Inhibitors of microsomal triglyceride transfer protein and apo-B secretion
The present invention relates to compounds which are inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion. These compounds can be useful for the prevention and treatment of various diseases, particularly atherosclerosis and its clinical sequelae, for lowering serum lipids, and related ailments. The invention further relates to pharmaceutical compositions comprising the compounds and to methods of treating diseases, such as hypertriglyceridemia, hyperchylomicronemia, atherosclerosis, obesity, and related conditions using the compounds. A method for decreasing apolipoprotein B (apo B) secretion is also provided.
1. A method of treating a condition selected from the group consisting of atherosclerosis, pancreatitis, obesity, hypercholesteremia, hypertriglyceridemia, hyperlipidemia, and diabetes, comprising administering to a mammal in need of such treatment an effective amount of a chemical compound having Formula 1, such that the condition is treated Formula (I):
wherein:
R 1 is alkyl, R 4 R 5 NC(O)CH 2 , cycloalkyl, heterocyclyl, or heterocyclylalkyl;
X 1 is a direct bond, O, S, —N(R 6 )—, C(O)NR 6 , or N(R 6 )C(O);
X 2 is O, —N(R 6 )—, or S;
X 3 is a direct bond, O, —N(R 6 )—, —CH 2 —, arylene, or S;
R 3 is H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroalkyl, aralkyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, —OH, alkoxy, aryloxy, —SH, thioalkyl, thioaryl, or NR 4 R 5 ;
R 4 and R 5 are, independently for each occurrence, H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroalkyl, aralkyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, or aryloxycarbonyl;
R 6 is, independently for each occurrence, H or alkyl;
m is 0 or 1; and
n is an integer from 0 to 3;
provided that if m is 0, X 3 is a direct bond or CH 2 ;
or a pharmaceutically acceptable salt, solvate, ester or hydrate thereof.
2. The method of claim 1 , wherein said condition is selected from atherosclerosis, pancreatitis, obesity, and diabetes.
3. The method as defined in claim 1 , wherein said condition is atherosclerosis.
4. A method of treating a condition selected from the group consisting of atherosclerosis, pancreatitis, obesity, hypercholesteremia, hypertriglyceridemia, hyperlipidemia, and diabetes, comprising administering to a mammal in need of such treatment an effective amount of a chemical compound having formula (II), such that the condition is treated formula (II):
wherein R 11 is selected from:
H; H 3 C—O—,
and R 12 is selected from:
and pharmaceutically acceptable salts, esters, isomers, or solvate thereof.
5. The method of claim 4 , wherein said condition is selected from atherosclerosis, pancreatitis, obesity, and diabetes.
6. The method as defined in claim 4 , wherein said condition is atherosclerosis.
7. The method of claim 1 , wherein the condition is diabetes.
8. The method of claim 4 , wherein the condition is diabetes.