Methods and compositions for treating obesity, preventing weight gain, promoting weight loss, promoting slimming, or treating or preventing the development of diabetes

Abstract

The present invention relates to compositions and kits including a chemical uncoupler, such as tyrphostin 9 or precursor or a salt thereof, and compositions including a chemical uncoupler, such as tyrphostin 9 in combination with one or more therapeutic agents, for example, L-carnitine, which are useful, for example, in treating obesity, preventing weight gain, promoting weight loss/slimming, and/or treating or preventing the development of diabetes.

1 . A method for preventing weight gain, promoting weight loss, promoting slimming, and/or treating or preventing the development of diabetes, said method comprising administering to a mammal in need thereof therapeutically or prophylactically effective amounts of tyrphostin 9 or [[a]] salt or precursor thereof and L-carnitine or derivative or salt thereof, wherein said tyrphostin 9 or salt or precursor thereof and said L-carnitine or derivative or salt thereof are administered substantially simultaneously, within one hour of each other, or sequentially. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein said L-carnitine or derivative or salt thereof is selected from the group consisting of: L-carnitine tartrate, L-carnitine chloride, L-carnitine bromide, L-carnitine orotate, L-carnitine acid aspartate, L-carnitine acid phosphate, L-carnitine fumarate, L-carnitine lactate, L-carnitine maleate, L-carnitine acid maleate, L-carnitine acid oxalate, L-carnitine acid sulfate, L-carnitine glucose phosphate, L-carnitine acid tartrate, L-carnitine iodate, L-carnitine aspartate, L-carnitine citrate, L-carnitine acid citrate, L-carnitine acid fumarate, L-carnitine glycerophosphate, L-carnitine mucate, L-carnitine oxalate, L-carnitine sulfate, L-carnitine trichloroacetate, L-carnitine trifluoroacetate, L-carnitine methanesulfonate, L-carnitine pamoate, L-carnitine acid pamoate, C 2-8  alkanoyl L-carnitines, C 2-8  alkanoyl L-carnitine chloride, C 2-8  alkanoyl L-carnitine bromide, C 2-8  alkanoyl L-carnitine orotate, C 2-8  alkanoyl L-carnitine acid aspartate, C 2-8  alkanoyl L-carnitine acid phosphate, C 2-8  alkanoyl L-carnitine fumarate, C 2-8 alkanoyl L-carnitine lactate, C 2-8  alkanoyl L-carnitine maleate, C 2-8 alkanoyl L-carnitine acid maleate, C 2-8  alkanoyl L-carnitine acid oxalate, C 2-8  alkanoyl L-carnitine acid sulfate, C 2-8  alkanoyl L-carnitine glucose phosphate, C 2-8  alkanoyl L-carnitine tartrate, C 2-8  alkanoyl L-carnitine acid tartrate, C 2-8  alkanoyl L-carnitine iodate, C 2-8  alkanoyl L-carnitine aspartate, C 2-8  alkanoyl L-carnitine citrate, C 2-8  alkanoyl L-carnitine acid citrate, C 2-8  alkanoyl L-carnitine acid fumarate, C 2-8  alkanoyl L-carnitine glycerophosphate, C 2-8  alkanoyl L-carnitine mucate, C 2-8 alkanoyl L-carnitine orotate, C 2-8  alkanoyl L-carnitine oxalate, C 2-8 alkanoyl L-carnitine sulfate, C 2-8  alkanoyl L-carnitine trichloroacetate, C 2-8  alkanoyl L-carnitine trifluoroacetate, C 2-8  alkanoyl L-carnitine methanesulfonate, C 2-8  alkanoyl L-carnitine pamoate, and C 2-8  alkanoyl L-carnitine acid pamoate. 
     
     
         5 . The method of  claim 1 , wherein tyrphostin 9 is present in a unit dosage form in an amount from about 2 mg to about 200 mg and L-carnitine or derivative or salt thereof is present in an amount from about 50 mg to about 5000 mg. 
     
     
         6 - 10 . (canceled) 
     
     
         11 . The method of  claim 1 , further comprising administering one or more therapeutic agent(s) selected from the group consisting of insulin, a sulfonylurea, a biguanide, an alpha-glucosidase inhibitor, a thiazolidinedione, a meglitinide, an antidiabetic agent, a statin, and a weight loss supplement. 
     
     
         12 . The method of  claim 1 , wherein said tyrphostin 9 or salt or precursor thereof and said L-carnitine or derivative or salt thereof is administered one or more times a day; is administered for at least two to thirty days; or is administered for more than thirty days. 
     
     
         13 . The method of  claim 1 , wherein said diabetes is type 2 diabetes. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , further comprising a lifestyle modification or a dietary intervention prior to, during, or subsequent to administration of said tyrphostin 9 or salt or precursor thereof and L-carnitine or derivative or salt thereof. 
     
     
         16 . The method of  claim 15 , wherein said lifestyle modification comprises an increase in physical activity; or said dietary intervention comprises a low-calorie diet or a very low calorie diet. 
     
     
         17 . The method of  claim 1 , further comprising the step of monitoring whether said subject experiences an improvement in a sign or symptom of obosity and/or diabetes. 
     
     
         18 . The method of  claim 17 , wherein an improvement in a sign or symptom of obosity and/or diabetes is selected from the group consisting of decreased hunger, weight loss, increased energy, decreased plasma glucose, decreased plasma triglyceride, increased insulin sensitivity, an improvement in body mass index, and improved renal and/or hepatic function. 
     
     
         19 . The method of  claim 1 , wherein administration of said tyrphostin 9 or salt or precursor thereof and L-carnitine or derivative or salt thereof provides a synergistic effect in decreasing plasma glucose or decreasing plasma triglyceride and/or treating obosity, preventing weight gain, promoting weight loss/slimming, or treating or preventing the development of diabetes. 
     
     
         20 . A method for preparing tyrphostin 9, said method comprising:
 a) providing 4-hydroxy-3,5 di-tert-butyl benzaldehyde; and   b) reacting said 4-hydroxy-3,5 di-tert-butyl benzaldehyde with malonodinitrile and an amine base catalyst, optionally in a solvent,   wherein said reacting produces tyrphostin 9.   
     
     
         21 . The method of  claim 20 , wherein said reacting is done by providing heat for about 1 hour. 
     
     
         22 . The method of  claim 20 , wherein said amine base catalyst is selected from a group consisting of ammonia, piperidine, pyridine, pyrrolidine, and sarcosine or addition salts thereof. 
     
     
         23 . The method of  claim 22 , wherein said addition salt of ammonia is ammonium acetate. 
     
     
         24 . The method of  claim 20 , wherein said solvent is selected from a group consisting of ethanol, methanol, and isopropanol. 
     
     
         25 . The method of  claim 24 , wherein said ethanol is anhydrous ethanol. 
     
     
         26 . A synergistic composition comprising a chemical uncoupler, or precursor, or salt thereof and L-carnitine, or salt, or derivative thereof, wherein the weight-to-weight ratio of L-carnitine, or salt, or derivative thereof to chemical uncoupler, or precursor, or salt thereof is greater than 10 but smaller than 700.