Polymorphic forms of (r)-4-(1-((3-(difluoromethyl)-1-methyl-1h-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-n-(isoxazol-3-yl)piperidine-1-carboxamide

Abstract

The present invention provides novel polymorphs of (R)-4-(1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide (I-491) that are useful for the treatment of cardiac disorders including systolic dysfunction, dilated cardiomyopathy (DCM), heart failure with reserved ejection fraction (HFrEF), and conditions associated with left and / or right ventricular systolic dysfunction or systolic reserve. The synthesis and characterization of the polymorphs is described, as well as methods for treating systolic dysfunction, DCM, HFrEF, and other forms of heart disease.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. provisional application No. 62 / 874,855, filed Jul. 16, 2019, the entire contents of which are hereby incorporated by reference.BACKGROUND OF THE INVENTION[0002]Heart failure (HF) is a global pandemic affecting about 26 million people worldwide. It is the most rapidly growing cardiovascular condition globally, with substantial morbidity, mortality, and cost burden to healthcare systems (Ponikowski et al., ESC Heart Fail. (2014) 1(1):4-25; Savarese and Lund, Card Fail Rev. (2017) 3(1):7-11). HF is the most common cause of hospitalization in patients older than 65 years (Ponikowski, supra; Savarese and Lund, supra; and Shah et al., J Am Coll Cardiol. (2017) 70(20):2476-86). The five-year mortality rate after HF hospitalization is about 42%, comparable to many cancers (Benjamin et al., Circulation (2019) 139:e56-e528).[0003]Heart failure is a clinical syndrome in which a patient's heart is unable to ...

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For some people with heart failure, the heart has difficulty pumping enough blood to support other organs in the body.

Those two conditions result in inadequate blood circulation to the body and congestion of the lungs.

Historically, HFpEF was termed diastolic heart failure; however, recent investigations suggest a more complex and heterogeneous pathophysiology.

Coronary artery disease (coronary heart disease) is a disease in which there is a narrowing of the passageway of the coronary arteries, and when severe, the narrowing causes inadequate blood supply to the heart muscle and may lead to the death of heart muscle cells (infarction).

Although these drugs attenuate some of the maladaptive consequences and improve clinical outcomes, none addresses the underlying causal pathways of myocardial dysfunction.

Their use is limited to short-term or destination therapy in patients with refractory or end-stage heart failure for the purpose of symptom relief, as chronic studies with these drugs have demonstrated increased mortality due to arrhythmias and ischemia.

There are currently no approved therapies for treating heart failure by targeting the contractile apparatus directly.

While many patients with DCM report minimal or no symptoms for extended periods of time, DCM is a progressive disease with a significant cumulative burden of morbidity and mortality.

Patients usually present with symptoms of heart failure: dyspnea, orthopnea, exercise intolerance, fatigue, abdominal discomfort and poor appetite.

The patient journey is punctuated by hospitalizations for decompensated heart failure and an increased risk for sudden arrhythmic death and death from pump failure.

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