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Publication Number
US-11608335-B2
Publication Date
2023-03-21
Expiration Date
Abstract
Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.
Core Innovation
The invention relates to compounds of Formula (II) and Formula (III), including pharmaceutically acceptable salts, solvates, diastereomeric mixtures, and individual enantiomers. The compounds are defined by broad variable substituent sets including R3, R4, R5, Ra, R7, R8, X1-X6, and R9-R18, with allowed options including H, halogen, alkyl, fluoroalkyl, heteroalkyl, monocyclic carbocycle, monocyclic heterocycle, CN, OR17, CO2R17, C(=O)N(R17)2, SO2R17, and SO2N(R17)2.
The disclosed compound set includes substituted heteroaromatic and fused bicyclic or benzodiazole-like scaffolds, with pyridine-like, pyrrolidine-like, azetidine-like, and related nitrogen-containing ring motifs. The structures are exemplified by fluorinated and chlorinated aromatic substituents, cyano groups, amino and amine-bearing side groups, hydroxyl variants, and stereochemical forms including racemic mixtures, diastereomeric mixtures, and individual enantiomers with (S) or other chiral labeling.
The disclosure further includes specific structural variants such as Formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), and Formula (V), together with enumerated example compounds and related synthetic scheme depictions. The compound examples are presented as specific substituted instances within the broader formula-defined families, and the text also ties the compounds to small molecule SSTR5-targeting variants.
A method aspect of the invention provides treatment of a disease or condition in a mammal by administering a small molecule somatostatin receptor subtype 5 (SSTR5) agonist. The agonist is at least 10 times more selective for modulating or binding to SSTR5 than for somatostatin receptor subtype 2 (SSTR2), and the treated conditions are hyperinsulinemic hypoglycemia, hypoglycemia due to endogenous insulin, drug induced hyperinsulinism, and hypoglycemia due to exogenous (injected) insulin.
Claims Coverage
The consolidated claim coverage includes three independent claim themes: compounds of Formula (II), compounds of Formula (III), and a method of treating insulin-related hypoglycemia or hyperinsulinism using a small molecule SSTR5 agonist with a defined selectivity constraint over SSTR2. The coverage centers on broadly parameterized compound families with extensive substituent definitions and pharmaceutically acceptable forms, together with the treatment-use claim.
Formula (II) compound family
A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomer, with variable substituent definitions for R3, R4, R5, each R6, Ra, R7, R8, X1-X6, and R9-R18, including halogen, CN, OR17, CO2R17, C(=O)N(R17)2, SO2R17, SO2N(R17)2, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, monocyclic carbocycle, monocyclic heterocycle, and N-containing heterocycle formation options.
Formula (III) compound family
A compound of Formula (III), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomer, with variable substituent definitions for R3, R4, R5, Ra, R7, R8, X1-X6, and R9-R18, including halogen, CN, OR17, CO2R17, C(=O)N(R17)2, SO2R17, SO2N(R17)2, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, monocyclic carbocycle, monocyclic heterocycle, and N-containing heterocycle formation options.
Selective SSTR5 agonist treatment
A method for treating a disease or condition in a mammal by administering a small molecule somatostatin receptor subtype 5 (SSTR5) agonist that is at least 10 times more selective for modulating or binding to SSTR5 than for somatostatin receptor subtype 2 (SSTR2), for hyperinsulinemic hypoglycemia, hypoglycemia due to endogenous insulin, drug induced hyperinsulinism, or hypoglycemia due to exogenous (injected) insulin.
The independent claims collectively cover two broad formula-defined small-molecule families, Formula (II) and Formula (III), with extensive substituent-variable and stereochemical coverage, and a distinct treatment method requiring administration of an SSTR5 agonist having at least 10 times selectivity over SSTR2 for specified insulin-related hypoglycemia conditions.
Stated Advantages
The small molecule SSTR5 agonist is at least 10 times more selective for modulating or binding to SSTR5 than for somatostatin receptor subtype 2 (SSTR2).
Selectively modulates or activates SSTR5.
Inhibits insulin secretion.
Promotes glucose release.
Provides treatment of hyperinsulinemic hypoglycemia, hypoglycemia due to endogenous insulin, drug induced hyperinsulinism, or hypoglycemia due to exogenous (injected) insulin.
Documented Applications
Treating hyperinsulinemic hypoglycemia in a mammal.
Treating hypoglycemia due to endogenous insulin in a mammal.
Treating drug induced hyperinsulinism in a mammal.
Treating hypoglycemia due to exogenous (injected) insulin in a mammal.
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