WO2004072255A2 - Methods of treating disease - Google Patents

Abstract

The invention relates to substituted-guanidinyl 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

Methods of Treating Disease

BACKGROUND

All cells rely on the regulated movement of inorganic ions across 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 permit these changes are proteinaceious pores consisting of one or multiple subunits, each containing two or more membrane-spanning domains. Most ion channels have selectivity for specific ions, primarily Na⁺, K⁺, Ca²⁺, or Cl^", by virtue of physical preferences for size and charge. Electrochemical forces, rather than active transport, drive ions across membranes, thus a single channel may allow the passage of millions of ions per second. Channel opening, or "gating" is tightly controlled by changes in voltage or by ligand binding, depending on the subclass of channel. Ion channels are attractive therapeutic targets due to their involvement in so many physiological processes, yet the generation of drugs with specificity for particular channels in particular tissue types remains a major challenge.

Voltage-gated ion channels open in response to changes in membrane potential. For example, depolarization of excitable cells such as neurons result in a transient influx of Na⁺ ions, which propagates nerve impulses. This change in Na⁺ concentration is sensed by voltage-gated K⁺ channels which then allow an efflux of K⁺ ions. The efflux of K⁺ ions repolarizes the membrane. Other cell types rely on voltage-gated Ca channels to generate action potentials. Voltage-gated ion channels also perform important functions in non-excitable cells, such as the regulation of secretory, homeostatic, and mitogenic processes. Ligand-gated ion channels can be opened by extracellular stimuli such as neurotransmitters (e.g., glutamate, serotonin, acetylcholine), or intracellular stimuli (e.g. cAMP, Ca²⁺, and phosphorylation).

Genetic or pharmacological perturbations in ion channel function can have dramatic clinical consequences. Long QT syndrome, epilepsy, cystic fibrosis, and episodic ataxia are a few examples of heritable diseases resulting from mutations in ion channel subunits. Toxic side affects such as arrhythmia and seizure which are triggered by certain drugs are due to interference with ion channel function (Sirois, J.E. and, Atchison, W.D., Neurotoxicology 1996; 17(l):63-84; Keating, M.T., Science 1996 272:681-685). Drugs are useful for the therapeutic modulation of ion channel activity, and have applications in treatment of many pathological conditions, including hyptertension, angina pectoris, myocardial ischemia, asthma, bladder overactivity, alopecia, pain, heart failure, dysmenorrhea, type II diabetes, arrhythmia, graft rejection, seizure, convulsions, epilepsy, stroke, gastric hypermotility, psychoses, cancer, muscular dystrophy, and narcolepsy (Coghlan, M.J., 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 growing number of identified ion channels and understanding of their complexity will assist in future efforts at therapies which modify ion channel function.

SUMMARY

The invention relates to heterocyclic compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds and compositions comprising them are useful for treating disease or disease symptoms, including those mediated by or associated with ion channels.

One aspect of the invention relates to a method of modulating calcium channel activity in a subject comprising administering a compound of formula (I):

wherein, wherein n is 0 orl ;

X is alkyl (C1-C5), alkenyl (C3-C5) or aikynyl (C3-C5); each R and R is independently selected from, cycloalkyl, aryl, heterocyclyl, or heteroaryl group, wherein R and^'R^ is optionally substituted with one to three substituents independently selected from hydrogen, hydroxyl, halogen, nitro, S0₃H, trifluoromethyl, trifluoromethoxy, alkyl (C1-C6 straight or branched), alkoxy (C1-C6 straight or branched), O-benzyl, O- phenyl, phenyl, 1,2-methylenedioxy, carboxyl, morpholinyl, piperidinyl, NR²R³ or NR²R³ carboxamides, and each R² and R³ is independently selected from hydrogen, alkyl (C1-C6 straight or branched), or (CH₂)R.

In another aspect, the invention relates to a method of inhibiting calcium channel activity in a subject comprising administering a compound of formula (I), wherein each of R and R_Ϊ is independently selected from, phenyl, naphthyl, acenaphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo-[b]furanyl, benzo[b]thiophenyl, lH-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.

In yet another aspect, the invention relates to a method of treating a calcium channel mediated disease or disease symptom in a subject comprising administering a compound of Formula (I).

In still yet another aspect, the invention relates to a method of treating a calcium channel mediated disease or disease symptom in a subject comprising administering a composition, wherein the composition comprises a compound of formula (I).

Embodiments may include one or more of the following. The calcium channel can be Ca_vl .3 or Ca_v2.2. The subject may be a mammal (dog, cat, horse) or a human. The disease or disease symptoms treated may be cardiovascular disease, angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, central nervous system disease, urinary incontinence, stroke, pain, traumatic brain injury, or a neuronal disorder. The compound of Formula (I) includes the compounds of Table 1.

In other aspects, the invention relates to a composition comprising a compound of any of the formulae herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier. The additional therapeutic agent can be a cardiovascular disease agent (e.g. thrombin inhibitor, diltiazem, digoxin), and/or central nervous system (CNS) disease agent.

Yet another aspect of this invention relates to a method of treating a subject (e.g., mammal, human, horse, dog, cat) having an ion channel-mediated disease or disease symptom (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 (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 effect. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).

In still 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 disease symptom (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 (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 effect. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).

The invention also relates to a method of making a compound described herein. Alternatively, the method includes taking any one of the intermediate compounds described herein and reacting it with one or 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 aforementioned compounds in the container, and a legend (e.g., a label or an insert) associated with the container and indicating administration of the compound for treating a disorder associated with ion channel modulation.

In other embodiments, the compounds, compositions, and methods delineated herein are any of the compounds of Table 1 herein or methods including them. 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

As used herein, the term "halo" refers to any radical of fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C^Cs indicates that the group may have from 1 to 5 (inclusive) carbon atoms in it. The term "lower alkyl" refers to a Ci- C₆ alkyl chain. The term "arylalkyl" refers to a moiety in which an alkyl hydrogen atom is replaced by an aryl group.

The term "alkoxy" refers to an -O-alkyl radical. The term "alkylene" refers to a divalent alkyl (i.e., -R-). The term "alkylenedioxo" refers to a divalent species of the structure -0-R-0-, in which R represents an alkylene.

The term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbon.

The term "aryl" refers to an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, wherein 0, 1, 2 or 3 atoms of each ring can be substituted by a substituent. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "heterocyclyl" refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said 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 may be substituted by a substituent.

The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said 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, 3, or 4 atoms of each ring may be substituted by a substituent.

The term "oxo" refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached 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 limitation, hydrogen, hydroxyl, halogen, nitro, sulfonyl, perfluoroalkyl, perfluoroalkoxy, alkyl (C1-C6 straight or branched), alkoxy (C1-C6 straight or branched), O-benzyl, O-phenyl, phenyl, carboxyl, ester, amino, cyclic amino, carboxamide, amide, guanidine, and amidine groups. In one aspect, the substituents on a group are independently, hydrogen, hydroxyl, halogen, nitro, S0₃H, trifluoromethyl, trifluoromethoxy, alkyl (C1-C6 straight or branched), alkoxy (C1-C6 straight or branched), O-benzyl, O-phenyl, phenyl, 1,2-methylenedioxy, carboxyl, morpholinyl, piperidinyl, amino orcarboxamides

The term "treating" or "treated" refers to administering a compound described herein to a subject with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a disease, the symptoms of the disease or the predisposition toward 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 (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, alternatively from about 0.5 to about 100 mg/Kg, 1 to about 50 mg/Kg, 3 to about 25 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.

Representative compounds useful in the compositions and methods delineated herein are exemplified in Table 1.

TABLE 1 N-(5-acenaphthyl)-N-(3-iodobenzyl)guanidine N-(5-acenaphthyl)-N-(cinnamyl)guanidine N-(5-acenaphthyl)-N-(4-iodobenzyl)guanidine N-(5-acenaphthyl)-N-(4-trifluoromethoxybenzyl)guanidine N-(5-acenaphthyl)-N-(4-benzyloxybenzyl)guanidine

N-(5-acenaphthyl)-N-benzylguanidine N-(5-acenaphthyl)-N-(4-isopropylbenzyl)guanidine N-(5-acenaphthyl)-N-(4-tert-butylbenzyl)guanidine N-(5-acenaphthyl)-N-(3-phenoxybenzyl)guanidine N-(5-acenaphthyl)-N-(4-benzyloxybenzyl)guanidine

N-(3-acenaphthyl)-N-benzylguanidine N-(3-acenaphthyl)-N-(4-tert-butylbenzyl)guanidine N-(3-acenaphthyl)-N-(4-isopropylbenzyl)guanidine N-(3-biphenyl)-N-(4-tert-butylbenzyl)guanidine N-(4-benzyloxybenzyl)-N-(4-benzyloxybenzyl)guanidine

N-(4-benzyloxyphenyl)-N-(4-tert-butylbenzyl)guanidine N-(4-n-butoxyphenyl)-N-(4-tert-butylbenzyl)guanidine N-(4-chloro- 1 -naphthyl)-N-(4-tert-butylbenzyl)guanidine N-(4-cyclohexylphenyl)-N-(4-isopropylbenzyl)guanidine N-(4-cyclohexylphenyl)-N-(4-tert-butylbenzyl)guanidine

N-(2-fluorenyl)-N-(4-tert-butylbenzyl)guanidine N-(44ιexylphenyl)-N-(4-hexylbenzyl)guanidine N-(3-iodophenyl)-N-(4-tert-butylbenzyl)guanidine N-(4-iodophenyl)-N-(4-tert-butylbenzyl)guanidine N-(4-iso-propylphenyl)-N-(4-tert-butylbenzyl)guanidine

N-(5-indanyl)-N-(4-tert-butylbenzyl)guanidine N- 3-methylthiophenyl)-N-(4-tert-butylbenzyl)guanidine

N- methoxy- 1 -naphthyl)-N-(4-tert-butylbenzyl)guanidine

N l-naphthyl)-N-(4-tert-butylbenzyl)guanidine

N l-naphthylmethyl)-N-(4-tert-butylbenzyl)guanidine

N-i 3-n-pentoxyphenyl)-N-(4-tert43utylbenzyl)guanidine

N-i 4-sec-butylphenyl)-N-(trans-cinnamyl)guanidine

N 4-sec-butylphenyl)-N-(4-tert-butylbenzyl)guanidine

N 3-sec-butylphenyl)-N-(4-tert-butylbenzyl)guanidine

N-i 4-sec-butylphenyl)-N-(4-benzyloxybenzyl)guanidine

N-i 4-sec-butylphenyl)-N-benzylguanidine

N- 4-tert-butylphenyl)-N-(4-tert-butylbenzyl)guanidine

N- 3-tert-butylphenyl)-N-(4-tert-butylbenzyl)guanidine

N 3-trifluoromethylphenyl)-N-(4-tert4Dutylbenzyl)guanidine

N 3-trifluoromethoxyphenyl)-N-(4-tert-butylbenzyl)guanidine

N 4-tert-Butyl-phenyl)-N-(3-phenyl-propyl)-guanidine

N 4-tert-Butyl-phenyl)-N-[3-(4-chloro-phenyl)-propyl]-guanidine

N- 4-tert-Butyl-phenyl)-N-[3-(4-chloro-phenyl)-allyl]-guanidine

N 4-tert-Butyl-phenyl)-N-[3-(4-chloro-phenyl)-prop-2-ynyl]-guanidine

N 4-tert-Butyl-phenyl)-N-(3-pyridin-4-yl-prop-2-ynyl)-guanidine

N 4-tert-Butyl-phenyl)-N-(3-pyridin-4-yl-allyl)-guanidine

N-i 4-tert-Butyl-phenyl)-N-(3-pyridin-4-yl-propyl)-guanidine

N-i 4-Isopropyl-phenyl)-N-(3-phenyl-allyl)-guanidine

Ion channel-modulating compounds can be identified through both in vitro (e.g., cell and non-cell based) and in vivo methods. These methods are described in detail in the Examples. Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). The compounds delineated herein are can be synthesized using conventional methods. The compounds delineated herein can be synthesized using conventional methods, as illustrated in Scheme 1.

SCHEME I

Ar(C ^H2

Secondary amines (lb) can be obtained by either reductive animation of an aldehyde with an amine (lb) or by alkylation of an amine (lb) with the appropriate halogen substrate. Formation of the guanidine (I) can be accomplished under a variety of conditions (see, K.

Feichtinger, et al, J. Org. Chem., 1998, <52;3804-3805; Y.F. Yong, et al, J. Org. Chem., 1997, 6^"2;1540-1542; M.C. Maillar, et al, J. Med. Chem., 1998, i;3048-3061).

The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art.

Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock,

Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M.

Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); 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 occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such 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 instances, the invention expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All 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 formulae described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a 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 readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives where a group which enhances aqueou^ solubility or active transport through the gut membrane is appended to the structure of formulae described herein.

The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. 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, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 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 undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)₄ salts. This invention also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quatemization.

The compounds of the formulae described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, preferably dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon 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. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, 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.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

The compositions delineated herein include the compounds of the formulae delineated herein, as well as additional therapeutic agents if present, in amounts effective for achieving a modulation of disease or disease symptoms, including ion channel-mediated disorders or symptoms thereof.

The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceuticaliy-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery 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 oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and 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 suspending medium. For this purpose, any bland fixed oil may 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 pharmaceuticaliy-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 which 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 agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this invention may be orally administered 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 which are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may 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 therefore will 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 application topically to the skin, the pharmaceutical composition should be formulated with a suitable 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 petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.

The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

A composition having the compound of the formulae herein and an additional agent (e.g., a therapeutic agent) can be administered using an implantable device. Implantable devices and related technology are known in the art and are useful as delivery systems where a continuous, or timed-release delivery of compounds or compositions delineated herein is desired. Additionally, the implantable device delivery system is useful for targeting specific points of compound or composition delivery (e.g., localized sites, organs). Negrin et al., Biomaterials, 22(6):563 (2001). Timed-release technology involving alternate delivery methods can also be used in this invention. For example, timed-release formulations based on polymer technologies, sustained- release techniques and encapsulation techniques (e.g., polymeric, liposomal) can also be used for delivery of the compounds and compositions delineated herein.

Also within the invention is a patch to deliver active chemotherapeutic combinations herein. A patch includes a material layer (e.g., polymeric, cloth, gauze, bandage) and the compound of the formulae herein as delineated herein. One side of the material layer can have a protective layer adhered to it to resist passage of the compounds or compositions. The patch can additionally include an adhesive to hold the patch in place on a subject. An adhesive is a composition, including those of either natural or synthetic origin, that when contacted with the skin of a subject, temporarily adheres to the skin. It can be water resistant. The adhesive can be placed on the patch to hold it in contact with the skin of the subject for an extended period of time. The adhesive can be made of a tackiness, or adhesive strength, such that it holds the device in place subject to incidental contact, however, upon an affirmative act (e.g., ripping, peeling, or other intentional removal) the adhesive gives way to the external pressure placed on the device or the adhesive itself, and allows for breaking of the adhesion contact. The adhesive can be pressure sensitive, that is, it can allow for positioning of the adhesive (and the device to be adhered to the skin) against the skin by the application of pressure (e.g., pushing, rubbing,) on the adhesive or device.

^* When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. The invention will be further described in the following examples. It should be understood that these examples are for illustrative purposes only and are not to be constmed as limiting this invention in any manner

EXAMPLES

Example 1 Representative compounds of the formulae herein are screened for activity against calcium channel targets in an assay essentially as described inJ. Neurosci., August 15, 2001, 21(16):5944-5951, W. Xu and D. Lipscombe, using transient expression and recording from Xenopus oocytes. The assay is performed using various calcium channels (e.g., Caγl.3 subfamily) whereby the modulation of the calcium channel is measured for each compound. Table 2 contains IC₅₀'s for representative compounds disclosed in the invention.

Table 2

Example 2

N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)guanidine^»HCl

Part 1 : Preparation of N-(4-sec-butylphenyl)-4-tert-butylbenzylamine

A mixture of 4-sec-butylaniline (2.89 g, 20 mmol) and triethylamine (2.5 g 25 mmol) in toluene (100 mL) was stirred at 4°C and 4-tert-butylbenzyl bromide (4.5 g, 20 mmol)was added slowly. The reaction was stirred for 15 hours at 23°C and a precipitate formed. The precipitates were filtered and the filtrate concentrated to dryness. Purification by column chromatography (Si0 , 5:l/hexane:methylene chloride) provided 4.6 g of N-(4-sec- butylphenyl)-4-tert-butylbenzylamine as an oil.

Part 2: Preparation of N-(4-sec-butylphenyl)-4-tert-butylbenzylamine»HCl To a solution of N-(4-sec-butylphenyl)-4-tert-butylbenzylamine (4.5 g) in diethylether (10 mL) was added an HCl ether solution at 4°C. The resulting mixture was warmed to 25°C, stirred for 10 minutes, evaporated and dried under vacuum to afford 4.7 g of N-(4-sec- butylphenyl)-4-tert-butylbenzylamine.HCl Part 3: Preparation of N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)guanidine^»HCl

A mixture of N-(4-sec-butylphenyl)-4-tert-butylbenzylamine^»HCl (0.8 g, 2.7 mmol) and cyanamide (2 g) in methanol was heated at 70°C for 70 hours. During the 70 hours, another two portions fo cyanamide (0.5g, each time) were added. The crude product was passed through a column (Si0₂, 9:l/methylene chloride :methanol) to provide a mixture of guanidine and cyanamide, which was dissolved in water (20 mL) and basified to pH 14. The

base was extracted with methylene chloride (2x20 mL) and the combined extracts concentrated. The residue was treated with methanolic^»HCl and dried under vacuum for 15 hours to provideθ.6 g of Example 1 as a white solid, mp: 177-178°C; ¹H MR (CD₃OD, 300 MHz): δ ppm 7.39-7.12 (m, ArH, 8H), 4.90 (s, CH₂, 1H), 4.88 (s, CH₂, 1H), 2.63 (m, CH, 1H), 1.57 (m, CH₂, 2H), 1.29 (s, CH₃, 9H), 1.21 (d, CH₃, 3H), 0.8 (t, CH₃,3H):

HRMS: 377.2524 (337.2518 Calcd. for C₂₂H₃₁N₃.

Example 3

N-(5-Acenaphthyl)-N-(4-tert-butylbenzyl)guanidine Part 1 : Preparation of 5-Acenaphthylamine

A mixture of 5 and 3-nitroacenaphthene was reduced with palladium on carbon in ethyl acetate under hydrogen at 40 psi pressure and the resulting amines were separated by recrystallization from cyclohexane/ethyl acetate.

Part 2: Preparation of N-(5-Acenaphthyl)-4-tert-butylbenzylamine A mixture of 5-acenaphthylamine (1.0 g, 6 mmol) and triethylamine (0.76 g 7.5 mmol) in toluene (50 mL) was stirred at 4°C and 4-tert-butylbenzyl bromide (1.36 g, 6 mmol)was added slowly. The reaction was stirred for 15 hours at 23 °C and a precipitate formed. The precipitates were filtered and the filtrate concentrated to dryness. Purification by column chromatography (Si0₂, 5:l/hexane:methylene chloride) provided 1.67 g of N-(5- Acenaphthyl)-4-tert-butylbenzylamine as an oil.

Part 3: Preparation of N-(5-Acenaphthyl)-4-tert-butylbenzylamine^»mesylate

To a solution of N-(5-acenaphthyl)-4-tert-butylbenzylamine (1.1 g) in diethylether (10 mL) was added methanesulfonic acid at 4°C. The resulting mixture was warmed to 25°C, stirred for 10 minutes, evaporated and dried under vacuum to afford g of N-(5-Acenaphthyl)-4-tert- butylbenzylamine^mesylate

Part 4: Preparation of N-(5-Acenaphthyl)-N-(4-tert-butylbenzyl)guanidine

A mixture of N-(5-acenaphthyl)-4-tert-butylbenzylamine»mesylate (3.5 mmol) and cyanamide (0.4 g) in methanol was heated at 70°C for 70 hours. During the 70 hours, another two portions fo cyanamide (0.5g, each time)were added. The crude product was passed through a column (Si0₂, 9:1 /methylene chloride :methanol) to provide a mixture of guanidine and cyanamide, which was dissolved in water (20 mL) and basified to pH 14. The guanidine»free base was extracted with methylene chloride (2x20 mL) and the combined extracts concentrated. The residue was treated with methanolic'HCl and dried under vacuum for 15 hours to provide 0.6 g of Example 2 as a white solid, mp: 85-86°C; 1H NMR (CD₃OD, 300 MHz): δ ppm 7.60-7.20 (m, ArH, 9H), 4.90 (s, CH₂, 2H), 3.41-3.31 (m, CH₂, 4H), 1.26 (s, CH₃, 9H): MS(EI): m/e 357.2 (M⁺: C₂₄H₂₇N₃.»l/4xH₂0); Calcd. (%): C, 79.62, H, 7.66, N, 11.60; Found (%): C, 79.74, H, 7.48, N, 11.79.

Examples 4-38

By the methods above and using appropriately substituted reagents, the following compounds were prepared having the specified physical characteristics.

Example 4 N-(3-sec-Butylphenyl)-N-(4-tert-butylbenzyl)guanidine»HCl mp: 190-191°C; 1H NMR (CD₃OD 300 MHz): δ ppm 7.38-6.81 (m, ArH, 8H), 4.86 (s, CH₂, 2H), 2.53 (m, CH, IH), 1.45 (m, CH₂, 2H), 1.29 (s, CH₃, 9H), 1.12 (d, CH₃, 3H), 0.71- (t, CH₃, 3H) : MS(EI): m/e 337.4 (M⁺: C₂₂H₃₁N₃); Anal (C₂₂H₃₁N₃ ^«HCl^«0.5xH₂0): Calcd. (%): C, 68.79, H, 8.68, N, 10.97; Found (%): C, 69.23, H, 8.35, N, 10.92.

Example 5

N-(5-Acenaphthyl)-N-(4-isopropylbenzyl)guanidine mp: 153-155°C; 1H NMR (CD₃OD, 300 MHz): δ ppm 7.60-7.10 (m, ArH, 9H), 5.17 (d, CH₂, IH), 4.57 (d, CH₂, IH), 3.45-3.40 (m, CH₂, 4H), .2.85 (m, CH, IH) 1.20 (d, CH₃, 6H): HRMS: 343.2048 (343.2048 calcd. for C₂₃H₂₅N₃).

Example 6

N-(3-tert-Butylphenyl)-N-(4-tert-butylbenzyl)guanidine»HCl mp: 291-292°C; 1H NMR (CDC1₃, 300 MHz): δ ppm 7.51-7.19 (m, ArH, 8H), 4.92 (s, CH₂, 2H), 1.34 (s, CH₃, 9H), 1.31 (s, CH₃, 9H): MS(EI): m/e 337.4 (M^": C₂₂H₃₁N₃); Anal (C₂₂H₃₁N₃'HC1): Calcd. (%): C, 70.66, H, 8.62, N, 11.24; Found (%): C, 70.50, H, 8.55, N, 11.29.

Example 7

N-(4-Cyclohexylphenyl)-N-(4-isopropylbenzyl)guanidine»HCl mp: 130-131°C; 1H NMR (CD₃OD, 300 MHz): δ ppm 7.35-7.12 (m, ArH, 8H), 4.92 (s, CH₂, 2H), 2.90 (m, CH, IH), 2.53 (m, CH, IH), 1.87-1.25 (m, CH₂, 10H) 1.12 (d, CH₃, 6H): HRMS: 349.2512 (349.2518 calcd. for C₂₃H₃₁N₃).

Example 8

N-(4-Cyclohexylphenyl)-N-(4-tert-butylbenzyl)guanidine»HCl mp: 219-220°C; 1H NMR (CDCI3, 300 MHz): δ ppm 7.45-7.18 (m, ArH, 8H), 4.88 (s, CH₂, 2H), 2.55 (s, CH, IH), 1.90-1.30 (m, CH₂, 10H), 1.32 (s, CH₃, 9H): MS(EI): m/e 363.2 (M : C₂₄H₃₃N₃); Anal (C₂ H₃₃N₃*HC1): Calcd. (%): C, 72.06, H, 8.57, N, 10.50; Found (%) C, 71.97, H, 8.32, N, 10.33. - .

Example 9 N-(2-Fluorenyl)-N-(4-tert-butylbenzyl)guanidine^»HCl mp: 155-157°C; 1H NMR (CDCI₃, 300 MHz): δ ppm 7.90-7.20 (m, ArH, 11H), 4.95 (s, CH₂,

2H), 3.95 (s, CH₂, 2H), 1.32 (m, CH₃, 9H): MS(EI): m/e 369.2 (WU: C₂₅H₂₇N₃); Anal (C₂₅H₂₇N₃«HC1Η₂0): Calcd. (%): C, 70.89, H, 7.14, N, 9.93; Found (%): C, 71.14, H, 6.88, N, 9.77.

Example 10

N-(4-sec-Butylphenyl)-N-(trans-cinnamyl)guanidine^»HCl mp: 169-170X; 1H NMR (CDC1₃, 300 MHz): δ ppm 7.40-7.20 (m, ArH, 9H), 6.88 (d, CH, IH), 6.25 (dt, CH, IH), 4.55 (d, CH₂, 2H), 2.66 (m, CH, IH), 1.60 (m, CH₂, 2H), 1.25 (d, CH₃, 3H), 0.83 (t, CH₃, 3H); Anal (C₂₀H₂₅N₃«HC1): Calcd. (%): C, 69.93, H, 7.64, N, 12.24; Found (%): C, 69.79, H, 7.45, N, 12.29.

Example 11 N-(4-n-Butoxyphenyl)-N-(4-tert-butylbenzyl)guanidine mp: 188-189°C; 1H NMR (CDC1₃, 300 MHz): δ ppm 7.44-6.90 (m, ArH, 8H), 4.84 (s, CH₂, 2H), 3.97 (t, CH₂, 2H), 1.73 (p, CH₂, 2H), 1.49 (p,^"CH₂, 2H), 1.32 (s, CH₃, 9H), 0.94 (t, CH₃, 9H): MS(EI): m/e 353.3 (M⁺: C₂₂H₃₁N₃0); Anal (C₂₂H₃ιN₃0 •HCl): Calcd. (%): C, 67.83, H, 8.29, N, 10.79; Found (%): C, 68.00, H, 8.18, N, 11.04. Example 12

N-(3-Biphenyl)-N-(4-tert-butylbenzyl)guanidine»HCL mp: 255-256°C; 1HNMR (CDC1₃, 300 MHz): δ ppm 7.70-7.15 (m, ArH, 13H), 4.93 (s, CH₂, 2H), 1.30 (s, CH₃, 9H): MS(EI): m e 357.3 (M⁺: C₂₄H₂₇N₃); Anal (C₂₄H₂₇N₃ 'HCl): Calcd. (%): C, 73.25, H, 7.18, N, 10.68; Found (%): C, 73.41, H, 7.18, N, 10.86. Example 13

N-(5-Indanyl)-N-(4-tert-butylbenzyl)guanidine

1HNMR (CDCI₃, 300 MHz): δ ppm 7.45-6.90 (m, ArH, 7H), 4.86 (s, CH₂, 2H), 2.87 (m, CH₂, 4H), 2.08 (m, CH₂, 2H), 1.29 (s, CH₃, 9H): MS(EI): m e 321.2 (M^": C₂ιH₂₇N₃).

Example 14 N-(3-Trifluoromethoxyphenyl)-N-(4-tert-butylbenzyl)guanidine

1HNMR (CDCI3, 300 MHz): δ ppm 7.65-7.10 (m, ArH, 8H), 4.94 (s, CH₂, 2H), 1.29 (s, CH₃,

9H): MS(EI): m/e 365.1 ( : C₁₉H₂₂F₃N₃0). Example 15

N-(4-sec-Butylphenyl)-N-benzylguanidine mp: 65-67°C; 1H NMR (CD₃OD, 300 MHz): δ ppm 7.30-6.90 (m, ArH, 8H), 4.98 (s, CH₂, 2H), 2.58 (m, CH, IH), 1.55 (m, CH₂, 2H), 1.20 (d, CH₃, 3H), 0.79 (t, CH₃, 3H): HRMS: 281.1891 (281.1891 Calcd. for C₁₈H₂₃N₃).

Example 16

N-(5-Acenaphthyl)-N-benzylguanidine mp: 138-140°C; 1H NMR (CD₃OD, 300 MHz): δ ppm 7.45-6.93 (m, ArH, lOH), 5.54 (d, CH₂, IH), 4.63 (d, CH₂,1H), 3.45-3.40 (m, CH₂, 4H): HRMS: 301.1559 (301.1589 Calcd. for C₂₀H₁₉N₃).

Example 17

N-(3-n-Pentoxyphenyl)-N-(4-tert-butylbenzyl)guanidine»HCl mp: 198-199°C; 1H MR (CD₃OD 300 MHz): δ ppm 7.41-7.20 (m, ArH, 8H), 4.93 (s, CH₂, 2H), 3.90 (t, OCH₂, 2H), 1.78-1.60 (m, CH₂, 2H), 1.44-1.40 (m, CH₂, 4H), 1.31 (s, CH₃, 9H), 1.31 (t, CH₃, 3H), MS(EI): m/e 367.3^: C₂₃H₃oN₃0); Anal (C₂₃H₃₀N₃O •HCl»0.5xH₂O): Calcd. (%): C, 66.98, H, 8.54, N, 10.17; Found (%): C, 66.98, H, 8.33, N, 10.05.

Example 18

N-(Methoxy- 1 -naphthyl)-N-(4-tert-butylbenzyl)guanidine

1H NMR (CDC1₃, 300 MHz): δ ppm 8.35-6.80 (m, ArH, lOH), 5.25 (d, CH₂, IH), 4.59 (d, CH₂, IH), 1.29 (s, CH₃, 9H): MS(EI): m/e 361.5 (M⁺: C₂₃H₂₇N₃0).

Example 19

N-(l-Naphthyl)-N-(4-tert-butylbenzyl)guanidine^»HCl mp: 241-242 ; 1HNMR (CDCI₃, 300 MHz): δ ppm 8.35-7.10 (m, ArH, 11H), 5.25 (d, CH₂, IH), 4.67 (d, CH₂, IH), 1.29 (s, CH₃, 9H): MS(EI): m/e 331 (M⁺: C₂₂H₂₅N₃); Anal (C₂₂H₂₅N₃'HC1): Calcd. (%): C, 71.82, H, 7.12, N, 11.42; Found (%): C, 71.79, H, 7.12, N, 11.43.

Example 20 N-(3-Iodophenyl)-N-(4-tert-butylbenzyl)guanidine»HCl mp: 271-272°C; 1H NMR (CD₃OD, 300 MHz): δ ppm 7.78-7.13 (m, ArH, 8H), 4.87 (s, CH₂, 2H), 1.30 (s, CH₃, 9H): MS(EI): m/e 407.33 (M*^": C₁₈H₂₂N₃I); Anal (C₁₈H₂₂N₃I •HCl): Calcd. (%): C, 48.72, H, 5.22, N, 9.47; Found (%): C, 48.90, H, 5.46, N, 9.52. Example 21

N-(4-Chloro- 1 -naphthyl)-N-(4-tert-butylbenzyl)guanidine^»HCl mp: 115-117°C; 1HNMR (CD₃OD, 300 MHz): δ ppm 8.37-7.13 (m, ArH, lOH), 5.25 (d, CH₂, IH), 4.69 (d, CH₂, IH), 1.26 (s, CH₃, 9H): MS(EI): m/e 365.1 (M⁺: C₂₂H₂₄C1N₃); Anal (C₂₂H₂₄C1N₃'HC1^«H₂0): Calcd. (%): C, 62.86, H, 6.47, N, 10.03; Found (%): C, 63.19, H, 6.27, N, 9.69.

Example 22

N-(4-tert-Butylphenyl)-N-(4-tert-butylbenzyl)guanidine^»HCl mp: 290-291°C; 1HNMR (CDC1₃, 300 MHz): δ ppm 7.51-7.18 (m, ArH, 8H), 4.93 (s, CH₂, 2H), 1.33 (s, CH₃, 9H), 1.31 (s, CH₃, 9H): MS(EI): m/e 338 (M^1": C₂₂H₃₁N₃); Anal (C₂₂H₃₁N₃ ^«HC1): Calcd. (%): C, 70.66, H, 8.62, N, 11.24; Found (%): C, 70.43, H, 8.42, N, 11.17.

Example 23

N-(4-Iodophenyl)-N-(4-tert-butylbenzyl)guanidine»HCl mp: 219-220°C; 1H NMR (CD₃OD, 300 MHz): δ ppm 7.81-7.02 (m, ArH, 8H), 4.89 (s, CH₂, 2H), 1.30 (s, CH₃, 9H): MS(EI): m/e 408 (M⁺: C₁₈H₂₂LN₃); Anal (Cι₈H₂₂IN₃»HCl): Calcd. (%): ^' C, 48.72, H, 5.22, N, 9.47; Found (%): C, 48.72, H, 5.26, N, 9.28.

Example 24

N-(l-Naphthylmethyl)-N-(4-tert-butylbenzyl)guanidine^»HCl mp: 134-135°C; 1H NMR (CDC1₃, 300 MHz): δ ppm 7.95-7.10 (m, ArH, 11H), 5.10 (s, CH₂, 2H), 4.58 (s, CH₂, 2H), 1.32 (s, CH₃, 9H): MS(EI): m e 346 (M*^": C₂₃H₂₇N₃); Anal (C₂₃H₂₇N₃'HC1'H₂0): Calcd. (%): C, 69.07, H, 7.56, N, 10.51; Found (%): C, 68.70, H, 7.71, N, 10.19.

Example 25 N-(5-Acenaphthyl)-N-(3-phenoxybenzyl)guanidine^»HCl mp: 100-lθrC; 1HNMR (CD₃OD, 300 MHz): δ ppm 7.62-6.80 (m, ArH, 14H), 5.20 (d, CH₂, IH), 4.70 (d, CH₂, IH), 3.46-3.40 (m, CH₂, 4H): MS(EI): m/e 393.5 (M^1": C₂₈H₂₃N₃0); Anal (C₂₈H₂₃ N₃0 •HCl): Calcd. (%): C, 72.63, H, 5.63, N, 9.77; Found (%): C, 72.77, H, 5.57, N, 9.67.

Example 26

N-(3-Trifluoromethylphenyl)-N-(4-tert-butylbenzyl)guanidine^»HCl mp: 281-282°C; 1H NMR (CD₃OD 300 MHz): δ ppm 7.63-7.13 (m, ArH, 8H), 4.92 (s, CH₂, 2H), 1.29 (s, CH₃, 9H): MS(EI): m/e 349.1 (M⁺: C₁₉H₂₂F₃N₃); Anal (C₁₉H₂₂F₃N₃ ^»HC1): Calcd. (%): C, 59.14, H, 6.01, N, 10.89; Found (%): C, 59.14, H, 6.12, N, 10.88.

Example 27

N-(3-Methylthiophenyl)-N-(4-tert-butylbenzyl)guanidine»HCl mp: 247-248°C; 1H NMR (CD₃OD, 300 MHz): δ ppm 7.42-7.15 (m, ArH, 8H), 4.87 (s, CH₂, 2H), 2.35 (s, SCH₃, 3H), 1.30 (s, CH₃, 9H): MS(EI): m/e 327.3 (M*: C₁₉H₂₅N₃S); Anal (C₁₉H₂₅N₃SΗC1): Calcd. (%): C, 62.70, H, 7.20, N, 11.55; Found (%): C, 62.81, H, 7.27, N, 11.57.

Example 28

N-(5 -Acenaphthyl)-N-(3 -iodobenzyl)guanidine^»HCl mp: 249-250°C; 1HNMR (CDCI₃, 300 MHz): δ ppm 7.62-7.00 (m, ArH, 9H), 5.46 (d, CH₂, IH), 4.75 (d, CH₂, IH), 3.49-3.42 (m, CH₂, 4H): MS(EI): m/e 427.1 (M⁺: C₂₀H₁₈IN₃); Anal

(C₂₀H₁₈IN₃*HC1): Calcd. (%): C, 51.80, H, 4.13, N, 9.06; Found (%): C, 52.00, H, 4.14, N, 9.00.

Example 29

N-(5-Acenaphthyl)-N-(cinnamyl)guanidine^»HCl mp: 205-206.5°C; 1H NMR (CDC1₃, 300 MHz): δ ppm 7.62-7.18 (m, ArH, 10H), 6.65 (d, CH₂, IH), 6.30 (d, CH₂, IH), 5.27 (m, =CH, 0.5H), 4.92 (m, =CH, 0.5H), 4.92 (m, =CH, IH), 3.57-

3.41 (m, CH₂, 4H): MS(EI): m/e 327.2 (M⁺: C₂₂H₂₁N₃); Anal (C₂₂H₂₁N₃»HCl^»3/4xH₂0): Calcd. (%): C, 70.01, H, 6.27, N, 11.13; Found (%): C, 70.21, H, 6.31, N, 11.10. Example 30

N-(5-Acenaphthyl)-N-(4-iodobenzyl)guanidine«HCl mp: 269-270°C; 1HNMR (CD₃OD, 300 MHz): δ ppm 7.65-7.00 (m, ArH, 9H), 5.20 (d, CH₂, IH), 4.70 (d, CH₂, IH), 3.46-3.40 (m, CH₂, 4H): MS(EI): m/e 427.2 (Wt: C₂₀H₁₈IN₃); Anal (C₂₀H₁₈IN₃'HCM .5xH₂0): Calcd. (%): C, 48.95, H, 4.52, N, 8.56; Found (%): C, 48.62, H, 4.42, N, 8.39.

Example 31

N-(5-Acenaphthyl)-N-(4-trifluoromethoxybenzyl)guanidine^,HCl mp: 120-122°C; 1HNMR (CD₃OD, 300 MHz): δ ppm 7.56-7.17 (m, ArH, 9H), 5.25 (d, CH₂, IH), 4.82 (d, CH₂, IH), 3.43-3.41 (m, CH₂, 4H): MS(EI): m/e 385.3 (M^1": C₂₁H₁₈F₃N₃0); Anal

(C₂₁H₁₈F₃N₃0^»HCl^»2xH₂0): Calcd. (%): C, 55.09, H, 5.06, N, 9.18; Found (%): C, 55.33, H, 4.78, N, 9.08.

Example 32

N-(5-Acenaphthyl)-N-(4-benzyloxyb.enzyl)guanidine^»HCl mp: 118-119°C; 1H NMR (CDCI₃, 300 MHz): δ ppm 7.56-6.86 (m, ArH, 14H), 5.31 (d, CH₂, IH), 5.02 (s, CH₂, 2H), 4.70 (d, CH₂, IH), 3.50-3.41 (m, CH₂, 4H): MS(EI): m/e 407.3 (M : C₂₇H₂₅N₃0); Anal (C₂₇H₂₅N₃0 •HCl): Calcd. (%): C, 73.04, H, 5.90, N, 9.46; Found (%): C, 72.93, H, 5.68, N, 9.30.

Example 33 N-(4-sec-Butylphenyl)-N-(4-benzyloxybenzyl)guanidine^»HCl mp: 84-85°C; 1H NMR (CD₃OD, 300 MHz): δ ppm 7.39-6.92 (m, ArH, 13H), 5.05 (s, OCH₂, 2H), 4.82 (s, CH₂, 2H), 2.62 (m, CH, IH), 1.60 (m, CH₂, 2H), 1.21 (d, CH₃, 3H), 0.82 (t, CH₃, 3H): MS(EI): m/e 387.3 (M^1": C₂₅H₂₉N₃0); Anal (C₂₅H₂₉N₃OΗCl^«0.6xH₂O): Calcd. (%): C, 69.09, H, 7.23, N, 9.66; Found (%): C, 68.86, H, 6.83, N, 9.80. Example 34

N-(4-Benzyloxybenzyl)-N-(4-benzyloxybenzyl)guanidine^»HCl mp: 193-194°C; 1H NMR (CD₃OD, 300 MHz): δ ppm 7.40-6.93 (m, ArH, 18H), 5.08 (s, OCH₂, 2H), 5.06 (s, OCH₂, 2H), 4.79 (s, CH₂, 2H): MS(EI): m/e 437.2 (M⁺: C₂₈H₂₇N₃0₂); Anal (C₂₈H₂₇N₃0₂ ^«HC1): Calcd. (%): C, 70.95, H, 5.95, N, 8.86; Found (%): C, 70.81, H, 5.71, N, 8.71. Example 35

N-(5-Acenaphthyl)-N-(4-benzyloxybenzyl)guanidine^»HCl mp: 140-141°C; 1HNMR (CDCI₃, 300 MHz): δ ppm 7.45-6.55 (m, ArH, 14H), 5.45-5.25 (m, CH₂, IH), 4.86 (s, CH₂, 2H), 4.65-4.45 (d, CH₂, IH), 3.50-3.25 (m, CH₂, 4H): MS(EI): m/e 407.4 (M⁺: C₂₇H₂₅N₃0); Anal (C₂₇H₂₅N₃0«HC1»H₂0): Calcd. (%): C, 70.40, H, 6.11, N, 9.10; Found (%):C, 70.42, H, 6.00, N, 9.18.

Example 36

N-(4-iso-Propylphenyl)-N-(4-tert-butylbenzyl)guanidine ^»HCl mp: 260-261 °C; 1H MR (CD₃OD 300 MHz): δ ppm 7.41-7.12 (m, ArH, 8H), 4.88 (s, CH₂, 2H), 3.00-2.80 (m, CH, IH), 1.30 (s, CH₃, 9H), 1.23 (d, CH₃, 3H): MS(EI): m/e 324 (M^1": C₂₁H₂₉N₃); Anal (C₂iH₂₉N₃»HCl-H₂0): Calcd. (%): C, 70.08, H, 8.40, N, 11.67; Found (%):C, 69.85, H, 8.25, N, 11.90.

Example 37

N-(4-Benzyloxyphenyl)-N-(4-tert-butylbenzyl)guanidine^»HCl mp: 178-179°C; 1H NMR (CD₃OD 300 MHz): δ ppm 7.50-7.00 (m, ArH, 13H), 5.08 (s, OCH₂, 2H), 4.84 (s, CH₂, 2H), 1.3(l(s, CH₃, 9H): MS(EI): m/e 388 (M*^": C₂₅H₂₉N₃0); HRMS: 387.2315 (Calcd. 387.2311).

Example 38

N-(4-Hexylphenyl)-N-(4-hexylbenzyl)guanidine»Mesylate mp: oil; 1H NMR (CD₃OD 300 MHz): δ ppm 7.30-7.05 (m, ArH, 8H), 4.86 (s, CH₂, 2H), 2.69 (s, -S0₃H, 2H), 2.64-2.55 (m, CH₂, 4H), 1.70-1.50 (m, CH₂, 4H), 1.40-1.25 (m, CH₂, 12H), 1.00-0.8 (m, CH₃, 6H): MS(EI): m/e 493.4 (M^1": C₂₈H₃9N₃); HRMS: 393.3166 (Calcd. 393.3160). All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.

It is to be understood that while 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.

Claims

WHAT IS CLAIMED IS:

1. A method of inhibiting calcium channel activity in a subject comprising administering to the subject a compound of formula (I):

wherein, wherein n is 0 orl; X is alkyl (C1-C5), alkenyl (C3-C5) or aikynyl (C3-C5); each R and R_\ is independently selected from, cycloalkyl, aryl, heterocyclyl, or heteroaryl group, wherein R and R_\ is optionally substituted with one to three substituents independently selected from hydrogen, hydroxyl, halogen, nitro, S0₃H, trifluoromethyl, trifluoromethoxy, alkyl (C1-C6 straight or branched), alkoxy (C1-C6 straight or branched), O-benzyl, O-phenyl, phenyl, 1,2-methylenedioxy, carboxyl, morpholinyl, piperidinyl, NR²R³ or NR²R³ carboxamides, and each R² and R³ is independently selected from hydrogen, alkyl (C1-C6 straight or branched), or (CH₂)R.

2. The method of claim 1 , wherein each of R and

is independently selected from, phenyl, naphthyl, acenaphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo-[b]furanyl, benzo[b]thiophenyl, lH-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.

3. The method of claim 1 , wherein, the calcium channel is Ca_v 1.3.

4. The method of claim 1, wherein the calcium channel is Ca_v2.2.

5. The method of claim 3 or 4, wherein the subject is a mammal.

6. The method of claim 3 or 4, wherein the subject is a human.

7. The method of claim 3 or 4, wherein the compound is a compound of Table 1.

8. A method of treating a calcium channel mediated disease or disease symptom in a subject comprising administering to the subject a compound of Formula (I) in claim 1.

9. The method of claim 8 , wherein the calcium channel is Ca_v 1.3.

10. The method of claim 9, wherein the disease or disease symptom is a cardiovascular disease or disease symptom.

11. The method of claim 9, wherein the disease or disease symptom is angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia or diabetes.

12. The method of claim 8, wherein the calcium channel is Ca_v2.2.

13. The method of claim 12, wherein the disease or disease symptom is a central nervous system disease or disease symptom.

14. The method of claim 12, wherein the disease or disease symptom is urinary incontinence, stroke, pain, traumatic brain injury, or a neuronal disorder.

15. A method of treating a calcium channel mediated disease or disease symptom in a subject comprising administering to the subject a composition, wherein the composition comprises a compound of formula (I) in claim 1.

16. The method of claim 15, wherein the calcium channel is Ca_v1.3.

17. The method of claim 16, wherein the disease or disease symptom is a cardiovascular disease or disease symptom.

18. The method of claim 16, wherein the disease or disease symptom is angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia or diabetes.

19. The method of claim 15, wherein the calcium channel is Ca_v2.2.

20. The method of claim 19, wherein the disease or disease symptom is a central nervous system disease or disease symptom.

21. The method of claim 19, wherein the disease or disease symptom is urinary incontinence, stroke, pain, traumatic brain injury, or a neuronal disorder.

22. The method of claims 8 or 15, wherein the subject is a mammal.

23. The method of claims 8 or 15, wherein the subject is a human.

24. The method of claims 8 or 15, wherein the compound is a compound of Table 1.