Use Of Chloroquine To Treat Metabolic Syndrome

Abstract

The present invention provides methods and compositions for modulating certain metabolic processes and for treating a variety of disorders associated with metabolic syndrome, including insulin related disorders, ischemia, oxidative stress, atherosclerosis, hypertension, obesity, abnormal lipid metabolism, and stroke by administering an effective dose of a chloroquine compound. The invention also provides methods and compositions relating to administering an effective dose of a chloroquine compound in combination with at least a second pharmaceutically active ingredient or compound including an antihyperglycemic diabetes treatment, an antihypertensive agent, an antithrombotic agent, and/or an inhibitor of cholesterol synthesis or absorption.

1 - 31 . (canceled) 
     
     
         32 . A pharmaceutical composition which comprises an amount of a chloroquine compound effective to increase Ataxia-Telangiectasia mutated (ATM) protein kinase activity in a mammal with metabolic syndrome and a pharmaceutically acceptable carrier. 
     
     
         33 . The pharmaceutical composition of  claim 32  which further comprises an effective amount of a second pharmaceutically active ingredient. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the second pharmaceutically active ingredient is a member selected from the group consisting of an antihyperglycemic diabetes treatment, an antihypertensive agent, an antithrombotic agent, and an inhibitor of cholesterol synthesis or absorption. 
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the antihypertensive agent is selected from the group consisting of an angiotensin converting enzyme inhibitor (ace inhibitor), an angiotensin receptor blocker (ARB), a beta-blocker, and a calcium channel blocker. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the beta blocker is selected from the group consisting of propranolol, atenolol, esmolol, metoprolol, labetalol, talinolol, timolol, carvedilol and acebutolol. 
     
     
         37 . The pharmaceutical composition of  claim 35 , wherein the calcium channel blocker is selected from the group consisting of nifedipine, verapamil, diltiazem, and nimodipine. 
     
     
         38 . The pharmaceutical composition of  claim 34 , wherein the inhibitor of cholesterol synthesis is selected from the group consisting of an inhibitor of HMG CoA reductase, squalene epoxidase, squalene synthetase, cholesterol sulfate, and phosphate synthetase. 
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the inhibitor of HMG CoA reductase is selected from the group consisting of atorvastatin, cerivastatin, simvastatin, lovastatin, pravastatin, compactin, fluvastatin, mevastatin, fluindostatin, and dalvastatin, cholesterol sulfate, cholesterol phosphate, 25-OH or 26-OH cholesterol, and oxygenated sterols. 
     
     
         40 . The pharmaceutical composition of  claim 34  wherein the antihyperglycemic diabetes treatment is selected from the group consisting of insulin, an insulin analog, actos (pioglitazone), avandia (rosiglitazone), a sulfonylurea, tolbutamide, a biguanide-type medication agent, phentolamine, and tolazemide. 
     
     
         41 . The pharmaceutical composition of  claim 34 , wherein the antithrombotic agent is selected from the group consisting of unfractionated heparin, low molecular weight (LMW) heparin, heparinoid, aspirin, ticlopidine, clopidogrel, dipyridamole, hirudin, and glycoprotein IIb/IIIa antagonists. 
     
     
         42 . The pharmaceutical composition of  claim 32  comprising about 1 mg to about 140 mg of the chloroquine compound. 
     
     
         43 . The pharmaceutical composition of  claim 32  comprising about 80 mg of the chloroquine compound. 
     
     
         44 . The pharmaceutical composition of  claim 32 , wherein the chloroquine compound is selected from the group consisting of chloroquine, chloroquine phosphate, hydroxychloroquine, chloroquine diphosphate, chloroquine sulphate, hydroxychloroquine sulphate, enantiomers thereof, pharmaceutically acceptable salts thereof, and mixtures thereof. 
     
     
         45 . The pharmaceutical composition of  claim 44 , wherein the chloroquine compound is selected from the group consisting of chloroquine, chloroquine phosphate, hydroxychloroquine, chloroquine diphosphate, and mixtures thereof. 
     
     
         46 . The pharmaceutical composition of  claim 45 , wherein the chloroquine compound is chloroquine. 
     
     
         47 . The pharmaceutical composition of  claim 45 , wherein the chloroquine compound is hydroxychloroquine. 
     
     
         48 . The pharmaceutical composition of  claim 32 , wherein the chloroquine compound is an essentially pure (+) isomer. 
     
     
         49 . The pharmaceutical composition of  claim 32 , wherein the chloroquine compound is an essentially pure (−) isomer. 
     
     
         50 . The pharmaceutical composition of  claim 32 , wherein the chloroquine compound is a mixture of isomers. 
     
     
         51 . The pharmaceutical composition of  claim 32 , wherein the chloroquine compound is selected from the group consisting of mefloquine, pyronaridine, piperaquine, amodiaquine, and quinidine, enantiomers thereof, pharmaceutically acceptable salts thereof, and mixtures thereof, or has a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  to R 6  are independently selected from hydrogen or alkyl, provided that no more than two substituents from R 1  to R 5  may be simultaneously alkyl; R 7  and R 8  is hydrogen, alkyl, alkenyl or aralkyl, or together with the N atom signify pyrrolidine or piperidine, which optionally can be substituted by alkyl, or octahydroindole or 3-azabicyclo[3,2,2]nonane; R 9  is hydrogen or halogen; R 10  is halogen or trifluoromethyl; and 
         n=0 or 1; or 
         wherein the symbols R 1  and R 3  is tri- or tetramethylene; R 2  and R 4  to R 6  is hydrogen; 
         n=0; and R 7  and R 8  are defined as above; or 
         wherein the symbols R 1  and R 7  is methylene or dimethylene and n=1, or 
         R 1  and R 7  are di- or trimethylene and n=0, or 
         R 3  and R 7  are di- or trimethylene and n=1, or 
         R 3  and R 7  are tri- or tetramethylene and n=0, or 
         R 5  and R 7  are tri- or tetramethylene and n=1, or 
         R 1  and R 5  are di- or tri-methylene and n=1, and 
         the remaining substituents are hydrogen, except R 8  which is alkyl, alkenyl or alkynyl; 
         wherein the symbols R 3  and R 5  is tri- or tetramethylene and n=1; all remaining substituents to R 6  are hydrogen; and R 7  and R 8  are alkyl, alkenyl or aralkyl or together with the n atom are pyrrolidine or piperidine, which optionally can be substituted by alkyl; R 9  is hydrogen or halogen; and R 10  is halogen or trifluoromethyl, 
       
       
         
           
           
               
               
           
         
         wherein R′ is an alkylene group which is 
       
       
         
           
           
               
               
           
         
         wherein n is 3 or 4, wherein R 1′  and R 2′  are methyl or ethyl; wherein R 3′  is hydrogen or isopropyl, wherein R 4′  and R 5′  are hydrogen, chloro, bromo, fluoro, trifluoromethyl or methoxy groups, and 
       
       
         
           
           
               
               
           
         
         Wherein R 1″  and R 2″  are each hydrogen, or join to form a cyclic structure of formula 
       
       
         
           
           
               
               
           
         
       
       and
 R 3″  and R 4″  are independently selected from hydrogen, C1-C 8  lower alkyl or hydroxy substituted C 1 -C 8  lower alkyl, 
 and enantiomers thereof, pharmaceutically acceptable salts thereof, and mixtures thereof. 
 
     
     
         52 . The pharmaceutical composition of  claim 32 , wherein the chloroquine compound is formulated in a sustained release formulation.