Antagonists of the glucagon receptor
The present invention provides for novel compounds of Formula (I) and pharmaceutically acceptable salts and co-crystals thereof which have glucagon receptor antagonist or inverse agonist activity. The present invention further provides for 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. The present invention also provides for processes of making the compounds of Formula I, including salts and co-crystals thereof, and pharmaceutical compositions comprising the same.
1. A method of treating a disease or condition responsive to decreased hepatic glucose production or responsive to lowered blood glucose levels, the method comprising the step of administering to an animal a therapeutically effective amount of a compound of general formula (I)
wherein: D is a substituted group selected from carbocyclic aryl, C 1-8 -alkyl carbocyclic aryl, or heteroaryl, wherein said group is substituted with L and, optionally, one or more additional substituents independently selected from optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 3-8 -cycloalkyl, optionally substituted C 4-8 -cycloalkenyl, optionally substituted C 3-8 -alkoxy, optionally substituted C 3-8 -alkylthio-, optionally substituted C 3-8 -cycloalkylalkoxy, optionally substituted C 3-8 -cycloalkylalkylthio-, optionally substituted C 3-8 -cycloalkyloxy, optionally substituted C 3-8 -cycloalkylthio, halogen, —CF 3 , —NO 2 , —CN,
L is a group selected from carbocyclic aryl, carbocyclic aryloxy-, carbocyclic arylalkoxy-, carbocyclic arylalketyl-, carbocyclic arylketyl-, carbocyclic aryl—NH—, carbocyclic aryl-N—C 1-3 -alkyl-, heteroaryloxy, heteroarylalkoxy, heteroarylketyl, heteroarylalketyl, and heteroaryl;
wherein L is optionally substituted with one, two, or three groups selected from halogen, CF 3 , hydroxyl, amido, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 3-6 -cycloalkyl, optionally substituted C 4-8 -cycloalkenyl, optionally substituted C 1-8 -alkyoxy, optionally substituted C 3-8 -alkylthio-, optionally substituted C 3-8 -cycloalkylalkoxy, optionally substituted C 3-8 -cycloalkylalkylthio, —NO 2 , or —CN,
R 2 is a group selected from hydrogen or C 1-8 -alkyl;
R 1 is a group selected from hydrogen, fluoro or C 1-8 -alkyl optionally substituted with fluoro up to perfluoro,
E is a group selected from C 1-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, carbocyclic aryl, or heteroaryl; wherein each group is optionally substituted with one to six groups independently selected from halogen, —CN, —C 1-6 -alkyl, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , optionally substituted C 3-8 -cycloalkyl, optionally substituted C 4-8 -cycloalkenyl, optionally substituted phenyl or optionally substituted five- or six-membered heteroaryl;
X is a group selected from phenylene, heterocyclic monoarylene, C 5-8 -cycloalkylene or C 5-8 -cycloalkenylene; wherein X is optionally substituted with one or two groups independently selected from halogen, —CN, —CF 3 , —OCF 3 , —OCHF 2 , —NO 2 , —OR 30 , C 1-6 -alkyl, C 2-6 -alkenyl, or C 1-6 -alkynyl;
R 30 is a group independently selected from hydrogen or C 1-6 -alkyl optionally substituted with fluoro up to perfluoro;
n is 0, 1, 2, or 3;
R 39 is a group selected from —OH, —NHOH, —NH 2 ; and
pharmaceutically acceptable salts, cocrystals and prodrugs thereof.
2. The method of claim 1 , wherein the compound has the following structure:
3. A method for treating a disease or condition selected from the group consisting of: Type I diabetes, Type II diabetes, impaired glucose tolerance, insulin resistance, postprandial hyperglycemia, fasting hyperglycemia, accelerated gluconeogenesis, increased or excessive (greater than normal levels) hepatic glucose output, hyperinsulinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis, obesity, Metabolic Syndrome X, the method comprising the step of administering to an animal a therapeutically effective amount of a compound of general formula (I)
wherein: D is a substituted group selected from carbocyclic aryl, C 1-8 -alkyl carbocyclic aryl, or heteroaryl, wherein said group is substituted with L and, optionally, one or more additional substituents independently selected from optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 3-8 -cycloalkyl, optionally substituted C 4-8 -cycloalkenyl, optionally substituted C 3-8 -alkoxy, optionally substituted C 3-8 -alkylthio-, optionally substituted C 3-8 -cycloalkylalkoxy, optionally substituted C 3-8 -cycloalkylalkylthio-, optionally substituted C 3-8 -cycloalkyloxy, optionally substituted C 3-8 -cycloalkylthio, halogen, —CF 3 , —NO 2 , —CN,
L is a group selected from carbocyclic aryl, carbocyclic aryloxy-, carbocyclic arylalkoxy-, carbocyclic arylalketyl-, carbocyclic arylketyl-, carbocyclic aryl—NH—, carbocyclic C 1-3 -alkyl-, heteroaryloxy, heteroarylalkoxy, heteroarylketyl, heteroarylalketyl, and heteroaryl;
wherein L is optionally substituted with one, two, or three groups selected from halogen, CF 3 , hydroxyl, amido, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted C 3-6 -cycloalkyl, optionally substituted C 4-8 -cycloalkenyl, optionally substituted C 1-8 -alkyoxy, optionally substituted C 3-8 -alkylthio-, optionally substituted C 3-8 -cycloalkylalkoxy, optionally substituted C 3-8 -cycloalkylalkylthio, —NO 2 , or —CN,
R 2 is a group selected from hydrogen or C 1-8 -alkyl;
R 1 is a group selected from hydrogen, fluoro or C 1-8 -alkyl optionally substituted with fluoro up to perfluoro,
E is a group selected from C 1-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, carbocyclic aryl, or heteroaryl; wherein each group is optionally substituted with one to six groups independently selected from halogen, —CN, —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —SCF 3 , optionally substituted C 3-8 -cycloalkyl, optionally substituted C 4-8 -cycloalkenyl, optionally substituted phenyl or optionally substituted five- or six-membered heteroaryl;
X is a group selected from phenylene, heterocyclic monoarylene, C 5-8 -cycloalkylene or C 5-8 -cycloalkenylene; wherein X is optionally substituted with one or two groups independently selected from halogen, —CN, —CF 3 , —OCF 3 , —OCHF 2 , —NO 2 , —OR 30 , C 1-6 -alkyl, C 2-6 -alkenyl, or C 1-6 -alkynyl;
R 30 is a group independently selected from hydrogen or C 1-6 -alkyl optionally substituted with fluoro up to perfluoro;
n is 0, 1, 2, or 3;
R 39 is a group selected from —OH, —NHOH, —NH 2 ; and
pharmaceutically acceptable salts, cocrystals and prodrugs thereof.
4. The method of claim 3 , wherein the compound has the following structure:
5. The method of claim 3 , wherein the disease or condition is Type II diabetes.
6. The method of claim 3 , wherein the disease or condition is obesity.
7. The method of claim 1 , wherein the animal is a mammal.
8. The method of claim 1 , wherein the animal is human.
9. The method of claim 3 , wherein the animal is a mammal.
10. The method of claim 3 , wherein the animal is human.