Crystalline forms of a KRas G12C inhibitor
Inventors
Andres, Patricia • Andrew, Samuel • Chen, Cheng Yi • GANCEDO, SUSANA DEL RIO • Gharbaoui, Tawfik • Nelson, Jennifer
Assignees
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Publication Number
US-12281113-B2
Publication Date
2025-04-22
Expiration Date
Abstract
The present invention relates to crystalline forms of a KRas G12C inhibitor and salt thereof. In particular, the present invention relates to crystalline forms of the KRas G12C inhibitor 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, pharmaceutical compositions comprising the crystalline forms, processes for preparing the crystalline forms and methods of use thereof.
Core Innovation
The invention relates to crystalline forms of the KRas G12C inhibitor 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (MRTX849), including crystalline Forms A, B, C, D, and E. Each crystalline form is characterized by X-ray powder diffraction (XRPD) peak-definitions based on specified 2θ peak sets and ranges, with amorphous free base addressed by comparison, including an absence of characteristic XRPD peaks and a low glass transition as described by DSC.
Solid-state characterization for the crystalline forms is supported using DSC, TGA, and DVS, including discussion of endothermic peaks or heat of fusion, degradation onset, and DVS isotherms or weight gain-loss. Hydrate indications are associated with Forms C and D, and the disclosed crystalline forms also encompass possible crystalline mixtures and specified high crystalline content levels, alongside comparison to amorphous material.
The crystalline forms are linked to pharmaceutical compositions and anti-cancer or anti-KRas G12C methods, including patient selection by KRas G12C mutation and related assay and kit language. The disclosed compositions include a therapeutically effective amount of the crystalline form with pharmaceutically acceptable excipients and/or diluents, and residual organic solvent aspects are addressed, including descriptions of crystalline forms being substantially free of residual organic solvents and residual organic solvent limits described by the claims.
Claims Coverage
The partial content identifies three independent claims covering crystalline Forms A, B, and C of the specified MRTX849 compound, each defined by XRPD requirements using at least one specified 2θ peak and, in dependent claims, additional peak constraints. Across the dependent claims, additional inventive features include expanded XRPD peak sets, DSC/TGA/DVS characterization references, hydrate specification for Form C, residual organic solvent limits, and pharmaceutical compositions containing the crystalline form with pharmaceutically acceptable excipients and/or diluents.
Crystalline Form A XRPD-defined peaks
Crystalline Form A of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile having an X-ray powder diffraction pattern comprising at least one peak at 2θ selected from 8.6±0.2, 14.6±0.2, 16.9±0.2 and 18.3±0.2.
Crystalline Form B XRPD-defined peaks
Crystalline Form B of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile having an X-ray powder diffraction pattern comprising at least one peak at 2θ selected from 16.7±0.2, 17.5±0.2 and 18.8±0.2.
Crystalline Form C XRPD-defined peaks
Crystalline Form C of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile having an X-ray powder diffraction pattern comprising at least one peak at 2θ selected from 16.4±0.2 and 19.7±0.2.
Across the identified independent claims, the scope is anchored on XRPD-defined crystalline Forms A, B, and C of MRTX849 using specified 2θ peaks. Dependent claims further refine the XRPD constraints, incorporate referenced DSC/TGA/DVS characterization, specify hydrate for Form C, and include residual organic solvent limits and pharmaceutical compositions containing the crystalline form with pharmaceutically acceptable excipients and/or diluents.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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