Dimethylaminoethanol salt of a GLP-1 receptor modulator
Inventors
Vidal, Ephraim • Bakale, Roger • Turnbull, Philip • Moser, David • Robbins, Andrew • Grant, Craig
Assignees
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Publication Number
US-11066395-B2
Publication Date
2021-07-20
Expiration Date
Abstract
Crystalline 2-hydroxy-N,N-dimethylethanaminium 1-(2-(5-(tert-butyl)-thiophene-2-carboxamido)-3-(4-(5-(4′-ethyl-[1,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate salt, and methods related to synthesis and therapeutic use of the same.
Core Innovation
The invention relates to a GLP-1 receptor modulator presented as a dimethylaminoethanol (deanol) salt, including crystalline Deanol-RP-101 and specific isomeric forms Deanol-RP-102, Deanol-RP-103, and Deanol-RP-104. The disclosure identifies Deanol-RP-101 as crystalline Deanol-RP-101 corresponding to the deanol salt of RP-101 free acid, and it frames the subject matter around solid forms of these deanol salts for GLP-1 receptor activity.
The disclosure states that crystalline Deanol-RP-101 improves crystallinity, solubility, and thermal behavior versus compounds such as Cpd. No. 76 / RP-101. It also describes solid-state characterization, including XRPD characterization of crystalline forms and characteristic XRPD peak positions for FIG. 1A, FIG. 2A, and FIG. 3A, with Tables 1A/1B/1C listing peak data for the crystalline forms.
The disclosure further specifies purity thresholds and describes solid-state characterization approaches including PLM, TGA, and DSC. It also includes therapeutic use conceptually through GLP-1 receptor activation/potentiation/agonism for diseases and metabolic conditions including various forms of diabetes, obesity/excessive appetite/insufficient satiety, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH), as well as pharmaceutical composition embodiments with pharmaceutically acceptable carriers/excipients.
Claims Coverage
The provided set includes one independent compound-structure claim and multiple independent crystalline-form claims, with claim-defining inventive features centered on a specified compound structure and XRPD-defined crystalline salt forms, plus a quantitative purity constraint and a pharmaceutical-composition constraint in refinements of the structure claim family. Overall, the coverage emphasizes structurally defined deanol salt compounds and specific XRPD-pattern crystalline variants.
A compound having the following structure
A compound defined by a particular chemical structure as specified in the claim family, with dependent refinement to the detailed structure using accompanying structure images/files.
Crystalline 2-hydroxy-N,N-dimethylethanaminium 1-(2-(5-(tert-butyl)-thiophene-2-carboxamido)-3-(4-(5-(4′-ethyl-[1′,1′-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate salt
A crystalline salt form of the specified complex compound, identified as crystalline 2-hydroxy-N,N-dimethylethanaminium ... azetidine-3-carboxylate salt.
Crystalline salt having an XRPD pattern as shown in FIG. 1A
A crystalline 2-hydroxy-N,N-dimethylethanaminium ... azetidine-3-carboxylate salt having an XRPD pattern as shown in FIG. 1A.
Crystalline salt having an XRPD pattern as shown in FIG. 2A
A crystalline 2-hydroxy-N,N-dimethylethanaminium ... azetidine-3-carboxylate salt having an XRPD pattern as shown in FIG. 2A.
Crystalline salt having an XRPD pattern as shown in FIG. 3A
A crystalline 2-hydroxy-N,N-dimethylethanaminium ... azetidine-3-carboxylate salt having an XRPD pattern as shown in FIG. 3A.
Crystalline salt with XRPD characteristic peaks listed in Table 1A
A crystalline salt exhibiting an XRPD pattern having characteristic peaks expressed in 2θ (+/−0.2° θ) distances as listed in Table 1A.
Crystalline salt with XRPD characteristic peaks listed in Table 1B
A crystalline salt exhibiting an XRPD pattern having characteristic peaks expressed in 2θ (+/−0.2° θ) distances as listed in Table 1B.
Crystalline salt with XRPD characteristic peaks listed in Table 1C
A crystalline salt exhibiting an XRPD pattern having characteristic peaks expressed in 2θ (+/−0.2° θ) distances as listed in Table 1C.
Across the independent claims provided, the claim coverage centers on a specified compound structure and crystalline salt forms of a particular complex compound defined by XRPD signatures. The XRPD-defined crystalline forms are further bounded by figure-referenced patterns (FIG. 1A, FIG. 2A, FIG. 3A) and by quantitative XRPD characteristic peaks expressed in 2θ with a stated tolerance, referencing peak lists in Tables 1A/1B/1C.
Stated Advantages
Improves crystallinity versus Cpd. No. 76 / RP-101.
Improves solubility versus Cpd. No. 76 / RP-101.
Improves thermal behavior versus Cpd. No. 76 / RP-101.
Documented Applications
Treatment via GLP-1 receptor activation/potentiation/agonism for diabetes, including type I diabetes, type II diabetes, and gestational diabetes as mentioned in the disclosure.
Treatment of obesity/excessive appetite/insufficient satiety via GLP-1 receptor activation/potentiation/agonism.
Treatment of non-alcoholic fatty liver disease (NAFLD).
Treatment of non-alcoholic steatohepatitis (NASH).
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