Compounds, compositions and methods
Inventors
Morgan, Bradley Paul • Muci, Alex • Lu, Pu-Ping • Tochimoto, Todd • Morgans, Jr., David J. • Kraynack, Erica Anne
Assignees
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Publication Number
US-12264133-B2
Publication Date
2025-04-01
Expiration Date
Abstract
Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
Core Innovation
The invention relates to substituted urea derivatives and specific small-molecule compounds identified by structural formulas, including Formula I and named formula members such as Formula 1D, Formula 1E, Formula 4B, and Formula 4C. The described chemical entities include variants defined by substituent variables and ring constraints, and are provided as such or as pharmaceutically acceptable salts, with further forms including chelate, non-covalent complex, prodrug, crystalline or amorphous forms, polymorphs, and solvates or hydrates.
A central aspect of the described approach is modulation or potentiation of cardiac myosin via sarcomere modulation and cardiac myosin activation. The patent describes use in treating heart disease, including systolic heart failure, congestive heart failure, and dilated cardiomyopathy, and states effects on contractile force via the cardiac sarcomere.
The disclosure further describes synthetic schemes for making the compounds, including conversion of precursor amines and isocyanates through named intermediates and multi-step transformations. The document also presents specific intermediate products and downstream compounds with mass spectrometry confirmation and tabulated mass-spec results.
Claims Coverage
The consolidated claim coverage includes independent compound claims for Formula 1D, Formula 1E, Formula 4B, and Formula 4C, each including pharmaceutically acceptable salts. The claim set also includes preparation-related inventive features tied to forming mixtures, contacting steps, reductions, solvent or media choices, and temperature constraints.
Formula 1D compound and pharmaceutically acceptable salt
A compound of Formula 1D, or a pharmaceutically acceptable salt thereof.
Formula 1E compound and pharmaceutically acceptable salt
A compound of Formula 1E, or a pharmaceutically acceptable salt thereof.
Formula 4B compound and pharmaceutically acceptable salt
A compound of Formula 4B, or a pharmaceutically acceptable salt thereof.
Formula 4C compound and pharmaceutically acceptable salt
A compound of Formula 4C, or a pharmaceutically acceptable salt thereof.
Contacting boc-piperazine with sodium triacetoxylborohydride and a Formula 1B/Formula 1C mixture
Preparing Formula 1D, or a pharmaceutically acceptable salt thereof, by contacting boc-piperazine and sodium triacetoxylborohydride with a mixture containing compounds of Formula 1B and Formula 1C.
Formula 1B/Formula 1C mixture ratio of 20:80
Using a mixture of the compound of Formula 1B and the compound of Formula 1C in a 20:80 ratio.
Contacting in a mixture of HOAc and DCM
Carrying out the contacting step in a mixture of HOAc and DCM.
Reducing Formula 1D using 10% Pd/C in MeOH under an atmosphere of H2
A method for preparing Formula 1E, or a pharmaceutically acceptable salt thereof, by reducing Formula 1D using 10% Pd/C in MeOH under an atmosphere of H2.
Reducing Formula 4B in the presence of Pt/C, K2CO3, and H2
A method prepares Formula 4C, or a pharmaceutically acceptable salt thereof, by reducing Formula 4B in the presence of Pt/C, K2CO3, and H2.
Reducing in THF
The reducing step is carried out in THF.
Internal reaction temperature of 30°C or less
The reducing method is performed with an internal reaction temperature of 30°C or less.
Preparing Formula 4B by admixing Formula 4A with methyl piperazine-1-carboxylate
The method specifies that Formula 4B is prepared by admixing Formula 4A with methyl piperazine-1-carboxylate.
Admixing with DIPEA in DCM
The admixing step is carried out in the presence of DIPEA in DCM.
Overall, the claim coverage spans multiple formula-defined compound classes and further refines these classes through dependent claims. The dependents specify contacting and reduction transformations, including defined reagents, solvents or media, a 20:80 mixture ratio, and temperature constraints.
Stated Advantages
Modulation/potentiation of cardiac myosin ATPase.
Treatment of heart disease including congestive heart failure and systolic dysfunction.
Effects on contractile force via the cardiac sarcomere.
Documented Applications
Modulation/potentiation of cardiac myosin ATPase for treating heart disease, including congestive heart failure and systolic dysfunction.
Treating systolic heart failure (including congestive heart failure (CHF)).
Treating dilated cardiomyopathy.
Modulating cardiac sarcomere and potentiating cardiac myosin for use as described in treating heart disease.
Cardiac myosin ATPase specificity and in vitro dose-response models are described.
Adult rat ventricular myocyte contractility and calcium transient assays using Fura-2 and IonOptix are described.
In vivo cardiac functional assessment using echocardiography and hemodynamics is described.
A left coronary artery occlusion heart failure model is described.
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