Glucagon receptor antagonists
AssigneeLigand Pharmaceuticals Incorporated
InventorsLin Zhi, Matthew P. Grote, Raja K. Reddy, Wenyu Li, William Craigo
Life of this patent
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Abstract
Provided herein are compounds, including enantiomerically pure forms thereof, and pharmaceutically acceptable salts or co-crystals and prodrugs thereof which have glucagon receptor antagonist or inverse agonist activity. Further, provided herein are pharmaceutical compositions and methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucagon receptor antagonist is indicated, including Type I and II diabetes, insulin resistance and hyperglycemia.
Claims30
A compound of Formula I:
- wherein:
- R1 is selected from the group consisting of hydrogen, halogen, an optionally substituted C1-6-alkyl, an optionally substituted C1-6-heteroalkyl, an optionally substituted C2-6-alkenyl, an optionally substituted C1-6-heteroalkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
- R2 is selected from the group consisting of hydrogen, halogen, and an optionally substituted C1-6-alkyl;
- R3 is selected from the group consisting of hydrogen, an optionally substituted C1-6-alkyl, and an optionally substituted C1-6-heteroalkyl;
- X is independently CH or N;
- L is selected from a group consisting of —OCHR3—, —SCHR3—, —NR3CHR3—, —CHR1CHR3—, —CHR3O—, —CHR3S—, —CHR3NR3—, -arylCHR3—, -arylO—, -heteroarylCHR3—, -heteroarylCHR3NH—, -heteroarylCHR3O—, -heteroarylO—, —CHR3aryl-, —CHR3heteroaryl-, —OCH2CHR3—, —NHCHR3aryl-, —OCHR3aryl-, and —NHCHR3heteroaryl-, where the aryl and the heteroaryl are independently optionally substituted;
- n is 1, 2, or 3;
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A compound of Formula II:
- wherein:
- R1 is selected from the group consisting of hydrogen, halogen, an optionally substituted C1-6-alkyl, an optionally substituted C1-6-heteroalkyl, an optionally substituted C2-6-alkenyl, an optionally substituted C1-6-heteroalkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
- R2 is selected from the group consisting of hydrogen, halogen, and an optionally substituted C1-6-alkyl;
- R3 is selected from the group consisting of hydrogen, an optionally substituted C1-6alkyl, and an optionally substituted C1-6-heteroalkyl;
- X is independently CH or N;
- L is selected from a group consisting of —OCHR3—, —SCHR3—, —NR3CHR3—, —CHR1CHR3—, —CHR3O—, —CHR3S—, —CHR3NR3—, -arylCHR3—, -arylO—, —-heteroarylCHR3—, -heteroarylCHR3NH—, -heteroarylCHR3O—, -heteroarylO—, —CHR3aryl-, —CHR3heteroaryl-, —OCH2CHR3—, —NHCHR3aryl-, —OCHR3aryl-, and —NHCHR3heteroaryl-, where the aryl and the heteroaryl are independently optionally substituted;
- n is 1, 2, or 3;
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A compound selected from Formulae (101) to (125):
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease responsive to a decrease in the hepatic glucose production or in the blood glucose level of a subject,
- wherein:
- R1 is selected from the group consisting of hydrogen, halogen, an optionally substituted C1-6-alkyl, an optionally substituted C1-6-heteroalkyl, an optionally substituted C2-6-alkenyl, an optionally substituted C1-6-heteroalkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
- R2 is selected from the group consisting of hydrogen, halogen, and an optionally substituted C1-6-alkyl;
- R3 is selected from the group consisting of hydrogen, an optionally substituted C1-6-alkyl, and an optionally substituted C1-6-heteroalkyl;
- X is independently CH or N;
- L is selected from a group consisting of —OCHR3—, —SCHR3—, —NR3CHR3—, —CHR1CHR3—, —CHR3O, —CHR3S, —CHR3NR3—, arylCHR3—, -arylO—, -heteroarylCHR3—, -heteroarylCHR3NH—, -heteroarylCHR3O—, -heteroarylO—, —CHR3aryl-, —CHR3heteroaryl-, —OCH2CHR3—, —NHCHR3aryl-, —OCHR3aryl-, and —NHCHR3heteroaryl-, where the aryl and the heteroaryl are independently optionally substituted;
- n is 1, 2, or 3.
A compound of Formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease responsive to a decrease in the hepatic glucose production or in the blood glucose level of a subject,
- wherein:
- R1 is selected from the group consisting of hydrogen, halogen, an optionally substituted C1-6-alkyl, an optionally substituted C1-6-heteroalkyl, an optionally substituted C2-6-alkenyl, an optionally substituted C1-6-heteroalkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
- R2 is selected from the group consisting of hydrogen, halogen, and an optionally substituted C1-6-alkyl;
- R3 is selected from the group consisting of hydrogen, an optionally substituted C1-6-alkyl, and an optionally substituted C1-6-heteroalkyl;
- X is independently CH or N;
- L is selected from a group consisting of —OCHR3—, —SCHR3—, —NR3CHR3—, —CHR1CHR3—, —CHR3O—, —CHR3S—, —CHR3NR3—, -arylCHR3—, -arylO—, -heteroarylCHR3—, -heteroarylCHR3NH—, -heteroarylCHR3O—, -heteroarylO—, —CHR3aryl-, —CHR3heteroaryl-, —OCH2CHR3—, —NHCHR3aryl-, —OCHR3aryl-, and —NHCHR3heteroaryl-, where the aryl and the heteroaryl are independently optionally substituted;
- n is 1, 2, or 3.
A compound selected from Formula (101) to (125), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease responsive to a decrease in the hepatic glucose production or in the blood glucose level of a subject:
Dependencies are inferred from the claim text.