WO2005034837A2 - 7H-IMIDAZO [1,2-α] PYRAZIN-8-ONE COMPOUNDS AS ION CHANNEL MODULATORS - Google Patents

Abstract

N-substituted imidazopyrazinone compounds such as N-alkylated/aralkylated 7H-imidazo[1,2­a]pyrazin-8-one compounds and related analogs are disclosed. Pharmaceutical compositions and kits containing the N-substituted imidazopyrazinone compounds, as well as therapeutic uses thereof, including treatment of arrhythmia, are also disclosed.

Description

EVIIDAZO COMPOUNDS AND USES THEREOF

[0001] This application claims benefit of U.S. Provisional Application No. 60/510,010, filed October 8, 2003, which is incorporated herein by reference in its entirety.

BACKGROUND

1. TECHNICAL FIELD

[0002] The present invention is generally directed towards N-substituted imidazopyrazinone compounds such as N-alkylated/aralkylated 7H-imidazo[l,2-α]pyrazin-8-one compounds and related analogs, pharmaceutical compositions and kits containing the N-substituted imidazopyrazinone compounds, and therapeutic uses thereof.

2. RELATED ART

[0003] Ion channels are ubiquitous membrane proteins in the cells of warm-blooded animals such as mammals. Critical physiological roles of these ion channels include control of the electrical potential across the membrane, mediation of ionic and fluid balance, facilitation of neuromuscular and neuronal transmission, rapid transmembrane signal transduction, and regulation of secretion and contractility.

[0004] For example, cardiac ion channels are proteins that reside in the cell membrane of cardiac cells and control the electrical activity of cardiac tissue. In response to external stimuli, such as changes in potential across these cell membranes, these ion channels can form a pore through the cell membrane, and allow movement of specific ions in or out of the cell. The integrated behavior of thousands of ion channels in a single cell results in an ionic current, and the integrated behavior of many of these ionic currents makes up the characteristic cardiac action potential. [0005] Arrhythmia is a variation from the normal rhythm of the heart beat and generally represents the end product of abnormal ion-channel structure, number or function. Both atrial (including supraventricular) arrhythmias and ventricular arrhythmias are known. The major cause of fatalities resulting from cardiac arrhythmias is the subtype of ventricular arrhythmias known as ventricular fibrillation (VF). Conservative estimates indicate that, in the U.S. alone, each year over one million Americans will have a new or recurrent coronary attack. About 650,000 of these occurances will be first heart attacks and 450,000 of these occurances will be recurrent attacks. About one-third of individuals experiencing these attacks will die as a result. At least 250,000 individuals a year die of coronary heart disease within 1 hour of the onset of symptoms and before they reach adequate medical aid. These are sudden deaths caused by cardiac arrest, usually resulting from ventricular fibrillation.

[0006] Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice and is a cause of morbidity in many individuals (Pritchett E.L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031-2; Kannel and Wolf, Am. Heart J. 123(l):264-7 Jan. 1992). The prevalence of AF is likely to increase as the population ages and it is estimated that 3-5% of patients over the age of 60 years have AF (Kannel W.B., Abbot R.D., Savage D.D., McΝamara P.M., N. Engl. J. Med. 306(17):1018-22, 1982; Wolf P.A., Abbot R.D., Kannel W.B. Stroke 22(8):983-8, 1991). While atrial flutter and AF are rarely fatal, they can impair cardiac function, and AF is also a major cause of stroke. (Hinton R.C., Kistler J.P., Fallon J.T., Friedlich A.L., Fisher CM., Am. J. Cardiol. 40(4) 5Q9- 13, 1977; Wolf P.A., Abbot R.D., Kannel W.B., Arch. Int. Med. 147(9):1561-4, 1987; Wolf P.A., Abbot R.D., Kannel W.B. Stroke 22(8):983-8, 1991; Cabin H.S., Clubb K.S., Hall C, Perlmutter R.A., Feinstein A.R., Am. J. Cardiol. 65(16):\\\2-6, 1990).

[0007] Antiarrhythmic agents have been developed to prevent or alleviate cardiac arrhythmia. For example, Class I antiarrhythmic compounds have been used to treat atrial supraventricular arrhythmias and ventricular arrhythmias. Treatment of ventricular arrhythmia is very important as such an arrhythmia can be fatal. Serious ventricular arrhythmias (ventricular tachycardia/flutter and ventricular fibrillation) occur most often in the presence of myocardial ischemia and/or infarction. Ventricular fibrillation often occurs in the setting of acute myocardial ischemia, before infarction fully develops. At present, there is no satisfactory pharmacotherapy for the treatment and or prevention of ventricular fibrillation during acute ischemia. In fact, many Class I antiarrhythmic compounds may actually increase mortality in patients who have had a myocardial infarction. [0008] Class la, Ic and HI antiarrhythmic drugs have been used to convert recent onset AF to sinus rhythm and prevent recurrence of the arrhythmia (Fuch and Podrid, 1992; Νattel S., Hadjis T., Talajic M., Drugs 48(3):345-71, 1994). However, drug therapy is often limited by adverse effects, including the possibility of increased mortality, and inadequate efficacy (Feld G.K., Circulation S5(6):2248-50, 1990; Coplen S.E., Antman E.M., Berlin J.A., Hewitt P., Chalmers T.C., Circulation 1991; 83(2):714 and Circulation 82(4):1106-16, 1990; Flaker G.C., Blackshear J.L., McBride R., Kronmal R.A., Halperin J.L., Hart R.G., J. Am. Coll. Cardiol. 20(3):527-32, 1992; CAST, N. Engl. J. Med. 321:406, 1989; Νattel S., Cardiovas. Res. 37(3):567-77, 1998). Conversion rates for Class I antiarrhythmics range between 50-90% (Νattel S., Hadjis T., Talajic M., Drugs 48(3):345-7l, 1994; Steinbeck G., Remp T., Hoffmann E., J. Cardiovas. Electrophysiol. 9(8 Suppl):S104-8, 1998). Class ffl antiarrhythmics appear to be more effective for terminating atrial flutter than for AF and are generally regarded as less effective than Class I drugs for termination of AF (Νattel S., Hadjis T., Talajic M., Drugs 48(3):345-71, 1994; Capucci A., Aschieri D., Villani G.Q., Drugs Aging _3(_):51-70, 1998). Examples of such drugs include ibutilide, dofetilide and sotalol. Conversion rates for these drugs range between 30-50% for recent onset AF (Capucci A., Aschieri D., Villani G.Q., Drugs Aging 13(l):5l-7 , 1998), and these drugs are also associated with a risk of the induction of ventricular tachyarrhythmias known as Torsades de Pointes. For ibutilide, the risk of ventricular proarrhythmia is estimated at -4.4%, with ~1.7% of patients requiring cardioversion for refractory ventricular arrhythmias (KoweyP.R., VanderLugt J.T., Luderer J.R., Am. J. Cardiol. 78(8A):46-52, 1996). Such events are particularly tragic in the case of AF as this arrhythmia is rarely fatal itself. [0009] Therefore, there is a continuing need in the art to identify new antiarrhythmic treatments, for both atrial/supraventricular arrhythmia and ventricular arrhythmia. The present invention fulfills this need, and further provides other related advantages.

[0010] Reports of Ν-substituted 7H-imidazo[l,2-α]pyrazin-8-ones of the present invention are limited (J.A. Deceuninck et al., Nucleic Acid Chem. (1991), Vol. 4, 144-51. Editor(s): L.B. Townsend and R.S. Tipson. Publisher: Wiley, New York, N.Y. and references cited therein).

SUMMARY OF THE INVENTION

[0011] In one embodiment, the present invention provides a method for modulating ion channel activity in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a N-substituted imidazopyrazinone compounds such as a N- alkylated/aralkylated 7H-imidazo[l,2-α]pyrazin-8-one compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

(I) wherein, independently at each occurrence, n is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8; X is selected from a direct bond, -C(R₃)=CH-, and -C(_ ,R₅)-Y-; Y is selected from a direct bond, O, S, and Cι-C alkylene;

R₂, R₁₅, Ri. and R₁₈ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, cyano, CHF₂, CH₂F, CF₃, C₂-C₇alkanoyloxy, Ci-Cβalkyl, C₃-C₈cycloalkyl, aryl, benzyl, CrCβalkoxy, C₂-C₇alkoxycarbonyl, d-Cβthioalkyl, CH₂N(R₁₃,R₁ ) and N(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from hydrogen, acetyl, methanesulfonyl, and Cι-C₆alkyl; R₃ is selected from hydrogen, Ci-Cβalkyl, C₃-C₈cycloalkyl, aryl, and benzyl;

Ri, R and R5 are independently selected from hydrogen, Q-C_.alkyl, aryl and benzyl, or R₄ and R₅, when taken together with the carbon to which they are attached, may form a spiro C₃-C₆cycloalkyl; A is selected from C₅-C₁₂alkyl, a C₃-C₁₃carbocyclic ring, and ring systems selected from formulae (II), (HI), (IV), (V), (VI) and (VS):

(π) where Re, R₇ and R₈ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C alkanoyloxy, Ci-Cβalkyl, -Cβalkoxy, C₂-C alkoxycarbonyl, Cι-C₆thioalkyl, cyano, aryl and N(Rj₃,R₁₄) where R₁₃ and Rj are independently selected from hydrogen, acetyl, methanesulfonyl, and Cι-C₆alkyl;

(ED (IV) where R₁₀ and Rπ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C alkanoyloxy, Cι-C₆alkyl, Cι-C₆alkoxy, C_-C alkoxycarbonyl, CrCβthioalkyl, cyano, aryl and N(Rι₃,Rι₄) where Rι₃ and R₁₄ are independently selected from hydrogen, acetyl, methanesulfonyl, and Cι-C₆alkyl;

(V) where R₁₂ is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C alkanoyloxy, Ci-Cβalkyl, -Cealkoxy, C₂-C alkoxycarbonyl, Cι-C₆thioalkyl, cyano, aryl and N(Rι₃,Rι₄) where R₁₃ and Rι are independently selected from hydrogen, acetyl, methanesulfonyl, and Cι-C₆alkyl; and Z is selected from CH, CH₂, 0, N and S, where Z may be directly bonded to "X" as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R₉ when Z is N, and R₉ is selected from hydrogen, Ci-Cβalkyl, C₃-C₈cycloalkyl, aryl and benzyl;

(VD (vn).

[0012] In another embodiment, the present invention provides a method for modulating ion channel activity in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C(R₄,R₅)-Y-, and R₄ and R₅, when taken together with the carbon to which they are attached form a spiro C_.-C_όcycloalkyl.

[0013] In another embodiment, the present invention provides a method for modulating ion channel activity in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C(R₄,Rs)-Y-, Y is a direct bond, and R₄ and R₅, when taken together with the carbon to which they are attached form a spiro C₃cycloalkyl.

[0014] In another embodiment, the present invention provides a method for modulating ion channel activity in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where ^, R₇ and R₈ are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, Cι-C₆alkyl, and -C_δalkoxy.

[0015] In another embodiment, the present invention provides a method for modulating ion channel activity in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (Et) where Rg, R₇ and R₈ are independently selected from hydrogen and trifluoromethyl. [0016] In another embodiment, the present invention provides a method for modulating ion channel activity in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (V), and Z is N or S. [0017] In another embodiment, the present invention provides a method for modulating ion channel activity in an in vitro setting comprising administering in vitro an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof.

[0018] In another embodiment, the present invention provides a method for modulating ion channel activity in an in vitro setting comprising administering in vitro an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C(R₄,Rs)-Y-, and R₄ and Rs_f when taken together with the carbon to which they are attached form a spiro C.-Cδcycloalkyl. [0019] In another embodiment, the present invention provides a method for modulating ion channel activity in an in vitro setting comprising administering in vitro an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C(R₄,R₅)-Y-, Y is a direct bond, and and R₅, when taken together with the carbon to which they are attached form a spiro C₃cycloalkyl.

[0020] In another embodiment, the present invention provides a method for modulating ion channel activity in an in vitro setting comprising administering in vitro an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (II) where Re, R₇ and R₈ are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, Ci-Cβalkyl, and Cι-C_alkoxy.

[0021] In another embodiment, the present invention provides a method for modulating ion channel activity in an in vitro setting comprising administering in vitro an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R₇ and R₈ are independently selected from hydrogen and trifluoromethyl.

[0022] In another embodiment, the present invention provides a method for modulating ion channel activity in an in vitro setting comprising administering in vitro an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (V), and Z is N or S.

[0023] In another embodiment, the present invention provides a compound of formula (VHI) which is the same as compound of formula (I) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, with the proviso that compound of formula (VHI) cannot be a compound of the following formula (DC):

or a compound of the following formula (X):

(X).

[0024] In another embodiment, the present invention provides a compound of formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C(R4,R5)-Y-, and 1^ and R₅, when taken together with the carbon to which they are attached form a spiro C₃-C₆cycloalkyl. [0025] In another embodiment, the present invention provides a compound of formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is

Y is a direct bond, and R₄ and R₅, when taken together with the carbon to which they are attached form a spiro C.cycloalkyl. [0026] In another embodiment, the present invention provides a compound of formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R and R₈ are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, Cι-C_alkyl, and d-Cβalkoxy.

[0027] In another embodiment, the present invention provides a compound of formula (V-H) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, Ri and R₈ are independently selected from hydrogen, and trifluoromethyl.

[0028] In another embodiment, the present invention provides a compound of formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (V), and Z is N or S. [0029] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof. [0030] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C(R ,R₅)-Y-, and and R₅, when taken together with the carbon to which they are attached form a spiro C₃-C₆cycloalkyl.

[0031] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is

-C(R ,R₅)-Y-, Y is a direct bond, and R and R₅, when taken together with the carbon to which they are attached form a spiro C.cycloalkyl.

[0032] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R and R₈ are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, d-C₆alkyl, and d-C₆alkoxy.

[0033] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R and R₈ are independently selected from hydrogen, and trifluoromethyl.

[0034] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for the manufacture of a composition or medicament that contains one or more such compounds.

[0035] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH), wherein X is -C(R₄,Rs)-Y-, and R₄ and R₅, when taken together with the carbon to which they are attached form a spiro C₃-C₆cycloalkyl; in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for the manufacture of a composition or medicament that contains one or more such compounds.

[0036] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH), wherein X is -C(R₄,Rs)-Y-, Y is a direct bond, and

R and R₅, when taken together with the carbon to which they are attached form a spiro Qcycloalkyl; in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for the manufacture of a composition or medicament that contains one or more such compounds.

[0037] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH), wherein A is selected from formula (H) where Re,

R₇ and Rs are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, Ci-Cβalkyl, and d-C₆alkoxy; in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for the manufacture of a composition or medicament that contains one or more such compounds.

[0038] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH) as defined above or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R₇ and R₈ are independently selected from hydrogen, and trifluoromethyl; in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for the manufacture of a composition or medicament that contains one or more such compounds.

[0039] In other embodiments, the present invention provides a composition or medicament that includes a compound according to formula (VIH), wherein A is selected from formula (V), and Z is N or S; in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for the manufacture of a composition or medicament that contains one or more such compounds.

[0040] In another embodiment, the present invention provides a compound of formula (I) or formula

(VIH); or composition containing a compound of formula (I) or formula (VHI), for use in methods for either modulating ion channel activity in a warm-blooded animal or for modulating ion channel activity in vitro.

[0041] Some of the ion channels to which the compounds, compositions and methods of the present invention have modulating effect are various potassium and sodium channels. These potassium and sodium ion channels may be voltage-activated (also known as voltage-gated) or ligand-activated (also known as ligand-gated), and may be present in cardiovascular and/or neuronal systems. More specifically, some of the cardiac and/or neuronal potassium ion channels are responsible for one or more early repolarising currents comprised of ionic currents which activate rapidly after depolarisation of membrane voltage and which effect repolarisation of the cells. The early repolarising currents comprise the transient outward potassium current (I_t0) and/or the ultrarapid delayed rectifier current (Iκur), and include at least one of the Kv4.2, Kv4.3, Kvl.2, Kv2.1, Kvl.4 and Kvl.5 currents. Other potassium ion channels may include the hERG channels. Furthermore, the voltage-activated sodium ion channels comprise the Na_vl, Na_v2 or Na_v3 series and may be present in cardiac, neuronal, skeletal muscle, central nervous and/or peripheral nervous systems. [0042] In other embodiment, the present invention provides pharmaceutical compositions that provide method for blocking and/or inhibiting the activity and/or conductance of ion channels in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I).

[0043] In other embodiment, the present invention provides pharmaceutical compositions that provide method for blocking and/or inhibiting the activity and/or conductance of ion channels in an in vitro setting comprising administering in an in vitro setting an effective amount of a compound of formula (I). In other embodiments, the present invention provides pharmaceutical compositions that contain at least one compound of formula (VHI), in an amount effective to treat a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or prevent a disease or condition in a warm-blooded animal that would otherwise occur, and further contains at least one pharmaceutically acceptable carrier, diluent or excipient.

[0044] In other embodiments, the present invention provides pharmaceutical compositions that contain at least one compound of formula (VIH), wherein X is -C(R₄,R₅)-Y-, and R and R₅, when taken together with the carbon to which they are attached form a spiro C₃-C₆cycloalkyl; in an amount effective to treat a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or prevent a disease or condition in a warm-blooded animal that would otherwise occur, and further contains at least one pharmaceutically . acceptable carrier, diluent or excipient.

[0045] In other embodiments, the present invention provides pharmaceutical compositions that contain at least one compound of formula (VIH), wherein X is -C(R4,Rs)-Y-, Y is a direct bond, and R₄ and R₅, when taken together with the carbon to which they are attached form a spiro C_.cycloalkyl; in an amount effective to treat a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or prevent a disease or condition in a warm-blooded ammal that would otherwise occur, and further contains at least one pharmaceutically acceptable carrier, diluent or excipient.

[0046] In other embodiments, the present invention provides pharmaceutical compositions that contain at least one compound of formula (VIH), wherein A is selected from formula (H) where Re, R₇ and R₈ are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, Ci-Cβalkyl, and d-C₆alkoxy; in an amount effective to treat a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or prevent a disease or condition in a warm-blooded animal that would otherwise occur, and further contains at least one pharmaceutically acceptable carrier, diluent or excipient.

[0047] In other embodiments, the present invention provides pharmaceutical compositions that contain at least one compound of formula (VHI), wherein A is selected from formula (H) where Re, R and R₈ are independently selected from hydrogen, and trifluoromethyl; in an amount effective to treat a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or prevent a disease or condition in a warm-blooded animal that would otherwise occur, and further contains at least one pharmaceutically acceptable carrier, diluent or excipient. [0048] In other embodiments, the present invention provides pharmaceutical compositions that contain at least one compound of formula (VIH), wherein A is selected from formula (V), and Z is N or S; in an amount effective to treat a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or prevent a disease or condition in a warm-blooded animal that would otherwise occur, and further contains at least one pharmaceutically acceptable carrier, diluent or excipient. [0049] The invention further provides for methods of treating a disease or condition in a warmblooded animal suffering from or having the disease or condition, and/or preventing a disease or condition from arising in a warm-blooded animal, wherein a therapeutically effective amount of a compound of formula (I) or formula (VIH), or a composition containing a compound of formula (I) or formula (VHI) is administered to a warm-blooded animal in need thereof.

[0050] Some of the diseases and conditions to which the compounds, compositions and methods of the present invention have applicability are as follows: arrhythmia including atrial/supraventricular arrhythmia and ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, ventricular flutter, diseases of the central nervous system, amyotrophic lateral sclerosis, convulsion, cardiovascular diseases such as diseases caused by elevated blood cholesterol or triglyceride levels, cerebral or myocardial ischemias, hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis, paramyotonia congenita, malignant hyperthermia, hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmune disorders, graft rejection in organ transplantation, graft rejection in bone marrow transplantation, heart failure, hypotension, Alzheimer's disease, AIDS-related dementia, dementia, alopecia, sexual dysfunction, impotence, demyelinating diseases, multiple sclerosis, epileptic spasms, seizures, depression, insomnia, anxiety, schizophrenia, Parkinson's disease, trigeminal pain, phantom limb pain, back pain, smoke cessation, respiratory disorders, cystic fibrosis, asthma, cough, inflammatory disorders, arthritis, allergies, urinary incontinence, irritable bowel syndrome, Crohn's disease, prostatic hyperplasia, insect bites, psoriasis, diseases or dysfunctions of ion channels and receptors, diseases of voltage-gated ion channels, paralysis, gastrointestinal disorders such as gastrointestinal inflammation and ulcer. In another embodiment, the present invention provides a pharmaceutical composition containing an amount of a compound of formula (VIH); effective to produce analgesia or local anesthesia in a warm-blooded animal in need thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. The invention further provides a method for producing analgesia or local anesthesia in a warm-blooded animal, which includes administering to a warm-blooded animal in need thereof an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutical composition containing a compound of formula (I) or formula (VIH). These compositions and methods may be used to relieve or forestall the sensation of pain in a warm-blooded animal. [0051] In another embodiment, the present invention provides a pharmaceutical composition containing an amount of a compound of formula (VIH); effective to enhance the libido in a warmblooded animal in need thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. The invention further provides a method for enhancing libido in a warm-blooded animal which includes administering to a warm-blooded animal in need thereof an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutical composition containing a compound of formula (I) or formula (VIH). These compositions and methods may be used, for example, to treat a sexual dysfunction, e.g., impotence in males, and/or to enhance the sexual desire of a patient without a sexual dysfunction. As another example, the therapeutically effective amount may be administered to a bull (or other breeding stock), to promote increased semen ejaculation, where the ejaculated semen is collected and stored for use as it is needed to impregnate female cows in promotion of a breeding program.

[0052] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VHI); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof.

[0053] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C( ₄,R₅)-Y-, and R₄ and R₅, when taken together with the carbon to which they are attached form a spiro C₃-C6cycloalkyl.

[0054] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded animal comprising admimstering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VHI); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture,' geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -CCR^Rs^Y-, Y is a direct bond, and R and R₅, when taken together with the carbon to which they are attached form a spiro C₃cycloalkyl.

[0055] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded animal comprising admimstering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R and Rs are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, d-C₆alkyl, and d-C₆alkoxy.

[0056] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (NIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R₇ and R₈ are independently selected from hydrogen and trifluoromethyl. [0057] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular aπhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (NIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (V), and Z is N or S.

[0058] In another embodiment, the present invention provides a method for the treatment and or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded ammal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VHI); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof.

[0059] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C(R₄,R₅)-Y-, and f j. and R5, when taken together with the carbon to which they are attached form a spiro C₃-C₆cycloalkyl.

[0060] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded ammal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C(R₄,R₅)-Y-, Y is a direct bond, and R₄ and R₅, when taken together with the carbon to which they are attached form a spiro C₃cycloalkyl.

[0061] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded animal comprising administering to a warm-blooded ammal in need thereof, an effective amount of a compound of formula (I) or formula (VHI); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, d-C₆alkyl, and d-Cealkoxy. [0062] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded animal comprising admimstering to a warm-blooded ammal in need thereof, an effective amount of a compound of formula (I) or formula (NIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R₇ and R₈ are independently selected from hydrogen and trifluoromethyl. [0063] In another embodiment, the present invention provides a method for the treatment and/or prevention of cardiac arrhythmia such as atrial/supraventricular arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, and ventricular flutter, in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VHI); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (V), and Z is Ν or S.

[0064] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof.

[0065] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -CQ ^R^-Y-, and ILj and R₅, when taken together with the carbon to which they are attached form a spiro C₃-C₆cycloalkyl. [0066] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C R₄,R₅)-Y-, Y is a direct bond, and R/j and R₅, when taken together with the carbon to which they are attached form a spiro C₃cycloalkyl.

[0067] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R and R₈ are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, Ci-Cβalkyl, and Ci-Cβalkoxy.

[0068] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R₇ and R₈ are independently selected from hydrogen and trifluoromethyl.

[0069] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (V), and Z is N or S.

[0070] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising admimstering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof.

[0071] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded ammal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C(R₄,R₅)-Y-, and R and R₅, when taken together with the carbon to which they are attached form a spiro C₃-C₆cycloalkyl. [0072] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein X is -C(R₄,R₅)-Y-, Y is a direct bond, and R and R₅, when taken together with the carbon to which they are attached form a spiro C.cycloalkyl.

[0073] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R₇ and R₈ are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, d-C₆alkyl, and d-C₆alkoxy.

[0074] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (H) where Re, R and R₈ are independently selected from hydrogen and trifluoromethyl.

[0075] In another embodiment, the present invention provides a method for the treatment and/or prevention of atrial fibrillation and/or atrial flutter in a warm-blooded animal comprising administering to a warm-blooded animal in need thereof, an effective amount of a compound of formula (I) or formula (VIH); or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein A is selected from formula (V), and Z is N or S.

[0076] In another embodiment, the present invention provides processes for the synthesis of the compound of formula (I).

[0077] These and other embodiments of the present invention will become evident upon reference to the following drawings and detailed description. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated to be so incorporated by reference. Although the foregoing summary and the ' following examples of the present invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit and scope of the patent application [0078] BRIEF DESCRIPTION OF THE DRAWINGS [0079] Figure 1: Mean AF duration induced by burst pacing (paced dogs). Data is presented as the mean ±SEM, n=3.

[0080] Figure 2: Mean AF duration induced by extrastimuli (paced dogs). Data is presented as the mean ±SEM, n=3.

[0081] Figure 3: Percentage of AF occurrences induced by extrastimuli (paced dogs). Data is presented as the mean ±SEM, n=3.

[0082] Figure 4: Right atrial ERP in the presence and absence of compound 1 (paced dogs).

Data is presented as the mean ±SEM, n=3.

DETAILED DESCRIPTION OF THE INVENTION

[0083] As noted above, the present invention is directed towards to N-substituted 7H-imidazo[l,2- α]pyrazin-8-one compounds, compositions containing the N-substituted 7H-imidazo[l,2-α]pyrazin-8- one compounds and various uses for the compounds and compositions. Such uses include modulation/blockade of ion channels in vitro or in vivo, the treatment and/or prevention of arrhythmias, the production of analgesia, and other uses as described herein. An understanding of the present invention may be aided by reference to the following definitions and explanation of conventions used herein.

Definitions and Conventions

[0084] In the formulae depicted herein, a bond to a substituent and/or a bond that links a molecular fragment to the remainder of a compound may be shown as intersecting one or more bonds in a ring structure. This indicates that the bond may be attached to any one of the atoms that constitutes the ring structure, so long as a hydrogen atom could otherwise be present at that atom. Where no particular substituent(s) is identified for a particular position in a structure, then hydrogen(s) is present at that position. For example, compounds of the invention containing the A-X-CHCΓ )- group where A equals formula (H)

(D) are intended to encompass compounds having the groμp (B):

(B) where the group (B) is intended to encompass groups wherein any ring atom that could otherwise be substituted with hydrogen, may instead be substituted with either Re, R or R₈, with the proviso that each of Re, R₇ and R₈ appears once and only once on the ring. Ring atoms that are not substituted with any of Re, R or R₈ are substituted with hydrogen. In those instances where the invention specifies that a non-aromatic ring is substituted with more than one R group, and those R groups are shown connected to the non-aromatic ring with bonds that bisect ring bonds, then the R groups may be present at different atoms of the ring, or on the same atom of the ring, so long as that atom could otherwise be substituted with a hydrogen atom.

[0085] Likewise, where the invention specifies compounds containing the A-X-CH(R - group where A equals the aryl group (V)

(V) the invention is intended to encompass compounds wherein -X-CH(Rι)- is joined through X to the aryl group (V) at any atom which forms the aryl group (V) so long as that atom of group (V) could otherwise be substituted with a hydrogen atom. Thus, there are seven positions (identified with the letters "a" through "g") in structure (V) where the -X-CH(R])- group could be attached, and it is attached at one of those seven positions. The R₁₂ group would occupy one and only one of the remaining six positions, and hydrogen atoms would be present in each of the five remaining positions. It is to be understood that when Z represents a divalent atom, e.g., oxygen or sulfur, then Z cannot be directly bonded to -X-CH(Rι)-.

[0086] When the invention specifies the location of an asymmetric divalent radical, then that divalent radical may be positioned in any possible manner that provides a stable chemical structure. For example, for compounds containing the A-X-CH(R - group where X is

the invention provides compounds having both the A-C(R ,R₅)-Y-CH(R₁)- and A-Y-C(R ,R₅)-CH(R₁)- groups. [0087] The compounds of the present invention may contain one or more asymmetric carbon atom(s) and thus may exist as enantiomers and diastereomers. Unless otherwise noted, the present invention includes all enantiomeric and diastereomeric forms of the N-substituted 7H-imidazo[l,2-α]pyrazin-8- one compounds of the invention. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the invention are included within the present invention. Thus, compounds of the present invention may occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. A racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers. [0088] The phrase "independently at each occurrence" is intended to mean (i) when any variable occurs more than one time in a compound of the invention, the definition of that variable at each occurrence is independent of its definition at every other occurrence; and (ii) the identity of any one of two different variables (e.g.,

and R₂) is selected without regard to the identity of the other member of the set. However, combinations of substituents and/or variables are permissible only if such combinations result in compounds that do not violate the standard rules of chemical valency.

[0089] In accordance with the present invention and as used herein, the following terms are defined to have following meanings, unless explicitly stated otherwise:

[0090] "Acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, j.-toluenesulfonic acid, salicylic acid and the like.

[0091] "Acyl" refers to branched or unbranched hydrocarbon fragments terminated by a carbonyl

-(C=O)- group containing the specified number of carbon atoms. Examples include acetyl

[CH₃C(=O)-, a C₂acyl] and propionyl [CH₃CH_C(=O)-, a C.acyl].

[0092] "Alkanoyloxy" refers to an ester substituent wherein the non-carbonyl oxygen is the point of attachment to the molecule. Examples include propanoyloxy [(CH₃CH C(=O)-O-, a C₃alkanoyloxy] and ethanoyloxy [CH₃C(=O)-O-, a C₂alkanoyloxy].

[0093] "Alkoxy" refers to an O-atom substituted by an alkyl group, for example, methoxy [-OCH₃, a

Cialkoxy].

[0094] "Alkoxyalkyl" refers to an alkylene group substituted with an alkoxy group. For example, methoxyethyl [CH₃OCH₂CH₂-] and ethoxymethyl (CH₃CH₂OCH₂-] are both C₃alkoxyalkyl groups.

[0095] "Alkoxycarbonyl" refers to an ester substituent wherein the carbonyl carbon is the point of attachment to the molecule. Examples include ethoxycarbonyl [CH₃CH₂OC(=O)-, a

C₃alkoxycarbonyl] and methoxycarbonyl [CH₃OC(=O)-, a C₂alkoxycarbonyl].

[0096] "Alkyl" refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms and having one point of attachment. Examples include w-propyl (a C_.alkyl), tso-propyl (also a C₃alkyl), and t-butyl (a Qalkyl).

[0097] "Alkylene" refers to a divalent radical which is a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, and having two points of attachment. An example is propylene [-CH₂CH₂CH₂-, a C₃ alkylene].

[0098] "Alkylcarboxy" refers to a branched or unbranched hydrocarbon fragment terminated by a carboxylic acid group [-COOH]. Examples include carboxymethyl [HOOC-CH₂-, a C₂alkylcarboxy] and carboxyethyl [HOOC-CH₂CH₂-, a C₃alkylcarboxy].

[0099] "Aryl" refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl (also known as heteroaryl groups) and biaryl groups, all of which may be optionally substituted. Carbocyclic aryl groups are generally preferred in the compounds of the present invention, where phenyl and naphthyl groups are preferred carbocyclic aryl groups. [0100] "Aralkyl" refers to an alkylene group wherein one of the points of attachment is to an aryl group. An example of an aralkyl group is the benzyl group [C₆H₅CH₂-, a C aralkyl group].

[0101] "Cycloalkyl" refers to a ring, which may be saturated or unsaturated and monocyclic, bicyclic, or tricyclic formed entirely from carbon atoms. An example of a cycloalkyl group is the cyclopentenyl group (C₅H -), which is a five carbon (C₅) unsaturated cycloalkyl group.

[0102] "Carbocyclic" refers to a ring which may be either an aryl ring or a cycloalkyl ring, both as defined above.

[0103] "Carbocyclic aryl" refers to aromatic groups wherein the atoms which form the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups such as phenyl, and bicyclic carbocyclic aryl groups such as naphthyl, all of which maybe optionally substituted.

[0104] "Haloalkyl" refers to alkyl groups including one or more fluorine, chlorine, bromine or iodine atoms.

[0105] "Heteroatom" refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms in the compounds of the present invention.

[0106] "Heteroaryl" refers to aryl groups having from 1 to 9 carbon atoms and the remainder of the atoms are heteroatoms, and includes those heterocyclic systems described in "Handbook of

Chemistry and Physics," 49th edition, 1968, R.C. Weast, editor; The Chemical Rubber Co.,

Cleveland, OH. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental

Heterocyclic Systems. Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like.

[0107] "Hydroxyalkyl" refers to a branched or unbranched hydrocarbon fragment bearing an hydroxy (-OH) group. Examples include hydroxymethyl (-CH₂OH, a dhydroxyalkyl) and

1-hydroxyethyl (-CHOHCH₃, a dhydroxyalkyl).

[0108] "Thioalkyl" refers to a sulfur atom substituted by an alkyl group, for example thiomethyl (CH₃S-, a dthioalkyl).

[0109] "Modulating" in connection with the activity of an ion channel means that the activity of the ion channel may be either increased or decreased in response to administration of a compound or composition or method of the present invention. Thus, the ion channel may be activated, so as to transport more ions, or may be blocked, so that fewer or no ions are transported by the channel. [0110] "Pharmaceutically acceptable carriers" for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985). For example, sterile saline and phosphate-buffered saline at physiological pH may be used. Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid and esters of _jP-hydroxybenzoic acid may be added as preservatives. Id. at 1449. In addition, antioxidants and suspending agents may be used. Id

[0111] "Pharmaceutically acceptable salt" refers to salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts). The compounds of the present invention may be used in either the free base or salt forms, with both forms being considered as being within the scope of the present invention.

[0112] The "therapeutically effective amount" of a compound of the present invention will depend on the route of administration, the type of warm-blooded animal, such as a human, being treated, and the physical characteristics of the specific warm-blooded animal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. [0113] Compositions described herein as "containing a compound of formula (VHT)" encompass compositions that contain more than one compound of formula (VIH).

Compounds of the Present Invention [0114] Compounds of the present invention are N-substituted 7H-imidazo[l,2-fl]pyrazin-8- ones which may be represented by formula (I) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

wherein, independently at each occurrence, n is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8;

X is selected from a direct bond, -C(R₃)=CH-, and -C( ₄,R₅)-Y-;

Y is selected from a direct bond, O, S, and Cι-C₄alkylene;

R₂, R₁₅, Rie and R₁₈ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, cyano, CHF₂, CH₂F, CF₃,

C₂-C₇alkanoyloxy, d-C₆alkyl, C₃-C₈cycloalkyl, aryl, benzyl, d-C₆alkoxy, C₂-C alkoxycarbonyl, d-Cethioalkyl, CH₂N(R₁₃,R₁₄) and N(R₁₃,R₁ ) where R₁₃ and R₁₄ are independently selected from hydrogen, acetyl, methanesulfonyl, and d-Cβalkyl;

R₃ is selected from hydrogen, Ci-Cβalkyl, C₃-C₈cycloalkyl, aryl, and benzyl;

Ri, R and R5 are independently selected from hydrogen, d-Cealkyl, aryl and benzyl, or 1^ and R₅, when taken together with the carbon to which they are attached, may form a spiro C₃-C₆cycloalkyl;

A is selected from d-d.alkyl, a C₃-C₁₃carbocyclic ring, and ring systems selected from formulae

(H), (HI), (IV), (V), (VI) and (VII):

(H) where Re, R₇ and R₈ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C₇alkanoyloxy, d-Cealkyl, d-C₆alkoxy, C₂-C₇alkoxycarbonyl, Ci-Cethioalkyl, cyano, aryl andN(Rι₃,R₁ ) where R₁₃ and R₁₄ are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C₆alkyl;

(HI) (IV) where R₁₀ and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C alkanoyloxy, Ci-Cealkyl, d-C₆alkoxy, C₂-C₇alkoxycarbonyl, d-Cethioalkyl, cyano, aryl and N(R₁₃,Rι ) where R₁₃ and R₁ are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-Cβalkyl;

(V) where R₁₂ is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C₇alkanoyloxy, CrCealkyl, d-C₆alkoxy, C₂-C₇alkoxycarbonyl, d-C₆thioalkyl, cyano, aryl and N(R₁₃,R₁₄) where R₁₃ and R₁ are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C₆alkyl; and Z is selected from CH, CH₂, O, N and S, where Z may be directly bonded to "X" as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R₉ when Z is N, and R₉ is selected from hydrogen, d-C₆alkyl, C₃-C₈cycloalkyl, aryl and benzyl;

(VI) (VH). [0115] Compounds of formula (I) are N-substituted 7H-imidazo[l,2-α]pyrazin-8-ones. More specifically, these N-substituted 7H-imidazo[l,2-α]pyrazin-8-ones may contain various substituents (R_2> Ri_5> Ri₆ and R₁₈) on the 7H-imidazo[l,2-α]pyrazin-8-one ring system and an N-alkyl/aralkyl side chain. The N-alkyl/aralkyl side chain of the compounds of the present invention is attached to the 7H- imidazo[l,2-α]pyrazin-8-one ring system and is linked by one or more methylene groups (CH₂) (n = 1, 2, 3, 4, 5, 6, 7 or 8) or directly (n = 0) to the remaining part (-CHR_Ϊ-X-A) of the chain. [0116] Depending upon the identity of X, the side chain, -CH(R -X-A, in formula (I) or formula (VIH) may take several forms. For example, a compound of formula (I) may have X as a -C(R₄,R₅)-Y- group, where Y may be any of a direct bond, an oxygen atom (O), a sulfur atom (S) or a Cι-C₄alkylene group. I and R₅ are independently selected from hydrogen, d-Cealkyl, aryl and benzyl, or ₄ and R₅, when taken together with the carbon to which they are attached, may form a spiro C₃-C₆cycloalkyl. Thus, compounds of the invention include compounds of formula (I) where I and R₅ are hydrogen and Y is a direct bond, such that X may be CH₂.

[0117] Alternatively, X may be an alkenylene moiety, e.g., a cis-oτ tra«5-alkenylene moiety,

C(R₃)=CH, where R₃ may be any of hydrogen, Cι-C₆alkyl, C₃-C₈cycloalkyl, aryl or benzyl. For compounds of formula (I) where X is an alkenylene moiety, X is preferably a trαws-alkenylene moiety.

[0118] The N-alkyl/aralkyl side chain component A is generally a hydrophobic moiety.

Typically, a hydrophobic moiety is comprised of non-polar chemical groups such as hydrocarbons or hydrocarbons substituted with halogens or ethers or heterocyclic groups containing nitrogen, oxygen, or sulfur ring atoms. Suitable hydrocarbons are C₅-C₁₂alkyl and C₃-C₁₃carbocyclic rings. Particularly preferred cyclic hydrocarbons include selected optionally substituted aromatic groups such as those represented by formulae (H), (HI), (IV) and (V).

[0119] A suitable "A" group within the compounds of the present invention is an optionally substituted phenyl ring represented by formula (H):

(π) where Re, R and Rg are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C₇alkanoyloxy, Ci-Cealkyl, d-Cβalkoxy, C₂-C₇alkoxycarbonyl, d-C₆thioalkyl, cyano, aryl and N(R₁₃,R₁₄) where R₁₃ and R₁ are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C₆alkyl. In another embodiment, Re, R and R₈ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, sulfamyl, trifluoromethyl, C₂-C₇alkanoyloxy, d-C₆alkyl, d-C₆alkoxy, C₂-C alkoxycarbonyl, d-Cόthioalkyl, cyano, aryl and N(R₁₃,R₁₄) where R₁₃ and R₁ are independently selected from hydrogen, acetyl, methanesulfonyl, and Cι-C₆alkyl. In a further embodiment, Re, R and R₈ are independently selected from from bromine, chlorine, fluorine, and nitro.

[0120] Other suitable "A" groups in compounds of the present invention are optionally substituted 1 -naphthyl groups as represented by formula (HI):

(HI) where R₁₀ and R_π are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C alkanoyloxy, d-C₆alkyl, d-C₆alkoxy, C₂-C₇alkoxycarbonyl, d-Cethioalkyl, cyano, aryl and N(R₁₃,R₁₄) where R₁₃ and R₁ are independently selected from hydrogen, acetyl, methanesulfonyl, and d-Cβalkyl. [0121] Other suitable "A" groups in compounds of the present invention are optionally substituted 2-naphthyl group as represented by formula (IV):

(IV) where R₁₀ and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C alkanoyloxy, Cι-C₆alkyl, d-C₆alkoxy, C₂-C₇alkoxycarbonyl, d-Cethioalkyl, cyano, aryl and N(R₁₃,R_i ) where R₁₃ and R₁₄ are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-Cealkyl, as defined above.

[0122] Other suitable "A" groups in compounds of the present invention are optionally substituted aromatic groups represented by formula (V):

(V) where R₁₂ is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, d-dalkanoyloxy, d-C₆alkyl, Cι-C₆alkoxy, C₂-C alkoxycarbonyl, d-Cethioalkyl, cyano, aryl and N(Rι₃,R₁ ) where R₁₃ and R₁₄ are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-Cβalkyl; and Z is selected from CH, CH₂, O, N and S, where Z may be directly bonded to "X" as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R₉ when Z is N, and R is selected from hydrogen, Ci-Cβalkyl, C -C₈cycloalkyl, aryl and benzyl. In another embodiment, Z is N. In a further embodiment, R₁₂ is selected from bromine, chlorine, fluorine, and nitro.

[0123] The aryl groups represented by formula (V) are derivatives of indene, indole, benzofuran, and thianaphthene when Z is methylene, nitrogen, oxygen, and sulfur, respectively. Preferred heterocyclic groups of formula (V) include indole where Z is NH, benzofuran where Z is O, and thianaphthene where Z is S.

[0124] Another suitable "A" group in compounds of the present invention is the acenaphthyl group. Still another suitable "A" group in compounds of the present invention is the fluorenyl group. [0125] In another embodiment, the invention provides a compound of formula (I) wherein independently at each occurrence, n is 0 or 1, and all other variables are as defined above for compounds of formula (I). [0126] In another embodiment, the invention provides a compound of formula (I) wherein X is -C(R₄,R₅)-Y-, and R₄ and R₅, when taken together with the carbon to which they are attached form a spiro C₃-C₆cycloalkyl; and all other variables are as defined above for compounds of formula (I).

[0127] In yet another embodiment, the invention provides a compound of formula (1) wherein

X is -C(R ,R₅)-Y-, Y is a direct bond, and R and R₅, when taken together with the carbon to which they are attached form a spiro C₃-C₅cycloalkyl; and all other variables are as defined above for compounds of formula (I).

[0128] In yet another embodiment, the invention provides a compound of formula (I) wherein

X is -CCR^Rs^Y-, Y is a direct bond, and ILj and R₅, when taken together with the carbon to which they are attached form a spiro C.cycloalkyl; and all other variables are as defined above for compounds of formula (I).

[0129] In another embodiment, the invention provides a compound of formula (I) wherein A is selected from formula (II) where Re, R and R₈ are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, Ci-Cβalkyl, and d-Cβalkoxy, with the proviso that said compound of formula (I) cannot be a compound of formula (IX) or formula (X). [0130] In yet another embodiment, the invention provides a compound of formula (I) wherein

A is selected from formula (H) where Re, R₇ and R₈ are independently selected from chlorine, hydrogen, and trifluoromethyl, with the proviso that said compound of formula (I) cannot be a compound of formula (EX) or formula (X).

[0131] In yet another embodiment, the invention provides a compound of formula (I) wherein

X is -C(R₄,R₅)-Y-, Y is a direct bond, and R₄ and R₅, when taken together with the carbon to which they are attached form a spiro C_.cycloalkyl; and A is selected from formula (II) where Re, R₇ and R₈ are independently selected from hydrogen and trifluoromethyl.

[0132] In another embodiment, the invention provides a compound of formula (I) wherein A is selected from formula (V), and Z is N or S; and all other variables are as defined above for compounds of formula (I).

[0133] In yet another embodiment, the invention provides a compound of formula (I) wherein

X is a direct bond or -C(R₄,Rs)-Y-, and A is represented by formula (V), and Z is N or S; and all other variables are as defined above for compounds of formula (I). [0134] The following are some examples (Compounds # 1 to 35) of the compounds of formula (I) or formula (VIH) of the present invention:

Outline of Methods of Preparation of Compounds of the Present Invention

[0135] The N-substituted 7H-imidazo[l,2-α]pyrazin-8-one compounds of the present invention may contain various substituents (R₂, R15, Rie and R₁₈) on the 7H-imidazo[l,2-α]pyrazin-8- one ring system and a N-alkyl/aralkyl side chain as shown in formula (I). The present invention provides synthetic methodology whereby these compounds may be prepared. Compounds of the present invention may be prepared in analogy with known synthetic methodology ( g., Ager et al., J. Med. Chem. 1988, 31, 1098-1115. Catarzi et al., J. Med. Chem. 1994, 37, 2846-2850. Campiani et al. J. Med. Chem. 2001, 44, 305-315. In "The Chemistry of Heterocyclic Compounds - The Pyrazines - Supplement by D.J. Brown: (a) Brown et al. Liq. Cryst. 1995, 19, 765; (b) Kruse et al. Rec Trav. Chim. Pays Bas. 1979, 98, 371; (c) Cain and Porter J. Chem. Soc, Perkin Trans 1 1981, 3111; (d) Jones and Rose J. Chem. Soc, Perkin Trans 1 1987, 2585; (e) Nishio et al. J. Chem. Soc, Perkin Trans 11984, 391; (e) Nishio et al. J. Chem. Soc, Perkin Trans 11988, 2921; (f) Kleyer and Koch J. Org. Chem. 1982, 47, 3145; (g) Yokoi et al. J. Chem. Res 1997, 10, 171. [0136] Scheme 1 outlines the reaction sequence for the preparation of compounds of the present invention.

VII VI Scheme 1

[0137] For those having skill in the art, it is understood that for certain substrates containing other reactive functional groups, appropriate protective groups are employed in the synthesis. Suitable protective groups are set forth in, for example, Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991).

[0138] More specifically, as shown in Scheme 1 the alcohol (ROH, Compound V) is activated according to procedures well known in the art. An "activated form" as used herein means that the hydroxyl group is converted into a good leaving group. The leaving group illustrated in Scheme 1 is a mesylate group, which is a prefeπed leaving group. The hydroxyl group may also be converted into other leaving groups according to procedures well known in the art. In a typical reaction, the alcohol compound V is treated with methanesulfonyl chloride in the presence of a base, such as triethylamine. The reaction is satisfactorily conducted at 0°C. An excess of the methanesulfonyl chloride, relative to the alcohol, is typically preferred to maximally convert the alcohol into the activated form. Such substrate alcohols are either commercially available or may be obtained by procedures in the art or adapted therefrom, where suitable procedures may be identified through the Chemicals Abstracts and Indices therefor, as developed and published by the American Chemical Society. [0139] In general, compounds of the present invention may be prepared by reacting an activated form of the selected alcohol V (1 mol) with an 7H-imidazo[l,2-a]pyrazin-8-one (1 mol, compound IV in scheme 1) pre-treated with, for example, sodium hydride (1.1 mol). The selected alcohol V (1 mol) may be activated by treatment with methanesulfonyl chloride (1.2 mol) and triethylamine (1.2 mol) to give the coπesponding mesylate. The mesylate is then added quickly in a suitable solvent such as anhydrous dimethylformamide (DMF) and the resultant reaction mixture is heated at 65°C for 15 h. When the reaction has proceeded to substantial completion, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques, and if necessary, can be purified by chromatography techniques.

[0140] 2-Amino-3-chloropyrazine (Compound I in Scheme 1) was prepared according to

Okada et al. Chem. Pharm. Bull. 1971, 19, 1344-1357.

[0141] 8-Halogeno imidazo[l,2-a]pyrazines (Compound VH in Scheme 1) can be prepared as described by Lumma et al. (J. Med. Chem. 1983, 26, 357-363). Sablayrolles et al. (J Med. Chem. 1984, 27, 206-212)or Meurer et al. (J. Med. Chem. 1992, 35, 3845-3857).

[0142] Subsequent acidic hydrolysis as described by Ohta et al. (J. Heterocyclic Chem. 1983,

20, 951) provide the corresponding 7H-imidazo[l,2-a]pyrazin-8-one (Compound IV in Scheme 1). [0143] When Rj₅ = CO₂Et, the corresponding 7H-imidazo[l,2-a]pyrazin-8-one (compound IV in Scheme 1) was obtained by reaction of the corresponding α-halogenoketone with 2-amino-3- benzyloxypyrazine (Compound HI in scheme 1). α-Halogenation of the corresponding 1,3-dicarbonyl compound was performed under mild conditions in the presence of NBS and a catalytic amount of a Lewis acid (Yang et al. J. Org. Chem. 2002, 67, 7429-7431).

[0144] The position 3 (Rj₅ = H) of the 7H-imidazo[l,2-a]pyrazin-8-one is reactive (labile hydrogen, compound VI in Scheme 1) and several derivatives can be derived from those compounds. Halogenation with NBS (N-bromosuccinimide) or ΝCS (N-chlorosuccinimide) could provide the corresponding halogenated compound (Compound VH in Scheme 1) R₁₅ = CI, Br; (Abe et al., J. Med. Chem. 1998, 41, 564-578).

[0145] The reaction sequences described above (and shown in Scheme 1) generate the substituted 7H-imidazo[l,2-a]ρyrazin-8-one VH as a free base. The free base may be converted, if desired, to the monohydrochloride salt by known methodologies, and subsequently, if desired, to other acid addition salts by reaction with inorganic or organic salts. Acid addition salts can also be prepared metathically by reacting one acid addition salt with an acid, which is stronger than that of the anion of the initial salt.

Preparation of 2-amino-3-chloropyrazine (Compound I): [0146] A thick-walled reaction vessel (250 mL) charged with 2,3-dichloropyrazine (14.9 g, 95 mmol) and 28-30% ammonium hydroxide (75 mL) was sealed in vacuo, submitted to a freeze-pump- thaw cycle and then heated with stirring to 135 °C for 15 h. Upon cooling of the reaction mixture, needles were observed to form from the reaction mixture. The supernatant was decanted off and the residual solid was solubilized in hot methanol. The methanolic solution was concentrated in vacuo and the resultant crude material (10.8 g) was recrystallized from methanol (150 mL) to yield 8.26 g of the title compound (67% yield), mp 167-168 °C; R_f 0.5 (EtOAc-hexanes, 1:1, v/v, +0.5% v/v *?rNH₂); 1H NMR (DMSO-^) δ 8.9 (s, IH), 8.7 (s, IH), 5.0 (br s, 2H)

Preparation of 8-chloro-2-methylimidazo[l,2-a]pyrazine (^"Compound Ha in Scheme 1): [0147] A mixture of l-bromo-2,2-dimethoxypropane (42.4 g, 231.5 mmol) and cone. HC1

(890 μL, 28.9 mmol) in water (6.25 mL) was heated to 90°C for 15 min, cooled to r.t. and quenched with NaHCO₃. 2-Amino-3-chloropyrazine (Compound I in Scheme 1, 0.2 g, 1.54 mmol) was added and the resultant mixture was heated to 90°C for 2h 30 min. The cooled reaction mixture was partitioned between 2M NaHCO₃ aq (100 mL) and dichloromethane (100 mL). The aqueous layer was separated and extracted with dichloromethane (5 x 100 mL). The combined organic extracts were dried over anhydr. Na₂SO₄ and concentrated in vacuo to yield the crude title compound. Purification by recrystallization from the minimum amount of hot dichloromethane provided 7.0 g (54 % yield) of the pure title compound. 1H NMR (CH₃OH-^) δ 8.38 (d, J4.5 Hz, IH), 7.88 (s, IH), 7.65 (d, J4.5 Hz, IH), 2.49 (s, 3H); MS (ESI) 167.8 ([M+H]⁺, CI³⁵), 169.8 ([M+H]⁺, CI³⁷) Preparation of 2-methyl-7H-imidazo[l,2-a1pyrazin-8-one (Compound IVa in Scheme

[0148] A mixture of 8-chloro-2-methylimidazo[l,2-a]pyrazine (Compound Ha in Scheme 1,

2.5 g, 15 mmol) and cone. HC1 (1.5 mL, 1.2 eq., 18 mmol) in water (20 mL) was refluxed for 3 h. The cooled reaction mixture was concentrated in vacuo and the residual solid was extracted with hot ethanol (4 x 100 mL). The combined ethanolic filtrates were treated with KHCO₃ (1.8 g, 1.2 eq., 18 mmol), the resultant insoluble material was filtered and the filtrate was concentrated in vacuo to provide 2.0 g (89% yield) of the title compound. 1H NMR (DMSO-d₆) δ 12.15 (br s, IH), 7.90 (s, IH), 7.68 (d, J5.5 Hz, IH), 7.20 (t, J5.5 Hz, IH), 2.38 (s, 3H)

Preparation of 8-chloro/bromo-2-isopropylimidazor 2-α]pyrazine (Compound Hb in Scheme 1):

[0149] A two-neck round bottom flask was charged with 2-amino-3-chloropyrazme

(Compound I in scheme 1, 5.01 g, 38.6 mmol), l-bromo-3-methyl-2-butanone (25.64 g, 155.4 mmol) and deionized water (20 mL). The reaction mixture was stirred arid heated at 90 °C until the reaction was completed as monitored by TLC. After 3.5 h, the reaction was quenched with a saturated solution of NaHCO₃ (75 mL) and deionized water (50 mL). The aqueous layer was extracted with dichloromethane (3 x 100 mL) and the combined organic layers were dried over anhydr. MgSO and subsequently concentrated in vacuo to yield a brown oil. The oil was diluted in a minimal amount of diethyl ether and triturated with hexanes to recrystallize the remaining unreacted 2-amino-3- chloropyrazine. The 2-amino-3-chloropyrazine was filtered off from the mother liquid, the filtrate was purified by a silica gel plug with ethyl acetate as eluent. The fractions containing the desired product were collected and concentrated in vacuo to yield an amber oil (5.89 g, 77.9% yield). 1H- NMR (DMSO-d₆) δ 10.67 -10.04 (m, 3H), 3.87 (qt, J6.9 Hz, IH), 1.74 (d, J7.0 Hz, 6H)

Preparation of 2-isopropyl-7H-imidazor 2-. yrazin-8-one hydrochloride (Compound IVb in Scheme 1):

[0150] A round bottom flask was charged with 8-chloro/bromo-2-isopropylimidazo[l,2-a] pyrazine (Compound Hb in scheme 1, 8.78 g, 44.87 mmol), 37% HC1 (5.31 mL) and deionized water (5.3 mL). The reaction mixture was heated to 90 °C for 2 h and allowed to cool to r.t. The solvent was removed in vacuo to yield the pyrazinone salt (6.93 g, 72% yield). 1H-NMR (DMSQ-d₆) δ 12.17 (br s, IH), 7.97 (s, IH), 7.65 (m, IH), 7.22 (m, IH), 3.15 - 3.05 (m, IH), 1.29 (d, J6.8 Hz, 6H)

Preparation of 8-chloro^omo-2-trifluoromethyl-imidazo 1,2-αl pyrazine (Compound He in Scheme 1):

[0151] To a suspension of 2-amino-3-chloropyrazine (Compound I in scheme 1, 4.0 g, 30.9 mmol) in DME (120 mL) was added 3-bromo-l,l,l-trifluoroacetone (15 mL, 144.5 mmol) and molecular sieves (4A, 1.06 g). The reaction mixture was heated at 90 °C for 24 h. The reaction was quenched by the addition of water (250 mL) and the aqueous layer was extracted with Et₂O (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydr. Na₂SO₄ and concentrated under reduced pressure to give 8-chloro/bromo-2-trifluoromethyl-imidazo [1,2- ] pyrazine (Compound He in Scheme 1), which was used for the next step without further purification. 1H-NMR (CDC1₃) δ 8.10 - 8.05 (m, 2H), 7.79 (dd, J 1.4 & 5.4 Hz, IH)

Preparation of 2-trifluoromethyl-7H-imidazo 2-α1pyrazin-8-one hydrochloride (Compound IVc in Scheme 1):

[0152] A round bottom flask was charged with 8-chloro/bromo-2-trifluoromethyl-imidazo

[1,2-α] pyrazine (0.4 g, 8 mmol) and 37% HC1 (0.24 mL) and deionized water (5 mL). The reaction mixture was heated at 90 °C for 24 h. After the completion of the reaction, the product was concentrated in vacuo to yield the title compound (0.32 g, 78% yield). 1H-NMR (DMSO- ) δ 11.4 (br s, IH), 8.40 (d, J0.7 Hz, IH), 7.49 (dd, J 1.2 & 5.6 Hz, IH), 6.98 (t, J5.7 Hz, IH)

Preparation of 2-amino-3-benzyloxypyrazine (Compound HI in scheme 1): [0153] Benzyl alcohol (4.55 g, 42.15 mmol) was added under an inert atmosphere dropwise to a suspension of sodium hydride (1.01 g, 42.13 mmol, 80%) in N-methylpyrrolidinone. Stirring of the reaction mixture was continued for 30 min. 2-Amino-3-chloropyrazine (Compound I in Scheme 1, 5.0 g, 38.6 mmol) was then added in incrememtal portions and the resultant mixture was heated at 80 °C for 24 h. The reaction mixture was subsequently cooled and water (200 mL) was added. The aqueous solution was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (2 x 100 mL), dried (MgSO ), and concentiated under reduced pressure to obtain a light brown residue. Addition of cold water to the residue, triggered crystallization of the desired product. The crystals were collected and dried over P₂O₅ (6.33 g, 82%). 1H-NMR (CDC1₃) δ 7.54 (d, J 3.1 Hz, IH), 7.45 - 7.32 (m, 6H), 5.38 (s, 2H), 4.78 (br s, 2H); MS (ESI) 202.2 ([M+H]*)

Preparation of 2-(4-methoxy-phenyl)-7H-imidazo[^"1.2-a]ρyrazine-8-one (Compound INd in scheme 1):

[0154] 2-Bromo-4'-methoxyacetophenone (1.64 g, 7.14 mmol) was added to a solution of 2- amino-3-benzyloxypyrazine (Compound HI in scheme 1, 1.5 g, 6.80 mmol) in ethanol (10 mL). The reaction mixture was refluxed for 5 h. The reaction mixture was allowed to cool to r.t. and an off- white coloured solid precipitated out. The solid was collected and washed with ice-cold ethanol to give a white solid (1.08 g, 66%). 1H-ΝMR (CDC1₃) δ 11.4 (d, J 4.2 Hz, IH), 8.23 (s, IH), 7.86 (t, J 2.9 Hz, IH), 7.83 (t, J2.1 Hz, IH), 7.52 (dd, J0.7 & 5.5 Hz, IH), 7.04 (t, J2.9 Hz, IH), 7.02 (t, J2.0 Hz, IH), 6.94 (t, J3.0 Hz, IH), 3.79 (s, 3H); MS (ESI) 242.0 ([M+H]^"1)

Preparation of 2-methyl-8-oxo-7,8-dihydro-imidazo l,2-a1pyrazine-3-carboxylic acid ethyl ester (Compound IVe in Scheme 1):

[0155] To a solution of ethyl acetophenone (10 g, 0.077 mol) in EtOAc (50 mL) was added

Mg(ClO )₂ (5.16 g, 0.023 mol) and N-bromosuccimide (15 g, 0.085 mol). The reaction mixture was stirred at r.t. under an inert atmosphere for 5 h and subsequently quenched by addition of water (100 mL). The aqueous layer was further extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO ), and concentrated under reduced pressure to give the product as a light yellow liquid. The crude product was purified by distillation at 60 °C under high vacuum to give 2-bromo-3-oxo-butyric acid ethyl ester as a colorless liquid (11 g, 69%). 1H-ΝMR (CDC1₃) δ 3.83 (br s, IH), 4.26 (q, J7.2 Hz, 2H), 2.41 (s, 3H), 1.28 (t, J7.1 Hz, 3H) [0156] 2-Bromo-3-oxo-butyric acid ethyl ester (15.6 g, 74.6 mmol) was added to a solution of

2-amino-3-benzyloxypyrazine (Compound HI in Scheme 1, 5 g, 24.9 mmol) in ethanol (20 mL). The reaction mixture was refluxed for 5 h. The reaction mixture was allowed to cool to r.t. and an off- white coloured solid precipitated out. The solid was collected and washed with ice-cold ethanol to give a white solid (1.08 g, 66%). 1H-NMR (OMSO-d₆) δ 11.6 (br s, IH), 7.97 (d, J5.7 Hz, IH), 7.00 (t, J 5.8 Hz, IH), 4.35 (q, J 7.1 Hz, 2H), 2.52 (s, 3H), 1.34 (t, J 7.1 Hz, 3H); MS (ESI) 222.0 ([M+H]-¹-)

Preparation of 8-oxo-2-trifluoromethyl-7.8-dihv(lro-imidazo[ 1.2-α]pyrazine-3- carboxylic acid ethyl ester (Compound IVf in scheme 1):

[0157] To a solution of ethyl 4,4,4-trifluoroacetophenone (10 g, 0.054 mol) in EtOAc (50 mL) was added Mg(ClO )₂ (3.64 g, 0.016 mol) and N-bromosuccimide (10.6 g, 0.06 mol). The reaction mixture was stirred at r.t. under an inert atmosphere for 4 h and then quenched by addition of water (100 mL). The aqueous layer was further extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO₄), and concentrated under reduced pressure to give the product as a light brown liquid. The crude product was purified by distillation at 60 °C under high vacuum to give 2-bromo-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (10 g, 71%). IR 3444 cm^"1 (vOH) & 1725 cm^"1 (vC=O); 1H-ΝMR (CDC1₃) spectral data contained signals consistent of a mixture of the enol and keto forms of the compound δ 5.19 (s, IH), 4.68 (d, J3.5 Hz, IH), 4.35 - 4.25 (m, 2H), 1.38 - 1.24 (m, 3H)

[0158] 2-Bromo-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (2.61 g, 9.9 mmol) was added to a solution of 2-amino-3-benzyloxypyrazine (Compound HI in Scheme 1, 1 g, 5.0 mmol) in ethanol (10 mL). The reaction mixture was refluxed for 5 h. Upon cooling, a yellow precipitate formed from the reaction mixture. The solid was collected and washed with ice-cold ethanol to give a light yellow solid (0.82g, 61%). 1H-NMR (CD₃OD-^) δ 8.23 (d, J5.9 Hz, IH), 7.10 (d, J5.9 Hz, IH), 4.47 (q, J 7.1 Hz, 2H), 1.41 (t, J7.1 Hz, 3H); MS (ESI) 276.0 ([M+H]⁺).

[0159] Previously reported synthetic procedures were used for the preparation of 1-aryl-l- hydroxymethylcyclopropane intermediates. The cyclopropane ring was formed by deprotonation of the benzylic carbon of the corresponding phenylacetronitrile followed by a nucleophilic attack on 1,2- dibromoethane (Singh, Rajendra K. (Monsanto Co., USA). US 4859232. Viresh H. Rawal, Christophe Michoud, and Robert F. Monestell J. Am. Chem. Soc, 1993, 3030-3031). Subsequent hydrolysis (Sargent, Bruce Jermey; Johnston, David Norman; Crew, Andrew Philip Austin (Boots Company PLC, UK) WO9500489,) of the cyano intermediate followed by reduction provided the desired alcohol. Preparation of l-(4-nitiOphenyl)-l-hvdroxymethylcyclopropane (Compound Va in scheme 1): [0160] 4-Nitrophenylacetonitrile (15.0 g, 92.5 mmol), 1,2-dibromoethane (24 mL, 277.5 mmol) and tetiabutylammonium bromide (29.8 g, 92.5mmol) in acetonitrile (150 mL) were placed into a 500-mL three-necked flask, attached to a thermocouple, an addition funnel and a nitrogen line. To this reaction mixture at room temperature, 50% sodium hydroxide (30 mL) was slowly added via the addition funnel (the color of the reaction mixture changed from a light brown to purple). An exothermic reaction was observed. The temperature ranged from 17 °C to 50. °C. The reaction was kept at 40 °C for about one hour after the addition, then it was analyzed by thin-layer chromatography (20% ethyl acetate/ 80% hexanes, R_f 0.30 for the product). The reaction mixture was diluted with dichloromethane (50 mL) followed by water (40 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL). The organic layer was separated, dried over magnesium sulfate and the solvent was removed by reduced pressure to yield a dark green solid (14.4 g, 76.1 mmol, 82% yield). 1H-NMR (DMSO-rf_.) δ 8.30 - 8.20 (d, 2H), 7.61 - 7.55 (d, 2H), 1.95 (t, 2H), 1.75 (t, 2H) [0161] l-(4-Nitrophenyl)-cyclopropanecarbonitrile (12.77g, 67.16 mmol) was placed into a 250 mL three-necked round-bottomed flask then water (79 mL) and cone, sulfuric acid (56 mL) were added. The solution was refluxed overnight and thin-layer chromatography was used to monitor the percentage completion of the reaction (100% ethyl acetate, R_f 0.49 for the product). The reaction mixture was cooled and the resultant precipitate was collected. The solid was washed with water (30 mL) and dried overnight under vacuum to give the title compound (8.67 g, 41.45 mmol, 62% yield). 1H-NMR (DMSO-d₆) δ 8.21 - 8.11 (d, 2H), 7.58 - 7.64 (d, 2H), 1.5 - 1.6 (t, 2H), 1.2 - 1.3 (t, 2H) [0162] A solution of l-(4-nitrophenyl)-cyclopropanecarboxylic acid (8.45 g 40.54 mmol) in anhydrous tetrahydrofuran (80 mL) in a 250 mL three-necked flaskwas stiπed at 0 °C then a 10 M solution of borane-methyl sulfide complex (9.0 mL, 89.2 mmol) was added drop-wise over a period of 10 min. The temperature was observed to increase to 5 °C from 0 °C upon addition of the borane-methyl sulfide. After approximately a period of one hour, the ice bath was removed, and the reaction was allowed to warm to r.t. overnight. The reaction mixture was monitored for completion by thin-layer chromatography (70% ethyl acetate/ 30% hexanes, R_f 0.38 for the product): The solution was cooled with an ice bath (the temperature reached - 0.6 °C), and then 2 M HC1 (7 mL) was added slowly to the reaction mixture. The maximum temperature of the reaction solution was 3.1 °C and about pH 2. The reaction mixture was stiπed at 10 °C for 30 min and then 1 M NaOH was added until pH 8 was reached. The solution was diluted with ethyl acetate (2 x 50 mL) and then the aqueous layer was extracted with ethyl acetate (2 x 75 mL). The organic layer was separated, dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude title compound (8.1 g) was purified using column chromatography (hexanes-ethyl acetate, 1:1, v/v) to give an orange colored solid (6.25 g 32.03 mmol, 79% yield). 1H-NMR (CDC1₃) δ 8.2 - 8.1 (d, 2H), 7.52 - 7.42 (d, 2H), 3.78 (s, 2H), l.l - 0.9 (m, 4H).

Preparation of_. 1 -(4-trifluoromethyl-phenyI)- 1 -hydroxymethylcyclopropane

(Compound Vb in scheme 1): [0163] Compound Vb was prepared starting from 4-trifluoromethyl-phenylacetonitrile and following a similar procedure as the one described to prepare Va. 1H-NMR (CDC1₃) δ 7.6 - 7.5 (d, 2H), 7.5 - 7.4 (d, 2H), 3.64 (s, 2H), 0.9 (s, 4H)

Preparation of 1 -(3 ,5-bis-trifluoromethyl-phenyl)- 1 -hydroxmethylcyclopropane (Compound Vc in scheme 1): [0164] Compound Vc was prepared starting from 3,5-bis-trifluoromethyl- phenylacetonitrile and following a similar procedure as the one described to prepare Va. 1H- NMR (CDC1₃) δ 7.82 (s, 2H), 7.74 (s, IH), 3.73 (d, IH), 1.56 (t, IH), 0.98 - 0.95 (m, 2H)

Preparation of [^"l-(5-chloro-l-methyl-lH-indol-3-yl)-cyclopropyl]-methanol

(Compound Vc in scheme 1): [0165] Methylation of 5-chloroindole using methyl iodide and NaOH in toluene in the presence of a phase transfer catalyst tetra-n-butylammonium hydrogen sulfate gave N-methyl-5- chloroindole in good yield. Formylation of N-methyl-5-chloroindole was carried out using dimethyl amine, formaldehyde and acetic acid to give (N-methyl-5-chloro-3- [dimethylamino)methyl]) indole which was subsequently converted to the iodine salt using methyl iodide. The reaction of this iodine salt with potassium cyanide in water under reflux for 24 hours afforded (N-methyl-5-chloro-indol-3-yl)-acetonitrile.

[0166] Cyclopropanation of (N-methyl-5-chloro-indol-3-yl)-acetonitrile proved difficult.

Eventually, cyclopropanation of (N-methyl-5-chloro-indol-3-yl)-acetonitrile using potassium bis(trimethylsilyl)amide and 1,2-dibromoethane provided a mixture of [l-(5-chloro-l-methyl- lH-indol-3-yl)-cyclopropyl]-methanol and 2-(5-chloro-l-methyl-lH-indol-3-yl)-ethanol. [0167] i) To a 1-L 3-neck round-bottom flask equipped with an overhead stirrer, 5- chloroindole (45 g, 0.3 mol) was dissolved in toluene (270 mL). The flask was then placed in a water bath and methyl iodide (63.2 g, 0.45 mol) was added to the flask and stirred for a few minutes. Then tetia-n-butylammom^'um hydrogen sulfate (100.8 g, 0.3 mol) and 50% aqueous ΝaOH (153 mL) were added and stirred vigorously. An exothermic reaction was observed. The reaction mixture was allowed to stir overnight. The reaction was monitored by TLC (EtOAc-w- Hexanes, 1:2, v/v, R_f 0.48 for the product). The organic layer was transfeπed to a 1-L separatory funnel. The flask was rinsed with toluene (3 x 50 mL) and the rinse added to the funnel. The combined organic layers were washed with water (3 x 100 mL), 1 Ν HC1 aqueous solution (2 x 100 mL) and dried over MgSO . The drying agent was filtered and solvent was removed in vacuo to give N-methyl-5-chloroindole (43.5 g) as pale yellow oil in 88.4% yield. 1H-ΝMR (CDC1₃) δ 7.58 (d, J2.4 Hz, IH), 7.24 (s, IH), 7.21 (s, IH), 7.17 (d, J2.4 Hz, IH), 7.14 (d, J 1.8 Hz, IH), 7.06 (d, J3.3 Hz, IH), 6.42 (d, J 1.2 Hz, IH), 3.77 (s, 3H)

[0168] ii) A 2-L 3-neck round bottom flask was equipped with a thermocouple and an overhead stiπer, 60% aqueous acetic acid (90.3 mL) and 40% aqueous dimethyl amine (113.1 mL) were added and cooled to 0 °C. To this mixture, 37% aqueous solution of formaldehyde (66.5 mL) was added drop-wise via an addition funnel. After stirring this mixture for 30 minutes at 0 °C, a cooled solution of N-methyl-5-chloroindole (59.2 g, 0.36 mol) in ethanol (350 mL) was added drop-wise via an addition funnel over 30 min, and the reaction mixture was allowed to warm to r.t. A condenser was attached and the reaction mixture was heated under reflux for 30 min and then stiπed at r.t. overnight. The reaction mixture was poured onto an ice cold 1 Ν aqueous ΝaOH solution (300 mL) and extracted with CH₂C1₂ (4 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over MgSO₄ and concentrated to give (N-methyl-5-chloro-3-[dimethylamino)methyl]) indole (69.5 g 87.4 % yield) as a yellow oil. 1H- ΝMR (CDC1₃) δ 7.73 (s, IH), 7.21 (s, 2H), 7.02 (s, IH), 3.74 (s, 3H), 3.51 (s, 2H), 2.31 (s, 6H) [0169] iii) N-Me l-5-chloro-3-[(dimethylamino)methyl] indole (69.5 g, 0.31 mol) was dissolved in absolute ethanol (370 mL) in a 1-L 3-neck round bottom flask with overhead stirring and cooled in an ice-water bath. To this methyl iodide was added. An exothermic reaction took place as the reaction mixture became cloudy. The reaction mixture was stiπed in ice-water bath for 1 hour and stiπed for an additional 2 hours at room temperature. The mixture was allowed to stand for 1 hour at room temperature and then cooled to 0°C. The solid was filtered, washed with cold absolute ethanol (2 x 50 mL) and anhydrous ether (3 x 50 mL). After drying under Ν₂, (N-methyl-5-chloro-3-[dimethylamino)methyl]) indole iodine salt (104 g, 76.3% yield) was obtained as a white solid.1H-ΝMR (DMSO-c ) δ 8.01 (d, J 2.1 Hz, IH), 7.71 (s, 2H), 7.57 (d, J9 Hz, IH), 7.24 (dd, J 1.8 & 8.7 Hz, IH), 4.59 (s, 2H), 3.86 (s, 3H), 3.05 (s, 9H)

[0170] iv) To a solution of potassium cyanide (70.86 g, 1.14 mol) in water (570 mL) in a 2-L 3-neck RBF with overhead stirring was added (N-methyl-5-chloro-3- [dimethylamino)methyl]) indole iodine salt (104 g, 0.29 mol). A condenser was attached. The reaction mixture was heated under reflux for 24 h. The reaction mixture was then cooled to room temperature and extracted with CH₂C1₂ (3 x 100 mL). The combined organic layers were washed with a saturated ΝaCl aqueous solution (2 x 100 mL), dried over MgSO₄ and concentrated to give a yellow solid (60 g). The solid was recrystallized using hot ethyl acetate (100 mL) to give (N-methyl-5-chloro-indol-3-yl)-acetonitrile as a pale yellow solid (18.8 g). The mother liquor was concentrated to give another 40 g of crude (N-methyl-5-chloro-indol-3-yl)- acetonitrile, which was purified using column chromatography. A 4.5-inch diameter column was wet packed with 1.2 kg of silica gel using n-hexane. About one inch of sea sand was place in top of silica gel. The height of the column was 15 inches. Approximately 1 L of hexane containing 3 μL of Et₃Ν was run through the column. The crude (N-methyl-5-chloro-indol-3-yl)-acetonitrile was dissolved in 50 mL of ethyl acetate and loaded on the column. The column was run at a flow rate of 2 inches/min. First, 2 L of «-hexane was used to elute the column followed by 2 L of 10 % ethyl acetate in n-hexane. Then, 5 L of 20% ethyl acetate in w-hexane and 4 L of 25 % ethyl -acetate in H-hexane were used to finish the column. The first 5 fractions were collected in 1 L portion and the rest of the fractions were collected in 500 mL portion. Fractions 10 to 15 were collected to give 10.8 g of pure (N-methyl-5-chloro-indol-3-yl)-acetonitrile as a white solid. 1H- MR (CDC1₃) δ 7.51 (dd, J0.9 & 1.5 Hz, IH), 7.21 -7.20 (m, 2H), 7.08 (s, IH), 3.75 - 3.74 (m, 2H), 3.74 - 3.73 (m, 3H)

[0171] v) (N-Methyl-5-chloro-indol-3-yl)-acetonitrile (14.6 g, 0.072 mol) was dissolved in anhydrous THF (730 mL) under Ν₂ and cooled to -8 °C using an ice-NaCl-H O bath and potassium bis(trimethylsilyl)amide (0.5 M solution, 715 mL, 0.357 mol) was added. The mixture was warmed to 45 °C and was held for 10 min and then cooled to 0 °C. 1,2- Dichloroethane (17.1 mL, 0.215 mol) was added dropwise and the mixture was allowed to warm to r.t. The reaction was quenched with water (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydr. MgSO₄ filtered and concentiated to give a brown oil (15.5 g) as a mixture of ) [l-(5-chloro-l-methyl-lH-indol-3-yl)-cyclopropyl]-cyanide (44.3% purity by HPLC area %) and 2-(5-chloro-l-methyl-lH-indol-3-yl)-acetonitrile (22.8% purity by HPLC area %). To this mixture was added water (30 mL) and concentrated sulfuric acid (20 mL) and heated under reflux for 12 h to give a brown solid (14.2 g) as a mixture of [l-(5-chloro-l-methyl-lH-indol-3- yl)-cyclopropyl]-carbonic acid (34.2% purity by HPLC area %) and 2-(5-chloro-l -methyl- 1H- indol-3-yl)-acetic acid (34.1% purity by HPLC area %).

[0172] This mixture was dissolved in anhydrous THF (80 mL), cooled to 0 °C and borane-methyl sulfide complex (11.7 mL, 123.3 mmol) was added dropwise. The reaction mixture was stirred overnight. The reaction mixture was cooled to 0 °C and 2 N aqueous HC1 solution (7 mL) was added dropwise. The resulting mixture was stiπed for 30 min and a dilute aqueous NaOH solution was added until the pH of the resulting reaction mixture was above 8. The reaction mixture was extracted with ethyl acetate (3 x 100 mL), dried over MgSO₄ and concentrated to give dark brown (15.8 g) oil as a mixture of [l-(5-chloro-l-methyl-lH-indol-3- yl)-cyclopropyl]-methanol (43.9% purity by HPLC area %) and 2-(5-chloro-l -methyl- lH-indol- 3-yl)-ethanol (48.4% purity by HPLC area %). The mixture was purified using column chromatography, a 1.125-inch column was wet packed with silica gel (45 g) using hexanes. A thin layer of sea sand was place evenly on top of the silica gel. A mixture of [l-(5-chloro-l- methyl- 1 H-indol-3-yl)-cyclopropyl]-methanol and 2-(5-chloro- 1 -methyl- 1 H-indol-3-yl)-ethanol (0.6 g) was dissolved in 5 mL of CH₂C1₂ and loaded in top of the packed column. More sea sand was added on top of the packed silica gel until 0.5 inch in height. The column was eluted with 200 mL of hexanes at a flow rate of 2 inches per minute. Then 200 mL of 10% ethyl acetate in hexanes was used followed by 200 mL of 20% ethyl acetate in hexanes and 400 mL of 33% ethyl acetate in hexane. The eluent was collected in 30 mL fractions. Fractions 18 and 19 were collected and the solvent was evaporated to afford [l-(5-chloro-l-methyl-lH-indol-3-yl)- cyclopropyl] -methanol (0.12 g, 86% purity by HPLC area %) as oil; fractions 20 to 23 were collected and solvent was evaporated to give oil (0.16 g) as a mixture of [l-(5-chloro-l-methyl- lH-indol-3-yl)-cyclopropyl]-methanol (36.6 % purity by HPLC area %) and 2-(5-chloro-l- methyl-lH-indol-3-yl)-ethanol (54.4% purity by HPLC area %); fractions 23 to 28 was collected and the solvent was evaporated to give 2-(5-chloro-l-methyl-lH-indol-3-yl)-ethanol (0.02 g). ^!H- NMR [l-(5-chloro-l-methyl-lH-indol-3-yl)-cyclopropyl]-methanol (CDC1₃) δ 7.69 (dd, J 0.9 & 1.8 Hz, IH), 7.19 - 7.17 (m, 2H), 7.00 (s, IH), 3.72 (s, 3H), 3.63 (s, 2H), 0.90 - 0.78 (m, 4H). 1H- NMR 2-(5-chloro-l-methyl-lH-indol-3-yl)-ethanol (CDC1₃) δ 7.56 (dd, J 1.2 & 1.8 Hz, IH), 7.19 - 7.14 (m, 2H), 6.95 (s, IH), 3.86 (t, J6.3 Hz, 2H), 3.23 (s, 3H), 2.96 (t, J5.7 Hz, 2H)

Preparation of 3-(5-chloro-indol-l-yl)-propan-l-ol (Compound Nd in Scheme 1): [0173] To a suspension of ΝaH (0.66 g, 22 mmol, ) in anhydrous DMF (20 mL) was added 5-chloroindole (3 g, 20 mmol) in anhydrous DMF (20 mL). The resultant mixture was stiπed at room temperature under Ar for 30 min. 3-(Bromopropoxy)-tert-butyldimethylsilane (4.9 mL, 21 mmol) was then added and the reaction mixture was stiπed at r.t. under Ar for 1.5 h. The reaction was quenched with H₂O (100 mL) and the aqueous layer was extracted with Et₂O (3 x 100 mL). The combined Et₂O layers were washed with brine (3 x 100 mL), dried over anhydr. Νa₂SO₄ and concentrated to give yield (6.8 g) of the product quantitatively. The product was used in the next step without further purification. 1H-NMR (CDC1₃) δ 7.5 (s, IH), 7.2 (m, 3H), 6.2 (s, IH), 4.2 (t, 2 H), 3.5 (t, 2 H), 1.9 (m, 2 H), 0.8 (s, 9 H), 0.0 (s, 6H) [0174] To a solution of l-[(3-tert-butyl-dimethyl-silanyloxy)-propyl]-5-chloro-lH-indole

(6.8 g, 20 mmol) in anhydrous TΗF (40 mL) was added TBAF (21 mL, 21 mmol). [0175] The reaction mixture was stiπed at r.t. under inert atmosphere for 20 min. The reaction was quenched with 1M aqueous ΗC1 (100 mL) and the aqueous layer was extracted with Et₂O (3 x 100 mL). The combined Et₂O layers were dried over anhydr. Na SO and concentrated to give a quantitative yield (4.8 g) of the title compound. The product was used in the following reactions without further purification. 1H-NMR (CDC1₃) δ 7.5 (s, IH), 7.2 (m, 3H), 6.4 (s, IH), 4.3 (t, 2H), 3.6 (t, 2H), 2.1 (t, 2H)

[0176] The reaction sequence described above (Scheme 1) generates the N-substituted

7H-imidazo[l,2-α]pyrazin-8-one as the free base. The free base may be converted, if desired, to the monohydrochloride salt by known methodologies, or alternatively, if desired, to other acid addition salts by reaction with inorganic or organic acids. Acid addition salts can also be prepared metathetically by reaction of one acid addition salt with an acid that is stronger than that giving rise to the initial salt.

[0177] It is recognized that there may be one or more chiral centers in the compounds used within the scope of the present invention and thus such compounds will exist as various stereoisomeric forms. All the various stereoisomers of the compounds disclosed herein are included within the scope of the invention. Though the compounds may be prepared as racemates and can conveniently be used as such, individual enantiomers also can be isolated or preferentially synthesized by known techniques if desired. Such racemates and individual enantiomers and mixtures thereof are intended to be included within the scope of the present invention. Pure enantiomeric forms if produced may be isolated by preparative chiral HPLC. The free base may be converted if desired, to the monohydrochloride salt by known methodologies, or alternatively, if desired, to other acid addition salts by reaction with other inorganic or organic acids. Acid addition salts can also be prepared metathetically by reacting one acid addition salt with an acid that is stronger than that of the anion of the initial salt. [0178] The present invention also encompasses the pharmaceutically acceptable salts, esters, amides, complexes, chelates, solvates, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs of the compounds of formula (I). Pharmaceutically acceptable esters and amides can be prepared by reacting, respectively, a hydroxy or amino functional group with a pharmaceutically acceptable organic acid, such as identified below. A prodrug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which is degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form. Generally, a prodrug has a different pharmakokinetic profile than the parent drug such that, for example, it is more easily absorbed across the mucosal epithelium, it has better salt formation or solubility and/or it has better systemic stability (e.g., an increased plasma half-life). [0179] Those skilled in the art recognize that chemical modifications of a parent drug to yield a prodrug include: (1) terminal ester or amide derivatives which are susceptible to being cleaved by esterases or lipases; (2) terminal peptides which may be recogmzed by specific or nonspecific proteases; or (3) a derivative that causes the prodrug to accumulate at a site of action through membrane selection, and combinations of the above techniques. Conventional procedures for the selection and preparation of prodrug derivatives are described in H. Bundgaard, Design of Prodrugs, (1985). Those skilled in the art are well-versed in the preparation of prodrugs and are well-aware of its meaning. [0180] The synthetic procedures described herein, especially when taken with the general knowledge in the art, provide sufficient guidance to those of ordinary skill in the art to perform the synthesis, isolation, and purification of the compounds of the present invention.

Compositions and Modes of Administration [0181] In another embodiment, the present invention provides compositions which include a N-substituted 7H-imidazo[l,2-α]pyrazin-8-one compound as described above in admixture or otherwise in association with one or more inert carriers, excipients and diluents, as well as optional ingredients if desired. These compositions are useful as, for example, assay standards, convenient means of making bulk shipments, or pharmaceutical compositions. An assayable amount of a compound of the invention is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of a compound of the invention will generally vary from about 0.001 wt% to about 75 wt% of the entire weight of the composition. Inert carriers include any material which does not degrade or otherwise covalently react with a compound of the invention. Examples of suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents such as acetonitrile, ethyl acetate, hexane and the like (which are suitable for use in in vitro diagnostics or assays, but typically are not suitable for administration to a warm-blooded animal); and pharmaceutically acceptable carriers, such as physiological saline. [0182] Thus, the present invention provides a pharmaceutical or veterinary composition

(hereinafter, simply refeπed to as a pharmaceutical composition) containing a N-substituted 7H- imidazo[l,2-α]pyrazin-8-one compound as described above, in admixture with a pharmaceutically acceptable carrier, excipient or diluent. The invention further provides a pharmaceutical composition containing an effective amount of a N-substituted 7H-imidazo[l,2- α]pyrazin-8-one compound as described above, in association with a pharmaceutically acceptable carrier.

[0183] The pharmaceutical compositions of the present invention may be in any form which allows for the composition to be administered to a patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Typical routes of administration include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, epidural, intiasternal injection or infusion techniques. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a patient take the form of one or more dosage units, where for example, a tablet, capsule or cachet may be a single dosage unit, and a container of N-substituted 7H-imidazo[l,2-α]pyrazin-8-one compound in aerosol form may hold a plurality of dosage units.

[0184] Materials used in preparing the pharmaceutical compositions should be pharmaceutically pure and non-toxic in the amounts used. The inventive compositions may include one or more compounds (active ingredients) known for a particularly desirable effect. For instance, epinephrine may be combined with a N-substituted 7H-imidazo[l,2-α]pyrazin-8- one compound of the invention, to provide a composition useful to induce local anesthesia. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of subject (e.g., human), the particular form of the active ingredient, the manner of administration and the composition employed. [0185] In general, the pharmaceutical composition includes a N-substituted 7H- imidazo[l,2-α]pyrazin-8-one compound as described herein, in admixture with one or more carriers. The carrier(s) may be particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup or injectable liquid. In addition, the carrier(s) may be gaseous, so as to provide an aerosol composition useful in, e.g., inhalatory administration.

[0186] When intended for oral administration, the composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

[0187] As a solid composition for oral administration, the composition may be formulated into a powder, granule, compressed tablet, pill, capsule, cachet, chewing gum, wafer, lozenges, or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following adjuvants may be present: binders such as syrups, acacia, sorbitol, polyvinylpyπolidone, carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tiagacanth or gelatin, and mixtures thereof; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; fillers such as lactose, mannitols, starch, calcium phosphate, sorbitol, methylcellulose, and mixtures thereof; lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, wetting agents such as sodium lauryl sulfate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent.

[0188] When the composition is in the form of a capsule, e.g., a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.

[0189] The composition may be in the form of a liquid, e.g., an elixir, syrup, solution, aqueous or oily emulsion or suspension, or even dry powders which may be reconstituted with water and/or other liquid media prior to use. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, prefeπed compositions contain, in addition to the present compounds, one or more of a sweetening agent, thickening agent, preservative (e.g., alkyl J-hydoxybenzoate), dye/colorant and flavor enhancer (flavorant). In a composition intended to be administered by injection, one or more of a surfactant, preservative (e.g., alkyl -hydroxybenzoate), wetting agent, dispersing agent, suspending agent (e.g., sorbitol, glucose, or other sugar syrups), buffer, stabilizer and isotonic agent may be included. The emulsifying agent may be selected from lecithin or sorbitol monooleate.

[0190] The liquid pharmaceutical compositions of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium ' bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.

[0191] A liquid composition intended for either parenteral or oral administration should contain an amount of the inventive compound such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition. Prefeπed oral compositions contain between about 4% and about 50% of the active N-substituted 7H-imidazo[l,2-β]pyrazin-8-one compound. Prefeπed compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 10% by weight of active compound. [0192] The pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment, cream or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentiation of the inventive compound of from about 0.1 to about 25% w/v (weight per unit volume). [0193] The composition may be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol. Low-melting waxes are prefeπed for the preparation of a suppository, where mixtures of fatty acid glycerides and/or cocoa butter are suitable waxes. The waxes may be melted, and the N-substituted 7H- imidazo[l,2-α]pyrazin-8-one compound is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0194] The composition may include various materials which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials which form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule or cachet. [0195] The composition in solid or liquid form may include an agent which binds to the

N-substituted 7H-imidazo[l,2-α]pyrazin-8-one compound and thereby assists in the delivery of the active components. Suitable agents which may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.

[0196] The pharmaceutical composition of the present invention may consist of gaseous dosage units, e.g., it may be in the form of an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system which dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. Prefeπed aerosols may be determined by one skilled in the art, without undue experimentation. [0197] Whether in solid, liquid or gaseous form, the pharmaceutical composition of the present invention may contain one or more known pharmacological agents used in methods for either modulating ion channel activity in a warm-blooded animal or for modulating ion channel activity in vitro, or used in the treatment or prevention of arrhythmia including atrial/supraventricular arrhythmia and ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, ventricular flutter, diseases of the central nervous system (CNS disorders), Lou Gehrig's disease (amyotiophic lateral sclerosis) convulsion, cardiovascular diseases (e.g. diseases caused by elevated blood cholesterol or triglyceride levels), cerebral or myocardial ischemias, hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis, paramyotonia congenita, malignant hyperthermia, hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmune disorders, graft rejection in organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease, AIDS-related dementia, dementia or other mental disorder, alopecia, sexual dysfunction, impotence, demyelinating diseases, multiple sclerosis (MS), epileptic spasms, seizures, depression, insomnia, anxiety, schizophrenia, Parkinson's disease, trigeminal pain, phantom limb pain, back pain, smoke cessation, respiratory disorders, cystic fibrosis, asthma, cough, inflammation and inflammatory disorders, arthritis, allergies, urinary incontinence, irritable bowel syndrome, irritable bowel syndrome Crohn's disease, prostatic hyperplasia, insect bites, psoriasis, diseases or dysfunctions of ion channels and receptors, diseases of voltage-gated ion channels, paralysis and gastrointestinal disorders such as gastrointestinal inflammation and ulcer. Other agents known to cause libido enhancement, analgesia or local anesthesia maybe combined with compounds of the present invention. [0198] The pharmaceutical compositions may be prepared by methodology well known in the pharmaceutical art. The N-substituted 7H-imidazo[l,2-α]pyrazin-8-one compounds of the invention may be in the form of a solvate in a pharmaceutically acceptable solvent such as water or physiological saline. Alternatively, the compounds may be in the form of the free base or in the form of a pharmaceutically acceptable salt such as the hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in the art. The appropriate salt would be chosen to enhance bioavailability and/or stability of the compound for the appropriate mode of employment (e.g., oral or parenteral routes of administration).

[0199] A composition intended to be administered by injection can be prepared by combining a N-substituted 7H-imidazo[l,2-α]pyrazin-8-one compound with water, and preferably buffering agents, so as to form a solution. The water is preferably sterile pyrogen-free water. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the N-substituted 7H- imidazo[l,2-α]pyrazin-8-one compound so as to facilitate dissolution or homogeneous suspension of the N-substituted 7H-imidazo[l,2-α]pyrazin-8-one compound in the aqueous delivery system. Surfactants are desirably present in aqueous compositions of the invention because the N-substituted 7H-imidazo[l,2-α]pyrazin-8-one compounds of the present invention may be hydrophobic. Other carriers for injection include, without limitation, sterile peroxide- free ethyl oleate, dehydrated alcohols, propylene glycol, as well as mixtures thereof. [0200] Suitable pharmaceutical adjuvants for the injecting solutions include stabilizing agents, solubilizing agents, buffers, and viscosity regulators. Examples of these adjuvants include ethanol, ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citrate buffers, and high molecular weight polyethylene oxide viscosity regulators. These pharmaceutical formulations may be injected intramuscularly, epidurally, intraperitoneally, or intravenously.

Pharmacological Aspects [0201] As noted above, the present invention provides for utilizing the compounds described above in in vitro and in vivo methods. In one embodiment, ion channels, such as cardiac potassium channels, are blocked in vitro or in vivo.

[0202] Ion channels are ubiquitous membrane proteins in the cells of warm-blooded animals such as mammals. Their critical physiological roles include control of the electrical potential across the membrane, mediation of ionic and fluid balance, facilitation of neuromuscular and neuronal transmission, rapid transmembrane signal transduction, and regulation of secretion and contractility.

[0203] Accordingly, compounds that are capable of modulating the activity or function of the appropriate ion channels will be useful in treating and or preventing a variety of diseases or disorders caused by defective or inadequate function of the ion channels. The compounds of the invention are found to have significant activity in modulating various ion channel activity both in vivo and in vitro.

[0204] In one aspect, the present invention provides a compound of formula (I) or composition containing a compound of formula (I), for use in methods for either modulating ion channel activity in a warm-blooded animal or for modulating ion channel activity in vitro. Some of the ion channels to which the compounds, compositions and methods of the present invention have modulating effect are various potassium and sodium channels. These potassium and sodium ion channels may be voltage-activated (also known as voltage-gated) or ligand-activated (also known as ligand-gated), and may be present in cardiac and/or neuronal systems. [0205] In another aspect, the present invention provides a compound of formula (I) or composition containing a compound of formula (I), for use in methods for either modulating activity of ion channel(s) in a warm-blooded animal or for modulating activity of ion channel(s) in vitro, wherein said ion channel(s) coπespond to some of the cardiac and/or neuronal ion channels that are responsible for one or more early repolarising currents comprising those which activate rapidly after membrane depolarisation and which effect repolarisation of the cells. [0206] In another aspect of the present invention, the above-mentioned early repolarising cuπents comprise the transient outward potassium cuπent (I_t0 for cardiac or I_A for neuronal) and/or the ultrarapid delayed rectifier cuπent (few); and include at least one of the Kv4.2, Kv4.3, Kv2.1, Kvl.3, Kvl.4, Kvl.2 and Kvl.5 cuπents.

[0207] In another aspect, the present invention provides a compound of formula (I) or composition containing a compound of formula (I), for use in methods for either modulating activity of ion channel(s) in a warm-blooded animal or for modulating activity of ion channel(s) in vitro, wherein said ion channel(s) coπespond to either the cardiac or neuronal ion channel(s) that are responsible for Kvl.5 cuπents.

[0208] In yet another aspect, the present invention provides a compound of formula (I) or composition containing a compound of formula (I), for use in methods for either modulating activity of ion channel(s) in a warm-blooded ammal or for modulating activity of ion channel(s) in vitro, wherein said ion channel(s) coπespond to the potassium channel encoded by the human ether-a-go-go related gene (HERG). [0209] Furthermore, the voltage-activated sodium ion channels comprise the Na_vl, Na_v2 or Na_v3 series and may be present in cardiac, neuronal, skeletal muscle, central nervous and/or peripheral nervous systems (e.g. hHlNa).

[0210] As noted earlier, modulating the activity of an ion channel as used above may imply but does not limit to blocking or inhibiting the conductance of the current through the ion channel.

[0211] Thus, the present invention provides for methods of treating a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or preventing a disease or condition from arising in a warm-blooded animal, wherein a therapeutically effective amount of a compound of formula (I), or a composition containing a compound of formula (I) is administered to a warm-blooded ammal in need thereof. Some of the diseases and conditions to which the compounds, compositions and methods of the present invention may be applied are as follows: arrhythmia including atrial/supraventricular arrhythmia and ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, ventricular flutter, diseases of the central nervous system, convulsion, cardiovascular diseases (e.g. diseases caused by elevated blood cholesterol or triglyceride levels), cerebral or myocardial ischemias, hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis, paramyotonia congentia, malignant hyperthermia, hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmune disorders, graft rejection in organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease, dementia and other mental disorder, alopecia, sexual dysfunction, impotence, demyelinating diseases, multiple sclerosis, amyotiophic lateral sclerosis, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, urinary incontinence, irritable bowel syndrome, and gastrointestinal disorders such as gastrointestinal inflammation and ulcer. [0212] Furthermore, the present invention provides a method for producing analgesia or local anesthesia in a warm-blooded animal which includes administering to a warm-blooded animal in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition containing a compound of formula (I). These methods may be used to relieve or forestall the sensation of pain in a warm-blooded animal. [0213] The invention further provides a method for enhancing libido in a warm-blooded animal which includes administering to a warm-blooded animal in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition containing a compound of formula (I). These compositions and methods may be used, for example, to treat a sexual dysfunction, e.g., impotence in males, and/or to enhance the sexual desire of a patient without a sexual dysfunction. As another example, the therapeutically effective amount may be administered to a bull (or other breeding stock), to promote increased semen ejaculation, where the ejaculated semen is collected and stored for use as it is needed to impregnate female cows in promotion of a breeding program.

[0214] Furthermore, the present invention provides a method in an in vitro setting, wherein a preparation that contains ion channels is contacted with an effective amount of a N- substituted 7H-irnidazo[l,2-α]pyτazin-8-one compound of the invention. Suitable preparations containing cardiac sodium channels and/or cardiac potassium channels include cells isolated from cardiac tissue as well as cultured cell lines. The step of contacting includes, for example, incubation of ion channels with a compound under conditions and for a time sufficient to permit modulation of the activity of the channels by the compound.

[0215] In another embodiment, the compounds described above are provided for treating arrhythmia. As used herein, "treating arrhythmia" refers to both therapy for arrhythmia and for the prevention of aπhythmias occurring in a heart that is susceptible to arrhythmia. An effective amount of a composition of the present invention is used to treat arrhythmia in a warm-blooded animal, such as a human. Methods of administering effective amounts of antiarrhythmic agents are well known in the art and include the administration of an oral or parenteral dosage form. Such dosage forms include, but are not limited to, parenteral dosage form. Such dosage forms include, but are not limited to, parenteral solutions, tablets, capsules, sustained release implants, and transdermal delivery systems. Generally, oral or intravenous administration is prefeπed. The dosage amount and frequency are selected to create an effective level of the agent without harmful effects. It will generally range from a dosage of from about 0.01 to about 100 mg/kg/day, and typically from about 0.1 to 10 mgkg where administered orally or intravenously for antiarrhythmic effect. [0216] Administration of compositions of the present invention may be carried out in combination with the administration of other agents. For example, it may be desired to administer an opioid antagonist, such as naloxone, if a compound exhibits opioid activity where such activity may not be desired. The naloxone may antagonize opioid activity of the administered compound without adverse interference with the antiarrhythmic activity. As another example, a N-substituted 7H-imidazo[l,2-α]pyrazin-8-one compound of the invention may be co-administered with epinephrine in order to induce local anesthesia. [0217] In order to assess whether a compound has a desired pharmacological activity with the present invention, it is subjected to a series of tests. The precise test to employ will depend on the physiological response of interest. The published literature contains numerous protocols for testing the efficacy of a potential therapeutic agent, and these protocols may be employed with the present compounds and compositions.

[0218] For example, in connection with treatment or prevention of arrhythmia, a series of four tests may be conducted. In the first of these tests, a compound of the present invention is given as increasing (doubling with each dose) intravenous infusion every 5 minutes to a conscious rat. The effects of the compound on blood pressure, heart rate and the ECG are measured continuously. Increasing doses are given until a severe adverse event occurs. The drug related adverse event is identified as being of respiratory, central nervous system or cardiovascular system origin. This test gives an indication as to whether the compound is modulating the activity of sodium channels and/or potassium channels, and in addition gives information about acute toxicity. The indices of sodium channel blockade are increasing P-R interval and QRS widening of the ECG. Potassium channel blockade results in Q-T interval prolongation of the ECG.

[0219] A second test involves administration of a compound as an infusion to pentobarbital anesthetized rats in which the left ventricle is subjected to electrical square wave stimulation performed according to a preset protocol described in further detail below. This protocol includes the determination of thresholds for induction of extrasystoles and ventricular fibrillation. In addition, effects on electrical refractoriness are assessed by a single extra beat technique. In addition effects on blood pressure, heart rate and the ECG are recorded. In this test, sodium channel blockers produce the ECG changes expected from the first test. In addition, sodium channel blockers also raise the thresholds for induction of extrasystoles and ventricular fibrillation. Potassium channel blockade is revealed by increasing refractoriness and widening of the Q-T intervals of the ECG.

[0220] A third test involves exposing isolated rat hearts to increasing concentrations of a compound. Ventricular pressures, heart rate, conduction velocity and ECG are recorded in the isolated heart in the presence of varying concentrations of the compound. The test provides evidence for direct toxic effects on the myocardium. Additionally, selectivity, potency and efficacy of action of a compound can be ascertained under conditions simulating ischemia. Concentrations found to be effective in this test are expected to be efficacious in the electrophysiological studies.

[0221] A fourth test is estimation of the antiarrhythmic activity of a compound against the arrhythmias induced by coronary artery occlusion in anaesthetized rats. It is expected that a good antiarrhythmic compound will have antiarrhythmic activity at doses which have minimal effects on either the ECG, blood pressure or heart rate under normal conditions. [0222] All of the foregoing tests are performed using rat tissue. In order to ensure that a compound is not having effects which are only specific to rat tissue, further experiments are performed in dogs and primates. In order to assess possible sodium channel and potassium channel blocking action in vivo in dogs, a compound is tested for effects on the ECG, ventricular epicardial conduction velocity and responses to electrical stimulation. An anesthetized dog is subjected to an open chest procedure to expose the left ventricular epicardium. After the pericardium is removed from the heart a recording/stimulation electrode is sewn onto the epicardial surface of the left ventricle. Using this array, and suitable stimulation protocols, conduction velocity across the epicardium as well as responsiveness to electrical stimulation can be assessed. This information coupled with measurements of the ECG allows one to assess whether sodium and/or potassium channel blockade occurs. As in the first test in rats, a compound is given as a series of increasing bolus doses. At the same time possible toxic effects of a compound on the dog's cardiovascular system is assessed.

[0223] The effects of a compound on the ECG and responses to electrical stimulation are also assessed in intact, anesthetized monkeys (Macaca fascicularis). this preparation, a blood pressure cannula and ECG electrodes are suitably placed in an anesthetized monkey. In addition, a stimulating electrode is placed onto the right atria and/or ventricle, together with monophasic action potential electrode. As in the tests described above, ECG and electrical stimulation response to a compound reveal the possible presence of sodium and/or potassium channel blockade. The monophasic action potential also reveals whether a compound widens the action potential, an action expected of a potassium channel blocker. [0224] As another example, in connection with the mitigation or prevention of the sensation of pain, the following test may be performed. To determine the effects of a compound of the present invention on an animal's response to a sharp pain sensation, the effects of a slight prick from a 7.5 g weighted syringe fitted with a 23G needle as applied to the shaved back of a guinea pig (Cavia porcellus) is assessed following subcutaneous administration of sufficient (50 μl, 10 mg/ml) solution in saline to raise a visible bleb on the skin. Each test is performed on the central area of the bleb and also on its periphery to check for diffusion of the test solution from • the point of administration. If the test animal produces a flinch in response to the stimulus, this demonstrates the absence of blockade of pain sensation. Testing may be carried out at intervals for up to 8 hours or more post- administration. The sites of bleb formation are examined after 24 hours to check for skin abnormalities consequent to local administration of test substances or of the vehicle used for preparation of the test solutions.

Other Compositions [0225] The present invention also provides kits that contain a pharmaceutical composition which includes one or more compounds of the above formulae. The kit also includes instructions for the use of the pharmaceutical composition for modulating the activity of ion channels, for the treatment of aπhythmia or for the production of analgesia and/or local anesthesia, and for the other utilities disclosed herein. Preferably, a commercial package will contain one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be an amount sufficient for the preparation of an intravenous injection. It will be evident to those of ordinary skill in the art that compounds which are light and/or air sensitive may require special packaging and/or formulation. For example, packaging may be used which is opaque to light, and/or sealed from contact with ambient air, and/or formulated with suitable coatings or excipients. [0226] The following examples and those described above are offered by way of illustration and not by way of limitation. In these examples, and unless otherwise specified, starting materials were obtained from well-known commercial supply houses, e.g., Sigma- Aldrich Company, and were of standard grade and purity. "Ether" and "ethyl ether" each refers to diethyl ether; "h" refers to hours; "min" refers to minutes; "GC" refers to gas chromatography; "v/v" refers to volume per volume; and ratios are weight ratios unless otherwise indicated.

Example 1 [0227] 2-methyl-7-[(l -phenyl- 1 -cyclopropane)methyl]-7H-imidazo[ 1 ,2-a]pyrazin-8-one monohydrochloride (Compound 1) [0228] To a chilled (0°C) solution of 1 -phenyl- 1-cycloρroρanemethanol (1.6 g, 10.8 mmol) and triethylamine (1.8 mL, 13 mmol) in dichloromethane (20 mL) was added dropwise neat CH₃SO₂Cl (1 mL, 13 mmol). The reaction mixture was stirred at 0°C for 40 min and then was allowed to warm to r.t. and further stiπed for another 2 h. The reaction mixture was further diluted with dichloromethane (40 mL) and washed with water (30 mL). The aqueous layer was separated and extracted thrice more with dichloromethane (3 x 20 mL). The organic extracts were combined, dried over anhydr. MgSO₄ and concentrated in vacuo to yield quantitatively the corresponding activated alcohol. [0229] To NaH (324 mg, 10.8 mmol, 80% dispersion in oil, pre-washed with hexanes) in anhydrous DMF (15 mL) was added a solution of 2-methyl-7H-imidazo[l,2-a]pyrazin-8-one (1.35 g, 9.05 mmol) in anhydrous DMF (15 mL). The resultant slurry was stirred under Ar for 45 min and then a solution of the activated alcohol (i) in anhydrous DMF (10 mL) was added dropwise. The reaction mixture was subsequently heated to 60°C for 16 h. The cooled reaction mixture was partitioned between water (30 mL) and EtOAc (40 mL). The aqueous layer was separated and extracted thrice more with EtOAc (3 x 40 mL). The combined organic extracts were back-washed with brine (5 x 50 mL), dried over MgSO₄ and concentiated in vacuo to yield the crude title compound. Subsequent trituration in hexanes (3 x 20 mL) yielded 1.23 g of the title compound as a free base. The free base was dissolved in dichloromethane (40 mL) and then treated with a saturated solution of anhydrous hydrogen chloride in dichloromethane. The resultant solution was stiπed for 15 min and then concentiated in vacuo, trituration in diethyl ether-hexanes provided 1.2 g (42% yield) of the title compound. IR 1671 cm^"1; 'H-NMR (DMSO-d_tf) δ 7.87 (s, IH), 7.64 (d, J 5.8 Hz, IH), 7.24 - 7.10 (m, 5H), 7.07 (d, J 5.8 Hz, IH), 4.20 (s, 2H), 2.36 (s, 3H), 1.14 (m, 2H), 0.86 (m, 2H); MS (ESI) 280.0 ([M+H]⁺) [0230] Compounds 2-12 (Examples 2-12) were prepared following a similar procedure as the one described for the preparation of Compound 1 (Example 1):

Example 2 [0231] 7-(2,4-Dichlorophenethyl)-7H-2-methylimidazo[l,2-α]pyrazin-8-one monohydrochloride (Compound 2) [0232] IR 1657 cm^"1; 1H-NMR (DMSO-d₆) δ 7.85 - 7.30 (m, 6H), 4.22 (t, 2H), 3.14 (t, 2H), 2.39 (s, 3H); MS (ESI) 322.0 ([M+H]*)

Example 3 [0233] 7-[3-(2,4-Dichlorophenyl)proρyl]-7H-2-methylimidazo[ 1 ,2-α]pyrazin-8-one monohydrochloride (Compound 3) [0234] IR 1667 cm^"1; 1H-NMR (DMSO-d₆) δ 7.87 - 7.39 (m, 6H), 4.04 (t, 2H), 2.75 (t, 2H), 2.40 (s, 3H), 1.99 (t, 2H); MS (ESI) 336.0 ([M+H]⁺)

Example 4 [0235] 2-Methyl-7-(4-nitiophenethyl)-7H-imidazo[ 1 ,2-α]pyrazin-8-one monohydrochloride (Compound 4) [0236] IR 1664 cm^"1; 1H-NMR (DMSO- *) δ 8.19 - 7.37 (m, 7H), 4.26 (t, 2H), 3.17 (t, 2H), 2.40 (s, 3H); MS (ESI) 299.0 ([M+H]⁴)

Example 5 [0237] 2-Methyl-7-(2-trifluoromethylρhenethyl)-7H-imidazo[l,2-α]pyrazine monohydrochloride (Compound 5) [0238] IR 1661 cm^"1; 1H-NMR (DMSO-d₆) δ 7.87 - 7.37 (m, 7H), 4.24 (t, 2H), 3.19 (t, 2H), 2.41 (s, 3H); MS (ESI) 321.8 ([M+H]⁺) Example 6 [0239] 2,3-Dimethyl-7-[2,4-dichlorophenethyl]-7H-imidazo[l,2-a]ρyrazin-8-one monohydrochloride (Compound 6) [0240] IR 1657 cm^"1; 1H-NMR (DMSO-c ) δ 7.73 - 7.36 (m, 5H), 4.25 (m, 2H), 3.14 (m, 2H), 2.42 (s, 3H), 2.38 (s, 3H); MS (ESI) 338.0 ([M+H]⁺)

Example 7 [0241] 2,3-Dimethyl-7-[3-(2,4-dichlorophenyl)propyl]-7H-imidazo[l,2-a]pyrazin-8-one monohydrochloride (Compound 7) [0242] IR 1657 cm^"1; 1H-NMR (DMSO-d₆) δ 7.76 - 7.35 (m, 5H), 4.06 (m, 2H), 2.75 (m, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 2.00 (m, 2H); MS (ESI) 352.0 ([M+H] )

Example 8 [0243] 2,3-Dimethyl-7-(4-mtrophenethyl)-7H-imidazo[l,2-a]pyrazin-8-one monohydrochloride (Compound 8) [0244] IR 1665 cm^"1; 1H-NMR (DMSO-o ) δ 8.20 - 7.49 (m, 6H), 4.28 (t, 2H), 3.18 (t, 2H), 2.40 (s, 3H), 2.37 (s, 3H); MS (ESI) 313.0 ([M+H]⁺)

Example 9 [0245] 2,3-Dimethyl-7-(2-trifluoromethylphenethyl)-7H-imidazo[l,2-a]pyrazin-8-one monohydrochloride (Compound 9) [0246] IR 1666 cm^"1; 1H-NMR (OMSO-d₆) δ 7.72 - 7.47 (m, 6H), 4.27 (t, 2H), 3.19 (t, 2H), 2.42 (s, 3H), 2.38 (s, 3H); MS (ESI) 336.2 ([M+H]^"1)

Example 10 [0247] 2,3-Dimethyl-7-[(l-phenyl-l-cyclopropane)methyl]-7H-imidazo[l,2-a]pyrazin-8- one monohydrochloride (Compound 10) [0248] IR 1665 cm^-1; 1H-NMR (DMSO-d₆) δ 7.60 - 7.15 (m, 7H), 4.25 (m, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 1.17 (m, 2H), 0.88 (m, 2H); MS (ESI) 294.0 ([M+H]⁺) Example 11 [0249] 7-(2,2-Diphenylethyl)-7H-2-methylimidazo[ 1 ,2-a]pyrazin-8-one monohydrochloride (Compound 11) [0250] IR 1666 cm^"1; 1H-NMR (DMSO-d₆) δ 7.70 - 7.00 (m, 13H), 4.63 (m, 3H), 2.34 (s, IH); MS (ESI) 330.0 ([M+H]*)

Example 12 [0251] 2,3-Dimethyl-7-(2,2-diphenylethyl)-7H-imidazo[ 1 ,2-a]pyrazin-8-one monohydrochloride (Compound 12) [0252] IR 1666 cm^"1; 1H-NMR (DMSO-d₆) δ 7.40 - 7.22 (m, 12H), 4.70 (m, 2H), 4.68 (m, IH), 2.34 (s, 6H); MS (ESI) 344.2 ([M+H]^"1)

Example 13 [0253] 3-Bromo-2-methyl-7-[(l -phenyl- 1 -cyclopropane)methyl]-7H-imidazo[ 1 ,2- α]pyrazin-8-one (Compound 13) [0254] 2-methyl-7-[(l -phenyl- 1 -cyclopropane)methyl]-7H-imidazo[ 1 ,2-α]pyrazin-8-one monohydrochloride (0.2 g, 0.63 mmol) was partitioned between 2M NaHCO₃ aq (30 mL) and dichloromethane (30 mL). The aqueous layer was separated and extracted once more with dichloromethane (30 mL). The combined organic extracts were dried over sodium sulfate and concentiated in vacuo to yield the free base suitable for the next step. [0255] The free base was subsequently dissolved in ethanol (25 mL) and N- bromosuccinimide (125 mg, 0.70 mmol) was added, then the resultant mixture was stiπed at room temperature for 2 h. The solvent was evaporated in vacuo and the residue was partitioned between water (30 mL) and dichloromethane (30 mL). The organic layer was collected, dried over sodium sulfate and concentrated in vacuo. The crude material was purified using dry column chromatography with eluant mixtures of EtOAC-hexanes (1:4, 1:2, 1:1, v/v, + 0.5% v/v /PrΝH₂) to yield 170 mg (68% yield) of the title compound. IR 1673 cm^"1; 1H-NMR (CDC1₃) δ 7.23 (m, 5H), 6.71 (d, J6Hz, IH), 6.11 (d, J6Hz, IH), 4.16 (s, 2H), 2.37 (s, 3H), 1.20-0.90 (m, 4H); MS (ESI) 358.2 ([M+H]⁺) [0256] Compounds 14-35 (Examples 14-35) were prepared following a similar procedure as the one described for the preparation of Compound 1 (Example 1):

Example 14 [0257] 2-Methyl-7-[(l-(4-trifluoromethyl-phenyl)-l-cyclopropane)methyl]-7H- imidazo[l,2-a]pyrazin-8-one monohydrochloride (Compound 14) [0258] IR 1664 cm^"1; 1H-NMR (DMSO-d₆) δ 7.90 (s, IH), 7.69 (d, J 5.8 Hz, IH), 7.57 (d, J 8 Hz, 2H), 7.47 (d, J8 Hz, 2H), 7.18 (d, J5.8 Hz, IH), 4.25 (s, 2H), 2.37 (s, 3H), 1.22 (m, 2H, CH₂), 0.92 (m, 2H, CH₂); MS (ESI) 348.0 ([M+H]⁺)

Example 15 [0259] 2-Isopropyl-7-[(l-phenyl-l-cyclopropane)methyl]-7H-imidazo[l,2-a]pyrazin-8- one (Compound 15) [0260] IR 1641cm^"1 (vC=O); 1H-NMR (CDC1₃) δ 7.24 - 7.18 (m, 5H), 6.99 (s, IH), 6.68 (d, J5.8 Hz, IH), 5.97 (d, J5.8 Hz, IH), 4.14 (s, 2H), 3.03 (qt, J6.9 Hz, IH), 1.31 (d, J6.9 Hz, 6H), 1.21-1.18 (m, 2H), 0.92-0.88 (m, 2H); MS (ESI) 308.1 ([M+H]⁺)

Example 16 [0261] 2-Isopropyl-7-[(l-(3,5-bis-trifluoromethyl-phenyl)-l-cyclopropane)methyl]-7H- imidazo[l,2-α]pyrazin-8-one monohydrochloride (Compound 16) [0262] IR 1687 cm^"1 (vC=O); 1H-NMR (DMSO-d₆) δ 7.92 (m, 4H), 7.64 (d, J 5.8 Hz, IH), 7.20 (d, J5.8 Hz, IH), 4.25 (s, 2H), 3.04 (qt, J6.9 Hz, IH), 1.26-0.99 (m, 10H); MS (ESI) 444 ([M+H]⁺)

Example 17 [0263] 2-Methyl-7-[(l-(3,5-bis-trifluoromethyl-phenyl)-l-cyclopropane)methyl]-7H- imidazo[l,2-α]pyrazin-8-one monohydrochloride (Compound 17) [0264] IR 1642 cm^"1 (vC=O); 1H-NMR (CD₃OD-^) δ 7.87 - 7.81 (m, 4H), 7.61 (d, J5.9 Hz, IH), 7.23 (d, J5.9 Hz, IH), 4.33 (s, 2H), 2.47 (s, 3H), 1.34 - 1.30 (m, 2H), 1.10 - 1.06 (m, 2H); MS (ESI) 416.0 ([M+H]⁺)

Example 18 [0265] 2-Trifluorome%l-7-[(l-(4-trifluoromethylphenyl)-l-cycloρroρane)methyl]-7H- imidazo[l,2-α]pyrazin-8-one monohydrochloride (Compound 18) [0266] IR 1641 cm^"1 (vC=O); 1H-NMR (DMSO- ) δ 8.38 (s, IH), 7.61 - 7.58 (m, 2H), 7.49_7.45 (m, 3H), 6.94 (d, J6.0 Hz, IH), 4.22 (s, 2H), 1.18 - 1.20 (m, 2H), 0.89 - 0.94 (m, 2H); MS (ESI) 402.2 ([M+H] )

Example 19 [0267] 8-Oxo-7-[(l-phenyl-l-cyclopropane)methyl]-2-trifluoromethyl-7,8-dihydro- imidazo[l,2-α]pyrazine-3-carboxylic acid ethyl ester (Compound 19) [0268] IR 1685 cm^"1 (vC=O); ¹H-NMR_! (CDC1₃) δ 7.87 (d, J6.1 Hz, IH), 7.24 (m, 5H), 6.25 (d, J 6.1 Hz, IH), 4.42 (q, J 7.1 Hz, 2H), 4.20 (s, 2H), 1.39 (t, J 7.1 Hz, 3H), 1.22 - 1.18 (m, 2H), 0.98 - 0.94 (m, 2H); MS (ESI) 406.01 ([M+H]^"")

Example 20 [0269] 7-[(l-Phenyl-l-cyclopropane)methyl]-2-trifluoromethyl-7H-imidazo[l,2- β]pyrazin-8-one (Compound 20) [0270] IR 1677 cm^"1, 1643 cm^"1 (vC=O); 1H-NMR (CD₃OD-^) δ 8.09 (d, IH, J 0.9 Hz), 7.30 - 7.18 (m, 6H), 6.64 (d, IH, J 5.9 Hz), 4.20 (s, 2H), 1.18 - 1.14 (m, 2H), 0.95 - 0.91 (m, 2H); MS (ESI) 334.0 ([M+H]^"")

Example 21 [0271] 7-[3-(5-Chloro-indol- 1 -yl)-ρroρyl]-2-trifluoromethyl-7H-imidazo[ 1 ,2-α]ρyrazin- 8-one (Compound 21) [0272] IR 1677 cm^"1, 1643 cm^"1 (vC=O); 1H-NMR. (OMSO-d₆) δ 8.38 (s, IH), 7.57 - 7.47 (m, 4H), 7.20 (d, J 5.9 Hz, IH), 7.10 (dd, J8.7 Hz & J 1.6 Hz, IH), 6.41 (d, J 2.9 Hz, IH), 4.24 (t, J7.1 Hz, IH), 3.93 (t, J7.0 Hz, 2H), 2.14 (qt, J7.1 Hz, IH); MS (ESI) 394.9 ([M+H]⁺)

Example 22 [0273] 7-[3-(5-Chloro-indol- 1 -yl)-propyl]-2-methyl-7H-imidazo[ 1 ,2-ajpyr azin-8-one (Compound 22) [0274] IR 1682 cm^"1, 1650 cm^"1 (vC=O); 1H-NMR (CDC1₃) δ 7.82 (s, IH), 7.70 (d, J5.8 Hz, IH), 7.55 (d, J 1.8 Hz, IH), 7.50 (d, J8.8 Hz, IH), 7.47 (d, J3.1 Hz, IH), 7.38 (d, J5.8 Hz, IH), 7.10 (dd, J 1.9 & 8.7 Hz, IH), 6.38 (d, J2.7 Hz, IH), 4.22 (t, J7.1 Hz, 2H), 3.97 (t, J 6.9 Hz, 2H), 2.37 (s, 3H), 2.17 (qt, J7.0 Hz, 2H); MS (ESI) 341.3 ([M+H] )

Example 23 [0275] N- {4-[ 1 -(2-Isopropyl-8-oxo-8H-imidazo[ 1 ,2- ]pyrazin-7-ylmethyl)-cyclopropyl]- phenyl}-bis-methanesulfonamide (Compound 23) [0276] IR 1676 cm^"1 (vCO), 1371 & 1164 cm^"1 (vS=O); 1H-NMR (CDC1₃) δ 7.37 - 7.34 (m, 2H), 7.24 - 7.21 (m, 2H), 7.01 (s, IH), 6.70 (d, J5.8 Hz, IH), 5.92 (d, J5.8 Hz, IH), 4.14 (s, 2H), 3.38 (s, 6H), 3.10 - 2.97 (qt, J 6.9 Hz, IH), 1.31 (d, J 6.9 Hz, 6H), 1.27 - 1.23 (m, 2H), 0.97-0.92 (m, 2H); MS (ESI) 479.2 ([M+H]⁺)

Example 24 [0277] 2-Methyl-8-oxo-7-[(l -phenyl-1 -cyclopropane)methyl]-7,8-dihydro-imidazo[ 1 ,2- α]pyrazine-3-carboxylic acid ethyl ester (Compound 24) [0278] IR 1678 cm^"1 (vC=O); 1H-NMR (CDC1₃) δ 7.82 (d, J6.0 Hz, IH), 7.24 - 7.21 (m, 5H), 6.13 (d, J 6.0 Hz, IH), 4.38 (q, J7.1 Hz, 2H), 4.18 (s, 2H), 2.63 (s, 3H), 1.39 (t, J7.1 Hz, 3H), 1.21 - 1.17 (m, 2H), 0.95 - 0.91 (m, 2H); MS (ESI) 352.0 ([M+H]⁺)

Example 25 [0279] 2-Methyl-8-oxo-7-[(l-(4-trifluoromethyl-phenyl)-l-cyclopropane)methyl]-7,8- dihydro-imidazo[l,2-<z]pyrazine-3-carboxylic acid ethyl ester (Compound 25) [0280] IR 1679 cm^"1 (vC=O); 1H-NMR (CDC1₃) δ 7.88 (d, J6.0 Hz, IH), 7.50 (d, J 8.0 Hz, 2H), 7.36 (d, J8.0 Hz, 2H), 6.21 (d, J6.0 Hz, IH), 4.38 (q, J7.1 Hz, 2H), 4.22 (s, 2H), 2.63 (s, 3H), 1.39 (t, J7.1 Hz, 3H), 1.26-1.23 (m, 2H), 0.98 - 0.94 (m, 2H); MS (ESI) 420.0 ([M+H]⁺)

Example 26 [0281] 7-[(l-(6-Chloro-l-methyl-lH-indol-3-yl)-l-cycloρropane)methyl]-2- trifluoromethyl-7H-imidazo[l,2-a]pyrazin-8-one (Compound 26) [0282] 1H-NMR (CDCI3) δ 7.56 (m, 2H), 7.20 - 7.10 (m, 2H), 6.78 (s, IH), 6.68 (d, J5.8 Hz, IH), 6.05 (d, J 5.8 Hz, IH), 4.17 (s, 2H), 3.66 (s, 3H), 1.23 - 1.20 (m, 2H), 0.86 - 0.83 (m, 2H); MS (ESI) 420.9 ([M+H]^"*)

Example 27 [0283] 7-[2-(6-Chloro-l-methyl-lH-indol-3-yl)-ethyl]-2-trifluoromethyl-7H- imidazo[l,2-α]pyrazin-8-one (Compound 27) [0284] 1H-NMR (CDCI3) δ 7.61 (m, IH), 7.49 (m, IH), 7.21 - 7.13 (m, 2H), 6.88 (d, J 5.8 Hz, IH), 6.85 (s, IH), 6.37 (d, J5.8 Hz, IH), 4.22 (t, J6.9 Hz, 2H), 3.69 (s, 3H), 3.16 (t, J 6.9 Hz, 2H); MS (ESI) 394.9 (|M+H]^' )

Example 28 [0285] 7-[(l-(4-Chloro-phenyl)-l-cycloρropane)methyl]-2-methyl-7H-imidazo[l,2- α]pyrazin-8-one monohydrochloride (Compound 28) [0286] IR 1691 & 1656 cm^"1 (vC=O); 1H-NMR (CD₃OD-^) δ 7.79 (s, IH), 7.52 (d, J5.9 Hz, IH), 7.31 - 7.18 (m, 4H), 7.02 (d, J 5.9 Hz, IH), 4.24 (s, 2H), 2.49 (d, J 0.9 Hz, 3H), 1.21 (dd, J6.4 & 4.8 Hz, 2H), 0.95 (dd, J6.1 & 4.6 Hz, 2H); MS (ESI) 314.0 ([M+H]^"*)

Example 29 [0287] 3-Bromo-7[-(l-phenyl-l-cyclopropane)methyl]-7H-imidazole[l,2-α]pyrazin-8- one (Compound 29) [0288] IR 1672 & 1632 cm^"1 (vC=O); 1H-NMR (CD₃OD-^) δ 7.50 (s, IH), 7.30 - 7.13 (m, 5H), 7.16 (d, J 6.0 Hz, IH), 6.69 (d, J 6.0 Hz, IH), 4.21 (s, 2H), 1.16 (dd, J 6.3 & 4.7 Hz, 2H), 0.93 (dd, J 5.9 & 4.4 Hz, 2H); MS (ESI) 343.9 ([M+H]⁺), 345.9 ([M+H]⁺²), 346.9 ([M+H]⁺³)

Example 30 [0289] 7-[3-(5-Chloro-indol-l-yl)-ρroρyl]-8-oxo-2-trifluoromethyl-7,8-dihydro- imidazo[l,2-α]pyrazine-3 -carboxylic acid ethyl ester (Compound 30) [0290] IR 1680 & 1645 cm^"1 (vC=O); 1H-NMR (DMSO-^) δ 7.89 (d, J 6.1 Hz, IH), 7.56 (d, J 1.9 Hz, IH), 7.51 (d, J8.8 Hz, IH), 7.47 (d, J3.1 Hz, IH), 7.39 (d, J6.1 Hz, IH), 7.10 (dd, J2.0 & 8.7 Hz, IH), 6.40 (dd, J0.5 & 3.1 Hz, IH), 4.41 (q, J7.1 Hz, IH), 4.25 (t, J7.0 Hz, 2H), 3.99 (t, J 7.0 Hz, 2H), 2.18 (qt, J 7.1 Hz, 2H), 1.33 (t, J 7.1 Hz, 3H); MS (ESI) 466.9 ([M+H] )

Example 31 [0291] 3-Bromo-7-[3-(5-chloro-indol-l-yl)-propyl]-7H-imidazo[l,2- ]pyrazin-8-one (Compound 31) [0292] 1H-NMR (CDC1₃) δ 7.56 (d, J 1.9 Hz, IH), 7.51 (s, IH), 7.21 - 7.10 (m, 3H), 6.98 (d, J 5.9 Hz, IH), 6.46 (d, J 5.9 Hz, IH), 6.41 (dd, J3.1 & 0.6 Hz, IH), 4.21 (t, J6.7 Hz, 2H), 3.92 (t, J 7.1 Hz, 2H), 2.32 (qt, J 7.1 Hz, 2H); MS (ESI) 404.8 ([M+H]^"1), 406.8 ([M+H]⁺²), 408.8 ([M+H]⁺³)

Example 32 [0293] 3-Bromo-7-phenethyl-7H-imidazo[l,2-«]pyrazin-8-one (Compound 32) [0294] 1H-NMR (CDC1₃) δ 7.50 (s, IH), 7.29 - 7.15 (m, 5H), 6.92 (d, J5.9 Hz, IH), 6.38 (d, J5.9 Hz, IH), 4.17 (t, J7.1 Hz, 2H), 3.05 (t, J7.1 Hz, IH); MS (ESI) 317.9 ([M+H]⁺), 319.9 ([M+H]⁺²)

Example 33 [0295] 8-Oxo-2-trifluoromethyl-7-[(l-(4-trifluoromethyl-phenyl)-l- cyclopropane)methyl]-7,8-dihydro-imidazo[l,2-α]pyrazine-3-carboxylic acid ethyl ester

(Compound 33) [0296] TR 1680 & 1636 cm^"1 (vO=O); 1H-NMR (CDC1₃) δ 7.94 (d, J 6.1 Hz, IH), 7.52 (d, J 8.1 Hz, 2H), 7.37 (d, J 8.0 Hz, 2H), 6.32 (d, J6.1 Hz, IH), 4.41 (q, J7.2 Hz, 2H), 4.23 (s, 3H), 1.39 (t, J7.1 Hz, 3H), 1.28 - 1.23 (m, 2H), 1.00 - 0.97 (m, 2H); MS (ESI): 473.9 ([M+H]*)

Example 34 [0297] 2-(4-Methoxy-phenyl)-7-[(l-(4-trifluoromethyl-phenyl)-l-cyclopropane)methyl]- 7H-imidazo[l,2-α]pyrazin-8-one (Compound 34) [0298] IR 1685 & 1650 cm^"1 (vC=O); 1H-NMR (DMSO-d₆) δ 8.17 (s, IH), 7.82 (d, J8.7 Hz, 2H), 7.58 (d, J 8.1 Hz, 2H), 7.49 - 7.47 (m, 3H), 7.01 (d, J 8.8 Hz, IH), 6.89 (d, J 5.8 Hz, IH), 4.23 (s, 2H), 3.77 (s, 3H), 1.22 - 1.19 (m, 2H), 0.93 - 0.91 (m, 2H); MS (ESI) 440.0 ([M+H] )

Example 35 [0299] 7-[3-(5-Nitro-indol-l-yl)-proρyl]-2-trifluoromethyl-7H-imidazo[l,2-α]ρyrazin-8- one (Compound 35) [0300] IR 1677 & 1644 cm^"1 (vC=O); 1H-NMR (DMSO-d₆) δ 8.55 (d, J2.2 Hz, IH), 8.38 (d, J 1.1 Hz, IH), 8.00 (dd, J2.3 & 9.1 Hz, IH), 7.72 - 7.68 (m, 2H), 7.54 (d, J5.9 Hz, IH), 7.21 (d, J5.9 Hz, IH), 6.74 (d, J3.1 Hz, 2H), 4.34 (t, J7.2 Hz, 2H), 3.94 (t, J7.0 Hz, 2H), 2.18 (qt, J 7.1 Hz, 2H); MS (ESI) 406.0 ([M+H]⁴)

Example 36 : Assessment of Antiarrhythmic Efficacy [0301] Antiarrhythmic efficacy may be assessed by investigating the effect of a compound on the incidence of cardiac aπhythmias in anesthetized rats subjected to coronary artery occlusion. Rats weighing 200-300 gm were subjected to preparative surgery and assigned to groups in a random block design. In each case, the animal was anesthetized with pentobarbital during surgical preparation. The left carotid artery was cannulated for measurement of mean arterial blood pressure and withdrawal of blood samples. The left jugular vein was also cannulated for injection of drugs. The thoracic cavity was opened and a polyethylene occluder was loosely placed around the left anterior descending coronary artery. The thoracic cavity was then closed. An ECG was recorded by insertion of electrodes placed along the anatomical axis of the heart. In a random and double-blind manner, an infusion of vehicle or the compound to be tested was given about 15 min post-surgery. After 5 minutes infusion, the occluder was pulled so as to produce a coronary artery occlusion. ECG, arrhythmias, blood pressure, heart rate and mortality were monitored for 15 minutes after occlusion. Aπhythmias were recorded as ventricular tachycardia (NT) and ventricular fibrillation (VF) and scored according to Curtis, M.J. and Walker, M.J.A., Cardiovasc. Res. 22:656 (1988) (see Table 1).

Table 1

Where: VPB = ventricular premature beats VT = ventricular tachycardia VF = ventricular fibrillation [0302] Rats were excluded from the study if they did not exhibit pre-occlusion serum potassium concentrations within the range of 2.9-3.9 mM. Occlusion was associated with increases in R-wave height and "S-T" segment elevation; and an occluded zone (measured after death by cardiogreen dye perfusion) in the range of 25%-50% of total left-ventricular weight. [0303] Results of the test compounds may be expressed as values of a given infusion rate in micromol/kg/min. (ED₅₀AA) which will reduce the arrhythmia score in treated animals to 50% of that shown by animals treated only with the vehicle in which the test compound(s) is dissolved. [0304] Compounds of the present invention were shown to be efficacious in the antiaπhythmic efficacy model. Example 37: Measurement of Cardiovascular and Behavioral Effects [0305] Preparative surgery was performed in Sprague Dawley rats weighing 200-300 gm and anaesthetized with 65mg/kg (i.p.) pentobarbital. The femoral artery and vein were cannulated using polyethylene (PE)-10 tubing. Prior to surgery, this PE-10 tubing had been annealed to a wider gauge (PE-50) tubing for externalization. The cannulated PE-lO/PE-50 tubing was passed through a trocar and exteriorised together with three (lead H) limb ECG leads (see below). The trocar was threaded under the skin of the back and out through a small incision at the mid-scapular region. A ground ECG electrode was inserted subcutaneously using a 20 gauge needle with the lead wire threaded through it. To place the other ECG electrodes, a small incision was made in the anterior chest region over the heart and ECG leads were inserted into the subcutaneous muscle layer in the region of the heart using a 20 guage needle. Other ECG leads were inserted into the subcutaneous muscle layer in the region near the base of the neck and shoulder (right side). The animal was returned to a clean recovery-cage with free access to food and water. The tieatment and observational period for each animal commenced after a 24- hour recovery period. [0306] A 15 min observational period was recorded followed by the intravenous infusion regime of the test compound at an initial dose of 2.0μmol/kg/min (at 1 ml/hr). This rate was doubled every 5 minutes until one of the following effects is observed: a) partial or complete convulsions (seizures) b) severe arrhythmias c) bradycardia below 120 beats/min d) hypotension below 50mmHg e) the dose exceeds 32 times the initial starting dose (i.e. 64 μmol/kg/min). [0307] Blood pressure (BP), heart rate (HR) and ECG variables were continuously recorded while behavioral responses were also monitored and the total accumulative drug dose and drug infusion rate at which the response (such as convulsion, piloerection, ataxia, restlessness, compulsive chewing, lip-smacking, wet dog shake etc.) occuπed were recorded. In some experiments, pulmonary artery pressure (PAP) was also monitored via a further cannula in the pulmonary artery. Blood samples [0308] Estimates of plasma concentrations of the test compound were determined by removing a 0.5 ml blood sample at the end of the experiment. Blood samples were centrifuged for 5 min at 4600 x g and the plasma decanted. Brain tissue samples were also extiacted and kept frozen (-20°C) along with the plasma samples for chemical analysis.

Data Analysis [0309] Electrocardiograph (ECG) parameters: PR, QRS, QT_Ϊ (peak of T-wave), QT₂ (midpoint of T-wave deflection) and hemodynamic parameters: BP, PAP and HR were analyzed using the automated analysis function in Lab View (National Instruments) with a customized autoanalysis software (Nortran Pharmaceuticals). The infused dose producing 25% from contiol (D₂₅) for all recorded ECG variables was determined. [0310] Results of the tests can be expressed as D₂₅ (micromol kg) which are the doses required to produce a 25% increase in the ECG parameter measured. The increases in P-R interval and QRS interval indicate cardiac sodium channel blockade while the increase in Q-T interval indicates cardiac potassium channel blockade. Table 2

O 200

[0311] a) ST refers to the threshold for rate of infusion to induce seizures (in μmol/kg/min); cumulative refers to the cumulative dose infused immediately prior to seizure onset (in μmol/kg); BP refers to the infusion rate producing a 25% increase in BP [0312] b) PAP refers to pulmonary artery pressure; BP refers to systemic blood pressure;

HR refers to heart rate; QT refers to the QT interval; NS means the effect of the compound was not significant at the maximum dose (25 mg/kg), otherwise the value indicates the percentage increase (or decrease) in the parameter noted at 25 mg/kg; 45 μg kg phenylephrine produces a 28% and 80% increase in PAP and BP in this assay respectively. [0313] c) Data has not been collected

[0314] As shown in Table 2, the compounds exhibited varying degrees of CNS liability measured in a conscious rat behavioral assay. Compound 1 did not produce seizures in conscious rats at cumulative doses less than 182 μmol/kg. In an anaesthetized rat electrophysiological screen, compounds 1 and 13 produced significant increases in effective refractory period (SI -SI interval=133 ms) at an infusion rate equal to one half of the infusion rate producing convulsions in conscious rats (increases of 38%, 57% and 28% respectively). Despite the putative role of Kvl.5 in regulating pulmonary artery pressure, compounds 1, 13 and 14 did not significantly increase pulmonary artery pressure at 25 mg kg despite exerting potent effects upon the QT interval. Other hemodynamic parameters including heart rate (HR) and systemic blood pressure (BP) were decreased and increased respectively by compound 14. Compound 1 did not alter any hemodynamic parameters appreciably and compound 13 produced only a small increase in BP (13%). None of the compounds tested had any appreciable effect upon the action potential duration in rabbit Purkinje fibers.

[0315] Compounds 1 and 13 share relatively less CNS liability, reasonable efficacy in increasing rat ERP and have little-to-no hemodynamic effects. Example 38: Canine Atrial-tachvpacing Model [0316] Conditioned mongrel dogs were instrumented during a sterile procedure with a tined atrial pacing lead inserted in the right atrial appendage under fluoroscopic guidance. Custom- modified pacemakers (Medtronic) were attached to the pacing lead and inserted in a subcutaneous pocket in the neck. After 24 hr for recovery, the pacemaker was programmed to stimulate the atria at 400 bpm for 1 week. In addition, AV block was created with radiofrequency ablation and a ventricular pacemaker installed to pace the ventricles at 80 bpm, to eliminate any possibility of excessive ventricular response rates causing a ventricular cardiomyopathy in atrial tachycardic (AT) dogs. [0317] At the terminal study, dogs were brought to the electrophysiology lab and anaesthetized with morphine (2 mg/kg sc) and α-chloralose (120 mg/kg iv). The atrial pacemaker was then deactivated and removed. The experimental progression was the determination of right atrial effective refractory periods (RA ERP) and right ventricular ERP (RV ERP), AF inducibility in left atrium (LA) at baseline, following 2 mg kg (i.v. infused over 5 minutes) + 0.5 mg/kg/h of compound 1 and following 10 mg/kg + 2.5 mg/kg/h of compound 1 (Figure 1). The mean AF duration was compared to the control (CTL). In addition, the LA ERP was determined in unpaced group. Baseline determinations of atrial ERP were determined with Si-Si intervals of 240, 300 and 360 ms basic cycle lengths (BCL) with 3 replications at each BCL (2-times the diastolic threshold) and RV ERP were determined at 400, 600 and 1000 ms BCL. Once the RA ERP and RA ERP were determined, the AF vulnerable window was examined with extrastimuli delivered at LA with an Si - S₂ interval between RA ERP -10 ms and RA ERP +40 ms (BCL = 360 or 300 ms) increasing in 5 ms steps. AF is characterized by an iπegular undulating baseline, indiscernable P-waves and this activity must have a duration of at least 1 second. When the episode of AF lasted longer than 1 minute, it was terminated with cardioversion (between 100 and 200 joules). Induction of AF was repeated until 10 episodes of AF were reached or the entire vulnerable window had been probed 15 times. When an extrastimuli produced AF, the SrS₂ interval is reset to RA ERP -10 ms and the cycle begins again. In unpaced group, AF was induced 10 times with LA burst pacing (10 Hz, 4 ms, 4 times the diastolic threshold, over 10 seconds) and the duration of AF was monitored. [0318] For assessment of termination of more sustained AF, AF was induced with left atrial burst pacing (10 Hz, 4 ms, 4 times the diastolic threshold, over 10 seconds, Figure 1) and the duration of AF was monitored. When the duration of AF was greater than 10 minutes, we began infusion of compound 1 loading dose (2 mg kg over 5 minutes, i.v. Figure 2). The vehicle for compound 1 was DMSO/15% + saline/15% + PEG400/70%, then it was changed to ethanol/5% + saline/95%. AF was monitored and if it was not terminated within 15 minutes post- infusion, it was terminated with a biphasic shock. The tieated animals were compared to a control animal (CTL in Fig. 2). When the burst pacing did not induce sustained AF (>5 minutes) tried to induce it again, but only repeated the induction 3 times. When after 3 attempts, sustained AF was still not obtained, continued with the protocol. [0319] After the 5 minute loading dose, a maintenance infusion dose was delivered at 0.5 mg kg/hr. Ten minutes after AF termination RA ERP, RV ERP and AF induction parameters were then measured in the same manner as described for the baseline determinations. Sustained AF was once again induced with burst pacing in the same manner as described for the 2 mg kg loading dose and if sustained (> 10 minutes), a loading dose of 10 mg/kg of compound 1 was infused (i.v., over 5 minutes). If AF was not terminated within 15 minutes post-infusion, terminated it with biphasic shock. After the 5-minute loading dose a continuous maintenance infusion dose of 2.5 mg/kg hr was then infused and the ERP and AF induction determinations were repeated, beginning 10 minutes after AF termination as described above. Statistical analysis: Student's t-test was used to compare results under control vs drug conditions. [0320] One dog died before drug administration B236 with 15 days atrial tachy-pacing, died by non-synchronized internal shock). Only one dog (B222) had sustained AF (>10 minutes), which was not terminated' within 15 minutes post-infusion of the highest dose of drug (10+2.5), was terminated with biphasic shock (200 J). Two other dogs (B261 and B290) had short-lasting AF (mean+SE, 18.6+5.2 s) that was not significantly affected by drug (Compound 1 2+0.5: 8+8 s, p=0.165; Compound 1 10+2.5: 7±7 s, p=0.087; Figure 2). In these dogs the percentage of occuπences of induced AF (AF vulnerability window; baseline: 91+9%) was not significantly affected by drug (Compound 1 2+0.5: 50±50%, p=0.5; Compound 1 10+2.5: 54.5±45.5%, p=0.5, Figure 3, compared to the control "CTL"). Figure 4 shows effects on right atrial ERP. Compound 1 increased right atrial ERP, with significant effect at the highest dose at BCL of 300 ms (p<0.05). [0321] Compound 1 showed clear efficacy against AF and atrial selectivity in AT dogs. No clear changes were seen in control dogs. Based on these results, additional dogs may be added to ensure analyzable data for increased significance of end-points.

Example 39: In Vitro Assessment of Inhibitory Activity of Ion Channel Modulating Compounds on Different Cardiac Ionic Currents

Cell culture: [0322] The relevant cloned ion channels (e.g. cardiac hHlNa, Kvl.4, Kvl.5, Kv4.2, Kv2.1, HERG etc.) were studied after stable tiansfection into HEK cells using the mammalian expression vector pCDNA3. Stable lines for each channel type were generated to allow individual study of the ion channel of interest. Solutions: [0323] For whole-cell recording the control pipette filling solution contained (in mM): KC1, 130; EGTA, 5; MgCl₂, 1; HEPES, 10; Na₂ATP, 4; GTP, 0.1; and was adjusted to pH 7.2 with KOH. The contiol bath solution contained (in mM): NaCl, 135; KCI, 5; sodium acetate, 2.8; MgCl₂, 1; HEPES, 10; CaCl₂, 1; and was adjusted to pH 7.4 with NaOH. The test ion channel modulating compound was dissolved to lOmM stock solutions in water and used at concentrations between 0.5 and lOOμM. Electrophysiological procedures: [0324] Coverslips containing cells were removed from the incubator before experiments and placed in a superfusion chamber (volume 250 μL) containing the control bath solution at 22°C to 23°C. All recordings were made via the variations of the patch-clamp technique, using an Axopatch 200 A amplifier (Axon Instruments, CA). Patch electrodes were pulled from thin- walled borosilicate glass (World Precision Instruments; FL) on a horizontal micropipette puller, fire-polished, and filled with appropriate solutions. Electrodes had resistances of 1.0-2.5 μohm when filled with control filling solution. Analog capacity compensation was used in all whole cell measurements. In some experiments, leak subtraction was applied to data. Membrane potentials were not coπected for any junctional potentials that arose between the pipette and bath solution. Data were filtered at 5 to 10 kHz before digitization and stored on a microcomputer for later analysis using the pClampδ software (Axon Instruments, Foster City, CA). Due to the high level of expression of channel cDNA's in HEK cells, there was no need for signal averaging. The average cell capacitance was quite small, and the absence of ionic cuπent at negative membrane potentials allowed faithful leak subtraction of data. Data analysis: [0325] The concentration-response curves for changes in peak and steady-state current produced by the test compound were computer-fitted to the Hill equation: f=l-l/[l+(IC₅₀[D])ⁿ] [1] where f is the fractional cuπent (f=Idrug Icontrol) at drug concentiation [D]; IC₅₀ is the concentration producing half-maximal inhibition and n is the Hill coefficient. [0326] Compounds of the present invention may be evaluated by this method. The results show that compounds of the present invention tested had a different degree of effectiveness in blocking various ion channels. Block was determined from the decrease in peak hHl Na⁺ cuπent, or in steady-state Kvl.5 and integrated Kv4.2 current in the presence of drug. To record Na⁺ current, cells were depolarized from the holding potential of -100 mV to a voltage of -30 mV for 10 ms to fully open and inactivate the channel. To record Kvl.5 and Kv4.2 cuπent, cells were depolarized from the holding potential of -80 mV to a voltage of +60 mV for 200 ms to fully open the channel. Cuπents were recorded in the steady-state at a range of drug concentrations during stimulation every 4 s. Reduction in peak current (Na⁺ channel), steady- state current (Kvl.5 channel) or integrated current (Kv4.2) at the test potential of -30 mV (Na⁺ channel) or +60 mV (Kvl.5 and Kv4.2 channel) was normalized to control cuπent, then plotted against the concentration of test compound. Data were averaged from 4 - 6 cells. Solid lines were fit to the data using a Hill equation. The IC₅₀ values in μM for some of the compounds of the present invention on various ion channels studied are summarized in the following table (Table 3): Table 3

[0327] The activity of other compounds of the present invention to modulate various ionic cuπents of interest may be similarly studied. [0328] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application is specifically and individually incorporated by reference.

[0329] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.

Claims

CLAIMSWe claim:

1. A method for modulating ion channel activity in a warm-blooded animal comprising admimstering to the warm-blooded animal in need thereof, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof:

(I) wherein, independently at each occurrence, n is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8; X is selected from a direct bond, -C(R₃)=CH-, and -C(R ,R₅)-Y-; Y is selected from a direct bond, O, S, and Cι-C alkylene;

R₂, R₁₅, R₁₆ and Rι₈ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, cyano, CHF₂, CH₂F, CF₃, C₂-C₇alkanoyloxy, Ci-Cβalkyl, C₃-C₈cycloalkyl, aryl, benzyl, CrCealkoxy, C₂-C₇alkoxycarbonyl, -Cβthioalkyl, CH N(R₁₃,R₁₄) and N(R₁₃,R₁₄) where Rj₃ and Rj are independently selected from hydrogen, acetyl, methanesulfonyl;

R₃ is selected from hydrogen, Ci-Cβalkyl, C₃-C₈cycloalkyl, aryl, and benzyl;

Rj, R and R₅ are independently selected from hydrogen, Cι-C₆alkyl, aryl and benzyl, or ₄ and R₅, when taken together with the carbon to which they are attached, may form a spiro C₃-C₆cycloalkyl; A is selected from C₅-C₁₂alkyl, a C₃-C₁₃carbocyclic ring, and ring systems selected from formulae (H), (IH), (TV), (V), (VI) and (VH):

(H) where Re, R and R₈ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C alkanoyloxy, d-Cealkyl, d-C₆alkoxy, C₂-C₇alkoxycarbonyl, d-Cethioalkyl, cyano, aryl and N(R₁₃,R₁ ) where R₁₃ and R₁₄ are independently selected from hydrogen, acetyl, methanesulfonyl, and d-Cealkyl;

(in) (IN) where R₁₀ and Rπ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C alkanoyloxy, d-Cealkyl, d-C₆alkoxy, C₂-C₇alkoxycarbonyl, d-Cethioalkyl, cyano, aryl and Ν(R₁₃,R₁₄) where R₁₃ and R₁₄ are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C₆alkyl;

(V) where R₁₂ is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C₂-C₇alkanoyloxy, d-C₆alkyl, Cι-C₆alkoxy, C₂-C₇alkoxycarbonyl, d-C_όthioalkyl, cyano, aryl and N(R₁₃,R₁₄) where R₁₃ and R₁ are independently selected from hydrogen, acetyl, methanesulfonyl, and d-Cealkyl; and Z is selected from CH, CH₂, O, N and S, where Z may be directly bonded to X when Z is CH or N, or Z may be directly bonded to R₉ when Z is N, and R₉ is selected from hydrogen, d-C₆alkyl, C₃-C₈cycloalkyl, aryl and benzyl;

(VI) (VH).

2. A method for modulating ion channel activity in vitro comprising administering an effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof.

3. The method of claims 1 or 2, wherein X is -C(R4,R₅)-Y-, and R and R₅, when taken together with the carbon to which they are attached, form a spiro C₃-C₆cycloalkyl.

4. A compound of formula (VIH) which is the same as the compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, with the proviso that compound of formula (VIH) cannot be a compound of the following formula (DC):

or a compound of the following formula (X):

5. A compound of claim 4, wherein X is -C(R₄,R₅)-Y-.

6. A compound of claim 5, wherein Y is a direct bond.

7. A compound of claim 6, wherein I _f and R₅, when taken together with the carbon to which they are attached, form a spiro C₃-C₆cycloalkyl.

8. A compound according to any one of claims 4-7, wherein A is selected from formula (H) and Re, R and R₈ are independently selected from bromine, chlorine, fluorine, hydrogen, hydroxy, trifluoromethyl, d-Cealkyl, d-C₆alkoxy, nitro, and N(R₁₃,R₁₄) where R₁₃ and Rι₄ are independently selected from hydrogen, acetyl, methanesulfonyl, and d-Cealkyl.

9. A compound according to any one of claims 4-8, wherein A is selected from formula (H) and Re, R₇ and R₈ are independently selected from hydrogen, and trifluoromethyl.

10. A compound according to any one of claims 4-9, wherein R , Rι₅, R₁₆ and R₁₈ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, nitro, cyano, CHF₂, CH₂F, CF₃, C -C₇alkanoyloxy, d-C₆alkyl, C₃-C₈cycloalkyl, aryl, benzyl, d-C₆alkoxy, and C₂-C₇alkoxycarbonyl.

11. A compound according to formula (I),

(I)

or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein independently in each occuπence, Ri, is independently selected from hydrogen, d-C₆alkyl, aryl and benzyl; R₂ is selected from the group consisting of hydrogen, d-C₆alkyl, and d-C₆ alkoxy; n is O, 1, 2, or 3; X is selected from a direct bond and -C(R4,Rs)-Y-; R and R₅ are independently selected from hydrogen, Cι-C₆ alkyl, aryl and benzyl, or R₄ and R₅, when taken together with the carbon to which they are attached, may form a spiro C₃-C₆cycloalkyl; Y is a direct bond; A is selected from formula (H) or formula (V), wherein Re, R , and R₈ are each independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, mtio, sulfamyl, trifluoromethyl, substituted or unsubstituted C_rC₆alkyl and N(Rι₃,Rι₄) where R₁₃ and R₁₄ are independently selected from hydrogen, acetyl, methanesulfonyl, and C_rC₆alkyl; Z is N, where N is directly bonded to R , and R₉ is hydrogen or C C₆alkyl; R₁₂ is selected from the group consisting of hydrogen, bromine, chlorine, fluorine, nitro, C_rC₆alkyl, and C_rC₆haloalkyl; R15 is selected from the group consisting of hydrogen, bromine, chlorine, fluorine, carboxy, C_rC₆ alkyl, C₂-C₇ alkanoyloxy; and R₁₆ and R,_s are hydrogen.

12. A compound according to formula (I),

(I)

or a pharmaceutically acceptable salt, ester, amide, complex, chelate, solvate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, wherein, independently in each occurrence, R] is hydrogen or phenyl; R₂ is selected from the group consisting of hydrogen, methyl, 2-isopropyl, trifluoromethyl, and methoxy; n is O, l, or 2; X is a direct bond or C(R₄, R₅), wherein R and R₅ are, in combination taken together with the carbon to which they are attached to form spiro C₃-cycloalkyl; A is formula (H) or (V), wherein Re, R , and R₈ are each independently selected from the group consisting of chloro, hydrogen, nitro, trichloromethyl, N(R13, R14), wherein R₁₃ and R₁₄ are each methane sulfanoyl; Z is N, where N is directly bonded to R₉, and R₉ is hydrogen or methyl; R₁₂ is selected from the group consisting of hydrogen, chlorine, nitro, and methyl; R₁₅ is selected from the group consisting of hydrogen, bromo, methyl, and ethanoyloxy; R₁₆ and Rj₈ are hydrogen.

13. A composition comprising a compound according to any one of claims 4-12.

14. The composition of claim 13 further comprising a pharmaceutically acceptable carrier, excipient or diluent.

15. Use of a compound according to any one of claims 4-12 or composition according to any one of claims 13-14 in a manufacture of a medicament.

16. A method for modulating ion channel activity in a warm-blooded animal comprising admimstering to a warm-blooded animal in need thereof, an effective amount of a compound according to any one of claims 4-12 or a composition of any one of claims 13-14.

17. A method for modulating ion channel activity in vitro comprising admimstering in vitro an effective amount of a compound according to any one of claims 4-12 or a composition of any one of claims 13-14.

18. A method for blocking or inhibiting the activity or conductance of ion channel in a warm-blooded animal comprising administering to the warm-blooded animal in need thereof, an effective amount of a compound of formula (T) as defined in claim 1 or a compound according to any one of claims 4-12 or a composition of any one of claims 13-14.

19. A method for blocking and/or inhibiting the activity and/or conductance of ion channel in an in vitro setting comprising administering in vitro an effective amount of a compound of formula (I) as defined in claim 1 or a compound according to any one of claims 4-12 or a composition of any one of claims 13-14.

20. The method of claims 1, 2, 3, 16, 17, 18, or 19 wherein said ion channel is a potassium channel.

21. The method of claim 20 wherein said potassium channel is a voltage-activated potassium channel.

22. The method of claim 21 wherein said voltage-activated potassium channel is responsible for Kvl .3, Kvl .5 or HERG cuπents.

23. The method of claims 1, 2, 3, 16, 17, 18, or 19 wherein said ion channel is responsible for one or more cardiac early repolarising cuπents comprising ionic cuπents which activate rapidly after membrane depolarisation and which effect repolarisation of the cell.

24. The method of claim 23 wherein said early repolarising currents comprise the cardiac transient outward potassium current (I_t0) and/or the ultiarapid delayed rectifier cuπent (fe_w)-

25. The method of claim 24 wherein the cardiac transient outward potassium current (I_to) and/or the ultiarapid delayed rectifier cuπent (fe_ur) comprise at least one of the Kv4.2, Kv4.3, Kv2.1, Kvl.4, Kvl.2 and Kvl.5 currents.

26. The method of claims 1, 2, 3, 16, 17, 18, or 19 wherein said ion channel is a cardiac potassium channel responsible for Kvl.5 cuπents.

27. The method of claims 1, 2, 3, 16, 17, 18, or 19 wherein said ion channel is responsible for one or more neuronal early repolarising cuπents comprising ionic cuπents which activate rapidly after membrane depolarisation and which effect repolarisation of the cell.

28. The method of claim 27 wherein the early repolarising cuπents comprise the neuronal transient outward potassium cuπent (IA) and/or the ultiarapid delayed rectifier cuπent (fe_w)-

29. The method of claim 28 wherein the neuronal transient outward potassium cuπent (I_A) and/or the ultiarapid delayed rectifier cuπent (feur) comprise at least one of the Kv4.2, Kv4.3, Kv2.1, Kvl.4, Kvl.2 and Kvl.5 cuπents.

30. The method of claims 1, 2, 3, 16, 17, 18, or 19 wherein said ion channel is a neuronal potassium channel responsible for Kvl.5 cuπents.

31. The method of claims 1, 2, 3, 16, 17, 18, or 19 wherein said ion channel is a sodium channel.

32. The method of claims 31 wherein said sodium channel is a voltage-activated sodium channel.

33. The method of claims 32 wherein said voltage-activated sodium channel is one of the Na_vl, Na_v2 or Na_v3 series.

34. The method of claims 33 wherein said sodium channel is a ligand-activated sodium channel.

35. The method of claims 31, 32, 33, or 34 wherein said sodium channel is a cardiac sodium channel.

36. The method of claims 31, 32, 33, or 34 wherein said sodium channel is a neuronal sodium channel.

37. The method of claims 31, 32, 33, or 34 wherein said sodium channel is a skeletal muscle sodium channel.

38. The method of claims 31, 32, 33, or 34 wherein said sodium channel is a central nervous system sodium channel.

39. The method of claims 31, 32, 33, or 34 wherein said sodium channel is a peripheral nervous system sodium channel.

40. A compound of formula (I) as defined in claim 1 ; or a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14; for use in a method for tieating or preventing aπhythmia in a warm-blooded animal in need thereof.

41. A compound of formula (I) as defined in claim 1; or a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14; for use in a method for treating or preventing atrial or supraventricular arrhythmia in a warm-blooded animal in need thereof.

42. A compound of formula (I) as defined in claim 1; or a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14; for use in a method for treating or preventing ventricular arrhythmia in a warm-blooded animal in need thereof.

43. A compound of formula (I) as defined in claim 1; or a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14; for use in a method for treating or preventing atrial fibrillation in a warm-blooded animal in need thereof.

44. A compound of formula (I) as defined in claim 1; or a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14; for use in a method for treating or preventing ventricular fibrillation in a warm-blooded animal in need thereof.

45. A compound of formula (I) as defined in claim 1; or a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14; for use in a method for treating or preventing atrial and/or ventricular flutter in a warm-blooded animal in need thereof.

46. A compound of formula (I) as defined in claim 1; or a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14; for use in a method for treating or preventing a disease or disorder from the group consisting of diseases of the central nervous system, amyotiophic lateral sclerosis, convulsion, cardiovascular diseases such as diseases caused by elevated blood cholesterol or triglyceride levels, cerebral or myocardial ischemias, hypertension, long-QT syndrome, stioke, migraine, ophthalmic diseases, diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis, paramyotonia congenita, malignant hyperthermia, hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmune disorders, graft rejection in organ transplantation, graft rejection in bone maπow transplantation, heart failure, hypotension, Alzheimer's disease, AJDS-related dementia, dementia, alopecia, sexual dysfunction, impotence, demyelinating diseases, multiple sclerosis, epileptic spasms, seizures, depression, insomnia, anxiety, schizophrenia, Parkinson's disease, trigeminal pain, phantom limb pain, back pain, smoke cessation, respiratory disorders, cystic fibrosis, asthma, cough, inflammatory disorders, arthritis, allergies, urinary incontinence, irritable bowel syndrome, Crohn's disease, prostatic hyperplasia, insect bites, psoriasis, diseases or dysfunctions of ion channels and receptors, diseases of voltage-gated ion channels, paralysis, gastrointestinal disorders such as gastrointestinal inflammation and ulcer in a warm-blooded animal in need of the tieatment or prevention.

47. A compound of formula (I) as defined in claim 1; or a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14; for use in a method for producing analgesia or local anesthesia in a warm-blooded animal in need thereof.

48. A method for producing analgesia or local anesthesia in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14.

49. A compound of formula (I) as defined in claim 1; or a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14; for use in a method for enhancing libido in a warm-blooded animal in need thereof.

50. A compound of formula (I) as defined in claim 1; or a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14; for use in a method for treating or preventing atrial contractile dysfunction in a warm-blooded animal in need thereof.

51. A method for treating or preventing atrial contractile dysfunction in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of a compound according to any one of claims 4-12; or a composition according to any one of claims 13- 14.

52. A method for treating or preventing arrhythmia in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14.

53. A method for tieating or preventing atrial or supraventricular arrhythmia in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amoimt of a compound according to any one of claims 4-12; or a composition according to any one of claims 13- 14.

54. A method for treating or preventing ventricular arrhythmia in a warm-blooded animal, comprising administering to a warm-blooded ammal in need thereof an effective amount of a compound according to any one of claims 4-12; or a composition according to any one of claims 13-

14.

55. A method for treating or preventing atrial fibrillation in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of a compound according to any one of claims 4-12; or a composition according to any one of claims 13-14.

56. A method for treating or preventing ventricular fibrillation in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of a compound according to any one of claims 4-12; or a composition according to any one of claims 13- 14.

57. A method for treating or preventing atrial and/or ventricular flutter in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of a compound according to any one of claims 4-12; or a composition according to any one of claims 13-

14.