HK1105868A - Benzofuranyl derivatives useful for the treatment of cardiac arrhythmia - Google Patents

Description

Novel compounds for treating cardiac arrhythmias and methods of use thereof

Cross reference to related applications

This patent application claims priority from U.S. provisional application No. 60/560,917 filed on 4/9/2004.

Technical Field

The present invention relates to the field of arrhythmia therapy, and in particular to novel compounds and related methods useful in such therapy.

Background

Congestive Heart Failure (CHF) is a disease that affects approximately 2% of the U.S. population (Sami, M.H. [1991] J.Clin.Pharmacol.31: 1081). Despite advances in the diagnosis and treatment of CHF, the prognosis remains poor, with mortality rates of greater than 50% 5 years from the time of diagnosis (McFate Smith, W. [1985] am. J. Cardiol.55: 3A; McKee, P.A., W.P.Castelli, P.M.McNamara, W.B.Kannel [1971] N.Engl. J.Med.285: 1441). In patients with CHF, the survival rate is lowest for patients with severely reduced left ventricular function and frequent episodes of ventricular arrhythmias. Patients with ventricular arrhythmias and ischemic cardiomyopathy have an increased risk of sudden death. Sudden death rates are three times higher in severe CHF patients with ventricular tachycardia than in severe CHF patients without tachycardia (Bigger, J.T., Jr. [1987] Circulation75(Supplement IV): 28). Because of the high incidence of sudden unexpected death in CHF patients, there is increasing interest in the prognosis of these patients for arrhythmias.

Although several compounds have been used to treat arrhythmias in patients with congestive heart failure, unfortunately, anti-arrhythmic drug therapy has been disappointing. Due to the decreased left ventricular function, the efficacy of antiarrhythmic drugs is significantly reduced, and only a small fraction of CHF patients respond to antiarrhythmic therapy. None of the antiarrhythmic drugs prevents sudden death in patients with CHF. Some antiarrhythmic drugs even result in increased mortality (the CAST investimators [1989] N.Engl.J.Med.321: 406).

Scientists believe that tachycardia and ventricular fibrillation have a variety of properties. Reentry is the fundamental mechanism of most persistent arrhythmias, which now appears to be well established and is recognized in the art. Therefore, prolonged ventricular repolarization, a method of preventing ventricular arrhythmias, is attracting attention again. This indicates that class III drugs may be selected for the treatment of arrhythmias. The class III drugs referred to herein are those in the Vaughan-Williams antiarrhythmic drug classification. Class III antiarrhythmic drugs extend the Effective Refractory Period (ERP) by extending the cardiac Action Potential Duration (APD), exerting major antiarrhythmic activity without affecting conduction. These electrophysiological changes, caused by blocking the cardiac potassium channels, are well known in the art. Class III antiarrhythmics are particularly attractive for use in CHF patients because blocking the cardiac potassium channels does not reduce the contractile capacity of the heart. Unfortunately, the use of existing class III drugs has been limited due to additional pharmacological activity, lack of good oral bioavailability, or poor toxicological properties. Currently only two class III drugs are marketed, brotylamine (for intravenous injection only) and amiodarone (intravenous and oral).

Amiodarone is an antiarrhythmic drug with vasodilating action, which may be beneficial for patients with severe heart failure. Amiodarone was shown to improve survival in patients after myocardial infarction with asymptomatic high-grade ventricular arrhythmias and proved effective in patients resistant to other antiarrhythmic drugs without compromising left ventricular function. The use of cardioprotective agents and methods of using amiodarone in combination with vasodilators and beta blockers in patients with coronary insufficiency has been described (U.S. patent No. 5,175,187). Further data describes amiodarone which, in combination with antihypertensive agents such as (S) -1- [ 6-amino-2- [ [ hydroxy (4-phenylbutyl) phosphinyl ] oxyl ] -L-proline (U.S. Pat. No. 4,962,095) and zofenopril (U.S. Pat. No. 4,931,464), reduces arrhythmias associated with CHF. Amiodarone, however, is a difficult drug to administer because it has many side effects, some of which are severe.

The most severe long-term toxicity of amiodarone comes from its distribution and elimination kinetics. It has slow absorption, low bioavailability and long half-life. These properties have clinically significant effects, including the need to administer a loading dose, delayed achievement of full antiarrhythmic effect, and prolonged clearance of the drug after withdrawal.

Amiodarone also has a negative interaction with many drugs including aprepidine, digoxin, flecainide, phenytoin, procainamide, quinidine, and warfarin. It also has pharmacodynamic interactions with catecholamines, diltiazem, propranolol and quinidine, leading to alpha and beta antagonism, sinus and hypotension, bradycardia and sinus arrest, and torsades de pointes and ventricular tachycardia, respectively. There is also evidence that amiodarone inhibits vitamin K dependent coagulation factors, thereby enhancing warfarin's anticoagulant effect.

A number of side effects limit the clinical use of amiodarone. Some important side effects that can occur include: corneal microdeposition, hyperthyroidism, hypothyroidism, liver dysfunction, alveolitis, photosensitivity, dermatitis, skin pigmentation, and peripheral neuropathy.

A compound of structural formula I:

and pharmaceutically acceptable salts thereof, wherein m is 0 to 4, n is 0 or 1, X₁And X₂Is H, lower alkyl or halogen, preferably iodine, R₁And R₂Is lower alkyl, R₃Optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. R₃Preference is given to (R) -2-butyl, (S) -2-butyl, (R) -3-methyl-2-butyl or (S) -3-methyl-2-butyl.

Preferred compounds have the following structural formula

And includes pharmaceutically acceptable salts thereof. Particularly preferred salts are citrate, (L) -tartrate, (D) -tartrate, fumarate, maleate. These compounds are useful for treating mammals, including humans, suffering from ventricular and supraventricular arrhythmias, including atrial fibrillation.

The metabolites produced by these compounds are useful for drug monitoring and have their own electrophysiological properties when administered to mammals, including humans.

Currently, there are no class III drugs available on the market that are safe for use in CHF patients. In the field of pharmaceutical research, the cardiovascular drug market is the largest and effective and safe class III antiarrhythmic drugs available for CHF patients are expected to bring considerable interest. Therefore, a drug that successfully improves the prognosis of CHF patients and is safer than amiodarone would be very useful and highly desirable. Various analogs of amiodarone have been described previously (U.S. Pat. Nos. 6,710,070; 6,683,195; 6,372,783; 6,362,223; 6,316,487; 6,130,240; 5,849,788; 5,440,054; and 5,364,880). The present invention further increases the scope of such compounds.

Disclosure of Invention

The present invention provides compounds with particular utility for treating life-threatening ventricular tachyarrhythmias, particularly patients with Congestive Heart Failure (CHF). The compounds of the invention also provide effective treatment of ventricular and supraventricular arrhythmias, including atrial fibrillation and reentrant tachyarrhythmias involving bypass.

More specifically, the novel compounds have the particular advantage of reducing the number of side effects observed with the drugs currently used for the treatment of these arrhythmias. For example, the compound currently selected for the treatment of cardiac arrhythmias is amiodarone, which can produce serious side effects. Because the compounds of the present invention are metabolites of compounds (e.g., 1 to 4), they are useful for therapeutic drug monitoring in patients receiving therapeutic doses of compounds 1 to 4. The metabolism of compound 1 is shown in the example given in scheme 1 below.

Scheme 1

Scheme 1 describes the metabolism of compound 1 in animals, including humans. "A" represents an ester cleavage metabolic reaction and "B" represents an N-dealkylation reaction. The flow chart 1 shows: the parent drug, compound 1, may undergo an ester cleavage metabolic reaction to form compound 5, or an N-deethylation reaction to form compound 6, compound 6 may be ester cleaved to compound 7, or N-deethylated to compound 8, which compound 8 may then be cleaved by esterase to compound 9. Although scheme 1 is intended as an illustrative example, the metabolic schemes for compounds 2, 3 and 4 are very similar to those for compound 1.

Drawings

FIG. 1 shows the time course of the effect of Compound 6(1 μ M) on intrA-atrial conduction (S-A interval).

FIG. 2 shows the time course of the effect of Compound 6(1 μ M) on atrioventricular nodal conduction (A-H interval).

FIG. 3 shows the time course of the effect of Compound 6(1 μ M) on Hill-Purkinje fibre transduction (H-V interval).

Figure 4 shows the time course of the effect of compound 6(1 μ M) on ventricular conduction (QRS interval).

FIG. 5 shows the time course of the effect of Compound 6(1 μ M) on ventricular repolarization (Q-T interval).

FIG. 6 shows Compound 6(1 μ M) repolarization (MAPD) to the ventricle₉₀) Time course of action.

FIG. 7 shows the time course of the effect of Compound 7(1 μ M) on intrA-atrial conduction (S-A interval).

FIG. 8 shows the time course of the effect of Compound 7(1 μ M) on atrioventricular nodal conduction (A-H interval).

FIG. 9 shows the time course of the effect of Compound 7(1 μ M) on Hill-Purkinje fibre transduction (H-V interval).

Figure 10 shows the time course of the effect of compound 7(1 μ M) on ventricular conduction (QRS interval).

FIG. 11 shows the time course of the effect of Compound 7(1 μ M) on ventricular repolarization (Q-T interval).

FIG. 12 shows Compound 7(1 μ M) repolarization (MAPD) to the ventricle₉₀) Time course of action.

Detailed Description

The novel compounds provided by the present invention are capable of producing the desired pharmacological properties of amiodarone, but do not have the undesirable physiological properties of amiodarone. In particular, the compounds of the invention can reduce long-term toxic symptoms (pulmonary fibrosis, corneal microdeposition, etc.). In addition, when compounds 1 through 4 are administered to mammals, including humans, the novel compounds are metabolites of compounds of structural formula I, such as compounds 1 through 4. Thus, these compounds are useful for monitoring drug levels and drug pharmacokinetics in patients receiving compounds 1 to 4.

The present invention provides a substantially pure compound of structural formula II:

and pharmaceutically acceptable salts thereof, wherein

R₁Is H or C₁-C₁₀An alkyl group;

R₂is H or optionally substituted C₁-C₁₀Alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl;

n is 0 to 4;

p is 0 or 1;

R₃and R₄Are each H or C₁-C₄An alkyl group.

By "substantially pure" is meant that the compound contains less than 20%, preferably less than 10%, more preferably less than 5% by weight of impurities. ("impurities" does not include pharmaceutically acceptable carriers, diluents, excipients, or the like.)

In a particularly preferred embodiment, R₁Is an ethyl group; r₂Is (S) -2-butyl, (R) -2-butyl, (S) -3-methyl-2-butyl or (R) -3-methyl-2-butyl; n-0 or 1, preferably n-1; p is 0; and R is₃And R₄Respectively H or methyl.

Specific examples herein are the following compounds (compound 6 to compound 9):

compound 6 Compound 7

And

compound 8 Compound 9

Particularly preferred compounds include (S) - {3- [4- (2-ethylamino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid sec-butyl ester; {3- [4- (2-ethylamino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid; (S) - {3- [4- (2-amino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid sec-butyl ester; {3- [4- (2-amino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid; (R) - {3- [4- (2-ethylamino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid sec-butyl ester; (R) - {3- [4- (2-amino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid sec-butyl ester; (S) - {3- [4- (2-ethylamino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid 1, 2-dimethylpropyl ester; (R) - {3- [4- (2-ethylamino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid 1, 2-dimethylpropyl ester; (S) - {3- [4- (2-amino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid 1, 2-dimethylpropyl ester; (R) - {3- [4- (2-amino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid 1, 2-dimethylpropyl ester.

The novel compounds may also be provided in the form of their salts. Accordingly, the invention includes pharmaceutically acceptable salts, such as acid addition salts of inorganic or organic acids, for example hydrochlorides, hydrobromides, p-toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, (L) -tartrates, (D) -tartrates, meso-tartrates and benzoates. Salts may also be derived from bases (organic and inorganic), such as alkali metal salts (e.g. magnesium or calcium salts), or organic amine salts, such as morpholine, piperidine, dimethylamine or diethylamine salts.

Having the benefit of the present disclosure, and as taught by, for example, U.S. patent nos. 6,710,070; 6,683,195, respectively; 6,372,783, respectively; 6,362,223, respectively; 6,316,487, respectively; 6,130,240, respectively; 5,849,788, respectively; 5,440,054, respectively; and 5,364,880, which are incorporated herein by reference, the compounds of the present invention are readily prepared by those skilled in the art.

Other modifications to the compounds disclosed herein will be readily apparent to those skilled in the art. Thus, analogs and salts of the example compounds are included within the scope of the invention. If the compounds of the invention are known, the chemical skilled person can synthesize these compounds from available substrates using known methods. The term "analogue" as used herein refers to a compound that is substantially identical to another compound, but may be modified by, for example, the addition of further pendant groups. The term "analog" as used herein may also refer to a compound that is substantially identical to another compound, but has atomic or molecular substitutions at certain positions of the compound.

Analogs of the example compounds can be readily prepared using well-known standard reactions. These standard reactions include, but are not limited to, hydrogenation, methylation, acetylation, halogenation, and acidification reactions. For example, by adding appropriate amounts of mineral acids (e.g., HCl, H)₂SO₄Etc.) or a strong organic acid, such as formic acid, oxalic acid, etc., to form an acid addition salt of the parent compound or a derivative thereof, to form a novel salt within the scope of the present invention. Various groups may also be added or modified within the exemplified compounds using synthetic type reactions according to known methods to produce other compounds within the scope of the invention.

Still further, the present invention relates to enantiomerically separated compounds, and compositions comprising compounds that block calcium ion channels. The compounds of the invention, in isolated enantiomeric form, are substantially separated from each other (i.e., enantiomeric excess). In other words, the "R" form of the compound is substantially separated from the "S" form of the compound, and thus the "S" form is in enantiomeric excess. In contrast, the "S" form of a compound is substantially separated from the "R" form of the compound, and thus the "R" form is in enantiomeric excess. In one embodiment of the invention, the isolated enantiomeric compound is at least about 80% enantiomeric excess. In a preferred embodiment, the compound is in at least about 90% enantiomeric excess. In a more preferred embodiment, the compounds are in at least about 95% enantiomeric excess. In a more preferred embodiment, the compound is in at least about 97.5% enantiomeric excess. In a most preferred embodiment, the compound is in at least about 99% enantiomeric excess.

One aspect of the invention further relates to the breakdown products produced when the therapeutic compounds of the invention are acted upon by a hydrolase, such as an esterase. The presence of these breakdown products in urine or serum can be used to monitor the clearance of the therapeutic compound from the patient.

Successful use of the novel compounds in the treatment of CHF is demonstrated by assessing the thermodynamic properties of the compounds, e.g., determining their partition coefficient between water and octanol, by determining their stability in buffer and human plasma to assess their clearance kinetics, and by assessing their electrophysiological properties in guinea pig heart specimens.

More particularly, the novel compounds are useful in the treatment of life-threatening ventricular tachyarrhythmias, particularly in patients with Congestive Heart Failure (CHF). Thus, the compounds of the present invention are effective not only in the treatment of ventricular tachyarrhythmias and non-severe ventricular arrhythmias, but also in the treatment of atrial fibrillation and reentrant tachyarrhythmias involving bypass. Compositions comprising novel compounds with a faster rate of clearance have many advantages over existing antiarrhythmic drugs such as amiodarone.

These advantages include:

(i) the effect is quicker to take effect and the like,

(ii) reduced long-term toxicity and easier management, an

(iii) The likelihood of drug interaction is lower.

In addition, the novel compounds may be included in a composition that includes a second active ingredient. The second active ingredient may be used for the co-or co-treatment of an arrhythmia, or for the treatment of an unrelated event that is present with, or caused by, an arrhythmia or CHF.

The compound of the invention has similar thermodynamic properties to amiodarone, but provides better characteristics, and can be rapidly metabolized into water-soluble metabolites in blood plasma. More specifically, the compounds of the present invention are class III drugs that have similar electrical, stereochemical and thermodynamic properties to amiodarone, but have an enzymatically labile ester group embedded in the structure, so that the drug is readily hydrolyzed in plasma to polar, water-soluble metabolites. The water-soluble metabolites can be eliminated by the kidney. This is clearly an advantage compared to amiodarone, which is mainly metabolized in the liver. In such cases, clearance of the new compound is increased, resulting in faster dissociation of the drug from the phospholipid binding site. Accumulation of the compound, depending on the steady state tissue concentration of the drug and thus the dose, is easily reversible. It was therefore concluded that when a drug comprising one of the new compounds is taken out of use, the drug is cleared from the body very quickly. The increase in clearance makes antiarrhythmic therapy with the compounds of the present invention or compositions comprising the compounds of the present invention more manageable.

In addition, the compounds of the present invention may be administered in combination with other compounds or combinations thereof. These compounds and compositions thereof may include other compounds known to be useful in the treatment of cardiac arrhythmias, cardioprotective agents, antibiotics, antiviral agents, or thrombolytic agents (e.g., streptokinase, tissue plasminogen activator, or recombinant tissue plasminogen activator). The compounds and compositions of the invention are particularly useful in treating life-threatening ventricular tachyarrhythmias, particularly patients with Congestive Heart Failure (CHF). Patients after myocardial infarction may also benefit from administration of the compounds and compositions of the invention; accordingly, the present invention also provides methods of treating a patient after a myocardial infarction. An "individual" or "patient" includes animals and humans in need of treatment for arrhythmia. In a preferred embodiment, the subject is a human.

Cardioprotective agents include vasodilators and beta blockers (such as those described in U.S. patent No. 5,175,187 or other drugs known to those skilled in the art) for patients with coronary insufficiency. Other cardioprotective agents include known antihypertensive agents such as (S) -1- [ 6-amino-2- [ [ hydroxy (4-phenylbutyl) phosphinyl ] hydrocarbyloxy ] -L-proline (U.S. Pat. No. 4,962,095) and zofenopril (U.S. Pat. No. 4,931,464) ]. Other cardioprotective agents include, but are not limited to, aspirin, heparin, warfarin, digitalis, digitoxin, nitroglycerin, isosorbide dinitrate, hydralazine, nitroprusside, captopril, enalapril, and lisinopril.

The compounds and compositions also provide effective treatment of ventricular and supraventricular arrhythmias, including atrial fibrillation and reentrant tachyarrhythmias involving bypass. The compounds and compositions of the invention are also useful in the treatment of ventricular and supraventricular arrhythmias, including atrial fibrillation and flutter, episodic supraventricular tachycardia, premature ventricular beats (VPB), persistent and non-persistent Ventricular Tachycardia (VT), and Ventricular Fibrillation (VF). Other non-limiting examples of arrhythmias that may be treated with the compounds of the present invention include: narrow QRS tachycardia (atrial, atrioventricular nodal, medial/lateral or bypass), ventricular tachycardia and ventricular arrhythmias in cardiomyopathy.

The compounds of the present invention have similar therapeutic effects as the unmodified parent compound. Thus, the speed and route of administration of the disclosed compounds is similar to those known to the skilled artisan and already used in the art. (see, e.g., Physicians' Desk reference.54)^th Ed.，Medical Economics Company，Montvale，NJ，2000。)

The compounds of the present invention may be formulated according to known methods for preparing effective pharmaceutical compositions. The formulations are described in detail in a number of documents well known and readily available to those skilled in the art. For example, Remington's pharmaceutical science, e.w. martin, describes formulations that can be used in conjunction with the present invention. Generally, the compositions of the present invention are formulated such that an effective amount of the biologically active compound is combined with a suitable carrier to facilitate effective administration of the composition.

Pharmaceutical compositions provided according to the invention comprise an effective amount of one or more compounds as active ingredient, together with one or more non-toxic pharmaceutically acceptable carriers or diluents. Examples of carriers for use in the present invention include ethanol, dimethylsulfoxide, glycerol, silica, alumina, starch, and similar carriers and diluents.

Further acceptable carriers may be solid or liquid. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

The disclosed pharmaceutical compositions may be subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage forms may be packaged preparations such as tablets, capsules and powders in paper or plastic containers or vials or ampoules. The unit dose may also be a liquid-based formulation, or formulated into a solid food, chewing gum or lozenge.

For the purposes of this invention, the following definitions will be used (unless specifically stated otherwise):

for simplicity, chemical moieties are defined to mean monovalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, these terms are also used to denote the corresponding multivalent moieties in a suitable structural environment as would be apparent to one of skill in the art. For example, when "alkyl" is broadly intended to mean a monovalent group (e.g., CH)₃-CH₂-) the divalent linking moiety may be "alkyl" in some cases, and in such cases, one of skill in the art would understand alkyl to refer to a divalent radical (e.g., -CH₂-CH₂-) corresponding to the term "alkenyl". (Again, where a divalent moiety is desired, and is referred to as an "aryl", those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene.) it is understood that all atoms are in their normal number of valences for bond formation (i.e., carbon is 4, N is 3, O is 2, S is 2, 4, or 6, depending on the oxidation state of S]. In some cases, it is possible to define the constituent parts, for example as (A)_a-B-, wherein a is 0 or 1. In this case, when a is 0, the constituent is B-, and when a is 1, the constituent is A-B-.

The term "hydrocarbyl" refers to a straight, branched or cyclic alkyl, alkenyl or alkynyl group, each as defined herein. "C₀"hydrocarbyl group is used to refer to a covalent bond. Thus, "C₀-C₃-hydrocarbyl "includes covalent bonds, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl and cyclopropyl.

The term "alkyl" as used herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, which may be optionally substituted with one, two or three substituents. Preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. "C₀"alkyl" (as in "C)₀-C₃In-alkyl groups) are covalent bonds (like "C)₀"hydrocarbyl group-like"). As used herein, "lower alkyl" refers to an alkyl moiety of 1 to 6 carbons.

The term "alkenyl" as used herein means an unsaturated straight or branched aliphatic group having 2 to 12 carbon atoms with one or more carbon-carbon double bonds, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, which may be optionally substituted with one, two or three substituents. Preferred alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term "alkynyl" as used herein refers to an unsaturated straight or branched aliphatic group having 2 to 12 carbon atoms with one or more carbon-carbon triple bonds, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, which may be optionally substituted with one, two or three substituents. Preferred alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

"hydrocarbylene," "alkenylene," or "alkynylene" is an alkyl, alkenyl, or alkynyl group, as defined above, that is located between and connects two other chemical groups. Preferred alkyl groups include, but are not limited to, methylene, ethenyl, propenyl, and butenyl. Preferred alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Preferred alkynylenes include, but are not limited to, ethynylene, propynyl, and butynyl.

The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having from 3 to 12 carbons, preferably from 3 to 8 carbons, more preferably from 3 to 6 carbons, wherein the cycloalkyl group may be optionally substituted. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term "heteroalkyl" refers to an alkyl group as defined above in which one or more carbon atoms in the chain is replaced with a heteroatom selected from O, S and N.

"aryl" means a C group containing one to three aromatic rings₆-C₁₄The aromatic hydrocarbon moiety may be optionally substituted. Preferably aryl is C₆-C₁₀And (4) an aryl group. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "aralkyl" or "arylalkyl" includes an aryl group covalently bonded to an alkyl group, both groups may be optionally substituted or unsubstituted, respectively. A preferred aralkyl group is (C)₁-C₆) Alkyl radical (C)₆-C₁₀) Aryl groups, including but not limited to benzyl, phenethyl, and naphthylmethyl.

A "heterocyclic" group (which may alternatively be referred to as "heterocyclyl" or "heterocycloalkyl") is an optionally substituted non-aromatic monocyclic, bicyclic, or tricyclic ring structure having about 3 to 14 atoms, one or more of which is selected from N, O and S. One ring of the bicyclic heterocycle or both rings of the tricyclic heterocycle may be aromatic, as in indane and 9, 10-dihydroanthracene. The heterocyclyl group may be optionally substituted on carbon by oxygen or one of the substituents listed above. The heterocyclyl group may also be substituted on nitrogen by alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, alone or on sulfur by oxygen or lower alkyl. Preferred heterocyclic groups include, but are not limited to, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholinyl. In certain preferred embodiments, the heterocyclic group is combined with an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocycles include, but are not limited to, tetrahydroquinoline and dihydrobenzofuran. Specifically, in compounds excluded from this term, the ring-shaped O or S atom is adjacent to another O or S atom.

The term "heteroaryl" as used herein refers to an optionally substituted group having 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms; in a cyclic arrangement, 6, 10 or 14 pi electrons are shared; in addition to carbon atoms, one or more heteroatoms selected from N, O and S. For example, heteroaryl groups can be pyrimidinyl, pyridyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl, and indolinyl. Preferred heteroaryl groups include, but are not limited to, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, triazolyl, and isoxazolyl.

"Heteroaralkyl" or "heteroarylalkyl" includes a heteroaryl group covalently bonded to an alkyl group, both of which are optionally substituted or unsubstituted, respectively. Preferred heteroalkyl groups include C₁-C₆Alkyl and heteroaryl having 5, 6, 9 or 10 ring atoms. In particular, compounds excluded from this term have adjacent ring-shaped O and/or S atoms. Examples of preferred heteroaralkyl groups include picolyl, pyridylethyl, pyrrylmethyl, pyrrylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl.

An "arylene", "heteroarylene" or "heterocycloalkylene" group is an aryl, heteroaryl or heterocyclyl group, as defined above, located between two other chemical groups and used to connect the two chemical groups.

Preferred heterocyclyl and heteroaryl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, dehydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolynyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoquinolinyl, thiocyanato, benzotriazolyl, benzotria, Isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, benzothiophenidinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, nitrophenyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, Pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1, 2, 5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, thiazinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl, and xanthenyl.

As used herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted", it is meant that the group may optionally have one to four non-hydrogen substituents, preferably one to three, more preferably one or two. Suitable substituents include, but are not limited to, halogen, hydroxy, oxygen (e.g., -CH-is substituted with oxygen to form-C (O)), nitro, haloalkyl, hydrocarbyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, amino, amido, alkylcarbamoyl, arylformyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkylsulfonyl, arylsulfonyl, sulfonamido, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkylcarbonyl, acyloxy, cyano, alkylthio, ureido, and ureidoalkyl. Preferably the substituent is as such, without further substitution (unless otherwise specifically stated):

(a) halogen, cyano, oxygen, alkyl, alkoxy, alkylthio, haloalkoxy, aminoalkyl, aminoalkoxy, carboxy, formyl, nitro, amino, amidino, carbamoyl, guanidino, C₃-C₇Heterocyclyl, heterocycloalkyl, heterocyclocarbonyl, hydroxyalkyl, alkoxyalkyl,

(b)C₁-C₅alkyl or alkenyl or arylalkyl imino, carbamoyl, carbamate, azido, carboxyamino, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, C₁-C₈Alkyl radical, C₁-C₈Alkenyl radical, C₁-C₈Alkoxy radical, C₁-C₈Alkoxycarbonyl, aryloxycarbonyl, C₂-C₈Acyl radical, C₂-C₈Amido, C₁-C₈Alkylthio, arylalkylthio, arylthio, heteroarylthio, C₁-C₈Alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C₁-C₈Alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C₀-C₆N-alkylcarbamoyl, C₂-C₁₅N, N-dialkylcarbamoyl radical, C₃-C₇Cycloalkyl, aroyl, aryloxy, heteroaryloxy, arylalkyl ether, C₃-C₇Heterocycloalkyl ethers, aryl in combination with cycloalkyl or a heterocycle or another aromatic ring, C₃-C₇Heterocyclyl, heteroaryl, arylcarbamoyl, or any ring bound or spiro-bound to a cycloalkyl, heterocyclyl or aryl group, wherein any of the foregoing groups which may be additionally substituted may be further optionally taken from another moiety listed above in (a)Generation; and

(c)-(CH₂)s-NR³⁰R³¹wherein s is 0 (wherein the nitrogen is directly bonded to the substituted moiety) to 6, R³⁰And R³¹Each independently hydrogen, cyano, oxygen, carbonylamino, amidino, C₁-C₈Hydroxyalkyl radical, C₁-C₃Alkylaryl, aryl-C₁-C₃Alkyl radical, C₁-C₈Alkyl radical, C₁-C₈Alkenyl radical, C₁-C₈Alkoxy radical, C₁-C₈Alkoxycarbonyl, aryloxycarbonyl, aryl-C₁-C₃Alkoxycarbonyl group, C₂-C₈Acyl radical, C₁-C₈Alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl, heterocyclyl or heteroaryl, each of which may be further optionally substituted with another moiety as recited in (a) above; or

R³⁰And R³¹Together with the N to which they are attached form a heterocycle or heteroaryl, each of which may be optionally substituted with 1 to 3 substituents of (a) above.

In addition, the substituents on the cyclic moiety (i.e., cycloalkyl, heterocyclyl, aryl, heteroaryl) include 5-6 member monocyclic moieties and 9-14 member bicyclic moieties that, in combination with the parent ring moiety, form a bicyclic or tricyclic fused ring system. For example, an optionally substituted phenyl group includes, but is not limited to, the following structures:

preferred substituents on the cyclic moiety (i.e., cycloalkyl, heterocyclyl, aryl, heteroaryl) also include those of formula-K¹-N(H)(R¹⁰) Wherein

K¹Is C₀-C₄A hydrocarbylene group;

R¹⁰is C₀-C₄alkylene-Z' and

z' is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which may be optionally substituted, optionally in combination with one or more aryl or heteroaryl rings, or one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings.

"haloalkyl" is a hydrocarbyl moiety wherein one to all hydrogens are replaced with one or more halogens.

The term "halogen" as used herein refers to chlorine, bromine, fluorine or iodine. The term "acyl" as used herein refers to an alkylcarbonyl or arylcarbonyl substituent. The term "amido" refers to an amide group (i.e., R-CO-NH-) attached to a nitrogen atom. The term "carbamoyl" refers to an amide group (i.e., NH) attached to the carbonyl carbon atom₂-CO-). The nitrogen atom of the amido or carbamoyl substituent may optionally be additionally substituted. The term "sulfonamido" refers to a sulfonamide substituent attached to a sulfur or nitrogen atom. The term "amino" refers to NH₂Alkylamino, arylamino and cyclic amino groups. The term "ureido" as used herein refers to a substituted or unsubstituted urea moiety.

The term "group" as used herein refers to a chemical moiety that contains one or more unpaired electrons.

Throughout the specification, preferred embodiments of one or more chemical substituents are identified. Combinations of these preferred embodiments are also preferred.

Some of the compounds of the present invention may have chiral centers and/or geometric isomeric centers (E-and Z-isomers), and it is to be understood that the present invention encompasses all such optical, diastereomeric and geometric isomers. The present invention also includes all tautomeric forms of the compounds disclosed herein. When the compounds of the present invention include chiral centers, the present invention includes pure enantiomers of these compounds, enriched enantiomeric mixtures of these compounds, and racemic mixtures of these compounds.

The following examples illustrate some aspects of the invention. These examples should not be construed as limiting.

EXAMPLE 1 electrophysiological Effect of Compound 6

Model for testing electrophysiological properties of compound 6 hearts were isolated using atrial paced (cycle time 300ms), 36 ℃ Krebs-Henseleit solution perfused in guinea pigs. The following are recorded:

electrophysiological recording: atrial and Escherichia coli electrograms.

And (3) EP determination: SA, AH, HV, QRS and QT intervals.

Compound 6 is administered into the perfusate line by an infusion pump. Time-dependent EP effects were determined at 1 μ M compound 6. Compound 6 was infused for 90 minutes and then rinsed for 90 minutes. Every 10 minutes, EP was measured. Analysis of data single factor repeated measures ANOVA analysis was used, followed by SNK test for multiple comparisons.

The results are shown in FIGS. 1-6.

EXAMPLE 2 electrophysiological Effect of Compound 7

Model for testing electrophysiological properties of compound 7 hearts were isolated using atrial paced (cycle time 300ms), 36 ℃ Krebs-Henseleit solution perfused in guinea pigs. The following are recorded:

electrophysiological recording: atrial and Escherichia coli electrograms.

And (3) EP determination: SA, AH, HV, QRS and QT intervals.

Compound 7 is administered into the perfusate line by an infusion pump. Time-dependent EP effects were measured at 1 μ M compound 7. Compound 7 was infused for 90 minutes and then rinsed for 90 minutes. Every 10 minutes, EP was measured. Analysis of data single factor repeated measures ANOVA analysis was used, followed by SNK test for multiple comparisons.

The results are shown in FIGS. 7-12.

EXAMPLE 3 Synthesis of Compounds

Thanks to the present disclosure and, for example, U.S. patent No. 6,710,070; 6,683,195, respectively; 6,372,783, respectively; 6,362,223, respectively; 6,316,487, respectively; 6,130,240, respectively; 5,849,788, respectively; 5,440,054, respectively; and 5,364,880, those skilled in the art will be readily able to prepare or isolate the compounds of the present invention. Schemes 2 and 3 provide synthetic steps for the preparation of compounds 6 and 7 (in the examples, the ester moiety is (S) -2-butyl).

Specific reaction conditions can be readily determined by one of ordinary skill in the art, given the benefit of this disclosure. In addition, one skilled in the art of chemist skilled will recognize that the same synthetic schemes can be used to prepare the compounds of the invention.

The flow chart is as follows: (a) benzyl bromide/triethylamine (b) tosyl chloride/triethylamine

The flow chart is as follows: (a) compound 12/KHCO₃toluene/Water (b) 1-chloroethylchloroformate/methanol (c) H₂SO₄。

Patents, patent applications, provisional applications, and publications, including all figures, cited herein are hereby incorporated by reference in their entirety to the same extent as if each individual figure were specifically and individually indicated to be incorporated by reference and were set forth in its entirety herein.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application.

Claims (15)

1. A substantially pure compound having structural formula II:

or a pharmaceutically acceptable salt thereof, wherein

R₁Is H or C₁-C₁₀An alkyl group;

R₂is H or optionally substituted C₁-C₁₀Alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl;

n is 0 to 4;

p is 0 or 1;

R₃and R₄Are each H or C₁-C₄An alkyl group.

2. A compound according to claim 1, wherein

R₁Is an ethyl group;

R₂is (S) -2-butyl, (R) -2-butyl, (S) -3-methyl-2-butyl or (R) -3-methyl-2-butyl;

n-0 or 1, most preferably n-1;

p is 0; and R₃And R₄Are each H or methyl.

3. A compound according to claim 2 wherein said n is 1.

4. A compound according to claim 1, selected from:

compound 6 Compound 7

And

compound 8 Compound 9

5. A compound according to claim 1 selected from

a) (S) - {3- [4- (2-ethylamino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid sec-butyl ester;

b) {3- [4- (2-ethylamino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid;

c) (S) - {3- [4- (2-amino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid sec-butyl ester;

d) {3- [4- (2-amino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid;

e) (R) - {3- [4- (2-ethylamino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid sec-butyl ester;

f) (R) - {3- [4- (2-amino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid sec-butyl ester;

g) (S) - {3- [4- (2-ethylamino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid 1, 2-dimethylpropyl ester;

h) (R) - {3- [4- (2-ethylamino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid 1, 2-dimethylpropyl ester;

i) (S) - {3- [4- (2-amino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid 1, 2-dimethylpropyl ester; and

j) (R) - {3- [4- (2-amino-ethoxy) -3, 5-diiodo-benzoyl ] -benzofuran-2-yl } -acetic acid 1, 2-dimethylpropyl ester.

6. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

7. A composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier, diluent or excipient.

8. A composition comprising a compound according to claim 3 and a pharmaceutically acceptable carrier, diluent or excipient.

9. A composition comprising a compound according to claim 4 and a pharmaceutically acceptable carrier, diluent or excipient.

10. A composition comprising a compound according to claim 5 and a pharmaceutically acceptable carrier, diluent or excipient.

11. A method of treating cardiac arrhythmia which comprises administering to a patient suffering from cardiac arrhythmia an effective amount of a composition according to claim 6.

12. A method of treating cardiac arrhythmia which comprises administering to a patient suffering from cardiac arrhythmia an effective amount of a composition according to claim 7.

13. A method of treating cardiac arrhythmia which comprises administering to a patient suffering from cardiac arrhythmia an effective amount of a composition according to claim 8.

14. A method of treating cardiac arrhythmia which comprises administering to a patient suffering from cardiac arrhythmia an effective amount of a composition according to claim 9.

15. A method of treating cardiac arrhythmia which comprises administering to a patient suffering from cardiac arrhythmia an effective amount of a composition according to claim 10.