MXPA06010035A - 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: 175187 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 the 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, hoostotic, 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 Cavl .2 (P-type or Q-type calcium currents), Cav2.2 (N-type calcium currents) and Cav2.3 (calcium type R). These currents are found almost exclusively in the central nervous system (CNS), peripheral nervous system (PNS) and neuroendocrine cells and constitute the predominant forms of calcium current from presynaptic voltage gate. The entrance of presynaptic calcium is modulated by some type of receptors coupled to protein G (GPCRs) and modulation of Cav2 channels are medium widely and highly effective 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 (a? 2.1, oc? 2 ... 2 and? 2.3, also known as a1R, a1B, and <X? 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 hereditary 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 (l): 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. Chem. 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 Ca "2 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 (Bowersox, 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 treatment of neuroprotection / apoplexy. 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 Cav2.2 modulators may be particularly effective in the treatment of this disorder. Although complete blockade of Cav2.2 can cause hypotension or impaired baroreceptor reflexes, partial inhibition by Cav2.2 modulators can reduce hypertension to a minimum reflex tachycardia (üneyama, OD 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, despite alterations in nerves, smooth muscle and 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 2d 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. In one aspect it is a compound of the formula (I) or a pharmaceutical salt thereof wherein, R3 is alkyl, alkoxyalkyl, Ar1 or Ar1-X-Y wherein, each Ar1 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is NR4, C (R4) 2 / or O; Y is C = 0 or lower alkyl; R1 is H, alkenyl, 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 H, (CH2) mC (0) OR4, (CH2) mC (0) Ar3, (CH2) mC (0) NRR5, (CH2) mC (0) N (OR4) R5, (CH2) ) mCH2OR4, Ar3, (CH2) nAr3; (CH2) nNR4R5, or (CH2) mAr3; each R4 is independently selected from H, or lower alkyl; each R5 is independently selected from H, lower alkyl or (CH2) pAr3; m is 1 or 2; n is 2 or 3; p is 0 or 1; each Ar3 is cycloalkyl, aryl, heterocyclyl; or heteroaryl, each optionally substituted with one or more substituents; each substituted by Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N02, OR6, SR5, S (0) 2OR6, NR6R7, cycloalkyl, perfluoroalkyl Ca-C2, perfluoroalkoxy Cx-C2, 1,2-methylenedioxy, C (0) OR6, C (0) NR6R7, OC (0) NR6R7, NR6C (0) NR6R7, C (NR6) NR6R7, NR6C (NR7) NR6R7, S (0) 2NR6R7, R8, C (0) R8, NR6C (0) R8, S (0) R8, or S (0) 2R8; each R6 is independently selected from hydrogen 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 4 cycloalkyl; each R7 is independently selected from hydrogen, (CH2) qAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C? -C alkylamino, C? -C4 dialkylamino or C3-C6 cycloalkyl, "each R8 is independently selected from (CH2) qAr4 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; each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C or C3-C6 cycloalkyl; and q is O or 1. Another aspect is a compound of any of the formulas herein (including any combination thereof): wherein, R3 is Ar1 and R1 is Ar2; wherein, R3 is independently, aryl or heteroaryl, each optionally substituted with one or more substituents; and R1 is independently, aryl or heteroaryl, each optionally substituted with one or more substituents; wherein R2 is (CH2) mC (O) OR4, (CH2) mC (O) Ar3 or (CH2) mC (0) NR4R5; wherein R2 is (CH2) mAr3 and Ar3 is aryl or heteroaryl each optionally substituted with one or more substituents; wherein R2 is (CH2) mC (O) NR4R5 and R5 is independently (CH2) pAr3, wherein Ar3 is aryl or heteroaryl, each optionally substituted with one or more substituents; wherein R2 is (CH2) nNRR5 or (CH2) mAr3; or wherein the compound of formula I is any of those in the tables herein. Another aspect is a composition having a compound 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 of treating a disease or symptoms of the disease in a subject in need of such treatment, which includes administering to the subject an effective amount of a compound (or composition thereof) of any of the formulas herein. The disease or symptom of the disease can be modulated by the calcium channel Cav2 (for example, Cav2.2). The disease or symptom of the disease may be angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, traumatic brain injury, or neuronal disorder. Another aspect is a method for modulating (eg, inhibitor, agonist, antagonism) calcium channel activity comprising contacting a calcium channel with a compound (or composition thereof) of any of the formulas herein. Other aspects are a method for modulating the activity of the calcium channel Cav2 in a subject in need thereof including administering to the subject a therapeutically effective amount of a compound (or composition thereof) of any of the formula herein. 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 test or diagnostic method). 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 of the intermediate 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 (e.g., 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 container. the ion channel. In other embodiments, the compounds, compositions, and methods delineated herein are any of the compounds of the tables herein or methods included therein. 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, C1-C5 indicates that the group can have from 1 to 5 (inclusive) carbon atoms in it. The term "lower alkyl" refers to a C 1 -C β 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 may be substituted by a substituent. Examples of the aryl groups include phenyl, naphthyl and the like. The term "heterocyclyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic monocyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if is bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, 0, or S if it is monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring can be replaced 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 yea bicyclic, or 1-9 heteroatoms if tricyclic, heteroatoms selected from O, 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." "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 group , heterocyclyl, or heteroaryl at any atom of that group Suitable substituents include, without limitation halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, , 2-methylenedioxy, C (0) OR5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5R6, C (NR6) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7 Each R5 is independently hydrogen, C1-C4 alkyl or C3-Cd cycloalkyl. Each R6 is i independently hydrogen, C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C? -C alkyl or C? -C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R7 is independently CyC6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4 alkyl or C1-C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl and C1-C4 alkyl in each R5, R6 and R7 can optionally be substituted with halogen, CN, C 1 -C 4 alkyl, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy, or 1,2-methylenedioxy. In one aspect, the substituents in a group 'are independently hydrogen, hydroxyl, halogen, nitro, SO 3 H, trifluoromethyl, trifluoromethoxy, straight or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy , O-benzyl, 0-phenyl, phenyl, 1,2-methylenedioxy, carboxyl, morpholinyl, piperidinyl, amino or 0C (0) NR5R6. Each R5 and R6 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 can be objective (that is, it is 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 R1 TABLE 1C TABLE ID A 'TABLE 1E TABLE IF TABLE 1G Ion channel modulator compounds can be identified through both in vitro (e.g., cell-based and non-cell based) 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 there is sufficient stability to allow manufactures and which maintain the integrity of the compound for a sufficient period of time to be useful for the purpose detailed herein (eg, therapeutic or prophylactic administration to a subject) The compounds delineated herein may be synthesized using conventional methods, as illustrated in the reaction scheme herein. In the reaction schemes herein , unless otherwise stated, the variables in the chemical formulas are as defined in other formulas in the present For example, Ar1, Ar3, R1, R3 and R4 in the reaction schemes are defined as in any of the formulas in the present, except where otherwise defined in the reaction schemes.

Reaction scheme 1 Treatment of ethyl ester (I) with hydrazine in the solvent (e.g., ethanol) provides hydrazide (II). The treatment of (II) with thioisocyanate (III) under basic aqueous conditions gives triazole thione (IV). N-alkylated triazole (Via) is produced from the reaction of (IV) with 3-bromo-proprionate or 4-bromobutyrate (V). Saponification of the ester (Via) gives the carboxylic acid (VIb).

Reaction scheme 2 (VII) (HIV). { DQ 00 ^ Alternatively, the triazole (IV) was prepared by the following sequence. Treatment of diethyl ethyl acetate (VII) with hydrazine in the solvent (e.g., ethanol) provides hydrazide (VIII). The treatment of (VIII) with thioisocyanate (III) under basic aqueous conditions gives triazole (IX) which again provides the aldehyde (X) under aqueous acidic conditions. The reductive amination of (X) and amine (XI) provides (IV).

Reaction scheme 3 (DO CXI! The reaction of carboxylic acid (VIb) with the appropriately substituted amine under standard coupling procedure provides the desired amide (VII). Reduction of the amide under common reduction conditions (eg, diborane or lithium aluminum hydride) provides the corresponding amine (VIII). Alternatively, treatment of (VIb) with the Weinreb reagent provides the amide (IX). Treatment of the amide (IX) under standard conditions with an organometallic reagent (e.g., aryl lithium or aryl magnesium halide) provides the ketone (X). The reduction of the ketone under a variety of conditions provides the desired product (XI).

Reaction scheme 4 The ester treatment (Via) under standard reduction conditions (eg, lithium aluminum hydride) gives the alcohol (XII). Treatment of (XII) under standard ether formation conditions (e.g., NaH, benzylbromide) gives (XIII).

Reaction scheme 5 (a.) { xm txv) An alternative route to obtain heteroaryl derivatives is to react the activated acid of (VIb) with the appropriate substrate followed by cyclization to provide the desired product. For example as detailed in Reaction Scheme E-5, the reaction of the activated acid of (VIb) with benzene-1,2-diamine provides the intermediate of e.mida (XIV), which is cyclized to provide the benzimidazole derivative (XV). 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 Organíc Transformations , 2nd. Ed., Iley-VCH Publishers (1999); T. 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 later editions of them. 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,? M. Journal of Medicinal Chemistry 1987, 30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Academic Publ .: Switzerland, 1991; pp 113-191; Digenis, G. A. et al. Handbook of Experimental Pharmacology 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; Pitman, 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 ratio of altered excretion. 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride. , bromohydrate, iodohydrate, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate , thiocyanate, tosylate and undesanoate. 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 (eg, sodium), alkaline earth metal (eg, magnesium), ammonium and N- (alkyl) 4+ salts. 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. Dosage and treatment regimens specific to 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 may 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 & amp;; Drug Discovery 6th edition, by Alfred Burger, Donald J. Abraham, ed. , Volumes 1 to 6, Wiley Interscience Publication, NY, 2003; 2) Ion Channels and Disease by Francis M. Ashcroft, Academic Press, NY, 2000; and 3) Calcium 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, e'tc), metabolic disease (eg, syndrome X, diabetes, obesity), pain (eg, acute pain, inflammatory pain, neuropathic pain, migraine, etc.), kidney or genital urinary disease (eg, glomerular nephritis) , urinary incontinence, 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 ( for example, 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, antioxidants, anti-inflammatory drugs, anti -trombotics, 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-steroidal anti-inflammatory drugs ("NSAIDs", eg, aspirin, ibuprofen, flumizole, acetaminophen, etc.), opioids (eg. example, 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 receptor antagonists, reuptake inhibitors, norepinephrine / serotonin (eg, duloxetine), tricyclic antidepressants (eg, doxepin, desipramine) or steroids. 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 endotelin-1 mother or antagonists (eg, progenitor 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 (eg, 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, succinides, valproic acid, carbamazepine, falba ato 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), steroids, 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 hydrogen 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 -, 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 the 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, Tween 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 is useful when the desired treatment involves areas or organs readily accessible 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, polyoxyethylene 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. Implantable 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 keep the patch in place on 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 (e.g., tearing, peeling, or other intentional removal) the adhesive gives a way to the external pressure placed on the device or the adhesive by itself, and allows breaking the adhesion contact. 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 (e.g., 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.? Eurosci, July 1, 2000, 20 (13): 4768-75, J. Pan and D. Lipsombe; and J.? eurosci., 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 A2 HEK assay HEK-293T / 17 cells were transiently transfected in a similar manner as described in FuGE? E 6 Package Insert Version 7, April 2002, Roche Applied Science, Indianapolis, IN. Cells are seeded at 2.5 x 10 5 cells in a 6 mL 2-well plate 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 covered to mix. 2 μg of DNA solution (0.8-2.0 μg / μL) is added 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 / 17 cells, it is distributed around the well, and it is stirred to ensure a 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 HE-293T cells / 17 transiently transfected. The full cell voltage clamp configuration of the patch clamp technique is employed to evaluate the 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 study state concentration), five pulses of 20-30 ms of voltage they are carried in stages up to around +10 V (the peak of the current voltage ratio) are administered at five Hz every 30 seconds from a waiting 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.

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 or central sensitization. Sprague-Dawley rats, males (Harían, Indianapolis, IN) are used 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. -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 syringe 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 without rapid agitation of the fast leg) and the time consumed from the bite or licking of the injured hind foot are recorded for each rat for 2 continuous minutes every 5 minutes for a total of 60 minutes after of formalin administration. 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). Compounds representative of the formulas herein are evaluated for activity against calcium channel targets.

Example 4 Compound 1 3 [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1, 2, 4] triazol-1-yl] -propionic acid, ester of ethyl Reaction scheme 5 Part 1. Preparation of 5- (2-Methoxy-phenyl) -4-p-tolyl-4H- [1,2, 4] triazole-3-thiol A mixture of 2-methoxybenzhydrazide (7.0 gm, 42 mmol) and isothiocyanate of p-tolyl (6.3 gm, 42 mmol) in ethanol (100 L) was heated to reflux for one hour then cooled. The reaction mixture was filtered and the filter cake was washed with cold ethanol (50 L). The filter cake was dissolved in aqueous 2N sodium hydroxide (100 mL) and heated overnight then cooled. The solution was neutralized with 6N hydrochloric acid and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give a white solid. Trituration of the solid with ethanol (100 mL) gave 5- (2-Methoxy-phenyl) -4-p-tolyl-4H- [1, 2,4] triazole-3-thiol (11 gm, 37 mmol) as a solid white.

Part 2. Preparation of 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1, 2, 4] triazol-1-yl] -propionic acid ethyl ester To a solution of 5- (2-methoxy-phenyl) -4-p-tolyl-4H- [1, 2, 4] triazole-3-thiol (0.9 g, 30.3 mmol) in DMF (100 mL ) was added a 1M solution of lithium bis (trimethylsilyl) amide in THF (30.3 mL) and ethyl 3-bromopropionate (5.48 g, 30.3 mmol) at room temperature. The mixture was heated at 60 ° C for 1 hour and cooled to room temperature. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum. The residue was purified by chromatography on silica (20% ethyl acetate in n-hexane) to give 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-acid. dihydro- [1, 2, 4] triazol-1-yl] -propionic, ethyl ester (10.08 g, 25.4 mmol) as a clear oil.

Compound 2 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -l-morpholin-4 -il-propan-l-one Reaction scheme 6 Part 1. Preparation of 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl ~, 5-dihydro- [1,2, 4] triazol-1-yl] -propionic acid One 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1, 2, 4] triazol-1-yl] -propionic acid ester; ethyl (10.08 g, 25.4 mmol) and lithium hydroxide hydrate (1.28 g, 30.48 mmol) was dissolved in 1,4-dioxane: water (4/1: w / w) and allowed to stir at room temperature for 3 hours . The reaction mixture was neutralized with aqueous HCl AN and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazole-1 acid. -yl] -propionic (8.99 g, 24.4 mmol) as a white solid.

Part 2. Preparation of 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -1- morpholin-4-yl-propan-1-one To a solution of 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1, 2, 4] triazol-1-yl] -propionic acid (0.50 g, 1.36 mmol, 1-3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.388 g, 2.03 mmol) and morpholine (0.177 g, 2.03 mmol) in THF (15 L) was stirred overnight at room temperature The reaction was quenched with water and extracted with ethyl acetate The organics were dried and concentrated in vacuo The residue was purified by chromatography on silica (20% acetone in n-hexane ) to give 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1, 2, 4] triazol-1-yl] -1-morpholine- 4-yl-propan-l-one (0.286 g, 0.65 mol) as a white solid.

Compound 3 2- [2- (lH-Benzoimidazol-2-yl) -ethyl] -5- (2-methoxy-phenyl) -4-p-tolyl-2,4-dihydro- [1,2,4] triazole -3-tiona Reaction scheme 7 Part 1. Preparation of 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -propionitrile A mixture of 5- (2-methoxy-phenyl) -4-p-tolyl-2,4-dihydro- [1, 2, 4] triazole-3-thione (1.1 g, 3.7 mmol) in dioxane (6 mL) was stirred and Triton B (20 drops) was added. The mixture was heated to 70 ° C and acrylonitrile (250 μL, 3.7 mmol) was added and heated an additional 3 hours. The cold mixture was partitioned between aqueous 0.1N HCl (10 L) and ethyl acetate (20 mL "). The organic layer was washed with water (10 mL) and brine (10 mL) and dried over sodium sulfate, it was filtered and the solvent was removed under reduced pressure to give a viscous yellow oil.Short chromatography (SiO2, 0.2: 3 ethyl acetate / hexane) gave 3- [3- (2-methoxy-phenyl) -5-thioxo -4-p-tolyl-4,5-dihydro- [1, 2, 4] triazol-1-yl] -propionitrile (1 g, 2.8 mmol) as a white foam.

Part 2. Preparation of 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolol-4,5-dihydro- [1,2,4] triazole-1-ethyl ester il] -propionimide A solution of propionitrile (0.5 g, 1.4 mmol) in 1: 1 ethanol / diethylether (20 mL) was cooled in an ice-water bath and HCl (g) was carefully bubbled into the solution for 10-20 minutes The reaction mixture was stirred at room temperature for 2-4 hours and the solvent was removed under reduced pressure to obtain 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p- ethyl ester. tolyl-4, 5-dihydro- [1, 2, 4] triazol-1-yl] -propionimide as a viscous yellow oil. The oil was used immediately without purification.

Part 3. Preparation of 2- [2- (lH-Benzoimidazol-2-yl) -ethyl] -5- (2-methoxy-phenyl) -4-p-tolol-2,4-dihydro- [1,2, 4] triazole-3-thione A mixture of the ethyl ester of propionimidic acid and benzene-1,2-diamine (0.227 g, 2.1 mmol) in ethanol (10 mL) was stirred and heated at 60 ° C overnight. The solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate (20 L) and saturated aqueous sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. Flash chromatography (Si02, 1: 1 ethyl acetate / dichloromethane) gave a colorless oil. The oil was dissolved in methanol (2 mL) and treated with 2M ethereal HCl (10 mL). The solvent was removed under reduced pressure to provide the mono HCl salt of Compound 3 (0.33 g) as a white solid.

Compound 4 5- (2-Methoxy-phenyl) -2- (2-pyridin-4-yl-ethyl) -4-p-tolyl-2,4-dihydro- [1,2,4] triazole-3-thione Part 1. Preparation of 5- (2-Methoxy-phenyl) -2- (2-pyridin-4-yl-ethyl) -4-p-tolyl-2,4-dihydro- [1, 2, 4] triazole- 3-thione A mixture of 5- (2-methoxy-phenyl) -4 ~ p-tolyl-2,4-dihydro- [1,2,4] triazole-3-thione (0.15 g, 0.50 mmol) in ethanol ( 10 mL) was stirred and 4-vinylpyridine (0.15 g, 1.0 mmol) was added. The mixture was heated overnight to reflux then cooled. The cold mixture was concentrated under vacuum and the residue was diluted with ethyl acetate. The organics were washed with water (10 mL) and brine (10 mL) and dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give a viscous yellow oil. Flash chromatography (Si02, 20% ethyl acetate / hexane) gave 5- (2-methoxy-phenyl) -2- (2-pyridin-4-yl-ethyl) -4-p-tolyl-2,4-dihydro - [1, 2, 4] triazole-3-thione (0.04 g, 0.09 mmol) as a white solid.

Compound 5 1- (4-Chloro-phenyl) -3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazole- 1-yl] -propan-1-one Reaction scheme 9 Part 1. Preparation of 1- (4-Chloro-phenyl) -3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] ] triazol-1-yl] -propan-1-one To a solution of 5- (2-methoxy-phenyl) -4-p-tolyl-4H- [l, 2,4] triazole-3-thiol (0.45 g , 1.5 mmol) in DMF (10 mL) was added a 1M solution of lithium bis (trimethylsilyl) amide in THF (1.5 mL) and beta-4-dichloropropiophenone (0.30 g, 1.5 mmol) at room temperature. The mixture was heated at 60 ° C for 1 hour and cooled to room temperature. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum. The residue was purified by chromatography on silica (20% ethyl acetate in n-hexane) to give 1- (4-chloro-phenyl) -3- [3- (2-methoxy-phenyl) -5-thioxo-4- p ~ tolyl-4, 5-dihydro- [1, 2, 4] triazol-1-yl] -propan-1-one (0.19 g, 0.41 mmol) as a white solid. 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 (17)

1. 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 R3 is alkyl, alkoxyalkyl, Ar1 or AV-X-Y wherein, each Ar1 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is NR4, C (R4) 2, or O; Y is C = 0 or lower alkyl; R1 is H, alkenyl, 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 R is independently selected from H, (CH2) mC (0) OR4, (CH2) raC (0) Ar3, (CH2) mC (0) NRR5, (CH2) mC (O) N (OR4) R5, Ar3, (CH2) nAr3; (CH2) nNR4R5, or (CH2) mAr3; each R4 is independently selected from H, or lower alkyl; each R5 is independently selected from H, lower alkyl or (CH2) pAr3; m is 1 or 2; n is 2 or 3; p is 0 or 1; each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each substituted by Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N02, OR6, SRe, S (0) 20R6, NR6R7, cycloalkyl, perfluoroalkyl Ci-Ca, perfluoroalkoxy C! -C2, 1,2-methylenedioxy, C (0) 0R6, C (0) NReR7, 0C (0) NR6R7, NR6C (0) NRsR7, C (NR6) NRGR7, NR6C (NR7) NR6R7, S (0) 2NR6R7, R8, C (0) R8, NR6C (0) R8, S (0) R8, or S (0) 2R8; each Rs is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, alkoxy A-C4, NH2, alkylamino C! -C4, dialkylamino L-C? Or C3-C3 cycloalkyl; each R7 is independently selected from hydrogen, (CH) gAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, alkylamino 'C? -C4, dialkylamino Cx-C or cycloalkyl C3-Ce; each R8 is independently selected from (CH2) qAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH, C 1 -C 1 alkylamino dialkylamino CX-C? Or C3-C6 cycloalkyl; - 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, C?-C4 alkoxy, NH2, C alqu-C4 alkylamino, dialkylamino C? -C4 or C3? -C6 cycloalkyl; and q is 0 or 1.
2. 2. The compound according to claim 1, characterized in that R3 is Ar1 and R1 is Ar23.
3. The compound according to claim 1 or 2 characterized in that, R3 is independently aryl or heteroaryl, each optionally substituted with one or more substituents; and R1 is independently aryl or heteroaryl, each optionally substituted with one or more substituents.
4. 4. The compound according to any of claims 1-3, characterized in that R2 is (CH2) mC (0) OR4; (CH2) mC (0) Ar3, or (CH2) mC (O) NR4R5.
5. 5. The compound according to any of claims 1-3, characterized in that R2 is (CH ^ mAr3 and Ar3 is aryl or heteroaryl each optionally substituted with one or more substituents.
6. 6. The compound according to any of claims 1-3, characterized in that R2 is (CH2) mC (0) NRR5 and R5 is independently (CH2) pAr3, wherein Ar3 is aryl or heteroaryl, each optionally substituted with one or more substituents.
7. 7. The compound according to any of claims 1-3, characterized in that R2 is (CH2) nNR4R5 or (CH ^ p? R3.
8. 8. The compound according to claim 1, characterized in that it is a compound of Table 1.
9. 9. A composition, characterized in that it comprises a compound of the formula I according to claim 1 and a pharmaceutically acceptable carrier.
10. 10. The composition according to claim 9, further characterized in that it comprises an additional therapeutic agent.
11. 11. A method for treating a disease or symptom of the disease in a condition that requires such treatment, characterized in that it comprises administering to the subject an effective amount of a compound according to any of claims 1-6.
12. 12. The method according to claim 1, characterized in that the disease or symptom of the disease is modulated by the calcium channel Cav2.
13. 13. The method according to claim 12, characterized in that the disease or symptom of the disease is modulated by the calcium channel Cav2.2.
14. 14. The method according to claim 11, characterized in that the disease or symptom of the disease is angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, traumatic brain injury, or a neuronal disorder.
15. 15. A method for modulating the activity of the calcium channel, characterized in that it comprises contacting a calcium channel with a compound of the formula I according to claim 1:
16. 16. A method for modulating the activity of the calcium channel Cav2 in a subject in need thereof, characterized in that it comprises administering to the subject a therapeutically effective amount of a compound according to any of claims 1-8.
17. 17. A method for modulating the activity of the calcium channel Cav2 in a subject in need thereof, characterized in that it comprises administering to the subject a therapeutically effective amount of a composition according to claim 9.