Glucagon Antagonists
AssigneeLigand Pharmaceuticals Incorporated
InventorLin ZHI
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 comprising the same as well as 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. Moreover, provided herein are methods of making or manufacturing compounds disclosed herein, including enantiomerically pure forms thereof, and pharmaceutically acceptable salts or co-crystals and prodrugs thereof.
Claims26
A method of treating, preventing, or ameliorating a disease of a subject, comprising administering to the subject the compound of Formula I:
- wherein
- R44 is H, CH3 or CH3CH2;
- R45 is C1-6-alkyl, alkenyl, alkoxy, C3-6-cycloalkyl, C4-8-cycloalkenyl, C4-8-bicycloalkenyl, aryl or heteroaryl, any of which can be optionally substituted with one or more substituents selected from C1-6alkyl, CF3, F, CN or OCF3;
- L is phenyl, indenyl, benzoxazol-2-yl, C3-6-cycloalkyl, C4-8-cycloalkenyl or C4-8-bicycloalkenyl, any of which can be optionally substituted with one or more substituents selected from F, Cl, CH3, CF3, OCF3 or CN;
- and
- R46 represents one or more substituents selected from H, F, Cl, CH3, CF3, OCF3 or CN;
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
2-13. (canceled)
17-20. (canceled)
22-28. (canceled)
30-160. (canceled)
A pharmaceutical composition comprising a combination of one or more pharmaceutically acceptable excipients or carriers, a modified beta-cyclodextrin and a compound of Formula I:
- wherein
- R44 is H, CH3 or CH3CH2;
- R45 is C1-6-alkyl, alkenyl, alkoxy, C3-6-cycloalkyl, C4-8-cycloalkenyl, C4-8-bicycloalkenyl, aryl or heteroaryl, any of which can be optionally substituted with one or more substituents selected from C1-6alkyl, CF3, F, CN or OCF3;
- L is phenyl, indenyl, benzoxazol-2-yl, C3-6-cycloalkyl, C4-8-cycloalkenyl or C4-8-bicycloalkenyl, any of which can be optionally substituted with one or more substituents selected from F, Cl, CH3, CF3, OCF3 or CN;
- and
- R46 represents one or more substituents selected from H, F, Cl, CH3, CF3, OCF3 or CN:
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
162-174. (canceled)
178-184. (canceled)
A method of making a compound of Formula I:
- wherein:
- R44 is H, CH3 or CH3CH2;
- R45 is C1-6-alkyl, alkenyl, alkoxy, C3-6-cycloalkyl, C4-8-cycloalkenyl, C4-8-bicycloalkenyl, aryl or heteroaryl, any of which can be optionally substituted with one or more substituents selected from C1-6alkyl, CF3, F, CN or OCF3;
- L is phenyl, indenyl, benzoxazol-2-yl, C3-6-cycloalkyl, C4-8-cycloalkenyl or C4-8-bicycloalkenyl, any of which can be optionally substituted with one or more substituents selected from F, Cl, CH3, CF3, OCF3 or CN;
- and
- R46 represents one or more substituents selected from H, F, Cl, CH3, CF3, OCF3 or CN;
- wherein the method comprises reacting a compound of Formula (II):
- with a compound of Formula (III):
- wherein Rb is Hydrogen or an activated group.
A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients or carriers and a compound of Formula I:
- wherein
- R44 is H, CH3 or CH3CH2;
- R45 is C1-6-alkyl, alkenyl, alkoxy, C3-6-cycloalkyl, C4-8-cycloalkenyl, C4-8-bicycloalkenyl, aryl or heteroaryl, any of which can be optionally substituted with one or more substituents selected from C1-6alkyl, CF3, F, CN or OCF3;
- L is phenyl, indenyl, benzoxazol-2-yl, C3-6-cycloalkyl, C4-8-cycloalkenyl or C4-8-bicycloalkenyl, any of which can be optionally substituted with one or more substituents selected from F, Cl, CH3, CF3, OCF3 or CN;
- and
- R46 represents one or more substituents selected from H, F, Cl, CH3, CF3, OCF3 or CN;
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
- wherein the pharmaceutical composition, when administered to a subject, reaches peak plasma concentrations in the subject at about 5 to about 8 hours.
A modified release dosage form comprising one or more pharmaceutically acceptable excipients or carriers and a compound of Formula I:
- wherein
- R44 is H, CH3 or CH3CH2;
- R45 is C1-6-alkyl, alkenyl, alkoxy, C3-6-cycloalkyl, C4-8-cycloalkenyl, C4-8-bicycloalkenyl, aryl or heteroaryl, any of which can be optionally substituted with one or more substituents selected from C1-6alkyl, CF3, F, CN or OCF3;
- L is phenyl, indenyl, benzoxazol-2-yl, C3-6-cycloalkyl, C4-8-cycloalkenyl or C4-8-bicycloalkenyl, any of which can be optionally substituted with one or more substituents selected from F, Cl, CH3, CF3, OCF3 or CN;
- and
- R46 represents one or more substituents selected from H, F, Cl, CH3, CF3, OCF3 or CN;
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Dependencies are inferred from the claim text.