MXPA06004946A - 1,4-dihydropyridine compounds, pharmaceutical compositions, and methods for the treatment of cardiovascular disease - Google Patents

Abstract

The present invention provides certain substituted 1,4-dihydropyridine compounds, including pure enantiomeric forms and pharmaceutical formulations thereof These compounds provide for elevation of&agr;-MyHC protein levels and&agr;-MyHC mRNA levels, and most frequently these same compounds provide simultaneous lowering of&bgr;-MyHC protein levels and&bgr;-MyHC mRNA levels. Thus, these compounds may be used alone or in conjunction with other drugs to treat heart failure.

Description

COMPOUNDS OF 1, 4-DIHYDROPYRIDINE, PHARMACEUTICAL COMPOSITIONS AND METHOD FOR THE TREATMENT OF CARDIOVASCULAR DISEASES BACKGROUND OF THE INVENTION This application claims the priority benefit of the provisional application of E. U. A. Serial No. 60 / 517,217, filed on November 3, 2003, the total content of which is incorporated herein by reference.

FIELD OF THE INVENTION This invention relates to pharmaceutical compositions and methods for the treatment of diseases mediated by the myocin heavy chain (MyHC), and in particular to heart failure.

RELATED TECHNIQUE Heart failure is a pathophysiological state in which the heart fails to pump blood at a rate corresponding to the requirements of the body's metabolizing tissues. It is caused in most cases about 95% of the time through myocardial insufficiency. The contractile proteins of the heart lie within muscle cells, the so-called myocytes, which constitute about 75% total myocardial volume. The two main contractile proteins are the thin actin filament and the thick myocyte filament. Each myoclonus filament contains two heavy chains and four light chains. The bodies of the heavy chains are interlaced, and each heavy chain ends in a head. Each lobe of the myocyte head of bi-lobes has an ATP binding pocket, in which it is in close proximity to the ATPase activity of myocin which cleaves ATP in its products. The rate of contraction of the cardiac muscle is controlled by the degree of ATPase activity in the head regions of the myocin molecules. The main determinant of the myocin ATPase activity and, therefore, the muscle contraction rate, is the relative amount of the two myocin heavy chain isomers a and β (MyHC). The aMyHC isoform has approximately 2-3 times more enzymatic activity than the ßMyHC isoform and, consequently, the shortening velocity of the cardiac muscle is related to the relative percentage of each isoform. For example, the ventricular myocardium of an adult rodent is approximately 80-90% of aMyHC, and only 10-20% of ßMyHC, which explains why its ATPase activity of myocin is 3-4 times greater than the ventricular myocardium of bovine, which contains 80-90% of ßMyHC.

When ventricular myocardial hypertrophy or cardiac deficiency is created in the rodent model, a change in the expression of the MyHC isoforms occurs, with a decrease in aMyHC and an increase in aMyHC. These "isoform exchanges" reduce the contractility of the hypertrophied rodent ventricle, eventually leading to myocardial deficiency. This pattern of altered MyHC gene expression has been referred to as a reversion to the "fetal" expression pattern because, during early fetal and neonatal development, ßMyHC also dominates in the rodent ventricular myocardium. It has been shown that myocardial function decreases with the age of the animals. The cellular and molecular mechanisms that account for the changes associated with age in the functioning of the myocardium have been studied mainly in rodents. Among other changes, marked exchanges occur in MyHC in rodents, and the change associated with age parallels ßMyHC in MyHC proteins. The ATPase activity of myocin decreases when the content of a-MyHC is decreased, and the altered cellular profile results in the contraction exhibiting a reduced rate and a prolonged time course. The human arterial myocardium can undergo exchanges of similar isoforms with hypertrophy or insufficiency, although the human ventricular myocardium, the basis for most cases of heart failure (greater than 90% of cases), has not consistently shown that this Pattern. Several studies have examined the tissue autopsy cases, but they do not find a biologically meaningful expression of the a-MyHC sophorma, in putatively normal hearts. Since it was believed that the expression of a-MyHC in normal hearts was not significant, down-regulation in a-MyHC was not believed to be possible based on myocardial insufficiency in humans. There is only one report that the amount of a-MyHC, although extremely small at first, was reduced in human myocardial insufficiency. (Bouvagnet, 1989). However, the most recent reports have demonstrated the existence of appreciable levels of a-MyHC in the human heart both in the mRNA and in the level of the protein. At the mRNA level, 23-34% of the total ventricular mRNA is derived from a-MyHC (Lowes et al., 1997; Nakao et al., 1997), while approximately 1-10% of the total myocin protein content is a-MyHC (Miyata et al., 2000; Reiser et al., 2001). These changes in MyHC content are sufficient to explain the decrease in ATPase activity in myocin and myofibrillar in human heart failure (Hajjar et al., 1992; Pagani et al., 1988). The data generated in the 90's suggest that heavy chain mycocin β mutations can be counted for approximately 30-40% of cases of familial hypertrophic cardiomyopathy (Watkins et al., 1992; Schwartz et al., 1995; Mariyy Roberts, 1995, Thierfelder et al., 1994, Walkins et al., 1995). A patient with no family history of hypertrophic cardiomyopathy had late-onset cardiac hypertrophy of unknown etiology and was shown to have a mutation in a-MyHC (Niimura et al., 2002). Two important studies have demonstrated a more convincing role for the MyHC soformas in cardiovascular disease. Lowes et al. (2002) demonstrated that the use of beta-blockers to treat dilated cardiomyopathy led to increased levels of a-MyHC and decreased levels of ß-MyHC that directly correspond to the improvement in the disease state. In fact, the changes in a-MyHC observed in these studies was the only factor that showed the correlation with improvement in cardiac function. Equally convincing, Abraham and others (2002) that myofoid heavy chain isoform changes directly contribute to the progression of the disease in dilated cardiomyopathy. These studies demonstrated the importance and necessity of an agent that can alter, if not reverse, the isoform exchange that occurs in the MyHC isoforms in cardiovascular disease.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, the present invention provides novel and optimally active chiral compounds of formula I, and pharmaceutically acceptable salts thereof.

Formula Ri and R5 are, independently, phenyl, pyridine, pyrimidine, thiophene, furan, oxazole, isoxazole, thiazole, isothiazole, imidazole and pyrazole, and either of R1 and R5 may be optionally substituted by one or more of halogen, NO2, CN, CF3, C-1.4 alkyl, Co-4-S alkyl, C0-4-O alkyl, C0-4-NH alkyl, (C? -4 alkyl) 2-N, C? _4 alkyl- SO, alkyl of C? _4-S02, SO2-NH-C0-4 alkyl, SO2N (C1-4 alkyi) 2, NHSO2- C1-4 alkyl, CONH-C0-4 alkyl, NHCO-alkyl C1.4 and COO-C0-4 alkyl; 2 is C 1-4 alkyl, R 3 and R 4 are C 0-4 alkyl; and the alkyl may be straight or branched chain; and n is 1-4; and also includes all diastereomers. A class of compounds within the embodiment of this invention are compounds of the formula I wherein R1 and R5 are, independently, phenyl, thiophene, furan, oxazole, and thiazole; and any of R1 and R5 may be optionally substituted by one or more of halogen, N02, CN, CF3, C1-4 alkyl, C0-4-S alkyl, C0-4-O alkyl, C0-4 alkyl - NH, (C1-4alkyl) 2-N, alkyl of CM-SO, alkyl of C1.4-SO2, S02-NH-alkyl of C0-, SO2N (C1-4alkyl) 2, NHS02-alkyl of C1-4, CONH- C0-4 alkyl. NHCO-C alquilo -4 alkyl and COO-C0-4 alkyl. A class of preferred compounds are the compounds of the formula I wherein R i and R 5 are independently phenyl, thiophene and furan; and any of Ri and R5 may be optionally substituted by one or more of halogen, N02, CN, CF3, C1-4 alkyl, C0-4-O alkyl, (C-? 4 alkyl) 2-N, S02 -NH-Co-4 alkyl, NHSO2- C 1-4 alkyl, NHSO 2 -C 4 alkyl, CONH- C 0-4 alkyl, NHCO-C 1 alkyl- and COO-C 0-4 alkyl, and 3 is C1-4 alkyl. A more preferred class of compounds are the compounds of formula I wherein R-i and R5 are, independently, phenyl, thiophene and furan; and any of R, and R5 may be optionally substituted by one or more of halogen, N02, CN, CF3, C-? -4 alkyl, C0-4-O alkyl, (C1-4 alkyl) 2-N , SO2-NH-C0-4 alkyl, NHSO2- C-? -4 alkyl, NHS02- C? -4l alkyl CONH- C0- alkyl, NHCO- C1-4 alkyl and COO- C0- alkyl 4, R2 and R3 are CH3, R is C0-1 alkyl and n is 1-2. An even more preferred class of compounds are the compounds of the formula I wherein R1 and R5 are phenyl and any of R1 and R5 may be optimally substituted by one or more of Br, Cl, F, NO2, CF3, CH3, CH30, (C? -) alkyl 2-N, alkyl of CONH-COo-4, alkyl of NHCO-C1-4- and alkyl of COO-C0-4, R2 and R3 are CH3, R4 is C0-1 alkyl and It's 1-2. Especially preferred are the compounds of Formula I wherein R 1 and R 5 are phenyl and any of R 1 and R 5 can be optimally substituted by one or more of Br, Cl, F, NO 2, CF 3, CH 3? CH3O, (Ci. 4 alkyl) 2-N, alkyl of CONH-CO0-4, alkyl of NHCO-C1-4- and alkyl of COO-C0-, 2 and R3 are CH3t R4 is H and n is 1. The more preferred compounds of Formula I are compounds wherein Ri and R5 are phenyl and any of Ri and R5 can be optimally substituted by one or more of Cl, F, N02, CF3, CH3 | CH30, R2 and R3 are CH3, R4 is H and n is 1. In a further embodiment of the invention, the formulation comprises the compounds of the formula I with this R-enantiomer being substantially purified from the S-enantiomer. The contemplated forms of the invention have the form R which is larger than 75% pure, greater than 80% pure, greater than 85% pure, greater than 90% pure, greater than 95% pure, greater than 96% pure, greater than 97% pure, greater than 98% pure, and greater than 99% pure. In a further embodiment of the invention, the formulation comprises the compounds of Formula II: Formula II and pharmaceutically acceptable salts thereof, wherein: Ri and R5 are independently phenyl, pyridine, pyrimidine, thiophene, furan, oxazole, isoxazole, thiazole, isothiazole, imidazole and pyrazole; and any of Ri and R5 may be optionally substituted by one or more of halogen N02, CN, CF3, C1-4 alkyl. C0-4-O alkyl, (C1.4 alkyl) 2-N1 S02-NH-C0-4 alkyl, NHSO2-C-, C4-4 alkyl, NHSO2-C4 alkyl, CONH- C0-4 alkyl, NHCO-C1-4 alkyl and COO- C0- alkyl 4, 2 is C1-4 alkyl, R3 and R4 are C0-4 alkyl. and alkyl may be straight or branched chain; and n is 1-4; and also includes all diastereomers. In specific embodiments of the invention, the compounds and pharmaceutical formulations listed above are administered in an amount and through a sufficient route to achieve up-regulation of m-mRNA levels of the heavy chain mRNA (a-MyHC) in cardiomyocytes. . Increasing up-regulation of a-MyHC protein levels is also contemplated. In a further aspect of the invention, the formulation is administered in an amount and a sufficient route to achieve an increase in the contractility of cardiomyocytes. In a further embodiment, a method is described for inducing reversal of remodeling that occurs in hypertrophic tissue or heart failure in vivo, comprising administering to a subject suffering from cardiac hypertrophy or heart failure a quantity of the claimed formulation that is sufficient to induce remodeling, remodeling is defined as the decrease in the expression of fetal genes and an increase in the expression of normal cardiac genes. It is contemplated that the formulations of the present invention will be administered to a cell, that cell being in contact with a cardiomyocyte. These cardiomyocytes are located in cardiac tissue and the heart can be the intact heart of a human patient. It is further contemplated that the formulations will be administered directly to the ventricle, and specifically to the left ventricle of the heart. The routes include intra-arteriai, intravenous, intramuscular and oral routes. The formulations of the present invention can also be combined with, added to, or mixed with pharmaceutical formulations or treatment regimens given to the patient or the heart or cardiomyocytes. These additional formulations may include, but are not limited to, "beta blockers", anti-hypertensives, cardiotonics, antithrombotic agents, vasodilators, hormone antagonists, endothelin antagonists, cytosine inhibitors, and / or blockers, calcium channel blockers, Phosphodiesterase inhibitors, angiotensin type 2 antagonists. These drugs can be given before, at the same time as, or after the compounds of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS The following drawings are part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention can be better understood by reference to one or more of these drawings in combination with the detailed description of the specific embodiments presented herein. Figure 1 Effect dependent on the concentration of compound 1 on the levels of protein of a-MyHC in a cytoblot assay. NRVM was cultured for three days in serum-free medium in the presence of different amounts of compound 1. At the end of the culture period, NRVM was fixed and analyzed for a-MyHC protein levels using monoclonal antibody BA-G5 specific for a-MyHC. The results were collected through RLU using a Packard fusion plate reader and normalized to the signal from the samples cultured in the absence of the compound (control, set at 100%). Figure 2 Effect of compound 1 on a-MyHC protein levels as detected by Western blotting. NRVM was stimulated with compound 1 at different concentrations for 3 days. The protein extracts were prepared, the proteins were separated through SDS-PAGE electrophoresis, transferred to a PVDF membrane, and detected with an anti-a-MyHC monoclonal antibody.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel optically active chiral compounds of Formula I: Formula I and pharmaceutically acceptable salts thereof, use the treatment of cardiovascular disease. The present inventors unexpectedly found that the R-enantiomer of certain 1,4-dihydropyridine compounds (Formula I) surprisingly provides for the elevation of a-MyHC protein levels and a-MyHC mRNA levels and more frequently these same compounds they provide for the simultaneous decrease of ß-MyHC protein levels and ß-MyHC mRNA levels. These modalities are described in more detail below. - I.- Cardiovascular diseases Cardiac deficiency is one of the causes that lead to morbidity and mortality in the world. In the United States alone, estimates indicate that three million people currently live with cardiomyopathy, and another four hundred thousand are diagnosed on an annual basis. Dilated cardiomyopathy (DCM), also referred to as "congestive cardiomyopathy", is the most common form of cardiomyopathy and has an estimated prevalence of about 40 per 100,000 individuals (Duryy et al., 1995). There are other causes of DCM, familial dilated cardiomyopathy has been indicated as representing approximately 20% of "idiopathic" DCM. Approximately half of the DCM cases are idiopathic, with the remainder being associated with known disease procedures. For example, serious myocardial damage can result from certain drugs used in cancer chemotherapy (eg, doxorubicin and daunorubicin). In addition, many DCM patients are chronic alcoholics. Fortunately, for these patients, the progression of myocardial dysfunction can be stopped or reversed if alcohol consumption is reduced or stopped earlier in the course of the disease. Peripartum cardiomyopathy is another idiopathic form of DCM, as it is a disease associated with the infectious sequelae. Cardiomyopathies including DCM are significant public health problems. Heart disease and its manifestations, including coronary artery disease, myocardial infarction, congestive heart failure and cardiac hypertrophy, clearly represent a major health risk in the United States today. The cost to diagnose, treat, and support patients suffering from these diseases is within trillions of dollars. Two particularly severe manifestations of heart disease are myocardial infarction and cardiac hypertrophy. With respect to infraction to myocardial infarction, typically thrombocytic coronary occlusion in a coronary artery occurs as a result of atherosclerosis and causes death of the myocardial cell. Because cardiomyocytes are terminally differentiated and generally incapable of cell division, they are usually replaced through scar tissue when they die during the course of myocardial infarction. Scar tissue is not contractile, fails to contribute to cardiac function, and usually plays a depressing role in cardiac function through expansion during cardiac contraction, or through increasing the size and effective radius of the ventricle , for example, it becomes hypertrophic. With respect to cardiac hypertrophy, one theory with respect to this is a disease that resembles aberrant development and, that is, raises the question of whether developmental signals in the heart can contribute to hypertrophic disease. Cardiac hypertrophy is an adaptive response of the heart to virtually all forms of cardiac disease, including those arising from hypertension, mechanical loading, myocardial infarction, cardiac arrhythmias, endocrine disorders, and genetic mutations in cardiac contractile protein genes. Since the hypertrophic response is initially a compensatory mechanism that increases cardiac output, sustained hypertrophy can lead to DCM, heart failure, and sudden death. In the United States, approximately half a million individuals are diagnosed with heart failure each year, with a mortality scale that reaches 50%. The causes and effects of cardiac hypertrophy have been extensively documented, but the underlying molecular mechanisms have not been fully elucidated. The understanding of these mechanisms is a major concern in the prevention and treatment of heart disease and will be crucial as the therapeutic modality in the design of new drugs that specifically activate cardiac hypertrophy and cardiac heart failure. Since pathological cardiac hypertrophy does not produce any symptoms until the cardiac damage is severe enough to produce a heart failure, the symptoms of cardiomyopathy are associated with heart failure. These symptoms include suffocation, fatigue during exercise, inability to lie down without suffocation (orthopnea), nocturnal dyspnea, paroxysmal, elongated cardiac dimensions, and / or swelling of the lower extremities. Patients also usually have increased blood pressure, extra heart sounds, heart murmurs, systemic and pulmonary embolism, chest pain, pulmonary congestion, and palpitations. In addition, DCM depleted ejected fractions (ie, measurement of both intrinsic systolic function and remodeling). The disease is also characterized by ventricular dilation and the damaging thickening of systolic function due to decreased myocardial contractility, which results in dilated heart failure in many patients. Affected hearts also undergo cell / chamber remodeling as a result of myocyte / myocardial dysfunction, which contributes to the "DCM phenotype". When the disease progresses, so do the symptoms. Patients with DCM also have a greatly increased incidence of life-time-treated arrhythmias, including ventricular tachycardia and ventricular fibrillation. In these patients, an episode of syncope (dizziness) concerns the presage of sudden death. The diagnosis of dilated cardiomyopathy typically depends on the demonstration of elongated heart chambers, particularly elongated ventricles. Elongation is commonly observable in chest X-rays, but is valued more accurately using echocardiograms. DCM is usually difficult to distinguish from acute myocarditis, valvular heart disease, coronary artery disease, and hypertensive heart disease. Once the diagnosis of dilated cardiomyopathy is made, every effort is made to identify and treat the potentially reversible causes and prevent further damage to the heart. For example, coronary artery disease and valvular heart disease should be ruled out. Anemia, abnormal tachycardia, nutritional deficiencies, alcoholism, thyroid disease and / or other problems need to be managed and controlled. As mentioned above, treatment with pharmacological agents still represents the main mechanism to reduce or eliminate manifestations of cardiac deficiency. Diuretics are the first line of treatment for moderate to moderate heart failure. Unfortunately, many of the commonly used diuretics (for example, thiazides) have numerous adverse effects. For example, certain diuretics can increase serum cholesterol and triglycerides. In addition, diuretics are generally ineffective for patients suffering from severe heart failure. If diuretics are ineffective, vasodilator agents can be used; inhibitors containing angiotensin (ACE) (eg, enalopril and lisinopril) not only provide symptomatic relief, but have also been reported to decrease mortality (Young et al., 1989). Again, however, ACE inhibitors are associated with adverse effects that result in being contraindicated in patients with certain disease states (eg, renal artery stenosis). Similarly, inotropic agent therapy (ie, a drug that improves cardiac output through increasing the strength of muscle contraction of the myocardium) is associated with a panoply of adverse reactions, including gastrointestinal problems and central nervous system dysfunction. . In this way, the pharmacological agents currently used have severe defects in populations of particular patients. The availability of new safe and effective agents could undoubtedly benefit patients who either can not use pharmacological modalities currently available or who do not receive adequate improvement of these modalities. The prognosis for patients with DCM is variable, and depends on the degree of ventricular dysfunction, with the majority of deaths occurring within five years after diagnosis. The inventors here describe a novel therapeutic composition and methods for treating cardiac hypertrophy and cardiac insufficiency.

II.- 1,4-Dihydropyridine Compounds As explained above, the present invention provides novel chiral optically active compounds of Formula I, pharmaceutically acceptable salts thereof, and their use in the treatment of cardiovascular disease. The compounds of Formula I are members of the class of compounds known as substituted 1,4-dihydropyridine compounds. As a chemical class, the 1,4-dihydropyridines are known to be useful for the treatment of hypertension and coronary artery spasm (angina) through a mecsm of action involving the binding to and blocking of calcium cels of type L in the vascular smooth muscle. However, there have been no previous reports that said compounds directly affect the expression levels of a-MyHC / β-MyHC. Direct effects on the heart are usually not observed in clinically used doses of calcium cel blockers of 1,4-dihydropyridine. These so-called calcium cel blocking drugs in The Pharmacological Basis Of Therapeutics by Goodman and Gilman (2001). Drugs of this class that have been approved for commercialization for human use are: amlodipine (Merck index, Number 491), aranidipine (Merck index, Number 772), - barnidipine (Merck index, Number 1005), benidipine (Merck index) , Number 1041), cilnidipine (Merck Index, Number 2297), efonidipine (Merck Index, Number 3555), felodipine (Merck Index, Number 3981), isradipine (Merck Index, Number 5262), lacidipine (Merck Index, Number 5347), Lercanidipine (Merck index, Number 5465), manidipine (Merck index, Number 5767); nicardipine (Merck index, Number 6520), nifedipine (Merck index, Number 6555), nilvadipine (Merck index, Number 6573), nimodipine (Merck index, Number 6579), nisolpidine (Merck index, Number 6593), and nitrendipine (Merck index) , Number 6606). The chemical structures of these calcium cel blocking drugs are shown in the following formula. ítrend pina None of these calcium cel blocker drugs have been shown to directly elevate the levels of α-MyHC protein or levels of α-MyHC mRNA, nor have they shown that they directly decrease ß-MyHC protein levels or of mRNA-MyHC. None of these calcium cel blocking drugs show activity in the a-MyHC and β-MyHC assays and the tests used to determine the novel biological activity of the compounds of the invention. Raizada and others. (1993), and Raizada and others. (1999), reported that nifedipine protected against a drop in the protein ratio of a-MyHC / ß-MyHC, in chronic hypertension and aged rats. However, the effect has not demonstrated, or is not believed to be, a direct effect on the regulation of MyHC, but rather an indirect effect on the calcium cel blocker through its antihypertensive effect. In fact, the use of ventricular myocytes from neonatal rats has been demonstrated through by Samarel et al., (1992), and Simpson et al. (1996), that in vitro, nifedipine caused a decrease in total MyHC. Finally, in a 12-week study through Yamazaki et al. (1998), spontaneously hypertensive rats treated with amlodipine maintained their a-MyHC / ß-MyHC ratios. Therefore, these traditional calcium cel blockers have not shown that they directly affect the proportions of a-MyHC / β-MyHC in cardiomyocytes. All the compounds of Formula I are chiral, that is, they are not super imposed on their mirror image, and optically active.

Some starting materials for a method of preparing the compounds of Formula I are available from ChemBridge. These available starting materials are racemates, ie, solid mixtures of R and S enantiomers. Commercially available structures of these starting materials are represented in Formula II. The individual enantiomers differ from each other in two forms. First, the plane of polarized light is rotated in equal and opposite directions. Secondly, and more importantly, they react independently, to different degrees and in unpredictable ways with other chiral compounds, especially with complex chiral biological structures such as those of the human body. In addition to the optical activity, the enantiomers usually use have some physical properties different from the racemates such as melting point and solubility. However, the enantiomers differ from each other only in the two aforementioned forms. Finally, the identity of each individual enantiomer must be tested experimentally because its physical properties and different interactions with chiral biological molecules and systems can not be predicted in advance. For reports see March (1992); and, Burke and Henderson (2002). The separation or resolution of the individual enantiomers from a racemate follows the methods known to one skilled in the art. More frequently, only one enantiomer of a racemate usually provides a desired biological or drug effect. In fact, in many cases, the less active or inactive enantiomer of the racemic drug interacts in an unrelated and negative, different manner providing undesirable, damaging or toxic side effects. Accordingly, individual enantiomer drugs are more preferred. When investigating series of compounds based on a mechanism of action, it is not possible to predict which enantiomer of a racemic compound will possess the desirable drug activity. This new and useful knowledge can only be obtained through experimentation and analysis of experimental results. The United States Food and Drug Administration (FDA) offers a continuing guide to the development of optically active drugs that are electronically available and can be researched at www.fda.gov/cder/guidance/index.htm. For the report see Strong (1999); and the policy statement FDA (1992); and De Camp (1989); also, observe the research guide of chiral active substances (1994). This invention relates to the unique properties associated with the R-enantiomer of the compounds of Formula I. Prior to this invention, the individual enantiomer compounds of Formula I were not observed or characterized. Prior to this invention, the compounds of Formula I and II are not known to have been administered to animals, humans, or other biological systems. Certain starting materials of the following Formula III, useful for the preparation of the compounds of Formula I, are known in the art: Formula III Where aryio = phenyl, furan 2-yl and thiophen-2-yl and substitutions thereof. Detailed preparations for these starting materials are found, for aryl = phenyl, in Krauze et al. (1984); Krauze et al. (1991); Krauze et al. (1998); Krauze and Dudurs (2000); Tirzite et al. (2002); Sharanin et al. (1985); Sharanin et al. (1986); and for aryl = furan-2-yl and thiophen 2-yl in Attaby et al. (1996).

III.- Methods to Treat Cardiovascular Diseases A. Therapeutic Regimens for Hypertrophy and Heart Failure The current medical management of cardiac hypertrophy in the configuration of cardiovascular disorders includes the use of at least two types of drugs: inhibitors of the renin-angiotensin system, and β-adrenergic blocking agents (Bristow , 1999). Therapeutic agents for treating pathological hypertrophy in the configuration of heart failure include inhibitors of the angiotensin II converting enzyme (ACE) and β-adrenergic receptor blocking agents (Eichhom and Bristow, 1996). Other pharmaceutical agents have been described for the treatment of cardiac hypertrophy include but are not limited to angiotensin II receptor antagonists (U.S. Patent No. 5,604,251) and neuropeptide Y antagonists (WO 98/33791). Despite the currently available pharmaceutical compounds, the prevention and treatment of cardiac hypertrophy and the subsequent heart failure continues to present a major therapeutic challenge. The non-pharmacological treatment is mainly used as an auxiliary for pharmacological treatment. A means for non-pharmacological treatment involves the reduction of sodium in the diet. In addition, non-pharmacological treatment also involves the elimination of certain precipitating drugs, including negative inotropic agents (eg, certain calcium channel blockers, and antiarrhythmic drugs such as disopyramide), cardiotoxins (eg, amphetamines), and volume expanders. plasma (for example, non-steroidal anti-inflammatory agents, and glucocorticoids). In one embodiment of the present invention methods are provided for the treatment of cardiac hypertrophy or heart failure using the compounds of Formula I. For purposes of the present application, the treatment comprises the reduction of one or more of the symptoms of hypertrophy. cardiac, such as reduced exercise capacity, reduced blood ejection volume, increased left verticus diastolic pressure, increased pulmonary capillary force pressure, reduced cardiac output, cardiac index, increased pulmonary artery pressures, systolic and diastolic dimension of the increased left ventricular end, increased left ventricular wall tension, wall tension, and wall thickness (the same results may be true for the right ventricle). In addition, the use of the present invention can prevent cardiac hypertrophy and its associated symptoms from arising. Another potential therapeutic method is to reverse the structural changes that occur in the heart in response to hypertrophy and heart failure, a procedure known as cardiac remodeling. Remodeling refers specifically to changes in gene expression that occur as the heart becomes sicker. In remodeling, the genes normally expressed during fetal development (fetal genes such as SERCA, a-MyHC, etc.), are expressed aberrantly (for a report, see Lowes et al., 2002, hereinafter incorporated by references) . Originally these changes were thought to be irreversible, so the only hope was to provide therapy to relieve the symptoms. However, it has eventually been discovered that the discharge of human heart failure through placement of the patient in a left ventricular assist device could reverse some of the remodeling changes (Dipla et al., 1998). Recently it has been shown that this inverse remodeling can occur through pharmaceutical therapies (Bristow et al., 2000). Through the use of acetylcholine esterase inhibitors, improvements in cardiac contractility have been seen and systolic function of the heart has been improved (Eichorn et al., 1996; Lowes et al., 2002). In addition, ß-adrenergic receptor blockers have been shown to up-regulate a-MyHC and SERCA mRNA levels through indirect action on cardiac targets (Lowes et al., 2002). It is therefore plausible to treat the underlying contractile defects in the remodeled heart through direct up-regulation of a-MyHC which could lead to an inversion of the remodeling procedure. Treatment regimens may vary depending on the clinical situation. However, long-term maintenance may seem appropriate in most circumstances.

B. Combined Therapy In another embodiment, the use of the present invention is contemplated in combination with other therapeutic modalities. In this way, in addition to the therapies described above, the patient could also be provided with "standard" pharmaceutical cardiac therapies. Examples of other therapies include, without limitation, the so-called "beta blockers", anti-hypertensive, cardiotonic, anti-thrombotic, vasodilators, hormone antagonists, iontrophores, diuretics, endothelin antagonists, calcium channel blockers, phosphodiesterase inhibitors. , ACE inhibitors, angiotensin type 2 antagonists, and cytosine blockers / inhibitors, and HDAC inhibitors. The combinations can be achieved through the contact of the cardiac cells with an individual composition or a pharmacological formulation that includes both agents, or through contact of the cell, with two different compositions or formulations, at the same time. Alternatively, the therapy using the claimed formulation may precede or follow the administration of another agent (s) through intervals on the scale of minutes to weeks. In modalities where several agents are applied separately to the cell, it could generally be ensured that a significant period of time will not expire between the time of each distribution, so that the agents would still be able to exert an advantageously combined effect on the cell . In such instances, it is contemplated that the cell could be contacted with both modalities within 12-24 hours of each other, more preferably, within about 6-12 hours of each, with a delay time of only about 12 hours being more preferred. In some situations, it may be desirable to extend the period of time for treatment significantly, however, a lapse of several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) between the respective administrations.

It is also conceivable that more than one administration of any of the claimed compounds or the other agent is desirable. In this regard, various combinations can be used. By way of illustration, when the present invention is "A" and the other agent is "B", the following permutations based on total administrations of 3 and 4 are illustrative: A / B / AB / A / BB / B / AA / A / BB / A / AA / B / BB / B / B / AB / B / A / BA / A / B / BA / B / A / BA / B / B / AB / B / A / AB / AB / AB / A / A / BB / B / B / AA / A / A / BB / A / A / AA / B / A / AA / A / B / AA / B / B / BB / A / B / BB / B / A / B Other combinations are also contemplated. Pharmacological therapeutic agents and methods of administration, dosages, etc. are well known to those skilled in the art (see for example, the "Physicians Desk Reference", Goodman &Gilman's "The Pharmacological Basis of Therapeutics", "Remington's Pharmaceutical Sciences" , and "Ther Merck Index, thirteenth edition", incorporated herein by reference in relevant parts), and may be combined with the invention in light of the. descriptions of this. Some variations in dosage will necessarily occur depending on the combination of the subject being treated. The person responsible for the administration, in any event, will determine the appropriate dose for the individual subject, and said individual indeterminations are within the experience of those skilled in the art.

Non-limiting examples of a pharmacological therapeutic agent that can be used in the present invention include an antihyperlipoprotein agent, an antiarterlosclerotic agent, an antithrombotic / fibrinolytic agent, a blood coagulant, an antiarrhythmic agent, an antihypertensive agent, a suppressive vessel, a agent for the treatment of congestive heart failure, an antianginal agent, an antibacterial agent, or a combination thereof. In addition, it should be noted that any of the following can be used to develop new target gene groups for cardiac therapy. Since many of these genes are expected to overlap, the new target genes are likely to develop. a.- Antihyperlipoprotein In certain embodiments, the administration of an agent that decreases the concentrations of one or more lipids and / or lipoproteins, known herein as "antihyperlipoproteinics" may be combined with a cardiovascular therapy according to the present invention, particularly in the treatment of atherosclerosis, fatness or blockages of vascular tissue. In certain aspects, an antihyperlipoprotein agent may comprise an aryloxy alkanoic / fibric acid derivative, a resin / bile acid sequestrant, a CoA reductase inhibitor of HMG, a nicotinic acid derivative, a thyroid hormone or thyroid hormone analogue, a miscellaneous agent or a combination thereof. i. Derivatives of Aryloxyalkanoic Acid / Fibric Acid Non-limiting examples derived from aryloxyalkanoic / fibric acid include beclobrate, enzafibrate, binifibrate, ciprofibrate, clinofibrate, clofibrate (S-atromide), clofibric acid, etofibrate, fenofibrate, gemfibrozil (lobid), nicofibrate, pirifibrate, ronifibrate, simfibrate and teofibrate. ii. Resin Sequestrants / Bile Acid Non-limiting examples of resin / bile acid sequestrants include cholestyramine (colibate, show), colestipol (colestid) and plidexide. iii. Coa Hmg Reductase Inhibitors Non-limiting examples of CoA HMG reductase inhibitors include lovastatin (mevacor), pravastatin (pravochol) or simvastatin (zocor). iv. Nicotinic Acid Derivatives Non-limiting examples of nicotinic acid derivatives include nicotinate, acepimox, niceritrol, nicoclonate, nicomol, and oxiniacic acid.

Y. Thyroid and Analog Hormones Non-limiting examples of thyroid hormones and analogs thereof include etoroxate, thyropetric acid and thyroxine. saw. Miscellaneous antihyperlipoproteinics Non-limiting examples of miscellaneous antihyperlipoproteinics include acifran, azacosterol, benfluorex, ß-benzalbutyramide, carnitine, chondroitin sulfate, clomestrone, detaxtran, sodium dextran sulfate, - 5,8,11, 14,17-eicosapentaenoic acid, erytadenine, furazabol, meglutol, meiinamide, mitatrienediol, ornithine, β-oryzanol, pantethine, pentaerythritol tetraacetate, α-pefilbutyramide, pirozadil, probucol (lorelco), β-sitosterol, piperazine salt of sultosulic acid, thiadenol, triparanol and xenbucin. b. Antisclerotic Non-limiting examples of an antiarteriosclerotic include pyridinol carbamate. c. Antithrombotic / Fibrinolytic Agents In certain embodiments, administration of an agent that aids in the removal or prevention of blood clots can be combined with administration of a modulator, particularly in the treatment of atherosclerosis and vascular (eg, arterial) blockages. Non-limiting examples of antithrombotic and / or fibrinolytic agents include anticoagulants, anticoagulant antagonists, antiplatelet agents, thrombolytic agents, thrombolytic agent antagonists, or combinations thereof. In certain aspects, antithrombotic agents that can be administered orally, ie, for example, aspirin and wafarin (coumadin), are preferred. i. Anticoagulants A non-limiting example of an anticoagulant includes acenocoumarol, ancrod, anisindione, bromindione, chlorindione, coumetarol, cyclocumarol, sodium dextran sulfate, dicumarol, diphenadione, ethyl biscoumacetate, ethylidene dicoumarol, fluindione, heparin, hirudin, sodium liapolate, oxazidione, pentosan polysulfate, phenindione, fenprocoumon, fosvitina, picotamida, thioclomarol and warfarin. ii. Antiplatelet Agents Non-limiting examples of antiplatelet agents include aspirin, a dextran, dipyridamole (persantine), heparin, sulfinpyranone (anthurium) and ticlopidine (ticlid). iii. Thrombolytic Agents Non-limiting examples of thrombolytic agents include the tissue plasminogen activator (activase), plasmid, pro-urokinase, urokinase (abokinase), streptokinase (streptase), anistreplase / APSAC (eminase). d. Blood Coagulants In certain modalities where a patient is suffering from a hemorrhage or a probability of bleeding, an agent that can improve blood coagulation can be used. Non-limiting examples of a blood coagulation promoting agent include thrombolytic agent antagonists and anticoagulant antagonists. i. Antagonists Anticoagulants Non-limiting examples of anticoagulant antagonists include protamine and vitamin K1. ii. Antagonists of Thrombolytic and Antithrombotic Agents Non-limiting examples of thrombolytic agent antagonists include aminocaproic acid (amicar) and tranexamic acid (amstat). Non-limiting examples of antithrombotic agents include anagrelide, argatroban, cilstazole, daltroban, difibrotide, enoxaparin, fraxlparin, indobufen, lamoparan, ozagrel, picotamide, plafibride, tedelparin, ticlopidine and triflusal. and. Antiarrhythmic Agents Non-limiting examples of antiarrhythmic agents include Class I antiarrhythmic agents (sodium channel blockers), Class II antiarrhythmic agents (beta-adrenergic blockers), Class II antiarrhythmic agents (drugs that prolong repolarization), antiarrhythmic agents of Class IV (calcium channel blockers), and miscellaneous antiarrhythmic agents. i. Sodium Channel Newsers Non-limiting examples of sodium channel blockers include class IA antiarrhythmic agents, Class IB, and Class IC. Examples of limiting agents of class IA antiarrhythmic agents include dipiramide (norpace), procainamide (pronestil) and quinidine (quinidex). Non-limiting examples of class IB antiarrhythmic agents include lidocaine (xylocaine), tocainide (tonecard) and mexiletine (mexityl). Non-limiting examples of class IC antiarrhythmic agents include encainide (enkaid) and flecainide (tambocor). ii. Beta-blockers Non-limiting examples of beta-blockers, on the other hand known as β-adrenergic blocker, β-adrenergic antagonists or Class II antiarrhythmic agents, include acebutolol (sectral), alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufurarol, bunitrolol, bupranolol, butyraline hydrochloridate, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol (brevibloc), indenolol, labetalol, levobunolol, mepindolol, metripranolol , metoprolol, moprolol, nadolol, nadoxolol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propanolol (inderal), sotalol (betapace), sulfinalol, talinolol, tertatolol, timolol, toliprolol and xibinolol. In certain aspects, the beta blocker comprises an aryloxypropanolamine derivative. Non-limiting examples of aryloxypropanolamine include acebutolol, alprenolol, arotinolol, betaxolol, bevantolol, bisoprolol, bopindolol, bunitrolol, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, epanolol, indenolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nipradilol, oxprenolol, penbutolol, pindolol, propranolol, talinolol, tertatolol, timolol and toliprolol. iii. Agents for Repolarization Prolongation Non-limiting examples of an agent that prolongs repolarization, also known as a Class III antiarrhythmic agent, include amiodarone (cordarone) and sotalol (betapace). iv. Calcium Channel Blockers / Antagonists Non-limiting examples of calcium channel blockers, somehow known as Class IV antiarrhythmic agents, include arylalkylamine (eg, bepridil, diltiazem, fendiline, gallopamil, prenylamine, terodiline, verapamil), a derivative dihydropyridine (felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine) a piperazide derivative (eg, cinnarizine, flunarizine, lidoflazine) or a miscellaneous calcium channel blocker such as benziclan, etafenone, magnesium, mibefradil or perexilin. In certain embodiments, a calcium channel blocker comprises a long-acting hydropyridine calcium antagonist (amlodipine). v. Miscellaneous Antiarrhythmic Agents Non-limiting examples of miscellaneous antiarrhythmic agents include adenosine (adenocardin), digoxin (lanoxin), acecainide, ajmaline, amoproxan, aprindine, bretythyl tosylate, bunaftin, butobendin, capobenic acid, cyphenylin, disopyranide, hydroquinidine, indecainide, bromide, ipatropium, bromide, lidocaine, loraxine, lorcalnide, meobentin, moricizin, primenol, prajmalin, propafenone, pirinoline, quinidine polygalacturonate, quinidine sulfate, and viquidil.

F. Antihypertensive agents Non-limiting examples of antihypertensive agents include alpha / beta sympatholytic blockers, alpha blockers, anti-angiotensin II agents, beta blockers, calcium channel blockers, vasodilators, and miscellaneous antihypertensives. i. Alpha Blockers Non-limiting examples of an alpha-blocker, also known as an α-adrenergic blocker or α-adrenergic blocker, include amosulalol, arotinolol, dapiprazole, doxazosin, ergoloid mesylates, fenspiride, indoramin, labetalol, nicergoline, prazosin, terazosin, tolazoline , trimazosin and yohimbine. In certain embodiments, the alpha blocker may comprise a quinazoline derivative. Non-limiting examples of quinazoline derivatives include alfuzosin, bunazosin, doxazosin, prazosin, terazosin and trimazosin. ii. Alpha / Beta Blockers In certain embodiments an antihypertensive agent is both an alpha and beta adrenergic antagonist. Non-limiting examples of alpha / beta blockers comprise labetalol (normodin, trandate).

Ii. Anti-Angiotensin II Agents Non-limiting examples of anti-angiotensin II agents include angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. Non-limiting examples of angiotensin converting enzyme inhibitors (ACE inhibitors) include alcepril, enalapril (vasotec), captopril, cilazapril, delpril, enalaprilat, fosinopril, lisinopril, moveltopril, perindopril, quinapril and ramipril. Non-limiting examples of angiotensin II receptor blockers, also known as an angiotensin II receptor antagonist, an ANG receptor blocker, or an ANG-II type I receptor blocker (ARBS), include angiocandesartan, eprosartan, irbesartan, they would beat and waltz. iv. Sympatholytics Non-limiting examples of a sympatholytic include a sympatholytic that acts centrally or a sympatholytic that acts peripherally. Non-limiting examples of a centrally acting olympic simpa, also known as a sympatholytic of the central nervous system (CNS), includes clonidine (catapres), guanabenz (wytensin) guanfacine (tenex) and methyldopa (aldomet). Non-limiting examples of sympatholytics that act peripherally include a ganglion-blocking agent, an adrenergic neuron-blocking agent, a β-adrenergic blocking agent, or an alpha-1 adrenergic blocking agent. Non-limiting examples of a ganglion blocking agent include mecamylamine (invert) and trimetaphan (arfonad). Non-limiting examples of an adrenergic neuron-blocking agent include guanethidine (ismelin) and reserpine (serpasil). Non-limiting examples of β-adrenergic blockers include cenitolol (sectral), atenolol (tenormin), betaxolol, (kerlone), carteolol (cartrol), labeyalol (normodin, trandallum), metoprolol (lopressor), nadanol (corgard), penbutolol (levatol) ), pindolol (visken), propranolol (inderal) and timolol (blockade). Non-limiting examples of alpha-adrenergic blockers include prazosin (minipress), doxazocin (cardura), and iarazosin (hytrin). v. Vasodilators In certain embodiments, a cardiovascular therapeutic agent may comprise a vasodilator vessel (e.g., a cerebral vasodilator vessel, a coronary vasculature vessel, or a peripheral vasodilator vessel). In certain preferred embodiments, a dilator vessel comprises a coronary dilator vessel. Non-limiting examples of a coronary dilator vessel include amotriphene, bendazole, benfurodil hemisuccinate, benziodarone, chloracizine, cromonar, cobenfurol, clonitrate, dilazep, dipyridamole, droprenilamine, efloxate, erythritil tetraniirane, etafenone, fendiline, froredila, ganglefena, herestrol bis (ß-diethyl aminoethyl ether), hexobendin, tosyl Ithramin, khellin, lindoflanin, mannitol hexanitol, medibazine, nicorglycerin, peniatriol ether, pentrinitrol, perhexilin, primefillin, iprapidyl, trichromyl, trimeiazidine, glycine and visnadine phosphate. In certain aspects, a dilator vessel may comprise a chronic therapy dilator vessel or a hypertensive emergency dilator vessel. Non-limiting examples of a chronic therapy dilator vessel include hydralazine (apresolin) and minoxidil (loniien). Non-limiting examples of a hypertensive emergency vasodilator include nilroprusside (nipride), diazoxide (hyperstat IV), hydralazine (apresoline), minoxidil (loniten) and verapamil. saw. Miscellaneous antihypertensive drugs Non-monoamine examples of miscellaneous antihypertensives include ajmaline, γ-butyric acid, bufenioda, cyclintainin, cyclosidomine, a tannase of cryptenamine, fenoldopane, flosequine, ketanserin, mebutamate, mecamylamine, methyldopa, methyl 4-pyridyl, iosemicarbazone, and muzolimine. pargyline, pempidine, pinacidil, piperoxan, primaperone, a protoveratrin, raubasin, rescimetol, rilmenidene, saralasin, sodium nitroruside, ticrinafen, trimetafan, camsylate, tyrosinase and urapidil. In certain aspects, an antihypertensive agent may comprise an arylethanolamine derivative, a benzothiadiazine derivative, an N-carboxyalkyl derivative (peptide / lacma), a dihydropyridine derivative, a guanidine derivative, a hydrazine / ialazine, an imidazole derivative, an quaternary ammonium compound, a reserpine derivative, or a sulfonamide derivative. Derivatives of arylethanolamine. Non-limiting examples of arylethanolamine derivatives include amosulalol, bufuralol, dilevalol, labetalol, pronetalol, sotalol and suifinaloi. Derivatives of benzoydiazine. Non-limiting examples of benzothiazide derivatives include alíizide, bendroflumeiazide, benzthiazide, benzylhydrochlorothiazide, butiazide, chlorothiazide, chlorthalidone, cyclopheniazide, cyclothiazide, diazoxide, epithiazide, eiazide, phenquizone, hydrochlorothiazide, hydroflumetizide, methiclotizide, meicharana, meiolazone, parafluizide, politizide, teiraclormethiazide and trichlormetiazide.

Derivatives of? / - carboxyalkyl (peptide / lacym). Non-limiting examples of? / -carboxyalkyl derivatives (peptide / lacium) include alacepril, capipril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moveltipril, perindopril, quinapril and ramipril. Derivatives of dihydropyridine. Non-limiting examples of dihydropyridine derivatives include amlodipine, felodipine, isradipine, nicardipine, nifedipine, nilvadipine, nisoldipine, and nitrendipine. Guanidine derivatives Non-limiting examples of guanidine derivatives include belanidine, debrisoquin, guanabenz, guanacline, guanadrel, guanzodine, guanethidine, guanfacine, guanoclor, guanoxabenz and guanoxan. Hydrazines / phthalazines Non-limiting examples of hydrazines / phthalazines include budralazine, cadralazine, dihydralazine, endralazine, hydracarbazine, hydralazine, peniprazine, pildralazine and lodrlazine. Imidazole derivatives. Non-limiting examples of imidazole derivatives include clonidine, lofexidine, phentolamine, iamenidine and tolonidine. Quaternary ammonium compounds. Non-limiting examples of quaternary ammonium compounds include azamethonium bromide, chlorisondamine chloride, hexamethonium, bis (meilylsulpharose), peniacinium, pentamethonium bromide, penyolinium tartrate, fenacipropium chloride and trimethidinium methosulfamide.

Reserpine derivatives. Non-limiting examples of reserpine derivatives include bieiaserpine, deserpidine, rescinamine, reserpine and siringopine. Derivatives of sulfonamide. Non-limiting examples of sulfonamide derivatives include ambuside, clopamide, furosemide, indapamide, kinase, tripamide and xipamide. g. Vasopressors Vasopressors are generally used to increase blood pressure during an attack, which may occur during a surgical procedure. Non-limiting examples of a vasopressor, also known as an antimicrobial, include aminosity methyl sulfate, angiotensin amide, dimetofrine, dopamine, etifelline, erylephrine, gepephrine, meraminol, midodrine, norepinephrine, foledrine, and synephrine. h. Trainer's Agencies for Congestive Heart Failure Non-limiting examples of agents for the treatment of congestive heart failure include antiangiogenic agents II, antimalarial agents for the reduction of load after loading, diuretics, and non-pyroic agents. i. Reduction Before Loading-After Loading In certain embodiments, an animal patient who can not tolerate an angiotensin antagonist can be brought with a combination therapy. Said therapy may combine the administration of hydralazine (apresolin) and isosorbide dinitraium (isordil, sorbitol). ii. Diuretics Nonlimiting examples of diuretics include a thiazide or benzothiadiazine derivative (eg, altiazide, bendroflumefazide, benzthiazide, benzylhydrochloride, buiazide, chloroiazide, chloroiazide, chlorthalidone, cyclopeniazide, epiiazide, eiazide, ethiazide, phenquizone, hydrochlorothiazide, hydroflumeiazide, methicothiazide, methicrane , metolazone, paraflutizide, polythiazide, erythromomethazide, trichlormeiazide), an organomercurial (eg, rimeric kidney, meraluride, mercamfamide, sodium mercapomerelin, mercmalmalic acid, mercunalinium dodium, mercuric chloride, mersalil), a pleridino (for example, furterene, triamterene), purines (eg, acefillin, 7-morpholinylmethylphillin, pamobrom, proteobromin, theobromine), steroids including aldosterone aniiagonists (canrenone, oleandrin, spironolacyone), a sulfonamide derivative (eg, acetazolamide, ambuside, azosemide, bumetanide, buzozolamide, chloraminophenam da, clofenamide, clopamide, chlorexolone, diphenylamine-4,4'-disulfonamide, disulfamide, ethoxzolamide, furosemide, indapamide, mefruside, metazolamide, piretanide, kinase, ioside, tripamide, xipamide), a uracil (for example, aminometradine, amisometradine) , a potassium-sparing antagonist (eg, amiloride, tramterene), or a miscellaneous diuretic such as aminocin, arbutin, clorazanil, ethacrynic acid, ethozoline, hydracarbazine, isosorbide, manniol, methochalcone, muzolimine, perexilin, ticmafen and urea. iii. Inotropic Agents Non-limiting examples of a positive inolropic agent, also known as cardiotonic, include acetyline, an acetyldigitoxin, 2-amino-4-picoline, amrinone, benfurodil hemisucinate, bucladesine, cerberosine, camfotamide, convalatoxin, cimarine, denopamine, desolase, digitaline , digitalis, digitoxin, digoxin, dobutamine, dopamine, dopexamine, enoximone, eriirofleine, fenalcomin, gitalin, gytoxin, glycocyamine, heptaminol, hydraslinin, ibopamine, a lanaioside, metamivam, milrinone, nerifoline, oleandrine, ouabain, oxyfedrine, prenalterol, proscillaridine, resibufogenina, escilaren, escilarenina, estrfantina, sulmazol, iobromina and xamoterol. In particular aspects, an inotropic agent is a cardiac glycoside, a beta-adrenergic agonist or a phosphodiesierase inhibitor. Non-limiting examples of a cardiac glycoside include digoxin (lanoxin) and digitoxin (crislodiginin). Non-limiting examples of β-adrenergic agonists include albuterol, bamtuterol, bitolterol, carbuterol, chlorprenaline, denopamine, dioxetedrine, dobutamine (dobutrex), dopamine (intropin), dopexamine, ephedrine, etafedrine, ethylnorepinephrine, fenoterol, formoterol, hexoprenaiine, ibopamine, isoetharine , isoproterenol, mabuirel, meiaproterenol, methoxyphenamine, oxyfedrine, pirbuterol, procaterol, protoquilol, reprolerol, rimiirol, ritodrine, soterenol, terbualine, uroquinolol, tulobuterol and xamoterol. Non-limiting examples of a phosphodiesterase inhibitor include amrinone (inocor). i. Antiangin Agents Antiangin agents may comprise organ nitrates, calcium channel blockers, beta blockers and combinations thereof. Non-limiting examples of organ nitrates, also known as nitro vasodilators, include nitroglycerin (nitro-bid, niírostat), isosorbide dinitrate (isordil, sorbitrate) and amyl nitrate (aspirol, vaporole).

C. Pharmaceutical Formulations It will be understood that in the explanation of formulations and methods of treatment, references to the compounds of Formula I and Formula II also include pharmaceutically acceptable salts, as well as pharmaceutical compositions comprising these compounds. Also provided are treatments for cardiovascular disease, which comprises administering to a subject an effective amount of a compound of formula I, its pharmaceutically acceptable salts and an acceptable pharmaceutical carrier or formulation.

In specific embodiments of the invention, the pharmaceutical formulation will be formulated for delivery through rapid release, other contemplated modalities include, but are not limited to timed release, delayed release, and sustained release. The formulation can be an oral suspension in either solid or liquid form. In other embodiments, it is contemplated that the formulation may be prepared for distribution through parenteral distribution, or used as a suppository, or may be formulated for subcutaneous, intravenous, intramuscular, intraperitoneal, sublingual, transdermal, or nasopharyngeal distribution. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, soft or hard capsules or syrups or elixirs. The compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and said compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. in order to provide an elegant and tasty preparation pharmaceutically. The tablets contain the active ingredient mixed with pharmaceutically acceptable non-toxic excipients, which are suitable for tablet application. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulation and disintegration agents, for example, corn starch, alginic acid; binding agents, for example, starch, gelatin or acacia and lubricating agents, for example, magnesium stearate, steric acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glycerol monostearate or glyceryl distearate can be used. They can also be coated by the technique described in the patent of US Pat. No. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for the control of the release (hereinafter they are incorporated by reference). Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the ingredient active is mixed with water or with an oily medium, for example peanut oil, liquid paraffin, or olive oil. The aqueous suspensions contain the active material mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumgacanthus, acacia gum; dispersing or wetting agents which can be naturally occurring phosphatides, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic alcohols of long chain, for example, heptadecaethylene-oxicetanol, or condensation products of ethylenic oxide with partial esters derived from fatty acids and a hexitol as monooleate of sorbifol of polyoxiephylene, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexyol anhydrides, for example monooleate of polyethylene sorbitan. Aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoane, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame. Oily suspensions may be formulated through the suspension of the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those previously described, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an oxidant as ascorbic acid.

Dispersible powders and granules suitable for the preparation of an aqueous suspension through the addition of water provide the mixed active ingredient on a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil emulsions in water. The oily phase can be a vegetable oil, for example olive oil, peanut oil or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally occurring phosphatides, for example, soybeans, lecithin and partial esters or esters derived from fatty acids and hexylal anhydrides, for example, sorbitan monooleate, and condensation products of said partial esters with oxide. of ephelene, for example, monooleate of sorbitana of chickenxieiileno. Emulsions may also contain sweeteners and flavors. The syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Said formulations may also contain an emollient, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known technique using the appropriate dispersing and wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic solvent or solvent, for example, as in 1,3-butanediol solution. Among the vehicles and acceptable solvents that can be used are the water, the solution of this Ringer and the solution of sodium chloride isoionic. In addition, fixed, sterile oils are conventionally used as a solvent or suspension medium. For this purpose, any soft fixed oil can be used including synthetic mono or triglycerides. In addition, fatty acids, such as oleic acid, will find use in the preparation of pesticides. The compounds of Formula I can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the core to release the drug. These materials are cocoa butter, and polyethylene glycols. For topical use, creams, ointments, jellies, gels, epidermal solutions or suspensions, etc., which contain the compound of formula I are used. For purposes of this application, topical application should include mouthwashes and gargles.

The formulation can also be administered as nanoparticles, liposomes, granules, inhalers, nasal solutions, or intravenous mixtures. The previously mentioned formulations are all contemplated for trapping patients suffering from cardiovascular disease. Cardiovascular disease includes but is not limited to pathological hypertrophy and chronic and acute heart failure. The amount of active ingredient in any formulation can vary to produce a dosage form that will depend on the particular administration and mode of administration. It is further understood that the specific dosage for a patient will depend on a variety of factors including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, the combination of the drug and the severity of the therapy that is experiencing the particular disease.

IV. Methods of Preparation and Synthesis The compounds of the present invention can be prepared according to the following methods.

A. Method A In many cases the compounds of formula I can be prepared from the appropriate racemate of Formula II through preparative chromatographic separation using a chiral solid phase. High performance liquid chromatography (HPLC) is the most common technique used for said separation. Liquid chromatography of high pressure, medium pressure, low pressure, and atmospheric pressure can be used for said separation. Many liquid phases and chiral solid phases are available for this lipo of application: for a report see Francotie (2001); and Anderson and Allenmark (2002). For a report on semipreparative applications see Inotsume and Nakano (2002); and Boaífo y oíros (2003). Relay examples are found in Dolle and others. (1997); and Alajarín and others. (nineteen ninety five). In other embodiments, the A method of racemate to be separated first can be derivatized with a derivatizing or chiral agent to improve the resolution and efficiency of the separation; the solid phase can be prepared as a printed polymer of one or the other of the enantiomers to be separated; in some cases the separations can be achieved using an achiral solid phase, with chiral additives in the liquid phase; in some cases separations can be achieved using an achiral solid phase and a racemate derivatized with a chiral reagent; for a report see Toyo'oka (2002).

B. Method B The general scheme of method B follows that in Krauze and Oros (1984); Krauze and hear you. (1988); Krauze and Dudurs (2000); Krauze and others. (1998); Sharanin and others. (1985; Sharanin et al. (1986); Tirzite et al. (2002), and Aííaby y oíros (1996). The aldehydes of the match material and 1,3-diketones are commercially available or of extensive processes for their preparation or of the related compound in the literature and readily adaptable by one skilled in the art. 2-Cyanothioacetamide is commercially available. Eilanol is a suitable solvent and piperidine and morpholine are suitable bases to catalyze the formation of the ring in step 1. Step 1 is typically conducted at room temperature but can be carried out at moderately higher or lower temperatures. Step 2 is a hydrolysis of the salt of the intermediate of A. If desired, A can be isolated and purified by crystallization or chromatography. Ethanol is a suitable solvent hypeperidine and morpholine are suitable bases to catalyze the alkylation in the vessel 3. The leaving groups of the alkylating agent other than bromine, for example, iodine or triflate, may also be useful in step 3. Step 3 it is typically conducted at room temperature but can be carried out at lower or moderately higher levels. Steps 1 and 3 can be combined without step 2 or the isolation of any intermediary. If necessary, the purification can be accomplished by one skilled in the art with standard procedures.

Method B with groups R as in Formula II.

C. Method C The racemate to be separated is first reacted with a chiral derivatization agent to produce a mixture of diastereomers. These diastereomers can then be separated by one skilled in the art using standard techniques such as crystallization or chromatography. After separation and isolation of the individual diastereomers the previously added chiral derivatization group is removed using methods known to one skilled in the art and the individual pure enantiomers are obtained, further purified if necessary and characterized. March (1992).

D. Method D The racemate to be separated is first reacted with a chiral agent that forms a diastereomeric salt mixture from the racemate. For example, chiral acids and chiral amines. The diastereomeric salts are then separated by one skilled in the art and crystallization techniques are often used. The separated diastereomeric salts are then fed into the chiral salt-forming agent by one skilled in the art to produce the individual enantiomers, which can also be purified if necessary, and characterized. March (1992).

E. Method E The desired enantiomer can be prepared by one skilled in the art through the application of chiral or asymmetric synthesis. In this method, a chiral and optically active starting material or construction blocker can be added during the synthesis dictated by the synnicized enaniomer. In another embodiment of the method E, a chiral, non-incorporated reagent of the final compound is used during the synthesis to direct the chirality-selective formation in the compound with the formation of a single enantiomer. The related examples are Iqbal and others. (1994); Meyers and Oppenlaender (1986); and Enders and others. (1988). For more reports see Lida and Mase (2002), and Hillier and Reider (2002). In another embodiment of the method E one skilled in the art can apply bioprocedures for the asymmetric synthesis of the desired enantiomers. For a report see Patel (2001), and Huisman and Gray (2002). In another embodiment of method E, one skilled in the art can use deracemization at some point during the synthesis of the desired enantiomers. Deracement procedures can be achieved through bioprocedure or non-bioprocedure techniques. March (1992). In another embodiment of method E one skilled in the art may be able to use kinetic resolution laser to achieve an asymmetric synthesis or separation of the desired enantiomers. March (1992).

F. Method F In certain cases one skilled in the art may be able to use the chiral recognition of the individual enantiomers through the chiral ligand to give a feasible separation of the enantiomers in a racemate. March (1992).

EXAMPLES The following examples are included to further illustrate the various aspects of the invention. It should be appreciated by one skilled in the art that the techniques described in the examples that follow represent techniques and / or compositions discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for your practice However, those skilled in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments described and still obtain an equal or similar result without departing without the spirit and scope of the invention. .

EXAMPLE 1 Preparation and culture of neonatal rat ventricular myocytes (NRVM) was carried out through the removal of the hearts of rat newborn puppies of 1-3 days of age, together with the alrio and the lungs. The venices were cut into smaller pieces and digested 3 times with collagenase for 20-30 minutes at 37 ° C. The myocytes were then separated from the other cell types using a Percoll gradient. The myocyte layer was collected, washed twice, and plated on Petri dishes and 10 cm in tissue culture grade for 1-2 hours. The non-adherent cells (myocytes) were removed and placed in 96-well plates of transverse iris visor coated with 0.2% gelatin for at least two hours. The gelatin solution was removed, and the myocytes were resuspended in the middle of glucose DMEM (Mediaic) with FBS irradiated with 10% vegetai / dextran charcoal (Hyclone) and 1% penicillin-eslreptomycin-glutamine (PSG, Gibco). 10,000 NRVM per cavity were plated in a volume of 100 μl, and incubated overnight at 37 ° C in 5% C02 in air. The next day, the medium was replaced with 100 μl of high medium in serum free DMEM glucose supplemented with PSG and 0.3% of Nutridota-SP (Roche). The compounds were reconstituted in 30 mM DMSO, and the aliquots were stored at -20 ° C. A dilution of 1: 1000 was prepared in serum-free DMEM medium supplemented with PSG and 0.3% of Nutridoma, and sonicated for 5 minutes at room temperature. After sonication, triple dilutions were prepared in the same medium. The diluted compounds were then added to the NRVM clumps in a volume of 100 μl. A concentrated 100 nM IHI solution (T3) was prepared, Calbiochem) in 100 mM NaOH, and added to a final concentration of 3 nM in DMEM medium supplemented with PSG and 0.3% of Nutridoma-SP (Roche). NRVM was cultured for 3 days before the detection of heavy chain protein levels of a-myocin (a-MyHC) in the cytoblot assay. For the cytoblot assay of a-MyHC, the NRVM cultures were analyzed for a-MyHC protein levels after three days in incubation. NRVM was washed twice with PBS, fixed with methanol for 30 minutes at 4 ° C, and washed twice more with PBS. The blocking solution consisting of PBS with 1% bovine serum albumin (BSA, Fisher Biotech) was added for one hour at room temperature before the addition of a saturation amount of the swelling envelope containing a specific antibody a- MyHC for 60 minutes at ambient temperature (BA-G5 hybridoma, ATTC). Two washes were carried out with PBS / 1% BSA, and a 1: 500 dilution of IgG of goat anti-ration HRP (Southern Biotech) diluted in PBS / 1% BSA was added for 60 minutes at room temperature. The excess antibody was removed with 3 washes of PBS, and a chemiluminescent substrate was added (Pierce SuperSignal Wesi Pico Chemiluminiscenie Substrate) for 5 minutes before quantification on a Packard fusion plate reader. The following compounds, commercially available from ChemBridge Corporation (San Diego, CA), showed a measurable aclivity in the assays based on a-MyHC and ß-MyHC and the tests used for the determination of the novel biological activity of the compounds of this invention. .

TABLE 1 As shown in Table 1, Compound 1 increased the levels of a-MyHC protein as determined from the a-MyHC cycloblot assay. Compound 1 was added to NRVM at scale concentrations of fres nM at 30 μM. After 3 days in NRVM incubation, α-MyHC protein levels were determined in the cyclobiol assay and quantified (Figure 1). The increasing amounts of compound 1 resulted in progressively higher levels of pro-a-MyHC levels relative to non-simulated NRVM (no compound was added, set at 100%). An increase in a-MyHC protein levels was first detected starting at 30 nM, with a maximum response observed at 3 μM. In six independent experiments, the concentration of compound 1 that gave a maximum average response was an average of 60 nM.

EXAMPLE 2 The following compounds of Formula IV are commercially available from ChemBridge Corporation (San Diego, CA).

None of the compounds of Formula IV show activity in the α-MyHC and β-MyHC assays and the tests used for the determination of the novel biological activity of the compounds of this invention.

Formula IV Where R -? = Phenol, and R2 = mephyl; R1 = 2-chlorophenyl, and R2 = meityl, ethyl, and CH2CONH Phenyl; R 1 = 4-chlorophenyl, and R 2 = meityl, eryl and 3-niirobenzyl; R =? = 4-bromophenyl, and R2 = 3-nitrobenzyl; R1 = 4-ethylphenyl, and R2 = CH2CONH2; R = 2-niiophenyl, 1 and R2 = butyl; R S-nitrophenyl, and R 2 = benzyl; R1 = 4-hydroxyphenyl, and R2 = CH2CONH2; R =? = Furan-2-yl, and R2 = butyl and 3-methylybuyl-2-enyl; R? = Furan-3-io, and R2 = 3-niromobenzyl; R = iophene-2-yl, and R 2 = buyl, 3-methylbutyl-2-enyl and benzyl; Y, R ^ S-methylthiophen ^ -yl, and R2 = butyl and benzyl EXAMPLE 3 compound 1 As an independent measure of changes in a-MyHC protein levels, NRVM stimulated with compound 1 was analyzed for a-MyHC protein levels through Western blotting. Protein extracts prepared from NRVM stimulated with a concentration scale of compound 1 from 10 nM to 10 μM were separated through SDS-PAGE and transferred to a PVDF membrane. The a-MyHC proiein levels were cleared through cytoblot using the same monoclonal ani-a-MyHC antibody used in the cytoblot assay. As shown in Figure 2, the increasing amounts of the α-MyHC protein were observed with increasing amounts of compound 1. This experiment verified that the changes in the α-MyHC proiein detected in the cytoblot assay were also evident to íravés of Western blotting. In addition, the increase in protein levels of a-MyHC observed with T3 were similar to the increase seen with concentrations more aliases of compound 1.

EXAMPLE 4 Preparation of and activation of a-MyHC through the pure enantiomers of compound 1.

The racemic compound 1 was dissolved in ethanol to give a concentration of 2 mg / ml and then hexane was added to give a final solution of 60% ethanol: 40% hexane. 40 microliters of aliquots were injected into this solution of compound 1 on a chiral HPLC column (Chiralpak AD-H, 250 mm x 10 mm, 3 ml / min, mobile phase = 60:40 of ethanohexane). The S-enantiomer of compound 1 was collected from a peak with a retention time of 6.75 minutes and the R-enantiomer of compound 1 was collected from a peak with a retention time of 8.25 minutes. The separated fractions of the R and S enantiomers of compound 1 were evaporated under nitrogen to yield 8 mg of each pure enantiomer as a solid. The test of each enantiomer according to Example 1 showed that the R-enantiomer is capable of selectively increasing the levels of a-MyHC protein with an MPE50 = 0.79 μM while the inactive S-enantiomer showed an MPE or > 32 μM. Both enantiomers showed antihypertrophic activity as measured by the methods of Example 5.

EXAMPLE 5 Anti-hypertrophic activity of racemic compound 1 and purified enantiomers of compound 1.

Neonatal rat ventricular myocytes (NRVM) were isolated from Sprague-Dawley rats 1 to 3 days old using enzymatic digestion and myocyte enrichment techniques. NRVM was cultured in medium containing serum for 18 hours. For the continuation of the culture, serum-free medium was used. The hypertrophy of NRVM was induced using pharmacological stimulation, including phenylephrine, endothelin-1 and angiotensin I. Hypertrophic responses were determined using methods including the following. The edition of the total cellular protein; secretion of the atrial naíriuretic factor; determination of the volume of the cell; determination of the expression of the so-called true fey genes such as the natriuretic factor. aírial, heavy chain skeleton lactin beia-myocin and alpha. The ANF secretion was the most sensitive assay for the measurement of hypertrophy, and the ELISA ANF IC5o was the most useful measurement to determine the anti-hypertrophic activity. The IC 50 for the racemate was measured as 0.427 μM, the S enantiomer was 0.389 μM and the R enantiomer was 1,101 μM. All compositions and methods described and claimed herein can be made and executed without undue experimentation in light of the present disclosure. Since the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations can be applied to the compositions and methods, and in the steps or sequence of the steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are both chemically and physiologically related can be substituted by agents described herein while the same or similar results will be achieved. All such similar sub-changes and obvious modifications for those skilled in the art are considered to be spirit, scope, and concept of the invention as defined in the appended claims. vi.- References The following references, to the extent that they provide an illusive procedure or other supplementary guidelines to those established here by reference. Patent of E.U.A. 5,604, 251. Patent of E.U.A. 4,265, 874. Patent of E.U.A. 4,256, 108. Patent of E.U.A. 4,166, 452. Abraham and Oíros, Mol Med., 8 (11): 750-60,2002. Alajarin and Oíros, J. Medicinal Chem., 38: 2830, 1995. Anderson and Alenmark, J. Biochem. Biophysical Methods, 54: 11, 2002.

Arai et al., Circ. Res., 72: 463, 1993. Attaby et al., Phosphorous, Sulfur, and Silicone and Related Elements, 119: 1, 1996. Boaíío 15: 494, 2003. Bouvagneí y oíros, Basic Res. Cardiol., 84: 91- 102, 1989. Brisiow, Circulation, 101 (5): 558-569, 2000. Brisiow, Cardiology, 92: 3-6, 1999. Burke and Henderson, Brií. J Anaesthesia, 88: 563, 2002. De Camp, Chirality, 1: 2,1989. Dipla et al., Circulation, 97 (23): 2316-2322, 1998. Doile et al., Bioorganic Med. Chem., 5: 749, 1997. Duryy oíros, Ann. Med., 27: 311-317, 1995. Eichhom and Blizzard, Circulation, 94: 2285-2296, 1996. Enders 29: 6437, FDA Policy Statement, 4: 1992. Francotte, J. Chromatography A, 906: 379.2001. Goodman & Gilman's The Pharmacological Basis Of Therapeutics, Hardam and Oros, ed., 10th ed., 32: 853-860; 35: 891-893, 2001. Hajjar et al. Circulation, 86 (6): 1819-1826, 1992. Hillier and Reider, Drug Discovery Today, 7: 2002. Huisman and Gray, Currenl Opinion in Biotechnology, 13: 352, 2002. lida and Mase, Currení Opinion 5: 834,2002. Inoisume and Nakano, J. Biophysical Meíhods, 54: 255,2002. Iqbal et al., Chiralty, 6: 515,1994. Krauze and Dudurs, Chemisíry of Heíerocyclic Compounds, 36: 693, 2000. Krauze and others, Khimiko-Farmatsevicheskii Zhurnal, 25:40, Krauze and others, Khimiko-Farmatsevticheskii Zhurnal, 22: 48, 955, 1988. Krauze et al., Khimiya Geerolsiklicheskikh Soedinenii, 1694, 1984. Krauze and Oryros, Teirahedron, 54: 9161, 1998. Lowes et al., J. Invest. Med., 43: 316A, 1995. Lowes et al., J. Clin. Invest., 100 (9): 2315-2324,1997. Lowes et al., N. Engl. J Med., 346 (18): 2002. March, Advanced Organic Chemistry, 4th. Chapter, page 4, page 94, 1992. Marian and Roberts, Circulation, 92: 1336-1347,1995. Meyers and Oppenlaender, J. Chem. Soc. Chem.

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Note for Guidance - Investigation of Chiral Active Substances. Brussels: Commission of the European Union, 111/3601/91, 1994. Pagani et al., Circ. Res., 63 (2): 380-385, 1988. Patel, Currení Opinion in Bioíech., 12: 587,2001. PCT Patent Application No. WO 98/33791 Raizada et al., Molecular and Cell Biochemistry, 198: 109, 1999. Raizada y oíros, Cardiovascular Res., 27: 1869, 1993. Reiser and others, Am. J. Physiol. Heart Circ. Physiol. 280 (4): H1814-H1820, 2001. Remington's Pharmaceutical Sciences, 15th ed., 1035-1038, 1570-1580, Mack Publishing Co., PA, 1980. Samarel et al., American J. Physiology, 263: C642, 1992. Schwartz and others, Circulation, 91: 532-540, 1995. Sharanin et al., Zhurrnal Organicheskoi Khimii, 22: 2600, 1986. Sharanin et al., Zhurrnal Organicheskoi Khimii, 21: 683, 1985. Simpson et al., American J. Physiology, 270: C1075, 1996. Strong, Food and Law Journal, 54: 463, 1999. The Merck Index, O'Neil and Oíros, 13th edition, 2001 Thierfelder and others, Cell, 77: 701-712, 1994. Tirzite et al., Chem. Heterocyclic Compounds, 38: 795, 2002. Toyo'oka, J. Biochemical and Biophysical Methods, 54: 25,2002. Waíkins y oíros, N. Enql. J. Med., 326: 1108-1114, 1992.

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Claims (30)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A composition comprising an optically active compound that has Formula I; Formula I and pharmaceutically acceptable salts thereof, wherein: R. and R5 are independently phenyl, pyridine, pyrimidine, thiophene, furan, oxazole, isoxazole, isoazole, isoiazole, imidazole and pyrazole, and any of Ri and R5 can be optionally substituted by one or more of halogen, NO2, CN, CF3, C? -4 alkyl, C0-4-S alkyl, C0-4-O alkyl, C0-4-NH alkyl, (C-? - alkyl) ) 2-N, C - ?.4-SO alkyl, C? -4 -4-SO2t S02-NH alkyl, C0-4 alkyl, S02N (C1-4 alkyl) 2, NHSO2- C1 alkyl -4, CONH- C 0 alkyl-, NHCO- C 0 -4 alkyl and COO- C 0 alkyl-; wherein R 2 is C 1 alkyl, R 3 and R are Co- alkyl; and alkyl can be a straight or branched chain; and where n is 1-4; and which additionally comprises all the diastereomers; wherein the composition is substantially free of the S-form. The composition according to claim 1, further characterized in that the R enaniomer of said compound is greater than 70% pure, greater than 75% pure, greater than 80% pure, greater than 85% pure, greater than 90% pure, greater than 95% pure, greater than 96% pure, greater than 97% pure, greater than 98% pure, or greater than 99% pure. 3. The composition according to claim 1, further characterized in that Ri and R5 are independently phenyto, iiophen, furan, oxazole and thiazole; and any of R-1 and R 5 may optionally be subsumed by one or more of halogen, NO 2, CN, CF 3, C 1 -4 alkyl, C 0-4-S alkyl, C 4 -4 -O alkyl, C 0 alkyl. -4- NH, (C-? 4 alkyl) 2-N, C 1-4 alkyl-SO, C 1-4 alkyl-SO 2, S0 2 -NH-C0-4 alkyl, S02N (C1-alkyl) -4) 2, NHSO2- C4-4 alkyl, CONH- C0-4 alkyl, NHCO-C1-4 alkyl and COO-C0-4 alkyl. 4. The composition according to claim 3, further characterized in that R-i and R5 are independently phenyl, thiophene, and furan; and any of Ri and R5 may optionally be subsitiated by one or more of halogen or N02, CN, CF3, alkyl of C.-4, alkyl of C0-4-O, (C1-4 alkyl) 2-N, S02 -NH-C0-4 alkyl, NHSO2-C- alkyl, CONH-C0-4 alkyl, NHCO-C1-4 alkyl and COO-C0.4 alkyl; and R3 is C? -4 alkyl. 5. - The composition according to claim 4, further characterized in that R2 is CH3; R3 is CH3; R is C0- alkyl; and n is 1-2. 6. The composition according to claim 5, further characterized in that Ri and R5 are independently phenyl; and any of R 1 and R 5 may optionally be subsided by one or more of Br, Cl, F, NO 2, CF 3, CH 3, CH 30, (C 1 -N alkyl, CONH- C 0 alkyl-, NHCO-C alkyl- and COO- C0- alkyl and R is H. The composition according to claim 6, further characterized in that n is 1. 8. The composition according to claim 7, further characterized in that R and R5 are independently phenyl, and any of Ri and R5 may optionally be substituted by one or more of Cl, F, N02, CF3, CH3, CH3O 9.- A pharmaceutical formulation comprising a compound having the Formula II: Formula II and pharmaceutically acceptable salts thereof, wherein: Ri and R5 are independently phenyl, pyridine, pyrimidine, thiophene, furan, oxazole, isoxazole, thiazole, isothiazole, imidazole and pyrazole, and any of Ri and R5 can optionally be substituted by one or more of halogen, N02, CN, CF3, C? - alkyl, C0-4-S alkyl, C0-4-O alkyl, C0-4-NH alkyl, (C1- alkyl) 2-N , C? -4-SO alkyl, C?-S02 alkyl, SO 2 -NH-C alquilo-4 alkyl, S02N (alkyl) "C1-4) 2, NHS02- C1-4alkyl, CONH-C0-4alkyl, NHCO-C1-4alkyl, and COO-Coalkyl- wherein R2 is C4-4alkyl , R3 and R4 are C0-4 alkyl, and alkyl may be straight or branched chain, and wherein n is 1-4, and also include the diastereomers 10. The formulation according to claim 9, 10 further characterized in that the compound is the R-enantiomer. 11. The formulation according to claim 10, further characterized in that the R-enantiomer comprises more than 70% of the compound, more than 75% of the compound, more than 80% of the compound. , more than 85% of the compound, more than 90% of the compound, more than 95% of the 15 compound, more than 96% of the compound, more than 97% of the compound, more than 98% of the compound, and more than 99% of the compound. 12. The formulation according to claim 10, further characterized because it is formulated for delivery through the route of rapid release, time release, delayed release, Sustained release, oral suspension, parenteral dissolution, suppository, subcutaneous intravenous, intramuscular, intraperitoneal, sublingual, transdermal or nasopharyngeal. 13. - The formulation according to claim 10, further characterized in that the compound is in solid form. 14. The formulation according to claim 10, further characterized in that the compound is in liquid form. 15. The formulation according to claim 10, further characterized in that the compound is formulated as an uncoated tablet, a covered tablet, a capsule, a powder, a troche, a granule, a liposome, a suppository, a solution, a colloid, an ointment, a cream, a vapor, a spray, a nanoparticle, an inhaler, a nasal solution, an iniravenous mixture, an epidermal solution, a buccal tablet, a syrup, a cream, a lotion, a emulsion, or an elixir. 16. The formulation according to claim 15, further characterized in that it additionally comprises one or more of a binding agent, a filler, a preservative, a tablet disintegrant, a flow regulator, a plasicifier, a wetting agent, a. Dispersant, an emulsifier, a solvent, a slow release agent, an antioxidant, or a driving gas. 17. The use of the formulation defined in claim 9, for the preparation of a medicament for treating a cardiovascular disease in a patient. 18. The use claimed in claim 17, wherein said formulation is administrable in one canine and through a sufficient route to achieve up-regulation of mRNA levels of a-MyHC in cardiomyocytes. 19. The use claimed in claim 17, wherein said formulation is administrable in an amount and through a sufficient route to achieve an up-regulation of the levels of a-MyHC proiein in cardiomyocytes. 20. The use claimed in claim 17, wherein said formulation is administrable in an amount and through a sufficient route to achieve an increase in the consistency of cardiomyocycles. 21. The use claimed in claim 17, wherein the cardiovascular disease includes pathological hypertrophy, chronic heart failure and acute heart failure. 22. The use of the pharmaceutical composition defined in claim 9, for the preparation of a medicament for modulating α-myosin in a cell. 23. The use claimed in claim 22, wherein said cell is an isolated cardiomyocyte. 24. The use claimed in claim 22, wherein said cardiomyocyte is located in the "heart tissue" 25. The use claimed in claim 24, wherein said heart tissue is in an intact heart. in a subject human being 26. The use claimed in claim 22, wherein said cardiomyocyte is located in a venlicle of an iniact heart. 27. - The use claimed in claim 26, wherein the venlricle is the left venlicle. 28. The use claimed in claim 17, wherein an additional pharmaceutical composition is additively administrable. 29. The use claimed in claim 28, wherein said additional pharmaceutical composition is selected from the group consisting of anti-hypertensive, beta-blockers, cardiomyocyte, anti-hypertensive, vasodilators, hormone antagonists, endoyelin antagonists, inhibitors / blockers of cytosine, calcium channel blockers, phosphodiesterase inhibitors and angiotensin type II antagonisms. 30. The use of the formulation defined in claim 9, for the preparation of a medicament for inducing the reversal of remodeling hypertrophic tissue or heart failure to a subject suffering from cardiac hypertrophy and / or heart failure.