MX2008007889A - Compositions and methods for modulating gated ion channels - Google Patents

Abstract

Disclosed are quinoline and quinazoline compounds which modulate the activity of the gated ion channels. Compounds that modulate these gated ion channels are useful in the treatment of diseases and disorders related to pain, inflammation, the neurological system, the gastrointestinal system and genitourinary system. Preferred compounds include quinoline or quinazoline derivatives substituted at the 4- position via N(H), C(O) or O moieties.

Description

COMPOSITIONS AND METHODS FOR MODULATING GUTTER ION CHANNELS Related Request This application claims priority of the Provisional Application E.U.A. No. 60 / 753,201, Attorney's Document No. PCI-032-1, filed on December 21, 2005, entitled "COMPOSITIONS AND METHODS FOR MODULATING THE GATE ION CHANNELS". The contents of any of the patents, patent applications, and references cited by this specification are hereby incorporated by reference in their entirety.

Field of the Invention The present invention relates to compositions that modulate the activity of gate ion channels and methods and uses thereof.

BACKGROUND OF THE INVENTION Mammalian cell membranes are important for the integrity and structural activity of many cells and tissues. Of particular interest is the study of transmembrane gate ion channels that act to directly and indirectly control a variety of pharmacological, physiological, and cellular processes. Numerous Gate ion channels have been identified and investigated to determine their participation in cellular function. Gate ion channels are involved in the reception, integration, transduction, conduction, and transmission of signals in a cell, for example, a neuronal or muscle cell. Gate ion channels can determine membrane excitability. The gate ion channels can also influence the resting potential of membranes, waveforms, and frequencies of action potentials, and excitation thresholds. Gate ion channels are typically expressed in electrically excitable cells, e.g., neuronal cells, and are multimeric. Gate ion channels can also be found in non-excitable cells (eg, fat cells or liver cells), where they can play a role in, for example, signal transduction. Among the numerous gate ion channels identified to date are channels that respond to, for example, voltage modulation, temperature, chemical environment, pH, ligand concentration and / or mechanical stimulation. Examples of specific modulators include: ATP, capsaicin, neurotransmitters (eg, acetylcholine), ions, eg, Na +, Ca +, K +, Cl ", H +, Zn +, Cd +, and / or peptides, eg, FMRF. The examples of channels of gate ions that respond to these stimuli are members of the gene superfamilies DEG / ENaC, TRPV and P2X. Members of the DEG / ENaC gene superfamily show a high degree of functional heterogeneity with a broad tissue distribution that includes transport epithelia as well as excitable neuronal tissues. The DEG / ENaC proteins are membrane proteins that are characterized by two transmembrane-spanning domains, intracellular N and C terminals and an extracellular circuit enriched with cysteine. Depending on their function in the cell, the DEG / ENaC channels are either constitutively active type epithelial sodium channels (ENaC) that are involved in sodium homeostasis, or activated by mechanical stimuli as postulated by degnepnas de C. el egans, or by ligands such as peptides as is the case for FaNaC from Hel ix aspersa which is an activated channel with amide peptide FMRF and is involved in neurotransmission, or by protons as in the case for acid-sensitive ion channels (ASICs ). The mammalian members of this family of genes known to date are aENaC (also known as SCNN1A or scnnlA), ßENaC (also known as SCNN1B or scnnlB),? ENaC (also known as SCNN1G or scnnlG), dENaC (also known as ENaCd) , SCNN1D, scnnlD and dNaCh), ASICla (also known as ASIC, ASIC1, BNaC2, hBNaC2, ASICalfa, ACCN2, Accn2 and accn2), ASIClb (also known as ASICbeta), ASIC2a (also known as BNC1, MDEG, Mdeg, MDEG1, BNaCl, ASIC2, ACCN1, Accnl and accnl), ASIC2b (also known as MDEG2, variant 2 ACCN1), ASIC3 (also known as hASIC3, DRASIC, TNaCl, SLNAC1, ACCN3, Accn3, accn3), ASIC4 (also known as BNaC4, SPASIC, ACCN4, Accn4 and accn4), BLINaC (also known as hINaC, ACCN5, Accn5 and accn5), and hINaC. For a recent review on this gene superfamily see Kellenberger, S. and Schild, L. (2002) Physiol. Rev. 82: 735, incorporated herein by reference. There are currently seven known members of the P2X gene superfamily; P2X? (also know as P2RX1), P2X2 (also known as P2RX2), P2X3 (also known as P2RX3), P2X (also known as P2RX4), P2X5 (also known as P2RX5), P2X6 (also known as P2RX6), and P2X7 (also known as P2RX7). The P2X protein structure is similar to the ASIC protein structure in that it contains two transmembrane spanning domains, intracellular N and C terminals and an extracellular circuit enriched with cysteine. All P2X receptors open in response to the release of extracellular ATP and are permeable to small ions and some have significant calcium permeability. P2X receptors are abundantly distributed in neurons, glia, epithelial, endothelial, bone, muscle and hematopoietic tissue. For one Recent review in this gene superfamily, see North, R.A. (2002) Physiol. Rev. 82: 1013, incorporated herein by reference. The receptor expressed in sensory neurons that react to the spicy ingredient in hot chili peppers to produce a burning pain is the capsaicma receptor (TRPV or vanilloid), denotes TRPV1 (also known as VR1, TRPVlalfa, TRPVlbeta). The TRPV1 receptor forms a non-selective cation channel that is activated by capsaicin and resiniferatoxm (RTX) as well as noxious heat (> 43 ° C), with evoked responses enhanced by protons, eg, H + ions. The acidic pH is also able to induce a slowly activated current that resembles the current sensitive to the native proton in some neurons of the dorsal root ganglia. The expression of TRPV1, although predominantly in primary sensory neurons, is also found in various nuclei of the brain and spinal cord (Physiol, Genomics 4: 165-174, 2001). Two structurally related receptors, TRPV2 (also known as VRL1 and VRL) and TRPV4 (also known as VRL-2, Trpl2, VROAC, OTRPC4), do not respond to capsaicin, acid or moderate heat, but rather are activated by high temperatures ( Catepna, MJ, et al (1999) Na ture, 398 (6726): 436-41). In addition, this family of receptors, for example, the TRPV or vanilloid family, which contains ECAC-1 receptors (also known as TRPV5 and CAT2, CaT2) and ECAC-2 (also known as TRPV6, CaT, ECaC, CAT1, CATL, and 0TRPC3) which are selective calcium channels (Peng, JB, et al. 2001) Genomics 76 (1-3): 99-109). For a recent review of TRPV (vanilloid) receptors, see Szallasi, A. and Blumberg, P.M. (1999) Pharmacol. Rev. 51: 159, incorporated herein by reference. The capacity of the members of the gate ions channels respond to various stimuli, for example, chemical stimuli (eg, protons), thermal and mechanical stimuli, and their location throughout the body, eg, primary sensory neurons of small diameter in the dorsal root ganglia and trigeminal ganglia, as well as the data derived from in vi tro and in vivo models, imply these channels in numerous diseases, disorders and neurological conditions. For example, it has been shown that the rat ASIC2a channel is activated by the same mutations as those that cause neuronal degeneration in C. elegans. In addition, these receptors are activated by increasing the extracellular proton, for example, H + concentration. By infusing low pH solutions into the skin or muscle as well as prolonging the intradermal infusion of low pH solutions, a change in extracellular pH is created that mimics hyperalgesia of chronic pain. In addition, transgenic mice, for example, transgenic mice ASIC2a, ASIC3, P2X3, all they have modified responses to noxious and noxious stimuli. Thus, the biophysical, anatomical and pharmacological properties of the gate ions channels are consistent with their participation in nociception. Research has shown that ASICs play a role in pain, diseases and neurological disorders, gastrointestinal diseases and disorders, genitourinary diseases and disorders, and inflammation. For example, it has been shown that ASICs play a role in pain sensation (Pnce, MP et al., Neuron, 2001; 32 (6): 1071-83; Chen, CC et al., Neurobiology 2002; 99 ( 13) 8992-8997), including visceral and somatic pain (Aziz, Q., Eur. J. Gastroenterol, Hepatol, 2001; 13 (8): 891-6); chest pain accompanying cardiac ischemia (Sutherland, SP et al (2001) Proc Nati Acad Sci USA 98: 711-716; Mamet, J. et al., J. Neuroscn 2002; 22 (24): 10662 - 70), and chronic hyperalgesia (Sluka, KA et al., Pain 2003; 106 (3): 229-39). Recently, ASIC antagonists were shown to be effective in inflammatory pain as well as in post-incisional pain (Dube, GR et al., Pain 2005; 117: 88-96; Voiley N. Curr Drug Targets Inflamm Allergy., 2004; 3: 71-9). ASICs in central neurons have shown that they possibly contribute to neuronal cell death associated with cerebral ischemia, stroke and epilepsy (Chesler, M., Physiol., Rev. 2003; 83: 1183-1221; Lipton, P, Physiol. Rev. 1999; 79: 1431-1568, Xiong Z.G. et al., Cell. 2004; 118: 687-98; Benvemste M. et al. , N Engl J Med. 2005; 352: 85-6; Gao J. et al., Neuron. 2005; 48: 635-46). ASICs have also shown that they contribute to the neural mechanisms of conditioned fear, smáptica plasticity, learning, and memory (emmie, JA et al., PNAS 2004; 101: 3621-6; emmie, J. et al., J. Neurosci 2003; 23 (13): 5496-5502; Wemmie, J. et al., Neuron, 2002; 34 (3): 463-77). ASICs have been shown to be involved in persistent pain related to inflammation and inflamed bowel (Wu, LJ et al., J. Biol. Chem. 2004; 279 (42): 43716-24; Yiangou, Y., et al. ., Eur. J. Gastroenterol, Hepatol, 2001; 13 (8): 891-6; Voiley N. Curr Drug Targets Inflamm Allergy, 2004; 3: 71-9), and Gastrointestinal Stasis (Holzer, Curr. Opm. Pharm. 2003; 3: 618-325). Recent studies in humans indicate that ASICs are the primary sensors of acid-induced pain (Ugawa et al., J. Clin Invest 2002; 110: 1185-90; Jones et al., J. Neuroscí., 2004; 24: 10974-9). Additionally, ASICs are also considered to play a role in gametogenesis and early embryonic development in Drosophila (Darboux, I. et al., J. Biol. Chem. 1998; 273 (16): 9424-9), mecanosensopal function and sensitive to the fundamental acid in the intestine (Page, AJ et al., Gastroenterology, 2004; 127 (6): 1739-47; Page, AJ et al., Gut. 2005; 54: 1408-15; Suguira T. et al. , J Neurosci, 2005; 25: 2617-27), and have shown that they are involved in endocrine glands (Grunder, S. et al., Neuroreport., 2000; 11 (8): 1607-11). Recent data also indicate that ASICs may play a role in acid sensitivity to human bone tissue (Jahr H. et al., Biochem Biophys Res Commun., 2005; 337: 349-54). Therefore, compounds that modulate these gate ions channels could be useful in the treatment of such diseases and disorders.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the invention provides a compound of Formula 1. In another aspect, the invention provides a compound of Formula 2. In another aspect, the invention provides a compound of Formula 3. In a , Formula 3 is represented by compound F; compound 31; compound 36; compound 37; compound 38; compound 39; compound 40; compound 50; compound 51; compound 52; compound 53 or compound 54. In one aspect, the invention provides a compound of formula 4. In one embodiment, formula 4 is represented by compound 35 or compound 10. In one aspect, the invention provides a compound of formula In one aspect, the invention provides a compound of the formula 5a. In one embodiment, formula 5a is represented by compound K; compound T; compound 32; compound 33; compound 101; compound 102; compound 103; compounds 104; compound 105; compound 106; compound 107; compound 108 or compound 111. In one aspect, the invention provides a compound of formula 6. In one aspect, the invention provides a compound of formula 6a. In one embodiment, formula 6a is represented by compound C, compound G; compound 34; compound 41; compound 42; compound 43; compound 44; compound 45; compound 46; compound 47; compound 48 or compound 49. In one aspect, the invention provides a compound of formula 7. In one embodiment, formula 7 is represented by compound A; compound D; compound H; compound L; compound M; compound N; compound 0; compound P; compound Q; compound 59; compound 60; compound 61 or compound 116.

In one aspect, the invention provides a compound of formula 8. In one embodiment, formula 8 is represented by compound B; compound R; compound S; compound 1; compound 2; compound 3; compound 4; compound 5; compound 6; compound 7; compound 8; compound 9; compound 10; compound 11; compound 12 compound 13; compound 14; compound 15; compound 16 compound 17; compound 18; compound 19; compound 20 compound; compound 22; compound 23; compound 24 compound 25; compound 26; compound 27; compound 28 compound 29; compound 30; compound 55 compound 56 compound 57 compound 58; compound 62 compound 63 compound 64 compound 65; compound 66 compound 67 compound 68 compound 69; compound 70 compound 71 compound 72 compound 73; compound 74 compound 75 compound 76 compound 77; compound 78 compound 79 compound 80 compound 81; compound 82 compound 83 compound 84 compound 85; compound 86 compound 87 compound 88 compound 89; compound 90 compound 91 compound 92 compound 93; compound 94 compound 95 compound 96 compound 97; compound 98 compound 99; compound 100; compound 109; compound 112; compound 113; compound 114; compound 115; compound 117; compound 118; compound 119; compound 120; compound 121; or compound 122. In one aspect, the invention provides a method for modulating the activity of a gate ion channel, comprising contacting a cell expressing a gate ion channel with an effective amount of a compound of the invention. . In another embodiment of the invention, contacting the cells with an effective amount of a compound of the invention inhibits the activity of the gate ion channel. In yet another embodiment, the gate ion channel comprises at least one subunit selected from the group consisting of a member of the gene superfamilies.

DEG / ENaC, P2X, and TRPV. In yet another embodiment, the gate ion channel comprises at least one subunit selected from the group consisting of aENaC, ENaC,? ENaC, dENaC, ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, ASIC4, BLINaC, hINaC, P2Xl7 P2X2, P2X3, P2X4, P2X5, P2XS, P2X7, TRPVl, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6. In another embodiment, the gate ion channel is homomultimépco. In yet another embodiment, the gate ion channel is heteromultimépco. In yet another embodiment, the gate ion channel DEG / ENaC comprises at least one subunit selected from the group consisting of aENaC, 3ENaC,? ENaC, dENaC, BLINaC, hINaC, ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4 . In another embodiment, the gate ion channel DEG / ENaC comprises at least one subunit selected from the group consisting of ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4. In yet another embodiment, the gate ion channel comprises ASICla and / or ASIC3. In yet another embodiment, the gate ion channel P2X comprises at least one subunit selected from the group consisting of P2X1; P2X2, P2X3, P2X4, P2X5, P2XS, and P2X7. In another embodiment, the TRPV gate ion channel comprises at least one subunit selected from the TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6 group. In yet another embodiment, heteromultimeric gate ion channels include the following combinations of gate ion channels: aENaC, 3ENaC and? ENaC; aANaC, ßENaC and dENaC; ASICla and ASIC3; ASIClb and ASIC3; ASIC2a and ASIC3; ASIC2b and ASIC3; ASICla, ASIC2a and ASIC3; P2XX and P2X2; P2XX and P2X5; P2X2 and P2X3; P2X2 and P2X6; P2X4 and P2X6; TRPVl and TRPV2; TRPV5 and TRPV6, and TRPVl and TRPV4. In yet another embodiment, heteromultimeric gate ion channels include the following combinations of gate ion channels: ASICla and ASIC2a; ASIC2a and ASIC2b; ASIClb and ASIC3; and ASIC3 and ASIC2b. In another embodiment of the invention, the activity of the gate ions channel is associated with pain. In yet another embodiment, the activity of the gate ions channel is associated with an inflammatory disorder. In yet another embodiment, the activity of the gate ions channel is associated with a neurological disorder. In another modality, the pain is selected from the group consisting of cutaneous pain, somatic pain, visceral pain and neuropathic pain. In yet another modality, the pain is acute pain or chronic pain. In yet another modality, cutaneous pain is associated with injuries, trauma, a cut, a laceration, a puncture, a burn, a surgical incision, an infection or acute inflammation. In another modality, somatic pain is associated with an injury, illness or disorder of the musculoskeletal and connective system. In yet another embodiment, the lesion, disease or disorder is selected from the group consisting of sprains, bone fracture, arthritis, psoriasis, eczema, and ischemic heart disease. In yet another modality, visceral pain is associated with an injury, disease or disorder of the circulatory system, the respiratory system, the gastrointestinal system, or the genitourinary system. In another embodiment, the disease or disorder of the circulatory system is selected from the group consisting of of ischemic heart disease, angina, acute myocardial infarction, cardiac arrhythmia, phlebitis, intermittent claudication, varicose veins and hemorrhoids. In still another embodiment, the disease or disorder of the respiratory system is selected from the group consisting of asthma, respiratory infection, chronic bronchitis and emphysema. In yet another embodiment, the disease or disorder of the gastrointestinal system is selected from the group consisting of gastritis, duodenitis, irritable bowel syndrome, colitis, Crohn's disease, gastrointestinal reflux disease, ulcers and diverticulitis. In another embodiment, the disease or disorder of the genitourinary system is selected from the group consisting of cystitis, urinary tract infections, glomerulonephritis, polycystic kidney disease, kidney stones and cancers of the genitourinary system. In yet another modality, somatic pain is selected from the group consisting of arthralgia, myalgia, chronic low back pain, pain of phantom limb, pain associated with cancer, dental pain, fibromyalgia, idiopathic pain disorder, chronic non-specific pain, chronic pelvic pain, post-operative pain, and referred pain. In yet another modality, neuropathic pain is associated with an injury, illness or disorder of the nervous system. In another embodiment, the lesion, disease or disorder of the nervous system is selected from the group consisting of neuralgia, neuropathy, headache, migraine, psychogenic pain, chronic head pain and spinal cord injuries. In another embodiment of the invention, the activity of the gate ion channel is selected from an inflammatory disorder of the musculoskeletal system and of connective tissue, the respiratory system, the circulatory system, the genitourinary system, the gastrointestinal system or the nervous system. . In another embodiment, the inflammatory disorder of the musculoskeletal system and of connective tissue is selected from the group consisting of arthritis, psoriasis, myocitis, dermatitis, bone cancer and eczema. In still another embodiment, the inflammatory disorder of the respiratory system is selected from the group consisting of asthma, bronchitis, sinusitis, pharyngitis, laryngitis, tracheitis, rhinitis, cystic fibrosis, respiratory infection and acute respiratory distress syndrome. In yet another modality, the disorder Inflammatory of the circulatory system is selected from the group consisting of vasculitis, hematuria syndrome, atherosclerosis, arteptis, phlebitis, carditis and coronary heart disease. In another embodiment, the inflammatory disorder of the gastrointestinal system is selected from the group consisting of inflammatory bowel disorder, ulcerative colitis, Crohn's disease, diverticulitis, viral infection, bacterial infection, peptic ulcer, chronic hepatitis, gingivitis, pepodentitis, stomatitis, gastritis. and gastrointestinal reflux disease. In yet another embodiment, the inflammatory disorder of the genitourinary system is selected from the group consisting of cystitis, polycystic kidney disease, nephritic syndrome, urinary tract infection, cystmosis, prostatitis, salpmgitis, endometriosis and genitourinary cancer. In another embodiment, the neurological disorder is selected from the group consisting of schizophrenia, learning disorder, bipolar disorder, depression, Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke, addiction, cerebral ischemia, neuropathy, pigment degeneration retmal, glaucoma, cardiac arrhythmia, zoster, chorea of Huntmgton, Parkmson's disease, anxiety disorders, panic disorders, phobias, anxiety hysteria, generalized anxiety disorder, and neurosis. In another aspect, the invention provides a method for treating pain in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the invention. In one embodiment, the subject is a mammal. In yet another embodiment, the mammal is a human. In yet another modality, the pain is selected from the group consisting of cutaneous pain, somatic pain, visceral pain and neuropathic pain. In another modality, the pain is acute pain or chronic pain. In another aspect, the invention provides a method for treating an inflammatory disorder in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the invention. In one embodiment, the subject is a mammal. In yet another embodiment, the mammal is a human. In yet another modality, the inflammatory disorder is an inflammatory disorder of the musculoskeletal system and connective tissue, the respiratory system, the circulatory system, the genitourinary system, the gastrointestinal system or the nervous system. In another aspect, the invention provides a method for treating a neurological disorder in a subject in need of same, which comprises administering an effective amount of a compound of the invention. In one embodiment, the subject is a mammal. In yet another embodiment, the mammal is a human. In yet another embodiment, the neurological disorder is selected from the group consisting of schizophrenia, bipolar disorder, depression, Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke, addiction, cerebral ischemia, neuropathy, reticular pigment degeneration, glaucoma. , cardiac arrhythmia, zoster, chorea of Huntmgton, Parkmson's disease, anxiety disorders, panic disorders, phobias, anxiety hysteria, generalized anxiety disorder, and neurosis. In another aspect, the invention provides a method for treating a disease or disorder associated with the genitourinary and / or gastrointestinal systems of a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the invention. In another embodiment, the subject is a mammal. In yet another embodiment, the mammal is a human. In yet another embodiment the disease or disorder of the gastrointestinal system is selected from the group consisting of gastritis, duodenitis, irritable bowel syndrome, colitis, Crohn's disease, ulcers and diverticulitis. In another modality, the disease or disorder of the genitourinary system is selected from the group consisting of cystitis, urinary tract infections, glomerulonephritis, polycystic kidney disease, kidney stones and cancers of the genitourinary system. In another embodiment of the invention, the methods further comprise administering an adjuvant composition. In yet another embodiment, the adjuvant composition is selected from the group consisting of opioid analgesics, non-opioid analgesics, local anesthetics, corticosteroids, non-spheroidal anti-inflammatory drugs, non-selective COX inhibitors, non-selective COX2 inhibitors, selective COX2 inhibitors, antiepileptics, barbiturates, antidepressants, marijuana, and topical analgesics.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a dose response curve of the inhibitory effect of compound R on hASICla activity as described in Example 1. HEK-293 cells, transiently expressing hASICla, were exposed to an acidic buffer solution. soft in the absence and presence of increased concentrations of compound R. The gate channel activity was determined by measuring the variation of intracellular calcium using a calcium-selective fluorescent pigment. The compound R inhibits depending on the dose, the hASIC activity induced by acid in these cells. Figures 2A and 2B illustrate the dose-dependent inhibitory effects of Compounds B and R on the acid-induced activation of the homologous hypersensing channels, as described in Example 2.

HEK293 cells were transfected with hASIClA. Acid-induced inward currents were recorded in the presence and absence of compounds using the whole-cell configuration of the membrane zoning method (voltage amplification mode). For each compound, a clear dose-dependent reduction in the current evoked by a mild pH stimulation was observed, indicating that compounds B and R are inhibitors of the activity of the gate ion channels. Figure 3A, 3B and 3C present a more detailed analysis of the effects of compound R on the hASICl and hASIC3 currents as described in example 2. In this example, the CHO cells were transfected with either hASICla or hASIC3 alone and current in the interior acid-mediated mode were recorded in the presence or absence of the compounds using the full-cell configuration of the zonal membrane method (voltage amplification mode). In Figure 3A, 1 μM of the compound R was able to reduce the HASICla current by about half, while the Figure 3B, 30 μM of compound R fails to inhibit the current mediated by hASIC3. Figure 3C shows the dose-dependent inhibition by the compound R of the acid-induced activation of the homologous recombinant hASIC channels, but without an hASIC3. These data indicate that compound R is selective for hASICla on hASIC3. Figures 4A, 4B, 4C and 4D illustrate the dose-dependent inhibitory effects of compounds B, R, 7 and 32, respectively, on the acid-induced activation of recombinant homologous hASIC channels, as described in Example 3. Acid-induced currents were recorded from Xenopus laevi oocytes, microinjected with a hASICla encoded by cDNA, using the two-electrode voltage clamp method in the absence or presence of the compounds. With each compound, there is a dose-dependent reduction in the current evoked by a mild pH stimulation which indicates that the compounds B, R, 7 and 32 are inhibitors of the activity of the acid-gate ion channels. Figure 5 illustrates the effects of Compound A on chemically induced spontaneous pain evoked by intraplantar injection of formalin in the rat (formalin model described in example 5). These results indicate that this compound causes a dose-dependent reduction of the intensity of pain as assessed by fear behavior. Figures 6A and 6B illustrate the effect of different concentrations of compound R on pain induced by formalma in rats. Figure 6A describes the overall pain behavior (e.g., fear, licking, biting) during the time after the formalplant injection of formalma and Figure 6B displays the number of episodes of licking and biting. These results indicate that Compound R causes a dose-dependent reduction of pain behavior in the rat. Figure 7 depicts the dose-dependent effect of Compound R on pain induced by formalma. The response to the dose relative to Compound A in the number of episodes of licking and biting in phase Ia of the formalma test is presented. The effective dose where the pain record is reduced by half (ED50) is -50 mg / kg. Figure 8 shows synthesis schemes for the preparation of compounds 36, 37 and 38. Figures 9A, 9B, 9C and 9D show synthesis schemes for the preparation of compounds 39 and 47, as well as prophetic schematic synthesis for the genetic compounds of the invention. Figure 10 shows synthesis schemes for the preparation of compound 108.

Figures HA and 11B show synthesis schemes for the preparation of compounds 103 and 104. Figure 12 shows synthesis schemes for the preparation of an intermediate that can be used for the preparation of the compounds of the invention. Figures 13A, 13B and 13C show synthetic schemes for the preparation of compounds 107, 105 and 106. Figures 14A and 14B show synthetic schemes for the preparation of compounds 111 and 109. Figures 15A, 15B and 15C show synthetic schemes for the preparation of compounds 12, 112 and 110.

Detailed Description of the Invention The present invention is based, at least in part, on the identification of compounds useful in the modulation of the activity of gate ion channels. Gate ion channels are involved in the reception, conduction, and transmission of signals in a cell (eg, an electrically excitable cell, eg, a neuronal or muscle cell). Gate ion channels can determine membrane excitability (the ability, for example, that a cell responds to a stimulus and converts it into a sensory impulse). The gate ion channels can also influence the resting potential of membranes, waveforms and frequencies of action potentials, and excitation thresholds. Gate ion channels are typically expressed in electrically excitable cells, eg, neuronal cells, and are multimepts; can form homomultimépcas structures (eg, composed of a type of subunit), or heteromultimépcas (eg, composed of more than one type of subunit). Gate ion channels can also be found in non-excitable cells (eg, fat cells or liver cells), where they can play a role in, for example, signal transduction. Gate ion channels are generally homomeric or heteromeric complexes composed of subunits, comprising at least one subunit belonging to the gene superfamilies DEG / ENaC, TRPV and / or P2X. Non-limiting examples of the DEG / ENaC receptor gene superfamily include Na + epithelial channels, eg, cENaC, / 3ENaC,? ENaC, and / or dENaC, mammalian degenerates (also referred to as MDEG, Na + brain channels).

(BNaC, BNC)) and acid-sensitive ion channels (ASICs), for example, ASIC1, ASICla, ASIClb, ASIC2, ASIC2a, ASIC2b, ASIC3, and / or ASIC4. Non-limiting examples of the P2X receptor gene superfamily include P2XX, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7. The non-limiting examples of TRPV receptor gene superfamily include TRPV1 (also referred to as VR1), TRPV2 (also referred to as VRL-1), TRPV3 (also referred to as VRL-3), TRPV4 (also referred to as VRL-2), TRPV5 (also referred to as ECAC-1), and / or TRPVβ (also referred to as ECAC-2). Non-limiting examples of heteromultimeric gate ions channels include o? ENaC, / 3ENaC and? ENaC; aENaC, / 3ENaC and dENaC; ASICla and ASIC2a; ASICla and ASIC2b; ASICla and ASIC3; ASIClb and ASIC3; ASIC2a and ASIC2b; ASIC2a and ASIC3; ASIC2b and ASIC3; ASICla, ASIC2a and ASIC3; ASIC3 and P2X, for example, P2XX, P2X2, P2X3, P2X4, P2X5, P2X6 and P2X7, preferably ASIC3 and P2X2; ASIC3 and P2X3; and ASIC3, P2X2 and P2X3 ASIC4 and at least one ASICla, ASIClb, ASIC2a, ASIC2b, and ASIC3; BLINaC (or hINaC) and at least one of ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4; dENaC and ASIC, for example, ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3 and ASIC4; P2XX and P2X2, P2X? and P2X5, P2X2 and P2X3, P2X2 and P2XS, P2X4 and P2X6, TRPVl and TRPV2, TRPV5 and TRPV6, TRPVl and TRPV4. Based on the above, there is a need for compositions that modulate the activity of ion channels and methods of using them for the treatment of conditions, diseases and disorders related to pain, inflammation, the neurological system, the gastrointestinal system and Genitourinary system.

Definitions As used herein, the term "acid" refers to functional groups of carboxylic acid, sulfonic acid, sulfinic acid, sulfamic acid, phosphonic acid, and boronic acid. The term "alkyl" includes saturated aliphatic groups, which include straight chain alkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), alkyl chain groups branched (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), cycloalkyl groups substituted by alkyl, and alkyl groups substituted by cycloalkyl. In addition, the expression "Cx-C alkyl", wherein x is 1-5 and y is 2-10 denotes a particular alkyl group (straight or branched chain) of a particular range of carbons. For example, the term C alquilo-C 4 alkyl includes, but is not limited to, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl and isobutyl. The term "alkyl" further includes alkyl groups which may further include oxygen, nitrogen, sulfur or phosphorus atoms by replacing one or more carbons of the hydrocarbon column. In one embodiment, a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its column (eg, C-Cio for straight chain, C3-C? Or para branched chain), and more preferably 6 or fewer carbons.

Similarly, preferred cycloalkyls have from 4-7 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. On the other hand, alkyl (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.) includes both "unsubstituted alkyl" as "substituted alkyl", the latter of which refers to alkyl portions having substituents by replacing a hydrogen at one or more carbons of the hydrocarbon column, which allows the molecule to carry out its function. The term "substituted" is intended to describe portions having substituents that replace a hydrogen in one or more atoms, for example C, 0 or N, of a molecule. Such substituents may include, for example, alkenyl, alkyl, halogen, hydroxyl, alkylcarbonyloxy, aplcarbomloxy, alkoxycarbonyloxy, aploxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, ammocarbonyl, alkylamcarbonyl, dialkylammocarbomyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphmate, ammo (including alkyl amino, dialkylamm, aplamm, diaplam, and alkylarylamm), acylam (including alkylcarbonylam, arylcarbonylamm, carbamoyl, and ureido), amide, ammonium, sulfhydryl, alkylthio, apthio, thiocarboxylate, sulphates, alkylsulfyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylamino, morpholmo, phenol, benzyl, phenyl, piperizma, cyclopentane, cyclohexane, pyridine, 5H-tetrazole, tpazol, pipepdma, or aromatic or heteroaromatic portion. Additional examples of substituents of the invention, which are not intended to be limiting, include selected portions of straight or branched alkyl (preferably C? -C5), cycloalkyl (preferably C3-Ca), alkoxy (preferably C? -C6), thioalkyl (preferably Ci-Cd), alkenyl (preferably C2-C3), alkylo (preferably C2-C6), heterocyclic, carbocyclic, aryl (for example, phenyl), aryloxy (for example, phenoxy), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenyloxyalkyl), aplacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and aplcarbonyl or another such acyl group, heteroarylcarbonyl group, or heteroaryl group (CR'R ") 0 3NR'R" (eg, -NH2), (CR'R ") 0 3CN (eg, -CN), -N02, halogen (eg, -F, - Cl, -Br, or -I), (CR 'R ") or 3C (halogen), (eg, -CF3), (CR'R") 0 3CH (halogen) 2, (CR 'R ") 0 3CH2 (halogen), (CR' R") 0 3C0NR 'R ", (CR'R ") 0 3 (CNH) NR'R", (CR 'R ") 0-3S (0) ± 2NR' R", (CR 'R ") 0 3CH0, (CR'R ") 0 30 (CR'R") or 3H, (CR 'R ") 03S (0) 0 3R' (eg, -S03H, -0S03H), (CR'R") 0 30 (CR'R ") 0 3H (for example, -CH2OCH3 and -0CH3), (CR'R ") 0 3S (CR'R") 0 3H (eg, -SH and -SCH3), (CR'R ") 0-3OH (eg, -OH), (CR 'R ") 0 3COR', (CR 'R") 0 3 (substituted or unsubstituted phenyl), (CR'R ") 0 _> (C3-C3 cycloalkyl) ), (CR'R ") or 3C02R '(eg, -C02H), or (CR' R") 0 30R ', or the side chain of any naturally occurring amino acid; wherein R 'and R "are each independently hydrogen, a C1-C5 group, C2-C5, C-C5 alqumilo or aplo. Such substituents may include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy , alcoxicarbomloxi, aploxicarboniloxi, carboxylate, alkylcarbonyl, alkoxycarbonyl, ammocarbonilo, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, fosfmato, cyano, ammo (including alkyl am or dialquilammo, aplammo, diarilammo and alquilarilam o), acilam or (including alquilcarbonilammo, arilcarbonilammo , carbamoyl and ureido), amidmo, immo, oxime, thiol, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, tpfluorometilo, cyano, azide, heterocyclyl, or an aromatic or heteroaromatic portion. In certain embodiments, one carbonyl portion (C = 0) can be further derivatized with an oxime moiety, eg, an aldehyde moiety can be derived as its oxime analogue (-C = N-0H). those skilled in the art that substituted portions in the hydrocarbon chain if they can be substituted by themselves, if appropriate. Cycloalkyls can also be substituted, for example, with the substituents described above. An "aralkyl" portion is an alkyl substituted with an aryl (eg, phenylmethyl (ie, benzyl)). The term "amine" or "ammo" shall be understood as being more broadly applicable in general terms to either a mole, or a functional group or moiety, as is generally understood in the art, and may be primary, secondary, or tertiary. The term "amine" or "ammo" includes compounds wherein a nitrogen atom is covalently bonded to at least one carbon, hydrogen or heteroatom. The terms include, for example, but are not limited to, "alkyl ammo", "arylamm", "diarylamm", "alkylarylammon", "alkylamido", "arylammoalkyl", "alkammoalkyl", "amide", "a gone", and "ammocarbonyl." The term "alkyl ammo" comprises groups and compounds wherein the nitrogen is linked to at least one additional alkyl group. The term "dialkyl ammo" includes groups in which the nitrogen atom is linked to at least two additional alkyl groups. The term "aplammo" and "diarylamin" include groups wherein nitrogen is linked to at least one or two aryl groups, respectively. The term "alquilaplam o", "alkylaryl" or "arylammoalkyl" refers to an aryl group which is linked to at least one alkyl group and less a group aplo. The term "alkalmoalkyl" refers to an alkyl, alkenyl, or alkyl group bonded to a nitrogen atom which is also linked to an alkyl group. The term "amide", "knot" or "am ocarbonyl" includes compounds or portions containing a nitrogen atom which is bonded to the carbon of a carbonyl group or a thiocarbonyl. The term includes "alkalmocarbonyl" groups or "alkylammocarbonyl" which include alkyl, alkenyl, aryl or alkyl groups linked to an am group or linked to a carbonyl group. This includes aplamcarbonyl and arylcarbonylammon groups which include aryl or heteroaryl moieties linked to a lower group which is bonded to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylammocarbonyl", "alkenylammocarbomyl", "alkylaminocarbonyl", "aplammocarbonyl", "alkylcarbonylamm", "alkenylcarbonylamm", "Alkylcarbonylamm", and "aplcarbonylamm" are included in the term "amide". Amides also include urea (ammocarbonylamm) groups and carbamates (oxycarbonylamm). In a partir embodiment of the invention, the term "amine" or "arrimo" refers to substituents of the formulas N (R8) R9 or C? -SN (R8) R9, wherein R8 and R9 are each, independently, selected from the group consisting of -H and - (C? _4) 0? G alkyl, wherein G is select from the group that consists of -COOH, -H, -P03H, -S03H, -Br, -Cl, -F, -0-alkyl Ci 4, -S-alkyl Ci 4, aplo, -C (0) 0-alkyl C? -C6, -C (0) alkyl Ci 4-C00H, -C (O) C? -C4 alkyl and -C (0) -ar? Lo, or N (R8) R9 is pyrrolyl, tetrazolyl, pyrrolidyl, p? Rrol? Dm? L-2 - Ona, dimethylpyrrolyl, ylidazolyl and morpholmo The term "aplo" includes groups, including 5- and 6-membered single ring aromatic groups which may include from zero to four heteroatoms, for example, phenyl, pyrrole, furan, thiophene, tlazole, isothiazole, imidazole, tpazol, tetrazole, pyrazole, oxazole, isoxazole, pipdma, pyrazole, pipdazm, and pyrimidine, and the like. Additionally, the term "aplo" includes multi-cyclic aryl groups, eg, tetracyclic, bicyclic, eg, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoa, isotherm, anthryl, fenantplo, naftridma. , mdol, benzofuran, purma, benzofuran, deazapurma, or mdoliz a. Those aryl groups having heteroatoms in the ring structure can also be referred to as "aryl heterocycles", "heterocycles", "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted in one or more ring positions with such substituents as described above, such as, for example, alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylammocarbonyl, aralkylammocarbonyl, alkenylammocarbonyl, alkylcarbonyl, aplcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, ammocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphmate, cyano, ammo (including alkyl amino, dialkylamm, arylamm, diaplam, and alkylamplam), acylamm ( including alkylcarbonylamine, arylcarbonylamine, carbamoyl and ureido), amide, ammonium, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfonyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylamino, or an aromatic or heteroaromatic moiety . The aplo groups can be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form a polycycle (eg, tetralma). The term "electron withdrawing group" or "electron withdrawing atom" (also referred to as "EWG") is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from atoms neighbors, that is, the substituent is electronegative with respect to neighboring atoms. A quantification of the level of electron withdrawal capacity is given by the constant Hammett sigma (S). This well known constant is described in many references, for example, J. March, Advanced Organic Chemistry, McGraw Hill Book Company, New York, (1977 edition) pp. 251-259. Hammett constant values are generally negative for groups that donate electron (S [P] = - 0.66 for NH2) and positive for groups that withdraw electron (S [P] = 0.78 for a nitro group), where S [P] indicates substitution for. Non-limiting examples of electron withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, carbonyl, thiocarbonyl, ester, ammonium, carboxylic acid, sulfonic acid, sulfamic acid, phosphonic acid, boronic acid, sulfate ester, hydroxyl ester, mercapto, cyano, cyanate, thiocyanate, isocyanate, isothiocyanate, carbonate, nitrate and nitro and the like. Atoms that withdraw electron include, but are not limited to, an oxygen atom, a nitrogen atom, a sulfur atom or a halogen atom, such as a fluorine, chlorine, bromine or iodine atom. It is understood that, unless otherwise indicated, reference is made herein to an acid functional group also encompassing salts of such functional group in combination with a suitable cation. It will be noted that the structures of some of the compounds of this invention include asymmetric carbon atoms. It should be understood accordingly that the isomers resulting from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis.

Additionally, the structures and other compounds and portions discussed in this application also include all tautomers thereof. The compounds described herein can be obtained through the synthetic strategies recognized in the art. The final products of the reactions described herein can be isolated by conventional techniques, for example, by extraction, crystallization, distillation, chromatography, etc. Additionally, the phrase "any combination thereof" implies that any number of the functional groups and molecules listed can be combined to create a large molecular architecture. For example, the terms "aplo" (representing phenyl), "C02X1" (where X1 = H) and Cx5 alkyl (that is, -CH3 and -CH2CH2CH2-) can be combined to form a substituent of 3-methoxy-4-propoxybenzoic acid. It will be understood that when the functional groups and molecules are combined to create a large molecular architecture, the hydrogens can be removed or added, as required to satisfy the valence of each atom.

As used herein, the terms "gate ion channel" or "gate channel" are used interchangeably and are intended to refer to a mammalian (eg, rat, mouse, human) multimépic complex that responds to, for example, voltage variations (eg membrane depopulation or hyperpolarization), temperature (eg, above or below 37 ° C), pH (eg, pH values above or below 7.4), concentration of ligand and / or mechanical stimulation. Examples of specific modulators include, but are not limited to, endogenous extracellular ligands such as anandamide, ATP, glutamate, cysteine, glycine, gamma-ammobutypic acid (GABA), histidine, serotonin (5HT), acetylcholine, epmefrma, norep efriña, protons, ions, for example, Na +, Ca ++, K +, Cl, H +, Zn +, and / or peptides, for example, Met-encephalon, Leu-encephalm, dmorf, neurotrophs, and / or the peptides related to RFamide , for example, FMRFamide and / or FLRFamide; for endogenous intracellular ligands such as cyclic nucleotides (eg, cyclic AMP, cyclic GMP), ATP, Ca ++ and / or G proteins; for exogenous extracellular ligands or modulators such as a-ammo-3-hydroxy-5-methyl-4-ε-solaxone propyanate (AMPA), amiloride, capsaic, capsazepma, epibatid, cadmium, barium, gadolinium, guanidium, cainate, N-methyl-D-aspartate (NMDA). The gate ion channels also include complexes that respond to toxins, examples which include, but are not limited to, Agatox (eg a-agatoxin IVA, IVB,? -agatoxin IVA, TK), Agitoxmas (Agitoxm) 2), Apamm, Argiotoxmas, Batracotox as, Brevetoxmas (for example Brevetoxm PbTx-2, PbTx-3, PbTx-9), Capbdotox as, Chlorotoxmas, Ciguatoxmas, Conotoxmas (eg a-conotox to Gl, GIA, Gil, IMI, MI, MU, SI, SIA, SU, and / or El; d-conotoxmas, μ-conotoxma GUIA, GIIIB, GIIIC and / or GS,? -conotoxma GVIA, MVIIA MVIIC, MVIID, SVIA and / or SVIB), Dendrotoxmas, Gramotoxmas (GsMTx-4,? -gramotoxma SIA), Grayanotoxmas, Hanatoxmas, Iberiotoxmas, Imperatoxmas, Jorotoxmas, Kaliotoxmas, Kurtoxmas, Leiurotoxma 1, Pricotox as, Psalmotoxmas, (for example, Psalmotoxma 1 (PcTxl)), Margatoxmas, Noxiustoxmas, Fpxotoxmas, PLTX II, Saxitoxmas, Stiodactila Toxins, sea anemone toxins (eg APETx2 from Anthopleura elegantissima), Tetrodotoxmas, Titius K-ot toxin, Escilatox as and / or tubocurarma. In a preferred embodiment, the compounds of the invention modulate the activity of ASICla and / or ASIC3. "Gate ion channel mediated activity" is a biological activity that is normally modulated (eg, inhibiting or promoting), either directly or indirectly, in the presence of a gate ions channel. The activities mediated by the ion channel of gateways include, for example, receiving, integrating, transducing, conducting, and transmitting signals in a cell, eg, a neuronal or muscle cell A biological activity that is mediated by a particular gate ion channel, eg ASICla or ASIC3, is referred to herein as a reference to the gate ion channel, eg, ASICla- or ASIC3- mediated activity. To determine the ability of a compound to inhibit a channel-ion channel-mediated activity, conventional assays can be used as described herein. "Neurotransmission," as used herein, is a process by which small signaling molecules, termed neurotransmitters, are rapidly passed in a regulated form from one neuron to another cell. Typically, the following depolarization associated with an incoming action potential, a neurotransmitter is selected from the presypt neuronal terminal. The neurotransmitter then diffuses through the optic rift to act on specific receptors in the postsmáptica cell, which is frequently a neuron but can also be another type of cell (such as muscle fibers in the neuromuscular junction). The action of neurotransmitters can be either excitatory, depolarizing the postsmaptic cell, or inhibitors, resulting in hyperpolarization. Neurotransmission is it can rapidly increase or decrease by neuromodulators, which typically act either pre-sptically or post-smaptically. The gate ion channel ASICla has been shown to possibly contribute to neurotransmission [Babmi et al. , J Biol Chem. 277 (44): 41597-603 (2002)]. Examples of gate ion channel mediated activities include, but are not limited to, pain (eg, inflammatory pain, acute pain, chronic malignant pain, chronic non-malignant pain, and neuropathic pain), disorders, diseases, and inflammatory disorders. of the genitourinary and gastrointestinal systems, and neurological disorders (for example, neurodegenerative or neuropsychiatric disorders). "Pain" is defined as an unpleasant sensation and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (International Association for the Study of Pam - IASP). Pain is most frequently classified based on duration (ie, acute pain vs chronic) and the preceding pathophysiology (es to is, nociceptive versus neuropathic pain). Acute pain can be described as an unpleasant experience with emotional and cognitive as well as sensory characteristics, which are presented in response to trauma and diseases in the tissues and serve as a defense mechanism. Acute pain is usually accompanied by a pathology (for example, trauma, surgery, childbirth, medical procedures, acute disease states) and the pain is resolved with the healing of the fundamental lesion.

Acute pain is mainly nociceptive, but it can also be neuropathic. Chronic pain is pain that extends beyond the healing period, with identified pathology levels that are often low and insufficient to explain the presence, intensity and / or degree of pain (American Pain Society - APS). Unlike acute pain, chronic pain serves non-adaptive purposes. Chronic pain may be nociceptive, neuropathic, or both, and is caused by injury (eg, trauma or surgery), malignant conditions, or a variety of chronic conditions (eg, arthritis, fibromyalgia, and neuropathy). In some cases, chronic pain exists de novo without apparent cause. "Nociceptive pain" is pain that results from damage to tissues and organs. Nociceptive pain is caused by the ongoing activation of pain receptors in either the superficial or deep tissues of the body. Nociceptive pain is also characterized as "somatic pain", including "skin pain" and "deep somatic pain", and "visceral pain". "Somatic pain" includes "skin pain" and "deep somatic pain". Cutaneous pain is caused by injuries, diseases and disorders of the skin and related organs.

Examples of conditions associated with cutaneous pain include, but are not limited to, cuts, burns, infections, lacerations, as well as traumatic injury and post-operative or surgical pain (eg, at the site of the incision). "Deep somatic pain" results from injuries, diseases or disorders of musculoskeletal tissues, including ligaments, tendons, bones, blood vessels and connective tissues. Examples of deep somatic pain or conditions associated with deep somatic pain include, but are not limited to, sprains, broken bones, arthralgia, vasculitis, myalgia, and myofascial pain. Arthralgia refers to pain caused by a joint that has been injured (such as a contusion, fracture or dislocation) and / or inflamed (eg, arthritis). Vaculitis refers to inflammation of blood vessels with pain. Myalgia refers to pain originating from the muscles. Myofascial pain refers to pain that derives from injuries or inflammation of the fascia and / or muscles. "Visceral" pain is associated with injury, inflammation or disease of the bodily organs and internal cavities, including but not limited to, the circulatory system, respiratory system, gastrointestinal system, genitourinary system, immune system, as well as ear, nose and throat. Visceral pain can also be associated with infectious and parasitic diseases that affect bodily organs and tissues. Visceral pain is extremely difficult to locate, and various lesions that exhibit visceral tissue "refer to" pain, where the sensation is localized to an area completely foreign to the sites of the lesions. For example, myocardial ischemia (the loss of blood flow to a part of the heart muscle tissue) is possibly the best known example of reference pain; The sensation can occur in the upper chest as a restricted feeling, or as a pain in the left shoulder, arm or even hand. The pain of the phantom limb is the sensation of pain of a limb that no longer has or no longer receives the physical signs of this - an experience almost universally reported by amputees and quadruple. "Neuropathic pain" or "neurogenic pain" is pain initiated or caused by a primary lesion, dysfunction or disturbance in the nervous system. "Neuropathic pain" can occur as a result of trauma, inflammation or disease of the peripheral nervous system ("peripheral neuropathic pain") and the central nervous system ("central pain"). For example, neuropathic pain can be caused by a nerve or nerves that are irritable, clenched, bruised, broken or inflamed (neuritis). There are many neuropathic pain syndromes, such as diabetic neuropathy, trigeminal neuralgia, post-therapeutic neuralgia ("zoster"), post-stroke pain, and complex regional pain syndromes (also called reflex sympathetic dystrophy or "RSD" and causalgia). As used herein, the term "inflammatory disease or disorder" includes diseases or disorders that are caused, at least in part, or exacerbated by inflammation, which is generally characterized by increased blood flow, edema, activation of immune cells (eg, proliferation, cytokine production, or increased phagocytosis), heat, redness, swelling, pain and loss of function in the affected tissue and organ. The cause of inflammation may be due to physical damage, chemicals, micro-organisms, tissue necrosis, cancer or other agents. Inflammatory disorders include acute inflammatory disorders, chronic inflammatory disorders, and recurrent inflammatory disorders. Acute inflammatory disorders are generally of relatively short duration, and last for a few minutes to around one to two days, although they may last for several weeks. The main characteristics of acute inflammatory disorders include increased blood flow, fluid exudation and plasma proteins (edema) and leukocyte migration, such as neutrophils. Chronic inflammatory disorders are generally long lasting, for example, weeks to months or years or more, and are associated histologically with the presence of lymphocytes and macrophages and with proliferation of blood vessels and connective tissue. Recurrent inflammatory disorders include disorders They reoccur after a period of time or have periodic episodes. Some disorders may fall within one or more categories. The terms "neurological disorder" and "neurodegenerative disorder" refer to injuries, diseases and dysfunctions of the nervous system, including the peripheral nervous system and central nervous system. Neurological disorders and neurodegenerative disorders include, but are not limited to, diseases and disorders that are associated with biological activity mediated by the gate ion channel. Examples of neurological disorders include, but are not limited to, Alzheimer's disease, epilepsy, cancer, neuromuscular diseases, multiple sclerosis, amyotrophic lateral sclerosis, stroke, cerebral ischemia, neuropathy (eg, neuropathy induced by chemotherapy, diabetic neuropathy). , degeneration of retmal pigment, chorea of Huntmgton, and Parkinson's disease, learning disorders, anxiety disorders (for example, phobic disorders (for example, agoraphobia, claustrophobia), panic disorders, phobias, anxiety hysteria, generalized anxiety disorder, and neurosis), and ataxia-telangiectasia. As used herein, "neuropathy" is defined as a failure of the nerves that carries information to and from the brain and spinal cord resulting in one or more of pain, loss of sensation, and inability to control the muscles. In some cases, the failure of the nerves that control blood vessels, intestines, and other organs results in abnormal blood pressure, digestion problems, and loss of other basic bodily processes. Peripheral neuropathy can involve damage to a single nerve or nerve group. (mononeuropathy) or can affect multiple nerves (polymeuropathy). The term "treat," "treat" or "treatment" includes the alleviation or alleviation of at least one symptom associated with pain, inflammation disorder, neurological disorder, genitourinary disorder or gastrointestinal disorder (eg, a symptom associated with or treated by activity mediated by gate ions channel). In certain embodiments, the treatment comprises modulating the interaction of a gate ion channel (eg, ASICla and / or ASIC3) with a compound that modulates the gate ion channel, which in turn decreases or mitigates at least one symptom associated with or caused by activity mediated by the gate ions channel being treated. For example, the treatment may be reduced by one or more symptoms of a disorder or complete eradication of a disorder. As used herein, the phrase "therapeutically effective amount" of the compound is the amount necessary or sufficient to treat or prevent pain, an inflammatory disorder, a neurological disorder, a gastrointestinal disorder or a genitourinary disorder, (e.g. to prevent the various morphological and somatic symptoms of an activity mediated by gate ions channel). In one example, an effective amount of the compound is an amount sufficient to alleviate at least one symptom of the disorder, eg, pain, inflammation, a neurological disorder, a gastrointestinal disorder or a genitourinary disorder, in a subject. The term "subject" is intended to include animals, which are capable of suffering from or suffer from a condition associated with the gate ions channel or disorder associated with the gate ions channel, or any disorder that directly or indirectly involves , the activity of gate ion channel. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain modalities, the subject is a human, for example, a human suffering from, at risk of suffering, or potentially capable of suffering from pain, inflammation, a neurological disorder, a gastrointestinal disorder or a genitourinary disorder (eg associated with the activity associated with the channel with door). The phrase "gate ion channel modulator" refers to compounds that modulate, that is, inhibit, promote or otherwise alter the activity of a gate ion channel. For example, the gate ion channel modulator can inhibit, promote or otherwise alter the response of a gate ion channel to, for example, voltage variations (eg, depopulation or membrane hyperpolarization), temperature (for example, higher or lower than 37 ° C), pH (for example, pH values higher or lower than 7.4), ligand concentration and / or mechanical stimulation. Examples of gate ion channel modulators include compounds of the invention (ie, Formulas 1, 2, 3, 4, 5a, 6, 6a, 7 and 8 including salts thereof, eg, a pharmaceutically acceptable salt). Additional examples of gate ion channel modulators include the compounds of Table A, Table B, Table C, Table D, Table E and Table F, or derivatives and fragments thereof, including salts thereof, for example, a pharmaceutically acceptable salt. In a particular embodiment, the ion channel modulators of gate of the invention, include the compounds of the Formulas 1, 2, 3, 4, 5, 5a, 6, 6a, 7 and 8, and the compounds of Table A, Table B, Table C, Table D, Table E and Table F, can be used to treat a disease or disorder associated with pain, inflammation, neurological disorder, gastrointestinal disorder or genitourinary disorder in a subject in need thereof. In another embodiment, the compounds of the invention can be used to treat an inflammatory disorder in a subject in need thereof.

Modulators of the Activity of the Ion Channel The present invention provides compounds that modulate the activity of a gate ion channel. In some embodiments, the compounds of the invention modulate the activity of a gate ion channel comprising at least one subunit belonging to the gene superfamilies DEG / ENaC, TRPV and / or P2X. In some embodiments, the compounds of the invention modulate the activity of the gate ion channel comprising at least one subunit selected from the group consisting of aENaC, ßENaC,? ENaC, dENaC, ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, ASIC4, BLINaC, hINaC, P2X1; P2X2, P2X3, P2X4, P2X5, P2X6, P2X7, TRPVl, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6. In still other embodiments, the compounds of the invention modulate the activity of the ion channel of gate DEG / ENaC comprising at least one subunit selected from the group consisting of aENaC, ENaC,? ENaC, dENaC, BLINaC, hINaC, ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4. In certain embodiments, the compounds of the invention modulate the activity of the gate ion channel DEG / ENaC comprising at least one subunit selected from the group consisting of ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4. In certain embodiments, the compounds of the invention modulate the activity of the gate ion channel DEG / ENaC comprising at least two subunits selected from the group consisting of ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4. In still other embodiments, the compounds of the invention modulate the activity of the gate ion channel DEG / ENaC comprising at least three subunits selected from the group consisting of ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4. In certain embodiments, the compounds of the invention modulate the activity of a gate ion channel comprising ASIC, that is, ASICla or ASIClb. In certain embodiments, the compounds of the invention modulate the activity of a gate ion channel comprising ASIC3. In certain embodiments, the compounds of the invention modulate the activity of a gate ion channel comprising ASICla and ASIC2a; ASICla and ASIC2a; ASICla and ASIC3; ASIClb and ASIC3; ASIC2a and ASIC2b; ASIC2a and ASIC3; ASIC2b and ASIC3; ASICla and ASIC3; and ASICla, ASIC2a and ASIC3. In other embodiments, the compounds of the invention modulate the activity of the P2X gate ion channel comprising at least one subunit selected from the group consisting of P2X? # P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7.

In certain embodiments, the compounds of the invention modulate the activity of a gate ion channel comprising P2X2, P2X3 or P2X4. In certain embodiments, the compounds of the invention modulate the activity of a gate ion channel comprising P2XX and P2X, P2XX and P2X5, P2X2 and P2X3, P2X2 and P2X6, and P2X4 and P2X6. In yet another aspect of the invention, the compounds of the invention modulate the activity of the TRPV gate ion channel comprising at least one subunit selected from the group TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6. In certain embodiments, the compounds of the invention modulate the activity of a gate ion channel comprising TRPV1 or TRPV2. In certain embodiments, the compounds of the invention modulate the activity of a gate ions channel comprising TRPV1 and TRPV2, TRPV1 and TRPV4, and TRPV5 and TRPV6. In a particular embodiment, the compounds of the invention include the compounds of formulas 1, 2 and 3, and compounds A, B, C, D, E, F, G, H, I, J and K that modulate the activity of ASICla and / or ASIC3.

In one aspect, the compound that modulates the activity of a gate ions channel is of Formula 1, (1) or a pharmaceutically acceptable salt thereof, wherein the dotted lines indicate a double or single bond, wherein when the dotted lines indicate a single bond the ring nitrogen may be linked to H or R ?; R1, R3 and R4 are each, independently, selected from the group consisting of hydrogen, substituted or unsubstituted amine, cyano, nitro, COOH, amide, halogen, haloalkylC5-5, nitro, substituted or not substituted substituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, hydroxyl, C5 alkyl-, wherein the Cx5 alkyl group may be interrupted by O, S or N (H), hydroxy-Cx5 alkyl, C alkenyl? _5, C? -5 alkyl, sulfonyl, sulfonamide, sulfonic acid, (CH2) 0-5? X5, (CH2) 0-5CO2Xe N (H) (CH2) 0 5OX5, and (CH2) 0-5C (O) N (X6) 2, wherein X6 is independently selected from the group consisting of hydrogen, Ct5 alkyl, amine, and -C02X1, wherein X1 selected from the group consisting of hydrogen, alkyl Ci 5, ammo, and substituted or unsubstituted aplo; and any combination thereof; R2 is selected from the group consisting of hydrogen, substituted or unsubstituted amine, amide, halogen, nitro, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, hydroxyl, C? -5 alkyl, wherein the alkyl group .5 can be interrupted by 0, S or N (H), hydroxyC1-5alkyl, Ci5 alkenyl, C5-5alkyl, sulfonyl, sulfone ida, sulfonic acid and -C02X1, wherein X1 is selected from the group consisting of hydrogen, Cx 5 alkyl, ammo, and substituted or unsubstituted aryl; and any combination thereof, or R2 is selected from the group consisting of Formulas I, II and III: wherein R8 is selected from the group consisting of 0, S and CH2; R6, R7, R9 and R10 are each, independently, selected from the group consisting of hydrogen, Ci alkyl. , wherein the Ci 5 alkyl group can be interrupted by O, S or N (H), amine, substituted or unsubstituted aryl and substituted or unsubstituted cycloalkyl; n is 0 or 1; m is 0 or 1; X2 is CH2, O or N (H); X3 and X4 are each, independently, N, C or C (H); dotted lines indicate a single or double link; X5 is selected from the group consisting of hydrogen, Ci5alkyl, C5alkoxy, substituted or unsubstituted (CH2) 0-4-phenol, (CH2) 0-4-c-clohexyl substituted or unsubstituted, (CH2) ) 0-4-benzo [1, 3] dioxol, wherein the C ?5 or CH2 alkyl groups can be interrupted by a carbonyl group or -C (0) 0-; and R5 is N, C or C (H); wherein R 3 and R 4, R 2 and R 3, R 1 and R 4 or R 2 and R 4 can also form a substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted 4, 5 or 6-membered heterocycle. In another embodiment of formula 1, dotted lines indicate a single or double bond, where when dotted lines indicate a single bond the ring nitrogen can be linked to H or Ri; R1, R3 and R4 are each, independently, selected from the group consisting of hydrogen, substituted or unsubstituted amine, cyano, nitro, COOH, amide, halogen, haloalkyl? 5, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, hydroxyl, Ci 5 alkyl, wherein the Cx 5 alkyl group may be interrupted by O, S or N (H), hydroxy-C alkyl? 5 / Ci 5 alkenyl, C 1-5 alkyloxy, sulfonyl, sulfonamide, sulfonic acid, (CH 2) 05OX6, (CH 2) o- 5C02XS N (H) (CH 2) 05OX 6, and (CH 2) 0 5C (0) N (X 6 ) 2, wherein X 6 is independently selected from the group consisting of hydrogen, Ci 5 alkyl, amine, and -CO 2 X 1, wherein X 1 selected from the group consisting of hydrogen, C 1 -C 5 alkyl, aryl, and substituted or unsubstituted aryl; R2 is selected from the group consisting of hydrogen, substituted or unsubstituted amine, amide, halogen, nitro, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, hydroxyl, Ci 5 alkyl, wherein the group Ci 5 alkyl can be interrupted by 0, S or N (H), hydroxyalkyl Cx 5, Cx 5 alkenyl, C 1 -C 5 alkyl, sulfonyl, sulfonamide, sulfonic acid and -C02X1, wherein X 1 is selected from the group which consists of hydrogen, Ci 5 alkyl, ammo, and substituted or unsubstituted aplo; or R2 is selected from the group consisting of Formulas I, II, III and IV: wherein R8 is selected from the group consisting of 0, S and CH2; R6, R7, R9 and R10 are each, independently, selected from the group consisting of hydrogen, C alquilo alkyl; , wherein the Ci 5 alkyl group can be interrupted by O, S or N (H), substituted or unsubstituted amine, substituted or substituted or unsubstituted cycloalkyl; n is 0 or 1; m is 0 or 1; X2 is CH2, O, N (C1-5 alkyl) or N (H); X3 and X4 are each, independently, N, C, or C (H); dotted lines indicate a single or double link; X5 is selected from the group consisting of hydrogen, C? -5 alkyl, Cx5 alkoxy, (CH2) 0-4-substituted or unsubstituted phenol, (CH2) 0-4-p? R? D or substituted or not replaced, C (0) Ph, (CH2) 04-c? Clohex? Substituted or unsubstituted, (CH2) or 4-benzo [1, 3] dioxol, wherein the C? -5 alkyl groups or CH2 can be interrupted by a carbonyl group or -C (0) 0-, and wherein the CH2 groups can be substituted with a C5 alkyl, halogen or CF3 group; a, b and c are each, independently, 0 or 1; X7 is C (H), N or O; X8 is H, CX 5 alkyl, aplo, OH, O-C?-5 alkyl or O-aryl; and R5 is N, C or C (H); wherein R 3 and R 4, R 2 and R 3, R 1 and R 4 or R 2 and R 4 can also form a substituted or unsubstituted aplo, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted 4, 5 or 6-membered heterocycle. In another embodiment of formula 1, dotted lines of Formula III indicate a single bond. Still in another modality of Formula 1, R2 is formula III, m = 0, X3 and X4 are N, and dotted lines indicate a single bond. In another embodiment of formula 1, Formula 1 is represented by Formula 2: (2) wherein R1, R2, R3, R4 and R5 have the stated meaning for Formula 1. In one embodiment of Formula 2, Formula 2 is represented by Formula 3: (3) wherein R1, R, R3, R4 and R5 have the stated meaning for Formula 1. In one embodiment of Formula 3, R1, R3 and R4 are each, independently, selected from the group consisting of hydrogen, halogen, CX 5 alkyl, C 5 O-alkyl, C 5 haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle; R is selected from the group consisting of hydrogen, substituted or unsubstituted amine, amide, halogen, nitro, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, hydroxyl, Cx 5 alkyl, wherein the group Ci 5 alkyl can be interrupted by 0, S or N (H), hydroxy-Ci 5 alkyl, Cx 5 alkenyl, C 1 -C 5 alkylo sulphonyl, sulfonamide, sulfonic acid and -C02X1, wherein X 1 selected from the group consisting of of hydrogen, C 5 alkyl, amino, and substituted or unsubstituted aryl; or R2 is selected from the group consisting of Formulas I, II and III: wherein R8 is selected from the group consisting of 0, S and CH2; Re, R7, R9 and R10 are each, independently, selected from the group consisting of hydrogen, Ci- 5 alkyl, wherein the C? 5 can be interrupted by 0, S or N (H), substituted or unsubstituted amine, substituted or substituted or unsubstituted cycloalkyl; n is 0 or 1; m is 0 or 1; X2 is CH2, O, N (alkyl d 5) or N (H); X3 and X4 are each, independently, N, C or C (H); the dotted lines they indicate a single or double bond; X5 is selected from the group consisting of hydrogen, Ci5alkyl, C5-5alkoxy, (CH2) or substituted or unsubstituted 4-phenol, (CH2) 0- -substituted or unsubstitutedcyclohexyl, (CH2) 0 4-benzo [1, 3] dioxol, wherein the Cx 5 or CH 2 alkyl groups can be interrupted by a carbonyl group or -C (0) 0-; and R5 is N or C (H). In one embodiment of Formula 3, dotted lines of Formula III indicate a single bond. In another embodiment of formula 3, R 3 and R 4 are each, independently, selected from the group consisting of H, halogen, hydroxyl, alkyl C 1 5 and alkoxy C? 5; R 2 is selected from the group consisting of Ci 5 alkyl, Ci 5 alkoxy, CO 2 H, and heterocycle; and R1 is selected from the group consisting of heterocycle, heterocycle substituted with CX5 alkyl, and phenyl substituted one or more times with hydroxyl, Ci5 alkyl or C5-5 alkoxy. In another embodiment of formula 3, R3 and R4 are each, independently, selected from the group consisting of H, Cl, Br, OH, and OCH3; R2 is selected from the group consisting of CH3, C02H, and piperidma; and R1 is selected from the group consisting of piperazm, piperazm substituted with CH3, and phenyl substituted one or more times with OH, OCH3 or CH3. In one embodiment of Formula 3, Formula 3 is represented by Formula 4: wherein R.sub.1, R.sub.2, R.sub.4 and R.sub.5 have the stated meaning for Formula 2. In one embodiment of Formula 4, R.sub.1 is selected from the group consisting of hydrogen, C.sub.5, C.sub.10 alkyl, fluorine. , bromine, trifluoromethyl, substituted or unsubstituted piperidma, substituted or unsubstituted piperazm, substituted or unsubstituted pyrid, substituted or unsubstituted morph, unsubstituted or substituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted diazepam and phenyl replaced or not replaced; R4 is selected from the group consisting of hydrogen, halogen, C? -5 alkyl, C02H and (CH2) 0 3? H; R2 is selected from the group consisting of hydrogen, substituted or unsubstituted amine, amide, halogen, C5 alkyl, wherein the C5-5 alkyl group can be interrupted by 0, S or N (H), and -C02X1, wherein X 1 selected from the group consisting of hydrogen, Ci 5 alkyl, amino, and substituted or unsubstituted aryl; or R2 is selected from the group consisting of Formulas I, II and III: wherein R8 is selected from the group consisting of 0, S and CH2; Rb R Ry and R 10 are each, independently, selected from the group consisting of hydrogen, Ci-5 alkyl, wherein the Ci 5 alkyl group can be interrupted by O, S or N (H), amine, substituted or not substituted substituted and substituted or unsubstituted cycloalkyl; n is 0 or 1; m is 0 or 1; X2 is CH2, 0 or N (H); X3 and X4 are each, independently, N, C or C (H); the dotted line indicates a single or double link; X5 is selected from the group consisting of hydrogen, Ci5alkyl, Ci5alkoxy, (CH2) or -4_ substituted or unsubstituted phenyl, (CH2) 0 -c? Clohex? Substituted or unsubstituted, (CH2) or -benzo [1,3] dioxol, wherein the Ci 5 or CH 2 alkyl groups can be interrupted by a carbonyl group or -C (0) 0-; and R5 is N or C (H). In another embodiment of formula 4, R1 is pyridine, which may be optionally substituted one or more times with OCH3, Cl, CH3, or N02; R5 is C (H); R2 is formula I or II; and R4 is halogen, (CH2) 0 3? H, or C02H. Still in another embodiment of Formula 4, R 2 is formula III, wherein n is 0, X 2 is N (H) or N (Ci 5 alkyl), X 3 is C (H), X4 is N and X5 is (CH2) 04-substituted or unsubstituted phenyl; R4 is H; and R1 is Cx alkyl. Still in another embodiment of Formula 4, R1 is selected from hydrogen, methyl, ethyl, methoxy, fluorine, bromine, trifluoromethyl, methyl substituted pipermine, methyl substituted diazepam, pyridine, phenyl, substituted phenyl with methyl and femlo independently substituted one or more times by methoxy, fluorine or bromine; R4 is selected from the group consisting of H, Cl, Br and F; R2 is selected from the group consisting of C? -5 alkyl, wherein the C? _5 alkyl group can be interrupted by O, S or N (H), and-C02X1, wherein X1 selected from the group consisting of hydrogen, alkyl C? _5, arrimo and substituted or unsubstituted aryl; or R2 is selected from Formula III: where n is 0 or 1; m is 0 or 1; X2 is CH2, 0 or N (H); X3 and X4 are each, independently, N, C or C (H); dotted lines indicate a single or double link; X5 is selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, (CH2) 0-4-substituted or unsubstituted phenyl, (CH2) 0-4-c? Clohex? Substituted or unsubstituted substituted, (CH2) 0-4-benzo [1, 3] dioxol, wherein the C? -5 or CH2 alkyl groups can be interrupted by a carbonyl group or -C (0) 0-; and R5 is N or C (H). In another modality, Formula 3 is represented by the Formula 5: (5) wherein R5 is N or C (H); R1 is selected from the group consisting of hydrogen, Ci5 alkyl, fluorine, bromine, tri-fluoromethyl, substituted or unsubstituted piperidma, substituted or unsubstituted piperizma, substituted or unsubstituted morpholm, unsubstituted or substituted imidazole, substituted or unsubstituted pyrazole substituted, substituted or unsubstituted diazepam and substituted or unsubstituted femlo; R 4 is selected from the group consisting of hydrogen, halogen, C x 5 alkyl, C 0 H and (CH2) 0 3OH; w is 0 or 1; and R11 and R12 are each, independently, selected from the group consisting of hydrogen, C? -5 alkyl, wherein the C? _5 alkyl group can be interrupted by O, S or N (H), and femlo substituted or unsubstituted, or R11 and R12 can form the following 6-membered ring: wherein X is selected from the group consisting of hydrogen, Ci 5 alkyl, C x 5 alkoxy, (CH 2) or 4-substituted or unsubstituted 4-phenol, (CH 2) 0 4-c ?clohex? substituted or unsubstituted, (CH 2) 0 4-benzo [1,3] dioxol, wherein the Cx 5 or CH 2 alkyl groups can be interrupted by a carbonyl group or -C (0) 0-. In another modality, Formula 3 is represented by the Formula 5a: (5a) wherein R5 is N or C (H); R 1 is selected from the group consisting of hydrogen, C 1 5 alkyl, C 5 alkyl, fluorine, bromine, trifluoromethyl, substituted or unsubstituted piperidine, substituted or unsubstituted pipermine, substituted morpholm or unsubstituted, substituted or unsubstituted, substituted or unsubstituted pyrazole, substituted or unsubstituted diazepam and substituted or unsubstituted phenyl; R4 is selected from the group consisting of hydrogen, halogen, C? -5 / C02H alkyl and (CH2) 0 3? H; w is 0 or 1; and R11 and R12 are each, independently, selected from the group consisting of hydrogen, Ci5 alkyl, wherein the C? 5 can be interrupted by O, S or N (H), and substituted or unsubstituted phenyl, or R11 and R12 can form the following 6-membered ring: wherein X5 is selected from the group consisting of hydrogen, C alquilo _ alkyl, C?-5 alkoxy, substituted or unsubstituted (CH 2) 0 4 -phenyl, (CH 2) 0 4-c?-clohexι substituted or unsubstituted, (CH2) 0-4-benzo [1, 3] dioxol, wherein the C1-5 alkyl or CH2 groups can be interrupted by a carbonyl group or -C (0) 0-. In one embodiment of Formula 5a, w is 0; R11 is H or CH3; R12 is (CH2)? -4C02H, (CH2)? -CH3, pipepdine substituted with benzyl or phenyl substituted with C02H; R ~ is hydrogen, CH3, CH2CH3, or phenyl substituted one or more times with chlorine or CH3; and R4 is hydrogen, chloro, or N02.

In an embodiment of Formula 5 Formula 5 is represented by Formula 6: wherein R4 is selected from the group consisting of hydrogen, halogen, C ?5 alkyl, C02H and (CH2) 0-3 HH; R 1 is selected from the group consisting of hydrogen, C 1 5 alkyl, fluorine, bromine, trifluoromethyl, substituted or unsubstituted pipepdma, substituted or unsubstituted pipepzma, substituted or unsubstituted morpholm, substituted or unsubstituted, substituted or unsubstituted pyrazole, substituted, substituted or unsubstituted diazepam and substituted or unsubstituted femlo; R5 is N or C (H); w is 0 or 1; and X5 is selected from the group consisting of hydrogen, C5_5alkyl, Ci5alkoxy, substituted or unsubstituted (CH2) 0-4-substituted or unsubstituted, (CH2) 0-4-c-clohexyl substituted or unsubstituted, (CH2) 0-4-benzo [1, 3] dioxol, wherein the C?-5 or CH 2 alkyl groups can be interrupted by a carbonyl group or -C (0) 0-. In another embodiment, Formula 5 is represented by Formula 6a: wherein R 4 is selected from the group consisting of hydrogen, halogen, Ci 5, 0-alkyl Ci 5, C02H alkyl and R1 is selected from the group consisting of hydrogen, C5 alkyl, fluorine, bromine, trifluoromethyl, substituted or unsubstituted piperidma, substituted or unsubstituted pipermin, substituted or unsubstituted morpholm, unsubstituted or substituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted diazepam and substituted or unsubstituted phenyl; R5 is N or C (H); w is 0 or 1; and X5 is selected from the group consisting of hydrogen, CX5 alkyl, Cx5 alkoxy, (CH2) or -4 substituted or unsubstituted phenyl, (CH2) 04-c? clohex? substituted or unsubstituted, (CH) 0 -benzo [1,3] dioxol, wherein the Cx 5 or CH 2 alkyl groups can be interrupted by a carbonyl group or -C (0) 0-. In one embodiment of Formula 6a, w is 1; X5 is (CH2) 0-4- substituted or unsubstituted phenyl, (CH2) 04-C (0) -substituted or unsubstituted phenyl, (CH2) 0-4-benzo [1,3] dioxol, CH3, or amide; R1 is pipodyl, phenyl independently substituted one or more times with 0CH3, Cl, or OH; and R4 is hydrogen, halogen, or OH. In another embodiment of Formula 2, Formula 6a is represented by Formula 7: (7) wherein R4 is selected from the group consisting of hydrogen, halogen, C? _5 alkyl, O-C C 5 alkyl, C02H and (CH 2) 0 3OH; R1 is selected from the group consisting of hydrogen, C1-5alkyl, fluorine, bromine, trifluoromet 1I0, substituted or unsubstituted pipepdma, substituted or unsubstituted pipermin, substituted or unsubstituted morpholm, unsubstituted or substituted imidazole, substituted or unsubstituted pyrazole substituted, substituted or unsubstituted diazepam and substituted or unsubstituted phenyl; R5 is N or C (H); and X5 is selected from the group consisting of hydrogen, Ci5alkyl, Ci5alkoxy, (CH2) 0-4-substituted or unsubstituted phenyl, (CH2) 04-c ?clohex? substituted or unsubstituted, (CH2) ) 0.4-benzo [1, 3] dioxol, where the C ?5 or CH2 alkyl groups can be interrupted by a carbonyl group or -C (0) 0-. In another embodiment of formula 7, X5 is H, C (0) 0-t-butyl, or phenyl substituted with CN or N0; R4 is halogen, and R1 is C? _5 alkyl. In another embodiment of Formula 3, Formula 3 is represented by Formula 8: (8) wherein R5 is N or C (H); R1 is selected from the group consisting of hydrogen, C ?5 alkyl, fluorine, bromine, trifluoromethyl, substituted or unsubstituted piperame, substituted or unsubstituted pipermin, substituted or unsubstituted morpholm, unsubstituted or substituted imidazole, substituted or unsubstituted pyrazole substituted, substituted or unsubstituted diazepam and substituted or unsubstituted phenyl; R4 is selected from the group consisting of hydrogen, halogen, C ?5 alkyl, C02H and (CH2) 0 3 H H; and R11 and R12 are each, independently, selected from the group consisting of hydrogen, C? -5 alkyl, Cx5-ammo alkyl, wherein the Ci5 alkyl group can be interrupted by O, S or N (H), Y substituted or unsubstituted phenyl, or Rlx and R12 can form the following 6-membered ring: where x and y are each, independently, 0 or 1; wherein X5 is selected from the group consisting of hydrogen, C? _5 alkyl, C? _5 alkoxy, (CH2) 0.4-substituted or unsubstituted aryl, (CH2) 0-4-substituted or unsubstituted cycloalkyl, (CH2) 0 -4-substituted or unsubstituted heterocycle, (CH2) 0-4-benzo [1, 3] dioxol, wherein the C? -5 or CH2 alkyl groups can be interrupted by a carbonyl group or -C (0) 0-; wherein the ring formed by R11 and R12 can be further substituted by C? -5 alkyl, halogen, or C02H. In one embodiment of Formula 8, R1 is selected from the group consisting of H, F, CH3, CF3, CN, and phenyl substituted with CH3; R4 is selected from the group consisting of hydrogen, F, OH, CH3, Br, Cl, 0CH3, N02 and CF3; and R11 and R12 are each, independently, selected from the group consisting of hydrogen, (CH2)? -halogen, and (CH2)? 4N (CH3) CH2Ph, or R11 and R12 can form the following ring: X5 where x and y are each, independently, 0 or 1; wherein X5 is selected from the group consisting of H, CH3, isopropyl, t-butyl, cyclopropyl, CH2-? sopropyl, CH2-t-butyl, CH2-c? clopropyl, CH2-c? clohex It, CH2-C02H, C (O) O-alkyl C? -5, C (0) Ph, (CH2)? 4-p? P? N? Lo, CH (CH3) Ph, CH (CF3) Ph, CH (F) Ph, and (CH2)? 4Ph, wherein the phenyl group can be independently substituted one or more times with chlorine, CN, C02H, N02, Cl or OCH3; wherein the ring formed by R11 and R12 can be further substituted by Cx 5 alkyl, halogen, or C02H. Preferred embodiments of Formulas 1, 2, 3, 4, 5, 5a, 6, 6a, 7 and 8 (including pharmaceutically acceptable salts thereof, as well as enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates of the same) are shown below in Table A, Table B, Table C, Table D, Table E and Table F, and are also considered to be "compounds of the invention". The compounds of the invention are also referred to as "gate ion channel inhibitors", as well as "ASIC inhibitors". ("OX" = OpusExpress, see Example 3, "Flex" FlexStation, see Example 1, "PC" = zonal membrane spacing, see Example 1) Acid addition salts of the compounds of the invention are more suitably formed of pharmaceutically acceptable acids, and include for example those formed with inorganic acids for example hydrochloric, hydrobromic, sulfuric or phosphoric acids and organic acids eg succinic acid, maleic acid , acetic or fumaric. Other non-pharmaceutically acceptable salts for example oxalates can be used for example in the isolation of the compounds of the invention, for laboratory use, or during the subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are solvates and hydrates of the invention. The conversion of a given compound salt to a salt of the desired compound is achieved by applying standard techniques, in which an aqueous solution of the given salt is treated with a base solution eg sodium carbonate or potassium hydroxide, for release the free base which is then extracted in an appropriate solvent, such as ether. The free base is then separated from the aqueous portion, dried, and treated with the corresponding acid to give the desired salt. The hydrolysable esters m vi or amides of certain compounds of the invention can be formed by treating those compounds having a free hydroxy or amino functionally with the acid chloride of the desired ester in the presence of a base in an inert solvent such as methylene chloride or chloroform. Suitable bases include triethylamine or pyridine. In contrast, compounds of the invention having a free carboxy group can be labeled using standard conditions which may include activation followed by treatment with the desired alcohol in the presence of a suitable base. Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic organic and inorganic acid addition salts such as the hydrochloride derived from hydrochloric acid, bromohydrate derived from hydrobromic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from phosphoric acid, sulphate derived from sulfuric acid, formate derived from formic acid, acetate derived of acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cmamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enanthate derived from enanthic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycollate derived from glycolic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from sulphonic methane, naphthalene-2-sulphonate derivative of naphthalene-2-sulfonic acid, phthalate derived from phthalic acid, salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succime derived from succinic acid, tartrate derived from acid tartaric, toluene-p-sulfonate derived from p-toluene sulfonic acid, and the like. Particularly preferred salts are sodium, lysine and Arginine of the compounds of the invention. Such salts can be formed by methods well known and described in the art. Other acids such as oxalic acid, which can not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt. Metal salts of a chemical compound of the invention include alkali metal salts, such as the sodium salt of a chemical compound of the invention containing a carboxy group. In the context of this invention the "onium salts" of N-containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred "onium salts" include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkyl-onium salts. The chemical compound of the invention can be provided in dissolvable or indissoluble forms together with pharmaceutically acceptable solvents such as water, ethanol, and the like. Dissolvable forms can also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, dissolvable forms are considered equivalents for indissoluble forms for the purposes of this invention.

A. Tereoisomers The chemical compounds of the present invention can exist in (+) and (-) forms as well as in racemic forms. The racemates of these isomers and the individual isomers per se are within the scope of the present invention. Racemic forms can be resolved at optical antipodes by known methods and techniques. One way to separate the diastereomeric salts is by the use of an optically active acid, and to release the optically active amine compound by treatment with a base. Another method for resolving racemates in the optical antipodes is based on chromatography in an optically active matrix. The racemic compounds of the present invention can thus be resolved in their optical antipodes, for example, by fractional crystallization of d- or 1- (tartrate, mandelate, or camphorsulfonate) salts for example. The chemical compounds of the present invention can also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an activated optically active carboxylic acid such as the derivatives of (+) or (-) phenylalanine, (+ ) or (-) femlglicma, (+) or (-) acid canfánico or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like. Additional methods for the solution of optical isomers are known in the art. Such methods include those described by Jaques J, Collet A, and ilen S m "Enaptiomers, Racema tes, and Resol utions", John Wiley and Sons, New York (1981). The optically active compounds can be prepared from optically active starting materials. In addition, some of the chemical compounds of the invention being oximes, can thus exist in two forms, form syn- and anti- (form Z- and E-), depending on the agreement of the substituents throughout the double bond -C = N-. A chemical compound of the present invention can thus be the syn- or anti-form (Z- and E- form), or it can be a mixture thereof. It will be understood that both forms syn- and anti- (form Z- and E-) of a particular compound is within the scope of the present invention, even when the compound is represented herein (ie, through the nomenclature or the pattern of the molecule) in one form or the other. It will be understood that all compounds of Formulas 1, 2, 3 and 4 described above will also include double bonds between adjacent atoms as required to satisfy the valence of each atom. That is, double bonds are add to provide the following number of double bonds to each of the following types of atoms: carbon: four bonds; nitrogen: three bonds; oxygen; two links; and sulfur; two-six links. In another embodiment, the invention relates to gate ion channel modulators of the invention, including salts thereof, for example, pharmaceutically acceptable salts. Particular embodiments of the invention relate to the modulator compounds of the invention, or derivatives thereof, including salts thereof, for example, pharmaceutically acceptable salts. In yet another embodiment, the invention pertains to pharmaceutical compositions comprising compounds that modulate the gate ions channel described herein and an acceptable pharmaceutical carrier. In another embodiment, the invention includes any novel compound or pharmaceutical compositions containing compounds of the invention described herein. For example, compounds and pharmaceutical compositions containing compounds set forth herein (e.g., compounds of the invention) are part of this invention, including salts thereof, e.g., pharmaceutically acceptable salts.

Tests The present invention relates to a method for modulating the activity of the gate ion channel. As used herein, the various forms of the term "modulated" include stimulation (e.g., increasing or upregulating a particular response or activity) and inhibition (e.g., lowering or downregulating a particular response or activity). In one aspect, the methods of the present invention comprise contacting a cell with an effective amount of a gate ion channel modulator compound, eg, a compound of the invention, thereby modulating the activity of an ion channel. of gate. In certain embodiments, the effective amount of the compound of the invention inhibits the activity of the gate ion channel. The gate ion channels of the present invention comprise at least one subunit that belongs to the DEG / ENaC, TRPV (also referred to as vanilloid) and / or super-boarder of the P2X gene. In one aspect the gate ion channel is comprised of at least one subunit selected from the group consisting of ENaC, ßENaC,? ENaC, dENaC, ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, ASIC4, BLINaC, hINaC,, P2X1 ( P2X2, P2X3, P2X4, P2X5, P2X6, P2X7, TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6 In one aspect, the gate ion channel DEG / ENaC is comprised of at least one subunit selected from the group consisting of from aANaC, ßENaC,? ENaC, dENaC, BLINaC, hINaC, ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4. In certain embodiments, the gate ion channel DEG / ENaC is comprised of at least one subunit selected from the group consisting of ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4. In certain embodiments, the gate ion channel is comprised of ASICla, ASIClb, or ASIC3.

In another aspect of the invention, gate ion channel P2X is comprised of at least one subunit selected from the group consisting of P2XX, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7. In yet another aspect of the invention, the TRPV gate ion channel is comprised of at least one subunit selected from the group TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6. In another aspect, the gate ion channel is a heteromultimer gate gate ion channel, including, but not limited to, aENaC, ßENaC and? ENaC; aANaC, ßENaC and dENaC; ASICla and ASIC2a; ASICla and ASIC2b; ASICla and ASIC3; ASIClb and ASIC3; ASIC2a and ASIC2b; ASIC2a and ASIC3; ASIC2b and ASIC3; ASICla, ASIC2a and ASIC3; ASIC3 and P2X, for example P2X1 (P2X2, P2X3, P2X4, P2X5, P2XS and P2X7, preferably ASIC3 and P2X2; ASIC3 and P2X3; and ASIC3, P2X2 and P2X3; ASIC4 and at least one of ASICla, ASIClb, ASIC2a, ASIC2b, and ASIC3; BLINaC (or hINaC) and at least one of ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4; dENaC and ASIC, for example ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3 and ASIC4; P2XX and P2X2, P2XX and P2X5, P2X2 and P2X3, P2X2 and P2X5, P2X4 and P2X6, TRPVl and TRPV2, TRPV5 and TRPV6, TRPVl and TRPV4.

Assays for determining the ability of a compound within the scope of the invention to modulate the activity of gate ions channels are well known in the art and are described herein in the Examples section. Other tests to determine the ability of a compound to modulate the activity of a gate ion channel are also readily available to the skilled artisan. The modulators of the gate ion channel of the invention can be identified using the following exclusion method, which method comprises the subsequent steps of (i) subjecting a cell containing a gate ion channel to the action of an activator selective, for example, protons by adjusting the pH to an acidic level, ATP by diluting sufficient quantities of ATP in the perfusion buffer or temperature by heating the perfusate buffer to temperatures above 37 ° C; (n) submitting a cell containing gate ions channel for the action of the chemical compound (the compound can be co-applied, pre-applied or post-applied); and (ni) monitoring the change in membrane potential or ionic current induced by the activator, e.g., protons, in the cell containing the gate ions channel. Alternatively, fluorescent imaging can be used to monitor the effect induced by the activator, for example, protons, in the cell containing the gate ion channel.

Cells containing the gate ion channel can be subjected to the action of protons by adjusting the pH to an acid level using any convenient buffer or acid, including organic acids such as formic acid, acetic acid, citric acid, acid Ascorbic acid, 2-morpholine methane sulfonic acid (MES) and lactic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid and nitric acid, percolop acid and phosphoric acid. In the methods of the invention, the current flow induced by the activator, for example, protons, through the membrane of the cell containing the gate ion channel can be monitored by electrophysiological methods, for example zoning techniques. or two-electrode voltage amplification. Alternatively, the change in membrane potential induced by the gate ion channel activators, eg, protons of the cell containing the gate ion channel can be monitored using fluorescence methods. When fluorescence methods are used, the cell containing the gate ion channel is incubated with a membrane potential indicating that the agent allows for a determination of changes in the membrane potential of cells, caused by aggregated activators, for example, protons. Such a membrane potential indicates that the agents include fluorescent indicators, preferably D? BAC4 (3), D? OC5 (3), D? OC2 (3), D? SBAC2 (3) and FMP pigments (membrane potential FLIPR).

(Molecular Devices). In another alternative embodiment, the change in gate ion channel activity induced by activators, e.g., protons, in the gate ions channel can be measured by evaluating changes in the cell concentration of certain ions, for example , calcium, sodium, potassium, magnesium, protons, and chloride in cells by fluorescence. Fluorescence assays can be performed on multiple well plates using plate readers, eg, FLIPR assay (Fluorescence Imaging Plate Reader) available from Molecular Devices), for example using fluorescent calcium indicators, for example as described in, for example, Sullivan E., et al. (1999) Methods Mol Biol. 114: 125-33, Jerman, J.C., et al. (2000) Br J Pharmacol 130 (4): 916-22, and U.S. Patent No. 6608671, the contents of each of which are incorporated herein by reference. When such fluorescence methods are used, the cell containing the gate ion channel is incubated with a selective ion indicating agent which allows for a determination of changes in the ionic concentration of the ion, caused by the aggregate activators, for example, protons Such ion indicating agents include fluorescent calcium indicators, preferably Fura-2, Fluo-3, Fluo-4, Fluo4FF, Fluo-5F, Fluo-5N, Calcium Green, Fura-Red, Indo-1, Indo-5F, and rod-2, fluorescent sodium indicators, preferably SBFI, Sodium Green, CoroNa Green, fluorescent potassium indicators, preferably PBFI, CD222, fluorescent magnesium indicators, preferably Mag-Fluo-4, Mag-Fura-2, Mag-Fura-5, Mag-Fura-Red, Mag-mdo-1, Mag-ro-2, Magnesium Green, fluorescent chloride indicators, preferably SPQ, Bis-DMXPQ, LZQ, MEQ, and MQAE, fluorescent pH indicators , preferably BCECF and BCPCF. When an indicator agent of the membrane potential is used, the ion gate channel containing the cells is incubated with FMP dye (from Molecular Devices) or other indicators of membrane potential change. The change in membrane potential is measured after the addition of activators, e.g., protons. Compounds that antagonize the gate ions channel of the invention show activity in concentrations below 2M, 1.5M, 1M, 500mM, 250mM, 100mM, 750μM, 500μM, 250μM, 100μM, 75μM, 50μM, 25μM , 10 μM, 5 μM, 2.5.μM, or below 1 μM. In its most preferred embodiment, compounds that antagonize ASIC show activity in the lower micromolar and nanomolar range. As used herein, the term "contact" (i.e., contacting a cell eg, a cell neuronal, with a compound) is intended to include the compound incubated and the cell together m vi tro (e.g., adding the compound to the cells in the culture) or administering the compound to a subject such that the compound and the cells of the subject get in touch m vi vo. The term "contact" is not intended to include exposure of cells to a modulator or compound that may occur naturally in a subject (ie, such exposure may occur as a result of a natural physiological process).

A. In Vitro Assays The gate ion channel polypeptides for use in the assays described herein can be easily produced by standard biological techniques or by chemical synthesis. For example, a host cell transfected with an expression vector containing a nucleotide sequence encoding the desired gate ion channel can be cultured under appropriate conditions to allow expression of the peptide to occur. Alternatively, the gate ion channel can be obtained by culturing a primary cell or an established cell line that can produce the gate ion channel. The methods of the invention can be practiced in vi tro, for example, in an exclusion separation test. of cell-based culture to exclude by exclusion the compounds that link, activate or potentially modulate the function of the gate ions channel. In such a method, the modulator compound can function by interacting with and removing any specific function of the gate ion channel in the sample or culture. Modulator compounds can also be used to control the activity of the gate ion channel in neuronal cell culture. Cells for use in m vi tro assays, in which the gate ions channels occur naturally, include several cells, such as cortical neuronal cells, in particular mouse or rat cortical neuronal cells, and human embryonic kidney cells ( HEK), in particular the HEK293 cell line. For example, cells can be cultured from human embryonic cells, human neonatal cells, and adult human cells. Primary cell cultures can also be used in the methods of the invention. For example, sensory neuronal cells can also be isolated and cultured from different animal species. The most widely used protocols use sensory neurons isolated from neonatal rat (Eckert, et al (1997) J Neurosci Methods 77: 183-190) and embryonic (Vasko, et al. (1994) J Neurosa 14: 4987-4997). The sensory neurons of the tpgermmal and dorsal root ganglion in culture show certain characteristics of sensory neurons m alive.

Alternatively, the gate ion channel, for example, a gate channel, eg, a proton gate ion channel, may be exogenous to the cell in question, and may in particular be introduced by recombinant DNA technology. , such as transfection, microinjection or infection. Such cells include hamster ovary cells Chinese (CHO), HEK cells, green monkey kidney cell line African (CV-1 or COS cells derived from CV-1, for example COS-1 and COS-7) oocytes from Xenopus laevis, or any other cell lines capable of expressing the gate ions channels. The nucleotide and amino acid sequences of the gate ion channels of the invention are known in the art. For example, the sequences of the channel with human gates can be found in Access to Genbank Gl Nos .: GI: 40556387 (ENaCalpha Homo sapiens); Gl 4506815 (ENaCalpha Homo sapiens); Gl = 4506816 (ENabeta Homo sapiens); Gl: 4506817 (ENabeta Homo sapiens); GI: 34101281 (ENaCdelta Homo sapiens); GI: 34101282 (ENaCdelta Homo sapiens); GI: 42476332 (ENaCgamma Homo sapiens); GI: 42476333 (ENaCgamma Homo sapiens); GI: 31442760 (HINAC Homo sapiens); GI: 31442761 (HINAC Homo sapiens); Gl: 21536350 (ASICla Homo sapiens); GI: 21536351 (ASICla Homo sapiens); Gl: 21536348 (ASIClb Homo sapiens); GI: 21536349 (ASIClb Homo sapiens); GI: 34452694 (ASIC2, transcript variant 1 of Homo sapiens); GI: 34452695 (ASIC2; isoform 1 of Homo sapiens); GI: 34452696 (ASIC2, variant of transcript 2 of Homo sapiens); GI: 9998944 (ASIC2, isoform 2 of Homo sapiens); GI: 4757709 (ASIC3, variant of transcript 1 of Homo sapiens); GI-4757710 (ASIC3, isoform 1 of Homo sapiens); GI: 9998945 (ASIC3; variant of transcript 2 of Homo sapiens); Gl: 9998946 (ASIC3; isoform 2 from Homo sapiens); Gl: 9998947 (ASIC3; transcript variant 3 from Homo sapiens); Gl: 9998948 (ASIC3; isoform 3 Homo sapiens); GI: 33519441 (ASIC4, variant of transcript 1 of Homo sapiens); GI: 33519442 (ASIC4, isoform 1 of Homo sapiens); Gl: 33519443 (ASIC4, variant of transcript 2 of Homo sapiens); GI: 33519444 (ASIC4, isoform 2 of Homo sapiens); GI: 27894283 (P2XX of Homo sapiens); GI: 4505545 (P2XX of Homo sapiens); GI: 28416917 (P2X2, transcript variant 1 of Homo sapiens); GI: 25092719 (P2X2, isoform A of Homo sapiens); GI: 28416922 (P2X2; variant of transcript 2 of Homo sapiens); GI: 28416923 (P2X2; isoform B from Homo sapiens); Gl: 28416916 (P2X2; variant of transcript 3 of Homo sapiens); GI: 7706629 (P2X2, isoform C of Homo sapiens); Gl: 28416918 (P2X2; variant of transcript 4 of Homo sapiens); Gl: 25092733 (P2X2; D isoform of Homo sapiens); Gl: 28416920 (P2X2; variant of transcript 5 of Homo sapiens); GI: 28416921 (P2X2; H isoform of Homo sapiens); Gl 28416919 (P2X2, variant of transcript 6 of Homo sapiens); Gl -27881423 (P2X2, isoform I from Homo sapiens); GI: 28416924 (P2X3 from Homo sapiens); GI: 28416925 (P2X3 of Homo sapiens); Gl: 28416926 (P2X4, variant of transcript 1 of Homo sapiens); GI: 28416927 (P2X4, isoform A of Homo sapiens); Gl: 28416928 (P2X4; variant of transcript 2 of Homo sapiens); GI: 28416929 (P2X4, isoform B of Homo sapiens); GI: 28416930 (P2X4, variant of transcript 3 of Homo sapiens); GI: 28416931 (P2X4; C isoform of Homo sapiens); Gl = 28416932 (P2X5; variant of transcript 1 of Homo sapiens); GI: 28416933 (P2X5, isoform A of Homo sapiens); Gl: 28416934 (P2X5, variant of transcript 2 of Homo sapiens); GI: 28416935 (P2X5, isoform B of Homo sapiens); GI: 28416936 (P2X5; variant of transcript 3 of Homo sapiens); GI: 28416937 (P2X5, isoform C of Homo sapiens); Gl: 38327545 (P2X6 Homo sapiens); GI: 4885535 (P2X6 Homo sapiens); GI: 34335273 (P2X7, transcript variant 1 of Homo sapiens); GI: 29294631 (P2X7, isoform A of Homo sapiens); Gl: 34335274 (P2X7; variant of transcript 2 of Homo sapiens); GI: 29294633 (P2X7, B isoform of Homo sapiens); GI: 18375666 (TRPVl, transcript variant 1 of Homo sapiens); Gl: 18375667 (TRPVl; vanilloid receptor of subtype 1 of Homo sapiens); GI: 18375664 (TRPVl; variant of transcript 2 of Homo sapiens); GI: 18375665 (TRPVl; vanilloid receptor of subtype 1 of Homo sapiens); GI: 18375670 (TRPVl; variant of transcript 3 of Homo sapiens); GI: 18375671 (TRPVl, vanilloid receptor of subtype 1 of Homo sapiens); Gl: 18375668 (TRPV1; variant of transcript 4 of Homo sapiens); Gl: 18375669 (TRPVl; vanilloid receptor of subtype 1 of Homo sapiens); GI: 7706764 (VRL-1, transcript variant 1 of Homo sapiens); Gl: 7706765 (VRL-1; vanilloid receptor-like protein 1 from Homo sapiens); Gl: 22547178 (TRPV2, variant of transcript 2 of Homo sapiens); GI: 20127551 (TRPV2, vanilloid receptor 1 type protein from Homo sapiens); GI: 22547183 (TRPV4, variant of transcript 1 of Homo sapiens); GI: 22547184 (TRPV4, isoform A of Homo sapiens); GI: 22547179 (TRPV4; transcript variant 2 of Homo sapiens); GI: 22547180 (TRPV4; isoform B of Homo sapiens); GI: 21361832 (TRPV5 of Homo sapiens); Gl: 17505200 (TRPV5 of Homo sapiens); GI: 21314681 (TRPV6 of Homo sapiens); GI: 21314682 (TRPV6 of Homo sapiens); Gl: 34452696 (ACCN1, transcript variant 2 of Homo sapiens). The contents of each of these registers are incorporated herein by reference. Additional entity, sequences for channels of other species are readily available and obtainable by those skilled in the art. A nucleic acid molecule encoding a gate ions channel for use in the methods of the present invention can be amplified using cDNA, mRNA, or genomic DNA as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The amplified nucleic acid can be cloned into an appropriate vector and characterized by analysis of DNA sequences. Using all or a portion of such nucleic acid sequences, the nucleic acid molecules of the invention can be isolated using standard cloning and hybridization techniques (eg, as described in US Pat.

Sambrook et al. , ed., Mol ecular Cloning: A Labora tory Manual, 2nd ed. , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989). Expression vectors, which contain a nucleic acid encoding a gate ions channel, eg, a gate ions channel subunit protein, eg, protein aENaC, ßENaC,? ENaC, dENaC, ASICla, ASIClb , ASIC2a, ASIC2b, ASIC3, ASIC4, BLINaC, hINaC, P2X ?, P2X2, P2X3, P2X4, P2X5, P2X6, P2X7, TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6 (or a portion thereof) are enter into cells using standard techniques and operably linked to the regulatory sequence. Such regulatory sequences are described, for example, in Goeddel, Me thods in Enzymology: Gene Expression Technology vol.185, Academic Press, San Diego, CA (1991). Regulatory sequences include those that direct the constitutive expression of a nucleotide sequence in many types of host cells and those that direct the expression of the nucleotide sequence only in certain host cells (for example, specific regulatory sequences in tissues).

It will be appreciated by those skilled in the art that the designation of the expression vector may depend on such factors such as the choice of the host cell to be transformed, the level of expression of the desired protein, and the like. The expression vectors of the invention can be introduced into host cells to which they produce proteins or peptides, including proteins or fusion peptides, encoded by nucleic acids as described herein. Examples of vectors for expression in yeast S. cerevi siae include pYepSecl (Baldan et al., 1987, EMBO J. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982, Cell 30: 933-943), pJRY88 (Schultz et al., 1987, Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, CA), and pPicZ (Invitrogen Corp, San Diego, CA). Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al., 1983, Mol. Cell Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989, Virology 170: 31-39). Examples of mammalian expression vectors include pCDM8 (Seed, 1987, Nature 329,840), pMT2PC (Kaufman et al., 1987, EMBO J. 6: 187-195), pCADN3. When used in mammalian cells, the control functions of expression vectors are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, Cytomegalovirus and Simian Virus 40. For other expression systems suitable for eukaryotic cells see chapters 16 and 17 of Sambrook et al.

B. In Vivo Assays The activity of the compounds of the invention as described herein modulates one or more gate ion channel activities (eg, a gate ion channel modulator, eg, a compound of the invention) can be tested in an animal model to determine the efficacy, toxicity, or side effects of treatment with such an agent. Alternatively, an agent identified as described herein may be used in an animal model to determine the mechanism of action of such an agent. Animal models for determining the ability of a compound of the invention to modulate a biological activity of gate ions channel are well known and readily available to those skilled artisans. Examples of animal models for pain and inflammation include, but are not limited to, the models listed in Table 1. Animal models for investigating neurological disorders include, but are not limited to, those described in Morris et al. , (Learn Motiv 1981, 12: 239-60) and Abeliovitch et al. , Cell 1993; 75: 1263-71). An example of an animal model to investigate mental and behavioral disorders is the Geller- Seif er, as described in Psychopharmacology (Berl). 1979 Apr 11, -62 (2).-117-21. Genito-upnapo models include methods to reduce the bladder capacity of test animals by infusion of either protamm sulfate and potassium chloride (See, Chuang, YC et al., Urology 61 (3): 664-670 (2003 )) or dilute acetic acid (See, Sasaki, K. et al., J. Urol. 168 (3): 1259-1264 (2002)) in the bladder. During disorders of the urinary tract involving the bladder using protamine sulfate administered transiently as described in Chuang et al. (2003) Urology 61: 664-70. These methods also include the use of a well-accepted model of urinary tract disorders involving the bladder using acetic acid administered transiently as described in Sasaki et al. (2002) J. Urol. 168: 1259-64. The efficacy to treat patients with spinal cord injuries can be tested using methods as described in Yoshiyama et al. (1999) Urology 54: 929-33. Animal models of neuropathic pain based on injuries inflicted on a nerve (mainly the sciatic nerve) are described in Bennett et al. , 1988, Pain 33: 87-107; Seltzer et al. , 1990, Pam 43: 205-218; Kim et al. , 1992, Pain 50: 355-363; Decosterd et al. , 2000, Pam 87: 149-158 and DeLeo et al. , 1994, Pain 56: 9-16. There are also models of diabetic neuropathy (diabetic neuropathy induced by STZ - Courteix et al., 1994, Pain 57: 153-160) and drug-induced neuropathies. (neuropathy induced by vincpstine - Aley et al., 1996, Neuroscience 73: 259-265; immunotherapy related to oncology, anti-GD2 antibodies - Slart et al. , 1997, Pam 60: 119-125). Acute pain in humans can be reproduced using chemical stimulation of murine animals: Martínez et al. , Pam 81: 179-186; 1999 (the contortion test - mtrapeptoneal acetic acid in mice), Dubuisson et al. Pain 1977; 4: 161-74 (formalin injection). Other types of acute pain models are described in hiteside et al. , 2004, Br J Pharmacol 141: 85-91 (the incision model, a posterior pain surgery model) and Johanek and Si one, 2004, Pam 109: 432-442 (a model of heat injuries). An animal model of inflammatory pain using complete Freunds adjuvant (plantar injection) is described in Jas et al. , 1998, Pain 75: 367-382. Tracapsular injection of irritants (adjuvant Freunds complete, iodoacetate, capsaicma, urate crystals, etc.) is used to develop models of arthritis in animals (Fernihough et al., 2004, Pam 112: 83-93; Coderre and Wall, 1987, Pain 28: 379-393; Otsuki et al. , 1986, Bram Res. 365: 235-240). A model of stress-induced hyperalgesia is described in Quintero et al. , 2000, Pharmacology, Biochemistry and Behavior 67: 449-458. Additional animal models for pain are considered in an article by Waiker et al. 1999 Molecular Medicine Today 5: 319-321, comparing models for different types of pain, which are acute pain, pain chronic / inflammatory and chronic / neuropathic pain, on the basis of behavioral signals. Animal models for depression are described by E. Tatarczynska et al. , Br. J. Pharmacol. 132 (7): 1423-1430 (2001) and P. J. M. Will et al. , Trends m Pharmacological Sciences 22 (7): 331-37 (2001)), models for anxiety are described by D. Treit, "Animal Models for the Study of Anti-anxiety Agents: A Review," Neuroscience & Biobehavioral Reviews 9 (2): 203-222 (1985). Additional animal models for pain are also described herein in the Exemplifications section. The gastrointestinal models can be found in: Gawad, K. A., et al. , Ambulatory long-term pH monitoring in pigs, Surg Endose, (2003); Johnson, S. E. et al. , Esophageal Acid Clearance Test ín Healthy Dogs, Can. J. Vet. Res. 53 (2): 244-7 (1989); and Cicente, Y. et al. , Esophageal Acid Clearance: More Volume-dependent Than Motility Dependent Healthy Piglets, J. Pediatr.

Gastroenterol. Nutr. 35 (2): 173-9 (2002). Models for a variety of setae can be used to assess visceromotor and pain responses for rectal distension. See, for example, Gunter et al. , Physiol. Behav., 69 (3): 379-82 (2000), Depoortere et al. , J. Pharmacol. and Exp. Ther., 294 (3): 983-990 (2000), Morteau et al. , Fund. Clin. Pharmacol., 8 (6): 553-62 (1994), Gibson et al. , Gastroenterology (Suppl 1), 120 (5): A19-A20 (2001) and Gschossmann et al. , Eur. J. Gastro. Hepat. , 14 (10): 1067-72 (2002) the entire contents which are each incorporated herein by reference. Gastrointestinal motility can be evaluated based on either the live recording of mechanical or electrical events associating intestinal muscle contractions in all animals or the activity of gastrointestinal intestinal muscle preparations from in vitro recordings in organ baths (See, for example, Yaun et al., Br. J. Pharmacol., 112 (4): 1095-1100 (1994), Jin et al., J. Pharm. Exp. Ther., 288 (1): 93. -97 (1999) and Venkova et al., J. Pharm. Exp. Ther., 300 (3): 1046-1052 (2002)). Tatersall et al. and Bountra et al. , European Journal of Pharmacology, 250: (1993) R5 and 249: (1993) R3-R4 and Milano et al. , J. Pharmacol. Exp. Ther., 274 (2): 951-961 (1995).

TABLE 1 Thermal Test A focused beam of Nocticeptive Pain Hargreaves light is projected onto a sharp small surface of (Yeomans et al Pain the hind paw of a 1994, 59: 85-94 rat with temperature rise.The withdrawal time is measured. analgesic results in prolonged latency Mechanical Test An increase in nociceptive pin pain or calibrated pressure is acute Randall applies to the leg of (Green et al., Br J Selitto the rats with a Pharmacol 1951; 6: direct pin The 572- 85. Randall et pressure intensity at Arch Int is measured.Pharmacodyn Ther Alternatively 1957; 111: 409-19) Increased pressure is applied to the paw using a clamp until the threshold pain is reached and the animals remove the paw ACUTE TONIC PAIN Chemical Test Formalin inflammatory formalin pain injected into the (Dubuisson et al., Hind paw of Pain 1977; 4: 161-74; animals (rat, mouse) Wheeler-Aceto et al.Psychopharmacology behavior of (Berl) 1991; 104: 35- pain (for example, 44 licking of the paw / unit of time) Chemistry Test Acid is injected visceral pain, acetic rithmg into the peritonitis peritoneal cavity of a rat. The measurement (Loux et al. Of the result is the Arzneimittelforschung number of cramps 1978, 28: 1644-7.) Abdominals per unit of time. A decrease in cramps is evidence of analgesic effect MODELS OF HYPERALGESIS / CHRONIC INFLAMMATORY PAIN MODELS Thermal Hargreaves and / or A Chronic Pain Agent or Randal & Mechanical sensitization (by associated with Selitto example, Freund's adjuvant complete inflammation (CFA), tissues, by carrageenan, turpentine example, pain etc.) is injected into the post-surgical, rats' foot creating (Hargreaves et al. Local and Pain 1988; 32: 77- Sensitization for Mechanical Stimulation Randall LO, (Randall &Selitto) and / or Selitto JJ. Arch Thermal (Hargreaves) 1 are Measured Compared to Pharmacodynl9? > 7; contralateral leg no 3: 409-19 Sensitized Thermal Model The posterior paw of Chronic pain Yeomans rat injected with associated with capsaicma, an inflammatory agent of sensitization to tissues, by small fibers C or DMSO, example, pain a postoperative agent. Surgical sensitization for (Yeomans et al., delta fibers A. A heat Pain 1994; 59: 85- radiant is applied with 94. gradient different from Otsuki et al., stimulated C fibers Bram Res 1986; differentially or fibers 365: 235-240.) delta A and discrimination between the effects mediated by both trajectories MALIGNANT CHRONIC PAIN (CANCER PAIN) Thermal Model and / or In this model, the cancer cancer pain of mechanical cells NCTC2472 of bones Bone mouse sarcoma (Schwei et al. , J. Osteolytic are used for Neuroscí. 1999; induce bone cancer 19: 10886-10897.) by injecting tumor cells into the medulla space of the femur bone and sealing the injection site Model of Thermal and / or Sarcoma Cells Neuropathic pain pain by mechanical Meth A malignant invasion of | around (Shimoyama et al., cancer (CIP) sciatic nerve in Pam 2002; 99: BALB / c mice and 167-174.) These animals develop signs of allodynia and thermal hralgia as tumor growths, which compress the nerve. The spontaneous pain (raised leg) is also visible CHRONIC NON-MALIGNANT PAIN Thermal Pain and / or Mechanical Muscle Fibromyalgia injections repeated from (Sluka et al., Pain saline 2003; 106: 229- acid in a muscle 239.) gastrocnemius produces hypersensitivity long-term, bilateral leg mechanics (this is hyperalgesia) without damage associated with the associated thermal UV radiation and / or the exposure of the mechanical inflammatory pain of the hind paw associated with the UV radiation radiation burns produces first and second allodynia highly reliable v plow Alternatively, the compounds may also be tested in transgenic non-human animals that contain exogenous sequences that encode one or more gate ion channels. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of animals Transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. Methods for generating transgenic animals by embryonic manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in the U.S. Patents. Us. 4,736,866 and 4,870,009, Patent of E.U.A. No. 4,873,191 and in Hogan, Manipulatmg the Mouse Embryo, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986. Similar methods were used for the production of other transgenic animals. A homologous recombinant animal can also be used to test the compounds of the invention. Such animals can be generated according to well-known techniques (see, for example, Thomar and Capecchi, 1987, Cell 51: 503, Li et al., 1992, Cell 69: 915, Bradley, Teratocarchoma and Embryonic Stem Cells: A Practical Approach, Robertson, Ed., IRL, Oxford, 1987, pp. 113-152; Bradley (1991) Current Opinion m Bio / Technology 2: 823-829 and in PCT Publication Nos. WO 90/11354, WO 91/01140 , WO 92/0968, and WO 93/04169). Other useful transgenic nonhuman animals can be produced which contain selected systems which allow regulation of transgene expression (See, for example, Lakso et al. (1992) Proc. Nati, Acad. Sci. USA 89: 6232-6236). Other examples of a recombining system is the FLP recombinase system of Saccharomyces cerevisiae (O'Gorman et al., 1991, Science 251: 1351-1355). Pharmaceutical Compositions The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically (or prophylactically) effective amount of a gate ion channel modulator, and preferably one or more compounds of the invention described above, and a pharmaceutically acceptable carrier or excipient. Suitable pharmaceutically acceptable carriers include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The carrier and composition can be sterile. The formulation must adapt to the mode of administration. The phrase "pharmaceutically acceptable carrier" is recognized in the art and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administration of compounds of the present invention to mammals. The carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying out or transporting the subject agent of an organ, or body portion, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the others ingredients of the formulation and not harmful to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch, - cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients, such as cocoa butter and waxes in suppository; oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, resin oil, tetraglycol and soybean oil; glycols, such as propylene glycol; polyols, such as glycepine, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate; polyethylene glycol ester and ethyl laurate, - agar; buffering agents, such as magnesium hydroxide, sodium hydroxide, potassium hydroxide, carbonates, triethylammolamine, acetates, lactates, potassium citrate and aluminum hydroxide, - alginic acid; pyrogen-free water, - isotonic saline solution; Rmger solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring and flavoring agents, preservatives and antioxidants may also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cistern chlorhydrate, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithm, propyl gallate, α-tocopherol, and derivatives such as vitamin E tocopherol and the like; and metal chelating agents, such as citric acid, ethylenediamma tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, sodium citrate and the like. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions (eg, NaCl), alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, cyclodextrin , magnesium stearate, talc, silicic acid, viscose paraffm, perfume oil, fatty acid esters, hydroxymethylcellulose, polyvinyl pyrrolidone, etc. The pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents, for example, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, dyes, sabotics and / or aromatic substances and the like which do not react deleteriously with the active compounds. The pharmaceutically acceptable carriers may also include a tonicity adjusting agent such as dextrose, glycepna, mannitol and sodium chloride. The composition, if desired, may also contain minor amounts of wetting agents or emulsifiers, or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. The oral formulation may include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrrolidone, sodium saccharin, cellulose, magnesium carbonate, etc. The composition can be formulated according to routine procedures as a pharmaceutical composition adapted for intravenous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. When necessary, the composition can also include a solubilizing agent and a local anesthetic to relieve pain at the site of the injection.

Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as a vial or sachet indicating the amount of active agent. Where the composition will be administered by infusion, this can be dispensed with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose / water. Where the composition is administered by injection, a vial of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration. The pharmaceutical compositions of the invention may also include an agent that controls the release of the modulator compound from the gate ion channel, thus providing a time-release or sustained release composition. The present invention also relates to prodrugs of the gate ion channel modulators, as well as pharmaceutical compositions comprising such prodrugs.

For example, the compounds of the invention which include functional acid groups or hydroxyl groups can be also prepare and administer as a corresponding ester with a suitable alcohol or acid. The ester can then be cleaved by endogenous enzymes within the subject to produce the active agent. The formulations of the present invention include those suitable for oral, nasal, topical, transmucosal, transdermal, buccal, sublingual, rectal, vaginal and / or parenteral administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any method well known in the art of pharmacy.

The amount of active ingredient that can be combined with a carrier material to produce a single dose form will generally have the amount of the compound that produces a therapeutic effect. Generally, out of a hundred percent, this amount can vary from around 1 percent to about ninety-nine percent active ingredient, preferably from about 5 percent to about 70 percent, more preferably from about 10 percent to about 30 percent. Methods for preparing these formulations or compositions include the step of carrying in association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared uniformly and intimately when carrying in association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations of the invention suitable for oral administration may be in the form of capsules, capsules, pills, tablets, lozenges (using a flavor base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as a liquid emulsion oil in water or water in oil, or as an elixir or syrup, or as a tablet (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth rinses and the like, each contains a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention can also be administered as a bolus, electuape or paste. In solid dose forms of the invention for oral administration (capsules, tablets, pills, pills, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; hemectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; delaying solution agents, such as paraffm; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; sorbents, such as kaolin clay and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, dism. example, sodium starch glycolate or crosslinked sodium carboxymethyl cellulose), surface active or dispersing agent. The molding tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets, and other solid dose forms of the pharmaceutical compositions of the present invention, such as pills, capsules, pills and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other well-known coatings in the pharmaceutical formulation technique. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying portions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres.

They can be sterilized by, for example, filtration through a bacteria retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. . These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredients only, or preferentially, in a certain portion of the composition. gastrointestinal tract, optionally, in a delayed form. Examples of embedded compositions that may be used include polymeric substances and waxes. The active ingredient may also be in micro-encapsulated form, if appropriate, with one or more of the excipients described above. Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cotton, peanut, corn, germ, olive, resinous and sesame oils), glycerol, alcohol of tetrahydrofuryl, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, agents sweeteners, sabopzantes, colorantes, perfumes and preservatives. The suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcpstamma cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectal or vaginal cavity and release the active compound. Formulations of the present invention which are suitable for vaginal administration also include lozenges, buffers, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be blended under sterile conditions with a pharmaceutically acceptable carrier, and with any of the preservatives, buffers, or propellants that may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof Powders and sprays may contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain ordinary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the additional advantage of providing controlled release of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The ratio of such a flux can be controlled by either providing a controlled membrane ratio or dispersing the active compound in a polymer or gel matrix. Ophthalmic formulations, ointments for eye, powders, solutions and the like are also contemplated to be within the scope of this invention. The pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted in sterile solutions. injectables or dispersions just before use, which may contain antioxidants, buffer solutions, bacteriostats, solutes that make the formulation isotonic with the blood of the intended recipient or suspending agents or thickeners. Examples of suitable aqueous or non-aqueous carriers that can be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as a lecithm, for the maintenance of the required particle size in the case of dispersions, and for the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be carried around the inclusion of agents that retard absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, slow absorption of the subcutaneous or intramuscular injection drug is desirable. This can be done by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The absorption ratio of the drug then depends on its dissolution ratio which, in turn, may depend on the size of the crystal and crystalline form. Alternatively, the delayed absorption of a drug form administered parenterally, it is carried out by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the drug to the polymer, and the nature of the particular polymer employed, the release rate of the drug can be controlled.

Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissue.

Methods of Administration The invention provides a method for treating a condition mediated by a gate ion channel activity, including, but not limited to, pain, inflammatory disorders, respiratory disorders, neurological disorders, gastrointestinal disorders and genitourinary disorders. The method comprises the step of administering to the subject a therapeutically effective amount of a gate ion channel modulator. The condition to be treated can be any condition that is mediated, at least in part, by the interaction of a gate ion channel (for example, ASICla and / or ASIC3). The amount of a given compound to be administered will be determined on an individual basis and will be determined, at least in part, by considering the size of the individual, the severity of the symptoms to be treated and the outcome sought. The gate ion channel activity modulators described herein may be administered alone or in a pharmaceutical composition comprising the modulator, an acceptable carrier or diluent and, optionally, one or more additional drugs. These compounds can be administered to humans and other animals for therapy by any suitable route of administration. The gate ion channel modulator can be administered subcutaneously, intravenously, parenterally, mtraperitoneally, metadermally, muscularly, topically, enterally (eg, orally), rectally, nasally, buccally, sublmgually, systemically, vammally, by dew-inhalation. , by pumping drug or by means of an implant vessel in dosage formulations containing carriers or vehicles physiologically acceptable, conventional non-toxic. The preferred method of administration is by oral delivery. The way in which this is administered (eg, syrup, elixir, capsule, tablet, solution, foams, emulsion, gel, sol) will depend in part on the way in which this is administered. For example, for mucosal administration (eg, oral mucosa, rectal mucosa, intestinal mucosa, bronchial mucosa), nose drops, aerosols, inhalants, nebulizers, drops for o or suppositories can be used.

The compounds and agents of this invention can be administered together with other biologically active agents, such as analgesics, eg, opiates, anti-inflammatory agents, eg, NSAIDs, anesthetics and other agents that can control one or more symptoms or causes of a condition mediated by the gate ions channel. In a specific embodiment, it may be desirable to administer the agents of the invention locally to a localized area in need of treatment, - this can be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, Transdermal patches, by injection, by means of a catheter, by means of a suppository, or by means of an implant, the implant is of a porous, non-porous or gelatinous material, including membranes, such as sialistic membranes or fibers. For example, the agent can be injected into the joints or urinary bladder. The compounds of the invention can, optionally, be administered in combination with one or more additional drugs which, for example, are known to treat and / or alleviate symptoms of the condition mediated by a gate ion channel (eg, ASICla and / or ASIC3). The additional drug can be administered simultaneously with the compound of the invention, or sequentially. For example, the compounds of the invention can be administered in combination with at least one analgesic, an anti-inflammatory agent, an anesthetic, a corticosteroid (eg, dexamethasone, treatment with beclomethasone diproprionate).

(BDP)), an anti-convulsant, an anti-depressant, an anti-nausea agent, an anti-psychotic agent, a cardiovascular agent (eg, a beta-blocker) or a cancer therapeutic. In certain embodiments, the compounds of the invention are administered in combination with a pain drug. As used herein, "pain medication" is intended to refer to analgesics, anti-mflamatory agents, anesthetics, corticosteroids, antiepileptics, barbiturates, antidepressants, and marijuana. The aforementioned combination treatments may be initiated before, concurrent with, or after administration of the compositions of the present invention. Accordingly, the methods of the invention may further include the step of administering a second treatment, such as a second treatment for the disease or disorder or to improve side effects of other treatments. Such second treatment may include, for example, anti-inflammatory medication and any treatment aimed at the treatment of pain.

Additionally or alternatively, in addition the treatment may include administration of drugs to further treat the disease or to treat a side effect of the disease or other treatments (eg, anti-nausea drugs, anti-mflamatory drugs, anti-depressants, anti-malarial drugs). -psiquiátpcos, anti-convulsivos, spheroids, cardiovascular drugs, and cancer chemotherapeutics). As used herein, an "analgesic" is an agent that relieves pain or reduces pain or any signs or symptoms thereof (e.g., hyperalgesia, allodynia, dysesthesia, hyperesthesis, hyperpathia, paresthesia) may result in the reduction of inflammation, for example, an anti-mflamatory agent. Analgesics can be subdivided into NSAIDs (non-spheroidal anti-inflammatory agents), narcotic analgesics, including opioid analgesic and non-narcotic analgesics. The NSAIDs can further be subdivided into non-selective COX (cyclooxygenase) inhibitors, and selective COX2 inhibitors. Opioid analgesics may be natural, synthetic or semi-synthetic opioid analgesics, and include for example morphine, codeine, meperidine, propxifen, oxycodone, hydromorphone, heroin, tramadol, and fentanyl. Non-opioid analgesics (also called non-opioid analgesics) include, for example, acetammofen, clonidine, NMDA antagonists, vanilloid receptor antagonists (eg, TRPVl antagonists), pregabalm, endocannabinoids and cannabinoids. Non-selective COX inhibitors include, but are not limited to acetylsalicylic acid (ASA), ibuprofen, naproxen, ketoprofen, piroxicam, etodolac, and bromfenac. Selective C0X2 inhibitors include, but are not limited to celecoxib, valdecoxib, parecoxib, and etoricoxib. As used herein an "anesthetic" is an agent that interferes with sensory perception, near the site of administration, a local anesthetic, or that results in alteration or loss of consciousness, for example, systemic anesthetic agents. Local anesthetics include but are not limited to lidocaine and buvicaine. Non-limiting examples of antiepileptic agents are carbamazepine, phenytoin and gabapentin. Non-limiting examples of antidepressants are amitriptyline and desmethylimiprimine. Non-limiting examples of anti-inflammatory drugs include corticosteroids (eg, hydrocortisone, cortisone, prednisone, prednisolone, methyl prednisone, triamcinolone, fluprednisolone, betamethasone, and dexamethasone), salicylates, NSAIDs, antihistamines, and H2 receptor antagonists.

The phrases "parenteral administration" and "parenterally administered" as used herein means modes of administration other than enteral or topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, mtrathecal, intracabular, intra-orbital injection , mtracardiaca, mtradermal, mtraperitoneal, transtracheal, subcutaneous, subcuticular, mtraarticular, subcapsular, subarachnoid, mtrasternal, and infusion. The phrases "systemic administration," "systemically administered," "peripheral administration" and "peripherally administered" as used herein means the administration of a compound, drug or other material different directly to the central nervous system, such that it enters the system of the subject and, thus, is subject to metabolism and other types of processes, for example, subcutaneous administration. Regardless of the route of administration selected, the compounds of the present invention, which can be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated in pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. experts in the art.

The current dose levels of the active ingredients in the pharmaceutical compositions of this invention can be varied in order to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular object, composition, and mode of administration, without be toxic to the subject. The selected dose level will depend on a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the excretion ratio of the particular compound employee, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and medical history of the subject being treated, and similar factors well known in the art. medical technique A physician or veterinarian having ordinary skill in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition.

For example, the dose of a compound of the invention can be determined by deriving dose response curves using an animal model for the condition to be treated.

For example, the doctor or veterinarian would initiate the dose of the compounds of the invention used in the composition Pharmaceutical at levels lower than those required in order to achieve the desired therapeutic effect and gradually increases the dose until the desired effect is reached. In general, an adequate daily dose of a compound of the invention will be such an amount of the compound that is the lowest effective dose to produce a therapeutic effect.

Such an effective dose will generally depend on the factors described above. Generally, the intravenous and subcutaneous dosages of the compounds of this invention for a subject, when used for the indicated analgesic effects, can range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 100 mg per kg per day, and still more preferably from about 1.0 to about 50 mg per kg per day. An effective amount is the amount treated by the state associated with the gate ions channel or the gate ions channel disorder. If desired, the effective daily dose of the active compound can be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in the form of unit doses.

While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition.

Methods of Treatment The above compounds can be used for administration to a subject for the modulation of an activity mediated by the gate ions channel, involved in, but not limited to, pain, inflammatory disorders, neurological disorders, and any abnormal function of cells, organs, or physiological systems that are modulated, at least in part, by an activity mediated by the gate ions channel. Additionally, it will be understood that the compounds may also alleviate or treat one or more additional symptoms of a disease or disorder discussed herein. Accordingly, in one aspect, the compounds of the invention can be used to treat pain, including acute, chronic pain, malignant and non-malignant somatic pain (including skin pain and deep somatic pain), visceral pain, and neuropathic pain. It will further be understood that the compounds may also alleviate or treat one or more additional signs or symptoms of pain and sensory deficits (eg, hyperalgesia, allodynia, dysesthesia, hyperesthesia, hyperpathia, paresthesia).

In some embodiments of this aspect of the invention, the compounds of the invention can be used to treat somatic or cutaneous pain associated with injuries, inflammation, diseases, and disorders of the skin and related organs including, but not limited to, cuts. , burns, lacerations, punctures, incisions, surgical pain, post-operative pain, orodental surgery, psoriasis, eczema, dermatitis, and allergies. The compounds of the invention can also be used to treat somatic pain associated with malignant and non-malignant neoplasm of the skin, and related organs (eg, melanoma, basal cell carcinoma). In other embodiments of this aspect of the invention, the compounds of the invention can be used to treat deep somatic pain associated with injuries, inflammation, diseases and disorders of musculoskeletal and connective tissues including, but not limited to, arthralgias, myalgias, fíbromialgias, myofascial pain syndrome, dental pain, low back pain, pain during delivery and delivery, surgical pain, pain after an operation, headaches, migraine, idiopathic pain disorder, sprains, fractures bone, bone injury, osteoporosis, severe burns, gout, arthritis, osteoarthritis, myositis, and dorsopathies. { for example, spondylolysis, subluxation, sciatica, and torticollis). The Compounds of the invention can also be used to treat deep somatic pain associated with malignant and non-malignant neoplasm of the musculoskeletal and connective tissues (eg, sarcomas, rhabdomyosarcomas, and bone cancer). In other embodiments of this aspect of the invention, the compounds of the invention can be used to treat visceral pain associated with injuries, inflammation, diseases or disorders of the circulatory system, the respiratory system, the genitourinary system, the gastrointestinal system and the oo, ears, nose and throat For example, the compounds of the invention can be used to treat visceral pain associated with injuries, inflammation and disorders of the circulatory system including, but not limited to, ischemic diseases, ischemic heart disease (eg, angina pectoris, acute myocardial infarction, coronary thrombosis, coronary insufficiency), diseases of the blood and lymphatic vessels (e.g. eg, peripheral vascular disease, intermittent claudication, varicose veins, hemorrhoids, embolism or thrombosis of the veins, phlebitis, thrombophlebitis lymphadenitis, lymphangitis), and visceral pain associated with malignant and non-malignant neoplasm of the circulatory system (eg, lmfornas, myelomas , disease Hodgkm In another example, the compounds of the invention can be used to treat visceral pain associated with injuries, inflammation, diseases and disorders of the respiratory system including, but not limited to, upper respiratory infections (eg, nasophagitis, sinusitis, and rhinitis), influenza, pneumonia (eg, bacterial, viral, parasitic and fungal), lower respiratory infections (eg, bronchitis, bronchiolitis, tracheobronchitis), interstitial lung disease, emphysema, bronchiectasis, asthmatic state, asthma, pulmonary fibrosis, chronic obstructive pulmonary diseases (COPD), diseases of the pleura, and visceral pain associated with malignant and non-malignant neoplasm of the respiratory system (eg, small cell carcinoma, lung cancer, neoplasm of the trachea, larynx) In another example, the compounds of the invention can be used to treat visceral pain associated with lesions, inflammation and disorders of the gastrointestinal system that includes, but is not limited to, injuries, inflammation, and disorders of the teeth and oral mucosa (eg, broken tooth, dental caries, periodontal disease, oral thrush, pulpitis, gingivitis, periodontitis, and stomatitis), of the esophagus, stomach and duodenum (eg, ulcers, dyspepsia, oesophagitis, gastritis, duodenitis, diverticulitis and appendicitis), of the intestines (eg, Crohn, paralytic ileus, intestinal obstruction, irritable bowel syndrome, neurogenic bowel, megacolon, inflammatory bowel disease, ulcerative colitis, and gastroenteritis), peritoneum (for example, peritonitis), liver (eg, hepatitis, necrosis of liver, liver infarction, hepatic veno-occlusive diseases), gall bladder, biliary tract and pancreas (eg, cholelithiasis, cholecystolithiasis, choledocholithiasis, cholecystitis, and pancreatitis), functional abdominal pain syndrome (FAPS), gastrointestinal motility, as well as visceral pain associated with malignant and non-malignant neoplasm of the gastrointestinal system (for example, neoplasm of the esophagus, stomach, small intestine, colon, liver and pancreas). In another example, the compounds of the invention can be used to treat visceral pain associated with injury, inflammation, diseases, and disorders of the genitourinary system including, but not limited to, injury, inflammation, and kidney disorders (e.g. , nephrolithiasis, glomerulonephritis, nephritis, interstitial nephritis, pyelitis, pyelonephritis), urinary tract (for example, including urolithiasis, uretitis, urinary tract infections), bladder (for example, cystitis, neuropathic bladder, neurogenic bladder dysfunction, overactive bladder, obstruction of the bladder neck), male genital organs (eg, prostatitis, orchitis and epididymitis), female genital organs (eg, pelvic inflammatory disease, endometriosis, dysmenorrhea, ovarian cysts), as well as pain associated with malignant and non-malignant neoplasm of the genitourinary system (eg, neoplasm of the bladder, prostate, breast, ovaries). In further embodiments of this aspect of the invention, the compounds of the invention can be used to treat neuropathic pain associated with injury, inflammation, diseases and disorders of the nervous system, including the central nervous system and peripheral nervous systems. Examples of such lesions, inflammation, diseases or disorders associated with neuropathic pain include, but are not limited to, neuropathy (eg, diabetic neuropathy, drug induced neuropathy, radiotherapy-induced neuropathy), neuritis, radiculopathy, radiculitis, diseases neurodegenerative (eg, muscular dystrophy), spinal cord injury, peripheral nerve injury, nerve injury associated with cancer, Morton's neuroma, headache (eg, non-organic chronic headache, headache type tension, group headache and migraine), multiple somatization syndrome, post-herpetic neuralgia (zoster), complex regional pain syndrome of trigeminal neuralgia (Also known as causalgia or Sympathetic Dystrophy Reflects), radiculalgia, phantom limb pain, chronic head pain, nerve trunk pain, sematoform pain disorder, central pain, non-cardiac pain, central pain after stroke. In another aspect, the compounds of the invention can be used to treat inflammation associated with lesions, diseases or disorders of the skin, subcutaneous tissues and related organs, the musculoskeletal and connective tissue system, the respiratory system, the circulatory system, the genitourinary system and the gastrointestinal system. In some embodiments of this aspect of the invention, examples of inflammatory conditions, diseases or disorders of the skin, and related organs that can be treated with the compounds of the invention include, but are not limited to, allergies, atopic dermatitis, psoriasis, and dermatitis In other embodiments of this aspect of the invention, the inflammatory conditions, diseases or disorders of the musculoskeletal and connective tissue system that can be treated with the compounds of the invention include, but are not limited to, arthritis, osteoarthritis, and myositis. In other embodiments of this aspect of the invention, inflammatory conditions, diseases or disorders of the Respiratory systems that can be treated with the compounds of the invention include, but are not limited to, allergies, asthma, rhinitis, neurogenic inflammation, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, nasophagitis, sinusitis, and bronchitis. In yet other embodiments of this aspect of the invention, the inflammatory conditions, disease or disorders of the circulatory system that can be treated with the compounds of the invention include, but are not limited to, endocarditis, pericarditis, myocarditis, phlebitis, lymphadenitis and atherosclerosis. . In further embodiments of this aspect of the invention, the inflammatory conditions, diseases or disorders of the genitourinary system that can be treated with the compounds of the invention include, but are not limited to, inflammation of the kidney (eg, nephritis, interstitial nephritis). ), bladder (eg, cystitis), urethra (eg, urethritis), male genitalia (eg, prostatitis), and female genitalia (eg, pelvic disease) inflammatory). In further embodiments of this aspect of the invention, inflammatory conditions, diseases or disorders of the gastrointestinal system that can be treated The compounds of the invention include, but are not limited to, gastritis, gastroenteritis, colitis (eg, ulcerative colitis), inflammatory bowel syndrome, Crohn's disease, cholecystitis, pancreatitis and appendicitis. In still further embodiments of this aspect of the invention, inflammatory conditions, diseases or disorders that can be treated with the compounds of the invention, but are not limited to inflammation associated with microbial infections (eg, bacterial, viral and fungal infections). ), physical agents (eg, burns, radiation, and trauma), chemical agents (for example, toxins and caustic substances), tissue necrosis and various types of immunological reactions and autoimmune diseases (for example, Lupus erythematosus). In another aspect, the compounds of the invention can be used to treat lesions, diseases or disorders of the nervous system including, but not limited to neurodegenerative diseases (eg, Alzheimer's disease, Duchenne's disease), epilepsy, sclerosis multiple, amyotrophic lateral sclerosis, stroke, cerebral ischemia, neuropathies (eg, neuropathy induced by chemotherapy, diabetic neuropathy), degeneration of retmal pigment, central nervous system trauma (eg, spinal cord injury), and cancer of the system nervous (eg, neuroblastoma, retinoblastoma, brain cancer, and glioma), and certain other cancers (eg, melanoma, pancreatic cancer). In additional aspects of the invention, the compounds of the invention can also be used to treat other skin disorders, and related organs (eg, hair loss), of the respiratory system (eg, asthma), of the system circulatory, (for example, cardiac arrhythmias and fib- tation and hyper sympathetic innervation), and of the genitourinary system (for example, neurogenic bladder dysfunction and overactive vein). The present invention provides a method for treating a subject that could benefit from the administration of a composition of the present invention. Any therapeutic indication that could benefit from a gate ion channel modulator can be treated by the methods of the invention. The method includes the step of administering to the subject a composition of the invention, such that the disease or disorder is treated. The invention further provides a method for preventing in a subject, a disease or disorder that can be treated with administration of the compositions of the invention. "At-risk" subjects may or may not have detectable disease, and may or may not have detectable disease exhibited prior to the treatment methods described in I presented. "At-risk" means that an individual who is determined to be more prone to develop a symptom based on conventional risk by evaluating methods or has one or more risk factors that correlate with development of a disease or disorder that can be treated in accordance with the methods of the invention. For example, risk factors include family history, medical history, and history of exposure to a substance in the environment that is known or suspected to increase the risk of the disease. Subjects at risk for a disease or condition that can be treated with the agents mentioned herein may also be identified by, for example, any or a combination of diagnostic or prognostic assays known to those skilled in the art. The administration of a prophylactic agent may occur prior to the manifestation of symptoms characteristic of the disease or disorder, such that the disease or disorder is prevented or, alternatively, delayed in its progression.

EXAMPLIFICATION OF THE INVENTION: The invention is further illustrated by the following example, which could be used to examine the modulating activity of the gate ion channel of the compounds of the invention. The example should not be interpreted as additional limitation. Animal models are used in all the Examples animal models are accepted and the demonstration of efficacy in these animal models is predictive of efficacy in humans.

Example 1: Identification of ASIC antagonist using calcium imaging agent Cell culture HEK293 cells expressing ASICla were grown in a culture medium (DMEM with 10% FBS), in a polystyrene culture flask (175 mm2) a 37 ° C in a humidified atmosphere of 5% C02. The confluence of the cells should be 80-90% on the day of plating. The cells were rinsed with 10 ml of PBS and resuspended by the addition of the culture medium and trituration with 25 ml of pipette. The cells were plated at a density of approximately 10 x 10 6 cells / ml (100 μl / well) in black walls, clear bottom, 96-well plates pre-heated with 10 mg / l poly-D-lysine (75 μl / well during > 30 min) . The cells in plates were allowed to proliferate for 24 hours loaded with pigment.

Loaded with fluorescent calcium pigment Flu-4 / AM The Fluo-4 / AM (1 mg, Molecular Probe) was dissolved in 912 μl DMSO. The 4 / AM (1 mM) stock solution was diluted with culture medium at a final concentration of 2 μM (loading solution). The culture medium is drawn from the wells, and 50 μl of the Fluo-4 / AM loading solution is added to each well. The cells were incubated at 37 ° C for 30 minutes. When CHO cells are used, probenecid at 2.5 mM (final concentration) is added to the loading solution.

Calcium measurements After the loading period, the loading solution is aspirated and the cells are washed twice with 100 μl of modified assay buffer (145 mM NaCl, 5 mM KCl, 5 mM CaCl2, 1 mM MagCl2, 10 mM HEPES, pH 7.4) to remove the extracellular pigment. Following the second wash, 100 μl of modified assay buffer is added to each well and the fluorescence is measured in FLIPR ™ or FlexStation ™ (Molecular Devices, USA), or any other knowledge of equipment suitable for skill in the art. When CHO cells are used, probenecid at 2.5 mM (final concentration) is added to the loading solution.

Loading with Fluorescent Membrane Potential (FMP) dye A vial of FMP (Molecular Devices) dye is resuspended in 10.5 ml of assay buffer (48.3 mM NaCl, 93 mM NMDG, 5 mM KCl, 5 mM CaCl2, 1 mM MgCl2, mM HEPES, pH 7.4). The culture medium of the wells is asiprated, and 100 μl of the FMP loading solution is added to each well. The cells are incubated at 37 ° C for 30 in.

Measurement of the membrane potential After the charge period, the charge solution is left on the cells and the fluorescence induced by the membrane potential is measured in FLIPR ™ or FlexStation ™ (Molecular Devices, USA), or any other suitable equipment known by those skilled in the art.

Parameters FLIPR (ASICla) Temperature: Ambient temperature (20-22 °) First addition: 50 μl of the test solution in a range of 30 μl / sec and a starting height of 100 μl. Second addition: 50 μl of MES solution (20 mM, 5 mM final concentration) at a range of 35 μl / sec and a starting height of 150 μl. Interval reading: pre-incubation 10 sec x 7 and 3 sec x 3 antagonist phases 3 sec x 17 and 10 sec x 12. The addition plates (compound test plate and MES plate) were placed in the side positions right and left in the FLUPR path, respectively. The cell plates were placed in the middle position and the program ASICla is carried out. FLIPR must then take the appropriate measures in accordance with the adjustments of the intervals above. The fluorescence obtained after the stimulation is corrected by the mean basal fluorescence (in the modified assay buffer).

Parameters FlexStation (ASICla) Temperature: Temperature 25 ° C First addition: 50 μl of the test solution in a range of 26 μl / sec and a starting height of 125 μl. Second addition: 50 μl of MES solution (20 mM, 5 M final concentration) at a range of 26 μl / sec and a starting height of 115 μl. Interval reading: pre-mcubation 120 sec, antagonist phase, addition of MES at 145 sec, and time reading against agonist 100 sec (total run time of 240 sec).

Fluorescence obtained after stimulation is corrected by the mean basal fluorescence (in Modified Assay Reagent Solution) For cells that coexpress the ASICla and ASIC3 channels (eg, HEK293 cells), the membrane potential dye (FMP dye) is used ) and FlexStation parameters as above.

Confirmation and characterization of hits of the active substances The calcium response of the peak induced by MES (or change in membrane potential) in the presence of the test substance is expressed relatively to the MES response alone. The test substances that block the calcium response induced by MES (or the change in membrane potential) are retested in triplicate. Confirmed hits are collected for further characterization by carrying out full dose response curves to determine the potency of each line compound as represented by the IC50 values (ie, the concentration of the test substance which inhibits 50 % of the calcium response induced by MES, see, for example, figure 1). A summary of the IC 50 values of the compounds of the invention as acquired in the calcium mobilization assay are shown below n = 3-7.

The data shown in Table H were acquired by using the FlexStation assay described in Example 1 on HEK293 cells expressing hASIC3 (h3) and / or hASICla (hla).

TABLE H * In one experiment, EC50 (μM) > 20 ** In one experiment, EC50 (μM) > 10 Example 2: Separation by exclusion and bioanalysis of ASIC antagonists in heterologous expression systems This example describes another in vitro evaluation of the activity of the compounds of the present invention. Another example of an m Vitro evaluation method consists of using mammalian heterologous expression systems, which are known to those skilled in the art and include a variety of mammalian cell lines such as COS, HEK, eg, HEK293. and / or cells CHO. The cell lines are transfected with gate ions channels and used to carry out electrophysiology as follows: All experiments were carried out at room temperature (20-25 °) at a voltage rise using cell zonal clamping methods complete conventional (Neher, E., et al., (1978) Pfluegers Arch. 375: 219-228). The amplifier used is the EPC-9 (HEKA-electronics, Lambrect, Germany) run on a Macintosh G3 computer by means of an ITC-16 interface. The experimental conditions are established with the Pulse Software that accompanies the amplifier. The data is filtered by step ba and is displayed directly to the hard disk in a range of 3 times the cut off frequency. The pipettes are pulled from the borosilicate glass using a horizontal electrode extractor (Zeitz-Instrumente, Augsburg, Germany). Pipette resistances are 2-3 MOhms in the salt solutions used in these experiments.

The pipette electrode is a clophed silver wire, and the reference is a silver chloride pelletizing electrode (In vivo Metric, Healdsburg, USA) attached to the experimental chamber. The electrodes are at zero with the pipette open in the bath just before sealing. The coverslips with the cells were transfected into an experimental 15 μl chamber mounted on the stage of an inverted microscope (IMT-2, Olympus) supplied with Nomarski optics. The cells were continuously superfused with extracellular saline at a range of 2. 5 ml / min. After the formation of a giga-seal, the complete cellular configuration was achieved by suction. Cells were maintained at a holding voltage of -60 mV and at the start of each present experiment was measured continuously for 45 s to measure a stable baseline.

The low pH solutions (< 7) are supplied to the chamber via a custom-made gravity-fed flow line, the tip of which is placed approximately 50 μM from the cell. The application is triggered when the pipe that is connected to the flow tube is compressed by a valve controlled by the Pulse software.

Initially, the lower pH (in general, pH 6.5) is applied for 5 s every 60 s. The application during the sample interval is 550 μs. After the stable responses are obtained, the extracellular saline solution as well as the Lower pH solution changes to solutions containing the compound to be tested. The compound occurs until responses of a repeatable amplitude are reached.

The amplitudes present were measured at the peak of the responses and the effect of the compounds was calculated as the amplitude in the equilibrium of the compound divided by the amplitude of the current evoked by the pulse just before the compound was included. The following salt solutions were used: the extracellular solution (mM): NaCl (140), KCl (4), CaCl 2 (2), MagCl 2 (4), HEPES (10, pH 7.4); mtcellular solution (mM): KCl (120), KOH (31), MgCl 2 (1,785), EGTA (10), HEPES (10, pH 7.2). In general, the compounds to be tested were dissolved in 50% DMSO at 500 times high concentration were used. The zonal plating experiments with Compound B and Compound R demonstrated the efficiency to inhibit the recombinant rat ASIC gate channels as illustrated in Figures 2A and 2B. CHO cells were transfected with hASICla and used to carry out the full dose inhibition curves with compound B, and compound R. The results were expressed as a fraction of the current control peak obtained in the absence of the test substance. These dies indicate that compounds B and R can reduce the activity of hASICla in this assay dependent on the dose.

Figure 3 compares the selectivity of Compound R for ASICla human against human ASIC3, both stably transfected in CHO cells. Figure 3A shows the effect of Compound R on the current amplitude of hASICla and the cosmetics. A concentration of 1 μM caused an average reduction of 50% in the current amplitude. This effect was reversed completely with the washing of the compound. In contrast, Figure 3B details the effects of Compound R on the amplitude and temperature of the hASIC3 currents evoked by the acid. Even at 30μM, compound R failed to reduce the amplitude of the current. Figure 3C compares the dose response relationship of Compound R on hASICla and hASIC3 [determined by measuring the area under the curve of the response (total charge transfer) and normalized to the control response]. Compound R clearly reduced the response evoked by the pH of hASICla in a dose-dependent manner, but not the hASIC3 indicating that this compound is selective against the specific subunits of ASIC.

Example 3: Separation by exclusion and Bioanalysis of ASIC antagonists in Xenopus leavis oocytes This example describes the in vitro evaluation of the activity of the compounds of the present invention.

Electrophysiological tests of two-electrode voltage amplification in Xenopus laevis oocytes expressing the gate ions channels are carried out as follows: The oocytes are surgically removed from the adult Xenopus laevis and treatment for 2 hours at room temperature with 1 mg / ml Type I collagenase (Sigma) in the Barth ba solution or gentle shaking. The oocytes selected in step IV-V are manually defoliated before the nuclear microinjection of 2.5-5 ng of a suitable expression vector, such as pCDNA3, which comprises the nucleotide sequence encoding a subunit protein of the ion channel of gate. In such an experiment, the oocytes express homomultimeric proton gate ion channels on their surface. In an alternative experiment, one, two, three or more vectors comprising the sequences encoding the distinct gate ion channel subunits are co-injected into the nucleus of the oocytes. In the latter case, the oocytes express heteromultimeric proton gate ion channels. For example, the ASIC2a and / or ASIC3 subunits in the pcDNA3 vector are co-injected in a 1: 1 cDNA range. After 2-4 days of expression at 19 ° C in the Barth solution containing 50 mg / ml gentamicm and 1.8 M CaCl2, gate ion channels are activated by applying an acid solution (pH < 7) and the currents are record in a two-electrode voltage amplification solution, using an OC-725B amplifier (Warner Instruments). Currents are acquired and digitized 500 Hz on an Apple Imac G3 computer with an A / D interface NB-MI0-16XL (National Instruments) and tracks are recorded after filtering at 100 Hz in Axograph (Axon Instruments) (Neher, E. and Sakmann, B. (1976) Nature 260: 799-802). Once spliced with the microelectrodes, the oocytes are continuously superfused at 10-12 ml / min with a modified Rmger solution containing 97 mM NaCl, 2 M KCl, 1.8 mM CaCl2, and 10 mM HEPES until reaching pH 7.4 with NaOH ( Control Rmger). The test Rmger solution is prepared by replacing the HEPES with MES and adjusting the pH to the desired acid value. The compounds of the present invention were prepared in both the test and control Rmger solutions and applied to the oocytes at room temperature through a computer controlled switching valve system. The osmolarity of all solutions was adjusted to 235 mOSm with colma chloride. Similarly, recordings can also be acquired in an automated multi-channel oocyte system such as OpusExpress ™ (Molecular Devices, Sunnyvale, USA). Figures 4A, 4B, 4C and 4D show the dose response ratio of Compounds A, R, 7 and 32, respectively, over the hASIC current evoked by the application of a pH 6.5 of the Ringer test solution in an OpusExpress ™ system. The logs are acquired from the oocytes expressed in the homomeric hASIC using a two-electrode voltage clamp configuration procedure as described herein. The data shown in these figures demonstrate that compound A effectively modulates the activity of these gate ion channels.

Example 4: Separation by exclusion and bioanalysis of ASIC antagonists in primary cell systems This example describes another m Vitro evaluation of the inhibitory activity of the compounds of the present invention using the electrophysiology of zonal zonation of the sensory neurons in the primary culture. Sensory neurons can be isolated and cultured in vitro from different animal species. The most widely used protocols use sensory neurons isolated from neonatal rats (Eckert, et al (1997) J Neuroscí Methods 77: 183-190) and embryonic rats (Vasko, et al. (194) J Neurosci 14: 4987-4997) . The sensory neurons of dorsal and trigemmal root ganglia in the culture exhibit certain characteristics of sensory neurons m vivo. The electrophysiology is carried out similarly as described above in example 2. In the staging mode of voltage, trans-membranes currents are recorded. In the current mode of posting, the change in transmembrane potential is recorded.

Example 5: Formalin Model - acute tonic pain model This example describes the live assessment of the inhibitory activity of the compounds of the present invention. A number of well-established models of pain are described in the literature and are well known to someone of skill in the art (see, for example, Table 1). This example describes the use of formality test. Male Sprague-Dawley rats are housed together in groups of three animals under standard conditions with unrestricted access to food and water. All experiments are conducted in accordance with the ethical guidelines for experimental pain research in conscious animals (Zimmerman, 1983). The evaluation of the fear behavior induced by formalma in normal non-injured rats (body weight 150-180 g) was made with the use of an automated nociceptor analyzer (University of California, San Diego, USA).

Briefly, this involves placing a C-shaped metal band (10 mm wide x 27 mm long) on the back leg of the rat to be tested. The rats (four rats are included in each test section) were then placed in a cylindrical plexiglass observation chamber (diameter 30.5 cm and height cm) for 20 minutes for the purposes of adaptation prior to administering drugs or vehicles according to the experimental paradigm followed. After adaptation, the individual rats are then restrained gently and formally (5% in saline, 50 μl s.c.) was injected into the plant surface of the hind paw using a 27G needle. The rats were then returned to their separate observation chambers, each of which was returned during a closed detection device consisting of two electromagnetic coils designed to produce an electromagnetic field in which the movement of the metal band could be detected. The analog signal is then digitized and a software algorithm (LabView) is applied to allow discrimination of fearful behavior of other leg movements. A sample interval of 1 minute was used and on the basis of the resulting response parameters 5 phases of the nociceptive behavior were identified and recorded: first phase (Pl; 0-5 min), inferred (Int; 6-15 min) , second phase (P2; 60 min). phase 2A (P2A; 16-40 mm) and phase 2B (P2B; 41-60 min). The nociceptive behavior was also determined manually every 5 minutes by measuring the amount of time spent in every four categories of behavior: 0, treatment of the injected hind legs is indistinguishable from that of the contralateral leg; 1, the injected leg has little or no weight placed on it; 2, the injected leg rises and does not come into contact with any surface; 3, the injected leg was licked, bitten or shook. A nociceptive record weighted in the range from 0 to 3 was calculated by multiplying the time spent in each category by the weight of the category, adding these products and dividing by the total time of each 5 minute block of time. (Coderre et al., Pain 1993; 54: 43). At the base of the resulting response patterns, 2 phases of the nociceptor environment were identified and recorded: first phase (Pl, 0-5 mm), inferred (Int, 6-15 mm), second phase (P2, 60 rtun) , phase 2A (P2A; 16-40 mm) and phase 2B (P2B; 41-60 min). The statistical analysis was carried out using a software package Prism ™ 4.01 (GraphPad, San Diego, CA, USA). The difference in response levels between the treatment groups and control vehicle group was analyzed using an ANOVA followed by the Bonferroni method for post-hoc pairwise comparisons. A value p < 0.05 is considered important. Figures 5-7 are representative examples of the dose dependent effect of compounds A and R in pain induced by injection of intraplantar formalin. Compound A was able to reduce the total pain recording behavior (hesitation, licking, nibbling) in phase 2 of the formality test (n = 6) when evaluated using the Automated Nociceptive Analyzer described above. Similar results are shown for compound R (Figures 6 and 7) (n = 6). In this example, the behavior for pain was evaluated by using the normal method described above.

Compound R had a dose-dependent effect on the overall behavior of the pain induced by the plantar-containing formalin (Figure 6A), and specifically the nibbling and licking behavior (Figure 6B). The dose dependence of this effect is captured and summarized in Figure 7 (the ED50 for Compound R in this assay is about 50 mg / kg). Together, these results indicate the efficacy of compounds A, and R to block acute tonic pain induced by formalin injection in the paw.

Example 6: Model CFA- chronic inflammatory pain model The injection of complete Freunds adjuvant (CFA) in the hind paw of the rat has been shown to produce a long-lasting inflammatory condition, which is associated with hyperalgesia and alodima of behavior in the injection site (Hylden et al., Pam 1989; 37: 229) (Blackburn-Munro et al., 2002). Rats (body weight 260 - 300 g) receive an injection s. c. of CFA (50% in saline, 100 μl, Sigma) on the surface of the plant of the hind leg under brief halothane anesthesia. After 24 h, these were tested for responses that carry the weight of the hind leg, as evaluated using an Incapacitance Tester (Linton Instrumentation, UK), (Zhu et al., 2005). The instrument incorporates a double channel scale that separately measures the weight of the animal distributed on each hind foot. While normal rats distribute their body weight equally between the two hind legs (50-50), the discrepancy in the weight distribution between an injured and uninjured leg is a natural reflection of the level of discomfort in the injured paw (nocifensive behavior) . The rats are placed in a plastic chamber designed so that each rear leg is on a separate transducer pad. The averager is placed to record the load on the transducer for a period of time of 5 s and two numbers displayed represent the distribution of the body weight of the rat on each leg in grams (g). For each rat, three readings are taken from each leg and then averaged. The weight differences carried side by side are calculated as the average of the absolute value of the difference between the two hind legs of three trials (right leg reading-rear leg reading).

Evaluation of thermal hyperalgesia. Baseline and retreats after treatment to a noxious thermal stimulus were measured according to Hargreaves (Hargreaves et al., 1988) using a leg analgesia test of the paw plant (IITC), Woodland Hills, Ca, model # 336). The intensity of the established stimulus was 30% of the maximum output and the cut time was set to 30 seconds. The rats were placed on a hot glass plate at 28 ° C and allowed to habituate to the test chambers for a minimum of 15 minutes prior to each test section. The thermal stimulus is applied to the surface of the paw plant and the laterality medium of three readings in each paw was used as the latency value for each time point. The thermal thresholds were defined as the latency in second to the first pain environment, which includes the withdrawal of non-offensive pain, fear, biting and / or licking of the paw stimulated. The mean and standard error of the medium (SEM) was determined by the injured and normal legs for each treatment group.

Example 7: Cloning and expression of ASICs The cDNA for ASICla and ASIC3 (or other ASIC subtypes) can be cloned from poly (A) + rat mRNA and put into expression vectors according to Hesselager et al. (J Biol Chem. 279 (12): 11006-15 2004). All the constructs are expressed in CH0-K1 cells (ATCC No. CCL61) or HEK293 cells.

The CH0-K1 cells are cultured at 37 ° C in a humidifying atmosphere of 5% C02 and 95% air and passed twice weekly. Cells are maintained in DMEM (10 mM HEPES, 2 mM glutamax) supplemented with 10% fetal bovine serum and 2 mM L-proline (Life Technologies). CHOKl cells are co-transfected with plasmids containing ASIC and a green fluorescent protein that enhances plasmid coding (EGFP) uses the transfection kit plus lipofectamma (Life Technologies) or lipofectamma 2000 (Invitrogen) according to the protocol of the maker. For each transfection, an amount of DNA is used that provides whole cell currents within a reasonable range (0.5 nA-10 nA), in order to avoid saturation of the membrane zoning amplifier (approximately 50 ng for ASICla and ASIC3 ). Electrophysiological measurements were made 16-48 hours after transfection. The cells were trypsimized and seeded on glass objects pre-coated with poly-D-lysine, at the time the electrophysiological recordings were made. Stable clones expressing ASIC channels are obtained by specific selection of antibiotics (ie, G418, Zeocm).

Example 8: Synthetic Procedure Synthetic Procedure for Representative Compound of Quinoline (Compound R) To a solution of 1-benzyl-4-hydroxy-piperidine (198mg, l.Ommol) in DMF (5ml) was added NaH (95%, 38mg, 1.5mmol), the suspension was stirred for 15min at room temperature, before Chloroquinoline (178mg, l.Ommol) was added. The reaction mixture was then heated at 150 ° C for 15 min using microwaves. DMF was evaporated and water was added to quench the reaction. The aqueous solution was extracted with EtOAc three times. The crude product was purified by column (Biotage) to give 230 mg of pure product in 70% yield. Synthetic Procedure for Representative Compound of Quinazoline (Compound K) Stage 1: Anthranilamide (1.36 g, 10 mmol) and potassium carbonate (2.07 g, 15 mmol) were suspended in 68 ml of ether and heated to reflux. P-toluoyl chloride (1.72ml, 13mmol) was slowly added to the mixture at reflux. After 3 h at reflux, the reaction mixture was allowed to cool to room temperature. The ether was evaporated, the resulting residue was filtered and washed with water and treated with ether to give a fairly pure product. Step 2: The crude product (2.2g) was suspended in 5% NaOH (40ml) and boiled for 12hr. After cooling, HOAc was added to bring the pH to 5. The solid was filtered and washed with water, then dried. The crude product was purified by column (Biotage) to give 1. 85g of pure product in 76% yield during two stages. Stage 3: To a suspension of hydroxiqumazolma (472mg, 2. 0mmol) in benzene (20ml) was added S0C12 (1.5ml, 20mmol).

The mixture was refluxed for 3-6 hours until it became a clear solution. The solvents were evaporated. The solid residue was dissolved in dichloromethane and washed with aqueous sodium bicarbonate solution, then dried. The crude product was purified by column (Biotage) to give 460mg of pure product in 90% yield. Stage 4: Chloroquinazol (254mg, l.Ommol) and ammobenzoic acid (137mg, l.Ommol) were dissolved in DMF (5ml), and the reaction mixture was heated at 150 ° C for 15 min using microwaves. DMF was evaporated and water was added to quench the reaction. The solid was filtered and washed with water then dried. The crude product was purified by column (Biotage) to give 286mg of pure product in 80% yield. 1HNMR (CDC13, 400Hz): d ppm 12.82 (ÍH, br.s), 10.09 (ÍH, s), 8.60 (ÍH, d, J = 8.0 Hz), 8.37 (2H, d, J = 8.0 Hz), 8.17 (2H, d, J = 8.0 Hz), 8.05 (2H, d, J = 8.0 Hz), 7.89 (2H, d, J = 3.2 Hz), 7.64 (HH, m), 7.36 (2H, d, J = 8.0 Hz), 2.39 (3H, s).

Synthetic Procedure for Representative Compound of Quinazoline (Compounds 32 and 33) (Stage 1 and 2) , - :. -] 1"-NH", K2C03_ '^ 2 5% N Ü H n -N? X-m ether "" "'" H reduced 2 ta- reflux _X? _-- i r To a stirred solution of anthranilamide (4.00g, 29.38mmol) in dry ether (30mL) was added K2C03 (5.70g, 41.14mmol) followed by propionyl chloride (3.30mL, 38.19mmol). The reaction mixture was stirred for 15 hours at room temperature then refluxed for 4 hours. The ether was removed and the white solid was filtered and washed with water. The product was suspended directly in a 5% solution of NaOH (40 mL) and refluxed for 3 hours. The The reaction mixture was neutralized with acetic acid and the precipitate was filtered and then washed with water. The white solid was dried under reduced pressure to yield 4.42g (86%) of the intermediary.

(Stage 3) orn j: To a stirred solution of quinazolinone (0.20g, 1.14mmol) in dry THF (6mL) was added phenyl ether (O.lßmL, 1.14mmol) followed by BOP (0.66g, 1.48mmol) and DBU (0.26mL, 1.71mmol). ). The amine was then added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature. The product (compound 33) was concentrated under reduced pressure and purified by flash chromatography. (Stage 4) '"-" "" N ""' '"-" • "Compound 33 Compound 32 To a stirred solution of compound 33 (60mg, 0.17mmol) in dry DMF (2mL) was added NaH (14.0mg, 0.58mmol) followed by Mel (50uL, 0.80mmol). The reaction mixture was stirred for 1 hour then quenched with water. The organic layer was removed and concentrated under reduced pressure. The product (compound 32) was isolated by PREP HPLC purification.

Synthetic Procedure for Representative Quinoline Compound (Compound 7) 6-Bromo-4-hydroxyallamine was synthesized as previously published (J. Org. Chem. 1964, 29, 3548; Biochem. Pharm., 1996, 52, 551). 4-Bromoanilma (2 g, 0.012 mol), ethyl acetoacetate (2.96 mL, 0.024 mmol) and 5 g of polyphosphoric acid were heated with stirring at 170 ° C per lh. The reaction was neutralized with 2% aqueous NaOH solution, and the precipitate of 4-hydroxyquadine was washed with water, triturated with ether and dried to give 6-bromo-4-hydroxyquinoline. POCl3 (5mL) was added to 6-bromo-4-hydroxyquamody (0.270g, 1134 mmoles) and the solution was heated to reflux per lh. The solvent was removed under reduced pressure, and ice water was added to the residue, which was basified with a % aqueous solution of NaOH. The solid was completely filtered, redissolved in ether and the insoluble was completely filtered. The filtrate was concentrated under reduced pressure to give 6-bromo-4-chloroquinindamine.

Br 6-bromo-4-chloroquinaldine (0.120 g, 0.468 mmol), 1-benzyl-4-hydroxypiperidine (0.045 g, 0.234 mmol) and 95% NaH (0.012 g; 0. 468 mmole) were dissolved in DMF (5 mL) and heated to 75 ° C in microwaves per lh. The reaction mixture was brought to room temperature and 0.5 mL of water was added. The solvent was removed under reduced pressure and the residue was diluted with water, extracted with ethyl acetate (3x20mL), washed with water, brine, dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (EtOAc / Hexanes: 20 / 80-100% EtOAc) to give Compound 7 (0.045g, 47%). Figure 8 shows a synthesis scheme for the preparation of compounds 36, 37 and 38.

Figures 9A, 9B, 9C and 9D show synthetic schemes for the preparation of compounds 39 and 47, as well as prophetic synthesis schemes for generic compounds of the invention. Figure 10 shows a synthesis scheme for the preparation of compound 108. Figures HA and 11B show synthesis schemes for the preparation of compounds 103 and 104. Figure 12 shows synthesis schemes for the preparation of an intermediate that can be used for the preparation of the compounds of the invention. Figures 13A, 13B and 13C show synthesis schemes for the preparation of compounds 107, 105 and 106.

Equivalents Those of experience in the art will recognize, or be able to ascertain by using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Incorporation by Reference The complete contents of all patents, published patent applications and other cited references they are hereby expressly incorporated herein by reference in their entireties.

Claims (94)

1. A method for modulating the activity of a gate ion channel, characterized in that it comprises contacting a cell expressing a gate ion channel with an effective amount of a compound represented by formula 1, and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotavars, tautomers, diastereomers, or racemates thereof; wherein the dotted lines indicate a single or double bond, where when the dotted lines indicate a single bond the nitrogen of the ring can be linked to H or Ri; R1, R3 and R4 are each, independently, selected from the group consisting of hydrogen, substituted or unsubstituted amine, cyano, nitro, COOH, amide, halogen, haloCi 5 -alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, hydroxyl, Ci 5 -alkyl, wherein the Ci 5-alkyl group can be interrupted by O, S or N (H), hydroxy-Ci 5 -alkyl, Cx 5 -alkenyl, Ci 5 -alkylene, sulfonyl, sulfone , sulfonic acid, (CH2) 0 5OX6, (CH2) 0-5CO2Xs N (H) (CH2) 0 5OX6, and (CH2) 0 5C (0) N (XG) 2, wherein X6 is independently selected from the group consisting of hydrogen, Ci 5 -alkyl, amine, and -C02X1, in where X1 is selected from the group consisting of hydrogen, C? 5-alkyl, ammo, and substituted or unsubstituted aryl; R2 is selected from the group consisting of hydrogen, substituted or unsubstituted amine, amide, halogen, nitro, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, hydroxyl, Cx 5 -alkyl, where the Cx 5-alkyl group can be interrupted by O, S or N (H), hydroxy-Cx 5 -alkyl, C? -5-alchemyl, Ci 5 -alkylene, sulfonyl, sulfonamide , sulfonic acid and -C02X1, wherein X1 is selected from the group consisting of hydrogen, Cx5-alkyl, amino, and substituted or unsubstituted aryl; or R2 is selected from the group consisting of Formulas I, II, III and IV: Wherein R8 is selected from the group consisting of O, S and CH2; R6, R7, R9 and R10 are each, independently, selected from the group consisting of hydrogen, C? -5-alkyl, wherein the Ct 5 -alkyl group can be interrupted by O, S or N (H) , amine, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; n is 0 or 1; m is 0 or 1, - X2 is CH2, O, N (C?, 5-alkyl) or N (H); X3 and X4 are each, independently, N, C, or C (H); dotted lines of Formula III indicate a single or double bond; X5 is selected from the group consisting of hydrogen, Ci- 5-alkyl, C? -5-alkox ?, (CH2) 04-phenol substituted or unsubstituted, (CH2) 0-4-p? Pd? whether unsubstituted or substituted, C (0) Ph, (CH2) or 4-c? clohex-substituted or unsubstituted, (CH2) or 4-benzo [1, 3] dioxol, wherein the Ci-alkyl groups or CH2 can be interrupted by a carbonyl group or -C (0) 0-, and wherein the CH2 groups can be substituted with a C? _5-alkyl, halogen or CF3 group; a, b and c are each, independently, 0 or 1; X7 is C (H), N or O; X8 is H, Ci 5-alkyl, aryl, OH, 0-C? 5-alkyl or 0-ari lo; and R5 is N, C or C (H); wherein R3 and R4, R2 and R3, R1 and R4 or R2 and R4 may also form a substituted or unsubstituted aplo, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycle of 4, 5, or 6 members.

2. The method according to claim 1, characterized in that the dashed lines of Formula III indicate a single bond.

3. The method according to claim 1, characterized in that R2 is formula III, m = 0, X3 and X4 are N, and dotted lines indicate a single bond.

4. The method according to claim 1, characterized in that Formula 1 is represented by Formula 2: wherein R1, R2, R3, R4 and R5 have the meaning set forth in claim 1.

The method according to claim 1, characterized in that Formula 2 is represented by Formula 3: 2 I heard (3) Where R1, R2, R3, R4 and R5 have the meaning set forth in claim 1.

6. The method according to claim 5, characterized in that R1, R3 and R4 are each, independently, selected from the group. which consists of hydrogen, halogen, Ci 5 -alkyl, O-Ci 5-alkylo, halo-C 5 -alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, -R 2 is selected from the group consisting of consists of hydrogen, substituted or unsubstituted amine, amide, halogen, nitro, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, hydroxyl, Ci 5 -alkyl, wherein the Ci 5- group can it be interrupted by 0, S or N (H), h? drox? -C? 5-alkyl, C5-alkenyl, Cx5-alkenyl, sulfonyl, sulfonamide, sulfonic acid and -C02X1, wherein X1 selected from the group consisting of hydrogen, Ci 5-alkyl, amino, and substituted or unsubstituted aryl, - or R2 is selected from the group consisting of Formulas I, II and III: wherein R8 is selected from the group consisting of O, S and CH2; R6, R

7, R9 and R10 are each, independently, selected from the group consisting of hydrogen, C? -5-alkyl, wherein the Cx 5-alkyl group can be interrupted by 0, S or N (H) , amine, substituted or unsubstituted aryl and substituted or unsubstituted cycloalkyl; n is 0 or 1; m is 0 or 1; X2 is CH2, O, N (CX 5 -alkyl) or N (H); X3 and X4 are each, independently, N, C or C (H), - dotted lines indicate a single or double bond; X5 is selected from the group consisting of hydrogen, C? 5-alkyl, Ci 5-alkox ?, (CH2) 0-4-substituted or unsubstituted phenol, (CH2) 0-4-c? Clohex? Substituted or unsubstituted, (CH2) 0 4-benzo [1, 3] dioxol, wherein the Cx 5-alkyl groups or CH2 can be interrupted by a carbonyl group or group-C (0) 0-; and R5 is N or C (H). The method according to claim 6, characterized in that the dashed lines of Formula III indicate a single bond.

8. The method according to claim 6, characterized in that R3 and R4 are each, independently, selected from the group consisting of H, halogen, hydroxyl, Ci 5 -alkyl and Ci 5 -alkoxy?; R2 is selected from the group consisting of Ci s-alkyl, Cx 5-alkox ?, C02H, and heterocycle; and R1 is selected from the group consisting of heterocycle, heterocycle substituted with Cx 5 -alkyl, and phenyl substituted one or more times with hydroxyl, Cx 5 -alkyl or Cx 5 -alkox ?.

9. The method according to claim 6, characterized in that R3 and R4 are each, independently, selected from the group consisting of H, Cl, Br, OH, and OCH3; R2 is selected from the group consisting of CH3, C02H, and piperidma; and R1 is selected from the group consisting of piperazm, piperazm substituted with CH3, and phenyl substituted one or more times with OH, 0CH3 or CH3.

10. The method according to claim 5, characterized in that Formula 3 is represented by Compound F; Compound 31; Compound 36; Compound 37; Compound 38; Compound 39; Compound 40, Compound 50; Compound 51; Compound 52; Compound 53 or Compound 54.

11. The method according to claim 4, characterized in that Formula 3 is represented by Formula 4: wherein R1, R2, R4 and R5 have the meaning set forth in claim 4.

The method according to claim 11, characterized in that R1 is selected from the group consisting of hydrogen, C? _5-alkyl, 0 -C? -5-alkyl, fluorine, bromine, trifluoromethyl, substituted or unsubstituted piperidma, substituted or unsubstituted piperazm, substituted or unsubstituted pipdma, substituted or unsubstituted morpholm, unsubstituted or substituted imidazole, substituted or unsubstituted pyrazole , substituted or unsubstituted diazepam and substituted or unsubstituted phenyl; R 4 is selected from the group consisting of hydrogen, halogen, C x 5 -alkyl, C0 2 H and (CH 2) 0 3 H H; R2 is selected from the group consisting of hydrogen, substituted or unsubstituted amine, amide, halogen, C? _5-alkyl, wherein the C? _5-alkyl group can be interrupted by O, S or N (H), and -CO2X1, wherein X1 selected from the group consisting of hydrogen, Ci 5 -alkyl, arrimo, and substituted or unsubstituted aryl; or R2 is selected from the group consisting of Formulas I, II and III: wherein R8 is selected from the group consisting of 0, S and CH2; R6, R7, R9 and R10 are each, independently, selected from the group consisting of hydrogen, C1-5-alkyl, wherein the C5-alkyl group can be interrupted by O, S or N (H), amine, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; n is 0 or 1; m is 0 or 1; X2 is CH2, O or N (H); X3 and X4 are each, independently, N, C or C (H); the dotted line indicates a single or double link; X5 is selected from the group consisting of hydrogen, C? _ 5-alkyl, C5-alkoxy ?, (CH2) 0-4-substituted or unsubstituted phenol, (CH2) 0-4-c-clohex-substituted or unsubstituted, (CH2) or 4-benzo [ 1, 3] dioxol, where the C? -5-alkyl groups or CH2 can be interrupted by a carbonyl group or -C (0) 0-; Y R5 is N or C (H).

13 The method according to claim 12, characterized in that R1 is pyridine, which can be optionally replace one or more times with OCH3, Cl, CH3, or N02; R5 is C (H); R2 is formula I or II; and R4 is halogen, (CH2) 0-3OH, or C02H.

14. The method according to claim 12, characterized in that R2 is Formula III, wherein n is 0, X2 is N (H) or N (C? _5-alkyl), X3 is C (H), X4 is N and X5 is (CH2) 0-4-substituted or unsubstituted phenyl; R4 is H; and R1 is C? -5-alkyl.

The method according to claim 12, characterized in that R1 is selected from hydrogen, methyl, ethyl, ethoxy, fluorine, bromine, trifluoromethyl, piperizine substituted by methyl, diazepane substituted by methyl, pipdma, phenyl, phenyl substituted by methyl and phenyl independently substituted one or more times by methoxy, fluoro or bromo; R4 is selected from the group consisting of H, Cl, Br and F; R2 is selected from the group consisting of C1-5-alkyl, wherein the C ^ -alkyl group can be interrupted by 0, S or N (H), and -C02X1, wherein X1 selected from the group consisting of hydrogen, C? -5-alkyl, arrimo and substituted or unsubstituted aryl; or R2 is selected from Formula III: where n is 0 or 1; m is 0 or 1; X2 is CH2, O or N (H); X3 and X4 are each, independently, N, C or C (H); dotted lines indicate a single or double link; X5 is selected from the group consisting of hydrogen, Ci-5-alkyl, Ci 5-alkox ?, (CH2) or 4-phenol substituted or unsubstituted, (CH2) or 4-c? Clohex? Substituted or unsubstituted, (CH2) 0 4-benzo [1, 3] dioxol, wherein the Cx 5-alkyl or CH2 groups can be interrupted by a carbonyl group or -C (0) 0-; and R5 is N or C (H).

16. The method according to claim 11, characterized in that Formula 4 is represented by Compound 35 or Compound 110.

17. The method according to claim 5, characterized in that Formula 3 is represented by Formula 5a: Where R5 is N or C (H); R1 is selected from the group consisting of hydrogen, C5-5alkyl, O-Ci5-alkyl, fluorine, bromine, trifluoromethyl, substituted or unsubstituted piperidine, substituted or unsubstituted pipermine, substituted or non-substituted morpholm substituted, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted diazepane and substituted or unsubstituted phenyl; R4 is selected from the group consisting of hydrogen, halogen, Ci 5 -alkyl, C02H and (CH2) 0 3? H; w is 0 or 1; and R11 and R12 are each, independently, selected from the group consisting of hydrogen, C? 5-alkyl, wherein the Ci 5-alkyl group can be interrupted by 0, S or N (H), and substituted or unsubstituted phenyl, or R 11 and R 12 can form the following 6-membered ring: wherein X5 is selected from the group consisting of hydrogen, C? -5-alkyl, C? _5-alkox ?, (CH2) 04-phenol substituted or unsubstituted, (CH2) 0.4-c? clohex? unsubstituted or substituted, (CH 2) 0 4-benzo [1,3] dioxol, wherein the C 5 -alkyl or CH 2 groups can be interrupted by a carbonyl group or -C (0) 0-.

18. The method according to claim 17, characterized in that it is 0; R11 is H or CH3; R12 is (CH2) 1-4CO2H, (CH2)? 4CH3, piperidyl substituted with benzyl or phenyl substituted with C02H; R1 is hydrogen, CH3, CH2CH3, or phenyl substituted one or more times with chlorine or CH3; and R4 is hydrogen, chloro, or N02.

19. The method according to claim 17, characterized in that Formula 5a is represented by Compound K; Compound T; Compound 32; Compound 33; Compound 101; Compound 102; Compound 103; Compound 104; Compound 105; Compound 106; Compound 107; Compound 108 or Compound 111.

20. The method according to claim 17, characterized in that Formula 5 is represented by the Formula 6a: (6a) wherein R4 is selected from the group consisting of hydrogen, halogen, C? -5-alkyl, 0-C? 5-alkyl, C02H and (CH2) 0 3OH; R1 is selected from the group consisting of hydrogen, C5-5alkyl, fluorine, bromine, trifluoromethyl, substituted or unsubstituted piperidma, substituted or unsubstituted pipermin, substituted or unsubstituted morphol, unsubstituted or substituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted diazepam and substituted or unsubstituted phenyl; R5 is N or C (H); w is 0 or 1; and X5 is selected from the group consisting of hydrogen, Cx-5-alkyl, C5-alkox ?, (CH2) or substituted or unsubstituted phenyl, (CH2) 04-c-clohex, whether or not substituted replaced, (CH2) or 4-benzo [1, 3] dioxol, wherein the C? _5-alkyl groups or CH2 can be interrupted by a carbonyl group or -C (O) O-.

21. The method according to claim 20, characterized in that w is 1, X5 is (CH2) or-4-substituted or unsubstituted phenyl, (CH2) 0-4-C (O) -substituted or unsubstituted phenyl, (CH2) 0_4-benzo [1, 3] dioxol, CH3, or amide; R1 is pyridyl, phenyl independently substituted one or more times with OCH3, Cl, or OH; and R4 is hydrogen, halogen, or OH.

22. The method according to claim 20, characterized in that Formula 6a is represented by Compound C; Compound G; Compound 34; Compound 41; Compound 42; Compound 43; Compound 44; Compound 45; Compound 46; Compound 47; Compound 48 or Compound 49.

The method according to claim 20, characterized in that Formula 6a is represented by Formula 7: wherein R4 is selected from the group consisting of hydrogen, halogen, Cx 5 -alkyl, O-Ci 5 -alkyl, C02H and (CH2) 03OH; R1 is selected from the group consisting of hydrogen, C5-5alkyl, fluorine, bromine, trifluoromethyl, substituted or unsubstituted pipepdma, substituted or unsubstituted pipermin, substituted or unsubstituted morpholm, unsubstituted or substituted imidazole, pyrazole substituted or unsubstituted, substituted or unsubstituted diazepam and substituted or unsubstituted phenyl; R5 is N or C (H); and X5 is selected from the group consisting of hydrogen, Ci-s-alkyl, unsubstituted or substituted C ?5-alkoxy ?, (CH2) 0-4, (CH2) or 4-c ?clohex? whether substituted or not substituted, (CH2) 04-benzo [1, 3] dioxol, wherein the Ci 5 -alkyl groups or CH can be interrupted by a carbonyl group or -C (0) O-.

24. The method according to claim 23, characterized in that X5 is H, C (O) O-t-butyl, or phenyl substituted with CN or N02; R4 is halogen, and R1 is C? 5-rent it

25. The method according to claim 23, characterized in that Formula 7 is represented by Compound A; Compound D; Compound H; Compound L; Compound M; Compound N; Compound 0; Compound P; Compound Q; Compound 59; Compound 60; Compound 61 or Compound 116.

26. The method according to claim 5, characterized in that Formula 3 is represented by the Formula 8: (8) wherein R5 is N or C (H); R1 is selected from the group consisting of hydrogen, C] .. 5-alkyl, fluorine, bromine, trifluoromethyl, substituted or unsubstituted piperidine, substituted or unsubstituted piperizine, substituted or unsubstituted morpholm, unsubstituted or substituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted diazepam and substituted or unsubstituted phenyl; R 4 is selected from the group consisting of hydrogen, halogen, C 1 5 -alkyl, C 0 H, and (CH 2) 0 3 → H; and R11 and R12 are each, independently, selected from the group consisting of hydrogen, C? 5-alkyl, Cx-5-alkyl-am or, where the Cx 5-alkyl group can be interrupted by O, S or N (H), and phenyl substituted or not substituted, or Rill and R can form the following 6-member ring: where x and y are each, independently, 0 or 1, - wherein X5 is selected from the group consisting of hydrogen, C? -5-alkyl, C? _5-alkox ?, (CH2) 0-4-aplo substituted or unsubstituted, (CH2) 0-4-c-substituted or unsubstituted, substituted (CH2) or -4-heterocyclo substituted or unsubstituted, (CH2) 04-benzo [1, 3] dioxol, wherein the C? _5-alkyl or CH2 groups can be interrupted by a carbonyl group or -C (0) 0-; wherein the ring formed by R11 and R12 can be further substituted by C? _5-alkyl, halogen, or C02H

27. The method according to claim 26, characterized in that R1 is selected from the group consisting of H, F , CH3, CF3, CN, and phenyl substituted with CH3; R4 is selected from the group consisting of hydrogen, F, OH, CH3, Br, Cl, OCH3, N02 and CF3; and R11 and R12 are each, independently, selected from the group consisting of hydrogen, (CH2)? 4-halogen, and (CH2)? _ 4N (CH3) CH2Ph, or R11 and R12 can form the next ring where x and y are each, independently, 0 or 1; wherein X5 is selected from the group consisting of H, CH3, isopropyl, t-butyl, cyclopropyl, CH2-? Sopropyl, CH2-t-butyl, CH2-c? Clopropyl, CH2-c? Clohexyl, CH2-C02H, C (0) 0- Ci s-alkyl, C (0) Ph, (CH2) 1-4-p? r? n? lo, CH (CH3) Ph, CH (CF3) Ph, CH (F) Ph, and (CH2)? - 4Ph, wherein the phenyl group can be independently substituted one or more times with chlorine, CN, C02H, N02, Cl or OCH3; wherein the ring formed by R11 and R12 can be further substituted by Cx 5 -alkyl, halogen, or C02H.

28. The method according to claim 26, characterized in that Formula 8 is represented by Compound B; Compound R; Compound S; Compound 1, Compound 2; Compound 3; Compound 4; Compound 5; Compound 6; Compound 7; Compound 8; Compound 9; Compound 10; Compound 11; Compound 12; Compound 13; Compound 14; Compound 15; Compound 16; Compound 17; Compound 18; Compound 19; Compound 20; Compound 21; Compound 22; Compound 23; Compound 24; Compound 25; Compound 26; Compound 27 Compound 28; Compound 29; Compound 30; Compound 55 Compound 56; Compound 57; Compound 58; Compound 62 Compound 63; Compound 64; Compound 65; Compound 66 Compound 67; Compound 68; Compound 69; Compound 70 Compound 71; Compound 72; Compound 73; Compound 74 Compound 75; Compound 76; Compound 77; Compound 78 Compound 79; Compound 80; Compound 81; Compound 82 Compound 83; Compound 84; Compound 85; Compound 86 Compound 87; Compound 88; Compound 89; Compound 90 Compound 91; Compound 92; Compound 93; Compound 94 Compound 95; Compound 96; Compound 97; Compound 98 Compound 99; Compound 100; Compound 109; Compound 112; Compound 113; Compound 114; Compound 115; Compound 117; Compound 118; Compound 119; Compound 120; Compound 121 or Compound 122.

29. The method according to any of claims 1-28, characterized in that contacting the cells with an effective amount of the compound inhibits the activity of the gate ions channel.

30. The method according to any of claims 1-28, characterized in that the gate ion channel is comprised of at least one sub-unit selected from the group consisting of a member of the DEG / ENaC, P2X gene superfamilies, and TRPV.

31. The method according to any of claims 1 to 28 the, wherein the ion channel gate is comprised of at least one selected from the group consisting subunit of aENaC, ßENaC,? ENaC, denac, ASICla, ASIClb, ASIC2A, ASIC2B , ASIC3, ASIC4, BLINaC, hINaC, P2X ?, P2X2, P2X3, P2X4, P2X5, P2X6, P2X7, TRPVl, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6.

32. The method according to claim 30 or 31, characterized in that the gate ion channel is homomultimeric.

33. The method according to claim 30 or 31, characterized in that the gate ion channel is heteromultimépco.

34. The method according to any of claims 30-33, wherein the channel gate DEG / ENaC ion is comprised of at least one selected from the group consisting subunit of aENaC, ßENaC,? ENaC, denac, BLINaC, hINaC, ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3, and ASIC4.

35. The method according to any of claims 30-33, wherein the channel gate DEG / ENaC ion is comprised of at least one selected from the group consisting subunit of ASICla, ASIClb, ASIC2A, ASIC2B, ASIC3, and ASIC4.

36. The method according to any of claims 30-33, characterized in that the gate ion channel comprises ASICla and / or ASIC3.

37. The method according to any of claims 30-33, characterized in that the gate ion channel P2X comprises at least one sub-node selected from the group consisting of P2XX, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7.

38. The method according to any of claims 30-33, characterized in that the gate ion channel TRPV comprises at least one sub-unit selected from the group of TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6.

39. The method according to claim 33, characterized in that the heteromultimeric gate ion channels include the following combinations of gate ion channels: aENaC, 3ENaC and? ENaC; aANaC, ßENaC and dENaC; ASICla and ASIC3; ASIClb and ASIC3; ASIC2a and ASIC3; ASIC2b and ASIC3; ASICla, ASIC2a and ASIC3; P2XX and P2X2; P2X? and P2X5; P2X2 and P2X3; P2X2 and P2X6; P2X4 and P2X6; TRPVl and TRPV2; TRPV5 and TRPV6; and TRPVi and TRPV4.

40. The method according to claim 33, wherein the heteromultimeric gate ion channels include the following combinations of ion channels of gate: ASICla and ASIC2a; ASIC2a and ASIC2b; ASIClb and ASIC3; and ASIC3 and ASIC2b.

41. The method according to any of claims 1-28, characterized in that the activity of the gate ion channel is associated with pain.

42. The method according to any of claims 1-28, characterized in that the activity of the gate ion channel is associated with an inflammatory disorder.

43. The method according to any of claims 1-28, characterized in that the activity of the gate ion channel is associated with a neurological disorder.

44. The method according to claim 41, characterized in that the pain is selected from the group consisting of cutaneous pain, somatic pain, visceral pain and neuropathic pain.

45. The method according to claim 41, characterized in that the pain is acute pain or chronic pain.

46. The method according to claim 44, characterized in that the cutaneous pain is associated with injury, trauma, a cut, a laceration, a puncture, a burn, a surgical incision, an infection or acute inflammation.

47. The method according to claim 44, characterized in that the somatic pain is associated with a lesion, disease or disorder of the connective and musculoskeletal system.

48. The method according to claim 47, characterized in that the lesion, disease or disorder is selected from the group consisting of dislocations, broken bones, arthritis, psoriasis, eczema, and ischemic heart disease.

49. The method according to claim 44, characterized in that the visceral pain is associated with a lesion, disease or disorder of the circulatory system, the respiratory system, the gastrointestinal system, or the genitourinary system.

50. The method according to claim 49, characterized in that the disease or disorder of the circulatory system is selected from the group consisting of ischemic heart disease, angina, acute myocardial infarction, cardiac arrhythmia, phlebitis, intermittent claudication, varicose veins and hemorrhoids. .

51. The method according to claim 49, characterized in that the disease or disorder of the respiratory system is selected from the group consisting of asthma, respiratory infection, chronic bronchitis and emphysema.

52. The method according to claim 49, characterized in that the disease or disorder of the gastrointestinal system is selected from the group consisting of gastritis, duodemtis, irritable bowel syndrome, colitis, Crohn's disease, gastrointestinal reflux disease, ulcers and diverticulitis.

53. The method according to claim 49, characterized in that the disease or disorder of the genitourinary system is selected from the group consisting of cystitis, urinary tract infections, glomerulonephritis, polycystic kidney disease, kidney stones and cancers of the genitourinary system. .

54. The method according to claim 49, characterized in that the somatic pain is selected from the group consisting of arthralgia, myalgia, chronic pain of the lower back, non-existent extremity pain, pain associated with cancer, dental pain, fibromyalgia, epileptic pain disorder, non-specific chronic pain, chronic pelvic pain, post-operative pain and referred pain.

55. The method according to claim 49, characterized in that neuropathic pain is associated with a lesion, disease or disorder of the nervous system.

56. The method according to claim 54, characterized in that the lesion, disease or disorder of the nervous system is selected from the group consisting of Neuralgia, neuropathy, headache, migraine, psychogenic pain, chronic cephalic pain and spinal cord injury.

57. The method according to any of claims 1-28, characterized in that the activity of the gate ions channel is selected from an inflammatory disorder of the connective and musculoskeletal tissue system, the respiratory system, the circulatory system, the genitourinary system, the gastrointestinal system or the nervous system.

58. The method according to claim 57, characterized in that the inflammatory disorder of the connective and musculoskeletal tissue system is selected from the group consisting of arthritis, psoriasis, myocitis, dermatitis and eczema.

59. The method according to claim 57, characterized in that the inflammatory disorder of the respiratory system is selected from the group consisting of asthma, bronchitis, sinusitis, pharyngitis, laryngitis, tracheitis, rhinitis, cystic fibrosis, respiratory infection and acute distension syndrome. respiratory

60. The method according to claim 57, characterized in that the inflammatory disorder of the circulatory system is selected from the group consisting of vasculitis, hematuria syndrome, atherosclerosis, arteritis, phlebitis, carditis and coronary heart disease.

61. The method according to claim 57, characterized in that the inflammatory disorder of the gastrointestinal system is selected from the group consisting of inflammatory bowel disorder, ulcerative colitis, Crohn's disease, diverticulitis, viral infection, bacterial infection, peptic ulcer, hepatitis. chronic, gingivitis, periodentitis, stomatitis, gastritis and gastrointestinal reflux disease.

62. The method according to claim 57, characterized in that the inflammatory disorder of the genitourinary system is selected from the group consisting of cystitis, polycystic kidney disease, nephritic syndrome, urinary tract infection, cystmosis, prostatitis, salpitis gitis, endometriosis and genitourinary cancer.

63. The method according to claim 43, characterized in that the neurological disorder is selected from the group consisting of schizophrenia, bipolar disorder, depression, Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke, addiction, cerebral ischemia, neuropathy, retinal pigment degeneration, glaucoma, cardiac arrhythmia, herpes zoster, chorea of Hunt gton, Parkinson's disease, disorders of anxiety, panic disorders, phobias, anxiety hysteria, generalized anxiety disorder, and neurosis.

64. A method for the treatment of pain in a subject in need thereof, characterized in that it comprises administering to the subject an effective amount of a compound of Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 5a, Formula 6, Formula 6a, Formula 7 or Formula 8.

65. The method according to claim 57, characterized in that the compound is selected from the group consisting of compounds listed in Table A, Table B, Table C, Table D, Table E and Table F.

66. The method according to any of claims 64-65, characterized in that the subject is a mammal.

67. The method according to claim 66, characterized in that the mammal is a human.

68. The method according to any of claims 64-65, characterized in that the pain is selected from the group consisting of cutaneous pain, somatic pain, visceral pain and neuropathic pain.

69. The method according to any of claims 57-59, characterized in that the pain is acute pain or chronic pain.

70. A method for the treatment of an inflammatory disorder in a subject who needs it, characterized in that it comprises administering to the subject an effective amount of a compound of Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 5a, Formula 6, Formula 6a, Formula 7 or Formula 8.

71. The method according to claim 70, characterized in that the compound is selected from the group consisting of compounds listed in Table A, Table B, Table C, Table D, Table E and Table F.

72. The method according to any of claims 70-71, characterized in that the subject is a mammal.

73. The method according to claim 72, characterized in that the mammal is a human.

74. The method according to any of claims 70-71, characterized in that the inflammatory disorder is inflammatory disorder of the connective and musculoskeletal tissue system, the respiratory system, the circulatory system, the genitourinary system, the gastrointestinal system or the gastrointestinal system. nervous system.

75. A method for the treatment of a neurological disorder in a subject in need thereof, characterized in that it comprises administering an effective amount of a compound of Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 5a, Formula 6, Formula 6a, Formula 7 or Formula 8.

76. The method according to claim 75, characterized in that the compound is selected from the group consisting of compounds listed in Table A, Table B, Table C, Table D, Table E and Table F.

77. The method according to any of claims 75-76, characterized in that the subject is a mammal.

78. The method according to claim 77, characterized in that the mammal is a human.

79. The method according to any of claims 75-76, characterized in that the neurological disorder is selected from the group consisting of schizophrenia, bipolar disorder, depression, Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, apoplexy, addiction. , cerebral ischemia, neuropathy, retinal pigment degeneration, glaucoma, cardiac arrhythmia, herpes zoster, chorea of Huntmgton, Parkinson's disease, anxiety disorders, panic disorders, phobias, anxiety hysteria, generalized anxiety disorder, and neurosis.

80. A method for the treatment of a disease or disorder associated with the genitourinary and / or gastrointestinal systems of a subject in need thereof, characterized in that it comprises administering to the subject an effective amount of a compound of Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 5a, Formula 6, Formula 6a, Formula 7 or Formula 8.

81. The method according to claim 80, characterized in that the compound is selected from the group consisting of compounds listed in Table A, Table B, Table C, Table D, Table E and Table F.

82. The method according to any of claims 80-81, characterized in that the subject is a mammal.

83. The method according to claim 79, characterized in that the mammal is a human.

84. The method according to any of claims 80-81, characterized in that the disease or disorder of the gastrointestinal system is selected from the group consisting of gastritis, duode itis, irritable bowel syndrome, colitis, Crohn's disease, ulcers and diverticulitis. .

85. The method according to any of claims 80-81, characterized in that the disease or disorder of the genitourinary system is selected from the group consisting of cystitis, urinary tract infections, glomerulonephritis, polycystic kidney disease, kidney stones and cancers of the genitourinary system.

86. The method according to any of claims 1, 64, 70, 75 or 80 characterized in that the The method further comprises administering an adjuvant composition.

87. The method according to claim 86, characterized in that the adjuvant composition is selected from the group consisting of opioid analgesics, non-opioid analgesics, local anesthetics, corticosteroids, non-spheroidal anti-inflammatory drugs, non-selective COX inhibitors, non-selective inhibitors, selective C0X2, selective inhibitors of C0X2, antiepileptics, barbiturates, antidepressants, marijuana, and topical analgesics.

88. A compound characterized in that it is represented by Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 5a, Formula 6, Formula 6a, Formula 7 or Formula 8.

89. The compound characterized in that it is selected from the group consisting of Compound F; Compound 31; Compound 36; Compound 37; Compound 38; Compound 39; Compound 40; Compound 50; Compound 51; Compound 52; Compound 53 and Compound 54.

90. The compound characterized in that it is selected from the group consisting of Compound 35 and Compound 110.

A compound characterized in that it is selected from the group consisting of Compound K; Compound T; Compound 32; Compound 33; Compound 101; Compound 102; Compound 103; Compound 104; Compound 105; Compound 106; Compound 107; Compound 108 and Compound 111.

92. The compound characterized in that it is selected from the group consisting of Compound C; Compound G; Compound 34; Compound 41; Compound 42; Compound 43; Compound 44; Compound 45; Compound 46; Compound 47; Compound 48 and Compound 49.

93. The compound characterized in that it is selected from the group consisting of Compound A; Compound D; Compound H; Compound L; Compound M; Compound N; Compound 0; Compound P; Compound Q; Compound 59; Compound 60; Compound 61 or Compound 116.

94. The compound characterized in that it is selected from the group consisting of Compound B; Compound R; Compound S; Compound 1, Compound 2; Compound 3; Compound 4; Compound 5; Compound 6; Compound 7; Compound 8; Compound 9; Compound 10; Compound 11; Compound 12; Compound 13; Compound 14; Compound 15; Compound 16; Compound 17; Compound 18; Compound 19; Compound 20; Compound 21; Compound 22; Compound 23; Compound 24; Compound 25; Compound 26; Compound 27; Compound 28; Compound 29; Compound 30; Compound 55; Compound 56; Compound 57; Compound 58; Compound 62; Compound 63; Compound 64; Compound 65; Compound 66; Compound 67; Compound 68; Compound 69; Compound 70; Compound 71; Compound 72; Compound 73; Compound 74; Compound 75; Compound 76; Compound 77; Compound 78; Compound 79; Compound 80; Compound 81; Compound 82; Compound 83; Compound 84; Compound 85; Compound 86; Compound 87; Compound 88; Compound 89; Compound 90; Compound 91; Compound 92; Compound 93; Compound 94; Compound 95; Compound 96; Compound 97; Compound 98; Compound 99; Compound 100; Compound 109; Compound 112; Compound 113; Compound 114; Compound 115; Compound 117; Compound 118; Compound 119; Compound 120; Compound 121 and Compound 122. SUMMARY OF THE INVENTION The present invention relates to compositions and methods for modulating the activity of gate ion channels.