USOO7638519B2

(12) United States Patent (10) Patent No.: US 7,638,519 B2 Bush et al. (45) Date of Patent: Dec. 29, 2009

(54) COMPOUNDS, PHARMACEUTICAL Al-Omran, "Aynthesis and biological effects of new derivatives of COMPOSITIONS, AND METHODS FOR THE benzotriazole as antimicrobial and antifungal agents. J. Heterocy TREATMENT OF CARDOVASCULAR clic Chem., 39:877-883, 2002. DISEASE Casnati et al., “Some synthetic applications of the reaction of reduc tive opening of the isoxazole ring.” Tet. Lett. 233-238, 1966. (75) Inventors: Erik Bush, Erie, CO (US); Larry Gewald et al., “Synthesen von 4-amino-thieno2.3—bpyridinen.” Melvin, Longmont, CO (US) Monatshefie fiur Chemie, 110:1189-1196, 1979. Kandeel, "Nitriles in heterocyclic synthesis: a novel synthesis of (73) Assignee: Myogen, Inc., Westminster, CO (US) some thieno2,3-diprimidine and thieno2,3-bpridine derivatives.” Heteroatom Chemistry, 7:29-33, 1966. (*) Notice: Subject to any disclaimer, the term of this Mohareb et al., “Synthetic potentialities of thiophene systems in patent is extended or adjusted under 35 heterocyclic synthesis: a novel synthesis of thieno2,3-bipyridine U.S.C. 154(b) by 438 days. derivatives.” Phosphorous, Sulfur and Silicon and the Related Ele ments, 155:215-233, 1999. (21) Appl. No.: 11/018,383 Strekowski et al., "A facile synthesis of 2-aryl- and 2-heteroaryl (22) Filed: Dec. 21, 2004 Substituted 4-aminoquinolines.” Heterocycles, 29:539-545, 1989. Strekowski et al., “Synthesis of 2,2,4-trisubstituted-1,2- (65) Prior Publication Data dihydroquinazolines,” J. Heterocyclic Chem... 26:923-928, 1989. Strekowski et al., “Synthesis of bis(2-arylguinolin-4-yl)amines by US 2005/0288331 A1 Dec. 29, 2005 lithium bis(trimenthylsilyl)amide-mediated cyclization of ketimines derived from 2-(trifluoromethy)anilines and aryl methyl ketones,” J. Related U.S. Application Data Org. Chem., 62:4193-4196, 1997. Thomsen and Torssell. “Synthesis of simple quinoline alkaloids. A (60) Provisional application No. 60/531,854, filed on Dec. novel quinazoline synthesis.” Acta Chimica Scandinavica, Series B. 23, 2003. Organic Chemistry and Biochemistry, B42:309-313, 1988. (51) Int. Cl. Young et al., Handbook of Applied Therapeutics, 7.1-7.12 and 9.1- CO7D 215/38 (2006.01) 9.10, 1989. A6 IK 38/45 (2006.01) Fitzgerald et al., “Possible role of valvular serotonin 5-HT2B recep tors in the cardiopathy associated with fenfluramine.” Molecular (52) U.S. Cl...... 514/256; 546/114 Pharmacology, 57: 75-81, 2000. (58) Field of Classification Search ...... 546/114; Knowles and Ramage, “Evidence for a role for central 5-HT, as well 514/256 as 5-HT2 receptors in cardiovascular regulation in anaesthetized See application file for complete search history. rates.” British Journal of Pharmacology, 128:530-542, 1999. (56) References Cited Ogawa et al., “Pharmacological profiles of R-96544, the active form of a novel 5-HT, receptor antagonist R-102444.” European Journal U.S. PATENT DOCUMENTS of Pharmacology, 457: 107-114, 2002. Villalón et al., "Serotonin receptors as cardiovascular targets.” Drug 5,093,493 A 3/1992 Thompson et al...... 544,126 Discov. Today, 2(7):294-300, 1997. 6,974,870 B2 * 12/2005 Cywin et al...... 546,114 7,119,102 B2 * 10/2006 Chen et al...... 514,301 Office Communication issued in European Application No. EP04815043, dated Feb. 29, 2008. FOREIGN PATENT DOCUMENTS Frishman et al., 'Serotonin and serotonin antagonism in cardiovas cular and non-cardiovascular disease,” J. Clin. Pharmacol., 35:541 WO WO 2006,103511 10, 2006 572, 1995. WO WO 2006/122944 11, 2006 WO WO 2006/125812 11, 2006 * cited by examiner OTHER PUBLICATIONS Primary Examiner D. Margaret Seaman Bush et al., “A Small molecular activator of cardiac hypertrophy (74) Attorney, Agent, or Firm Fulbright & Jaworski uncovered in a chemical screen for modifiers of the calcineurin signaling pathway.” Proc. Natl. Acad. Sci. USA, 101:2870-2875, (57) ABSTRACT 2004. Kireev et al., “Molecular modeling and quantitative structure-activity studies of anti-HIV-1 2-heteroarylguinoline-4-amines.” Eur: J. Med. The present invention provides certain compounds, pharma Chem., 30:395-402. Ming et al., “Heterocondensed Pyridines by Cycloaddition-Extru ceutical formulations thereof, and methods for the treatment sion Sequence of Bi- and Tricyclic 1.3-Oxaziones with N,N-Diethyl of conditions mediated by 5-HT2 receptors. These com 1-propynylamine.” Chem. Ber. 120: 1427-1431, 1987. pounds provide for modulation of the signals mediated by Pinard et al., “4-Aminoquinolines as a Novel Class of NR1/2B Sub 5-HT2 receptors, specifically those receptors in the cardio type Selective NMDA Receptor Antagonists.” Bioorganic & Med. vascular system. Thus, these compounds may be used alone Chem. Lett., 12:2615-2619, 2002. or in conjunction with other drugs to treat cardiovascular Strekowski et al., “Synthesis and Quantitative Structure-Activity diseases such as, but not limited to, muscle atrophy, cardiac Relationship Analysis of 2-(Aryl or Heteroaryl)cquinolin-4-amines, a hypertrophy, heart failure, and primary pulmonary hyperten New Class of Anti-HIV-1 Agents.” J. Med. Chem., 34:1739-1746, S1O. 1991. Valentiet al., "Acetylcholinesterase inhibition by tacrine analogues.” Bioorg. & Med. Chem. Lett., 7:2599-2602, 1997. 4 Claims, No Drawings US 7,638,519 B2 1. 2 COMPOUNDS, PHARMACEUTICAL disease associated with infectious sequelae. In Sum, cardi COMPOSITIONS, AND METHODS FOR THE omyopathies, including DCM, are significant public health TREATMENT OF CARDOVASCULAR problems. DISEASE Heart disease and its manifestations, including coronary artery disease, myocardial infarction, congestive heart fail This application claims benefit of priority to U.S. Provi ure, PPH, and cardiac hypertrophy, clearly present a major sional Application Ser. No. 60/531,854, filed Dec. 23, 2003, the entire contents of which are hereby incorporated by ref health risk in the United States today. The cost to diagnose, CCC. treat and Supportpatients Suffering from these diseases is well 10 into the billions of dollars. Two particularly severe manifes BACKGROUND OF THE INVENTION tations of heart disease are myocardial infarction and cardiac hypertrophy. With respect to myocardial infarction, typically I. Field of the Invention an acute thrombocytic coronary occlusion occurs in a coro This invention relates to compounds, pharmaceutical com nary artery as a result of atherosclerosis and causes myocar positions and methods for the treatment of cardiovascular 15 dial cell death. Because cardiomyocytes, the heart muscle diseases that are mediated by serotonin receptors (5-HT2R), cells, are terminally differentiated and generally incapable of and in particular, muscle atrophy, heart failure, cardiac hyper cell division, they are generally replaced by Scar tissue when trophy and primary pulmonary hypertension (PPH). they die during the course of an acute myocardial infarction. II. Description of Related Art Scar tissue is not contractile, fails to contribute to cardiac Muscle atrophy refers to the wasting or loss of muscle function, and often plays a detrimental role in heart function tissue resulting from disease or lack of use. The majority of by expanding during cardiac contraction, or by increasing the muscle atrophy in the general population results from disuse. size and effective radius of the ventricle, for example, becom People with sedentary jobs and senior citizens with decreased ing hypertrophic. activity can lose muscle tone and develop significant atrophy. With respect to cardiac hypertrophy, one theory regards This type of atrophy is reversible with vigorous exercise. 25 this as a disease that resembles aberrant development and, as Bed-ridden people can undergo significant muscle wasting. Such, raises the question of whether developmental signals in Astronauts, free of the gravitational pull of Earth, can develop the heart can contribute to hypertrophic disease. Cardiac decreased muscle tone and loss of calcium from their bones hypertrophy is an adaptive response of the heart to virtually following just a few days of weightlessness. all forms of cardiac disease, including those arising from Muscle atrophy resulting from disease rather than disuse is 30 hypertension, mechanical load, myocardial infarction, car generally one of two types, that resulting from damage to the diac arrhythmias, endocrine disorders, and genetic mutations nerves that supply the muscles, and disease of the muscle in cardiac contractile protein genes. While the hypertrophic itself. response is initially a compensatory mechanism that aug Examples of diseases affecting the nerves that control ments cardiac output, Sustained hypertrophy can lead to muscles would be poliomyelitis, amyotrophic lateral Sclero 35 DCM, heart failure, and sudden death. In the United States, sis (ALS or Lou Gehrig's disease), and Guillain-Barre syn approximately half a million individuals are diagnosed with drome. Examples of diseases affecting primarily the muscles heart failure each year, with a mortality rate approaching would include muscular dystrophy, myotonia congenita, and 50%. myotonic dystrophy as well as other congenital, inflamma The causes and effects of cardiac hypertrophy have been tory, or metabolic myopathies (muscle diseases). 40 extensively documented, but the underlying molecular Common causes of muscle atrophy include: age-related mechanisms have not been elucidated. Understanding these muscle wasting, cerebrovascular accident (stroke), spinal mechanisms is a major concern in the prevention and treat cord injury, peripheral nerve injury (peripheral neuropathy), ment of cardiac disease and will be crucial as a therapeutic other injury, prolonged immobilization, osteoarthritis, rheu modality in designing new drugs that specifically target car matoid arthritis, prolonged corticosteroid therapy, diabetes 45 diac hypertrophy and cardiac heart failure. As pathologic (diabetic neuropathy), burns, poliomyelitis, amyotrophic lat cardiac hypertrophy typically does not produce any symp eral sclerosis (ALS or Lou Gehrig's disease), Guillain-Barre toms until the cardiac damage is severe enough to produce syndrome, muscular dystrophy, myotonia congenital, myo heart failure, the symptoms of cardiomyopathy are those tonic dystrophy, myopathy, cancer-related cachexia, AIDS associated with heart failure. These symptoms include short related cachexia. 50 ness of breath, fatigue with exertion, the inability to lie flat Cardiovascular diseases, and in particular heart failure, are without becoming short of breath (orthopnea), paroxysmal among the leading causes of morbidity and mortality in the nocturnal dyspnea, enlarged cardiac dimensions, and/or world. In the U.S. alone, estimates indicate that 3 million swelling in the lower legs. Patients also often present with people are currently living with cardiomyopathy and another increased blood pressure, extra heart Sounds, cardiac mur 400,000 are diagnosed on a yearly basis. Dilated cardiomy 55 murs, pulmonary and systemic emboli, chest pain, pulmonary opathy (DCM), also referred to as “congestive cardiomyopa congestion, and palpitations. In addition, DCM causes thy, is the most common form of the cardiomyopathies and decreased ejection fractions (i.e., a measure of both intrinsic has an estimated prevalence of nearly 40 per 100,000 indi systolic function and remodeling). The disease is further viduals (Durand et al., 1995). Although there are other causes characterized by Ventricular dilation and grossly impaired of DCM, familial dilated cardiomyopathy has been indicated 60 systolic function due to diminished myocardial contractility, as representing approximately 20% of "idiopathic' DCM. which results in dilated heart failure in many patients. Approximately half of the DCM cases are idiopathic, with the Affected hearts also undergo cell/chamber remodeling as a remainder being associated with known disease processes. result of the myocyte/myocardial dysfunction, which contrib For example, serious myocardial damage can result from utes to the “DCM phenotype.” As the disease progresses so do certain drugs used in cancer chemotherapy (e.g., doxorubicin 65 the symptoms. Patients with DCM also have a greatly and daunoribucin), or from chronic alcohol abuse. Peripartum increased incidence of life-threatening arrhythmias, includ cardiomyopathy is another idiopathic form of DCM, as is ing ventricular tachycardia and Ventricular fibrillation. In US 7,638,519 B2 3 4 these patients, an episode of syncope (dizziness) is regarded wherein R may be H, OH, C-alkyl-O, SH, C-alkyl-S, as a harbinger of Sudden death. CH NRsRo, and NRR, and R may be H. Co-alkyl, and Diagnosis of dilated cardiomyopathy typically depends C-cycloalkyl. R is phenyl, pyridine, pyrimidine, upon the demonstration of enlarged heart chambers, particu thiophene, furan, oxazole, isoxazole, thiazole, isothiazole, larly enlarged ventricles. Enlargement is commonly observ imidazole, pyrazole and pyrrole, and any of Rs may be option able on chest X-rays, but is more accurately assessed using ally substituted by one or more of halogen, NO, CN, CF, echocardiograms. DCM is often difficult to distinguish from C-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. (C- acute myocarditis, valvular heart disease, coronary artery alkyl)-N, C-alkyl-SO, C-alkyl-SO, SONH-Co disease, and hypertensive heart disease. Once the diagnosis of 10 alkyl, SON(C-alkyl). NHSO, C-alkyl, CONH dilated cardiomyopathy is made, every effort is made to iden Co-alkyl, NHCO-C-alkyl and COO Co-alkyl; R and tify and treat potentially reversible causes and prevent further Rs are, independently, H, and both R and Rs cannot simul heart damage. For example, coronary artery disease and val taneously be H, C-alkyl, C-cycloalkyl; R and Rs may Vular heart disease must be ruled out. Anemia, abnormal also be independently, but not simultaneously, phenyl, pyri tachycardias, nutritional deficiencies, alcoholism, thyroid 15 dine, pyrimidine, thiophene, furan, oxazole, isoxazole, thia disease and/or other problems need to be addressed and con Zole, isothiazole, imidazole, pyrazole, cyclohexyl, cyclohex trolled. enyl, cyclopentyl, cyclopentenyl, tetrahydropyridine, As mentioned above, treatment with pharmacological tetrahydrothiophene, and tetrahydrofuran, anaromatic ring or agents still represents the primary mechanism for reducing or a non-aromatic ring, excluding 3-methyl-2-phenyl-5.6.7.8- eliminating the manifestations of heart failure. Diuretics con tetrahydro-benzo 4,5thieno2,3-bipyridin-4-ylamine and stitute the first line of treatment for mild-to-moderate heart failure. Unfortunately, many of the commonly used diuretics 2-phenyl-quinolin-4-ylamine. In certain embodiments, the (e.g., the thiazides) have numerous adverse effects. For aromatic ring may be optionally Substituted by one or more of example, certain diuretics may increase serum cholesterol halogen, NO, CN, CF, C-alkyl, Co-alkyl-S, Co-alkyl and triglycerides. Moreover, diuretics are generally ineffec 25 O. Co-alkyl-NH. (Co-alkyl)-N, C-alkyl-SO, C tive for patients suffering from severe heart failure. alkyl-SO, SONH Co-alkyl, SON(C-alkyl). If diuretics are ineffective, vasodilatory agents may be NHSO, C-alkyl, CONH Co-alkyl, NHCO-C- used; the angiotensin converting (ACE) inhibitors (e.g., ena alkyl and COO Co-alkyl. In yet further embodiments, the lopril and lisinopril) not only provide symptomatic relief, 30 non-aromatic ring may be optionally substituted by one or they also have been reported to decrease mortality (Young et more of C-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl al., 1989). Again, however, the ACE inhibitors are associated NH, (C-alkyl)-N, C-alkyl-SO, C-alkyl-SO, with adverse effects that result in their being contraindicated SONH Co-alkyl, SON(C-alkyl). NHSO, C in patients with certain disease states (e.g., renal artery Steno alkyl, CONH Co-alkyl, NHCO C-alkyl and COO sis). Similarly, inotropic agent therapy (i.e., a drug that 35 Co-alkyl. improves cardiac output by increasing the force of myocar In one embodiment, where R is H, then R is H. Co-alkyl, dial muscle contraction) is associated with a panoply of Co-cycloalkyl, OH, C-alkyl-O, SH, C-alkyl-S, CH2— adverse reactions, including gastrointestinal problems and NRR, or NRR. In another embodiment where R is Hand central nervous system dysfunction. R is also H, C-alkyl or Cle-cycloalkyl; then R is either H. Thus, the currently used pharmacological agents have 40 Co-alkyl, C-cycloalkyl, OH, C-alkyl-O, SH, C severe shortcomings in particular patient populations. The alkyl-S, CH NRR and NR.R. prognosis for patients with DCM is variable, and depends In certain embodiments, X and Y are null, and then Ra and upon the degree of ventricular dysfunction, with the majority Rs taken together may form a ring selected from phenyl, of deaths occurring within five years of diagnosis. Thus, the 45 pyridine, pyrimidine, thiophene, furan, oxazole, isoxazole, availability of new, safe and effective agents would undoubt thiazole, isothiazole, imidazole, pyrazole, pyrrole, N-meth edly benefit patients who either cannot use the pharmacologi ylpyrrole, cyclohexenyl, cyclopentenyl, tetrahydropyridine, cal modalities presently available, or who do not receive dihydrothiophene and dihydrofuran, an aromatic ring, or a adequate relief from those modalities. non-aromatic ring. In other embodiments, the aromatic ring 50 may be optionally substituted by one or more of halogen, SUMMARY OF THE INVENTION NO, CN, CF, C-alkyl, Co-alkyl-S, Co-alkyl-O, Co alkyl-NH. (C-alkyl)-N, C-alkyl-SO, C-alkyl-SO, The present invention provides for the active compounds of SONH CO-alkyl, SON(C-alkyl). NHSO, C Formula I, all isomers, positional isomers, diastereomers and alkyl, CONH Co-alkyl, NHCO C-alkyl and COO enantiomers, and pharmaceutically acceptable salts thereof, 55 Co-alkyl. In yet further embodiments the non-aromatic ring and all hydrates, and all crystal polymorphs: may be optionally Substituted by one or more of C-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. (Co-alkyl)-N. C-alkyl-SO, C-alkyl-SO, SONH Co-alkyl, SON Formula I R (Co-alkyl). NHSO, C-alkyl, CONH-Co-alkyl, 60 NHCO C-alkyl and COO Co-alkyl. R6 X R2 n1R N In a variety of embodiments R and R, may be null, H, or are independently but not simultaneously phenyl, pyridine, Rs 2 R1'ny N R3 pyrimidine, thiophene, furan, oxazole, isoxazole, thiazole, 65 isothiazole, imidazole and pyrazole, and R or R, may be optionally substituted by one or more of halogen, NO, CN, CF, C-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. US 7,638,519 B2 5 (Co-alkyl)-N, C-alkyl-SO, C-alkyl-SO, SONH II. Compositions Co-alkyl, SON(C-alkyl). NHSO, C-alkyl, A. Drug Compound CONH Co-alkyl, NHCO-C-alkyl and COO Co The present invention provides for the active compounds of alkyl. Formula I: In certain embodiments R and Rs form a ring, and R and 5 R, taken together may further form a ring selected from Formula I cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, tet R rahydropyridine, hexahydropyridine, dihydrothiophene, tet R6 n1 X R rahydrothiophene, dihydrofuran and tetrahydrofuran, and 10 R N each ring may be optionally Substituted by one or more of Rs 2 C-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. (C- R-1 ny N R3 alkyl)-N, C-alkyl-SO, C-alkyl-SO, SONH-Co alkyl, SON(C-alkyl). NHSO, C-alkyl, CONH 15 Co-alkyl, NHCO-C-alkyl and COO Co-alkyl. Included are all isomers, positional isomers, diastereomers In other embodiments Rs. Ro and Ro are independently H. and enantiomers, and pharmaceutically acceptable salts C-alkyl, C-cycloalkyl, C-alkyl-SO and CO-C- thereof, and all hydrates, and all crystal polymorphs. The alkyl; wherein alkyl may be straight or branched chain. In yet substituents of Formula I may be defined as follows: R may be H, OH, C-alkyl-0, SH, C-alkyl-S, CH NRR, and further embodiments, X is null, O, S and NR. NRRo; and R may be H. Co-alkyl, and C-cycloalkyl. R In another embodiment, it is envisioned to use the present is phenyl, pyridine, pyrimidine, thiophene, furan, oxazole, invention in combination with other therapeutic modalities. isoxazole, thiazole, isothiazole, imidazole, pyrazole and pyr Thus, in addition to the therapies described above, one may role, and any of R may be optionally Substituted by one or also provide to the patient more “standard pharmaceutical 25 more of halogen, NO, CN, CF, C-alkyl, Co-alkyl-S, cardiac therapies. Examples of other therapies include, with Co-alkyl-O, Co-alkyl-NH. (Co-alkyl)-N, C-alkyl out limitation, so-called “beta blockers.” anti-hypertensives, SO, C-alkyl-SO, SONH Co-alkyl, SON(C- cardiotonics, anti-thrombotics, vasodilators, hormone alkyl). NHSO, C-alkyl, CONH Co-alkyl, NHCO— antagonists, iontropes, diuretics, endothelin antagonists, cal C-alkyl and COO Co-alkyl; R and Rs are, indepen dently, H, and both R and Rs cannot simultaneously be H. cium channel blockers, phosphodiesterase inhibitors, ACE 30 Co-alkyl, C-cycloalkyl; R and Rs may also be indepen inhibitors, angiotensin type 2 antagonists and cytokine block dently, but not simultaneously, phenyl, pyridine, pyrimidine, ers/inhibitors, and HDAC inhibitors. thiophene, furan, oxazole, isoxazole, thiazole, isothiazole, It will be understood that in the discussion of formulations imidazole, pyrazole, cyclohexyl, cyclohexenyl, cyclopentyl, and methods of treatment, references to the compounds of 35 cyclopentenyl, tetrahydropyridine, tetrahydrothiophene, and Formula I are meant to also include the pharmaceutically tetrahydrofuran, an aromatic ring or a non-aromatic ring. In acceptable salts, as well as pharmaceutical compositions certain embodiments, the aromatic ring may be optionally substituted by one or more of halogen, NO, CN, CF, C comprising these compounds. Also provided are treatments alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. (C- comprising administering to a subject an effective amount of alkyl)-N, C-alkyl-SO, C-alkyl-SO, SONH-Co a compound of Formula I, its pharmaceutically acceptable 40 alkyl, SON(C-alkyl). NHSO, C-alkyl, CONH salts, and a pharmaceutically acceptable carrier or formula Co-alkyl, NHCO-C-alkyl and COO Co-alkyl. In yet tion. further embodiments, the non-aromatic ring may be option The term “null shall mean that the named substitution is ally substituted by one or more of C-alkyl, Co-alkyl-S, absent. Co-alkyl-O, Co-alkyl-NH. (Co-alkyl)-N, C-alkyl 45 SO, C-alkyl-SO, SONH Co-alkyl, SON(C- “Cardiovascular disease' includes, but is not limited to, alkyl). NHSO, C-alkyl, CONH Co-alkyl, NHCO— pathological hypertrophy, chronic and acute heart failure. C-alkyl and COO Co-alkyl. DETAILED DESCRIPTION OF THE INVENTION In one embodiment, where R is H, then R is H. Co-alkyl, 50 Co-cycloalkyl, OH, C-alkyl-O, SH, C-alkyl-S, CH2— NRR, or NRR. In another embodiment where R is Hand I. The Present Invention R is also H, C-alkyl or Cle-cycloalkyl; then R is either H. In light of the limitations of the current therapies, and in C-alkyl, C-cycloalkyl, OH, C-alkyl-O, SH, C accordance with the present invention, the inventors herein alkyl-S, CH NRR and NR.R. 55 In certain embodiments, X and Y are null, and then R and describe compounds that bind to and modulate the signaling Rs taken together may form a ring selected from phenyl, induced by 5-hydroxytryptamine (5-HT2) receptors. These pyridine, pyrimidine, thiophene, furan, oxazole, isoxazole, compounds are not only cardioprotective, but also have the thiazole, isothiazole, imidazole, pyrazole, pyrrole, N-meth ability to modulate non-cardiac muscle cell growth. These ylpyrrole, cyclohexenyl, cyclopentenyl, tetrahydropyridine, receptors are a starting point for a number of important sig 60 dihydrothiophene and dihydrofuran, an aromatic ring, or a naling pathways already known to be important in the cellular non-aromatic ring. In other embodiments, the aromatic ring cascade towards a variety of cardiovascular and muscular may be optionally substituted by one or more of halogen, conditions. Thus, and in accordance with the present inven NO, CN, CF, C-alkyl, Co-alkyl-S, Co-alkyl-O, Co tion, the inventors describe herein compounds, pharmaceuti alkyl-NH. (C-alkyl)-N, C-alkyl-SO, C-alkyl-SO, cal formulations, and methods of treatment which comprise 65 SONH Co-alkyl, SON(C-alkyl). NHSO, C modulating the expression of and function of 5-HT2 recep alkyl, CONH Co-alkyl, NHCO C-alkyl and COO tOrS. Co-alkyl. In yet further embodiments the non-aromatic ring US 7,638,519 B2 7 may be optionally Substituted by one or more of C-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. (C-alkyl)-N. C-alkyl-SO, C-alkyl-SO, SONH Co-alkyl, SON CN (Co-alkyl). NHSO, C-alkyl, CONH-Co-alkyl, NHCO-C-alkyl and COO Co-alkyl. 5 O -- In a variety of embodiments R and R, may be null, H, or C NH2 are independently but not simultaneously phenyl, pyridine, TSOH He pyrimidine, thiophene, furan, oxazole, isoxazole, thiazole, Toluene isothiazole, imidazole and pyrazole, and R or R, may be 10 Heat optionally substituted by one or more of halogen, NO, CN, Water Removal CF, C-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. OCH (C-alkyl)-N, C-alkyl-SO, C-alkyl-SO, SONH Co-alkyl, SON(C-alkyl). NHSO, C-alkyl, He1) LDA CONH Co-alkyl, NHCO C-alkyl and COO Co 15 o Ether - 60° to 20° C. alkyl. 2) Water In certain embodiments Ra and Rs form a ring, and R and C C 3) Chromatography R, taken together may further form a ring selected from OCH cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, tet NH2 rahydropyridine, hexahydropyridine, dihydrothiophene, tet rahydrothiophene, dihydrofuran and tetrahydrofuran, and N each ring may be optionally Substituted by one or more of Co-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. (C- 2 alkyl)-N, C-alkyl-SO, C-alkyl-SO, SONH-Co C N alkyl, SON(C-alkyl). NHSO, C-alkyl, CONH 25 Co-alkyl, NHCO-C-alkyl and COO Co-alkyl. OCH In other embodiments Rs. Ro and Ro are independently H. Co-alkyl, C-cycloalkyl, C-alkyl-SO and CO-C- Substituted thieno 2,3-bipyridines can be prepared via the alkyl; wherein alkyl may be straight or branched chain. In yet 30 methods of Thompson et al., U.S. Pat. No. 5,093,493; Gewald further embodiments, X is null, O, S and NR. et al., Monatshefte fur Chemie, 110:1189-1196, 1979, Het It will be understood that in the discussion of formulations eroatom Chemistry, 7:29-33, 1966, J. Heterocyclic Chem., and methods of treatment, references to the compounds of 39:877-883, 2002; Phosphorous, Sulfur and Silicon and the Formula I are meant to also include the pharmaceutically Related Elements, 155:215-233, 1999. As a further example acceptable salts, as well as pharmaceutical compositions of substituted thieno 2,3-bipyridines the preparation of the comprising these compounds. Also provided are treatments following product is illustrated. comprising administering to a subject an effective amount of a compound of Formula I, its pharmaceutically acceptable CN salts, and a pharmaceutically acceptable carrier or formula 40 tion. N -- B. Methods of Preparation and Synthesis NH2 The compounds of the present invention can be prepared S according to the following methods or through modifications F O O F 1) AlCl3 45 to these methods by one skilled in the art or in some cases with Nitrobenzene additions to these methods of other methods readily known to Heat 2) Water one skilled in the art. The following methods are illustrative 3) Chromatography examples and do not limit or exclude other methods one skilled in the art may readily utilize or adapt to prepare com pounds of this invention. One skilled in the art will also know 50 that many starting materials and intermediates are readily available from various commercial Sources or are known through methods reported in the literature or can be obtained through synthetic procedures readily known to one skilled in 55 the art. Substituted 2-aryl and 2-heteroaryl-4-aminoquinolines can be prepared via the methods of Strekowski et al., Hetero cycles, 29:539-545, 1989: Strekowski et al., J. Org. Chem., III. Formulations 62:4193-4196, 1997: Strekowski et al., J. Heterocyclic 60 In specific embodiments of the invention the pharmaceu Chem., 26:923-928, 1989, Phosphorous, Sulfur and Silicon tical formulation will be formulated for delivery via rapid and the Related Elements, 166:303-314, 2000, Acta Chimica release, other embodiments contemplated include but are not Scandinavica, Series B. Organic Chemistry and Biochemis limited to timed release, delayed release, and Sustained try, B42:309-313, 1988; and Tet. Lett., 233-238, 1966. As a release. The formulation can be an oral Suspension in either further example of substituted 2-aryland 2-heteroaryl-4-ami 65 the solid or liquid form. In further embodiments, it is contem noquinolines the preparation of the following product is illus plated that the formulation can be prepared for delivery via trated. parenteral delivery, or used as a Suppository, or beformulated US 7,638,519 B2 10 for Subcutaneous, intravenous, intramuscular, intraperito Dispersible powders and granules Suitable for preparation neal, Sublingual, transdermal, or nasopharyngeal delivery. of an aqueous Suspension by the addition of water provide the The pharmaceutical compositions containing the active active ingredient in admixture with a dispersing or wetting ingredient may be in a form Suitable for oral use, for example, agent, Suspending agent and one or more preservatives. Suit as tablets, troches, lozenges, aqueous or oily Suspensions, able dispersing or wetting agents and Suspending agents are dispersible powders or granules, emulsions, hard or soft cap exemplified by those already mentioned above. Additional Sules, or syrups or elixirs. Compositions intended for oral use excipients, for example Sweetening, flavoring and coloring may be prepared according to any method known to the art for agents, may also be present. the manufacture of pharmaceutical compositions and Such The pharmaceutical compositions of the invention may compositions may contain one or more agents selected from 10 also be in the form of oil-in-water emulsions. The oily phase the group consisting of Sweetening agents, flavoring agents, may be a vegetable oil, for example olive oil or arachis oil, or coloring agents and preserving agents in order to provide a mineral oil, for example liquid paraffin or mixtures of these. pharmaceutically elegant and palatable preparations. Tablets Suitable emulsifying agents may be naturally-occurring contain the active ingredient in admixture with non-toxic phosphatides, for example soybean, lecithin, and esters or pharmaceutically acceptable excipients, which are suitable 15 partial esters derived from fatty acids and hexitol anhydrides, for the manufacture of tablets. These excipients may be for for example Sorbitan monooleate, and condensation products example, inert diluents, such as calcium carbonate, sodium of the said partial esters with ethylene oxide, for example carbonate, lactose, calcium phosphate or Sodium phosphate: polyoxyethylene Sorbitan monooleate. The emulsions may granulating and disintegrating agents, for example, corn also contain Sweetening and flavouring agents. starch, or alginic acid; binding agents, for example starch, Syrups and elixirs may be formulated with Sweetening gelatin or acacia, and lubricating agents, for example, mag agents, for example glycerol, propylene glycol, Sorbitol or nesium Stearate, Stearic acid or talc. The tablets may be Sucrose. Such formulations may also contain a demulcent, a uncoated or they may be coated by known techniques to delay preservative and flavoring and coloring agents. The pharma disintegration and absorption in the gastrointestinal tract and ceutical compositions may be in the form of a sterile inject thereby provide a Sustained action over a longer period. For 25 able aqueous or oleagenous Suspension. This suspension may example, a time delay material Such as glyceryl monostearate beformulated according to the known art using those Suitable or glyceryl distearate may be employed. They may also be dispersing or wetting agents and Suspending agents which coated by the technique described in the U.S. Pat. Nos. 4,256, have been mentioned above. The sterile injectable prepara 108; 4,166,452; and 4,265,874 to form osmotic therapeutic tion may also be a sterile injectable solution or Suspension in tablets for control release (hereinafter incorporated by refer 30 a non-toxic parenterally-acceptable diluent or solvent, for ence). example as a solution in 1,3-butane diol. Among the accept Formulations for oral use may also be presented as hard able vehicles and solvents that may be employed are water, gelatin capsules wherein the active ingredient is mixed with Ringer's Solution and isotonic sodium chloride solution. In an inert Solid diluent, for example, calcium carbonate, cal addition, Sterile, fixed oils are conventionally employed as a cium phosphate or kaolin, or as Soft gelatin capsules wherein 35 Solvent or Suspending medium. For this purpose any bland the active ingredient is mixed with water oran oil medium, for fixed oil may be employed including synthetic mono- or example peanut oil, liquid paraffin, or olive oil. diglycerides. In addition, fatty acids Such as oleic acid find Aqueous Suspensions contain the active material in admix use in the preparation of injectables. ture with excipients Suitable for the manufacture of aqueous Compounds of Formula I may also be administered in the Suspensions. Such excipients are Suspending agents, for 40 form of Suppositories for rectal administration of the drug. example sodium carboxymethylcellulose, methylcellulose, These compositions can be prepared by mixing the drug with hydroxy-propylmethycellulose, Sodium alginate, polyvinyl a suitable non-irritating excipient which is solid at ordinary pyrrollidone, gum tragacanth and gum acacia; dispersing or temperatures, but liquid at the rectal temperature and will wetting agents may be a naturally-occurring phosphatide, for therefore melt in the rectum to release the drug. Such mate example lecithin, or condensation products of an alkylene 45 rials are cocoa butter and polyethylene glycols. oxide with fatty acids, for example polyoxyethylene Stearate, For topical use, creams, ointments, jellies, gels, epidermal or condensation products of ethylene oxide with long chain Solutions or Suspensions, etc., containing the compound of aliphatic alcohols, for example heptadecaethylene-oxycet Formula I are employed. For purposes of this application, anol, or condensation products of ethylene oxide with partial topical application shall include mouthwashes and gargles. esters derived from fatty acids and a hexitol Such as polyoxy 50 The formulation may also be administered as nanopar ethylene Sorbitol monooleate, or condensation products of ticles, liposomes, granules, inhalants, nasal Solutions, or ethylene oxide with partial esters derived from fatty acids and intravenous admixtures hexitol anhydrides, for example polyethylene sorbitan The amount of active ingredient in any formulation may monooleate. The aqueous Suspensions may also contain one vary to produce a dosage form that will depend on the par or more preservatives, for example ethyl, or n-propyl, p-hy 55 ticular treatment and mode of administration. The previously droxybenzoate, one or more coloring agents, one or more mentioned formulations are all contemplated for treating flavoring agents, and one or more Sweetening agents, such as patients suffering from cardiovascular disease. It is further Sucrose, saccharin or aspartame. understood that specific dosing for a patient will depend upon Oily suspensions may be formulated by Suspending the a variety of factors including age, body weight, general active ingredient in a vegetable oil, for example arachis oil, 60 health, sex, diet, time of administration, route of administra olive oil, Sesame oil or coconut oil, or in mineral oil Such as tion, rate of excretion, drug combination and the severity of liquid paraffin. The oily Suspensions may contain a thicken the particular disease undergoing therapy. ing agent, for example beeswax, hard paraffin or cetyl alco hol. Sweetening agents such as those set forth above, and IV. Cardiovascular Diseases flavoring agents may be added to provide a palatable oral 65 A. Heart Failure and Hypertrophy preparation. These compositions may be preserved by the Heart disease and its manifestations, including coronary addition of an anti-oxidant such as ascorbic acid. artery disease, myocardial infarction, congestive heart failure US 7,638,519 B2 11 12 and cardiac hypertrophy, clearly presents a major health risk and triglycerides. Moreover, diuretics are generally ineffec in the United States today. The cost to diagnose, treat and tive for patients suffering from severe heart failure. Support patients suffering from these diseases is well into the If diuretics are ineffective, vasodilatory agents may be billions of dollars. One particularly severe manifestations of used; the angiotensin converting (ACE) inhibitors (e.g., ena heart disease is cardiac hypertrophy. Regarding hypertrophy, 5 lopril and lisinopril) not only provide symptomatic relief, one theory regards this as a disease that resembles aberrant they also have been reported to decrease mortality (Young et development and, as such, raises the question of whether al., 1989). Again, however, the ACE inhibitors are associated developmental signals in the heart can contribute to hyper with adverse effects that result in their being contraindicated trophic disease. Cardiac hypertrophy is an adaptive response in patients with certain disease states (e.g., renal artery Steno of the heart to virtually all forms of cardiac disease, including 10 sis). Similarly, inotropic agent therapy (i.e., a drug that those arising from hypertension, mechanical load, myocar improves cardiac output by increasing the force of myocar dial infarction, cardiac arrhythmias, endocrine disorders, and dial muscle contraction) is associated with a panoply of genetic mutations in cardiac contractile protein genes. While adverse reactions, including gastrointestinal problems and the hypertrophic response is initially a compensatory mecha central nervous system dysfunction. nism that augments cardiac output, Sustained hypertrophy 15 Thus, the currently used pharmacological agents have can lead to DCM, heart failure, and sudden death. In the severe shortcomings in particular patient populations. The United States, approximately half a million individuals are availability of new, safe and effective agents would undoubt diagnosed with heart failure each year, with a mortality rate edly benefit patients who either cannot use the pharmacologi approaching 50%. cal modalities presently available, or who do not receive The causes and effects of cardiac hypertrophy have been adequate relief from those modalities. The prognosis for extensively documented, but the underlying molecular patients with DCM is variable, and depends upon the degree mechanisms have not been fully elucidated. Understanding of ventricular dysfunction, with the majority of deaths occur these mechanisms is a major concern in the prevention and ring within five years of diagnosis. treatment of cardiac disease and will be crucial as a therapeu MEF-2, MCIP, Calcineurin, NF-AT3, and Histone Deac tic modality in designing new drugs that specifically target 25 tylases (HDACs) are all proteins and genes that have been cardiac hypertrophy and cardiac heart failure. The symptoms recently implicated as intimately involved in the development of cardiac hypertrophy initially mimic those of heart failure of and progression of heart disease, heart failure, and hyper and may include shortness of breath, fatigue with exertion, trophy. Manipulation, modulation, and/or inhibition of any or the inability to lie flat without becoming short of breath (or all of these genes and/or proteins holds great promise in the thopnea), paroxysmal nocturnal dyspnea, enlarged cardiac 30 treatment of heart failure and hypertrophy. These genes are all dimensions, and/or Swelling in the lower legs. Patients also involved in a variety of cascades that eventually lead to both often present with increased blood pressure, extra heart heart failure and hypertrophy. As such, if there was a way to Sounds, cardiac murmurs, pulmonary and systemic emboli, inhibit these genes or to perhaps prevent the activation of chest pain, pulmonary congestion, and palpitations. In addi these genes in the first place, that would represent a signifi tion, DCM causes decreased ejection fractions (i.e., a mea 35 cant leap in the treatment of cardiac disease. The 5-HT2 sure of both intrinsic systolic function and remodeling). The Subtype of the serotonin receptors are such a potential target, disease is further characterized by ventricular dilation and for they are indirectly associated with all of these cascades grossly impaired systolic function due to diminished myocar and thus may representatherapeutic bottleneck for inhibiting dial contractility, which results in dilated heart failure in many the transcriptional and translational pathways associated with patients. Affected hearts also undergo cell/chamber remodel 40 heart failure and hypertrophy. ing as a result of the myocyte/myocardial dysfunction, which B. Primary Pulmonary Hypertension contributes to the “DCM phenotype.” As the disease Pulmonary hypertension is a disease characterized by progresses so do the symptoms. Patients with DCM also have increased pulmonary arterial pressure and pulmonary vascu a greatly increased incidence of life-threatening arrhythmias, lar resistance of the vessels, as well as vascular remodeling including ventricular tachycardia and Ventricular fibrillation. 45 which leads to narrowed lumens of the vessels. Pulmonary In these patients, an episode of syncope (dizziness) is hypertension can be primary, i.e., of unknown or unidentifi regarded as a harbinger of Sudden death. able cause, or can be secondary to a known cause Such as Diagnosis of hypertrophy typically depends upon the dem hypoxia or congenital heart shunts. The term “primary pull onstration of enlarged heart chambers, particularly enlarged monary hypertension’ (PPH) generally refers to a condition Ventricles. Enlargement is commonly observable on chest 50 in which there is elevated arterial pressures in the small pull X-rays, but is more accurately assessed using echocardio monary arteries. Pulmonary hypertension generally occurs grams. DCM is often difficult to distinguish from acute myo independently of and is unrelated to systemic hypertension. carditis, valvular heart disease, coronary artery disease, and In vitro studies have concluded that changes in Ca (++) con hypertensive heart disease. Once the diagnosis of dilated centrations may be involved in pulmonary tissue damage cardiomyopathy is made, every effort is made to identify and 55 associated with pulmonary hypertension. (Farruck et al., treat potentially reversible causes and prevent further heart 1992). A subject having pulmonary hypertension as used damage. For example, coronary artery disease and valvular herein is a Subject having a right ventricular systolic or a heart disease must be ruled out. Anemia, abnormal tachycar pulmonary artery systolic pressure, at rest, of at least 20 dias, nutritional deficiencies, alcoholism, thyroid disease mmHg. Pulmonary hypertension is measured using conven and/or other problems need to be addressed and controlled. 60 tional procedures well-known to those of ordinary skill in the As mentioned above, treatment with pharmacological art. agents still represents the primary mechanism for reducing or Pulmonary hypertension may either be acute or chronic. eliminating the manifestations of heart failure. Diuretics con Acute pulmonary hypertension is often a potentially revers stitute the first line of treatment for mild-to-moderate heart ible phenomenon generally attributable to constriction of the failure. Unfortunately, many of the commonly used diuretics 65 smooth muscle of the pulmonary blood vessels, which may be (e.g., the thiazides) have numerous adverse effects. For triggered by Such conditions as hypoxia (as in high-altitude example, certain diuretics may increase serum cholesterol sickness), acidosis, inflammation, or pulmonary embolism. US 7,638,519 B2 13 14 Chronic pulmonary hypertension is characterized by major However, current LVADs are not permanent solutions for structural changes in the pulmonary vasculature, which result heart failure but are considered bridges to transplantation. in a decreased cross-sectional area of the pulmonary blood As a final alternative, there is an experimental Surgical vessels. This may becaused by, for example, chronic hypoxia, procedure for severe heart failure available called cardiomyo thromboembolism, or unknown causes (idiopathic or primary plasty (Dumcius et al., 2003). This procedure involves pulmonary hypertension). detaching one end of a muscle in the back, wrapping it around Despite the possibility of a varied etiology, cases of pri the heart, and then Suturing the muscle to the heart. An mary pulmonary hypertension tend to comprise a recogniz implanted electric stimulator causes the back muscle to con able entity. Approximately 65% are female and young adults tract, pumping blood from the heart. To date, none of these are most commonly afflicted, though it has occurred in chil 10 treatments have been shown to cure heart failure, but can at dren and patients over 50. Life expectancy from the time of least improve quality of life and extend life for those suffering diagnosis is short, about 3 to 5 years, though occasional this disease. reports of spontaneous remission and longer Survival are to be As with heart failure, there are no known cures to hyper expected given the nature of the diagnostic process. Gener trophy. Current medical management of cardiac hypertrophy, ally, however, progress is inexorable via syncope and right 15 in the setting of a cardiovascular disorder includes the use of heart failure and death is quite often sudden. At least 6% of at least two types of drugs: inhibitors of the rennin-angio individuals diagnosed with PPH have a known family history tensin System, and B-adrenergic blocking agents (Bristow, of the disorder. The disease can be classified as being either 1999). Therapeutic agents to treat pathologic hypertrophy in familial (more than one affected relative has been identified in the setting of heart failure include angiotensin II converting at least 6% of cases (familial PPH; MIM 178600) or sporadic. enzyme (ACE) inhibitors and O-adrenergic receptor blocking agents (Eichhorn & Bristow, 1996). Other pharmaceutical V. Methods of Treating Cardiovascular Diseases agents that have been disclosed for treatment of cardiac A. Therapeutic Regimens for Heart Failure and Hypertro hypertrophy include angiotensin II receptorantagonists (U.S. phy Pat. No. 5,604,251) and neuropeptide Y antagonists (PCT Heart failure of some forms may curable and these are dealt 25 Publication No. WO 98/33791). with by treating the primary disease. Such as anemia or thy Non-pharmacological treatment is primarily used as an rotoxicosis. Also curable are forms caused by anatomical adjunct to pharmacological treatment. One means of non problems, such as a heart valve defect. These defects can be pharmacological treatment involves reducing the Sodium in Surgically corrected. However, for the most common forms of the diet. In addition, non-pharmacological treatment also heart failure—those due to damaged heart muscle—no 30 entails the elimination of certain precipitating drugs, includ known cure exists. Treating the symptoms of these diseases ing negative inotropic agents (e.g., certain calcium channel helps, and some treatments of the disease have been success blockers and antiarrhythmic drugs like disopyramide), car ful. The treatments attempt to improve patients’ quality of life diotoxins (e.g., amphetamines), and plasma Volume expand and length of Survival through lifestyle change and drug ers (e.g., nonsteroidal anti-inflammatory agents and gluco therapy. Patients can minimize the effects of heart failure by 35 corticoids). controlling the risk factors for heart disease, but even with As can be seen from the discussion above, there is a great lifestyle changes, most heart failure patients must take medi need for a successful treatment approach to heart failure and cation, many of whom receive two or more drugs. hypertrophy. In one embodiment of the present invention, Several types of drugs have proven useful in the treatment methods for the treatment of cardiac hypertrophy, PPH, or of heart failure: Diuretics help reduce the amount of fluid in 40 heart failure utilizing the compounds of Formula I are pro the body and are useful for patients with fluid retention and vided. For the purposes of the present application, treatment hypertension; and digitalis can be used to increase the force of comprises reducing one or more of the symptoms of heart the heart’s contractions, helping to improve circulation. failure, PPH, or cardiac hypertrophy, such as reduced exercise Results of recent studies have placed more emphasis on the capacity, reduced blood ejection Volume, increased left ven use of ACE inhibitors (Manoria and Manoria, 2003). Several 45 tricular end diastolic pressure, increased pulmonary capillary large studies have indicated that ACE inhibitors improve sur wedge pressure, reduced cardiac output, cardiac index, vival among heart failure patients and may slow, or perhaps increased pulmonary artery pressures, increased left ven even prevent, the loss of heart pumping activity (for a review tricular end systolic and diastolic dimensions, and increased see DeFeo et al., 2003; DiBianco, 2003). left ventricular wall stress, wall tension and wall thickness, 50 elevated right ventricular systolic pressure, and elevated pull Patients who cannot take ACE inhibitors may get a nitrate monary arterial systolic pressures. In addition, use of com and/or a drug called hydralazine, each of which helps relax punds of Formula I may prevent cardiac hypertrophy, heart tension in blood vessels to improve blood flow (Ahmed, failure, or PPH and their associated symptoms from arising. 2003). B. Treatment for PPH Heart failure is almost always life-threatening. When drug 55 The treatment of pulmonary hypertension by the parenteral therapy and lifestyle changes fail to control its symptoms, a administration of certain prostaglandin endoperoxides, such heart transplant may be the only treatment option. However, as prostacyclin (also known as flolan), is also known and is the candidates for transplantation often have to wait months or subject of U.S. Pat. No. 4,883,812. Prostacyclin has been even years before a suitable donor heart is found. Recent administered by inhalation and is used to treat pulmonary studies indicate that some transplant candidates improve dur 60 hypertension by inhalation (Siobal et al., 2003). A subject at ing this waiting period through drug treatment and other risk of developing pulmonary hypertension may be treated therapy, and can be removed from the transplant list (Conte et prophylactically to reduce the risk of pulmonary hyperten al., 1998). Sion. A subject with an abnormally elevated risk of pulmonary Transplant candidates who do not improve Sometimes need hypertension is a subject with chronic exposure to hypoxic mechanical pumps, which are attached to the heart. Called 65 conditions, a Subject with Sustained vasoconstriction, a Sub left ventricular assist devices (LVADs), the machines take ject with multiple pulmonary emboli, a subject with cardi overpart or virtually all of the heart’s blood-pumping activity. omegaly and/or a subject with a family history of pulmonary US 7,638,519 B2 15 16 hypertension. These treatments, as with treatments for heart the individual Subject, and Such individual determinations are failure and hypertrophy, are not sufficient and thus there is a within the skill of those of ordinary skill in the art. need to discover methods of treating these diseases that stop Non-limiting examples of a pharmacological therapeutic the transcriptional and translational cascades that lead to agent that may be used in the present invention include an heart damage. antihyperlipoproteinemic agent, an antiarteriosclerotic agent, C. Combined Therapy an antithrombotic/fibrinolytic agent, a blood coagulant, an In another embodiment, it is envisioned to use compounds antiarrhythmic agent, an antihypertensive agent, a vasopres of Formula I in combination with other therapeutic modali Sor, a treatmentagent for congestive heart failure, an antiangi ties. Thus, in addition to the therapies described above, one nal agent, an antibacterial agent or a combination thereof. may also provide to the patient more 'standard pharmaceu 10 In addition, it should be noted that any of the following may tical cardiac therapies. Examples of other therapies include, be used to develop new sets of cardiac therapy target genes as without limitation, so-called “beta blockers anti-hyperten B-blockers were used in the present examples (see below). sives, cardiotonics, anti-thrombotics, vasodilators, hormone While it is expected that many of these genes may overlap, antagonists, inotropes, diuretics, endothelin antagonists, cal new gene targets likely can be developed. cium channel blockers, phosphodiesterase inhibitors, ACE 15 1. Antihyperlipoproteinemics inhibitors, angiotensin type 2 antagonists and cytokine block In certain embodiments, administration of an agent that ers/inhibitors, HDAC inhibitors, or TRP channel inhibitors. lowers the concentration of one of more blood lipids and/or Combinations may be achieved by contacting cardiac cells lipoproteins, knownhereinas an “antihyperlipoproteinemic.” with a single composition or pharmacological formulation may be combined with a cardiovascular therapy according to that includes both agents, or by contacting the cell with two the present invention, particularly in treatment of atherscle distinct compositions or formulations, at the same time, rosis and thickenings or blockages of vascular tissues. In wherein one composition includes the expression construct certain aspects, an antihyperlipoproteinemic agent may com and the other includes the agent. Alternatively, the therapy prise an aryloxyalkanoic/fibric acid derivative, a resin/bile using compounds of Formula I may precede or follow admin acid sequesterant, a HMG CoA reductase inhibitor, a nico istration of the other agent(s) by intervals ranging from min 25 tinic acid derivative, a thyroid hormone or thyroid hormone utes to weeks. In embodiments where the other agent and analog, a miscellaneous agent or a combination thereof. expression construct are applied separately to the cell, one a. Aryloxyalkanoic Acid/Fibric Acid Derivatives would generally ensure that a significant period of time did Non-limiting examples of aryloxyalkanoic/fibric acid not expire between the time of each delivery, such that the derivatives include beclobrate, enZafibrate, binifibrate, agent and expression construct would still be able to exert an 30 ciprofibrate, clinofibrate, clofibrate (atromide-S), clofibric advantageously combined effect on the cell. In Such acid, etofibrate, fenofibrate, gemfibrozil (lobid), nicofibrate, instances, it is contemplated that one would typically contact pirifibrate, ronifibrate, simfibrate and theofibrate. the cell with both modalities within about 12-24 hours of each b. Resins/Bile Acid Sequesterants other and, more preferably, within about 6-12 hours of each Non-limiting examples of resins/bile acid sequesterants other, with a delay time of only about 12 hours being most 35 include cholestyramine (cholybar, questran), colestipol preferred. In some situations, it may be desirable to extend the (colestid) and polidexide. time period for treatment significantly, however, where sev c. HMG CoA Reductase Inhibitors eral days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 Non-limiting examples of HMG CoA reductase inhibitors or 8) lapse between the respective administrations. include lovastatin (mevacor), pravastatin (pravochol) or sim It also is conceivable that more than one administration of 0 vastatin (Zocor). either a compound of Formula I, or the other agent will be d. Nicotinic Acid Derivatives desired. In this regard, various combinations may be Non-limiting examples of nicotinic acid derivatives employed. By way of illustration, where the compound of include nicotinate, acepimox, niceritrol, nicoclonate, nico Formula I is 'A' and the other agent is “B,” the following mol and oxiniacic acid. permutations based on 3 and 4 total administrations are exem 45 e. Thryroid Hormones and Analogs plary: Non-limiting examples of thyroid hormones and analogs thereof include etoroXate, thyropropic acid and thyroxine. f. Miscellaneous Antihyperlipoproteinemics Non-limiting examples of miscellaneous antihyperlipo ABABABBBAAAABBAAABBBBBABBAB 50 proteinemics include acifran, azacosterol, benfluorex, b-ben AAB.BABABABB, ABBAAB, ABABAABBBBA Zalbutyramide, carnitine, chondroitin Sulfate, clomestrone, AAABBAAAABAAAABAABBBBABBBBAB detaXtran, dextran Sulfate sodium, 5,8,11,14, 17-eicosapen taenoic acid, eritadenine, farazabol, meglutol, melinamide, mytatrienediol, ornithine, g-ory Zanol, pantethine, pen Other combinations are likewise contemplated. 55 taerythritol tetraacetate, a-phenylbutyramide, pirozadil, D. Adjunct Therapeutic Agents probucol (lorelco), b-sitosterol, Sultosilic acid-piperazine Pharmacological therapeutic agents and methods of salt, tiadenol, triparanol and Xenbucin. administration, dosages, etc., are well known to those of skill 2. Antiarteriosclerotics in the art (see for example, the “Physicians Desk Reference.” Non-limiting examples of an antiarteriosclerotic include Goodman & Gilman’s “The Pharmacological Basis of Thera 60 pyridinol carbamate. peutics.” “Remington’s Pharmaceutical Sciences.” and “The 3. Antithrombotic/Fibrinolytic Agents Merck Index. Thirteenth Edition, incorporated herein by In certain embodiments, administration of an agent that reference in relevant parts), and may be combined with the aids in the removal or prevention of blood clots may be invention in light of the disclosures herein. Some variation in combined with administration of a modulator, particularly in dosage will necessarily occur depending on the condition of 65 treatment of athersclerosis and vasculature (e.g., arterial) the subject being treated. The person responsible for admin blockages. Non-limiting examples of antithrombotic and/or istration will, in any event, determine the appropriate dose for fibrinolytic agents include anticoagulants, anticoagulant US 7,638,519 B2 17 18 antagonists, antiplatelet agents, thrombolytic agents, throm nipradillol, Oxprenolol, penbutolol, pindolol, practolol, prone bolytic agent antagonists or combinations thereof. thalol, propanolol (inderal), Sotalol (betapace), Sulfinalol, In certain aspects, antithrombotic agents that can be admin talinolol, tertatolol, timolol, toliprolol and xibinolol. In cer istered orally, such as, for example, aspirin and wafarin (cou tain aspects, the beta blocker comprises an aryloxypropano madin), are preferred. lamine derivative. Non-limiting examples of aryloxypro a. Anticoagulants panolamine derivatives include acebutolol, alprenolol. A non-limiting example of an anticoagulant include aceno arotinolol, atenolol, betaxolol, bevantolol, bisoprolol, bopin coumarol, ancrod, anisindione, bromindione, clorindione, dolol, bunitrolol, butofilolol, carazolol, carteolol, carvedilol, coumetarol, cyclocumarol, dextran Sulfate sodium, dicuma celiprolol, cetamolol, epanolol, indenolol, mepindolol. rol, diphenadione, ethyl biscoumacetate, ethylidene dicou 10 metipranolol, metoprolol, moprolol, nadolol, nipradillol, marol, fluindione, heparin, hirudin, lyapolate Sodium, oXprenolol, penbutolol, pindolol, propanolol, talinolol, terta oxazidione, pentosan polysulfate, phenindione, phenprocou tolol, timolol and toliprolol. mon, phosvitin, picotamide, tioclomarol and warfarin. c. Repolarization Prolonging Agents b. Antiplatelet Agents Non-limiting examples of an agent that prolong repolar Non-limiting examples of antiplatelet agents include aspi 15 ization, also known as a Class III antiarrhythmic agent, rin, a dextran, dipyridamole (persantin), heparin, Sulfinpyra include amiodarone (cordarone) and Sotalol (betapace). none (anturane) and ticlopidine (ticlid). d. Calcium Channel Blockers/Antagonist c. Thrombolytic Agents Non-limiting examples of a calcium channel blocker, oth Non-limiting examples of thrombolytic agents include tis erwise known as a Class IV antiarrhythmic agent, include an Sue plasminogenactivator (activase), plasmin, pro-urokinase, arylalkylamine (e.g., bepridile, diltiazem, fendiline, gallo urokinase (abbokinase) streptokinase (streptase), anistre pamil, prenylamine, terodiline, Verapamil), a dihydropyri plase/APSAC (eminase). dine derivative (felodipine, isradipine, nicardipine, nife 4. Blood Coagulants dipine, nimodipine, nisoldipine, nitrendipine) a piperaZinde In certain embodiments wherein a patient is suffering from derivative (e.g., cinnarizine, flunarizine, lidoflazine) or a a hemhorrage oran increased likelyhood of hemhorraging, an 25 micellaneous calcium channel blocker Such as bencyclane, agent that may enhance blood coagulation may be used. Non etafenone, magnesium, mibefradil or perhexiline. In certain limiting examples of a blood coagulation promoting agent embodiments a calcium channel blocker comprises a long include thrombolytic agent antagonists and anticoagulant acting dihydropyridine (amlodipine) calcium antagonist. antagonists. e. Miscellaneous Antiarrhythmic Agents a. Anticoagulant Antagonists 30 Non-limiting examples of miscellaneous antiarrhymic Non-limiting examples of anticoagulant antagonists agents include adenosine (adenocard), digoxin (lanoxin), include protamine and vitamine K1. acecainide, ajmaline, amoproxan, aprindine, bretylium tosy b. Thrombolytic Agent Antagonists and Antithrombotics late, bunaftine, butobendine, capobenic acid, cifenline, dis Non-limiting examples of thrombolytic agent antagonists opyramide, hydroquinidine, indecainide, ipatropium bro include amiocaproic acid (amicar) and tranexamic acid (am 35 mide, lidocaine, lorajmine, lorcainide, meobentine, stat). Non-limiting examples of antithrombotics include moricizine, pirmenol, prajmaline, propafenone, pyrinoline, anagrelide, argatroban, cilstaZol, daltroban, defibrotide, quinidine polygalacturonate, quinidine Sulfate and Viquidil. enoxaparin, fraxiparine, indobufen, lamoparan, oZagrel, 6. Antihypertensive Agents picotamide, plafibride, tedelparin, ticlopidine and triflusal. Non-limiting examples of antihypertensive agents include 5. Antiarrhythmic Agents 40 sympatholytic, alpha/beta blockers, alpha blockers, anti-an Non-limiting examples of antiarrhythmic agents include giotensin II agents, beta blockers, calcium channel blockers, Class I antiarrhythmic agents (sodium channel blockers), vasodilators and miscellaneous antihypertensives. Class II antiarrhythmic agents (beta-adrenergic blockers), a. Alpha Blockers Class II antiarrhythmic agents (repolarization prolonging Non-limiting examples of an alpha blocker, also known as drugs), Class IV antiarrhythmic agents (calcium channel 45 an a-adrenergic blocker or an a-adrenergic antagonist, blockers) and miscellaneous antiarrhythmic agents. include amoSulalol, arotinolol, dapiprazole, doxazosin, a. Sodium Channel Blockers ergoloid mesylates, fenspiride, indoramin, labetalol, nicer Non-limiting examples of sodium channel blockers goline, prazosin, teraZosin, tolaZoline, trimaZosin and yohim include Class IA, Class IB and Class IC antiarrhythmic bine. In certain embodiments, an alpha blocker may comprise agents. Non-limiting examples of Class IA antiarrhythmic 50 a quinazoline derivative. Non-limiting examples of quinaZo agents include disppyramide (norpace), procainamide (pron line derivatives include alfuZosin, bunaZosin, doxazosin, pra estyl) and quinidine (quinidex). Non-limiting examples of Zosin, teraZosin and trimaZosin. Class IB antiarrhythmic agents include lidocaine (Xylocalne), b. Alpha/Beta Blockers tocainide (tonocard) and mexiletine (mexitil). Non-limiting In certain embodiments, an antihypertensive agent is both examples of Class IC antiarrhythmic agents include encain 55 an alpha and beta adrenergic antagonist. Non-limiting ide (enkaid) and flecainide (tambocor). examples of an alpha/beta blocker comprise labetalol (nor b. Beta Blockers modyne, trandate). Non-limiting examples of a beta blocker, otherwise known c. Anti-Angiotension II Agents as a b-adrenergic blocker, a b-adrenergic antagonistora Class Non-limiting examples of anti-angiotension II agents II antiarrhythmic agent, include acebutolol (sectral), alpre 60 include angiotensin converting enzyme inhibitors and angio nolol, amoSulalol, arotinolol, atenolol, befunolol, betaxolol. tension II receptor antagonists. Non-limiting examples of bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol. angiotension converting enzyme inhibitors (ACE inhibitors) bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, include alacepril, enalapril (vasotec), captopril, cilaZapril, butofilolol, carazolol, carteolol, carvedilol, celiprolol, ceta delapril, enalaprilat, fosinopril, lisinopril, moveltopril, perin molol, cloranolol, dilevalol, epanolol, esmolol (brevibloc), 65 dopril, quinapril and ramipril. Non-limiting examples of an indenolol, labetalol, levobunolol, mepindolol, metipranolol, angiotensin II receptor blocker, also known as an angioten metoprolol, moprolol, nadolol, nadoxolol, nifenalol, sion II receptor antagonist, an ANG receptor blocker or an US 7,638,519 B2 19 20 ANG-IL type-1 receptor blocker (ARBS), include angiocan Benzothiadiazine Derivatives. Non-limiting examples of desartan, eprosartan, irbesartan, losartan and Valsartan. benzothiadiazine derivatives include althizide, bendroflume d. Sympatholytics thiazide, benzthiazide, benzylhydrochlorothiazide, buthiaz Non-limiting examples of a sympatholytic include a cen ide, chlorothiazide, chlorthalidone, cyclopenthiazide, trally acting sympatholytic or a peripherially acting sym cyclothiazide, diaZoxide, epithiazide, ethiazide, fenduizone, patholytic. Non-limiting examples of a centrally acting sym hydrochlorothizide, hydroflumethizide, methyclothiazide, patholytic, also known as an central nervous system (CNS) meticrane, metolaZone, paraflutizide, polythizide, tetrachlo sympatholytic, include clonidine (catapres), guanabenz rmethiazide and trichlormethiazide. (wytensin) guanfacine (tenex) and methyldopa (aldomet). N-carboxyalkyl (peptide/lactam) Derivatives. Non-limit Non-limiting examples of a peripherally acting sym 10 ing examples of N-carboxyalkyl (peptideflactam) derivatives patholytic include a ganglion blocking agent, an adrenergic include alacepril, captopril, cilaZapril, delapril, enalapril, neuron blocking agent, a B-adrenergic blocking agent or a enalaprilat, fosinopril, lisinopril, moveltipril, perindopril, alpha1-adrenergic blocking agent. Non-limiting examples of quinapril and ramipril. a ganglion blocking agent include mecamylamine (inversine) Dihydropyridine Derivatives. Non-limiting examples of and trimethaphan (arfonad). Non-limiting of an adrenergic 15 dihydropyridine derivatives include amlodipine, felodipine, neuron blocking agent include guanethidine (ismelin) and isradipine, nicardipine, nifedipine, nilvadipine, nisoldipine reserpine (serpasil). Non-limiting examples of a B-adrenergic and nitrendipine. blocker include acenitolol (sectral), atenolol (tenormin), Guanidine Derivatives. Non-limiting examples of guani betaxolol (kerlone), carteolol (cartrol), labetalol (normodyne, dine derivatives include bethanidine, debrisoquin, guana trandate), metoprolol (lopressor), nadanol (corgard), penb benz, guanacline, guanadrel, guanaZodine, guanethidine, utolol (levatol), pindolol (visken), propranolol (inderal) and guanfacine, guanochlor, guanoxabenz, and guanoxan. timolol (blocadren). Non-limiting examples of alpha-1-adr Hydrazines/Phthalazines. Non-limiting examples of energic blocker include praZosin (minipress), doxazocin (car hydrazines/phthalazines include budralazine, cadralazine, dura) and teraZosin (hytrin). dihydralazine, endralazine, hydracarbazine, hydralazine, e.Vasodilators 25 pheniprazine, pildralazine and todralazine. In certain embodiments a cardiovasculator therapeutic Imidazole Derivatives. Non-limiting examples of imida agent may comprise a vasodilator (e.g., a cerebral vasodilator, Zole derivatives include clonidine, lofexidine, phentolamine, a coronary vasodilator or a peripheral vasodilator). In certain tiamenidine and tolonidine. preferred embodiments, a vasodilator comprises a coronary Quanternary Ammonium Compounds. Non-limiting vasodilator. Non-limiting examples of a coronary vasodilator 30 examples of quanternary ammonium compounds include include amotriphene, bendazol, benfurodil hemisuccinate, aZamethonium bromide, chlorisondamine chloride, hexam benZiodarone, chloracizine, chromonar, clobenfurol, cloni ethonium, pentacynium bis(methylsulfate), pentamethonium trate, dilaZep, dipyridamole, droprenilamine, efloxate, eryth bromide, pentolinium tartrate, phenactropinium chloride and rity1 tetranitrane, etafenone, fendiline, floredil, ganglefene, trimethidinium methosulfate. herestrol bis(b-diethylaminoethyl ether), hexobendine, itra 35 Reserpine Derivatives. Non-limiting examples of reserpine min tosylate, khellin, lidoflanine, mannitol hexanitrane, derivatives include bietaserpine, deserpidine, rescinnamine, medibazine, nicorglycerin, pentaerythritol tetranitrate, pen reserpine and Syrosingopine. trinitrol, perhexiline, pimethylline, trapidil, tricromyl, tri Sulfonamide Derivatives. Non-limiting examples of sul metazidine, troInitrate phosphate and Visnadine. fonamide derivatives include ambuside, clopamide, furo In certain aspects, a vasodilator may comprise a chronic 40 semide, indapamide, quinethaZone, tripaamide and Xipam therapy vasodilator or a hypertensive emergency vasodilator. ide. Non-limiting examples of a chronic therapy vasodilator 7. Vasopressors include hydralazine (apresoline) and minoxidil (loniten). Vasopressors generally are used to increase blood pressure Non-limiting examples of a hypertensive emergency vasodi during shock, which may occur during a Surgical procedure. 45 Non-limiting examples of a vasopressor, also known as an lator include nitroprusside (nipride), diaZoxide (hyperstat antihypotensive, include amezinium methyl sulfate, angio IV), hydralazine (apresoline), minoxidil (loniten) and Vera tensin amide, dimetofrine, dopamine, etifelmin, etillefrin, pamil. gepefrine, metaraminol, midodrine, norepinephrine, f. Miscellaneous Antihypertensives pholedrine and synephrine. Non-limiting examples of miscellaneous antihyperten 50 8. Treatment Agents for Congestive Heart Failure sives include ajmaline, gaminobutyric acid, bufeniode, cicle Non-limiting examples of agents for the treatment of con tainine, ciclosidomine, a cryptenamine tannate, fenoldopam, gestive heart failure include anti-angiotension II agents, after floseduinan, ketanserin, mebutamate, mecamylamine, meth load-preload reduction treatment, diuretics and inotropic yldopa, methyl 4-pyridyl ketone thiosemicarbazone, agents. muZolimine, pargyline, pempidine, pinacidil, piperoxan, pri 55 a. Afterload-Preload Reduction maperone, a protoveratrine, raubasine, rescimetol, ril In certain embodiments, an animal patient that can not menidene, Saralasin, sodium nitrorusside, ticrynafen, tri tolerate an angiotension antagonist may be treated with a methaphan camsylate, tyrosinase and urapidil. combination therapy. Such therapy may combine adminstra In certain aspects, an antihypertensive may comprise an tion of hydralazine (apresoline) and isosorbide dinitrate (isor arylethanolamine derivative, a benzothiadiazine derivative, a 60 dil, sorbitrate). N-carboxyalkyl (peptide/lactam) derivative, a dihydropyri b. Diuretics dine derivative, a guanidine derivative, a hydrazines/phthala Non-limiting examples of a diuretic include a thiazide or Zine, an imidazole derivative, a quanternary ammonium com benzothiadiazine derivative (e.g., althiazide, bendroflumet pound, a reserpine derivative or a Suflonamide derivative. hazide, benzthiazide, benzylhydrochlorothiazide, buthiazide, Arylethanolamine Derivatives. Non-limiting examples of 65 chlorothiazide, chlorothiazide, chlorthalidone, cyclopenthi arylethanolamine derivatives include amosulalol, bufuralol, azide, epithiazide, ethiazide, ethiazide, fenguizone, hydro dilevalol, labetalol, pronethalol, Sotalol and sulfinalol. chlorothiazide, hydroflumethiazide, methyclothiazide, meti US 7,638,519 B2 21 22 Crane, metolaZone, paraflutizide, polythizide, dioverter defibrillator to the subject, mechanical circulatory tetrachloromethiazide, trichlormethiazide), an organomercu Support or a combination thereof. Non-limiting examples of a rial (e.g., chlormerodrin, meralluride, mercamphamide, mer mechanical circulatory Support that may be used in the captomerin Sodium, mercumallylic acid, mercumatilin present invention comprise an intra-aortic balloon counter dodium, mercurous chloride, mersalyl), a pteridine (e.g., fur 5 pulsation, left ventricular assist device or combination terene, triamterene), purines (e.g., acefylline, 7-morpholi thereof. nomethyltheophylline, pamobrom, protheobromine, theo bromine), Steroids including aldosterone antagonists (e.g., VI. REFERENCES canrenone, oleandrin, spironolactone), a Sulfonamide deriva tive (e.g., acetazolamide, ambuside, azosemide, bumetamide, 10 The following references, to the extent that they provide butazolamide, chloraminophenamide, clofenamide, clopam exemplary procedural or other details Supplementary to those ide, clorexolone, diphenylmethane-4,4'-disulfonamide, dis set forth herein, are specifically incorporated herein by refer ulfamide, ethoXZolamide, furosemide, indapamide, mefru CCC. side, methazolamide, piretanide, quinethaZone, torasemide, U.S. Pat. No. 4,265,874. tripamide, Xipamide), a uracil (e.g., aminometradine, ami 15 U.S. Pat. No. 4,256,108. Sometradine), a potassium sparing antagonist (e.g., U.S. Pat. No. 4,166,452. amiloride, triamterene) or a miscellaneous diuretic Such as U.S. Pat. No. 5,093,493 aminozine, arbutin, chlorazanil, ethacrynic acid, etoZolin, Acta Chimica Scandinavica, Series B. Organic Chemistry hydracarbazine, isosorbide, mannitol, metochalcone, and Biochemistry, B42:309-313, 1988. muZolimine, perhexiline, ticmafen and urea. Durand et al., Ann. Med., 27:311-317, 1995. c. Inotropic Agents Gewald et al., Monatshefte fur Chemie, 110:1189-1196, Non-limiting examples of a positive inotropic agent, also 1979. known as a cardiotonic, include acefylline, an acetyldigi Heteroatom Chemistry, 7:29-33, 1966. toxin, 2-amino-4-picoline, amrinone, benfurodil hemisucci J. Heterocyclic Chem., 39:877-883, 2002. nate, bucladesine, cerberosine, camphotamide, convalla 25 Phosphorous, Sulfur and Silicon and the Related Elements, toxin, cymarin, denopamine, deslanoside, digitalin, digitalis, 155:215-233, 1999. digitoxin, digoxin, dobutamine, dopamine, dopexamine, Phosphorous, Sulfur and Silicon and the Related Elements, enoXimone, erythrophleine, fenalcomine, gitalin, gitoxin, 166:303-314, 2000. glycocyamine, heptaminol, hydrastinine, ibopamine, a lana Strekowski et al., Heterocycles, 29:539-545, 1989. toside, metamivam, milrinone, nerifolin, oleandrin, Ouabain, 30 Strekowski et al., J. Heterocyclic Chem., 26:923-928, 1989. oxyfedrine, prenalterol, proscillaridine, resilbufogenin, Scil Strekowski et al., J. Org. Chem., 62:4193-4-196, 1997. laren, scillarenin, strphanthin, Sulmazole, theobromine and Tet. Lett., 233-238, 1966. Young et al., Handbook of Applied Xamoterol. Therapeutics, 7.1-7.12 and 9.1-9.10, 1989. In particular aspects, an intropic agent is a cardiac glyco What is claimed is: side, a beta-adrenergic agonist or a phosphodiesterase inhibi 35 1. A compound having the Formula I: tor. Non-limiting examples of a cardiac glycoside includes digoxin (lanoxin) and digitoxin (crystodigin). Non-limiting examples of a B-adrenergic agonist include albuterol, bam Formula I buterol, bitolterol, carbuterol, clenbuterol, clorprenaline, R denopamine, dioxethedrine, dobutamine (dobutrex), dopam 40 R6 X R2 ine (intropin), dopexamine, ephedrine, etafedrine, ethylnore N1R N pinephrine, fenoterol, formoterol, hexoprenaline, ibopamine, Rs 2 isoetharine, isoproterenol, mabuterol, metaproterenol, meth R-1 ''ny N R3 oxyphenamine, oxyfedrine, pirbuterol, procaterol, protoky lol, reproterol, rimiterol, ritodrine, soterenol, terbutaline, tre 45 toquinol, tulobuterol and Xamoterol. Non-limiting examples and pharmaceutically acceptable salts thereof, wherein: of a phosphodiesterase inhibitor include amrinone (inocor). R is NRR, wherein RandR are each H: d. Antianginal Agents R is Co-alkyl, or C-cycloalkyl; Antianginal agents may comprise organonitrates, calcium R is phenyl, pyridine, pyrimidine, thiophene, furan, channel blockers, beta blockers and combinations thereof. 50 Oxazole, isoxazole, thiazole, isothiazole, imidazole, Non-limiting examples of organonitrates, also known as pyrazole and pyrrole, and any of Rs may be optionally nitrovasodilators, include nitroglycerin (nitro-bid, nitrostat), substituted by one or more of halogen, NO, CN, CF, isosorbide dinitrate (isordil, sorbitrate) and amyl nitrate (as Co-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. pirol, vaporole). (Co-alkyl)-N, C-alkyl-SO, C-alkyl-SO, E. Surgical Therapeutic Agents 55 SONH Co-alkyl, SON(C-alkyl). NHSO In certain aspects, the secondary therapeutic agent may C-alkyl, CONH Co-alkyl, NHCO-C-alkyl comprise a Surgery of Some type, which includes, for and COO Co-alkyl; example, preventative, diagnostic or staging, curative and X and Y are null; palliative Surgery. Surgery, and in particular a curative Sur Ra and Rs taken together form a thiophene, which may be gery, may be used in conjunction with other therapies, such as 60 optionally substituted by one or more of halogen, NO, the present invention and one or more other agents. CN, CF, Calkyl, Co-alkyl-S, Co-alkyl-O, Co Such Surgical therapeutic agents for vascular and cardio alkyl-NH, C-alkyl)-N, C-alkyl-SO, C-alkyl vascular diseases and disorders are well known to those of SO, SONH Co-alkyl, SON(C-alkyl). NHSO skill in the art, and may comprise, but are not limited to, C-alkyl, CONH Co-alkyl, NHCO C-alkyl performing Surgery on an organism, providing a cardiovas 65 and COO Co-alkyl; cular mechanical prostheses, angioplasty, coronary artery Re and R7 are null, H, or are independently but not simul reperfusion, catheter ablation, providing an implantable car taneously phenyl, pyridine, pyrimidine, thiophene, US 7,638,519 B2 23 24 furan, oxazole, isoxazole, thiazole, isothiazole, imida and pharmaceutically acceptable salts thereof, wherein: Zole and pyrazole, and any of R or R, may be optionally R is NRR, wherein Rs and Rs are each H: substituted by one or more of halogen, NO, CN, CF, R is Co-alkyl or C-cycloalkyl, Co-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. R is phenyl, pyridine, pyrimidine, thiophene, furan, (Co-alkyl)-N, C-alkyl-SO, C-alkyl-SO, Oxazole, isoxazole, thiazole, isothiazole, imidazole, SONH-Co-alkyl, SON(C-alkyl). NHSO, C pyrazole and pyrrole, and any of Rs may be optionally alkyl, CONH Co-alkyl, NHCO-C-alkyl and substituted by one or more of halogen, NO, CN, CF, COO-Co-alkyl: Co-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. alkyl may be straight or branched chain; (Co-alkyl)-N, C-alkyl-SO, C-alkyl-SO, further comprising all isomers, positional isomers, diaste 10 SONH Co-alkyl, SON(C-alkyl). NHSO-C- reomers, enantiomers and salts thereof, and alkyl, CONH Co-alkyl, NHCO C-alkyl and excluding 3-methyl-2-phenyl-5,6,7,8-tetrahydro-benzo4. COO Co-alkyl; 5thieno 2,3-bipyridin-4-ylamine. X and Y are null; 2. The compound of claim 1, wherein R is phenyl, pyri Ra and Rs taken togetherformathiophene ring, which may dine, thiophene or furan and any of R may be optionally 15 be optionally Substituted by one or more of halogen, substituted by one or more of halogen, NO, CN, CF, C NO, CN, CF, C-alkyl, Co-alkyl-S, Co-alkyl-O. alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. (C- Co-alkyl-NH. (C-alkyl)-N, C-alkyl-SO, C alkyl)-N, C-alkyl-SO, C-alkyl-SO, SONH-Co alkyl-SO, SONH Co-alkyl, SON(C-alkyl). alkyl, SON(C-alkyl). NHSO, C-alkyl, CONH-Co NHSO, C-alkyl, CONH Co-alkyl, NHCO-C- alkyl, NHCO C-alkyl and COO Co-alkyl. alkyl and COO Co-alkyl; 3. The compound of claim 1, wherein R and R, are H. Re and R7 are null, H, or are independently but not simul 4. A pharmaceutical composition comprising at least one taneously phenyl, pyridine, pyrimidine, thiophene, compound of the formula below or a physiologically accept furan, oxazole, isoxazole, thiazole, isothiazole, imida able salt thereof in an amount effective to relieve said condi Zole and pyrazole, and any of R or R, may be optionally tion together with at least one physiologically acceptable 25 substituted by one or more of halogen, NO, CN, CF, carrier or exipient: Co-alkyl, Co-alkyl-S, Co-alkyl-O, Co-alkyl-NH. (C-alkyl)-N, C-alkyl-SO, C-alkyl-SO, SONH Co-alkyl, SON(C-alkyl). NHSO R C-alkyl, CONH Co-alkyl, NHCO-C-alkyl 30 R6 X R2 and COO Co-alkyl; n1R N alkyl may be straight or branched chain; Rs 2 further comprising all isomers, positional isomers, diaste R-1 ny N R3 reomers and enantiomers. UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,638,519 B2 Page 1 of 1 APPLICATION NO. : 1 1/O18383 DATED : December 29, 2009 INVENTOR(S) : Bush et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

On the Title Page:

The first or sole Notice should read --

Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 1018 days.

Signed and Sealed this Ninth Day of November, 2010

David J. Kappos Director of the United States Patent and Trademark Office