Crystalline solid forms of N-(1-((2-(dimethylamino)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butanamide and methods of their synthesis
Inventors
BEDNARZ, Mark Stephen • DAI, Kuangchu • ECKERT, Jeffrey Manning • Lim, Ngiap-Kie • SIROIS, Lauren • Wu, Wenxue • Zhao, Matthew Mangzhu
Assignees
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Publication Number
US-10968192-B2
Publication Date
2021-04-06
Expiration Date
Abstract
Methods of preparing, and solid forms of N-(1-((2-(dimethylamino)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butanamide, and salts, solvates and cocrystals thereof, are disclosed.
Core Innovation
The disclosure relates to a crystalline form of N-(1-((2-(dimethylamino)ethyl)-amino)-2-methyl-1-oxopropan-2-yl)-4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butanamide L-proline, and to polymorph/cocrystal formation for compound I with L-proline. The disclosed crystalline forms are referred to as Form I, Form II, and Form III, with XRPD crystalline characterization and stated melting points for solid-state identification.
The crystalline forms are identified as Form II and Form III, and the disclosure includes characterization by DSC melting point and XRPD peak positions. Form II is characterized by a DSC melting point of about 147 ± 5.0°C and XRPD peaks at 2θ values including 4.5, 5.3, 10.5, 12.1, 17.1, 18.8, 19.3, 22.3, 26.1, and 26.2 (± 0.5°), while Form III is characterized by a DSC melting point of about 150 ± 5.0°C and XRPD peaks at 2θ values including 4.2, 7.5, 8.3, 10.9, 12.5, 14.7, 16.6, 17.7, 19.8, and 20.6 (± 0.5°).
The disclosure emphasizes crystalline/amorphous mixtures with defined weight fractions and indicates that these specific crystalline forms provide advantages in pharmaceutical manufacture. Form III is stated to be preferred due to stability, and the disclosure also provides general therapeutic use for metabolic diseases, including diabetes, using administration of the crystalline solid forms and related pharmaceutical compositions.
Claims Coverage
The patent document provides one independent claim directed to a crystalline form of the named compound as an L-proline co-crystal, with dependent claims refining the form by specified DSC melting points and XRPD peak positions, including a stated peak tolerance. In total, the claim coverage corresponds to the two crystalline variants distinguished by melting point and XRPD peak sets.
Crystalline form of N-(1-((2-(dimethylamino)ethyl)-amino)-2-methyl-1-oxopropan-2-yl)-4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butanamide L-proline co-crystal
A crystalline form of the named SGLT1 inhibitor compound as an L-proline co-crystal.
Crystalline form with DSC melting point 147 ± 5.0°C
The crystalline form has a melting point of 147 ± 5.0°C.
Crystalline form with XRPD peaks at 4.5, 5.3, 10.5, 12.1, 17.1, 18.8, 19.3, 22.3, 26.1, and 26.2 ± 0.5 degrees 2θ
The crystalline form has an X-ray powder diffraction pattern comprising peaks at one or more of 4.5, 5.3, 10.5, 12.1, 17.1, 18.8, 19.3, 22.3, 26.1, and 26.2 ± 0.5 degrees 2θ.
Crystalline form with DSC melting point 150 ± 5.0°C
The crystalline form has a melting point of 150 ± 5.0°C.
Crystalline form with XRPD peaks at 4.2, 7.5, 8.3, 10.9, 12.5, 14.7, 16.6, 17.7, 19.8, and 20.6 ± 0.5 degrees 2θ
The crystalline form has an X-ray powder diffraction pattern comprising peaks at one or more of 4.2, 7.5, 8.3, 10.9, 12.5, 14.7, 16.6, 17.7, 19.8, and 20.6 ± 0.5 degrees 2θ.
Claim coverage is focused on specific crystalline L-proline co-crystal forms of the named SGLT1 inhibitor, distinguished by DSC melting point values and corresponding XRPD peak sets, encompassing the two crystalline variants described.
Stated Advantages
Provides advantages in pharmaceutical manufacture.
Form III is preferred due to stability.
Documented Applications
Therapeutic use for metabolic diseases, including diabetes, via administration of the crystalline solid forms and related pharmaceutical compositions.
Treatment/administration for metabolic disease, including diabetes type 1 and diabetes type 2, where the target is described as an SGLT1 inhibitor.
Formation of pharmaceutical compositions.
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