Polymorphs of (R)-N-(5-(5-isopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyl-2H-tetrazole-5-carboxamide
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Publication Number
US-12649732-B2
Publication Date
2026-06-09
Expiration Date
Abstract
Provided herein are polymorphs of (R)—N-(5-(5-isopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyl-2H-tetrazole-5-carboxamide, compositions thereof, methods of preparation thereof, and methods of their uses.
Core Innovation
The disclosed invention relates to polymorphic forms of (R)-N-(5-(5-isopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyl-2H-tetrazole-5-carboxamide. Form I and Form II are defined as polymorphs that are distinguishable by X-ray powder diffraction (XRPD) peak patterns at specified 2-theta angles, and the document also describes DSC and TGA behavior and DVS moisture uptake and stability.
The problem addressed is that the polymorphic form of (R)-N-(5-(5-isopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyl-2H-tetrazole-5-carboxamide can exist as different polymorphs, requiring identification and distinction of Form I and Form II for characterization, stability, and formulation use. The disclosed XRPD peak sets and thermal/moisture measurements provide a basis for distinguishing the polymorphs and evaluating their stability.
The document further provides composition embodiments that include Form I, Form II, or mixtures. Preparation routes are outlined in which Form I is obtained via a solvent/cooling or evaporation process, and Form II is obtained by solvent conversion from Form I using n-propyl acetate.
Claims Coverage
The independent claim covers polymorphs of the specified (R)-tetrazole carboxamide in either Form I or Form II, with each form defined by an XRPD peak position pattern. The independent-claim coverage includes two XRPD-defined polymorph variants, and dependent claims further add characterization constraints and preparation routes for Form I and Form II.
XRPD-defined polymorph characterization for Form I and Form II
A polymorph of (R)-N-(5-(5-isopropyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methyl-2H-tetrazole-5-carboxamide of Form I or Form II, wherein Form I is characterized by an XRPD pattern comprising peaks at 2-theta angles 7.1±0.2, 14.2±0.2, 14.9±0.2, 16.2±0.2, and 18.3±0.2 degrees; and Form II is characterized by an XRPD pattern comprising peaks at 2-theta angles 14.9±0.2, 16.0±0.2, 18.8±0.2, 22.5±0.2, and 25.8±0.2 degrees.
DSC-measured endotherm and/or exotherm onset temperature constraints for Form II
Form II is characterized by DSC-measured endotherm and/or exotherm onset temperatures of 133±2°C, 135±2°C, and 152±2°C.
Solvent/cooling or evaporation preparation of Form I
A method for preparing a polymorph of Form I wherein the polymorph is prepared by mixing the specified (R)-tetrazole carboxamide with a solvent comprising acetonitrile and then cooling or evaporating the mixture.
Anti-solvent water addition for Form I preparation method
The method for preparing a polymorph of Form I further includes adding water as an anti-solvent prior to performing step (2).
Solvent conversion of Form I using n-propyl acetate to obtain Form II
A method prepares a polymorph of Form II by forming a mixture of polymorphic Form I with an n-propyl acetate-containing solvent and then removing the solvent.
Overall, the claim set is centered on distinguishing Form I and Form II by XRPD peak position patterns for the specified (R)-tetrazole carboxamide, with additional dependent coverage adding DSC onset temperature constraints and outlining preparation and conversion routes.
Stated Advantages
Enables differentiation of polymorphs Form I and Form II using XRPD peak patterns.
Supports characterization of thermal behavior (DSC/TGA) and moisture uptake/stability (DVS) for Form I and Form II.
Provides composition embodiments using Form I, Form II, or mixtures.
Documented Applications
Treating and/or preventing heart disease, including hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF), via cardiac myosin inhibition.
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