Novel monascuspurpurones, preparation process thereof, and uses of the monascuspurpurones

Abstract

The present invention relates to a novel monascuspurpurone compound of formula (I): or a pharmaceutically acceptable derivative thereof as described in the specification, the process for preparation of the same, and the composition comprising the same. The uses of a monascuspurpurone compound for promoting adipocyte differentiation, for increasing the activity of PPARγ and/or C/EBPα, for lowering blood glucose, for preventing and/or treating a disease or disorder related to insulin resistance, and for preventing and/or treating metabolic syndrome or its complications are also provided.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable derivative thereof, 
         wherein R 1  and R 2  are independently selected from the group consisting of alkyl, alkenyl, and carbonyl and R 3  is alkyl. 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  and R 2  are independently C 1 -C 10  alkyl, C 2 -C 7  alkenyl or C 1 -C 10  carbonyl. 
     
     
         3 . The compound according to  claim 1 , wherein R 3  is C 1 -C 10  alkyl. 
     
     
         4 . The compound according to  claim 1 , wherein R 1  is hexanoyl. 
     
     
         5 . The compound according to  claim 1 , wherein R 2  is 2-oxopentyl. 
     
     
         6 . The compound according to  claim 1 , wherein R 3  is methyl. 
     
     
         7 . The compound according to  claim 1 , wherein the compound is rel-(1S,7aR,3aR)-1-hexanoyl-5,13-dimethyl-6-(2-oxopentyl)-7a,7-dihydrobenzofuran-2,4-dione or a pharmaceutically acceptable derivative thereof. 
     
     
         8 . A composition comprising the compound of  claim 1  or a pharmaceutically acceptable derivative thereof and optionally a pharmaceutically acceptable carrier or excipient. 
     
     
         9 . A process for the preparation of the compound of  claim 1  or a pharmaceutically acceptable derivative thereof, which process comprises the steps of:
 (a) fermenting rice with an isolated strain of  Monascus  spp. to obtain red yeast rice; 
 (b) extracting the dried red yeast rice with methanol, ethanol or ethyl acetate; 
 (c) extracting the extract obtained in step (b) between ethyl acetate and H 2 O to obtain an ethyl acetate-soluble fraction; 
 (d) eluting the ethyl acetate-soluble fraction through a silica gel chromatographic column with eluents; and 
 (e) purifying the eluted fraction of (d) with silica gel chromatographic column and/or preparative thin layer chromatography (TLC) to obtain the compound. 
 
     
     
         10 . The process according to  claim 9 , wherein the isolated strain is Monascus purpureus. 
     
     
         11 . The process according to  claim 10 , wherein the isolated strain is Monascus purpureus M615 (DSM 24162). 
     
     
         12 . The process according to  claim 9 , wherein step (a) comprises fermenting rice with an isolated strain of  Monascus  spp. in the presence of tartaric acid to obtain red yeast rice. 
     
     
         13 . A red yeast rice extract obtained by a process comprising:
 (a) fermenting rice with an isolated strain of  Monascus  spp. to obtain red yeast rice; and   (b) extracting the red yeast rice by methanol, ethanol or ethyl acetate.   
     
     
         14 . The red yeast rice extract according to  claim 13 , wherein the isolated strain is  Monascus purpureus.    
     
     
         15 . The red yeast rice extract according to  claim 14 , wherein the isolated strain is  Monascus purpureus  M615 (DSM 24162). 
     
     
         16 . The red yeast rice extract according to  claim 13 , wherein step (a) comprises fermenting rice with an isolated strain of  Monascus  spp. in the presence of tartaric acid to obtain red yeast rice. 
     
     
         17 . A composition comprising the red yeast rice extract of  claim 12  and a pharmaceutically acceptable carrier or excipient. 
     
     
         18 . A method for promoting adipocyte differentiation in a subject, which comprises administering to said subject an effective amount of the compound of formula (I) or a pharmaceutically acceptable derivative thereof of  claim 1 . 
     
     
         19 . A method for promoting adipocyte differentiation in a subject, which comprises administering to said subject an effective amount of the red yeast rice extract of  claim 13 . 
     
     
         20 . A method of preventing and/or treating a disease or disorder related to insulin resistance in a subject, which comprises administering to said subject an effective amount of the compound of formula (I) or a pharmaceutically acceptable derivative thereof of  claim 1 . 
     
     
         21 . A method for preventing and/or treating a disease or disorder related to insulin resistance in a subject, which comprises administering to said subject an effective amount of the red yeast rice extract of  claim 13 . 
     
     
         22 . A method for increasing the activity of PPARγ and/or C/EBPα in a subject in need thereof, which comprises administering to said subject an effective amount of the compound of formula (I) or a pharmaceutically acceptable derivative thereof of  claim 1 . 
     
     
         23 . A method of increasing the activity of PPARγ and/or C/EBPα in a subject in need thereof, which comprises administering to said subject an effective amount of the red yeast rice extract of  claims 13 . 
     
     
         24 . A method of lowering blood glucose in a subject, which comprises administering to said subject an effective amount of the compound of formula (I) or a pharmaceutically acceptable derivative thereof of  claim 1 . 
     
     
         25 . A method of lowering blood glucose in a subject, which comprises administering to said subject an effective amount of the red yeast rice extract of  claim 13 . 
     
     
         26 . A method of preventing and/or treating metabolic syndrome or its complication in a subject, which comprises administering to said subject an effective amount of the compound of formula (I) or a pharmaceutically acceptable derivative thereof of  claim 1 . 
     
     
         27 . The method of  claim 26 , wherein the metabolic syndrome or its complication is selected from the group consisting of abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance or glucose intolerance, type 2 diabetes and cardiovascular disease. 
     
     
         28 . The method of  claim 27 , wherein a second therapeutic agent for preventing or treating metabolic syndrome or its complication is administered to the subject. 
     
     
         29 . The method of  claim 28 , wherein the second therapeutic agent is selected from the group consisting of statins, fibrates, nicotinic acid; diuretics, angiotensin-converting enzyme (ACE) inhibitors; metformin, insulin, sulfonylurea (SU), biguanide, α-glucosidase inhibitors and thiazolidinediones (TZDs). 
     
     
         30 . A method of preventing and/or treating metabolic syndrome or its complication in a subject, which comprises administering to said subject an effective amount of the red yeast rice extract of  claim 13 . 
     
     
         31 . The method of  claim 30 , wherein the metabolic syndrome or its complication is selected from the group consisting of abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance or glucose intolerance, type 2 diabetes and cardiovascular disease. 
     
     
         32 . The method of  claim 31 , wherein a second therapeutic agent for preventing or treating metabolic syndrome or its complication is administered to the subject. 
     
     
         33 . The method of  claim 32 , wherein the second therapeutic agent is selected from the group consisting of statins, fibrates, nicotinic acid; diuretics, angiotensin-converting enzyme (ACE) inhibitors; metformin, insulin, sulfonylurea (SU), biguanide, α-glucosidase inhibitors and thiazolidinediones (TZDs).