Pyrazolopyridine derivative having GLP-1 receptor agonist effect
Inventors
Yoshino, Hitoshi • Tsuchiya, Satoshi • Matsuo, Atsushi • Sato, Tsutomu • Nishimoto, Masahiro • OGURI, Kyoko • Ogawa, Hiroko • Nishimura, Yoshikazu • Furuta, Yoshiyuki • Kashiwagi, Hirotaka • Hori, Nobuyuki • Kamon, Takuma • Shiraishi, Takuya • YOSHIDA, Shoshin • Kawai, Takahiro • Tanida, Satoshi • Aoki, Masahide
Assignees
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Publication Number
US-12331050-B2
Publication Date
2025-06-17
Expiration Date
Abstract
The present invention provides a compound having the basic structure shown by Formula (I) in which the indole ring and the pyrazolopyridine structure is bound through a substituent, a salt thereof or a solvate of either the compound or a salt of the compound, as well as a preventative agent or a therapeutic agent for non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity containing such compound, salt or solvate as an active ingredient.
Core Innovation
The disclosure describes compounds of Formula (I) and related formula-defined compounds, including salts, solvates, and hydrates, together with pharmaceutical compositions and therapeutic/preventive uses. The compounds are described as GLP-1 receptor agonist compounds, including indole-pyrazolopyridine linked compounds, substituted pyrazolo[4,3-c]pyridine derivatives, and indole/pyrazolo[4,3-c]pyridine/oxadiazole-containing compounds.
The disclosed subject matter provides substituted heterocyclic small-molecule structures, including oxadiazol-5-one-containing indole-pyrazolo[4,3-c]pyridine/imidazole derivatives with stereochemical designations such as (1S,2S) and (4S). The structures include variants labeled SMD-TFA05-1, SMD-TFA05-2, SMD-TFA05-3, SMD-FA05-1, SMD-FA05-2, SMD-FA05-3, and SQD-FA05-1, together with named example compounds and corresponding [M+H]+ mass values, LC/MS retention data, and depicted molecular structures.
The compound family shows systematic variation in aryl and heteroaryl substituents on a common fused scaffold that includes pyrazolo[4,3-c]pyridine, indole, imidazole or 2-oxoimidazol-1-yl, indazole-5-yl, and 1,2,4-oxadiazol-5-one motifs. The document also describes additional example compounds and solid forms, including crystal forms, salts, a monosodium salt hydrate crystal, and a hemicalcium salt hydrate.
Claims Coverage
The provided claim coverage centers on formula-defined compound scope, with independent claims for formula 11k, formula 31i, formula 31k, and formula 67a, or their salts. The 11k family further includes named intermediate conversions and an extension beyond 11k to 11l and 31l.
Compound represented by formula 11k or a salt thereof
A compound represented by formula 11k, or a salt thereof.
Compound represented by formula 31i or a salt thereof
A compound represented by formula 31i, or a salt thereof.
Compound represented by formula 31k or a salt thereof
A compound represented by formula 31k, or a pharmaceutically acceptable salt of that compound.
Compound represented by formula 67a or a salt thereof
A compound represented by formula 67a, or a salt thereof.
Conversion of compound 11j to compound 11k
Compound 11j is treated in THF with methylsulfonic acid, combined with tripotassium phosphate solution in water and di-tert-butyl bicarbonate, and then water is added and extraction is performed to obtain compound 11k.
Conversion of compound 11b to compound 11h via compound 11g
Compound 11b is reacted in NMP with methanesulfonic acid, then toluene, potassium carbonate, and water are used before introducing compound 11g with pyridine hydrochloride and toluene, and sodium hydroxide solution is used to obtain compound 11h.
Formation of compound 11g from compound 11f
Potassium tert-butoxide is added to a mixture containing compound 11f, followed by 2N HCl and extraction to obtain compound 11g.
Formation of compound 11f from compound 11c
Compound 11c is combined with ethanol and TEA, ethyl acrylate is added, a mixture containing compound 11e is formed, and then di-tert-butyl decarbonate and N-methyl-piperazine are added, followed by addition of an HCl solution and extraction with toluene to obtain compound 11f.
Further conversion beyond 11k to 11l and 31l
Compound 11k is converted to compound 11l, and compound 11l is reacted with compound 31k to make compound 31l.
Overall, the claim coverage is directed to specific compound scopes defined by formulas 11k, 31i, 31k, and 67a, with the 11k family further refined by process-linked conversions among named intermediates and extending from 11k to 11l and then to 31l.
Stated Advantages
GLP-1-like activity.
Expected sufficient oral bioavailability.
Non-invasive oral administration.
Blood glucose reduction effects.
The compounds are associated with GLP1R cAMP activation.
The compounds are associated with in vivo insulin/glucose lowering and anorexigenic effects in cynomolgus monkeys.
Pharmacokinetics are reported for Example compound 67, including Tmax, Cmax, and AUC0-24h.
Documented Applications
Prevention and/or treatment of Type 2 diabetes.
Prevention and/or treatment of obesity.
Therapeutic/preventive use in a broader disease list.
Treating and/or preventing Type 2 diabetes and related conditions using compounds of Formula (I), including salts, solvates, and hydrates.
GLP1R cAMP activation assays in GLP1R-HEK293 and related GLP-1 (7-37) context.
In vivo insulin/glucose lowering and anorexigenic effects in cynomolgus monkeys.
Pharmacokinetic evaluation of Example compound 67.
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