physiologically acceptable salt or solvate (including hydrates) thereof, with other chemical components such as physiologically suitable carriers and excipients.

[0215] Pharmaceutical preparations containing compounds of Formula I and any compounds described herein can be conveniently presented in unit dose form and prepared by any method well known in the pharmaceutical field. Preferred unit dose preparations are preparations containing active ingredients or pharmaceutically acceptable salts thereof in an effective dose or an appropriate portion thereof. The size of the preventive or therapeutic dose generally varies with the nature and severity of the condition to be treated and the route of administration. The dose and possible dose frequency will also vary according to the age, weight and response of the individual patient. In general, the dose is 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 a single dose or in separate doses. In some embodiments, the dose may be from about 50 mg to about 500 mg, and preferably from about 100 mg to about 500 mg. Such a dose may be administered 1, 2, 3, 4, 5, 6 or more times in a day. It may be recommended that children, patients over 65 years of age and patients with impaired renal or liver function initially receive a low dose and adjust the dose based on individual response and / or blood levels. As will be apparent to those skilled in the art, it may be necessary to use dosages outside of these ranges in some cases. Furthermore, it is noted that the clinician or treating physician knows how and when to interrupt, adjust or terminate therapy in conjunction with the response of the individual patient.

[0216] Therefore, the pharmaceutical preparations for use according to the present invention can be prepared in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants, which help to process the active compound into a pharmaceutically usable product. The carrier must be acceptable in the sense that it is compatible with the other ingredients of the preparation and harmless to its recipient. The appropriate formulation depends on the selected route of administration.

[0217] Compounds that inhibit T channels can be formulated into pharmaceutical preparations and administered to mammalian subjects, such as human patients, by intravenous, intramuscular, topical, transdermal, intradermal, intraarticular or subcutaneous routes in a variety of forms suitable for the chosen route of administration, i.e., oral, rectal, topical (including dermal, buccal, sublingual and intraocular) or parenteral.

[0218] For oral administration, the compound can be easily formulated by combining the active compound with a pharmaceutically acceptable carrier well known in the art. Such a carrier can prepare the compound of the present invention into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by patients. Pharmaceutical products for oral use can be prepared using solid excipients, optionally grinding the resulting mixture, and processing the mixture of particles after adding suitable adjuvants (if necessary) to obtain tablets or dragee cores. Suitable excipients are particularly fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose products such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; and / or physiologically acceptable polymers such as polyvinyl pyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinyl pyrrolidone, agar or alginic acid or its salts such as sodium alginate can be added.

[0219] Additionally, enteric coatings may be useful because it may be desirable to protect the compounds of the invention from exposure to the gastric environment.

[0220] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or a liquid polyethylene glycol. In addition, a stabilizer may be added.

[0221] Formulations for topical administration in the mouth (e.g., buccal or sublingual) include lozenges containing the active ingredient in a flavored basis such as sucrose and acacia or tragacanth and pastilles containing the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia. All formulations for oral administration should be in dosages suitable for the chosen route of administration.

[0222] For injection, the compounds of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution or physiological saline buffer. For transmucosal and transdermal administration, penetrants suitable for the barrier to be penetrated can be used in the formulation. Such penetrants, including, for example, DMSO or polyethylene glycol, are known in the art.

[0223] For administration by inhalation, the compounds for use according to the invention are conveniently delivered in an aerosol spray presentation form from a pressurized pack or nebulizer, using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated as a powder mix containing the compound and a suitable powder base such as lactose or starch.

[0224] Pharmaceutical preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, antibacterial agents and solutes, which make the preparation isotonic with the blood of the intended recipient. Preparations also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Pharmaceutical preparations for parenteral administration with aqueous solutions include active ingredients in water-soluble form. In addition, the suspension of active compounds may be prepared into suitable 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 include substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also include suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions.

[0225] The preparation can exist in unit doses of multiple dose containers such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, such as saline, phosphate buffered saline (PBS) or the like, just before use. Immediate injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the aforementioned kind.

[0226] The compounds of the invention may also be formulated in rectal preparations such as suppositories or retention enemas, using, eg, conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0227] Depending on the severity and responsiveness of the condition to be treated, administration may also be a single administration of a sustained-release formulation, wherein the course of treatment lasts from several days to several weeks or until a cure is achieved or a reduction in the disease state is achieved. Of course, the amount of the formulation to be administered will depend on many factors, including the subject being treated, the severity of the pain, the mode of administration, and the judgment of the prescribing physician. The compounds of the present invention may be administered orally or via injection at a dose of 0.001 mg / kg to 250 mg / kg per day. The dosage range for adults is typically from 0.5 mg / day to 10 g / day. Tablets or other presentation forms provided in discrete units may conveniently contain a certain amount of the compound of the present invention, which is effective at such a dose or as a multiple of such a dose, such as units containing 5 mg to 500 mg, typically about 10 mg to 200 mg. The exact amount of the compound administered to the patient will be the responsibility of the attending physician. However, the dosage used will depend on many factors, including the age and sex of the patient, the exact disorder being treated, and its severity. In addition, the route of administration may vary depending on the condition and its severity.

[0228] As used herein and as will be understood by those skilled in the art, the expression "compound" is intended to include salts, solvates and inclusion complexes of the compound. The term "solvate" refers to a compound described herein and / or a compound of Formula I in a solid state in which molecules of a suitable solvent are incorporated into the crystal lattice. Suitable solvents for therapeutic administration are physiologically tolerable at the dose administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. Typically, a solvate is formed by dissolving the compound in an appropriate solvent and separating the solvate by cooling or using an antisolvent. Solvates are typically dried or azeotroped at ambient conditions. 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 frequently used inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes (natural and synthetic) are specifically included in the claims.

[0229] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, including inorganic acids and bases and organic acids and bases. When the compound of the present invention is alkaline, the salt can be prepared from a pharmaceutically acceptable non-toxic acid including inorganic acids and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetate, benzenesulfonate (besylate), benzoate, camphorsulfonate, citrate, vinylsulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, mesylate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, p-toluenesulfonate, etc. When the compound contains an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0230] The term "prevention" as used herein refers to the pre-administration of a medicament to forestall or mitigate an attack. One of ordinary skill in the medical field (to which the method claims of the present invention relate) recognizes that the term "prevention" is not an absolute term. In the medical field, it is understood 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.

[0231] It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0232] The preparation can be present in a packaging device or a dispenser, which can contain one or more unit dosage forms containing active ingredients. Examples of packaging devices include metal foil or plastic foil, such as blister packages and sprayers for inhalation. The packaging device or dispenser can be accompanied by instructions for use for administration. The preparation comprising the compound of the present invention formulated in a compatible pharmaceutical carrier can also be placed in an appropriate container and marked for the treatment of a specified condition.

[0233] Some embodiments described herein are described as “comprising” or “comprises” with respect to their various elements. In alternative embodiments, those elements may be described with the transitional phrase “consisting essentially of” or “consists essentially of” as applied to those elements. In further alternative embodiments, those elements may be described with the transitional phrase “consisting of” or “consists of” as applied to those elements. Thus, for example, if a compound, formulation, or method is disclosed herein as comprising A and B, alternative embodiments of the compound, formulation, or method that “consist essentially of A and B” and alternative embodiments of the compound, formulation, or method that “consist of A and B” are also considered to have been disclosed herein. Likewise, embodiments described as “consisting essentially of” or “consisting of” with respect to their various elements may also be described as “comprising” as applied to those elements. Finally, embodiments described with respect to their various elements as "consisting essentially of" may also be described as "consisting of" as applied to those elements, and embodiments described with respect to their various elements as "consisting of" may also be described as "consisting essentially of" as applied to those elements.

[0234] When a compound or preparation is described as "consisting essentially of the listed ingredients," the compound or preparation contains the ingredients explicitly listed, and may contain other ingredients that do not substantially affect the condition being treated. That is, the compound or preparation does not contain any other ingredients other than those explicitly listed that do substantially affect the condition being treated; or if the compound or preparation does contain additional ingredients other than those listed that substantially affect the condition being treated, the compound or preparation does not contain those additional ingredients in sufficient concentrations or amounts to substantially affect the condition being treated. When a method is described as "consisting essentially of the listed steps," the method includes the listed steps, and may include other steps that do not substantially affect the condition being treated, but the method does not include any other steps other than those explicitly listed that substantially affect the condition being treated.

[0235] The following examples are provided to illustrate the present invention but not to limit the same. The compounds disclosed herein are numbered with the prefix EX- or AFA- and continue. Example

[0236] Example A

[0237] In vivo effects of EX / AFA compounds in a representative allergic cough model in guinea pigs

[0238] Guinea pigs (male, 280 g body weight, Hartley Crl: HA, Charles River) were maintained at 21 ± 2 °C, 55 ± 10% humidity, 12 h on-12 h off light cycle, with food and water available ad libitum for at least 1 week prior to testing. Cough was induced by citric acid aerosol inhalation and cough assessment was performed by manual scoring ( Gallico, Borghi et al.1994 ). Individual animals were placed in a 4L plexiglas observation chamber continuously filled with 17.5% citric acid aerosol. Animal cough counts were recorded for 5 min. Coughing can be identified based on the sound associated with rapid inhalation followed by rapid exhalation. Only animals with cough counts ≥ 10 times / 5 min were selected for the experiment. The selected animals were then randomly divided into 5 groups, n = 8 / group. Five days after the screening test, based on its PK profile, the representative AFA compound EX-17 was administered at 0 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg 30 minutes before citric acid inhalation, while the benchmark dextromethorphan hydrobromide (60 mg / kg, po) was administered 60 minutes before citric acid inhalation. EX-17 produced a dose-dependent inhibition of the number of cough events, with a reduction of 7.2%, 23.3% and 36.8% at doses of 3 mg / kg, 10 mg / kg and 30 mg / kg, respectively ( Figure 1A At 30 mg / kg, EX-17 produced an inhibition comparable to that of dextromethorphan (40.0% at 60 mg / kg po). The latency to first cough has been used as an additional parameter to evaluate antitussive properties. EX-17 also resulted in an increase in the latency to first cough in a dose-dependent manner. Under the experimental conditions, only EX-17 at 30 mg / kg and dextromethorphan hydrobromide (60 mg / kg, po) reached significance ( Figure 1B ).

[0239] Using the same testing protocol, based on their PK profiles, three more representative EX-compounds EX-128, EX-130 and EX-132 (each 30 mg / kg, po) or vehicle were tested by oral administration 30 minutes before citric acid inhalation, while dextromethorphan hydrobromide (60 mg / kg, po) was orally administered 60 minutes before citric acid inhalation. Compared with the vehicle control, compounds EX-128 and dextromethorphan significantly reduced the number of cough events, with a 39.1% and 42.6% reduction, respectively ( Figure 2AEX-130 and EX-132 showed a trend towards reducing the number of cough events, with a 33% and 15.7% reduction, respectively, without reaching significance. The latency to first cough was increased by the three compounds and baseline, but none of them reached significant levels under the experimental conditions ( Figure 2B ).

[0240] References

[0241] Canning, BJ and Chou, YL (2004).“ CoughSensors. I.Physiological and Pharmacological Properties of the Afferent Nerves Regulating Cough ” in “Pharmacology and Therapeutics of Cough” ed.Chung and Widdicomb,pp23-47,Handbook of Experimental Pharmacology ISSN 0171-2004

[0242] Gallico, L., A. Borghi, C. Dalla Rosa, R. Ceserani and S. Tognella (1994). "Moguisteine: a novel peripheral non-narcotic antitussive drug." J Pharmacol 112(3):795-800.

[0243] Irwin, RS, MJ Rosen and SS Braman (1977). "Cough. A comprehensive review." Arch InternMed 137(9):1186-1191.

[0244] Kase, Y., Y. Wakita, G. Kito, T. Miyata, T. Yuizono and M. Kataoka (1970). "Centrally-induced coughs in the cat." LifeSci 9(1):49-59.

[0245] North,RA(2016)."P2X receptors."Philos Trans R Soc Lond B BiolSci371(1700).

[0246] 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.

[0247] Example B: In vivo effects of AFA / EX compounds in two representative itch models in mice

[0248] A representative panel of AFA / EX compounds was investigated on a variety of 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 10 selected AFA compounds differentially modulated different ionic currents mediated by the selected ion channels. Therefore, the panel of compounds was next investigated for their effects on itch scratching behavior in two well-established itch models in mice.

[0249] The neck itch model was adopted. 2-3 days before the experiment, the neck of mice (C57BL / 6, male, 3-4 months old) was shaved. On the day of behavioral testing, mice were individually placed in a small plastic chamber (12cm L×9.5W×12H), which was inserted into a common home cage for at least 30min for habituation, and the behavioral baseline was recorded using a camera and piezoelectric layer sensor operated by a validated home cage behavior monitoring system SmartCage, which can simultaneously monitor multiple mouse scratching behaviors.

[0250] Treatment with individual test articles (10 representative AFA compounds, each at 30 mg / kg) or vehicle (0.5% hydroxypropylcellulose in water containing 2% DMSO) was injected intraperitoneally (ip) 30 min before itch induction. 50 μl of the itch-inducing agent chloroquine or histamine was injected intradermally into the scruff of the neck of the mice. The mice were returned to their rooms immediately after injection and recorded continuously for 30 min by a piezoelectric layer sensor. The itch-scratching behavior was manually scored and confirmed in real time by video and / or offline piezoelectric recording. The itch behavior was quantified by counting the number of scratches in a blinded manner to the treatment modality. The scratches were counted when the mouse lifted its hind paw to scratch the shaved area and returned the paw to the ground or mouth to lick. The piezoelectric signal, which had a large and regular waveform that was distinguishable from normal home cage activity, was analyzed offline to objectively quantify the occurrence and duration of scratching.

[0251] These studies revealed the unexpected finding that compounds differentially modulated itch-scratch behavior in these two different itch models, even for T-type Ca v3.2 Compounds with similar potency in the channel ( Figure 3A AFA-221 (EX-31), AFA-281 (EX-130), and AFA-358 exerted effective and equivalent effects on both chloroquine-induced and histamine-induced itch, whereas AFA-309, AFA-258 (Z944), AFA-322 (EX-132), and AFA-206 (EX-55) preferentially inhibited histamine-induced itch ( Figure 3B ).

[0252] In conclusion, using itch-scratch behavioral phenotyping, one can discover new compounds with the potential to treat chronic itch disorders.

[0253] Table 1. Effects of representative AFA compounds on recombinant and native ion channels

[0254]

[0255] h = human isoform; Use Dep = use-dependent inhibition; DRG = dorsal root ganglion; hERG = human ether-a-go-go related gene (hERG) potassium (K + )aisle

[0256] Additional references

[0257] Avdonin PV,Buhler FR,Tkachuk VA(2000)Ca2+-agonistic effect of aT-typeCa-channel blocker mibefradil(Ro 40-5967).Membr Cell Biol13:645-655.

[0258] Caviedes BE,Herranz JL(2001)[Use of antiepileptic drugs in nonepileptic disorders].Rev Neurol 33:241-249.

[0259] Chaplan SR,Bach FW,Pogrel JW,Chung JM,Yaksh TL(1994)Quantitativeassessment of tactile allodynia in the rat paw.Journal of neurosciencemethods 53:55-63.

[0260] 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 neurology35:304-311.

[0261] Choi S,Na HS,Kim J,et al.(2007)Attenuated pain responses in micelacking Ca(V)3.2T-type channels.Genes Brain Behav 6:425-431.

[0262] Cribbs LL,Gomora JC,Daud AN,Lee JH,Perez-Reyes E(2000)Molecularcloning and functional expression of Ca(v)3.1c,a T-type calciumchannel fromhuman brain.FEBS Lett 466:54-58.

[0263] Decosterd I,Woolf CJ(2000)Spared nerve injury:an animal model ofpersistent peripheral neuropathic pain.Pain 87:149-158.

[0264] Gomora JC,Daud AN,Weiergraber M,Perez-Reyes E(2001)Block of clonedhuman T-type calcium channels by succinimide antiepileptic drugs.MolPharmacol 60:1121-1132.

[0265] Han HA,Cortez MA,Snead OC III.(2012)GABA B Receptor and AbsenceEpilepsy.In:Noebels JL,Avoli M,Rogawski MA,Olsen RW,Delgado-Escueta AV,editors.Jasper's Basic Mechanisms of the Epilepsies[Internet].4thedition.Bethesda(MD):National Center for BiotechnologyInformation(US)

[0266] Huguenard JR(1998)Low-voltage-activated(T-type)calcium-channelgenesidentified.Trends Neurosci 21:451-452.

[0267] Huguenard JR(2002)Block of T-Type Ca(2+)Channels Is anImportantAction of Succinimide Antiabsence Drugs.Epilepsy Curr 2:49-52.

[0268] Jagodic MM,Pathirathna S,Joksovic PM,Lee W,Nelson MT,Naik AK,Su P,Jevtovic-Todorovic V,Todorovic SM(2008)Upregulation of the T-typecalciumcurrent in small rat sensory neurons after chronic constrictiveinjury ofthe sciatic nerve.J Neurophysiol 99:3151-3156.

[0269] Jagodic MM,Pathirathna S,Nelson MT,Mancuso S,Joksovic PM,RosenbergER,Bayliss DA,Jevtovic-Todorovic V,Todorovic SM(2007)Cell-specificalterations of T-type calcium current in painful diabeticneuropathy enhanceexcitability of sensory neurons.J Neurosci 27:3305-3316.

[0270] Jarvis MF,Scott VE,McGaraughty S,Chu KL,Xu J,Niforatos W,Milicic I,Joshi S,Zhang Q,Xia Z(2014)A peripherally acting,selectiveT-type calciumchannel blocker,ABT-639,effectively reduces nociceptive andneuropathic painin rats.Biochemical pharmacology 89:536-544.

[0271] Jenkins ID,Lacrampe F,Ripper J,Alcaraz L,Le PV,Nikolakopoulos G,deAlmeida Leone P,White RH,Quinn RJ(2009)Synthesis of four novelnatural productinspired scaffolds for drug discovery.The Journal of organicchemistry 74:1304-1313.

[0272] Kim SH,Chung JM(1992)An experimental model for peripheralneuropathyproduced by segmental spinal nerve ligation in the rat. Pain. 50(3):355-63.

[0273] 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 vitrocharacterization of T-typecalcium channel antagonist TTA-A2 and in vivoeffects on arousal in mice.JPharmacol Exp Ther 335:409-417.

[0274] 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-typecalcium channel blockade alleviates hyperalgesia in ob / obmice.Diabetes 58:2656-2665.

[0275] Lee M(2014)Z944:a first in class T-type calcium channel modulatorforthe treatment of pain.Journal of the peripheral nervous system:JPNS 19Suppl2:S11-12.

[0276] Messinger RB,Naik AK,Jagodic MM,Nelson MT,Lee WY,Choe WJ,Orestes P,Latham JR,Todorovic SM,Jevtovic-Todorovic V(2009)In vivosilencing of the Ca(V)3.2 T-type calcium channels in sensory neuronsalleviates hyperalgesia inrats with streptozocin-induced diabetic neuropathy.Pain 145:184-195.

[0277] Nahab FB,Handforth A,Brown T,et al.,(2012)Octanoic acidsuppressesharmaline-induced tremor in mouse model of essentialtremor.Neurotherapeutics,9:635-638

[0278] Nelson SC,Friedman HS,Oakes WJ,Halperin EC,Tien R,Fuller GN,Hockenberger B,Scroggs MW,Moncino M,Kurtzberg J,et al.(1992)Successfultherapy for trilateral retinoblastoma.Am J Ophthalmol 114:23-29.

[0279] Perez-Reyes E(2003)Molecular physiology of low-voltage-activatedt-type calcium channels.Physiol Rev 83:117-161.

[0280] Perez-Reyes E(2010)G protein-mediated inhibition of Cav3.2 T-typechannels revisited.Molecular pharmacology 77:136-138.

[0281] Perez-Reyes E,Van Deusen AL,Vitko I(2009)Molecular PharmacologyofHuman Cav3.2 T-Type Ca2+Channels:Block by Antihypertensives,Antiarrhythmics,and Their Analogs.Journal of Pharmacology andExperimental Therapeutics 328:621-627.

[0282] Pexton T,Moeller-Bertram T,Schilling JM,Wallace MS(2011)Targetingvoltage-gated calcium channels for the treatment of neuropathicpain:a reviewof drug development.Expert opinion on investigational drugs 20:1277-1284.

[0283] Pogatzki-Zahn EM,Wagner C,Meinhardt-Renner A(2003)Spinalglutamatereceptor antagonists differentiate primary and secondarymechanicalhyperalgesia caused by incision.Pain 105(1-2):97-107.

[0284] Sanguinetti,MC,Jiang C,Curran ME,Keating MT(1995)A mechanisticlinkbetween an inherited and an acquired cardiac arrhythmia:hERG encodesthe IKrpotassium channel.Cell,81:299-307.

[0285] Talley EM,Cribbs LL,Lee JH,Daud A,Perez-Reyes E,Bayliss DA(1999)Differential distribution of three members of a gene family encodinglowvoltage-activated(T-type)calcium channels.J Neurosci 19:1895-1911.

[0286] Todorovic SM,Jevtovic-Todorovic V(2011)T-type voltage-gatedcalciumchannels as targets for the development of novel paintherapies.Britishjournal of pharmacology 163:484-495.

[0287] Tringham E,Powell KL,Cain SM,Kuplast K,Mezeyova J,Weerapura M,EduljeeC,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 channelblockers that attenuate thalamic burst firing andsuppress absenceseizures.Science translational medicine 4:121ra119.

[0288] Uebele VN,Gotter AL,Nuss CE,Kraus RL,Doran SM,Garson SL,ReissDR,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 calciumchannels inhibits high-fat diet-induced weight gain in mice.J Clin Invest119:1659-1667.

[0289] Wang Y,Liu JJ,Dransfield PJ,Zhu L,Wang Z,Du X,Jiao X,Su Y,LiAR,BrownSP,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 GPR40Full Agonists ContainingTricyclic Spirocycles.ACS medicinal chemistry letters4:551-555.

[0290] 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,DawsonES,Li M,McManus O,Jones CK,Daniels JS,Hopkins CR,Xie XS,Conn PJ,Weaver CD,Lindsley CW(2011)TheDiscovery and Characterization of ML218:A Novel,CentrallyActive T-TypeCalcium Channel Inhibitor with Robust Effects in STN Neurons andin aRodent Model of Parkinson's Disease.ACS chemical neuroscience 2:730-742.

[0291] Xie X,Brogan JT,Schulte ML,Mi D,Yu H,Dawson ES,Li M,McManusO,EngersJ,Lewis LM,Thompson A,Jones CK,Weaver CD,Lindsley CW(2010)Scaffold HoppingAffords a Highly Selective in vitro and in vivoT-Type Calcium Inhibitor ProbeFree From IP Issues.In:Probe Reports fromthe NIH Molecular Libraries ProgramBethesda(MD).

[0292] Xie X,Lancaster B,Peakman T,Garthwaite J(1995)Interaction oftheantiepileptic drug lamotrigine with recombinant rat brain type IIA Na+channels and with native Na+channels in rat hippocampalneurones.PflugersArchiv:European journal of physiology 430:437-446.

[0293] Xie X,Van Deusen AL,Vitko I,Babu DA,Davies LA,Huynh N,ChengH,Yang N,Barrett PQ,Perez-Reyes E(2007)Validation of high throughputscreening assaysagainst three subtypes of Ca(v)3 T-type channels usingmolecular andpharmacologic approaches.Assay and drug developmenttechnologies 5:191-203.

[0294] Yang ZQ,Barrow JC,Shipe WD,Schlegel KA,Shu Y,Yang FV,Lindsley CW,Rittle KE,Bock MG,Hartman GD,Uebele VN,Nuss CE,FoxSV,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,WoltmannRF,Magee MM,Koblan KS,Renger JJ(2008)Discovery of 1,4-substituted piperidinesas potentand selective inhibitors of T-type calcium channels.J Med Chem51:6471-6477.

[0295] 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.

[0296] Zhang YF,Gibbs JW,3rd,Coulter DA(1996)Anticonvulsant drug effectsonspontaneous thalamocortical rhythms in vitro:ethosuximide,trimethadione,anddimethadione.Epilepsy Res 23:15-36。

Claims

1. Use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating pruritus, wherein the compound is selected from the group consisting of: EX-31 EX-55 EX-130 EX-132 AFA-258 AFA-309 or AFA-358 2. The use according to claim 1, wherein the pruritus is caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, exposure to toxic plants, exposure to chemicals, exposure to smoke, insect bites, or allergic reactions to food allergens.

3. The use according to claim 1, wherein the drug is administered orally or nasally.

4. Use of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating pruritus, wherein the compound is selected from the group consisting of: EX-31 EX-130 or AFA-358 5. The use according to claim 4, wherein the pruritus is caused by atopic dermatitis, psoriasis, renal failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, exposure to toxic plants, exposure to chemicals, exposure to smoke, insect bites or allergic reactions to food allergens.

6. The use according to claim 4, wherein the drug is administered orally or nasally.

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