MXPA06010029A - Ion channel modulators - Google Patents

Abstract

The invention relates to compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds, compositions, and methods described herein can be used for the therapeutic modulation of ion channel function, and treatment of disease and disease symptoms, particularly those mediated by certain calcium channel subtype targets.

Description

ION CHANNEL MODULATORS Background of the Invention All cells depend on the regulated movement of inorganic ions through cell membranes to perform essential physiological functions. Electrical excitability, synaptic plasticity, and signal transduction are examples of processes in which changes in ion concentration play a critical role. In general, the ion channels that allow these changes are protein pores consisting of one or multiple subunits, each containing two or more membrane coverage domains. Most ion channels have selectivity for specific ions, mainly Na +, K +, Ca2 +, or Cl ", by virtue of physical preferences for size and charge.The electrochemical forces, instead of the active transport, lead the ions to Through the membranes, in this way a single channel can allow the passage of millions of ions per second.The opening of the channel, or "gate" is controlled closely by changes in voltage or by ligand binding, depending on the subclass of the canal Ion channels are attractive therapeutic targets because they are involved in many physiological processes, although the generation of drugs with Ref: 175193 Specificity for particular channels in particular tissue types maintains a greater challenge. Voltage gate ion channels open in response to changes in membrane potential. For example, the depolarization of excitable cells such as neurons results in a transient influx of Na + ions, which propagate nerve impulses. This change in Na + concentration is sensitive by voltage gate K + channels, which then allow an efflux of K + ions. The efflux of K + ions repolarizes the membrane. Other cell types depend on the voltage gate Ca2 + channels to generate action potentials. Voltage gate ion channels also perform important functions in non-excitable cells, such as the regulation of secretion, homeostatic, and mitogenic processes. The ligand gate ion channels can be opened by extracellular stimuli such as neurotransmitters (eg, glutamate, serotonin, acetylcholine), or intracellular stimuli (eg, cAMP, Ca2 +, and phosphorylation). The Cav2 family of voltage gate calcium channels consists of 3 major subtypes Cav2.1 (calcium currents of type P or Q), Cav2.2 (calcium currents of N type) and Cav2.3 (calcium currents of type R). These currents are found almost exclusively in the central nervous system (CNS), peripheral nervous system (SNP) and neuroendocrine cells and constitute the predominant forms of presynaptic voltage gate calcium current. The entrance of presynaptic calcium is modulated by some type of receptors coupled to the G protein (GPCRs) and modulation of Cav2 channels are widely and highly effective means for the regulation of neurotransmission. The subunit composition of the Cav2 channels are defined by their subunit, which forms the pore and contains the voltage sensitive gates (ax2.1, a? 2.2 and ax2.3, also known as a1A. «IB. And oc? E respectively) and subunits ß, a2d and?. Genetic or pharmacological disturbances in the function of the ion channel can have dramatic clinical consequences. Long QT syndrome, epilepsy, cystic fibrosis, and episodic ataxia are some examples of inherited diseases that result from mutations in the ion channel subunits. Toxic side effects such as arrhythmia and stroke that are triggered by certain drugs are due to interference with the function of ion channels (Sirois, JE and, Atchison, WD, Neurotoxicology 1996; 17 (1): 63-84).; Keating, MT, Science 1996 272: 681-685). The drugs are useful for the therapeutic modulation of ion channel activity, and have applications in the treatment of many pathological conditions, including hypertension, angina pectoris, myocardial ischemia, overactivity of the bladder, alopecia, pain, heart failure, dysmenorrhea, type II diabetes, arrhythmia, graft rejection, stroke, seizures, epilepsy, infarction, gastric hypermobility, psychosis, cancer, muscular dystrophy, and narcolepsy (Coghlan, MJ, et al., J. Med. Chern., 2001, 44: 1627-1653; Ackerman. M.J., and Clapham, D.E. N. Eng. J. Med. 1997, 336: 1575-1586). The increasing number of ion channels identified and the understanding of their complexity help in future therapy efforts, which modify the function of the ion channel. The therapeutic modulation of Cav2 channel activity has applications in the treatment of many pathological conditions. All the primary sensory afferents provide input to neurons in the dorsal horns of the spine and in the dorsal root ganglion neurons in the dorsal horn and calcium influx through the Cav2.2 channels triggering the release of neurotransmitters from terminals of the presynaptic nerve in the spine. Therefore, blockade of Cav2.2 channels is expected to be broadly effective because these channels are on a common downward trajectory of the wide variety of pain-mediating receptors (Julius, D. and Basbaum, AI Nature 2001, 413: 203-216). In fact, intrathecal injection of Cav2.2 selective conopeptide ziconitide (SNX-111) has been shown to be widely effective against both neuropathic and inflammatory pain in animals and humans (Bo ersox, SS et al, J Pharmacol Exp. Ther 1996, 279: 1243-1249). Ziconitide has also been shown to be highly effective as a neuropathic agent in rat models of global or focal ischemia (Colburne, F. et al, Stroke 1999, 30: 662-668). Thus, it is reasonable to conclude that the modulation of Cav2.2 has implications in the neuroprotection / apoplexy treatment. The Cav2.2 channels are located in the periphery and mediate the release of catecholamine from sympathetic neurons and adrenal chuffin cells. Some forms of hypertension result from elevated sympathetic tone and modulators. Cav2.2 could be particularly effective in the treatment of this disorder. Although complete blockade of Cav2.2 may cause hypotension or impaired baroreceptor reflexes, partial inhibition by Cav2.2 modulators may reduce hypertension to a minimum reflex tachycardia (Uneyama, 0. D. Int. J. Mol Med. 1999 3: 455-466). Overactivity of the bladder (OAB) is characterized by storage symptoms such as urgency, frequency and nocturia with or without stimulation of incontinence, which results from overactivity of the muscle in the bladder. OAB can lead to incontinence stimulation. The etiology of OAB and painful bladder syndrome is unknown, although alterations in nerves, smooth muscle and urothelium can cause OAB (Steers, W. Rev. Urol, 4: S7-S18). There is evidence to suggest that the reduction of bladder overactivity can be indirectly effected by the inhibition of Cav2.2 and / or Cavl channels. The location of Cav2.1 channels in the superficial laminae of the dorsal horn of the spine suggests that these channels are involved in the perception and maintenance of certain forms of pain (Vanegas, H. and Schaible, H. Pain 2000, 85: 9 -18). The complete elimination of Cav2.1 calcium currents alters the synaptic transmission resulting in severe ataxia. Gabapentin has been used clinically for many years as an aid therapy for the treatment of epilepsy. In recent years, it has emerged as a leading treatment for neuropathic pain. Clinical trials have shown that gabapentin is effective for the treatment of post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, migraine and fibromyalgia (Mellegers, P.G. et al Clin J Pain 2001, 17: 284-295). Gabapentin was designed as a metabolically stable GABA imitator, but most studies have no effect on GABA receptors. The a2d subunit of the Cav2.1 channel has been identified as a high affinity binding site for gabapentin in the CNS. There is evidence to suggest that gabapentin could inhibit neurotransmission in the spine by interfering with the function of the a2d subunits, thereby inhibiting presynaptic calcium currents.

Brief Description of the Invention The invention relates to heterocyclic compounds, compositions comprising the compounds, and methods of using the compounds and compositions of the compound. The compounds and compositions comprising them are useful for treating diseases or symptoms of diseases, including those mediated by or associated with ion channels. An aspect is a compound of the formula (I) or a pharmaceutical salt thereof wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; R1 is Ar2 or lower alkyl optionally substituted with Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each R2 is independently selected from (CH2) mC02R3, (CH2) mC0Ar3, (CH2) mC0NR3R4, (CH2) mAr3, (CH2) n0R3; (CH2) 3Ar3 or (CH2) nNR3R4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R7 or (CH2) pAr3; or each R3 and R4 are taken together with the nitrogen atom which is bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally an NR4, O or S and each heterocyclic ring is optionally substituted with one or more lower alkyl groups;, each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each m is independently 0 or 1; each n is independently 1 or 2; each p is independently 0 or 1; each substituent for Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) 0R5, C (0) ÑR5R6, 0C (0) NR5R6, NR5C (O) NR5R6, C (NR5) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH, alkylamino Ca-C4, dialkylamino C? -C4 or C3-C6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) pAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, alkylamino 1.-C4, dialkylamino C-C4 or cycloalkyl C3-C6; each R7 is independently selected from (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy / NH 2, C 1 -C 4 alkylamino / C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; and each Ar4 is independently selected from C3-C3 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, Cx-C alkoxy, NH2, C1-C4 alkylamino, C3-C4 dialkylamino or 1,2-methylenedioxy. Other aspects are those compounds (of any of the formulas herein (including any combination thereof): wherein each R2 is independently (CH2) mC02R3, (CH2) mC0Ar3, (CH2) mCONR3R4, (CH2) nAr3 or (CH2) nNR3R4; Wherein, R 1 is C 2 -C 2 alkyl substituted with Ar 2; and Ar2 is optionally substituted with one or more substituents; Wherein, R1 is Ar2; Ar2 is optionally substituted with one or more substituents; Wherein, R2 is (CH2) raC (0) OR3, (CH2) mC (0) Ar3 or (CH2) mC (O) NR3R4 and each is independently 0 or 1; and each Ar3 is optionally substituted with one or more substituents; wherein, R2 is (CH2) nNR3R4 and n is 1; wherein, R2 is (CH2) nNR3R4 and n is 2; wherein, R2 is (CH2) mAr3 and m is 0; and Ar3 is optionally substituted with one or more substituents; wherein, R2 is (CH2) mAr3 and m is 1; and Ar3 is optionally substituted with one or more substituents; wherein each Ar1, Ar2, Ar3 and Ar4 is independently selected from cycloalkyl, phenyl, naphthyl, acenaphtyl, indenyl, azulenyl, fluorenyl, anthracenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl -, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, indolyl, .isoindolyl, 3H-indolyl, indolinyl, benzo- [b] furanyl, benzo [b] thiophenyl, - lH -indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, "quinolinyl, tetrahydro-isoquinolinyl, isoquinolinyl, tetrahydro-quinoline, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, peridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, each optionally substituted with one or more substituents; wherein, the compound is of the formula (I): wherein, Ar 1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each Ar2 is independently selected from aryl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 1 wherein each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5R5, C (0) R7, S (0 ) 2) R7 or (CH2) pAr3; or each R3 and R4 are taken together with the nitrogen atom which is bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally an NR4, O or S and each heterocyclic ring it is optionally substituted with one or two lower alkyl groups; each p is independently 0 or 1; and each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; wherein the compound is of the formula (I): wherein, Ar 1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each Ar2 is independently selected from aryl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 2 wherein, each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5Rs, C (0) R7, S (0 ) 2) R7 or (CH2) pAr3, - or each R3 and R4 are taken together with the nitrogen atom which is bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally an NR4, O or S and each heterocyclic ring is optionally substituted with one or two lower alkyl groups; each p is independently 0 or 1; and each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; Wherein the compound is of the formula (I): (I) wherein, Ar1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; , each Ar2 is independently selected from heterocyclyl or heteroaryl each optionally 'substituted with one to three substituents; R2 is (CH2) mAr3 and m is 0; each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, OR5, NR5R6, perfluoroalkyl C _.- C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C alkylamino, C? -C4 dialkylamino; each R6 is independently selected from hydrogen, (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C alkylamino, C? -C4 dialkylamino; each p is independently 0 or 1; and each Ar 4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 perfluoroalkyl. , perfluoroalkoxy L-C2, 1,2-methylenedioxy; Wherein the compound is of the formula (I): wherein, Ar 1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each Ar2 is independently selected from heterocyclyl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) mAr3 and m is 1; each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2 / 1,2-methylenedioxy; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4; each Rd is independently selected from hydrogen, (CH 2) pAr 4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, L-C 4 alkoxy, NH 2, C 1 -C 4 alkylamino / C 1 -C 4 dialkylamino; each p is independently 0 or -1; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one up to three independently selected substituents halogen, OH, C3-C4 alkoxy, NH2, C4-4 alkylamino, C1-C4 dialkylamino, perfluoroalkyl Ca-C2 , perfluoroalkoxy C, L-C2, 1,2-methylenedioxy; Wherein the compound is of the formula (I): wherein, Ar 1 is phenyl substituted with one to three substituents; R1 is Ar2 and Ar2 phenyl substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 1; each R3 is independently selected from H or lower alkyl; each R4 is (CH2) pAr3; each p is independently 0 or 1; each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C _. C2, 1,2-methylenedioxy; each R 5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C alkylamino, C 3 -C 4 dialkylamino; each R6 is independently selected from hydrogen, (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C1-C4 alkoxy, NH2, C4-C4 alkylamino, C1-C4 dialkylamino; and each Ar 4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 perfluoroalkyl. , perfluoroalkoxy _-C2, 1,2-methylenedioxy; Wherein the compound is of the formula (I): wherein, Ar 1 is phenyl substituted with one to three substituents; R1 is Ar2 and Ar2 phenyl substituted with one to three substituents, - R2 is (CH2) nNR3R4 and n is 1; each R3 and R4 are taken together with the nitrogen atom which is bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally an NR4, O or S and each heterocyclic ring is optionally substituted with one or two lower alkyl groups; each substituent for Ar1 and Ar2 is independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy Ca-C, 1,2-methylenedioxy each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected of halogen, OH, C3-C4 alkoxy, NH2, C1-C4 alkylamino, dialkylamino C? -C4; each Rs is independently selected from hydrogen, (CH) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C1-C4 alkoxy, NH2, C4-alkylamino, C4-C4 dialkylamino; each p is independently 0 or 1; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three independently selected substituents halogen, OH, C1-C4 alkoxy, NH2, C?-C4 alkylamino, dialkylamino C?-C4, perfluoroalkyl Cx-C2, C 1 -C 2 perfluoroalkoxy-1,2-methylenedioxy; Wherein the compound is of the formula (I): wherein, Ar 1 is phenyl substituted with one to three substituents; R1 is Ar2 and Ar2 phenyl substituted with one to three substituents; R2 is (CH2) mAr3 and m is 0; each Ar3 is benzimidazol-2-yl optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar3 is each independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C1-C4 alkoxy, H2, C1-C4 alkylamino, dialkylamino C? -C4; each R6 is independently selected from hydrogen, (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino; each p is independently 0 or 1; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three independently selected substituents halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino, perfluoroalkyl C? -C2, perfluoroalkoxy C1-C2, 1,2-methylenedioxy; or wherein the compound of the formula (I) is any of those in Table I herein. Another aspect is a method for modulating (eg, inhibiting, agonizing, antagonizing) calcium channel activity including contacting a compound, or pharmaceutically acceptable salt thereof, of any of the formulas herein (or composition thereof). ) with a calcium channel. Another aspect is a method for modulating (eg, inhibiting, agonizing, antagonizing) calcium channel activity in a subject that includes administering to the subject an effective amount of a compound, or pharmaceutical salt thereof, of any of the formulas in the present (or composition thereof). Another aspect is a method for treating a calcium channel mediated disease in a subject that includes administering to the subject an effective amount of a compound, or pharmaceutical salt thereof, of any of the formulas herein (or composition thereof) . In the methods herein, the calcium channel can be Cav2 (eg, Cav2.2). The calcium channel Cav2 that mediates the disease or symptoms of the disease can be a disease of the nervous system or symptom of the disease or it can be cardiovascular disease or symptom of the disease. Another aspect is a method for treating calcium channel Cav2 mediated by acute pain, inflammatory pain, or neuropathic pain in a subject which includes administering to the subject an effective amount of a compound, or pharmaceutical salt thereof, of any of the formulas in the present (or composition thereof). Another aspect is a method for treating calcium channel Cav2 mediated by urinary incontinence or overactive bladder in a subject which includes administering to a subject an effective amount of a compound, or pharmaceutical salt thereof, of any of the formulas herein ( or composition thereof) -. Another aspect is a method for treating the calcium channel Cav2 mediated by stroke, traumatic brain injury or neuronal disease in a subject which includes administering to a subject an effective amount of a compound, or pharmaceutical salt thereof, of any of the formulas in the present (or composition thereof). Another aspect is a method for treating calcium channel Cav2 mediated by hypertension in a subject that includes administering to the subject an effective amount of a compound, or pharmaceutical salt thereof, of any of the formulas herein (or composition thereof). . Another aspect is a method for treating a disease mediated by the calcium channel in a human in need of such treatment including administration to the human of a compound, or pharmaceutical salt thereof, of any of the formulas herein (or composition thereof). ).

Another aspect is a composition that includes a compound, or pharmaceutically acceptable salt thereof, of any of the formulas herein and a pharmaceutically acceptable carrier. The composition may also include an additional therapeutic agent. Another aspect is a method for treating a disease or symptom of the disease in a subject that includes administering to the subject in need of such treatment an effective amount of a compound, or pharmaceutical salt thereof, of any of the formulas herein ( or composition thereof). The disease or symptom of the disease may be nervous system disease, cardiovascular disease, acute pain, inflammatory pain, or neuropathic pain, urinary incontinence, overactive bladder, calcium channel stroke, traumatic brain injury, neuronal disorder, or hypertension. In another aspect, the invention relates to a composition comprising a compound of any of the formulas herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier. The additional therapeutic agent can be a cardiovascular disease agent and / or a disease agent of the nervous system. A disease agent of the nervous system refers to a disease agent of the peripheral nervous system (PNS) and / or disease agent of the central nervous system (CNS).

Yet another aspect of this invention relates to a method of treating a subject (e.g., mammal, human, horse, dog, cat) having a disease or symptom of the disease (including, but not limited to, angina, hypertension). , congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, traumatic brain injury, or a neuronal disorder). The method includes administering to the subject (which includes a subject identified as needing such treatment) an effective amount of a compound described herein, or a composition described herein to produce such an effect. A subject who needs such treatment may be in the judgment of a subject or a health care professional and may be subjective (for example, opinion) or objective (for example, measured by a method of testing or diagnosis). ). Yet another aspect of this invention relates to a method of treating a subject (e.g., mammal, human, horse, dog, cat) having a disease mediated by the ion channel or symptom of the disease (including, but not it is limited to angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, traumatic brain injury, or a neuronal disorder). The method includes administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce such an effect. Identifying a subject that needs such treatment can be in the judgment of a subject or a health care professional and can be subjective (for example, opinion) or objective (for example, measured by a method of testing or diagnosis) . The invention "also relates to a method for making a compound described herein, the method includes any of the reactions or reagents as outlined in the reaction schemes or examples herein.Alternatively, the method includes taking any the intermediary compounds described herein and reacting this with one or more chemical reagents in one or more steps to produce a compound described herein.Also within the scope of this invention is a packaged product.The packaged product includes a container, one of the above compounds in the container, and a legend (eg, a label or an insert) associated with the container and indicating the administration of the compound to treat a disorder associated with modulation in the ion channel. , the compounds, compositions, and methods outlined herein are any of the compounds of the tables in the foregoing. present or methods included.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Detailed Description of the Description As used herein, the term "halo" refers to any radical of fluorine, chlorine, bromine or iodine .-- The term "alkyl" refers to a hydrocarbon chain which may be a straight chain. or branched chain, which contains the indicated number of carbon atoms For example, C? -C5 indicates that the group may have from 1 to 5 (inclusive) carbon atoms in it.The term "lower alkyl" refers to a Cx-C6 alkyl chain The term "arylalkyl" refers to a portion in which a hydrogen atom is replaced by an aryl group.

The term "alkoxy" refers to an -O-alkyl radical. The term "alkylene" refers to an alkyl divalent (ie, -R-). The term "alkylene dioxo" refers to a divalent species of the structure -O-R-O-, in which R represents an alkylene. The term "cycloalkyl" as used herein includes partially saturated and unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons. The term "aryl" refers to a 6-membered monocyclic hydrocarbon ring or multicyclic aromatic ring system of 10 to 14 members wherein 0, 1, 2, 3, or 4 atoms of each ring can be substituted by a substituent. Examples of the aryl groups include phenyl, naphthyl and the like. The term "heterocyclyl" refers to a. 5-8 membered non-aromatic monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic, or 1-9 heteroatoms if is tricyclic, the heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring can be substituted by a substituent. The term "heteroaryl" refers to a 5-8 membered aromatic monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic, or 1-9 heteroatoms if tricyclic, heteroatoms selected from 0, N, or S (eg, carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if is monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring can be substituted by a substituent.

The term "oxo" refers to an oxygen atom, which forms a carbonyl when bonded to a carbon, an N-oxide when bound to nitrogen, and a sulfoxide or sulfone when bonded to sulfur. The term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted by substituents. The term "substituents" refers to a group "substituted" on an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group at any atom of that group.

Suitable substituents include, without halogen limitation, CN, N02, 0RS, SR5, S (0) 2OR5, RSRS, oxo, perfluoroalkyl C? -C2, perfluoroalkoxy Cx-C2, 1, 2-methylenedioxy, C (0) 0R5, C (0) NR5Rs, OC (0 ) R5R6, NR5C (0) NR5R6, C (NR6) NR5Rd, R5C (R6) NR? R6, S (0) 2NR5R6, R7, C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7. Each Rs is independently hydrogen, C 1 -C 4 alkyl or C 3 -C 3 cycloalkyl. Each Rs is independently hydrogen, C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, Ca-C4 alkyl or C?-C4 alkyl substituted with C3-Cß cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R 7 is independently C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C3-Cg cycloalkyl, aryl, heterocyclyl, heteroaryl and C? -C4 alkyl in each R5, R6 and R7 can optionally be substituted with halogen, CN, C? -C4 / OH alkyl, C-alkoxyL-C, NH2, C? -C4 alkylamino / dialkylamino C? -C4, perfluoroalkyl C? -C2, perfluoroalkoxy C3.-C2, or 1,2-methylenedioxy. In one aspect, the substituents in a group are independently, hydrogen, hydroxyl, halogen, nitro, S03H, trifluoromethyl, trifluoromethoxy, straight or branched alkyl (C6-6), alkoxy (straight or branched Ci-Cg), O-benzyl , O-phenyl, phenyl, 1,2-methylenedioxy, carboxyl, morpholinyl, piperidinyl, amino or OC (0) NR5R6. Each R5 and Re is as described above. The term "treat" or "treatise" refers to administering a compound described herein to a subject for the purpose of curing, healing, alleviating, alleviating, altering, remedying, alleviating, ameliorating or affecting a disease, the symptoms of the disease or predisposition towards the disease. "An effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (that is, it "measured by some test or marker) or subjective (ie, the subject gives an indication of or feels an effect.) An effective amount of the compound described above may be in the range from about 0.1 mg / Kg to about 500. mg / Kg. The effective dose also varies depending on the route of administration, as well as the possibility of co-use with other reagents Representative compounds useful in the compositions and methods are delineated herein: TABLE 1A TABLE IB Ion channel modulator compounds can be identified through both in vitro (e.g., cell-based and cell-free) and in vivo methods. Representative examples of these methods are described in the examples herein. The combinations of the substituents and variables descried by this invention are only those that result in the formation of the stable compounds. The term "stable", as used herein, refers to compounds in which sufficient stability is possessed to allow manufactures and which maintain the integrity of the compound for a sufficient period of time to be useful for the purpose detailed in the present (for example, therapeutic or prophylactic administration to a sutto). The compounds delineated herein can be synthesized using conventional methods, as illustrated in the reaction schemes herein. In the reaction schemes herein, unless stated otherwise, the variables in the chemical formulas are as defined in other formulas herein. For example, Ar1, Ar3, R3 and R4 in the reaction schemes are defined as in any of the formulas herein, except where they are otherwise defined in the reaction schemes.

Reaction scheme 1 The treatment of an aryl nitrile with an alcohol under acidic conditions provides the alkoxy imidate intermediate, which is treated with the appropriate substituted amine under catalytic conditions (eg, ethanolic HCl, CuCl, Ln ions (IIl)) to provide the idine (I) replaced. Treatment of amidine (I) with a bromopyruvate or 4-bromo-3-p-x-butyrate or a 5-bromo-oxo-pentanoate under basic conditions provides the imidiazole ester (lia), which is hydrolyzed to provide the derivative of corresponding acid (Ilb).

Reaction scheme 2 * mesOol The reaction of the acid (Ilb) with the appropriately substituted amine under the standard coupling procedure provides the desired amide (III). Reduction of the amide with common reducing agents such as diborane or lithium aluminum hydride provides the corresponding amine (IV). Alternatively the treatment of the acid (Ilb) with the Weinreb reagent provides the amide (V). Treatment of the amide under standard condition with an organometallic reagent (eg, aryl lithium or aryl magnesium halide) provides the ketone (VI). The reduction of the ketone under a variety of conditions provides the desired product (VII).

Reaction scheme 3 Ar * is arito or heb = roarito pes 0, 1, 263 Alternatively the treatment of the amidine (I) with (X) provides the desired imidazole (VII).

Reaction scheme 4 An alternative route to obtain heteroaryl derivatives is to react the activated acid of (Ilb) with the appropriate substrate followed by cyclization to provide the desired product. For example as i is detailed in reaction scheme 4, the reaction of the activated acid of (Ilb) with benzene-1,2-diamine provides the amide intermediate (VIII), which is cyclized to provide the benzimidazole derivative ( IX) • Reaction scheme 5 The treatment of the carboxylic acid (Ilb) under standard reduction conditions (for example, lithium aluminum hydride) gives (XI). The treatment of (XI) under conditions of standard ether forms (e.g., NaH, halo-R4) gives (XII). The synthesized compounds can be separated from the reaction mixture and then purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, additional methods for synthesizing the compounds of the formulas herein will be apparent to those of ordinary skill in the art. Additionally, the various synthetic steps can be performed in an alternating sequence in order to give the desired compounds. Synthetic chemistry transformations and protective group methodologies (protection and deprotection) useful in the synthesis of the compounds described herein are known in the art and include, for example, those such as those described in R. Larock, Comprehensive Organic Transformations , 2nd. Ed., Wiley-VCH Publishers (1999); T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1999); and L. Paquette, ed. , Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The compounds of this invention may contain one or more asymmetric centers and thus be presented as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All of these isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such cases, the invention expressly includes all tautomeric forms of the compounds described herein (for example, alkylation of a ring system may result in alkylation at sites multiple, the invention expressly includes all these reaction products). Such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.

As used herein, the compounds of this invention, including the compounds of the formulas described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A "pharmaceutically acceptable derivative or prodrug" means any salt, ester, salt of an ester, or other pharmaceutically acceptable derivative of a compound of this invention which, during administration to a recipient, is capable of providing (directly or indirectly) the compound of this invention. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more rapidly absorbed in the blood) or that increase the release from the precursor compound to the biological compartment (for example, the brain or lymphatic system) in relation to the precursor species. Preferred prodrugs include derivatives wherein a group that increases aqueous solubility or active transport through the intestinal membrane is added to the structure of the formulas described herein. See, for example, Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H. Design of Prodrugs; Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen, N. M.

Journal of Medicinal Chemistry 1987, 30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Acade ic Publ. : Switzerland, 1991; pp 113-191; Digenis, G. A. et al. Handbook of Experimental Phar Acology 1975, 28, 86-112; Friis, G. J .; Bundgaard, H. A Textbook of Drug Design and Development; 2 ed.; Overseas Publ .: Amsterdam, 1996; pp 351-385; Pit an, I. H. Medicinal Research Reviews 1981, 1, 189-214; Sinkula, A. A .; Yalkowsky Journal of Pharmaceutical Sciences 1975, 64, 181-210; Verbiscar, A. J.; Abood, L. G Journal of Medicinal Chemistry 1970, 13, 1176-1179; Stella, V. J .; Himmelstein, K. J. Journal of Medicinal Chemistry 1980, 23, 1275-1282; Bodor, N.; Kaminski, J. J. Annual Reports in Medicinal Chemistry 1987, 22, 303-313. The compounds of this invention can be modified by appropriate functionalities added to increase the selective biological properties. Such modifications are known in the art and include those that increase biological penetration in a given biological compartment (eg, blood, lymphatic system, nervous system), increased oral availability, increased solubility to allow administration by injection, altered metabolism and altered excretion ratio. The pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.

Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, anforsulfonate, digluconate, dodecylsulfate, ethanesulfonate, forute, fumarate, glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, chlorohydrate, bromohydrate, iodohydrate, 2-hydroxyethanesulfonate, lactate, aleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulphate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, although not by themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates for obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Suitable base salt derivatives include alkali metal salts (eg, sodium), alkaline earth metal (eg, magnesium), ammonium and N- (alkyl) A • This invention also divides the quaternization of any of the nitrogen-containing groups of the compounds described herein. The soluble or dispersible products in water or oil can be obtained by such quaternization. The compounds of the formulas described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitonally, intramuscularly, or subcutaneously.; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dose in the range from about 0.5 to about 100 mg / kg of body weight, alternatively doses between 1 mg and 1000 mg / dose, every 4 to 120 hours, or in accordance with the requirements of the particular drug. The methods herein contemplate the administration of an effective amount of the compound or composition of compound to achieve the desired or established effect. Typically, the compositions of this invention will be administered from about 1 to about 6 times a day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dose form will vary depending on the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound. Lower or higher doses than those recited above may be required. The specific dose and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, sex, diet, time of administration, rate of excretion, combination of the drug, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition- or symptoms, and the judgment of the treating physician. During the improvement of the patient's condition, a maintenance dose of a compound, composition or combination of this invention can be administered, if - necessary. Subsequently, the dose or frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is maintained when the symptoms have been alleviated to the desired level, the treatment would be stopped. Patients may, however, require intermittent treatment on a long-term basis on any recurrence of the symptoms of the disease. The compositions delineated herein include the compounds of the formulas delineated herein, as well as additional therapeutic agents present, in amounts effective to achieve a modulation of disease or symptoms of the disease, including disorders mediated by the ion channel or symptoms. of the same.

References that include examples of additional therapeutic agents are: 1) Burger's Medicinal Chemistry & Drug Discovery 6th edition, by Alfred Burger, Donald J. Abraham, ed. , Volumes 1 to 6, Wiley Interscience Publication, W £, 2003; 2) Ion Channels and Say by Francis M. Ashcroft, Academic Press, NY, 2000; and 3) Calciu Antagonists in Clinical Medicine 3rd edition, Murray Epstein, MD, FACP, ed. , Hanley & Belfus, Inc., Philadelphia, PA, 2002. Additional therapeutic agents include but are not limited to agents for the treatment of cardiovascular disease (eg, hypertension, angina, atrial fibrillation, stroke prevention, heart failure, acute myocardial ischemia, etc), metabolic disease (eg, syndrome X, diabetes, obesity), -pain (eg, acute pain, inflammatory pain, neuropathic pain, migraine, etc.), renal or genitourinary disease (eg, glomerular nephritis, incontinence urinary, nephrotic syndrome), abnormal cell growth (eg, oncology, fibrotic disease), nervous system disease (eg, epilepsy, stroke, migraine, traumatic brain injury or neuronal disorder, etc.), respiratory disease (e.g. , asthma, COPD, pulmonary hypertension) and their symptoms of the disease. Examples of additional therapeutic agents for the treatment of cardiovascular disease and symptoms of the disease including but not limited to antihypertensive agents, ACE inhibitors, angiotensin II receptor antagonists, statins, β-blockers, anti-oxidants, anti-inflammatory drugs, anti -trombotic, anti-coagulants or antiarrhythmics. Examples of additional therapeutic agents for the treatment of metabolic disease and symptoms of the disease include but are not limited to ACE inhibitors, angiotensin II antagonists, fibrates, thiazolidinediones or antidiabetic drugs of sulfonylurea. Examples of additional therapeutic agents for the treatment of pain and its symptoms include but are not limited to non-spheroidal anti-inflammatory drugs.

("NSAIDS", eg, aspirin, ibuprofen, flumizole, acetaminophen, etc.), opioids (eg, morphinal, fentanyl, oxicodene), and agents such as gabapentin, ziconitide, tramadol, dextromethorphan, carbamazepine, lamotrigine, baclofen or capsaicin Examples of additional therapeutic agents for treatment of genital and / or renal urinary syndromes and their symptoms including but not limited to alpha-1 (eg, doxazosin), anti-muscarinic (eg, tolterodine) adrenergic antagonists, reuptake inhibitors, norepinephrine / serotonin (eg, duloxetine), tricyclic antidepressants (eg, doxepin, desipramine) or spheroids. Examples of additional therapeutic agents for treatment of abnormal cell growth syndromes and their symptoms include but are not limited to anti-cytokine therapies (eg, biological anti-TNF and anti-IL-1, p38 MAPK inhibitors), cell therapies mother or antagonists endotelin-1 (for example, progeny cells). Examples of additional therapeutic agents for the treatment of stroke and symptoms of the disease include but are not limited to neuroprotective agents and anticoagulants (e.g., alteplase (TPA), abciximab) •. Examples of additional therapeutic agents for the treatment of epilepsy and its symptoms include but are not limited to analogue GABA, hydantoins, barbiturates, phenyl triazines, succinimides, valproic acid, carbamazepine, falbamate and leveracetam. Examples of additional therapeutic agents for the treatment of migraine include but are not limited to serotonin / 5-HT receptor agonists (eg, sumatriptan, etc.). Examples of additional therapeutic agents for the treatment of respiratory diseases and their symptoms include but are not limited to anticholinergics (e.g., thiotropin), spheroids, anti-inflammatory agents, anti-cytokine agents or PDE inhibitors. The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is non-toxic when administered in doses sufficient to administer a therapeutic amount of the compound. Carriers, adjuvants and pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchange, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) as -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymer delivery matrices, whey proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glyceride of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium acid phosphate, potassium acid phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethylcellulose or, polyacrylates, waxes, polyethylene polyoxypropylene blocking polymers, polyethylene glycol and lanolin. Cyclodextrins such as a-, β-, and β-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other soluble derivatives may also be advantageously used to increase the administration of compounds of the formulas described herein. The pharmaceutical compositions of this invention can be administered orally, parenterally, by spray inhalation, topically, rectally, nasally, buccally, vaginally or by means of an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any of conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffer solutions to increase the stability of the formulated compound or its administration form. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleagenous suspension. This suspension can be formulated in accordance with techniques known in the art using suitable wetting or dispersing agents (such as, for example, T een 80) and suspending agents. The sterile injectable preparation can also be a suspension or sterile injectable solution in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil can be employed including synthetic mono or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying or bioavailability enhancing agents that are commonly used in the manufacture of liquid, pharmaceutically acceptable solid or other dosage forms may also be used for the purposes of the formulation. The pharmaceutical compositions of this invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When the aqueous suspensions and / or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase is combined with emulsifiers and / or suspending agents. If desired, certain sweeteners and / or flavorings and / or coloring agents may be added. The pharmaceutical compositions of this invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active components.

Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. Topical administration of. The pharmaceutical compositions of this invention are useful when the desired treatment involves rapidly accessible areas or organs by topical application. For topical application to the skin, the pharmaceutical composition may be formulated with an appropriate ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white gasoline, propylene glycol, polyoxypropylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with an appropriate cream or lotion containing the active compound suspended or dissolved in a carrier with appropriate emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention can also be applied topically in the lower intestinal tract by the rectal formulation of the suppository or in an appropriate enema formulation. Topically transdermal patches are also included in this invention.

The pharmaceutical compositions of this invention can be administered by nasal spray or inhalation. Such compositions are prepared in accordance with techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, benzyl alcohol employed or other appropriate preservatives, absorption promoters to increase bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. A composition having the compound of the present formulas and an additional agent (e.g., a therapeutic agent) can be administered using an implantable device. The irreplaceable devices and related technologies are known in the art and are useful as delivery systems where a continuum, or prolonged release of compounds or compositions delineated herein, is desired. Additionally, the implantable device administration system is useful for specific points of compound or composition release direction (eg, localized sites, organs). Negrin et al., Biomaterials, 22 (6): 563 (2001). The extended release technology involves alternative release methods that can also be used in this invention. For example, sustained release formulations based on polymer technologies, sustained release techniques and encapsulation techniques (eg, polymeric, liposomal) can also be used for administration of the compounds and compositions delineated herein. Also within the invention is a patch for administering active chemotherapeutic combinations herein. The patch includes a layer of material (eg, polymeric, cloth, gauze, bandage) and the compound of the formulas herein as set forth herein. One side of the material layer may have a protective layer adhering to it to resist the passage of the compounds or compositions. The patch may additionally include an adhesive to hold the patch in place in a subject. The adhesive is a composition, including that of either natural or synthetic origin, which, when in contact with the subject's skin, temporarily adheres to the skin. It can be water resistant. The adhesive can be placed on the patch to keep it in contact with the subject's skin for an extended period of time. The adhesive can be made of a tack, or adhesive strength, such that it holds the device in place of the subject for incidental contact, however, during an affirmative act (eg, tearing, peeling, or other intentional removal) the adhesive gives a path to the external pressure placed on the device or the adhesive by itself, and allows the adhesion contact to be broken. The adhesive may be pressure sensitive, that is, it may allow the adhesive (and the device to adhere to the skin) to be placed against the skin by the application of pressure (for example, by pressing, rubbing) on the adhesive or device. When the compositions of this invention comprise a combination of a compound of the formulas described herein and one or more additional therapeutic or prophylactic agents, both the additional compound and agent should be present at dose levels of between about 1 to 100% , and more preferably between about 5 to 95% of the dose normally administered in a monotherapy regimen. The additional agents can be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents can be part of a single dose form, mixed together with the compounds of this invention in a simple composition. The invention will be further described in the following examples. It will be understood that these examples are for illustrative purposes only and are not construed as limiting this invention in any way.

Example to Oocyte Assay Compounds representative of the formulas herein are separated by exclusion for activity against calcium channel targets in an assay essentially as described in Neuron, January 1997, 18 (11): 153-166, Lin. et. to the; J. Neurosci, July 1, 2000, 20 (13): 4768-75, J. Pan and D. Lipsombe; and J. Neurosci., August 15, 2001, 21 (16): 5944-5951, W. Xu and D. Lipscombe, using a heterologous expression system of Xenopus oocyte. The assay is carried out in several calcium channels (for example, subfamily Cavl .2 or Cavl. 3) therefore the modulation of the calcium channel is measured for each compound. Table 2 contains the IC50's for the representative compounds described "in the invention.

Table 2 Example 2 HEK assay HEK-293T / 17 cells were transiently transfected "in a similar manner as described in FuGENE 6 Package Insert Version 7, April 2002, Roche Applied Science, Indianapolis, IN. Cells are seeded at 2.5 x 10. cells in a 6-well plate of 2 mL in an incubator overnight and reach a confluence of 30 ~ 40% In a small sterile tube, sufficient serum-free medium is added as a diluent for the FuGENE transfection reagent (Roche Applied Science, Indianapolis, IN), up to a total volume of 100 μL 3 μL of FuGENE 6 reagent was added directly in this medium The medium is gently capped to mix 2 μg of DNA solution (0.8-2.0 μg) is added / μL) to the previously diluted FuGENE 6 reagent The DNA / Fugene 6 mixture is pipetted gently to mix the contents and incubate for about 15 minutes at room temperature The complex mixture is then added to the HEK-293T cells / 17, It is distributed around the well, and is stirred to ensure uniform dispersion. The cells are returned to the incubator for 24 hrs. The transfected cells are then plated back to a density of 2.5X105 in a 35mm dish with 5 glass slides and grown in low serum (1%) medium for 24 hrs. The slides with isolated cells are then transferred into the chamber current and the calcium channel (eg type L, type N, etc.) or other currents to exclude by exclusion the counter are recorded from HEK-293T cells / 17 transiently transfected.

The full-cell voltage clamp configuration of the patch clamp technique is employed to evaluate voltage-dependent calcium currents essentially as described by Thompson and Wong (1991) J. Physiol, 439: 671-689. To record the calcium channel currents (for example, type L, type N, etc.) for evaluation of the inhibitory potency of compounds (analysis of response to the concentration of study state), five pulses of 20-30 ras voltage they are carried in stages up to about +10 mV (the peak of the current voltage ratio) are administered at five Hz every 30 seconds from a holding potential at -100mV. The evaluations of the compound are carried out essentially as described by Sah DW and Bean BP (1994) Mol Pharmacol 45 (1): 84-92. Table 3 contains the IC50 for the representative compounds.

Table 3 Example 3 Formalin Test Compounds representative of the formulas herein are separated by exclusion for activity in the formalin test. The formalin test is widely used as a model of acute inflammatory and tonic pain (Dubuisson & Dennis, 1977 Pain 4: 161-174; Wheeler-Aceto et al, 1990, Pain 40: 229-238; Coderre et al, 1993, Pain 52: 259-285). The test involves administration to the hind paw of the rat of dilute formalin solution followed by monitored behavioral signals (ie, kickback, stings and licks) during the "late phase" (11 to 60 minutes after injection) of the response to formalin that reflects both peripheral nerve activity and central sensitization. Sprague-Dawley rats are used, males (Harían, Indianapolis, IN) weighing approximately 225-300 g with n = 6-8 for each treatment group. Depending on the pharmacokinetic profile and the route of administration, the vehicle or dose of the test compound is administered to each rat by an intaperitoneal or oral route 30-120 minutes before formalin. Each animal is acclimated to a chamber for 60 minutes before the administration of formalin, which is 50μL of a 5% solution injected subcutaneously on the surface of the plant of a hind paw using a 300μL microsyringe and a measuring needle 29. A mirror is placed at an angle behind the cameras to increase the views of the legs of the animals. The number of kickbacks (legs raised with or are agitation of the fast leg) and the time consumed from the bite or licking of the injured hind leg are recorded for each rat for 2 continuous minutes every 5 minutes for a total of 60 minutes after 'the administration of formalin. A sample of terminal blood is harvested for analysis of compound concentration in the plasma. Between the group comparisons of the total number of recums or the time consumed of pitting and / or licking during the early or late phase, they are conducted using a one-way analysis of variation (ANOVA). The p <; 0.05 is considered statistically important and p = 0.05-1.0 is considered evidence of a statistical trend. The data is presented graphically as means ± S.E.M. for each 5 minute interval of the experimental observation period of 60 minutes. The compounds are considered effective on the basis of their ability to inhibit the number of backbites or the time consumed from stinging and / or licking during the late phase of the response to formalin. Compounds representative of the formulas herein are evaluated for activity against calcium channel targets. Compounds representative of the formulas herein are evaluated for activity against calcium channel targets.

Example 4 Compound 1 [1- (4- { 2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -ethyl}. (4-fluoro-phenyl) -methyl-amine Reaction scheme 6 Part 1. Preparation of N- (4-chloro-phenyl) -2-methoxy-benzamidine To a solution of 4-chloroaniline (25 g, 197 mol) in THF (250 mL) at 0 ° C a 1M solution of sodium bis (trimethylsilyl) amide in THF (207 mL, 1.06 eq) was added dropwise over a period of 30 to 60 minutes. After the addition was complete, a solution of 2-methoxy benzonitrile (27.6 g, 209 mmol) in THF (125 mL) was added dropwise over a period of 15 to 30 minutes at room temperature and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give dark oil which solidified during standing. Titration with hexane and a minimum amount of ethyl acetate gave after filtration N- (4-chloro-phenyl) -2-methoxy-benzamidine (34 g, 131 mmol) as a gray solid.

Part 2. Preparation of [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid ethyl ester A mixture at 50 ° C of N- (4-chloro-phenyl) -2-methoxy-benzamidine (9 g, 34.6 mmol) and potassium carbonate acid (10.38 g, 103.8 mmol, 3 eq) in acetonitrile (100 mL) was treated with an ethyl ester solution of 4-bromo-3-oxo-butyric acid (10 g, 48 mmol) in acetonitrile (50 L) dropwise over 30 minutes. The reaction mixture was brought to reflux for 2 hours, cooled and filtered. Under vacuum the solvent was removed from the filtrate to give a dark oil.

Flash chromatography (Si02, 50% ethyl acetate in hexane) gave the ethyl ester of [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic (16 g, 17 mmol) as a viscous, dark oil.

Part 3. Preparation of [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid To a solution of the ethyl ester of [1- ( 4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid (1.5 g, 4.04 mmol) in THF (40 mL) was added aqueous 1N sodium hydroxide (12 g). mL) and the mixture is allowed to stir for 1 hour at 70 ° C and cooled. The reaction was quenched with water and adjusted to pH 6 with aqueous 6N sodium hydroxide and extracted with ethyl acetate. The combined organics were washed with water, dried and concentrated under vacuum to give [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid (0.49). g, 1.43 mmol) as a white solid.

Part 4. Preparation of 2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -N- (4-fluoro-phenyl) -N-methyl -acetamide A mixture of [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid (0.25 g, 0.73 mmol) and 1- (3- hydrochloride) dimethylaminopropyl) -3-ethylcarbodiimide (0.28 g, 1.46 mmol) and 4-fluoro-N-methylaniline (0.082 mL, 0.73 mmol) in pyridine (3 mL) was stirred at room temperature overnight. The solvent was removed in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organics were dried, concentrated under reduced pressure and the residue was purified by chromatography (Si02, 3% methanol in methylene chloride) to give 2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) ) -lH-imidazol-4-yl] -N- (4-fluoro-phenyl) -N-methyl-acetamide (0.16 g, 0.36 mmol) as an oil.

Part 5. Preparation of [1- (4- { 2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -ethyl.}. - (4-fluoro-phenyl) -methyl-amine To a solution of 2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -N- (4-fluoro-phenyl) -N-methyl-acetamide (0.07 g, 0.16 mmol) in toluene (5 mL) at 0 ° C was added borane-dimethylsulfide complex (2M in THF, 0.16 mL, 0.31 mmol) and the reaction was heated to reflux overnight.The mixture was cooled and diluted with methanolic HCl (3 mL), it was refluxed for 1 hour, cooled and concentrated under vacuum. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organics were dried, and concentrated under vacuum to give a white solid. The solid was taken up in methanol and treated with HCl in ether to give [1- (4-. {2- 2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -1H-imidazole -4-yl] -ethyl.} - (4-fluoro-phenyl) -methyl-amine (0.06 g, 0.013 mmol) as a white solid.

Compound 2 2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-ylmethyl] -IH-benzoimidazole Reaction scheme Part 1. Preparation of N- (2-Amino-phenyl) -2- [1- (4-chlorophenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetamide A mixture of [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid (0.87 g, 2.56 mmol) and 1- (3-dimethylaminopropyl) hydrochloride -3-ethylcarbodiimide (0.73 g, 3.83 mmol) and 1,2-phenylenediamine (0.28 g, 2.56 mmol) in pyridine (5 mL) was stirred at room temperature overnight. The solvent was removed in vacuo and treated with water and made basic with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organics were dried and concentrated to give N- (2-amino-phenyl) -2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] - acetamide (0.86 g, 1.99 mmol) as an oil.

Part 2. Preparation of 2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-ylmethyl] -lH-benzoimidazole A solution of N- (2-amino- phenyl) -2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetamide (0.86 g, 1.99 mmol) in glacial acetic acid (8 mL ) was heated at 70 ° C for 30 minutes. The mixture was cooled and added dropwise to a saturated aqueous sodium bicarbonate and the pH adjusted to 7 with sodium hydroxide pellets. The mixture was extracted with ethyl acetate, the organics were dried and concentrated in vacuo to give an oil. Treatment of the oil with HCl in ether gave 2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-ylmethyl] -lH-benzoimidazole (0.44 g, 0.9%). mmol) as a white solid.

Compound 3 2- [2- (2-Methoxy-phenyl) -l-p-tolyl-lH-imidazol-4-ylmethoxymethyl] -1-methyl-lH-benzoimidazole Reaction Scheme 8 Part 1. Preparation of [2- (2-Methoxy-phenyl) -1-p-tolyl-lH-imidazol-4-yl] -methanol To a solution -78 ° C of 2- (2-) ethyl ester methoxy-phenyl) -lp-tolyl-lH-imidazole-4-carboxylic acid (2.0 g, 6.0 mmol) in THF (10 mL) was added dropwise 1M lithium aluminum hydride in ether (6.0 mL, 6.0 mmol). The mixture was warmed to room temperature, stirred for 4 hours and quenched with three drops of methanol. The solvents were removed. The residue was partitioned between methylene chloride and water. The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO 4, filtered and concentrated under vacuum. Column chromatography (Si02, ethyl acetate) gave [2- (2-methoxy-phenyl) -l-p-tolyl-lH-imidazol-4-yl] -methanol (1.1 g, 3.7 mmol) as a solid.

Part 2. Preparation of 2- [2- (2-Methoxy-phenyl) -1-p-tolyl-lH-imidazol-4-ylmethoxymethyl] -1-methyl-lH-benzoimidazole To a solution of [2- (2- methoxy-phenyl) -1-b-tolyl-lH-imidazol-4-yl] -methanol (100 mg, 0.34 mmol) in THF (5 mL) was added NaH (15 mg, 0.34 mmol). The mixture was stirred at room temperature for 30 minutes and 2-chloromethyl-1-methyl-1H-benzoimidazole (61 mg, 0.34 mmol) was added. The mixture was refluxed for 1 hour, cooled to room temperature and quenched with water. The mixture was extracted with ether. The organic layer was washed with water, brine, dried over anhydrous Na 2 SO 4, filtered and concentrated under vacuum. Column chromatography (Si02, ethyl acetate) yielded 2- [2- (2-methoxy-phenyl) -1-p-tolyl-lH-imidazol-4-ylmethoxymethyl] -1-methyl-lH-benzoimidazole (86 mg , 0.20 mmol) as an oil. The compounds in the tables herein are prepared in a similar manner as described above and in the General Reaction Schemes. All references cited herein, whether in print, electronic, computer readable storage or otherwise, are expressly incorporated for references in their entirety, including but not limited to, abstracts, articles, newspapers, publications, texts , treaties, internet network sites, databases, patents, and patent publications. It will be understood that although the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. It is noted that with this date, the best method known to the applicant to carry out the practice of said invention, is that which is clear from the present description of the invention.

Claims (39)

Claims: Having described the invention as above, the content of the following claims is claimed as property. 1. A compound of the formula (I) or a pharmaceutical salt thereof characterized in that, Ar1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; , R1 is Ar2 or optionally substituted lower alkyl each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each R2 is independently selected from (CH2) mC02R3, (CH2) mC0Ar3, (CH2) mC0NR3R4, (CH2) mAr3, or (CH2) nNR3R4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R7 or (CH2) pAr3; each R3 and R4 are taken together with the nitrogen atom which is bonded to form a 4-7 membered heterocyclic ring wherein, a carbon atom in each heterocyclic ring is optionally an NR4, 0 or S and each heterocyclic ring is optionally substituted with one or more lower alkyl groups; each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each m is independently 0 or 1; each n is independently 1 or 2; each p is independently 0 or 1; each substituent for Ar3 is independently selected from halogen, CN, NO, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C3-C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) 0R5, C (0) NR5R6, OC (0) NR5R6, NR5C (O) NR5R6, C (NR5) NR5R6, NR5C (NRd) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, alkoxy

1.-C4, NH2, alkylamino C! -C, dialkylamino Cx-C4 or cycloalkyl C3-C6; each Rs is independently selected from hydrogen, (CH2) pAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C1-C4 alkylamino, dialkylamino C? -C or cycloalkyl C3-C6; each R7 is independently selected from (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C -C alkoxy, NH 2, C 1 -C alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; and each Ar4 is independently selected from C3-C3 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, Cx-C alkoxy, NH, alkylamino C, L-C4, dialkylamino C? C or 1,2-methylenedioxy.

2. The compound of the formula (I) according to claim 1, characterized in that: R 1 is C 2 -C 2 alkyl substituted with Ar 2; and Ar2 is optionally substituted with one or more substituents.

3. The compound of the formula (I) according to claim 1, characterized in that: R1 is Ar2; Ar2 is optionally substituted with one or more substituents.

4. The compound of the formula (I) according to claim 3, characterized in that: R2 is (CH2) mC (0) OR3, (CH2) mC (O) Ar3 or (CH2) mC (0) NR3R4 and each m is independently 0 or 1; and each Ar3 is optionally substituted with one or more substituents.

5. The compound of the formula (I) according to claim 3, characterized in that: R2 is (CH2) nNR3R4 and n is 1.

6. The compound of the formula (I) according to claim 3, characterized in that: R2 is (CH2) nNR3R4 and n is 2.

7. The compound of the formula (I) according to claim 3, characterized in that: R2 is (CH2) mAr3 and m is 0; and Ar3 is optionally substituted with one or more substituents.

8. The compound of the formula (I) according to claim 3, characterized in that: R2 is (CH2) mAr3 and m is 1; and Ar3 is optionally substituted with one or more substituents.

9. The compound of the formula (I) according to claim 1, characterized in that: each Ar1, Ar2, Ar3 and Ar4 is independently selected from cycloalkyl, phenyl, naphthyl, acenaphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, furyl, thienyl , pyridyl, pyrrolyl, oxazoyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, oxadiazyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, IH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, tetrahydro-iso quinolinyl, isoquinolinyl, tetrahydro-quinoline, cinnolinyl, phthalazinyl, 'quinazolinyl, quinoxalinyl, naphthyridinyl , peridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, each optionally substituted with one or more substituents.

10. The compound of the formula (I) according to claim 1 characterized in that Ar1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each Ar2 is independently selected from aryl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 1 wherein each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5Rd, S (0) 2NR5R6, C (0) R7, S (0 ) 2) R7 or (CH2) pAr3; or each R3 and R4 are taken together with the nitrogen atom which is bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally an NR4, O or S and each heterocyclic ring it is optionally substituted with one or two lower alkyl groups; each p is independently 0 or 1; and each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents.

11. The compound of the formula (I) according to claim 1 characterized in that, Ar1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each Ar2 is independently selected from aryl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 2 wherein each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5Re, S (0) 2NR5R6, C (0) R7, S (0 ) 2) R7 or (CH2) pAr3; or each R3 and R4 are taken together with the nitrogen atom which is bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally a NR4, 0 or S and each heterocyclic ring it is optionally substituted with one or two lower alkyl groups; each p is independently 0 or 1; and each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents.

12. The compound of the formula (I) according to claim 1 characterized in that, Ar1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each Ar2 is independently selected from heterocyclyl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) mAr3 and m is 0; each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; each substituent - for Ar1, Ar2 and Ar3 is independently selected from halogen, OR5, NR5R5, C -C2 perfluoroalkyl, perfluoroalkoxy C -C2, "1,2-methylenedioxy; each R5 is independently selected from hydrogen or lower alkyl optionally substituted? with one or more substituents selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, each R 6 is independently selected from hydrogen, (CH 2) pAr 4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino, each p is independently 0 or 1, and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one up to three substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH, C 1 -C 4 alkylamino, C 3 -C 4 dialkylamino, C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy, 1,2-methylenedioxy.

13. The compound of the formula (I) according to claim 1 characterized in that, Ar1 is aryl or heteroaryl each optionally substituted with one to three substituents; each Ar2 is independently selected from heterocyclyl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) mAr3 and m is 1; each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar is independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C? ~ C2, 1,2-methylenedioxy; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, CX-C4 alkoxy, NH2, CX-C4 alkylamino, CX-C4 dialkylamino; each Rs is independently selected from hydrogen, (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, CX-C4 alkoxy, NH2, CX-C4 alkylamino, CX-C4 dialkylamino; each p is independently 0 or 1; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three independently selected substituents halogen, OH, CX-C4 alkoxy, NH2, CX-C alkylamino, CX-C4 dialkylamino, CX-C2 perfluoroalkyl, CX perfluoroalkoxy -C2, 1, 2-methylenedioxy.

14. The compound of the formula (I) according to claim 1 characterized in that, Ar1 is phenyl substituted with one to three substituents; R1 is Ar2 and Ar2 phenyl substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 1; each R3 is independently selected from H or lower alkyl; each R4 is (CH2) pAr3; each p is independently 0 or 1; each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy Cx-C2, 1,2-methylenedioxy; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C1-C4 alkoxy, NH, C1-C4 alkylamino, dialkylamino C-C4; each R6 is independently selected from hydrogen, (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C3-C4 alkoxy, NH2, C1-C4 alkylamino, C4-C4 dialkylamino; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three independently selected substituents halogen, OH, Cj-C alkoxy, NH2, C-C4 alkylamino, dialkylamino C1-C4, perfluoroalkyl Cx-C2, perfluoroalkoxy Cx -C2, 1, 2-methylenedioxy.

15. The compound of the formula (I) according to claim 1 characterized in that, Ar1 is phenyl substituted with one to three substituents; R1 is Ar2 and Ar2 phenyl substituted with one to three substituents, - R2 is (CH2) nNR3R4 and n is 1; each R3 and R4 are taken together with nitrogen atom to which they are bonded to form a 4-7 membered heterocyclic ring wherein, a carbon atom in each heterocyclic ring is optionally an NR4, O or S and each heterocyclic ring is optionally substituted with one or two lower alkyl groups; each substituent for Ar1 and Ar2 is independently selected from halogen, OR5, NR5Rd, CX-C2 perfluoroalkyl, CX-C2 perfluoroalkoxy, 1,2-methylenedioxy each R5 is independently selected from hydrogen or optionally substituted lower alkyl with one or more substituents selected from halogen, OH, Cx-C4 alkoxy, NH2, CX-C4 alkylamino, CX-C4 dialkylamino; each Rs is independently selected from hydrogen, (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, CX-C4 alkoxy, NH2, CX-C4 alkylamino, CX-C4 dialkylamino; each p is independently 0 or 1; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three independently selected substituents halogen, OH, CX-C4 alkoxy, NH2, CX-C4 alkylamino, CX-C4 dialkylamino, CX-C2 perfluoroalkyl, perfluoroalkoxy Cx-C2, 1, 2-methylenedioxy.

16. The compound of the formula (I) according to claim 1 characterized in that, Ar1 is phenyl substituted with one to three substituents; R1 is Ar2 and Ar2 phenyl substituted with one to three substituents; R2 is (CH) raAr3 and m is 0; each Ar3 is benzimidazol-2-yl optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar3 is each independently selected from halogen, OR5, NR5R6, perfluoroalkyl Cx-C2, perfluoroalkoxy Cx-C2, 1,2-methylenedioxy; each R 5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C x C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino; each R6 is independently selected from hydrogen, (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino; each p is independently 0 or 1; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three independently selected substituents halogen, OH, C1-C4 alkoxy, NH2, CX-C4 alkylamino, CX-C4 dialkylamino, CX-C2 perfluoroalkyl, CX perfluoroalkoxy -C2 / 1, 2-methylenedioxy.

• 17. The compound of the formula (I) according to claim 1, characterized in that it is any of those in Table 1 herein.

18. A method for inhibiting calcium channel activity, characterized in that it comprises contacting a compound of the formula (I) according to any of claims 1 to 17 with a calcium channel.

19. A method for inhibiting calcium channel activity in a subject, characterized in that it comprises administering to the subject an effective amount of a compound of the formula (I) according to any of claims 1 to 17.

20. A method for treating a disease mediated by the calcium channel in a subject, characterized in that it comprises administering to the subject an effective amount of a compound of the formula (I) according to any of claims 1 to 17.

21. The method according to any of claims 18-20, characterized in that the calcium channel is Cav2.

22. The method according to any of claims 18-20, characterized in that the calcium channel is Cav2.2.

23. The method according to claim 20, characterized in that the disease mediated by the calcium channel Cav2 or symptom of the disease is a disease of the nervous system or symptom of the disease.

24. The method according to claim 20, characterized in that the disease mediated by the calcium channel Cav2.2 or symptom of the disease is a disease of the nervous system or symptom of the disease.

25. The method according to claim 20, characterized in that the disease mediated by the calcium channel Cav2 or symptom of the disease is a cardiovascular disease or symptom of the disease.

26. The method according to claim 25, characterized in that the disease mediated by the calcium channel Cav2. 2 or symptom of the disease is a cardiovascular disease or symptom of the disease.

27. A method for treating acute pain mediated by the calcium channel 'Cav2, inflammatory pain, or neuropathic pain in a subject, characterized in that it comprises administering to the subject an effective amount of a compound of the formula (I) in accordance with any of claims 1 to 17.

28 A method according to claim 27, characterized in that the calcium channel Cav2 is Cav2. 2 .

29 A method for treating urinary incontinence or overactive bladder mediated by the calcium channel Cav2 in a subject, characterized in that it comprises administering to a subject an effective amount of a compound of the formula (I) according to any of claims 1 to 17.

30. The method according to claim 29, characterized in that the calcium channel Cav2 is Cav2.2.

31. A method for treating stroke, traumatic brain injury or neuronal calcium channel disorder Cav2 in a subject, characterized in that it comprises administering to a subject an effective amount of a compound of the formula (I) according to any one of claims 1 to 17 .

32. The method according to claim 31, characterized in that the calcium channel Cav2 is Cav2.2.

33. A method for treating hypertension mediated by the calcium channel. Cav2 in a subject, characterized in that it comprises administering to the subject an effective amount of a compound of the formula (I) according to any of claims 1 to 17.

34. The method according to claim 33, characterized in that the calcium channel Cav2 is Cav2.2.

35. A method for treating a disease mediated by the calcium channel in a human in need of such treatment, characterized in that it comprises the administration of a compound of the formula (I) according to claim 1.

36. A composition, characterized in that it comprises a compound of the formula I according to claim 1 and a pharmaceutically acceptable carrier.

37. The composition according to claim 36, further characterized in that it comprises an additional therapeutic agent.

38. A method for treating a disease or symptom of the disease in a subject, characterized in that it comprises administering to the subject in need of such treatment an effective amount of a compound of formula (I) in any of claims 1 to 17.

39. The method according to claim 38, characterized in that the disease or symptom of the disease is nervous system disease, cardiovascular disease, acute pain, inflammatory pain or neuropathic pain, urinary incontinence, overactive bladder, apoplexy in the calcium channel, injury traumatic brain, neuronal disease or hypertension.